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Mitochondria-Targeted Antioxidant Peptides
Milagros Rocha, Antonio Hernandez-Mijares, Katherinne Garcia-Malpartida, Celia Bañuls, Lorena Bellod, Victor M Victor
[Abstract] [FULL-TEXT INQUIRY] [PMID: 20687871 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00133]


Peptidomimetic Competitive Inhibitors of Protein Tyrosine Phosphatases
Kui Shen, Lixin Qi, Lynn Stiff
[Abstract] [FULL-TEXT INQUIRY] [PMID: 20687872 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00134]


Epitope Discovery and Their Use in Peptide Based Vaccines
Nadine L. Dudek, Patrick Perlmutter, Marie-Isabe Aguilar, Nathan P. Croft and Anthony W. Purce
[Abstract] [FULL-TEXT INQUIRY] [PMID: 20687873 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00135]


Gene targeting and expression modulation by Peptide Nucleic Acids (PNA)
Peter E. Nielsen
[Abstract] [FULL-TEXT INQUIRY] [PMID: 20687874 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00136]


Synthetic peptides derived from the C-terminal region of Lys49 phospholipase A₂ homologues from Viperidae snake venoms: biomimetic activities and potential applications
Bruno Lomonte, Yamileth Angulo and Edgardo Moreno
[Abstract] [FULL-TEXT INQUIRY] [PMID: 20687875 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00137]


Peptides Targeting gap Junctional Structures
Jean-Claude Hervé, Stefan Dhein
[Abstract] [FULL-TEXT INQUIRY] [PMID: 20687876 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00139]


HDL Apolipoprotein-Related Peptides in the Treatment of Atherosclerosis and Other Inflammatory Disorders
G. S. Getz, G. D. Wool, and C. A. Reardon
[Abstract] [FULL-TEXT INQUIRY] [PMID: 20687877 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00140]


Chemical Modifications Designed to Improve Peptide Stability: incorporation of Non-Natural Amino Acids, Pseudo-Peptide Bonds, and Cyclization
Luca Gentilucci, Rossella De Marco, Lucia Cerisoli
[Abstract] [Purchase Article] [PMID: 20687878 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00141]


Ligand-Based Peptide Design and Combinatorial Peptide Libraries to Target G Protein-Coupled Receptors
Christian W. Gruber, Markus Muttenthaler and Michael Freissmuth
[Abstract] [FULL-TEXT INQUIRY] [PMID: 20687879 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00142]


Antimicrobial Peptides and Peptaibols, Substitutes for Conventional Antibiotics
Hervé DUCLOHIER
[Abstract] [FULL-TEXT INQUIRY] [PMID: 20687880 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00143]


Neuropeptides as Therapeutic Approach to Autoimmune Diseases
Elena Gonzalez-Rey, Virginia Delgado-Maroto, Luciana Souza Moreira and Mario Delgado
[Abstract] [FULL-TEXT INQUIRY] [PMID: 20687881 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00144]


Bcl-2 family proteins as therapeutic targets
Peter E Czabotar and Guillaume Lessene
[Abstract] [FULL-TEXT INQUIRY] [PMID: 20687882 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00145]


Orexins/Hypocretins: Pain Regulation and Cellular Actions
Lih-Chu Chiou, Hsin-Jung Lee, Yu-Cheng Ho, Shih-Pin Chen, Yan-Yu Liao, Chia-Hau Ma, Pi-Chuan Fan, Jong-Ling Fuh, and Shuu-Jiun Wang
[Abstract] [FULL-TEXT INQUIRY] [PMID: 20687883 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00146]


Optimization and High-Throughput Screening of Antimicrobial Peptides
Sylvie E. Blondelle and Karl Lohner
[Abstract] [FULL-TEXT INQUIRY] [PMID: 20687884 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00147]


Editorial: Current status of Drug Eluting Stents
[Abstract] [PMID: 21208179 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00157]


Genome-Wide Association Studies: Is there a Genotype for Cognitive Decline in Older Persons with Type 2 Diabetes?
Angela Marie Abbatecola, Fabiola Oliveri, Andrea Corsonello, Roberto Antonicelli, Francesco Corica, Fabrizia Lattanzio
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21352095 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00182]


Review on the protective effects of PACAP in models of neurodegenerative diseases in vitro and in vivo
Reglodi D, Kiss P, Lubics A, Tamas A
[Abstract] [Purchase Article] [PMID: 21524257 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00183]


Role of PACAP in neural stem/progenitor cell and astrocyte - from neural development to neural repair
Tomoya Nakamachi, Jozsef Farkas, Jun Watanabe, Hirokazu Ohtaki, Kenji Dohi, Satoru Arata and Seiji Shioda
[Abstract] [Purchase Article] [PMID: 21524256 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00184]


PACAP is Implicated in the Stress Axes
Hitoshi Hashimoto, Norihito Shintani, Mamoru Tanida, Atsuko Hayata, Ryota Hashimoto, Akemichi Baba
[Abstract] [Purchase Article] [PMID: 21524255 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00185]


The role of the PACAP signaling system in depression
Albert Pinhasov, Elimelech Nesher, Moshe Gross, Gadi Turgeman, Anatoly Kreinin and Gal Yadid
[Abstract] [Purchase Article] [PMID: 21524254 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00186]


Strategies to Convert PACAP from a Hypophysiotropic Neurohormone into a Neuroprotective Drug
S. Bourgault, D. Chatenet, O. Wurtz, N.D. Doan, J. Leprince, H. Vaudry, A. Fournier and D. Vaudry
[Abstract] [Purchase Article] [PMID: 21524253 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00187]


Immunomodulatory roles of VIP and PACAP in models of multiple sclerosis
Catalina Abad and James A. Waschek
[Abstract] [Purchase Article] [PMID: 21524252 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00188]


VIP-induced neuroprotection of the developing brain
Sandrine Passemard, M.D., Ph.D., Paulina Sokolowska, Ph.D., Leslie Schwendimann, Tech., and Pierre Gressens, M.D., Ph.D.
[Abstract] [Purchase Article] [PMID: 21524251 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00189]


NAP (Davunetide) Provides Functional and Structural Neuroprotection
Illana Gozes
[Abstract] [Purchase Article] [PMID: 21524250 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00190]


Editorial: VIP and PACAP: Novel Approaches to Brain Functions and Neuroprotection
Seiji Shioda
[PMID: 21524249 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00191]


Gender differences in the effects of angiotensin receptor blockers on cardiovascular disease
Hiroshi Yoshida, Giuseppe Rosano, Mitsuyuki Shimizu, Seibu Mochizuki, Michihiro Yoshimura
[Abstract] [Purchase Article] [PMID: 21449891 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00192]


Gender differences in the clinical presentation of heart disease
Peter Collins, MD, Cristiana Vitale, MD, Ilaria Spoletini, Giuseppe Barbaro, MD
[Abstract] [Purchase Article] [PMID: 21449890 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00193]


The effect of gender on cardiovascular pharmacology
Flavia Franconi, Ciriaco Carru, Walter Malorni Stefano Vella Giuseppe Mercuro
[Abstract] [Purchase Article] [PMID: 21449889 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00194]


Gender related issues in the management of heart failure
Stefan Anker, Giuseppe Caminiti, Maurizio Volterrani
[Abstract] [Purchase Article] [PMID: 21449888 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00195]


The importance of gender differences in the diagnosis and management of cardiovascular disease
Graciana Ciambrone, Juan Carlos Kaski
[Abstract] [Purchase Article] [PMID: 21449887 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00196]


Gender Differences In The Treatment Of Ischemic Heart Disease
Marcin Barylski, Dimitri P. Mikhailidis, Maciej Ciebiada, Maciej Banach
[Abstract] [Purchase Article] [PMID: 21449886 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00197]


Gender-Specific Aspects in Primary and Secondary Prevention of Cardiovascular Disease
G Mercuro, A Bina, E. Manconi, M. Deidda
[Abstract] [Purchase Article] [PMID: 21449885 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00198]


Gender Specific Aspects Of Cell Death In The Cardiovascular System
Marina Pierdominici, Elena Ortona, Flavia Franconi, Massimiliano Caprio, Elisabetta Straface and Walter Malorni
[Abstract] [Purchase Article] [PMID: 21449884 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00199]


Editorial: Gender differences in cardiovascular diseases. A need for action
Giuseppe M.C. Rosano, Giuseppe Barbaro
[Abstract] [Purchase Article] [PMID: 21449883 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00200]


Editorial:
[BSP/CPD/E-Pub/00226]


Cancer Targeted Metallic Nanoparticle: Targeting Overview, Recent Advancement and Toxicity Concern
Sohail Akhter, Mohammad Zaki Ahmad, Anjali Singh, Iqbal Ahmad, Mahfoozur Rahman, Mohammad Anwar, Gaurav Kumar Jain, Farhan Jalees Ahmad and Roop Krishen Khar
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21568874 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00228]


Application of Nanomedicine in Cardiovascular Diseases and Stroke
Kye S. Kim, Gilson Khang, Dongwon Lee
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21631424 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/000238]


Vitamin D therapy in cardiac hypertrophy and heart failure
J. Ruth Wu-Wong
[Abstract] [Purchase Article] [PMID: 21631424 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/000239]


Mechanisms and Inhibitors of Apoptosis in Cardiovascular Diseases
Sylvia S. Singh and Peter M. Kang
[Abstract] [Purchase Article] [PMID: 21631422 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/000240]


Phosphoinositide-3 kinase signaling in cardiac hypertrophy and heart failure
Toshinori Aoyagi and Takashi Matsui
[Abstract] [Purchase Article] [PMID: 21631421 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/000241]


Neuregulin1 as Novel Therapy for Heart Failure
Xinhua Yan and James P. Morgan
[Abstract] [Purchase Article] [PMID: 21631420 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/000242]


Nitric Oxide and Protection against Cardiac Ischemia
Zhengyuan Xia and Paul M. Vanhoutte
[Abstract] [Purchase Article] [PMID: 21631419 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/000243]


Editorial: Novel Pharmacological Therapies for Cardiac Hypertrophy and Heart Failure
Peter M. Kang, M.D.
[PMID: 21631418 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/000244]


Pharmaceutical Approaches of Binge Drinking
Benjamin Rolland, Laurent Karila, Dewi Guardia, Olivier Cottencin
[Abstract] [Purchase Article] [PMID: 21524262 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/000253]


The uniqueness of the Trypanosoma cruzi mitochondrion: Opportunities to identify new drug target for the treatment of Chagas disease
Lisvane Paes Vieira, Brian Suárez Mantilla, Maria Julia Barisón, Carsten Wrenger and Ariel Mariano Silber
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21718252 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/000258]


Principles and therapeutic relevance for targeting mitochondria in aging and neurodegenerative diseases
Gaetano Serviddio, Antonino Davide Romano, Tommaso Cassano, Francesco Bellanti, Emanuele Altomare and Gianluigi Vendemiale
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21718251 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/000259]


Mitochondrial Drug Target In Cell Death And Cancer
Gustavo Ferrín, Clara I. Linares, Jordi Muntané
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21718250 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/000260]


Mitochondrial toxicity in HAART: an overview of in vitro evidence
Nadezda Apostolova, Ana Blas-García, and Juan V. Esplugues
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21718249 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/000261]


Drug-induced Cardiac Mitochondrial Toxicity and Protection: From Doxorubicin to Carvedilol
Gonçalo C. Pereira, Ana M. Silva, Cátia V. Diogo, Filipa S. Carvalho, Pedro Monteiro, Paulo J. Oliveira
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21718248 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/000262]


Mitochondrial Therapeutics for Cardioprotection
Raquel S. Carreira, Pamela Lee, and Roberta A. Gottlieb
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21718247 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/000263]


New Insights in Drug-Induced Mitochondrial Toxicity
Sashi Nadanaciva and Yvonne Will
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21718246 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/000264]


Mitophagy and Disease: New Avenues for Pharmacological Intervention
Robert Taylor and Scott J. Goldman
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21718245 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/000265]


Mitochondrial dysfunction and targeted drugs: a focus on diabetes
Victor M Victor, Milagros Rocha, Celia Bañuls, Lorena Bellod, Antonio Hernandez-Mijares
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21718244 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/000266]


Editorial:
“Mitochondria as a pharmacological target: a clue for efficacy and a reason for toxicity”
Nadezda Apostolova
[PMID: 21718243 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/000267]


The Urokinase Receptor In Hematopoietic Stem Cells Mobilization
Francesco Blasi
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21711240 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00268]


Clinical applications of the urokinase receptor (uPAR) for cancer patients
Martin C. Boonstra, Hein W. Verspaget, Sjam Ganesh, Frank J.G.M. Kubben, Alexander L. Vahrmeijer, Cornelis J.H. van de Velde, Peter J.K. Kuppen
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21711239 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00269]


The urokinase receptor system, a key regulator at the intersection between inflammation, immunity, and coagulation
Mario Del Rosso, Francesca Margheri, Simona Serratì, Anastasia Chillà, Anna Laurenzana, Gabriella Fibbi
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21711238 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00270]


The Urokinase Receptor Interactome
Gabriele Eden, Marco Archinti, Federico Furlan, Ronan Murphy, and Bernard Degryse
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21711237 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00271]


Regulation of the Urokinase Receptor (uPAR) by LDL Receptor-related Protein-1 (LRP1)
Steven L. Gonias, Alban Gaultier, and Minji Jo
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21711236 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00272]


The Urokinase-Type Plasminogen Activator And The Generation Of Inhibitors Of Urokinase Activity And Signaling
Maria Vincenza Carriero and Maria Patrizia Stoppelli
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21711235 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00273]


Development of Novel Therapeutics Targeting the Urokinase Plasminogen Activator Receptor (uPAR) and Their Translation Toward the Clinic
Andrew P. Mazar, Richard W. Ahn, and Thomas V. O’Halloran
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21711234 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00274]


The role of the urokinase receptor in epilepsy, in disorders of language, cognition, communication and behavior, and in the central nervous system
Nadine Bruneau, Pierre Szepetowski
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21711233 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00275]


Urokinase receptor (uPAR) ligand based recombinant toxins for human cancer therapy
Maddalena de Virgilio and Franco Silvestris
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21711232 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00276]


Editorial: The Urokinase Receptor System As Strategic Therapeutic Target: Challenges For The 21^st Century
Bernard Degryse
[PMID: 21711231 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00277]


Kinins as therapeutic agents in cardiovascular and renal diseases
François Alhenc-Gelas, Nadine Bouby, Christine Richer, Louis Potier, Ronan Roussel and Michel Marre
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21728987 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00278]


Antimalarial peptides: the long and the short of it
A. Bell
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21728986 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00279]


Peptoids: Bio-Inspired Polymers as Potential Pharmaceuticals
Michelle T. Dohm, Rinki Kapoor and Annelise E. Barron
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21728985 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00280]


Peptide And Non-Peptide Antagonists Targeting Endothelin Receptors In Physiology And Pathology
Martin Houde, Julie Labonté, Pedro D’Orléans-Juste
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21728984 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00281]


Peptides targeting estrogen receptor alpha -potential applications for breast cancer treatment
Guy Leclercq, Dominique Gallo, Janine Cossy, Ioanna Laïos, Denis Larsimont, Guy Laurent and Yves Jacquot
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21728983 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00282]


Bioactive peptide-modified biomaterials for bone regeneration
Jue-Yeon Lee, Young-Suk Choi, Seung-Jin Lee, Chong-Pyoung Chung and Yoon-Jeong Park
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21728982 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00283]


Anti-Cancer Peptides From Ras-P21 And P53 Proteins
Matthew R. Pincus1, Maly Fenelus, Ehsan Sarafraz-Yazdi,Victor Adler,Wilbur Bowne and Josef Michl
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21728981 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00284]


Novel Aβ Isoforms In Alzheimer´s Disease – Their Role In Diagnosis And Treatment
Erik Portelius, Niklas Mattsson, Ulf Andreasson, Kaj Blennow, Henrik Zetterberg
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21728980 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00285]


Protection against Tauopathy by the Drug Candidates NAP (Davunetide) and D-SAL: Biochemical, Cellular and Behavioral Aspects
Natalia Shiryaev, Regina Pickman, Eliezer Giladi and Illana Gozes
[Abstract] [Purchase Article] [PMID: 21728979 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00286]


Peptide Mimetics of Neurotrophins and their Receptors
S.D. Skaper
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21728978 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00287]


Peptides as tight junction modulators
Azusa Takahashi, Masuo Kondoh, Miki Kodaka, Kiyohito Yagi
[Abstract] [Purchase Article] [PMID: 21728977 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00288]


Novel neuropeptides as ligands of orphan G protein-coupled receptors
Yan Zhang, Zhiwei Wang, Gregory Scott Parks, Olivier Civelli
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21728976 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00289]


Editorial: "Therapeutic potential of peptide motifs "- Part V
Jean-Claude Hervé
[PMID: 21728975 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00290]


Biomedical Application of Metallodendrimers and Dendrimer Nanocomposites
Yi-HsuanTang, Adela Ya-Ting Huang, Po-Yu Chen, Hui-Ting Chen, Chai-Lin Kao
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21736548 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00291]


Recent progress toward hydrogen medicine: Potential of molecular hydrogen for preventive and therapeutic applications
Shigeo Ohta
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21736547 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00292]


Design of Magnetic Nanoparticles-Assisted Drug Delivery System
Guo-Jing Chen and Li-Fang Wang
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21736546 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00293]


The possible involvement of glycogen synthase kinase-3 (GSK-3) in diabetes, cancer and central nervous system diseases
Amar S,  Belmaker RH and Agam G
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21736545 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00294]


Gas Bioengineering Using Hemoglobin-Vesicles For Versatile Clinical Applications
Hiromi Sakai, Shinji Takeoka, Koichi Kobayashi
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21736544 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00295]


Development of Microwave Antennas for Thermal Therapy
Koichi Ito and Kazuyuki Saito
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21736543 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00296]


Jun dimerization protein 2 in oxygen restriction; control of senescence
Shin-Wei Wang, Jiag-Ki Lee, Chia-Chen Ku, Shyh-Shin Chiou, Ming-Feng Ho, Deng-Chyang Wu and Kazunari K. Yokoyama
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21736542 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00297]


Walking the oxidative stress tightrope: a perspective from the naked mole-rat, the longest living rodent
Karl A. Rodriguez, Ewa Wywial, Viviana I. Perez, Adrian J. Lambert, Yael H. Edrey, Kaitlyn N. Lewis, Kelly Grimes, Merry L. Lindsey, Martin D. Brand, Rochelle Buffenstein
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21736541 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00298]


The principle and the potential approach to ROS-dependent cytotoxicity by non-pharmaceutical therapies: optimal use of medical gases with antioxidant properties
Mami Noda, Kyota Fujita, Chih-Hung Lee, Tohru Yoshioka
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21736540 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00299]


Tocotrienols and its Role in Cardiovascular Health- a Lead for Drug Design
Hannah R Vasanthi, R P Parameswari and Dipak K. Das
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21774785 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00300]


Mitochondria as Possible Pharmaceutical Targets for the Effects of Vitamin E and its Homologues in Oxidative Stress-Related Diseases
Hideyuki J. Majima, Hiroko P. Indo, Shigeaki Suenaga, Hirofumi Matsui, Hsiu Chuan Yen and Toshihiko Ozawa
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21774784 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00301]


The 21st Century Form of Vitamin E - Tocotrienol
Jayeeta Bardhan, Runu Chakraborty & Utpal Raychaudhuri
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21774783 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00302]


Tocotrienols and Cardiovascular Health
Kailash Prasad
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21774782 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00303]


Nutrapharmacology Of Tocotrienols For Metabolic Syndrome
Wong Weng-Yew and Lindsay Brown
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21774781 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00304]


Cellular Protection And Therapeutic Potential Of Tocotrienols
Betul Catalgol, Saime Batirel, Nesrin Kartal Ozer
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21774780 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00305]


γ-Tocotrienol Induces Apoptosis in Human T Cell Lymphoma Through Activation of Both Intrinsic and Extrinsic Pathways
Chandan Wilankar, Nazir M. Khan, Rahul Checker, Deepak Sharma, Raghavendra Patwardhan, Vikram Gota, Santosh Kumar Sandur and T. P. A. Devasagayam
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21774779 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00306]


Vitamin E in oxidant stress-related cardiovascular pathologies: focus on experimental studies
Belma TURAN and Guy VASSORT
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21774778 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00307]


Editorial: Tocotrienols: Potential Drug Targets For Cardiovascular, Cancer And Eurologicl Diseases
Dipak K. Das
[PMID: 21774785 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00308]


Gene Therapy For Lysosomal Storage Diseases: Progress, Challenges and Future Prospects
Sergey S. Seregin, and Andrea Amalfitano
[Abstract] [Purchase Article] [PMID: 21774776 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00309]


Gene Transfer For Inherited Metabolic Disorders Of The Liver: Immunological Challenges
Stephanie C. Gordts, Eline Van Craeyveld, Frank Jacobs, Bart De Geest
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21774775 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00310]


Gene Therapy For Familial Hypercholesterolemia
Eline Van Craeyveld, Frank Jacobs, Stephanie C. Gordts, Bart De Geest
[Abstract] [Purchase Article] [PMID: 21774774 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00311]


Gene Transfer For Inborn Errors Of Metabolism of the Liver: The Clinical Perspective
David Cassiman
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21774773 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00312]


Adeno-Associated Viral Vectors For Correction of Inborn Errors of Metabolism: Progressing Towards Clinical Application
Frank Jacobs, Lili Wang
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21774772 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00313]


Retroviral Vector-Mediated Gene Therapy For Metabolic Diseases: An Update
Nicolas Ferry, Virginie Pichard, Dominique Aubert Sébastien Bony and Tuan Huy Nguyen
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21774771 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00314]


Perinatal gene transfer to the liver
Tristan R. McKay, Ahad A. Rahim, Suzanne M.K. Buckley, Natalie J. Ward, Jerry K.Y.Chan, Steven J. Howe, Simon N. Waddington
[Abstract] [Purchase Article] [PMID: 21774770 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00315]


Liver-Directed Gene Therapy with Helper-Dependent Adenoviral Vectors: Current State of the Art and Future Challenges
Francesco Vetrini and Philip Ng
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21774769 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00316]


Molecular targeted approaches for treatment of pancreatic cancer
Z.-q. Huang, A.K. Saluja, V. Dudeja, S.M. Vickers, and D.J. Buchsbaum
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00317]


New Perspectives in Glioma Immunotherapy
Antonio Daga, Cristina Bottino, Roberta Castriconi, Rosaria Gangemi, Silvano Ferrini
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00318]


Preclinical Development of Novel Anti-Glioma Drugs Targeting the Endoplasmic Reticulum Stress Response
Axel H. Schönthal, Thomas C. Chen, Florence M. Hofman, Stan G. Louie, Nicos A. Petasis
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00319]


Bioenergetics pathways and therapeutic resistance in gliomas: emerging role of mitochondria
Corinne E. Griguer and Claudia R. Oliva
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00320]


Collateral Damage Control in Cancer Therapy: Defining the Stem Identity in Gliomas
David Hsieh
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00321]


Targeting the AKT Pathway in Glioblastoma
Kelli A. McDowell, Gregory J. Riggins, and Gary L. Gallia
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00322]


The role of integrins in glioma biology and anti-glioma therapies
Ghazaleh Tabatabai, Jörg-Christian Tonn, Roger Stupp, Michael Weller
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00323]


Glioma Stem Cell Maintenance: The Role of the Microenvironment
John M. Heddleston, Masahiro Hitomi, Monica Venere, William A. Flavahan, Kenneth Yang, Youngmi Kim, Sana Minhas, Jeremy N. Rich, Anita B. Hjelmeland
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00324]


Targeting ErbB receptors in high-grade glioma
Sabina Berezowska, Jürgen Schlegel
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00325]


Editorial: Designing New Drugs For High Grade Gliomas
Guido Frosina
[BSP/CPD/E-Pub/00326]


Opioid Transport By Atp-Binding Cassette (Abc) Transporters At The Blood-Brain Barrier: Implications For Neuropsychopharmacology
Nicolas Tournier, Xavier Declèves, Bruno Saubaméa, Jean-Michel Scherrmann, and Salvatore Cisternino
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00327]


In Vitro Modeling Of The Blood-Brain Barrier: Simplicity Versus Complexity
Omolara O. Ogunshola
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00328]


Getting To Know The Cast - Cellular Interactions And Signaling At The Neurovascular Unit
Maarja Mäe, Annika Armulik and Christer Betsholtz
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00329]


Do abc transporters cause pharmacoresistance in epilepsy?  Problems and approaches in determining which antiepileptic drugs are affected
Wolfgang Löscher, Carlos Luna-Tortós, Kerstin Römermann and Maren Fedrowitz
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00330]


The Abc Of The Blood-Brain Barrier - Regulation Of Drug Efflux Pumps
Valeska Reichel, Anne Mahringer, Melanie Ott, Isolde Reimold, Gert Fricker
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00331]


The Role Of The Abc Transporter P-Glycoprotein In The Transport Of Β-Amyloid Across The Blood-Brain Barrier
Silke Vogelgesang , Gabriele Jedlitschky, Anja Brenn, Lary C. Walker
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00332]


Blood-Brain Barrier P-Glycoprotein Function In Neurodegenerative Disease
A.L. Bartels
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00333]


Abc-Transporters In Inflammatory Brain Disease
Chan A, Gold R, von Ahsen N
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00334]


The Clinical Impact of ABCB1 Polymorphisms on the Treatment of Psychiatric Diseases
Marcus C. Rosenhagen and Manfred Uhr
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00335]


Breast Cancer Resistance Protein and P-glycoprotein in Brain Cancer: Two Gatekeepers Team Up
Sagar Agarwal, Anika M.S. Hartz, William F. Elmquist, Björn Bauer
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00336]


Atp-Binding Cassette Transporters At The Blood-Brain Barrier In Ischaemic Stroke
Pauline Patak, MD and Dirk M. Hermann, MD
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00337]


Editorial: Bringing Drugs Into The Injured Brain And Keeping Them There
Dirk M. Hermann, MD and Pauline Patak, MD
[BSP/CPD/E-Pub/00338]


Cytokine Signaling Modulates Blood-Brain Barrier Function
Weihong Pan, Kirsten P. Stone, Hung Hsuchou, Vamshi K. Manda, Yan Zhang and  Abba J. Kastin
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00339]


Population Pharmacokinetics and its Role in Anti-tuberculosis Drug Development & Optimization of Treatment
Eric Free Egelund, Aline Bergesch Barth, Charles Arthur Peloquin
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21834766 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00340]


Positron Emission Tomography in the diagnosis and treatment management of Tuberculosis
J.G.W. Kosterink
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21834765 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00341]


Treatment of central nervous system tuberculosis infections and neurological complications of tuberculosis treatment
J.J. van der Harst and G.J. Luijckx
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21834764 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00342]


Dried blood spots: a new tool for tuberculosis treatment optimization
D.H.Vu, J.W.C Alffenaar, P. M. Edelbroek, J.R.B.J. Brouwers, and D.R.A. Uges
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21834763 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00343]


Drug susceptibility testing for optimizing tuberculosis treatment
Sami O. Simons, and Dick van Soolingen
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21834762 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00344]


In vitro and in vivo modeling of anti-tuberculosis drugs and its impact on optimization of doses and regimens
Shashikant Srivastava and Tawanda Gumbo
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21834761 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00345]


Immunology in Tuberculosis:  Challenges in Monitoring of Disease Activity and identifying Correlates of Protection
Richard van Altena, Sridevi Duggirala, Matthias I.P.Gröschel, Tjip and S. van der Werf
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21834760 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00346]


Fluoroquinolones, the cornerstone of treatment of drug-resistant tuberculosis: a pharmacokinetic and pharmacodynamic approach
A.D. Pranger, J.W.C. Alffenaar and R.E. Aarnoutse
[Abstract] [Purchase Article] [PMID: 21834759 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00347]


Editorial: “Tuberculosis; opportunities for treatment optimization”
[PMID: 21834758 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00348]


Stem Cell-Based Immunomodulation In Type 1 Diabetes: Beyond The Regenerative Approach
Biancamaria Longoni and Franco Mosca
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00349]


Novel therapeutic approaches to autoimmune demyelinating disorders
Lara Sanvito, Cris S Constantinescu and Bruno Gran
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00350]


Manipulating thymic apoptosis for future therapy of autoimmune diseases
Domenico V. Delfino, Nicola Pozzesi, Sara Pierangeli, Emira Ayroldi and Alessandra Fierabracci
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00351]


A pathogenetic approach to autoimmune skin disease therapy: Psoriasis and biological drugs, unresolved issues, and future directions
Emira Ayroldi, Alessandra Bastianelli, Lorenza Cannarile, Maria Grazia Petrillo, Domenico V Delfino and Alessandra Fierabracci
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00352]


Experimental Strategies In Autoimmunity: Antagonists Of Cytokines And Their Receptors, Nanocarriers, Inhibitors Of Immunoproteasome, Leukocyte Migration And Protein Kinases
Alessandra Fierabracci and Emira Ayroldi
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00353]


The Chemokine System As A Therapeutic Target In Autoimmune Thyroid Diseases: A Focus On The Interferon-γ Inducible Chemokines And Their Receptors
Mario Rotondi and Luca Chiovato
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00354]


B Cell Modulation Strategies In Autoimmunity: The Sle Example
M. Manuela Rosado, Andrea Picchianti Diamanti, Federica Capolunghi and Rita Carsetti
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00355]


Immunotherapy-based Strategies for the Treatment of Autoimmune Diabetes: Searching for the Cure
Brett E. Phillips and Massimo Trucco
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00356]


Anti-TNF treatment in Rheumatoid Arthritis
Janina Geiler, Maya Buch and Michael F McDermott
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00357]


Update on Intravenous Immunoglobulins (IVIg) Mechanisms of Action and Off-Label use in Autoimmune Diseases
Uriel Katz and Gisele Zandman-Goddard
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00358]


Clinical update on the use of immuno modulators antiCD3, GAD, Diapep277, anti-IL1 in Type 1 Diabetes
Paolo Pozzilli, Chiara Guglielmi, Daria Maggi, Angela Carlone, Raffaella Buzzetti and Silvia Manfrini
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00359]


Editorial:
Hot topic: new prospects for treatment of autoimmune diseases
Alessandra Fierabracci MD PhD
[BSP/CPD/E-Pub/00360]


Epidemiology And Costs Of Hypertension-Related Disorders
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00361]
Aldo Leone, Linda Landini and Aurelio Leone


Susceptibility genes in Hypertension
Armani C. Botto N and Andreassi MG
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00362]


Smoking and Hypertension: effects on clinical, biochemical and pathological variables due to isolated or combined action on cardiovascular system
Linda Landini and  Aurelio Leone
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00363]


Endothelial Progenitor Cells in Prehypertension
Rossella Di Stefano, Maria Chiara Barsotti, Francesca Felice, Charalambos Vlachopoulos and  Alberto Balbarini
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00364]


Hypertension In The Elderly: An Evidence-Based Review
A. Virdis, R.M. Bruno, M. Fritsch Neves, S. Taddei and L. Ghiadoni
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00365]


Cognitive decline as a consequence of essential hypertension
Davide Grassi, Livia Ferri, Paola Cheli, Paolo Di Giosia and Claudio Ferri
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00366]


Vascular abnormalities in essential hypertension
Isabella Sudano, Susanne Roas and Georg Noll
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00367]


Blood Pressure And Vascular Alterations With Growth In Childhood
Stefano Masi, Alexander Jones, Marietta Charakida, Francis O’Neill, Francesco D’Aiuto, Agostino Virdis, Stefano Taddei, John Eric Deanfield and Lorenzo Ghiadoni
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00368]


Markers of arrhythmogenic risk in hypertensive subjects
Andrea Barison, Giuseppe Vergaro, Luigi Emilio Pastormerlo, Lorenzo Ghiadoni, Michele Emdin and Claudio Passino
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00369]


Ectopic fat storage, insulin resistance, and hypertension
Anna Maria Sironi, Rosa Sicari, Franco Folli and Amalia Gastaldelli
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00370]


Developments In Imaging Technologies Related To Hypertensive Cardiovascular Diseases
Maria Filomena Santarelli, Linda Landini, Vincenzo Positano, Simona Buralli, and Luigi Landini
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00371]


Editorial: Modifying cardiovascular risk factors: epidemiology and characteristics of hypertension-related disorders
Aurelio Leone and Luigi Landini
[BSP/CPD/E-Pub/00372]


Targeting Protein-Protein and Protein-Nucleic Acid Interactions for Anti-HIV Therapy
Mattia Mori, Fabrizio Manetti and Maurizio Botta
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00373]


Cardiac cell therapy and bypass surgery
Yeong-Hoon Choi, Boris Nasseri and Christof Stamm
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21919882 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00374]


Endothelial Progenitor Cells: Quod Erat Demonstrandum?
Dirk STRUNK
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21902665 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00375]


Cell Therapy for the Treatment of Chronic Ischemic Heart Disease
Sander F. Rodrigo, Jan van Ramshorst, Saskia L.M.A. Beeres, Jeroen J. Bax, Martin J. Schalij and Douwe E. Atsma
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21919880 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00376]


The Role of Chemokines, Cytokines and Adhesion Molecules in Stem Cell
Trafficking and Homing
Y. Cui and P. Madeddu
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21919879 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00377]


Mesenchymal stromal cells: a promising cell source for the treatment of inflammatory cardiomyopathy
C. Tschöpe, K. Miteva, H.-P. Schultheiss and  S. Van Linthout
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21919878 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00378]


Stem cell therapy for the treatment of myocardial infarction
D.F. Dauwe and S. Janssens
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21919877 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00379]


The Future of Induced Pluripotent Stem Cells for Cardiac Therapy and Drug Development
Lieven Thorrez and Maurilio Sampaolesi
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21919876 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00380]


Stem Cells In Cardiovascular Regeneration From Preservation Of Endogenous Repair To Future Cardiovascular  Therapies
Christian Templin, Nicolle Kränkel, Thomas F. Lüscher and Ulf Landmesser
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21919874 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00381]


Effects of mesenchymal stromal cells on diabetic cardiomyopathy
S. Van Linthout, F. Spillmann, H.-P. Schultheiss, and C. Tschöpe
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00382]


Editorial: Cardiac Cell Therapy: anno 2011
[PMID: 21902673 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00383]


Role and Treatment of Mitochondrial DNA-Related Mitochondrial Dysfunction in Sporadic Neurodegenerative Diseases
Russell H. Swerdlow
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21902672 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00384]


The Mitochondrial Dynamics of Alzheimer's Disease and Parkinson's Disease Offer Important Opportunities for Therapeutic Intervention
David J. Bonda, Mark A. Smith, George Perry, Hyoung-gon Lee, Xinglong Wang and Xiongwei Zhu
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21902671 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00385]


New Insights into the Mechanisms of Mitochondrial Preconditioning-Triggered Neuroprotection
Sónia C. Correia, Susana Cardoso, Renato X. Santos, Cristina Carvalho, Maria S. Santos, George Perry, Mark A. Smith and Paula I. Moreira
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21902670 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00386]


The mitochondrial cascade hypothesis for Parkinson's disease
Sandra M Cardoso
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21902669 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00387]


Epigenetics in Alzheimer's disease: a focus on DNA modifications
Natacha Coppieters and Mike Dragunow
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21902668 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00388]


Microtubules (tau) as an Emerging Therapeutic Target: NAP (Davunetide)
Illana Gozes
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21902667 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00389]


Role of Sirtuins and Calorie restriction in Neuroprotection: Implications in Alzheimer's and Parkinson's Diseases
Sarika Srivastava and Marcia C. Haigis
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21902666 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00390]


Gene therapy for Parkinson's and Alzheimer's diseases: from the bench to clinical trials
Rui Jorge Nobr and Luís Pereira de Almeida
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21902665 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00391]


Therapeutic Intervention at Cellular Quality Control Systems in Alzheimer's and Parkinson's diseases
Daniela M Arduino, A Raquel Esteves, Diana FF Silva, Diogo Martins-Branco, Daniel Santos, Diana F. Gomes Pimentel and Sandra M Cardoso
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21902664 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00392]


Importance of iron chelation in free radical-induced oxidative stress and human disease Klaudia Jomova and Marian Valko
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21902663 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00393]


Targeting Mitochondrial Bioenergetics for Alzheimer's Prevention and Treatment
Jia Yao and Roberta Diaz Brinton
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21902662 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00394]


Emerging Treatments For Autoimmune Hepatitis
Albert J. Czaja
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21902661 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00395]


Editorial: Architecture and design of non-drug therapy for reactive oxygen spcecies (ROS)-induced diseases
[PMID: 21902661 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00396]


Defective autophagy in fibroblasts may contribute to fibrogenesis in autoimmune processes
Domenico Del Principe, Rosa Vona , Luciana Giordani , Elisabetta Straface and Anna Maria Giammarioli
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00397]


Intracellular redox signaling as therapeutic target for novel antiviral strategy
Lucia Nencioni, Rossella Sgarbanti, Donatella Amatore, Paola Checconi, Ignacio Celestino, Dolores Limongi, Simona Anticoli, Anna Teresa Palamara and Enrico Garaci
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00398]


Metabolic Therapy: Lessons From Liver Diseases
Carmen garcia-ruiz, montserrat marí, anna colell, albert morales and jose c. Fernandez-checa
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00399]


Antioxidant pathways in Alzheimer’s disease: possibilities of intervention
Viña, J, LLoret A, Giraldo, E, Badia MC and  Alonso MD
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00400]


Mtor Signaling And Metabolic Regulation Of T Cells: New Potential Therapeutic Targets In Autoimmune Diseases
Marina Pierdominici, Davide Vacirca, Federica Delunardo and Elena Ortona
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00401]


Unmasking Sex-Based Disparity in Neuronal Metabolism
Mioara. D. Manole, Roya Tehranian-DePasquale, Lina Du, Hülya Bayır, Patrick M. Kochanek, and Robert S. B. Clark
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00402]


Nitric Oxide-Derived Oxidants With A Focus On Peroxynitrite: Molecular Targets, Cellular Responses And Therapeutic Implications
Calcerrada P, Peluffo G and Radi R.
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00403]


The role of mitochondrial function in glutamate-dependent metabolism in neuronal cells
Smaili, S.S. Ureshino, R.P. Rodrigues, L. Rocha, K.K. Carvalho, J.T. Oseki, K.T. Bincoletto, C. Lopes and G.S. Hirata, H.
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00404]


Optimization of Cardiac Metabolism in Heart Failure
Tomohisa Nagoshi, Michihiro Yoshimura, Giuseppe M. C. Rosano, Gary D. Lopaschuk and Seibu Mochizuki
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00405]


Muscle metabolism and exercise capacity in cachexia
Volker Adams, Stefan D. Anker and  Gerhard Schuler
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00406]


Editorial: “Cell metabolism as therapeutic target in human disease”
[Purchase Article] [BSP/CPD/E-Pub/00407]


Editorial“There is More to Predicting Vascular Disease than just Established Risk Factors”
Manfredi Rizzo and Dimitri P. Mikhailidis
[PMID: 22074430 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00408]


(Pro)renin Receptor as a New Drug Target
Basma A.M. Ahmed, Ondrej Seda and Julie L. Lavoie
[Abstract] [FULL-TEXT INQUIRY] [PMID: 22074431 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00409]


Lipid Lowering Drugs and Gallstones: A Therapeutic Option?
Eirini Lioudaki, Emmanuel S. Ganotakis and Dimitri P. Mikhailidis
[Abstract] [FULL-TEXT INQUIRY] [PMID: 22074432 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00410]


Liver Enzymes: Potential Cardiovascular Risk Markers?
Eirini Lioudaki, Emmanuel S Ganotakis and Dimitri P. Mikhailidis
[Abstract] [FULL-TEXT INQUIRY] [PMID: 22074433 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00411]


Is Bilirubin a Marker of Vascular Disease and/or Cancer and is it a Potential Therapeutic Target?
Lars H. Breimer and Dimitri P. Mikhailidis
[Abstract] [FULL-TEXT INQUIRY] [PMID: 22074434 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00412]


Therapeutic Modulation of Lipoprotein-associated Phospholipase A2 (Lp-PLA2)
Alexandros D. Tselepis, Manfredi Rizzo and Ioannis A. Goudevenos
[Abstract] [FULL-TEXT INQUIRY] [PMID: 22074435 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00413]


Heat Shock Protein-60 and Risk for Cardiovascular Disease
Manfredi Rizzo, Alberto J.L. Macario, Everly Conway de Macario, Ioanna Gouni-Berthold, Heiner K. Berthold, Giovam Battista Rini, Giovanni Zummo and Francesco Cappello
[Abstract] [FULL-TEXT INQUIRY] [PMID: 22074436 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00414]


Statin Discontinuation in High-Risk Patients: A Systematic Review of the Evidence
Yessica-Haydee Gomez Sandoval, Michael V. Braganza and Stella S. Daskalopoulou
[Abstract] [FULL-TEXT INQUIRY] [PMID: 22074437 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00415]


Role of Physician Gender in the Quality of Care of Cardiometabolic Diseases
I. Gouni-Berthold and H.K. Berthold
[Abstract] [FULL-TEXT INQUIRY] [PMID: 22074438 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00416]


Evaluation of the Possible Contribution of Antioxidants Administration in Metabolic Syndrome
Mohamed Haidara, Dimitri P Mikhailidis, Hanaa Z. Yassin, Branislava Dobutovic, Katarina T. Smiljanic, Sanja Soskic, Shaker A. Mousa, Manfredi Rizzo and Esma R. Isenovic
[Abstract] [FULL-TEXT INQUIRY] [PMID: 22074439 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00417]


Editorial: [Hot Topic: Targeting mast cells and basophils in allergy and beyond: Emerging concepts (Guest Editor: Petr Heneberg)]
[BSP/CPD/E-Pub/00418]


Targeting Cardiac Mast Cells: Pharmacological Modulation of the Local Renin-Angiotensin System
Alicia C. Reid, Jacqueline A. Brazin, Christopher Morrey, Randi B. Silver and Roberto Levi
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00419]


Mast cells and basophils: Trojan horses of conventional Lin- stem/progenitor cell isolates
Petr Heneberg
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00420]


Mast cells in tissue healing: From skin to the gastrointestinal tract
Rory Kennelly, John B.Conneely, David Bouchier-Hayes and Desmond C. Winter
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00421]


IL-19 as a Potential Therapeutic in Autoimmune and Inflammatory Diseases
Yasu-Taka Azuma, Hidemitsu Nakajima and Tadayoshi Takeuchi
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00422]


Interleukin-25: key regulator of inflammatory and autoimmune diseases
David Saadoun, Benjamin Terrier and Patrice Cacoub
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00423]


CD164 as a basophil activation marker
Anna Wolanczyk-Medrala Wojciech Barg and Wojciech Medrala
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00424]


Mast cells as sources and targets of membrane vesicles
Irit Shefler, Pazit Salamon, Alon Y. Hershko and Yoseph A. Mekori
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00425]


Autoimmunity-inducing Metals (Hg, Au and Ag) Modulate Mast Cell Signaling, Function and Survival
Yoshihiro Suzuki, Toshio Inoue and Chisei Ra
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00426]


PIP3 Regulation as Promising Targeted Therapy of Mast-cell-mediated Diseases
Bruce J. Shenker, Hydar Ali and Kathleen Boesze-Battaglia
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00427]


Mast cells as targets of pimecrolimus
Zhongcai Ma and Zongjiu Jiao
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00428]


Modulation Of Mast Cell And Basophil Functions By Benzene Metabolites
Massimo Triggiani, Stefania Loffredo, Francescopaolo Granata, Rosaria I. Staiano and Gianni Marone
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00429]


Editorial: New Developments in Therapy for Oxidative Stress-Related Diseases: Patophysiological and Clinical Consequences
[BSP/CPD/E-Pub/00430]


Oxidative stress and mitochondrial dysfunction in type 2 diabetes
Victor M Victor, Milagros Rocha and Antonio Hernandez-Mijares
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00431]


Females Live Longer than Males: Role of Oxidative Stress.
Jose Viña, Juan Gambini, Raul López-Grueso, Khira M. Abdelaziz, Mariona Jove and Consuelo Borras
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00432]


Strategies to Improve the Functions and Redox State of the Immune System in Aged Subjects
Mónica De la Fuente, Julia Cruces, Oskarina Hernandez  and Eduardo Ortega
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00433]


New Insights into Redox-Modulated Cell Signaling
Gabriella Leonarduzzi, Barbara Sottero, Gabriella Testa, Fiorella Biasi and Giuseppe Poli
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00434]


Protein oxidative modification in the ageing organism and the role of the ubiquitin proteasomal system
Marc Kästle and Tilman Grune
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00435]


Isolated mitochondrial complex I deficiency: Explorative data analysis of patient cell parameters
Lionel Blanchet, Lutgarde M.C. Buydens, Jan A.M. Smeitink, Peter H.G.M. Willems and Werner J.H. Koopman
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00436]


Targeting Mitochondria in Fighting Cancer
Vladimir Gogvadze
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00437]


Mitochondria sentencing about cellular life and death: a matter of oxidative stress
Nadezda Apostolova, Ana Blas-Garcia  and Juan V. Esplugues
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00438]


A review on the role of phytosterols: New insights into cardiovascular risk
Milagros Rocha, Celia Bañuls, Lorena Bellod, Ana Jover, Víctor M Víctor and Antonio Hernández-Mijares
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00439]


Oxidative stress and mitochondrial impairment after treatment with anti-HIV drugs: clinical implications
Ana Blas-García, Nadezda Apostolova and Juan V. Esplugues
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00440]


Pleiotropic effects of glucagon-like peptide-1 (GLP-1)-based therapies on vascular complications in diabetes
Sho-ichi Yamagishi and Takanori Matsui
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00441]


Thrombin Binding Aptamer, more than a simple aptamer: Chemically modified derivatives and biomedical applications
Anna Aviñó, Carme Fàbrega, María Tintoré and Ramon Eritja
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00442]


Melatonin, a promising valuable supplement in inflammatory bowel disease: A comprehensive review of evidences
Shilan Mozaffari and Mohammad Abdollahi
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00443]


Editorial:
[BSP/CPD/E-Pub/00444]


Pathophysiology of atherosclerosis: The role of inflammation
Dimitris Tousoulis MD PhD FACC, Anna-Maria Kampoli MD, Nikolaos Papageorgiou MD, Emmanuel Androulakis MD, Charalambos Antoniades MD PhD, Kostantinos Toutouzas MD and Christodoulos Stefanadis MD FACC
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00445]


Inflammatory disorders and atherosclerosis: New therapeutic approaches
Marietta Charakida MD, PhD, Frank O’Neil MS, Stefano Masi MD, Nikolaos Papageorgiou MD and Dimitris Tousoulis MD, PhD
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00446]


Inflammation in hypertension: current therapeutic approaches
Emmanuel Androulakis MD, Dimitris Tousoulis MD PhD FACC, Nikolaos Papageorgiou MD, George Latsios MD, Gerasimos Siasos MD, Costas Tsioufis MD, Anastasios Giolis MD and Christodoulos Stefanadis MD FACC
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00447]


Inflammatory markers in hyperlipidemia: from experimental models to clinical practice
Gerasimos Siasos MD,MSc,PhD, Dimitris Tousoulis MD,PhD,FACC, Evangelos Oikonomou MD, Marina Zaromitidou MD, Christodoulos Stefanadis MD,PhD,FACC, FESC and Athanasios G. Papavassiliou MD,PhD
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00448]


Potential pathogenic inflammatory mechanisms of endothelial dysfunction induced by Type 2 Diabetes Mellitus
Anna-Maria Kampoli MD, Dimitris Tousoulis MD PhD FACC, Alexandros Briasoulis MD, George Latsios MD, Nikolaos Papageorgiou MD and Christodoulos Stefanadis, MD FACC
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00449]


The role of T and B cells in atherosclerosis: potential clinical implications
I.E. Dumitriu MD, PhD and J.C. Kaski MD, DSc, FACC, FESC, FRCP
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00450]


Anti-inflammatory treatment of Acute Coronary Syndromes
R. Della Bona, G. Liuzzo, D. Pedicino and F. Crea
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00451]


Vulnerable plaque and inflammation. Potential clinical strategies
Maria Drakopoulou, MD, Konstantinos Toutouzas, MD, Archontoula Michelongona, MD, Dimitris Tousoulis,  MD PhD FACC and Christodoulos Stefanadis, MD FACC
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00452]


Gene Therapy Targeting Inflammation In Atherosclerosis
Tim Van-Assche PhD, Véronique Huygelen PhD, Mark J. Crabtree PhD and haralambos Antoniades MD PhD
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00453]


Cyclotides, a novel ultrastable polypeptide scaffold for drug discovery
Andrew Gould, Teshome L Aboye, Julio A Camarero and Yanbin Ji
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00454]


Resident Cardiac Stem Cells
Frati C. Savi M. Graiani G. Lagrasta C. Cavalli S. Prezioso L. Rossetti P. Mangiaracina C. Ferraro F. Madeddu D. Musso E. Stilli D. Rossini A. Falco A. De Angelis A. Rossi F. Urbanek K. Leri A. Kajstura J. Anversa P. Quaini E. and Quaini F
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00455]


Editorial:
[BSP/CPD/E-Pub/00456]


The Vulnerability to Schizophrenia Mainstream Research Paradigms and Phenomenological Directions
Giovanni Stanghellini and Paolo Fusar-Poli
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00457]


The Ultra High Risk Approach to Define Psychosis Risk
Alison R. Yung, Paolo Fusar-Poli and Barnaby Nelson
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00458]


Basic Symptoms and the Prediction of First-Episode Psychosis
Frauke Schultze-Lutter, Stephan Ruhrmann, Paolo Fusar-Poli, Andreas Bechdolf, Benno G. Schimmelmann and Joachim Klosterkötter
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00459]


Rationale and first results of developing at-risk (prodromal) critria for bipolar disorder
A. Bechdolf, A. Ratheesh, S.W. Wood, T. Tecic, P. Conus, B. Nelsonb, S.M. Cotton, A.M. Chanen, G.P. Amminger, S. Ruhrmanna, F Schultze-Lutter, J. Klosterkötter, P. Fusar Poli k, A.R. Yung, M. Berk and P.D. McGorry
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00460]


Can we detect psychotic-like experiences in the general population?
Nelson, B. Fusar-Poli, P and Yung, A.R
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00461]


Reliability And Validityof The Comprehensive Assessment Of The At Risk Mental State, Italian Version (Caarms-I)
Fusar-Poli P, Hobson R, Raduelli M and Ballotin U
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00462]


Abnormal bodily experiences may be a marker of early schizophrenia?
Giovanni Stanghellini, Massimo Ballerini, Paolo Fusar Poli and John Cutting, Psych
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00463]


Neurocognition in the Psychosis Risk Syndrome: A Quantitative and Qualitative Review
Anthony J. Giuliano, Huijun Li, Raquelle I. Mesholam-Gately, Shannon Sorensonb, Kristen A. Woodberry  and Larry J. Seidman
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00464]


Neuroimaging and resilience factors - staging of the at-risk mental state?
Renata Smieskova, Paolo Fusar-Poli, Anita Riecher-Rössler and Stefan Borgwardt
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00465]


The Relationship of Developmental Changes in WM to the Onset of Psychosis
Katherine H. Karlsgodt, Sarah C. Jacobson, Marc Seal and Paolo Fusar-Poli
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00466]


Relationship between gyrification and functional connectivity of the prefrontal cortex in subjects at high genetic risk of schizophrenia
Maria R Dauvermann, Prerona Mukherjee, William T Moorhead, Andrew C Stanfield, Paolo Fusar-Poli, Stephen M Lawrie and Heather C Whalley
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00467]


Episodic memory dysfunction in individuals at high-risk of psychosis: a systematic review of neuropsychological and neurofunctional studies
Isabel Valli, Stefania Tognin, Paolo Fusar-Poli and Andrea Mechelli
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00468]


From the prodrome to chronic schizophrenia: the neurobiology underlying psychotic symptoms and cognitive impairments
Howes sych, Fusar-Poli, Bloomfield Selvaraj and McGuire sych
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00469]


Glutamate and Psychosis Risk
Alice Egerton Paolo Fusar-Poli and James M. Stone
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00470]


Neurophysiological Alterations in the Prepsychotic Phases
Nicolas A. Crossley, Miguel Constante, Paolo Fusar-Poli and Elvira Bramon
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00471]


Brain Structural Abnormalities at the Onset of Schizophrenia and Bipolar Disorder: A Meta-analysis of Controlled Magnetic Resonance Imaging Studies
Luca De Peria, Alessandra Crescinia, Giacomo Destea, Paolo Fusar-Polia, Emilio Sacchettia, and Antonio Vitaa
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00472]


Cingulate Volume Abnormalities in Emerging Psychosis
Michel Röthlisberger, Anita Riecher-Rössler, Jacqueline Aston, Paolo Fusar-Poli, Ernst-Wilhelm Radü and Stefan Borgwardt
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00473]


Biochemical Markers of Impending Psychosis
Enzo Emanuele, Valentina Martinelli, Vera Abbiati, Paolo Fusar-Poli and Pierluigi Politi
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00474]


Genetic Vulnerability to Psychosis and Cortical Function: Epistatic Effects between DAAO and G72
Mechelli Andrea, Paolo Fusar-Poli, Prata Diana, Papagni Sergio Alessandro, Tognin Stefania, Kambeitz Joseph, Fu Cynthia, Picchioni Marco, Walshe Muriel, Toulopoulou Timothea, Bramon Elvira, Murray Robin and McGuire Philip
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00475]


Immigration, Social Environment and Onset of Psychotic Disorders
François Bourque, Elsje van der Ven, Paolo Fusar-Poli and Ashok Malla
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00476]


Stress and the Prodromal Phase of Psychosis
Carrie W. Holtzman
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00477]


Cognitive remediation in the early course of schizophrenia: a critical review
Stefano Barlati, Luca De Peri, Giacomo Deste, Paolo Fusar-Poli and Antonio Vita
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00478]


Cannabis Abuse and Vulnerability to Psychosis: Targeting Preventive Services
Anna Kolliakou, Paolo Fusar-Poli and Zerrin Atakan
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00479]


Pharmacological Prevention and Treatment in Clinical At-Risk States for Psychosis
Stephan Ruhrmanna, Joachim Klosterköttera, Mitja Bodatscha, Andreas Bechdolfa, Benno Graf Schimmelmann, Alexandra Nikolaidesa, Desiree Hilbolla and Frauke Schultze-Lutterb
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00480]


Cognitive Behavioral Therapy in Prodromal Psychosis
Jean Addington, Catherine Marshall and Paul French
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00481]


Psychoeducation in Subjects at Elevated Risk for Psychosis - A Critical Review
Marta Hauser and Georg Juckel
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00482]


Neuroprotective Effects of Low-dose Lithium in Individuals at Ultra-high Risk for Psychosis. A Longitudinal MRI/MRS Study
Gregor E. Berger, Stephen J Wood, Margaret Ross, Clare A. Hamer, R. Mark Wellard, Gaby Pell, Lisa Phillips, Barnaby Nelson, Paul Amminger, Alison R. Yung, Graeme Jackson, Dennis Velakoulis, Christos Pantelis, Husseini Manji and Patrick D. McGorry
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00483]


Polyunsaturated Fatty Acids in Emerging Psychosis
Nilufar Mossaheb, Monika Schloegelhofer, Miriam R. Schaefer, Paolo Fusar-Poli, Stefan Smesny, Pat McGorry, Gregor Berger and G. Paul Amminger
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00484]


Economic Impact of Early Detection and Early Intervention of Psychosis
Lucia R. Valmaggia, Philip K McGuire, Paolo Fusar-Poli, Oliver Howes and Paul McCrone
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00485]


Philosophical issues in the Prodromal Phase of Psychosis
Matthew Broome and Paolo Fusar-Poli
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00486]


Ethical Implications for Clinical Practice and Future Research in “At Risk” Individuals
Fiza Singh, Heline Mirzakhanian, Paolo Fusar-Poli, Camilo de la Fuente-Sandoval and Kristin S. Cadenhead
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00487]


The Multiple Layers of Signaling Selectivity at Protease-Activated Receptors
Iason Kyriazis, John Ellul, Paraskevi Katsakiori, George Panayotakopoulos and Christodoulos Flordellis
[Abstract] [FULL-TEXT INQUIRY] [PMID: 22229576 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00488]


The G-protein Coupled Receptor Family: Actors with Many Faces
Liapakis George, Cordomí Arnau and Pardo Leonardo
[Abstract] [FULL-TEXT INQUIRY] [PMID: 22229577 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00489]


Beta-arrestin Biased Agonism/Antagonism at Cardiovascular Seven Transmembrane-
spanning Receptors
Anastasios Lymperopoulos
[Abstract] [FULL-TEXT INQUIRY] [PMID: 22229558 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00490]


GRK2 Inhibition in Heart Failure: Something Old, Something New
Anastasios Lymperopoulos, Giuseppe Rengo and Walter J. Koch
[Abstract] [FULL-TEXT INQUIRY] [PMID: 22229578 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00491]


Probing Heterotrimeric G Protein Activation: Applications to Biased Ligands
Colette Denis, Aude Saulière, Ségolène Galandrin, Jean-Michel Sénard and Céline Galés
[Abstract] [FULL-TEXT INQUIRY] [PMID: 22229559 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00492]


The Plasticity of the 7TMR Signaling Machinery and the Search for Pharmacological
Selectivity
Christodoulos S. Flordellis
[Abstract] [FULL-TEXT INQUIRY] [PMID: 22229579 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00493]


GRK2 at the control shaft of cellular metabolism
Michele Ciccarelli, Ersilia Cipolletta and Guido Iaccarino
[Abstract] [FULL-TEXT INQUIRY] [PMID: 22229580 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00494]


Current Opinions and Perspectives on the Pathogensis of Parkinson’s Disease: Overviewing the Role of Immune System
Maria Antonietta Panaro and Antonia Cianciulli
[Abstract] [FULL-TEXT INQUIRY] [PMID: 22229581 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00495]


Current treatment strategies for multiple sclerosis – efficacy versus neurological adverse effects
Martin S. Weber, Til Menge, Klaus Lehmann-Horn, Helena C. Kronsbein, Uwe Zettl, Johann Sellner, Bernhard Hemmer and Olaf Stüve
[Abstract] [FULL-TEXT INQUIRY] [PMID: 22229582 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00496]


Enkephalin degrading enzymes: Metalloproteases with high potential for drug development
Tejinder Pal Khaket, Jasbir Singh, Pooja Attri and Suman Dhanda
[Abstract] [FULL-TEXT INQUIRY] [PMID: 22229560 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00497]


Editorial:
[BSP/CPD/E-Pub/00498]


Mining PeptideAtlas for Biomarkers and Therapeutics in Human Disease
Sarah Killcoyne, Eric W. Deutsch and John Boyle
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00499]


Peptides for therapy and diagnosis of Alzheimer’s disease
Susanne Aileen Funke and Dieter Willbold
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00500]


Ghrelin and the brain-gut axis as a pharmacological target for appetite control
Inge Seim, Magdy El-Salhy, Trygve Hausken, Doris Gundersen and Lisa Chopin
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00501]


Short peptide modules for enhancing intestinal barrier function
Soichi Tanabe
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00502]


Peptides in Oral Diseases
Alberta Lucchese, Agostino Guida, Massimo Petruzzi, Giovanni Capone, Luigi Laino and Rosario Serpico
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00503]


Apelin in the Control of Body Fluid Homeostasis and Cardiovascular Functions
Cécile Galanth, Annette Hus-Citharel, Bo Li and Catherine Llorens-Cortès
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00504]


Thymosin β4 Protein Therapy for Cardiac repair
Karina N. Dubé, Sveva Bollini, Nicola Smart and Paul R. Riley
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00505]


Therapeutic potential of host defense peptides in antibiotic-resistant infections
Nicole J Afacan, Amy TY Yeung, Olga M Pena and Robert EW Hancock
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00506]


Peptides in Melanoma Therapy
Simone Mocellin
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00507]


Circumscribing the Conformational Peptide Epitope Landscape
Guglielmo Lucchese, Michele Calabro and Darja Kanduc
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00508]


Editorial: Treatment of Atherosclerosis as an inflammatory disease
[BSP/CPD/E-Pub/00509]


Anti-Inflammatory Effects of Anti-Platelet Treatment in Atherosclerosis
H. Cohen Arazi and J.J. Badimon
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00510]


Inflammation in Ischemic Stroke Subtypes
Antonino Tuttolomondo, Domenico Di Raimondo, Rosaria Pecoraro, Valentina Arnao, Antonio Pinto and Giuseppe Licata
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00511]


Effects of Physical Exercise on Inflammatory Markers of Atherosclerosis
A. Pinto, D. Di Raimondo, A. Tuttolomondo, C. Buttà, G. Milio and G. Licata
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00512]


Atherosclerosis as an Inflammatory Disease
Antonino Tuttolomondo, Domenico Di Raimondo, Rosaria Pecoraro, Valentina Arnao, Antonio Pinto and Giuseppe Licata
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00513]


Inflammation in Peripheral Arterial Disease (PAD)
Salvatore Santo Signorelli, Massimiliano Anzaldi and Valerio Fiore
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00514]


Inflammation in Coronary Artery Disease and Acute Myocardial Infarction - is the Stage Set for Novel Therapies?
Roland Klingenberg and Thomas F. Lüscher
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00515]


Acute Coronary Syndromes as Auto-Inflammatory Disorders
Makoto Suzuki
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00516]


Editorial: Novel Potential Therapeutic Approaches for Schizophrenia
[BSP/CPD/E-Pub/00517]


Engineering of Conotoxins for the Treatment of Pain
Bodil B. Carstens, Richard J. Clark, Norelle L. Daly, Peta J. Harvey, Quentin Kaas and David J. Craik
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00518]


The Multifaceted Activities of Mammalian Defensins
Eusondia Arnett and Stéphanie Seveau
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00519]


Plant Defensins And Defensin-Like Peptides - Biological Activities And Biotechnological Applications
André de Oliveira Carvalho and Valdirene Moreira Gomes
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00520]


Cyclotides, a novel ultrastable polypeptide scaffold for drug discovery
Andrew Gould, Yanbin Ji, Teshome L. Aboye and Julio A. Camarero
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00521]


Sunflower trypsin inhibitor 1 as a molecular scaffold for drug discovery
Adam Lesner, Anna Łęgowska, MagdalenaWysocka and Krzysztof Rolka
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00522]


Circular micro-proteins and mechanisms of cyclization
Brendon F. Conlan and Marilyn A. Anderson
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00523]


Natural and Engineered Cystine Knot Miniproteins for Diagnostic and Therapeutic
Applications
Harald Kolmar
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00524]


Structure and Modeling of Knottins, a Promising Molecular Scaffold for Drug Discovery
Jérôme Gracy and Laurent Chiche
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00525]


Crotamine, a Small Basic Polypeptide Myotoxin from Rattlesnake Venom with Cell-
Penetrating Properties
Gandhi Rádis-Baptista and Irina Kerkis
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00526]


In Vivo Bio-imaging Using Chlorotoxin-based Conjugates
Mark R. Stroud, Stacey J. Hansen and James M. Olson
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00527]


Structure-activity studies on alpha-conotoxins
Markus Muttenthaler, Kalyana B. Akondi and Paul F. Alewood
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00528]


“Liking” and “Wanting” Linked to Reward Deficiency Syndrome (RDS): Hypothesizing Differential Responsivity in Brain Reward Circuitry
Kenneth Blum, Eliot Gardner, Marlene Oscar-Berman and Mark Gold
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00529]


Recent Progress in Small Molecule CCR5 Antagonists as Potential HIV-1 Entry Inhibitors
Wenwen Chen, Peng Zhan, Erik De Clercq and Xinyong Liu
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00530]


Editorial: Inhibition of the Renin-Angiotensin-Aldosterone System: How to Obtain This
[BSP/CPD/E-Pub/00531]


Renin-Angiotensin Antagonists: Therapeutic Effects Beyond Blood Pressure
Aldo Pende and Franco Dallegri
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00532]


Role of the Renin-Angiotensin-Aldosterone System in the Pathogenesis of Atherosclerosis
Alessandro Durante MD, Giovanni Peretto MD, Alessandra Laricchia MD, Francesco Ancona MD, Marco Spartera MD, Antonio Mangieri MD, Domenico Cianflone MD
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00533]


Vaccination Against High Blood Pressure
Duncan J. Campbell
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00534]


Combinations of Renin-Angiotensin-Aldosterone System Antagonists: True Advantages?
Franco Veglio, Elisabetta Puglisi, Alberto Milan and Paolo Mulatero
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00535]


Role of Renin-Angiotensin system in Inflammation, Immunity and Aging
Luciano S. A. Capettini, Fabrizio Montecucco, François Mach, Nikos Stergiopulosa, Robson A. S. Santos, Rafaela F. da Silva
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00536]


Renin-Angiotensin-Aldosterone System Antagonists and the Prevention of Type 2 Diabetes Mellitus
Robert Stöhr and Nikolaus Marx
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00537]


RAAS Inhibition and Renal Protection
Leoncini Giovanna, Viazzi Francesca and Pontremoli Roberto
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00538]


Editorial: Modulation and new mediators in inflammation
[BSP/CPD/E-Pub/00539]


Mast cells in allergic and inflammatory diseases
Nikolaos Sismanopoulos, Danae-Anastasia Delivanis, Konstantinos-Dionysios Alysandratos, Asimenia Angelidou, Anastasia Therianou, Dimitrios Kalogeromitros and Theoharis C. Theoharides
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00540]


Immunobiology Of Antigen-Specific Immunoglobulin Free Light Chains In Chronic Inflammatory Diseases
Tom Groot Kormelink, Philip W. Askenase and Frank A. Redegeld
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00541]


The nervous system as a critical regulator of immune responses underlying allergy
Paul Forsythe
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00542]


The mechanism of adjuvanticity of aluminium-containing formulas
Kaat Fierens and Mirjam Kool
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00543]


The pollen enigma: modulation of the allergic immune response by non-allergenic, pollen-derived compounds
Stefanie Gilles, Heidrun Behrendt,Johannes Ring and Claudia Traidl-Hoffmann
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00544]


Inflammasome signaling in pathogenesis of lung diseases
Esmaeil Mortaz, Mohammad Reza  Masjedi, Abdolamir Allameh and Ian M Adcock
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00545]


A critical appraisal of the functional evolution of P2Y12 antagonists as antiplatelet drugs
Fayaz S. M. A. and Rajanikant G. K.
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00546]


Dendritic cells in pathogenesis of COPD
Masoumeh Ezzati Givi, Frank A. Redegeld, Gert Folkerts and Esmaeil Mortaz
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00547]


Local inflammation in chronic upper airway disease
Lien Calus, Thibaut Van Zele, Lara Derycke, Olga Krysko, Tineke Dutre, Peter Tomassen, Melissa Dullaers, Claus Bachert and Philippe Gevaert
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00548]


Interleukin-7: a key mediator in T cell-driven autoimmunity, inflammation, and tissue destruction
Angela Bikker, C. Erik Hack, Floris P.J.G. Lafeber and Joel A.G. van Roon
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00559]


Immune Cell-Derived Vesicles: Modulators And Mediators Of Inflammation
Esther N.M. Nolte-‘t Hoen and Marca H.M. Wauben
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00550]


Difficulties in describing allergic disease modulation by pre-, pro- and synbiotics
Prescilla V. Jeurink, Anneke Rijnierse, Rocio Martin, Johan Garssen and Léon M. J. Knippels
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00551]


Long chain n-3 polyunsaturated fatty acids in the prevention of allergic and cardiovascular disease
LWJ van den Elsen, J Garssen and LEM Willemsen
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00552]


Sympathetic Nervous System Dysfunction in MS Linking Neurodegeneration to a Reduced Response to Therapy
Zohi Sternberg
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00553]


Editorial: Stem Cells And Tissue Regeneration
Roberta Di Pietro
[BSP/CPD/E-Pub/00555]


Stem cell ageing and apoptosis
Stefania Fulle, Lucia Centurione,Rosa Mancinelli, Silvia Sancilio, Francesco Antonio Manzoli and Roberta Di Pietro
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00556]


Clinical Applications And Biosafety Of Human Adult Mesenchymal Stem Cells
E. Mariani  and A. Facchini
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00557]


The Architectural Organization of Human Stem Cell Cycle Regulatory Machinery
Gary S. Stein, Janet L. Stein, Andre van J. Wijnen, Jane B. Lian, Martin Montecino, Ricardo Medina, Kristie Kapinas, Prachi Ghule, Rodrigo Grandy, Sayyed K. Zaidi and Klaus A. Becker
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00558]


Neural stem cell niches in health and diseases
Ilaria Decimo, Francesco Bifari, Mauro Krampera and Guido Fumagalli
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00559]


Targeting the Cancer Initiating Cell: The Ultimate Target for Cancer Therapy
James A. McCubrey, Linda S. Steelman, Stephen L. Abrams, Negin Misaghian, William H. Chappell, Jörg Bäsecke, Ferdinando Nicoletti, Massimo Libra, Giovanni Ligresti, Franca Stivala, Danijela Maksimovic-Ivanic, Sanja Mijatovic, Giuseppe Montalto, Melchiorre Cervello, Piotr Laidler, Antonio Bonati, Camilla Evangelisti, Lucio Cocco and Alberto M. Martelli
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00560]


Amniotic Fluid Stem Cells: a Promising Therapeutic Resource for Cell-Based Regenerative Therapy
Ivana Antonucci, Andrea Pantalone, Stefano Tetè, Vincenzo Salini, Cesar Borlongan, David Hess and Liborio Stuppia
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00561]


Nuclear PI-PLCβ1 and Myelodysplastic Syndromes: Genetics and Epigenetics
Matilde Y. Follo, Sara Mongiorgi, Carlo Finelli, Manuela Piazzi, Irene Faenza, Giulia Ramazzotti, Patrizia Santi, James A. McCubrey, Alberto M. Martelli and Lucio Cocco
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00562]


Role of miRNAs in Muscle Stem Cell Biology: Proliferation, Differentiation and Death
Stefania Crippa, Marco Cassano and Maurilio Sampaolesi
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00563]


The Combined Use Of Mesenchymal Stromal Cells And Scaffolds For Bone Repair
Gabriela Ciapetti, Donatella Granchi and Nicola Baldini
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00564]


Chromatin modification and senescence
Giovanni Di Bernardo, Marilena Cipollaro and Umberto Galderisi
[Abstract] [FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00565]



Abstracts


Mitochondria-Targeted Antioxidant Peptides
Milagros Rocha, Antonio Hernandez-Mijares, Katherinne Garcia-Malpartida, Celia Bañuls, Lorena Bellod, Victor M Victor
[FULL-TEXT INQUIRY] [PMID: 20687871 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00133]

Overproduction of reactive oxygen species (ROS) under pathophysiologic conditions is part of the disease process. These ROS are released from different sources, and in particular from mitochondria. Although the molecular mechanisms responsible for mitochondria-mediated disease processes are unclear, oxidative stress seems to play an important role. ROS are essential to cell function, but adequate levels of antioxidant defenses are required in order to avoid the harmful effects that excessive ROS production can produce. Mitochondrial oxidative stress damage and dysfunction contribute to a number of cell pathologies that manifest themselves through a range of conditions. The antioxidants available until now have not proved to be particularly effective against many of these disorders. It is possible that these antioxidants do not reach the sites of free radical generation, especially when mitochondria are the primary source of ROS. Recent developments in mitochondria-targeted antioxidants have moved closer to providing protection against mitochondrial oxidative damage. The SS (Szeto-Schiller) peptide antioxidants represent a novel approach that employs the targeted delivery of antioxidants to the inner mitochondrial membrane. These SS peptides scavenge hydrogen peroxide and peroxynitrite and inhibit lipid peroxidation. By reducing mitochondrial ROS, they inhibit mitochondrial permeability transition and cytochrome c release, thus preventing oxidant-induced cell death. Preclinical studies support the use of these peptides for ischemia-reperfusion injury and neurodegenerative disorders. Although peptides have often been considered to be poor drug candidates, the few that have been studied are promising agents for the treatment of diseases.
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Peptidomimetic Competitive Inhibitors of Protein Tyrosine Phosphatases
Kui Shen, Lixin Qi, Lynn Stiff
[FULL-TEXT INQUIRY] [PMID: 20687872 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00134]

This review discusses the development of the active site-directed protein tyrosine phosphatase (PTP) inhibitors based on peptides and some closely related nonpeptidic scaffolds. A straightforward approach is to substitute various nonhydrolyzable analogs for the phosphotyrosine (pTyr) of optimal or physiological phosphopeptide substrates of PTPs. The advances in small molecule peptidic PTP inhibitors and their nonpeptidic derivatives have been greatly aided by X-ray crystallographic and NMR spectrometric studies. Given the importance of PTPs in disease-associated signal transduction and the continuing progress in PTP drug discovery, some clinically useful PTP inhibitors may emerge in the near future.
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Epitope Discovery and Their Use in Peptide Based Vaccines
Nadine L. Dudek, Patrick Perlmutter, Marie-Isabe Aguilar, Nathan P. Croft and Anthony W. Purce
[FULL-TEXT INQUIRY] [PMID: 20687873 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00135]

With recent advances in the design and delivery of peptide-based therapeutics there has been a growing interest on the use of peptides in vaccine design. Moreover, functional dissection and proteomic analysis of the immunogenic epitopes of proteins from pathogenic micro-organisms, cancers and self-tissues targeted by autoimmune responses, have broadened the range of target epitopes and given clues to enhancing peptide immunogenicity. Consistent with these observations; peptides can be synthesised with defined chemical modifications to mimic natural epitopes and/or deliberately introduce protease resistant peptide bonds to regulate their processing independent of tissue specific proteolysis and to stabilize these compounds in vivo. We discuss the potential of peptide-based vaccines for the treatment of chronic viral diseases and cancer and review recent developments in the field of epitope discovery and peptide-based vaccines.
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Gene targeting and expression modulation by Peptide Nucleic Acids (PNA)
Peter E. Nielsen
[FULL-TEXT INQUIRY] [PMID: 20687874 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00136]

Peptide nucleic acids (PNA) are artificial structural mimics of nucleic acids capable of sequence specific hybridization to both RNA and DNA. Thus they have obvious potential as gene targeting agents for drug discovery approaches. An overview with emphasis on recent progress on RNA “interference” (antisense), targeting of duplex DNA and gene targeted repair and transcription interference using PNA, as well as on PNA delivery and potential PNA anti-infectives is given.
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Synthetic peptides derived from the C-terminal region of Lys49 phospholipase A₂ homologues from Viperidae snake venoms: biomimetic activities and potential applications
Bruno Lomonte, Yamileth Angulo and Edgardo Moreno
[FULL-TEXT INQUIRY] [PMID: 20687875 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00137]

Lys49-phospholipase A2 homologues constitute a large family of toxins present in the venoms of viperid snake species, which despite lacking catalytic activity, cause significant skeletal muscle necrosis. The main structural determinants of this toxic effect have been experimentally mapped to a region near their C-terminus (115-129), which combines cationic and hydrophobic/aromatic amino acid residues. Short (13-mer) synthetic peptides representing this C-terminal region can mimick several of the effects of Lys49 PLA2 homologues. In addition to their ability to damage muscle cells, these peptides display antibacterial, antiendotoxic, antifungal, antiparasite, and antitumor activities, as well as VEGF-receptor 2 (KDR)-binding and heparin-binding properties. Modifications of their sequences have shown possibilities to enhance their effects upon prokaryotic cells, while decreasing toxicity for eukaryotic cells. This review presents an updated summary on the biomimetic actions exerted by such peptides, and highlights their potential value as molecular tools or as drug leads in diverse biomedical areas.
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Peptides Targeting gap Junctional Structures
Jean-Claude Hervé, Stefan Dhein
[FULL-TEXT INQUIRY] [PMID: 20687876 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00139]

Cells of multicellular organisms need to communicate and have evolved different mechanisms of intercellular communication, the most direct and quickest of which is through channels that directly link the cytoplasms of adjacent cells. In metazoans, intercellular channels result from the docking of two hemichannels, hexameric torus of junctional proteins (connexins being the most known) around an aqueous pore. Junctional channels and hemichannels are not passive conduits as they had been regarded for a long time but their permeability is finely tuned by complex mechanisms that have just begun to be identified, the delay being partly due to limited availability of specific pharmacological tools. Peptides have a number of advantages over other molecules in terms of specificity and affinity for targets. Some of them interact with membrane receptors, activating a signaling transduction cascade leading to modifications in the expression of gap junctional proteins or the functional state of channels. A second approach is based on the use of so-called mimetic peptides (also known as gap peptides) that mimic a short sequence of gap junction proteins and have been shown to attenuate processes downstream of the putative channel activity. They also represent very useful tools to investigate the structure of domains of gap junction proteins. This review presents an overview of the literature on peptides targeting gap junctional structures.
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HDL Apolipoprotein-Related Peptides in the Treatment of Atherosclerosis and Other Inflammatory Disorders
G. S. Getz, G. D. Wool, and C. A. Reardon
[FULL-TEXT INQUIRY] [PMID: 20687877 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00140]

Elevations of HDL levels or modifying the inflammatory properties of HDL are being evaluated as possible treatment of atherosclerosis, the underlying mechanism responsible for most cardiovascular diseases. A promising approach is the use of small HDL apoprotein-related mimetic peptides. A number of peptides mimicking the repeating amphipathic α-helical structure in apoA-I, the major apoprotein in HDL, have been examined in vitro and in animal models. Several peptides have been shown to reduce early atherosclerotic lesions, but not more mature lesions unless coadminstered with statins. These peptides also influence the vascular biology of the vessel wall and protect against other acute and chronic inflammatory diseases. The biologically active peptides are capable of reducing the pro-inflammatory properties of LDL and HDL, likely due to their high affinity for oxidized lipids. They are also capable of influencing other processes, including ABCA1 mediated activation of JAK-2 in macrophages, which may contribute to their anti-atherogenic function. The initial studies involved monomeric 18 amino acid peptides, but tandem peptides are being investigated for their anti-atherogenic and anti-inflammatory properties as they more closely resemble the repeating structure of apoA-I. Peptides based on other HDL associated proteins such as apoE, apoJ and SAA have also been studied. Their mechanism of action appears to be distinct from the apoA-I based mimetics.
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Chemical Modifications Designed to Improve Peptide Stability: incorporation of Non-Natural Amino Acids, Pseudo-Peptide Bonds, and Cyclization
Luca Gentilucci, Rossella De Marco, Lucia Cerisoli
[Purchase Article] [PMID: 20687878 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00141]

Functions and properties of native peptides vary from highly specific antibiotics or cytotoxic antitumor drugs, to hormones, neurotransmitters, immunomodulators, etc. Despite their potential utility as therapeutic agents, there are problems connected with the use of natural peptides, due to the low stability against proteolysis, resulting in a short duration of in vivo activity, and in a low bioavailability. One way to overcome these disadvantages is the use of modified peptides, the so called peptidomimetics. Overall, the less peptide character in a drug candidate, the more stable it is towards protease cleavage. A huge number of non-peptidic scaffolds have been reported in the literature; nevertheless, several cases have failed to reproduce the activity of the precursor peptide when the scaffold itself contains relevant pharmacophore elements. Therefore, quasi-peptides still maintain their appeal for applications in medicinal chemistry. For the large number of different unnatural amino acids and peptidomimetics, the overview cannot be all-inclusive. This review focuses on modified peptides in which the peptide character is still preponderant, with particular emphasis on the chemical methodologies utilized to introduce the modifications.
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Ligand-Based Peptide Design and Combinatorial Peptide Libraries to Target G Protein-Coupled Receptors
Christian W. Gruber, Markus Muttenthaler and Michael Freissmuth
[FULL-TEXT INQUIRY] [PMID: 20687879 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00142]

G protein-coupled receptors (GPCRs) are considered to represent the most promising drug targets; it has been repeatedly said that a large fraction of the currently marketed drugs elicit their actions by binding to GPCRs (with cited numbers varying from 30-50%). Closer scrutiny, however, shows that only a modest fraction of (~60) GPCRs are, in fact, exploited as drug targets, only ~20 of which are peptide-binding receptors. The vast majority of receptors in the humane genome have not yet been explored as sites of action for drugs. Given the drugability of this receptor class, it appears that opportunities for drug discovery abound. In addition, GPCRs provide for binding sites other than the ligand binding sites (referred to as the “orthosteric site”). These additional sites include (i) binding sites for ligands (referred to as “allosteric ligands”) that modulate the affinity and efficacy of orthosteric ligands, (ii) the interaction surface that recruits G proteins and arrestins, (iii) the interaction sites of additional proteins (GIPs, GPCR interacting proteins that regulate G protein signaling or give rise to G protein-independent signals). These sites can also be targeted by peptides. Combinatorial and natural peptide libraries are therefore likely to play a major role in identifying new GPCR ligands at each of these sites. In particular the diverse natural peptide libraries such as the venom peptides from marine cone-snails and plant cyclotides have been established as a rich source of drug leads. High-throughput screening and combinatorial chemistry approaches allow for progressing from these starting points to potential drug candidates. This will be illustrated by focusing on the ligand-based drug design of oxytocin (OT) and vasopressin (AVP) receptor ligands using natural peptide leads as starting points.
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Antimicrobial Peptides and Peptaibols, Substitutes for Conventional Antibiotics
Hervé DUCLOHIER
[FULL-TEXT INQUIRY] [PMID: 20687880 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00143]

In this review, the antimicrobial properties of a number of peptides are described. We first deal with helical linear peptides such as the well-known gramicidin, magainins, melittin, and other less well-known or more recently discovered peptides. Then, beta-sheet peptides (defensins isolated from insects and also from mammalian tissues) and cyclic peptides like amphotericin B are described before the properties of peptaibols (containing the non-coded amino acid Aib) are discussed. Alamethicin remains the prototype of this class and its biophysical properties (mostly focussing on channel- or pore-formation in planar lipid bilayers) were and are still intensively studied. On the whole, we show how biophysical studies can explain the antimicrobial action of this ever expanding family of peptides.
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Neuropeptides as Therapeutic Approach to Autoimmune Diseases
Elena Gonzalez-Rey, Virginia Delgado-Maroto, Luciana Souza Moreira and Mario Delgado
[FULL-TEXT INQUIRY] [PMID: 20687881 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00144]

Because there are no particular molecular signatures of self, autoimmunity is the inevitable evolutionary price of being able to make effective responses against a wide variety of pathogens by the immune system. Without the various phenomena referred to as immune tolerance, the organism would surely self-destruct. Considerable evidence suggests that various endogenous neuropeptides play a major role in the education of our immune system to be self-tolerant. The fact that neuropeptides regulate various layers involved in maintenance of tolerance, including regulation of the balance between pro-inflammatory and anti-inflammatory responses and between self-reactive Th1/Th17 cells and regulatory T cells, makes them attractive candidates for the development of new therapies for the treatment of autoimmune disorders. Here we use the vasoactive intestinal peptide of a prototype of immunomodulatory neuropeptide to review the most relevant data found for other neuropeptides with similar characteristics, including melanocyte-stimulating hormone, urocortin, adrenomedullin, neuropeptide Y, cortistatin and ghrelin. We also evaluate the challenges that must be overcome before achieving their clinical application and offer our opinion on how a physiologically functional neuropeptide system contributes to general health.
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Bcl-2 family proteins as therapeutic targets
Peter E Czabotar and Guillaume Lessene
[FULL-TEXT INQUIRY] [PMID: 20687882 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00145]

The mitochondrion provides the stage for the interplay of molecular interactions that regulate apoptosis via the intrinsic pathway. The release of apoptogenic factors from this compartment constitutes a critical juncture in this apoptotic pathway. Regulation of the integrity of the outer mitochondrial membrane (OMM) is the task of the Bcl-2 family of proteins. A network of interactions between the various subgroups of the family decides the apoptotic fate of a cell and, as such, an imbalance within this network can lead to a variety of disease states. In particular, over-expression of pro-survival Bcl-2 family proteins is a hallmark of many cancers. Here we discuss recent advances in targeting the Bcl-2 family with both peptides and small molecules.
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Orexins/Hypocretins: Pain Regulation and Cellular Actions
Lih-Chu Chiou, Hsin-Jung Lee, Yu-Cheng Ho, Shih-Pin Chen, Yan-Yu Liao, Chia-Hau Ma, Pi-Chuan Fan, Jong-Ling Fuh, and Shuu-Jiun Wang
[FULL-TEXT INQUIRY] [PMID: 20687883 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00146]

Orexin A and B (also named hypocretin 1 and 2) are 33 and 28 amino acid-contaning neuropeptides, respectively, derived from prepro-orexin (prepro-hypocretin) which is localized in the the lateral and perifonical areas of the hypothalamus. Two G-protein coupled receptor subtypes, OX1 and OX2, were identified. Orexin-containing fibers and OX receptors are widely distributed in the central nervous system. Orexins have been implicated in the rousal, rewarding, energy homeostasis, autonomic central control and antinociceptive systems. Subtype-selective peptide agonists and antagonists and non-peptide antagonists, but not non-peptide agonists, have been developed. This review summarizes the studies investigating the antinociceptive effects of orexins in various animal models of pain, including trigeminovascular pain, and their cellular mechanisms. Orexins are antinociceptive at both spinal and supraspinal levels. The antinociceptive effect of orexin A is comparable to opioids but orexin B is less or not effective. This effect is opioid-independent and mainly mediated through OX1 receptors. Some animal studies suggest that endogenous orexins may be released during postoperative and inflammatory, but not acute, pain states, or during some stress conditions, which may contribute to stress-inuced analgesia. Purinergic P2X and glycine receptors are proposed to be involved in orexin-induced spinal antinociception. The supraspinal sites of actions might involve the posterior hypothalamus, which contributes to the trigeminovascular nociception, and the ventrolateral periaqueductal gray, which mediates descending pain inhibition. Endocannobinoids and nociceptin/orphanin FQ were found to interplay with orexins in nocicpetive processing. Further studies are required to elucidate the receptor subtype-specific mechanism(s) and clinical implications of orexin-induced antinociception.
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Optimization and High-Throughput Screening of Antimicrobial Peptides
Sylvie E. Blondelle and Karl Lohner
[FULL-TEXT INQUIRY] [PMID: 20687884 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00147]

While a well-established process for lead compound discovery in for-profit companies, high-throughput screening is becoming more popular in basic and applied research settings in academia. The development of combinatorial libraries combined with easy and less expensive access to new technologies have greatly contributed to the implementation of high-throughput screening in academic laboratories. While such techniques were earlier applied to simple assays involving single targets or based on binding affinity, they have now been extended to more complex systems such as whole cell-based assays. In particular, the urgent need for new antimicrobial compounds that would overcome the rapid rise of drug-resistant microorganisms, where multiple target assays or cell-based assays are often required, has forced scientists to focus onto high-throughput technologies. Based on their existence in natural host defense systems and their different mode of action relative to commercial antibiotics, antimicrobial peptides represent a new hope in discovering novel antibiotics against multi-resistant bacteria. The ease of generating peptide libraries in different formats has allowed a rapid adaptation of high-throughput assays to the search for novel antimicrobial peptides. Similarly, the availability nowadays of high-quantity and high-quality antimicrobial peptide data has permitted the development of predictive algorithms to facilitate the optimization process. This review summarizes the various library formats that lead to de novo antimicrobial peptide sequences as well as the latest structural knowledge and optimization processes aimed at improving the peptides selectivity.
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Editorial: Current status of Drug Eluting Stents
[PMID: 21208179 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00155]

Coronary stent implantation has become a well-established therapy in the management of coronary artery disease. Although the STRESS (Stent Restenosis Study) and BENESTENT (Belgium-Netherlands Stent) trials demonstrated convincingly that stenting is superior to PTCA with respect to restenosis in de novo lesions, there is however a still high incidence (10 to 50%) of restenosis following stent implantation depending on lesion and patient characteristics.

Improvements in stent design and implantation techniques resulted in an increase in the use of coronary stents and today in most centers in USA and Europe stenting has become the predominant form of nonsurgical revascularization and accounts for about 80% of all procedures.

Coronary stents provide luminal scaffolding that virtually eliminates elastic recoil and remodeling. Stents, however, do not decrease neointimal hyperplasia and in fact lead to an increase in the proliferative component of restenosis.

Agents that inhibit cell-cycle progression indirectly have also have been tested as inhibitors of vascular proliferation. Sirolimus (Rapamune, Rapamycin), a macrolide antibiotic with immunosuppressive properties and its analogues , Paclitaxel (Taxol) inhibit neointimal formation in animal models when loaded onto coated stents.

Preliminary clinical studies with drug eluting stents produced dramatic results eventually eliminating restenosis in large and mid-size arteries. This was later confirmed in large randomized clinical trials and demonstrated the benefit of DES in patients with a high risk for restenosis.

There is no doubt that DES dramatically reduces the rate of angiographic restenosis and the clinical need for repeat revascularization procedures. DES enables cardiologists to perform procedures in complex lesions, in which surgery would have been the only option before the advent of DES. However, so far no beneficial effect on death and re-infarction was observed in any of the randomized clinical trials. There are still concerns regarding an increase in the rate of late stent thrombosis.

Certainly DES technology is a definitive step forward in our desire to optimize the results of PCI. However, before we can recommend a DES for every patient and every lesion, the long-term safety and efficacy issues have to be solved.
In this issue, a multidisciplinary team of international experts discuss all the most relevant topics on stent-based treatment techniques including polymer coating designs[1], mechanism of action of different pharmaceuticals on restenosis [2,3] comprehensive reviews of major clinical studies[4,5], new stents for vulnerable plague[6], next generation DES developments including biodegradable and bioabsorbable stents[7], discussion of duration of dual antiplatelet therapy[8] alongside with pathobiology of stent thrombosis[9] .

References:
1. Polymers for drug-eluting stents Vipul Davé and Robert Falotico Curr Pharm Des 2010, XXX
2. Antiproliferative compounds for the prevention of restenosis Mark C. Lavigne, Michael J. Eppihimer, Ruth Cheng, and James J. Barry Curr Pharm Des 2010, XXX
3. Sirolimus and its analogues and its effect on vascular diseases
Steven J. Adelman, Ph.D. Curr Pharm Des 2010, XXX
4.Clinical studies with Sirolimus, Evrolimus, Biolimus A9, Zotarilimus
Drug-Eluting Stents systems Curr Pharm Des 2010, XXX
Bimmer E Claessen, José P S Henriques and George D Dangas Curr Pharm Des 2010, XXX
5. Clinical studies with Paclitaxal – Eluting stent systems
Kirk Garratt Curr Pharm Des 2010, XXX
6. Drug Eluting Stents for Vulnerable Plague
Konstantinos Toutouzas, Andreas Synetos, Christodoulos Stefanadis Curr Pharm Des 2010, XXX
7. Next Generation Drug-Eluting stent systems:
Biodegradable and Bioabsorbable Stents
Ron Waksman and Rajbabu Pakala, Curr Pharm Des 2010, XXX
8. Stent thrombosis and duration of dual antiplatelet therapy
Alfonso Ielasi , Rasha Al-Lamee, and Antonio Colombo Curr Pharm Des 2010, XXX
9 Pathobiology of stent thrombosis after drug-eluting stent implantation
Marc Vorpahl, Saami K. Yazdani, Masataka Nakano, Elena Ladich, Frank D. Kolodgie, Aloke V. Finn, Renu Virmani Curr Pharm Des 2010, XXX
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Genome-Wide Association Studies: Is there a Genotype for Cognitive Decline in Older Persons with Type 2 Diabetes?
Angela Marie Abbatecola, Fabiola Oliveri, Andrea Corsonello, Roberto Antonicelli, Francesco Corica, Fabrizia Lattanzio
[FULL-TEXT INQUIRY] [PMID: 21352095 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00182]

There is a dramatic increase in the number of elderly persons on a worldwide scale with an increase in chronic comorbidities, especially type 2 diabetes (T2DM) and dementia. Although cognitive faculties commonly deteriorate in non-diabetic persons as they age, several studies have concluded that diabetes is uniquely associated with cognitive decline and is associated with a two-fold risk of Alzheimer’s Disease (AD). Studies have also suggested that good glycemic has shown to improve cognitive status, however whether the use of specific anti-diabetic oral agents may play an additional role in controlling against cognitive deterioration is unknown. In addition, excitotoxicity from the overstimulation of glutamate receptors is considered a major cause of neuron death in AD and statins may be promising agents for protecting against memory loss.

Possible pathophysiologic mechanisms common to both T2DM and AD are glucose toxicity and a direct effect of insulin on amyloid metabolism. In fact, AD and T2DM have comparable pathological features in the islet and brain (amyloid derived from amyloid β protein (β-amyloid) in the brain in AD and islet amyloid derived from islet amyloid polypeptide in the pancreas in T2DM). Evidence is growing linking precursors of amyloid deposition in the brain and pancreas to the pathogenesis of AD and T2DM, respectively. Indeed, the need to identify agents capable of correcting such pathological features may in turn significantly protect against the accumulation of β-amyloid in the brain, known to interfere with correct cognitive function. Cholesterol may also be directly involved in β-amyloid aggregation: abnormal oxidative metabolites such as cholesterol-derived aldehydes can modify β-amyloid, firstly promoting Schiff base formation, then accelerating the early stages of amyloidogenesis.

At the moment, genome-wide association studies (GWAS) have begun to elucidate the genetic architecture of chronic diseases including, T2DM and AD. Thus, one of the challenges for a successful GWAS in the future will be to identify a genotype in older persons with T2DM for good drug response, which in turn may protect against cognitive decline and AD. The literature has suggested that the use of insulin sensitizers and statins are correlated with a lower rate of cognitive decline in older persons. In this paper, we will explore recent findings regarding diverse single nucleotide polymorphisms from GWAS on T2DM, AD and both. We will also shed light on future pathways, as the basis of improving drug and diagnostics development for a better integration of genetic studies for precise drug-development focusing on the role of genetic variation in maintaining metabolic control and cognitive performance.
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Review on the protective effects of PACAP in models of neurodegenerative diseases in vitro and in vivo
Reglodi D, Kiss P, Lubics A, Tamas A
[Purchase Article] [PMID: 21524257 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00183]

Pituitary adenylate cyclase activating polypeptide (PACAP) is a pleiotropic and multifunctional peptide exerting its effects via 3 main receptors (PAC1, VPAC1 and VPAC2). PACAP is now considered to be a potent neurotrophic and neuroprotective peptide. It plays an important role during the embryonic development of the nervous system. PACAP also protects neurons against various toxic insults in neuronal cultures of diverse origins. In vivo, PACAP shows neuroprotection in models of ischemic and traumatic brain injuries, and those of neurodegenerative diseases. The present review summarizes the findings on the neuroprotective potential of PACAP in models of neurodegenerative diseases, with special focus on in vitro and in vivo models of Parkinson`s disease, Huntington chorea and Alzheimer`s disease. Based on these observations, both endogenous and exogenously administered PACAP or its novel analogs, fragments offer a novel therapeutic approach in treatment of neurodegenerative diseases.
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Role of PACAP in neural stem/progenitor cell and astrocyte - from neural development to neural repair
Tomoya Nakamachi, Jozsef Farkas, Jun Watanabe, Hirokazu Ohtaki, Kenji Dohi, Satoru Arata and Seiji Shioda
[Purchase Article] [PMID: 21524256 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00184]

After central nervous system (CNS) injury, reactive astrocytes display opposing functions, inducing neural repair and axonal regeneration via the release of growth factors, or forming a glial scar which acts as a barrier to axonal regeneration. Endogenous neural stem/progenitor cells have also recently been identified at the site of CNS injury, where they have been shown to differentiate into mature neurons in an animal model of ischemia. However, the pathophysiological mechanisms underpinning the contribution of reactive astrocytes and neural stem/progenitor cells to neural repair are still to be fully elucidated. Pituitary adenylate cyclase activating polypeptide (PACAP) is widely expressed in the CNS, where it has been shown to exert numerous biological effects. This review will summarize the current state of knowledge regarding the expression of PACAP and its receptors during neural development, as well as the involvement of PACAP in astrocytes and neural stem/progenitor cell biology. In addition, we will also discuss emerging evidence that implicates PACAP in neurogenesis and neural repair in response to brain pathophysiology.
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PACAP is Implicated in the Stress Axes
Hitoshi Hashimoto, Norihito Shintani, Mamoru Tanida, Atsuko Hayata, Ryota Hashimoto, Akemichi Baba
[Purchase Article] [PMID: 21524255 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00185]

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a highly conserved pleiotropic neuropeptide that functions as a neurotransmitter, neuromodulator and neurotrophic factor. Accumulating evidence implicates PACAP as an important regulator of both central and/or peripheral components of the stress axes, particularly exposure to prolonged or traumatic stress. Indeed, PACAP and its cognate receptors are widely expressed in the brain regions and peripheral tissues that mediate stress-related responses. In the sympathoadrenomedullary system, PACAP is required for sustained epinephrine secretion during metabolic stress. It is likely that PACAP regulates autonomic function and contributes to peripheral homeostasis by maintaining a balance between sympathetic and parasympathetic activity, favoring stimulation of the sympathetic system. Furthermore, PACAP is thought to act centrally on the paraventricular nucleus of the hypothalamus to regulate both the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system. Intriguingly, PACAP is also active in brain structures that mediate anxiety- and fear-related behaviors, and the expression of PACAP and its receptors are dynamically altered under pathologic conditions. Thus PACAP may influence both hard-wired (genetically determined) stress responses and gene-environment interactions in stress-related psychopathology. This article aims to overview the molecular mechanisms and psychiatric implications of PACAP-dependent stress responses.
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The role of the PACAP signaling system in depression
Albert Pinhasov, Elimelech Nesher, Moshe Gross, Gadi Turgeman, Anatoly Kreinin and Gal Yadid
[Purchase Article] [PMID: 21524254 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00186]

Major Depressive Disorder (MDD) is a psychiatric condition that represents an important public health concern in modern society. Current pharmacological antidepressant treatments improve depressive symptoms through complex mechanisms that are incompletely understood. There is a consensus that in the clinic they act through the modulation of monoaminergic neurotransmission, primarily involving the serotonin and norepinephrine systems. Recent studies have suggested that action of antidepressants on synaptic plasticity is mediated by their regulatory influence not only upon small-molecule neurotransmitters, but also via neuropeptides which may act both as neurotransmitters and as neuromodulators. Prominent among these neuropeptides is PACAP, whose signaling system is intensively studied for its pleiotropic involvement in various physiological and pathological conditions. This review outlines the current knowledge concerning the PACAP signaling system's involvement in depressive disorders.
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Strategies to Convert PACAP from a Hypophysiotropic Neurohormone into a Neuroprotective Drug
S. Bourgault, D. Chatenet, O. Wurtz, N.D. Doan, J. Leprince, H. Vaudry, A. Fournier and D. Vaudry
[Purchase Article] [PMID: 21524253 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00187]

In neurological insults, such as cerebral ischemia and traumatic brain injury, complex molecular mechanisms involving inflammation and apoptosis are known to cause severe neuronal cell loss, emphasizing the necessity of developing therapeutic strategies targeting simultaneously these two processes. Over the last decade, numerous in vitro and in vivo studies have demonstrated the unique therapeutical potential of pituitary adenylate cyclase-activating polypeptide (PACAP) for the treatment of neuronal disorders involving apoptotic cell death and neuroinflammation. The neuroprotective activity of PACAP is based on its capacity to reduce the production of deleterious cytokines from activated microglia, to stimulate the release of neuroprotective agents from astrocytes and to inhibit pro-apoptotic intracellular pathways. However, the use of PACAP as a clinically applicable drug is hindered by its peptidic nature. As most natural peptides, native PACAP shows poor metabolic stability, low bioavailability, inadequate distribution and rapid blood clearance. Moreover, injection of PACAP to human can induce peripheral adverse side effects. Therefore, targeted chemical modifications and/or conjugation of PACAP to different macromolecules are required to improve the pharmacokinetic and pharmacological properties of PACAP. This review presents the chemical, biochemical and pharmacological strategies that are currently under development to convert PACAP from a hypophysiotropic neurohormone into a clinically relevant neuroprotective drug.
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Immunomodulatory roles of VIP and PACAP in models of multiple sclerosis
Catalina Abad and James A. Waschek
[Purchase Article] [PMID: 21524252 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00188]

Multiple sclerosis (MS) is a progressive neurodegenerative disease affecting myelin and axons, which is perpetuated by autoreactive lymphocytes and other inflammatory cell types. Because of the multifactorial nature of this disease, therapies targeting a single process may not be sufficient to halt its progression. VIP and PACAP are two neuropeptides shown to regulate multiple aspects of innate and adaptive immunity, and can also act independently on neural cells to promote their survival and regeneration. Animal studies have proven the efficacy of these peptides for the treatment of several models of neural inflammatory disorders, including those which, like MS, have major Th1/Th17 components. In this review, the immunomodulatory actions of VIP and PACAP will be discussed, with particular emphasis on their potential significance in MS.
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VIP-induced neuroprotection of the developing brain
Sandrine Passemard, M.D., Ph.D., Paulina Sokolowska, Ph.D., Leslie Schwendimann, Tech., and Pierre Gressens, M.D., Ph.D.
[Purchase Article] [PMID: 21524251 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00189]

Excitotoxicity is a key molecular mechanism of perinatal brain damage and is associated with cerebral palsy and long term cognitive deficits. VIP induces a potent neuroprotection against perinatal excitotoxic white matter damage. VIP does not prevent the initial appearance of white matter lesion but promotes a secondary repair with axonal regrowth. This plasticity mechanism involves an atypical VPAC2 receptor and BDNF production. Stable VIP agonists mimic VIP effects when given systemically and exhibit a large therapeutic window. Unraveling cellular and molecular targets of VIP effects against perinatal white matter lesions could provide a more general rationale to understand the neuroprotection of the developing white matter against excitotoxic insults.
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NAP (Davunetide) Provides Functional and Structural Neuroprotection
Illana Gozes
[Purchase Article] [PMID: 21524250 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00190]

NAP (davunetide) is an eight amino acid peptide (NAPVSIPQ) that has been shown to provide potent neuroprotection, in vitro and in vivo. In human clinical trials, NAP has been shown to increase memory scores in patients suffering from amnestic mild cognitive impairment, a precursor to Alzheimer's disease and to enhance functional daily behaviors in schizophrenia patients. NAP is derived from activity-dependent neuroprotective protein (ADNP) a molecule that is essential for brain formation, interacting with chromatin associated protein alpha and the chromatin remodeling complex SWI/SNF and regulating >400 genes during embryonic development. Partial loss in ADNP results in cognitive deficits and pathology of the microtubule associated protein tau (tauopathy) that is ameliorated in part by NAP replacement therapy. Recent studies increased the scope of NAP neuroprotection and provided further insights into the NAP mechanisms of action. Thus, it has been hypothesized that the presence of tau on axonal microtubules renders them notably less sensitive to the microtubule-severing protein katanin, and NAP was shown to protect microtubules from katanin disruption in the face of reduced tau expression. Parallel studies showed that NAP reduced the number of apoptotic neurons through activation of PI-3K/Akt pathway in the cortical plate or both PI-3K/Akt and MAPK/MEK1 kinases in the white matter. The interaction of these disparate yet complementary pathways is the subject of future studies toward human brain neuroprotection in the clinical scenario.
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Editorial: VIP and PACAP: Novel Approaches to Brain Functions and Neuroprotection
[PMID: 21524249 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00191]

In 1970 and 1972, Sami Said and Victor Mutt identified and isolated “vasoactive intestinal polypeptide” (VIP) from porcine intestine based on its ability to increase peripheral blood flow and decrease arterial blood pressure in dogs [1,2]. In 1989 Akira Arimura and his colleagues isolated pituitary adenylate cyclase-activating polypeptide (PACAP) based on its ability to stimulate the production of cyclic AMP in rat pituitary cells [3]. VIP and PACAP serve as hormones, transmitters, modulators, and tropic factors, which act in both the central (CNS) and the peripheral nervous systems (PNS) through specific high-affinity receptors. Their actions are versatile and diverged within an organism as pleiotropic neuropeptides. In 1999, the laboratory of Illana Gozes in collaboration with the laboratory of Douglas Brenneman discovered the VIP-regulated activity-dependent neuroprotective protein (ADNP) and identified an ADNP derived peptide) NAP (NAPVISPQ) [4]. NAP (davunetide) is now being developed as a drug candidate in progressive supreanuclear palsy, a rare fatal disease often misdiagnosed as Parkinson disease (for further discussion, see this issue).

The various VIP and PACAP receptors are differentially expressed in discrete areas in the CNS and PNS as well as other peripheral organs and tissues. VIP and PACAP receptors have been identified in numerous tissues, and three different types are discerned. Two of these (VPAC1 and VPAC2) bind PACAP and VIP with similar high affinity. The third type, PAC1 is a PACAP specific receptor. PAC1 binds PACAP with high affinity and usually interacts with VIP only at high VIP concentration. PAC1 is also unique because it exists in at least thirteen different forms derived forms derived by alternate mRNA splicing. These different splice variants regulate receptor ligand affinity and specificity, and coupling to adenylte cylase and phosopholipase C pathways [5]. PAC1, VPAC1 and VPAC2 have been identified not only in the nervous system but in endocrine glands such as the pituitary, the thyroid, the gonads and the adrenal, as well as in the gastrointestinal tract, liver, pancreas, respiratory system, cardiovascular system, immune system, bones and tumor cells. Although a very large number of functions are described, it is likely that new roles for PACAP and VIP will be discovered followed by therapeutic applications.

PACAP, VIP and its related peptides are shown to play very important roles in controlling homeostasis throughout the animal kingdom from sea squirt to humans. Both VIP and PACAP appear to play important, but distinct roles in circadian rhythms, nerve injury, ischemia and excitotoxicity, pain, epilepsy, schizophrenia, Alzheimer’s disease, emotional and psychomotor behavior, neurodevelopment and immune response [5,6] (for further discussion, see this issue).

In this special issue, leading international experts discuss most relevant topics on novel potential targets for VIP, PACAP and NAP. The special issue will strongly contribute to progress not only in basic research in this field but also in translational research and it may encourage moving forward toward human translational research. Finally, we would like to thank all the contributors to this special issue for their excellent participation.

REFERENCES
[1] Said SI, Mutt V. Polypeptide with broad biological activity: isolation from small intestine. Science 1970, 169:1217-1218.
[2] Said SI, Mutt V. Isolation from porcine-intestinal wall of a vasoactive octapeptide related to secretin and to glucagon. Eur J Biochem 1972, 28: 199-204.
[3] Miyata A, Arimura A, Dahl RD, Minamino N, Uehara A, Jinang L, Culler MD, Coy DH. Isolation of a novel 38 residue-hypothalamic polypeptide which stimulates adenylate cyclase in pituitary cells. Biochem Biophys Res Commun 1989 164: 567-574.
[4] Bassan M, Zamostiano R, Davidson A, Pinhasov A, Gialdndi E, Perl O, Bassan H, Blat C, Gibney G, Glaznr G, Brenneman DE, Gozes I. Complete sequence of a novel protein containing a femtomolar-activity-dependent neuroprotective peptide. 1999, J Neurochem 72: 1283-1293.
[5] Shioda S, Wascheck. Type II Family of GPCRs –VIP & PACAP receptors. pp 527-545 In Understanding G-Protein-coupled Receptors and their Role in the CNS. Edit by Pangalos MN and Davises CH. Oxford University Press 2002
[6] Gozes I. VIP-PACAP 2010: My own perspectives on modulation of cognitive and emotional behavior. J Mol Neurosci 2010, 42: 261-263.

Seiji Shioda
Department of Anatomy
Showa University School of Medicine
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Gender differences in the effects of angiotensin receptor blockers on cardiovascular disease
Hiroshi Yoshida, Giuseppe Rosano, Mitsuyuki Shimizu, Seibu Mochizuki, Michihiro Yoshimura
[Purchase Article] [PMID: 21449891 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00192]

Women tend to develop hypertension later as they transition into menopause, and during and after menopause the development of hypertension in women is independent of age and body mass index (BMI) but is related to menopause itself. One of the mechanisms of hypertension development in postmenopausal women is believed to be the lack of estrogen leading to vasoconstriction due to both renin-angiotensin-aldosterone (RAA)-sensitive and sodium-sensitive pathways. Nowadays, we have many medications of antihypertensive therapy, including ACE inhibitor and angiotensin receptor blocker (ARB) in addition to diuretics, beta-blockers, calcium channel blockers. The present review summarizes gender differences in the effects of ARB on blood pressure lowering and cardiovascular outcomes from the published reports of large-scaled, randomized clinical trials and its substudy on sex-specific difference. Many antihypertensive drugs have been developed, and the benefit of blood pressure lowering therapy for the prevention of cardiovascular disease would be expected not only in men but also in women as indicated in the large-scaled clinical studies with ARB.
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Gender differences in the clinical presentation of heart disease
Peter Collins, MD, Cristiana Vitale, MD, Ilaria Spoletini, Giuseppe Barbaro, MD
[Purchase Article] [PMID: 21449890 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00193]

The clinical presentation of heart disease is different between men and women and this distinction is pivotal for a correct diagnosis and an adequate treatment. However, the definition of symptoms classically associated with heart disease is mainly based on the characteristics of those reported in men.

Chest pain or chest discomfort in women are therefore often regarded as “atypical” and these symptoms tend to be misdiagnosed and under-treated. Further, women are less likely to receive appropriate invasive and non invasive investigations. They are less likely to refer for medical help and tend to present late in the process of the cardiovascular disease, with delays in the start of effective treatment.

Therefore, a gender-specific assessment of cardiovascular risk is strongly advised for patients presenting with symptoms suggestive of heart disease.
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The effect of gender on cardiovascular pharmacology
Flavia Franconi, Ciriaco Carru, Walter Malorni Stefano Vella Giuseppe Mercuro
[Purchase Article] [PMID: 21449889 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00194]

Cardiovascular diseases differ between men and women as do outcomes after therapeutic interventions. Management of these diseases, however, is generally guided by evidence from trials conducted predominantly in men, with few studies focused on women alone. Our goal is to review the gender differences in cardiovascular therapies, which show many areas of uncertainty regarding women due to their small enrolment in clinical trials; thus, in some cases, firm conclusions about efficacy in women are difficult to obtain. Nevertheless, female gender appears to suffer from more adverse drug effects [ADE] than the male gender. For example, women are significantly more likely to experience drug-induced QT-prolongation and torsade-de-pointes arrhythmia and many other types of ADE.

The major sex-specific differences present in pharmacokinetics, especially for the major drug metabolizing enzymes, the cytochromes P450 family, but also for phase II reactions such as glucuronidation, are discussed. Pharmacodynamic mechanisms underlying sex/gender differences are not clearly elucidated yet; however, this highlights the need for more studies focusing on women in order to optimize gender-specific therapy and, therefore, improve clinical outcomes in women with cardiovascular diseases.
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Gender related issues in the management of heart failure
Stefan Anker, Giuseppe Caminiti, Maurizio Volterrani
[Purchase Article] [PMID: 21449888 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00195]

Heart failure (HF) represents a growing health issue with significant morbidity, expense, and mortality in western world. Despite a similar prevalence between gender our knowledge about this disease mostly come from studies perfomed in men. Instead, until now women have been under-represented in HF trials and this limits our knowledge of HF in women to extrapolation of findings from men. However according to the available data women with HF differ from men regarding pathophysiology, clinical presentation and prognosis. Women with HF often present at an older age, have a better systolic function, suffer from more comorbidities, have an higher rate of hospital admissions and have a better age-adjusted survival compared to men. Moreover pharmacodynamic specificities related to gender have been described. Taken together these gender-related differences can affect response to several kinds of treatments and the general clinical approach to the patient by the physician. The understanding of these differences may improve the clinical management of HF and possible new gender-specific diagnostic and therapeutic options may be developed. To this aim, it remains mandatory. to increase the number of female patients with HF enrolled in clinical trials.
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The importance of gender differences in the diagnosis and management of cardiovascular disease
Graciana Ciambrone, Juan Carlos Kaski
[Purchase Article] [PMID: 21449887 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00196]

For many years, the majority of the observational and epidemiological studies assessing coronary artery disease patients, national and international clinical guidelines, registries and randomized trials have focused almost exclusively on men whereas women were usually excluded in most series. This underrepresentation of women in the medical literature in this field has resulted in few data being available regarding the clinical course of the condition, its management and clinical outcomes in this specific population, despite the relatively high prevalence of ischemic heart disease in women. The situation has changed -at least partially- in the past few years with publications focusing on this issue and reporting the existence of inequalities between genders regarding the diagnosis and treatment of coronary heart disease. This article will briefly review gender differences in the clinical presentation, diagnostic strategies and prognosis of coronary heart disease.
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Gender Differences In The Treatment Of Ischemic Heart Disease
Marcin Barylski, Dimitri P. Mikhailidis, Maciej Ciebiada, Maciej Banach
[Purchase Article] [PMID: 21449886 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00197]

Ischemic heart disease (IHD) is a leading cause of mortality and morbidity in most developed countries. Many studies revealed gender differences in the presentation, prevalence, and clinical outcomes of IHD. Compared with females, ST-segment elevation myocardial infarction is more often diagnosed in men. They also have a higher prevalence of IHD. These findings indicate that gender may have an important influence on IHD. Appropriate prevention, rapid diagnosis, and optimal treatment may essentially improve the care of all patients. It is therefore necessary to take into account gender differences in the features of IHD between males and females.
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Gender-Specific Aspects in Primary and Secondary Prevention of Cardiovascular Disease
G Mercuro, A Bina, E. Manconi, M. Deidda
[Purchase Article] [PMID: 21449885 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00198]

Gender differences in biological substrates of disease determine different clinical manifestations of CV disease with important implications for prevention, diagnosis and therapy in the two sexes.

In women, the activity of sex hormones reduces the influence of CV risk factors during the reproductive age, and delays the onset of CHD of 2 decades compared to men. However, women as men suffer from CV events, and in women mortality from all CV causes is greater than the sum of the next 7 causes of death together. Women are more likely than men to die of a first myocardial infarction a probability of developing heart failure or a second infarction than their male counterparts.

The levels of lipid components vary in different ages of life and in the two genders. TC and LDL increase in men between 35 and 50 years of age. On the contrary LDL levels do not change significantly in fertile women in which they have a lower predictive value for CHD than in men, HDL levels are higher in premenopausal women than in men of the same age and their role in predicting CHD is considerably higher in women. High triglycerides and Lp(a) are more important as a risk factor in women than in men.

Because of the greater incidence of cardiovascular diseases in men until the early 80s, the information about the importance of risk factors associated with an increased risk of cardiovascular events has been gathered mainly in men and transferred to women. Most studies on lipid-lowering therapy did not have the adequate statistical power to show significant reductions in CV events in women. Regarding the indications for use of statins in daily practice, current data suggest that in secondary prevention statins are equally effective in both genders while in primary prevention the CV benefits of lipid-lowering therapy in women are less clear than in men and therefore should be used according to the degree of risk calculated from the available score systems.
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Gender Specific Aspects Of Cell Death In The Cardiovascular System
Marina Pierdominici, Elena Ortona, Flavia Franconi, Massimiliano Caprio, Elisabetta Straface and Walter Malorni
[Purchase Article] [PMID: 21449884 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00199]

It has become apparent over the past few decades that several factors can determine lethal or sublethal alterations of cardiovascular system cell function such as inflammatory reaction products, peptides and hormones. In turn, the loss of cellular components from the blood vessels wall and the heart tissue contributes to the development of cardiovascular diseases (CVD). Hence, in the recent years, the efforts of several research groups have specifically been devoted to deeply investigate the implication of the main forms of cell injury, necrosis, apoptosis and autophagy, in the development of cardiac and blood vessel alterations associated with human diseases. Furthermore, several lines of evidence demonstrate that CVD clearly display significant gender differences in terms of onset, progression and outcome. Cardiovascular cells contain functional estrogen and androgen receptors and are targets for sex hormone action, which can influence many physiological and pathological processes, including vascular and myocardial cell homeostasis. However, hormones are important but not unique actors in this issue, further genetic and epigenetic determinants being involved. This review focuses on recent studies on the effects of gender differences, including sex hormones, on cardiac and vascular cell injury and death and their influence in determining atherosclerosis, heart failure and other main human CVD.
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Editorial: Gender differences in cardiovascular diseases. A need for action
Giuseppe M.C. Rosano, Giuseppe Barbaro
[Purchase Article] [PMID: 21449883 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00200]

In the past decades attention has been focused on gender differences in the access to health care resources and therapies but little emphasis has been put on the understanding of the basic mechanisms of gender differences and different action of cardiovascular drugs.

The basic mechanisms underlying cell death and apoptosis which affect the way organs and systems respond to injury differ in the two sexes. It is known that estrogens improve endothelial repair after vascular injury but the gender differences in apoptosis and repair are not well understood. Malorni et al discuss the basic mechanisms related to gender differences in apoptosis and cell death suggesting that these differences may explain, at least in part, those seen in physiology and in disease states.

It is well known that men and women differ in the onset of cardiovascular diseases but that they level off later in life, it is also known that sex hormones have cardiovascular effect but little is known on their sex specific effect. In this issue Vitale et al detail the sex specific effect of sex hormones explaining why the same hormone may have different effect in the two sexes according to the underlying levels of the other sex hormones.

Men and women have a different susceptibility to cardiovascular disease a different presentation and response to treatment and Banach, Anker, Kaski and Mercuro report on the gender differences in the treatment of cardiovascular diseases, heart failure and prevention.

Most drugs have a different pharmacokinetic and pharmacodynamic properties in men, women. Furthermore, the effect of drugs may differ considerably between the two sexes and between adults and elderly. Several cardiovascular drugs have been approved for use in both sexes when there was evidence of effect only or predominantly in one of the two sexes. For example, statins have been approved for use in primary prevention of cardiovascular disease when the scientific evidence was gathered only in men (WOSCOPS), in some EU member states aspirin is approved for primary prevention of cardiovascular disease when its role in women is lacking, several anti-hypertensive drugs (especially first and second generation) have been approved and have indication for treatment of hypertension with similar dosages for the two sexes without a clear evidence of specific benefit in women. The Value study has shown that Valsartan is effective in men and much less in women and this evidence has also been reported for other cardiovascular drugs.

Scientific guidelines only recently have started to highlight the differences between young and adults while only seldom take into account the gender differences or the lack of evidence for the effectiveness of some drugs in one of the two sexes. More recently the Regulatory Agencies have become more cautious on the possible gender difference in the effectiveness and safety of drugs. However, a gap still exists in recognizing the gender differences in the effectiveness and safety and in giving specific marketing authorizations according to the sex specific effect of the drugs. On ethical grounds drug companies should be more cautious in assessing the effectiveness of drugs according to age and sex. However, realistically this does not happen because of the interest to market the same drug for the wider range of users. It becomes evident that there is a need to develop gender specific guidelines for the scientific and regulatory evaluation of drugs and gender specific approvals when this is needed. Franconi et al will discuss the issues related to the gender differences in cardiovascular pharmacology.

There is still much needed to understand and solve the gender bias in cardiovascular medicine. However, this can be solved only using a scientifically correct and rigorous approach. Cardiovascular drugs should be developed according to their specific effect, the development should include patients of both sexes recruited according to the expected effect of the drugs in each sex. For most drugs unequal numbers of men and women will be required to show efficacy.

Address for Correspondence
Giuseppe M.C. Rosano, MD, PhD
Department of Medical Sciences
IRCCS San Raffaele Pisana,
via della Pisana, 235, 00163 Rome, Italy
tel. +39 06 52252409
Fax +39 06 52252465
Email: giuseppe.rosano@sanraffaele.it
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Editorial:
[BSP/CPD/E-Pub/00226]

Sleep disorders are increasingly recognized as a serious medical problem in the general population as well as to an individual’s well being. [1] Moreover, excessive daytime sleepiness (EDS) continues to be an important public health concern. EDS related to sleep disorders is present in about 10% of adults. Complaints such as non-restorative sleep, insomnia, and EDS are obtained from at least 50% of subjects in general population–based epidemiological surveys. [2,3,4] Medications available for treatment of various sleep disorders and their consequent impact on the quality of life represents an important aspect of public health expenses. [5-7] On the other hand, pharmacological advances for sleep disorders treatment represent exciting discoveries and may ultimately change the course of how we treat sleep-related disorders.

Insomnia is the most common sleep disorder with a prevalence of 10-15% in the United States adult population. [2,3] Currently approved pharmacologic treatments for insomnia include benzodiazepine receptor agonists, non-benzodiazepine receptor agonists, and melatonin receptor agonist. In addition, unapproved medications are commonly prescribed including sedating antidepressants, antipsychotics, anti-histamines, and herbal supplements. Many unapproved and approved hypnotics are associated with significant side-effect profile including cognitive and psychosocial impairment, anterograde amnesia, rebound insomnia, development of tolerance, addiction, and even death by overdose. It is not surprising that new pharmacological compounds are vigorously being investigated. In addition, Major Depressive Disorder is a common psychiatric disorder co-existing with insomnia, [8-9] and the investigation of melatonin agonists such as agomelatine has demonstrated interactions between circadian rhythm disorders, sleep, mood, and important clinical benefits with this new type of drug.

Evidence from research has demonstrated that the neuropeptide hypocretin (orexin) is critical in arousal and stabilization of wakefulness. This discovery has paved the way for new and exciting research on pharmacological modulation of the hypocretin system in an effort to find new treatment modalities for insomnia. In addition, there is evidence that hypocretin is involved in energy homeostasis and reward behavior beyond its pivotal role in sleep/wake regulation. [10,11].

Obstructive Sleep Apnea (OSA) is the most common sleep-related breathing disorder, affecting 5-10% of the adult population. It is increasingly being recognized as an important public health problem leading to driving and industrial accidents. [12,13] The gold-standard treatment for OSA with nasal CPAP is associated with variable compliance rates and therefore less than optimal treatment success. Usage of pharmacological agents to treat OSA has been in question for a long time, however in the recent past, studies have accumulated and results are just coming in. Research on sleep is focused on finding new compounds to treat EDS: from histamine (H3) receptor antagonist and inverse agonist, to GABA-β agonists, to sodium oxybate. Discovery of new compounds that are successful in treating EDS will benefit disorders that cause excessive sleepiness including narcolepsy with cataplexy, obstructive sleep apnea, and shift-work.

Treatment of sleep-related problems in children is a dilemma for the pediatrician and sleep specialist. As of recent, investigation on dopamine agonists has been performed in children with Restless Leg Syndrome (RLS), a syndrome that has a prevalence of approximately 2%. Moreover, the frequency of attention deficit/hyperactivity syndrome (ADHD), depression, and anxiety is higher in children with RLS compared to the general population. The discussion of various pharmacological treatment approaches will be much appreciated in the pediatric community, as will the discussion on various compounds used in ADHD treatment and their impact on sleep, as sleep problems are both part of the symptoms themselves, as well as complications of treatment. [14,15].

Similar to a double-edged sword, pharmacologic therapy has its risks and benefits which can be seen in individuals with chronic opioid use. The use of opioid medications has increased by approximately 600% in the last 10 years with a corresponding rise in pain management, greater attention paid to the treatment of pain syndromes, and higher percentage of prescriptions for opioid medications by general practitioners. This has led to an increase in the prevalence and types of breathing disorders during sleep including central sleep apnea, which are often not well recognized or understood, and is a challenge to treat. [16]

This issue of Current Pharmaceutical Design focuses on advances in pharmacological treatment of the major sleep-related disorders. Current research, advances in pharmacologic therapy, as well as prospective pharmacological compounds for the treatment of sleep-related disorders will be discussed.

1. Skaer, TL and Sclar, DA. Economic implications of sleep disorders. Pharmacoeconomics. 2010; 28(11):1015-23.
2. Foundation NS. Sleep in America poll. Data from 2002, 2003, 2004, and 2005 sleep polls. Washington D.C.; 2005.
3. Ohayon M. Epidemiology of insomnia: what we know and what we still need to learn. Sleep Med Rev 2002; 6:97-111.
4. Sarsour K, Van Brunt DL, Johnston JA, et al. Associations of nonrestorative sleep with insomnia, depression, and daytime function. Sleep Med 2010; 11:965-972.
5. Stewart R, Besset A, Bebbington P, et al. Insomnia comorbidity and impact and hypnotic use by age group in a national survey population aged 16-74 years. Sleep 2006; 29(11):1391-7.
6. Daley M, Morin CM, LeBlanc M, et al. The economic burden of insomnia: direct and indirect costs for individuals with insomnia syndrome, insomnia symptoms, and good sleepers. Sleep 2009; 32(1):55-64.
7. Ozminkowski RJ, Wang S, Walsh JK. The direct and indirect costs of untreated insomnia in adults in the United States. Sleep 2007; 30:263-73.
8. Baglioni C, Battagliese G, Feige B, et al. Insomnia as a predictor of depression: A meta-analytic evaluation of longitudinal epidemiological studies. J Affect Disord 2011.
9. Buysse DJ, Angst J, Gamma A, et al. Prevalence, course, and comorbidity of insomnia and depression in young adults. Sleep 2008; 31(4):473-80.
10. Tsujino, N and Sakurai T. Orexin/Hypocretin: A Neuropeptide at the Interface of Sleep, Energy Homeostasis, and Reward System. Pharmacol Rev 2009; 61(2):162-176.
11. Nishino S. The Hypocretin/Orexin System in Health and Disease. Biol Psychiatry 2003; 54:87-95.
12. Tregear S, Reston J, Schoelles K, et al. Obstructive Sleep Apnea and risk of motor vehicle crash: systematic review and meta-analysis. J Clin Sleep Med 2009; 5(6):573-81.
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Cancer Targeted Metallic Nanoparticle: Targeting Overview, Recent Advancement and Toxicity Concern
Sohail Akhter, Mohammad Zaki Ahmad, Anjali Singh, Iqbal Ahmad, Mahfoozur Rahman, Mohammad Anwar, Gaurav Kumar Jain, Farhan Jalees Ahmad and Roop Krishen Khar
[FULL-TEXT INQUIRY] [PMID: 21568874 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00228]

The targeted delivery of theranostic agents to the cancer cells is one of the major challenges and an active field of research in the development of cancer chemotherapeutic approaches. Theranostic metallic nanoparticles (TMNPs) have garnered increasing attention in recent years as a novel tool for theranostic application such as imaging, diagnosis, and therapeutic delivery of active agents to tumour specific cells. This paper attempts to unveil the multidimensional theranostic aspects of multifunctional metallic nanoparticles (MNPs) including passive and active targeting (HER2, Folate, Angiogenesis etc.) as well as the RES escaping approach. Special attention is given to the theranostic application of MNPs in oncology. Patents issued by the US office in this nanotechnological arena are also included emphasizing the importance of MNPs in current cancer treatment/imaging research scenario. Keeping in mind the blooming research in clinical application directed nanotechnology; toxicity concerns related with MNPs are. also discussed, in element.
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Application of Nanomedicine in Cardiovascular Diseases and Stroke
Kye S. Kim, Gilson Khang, Dongwon Lee
[FULL-TEXT INQUIRY] [PMID: 21631424 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/000238]

Nanomedicine is using nanotechnology in the medical application, which could range from medical use of nanomaterials in drug delivery and bio-imaging to development of nano-scale devices and sensors for diagnosis and therapy. Nanomedicine could also include methods to evaluate nanomaterials solely to ensure safe use through careful monitoring for potential toxicity. In this review, we will outline some of the potential uses of nanotechnology in different fields of medicine with special emphasis on cardiovascular diseases and stroke, based on pathophysiologic basis.We will also review some of the known nanomaterials that are alreadybeing utilized indiagnosis and treatment, commonly the FDA approved nanomaterials and others that have demonstrated to be promising in clinical applications. Finally, we will discuss the potential limitations of using nanotechnology in medical applications. Since nanomedicine is now emerging and still in development, this review is not intended as a comprehensive or conclusive overview of nanomedicine. Instead, we hope to provide examples of what are available currently, and to demonstrate the enormous potentials of nanomedicine in order to meet the unresolved needs and new challenges of medicine.
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Vitamin D therapy in cardiac hypertrophy and heart failure
J. Ruth Wu-Wong
[Purchase Article] [PMID: 21631424 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/000239]

Vitamin D3 is made in the skin, modified in the liver to form 25(OH)D, and then further hydroxylated in the kidney to form the active hormone, 1,25-dihydroxyvitamin D3 (calcitriol). Calcitriol binds to and activates the vitamin D receptor (VDR), a nuclear receptor, to regulate numerous downstream signaling pathways in different cells and tissues. Emerging evidence suggests that VDR plays an important role in modulating cardiovascular, immunological, metabolic and other functions. Data from preclinical, epidemiological and clinical studies have shown that deficiency in VDR activation is associated with an increased risk for cardiovascular disease (CVD). Results from interventional trials using either nutritional vitamin D or VDR agonists (VDRAs), support the idea that VDR activation is beneficial for improving the underlying factors of CVD such as hypertension, endothelial dysfunction, atherosclerosis, vascular calcification, cardiac hypertrophy and progressive renal dysfunction. Furthermore, a majority of chronic kidney disease (CKD) patients die of CVD and VDRA therapy is associated with a survival benefit in both pre-dialysis and dialysis CKD patients. Most of the studies measured serum 25(OH)D as an indication for vitamin D deficiency, which does not truly reflect the VDR activation status. Although VDR plays an important role in regulating cardiovascular function and VDRAs may be potentially useful for treating CVD, at present VDRAs are not indicated for the treatment of CVD.
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Mechanisms and Inhibitors of Apoptosis in Cardiovascular Diseases
Sylvia S. Singh and Peter M. Kang
[Purchase Article] [PMID: 21631422 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/000240]

Apoptosis or progress of programmed cell death is a tightly regulated process which plays an important role in various cardiovascular diseases particularly in myocardial infarction, reperfusion injury, and heart failure. Over the past two decades, investigations of several pathways have broadened our understanding of programmed cell death. Many anti-apoptotic interventions have targeted ischemia-reperfusion, however only a limited number have been considered at the chronic stage of heart failure. Endogenous inhibitors, caspase inhibitors, PARP-1 inhibitors, as well as various other agents have been implicated as anti-apoptotic interventions. This review summarizes the apoptotic pathways associated with heart failure, discusses the current anti-apoptotic interventions available and reviews the clinical implications.
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Phosphoinositide-3 kinase signaling in cardiac hypertrophy and heart failure
Toshinori Aoyagi and Takashi Matsui
[Purchase Article] [PMID: 21631421 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/000241]

Heart failure, a major symptom in the progression of cardiac hypertrophy, is a critical risk factor for cardiac death. A large body of research has investigated cardioprotective mechanisms that prevent or minimize hypertrophy, identifying a variety of specific peptide hormones, growth factors, and cytokines with cardioprotective properties. Recent investigation of the downstream effector pathways for these growth factors has identified molecules involved in the progression of cardiac hypertrophy and heart failure, including phosphoinositide 3-kinase (PI3K), Akt and mammalian target of rapamycin (mTOR). Using genetically modified transgenic or knockout mice and adenoviral targeting to manipulate expression or function in experimental models of heart failure, several investigators have demonstrated that the PI3K-Akt pathway regulates cardiomyocyte size, survival, angiogenesis, and inflammation in both physiological and pathological cardiac hypertrophy. In this review, we discuss the reciprocal regulation of PI3K, Akt and mTOR in cardiomyocytes and their association with cardiac disease.
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Neuregulin1 as Novel Therapy for Heart Failure
Xinhua Yan and James P. Morgan
[Purchase Article] [PMID: 21631420 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/000242]

Neuregulin1 proteins (NRG1s) are epidermal growth factor (EGF) family members which are ligands for the ErbB receptor tyrosine kinases (RTKs). A decade of research has revealed that the NRG1-ErbB signaling is essential for the cardiac development and pivotal for maintaining the physiological function of the adult heart. The first evidence regarding the protective effect of the ErbB2 signaling in the adult heart came from clinical trials in breast cancer patients using Trastuzumab, a monoclonal antibody that blocks the ErbB2 receptor. The incidence of the New York Heart Association (NYHA) class III/IV heart failure increased five-fold in patients treated concurrently with chemotherapy drug doxorubicin and Trastuzumab compared to those treated with doxorubicin alone. Subsequent studies further show that stimulation of the ErbB2 signaling by NRG1s improves cardiomyocyte survival, growth and proliferation, maintains cardiac myofibril structure, counterbalances excessive β-adrenergic signaling and promotes angiogenesis in the heart. Injections of recombinant NRG1s improve cardiac function in animal models with myocardial infarction, doxorubicin, viral infection or pacing -induced heart failure. Recent clinical trials show that NRG1s are effective for improving the cardiac function in heart failure patients. These results suggest that NRG1s may become a new drug for the treatment of heart failure. NRG1s stimulate RTKs. This is different from Beta-blockers, ACE inhibitors (Angiotensin-Converting Enzyme) and Angiotensin II receptor blockers which inhibit the excessive activation of G-protein coupled receptors (GPCRs). A clear understanding of how NRG1-ErbB signaling regulates cardiac function is essential for successful use of NRG1s for heart failure. Here, we review the current knowledge of the NRG1-ErbB signaling in the heart and discuss the potential use of NRG1s as novel therapy for heart failure.
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Nitric Oxide and Protection against Cardiac Ischemia
Zhengyuan Xia and Paul M. Vanhoutte
[Purchase Article] [PMID: 21631419 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/000243]

Nitric oxide (NO) is produced in almost all tissues and it exerts a variety of biological actions under both physiological and pathological conditions. It is synthesized by three distinct enzymes: endothelial (eNOS), neuronal (nNOS) and inducible (iNOS) nitric oxide synthases. NO is a cardioprotective mediator in powerful cardioprotective processes such as pre- and post-conditioning ischemia; they operate largely in a NO-dependent manner. However, the activity of different NOSs isoforms as well as, the bioavailability of NO can be affected by a variety of disease conditions (in particular diabetes) and pathological situations associated with significantly elevated levels of the pro-inflammatory cytokine tumor necrosis factor-α (TNF-α). These adversely affect NO-signaling, as well as the efficacy and safety of treatments with NO or NO-containing agents.

This brief review focuses on the role of NO in ischemic myocardial protection with emphasis on its contribution to ischemic pre-and post-conditioning cardioprotection. The impact of pathologic conditions on NO bioavailability and NO-signaling and its potential means for improvement, will also be discussed.
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Editorial: Novel Pharmacological Therapies for Cardiac Hypertrophy and Heart Failure
Peter M. Kang,
[PMID: 21631418 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/000244]

Cardiovascular disease is the most common cause of morbidity and mortality in the developed countries, and it accounted for over 600,000 deaths (25% of total mortality) in the U.S. in 2007 [1]. However, despite significant progress in the treatment of cardiovascular diseases, the mortality rate from heart failure still remains very high. Because cardiac hypertrophy is associated with most forms of heart failure, the mechanisms and related therapies for cardiac hypertrophy have remained a central focus of basic and clinical research [2, 3]. New targets are emerging continuously and novel delivery strategies are being developed. Consequently, cardiovascular pharmacology is a rapidly developing field with numerous new cardiovascular drugs continually being discovered, and being tested in preclinical studies and clinical trials.In this issue, we will review novel therapies that are on the horizon for the treatment of cardiac hypertrophy and heart failure. Review of these new and emerging pharmacological therapies will not only be interesting, but also will be important for clinical practice. Although complete list of all novel pharmacological therapies is not possible, this review series compile those therapies that hold promise in the near future. Specialists in various fields will contribute their expertise, experience and knowledge on current and emerging cardiovascular pharmacological therapies.

Leading off the series, Xia and Vanhoutte, an internationally renowned authority on nitric oxide, will review current status of nitric oxide (NO) inhibition for hypertension and cardiac hypertrophy. They will specifically focus on the role of NO in ischemic myocardial protection with emphasis on its contribution to ischemic pre-and post-conditioning cardioprotection. Singh and Kang will review emerging therapies to inhibit apoptosis in cardiovascular diseases. We will discuss what is currently known about the molecular mechanisms of cardiac apoptosis, and review the potential uses of anti-apoptotic therapies for heart failure. Wu-Wong will review our current understanding of vitamin D signaling in cardiovascular diseases. She will discuss preclinical and clinical studies that support (or argue against) the potential use of vitamin D therapy for left ventricular hypertrophy and heart failure, as well as its broad use for end stage renal disease and vascular diseases. Yan and Morgan, experts on pharmacological therapy for heart failure, will review the current knowledge of the neuregulin 1 (NRG1) and eukaryotic ribosome biogenesis protein 1 (Erb1) signaling in the heart and discuss the potential use of NRG1s as novel therapy for heart failure. Ayogi and Matsui will review the role of phosphatidylinositol 3-kinases (PI3K) signaling in the treatment of cardiac hypertrophy and heart failure. They will discuss the reciprocal regulation of PI3K, serine/threonine protein kinase Akt/PKB and the mammalian target of rapamycin (mTOR) in cardiomyocytes and their association with cardiac disease. For our final review in the series, Kim and Lee will review the role of nanotechnology in medicine. Particularly, they will discuss several novel strategies to use nanomaterial-based diagnosis and therapy in cardiovascular and neurovascular diseases.

References

[1] Lloyd-Jones D, Adams RJ, Brown TM, Carnethon M, Dai S, De Simone G, et al. Heart disease and stroke statistics--2010 update: a report from the American Heart Association. Circulation 2010; 121: e46-e215.
[2] Cohn JN, Bristow MR, Chien KR, Colucci WS, Frazier OH, Leinwand LA, et al. Report of the National Heart, Lung, and Blood Institute Special Emphasis Panel on Heart Failure Research. Circulation 1997; 95: 766-70.
[3] Levy D, Garrison RJ, Savage DD, Kannel WB, Castelli WP. Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl J Med 1990; 322: 1561-6.

Peter M. Kang, MD,
Cardiovascular Institute, Beth Israel Deaconess Medical Center,
3 Blackfan Circle, CLS 910, Boston, MA 02215.
Tel: (617) 735-4290;
Fax: (617) 735-4207;
E-mail: pkang@bidmc.harvard.edu
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Pharmaceutical Approaches of Binge Drinking
Benjamin Rolland, Laurent Karila, Dewi Guardia, Olivier Cottencin
[Purchase Article] [PMID: 21524262 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/000253]

Binge Drinking (BD) is often considered to be recurrent alcohol abuse amongst adolescents and young adults. However, the close link between adolescence and impulsivity has led many authors to define BD as intoxication-seeking behaviour. Medications may sometimes be justified because of the major short-term and long-term risks that underlie the most severe BD-related behaviours. The most common consequences in the long run are the occurrence of alcohol dependence, psycho- and neurodevelopmental disruptions and alcohol liver disease. To understand the specificities of BD among other forms of alcohol addiction, this article is based on a two-headed conception of alcohol dependence: on one hand, psychological dependence, which refers to the behavioural habituation of alcohol intake, clinically results in craving and is neurobiologically supported by the reward system, particularly the dopaminergic mesolimbic pathway (MLP); on the other hand, physical dependence, which refers to the pharmacological tolerance induced by chronic alcohol intake, results in Alcohol Withdrawal Syndrome (AWS) and is neurobiologically supported by the imbalance between GABA and Glutamate-NMDA neurotransmission. Medications for psychological dependence include anticraving drugs, which all act by regulating MLP. Medications for physical dependence on alcohol include GABA-A and perhaps GABA-B agonists and some NMDA antagonists. In practice, many alcohol-dependence treatments seem to have a dual action.

This article proposes an attempt to classify current and forthcoming medications for alcohol addiction based on this two-headed approach to treating alcohol dependence. Drawing from this classification, specific therapeutic schemes for treating BD are proposed, with currently approved alcohol medications and possible future treatments. These schemes are justified by recent literature on the subject and propose to prioritize pure anticraving medications, taking into account the clinical specificities of BD. Furthermore, these schemes also mention harm-reductive neuroprotective and hepatoprotective strategies, which could be included in the arsenal of possible medications for BD in the near future.
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The uniqueness of the Trypanosoma cruzi mitochondrion: Opportunities to identify new drug target for the treatment of Chagas disease
Lisvane Paes Vieira, Brian Suárez Mantilla, Maria Julia Barisón, Carsten Wrenger and Ariel Mariano Silber
[FULL-TEXT INQUIRY] [PMID: 21718252 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/000258]

Trypanosoma cruzi is the causative agent of Chagas´ disease, which affects some 8 – 10 million people in the Americas. The only two drugs approved for the etiological treatment of the disease in humans were launched more than 40 years ago and have serious drawbacks. In the present work, we revisit the unique characteristics of T. cruzi mitochondria and mitochondrial metabolism. The possibility of taking advantage of these peculiarities to target new drugs against this parasite is also discussed.
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Principles and therapeutic relevance for targeting mitochondria in aging and neurodegenerative diseases
Gaetano Serviddio, Antonino Davide Romano, Tommaso Cassano, Francesco Bellanti, Emanuele Altomare and Gianluigi Vendemiale
[FULL-TEXT INQUIRY] [PMID: 21718251 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/000259]

aging is a physiologic state in which a progressive decline of organ functions may be accompanied by developing age-related diseases and neurodegenerative diseases. The causes of such conditions remain unknown, being probably related to a multifactor process. To date, the Free Radical and Mitochondrial theories seem to be the two most prominent that could explain both how and why aged people develop certain disorders, providing a rationale for treatment. Several reports demonstrate that mitochondria play a key role in aging and some neurodegenerative diseases. Damaged mitochondria produce increased amounts of Reactive Oxygen Species (ROS), leading, in turn, to progressive augmentation in damage. Dysfunctional mitochondria enhance susceptibility to cell death. Indeed, at cell level mitochondria act as an energetic hub determining cell final fate through caspase-dependent apoptosis. Thus, if aging results from oxidative stress, it may be corrected by environmental, nutritional and pharmacological strategies. In this review we summarize the role of mitochondria dysfunction occurring in aging and neurodegenerative disease, describing novel mitochondria-targeted therapy approach and the new selective molecules and nanocarriers technology as potentially effective in targeting mitochondrial dysfunction
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Mitochondrial Drug Target In Cell Death And Cancer
Gustavo Ferrín, Clara I. Linares, Jordi Muntané
[FULL-TEXT INQUIRY] [PMID: 21718250 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/000260]

Mitochondria are involved in different physiological and pathological processes that are crucial for tumor cell physiology, growth and survival. Since cancer cells have frequently disrupted different cell death pathways that promote their survival, mitochondria may be key organelles to promote cell death in cancer cells. The present review is focused in the different experimental and therapeutic cancer strategies addressed to either target mitochondria directly, or use mitochondria as mediators of apoptosis. While the first group includes drugs that act on glycolysis, β-oxidation, electron transport chain, mitochondrial permeability and the Bcl-2/IAP family protein, the second one consists of those drugs that cause cell death through the intrinsic apoptosis pathway by promoting ROS generation or by modulating mitochondrial protein involved in apoptosis induction.
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Mitochondrial toxicity in HAART: an overview of in vitro evidence
Nadezda Apostolova, Ana Blas-García, and Juan V. Esplugues
[FULL-TEXT INQUIRY] [PMID: 21718249 PubMed - indexed for MEDLINE][BSP/CPD/E-Pub/000261]

The combined antiretroviral therapeutic approach currently employed for the treatment of HIV infection, known as Higly Active Antiretroviral Therapy (HAART), has dramatically reduced AIDS-related morbidity and mortality. However, the adverse reactions associated with the long term use of this therapy have now become a major issue and researchers have focused on understanding the cellular mechanisms underlying these drug-induced detrimental effects which englobe a large list of different events including rash and hypersensibility reactions, hepatotoxicity, metabolic disturbances including lipodystrophy, and other metabolic syndrome-like disturbances such as hyperlactatemia, hyperlipedimia, insulin resistance and pancreatitis. Other events include CNS toxic effects, peripheral neuropathies as well as nephrotoxicity and increased risk of cardiovascular diseases.

Many of these reactions have been shown to develop as e result of mitochondrial dysfunction. The mitochondrial effect of N(t)RTI (Nucleos(t)ide Reverse Transcriptase Inhibitors) class of drugs, which has been widely studied, is believed to originate from the inhibitory action of these drugs on DNA polymerase gamma, the enzyme responsible for replication of mitochondrial DNA.  However, additional mitochondrial targets have also been described and need to be considered. As to NNRTI (Non-Nucleoside-Transcriptase Inhibitor) or PI (Protease Inhibitors), evidence of the implication of mitochondria has also been reported, however the details of the mechanisms underlying these actions are still not fully known.

This review covers the current knowledge of mitochondrial toxicities, particularly the available in vitro evidence, regarding the most commonly used groups of HIV drugs. Novel findings of mtDNA-independent mitochondrial dysfunction have received special attention.
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Drug-induced Cardiac Mitochondrial Toxicity and Protection: From Doxorubicin to Carvedilol
Gonçalo C. Pereira, Ana M. Silva, Cátia V. Diogo, Filipa S. Carvalho, Pedro Monteiro, Paulo J. Oliveira
[FULL-TEXT INQUIRY] [PMID: 21718248 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/000262]

Mitochondria have long been involved in several cellular processes beyond its role in energy production. The importance of this organelle for cardiac tissue homeostasis has been greatly investigated and its impairment can lead to cell death and consequent organ failure. Several compounds have been described in the literature as having direct effects on cardiac mitochondria which can provide a mechanistic explanation for their toxicological or pharmacological effects. The present review describes one classic example of drug-induced cardiac mitochondrial toxicity and another case of drug-induced mitochondrial protection. For the former, we present the case for doxorubicin, an anticancer agent whose treatment is associated with a cumulative and dose-dependent cardiomyopathy with a mitochondrial etiology. Following this, we present the case of carvedilol, a β-blocker with intrinsic antioxidant activity, which has been described to protect cardiac mitochondria from oxidative injury. The final part of the review integrates information from the previous chapters, demonstrating how carvedilol can contribute to reduce doxorubicin toxicity on cardiac mitochondria. The two referred examples result in important take-home messages: a) drug-induced cardiac mitochondrial dysfunction is an important contributor for drug-associated organ failure, b) protection of mitochondrial function is involved in the beneficial impact of some clinically-used drugs and c) a more accurate prediction of toxic vs. beneficial effects should be an important component of drug development by the pharmaceutical industry.
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Mitochondrial Therapeutics for Cardioprotection
Raquel S. Carreira, Pamela Lee, and Roberta A. Gottlieb
[FULL-TEXT INQUIRY] [PMID: 21718247 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/000263]

Mitochondria represent approximately one-third of the mass of the heart and play a critical role in maintaining cellular function—however, they are also a potent source of free radicals and pro-apoptotic factors. As such, maintaining mitochondrial homeostasis is essential to cell survival.  As the dominant source of ATP, continuous quality control is mandatory to ensure their ongoing optimal function.  Mitochondrial quality control is accomplished by the dynamic interplay of fusion, fission, autophagy, and mitochondrial biogenesis.  This review examines these processes in the heart and considers their role in the context of ischemia-reperfusion injury.  Interventions that modulate mitochondrial turnover, including pharmacologic agents, exercise, and caloric restriction are discussed as a means to improve mitochondrial quality control, ameliorate cardiovascular dysfunction, and enhance longevity.
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New Insights in Drug-Induced Mitochondrial Toxicity
Sashi Nadanaciva and Yvonne Will
[FULL-TEXT INQUIRY] [PMID: 21718246 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/000264]

Drug-induced mitochondrial toxicity is rapidly gaining recognition within the pharmaceutical industry as a contributor to compound attrition and post-market drug withdrawals. This article describes the mechanisms which lead to drug-induced mitochondrial toxicity, discusses high-throughput in vitro assays which are currently being used to identify mitochondrial dysfunction, and provides an overview on some of the drugs which impair mitochondrial function. While considerable progress has been made in the development of high-throughput assays to screen for mitochondrial impairment in vitro, much remains to be done. This includes the development of in silico models to predict drug-induced mitochondrial impairment, wider acceptance of suitable animal models, identification and validation of relevant biomarkers, and the translation of in vitro/in vivo results to clinical outcomes
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Mitophagy and Disease: New Avenues for Pharmacological Intervention
Robert Taylor and Scott J. Goldman
[FULL-TEXT INQUIRY] [PMID: 21718245 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/000265]

The process of intracellular macromolecular degradation known as macroautophagy has long been associated with the degradation of mitochondria.  Recent studies have provided evidence that the process of mitochondria degradation via autophagy, now referred to as mitophagy, appears to be specifically targeted to mitochondria and highly regulated under both physiologic and pathologic conditions.  This article provides a review of key developments in mitophagy research, including background information on the history, mechanisms, and regulation of macroautophagy, as well as discoveries that have enhanced our understanding of the specificity and independent regulation of mitophagy.  This is followed by an analysis of how our current understanding of the mechanics and regulation of mitophagy may be exploited to yield pharmacological interventions for mitochondria-associated diseases.  As yet, the potential for mitophagy-related pharmacological treatments for disease remains largely untapped.  However, rapid progress in our understanding of both mitophagy and the pathology of mitochondria-related diseases is leading us towards the convergence of science and medicine which will inevitably result in new and potent pharmacological therapies for the treatment of these maladies.
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Mitochondrial dysfunction and targeted drugs: a focus on diabetes
Victor M Victor, Milagros Rocha, Celia Bañuls, Lorena Bellod, Antonio Hernandez-Mijares
[FULL-TEXT INQUIRY] [PMID: 21718244 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/000266]

Diabetes is a severe, heterogeneous, multifactorial, chronic disease. Diabetes and oxidative stress are related to continuous and acute overproduction of reactive oxygen species (ROS). These ROS are released principally from mitochondria, but also have other sources. Oxidative stress seems to play an important role in mitochondria-mediated disease processes, though the exact molecular mechanisms responsible remain elusive. ROS are necessary for the proper functioning of the cell, but their excessive production can be harmful, making antioxidant defenses essential. Some substances with antioxidant properties, such as vitamins C and E, have been used to eradicate the oxidative stress associated with diabetes. The results of clinical trials employing anti-oxidative stress reagents in patients with diabetes are contradictory, perhaps due to inadequate study design or the specific targets selected. This review considers the process of diabetes from a mitochondrial perspective and evaluates strategies currently under development for the targeted delivery of antioxidants or other molecules to mitochondria. The evidence compiled herein endorses the selective targeting of specific molecules to mitochondria as an effective strategy for modulating mitochondrial respiration and ROS production and protecting mitochondria against oxidative stress.
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Editorial: “Mitochondria as a pharmacological target: a clue for efficacy and a reason for toxicity”
Nadezda Apostolova
[PMID: 21718243 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/000267]

Mitochondria have been in the focus of intense biomedical research over the last 10 years. The complex participation of these organelles in cellular pathophysiology arises from their versatile function which includes bioenergetics, ROS generation and redox balance, Ca²⁺ homeostasis maintainance, thermogenesis, essential anabolic pathways as well as active regulation of several cell survival/death pathways. Importantly, mitochondrial dysfunction such as impaired oxidative phosphorylation and/or increased oxidative stress, together with the involvement of these organelles in apoptosis and the alterations of the selective process of their degradation, known as mitophagy, have been recently described as essential pathophysiological mechanisms, involved not only in “classical” human mitochondrial diseases but also actively engaged in the initiation, the development and the out-come of other congenital and acquired pathologies such as diabetes [1], cancer [2], cardiovascular diseases [3] and neurodegenerative disorders [4]. Pharmacological agents with mitochondrial action and selective mitochondria-targeted drugs display major therapeutic potential. In the field of liver cancer, Muntane J and coll. (IMIBIC, “Reina Sofia” University Hospital, Córdoba, Spain) describe that several mitocans such as Hexokinase II inhibitors, ETC and VDAC/ANT-targeting drugs as well as BH3 mimetics can induce apoptosis through mitochondrial depolarization and thus exerting an anti-tumor effect [2]. Also, the inhibition of the glucose transport or glycolysis (fasentin, apigenin, the polyphenolic compounds WZB27 and WZB115) has been suggested as a promising anti-cancer treatment. Victor VM and coll. (University Hospital Doctor Peset Foundation and University of Valencia, Valencia, Spain) review the beneficial effects of mitochondrial modulation in diabetes and diabetes-related disorders such as diabetic kidney disease [1]. Mainly in vitro studies have proven useful several antioxidants such as idebenone (CoQ10 analogue), overexpression of antioxidant enzymes and small SOD mimetic molecules, however their beneficial effects have not always been reproduced in animal models or humans. There is evidence however, that selective targeting of mitochondria with specific compounds such as MitoQ, a mitochondria-targeted antioxidant, promises to be an efficient therapeutic strategy for mitochondrial protection in diabetes. In addition, mitochondria-targeted therapy is also relevant as a pharmacological approach for aging and neurodegenerative diseases such as Parkinsons´s Disease, Alzheimer´s disease and amyotrophic lateral sclerosis [4]. Serviddio G. and coll. (Department of Medical and Occupational Sciences, University of Foggia, Foggia, Italy) review the effects of lipophilic cations such as MitoQ, MitoVitE and MitoPBN, Szeto-Schiller (SS) peptides, TAT fusion peptides and protein conjugates with mitochondria signal peptides (MSP). Novel mitochondria-targeted molecules such as XJB-5-131 and the multifunctional envelope-type nano-device (MEND) have also been described [4]. Two reviews of this thematic issue focus on mitochondrial turnover processes such as mitochondrial biogenesis and particularly mitophagy as novel/future avenues for pharmacological intervention [3,5]. Among other cardioprotective mitochondrial agents and stimuli, Gottlieb RA and coll. (BioScience Center, San Diego State University, San Diego, CA, USA) specifically point to caloric restriction, exercise and the use of resveratrol, a natural stilbenoid with antioxidant properties, as triggers of mitophagy and biogenesis [3]. Goldman SJ and Taylor R (Veterinary Support & Oversight Branch, U.S. Army Research Institute of Environmental Medicine, Natick, MA, USA) provide a detailed review of the cellular mechanisms involved in autophagy/mitophagy and their relation with the pathogenesis of neurodegeneration and cardiovascular diseases. Many of these conditions manifest accumulation of abnormal mitochondria and alterations in mitochondrial dynamics [5]. Our increasing understanding of the mitophagy-related diseases generates an expanding list of potential targets for pharmacological interventions which call to be explored. Mitochondrial therapeutics can also be relevant to the management of chronic parasitic infections exemplified in Chagas disease, a common trypanosomiasis. In a comprehensive review, Silber AM and coll. (Departament of Parasitology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brasil) provide an insight into Trypanosoma cruzi mitochondria as drug targets [6]. The aminoacid metabolism has been given special emphasis. Several aminoacid-metabolizing enzymes such as arginine kinase and proline racemase as well some mitochondrial enzymes such as NADH-fumarate reductase have the potential to be specific targets in Chagas treatment as they have been indentified in the parasite but are absent in mammalian cells. T. cruzi also displays specificities regarding mitochondrial energetics and ROS generation which can be pharmacologically exploited. For instance, the fact that this parasite lacks catalase and peroxidase but possesses tryparedoxins, trypanothione and trypanothione reductase, homologues of which do not exist in the mammalian host, is an important issue in trypanoicidal drug engineering [6]. 

In summary, considering these very promising findings, it seems that modulation of mitochondrial function will be pursued in the novel therapeutic strategies designed to combat some of the current most common human diseases. 

On the other side, there is a rapidly growing list of drug-induced mitochondrial effects which can lead to the generation of severe drug-related adverse events [7]. The interaction of drugs of clinical interest with specific mitochondrial targets and the repercussion of such interactions need to be evaluated in detail. This will certainly unable the prognosis and the treatment of a great number of drug-related detrimental reactions. Moreover, drug-induced mitotoxicity has been suggested to even contribute to the development of other mitochondria-related pathologies. Several drug groups (anti-diabetic, lipid-lowering drugs, antiretrovirals, NSAID) have been attributed mitochondrial toxicity and this occurs through different mechanisms including interference with bionergetics, ROS generation, mitochondria-mediated apoptosis, mtDNA replication etc. This has been described by Nadanaciva S and Will Y (Compound Safety Prediction, Pfizer Global R&D, Groton, CT, USA) who also provide a thorough overview of the methodological and technical challenges in detection of drug-induced mitotoxicity [7]. Doxorubicin (DXR) is one of the most potent anti-cancer agents employed in clinical practice. Despite the fact that clinicians have been aware of its cardiotoxic effects for nearly 20 years now, DXR is still used. Oliveira PJ and coll (Center for Neuroscience and Cell Biology, Department of Life Sciences, University of Coimbra, Coimbra, Portugal) delve in the complex mitochondrial role present in the cardiotoxic effects induced by this drug and provide some insights in the way that DOX-associated toxicity could be prevented or monitored. Finally, they also provide clues about the intriguing question regarding the organ-specificity of the toxic effect induced by DXR and its relation with other organs and tissues [8]. An interesting approach to combat drug-induced cardiac mitotoxicity is offered by the use of drug-induced mitochondrial protection, as suggested for the non-selective β-blocker carvedilol. A beneficial outcome of such interaction has been shown in DXR-treated rats and some promising results have been obtained in human clinical trails [8]. A very complex mitochondrial implication has also been reported for the antiretroviral drugs applied in HIV treatment and this constitutes the origin of many clinically relevant adverse events related to this therapy including myopathy, neuropathy, alterations in the lipid metabolism and hepatotoxicity. The review by Apostolova N. and coll. (Faculty of Medicine, University of Valencia and CIBERehd, Valencia, Spain) scrutinizes the long list of mitochondrial mechanisms of interference associated with these drugs which includes besides the traditional target Pol-γ, the solely DNA polymerase responsible for mtDNA replication, several other, mtDNA-independent effects. One such interaction is the direct inhibitory action on ETC and the process of oxidative phosphorylation. These reactions are particularly important for protease inhibitors and NNRTI- groups of anti-HIV drugs which do not impair mtDNA replication and whose mitochondrial effects are largely unexplored [9].

In all, the intense and rapidly developing mitochondrial research has produced a new field of biomedical knowledge denominated “mitochondrial pharmacology”. Its present projection is to explore novel drug targets and drug-induced mechanisms of mitochondrial dysfunction in addition to dissecting the basic mitochondrial involvement in cellular pathogenic processes. All these findings have the final aim to generate models for successful mitochondrial therapeutic management.

References:

[1] Victor VM, Rocha M, Bañuls C, Bellod L and Hernandez-Mijares A. Mitochondrial dysfunction and targeted drugs: a focus on diabetes. Current Pharmaceutical Design 2011, ????
[2] Ferrín F, Linares CI and Muntané J. Mitochondrial drug targets in cell death and cancer. Current Pharmaceutical Design 2011, ????
[3] Carreira RS, Lee P and Gottlieb RA. Mitochondrial Therapeutics for Cardioprotection. Current Pharmaceutical Design 2011, ????
[4] Serviddio G, Romano AD, Cassano T, Bellanti F, Altomare E and Vendemiale G. Principles and therapeutic relevance for targeting mitochondria in aging and neurodegenerative diseases. Current Pharmaceutical Design 2011, ????
[5] Taylor R and Goldman SJ. Mitophagy and Disease: New Avenues for Pharmacological Intervention. Current Pharmaceutical Design 2011, ????
[6] Paes LS, Suárez Mantilla B, Barisón MJ, Wrenger C and Silber AM. The uniqueness of the Trypanosoma cruzi mitochondrion: Opportunities to identify new drug target for the treatment of Chagas disease. Current Pharmaceutical Design 2011, ????
[7] Nadanaciva S. and Will Y. New Insights in Drug-Induced Mitochondrial Toxicity. Current Pharmaceutical Design 2011, ????
[8] Pereira GC, Silva AM, Diogo CV, Carvalho FS, Monteiro P and Oliveira PJ. Drug-induced Cardiac Mitochondrial Toxicity and Protection: From Doxorubicin to Carvedilol. Current Pharmaceutical Design 2011, ????
[9] Apostolova N, Blas-García A and Esplugues JV. Mitochondrial toxicity in HAART: an overview of in vitro evidence. Current Pharmaceutical Design 2011, ????

Abbreviations:

ETC (Electron transport chain), mtDNA (Mitochondrial DNA), NNRTI (Non-nucleoside reverse transcriptase inhibitors), NSAID (Non-steroidal anti-inflammatory drugs), ROS (Reactive oxygen species), VDAC/ANT (Voltage-dependent anion channel/Adenine nucleotide translocator)
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The Urokinase Receptor In Hematopoietic Stem Cells Mobilization
Francesco Blasi
[FULL-TEXT INQUIRY] [PMID: 21711240 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00268]

The receptor for urokinase plasminogen activator (uPAR) is required in hematopoietic stem/progenitor cells (HSC, HPC) mobilization in the mouse. Indeed, uPAR Ko mice are deficient both in retention and mobilization of HSC and HPC, because uPAR causes their retention in the BM through its interaction with the α4β1 integrin and at the same time its removal promotes their migration. Normally, the membrane signal is cleaved by plasmin which on one side releases the cells from their osteoblasts interaction and on the other produces a cleaved soluble uPAR product that stimulates mobilization. Available data suggest that a similar mechanism may take place in humans.
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Clinical applications of the urokinase receptor (uPAR) for cancer patients
Martin C. Boonstra, Hein W. Verspaget, Sjam Ganesh, Frank J.G.M. Kubben, Alexander L. Vahrmeijer, Cornelis J.H. van de Velde, Peter J.K. Kuppen
[FULL-TEXT INQUIRY] [PMID: 21711239 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00269]

Since decades the urokinase plasminogen activator (uPA) system has been associated with the invasion of malignant cells. The receptor of urokinase (uPAR) is one of the key players in this proteolytic cascade, because it focuses uPA’s proteolytic activity to the cell surface and in addition functions as a signaling receptor. uPAR is highly expressed in virtually all human cancers, suggesting possible clinical applications as diagnostic marker, predictive tool of survival or clinical response, and as a target for therapy and imaging. This review summarizes the possibilities of uPAR in clinical applications for cancer patients.
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The urokinase receptor system, a key regulator at the intersection between inflammation, immunity, and coagulation
Mario Del Rosso, Francesca Margheri, Simona Serratì, Anastasia Chillà, Anna Laurenzana, Gabriella Fibbi
[FULL-TEXT INQUIRY] [PMID: 21711238 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00270]

The urokinase plasminogen activator (uPA) and its receptor (uPAR) provide a cell surface integrated multimolecular complex that exerts pleiotropic functions influencing the development of inflammatory, immune,  coagulation and fibrinolytic responses. Here we review the evidences indicating a role of the uPA/uPAR system in the regulation of the innate immune system in the inflammation process, of the adaptive immune response, as well as the role of fibrin and fibrin degradation products at the cross-road between coagulation and inflammation. Comparative studies have clearly highlighted the notion that coagulation and immunity are co-regulated and intertwined. The implication is that the vertebrate blood clotting system is evolutionarily a by product of the innate immune system, where the blood clotting proteases have diverged from those comprising the complement system. Differences have emerged gradually, as shown by the acquisition of unique protein structures, such as kringle domains and gla (glutammic acid) domains, in order to comply with the increasingly complex vertebrate systems and to defend higher organisms against a range of infections and injuries. Plasminogen activation also controls the formation of complement anaphylotoxins (responsibe for vasodilatation, increase of venular permeability and leukocyte chemotaxis) and of bradykinin (which accounts for vasodilatation, increase of venular permeability and pain) by regulating the plasma contact system. The urokinase plasminogen activator and its cellular receptor, expressed on the surface of human leukocytes, provide a functional unit that, by regulating interaction of leukocytes with extracellular matrix, as well as its degradation, is critical for the migration of leukocytes and for their movement in the damaged tissues.
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The Urokinase Receptor Interactome
Gabriele Eden, Marco Archinti, Federico Furlan, Ronan Murphy, and Bernard Degryse
[FULL-TEXT INQUIRY] [PMID: 21711237 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00271]

The urokinase receptor (uPAR) was originally identified as the membrane receptor of the serine protease urokinase (uPA), thereby implicated in the plasminogen activation cascade and regulation of pericellular proteolysis. Later on, vitronectin was showed to be another major ligand providing uPAR with a role in cell adhesion. Other unrelated ligands have been subsequently reported including for example factor XII and SRPX2 expanding the functions of uPAR to unexpected biological areas such as the initiation of the coagulation cascade or the regulation of language development. Due to its glycosylphosphatidylinositol (GPI) anchor, uPAR has no intracellular domain and thus exerts its signaling capacity through lateral interactions with other components of the plasma membrane that actually mediate uPAR-induced signals. As yet, a total 42 proteins interacting directly with uPAR can be numbered comprising 9 soluble ligands and 33 lateral partners. The fact that uPAR interacts with members of three major families of membrane receptors i.e. G protein-coupled receptors, receptor tyrosine kinases, and integrins implies that the actual number of components constituting the uPAR interacome is extremely high. For example, 146 factors belong to the integrin adhesome. Moreover, in the light of the wide diversity of the components of the uPAR interactome, uPAR appears to be an essential player of major biological systems including the blood coagulation, complement and plasma kallikrein-kinin cascades. This review describes the soluble ligands and lateral partners of the uPAR interactome, the mechanisms regulating uPAR interactions and their proved and/or potential biological functions.
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Regulation of the Urokinase Receptor (uPAR) by LDL Receptor-related Protein-1 (LRP1)
Steven L. Gonias, Alban Gaultier, and Minji Jo
[FULL-TEXT INQUIRY] [PMID: 21711236 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00272]

LDL receptor-related protein (LRP1) is an endocytic receptor for multiple ligands, including proteases, growth factors, apolipoproteins, and extracellular matrix proteins.  In some cell types, including neurons, neuron-like cells, and Schwann cells, ligand-binding to LRP1 triggers robust cell-signaling.  This “direct” pathway by which LRP1 regulates cell-signaling promotes cell survival and cell migration.  LRP1 also regulates the composition of the plasma membrane proteome.  Although multiple mecha­nisms are involved, LRP1 and receptors in the same gene family facilitate the endocytosis of other plasma membrane proteins.  When LRP1 regulates the abundance or trafficking of another cell-signaling receptor in the plasma membrane, activation of important cell-signaling pathways may be con­trolled “indirectly” by LRP1.  The urokinase receptor (uPAR) was the first cell-signaling receptor identified as a member of the LRP1-regulated plasma membrane proteome.  Because LRP1 down-regulates cell-surface uPAR by facilitating its endocytosis, under some conditions, uPAR-initiated cell-signaling may be inhibited by LRP1.  However, the relationship between LRP1 and uPAR is complicated because uPAR endocytosis may be necessary for sustained uPAR-initiated cell-signaling.  Certain cell-signaling factors, including ERK, phosphatidylinositol 3-kinase, and Rac1 are regulated by LRP1, directly, and indirectly through uPAR.  Thus, the predominant effect of LRP1 on cell-signaling, in different cell types, may depend on the abundance of LRP1 and uPAR and on the availability of ligands for LRP1 and uPAR.  Opportunities for targeting the uPAR-LRP1 system through drug discovery are discussed.
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The Urokinase-Type Plasminogen Activator And The Generation Of Inhibitors Of Urokinase Activity And Signaling
Maria Vincenza Carriero and Maria Patrizia Stoppelli
[FULL-TEXT INQUIRY] [PMID: 21711235 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00273]

Urokinase (uPA) was originally identified in human urine for its ability to catalyse the transformation of plasminogen into its active form, plasmin which degrades fibrin and extracellular matrix components. Two major, functionally independent regions have been identified in the uPA molecule: a non-catalytic N-terminal region (residues 1-135) and a large catalytic region (residues 159-411) spaced by the “connecting peptide” (residues 136-158). Binding of uPA to its specific surface receptor (uPAR) amplifies cell surface plasminogen activation, thus enhancing pericellular proteolysis. uPAR, linked to the lipid bilayer via a glycosylphosphatidylinositol anchor, mediates signaling through the assembly of a multiprotein complex with transmembrane receptors, like the integrins, EGFR, GPCRs. Receptor engagement with uPA results in a variety of cell responses, including increased proliferation, survival, migration and invasion. These responses may be enhanced by the concomitant binding of the uPA “connecting peptide” region to αvβ5 integrin, thus favoring uPAR-integrin association. Receptors engaged with uPA exhibit a high affinity for vitronectin, stimulating cell adhesion. The uPA/uPAR system is regarded as one of the key systems driving tumour invasion and metastases. Different strategies to prevent the activity of the protease, as well as the interactions of uPAR with integrins and GPCRs have been designed. Many preclinical studies are ongoing and, at least, two uPA-related compounds have reached Phase II clinical trials. The aim of this review is to provide a comprehensive picture of the functionally relevant interactions, together with a description of the promising compounds and strategies to control uPA activity and signaling in human pathologies.
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Development of Novel Therapeutics Targeting the Urokinase Plasminogen Activator Receptor (uPAR) and Their Translation Toward the Clinic
Andrew P. Mazar, Richard W. Ahn, and Thomas V. O’Halloran
[FULL-TEXT INQUIRY] [PMID: 21711234 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00274]

The urokinase plasminogen activator receptor (uPAR) mediates cell motility and tissue remodeling.  Although uPAR may be expressed transiently in many tissues during development and wound healing, its constitutive expression appears to be associated with several pathological conditions, including cancer.  uPAR expression has been demonstrated in most solid tumors and several hematologic malignancies including multiple myeloma and acute leukemias.Unlike many tumor antigens, uPAR is present not only in tumor cells but also in a number of tumor-associated cells including angiogenic endothelial cells and macrophages.   The expression of uPAR has been shown to be fairly high in tumor compared to normal, quiescent tissues, which has led to uPAR being proposed as a therapeutic target, as well as a targeting agent, for the treatment of cancer.  The majority of therapeutic approaches that have been investigated to date have focused on inhibiting the urokinase plasminogen activator (uPA)-uPAR interaction but these have not led to the development of a viable uPAR targeted clinical candidate.  Genetic knockdown approaches e.g. siRNA, shRNA focused on decreasing uPAR expression have demonstrated robust antitumor activity in pre-clinical studies but havebeen hampered by the  obstacles of stability and drug delivery that have limited the field of RNA nucleic acid based therapeutics. More recently, novel approaches that target interactions of uPAR that are downstream of uPA binding e.g. with integrins or that exploit observations describing the biology of uPAR such as mediating uPA internalization and signaling have generated novel uPAR targeted candidates that are now advancing towards clinic evaluation.  This review will discuss some of the pitfalls that have delayed progress on uPAR-targeted interventions and will summarize recent progress in the development of uPAR-targeted therapeutics.
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The role of the urokinase receptor in epilepsy, in disorders of language, cognition, communication and behavior, and in the central nervous system
Nadine Bruneau, Pierre Szepetowski
[FULL-TEXT INQUIRY] [PMID: 21711233 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00275]

As a key component of the plasminogen activation system, uPAR, the receptor for the plasminogen activator of the urokinase type, is involved in many physiological and pathological processes. Besides its classical roles, there has been increased evidence that uPAR or uPAR-associated pathways, participate in the development, in the functioning and in the pathology of the central nervous system. Qualitative and quantitative changes in the expressions of uPAR and of its canonical ligand uPA have been observed in a large variety of epileptic disorders, either in human or in animal models, as well as in other brain diseases (stroke and brain trauma, multiple sclerosis, Alzheimer’s disease, cerebral malaria, HIV-associated leukoencephalopathy and encephalitis). The variety of such pathological conditions and the different brain areas and cell types involved, likely reflects the wide range and the complexity of the multiple and somehow intertwined pathophysiological mechanisms related with uPAR. In the mouse, the knock-out of the Upar-encoding gene (Plaur) leads to significant and nearly complete loss in parvalbumin-containing interneurons during brain development. This is associated with increased susceptibility to spontaneous and chemically-induced seizures and with increased anxiety and impaired social interactions. The recent identification of the novel uPAR ligand SRPX2 (Sushi repeat protein, X-linked 2) and the regulation of both the SRPX2 and PLAUR genes by transcription factor FOXP2 has shed novel and exciting insights into the role of uPAR-related molecular networks in rolandic epilepsy, in developmental verbal dyspraxia, in perisylvian polymicrogyria, and generally in disorders of the speech areas and circuits. uPAR, its regulators and partners, as well as other proteins containing Ly-6/uPAR/alpha-neurotoxin domains, represent key entry points for present and future studies not only on speech-related disorders but also on epilepsy and autism spectrum disorders.
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Urokinase receptor (uPAR) ligand based recombinant toxins for human cancer therapy
Maddalena de Virgilio and Franco Silvestris
[FULL-TEXT INQUIRY] [PMID: 21711232 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00276]

The urokinase receptor (uPAR) exerts essential functions in the pathophysiology of cancers and therefore constitutes an important drug target. In order to generate efficient drugs against uPAR, a new approach includes chimeric proteins associating one molecular address to specifically target uPAR and one bacterial or plant toxin that will eventually kill the tumoural cell. Using this frame, several recombinant toxins have been designed namely DTAT, DTAT13, EGFATFKDEL 7 mut, and ATF-SAP. As molecular address, all of these fusion proteins use the amino-terminal fragment of urokinase that binds with high affinity to uPAR through its growth factor domain (GFD). The various toxin moieties were derived from either diphtheria toxin, Pseudomonas exotoxin A (PE38), or saporin. In this review, we describe the rational, design, production and therapeutic anti-cancer potential of these chimeric toxins.
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Editorial: The Urokinase Receptor System As Strategic Therapeutic Target: Challenges For The 21^st Century
Bernard Degryse
[PMID: 21711231 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00277]

Abstract of the Editorial

The story that led to the discovery of urokinase receptor (uPAR) system started in 1947 with the report of MacFarlane and Pilling who identified but did not named urokinase (uPA). Today, the uPAR system is recognized as one very important actor in tumourigenesis and is even considered as a valuable tumour marker. Its critical functions justify the important effort of translational research that has produced many inhibitors which unfortunately failed to be transferred in the clinic. However, the role of the uPAR system in cancer development should not shade the vital functions of this system in hematopoietic stem cells mobilization, cognitive functions including language development, inflammation, innate immunity, coagulation and fibrinolysis. All these topics are covered in this special theme issue of the journal Current Pharmaceutical Design that comprises 9 reviews written by leading scientists. Other aspects are also embraced by additional articles including the first attempt to depict the complete atlas of the uPAR interactome, and the regulation of the uPAR system by the LDL receptor-related protein-1 (LRP-1).

Text of the Editorial

Back in 1947, when urokinase (uPA) was discovered no one would have predicted that this enzyme without a proper name will form with its yet unknown receptor the basis of one of most fascinating and challenging molecular system [1].  The unnamed enzyme received its name in 1952 [2], and research evolved slowly till 1985. That year, the urokinase receptor (uPAR) was cloned, and the complexity of the uPAR system inexorably started to emerge [3, 4]. Since then, the story has become more and more interesting. The evolution and sometimes revolution of our knowledge on this system has seen many sensational turns of events. Like in classic fairy tale, the characters are not exactly what they appeared to be at the first glance. uPA is not just another protease but one of the signalling ligands of uPAR that even binds to integrins. uPAR itself, is an adhesion and a full signalling receptor rather than the mere receptor for urokinase. Moreover, the plasminogen activator inhibitor-1 (PAI-1), the physiologic inhibitor of urokinase, is not simply an inhibitor of proteases. PAI-1 is a motogenic factor acting through the binding to the LDL receptor related protein (LRP-1), which is not only an endocytic receptor but also a signalling receptor.

With such tricky characters the story is far from being over. Yet, no frog was transformed into a handsome prince by a young princess but who really knows what to expect next? uPAR seems to always metamorphose and gains new roles, and scientists are particularly delighted in reporting the most dramatic. Do you want examples? uPAR has been showed to exert capital functions in hematopoeitic stem cell mobilization [5], and more recently has unexpectedly become an essential actor of language development and other cognitive functions [6]. The molecular bases of language are largely unknown. The SRPX2 gene is one of the two genes to have ever been connected with language development. Guess what? uPAR is indeed the receptor of the secreted protein SRPX2 [6]. Therefore, without the help of any magic spell, uPAR has become the only known membrane receptor to be involved in the regulation of language, the primordial cognitive function which is at the basis of human civilization.

This special issue of the journal Current Pharmaceutical Design is particularly dedicated to the uPAR system as therapeutic target. When I chose this topic, my prime motivation as Executive Guest Editor was to provide the reader with an overview of the most recent research and development written by top leading scientists. Dissemination of knowledge is one important goal. In addition, the review articles are unique media that permit to the authors to express more freely their opinion on present research and speculation for future challenges. However, I was also particularly sensitive to the fact that although the uPAR system exerts critical functions in cancers to date no inhibitor is available in the clinic [7]. This lack of drug is particularly cruel because cancers are still a major cause of death in Western societies. I sincerely do hope that this theme issue will help rising the interest in the uPAR system stimulating both academic and non-academic research.

In the introductory article, Gabriele Eden et al. gather pertinent information on the identity and functions of the molecular partners of uPAR that constitutes the uPAR interactome, describe the complex organization of this system and the complicated connections between the various members. This article represents an unprecedented effort to describe the whole atlas of the uPAR system. The wide diversity of the components of the uPAR interactome reflects the adaptability of the uPAR system in order to meet the specific cellular requirement during biological processes such as cell migration.

The functions of uPAR are then discussed in the first part of this issue. Due to its crucial role in tumoural cell invasion, proliferation and metastasis, the role of uPAR in oncology has been the most studied. Martin Boonstra and Colleagues explain us why uPAR and its soluble forms are now considered as tumour markers. Among the benefits that may be expected for human health, tumour imaging using probes targeting uPAR is certainly an exciting application residing in the fact that uPAR is localized at the leading edge of the invasive tissue which may help surgeons discriminating the tumour from the normal surrounding tissue during resection.

The more recent knowledge on the role of uPAR in hematopoietic stem cell mobilization is presented by Francesco Blasi. uPAR is involved in both homing (from blood into bone marrow) and mobilization (from bone marrow to blood) of hematopoietic stem cells. Presently, mobilization of hematopoietic stem cells is used in peripheral blood stem cell donation for the therapy of lymphoproliferative diseases such as multiple myeloma, lymphoma and leukaemia. Therefore, the research effort required for a better understanding of this novel uPAR function will certainly lead to therapeutic improvement.

In the next article, Nadine Bruneau and Pierre Szepetowski summarize all the data available on the most recent development of the research on uPAR in the central nervous system. Striking experimental data suggest that uPAR is an important new player modulating cognitive functions. uPAR is indeed involved in human diseases such as autism, schizophrenia, and epilepsy. This review sheds light on the beginning of a new era that will lead to the full exploration of the role of uPAR in the central nervous system and hopefully in the comprehension of the molecular mechanism of language.

Finally, in the last article of this first part, Mario Del Rosso et al. decipher the intricate connections between uPAR, and its ligands factor XII and high molecular weight kinin-free kininogen (HKa) that regulate coagulation, innate immunity, inflammation and fibrinolysis. Here again, the exceptional flexibility of the uPAR system provides the appropriate macromolecular receptor complexes suited for the induction of these complicated responses. uPAR is thus implicated in the organization the defense of the body, a vital role that is detailed in this in-depth review.

The second part is devoted to the other members of the uPAR system. Maria Vincenza Carriero and Maria Patrizia Stoppelli focus on uPA and explain how to use the particular domains of this protease to design inhibitors of uPA and uPAR. The authors illustrate the various strategies that have been used so far to develop these inhibitors, and also new approaches that may be fruitful for future translational research. An overview of existing compounds affecting the uPAR system concludes this article.

The LDL receptor related protein (LRP-1) is a member of the LRP family of endocytic receptors. LRP-1 is a fascinating membrane receptor that binds more than 30 ligands and serves not only as endocytic receptor but also as signaling receptor. These dual functions are well exemplified by the relationship of LRP-1 with uPAR and PAI-1. On the one hand, LRP-1 is responsible of the internalization of uPAR. This mechanism allows to control efficiently uPA-dependent cell migration, and even promotes cell detachment through the internalization of uPAR-associated integrins. On the other hand, LRP-1 is the motogenic receptor of PAI-1 activating intracellular signaling and cell migration [8]. In their review, Steven Gonias and Colleagues also remind us the advantage of targeting LRP-1 in cancer therapy.

Two more papers constitute the third and last part of this special issue on the uPAR system. Translational research is the common topic of these articles. Andrew Mazar et al. justify the choice of uPAR as therapeutic target. They describe the drawbacks that prevented the present inhibitors to advance towards the clinic, and recapitulate the challenges that have to be faced in order to design efficient anti-uPAR drugs. Recently developed compounds may eventually compensate the present grievous lack of anti-uPAR drug in the clinic.

Maddalena de Virgilio and Franco Silvestris conclude this issue by concretely illustrating the difficulty to generate new inhibitory molecules against uPAR. The original approach that has been chosen led to the formation of chimeric toxins which combines a molecular address targeting uPAR with a plant or bacterial toxin representing the deadly moiety of the inhibitor. These chimeric toxins have received the license to kill tumoural cells but will these chimeric toxins be successful with the always elusive cancer cells?.

I am very grateful to all the authors that have accepted to share with us their experience and knowledge of the uPAR system. Also, I warmly acknowledge the altruistic work of evaluation performed by the reviewers. Finally, I thank very much Prof. Williams A. Banks Editor-in-Chief of the journal Current Pharmaceutical Design for his kind invitation to serve as Executive Guest Editor of the present issue, and all the staff of the journal for their help.

References for the Editorial

[1] MacFarlane RG, Pillig, J. Fibrinolytic activity of normal urine. Nature 1947; 159: 779.
[2] Sobel GW, Mohler SR, Jones NW, Dowdy ABC, Guest MM. Urokinase: an activator of plasma profibrinolysin extracted from urine. Am J Physiol 1952; 171: 768-69.
[3] Stoppelli MP, Corti A, Soffientini A, Cassani G, Blasi, F, Assoian RK. Differentiation-enhanced binding of the amino terminal fragment of human urokinase plasminogen activator to a specific receptor on U937 monocytes. Proc Natl Acad Sci USA 1985; 82: 4939-43.
[4] Vassalli J-D, Baccino D, Belin D. A cellular binding site for the Mr 55,000
form of the human plasminogen activator urokinase. J Cell Biol 1985; 100: 88-92.
[5] Selleri C, Montuori N, Ricci P, et al. Involvement of the urokinase-type plasminogen activator receptor in hematopoietic stem cell mobilization. Blood 2005; 105: 2198-2205.
[6] Royer-Zemmour B, Ponsole-Lenfant M, Gara H, et al. Epileptic and developmental disorders of the speech cortex: ligand/receptor interaction of wild-type and mutant SRPX2 with the plasminogen activator receptor uPAR. Hum Mol Genet 2008; 17: 3617-30.
[7] Archinti M, Britto M, Eden G, Furlan F, Murphy R, Degryse B. The urokinase receptor in the central nervous system. CNS Neurol Disord Drug Targets 2011; 10: 271-94.
[8] Degryse B, Neels JG, Czekay RP, Aertgeerts K, Kamikubo Y, Loskutoff DJ. The low density lipoprotein receptor-related protein is a motogenic receptor for plasminogen activator inhibitor-1. J Biol Chem 2004; 279: 22595-604.

Bernard Degryse
School of Health and Human Performance,
Dublin City University,
Glasnevin, Dublin 9,
Ireland
E-mail: bdegryse@yahoo.com
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Kinins as therapeutic agents in cardiovascular and renal diseases
François Alhenc-Gelas, Nadine Bouby, Christine Richer, Louis Potier, Ronan Roussel and Michel Marre
[FULL-TEXT INQUIRY] [PMID: 21728987 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00278]

A fair amount of data indicates that bradykinin and lysyl-bradykinin exert arterial, cardiac and renal effects which afford protection against organ damage in diseases, especially in the settings of ischemia or diabetes. The concept of kinins acting as therapeutic agents is supported by the wide use of angiotensin I-converting enzyme (ACE) inhibitors. These inhibitors indeed potentiate kinin action by inhibiting kinin degradation. Experimental evidence strongly suggests that the cardiac and renal effects of ACE inhibitors are due, at least in part, to kinins. Angiotensin AT1 receptor antagonists act also partly through kinins. This paper reviews available evidence supporting a role for kinins in the therapeutic effect of current drugs. It then discusses the opportunity to develop new drugs based on kinin action. Direct activation of the kinin B2 receptor by pharmacological agonists might provide higher therapeutic benefit than existing kinin-potentiating drugs. Possible occurrence of side effects is however a concern.
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Antimalarial peptides: the long and the short of it
A. Bell
[FULL-TEXT INQUIRY] [PMID: 21728986 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00279]

Antimicrobial peptides include a diverse array of both natural and synthetic molecules varying greatly in size, charge, hydrophobicity and secondary-structural features. Although better known as antibacterial agents, many peptides have demonstrated activity against the malarial parasite Plasmodium either in its vertebrate blood stages or mosquito stages or both. The antimalarial peptides reviewed here consist of (i) cationic, amphipathic 'host-defence' peptides including some (e.g. defensins and cecropins) that are naturally produced by mosquitos, (ii) other membrane-active peptide antibiotics such as gramicidins, (iii) hydrophobic peptides, most notably cyclosporins, (iv) thiopeptides, such as thiostrepton, and (v) some other naturally occurring or synthetic peptides. Many of these peptides affect membrane integrity and some are selective for parasite membranes over those of the host, while others are thought to have more specific intracellular targets. The mechanisms of action of the majority of antimalarial peptides are however either uncertain or totally unknown. Very few of these agents have been tested in rodent malaria models and none has undergone significant pre-clinical or clinical development for malaria. Issues such as metabolic lability, high cost, and a lack of information about systemic toxicity are likely to be serious obstacles to further development of peptides as antimalarial drugs. On the other hand, they offer potential advantages, including the possibility of being much less prone to resistance than the drugs in current use. An alternative to conventional chemotherapy, namely the release of malaria-refractory, transgenic mosquitos overproducing antimalarial peptides, has already passed the 'proof of concept' stage.
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Peptoids: Bio-Inspired Polymers as Potential Pharmaceuticals
Michelle T. Dohm, Rinki Kapoor and Annelise E. Barron
[FULL-TEXT INQUIRY] [PMID: 21728985 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00280]

Peptoids are a developing class of peptide-like oligomers originally invented for drug discovery in the early 1990's. While peptides hold great promise for therapeutic applications, current development of peptide-based pharmaceuticals is hindered by their potential for misfolding and aggregation, and particularly, for rapid in vivo degradation post-administration. Researchers have investigated alternative peptide-like constructs that may be able to circumvent such complications. Peptoids comprise a peptide-based backbone and N-substituted glycines for side chain residues, resulting in complete protease-resistance. Synthesis of peptoid sequences up to 50 units in length allows for controlled sequence composition and incorporation of diverse side chain chemistries. Though the landscape of peptoid structure is not clearly defined, secondary, tertiary, loop, turn, and random structures have been identified. As protease-resistant isomers of peptides, peptoids are being developed as versatile molecular tools in biochemistry and biophysics, and are becoming attractive candidates for therapeutic and diagnostic applications. Peptoids have thus far demonstrated bioactivity as protein mimics and as replacements for small molecule drugs. In this review, we discuss the most recent advances in peptoid research on the therapeutic front in the last few years, including in vitro and in vivo studies in the fields of lung surfactant therapy, antimicrobial agents, diagnostics, and cancer. We particularly focus on the biophysical activity of lipid-associated peptoids and their potential therapeutic applications.
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Peptide And Non-Peptide Antagonists Targeting Endothelin Receptors In Physiology And Pathology
Martin Houde, Julie Labonté, Pedro D’Orléans-Juste
[FULL-TEXT INQUIRY] [PMID: 21728984 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00281]

As for other peptide such as bradykinin, neurokinins and angiotensins, peptide antagonists for endothelin-1 (ET-1) have been early on developed towards the pharmacological characterization of both ET_A and ET_B receptors. Interestingly, unlike the previously mentioned three peptides, receptors for ET-1 were cloned and purified prior to the report of ET_Aand ET_Breceptor antagonists such as BQ-123 and BQ-788. The availability of such pharmacological tools and the use of molecular approaches have certainly fast-tracked the development of non-peptide ET receptor antagonists for clinical applications. Albeit rapid degradation by gastric enzymes, short half-life in plasma and hepatotoxicity of peptide receptor antagonists limit their use in clinical settings, those molecules have been of importance in the identification of mediators and modulators of ET-1 induced properties in vitro and in vivo, as described further in this review. Peptide antagonists acting selectively or, with equivalent affinities against ET_A and ET_B receptors were reported prior to the advent of clinically relevant non-peptide blockers such as Bosentan. Confounding mechanisms involving, for example, the endogenous modulators nitric oxide and prostacyclin as well as allosteric interactions between ET receptor types, have also been clarified with the use of peptide antagonists for endothelins. Finally, peptide antagonists were also used to identify the precise pharmacology of ET-1 precursors such as big-endothelin-1 and ET-1 (1-31). The present review will thus attempt to summarize the knowledge to date and future perspectives related to use of peptide antagonists targeting endothelin receptors in physiological and pathological settings.
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Peptides targeting estrogen receptor alpha -potential applications for breast cancer treatment
Guy Leclercq, Dominique Gallo, Janine Cossy, Ioanna Laïos, Denis Larsimont, Guy Laurent and Yves Jacquot
[FULL-TEXT INQUIRY] [PMID: 21728983 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00282]

Activation of the estrogen receptor alpha (ERα) is of prime importance for the development of hormone-dependent breast cancers. Hence, drugs able to impede the emergence of an active folding of ERα have been used for a long time as a first line therapeutic strategy. Aromatase inhibitors that block estradiol synthesis and / or antiestrogens that compete with hormone binding to the receptor are routinely prescribed. Unfortunately, emergence of tumor resistance almost invariably results from currently used antihormonal approaches. One may anticipate that a "multi-target" strategy affecting key regulatory domains distinct from ligand binding pocket of ERα may help to circumvent this problem. To reach this goal, the synthesis of peptides that may specifically inhibit intra- or inter-molecular interactions has been proposed. This paper describes functional motifs potentially suitable for the design of such antagonists. Activity of available peptidic and non-peptidic mimics of these motifs is also reviewed.
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Bioactive peptide-modified biomaterials for bone regeneration
Jue-Yeon Lee, Young-Suk Choi, Seung-Jin Lee, Chong-Pyoung Chung and Yoon-Jeong Park
[FULL-TEXT INQUIRY] [PMID: 21728982 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00283]

Bioactive biomaterials are desirable as tissue engineering scaffolds by virtue of their capability to mimic the natural environment of the extracellular matrix. Bioactive biomaterials have been achieved by incorporating synthetic short peptide sequences into suitable materials either by surface modification or by bulk incorporation. The goal is to enhance cell attachment and other basic functions. Bioactive peptides can be obtained from biological or chemically synthesized sources, increasing their specific cellular responses for tissue growth and development. Compared to using an entire growth factor in regenerative therapy, these peptides demonstrate potential advantages such as overcoming possible immunogenicity, being less susceptible to degradation, and producing fewer tumor-related side effects. Biomaterial scaffolds modified with peptides can provide biological ligands for cell-scaffold interactions that promote cell attachment, proliferation, and differentiation. Peptide-based biomaterial scaffolds can be fabricated to form two- and three-dimensional structures. This review discusses cell-binding, biominerailization inducing peptides, and receptor-binding peptides for bone regeneration. This review also addresses issues related to peptide immobilization as well as potential complications that may develop as a result of using these versatile bioactive peptides. The development of self-assembled peptide amphiphiles with the goal of generating new three-dimensional scaffolds for tissue engineering is also summarized.
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Anti-Cancer Peptides From Ras-P21 And P53 Proteins
Matthew R. Pincus, Maly Fenelus, Ehsan Sarafraz-Yazdi,Victor Adler,Wilbur Bowne and Josef Michl
[FULL-TEXT INQUIRY] [PMID: 21728981 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00284]

We have employed computer-based molecular modeling approaches to design peptides from the ras-p21 and p53 proteins that either induce tumor cell reversion to the untransformed phenotype or induce tumor cell necrosis without affecting normal cells. For ras-p21, we have computed and superimposed the average low energy structures for the wild-type protein and oncogenic forms of this protein and found that specific domains change conformation in the oncogenic proteins. We have synthesized peptides corresponding to these and found that ras peptides, 35-47 (PNC-7) and 96-110 (PNC-2), block oncogenic ras-p21-induced oocyte maturation but have no effect on insulin-induced oocyte maturation that requires activation of endogenous wild-type ras-p21. These results show signal transduction pathway differences between oncogenic and activated wild-type ras-p21. Both peptides, attached to a membrane-penetrating peptide (membrane residency peptide or MRP), either induce phenotypic reversion to the untransformed phenotype or tumor cell necrosis of several ras-transformed cell lines, but have no effect on the growth of normal cells. Using other computational methods, we have designed two peptides, PNC-27 and 28, containing HDM-2-protein-binding domain sequences from p53 linked on their C-termini to the MRP that induce pore formation in the membranes of a wide range of cancer cells but not any normal cells tested. This is due to the expression of HDM-2 in the cancer cell membrane that does not occur in normal cells. These peptides eradicate a highly malignant tumor in nude mice with no apparent side effects. Both ras and p53 peptides show promise as anti-tumor agents in humans.
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Novel Aβ Isoforms In Alzheimer´s Disease – Their Role In Diagnosis And Treatment
Erik Portelius, Niklas Mattsson, Ulf Andreasson, Kaj Blennow, Henrik Zetterberg
[FULL-TEXT INQUIRY] [PMID: 21728980 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00285]

The last decades have witnessed an explosion in studies of the role of amyloid-β (Aβ) in the progress of the neurodegenerative disorder Alzheimer´s disease (AD) and it is now widely accepted that Aβ is related to the pathogenesis of AD. For example, studies have shown that Aβ is neurotoxic and that the neurotoxicity of Aβ is related to its aggregation state. The concentration of the 42 amino acid form of Aβ (Aβ1-42) is reduced in the cerebrospinal fluid (CSF) from AD patients, which is believed to reflect the AD pathology with plaques in the brain acting as sinks. Less well investigated, however, is the ability of other Aβ isoforms to distinguish AD patients from controls and to identify treatment effects in clinical trials. Recently, novel C-truncated forms of Aβ (Aβ1-14, Aβ1-15, and Aβ1-16) were identified in human CSF. The presence of these small peptides is consistent with a catabolic amyloid precursor protein cleavage pathway by β- followed by α-secretase. It has been shown that Aβ1-14, Aβ1-15, and Aβ1-16 increase dose-dependently in response to γ-secretase inhibitor treatment while Aβ1-42 levels are unchanged. Here, we review the many aspects of Aβ and its isoforms with special focus on their potential role as diagnostic and theragnostic markers.
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Protection against Tauopathy by the Drug Candidates NAP (Davunetide) and D-SAL: Biochemical, Cellular and Behavioral Aspects
Natalia Shiryaev, Regina Pickman, Eliezer Giladi and Illana Gozes
[Purchase Article] [PMID: 21728979 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00286]

Activity-dependent neuroprotective protein (ADNP) is essential for brain formation and partial deficiency in ADNP results in cognitive deficits coupled with tauopathy and neuronal cell death. Our previous results indicated that a peptide snippet from ADNP, NAPVSIPQ (NAP, generic name, davunetide) can restore in part ADNP deficiencies. NAP interacts with tubulin and this interaction is displaced by the NAP related peptide that is derived from activity-dependent neurotrophic factor (ADNF), SALLRSIPA (SAL) and its all D-amino acid peptide derivative (D-SAL, also known as AL-309). Both NAP and D-SAL were shown to protect neurons against amyloid beta toxicity however the mechanism of protection is still under investigation. In addition, NAP protects against tau hyperphosphorylation associated with ADNP deficiency, in vivo. To investigate whether the mechanism of in vitro neuroprotection relates to the in vivo protection against tauopathy and to draw potential additional parallelism between NAP and D-SAL, we asked if: 1]NAP and D-SAL protect against amyloid beta related tau hyperphosphorylation in vitro; and 2] D-SAL protects against haploinsufficiency in ADNP, inhibiting tauopathy in vivo. Assessment of NAP and D-SAL neuroprotection in primary cortical neuro-glial cultures treated with amyloid beta showed that both peptides reduced toxin-related neuronal damage and protected against tau hyperphosphorylation. In vivo, chronic D-SAL administration protected against tau hyperphosphorylation associated with ADNP deficiency (ADNP+/- mice), showing for the first time protection against deficits in odor discrimination and in social recognition. These studies associate neuroprotection in vivo and in vitro and provide a broad base for future drug development based on NAP and D-SAL against multiple neurodegenerative conditions.
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Peptide Mimetics of Neurotrophins and their Receptors
S.D. Skaper
[FULL-TEXT INQUIRY] [PMID: 21728978 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00287]

Neurotrophic factors were originally identified based on their ability to prevent naturally occurring cell death in the developing nervous system. Many of these proteins also promote survival after injury or protect neurons in toxin-disease models in animals. In addition to neuroprotective effects, these factors exert trophic effects on neurons, stimulating increases in neuronal metabolism, cell size, and process outgrowth. These properties underlie expectations for neurorestoration, in which growth of new axons and synapses could lead to functional improvement, which is of great interest for those patients who are already significantly disabled by disease. Preclinical and clinical data suggest that subcutaneous or intravenous administration of neurotrophic factors may be effective for the treatment of peripheral nervous system diseases. However, even though these proteins are natural products, they do present specific problems when used as therapeutic agents. They cannot be given orally, present uncertain pharmacokinetic behaviour, and large-scale production is labor- and cost-intensive. Neurotrophic factor treatment of central nervous system diseases presents an even more complex scenario, since they are not able to cross the blood-brain barrier and must be given intracerebrally. Although there is an active search for alternative delivery strategies, for central nervous system diseases in particular the advantages of small molecule mimetics over proteins are evident. Small organic molecules can be modified to penetrate freely into the brain parenchyma and can be designed for oral administration. There are several possible approaches for replacing neurotrophic proteins with small molecule mimetics. For therapeutic use in the peripheral nervous system, neurotrophic proteins could be replaced by active peptide fragments with receptor binding properties similar to the full-length protein, but improved pharmacokinetic properties and lower production costs. In principle, it should be possible to replace the entire protein or fully active peptide fragment by a non-peptidic molecule binding to the same receptor site. It may be possible to regulate neurotrophic factor receptor activity by allosterically-acting molecules which influence the functional efficacy of the receptors. Other strategies include intracellular effector-targeting approaches, which are based on knowledge of signaling pathways involved in neuronal cell survival and demise, and which can be agonised or antagonised to promote neuroprotection. This chapter will begin with a brief overview on the biology neurotrophic proteins, followed with a description of strategies taken towards the development of small molecule mimetics for neurotrophic factors and the emerging drug candidates. The latter will encompass both receptor-directed as well as intracellular signalling approaches.
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Peptides as tight junction modulators
Azusa Takahashi, Masuo Kondoh, Miki Kodaka, Kiyohito Yagi
[Purchase Article] [PMID: 21728977 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00288]

The first step in drug absorption is the passage of drug molecules across epithelial cell sheets. Epithelial cell sheets are pivotal for the maintenance of homeostasis in the body by acting as a biological barrier that separates the inside of the body from the outside environment. Intercellular space between the adjacent epithelial cells is tightly sealed by tight junctions (TJs), which prevent solutes from freely moving across the epithelial cell sheets. Modulation of the TJ barrier has been a potent strategy for drug absorption. Absorption enhancers have been investigated since the 1980s, and sodium caprate is clinically used as an absorption enhancer. However, the biochemical constituents and structures of TJs were not elucidated until 1993. Occludin, a tetra-transmembrane protein, was identified to be a structural component of TJs in 1993. Claudin, another tetra-transmembrane protein, was identified as a structural and functional component of TJs in 1998. Modulation of occludin- or claudin-barrier is novel methods to enhance drug absorption. Recently, synthetic TJ-binding peptides, a kinase of claudin and peptide fragments of toxins have been developed. In the present review, we summarize the recent progress in TJ-modulating peptides and discuss their potencies.
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Novel neuropeptides as ligands of orphan G protein-coupled receptors
Yan Zhang, Zhiwei Wang, Gregory Scott Parks, Olivier Civelli
[FULL-TEXT INQUIRY] [PMID: 21728976 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00289]

Neuropeptides control a wide spectrum of physiological functions. They are central to our understanding of brain functions. They exert their actions by interacting with specific G protein-coupled receptors. We however have not found all the neuropeptides that exist in organisms. The search for the novel neuropeptides is thus of great interest as it will lead to a better understanding of brain function and disorders. In this review, we will discuss the historical as well as the current approaches to neuropeptide discovery, with a particular emphasis on the orphan GPCR-based strategies. We will also discuss two novel peptides, neuropeptide S and neuromedin S, as examples of the impact of neuropeptide discovery on our understanding of brain functions. Finally, the challenges facing neuropeptide discovery will be discussed.
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Editorial: "Therapeutic potential of peptide motifs "- Part V
Jean-Claude Hervé
[PMID: 21728975 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00290]

The production of new molecular entities endowed with salutary medicinal properties is a formidable challenge; synthetic molecules that can bind with high sequence specificity to a chosen target in a protein or gene sequence are of major interest in medicinal and biotechnological contexts. The general awareness of the importance of peptides in physiology and pathophysiology has markedly increased over the last few years. With progresses in the analysis of whole genomes, the knowledge base in gene sequence and expression data useful for protein and peptide analysis has drastically increased. The medical need for relevant biomarkers is enormous. Peptides have a number of advantages over small molecules in terms of specificity and affinity for targets, and over antibodies in terms of size. Novel therapeutic peptides currently derived from active pre-existing peptides or from high-throughput screening and are optimized following a rational drug design approach. Molecules of interest have to prove their ability to influence the disease outcome in animal models and must respond to a set of criteria based on toxicity studies, ease of administration, cost of their synthesis and logistic for clinical use to validate it as a good candidate in a therapeutic perspective. Peptides can indeed be regarded as ideal agents (as "magic bullets") for diagnostic and therapeutic applications because of their fast clearance, rapid tissue penetration, and low antigenicity, and also of their easy production, allowing innumerable biological applications. They can easily be engineered to improve their biological activities as well as their stability and their efficient delivery to specific targets. This fifth themed issue of Current Pharmaceutical Design, for which I have the honour to be Executive Guest Editor, addresses topical issues to some of these potential utilizations of peptide motifs for a variety of genetic and acquired diseases.

Alzheimer's disease, the most common form of age-related neurodegenerative disorder, is characterized by the presence of extracellular senile plaques, neurofibrillary tangles and neuronal loss in the brain. Senile plaques are composed of aggregations of small peptides called amyloid β (Aβ). Aβ is produced during normal cell metabolism through proteolytic processing of the amyloid precursor protein, expressed constitutively by many cell types throughout life. Recent studies have shown that Aβ is neurotoxic and that this neurotoxicity is related to its aggregation state into insoluble β-sheet fibrils. Erik Portelius, Niklas Mattsson, Ulf Andreasson, Kaj Blennow and Henrik Zetterberg [1] present an overview of the many aspects of Aβ and its isoforms with special focus on their potential role as diagnostic and theragnostic markers. The major constituent of neurofibrillary tangles is, Tau, a microtubule-associated protein, whose increased hyperphosphorylation is known to cause memory impairments. In the amyloid cascade hypothesis, toxic concentrations of Aβ would trigger changes in Tau and consequent neurofibrillary tangle formation. Natalia Shiryaev, Regina Pickman, Eliezer Giladi, and Illana Gozes [2] examine the protecting effects of chronic daily administration of short peptide snippets against deficits in spatial memory and the underlying tauopathy.

Endothelins (ETs) are peptides produced primarily in the endothelium and playing a key role in vascular homeostasis. The ET system consists of three ET isoforms (ET-1, -2 and -3) and two G-protein-coupled receptors, ET(A) and ET(B). In the cardiovascular system, ETs, particularly ET-1, are expressed in smooth muscle cells, cardiomyocytes, fibroblasts, and notably in vascular endothelial cells, and many of the cardiovascular complications associated with aging and cardiovascular risk factors (including e.g. hypertension, atherosclerosis or fibrosis) appear initially attributable, at least in part, to endothelial dysfunction. Martin Houde, Julie Labonté and Pedro D'Orléans-Juste [3] summarize the knowledge to date and future perspectives related to use of peptide antagonists targeting endothelin receptors in physiological and pathological settings.

Neuropeptides are peptides released by neurons to communicate with each other by acting on cell surface receptors, particularly G protein-coupled receptors (GPCRs) to control a wide spectrum of physiological functions. Genomic sequencing efforts have yielded a large number of cDNA sequences that potentially encode novel candidate peptide precursors, as well as hundreds of GPCRs with no known cognate ligands, termed "orphan GPCRs", that became the roots of reverse pharmacology, in which receptors are attempted to be matched to potential transmitters. Yan Zhang, Zhiwei Wang, Gregory Scott Parks and Olivier Civelli. [4] retrace the history of the orphan GPCRs and of the discoveries of their endogenous ligands and discuss the difficulties that the search for new ligands is presently encountering and the challenges facing neuropeptide discovery.

Estrogen receptors (ERs), activated by the hormone 17β-estradiol, belong to the steroid receptor family, which is part of the nuclear receptor superfamily. ERα and ERβ, the two ER subtypes, regulate different genes by binding to different regulatory elements and recruiting different transcription and chromatin remodelling factors that are expressed in a cell-specific manner. Estrogen antagonists, commonly known as antiestrogens, are compounds able to block the binding of 17β-estradiol to its receptors, preventing thereby their physiological/pathological actions. Guy Leclercq, Dominique Gallo, Janine Cossy, Ioanna Laïos, Denis Larsimont, Guy Laurent and Yves Jacquot [5] present an overview of the literature on peptides targeting ERβ, whose activation is of prime importance for the development of hormone-dependent breast cancers.

The pathogenesis of arterial hypertension frequently involves an increase in systemic vascular resistance (via e.g. a vasoconstriction) and impairment of salt excretion in the kidney (inappropriate salt retention despite elevated blood pressure). Kinins (bradykinin and lys-bradykinin) are endogenous vasodilators and natriuretic peptides known best for their ability to antagonize angiotensin-induced vasoconstriction and sodium retention. This concept of kinins is supported by the wide use of angiotensin I-converting enzyme (ACE) inhibitors. These agents indeed potentiate kinin action by inhibiting kinin degradation, and experimental evidence strongly suggests that the cardiac and renal effects of ACE inhibitors are due, at least in part, to kinins. Angiotensin AT1 receptor antagonists act also partly through kinins. François Alhenc-Gelas, Nadine Bouby, Christine Richer, Louis Potier, Ronan Roussel and Michel Marre [6] present available evidence supporting a role for kinins in the therapeutic effect of current drugs and discusses the opportunity to develop new drugs based on kinin action.

The fabrication of biomaterials inducing active biomineralization for bone regeneration represents a high demand in the development of clinical regenerative medicine. Biocompatible materials are expected to mimic the natural environment of the extracellular matrix, which supports organ and tissue structure and function, and also regulates basic cellular functions like proliferation, growth, migration, differentiation, and survival. Bioactive biomaterials have been achieved by incorporating synthetic short peptide sequences into suitable materials either by surface modification or by bulk incorporation. Jue-Yeon Lee, Young-Suk Choi, Seung-Jin Lee, Chong-Pyoung Chung, and Yoon-Jeong Park [7] provide an up-to-date overview of the cell-binding, biomineralization-inducing peptides and receptor-binding peptides for bone regeneration. They also address issues related to peptide immobilization as well as potential complications that may develop as a result of using these versatile bioactive peptides.

RAt Sarcoma (Ras) are a protein subfamily of small GTPases involved in cellular signal transduction, and ras-gene is known to be an oncogene causing fibrosarcomas in rats and was the first oncogene to be discovered in humans in a human bladder cancer. Activated forms of human ras gene encode structurally and immunologically related proteins of molecular weight of approximately 21,000, designated "p21". P53 is a nuclear phosphoprotein which regulates the cell cycle and, thus, functions as a tumour suppressor and is involved in preventing cancer. Matthew R. Pincus, Maly Fenelus, Ehsan Sarafraz-Yazdi, Victor Adler, Wilbur Bowne and Josef Michl [8] summarize data obtained with computer-based molecular modelling approaches to design peptides from the ras-p21 and p53 proteins that either induce tumour cell reversion to the untransformed phenotype or induce tumour cell necrosis without affecting normal cells.

The different (e.g. gastrointestinal, renal, respiratory or epidermal) epithelia and endothelia function as selective barriers between the outside environment and underlying tissue, where tight junctions (TJ, membrane specialisation areas of adjacent cells) form a virtually impermeable barrier. Several transport routes exist (for example via transporters, adsorptive and receptor-mediated transcytosis) to enhance drug permeability through these barriers. Recent advances in barrier research led to a promising strategy for drug delivery via the modulation of TJ components to safely and reversibly allow molecules to pass through the TJ-based cellular barriers. Azusa Takahashi, Masuo Kondoh, Miki Kodaka, Kiyohito Yagi [9] discuss recent progress in the development of TJ-modulating peptides, and examine the potencies of these peptides.

Neurotrophins, a family of proteins that induce the survival, development, and function of neurons, regulate cell survival, death, differentiation and growth. Biological effects of each of the four mammalian neurotrophins are mediated through activation of one or more of the three members of the tropomyosin-related kinase (Trk) family of receptor tyrosine kinases. Neurotrophins and their receptors have been validated for pathologies including neurodegenerative disorders of the central nervous system and the peripheral nervous system, certain types of cancers, asthma and inflammation. Given the difficulties inherent with a protein therapeutic approach to treating central nervous system disorders, increasing attention has turned to the development of alternative strategies and, in particular, small molecule mimetics. Stephen D. Skaper [10] briefly surveys the biology of neurotrophic proteins before to present the different strategies taken towards the development of small molecule mimetics for neurotrophic factors and the emerging drug candidates.

Malaria, a mosquito-borne tropical disease that involves high fevers, shaking chills, flu-like symptoms, and anemia, continues to be one of mankind's most intractable infectious-disease problems. Human malaria is caused by one of five species of protozoal parasites of the genus Plasmodium, of which Plasmodium falciparum is the most virulent, the best characterized, and (along with Plasmodium vivax) the most common. The antimalarial peptides include a diverse array of natural or synthetic molecules widely varying in size, charge, hydrophobicity and secondary-structural features. Many of them affect membrane integrity, some are selective for parasite membranes over those of the host, while others are thought to have more specific intracellular targets. Angus Bell [11] presents an overview of their potential advantages, including the possibility of being much less prone to resistance than the drugs in current use.

A plethora of human pathogens are now resistant to all clinically significant antibiotics, causing a crisis in the treatment and management of infectious diseases but also presenting a clear danger to future public health (in clinical environment, with nosocomial infections for example). One of the new and promising drug candidates is derived from naturally occurring antimicrobial peptides, particularly peptidomimetics able to resist to rapid in vivo degradation by proteases. Peptoids comprise a peptide-based backbone and N-substituted glycines for side chain residues, resulting in complete protease-resistance. They are well suited for combinatorial approaches to drug discovery because large libraries can be easily synthesized from available primary amines, leading to secondary structures such as helices, loops, and turns, enabling the discovery of bioactive peptoids. Michelle T. Dohm, Rinki Kapoor, and Annelise E. Barron [12] explain how peptoids are becoming attractive candidates for therapeutic and diagnostic applications.

I wish to thank all the authors and co-authors for their commitments and the anonymous reviewers who contributed by their constructive remarks to the excellence of this issue.

References

[1] Portelius E, Mattsson N, Andreasson U, Blennow K, Zetterberg H. Novel Aβ isoforms in Alzheimer´s disease – their role in diagnosis and treatment. Curr Pharm Des. 2011; (??): ????-????.
[2] Shiryaev N, Pickman R, Giladi E, Gozes I. Protection against Tauopathy by the Drug Candidates NAP (Davunetide) and D-SAL: Biochemical, Cellular and Behavioral Aspects. Curr Pharm Des. 2011; (??): ????-????.
[3] Houde M, Labonté J, D’Orléans-Juste P. Peptide and non-peptide antagonists targeting endothelin receptors in physiology and pathology. Curr Pharm Des. 2011; (??): ????-????.
[4] Zhang Y, Wang Z, Parks GS, Civelli O. Novel neuropeptides as ligands of orphan G protein-coupled receptors. Curr Pharm Des. 2011; (??): ????-????.
[5] Leclercq G, Gallo D, Cossy J, Laïos I, Larsimont D, Laurent G, Jacquot Y. Peptides targeting estrogen receptor alpha - potential applications for breast cancer treatment. Curr Pharm Des. 2011; (??): ????-????.
[6] Alhenc-Gelas F, Bouby N, Richer C, Potier L, Roussel R, Marre M. Kinins as therapeutic agents in cardiovascular and renal diseases. Curr Pharm Des. 2011; (??): ????-????.
[7] Lee JY, Choi YS, Lee SJ, Chung CP, Park¨YJ. Bioactive peptide-modified biomaterials for bone regeneration. Curr Pharm Des. 2011; (??): ????-????.
[8] Pincus MR, Fenelus M, Sarafraz-Yazdi E, Adler V, Bowne W, Michl J. Anti-cancer peptides from Ras-P21 and P53 proteins. Curr Pharm Des. 2011; (??): ????-????.
[9] Takahashi A, Kondoh M, Kodaka M, Yagi K. Peptides as tight junction modulators. Curr Pharm Des. 2011; (??): ????-????.
[10] Skaper SD. Peptide Mimetics of Neurotrophins and their Receptors. Curr Pharm Des. 2011; (??): ????-????.
[11] Bell A. Antimalarial peptides: the long and the short of it. Curr Pharm Des. 2011; (??): ????-????.
[12] Dohm MT, Kapoor R, Barron AE. Peptoids: Bio-Inspired Polymers as Potential Pharmaceuticals. Curr Pharm Des. 2011; (??): ????-????.


Jean-Claude Hervé
Institut de Biologie et Physiologie Cellulaires
UMR CNRS 6187, PBS, 1, rue Georges Bonnet
86022 POITIERS Cédex, France
Jean.Claude.Herve@univ-poitiers.fr
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Biomedical Application of Metallodendrimers and Dendrimer Nanocomposites
Yi-HsuanTang, Adela Ya-Ting Huang, Po-Yu Chen, Hui-Ting Chen, Chai-Lin Kao
[FULL-TEXT INQUIRY] [PMID: 21736548 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00291]

Dendrimers are polymeric compounds with highly branched structures and functionally tunable peripheral groups.Because of their low polydispersity, high degree of molecular uniformity, and precisely controlled structure, dendrimersare excellent models for demonstrating a variety of biological activities. With the attachment of metals ions and or metals, metallodendrimersor dendrimer nanocomposites, respectively, provide diverse characters for a variety of applications. Functionalizationwith additional moieties, such as targeted peptidesor chromophores, yields metallodendrimers that can find powerful applications and exceed the capabilities of non-dendritic molecules or smallmolecule analogs. This reviewintroducesthe background of metallodendrimers and dendrimer nanocomposites. Biomedical applications of metallodendrimers and dendrimer nanocomposites will be discussed, including biomimetic catalysts, imaging contrast agents(especially for MRI imaging), or biomedical sensors and therapeutic agents.
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Recent progress toward hydrogen medicine: Potential of molecular hydrogen for preventive and therapeutic applications
Shigeo Ohta
[FULL-TEXT INQUIRY] [PMID: 21736547 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00292]

Persistent oxidative stress is one of the major causes of most lifestyle-related diseases, cancer and the aging process. Acute oxidative stress directly causes serious damage to tissues. Despite the clinical importance of oxidative damage, antioxidants have been of limited therapeutic success. We have proposed that molecular hydrogen (H₂) has potential as a “novel” antioxidant in preventive and therapeutic applications [Ohsawa et al., Nat Med. 2007: 13; 688-94]. H₂ has a number of advantages as a potential antioxidant: H₂ rapidly diffuses into tissues and cells, and it is mild enough neither to disturb metabolic redox reactions nor to affect reactive oxygen species (ROS) that function in cell signaling, thereby, there should be little adverse effects of consuming H₂. There are several methods to ingest or consume H₂, including inhaling hydrogen gas, drinking H₂-dissolved water (hydrogen water), taking a hydrogen bath, injecting H₂-dissolved saline (hydrogen saline), dropping hydrogen saline onto the eye, and increasing the production of intestinal H₂ by bacteria. Since the publication of the first H₂ paper in Nature Medicine in 2007, the biological effects of H₂ have been confirmed by the publication on more than 38 diseases, physiological states and clinical tests in leading biological/medical journals, and several groups have started clinical examinations. Moreover, H₂ shows not only effects against oxidative stress, but also various anti-inflammatory and anti-allergic effects. H₂ regulates various gene expressions and protein-phosphorylations, though the molecular mechanisms underlying the marked effects of very small amounts of H₂ remain elusive.
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Design of Magnetic Nanoparticles-Assisted Drug Delivery System
Guo-Jing Chen and Li-Fang Wang
[FULL-TEXT INQUIRY] [PMID: 21736546 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00293]

Magnetic nanoparticles (MNPs) have been designed for multifaceted applications such as contrast agents in magnetic resonance imaging (MRI) diagnosis, drug/gene carriers for different kinds of therapeutic agents, tissue repair, hyperthermia, immunoassay, and cell separation/sensing. This review highlights synthesis methods, stabilizers used for surface coating on MNPs, and target ligands for ferrying payloads to an interested disease area. Some of the recent biomedical applications of MNPs in the field of drug and DNA targeting delivery are extensively reviewed.
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The possible involvement of glycogen synthase kinase-3 (GSK-3) in diabetes, cancer and central nervous system diseases
Amar S,  Belmaker RH and Agam G
[FULL-TEXT INQUIRY] [PMID: 21736545 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00294]

Glycogen synthase kinase (GSK) is a key enzyme in multiple cell processes.  Since many pharmacological compounds that have effects on common metabolic pathways may have uses in many different diseases, we review here the possible involvement of glycogen synthase kinase 3 in diabetes, cancer and CNS diseases.  Moreover, diabetes has recently been strongly linked to CNS diseases such as schizophrenia and bipolar illness.  GSK is both directly and indirectly inhibited by lithium, a key compound for treatment of bipolar disorder.  Several antipsychotic drugs also affect the GSK3 mediated pathways and postmortem study of brain in schizophrenia led to reports of alterations of GSK3 activity or mRNA message.  However, other reports are contradictory.  Development of GSK3 inhibitors for CNS diseases is complicated by the importance of GSK3  in glucose metabolism and pancreas function and the possible effect of GSK3 inhibition to be oncogenic.  Further development of GSK inhibitors for clinical trials should be approached with caution.
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Gas Bioengineering Using Hemoglobin-Vesicles For Versatile Clinical Applications
Hiromi Sakai, Shinji Takeoka, Koichi Kobayashi
[FULL-TEXT INQUIRY] [PMID: 21736544 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00295]

Blood transfusion systems have greatly benefited human health and welfare. Nevertheless, some problems remain: possibility of infection, blood type mismatching, immunological response, and a short shelf life that is insufficient for stockpiling for emergency situations. Realization of artificial O₂ carriers is anticipated to solve such problems. During the long development of hemoglobin (Hb)-based O₂ carriers, many side effects of cell-free Hb molecules have arisen, and have implied the physiological importance of the cellular structure of red blood cells (RBCs). Therefore, Hb-vesicles (HbVs) have been developed as artificial red cells that encapsulate a concentrated Hb solution in thin lipid bilayer vesicles. This Hb encapsulation can shield various toxic effects of molecular Hbs, especially reactions with endogenous NO and CO as vasorelaxation factors. Physicochemical analyses have clarified that Hb encapsulation retards these gaseous reactions significantly. “Gas Bioengineering” is intended to create systems using bioengineering and chemical engineering techniques to facilitate the transport of or regulate the concentration of endogenous or exogenous gaseous molecules (such as O₂, NO, and CO) that are sometimes vital and sometimes toxic to humans. Gas bioengineering using HbVs underscores the potential of HbVs as a transfusion alternative and promises its use for other clinical applications that remain unattainable using RBC transfusion.
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Development of Microwave Antennas for Thermal Therapy
Koichi Ito and Kazuyuki Saito
[FULL-TEXT INQUIRY] [PMID: 21736543 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00296]

There are several different ways for cancer treatment including operation, radiation therapy, chemotherapy, gene therapy, immunotherapy, ablation and hyperthermia. Techniques utilizing temperature elevation over the tumor region are usually called as thermal therapies. In this paper, we will focus on hyperthermia which is one of the promising cancer treatments utilizing the difference of thermal sensitivity between the tumor and normal tissue. In addition, microwave energy is a heating source used for localized hyperthermia. Depending on the position and size of the target tumor, several types of antennas, which radiate microwave energy to the target, can be selected. This paper describes two types of heating schemes which can be used with microwave energy, and provides brief explanations of the basic engineering involved. In addition, methods used for evaluations of antenna performance are described.
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Jun dimerization protein 2 in oxygen restriction; control of senescence
Shin-Wei Wang, Jiag-Ki Lee, Chia-Chen Ku, Shyh-Shin Chiou, Ming-Feng Ho, Deng-Chyang Wu and Kazunari K. Yokoyama
[FULL-TEXT INQUIRY] [PMID: 21736542 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00297]

Senescent cells show a series of alterations, including a flat and enlarged morphology, increase in nonspecific acidic β-galactosidase activity, chromatin condensation, and changes in gene expression patterns. The onset and maintenance of senescence are regulated by two tumor suppressor proteins, p53 and Rb, whose expression is controlled by two distinct proteins, p19^Arf and p16^Ink4a, respectively, which are encoded by the cdkn2a locus. Transcription factor Jun dimerization protein 2 (JDP2) which binds directly to histones and DNA, inhibits the acetylation and methylation of core histones and of reconstituted nucleosomes that contain JDP2-recognition DNA sequences. JDP2-deficient mouse embryonic fibroblasts are known to be resistant to replicative senescence. Oxygen induces the expression of the JDP2 gene and JDP2 then inhibits the recruitment of polycomb repressive complexes (PRCs1 and 2) to the promoter of the gene encoding p16^Ink4a, resulting in the inhibition of methylation of lysine 27 of histone H3. These findings suggest that chromatin-remodeling factors, including the PRC complex controlled by JDP2, are important players in the senescence. The newly defined mechanisms that underlie the action of oxygen in the induction of JDP2 and cellular senescence are reviewed.
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Walking the oxidative stress tightrope: a perspective from the naked mole-rat, the longest living rodent
Karl A. Rodriguez, Ewa Wywial, Viviana I. Perez, Adrian J. Lambert, Yael H. Edrey, Kaitlyn N. Lewis, Kelly Grimes, Merry L. Lindsey, Martin D. Brand, Rochelle Buffenstein
[FULL-TEXT INQUIRY] [PMID: 21736541 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00298]

Reactive oxygen species (ROS), by-products of aerobic metabolism, cause oxidative damage to cells and tissue and not surprisingly many theories have arisen to link ROS-induced oxidative stress to aging and health. While studies clearly link ROS to a plethora of divergent diseases, their role in aging is still debatable. Genetic knock-down manipulations of antioxidants alter the levels of accrued oxidative damage, however, the resultant effect of increased oxidative stress on lifespan are equivocal. Similarly the impact of elevating antioxidant levels through transgenic manipulations yield inconsistent effects on longevity. Furthermore, comparative data from a wide range of endotherms with disparate longevity remain inconclusive. Many long-living species such as birds, bats and mole-rats exhibit high-levels of oxidative damage, evident already at young ages. Clearly, neither the amount of ROS per se nor the sensitivity in neutralizing ROS are as important as whether or not the accrued oxidative stress leads to oxidative-damage-linked age-associated diseases. In this review we examine the literature on ROS, its relation to disease and the lessons gleaned from a comparative approach based upon species with widely divergent responses. We specifically focus on the longest lived rodent, the naked mole-rat, which maintains good health and provides novel insights into the paradox of maintaining both an extended healthspan and lifespan despite high oxidative stress from a young age.
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The principle and the potential approach to ROS-dependent cytotoxicity by non-pharmaceutical therapies: optimal use of medical gases with antioxidant properties
Mami Noda, Kyota Fujita, Chih-Hung Lee, Tohru Yoshioka
[FULL-TEXT INQUIRY] [PMID: 21736540 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00299]

Regulation of cellular redox balances is important for the homeostasis of human health.  Thus, many important human diseases, such as inflammation, diabetes, glaucoma, cancers, ischemia and neurodegenerative diseases, have been investigated in the field of reactive oxygen species (ROS) and oxidative stress. To overcome the harmful effect of oxidative stress and ROS, one can directly eliminate them by medical gases such as carbon monoxide (CO), hydrogen sulphide (H₂S), and molecular hydrogen (H₂), or one can induce ROS-resistant proteins and antioxidant enzymes to antagonize oxidative stresses. This article reviews the molecular mechanisms how these medical gasses work as antioxidants, and how ROS resistant proteins are produced in the physiological context. Targeted therapeutic modalities to scavenge or prevent ROS might be applied in the prevention and treatment of ROS-related diseases in the near future.
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Tocotrienols and its Role in Cardiovascular Health- a Lead for Drug Design
Hannah R Vasanthi, R P Parameswari and Dipak K. Das
[FULL-TEXT INQUIRY] [PMID: 21774785 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00300]

The worldwide cardiovascular disease (CVD) burden has resulted in an intense interest in pharmaceutical approaches to combat this multifactorial disease. Vitamins are high-flying among natural or endogenous compounds, considered to be beneficial to human health and have become attractive targets for research. Of all the vitamins, tocopherols and tocotrienols, parent congeners in the vitamin E family, are found to be effective in decreasing mortality due to CVD. As understanding of the antioxidant effect of this vitamin evolved, tocotrienols gained eminence in recent years and researchers begun to further study the biological effects of it. Tocotrienols have several cardioprotective effects; including antagonizing the oxidation of low density lipoproteins, anti atherosclerotic, inhibiting platelet aggregation and monocyte adhesion, preventing smooth muscle proliferation and various other cardiovascular disorders. Recent studies have also revealed the molecular targets of the tocotrienols and their roles in cancer, bone resorption, diabetes and neurological diseases at both preclinical and clinical levels. The multitargeted role of tocotrienols in most degenerative diseases proves it to be an ideal candidate as a nutraceutical/pharmaceutical agent for useful exploitation.
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Mitochondria as Possible Pharmaceutical Targets for the Effects of Vitamin E and its Homologues in Oxidative Stress-Related Diseases
Hideyuki J. Majima, Hiroko P. Indo, Shigeaki Suenaga, Hirofumi Matsui, Hsiu Chuan Yen and Toshihiko Ozawa
[FULL-TEXT INQUIRY] [PMID: 21774784 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00301]

It is well known that vitamin E functions as an antioxidant, and it is expected to exert an antioxidant effect when taken as a supplement. However, a number of cohort studies have shown that vitamin E does not alleviate oxidative stress and could even worsen it. Recently, Wang et al. investigated whether vitamin E intake was associated with amyotrophic lateral sclerosis (ALS) based on data from 5 cohort studies with 1,055,546 participants, of which 805 of them had developed ALS. They concluded in this large pooled prospective study, in which long-term vitamin E supplementation was associated with lower ALS rates, and therefore, a possible protective effect of vitamin E deserves further consideration. Performing further large cohort studies may reveal similar findings for other oxidative stress-related diseases. It is still controversial if antioxidants such as vitamin E provide a clinical therapeutic effect against oxidative stress-related diseases. If effective, the dose at which they should be administered and the duration of supplement exposure should be of interest. Vitamin E reduces production of reactive oxygen species by mitochondria and elicits further reactions in cells. It should be noted that mitochondria are important targets for vitamin E and its homologues. Therefore, a proper usage of vitamin E in subjects under high oxidative stress, due to its individually targeting property, will arise its importance in healthy life.
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The 21st Century Form of Vitamin E - Tocotrienol
Jayeeta Bardhan, Runu Chakraborty & Utpal Raychaudhuri
[FULL-TEXT INQUIRY] [PMID: 21774783 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00302]

Vitamin E family constitutes of tocopherol and tocotrienol. Each form has several isomers: alpha,beta, gamma, delta, desmo and didesmo. Although tocopherol is known much earlier, tocotrienol has been discovered more recently.Tocotrienol has higher antioxidant potential than tocopherol. Research shows that tocotrienol can inhibit the induced oxidative damage to lipids and proteins.Cholesterol biosynthesis pathway requires HMG Co A reductase. Tocotrienol degrades HMG Co A reductase protein and in turn lowers cholesterol synthesis. Tocotrienol can reverse ischemia-reperfusion which mediates cardiac dysfunction and induces c-Src protein expression. Tocotrienol prevents oxytosis and offers protection against Alzheimer's disease, Parkinson's disease, Hungtington's disease. Tocotrienol exerts anticancer property through cell cycle arrest, induction of apoptosis, inhibition of angiogenesis; antitumor activity. Tocotrienol also possesses anti-inflammatory, antidiabetic, antiadipogenic and antiatherogenic effect.
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Tocotrienols and Cardiovascular Health
Kailash Prasad
[FULL-TEXT INQUIRY] [PMID: 21774782 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00303]

This review emphasizes the effects of tocotrienols on the risk factors for atherosclerosis, plaque instability and thrombogenesis, and compares these effects with tocopherol. Tocotrienols reduce serum lipids and raise serum HDL-C. Alpha-tocopherol, on the other hand, has no effect on serum lipids. Tocotrienols have greater antioxidant activity than tocopherols. Both reduce the serum levels of C-reactive protein (CRP) and advanced glycation end products, and expression of cell adhesion molecules. The CRP-lowering effects of tocotrienols are greater than tocopherol. Tocotrienols reduce inflammatory mediators, δ-tocotrienol being more potent, followed by γ- and α-tocotrienol. Tocotrienols are antithrombotic and suppress the expression of matrix metalloproteinases. They suppress, regress and slow the progression of atherosclerosis, while tocopherol only suppresses, and has no effect on regression and slowing of progression of atherosclerosis. Tocotrienol reduces risk factors for destabilization of atherosclerotic plaques. There are no firm data to suggest that tocotrienols are effective in reducing the risk of cardiac events in established ischemic heart disease. Alpha-tocopherol is effective in primary prevention of coronary artery disease (CAD), but has no conclusive evidence that it has beneficial effects in patients with established ischemic heart disease. Tocotrienols are effective in reducing ischemia-reperfusion cardiac injury in experimental animals and has the potential to be used in patients undergoing angioplasty, stent implantation and aorto-coronary bypass surgery. In conclusion, experimental data suggest that tocotrienols have a potential for cardiovascular health, but long-term randomized clinical trials are needed to establish their efficacy in primary and secondary prevention of CAD.
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Nutrapharmacology Of Tocotrienols For Metabolic Syndrome
Wong Weng-Yew and Lindsay Brown
[FULL-TEXT INQUIRY] [PMID: 21774781 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00304]

Metabolic syndrome is defined as a set of health risk factors that are associated with an increased chance of cardiovascular diseases and type 2 diabetes. These include abdominal obesity, hyperglycemia, impaired glucose tolerance, dyslipidemia, and hypertension. Interventions in metabolic syndrome include lifestyle interventions such as a healthy diet using functional foods together with increased physical activity to induce weight loss as the first aim of treatment. Nutraceuticals such as tocotrienols and tocopherols as members of the vitamin E family may be more targeted interventions. This review evaluates the effects of tocotrienols on the risk factors of metabolic syndrome using data from human, animal and in vitro studies. Tocotrienols improved lipid profiles and reduced atherosclerotic lesions, decreased blood glucose and glycated hemoglobin concentrations, normalized blood pressure, and inhibited adipogenesis. The differences in responses between tocopherols and tocotrienols in preventing obesity, diabetes, hypertension, artherosclerosis, ischemia, and inflammation suggest that different receptors or signaling mechanisms may be involved.
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Cellular Protection And Therapeutic Potential Of Tocotrienols
Betul Catalgol, Saime Batirel, Nesrin Kartal Ozer
[FULL-TEXT INQUIRY] [PMID: 21774780 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00305]

Tocotrienols, components belonging to vitamin E members, are used as potent therapeutics in the treatment of several diseases. Recent studies suggested tocotrienol to have better activity in many situations compared to tocopherols. Tocotrienols have been shown to lower the atherogenic apolipoprotein B and lipoprotein plasma levels. Additionally, tocotrienols with their anti-tumor effect together with anti-angiogenic and anti-thrombotic effects may serve as effective agents in cancer therapy. Besides these effects, some properties such as water insolubility and low stability limits the usage of tocotrienols in the clinic. However recent studies tried to increase the bioavailability with esterification and combination use. These efforts for the clinical usage of tocotrienols may help them to take a wide place in the clinic and additional studies are needed to identify their therapeutical mechanisms
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γ-Tocotrienol Induces Apoptosis in Human T Cell Lymphoma Through Activation of Both Intrinsic and Extrinsic Pathways
Chandan Wilankar, Nazir M. Khan, Rahul Checker, Deepak Sharma, Raghavendra Patwardhan, Vikram Gota, Santosh Kumar Sandur and T.P.A. Devasagayam
[FULL-TEXT INQUIRY] [PMID: 21774779 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00306]

Tocotrienols are members of vitamin E family and possess broad biological activities including antioxidant, anti-inflammatory and antitumor effects. In the present study, we examine the potential of α-tocotrienol (AT) and γ-tocotrienol (GT) in inhibiting the proliferation of human T cell lymphoma Jurkat cells and elucidate the pathways involved in anti tumor effects of GT. Only GT but not AT inhibited proliferation and induced apoptosis in Jurkat cells in a dose dependent manner. GT treatment resulted in elevated mitochondrial ROS production, activation of JNK and suppression of ERK and p38 MAPK. GT also induced calcium release, loss of mitochondrial membrane potential and cytochrome c release from the mitochondria. These changes were accompanied by increase in Bax expression with a concomitant decrease in Bcl-xl expression suggesting activation of mitochondrial apoptotic pathway. GT induced increase in mitochondrial ROS was abrogated by catalase. Besides, GT also up-regulated surface expression of Fas and FasL on Jurkat cells. Further, caspase activation and PARP degradation was also seen in cells treated with GT. Inhibitors of caspase-8 and caspase-9 significantly abrogated GT mediated apoptosis. In contrast GT was not toxic to normal human peripheral blood mononuclear cells suggesting differential cytotoxicity towards normal lymphocytes and transformed lymphoma cells. Cellular uptake studies with tocotrienols showed higher intracellular accumulation of GT as compared to AT which may be responsible for its better antitumor activity. Our results show antitumor effects of GT in human lymphoma cells via increased mitochondrial ROS generation and activation of both intrinsic and extrinsic apoptotic pathways.
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Vitamin E in oxidant stress-related cardiovascular pathologies: focus on experimental studies
Belma TURAN and Guy VASSORT
[FULL-TEXT INQUIRY] [PMID: 21774778 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00307]

The scope of this review is to summarize the important roles of vitamin E family members as protective agents in cardiovascular pathologies of different types of disease states and particularly in diabetes, including some of our research results, to illustrate how this recent knowledge is helping to better understand the roles of the vitamin E family in biology, in animals and humans specifically. Cardiovascular disease, a general name for a wide variety of diseases, disorders and conditions, is caused by disorders of the heart and blood vessels. Cardiovascular disease is the world's largest killers, claiming 17.1 million lives a year. Cardiovascular complications result from multiple parameters including glucotoxicity, lipotoxicity, fibrosis. Obesity and diabetes mellitus are also often linked to cardiovascular disease. In fact, cardiovascular disease is the most life-threatening of the diabetic complications and diabetics are 2- to 4-fold more likely to die of cardiovascular-related causes than non-diabetics. In order to prevent the tendency of cardiovascular disease, primary prevention is needed by modifying risk factors. Several recent studies, besides earlier ones, have reported beneficial effects of therapy with antioxidant agents, including trace elements, vitamins (E and/or C), other antioxidants, against the cardiovascular dysfunction. Hence, the use of peroxisome proliferator-activated receptor-? (PPAR ) agonists to reduce fatty acid oxidation, of trace elements such as selenium as antioxidant and other antioxidants such as vitamins E and C, contributes to the prevention of these dysfunctions. Moreover, therapy with antioxidants and the above vitamins to prevent or delay the onset and development of cardiovascular complications in diabetic patients and animal models has been investigated although these studies showed inconsistent results.
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Editorial: Tocotrienols: Potential Drug Targets For Cardiovascular, Cancer And Eurologicl Diseases
Dipak K. Das
[PMID: 21774785 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00308]

Tocotrienols are a form of vitamin E that have been under the shadow of the popular vitamin E form, α-tocopherol. There are eight forms of vitamin E: four tocopherols (alpha, beta, gamma, delta) and four tocotrienols (alpha, beta, gamma, delta). Tocorienol and tocopherol are similar in that both have the same head called chromanol nucleus, the site of antioxidant activities. Alpha-tocopherol (α-tocopherol) is the most common form in the diet, which is mainly available from many cereal, grains, and oils. Tocotrienols on the other hand are only minor components present in plants several sources with relatively high levels of tocotrienols include palm oil, rice bran oil and cereals. While the research on tocotrienols has been traditionally neglected, a number of the most recent studies have shown the potential of tocotrienols for the prevention of many human diseases. The studies also revealed the molecular targets of the tocotrienols and their roles in cancer, bone resorption, diabetes, cardiovascular diseases and neurological problems in both preclinical and clinical levels. Such multi-targeted role of tocotrienols in most degenerative diseases proves them to be ideal candidates for potential nutraceuticals/pharmaceutical agents.

Eight reviews are carefully selected from the authorities of tocotrienol research. In one of the reviews, Professor Kailash Prasad from the University of Saskatchewan, Saskatoon, Canada, has discussed beneficial effects of tocotrienols in cardiovascular health. The review emphasis the effects of tocotrienols on the risk factors for atherosclerosis, plaque instability and thrombogenesis and compared these effects with those of tocopherol. The cardio protective effects of tocotrienols on ischemic injury and its potential beneficial effects on the patients undergoing angioplasty, stent implantation and aorto-coronary bypass surgery are discussed. The authors recognized that although tocotrienols possess potential for cardiovascular health, long-term randomized clinical trial are needed to establish their efficacy in primary and secondary prevention of coronary heart disease.

The second review by Professor Belma Turan of the Ankara University and Professor Guy Vassort of the INSERM U, Montpellier, France, deals with the antioxidant action of tocopherols and tocotrienols. This review has recognized the fact that tocotrienols possess antioxidative properties 1600 times more than tocopherols and only tocotrienols in nanomolar concentration can protect neuronal cells from glutamate-induced cell death ( ). The authors have emphasized the use of optimal doses of tocopherol/tocotrienols because at high dosage of over 400 IU/day vitamin E may increase all-cause mortality and should be avoided. At higher doses only vitamin E does not show any health benefits, it is associated with an increase in total mortality, heart failure and hemorrhagic shock ( ).

The next review by Professor Vasanthi and Dr. Parameswai from Pondicherry University and Professor Dipak K Das from the University of Connecticut School of Medicine, U.S.A. have discussed the importance of tocotrienols in cardiovascular health based on their mechanisms of action. This review discusses how antagonizing the oxidation of low-density lipoproteins inhibition of platelet aggregation is secondary to inhibition of monocyte adhesion and prevention of smooth muscle proliferation. This review recognizes the importance of gamma tocotrienol in heart diseases. A multitude of cardiovascular diseases can be prevented with gamma tocotrienol including hypercholesterolemia, atherosclerosis, ischemic heart disease, hypertension, diabetes and obesity. The supplementation of gamma tocotrienol appears to be essential as dietary sources can provide very little amount of tocotrienol.

Wilankar et al from the Bhaba Atomic Research Center, BARC, and the University of Wisconsin-Madison, Wisconsin, USA, discusses the chemopreventive and chemotherapeutic roles of tocotrienols in the next review. It is a highly original paper, which examined the potential of α-tocotrienol and γ-tocotrienol in inhibiting the proliferation of human T cell lymphoma Jurkat cells and elucidation of pathways involved in anti-tumor effects of γ-tocotrienol. Only γ-tocotrienol, but not α-tocotrienol inhibited proliferation and induced apoptosis in Jurkat cells in a dos dependent manner. Their results show antitumor effects of γtocotrienol in human lymphoma cells via increased mitochondrial reactive oxygen species generation and activation of both intrinsic and extrinsic apoptotic pathways.

The authors of the next review are from Japan led by renowned scientist Professor Hideyuki J. Majima who discussed about the effects of vitamin E on oxidative stress-related diseases. He has provided the results of a number of clinical trial with α-tocopherol. For example, the results of clinical trial with Vitamin E on amyotrophic lateral sclerosis (ALS) from 5 cohort studies with 1,055,546 patients showed that only 805 had developed ALS. The authors concluded that in this large pooled prospective study, long-term vitamin E supplementation was associated with lower ALS rates. He has shown how α-tocopherol reduces production of reactive oxygen species by mitochondria and elicits further reactions in cells indicating that mitochondria are important targets for vitamin E family.

The next review was selected by Drs Jayeeta Bardhan and her coworkers from the Centre for Medicinal Food and Applied Nutrition of Jadavpur University about the modern form of vitamin E. i.e., tocotrienol. The authors have discussed about two more isomers of tocotrienols, desmo and didesmo tochotrienols that is exclusively present in rice bran oil. This review discusses ho these isomers can reverse ischemia/reperfusion induced cardiac dysfunction by inhibiting c-Src protein expression. They have also added the evidence that tocotrienols can prevent oxytosis and offers protection against Alzheimer's disease, Parkinson's disease and Huntington disease. In addition, antidiabetic and antiadipogenic properties of tocotrienols have been discussed in this review.

Wong Weng Yew and Lindsay Brown from the University of Southern Queensland, Australia has contributed a review on nutrapharmacology of the metabolic syndrome with tocotrienols. This review evaluates the effects of tocotrienols on the risk factors of metabolic syndrome using data from human and animal studies. Tocotrienols improved lipid profiles and decreased blood glucose and glycated hemoglobin concentrations and inhibited adipogenesis. They have specially discussed the differences in responses between tocopherols and tocotrienols in preventing obesity, diabetes, and hypertension and suggest that different receptors or signaling mechanisms may be involved for tocotrienols and tocopherols.

The last review is by Betul Catalgol et al from the Marmara University, Haydarpasa, Istanbul on the therapeutic potential of tocotrienols. They have discussed how tocotrienols can lower the apolipoprotein B and lipoprotein plasma levels. Tocotrienols with their anti-tumor effect together with anti-angiogenic and anti-thrombotic effects may serve as effective agents in cancer therapy. They have mentioned that because of insolubility in water and low stability, usage of tocotrienol in the clinic is still limited. However, increase in bioavailability with esterification has been successful, and warrants their use in clinics.

The editor of these reviews expects that all the aspects of drug targeting with tocotrienols are well covered by the reviews and the one original article is useful for using tocotrienol in the clinical arena with therapeutic amount of γ-tocotrienol. Tocotrienol still belongs to nutraceuticals, but it is now FDA approved for use as food supplement. It is hoped that in near future, tocotrienols can be used as drug and these reviews can help in designing tocotrienols as drugs.
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Gene Therapy For Lysosomal Storage Diseases: Progress, Challenges and Future Prospects
Sergey S. Seregin, and Andrea Amalfitano
[Purchase Article] [PMID: 21774776 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00309]

Lysosomal Storage Diseases (LSDs) comprise a group of over fifty inherited metabolic disorders, with their hallmark feature being deficient catabolism and accumulation (storage) of macromolecules in the lysosomes due to genetic deficiency of specific lysosomal enzymes. The combined incidence of LSDs is estimated to be ~1 in 7,000 births. LSD symptoms can vary significantly, primarily due to the nature of the gene defect (null or missense mutations) as well as which cells are affected. Cumulatively, LSDs place a significant burden on patients and their families, causing much in the way of morbidity and mortality. Currently, there is no cure for any LSD. This review will describe currently available treatment options for LSD patients, and then focus upon gene therapy prospects for various LSDs. Worldwide, researchers have accumulated significant data in humans affected by LSDs, as well as several small and large animal models. As a result, various viral and non-viral gene transfer platforms have been developed and specifically optimized to treat LSDs. In this review we will describe advances suggesting that the LSDs may be some of the most amenable diseases to treat by gene therapy based approaches. However, to overcome the several remaining limitations encountered by these approaches, a deep understanding of the biology of the LSDs is required, as well the host innate and adaptive immune responses to the act of gene transfer.
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Gene Transfer For Inherited Metabolic Disorders of The Liver: Immunological Challenges
Stephanie C. Gordts, Eline Van Craeyveld, Frank Jacobs, Bart De Geest
[FULL-TEXT INQUIRY] [PMID: 21774775 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00310]

Hepatocytes are a key target for gene transfer directed at correction of inborn errors of metabolism. The theoretical potential of hepatocyte-directed gene transfer contrasts with the hurdles for clinical translation of this technology. Innate immune responses following gene transfer are initiated by recognition of pathogen-associated molecular patterns by pattern recognition receptors like Toll-like receptors. Adaptive immune responses may constitute the most significant hurdle for efficient gene transfer. Besides the challenge imposed by adaptive immune responses against the vector and the potential problem of pre-existing immunity, immune responses against the transgene product may also constitute an obstacle.

The liver is a tolerogenic organ. Naive T cells encounter liver antigens initially in the liver, rather than in lymphoid tissue. Lymph nodes and the spleen are anatomical compartments that provide a particular microarchitecture and microenvironment for the induction of immunity. In contrast, antigen presentation in the liver takes place in a completely different microarchitecture and microenvironment. This is a key aspect of the hepatic adaptive immune tolerance induction. Consistent with the tolerogenic nature of the liver microenvironment, the risk of antibody formation against the transgene product may be limited in the setting of hepatocyte-directed gene transfer and specifically by restricting transgene expression to hepatocytes by use of hepatocyte-specific expression cassettes. However, it is unclear to which extent animal experimental data following gene transfer predict immune responses in humans. Extrapolations from animals to humans are required but should be performed with sufficient insight into the dramatic species differences of the immune system.
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Gene Therapy For Familial Hypercholesterolemia
Eline Van Craeyveld, Frank Jacobs, Stephanie C. Gordts, Bart De Geest
[Purchase Article] [PMID: 21774774 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00311]

Familial hypercholesterolemia (FH) is an inherited metabolic disorder characterized by high levels of plasma low density lipoproteins (LDL) and an increased risk of premature atherosclerosis and coronary heart disease. LDL receptor (LDLr) deficiency is the most prevalent cause of FH. Therefore, hepatocyte-directed LDLr gene transfer constitutesan important strategy for the treatment of this monogeneticdisease. Nowadays, homozygous FH patients are treated with lipid-lowering drugs complemented by plasma or LDL apheresis. Liver transplantation can restore metabolism of apolipoprotein B containing lipoproteins, butrequires lifelong immunosuppression to prevent organ rejection. Recently, significant progress in gene transfer technologyhas encouraged investigators to further develop LDLr gene transfer approaches for the treatment of FH. In experimental animal models of FH, LDLr overexpression following viral vector-based gene transfer has been shown to be associated with long-term stable correction of hyperlipidemia, with attenuation of atherosclerosis progression, and in certain cases even with lesion regression.

The first part of this review provides a thorough overview of familial hypercholesterolemia including its diagnosis, lipoprotein metabolism, and current management. In the second part, we critically review experimental LDLr gene transfer studies demonstrating the progress that has been made from the initial proof of principle studies to recent investigations showing dramatic regression of atherosclerosis in experimental models.
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Gene Transfer For Inborn Errors of Metabolism of the Liver: The Clinical Perspective
David Cassiman
[FULL-TEXT INQUIRY] [PMID: 21774773 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00312]

There are numerous inborn errors of metabolism of the liver, and they are all rare to very rare. To get a clear picture of the indications for gene transfer in these conditions, it is essential to get a clear view on the current (lack of) insight in the pathophysiology of these disorders, the current treatment options and hence on the window of opportunity for new treatments as gene transfer. The aim of this review, is to illustrate the problems related to treatment of inborn errors of metabolism of the liver. General aspects defining the quest for treatments for very rare diseases are touched upon, but for the sake of clarity, this review is restricted to five illustrative examples: Crigler-Najjar type I, the urea cycle defects, phenylketonuria, classic galactosemia and propionic acidemia. These examples reflect the problems that are currently experienced and can be expected, when gene transfer trials for these disorders are undertaken.
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Adeno-Associated Viral Vectors For Correction of Inborn Errors of Metabolism: Progressing Towards Clinical Application
Frank Jacobs, Lili Wang
[FULL-TEXT INQUIRY] [PMID: 21774772 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00313]

Gene therapy holds great promise for the treatment of inherited metabolic disease. Among different vector systems used to date, vectors based on adeno-associated virus (AAV) have shown great potentialfor systemic expression of therapeutic transgenes. The main advantages of AAV are the beneficialsafety profile and the possibility to generate long-term transgene expression withoutthe necessity for chromosomal integration. Successful transduction of hepatocytes in the absence of immunological complications has been achieved in a number of animal species, including mice, dogs and nonhuman primates. Despite this plethora of successfulstudies, clinical applications have been lagging.Up to date, one clinical trial for liver-directed gene transfer has been performed and results underscored the important role of neutralizing antibodies towards the AAV capsid and the generation of cytotoxic T cell responses against transduced hepatocytes. Recently, a wide variation of novel AAV serotypes has emerged that shows great promise for improved gene transfer efficiency. However, one important factor hampering clinical progress has been the large degree of variability in terms of transduction efficiency and transgene expression levels of different AAV serotypes and the subsequent difficulties in the selection of a single serotype for clinical development. The aim of this review is to critically reevaluate pre-clinical data obtained in animal models of metabolic diseases in light of the progress that has been achieved in liver-directed gene transfer using AAV vectors. Using this evidence-based rationale, wehave selected AAV8 as the serotype that combines the most favorable features for clinical applications of hepatic gene transfer.
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Retroviral Vector-Mediated Gene Therapy For Metabolic Diseases: An Update
Nicolas Ferry, Virginie Pichard, Dominique Aubert Sébastien Bony and Tuan Huy Nguyen
[FULL-TEXT INQUIRY] [PMID: 21774771 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00314]

Retroviral vectors have been used for several decades for the transfer of therapeutic genes to various cells or organs including the liver. Initial studies aimed at treating inherited liver deficiencies were carried out with murine oncoretroviral vectors either delivered directly to the organ or using an ex vivo strategy that entailed harvest of the hepatocytes, transduction during a culture phase and further reinfusion to the patient. However, although a clinical trial was performed in the early 1990s, a complete cure of animal models of metabolic diseases was rarely achieved. The advent of lentiviral vectors derived from HIV1 profoundly changed the field and this vector type now appears to be of the most attractive for liver directed gene therapy. Indeed, lentiviral vectors do not require complete cell division to transduce the target cells. There are however still bottlenecks that limit the clinical development of gene therapy using retroviral vectors. In the present review we will specifically focus on specific aspects such as the risk of insertional mutagenesis, the potential requirement of cell cycle activation to enhance transduction and the major issue of an immune response directed against the transgene as well as some specific aspects of ex vivo gene transfer. Finally we will briefly consider the future developments of these vectors made possible by the availability of new techniques in cell and molecular biology.
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Perinatal gene transfer to the liver
Tristan R. McKay, Ahad A. Rahim, Suzanne M.K. Buckley, Natalie J. Ward, Jerry K.Y.Chan, Steven J. Howe, Simon N. Waddington
[Purchase Article] [PMID: 21774770 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00315]

The liver acts as a host to many functions hence raising the possibility that any one may be compromised by a single gene defect. Inherited or de novo mutations in these genes may result in relatively mild diseases or be so devastating that death within the first weeks or months of life is inevitable. Some diseases can be managed using conventional medicines whereas others are, as yet, untreatable. In this review we consider the application of early intervention gene therapy in neonatal and fetal preclinical studies. We appraise the tools of this technology, including lentivirus, adenovirus and adeno-associated virus (AAV)-based vectors. We highlight the application of these for a range of diseases including hemophilia, urea cycle disorders such as ornithine transcarbamylase deficiency, organic acidemias, lysosomal storage diseases including mucopolysaccharidoses, glycogen storage diseases and bile metabolism. We conclude by assessing the advantages and disadvantages associated with fetal and neonatal liver gene transfer.
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Liver-Directed Gene Therapy with Helper-Dependent Adenoviral Vectors: Current State of the Art and Future Challenges
Francesco Vetrini and Philip Ng
[FULL-TEXT INQUIRY] [PMID: 21774769 PubMed - indexed for MEDLINE] [BSP/CPD/E-Pub/00316]

Successful liver-directed gene therapy has the potential to revolutionize medicine. Helper-dependent adenoviral vectors (HDAds) are devoid of all viral coding sequences and have shown tremendous potential for liver-direct gene therapy. In small and large animals, hepatic transduction with HDAd has resulted in high level, long-term transgene expression without chronic toxicity in a variety of disease models. Recent advancements in the large-scale manufacture of HDAd have permitted contemplation of clinical application. However, dose-dependent activation of the host innate inflammatory response remains an obstacle for clinical translation. Recent advancements in vector capsid modifications, immune modulation regimes, as well as novel routes of vector administration may yet permit clinical liver-directed gene therapy with HDAd.
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Molecular targeted approaches for treatment of pancreatic cancer
Z.-q. Huang, A.K. Saluja, V. Dudeja, S.M. Vickers, and D.J. Buchsbaum
[FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00317]

Human pancreatic cancer remains a highly malignant disease with almost similar incidence and mortality despite extensive research.  Many targeted therapies are under development.  However, clinical investigation showed that single targeted therapies and most combined therapies were not able to improve the prognosis of this disease, even though some of these therapies had excellent anti-tumor effects in pre-clinical models.  Cross-talk between cell proliferation signaling pathways may be an important phenomenon in pancreatic cancer, which may result in cancer cell survival even though some pathways are blocked by targeted therapy.  Pancreatic cancer may possess different characteristics and targets in different stages of pathogenesis, maintenance and metastasis.  Sensitivity to therapy may also vary for cancer cells at different stages.  The unique pancreatic cancer structure with abundant stroma creates a tumor microenvironment with hypoxia and low blood perfusion rate, which prevents drug delivery to cancer cells.  In this review, the most commonly investigated targeted therapies in pancreatic cancer treatment are discussed.  However, how to combine these targeted therapies and/or combine them with chemotherapy to improve the survival rate of pancreatic cancer is still a challenge.  Genomic and proteomic studies using pancreatic cancer samples obtained from either biopsy or surgery are recommended to individualize tumor characters and to perform drug sensitivity study in order to design a tailored therapy with minimal side effects.  These studies may help to further investigate tumor pathogenesis, maintenance and metastasis to create cellular expression profiles at different stages.  Integration of the information obtained needs to be performed from multiple levels and dimensions in order to develop a successful targeted therapy.
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New Perspectives in Glioma Immunotherapy
Antonio Daga, Cristina Bottino, Roberta Castriconi, Rosaria Gangemi, Silvano Ferrini
[FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00318]

Glioblastoma (GBM) is a deadly tumor, which in spite of surgery and radio/chemotherapy frequently undergoes relapses related to the infiltration of the normal parenchyma and to resistance to cytotoxic and radiation therapy. Immunotherapy may represent a promising approach, which may complement existing therapies with the aim of eliminating residual tumor cells, through their selective targeting by immune effector cells or antibodies. This goal can be achieved through different approaches, based either on the induction of an immune response of the host, or by the injection of in vitro generated effector cells or monoclonal antibodies. Recent advances in the immunobiology of GBM and of its stem cell compartment will help in the development of more effective immunotherapy protocols. To this aim, the identification of antigens and receptors involved in GBM/immune cell interactions and of GBM immune escape mechanisms will provide new targets and tools. In this review we will discuss active immunotherapy approaches, including molecular-defined, GBM cell-based and dendritic-cell based vaccines. In addition, cytokines such as interferons and several interleukins can be used to enhance the immune response, both as recombinant molecules and by gene transfer technologies. Monoclonal antibodies or other ligands specific for GBM- or neovasculature-associated targets are now available in different genetically modified formats and can be used as such or for the targeted delivery of active compounds. Finally the in vitro activation and expansion of specific or innate immunity effector cells endowed with anti-GBM properties may provide an additional weapon for adoptive imunotherapy approaches.
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Preclinical Development of Novel Anti-Glioma Drugs Targeting the Endoplasmic Reticulum Stress Response
Axel H. Schönthal, Thomas C. Chen, Florence M. Hofman, Stan G. Louie, Nicos A. Petasis
[FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00319]

The endoplasmic reticulum (ER) stress response represents a cellular “yin-yang” process, where low to moderate activity is cell protective and supports chemoresistance (yang), but where more severe conditions will aggravate these mechanisms to the point where they abandon their protective efforts and instead turn on a cell death program (yin). Because tumor cells frequently experience chronic stress conditions (due to hypoxia, hypoglycemia, acidification, etc.), the protective yang components of their ER stress response are continuously engaged and thus less able to neutralize additional insults taxing the ER stress response. This tumor-specific situation may provide therapeutic opportunities for pharmacologic intervention, where further aggravation of ER stress would lead to the activation of pro-apoptotic yin components and result in tumor cell death. This review will describe the yin-yang principle of ER stress, and will present pharmacologic agents and combination strategies aimed at exploiting the ER stress response for improved therapeutic outcomes, particularly in the setting of difficult to treat tumor types such as glioblastoma.
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Bioenergetics pathways and therapeutic resistance in gliomas: emerging role of mitochondria
Corinne E. Griguer and Claudia R. Oliva
[FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00320]

Cancer metabolism has gained considerable interest, since significant studies have indicated a close relationship between the activation of various oncogenes and alterations of cellular metabolism. Furthermore, several lines of evidence have shown that metabolic imaging can significantly impact malignant glioma patient management and monitoring of tumor response to therapy. In this context, mitochondria play a central role in cellular energy production, apoptosis and free radical generation. Mitochondrial malfunctions have been associated with development of many cancers, including brain tumors. Glioblastoma multiforme (GBM) is the most common primary intracranial neoplasm and its almost uniform lethality is exemplified by a median survival of 12-15 months. Current management consists of a combination of surgery, radiotherapy and chemotherapy. Despite aggressive treatment approaches, recurrence occurs in 90% of GBM patients. One cause of this poor outcome is development of a multidrug-resistance (MDR) phenotype. We and others have described in detail the bioenergetic pathways central to glioma growth and progression. One of the most striking observations is that glioma cells which rely on glycolytic metabolism readily adapt to bioenergetic stress by engaging their mitochondrial pathway in order to survive and grow.  This suggests that mitochondrial function plays a critical role in the biology of gliomas. Still, the role that mitochondrial function has in development of chemoresistance in malignant brain tumors is largely unknown. Our goal in this review is to describe the current knowledge on the role of mitochondria function in the development of chemoresistance in glioma. Particular emphasis will be on ABC transporters.

 We will discuss the significance of these research areas in the context of development of more effective, targeted therapeutic modalities and diagnostic strategies for malignant glioma patients.
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Collateral Damage Control in Cancer Therapy: Defining the Stem Identity in Gliomas
David Hsieh
[FULL-TEXT INQUIRY] [BSP/CPD/E-Pub/00321]

The discovery of discrete functional components in cancer systems advocates a paradigm shift in the