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Three decades of P-gp inhibitors: skimming through several generations and scaffolds
A. Palmeira, E Sousa, M. H. Vasconcelo and M. M. Pinto
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00268]


Nonmuscle Myosin Heavy Chain and Histone H3 are Intracellular Binding Partners of Lithospermic Acid B and Mediate its Antiproliferative Effect on VSMCs
Y. H. Cho, E.Y. Lim, J.M. Kim, M. Jung, H.C. Lee, M.R. Seo and E.J. Lee
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00272]


Editorial: Pharmacotherapeutic Implications of Host-Pathogen Interactions: Emerging Concepts
Petr Heneberg

Guest Editor:
Petr Heneberg
Third Faculty of Medicine
Charles University in Prague
Ruská 87
CZ-100 00 Prague
Czech Republic
Tel: 00420-775 311 177
E-mail: petr.heneberg@lf3.cuni.cz
[BSP/CMC/E-Pub/00295]


Inflammatory Responses to Respiratory Syncytial Virus (RSV) Infection and the Development of Immunomodulatory Pharmacotherapeutics
H.F. Rosenberg and J.B. Domachowske
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00296]


Mast Cells as Critical Effectors of Host Immune Defense against Gram-negative Bacteria
T. Matsuguchi
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00297]


Leishmaniasis: Prevention, Parasite Detection and Treatment
T. Kobets, I. Grekov and M. Lipoldová
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00298]


Redox Regulation in Malaria: Current Concepts and Pharmacotherapeutic Implications
M. Goyal, A. Alam and U. Bandyopadhyay
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00299]


Current Advances in Detection and Treatment of Babesiosis
J. Mosqueda, A. Olvera, G. Aguilar-Tipacamú and G.J. Cantó
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00300]


Reactive Oxygen Production Induced by the Gut Microbiota: Pharmacotherapeutic Implications
R.M. Jones, J.W. Mercante and A.S. Neish
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00301]


Finding the Smoking Gun: Protein Tyrosine Phosphatases as Tools and Targets of Unicellular Microorganisms and Viruses
P. Heneberg
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00302]


Granulocytes in Helminth Infection - Who is Calling the Shots?
B.L. Makepeace, C. Martin, J.D. Turner and S. Specht
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00303]


Non-Alcoholic Steatohepatitis: What Can We Learn from Animal Models?
C. C. Almonacid-Urrego, S. Sánchez-Campos, M.J. Tuñón and J. González-Gallego
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00304]


Update on the Slow Delayed Rectifier Potassium Current (IKs): Role in Modulating Cardiac Function
Zhenzhen Liu, Lupei Du and Minyong Li
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00305]


Plant Polyphenols and Oral Health: Old Phytochemicals for New Fields
E.M. Varoni, G. Lodi, A. Sardella, A. Carrassi and M. Iriti
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00306]


Converting Peptides into Drug Leads by Lipidation
L. Zhang and G. Bulaj
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00307]


Privileged Structures – Dream or Reality: Preferential Organization Of Azanaphthalene Scaffold
Jaroslaw Polanski, Agata Kurczyk, Andrzej Bak and Robert Musiol
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00308]


Role of Ligand-Based Drug Design Methodologies toward the Discovery of New Anti-Alzheimer Agents: Futures Perspectives in Fragment-Based Ligand Design
Alejandro Speck-Planche, Feng Luan and M. Natália D.S. Cordeiro
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00309]


Molecular Property Filters Describing Pharmacokinetics and Drug Binding
A.T. García-Sosa, U. Maran and C. Hetényi
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00310]


Molecular docking of opiates and opioid peptides, a tool for the design of selective agonists and antagonists, and for the investigation of atypical ligand-receptor interactions
Luca Gentilucci, Alessandra Tolomelli, Rossella De Marco and Roberto Artali
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00311]


Ion Pore Formation in Lipid Bilayers and Related Energetic Considerations
Ashrafuzzaman and J. Tuszynski
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00312]


Possible Involvement of Angiogenesis in Chronic Liver Disease: Interaction among Renin-Angiotensin-Aldosterone System, Insulin Resistance and Oxidative Stress
K. Kaji, H. Yoshiji, Y. Ikenaka, R. Noguchi, Y. Aihara, Y. Shirai, A. Douhara and H. Fukui
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00313]


The Protective Effects of Natural Products on Blood-Brain Barrier Breakdown
A. Kam, K.M. Li, V. Razmovski-Naumovski, S. Nammi, K. Chan, Y. Li and G.Q. Li
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00314]


Cognitive, Psychological and Psychiatric Effects of Ionizing Radiation Exposure
D. Marazziti, S. Baroni, M. Catena-Dell’Osso, D. Ceresoli, L. Dell’Osso, C. Conversano and E. Picano
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00315]


Selective Serotonin Reuptake Inhibitors (SSRIs): Therapeutic Drug Monitoring and Pharmacological Interactions
R. Mandrioli, L. Mercolini, M.A. Saracino and M.A. Raggi
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00316]


UDP-3-O-(R-3-hydroxymyristoyl)-N-Acetylglucosamine Deacetylase (LpxC) Inhibitors: A New Class of Antibacterial Agents
J. Zhang, L. Zhang, X. Li and W. Xu
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00317]


How is Gene Transfection Able to Improve Current Chemotherapy? The Role of Combined Therapy in Cancer Treatment
J. Prados, P.J. Álvarez, C. Melguizo, F. Rodriguez-Serrano, E. Carrillo, H. Boulaiz, C. Vélez, J.A. Marchal, O. Caba, R. Ortiz, A. Rama and A. Aranega
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00318]


Novel Patented Src Kinase Inhibitor
Xiao-Ling Lu, Xiao-Yu Liu, Xin Cao and Bing-Hua Jiao
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00319]


Modulation of Inflammatory Immune Reactions by Low-Dose Ionizing Radiation: Molecular Mechanisms and Clinical Application
F. Rödel, B. Frey, U. Gaipl, L. Keilholz, C. Fournier, K. Manda, H. Schöllnberger, G. Hildebrandt and C. Rödel
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00320]


Induction of Abscopal Anti-Tumor Immunity and Immunogenic Tumor Cell Death by Ionizing Irradiation – Implications for Cancer Therapies
B. Frey, Y. Rubner, R. Wunderlich, E.-M. Weiss, A.G. Pockley, R. Fietkau and U.S. Gaipl
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00321]


The Effect of Chemotherapy/Radiotherapy on Cancerous Pattern Recognition by NK Cells
B. Rosental, M.Y. Appel, R. Yossef, U. Hadad, M. Brusilovsky and A. Porgador
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00322]


Radiation-Induced Stress Proteins – the Role of Heat Shock Proteins (HSP) in Anti-Tumor Responses
T.E. Schmid and G. Multhoff
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00323]


The Interaction of NK Cells and Dendritic Cells in the Tumor Environment: How to Enforce NK Cell & DC Action Under Immunosuppressive Conditions?
B. Jacobs and E. Ullrich
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00324]


ChemoImmunoModulation: Immune Regulation by the Antineoplastic Chemotherapeutic Agents
M.R. Shurin, H. Naiditch, D.W. Gutkin, V. Umansky and G.V. Shurin
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00325]


In Vitro – In Vivo Correlation of Gene Expression Alterations Induced by Liver Carcinogens
T. Heise, M. Schug, D. Storm, H. Ellinger-Ziegelbauer, H.J. Ahr, B. Hellwig, J. Rahnenführer, A. Ghallab, G. Guenther, J. Sisnaiske, R. Reif, P. Godoy, H. Mielke, U. Gundert-Remy, A. Lampen, A. Oberemm and J.G. Hengstler
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00326]


Chemical Metabolism of Medicinal Compounds from Natural Botanicals
Q. Lu and J.-G. Jiang
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00327]


Bcl-2 Inhibitors: Emerging Drugs in Cancer Therapy
C. Bodur and H. Basaga
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00328]


Hot topic: Modulation of the Immune System by Ionizing Irradiation and Chemotherapeutic Agents – Contribution of Immune Activation and Blocking of Immune Suppression to Cancer Therapy Success
Udo S. Gaipl


Guest Editor:
Udo S. Gaipl
Department of Radiation Oncology
Radiation Immunobiology
University Hospital Erlangen
Friedrich-Alexander University of Erlangen-Nürnberg
Universitätsstr. 27
91054 Erlangen
Germany
Tel: +49-9131-85-32311
Fax: + 49-9131-85-39335
E-mail: udo.gaipl@uk-erlangen.de
[BSP/CMC/E-Pub/00329]


Hot topic: Coming Back to Nature: Plants as a Vital Source of Pharmaceutically Important Metabolites
Milen I. Georgiev

Guest Editor:
Milen I. Georgiev
Institute of Microbiology,
Bulgarian Academy of Sciences,
139 Ruski blvd., 4000 Plovdiv,
Bulgaria,
Tel/Fax: +359 32 642 430,
E-mail: milengeorgiev@gbg.bg
[BSP/CMC/E-Pub/00330]


Power from the Garden: Plant Compounds as Inhibitors of the Hallmarks of Cancer
B. Orlikova and M. Diederich
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00331]


Anti-Inflammatory Agents from Plants: Progress and Potential
M.C. Recio, I. Andújar and J.L. Ríos
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00332]


Anti-Inflammatory Iridoids of Botanical Origin
A. Viljoen, N. Mncwangi and I. Vermaak
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00333]


The Potential of Secondary Metabolites from Plants as Drugs or Leads Against Protozoan Neglected Diseases – Part I
T.J. Schmidt, S.A. Khalid, A.J. Romanha, T.M.A. Alves, M.W. Biavatti, R. Brun, F.B. Da Costa, S.L. de Castro, V.F. Ferreira, M.V.G. de Lacerda, J.H.G. Lago, L.L. Leon, N.P. Lopes, R.C. das Neves Amorim, M. Niehues, I.V. Ogungbe, A.M. Pohlit, M.T. Scotti, W.N. Setzer, M. de N.C. Soeiro, M. Steindel and A.G. Tempone
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00334]


The Potential of Secondary Metabolites from Plants as Drugs or Leads Against Protozoan Neglected Diseases - Part II
T.J. Schmidt, S.A. Khalid, A.J. Romanha, T.M.A. Alves, M.W. Biavatti, R. Brun, F.B. Da Costa, S.L. de Castro, V.F. Ferreira, M.V.G. de Lacerda, J.H.G. Lago, L.L. Leon, N.P. Lopes, R.C. das Neves Amorim, M. Niehues, I.V. Ogungbe, A.M. Pohlit, M.T. Scotti, W.N. Setzer, M. de N.C. Soeiro, M. Steindel and A.G. Tempone
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00335]


Nature Against Depression
A.T. El-Alfy, E.A. Abourashed and R.R. Matsumoto
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00336]


Phytochemicals from Plants to Combat Cardiovascular Disease
H.R. Vasanthi, N. ShriShriMal and D.K. Das
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00337]


Current Concepts on Selected Plant Secondary Metabolites With Promising Inhibitory Effects Against Enzymes Linked to Alzheimer’s Disease
I.E. Orhan
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00338]


Novel Tyrosinase Inhibitors From Natural Resources – Their Computational Studies
M.T.H. Khan
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00339]


Modulation of k-Ras Signaling by Natural Products
S.B. Bharate, B. Singh and R.A. Vishwakarma
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00340]


Chios Gum Mastic: A Review of its Biological Activities
S. Paraschos, S. Mitakou and A.-L. Skaltsounis
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00341]


An Artificial Neural Network Model for Predicting the Subcellular Localization of Photosensitisers for Photodynamic Therapy of Solid Tumours
R. Tejedor-Estrada, S. Nonell, J. Teixidó, M.L. Sagristá, M. Mora, A. Villanueva, M. Cañete and J.C. Stockert
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00342]


Activity of Epiisopiloturine Against Schistosoma mansoni
L.M. Veras, M.A. Guimarães, Y.D. Campelo, M.M. Vieira, C. Nascimento, D. F. Lima, L. Vasconcelos, E. Nakano, S.S. Kuckelhaus, M.C. Batista, J.R. Leite and J. Moraes
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00343]


Mitochondrial Disturbances, Tryptophan Metabolites and Neurodegeneration: Medicinal Chemistry Aspects
L. Szalárdy, P. Klivényi, D. Zádori, F. Fülöp, J. Toldi and L. Vécsei
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00344]


Syntheses and In-vitro Evaluation of Novel Adamantane Based γ-Secretase Inhibitors
Adegoke O. Adeniji, Ryan M. Wells and Adeboye Adejare
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00345]


Recent Advances in the Research of 2,3-Diaryl-1,3-thiazolidin-4-one Derivatives as Potent HIV-1 Non-nucleoside Reverse Transcriptase Inhibitors
Ye Tian, Peng Zhan, Diwakar Rai, Jiyan Zhang, Erik De Clercq and Xinyong Liu
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00346]


Bifunctional Chelators in the Design and Application of Radiopharmaceuticals for Oncological Diseases
Dikran Sarko, Michael Eisenhut, Uwe Haberkorn and Walter Mier
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00347]


Iron Chelators for the Treatment of Cancer
Yu Yu, Elaine Gutierrez, Zaklina Kovacevic, Federica Saletta, Peyman Obeidy, Yohan Suryo Rahmanto and Des R. Richardson
[Abstract] [Purchase Article] [BSP/CMC/E-Pub/00348]


Deciphering the Antimicrobial Activity of Phenanthroline Chelators
Malachy McCann, Andrew Kellett, Kevin Kavanagh, Michael Devereux and André L. S. Santos
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00349]


Antimicrobial Action of Chelating Agents: Repercussions on the Microorganism Development, Virulence and Pathogenesis
André L.S. Santos, Cátia L. Sodré , Roberta S. Valle , Bianca A. Silva , Érika A. Abi-chacra , Lívia V. Silva , Ana Luiza Souza-Gonçalves , Leandro S. Sangenito , Diego S. Gonçalves , Lucieri O.P. Souza , Vanila F. Palmeira, Claudia M. d’Avila-Levy , Lucimar F. Kneipp , Andrew Kellett , Malachy McCann and Marta H. Branquinha
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00350]


Metal transport and homeostasis within the human body. Toxicity associated with transport abnormalities
Slawomir Potocki, Magdalena Rowinska-Zyrek, Danuta Witkowska, Monika Pyrkosz, Agnieszka Szebesczyk, Karolina Krzywoszynska and Henryk Kozlowski
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00351]


Hydroxypyri(mi)dine-based chelators as antidotes of toxicity due to Aluminium and Actinides
M Amélia Santos,M Alexandra Esteves and Sílvia Chaves
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00352]


Chelating agents for metal intoxication
Guido Crisponi, Valeria Marina Nurchi Miriam Crespo Alonso and Leonardo Toso
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00353]


Chelating agents for the treatment of systemic iron overload
Yongmin Ma, Tao Zhou, Xiaole Kong and Robert C Hider
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00354]


Selective Divalent Copper Chelation for the Treatment of Diabetes Mellitus
Garth J S Cooper
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00355]


Hot Topic: Chelating agents in different human diseases
Guest Editor: Valeria Marina Nurchi


Valeria Marina Nurchi
Dipartimento di ScienzeChimiche
UniversitàdegliStudi di Cagliari
CittadellaUniversitaria
09042 Monserrato-Cagliari
Italia
Email: nurchi@unica.it
[BSP/CMC/E-Pub/00356]


Sirtuin Modulators: Mechanisms and Potential Clinical Implications
S. Sánchez-Fidalgo, I.V. Lama, M. Sánchez-Hidalgo and C.A. de la Lastra
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00356]


CuAAC Click Chemistry Accelerates the Discovery of Novel Chemical Scaffolds as Promising Protein Tyrosine Phosphatases Inhibitors
X.-P. He, J. Xie, Y. Tang, J. Li and G.-R. Chen
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00357]


Supramolecular Approaches for Drug Development
K. Kawakami, M. Ebara, H. Izawa, N.M. Sanchez-Ballester, J.P. Hill and K. Ariga
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00358]


Recent Advances in the Development of 14-Alkoxy Substituted Morphinans as Potent and Safer Opioid Analgesics
M. Spetea and H. Schmidhammer
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00359]


Role of microRNAs in Gynecological Pathology
J. Gilabert-Estellés, A. Braza-Boïls, L.A. Ramón, E. Zorio, P. Medina, F. España and A. Estellés
[Abstract] [Purchase Article] [BSP/CMC/E-Pub/00360]


The Quinoline Imidoselenocarbamate EI201 Blocks AKT/mTOR Pathway and Targets Cancer Stem Cells Leading to a Strong Antitumor Activity
E. Ibáñez, A. Agliano, C. Prior, P. Nguewa, M. Redrado, I. González, D. Plano, J.A. Palop, C. Sanmartín and A. Calvo
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00361]


Cadmium and Its Epigenetic Effects
B. Wang, Y. Li, C. Shao, Y. Tan and L. Cai
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00362]


Hot Topic: Transthyretin: A Small Protein in the Big World of Amyloidoses
Guest Editors: Adriano Martinelli and Gabriella Ortore


Adriano Martinelli
Dip. Scienze Farmaceutiche
Via Bonanno 6,
56126 PISA
Tel ++39 050 2219556
E-mail marti@farm.unipi.it

Gabriella Ortore
Dip. Scienze Farmaceutiche
Via Bonanno 6,
56126 PISA
Tel ++39 050 2219572
E-mail ortore@farm.unipi.it
[BSP/CMC/E-Pub/00363]


Diagnosis and Therapeutic Approaches to Transthyretin Amyloidosis
Y. Ando and M. Ueda
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00364]


Nearly 200 X-Ray Crystal Structures of Transthyretin: What Do They Tell Us About This Protein and the Design of Drugs for TTR Amyloidoses?
S.K. Palaninathan
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00365]


Transthyretin Deposition in Familial Amyloidotic Polyneuropathy
M.J. Saraiva, J. Magalhães, N. Ferreira and M. R. Almeida
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00366]


Methods to Evaluate the Inhibition of TTR Fibrillogenesis Induced by Small Ligands
G. Arsequell and A. Planas
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00367]


TTR Fibril Formation Inhibitors: Is there a SAR?
S. Nencetti and E. Orlandini
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00368]


Computational Studies on Transthyretin
G. Ortore and A. Martinelli
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00369]


Clinical utility of biomarkers in premature atherosclerosis
Anna-Maria Kampoli, Dimitris Tousoulis, Nikolaos Papageorgiou, Zoi Pallatza, Georgia Vogiatzi, Alexandros Briasoulis, Emmanouel Androulakis, Costas Toutouzas, Pavlos Stougianos, Costas Tentolouris and Christodoulos Stefanadis
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00370]


Evaluating oxidative stress in human cardiovascular disease: Methodological aspects and considerations
Regent Lee, Marios Margaritis, Keith M Channon and Charalambos Antoniades
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00371]


Assessment of Acute Coronary Syndromes: Focus on Novel Biomarkers
Dimitris Tousoulis, George Hatzis, Nikolaos Papageorgiou, Emmanuel Androulakis, George Bouras, Anastasios Giolis, Konstantinos Bakogiannis, Gerasimos Siasos, George Latsios, Charalambos Antoniades and Christodoulos Stefanadis
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00372]


Predictive Value of Biomarkers in Patients with Heart Failure
Dimitris Tousoulis, Evangelos Oikonomou, Gerasimos Siasos, Evangelos D. Papadimitriou, Maria Limperi, Christina Chrysohoou, Marietta Charakida, Athanasios Trikas, Athanasios G. Papavassiliou and Christodoulos Stefanadis
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00373]


Monitoring Calcific Aortic Valve Disease: The Role of Biomarkers
George Latsios, Dimitris Tousoulis, Emmanuel Androulakis, Nikolaos Papageorgiou, Andreas Synetos, Costas Tsioufis,  Kostas Toutouzas and Christodoulos Stefanadis
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00374]


Biomarkers Determining Cardiovascular Risk in Patients with Kidney Disease
Gerasimos Siasos, Dimitris Tousoulis, Stavroula Michalea, Evangelos Oikonomou, Christina Kolia, Stamatis Kioufis, Andreas Synetos, Athanasios G. Papavassiliou and Christodoulos Stefanadis
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00375]


Circulating endothelial progenitor cells as biomarkers for prediction of cardiovascular outcomes
Konstantinos Bakogianis, Dimitris Tousoulis, Emmanuel Androulakis, Alexandros Briasoulis, Nikolaos Papageorgiou, Georgia Vogiatzi, Anna-Maria Kampoli, Marietta Charakida, Gerasimos Siasos, George Latsios, Charalambos Antoniades and Christodoulos Stefanadis
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00376]


Biomarkers as a guide of medical treatment in cardiovascular diseases
Vavuranakis M, Kariori M, Kalogeras K, Vrachatis D, Moldovan C, Tousoulis D and Stefanadis C
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00377]


Functional, Genetic and Biochemical Biomarkers of Peripheral Arterial DiseaseMarietta Charakida, Stefano Masi and Dimitris Tousoulis
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00378]


The Role of microRNAs in Cardiovascular Disease
Nikolaos Papageorgiou, Dimitris Tousoulis, Emmanuel Androulakis, Gerasimos Siasos, Alexandros Briasoulis, Georgia Vogiatzi, Anna-Maria Kampoli, Eleftherios Tsiamis, Costas Tentolouris and Christodoulos Stefanadis
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00379]


Biomarkers associated with vulnerable atheromatous plaque
Toshio Imanishi and Takashi Akasaka
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00380]


Hot Topic: Biomarkers In Cardiovascular Disease
Guest Editor: Dimitris Tousoulis
[BSP/CMC/E-Pub/00381]


Chelating agents for neurodegenerative diseases
Roberta J Ward, David T Dexter and Robert R Crichton
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00382]


Compounds derived from endophytes: A review of phytochemistry and pharmacology
Rosa Martha Perez Gutierrez, Adriana Maria Neira Gonzalez and Alethia Muñiz Ramirez
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00383]


New therapeutic approaches by using microorganism-derived compounds
Amedeo Amedei and Mario Milco D'Elios
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00384]


Pitfalls in Lung Cancer Molecular Pathology: How to Limit them in Routine Practice?
M. Ilie and P. Hofman
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00385]


The Progress of Selective Fluorescent Chemosensors by Boronic Acid
S. Huang, M. Jia, Y. Xie, J. Wang, W. Xu and H. Fang
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00386]


The Chemistry and Biology of the Bryostatins: Potential PKC Inhibitors in Clinical Development
B.-F. Ruan and H.-L. Zhu
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00387]


Some Recent Approaches of Biologically Active Substituted Pyridazine and Phthalazine Drugs
M. Asif
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00388]


Disulfide Linkage: A Potent Strategy in Tumor-Targeting Drug Discovery
J. Wang, S. Li, T. Luo, C. Wang and J. Zhao
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00389]


Protocatechuic Acid and Human Disease Prevention: Biological Activities and Molecular Mechanisms
R. Masella, C. Santangelo, M. D’Archivio, G. LiVolti, C. Giovannini and F. Galvano
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00390]


Discovery of Selective Small Molecular TACE Inhibitors for the Treatment of Rheumatoid Arthritis
N.-G. Li, Z.-H. Shi, Y.-P. Tang, Wei-Li, Lian-Yin and J.-A. Duan
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00391]


Mechanisms Involved in the Protective Effects of Metformin Against Nonalcoholic Fatty Liver Disease
V.J. Barbero-Becerra, J.J. Santiago-Hernandez, F.A. Villegas-Lopez, N. Mendez-Sanchez, M. Uribe and N.C. Chavez-Tapia
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00392]


Intracellular Signaling Pathways Modulated by Phenolic Compounds: Application for New Anti-Inflammatory Drugs Discovery
G. Costa, V. Francisco, M.C. Lopes, M.T. Cruz and M.T. Batista
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00393]


Recent Advances in the Medicinal Chemistry of Aurones
R. Haudecoeur and A. Boumendjel
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00394]


Recent Progress and Future Potential for Metal Complexes as Anticancer Drugs Targeting G-quadruplex DNA
J. Zhang, F. Zhang, H. Li, C. Liu, J. Xia, L. Ma, W. Chu, Z. Zhang, C. Chen, S. Li and S. Wang
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00395]


Extraction, Characterization and In Vivo Neuromodulatory Activity of Phytosterols from Microalga Dunaliella Tertiolecta
M. Francavilla, M. Colaianna, M. Zotti, M.G. Morgese, P. Trotta, P. Tucci, S. Schiavone, V. Cuomo and L. Trabace
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00396]


Screening of 64 Tryptamines at NMDA, 5-HT1A, and 5-HT2A Receptors: A Comparative Binding and Modeling Study
M.L. Berger, R. Palangsuntikul, P. Rebernik, P. Wolschann and H. Berner
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00397]



Abstracts

Three decades of P-gp inhibitors: skimming through several generations and scaffolds
A. Palmeira, E Sousa, M. H. Vasconcelo and M. M. Pinto
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00268]

Many tumor cells become resistant to commonly used cytotoxic drugs due to the overexpression of ATP-binding cassette (ABC) transporters, namely P-glycoprotein (P-gp). The discovery of the reversal of multidrug resistance (MDR) by verapamil occuredin 1981, and in 1968MDR Chinese hamster cell lines had been isolated for the first time. Since then, P-gp inhibitors have been intensively studied as potential MDR reversers. Initially, drugs to reverse MDR were not specifically developed for inhibiting P-gp; in fact, they had other pharmacological properties, as well as a relatively low affinity for MDR transporters. An example of this first generation P-gp inhibitors is verapamil. The second generation included more specific with less side-effect inhibitors, such as dexverapamil or dexniguldipine. A third generation of P-gp inhibitors comprised compounds such as tariquidar, with high affinity to P-gp at nanomolar concentrations. These generations of inhibitors of P-gp have been examined in preclinical and clinical studies; however, these trials have largely failed to demonstrate animprovement in therapeutic efficacy. Therefore, new and innovative strategies, such as the fallback to natural products, the design of peptidomimetics and dual activity ligands emerged as a fourth generation of P-gp inhibitors. The chemistry of P-gp inhibitors, as well as theirin vitro, in vivo and clinical trialsare discussed, and the most recent advances concerning P-gp modulators are reviewed.
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Nonmuscle Myosin Heavy Chain and Histone H3 are Intracellular Binding Partners of Lithospermic Acid B and Mediate its Antiproliferative Effect on VSMCs
Y. H. Cho, E.Y. Lim, J.M. Kim, M. Jung, H.C. Lee, M.R. Seo and E.J. Lee
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00272]

Lithospermic acid B (LAB), an active component of danshen, is known to inhibit the proliferation of vascular smooth muscle cells (VSMCs) and has pharmacological activity scavenging free radicals in VSMCs. However, the precise mechanism through which LAB exerts its antiproliferative effect is unclear. Therefore, we investigated how LAB regulates cellular proliferation in primary cultured rat VSMCs. Using fluorescein isothiocyanate (FITC)-conjugated LAB to track its cellular localization, we show that LAB localizes to the nucleus, specifically to the nucleolus, where it binds to histone H3, leading to the inhibition of the platelet-derived growth factor (PDGF)-induced phosphorylation of histone H3. LAB also only moves into the nucleus during the normal expression of nonmuscle myosin heavy chain (NMHC-IIA), which is associated with LAB in VSMCs. Notably, LAB suppressed the PDGF-induced phosphorylation of Akt and the expression of cyclin D2 in the presence of NMHC-IIA expression. Knockdown of NMHC-IIA expression impeded the function of LAB, which was then unable to inhibit the PDGF-induced proliferation of VSMCs. We conclude that LAB modulates the PDGF-induced proliferation of VSMCs by interacting with NMHC-IIA, which allows LAB to localize in the nucleus and to suppress the PDGF-induced proliferation of VSMCs.
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Editorial: Pharmacotherapeutic Implications of Host-Pathogen Interactions: Emerging Concepts
Petr Heneberg

Guest Editor:
Petr Heneberg
Third Faculty of Medicine
Charles University in Prague
Ruská 87
CZ-100 00 Prague
Czech Republic
Tel: 00420-775 311 177
E-mail: petr.heneberg@lf3.cuni.cz
[BSP/CMC/E-Pub/00295]

Although the parasitology belongs to one of the longest established disciplines, the recent methodical advances led to the substantial broadening of the possibilities for the detection and treatment of parasitic diseases. However, the exact mechanisms involved in the parasite establishment and survival are frequently unclear and only recently uncovered. At the cellular level, the emerging mechanisms, discussed in this journal issue, include the newly recognized role of mast cells in the host defense against bacterial pathogens, and the role of granulocytes in the host defense against helminths. At the protein level, we discuss here the emerging role of protein tyrosine phosphatases as both targets and tools of nonmetazoan pathogens and viruses. At the level of small signaling molecules, we attempt here to highlight the role of reactive oxygen species as molecules involved both in the host defense, but also produced by some human pathogens and commensals. Scientometric analysis of the fields covered by this journal issue is provided.
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Inflammatory Responses to Respiratory Syncytial Virus (RSV) Infection and the Development of Immunomodulatory Pharmacotherapeutics
H.F. Rosenberg and J.B. Domachowske
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00296]

Respiratory syncytial virus (RSV; Family Paramyxoviridae, Genus Pneumovirus) is a major respiratory pathogen of infants and children and an emerging pathogen of the elderly. Current management of RSV disease includes monoclonal antibody prophylaxis for infants identified as high risk and supportive care for those with active infection; there is no vaccine, although several are under study. In this manuscript, we review published findings from human autopsy studies, as well as experiments that focus on human clinical samples and mouse models of acute pneumovirus infection that elucidate basic principles of disease pathogenesis. Consideration of these data suggests that the inflammatory responses to RSV and related pneumoviral pathogens can be strong, persistent, and beyond the control of conventional antiviral and anti-inflammatory therapies, and can have profound negative consequences to the host. From this perspective, we consider the case for specific immunomodulatory strategies that may have the potential to alleviate some of the more serious sequelae of this disease.
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Mast Cells as Critical Effectors of Host Immune Defense against Gram-negative Bacteria
T. Matsuguchi
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00297]

Mast cells are best known as central effector cells in IgE-mediated type I allergic diseases including asthma and hay fever. An increasing amount of evidence, however, has demonstrated that mast cells are sentinel cells playing a critical role in host defense against invading microbes. Mast cells are located immediately beneath the epithelial surfaces exposed to the outer environment, such as genitourinary and gastrointestinal tracts, skin, and airways. This review discusses recent studies on the critical roles of mast cells in host defense against Gram-negative bacterial infection. Mast cells are equipped with multiple receptors detecting the invading Gram-negative bacteria in both direct (opsonin-independent) and indirect (opsonin-dependent) mechanisms. The former includes Toll-like receptors (TLRs), CD48, and nucleotide-binding oligomerization (NOD) proteins, while the latter includes Fcγ receptors (FcγRs) and complement receptors. In addition to the detecting systems, mast cells are also armed with versatile tools to combat and kill Gram-negative bacteria. In response to the recognition of the Gram-negative bacterial infection, mast cells secrete various types of mediators which either regulate host immune system or directly attack the bacteria. Mast cells can also phagocytize and subsequently display the bacterial antigens on their cell surfaces. Moreover, recent findings have revealed the formation of extra-cellular traps by mast cells. Finally this review will especially focus on recent findings on LPS signaling in mast cells, both the functional outcome and the molecular mechanisms.
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Leishmaniasis: Prevention, Parasite Detection and Treatment
T. Kobets, I. Grekov and M. Lipoldová
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00298]

Leishmaniasis remains a public health problem worldwide, affecting approximately 12 million people in 88 countries; 50 000 die of it each year. The disease is caused by Leishmania, obligate intracellular vector-borne parasites. In spite of its huge health impact on the populations in vast areas, leishmaniasis is one of the most neglected diseases. No safe and effective vaccine currently exists against any form of human leishmaniasis. The spectrum and efficacy of available antileishmanial drugs are also limited. First part of this review discusses the approaches used for the vaccination against leishmaniasis that are based on the pathogen and includes virulent or attenuated parasites, parasites of related nonpathogenic species, whole killed parasites, parasites’ subunits, DNA vaccines, and vaccines based on the saliva or saliva components of transmitting phlebotomine vector. Second part describes parasite detection and quantification using microscopy assays, cell cultures, immunodetection, and DNA-based methods, and shows a progress in the development and application of these techniques. In the third part first-line and alternative drugs used to treat leishmaniasis are characterized, and pre-clinical research of a range of natural and synthetic compounds studied for the leishmanicidal activity is described. The review also suggests that the application of novel strategies based on advances in genetics, genomics, advanced delivery systems, and high throughput screenings for leishmanicidal compounds would lead to improvement of prevention and treatment of this disease.
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Redox Regulation in Malaria: Current Concepts and Pharmacotherapeutic Implications
M. Goyal, A. Alam and U. Bandyopadhyay
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00299]

Malaria imposes a serious threat to human and becomes more prevalent due to the emergence of drug resistant parasite. Understanding of the underlying mechanism of drug resistance and identification of novel drug targets are key effective processes for the management of malaria. Malaria parasite is highly susceptible to oxidative stress but lives in a pro-oxidant rich environment containing oxygen and iron, which produce a large amount of reactive oxygen species. Management of oxidative stress in malaria parasite is tightly regulated through active redox and antioxidant defense systems. The elevation of oxidative stress as a result of inhibition of any component of this defense system leads to redox imbalance and ultimately parasite death. Therefore, redox system plays an indispensable role for the survival of parasite within the host. Identification of key molecules, which disrupt parasite redox balance by altering key redox reactions and promote oxidative stress in parasites, would be an effective approach to develop novel antimalarial drugs. During the last few decades, contributions by researchers around the globe provide even better understanding of redox biology of malaria parasite. Here, in this review, we are highlighting the knowledge gathered so far regarding the essential redox-active processes and their components in malaria parasite to overcome elevated oxidative insults. We have also given maximum efforts to enlist currently used redox-active antimalarials, their mode of action and pharmacotherapeutic implications.
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Current Advances in Detection and Treatment of Babesiosis
J. Mosqueda, A. Olvera, G. Aguilar-Tipacamú and G.J. Cantó
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00300]

Babesiosis is a disease with a world-wide distribution affecting many species of mammals with a major impact on cattle and man. The major impact occurs in the cattle industry where bovine babesiosis has had a huge economic impact due to loss of meat and beef production of infected animals and death. Nowadays to those costs there must be added the high cost of tick control, disease detection, prevention and treatment. In almost a century and a quarter since the first report of the disease, the truth is: there is no a safe and efficient vaccine available, there are limited chemotherapeutic choices and few low-cost, reliable and fast detection methods. Detection and treatment of babesiosis are important tools to control babesiosis. Microscopy detection methods are still the cheapest and fastest methods used to identify Babesia parasites although their sensitivity and specificity are limited. Newer immunological methods are being developed and they offer faster, more sensitive and more specific options to conventional methods, although the direct immunological diagnoses of parasite antigens in host tissues are still missing. Detection methods based on nucleic acid identification and their amplification are the most sensitive and reliable techniques available today; importantly, most of those methodologies were developed before the genomics and bioinformatics era, which leaves ample room for optimization. For years, babesiosis treatment has been based on the use of very few drugs like imidocarb or diminazene aceturate. Recently, several pharmacological compounds were developed and evaluated, offering new options to control the disease. With the complete sequence of the Babesia bovis genome and the B. bigemina genome project in progress, the post-genomic era brings a new light on the development of diagnosis methods and new chemotherapy targets. In this review, we will present the current advances in detection and treatment of babesiosis in cattle and other animals, with additional reference to several apicomplexan parasites.
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Reactive Oxygen Production Induced by the Gut Microbiota: Pharmacotherapeutic Implications
R.M. Jones, J.W. Mercante and A.S. Neish
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00301]

The resident prokaryotic microbiota of the mammalian intestine influences diverse homeostatic functions, including regulation of cellular growth, maintenance of barrier function, and modulation of immune responses. However, it is unknown how commensal prokaryotic organisms mechanistically influence eukaryotic signaling networks. Recent data has demonstrated that gut epithelia contacted by enteric commensal bacteria rapidly generate reactive oxygen species (ROS). While the induced generation of ROS via stimulation of formyl peptide receptors is a cardinal feature of the cellular response of phagocytes to pathogenic or commensal bacteria, evidence is accumulating that ROS are also similarly elicited in other cell types, including intestinal epithelia, in response to microbial signals. Additionally, ROS have been shown to serve as critical second messengers in multiple signal transduction pathways stimulated by proinflammatory cytokines and growth factors. This physiologically-generated ROS is known to participate in cellular signaling via the rapid and transient oxidative inactivation of a defined class of sensor proteins bearing oxidant-sensitive thiol groups. These proteins include tyrosine phosphatases that serve as regulators of MAP kinase pathways, cytoskeletal dynamics, as well as components involved in control of ubiquitination-mediated NF-κB activation. Consistently, microbial-elicited ROS has been shown to mediate increased cellular proliferation and motility and to modulate innate immune signaling. These results demonstrate how enteric microbiota influence regulatory networks of the mammalian intestinal epithelia. We hypothesize that many of the known effects of the normal microbiota on intestinal physiology, and potential beneficial effects of candidate probiotic bacteria, may be at least partially mediated by this ROS-dependent mechanism.
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Finding the Smoking Gun: Protein Tyrosine Phosphatases as Tools and Targets of Unicellular Microorganisms and Viruses
P. Heneberg
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00302]

Protein tyrosine phosphatases (PTPs) are increasingly recognized as important effectors of host-pathogen interactions. Since Guan and Dixon reported in 1990 that phosphatase YopH serves as an essential virulence determinant of Yersinia, the field shifted significantly forward, and dozens of PTPs were identified in various microorganisms and even in viruses. The discovery of extensive tyrosine signaling networks in non-metazoan organisms refuted the moth-eaten paradigm claiming that these organisms rely exclusively on phosphoserine/phosphothreonine signaling. Similarly to humans, phosphotyrosine signaling is thought to comprise a small fraction of total protein phosphorylation, but plays a disproportionately important role in cell-cycle control, differentiation, and invasiveness. Here we summarize the state-of-art knowledge on PTPs of important non-metazoan pathogens (Listeria monocytogenes, Staphylococcus aureus, Porphyromonas gingivalis, Caulobacter crescentus, Yersinia, Synechocystis, Leishmania, Plasmodium falciparum, Entamoeba histolytica, etc.), and focus also at the microbial proteins affecting directly or indirectly the PTPs of the host (Mycobacterium tuberculosis MTSA-10, Bacillus anthracis anthrax toxin,streptococcal β protein, Helicobacter pylori CagA and VacA, Leishmania GP63 and EF-1α, Plasmodium hemozoin, etc.). This is the first review summarizing the knowledge on biological activity and pharmacological inhibition of non-metazoan PTPs, with the emphasis of those important in host-pathogen interactions. Targeting of numerous non-metazoan PTPs is simplified by the fact that they act either as ectophosphatases or are secreted outside of the pathogen. Interfering with tyrosine phosphorylation represents a powerful pharmacologic approach, and even though the PTP inhibitors are difficult to develop, lifting the fog of phosphatase inhibition is of the great market potential and further clinical impact.
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Granulocytes in Helminth Infection - Who is Calling the Shots?
B.L. Makepeace, C. Martin, J.D. Turner and S. Specht
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00303]

Helminths are parasitic organisms that can be broadly described as “worms” due to their elongated body plan, but which otherwise differ in shape, development, migratory routes and the predilection site of the adults and larvae. They are divided into three major groups: trematodes (flukes), which are leaf-shaped, hermaphroditic (except for blood flukes) flatworms with oral and ventral suckers; cestodes (tapeworms), which are segmented, hermaphroditic flatworms that inhabit the intestinal lumen; and nematodes (roundworms), which are dioecious, cylindrical parasites that inhabit intestinal and peripheral tissue sites. Helminths exhibit a sublime co-evolution with the host´s immune system that has enabled them to successfully colonize almost all multicellular species present in every geographical environment, including over two billion humans. In the face of this challenge, the host immune system has evolved to strike a delicate balance between attempts to neutralize the infectious assault versus limitation of damage to host tissues. Among the most important cell types during helminthic invasion are granulocytes: eosinophils, neutrophils and basophils. Depending on the specific context, these leukocytes may have pivotal roles in host protection, immunopathology, or facilitation of helminth establishment. This review provides an overview of the function of granulocytes in helminthic infections.
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Non-Alcoholic Steatohepatitis: What Can We Learn from Animal Models?
C. C. Almonacid-Urrego, S. Sánchez-Campos, M.J. Tuñón and J. González-Gallego
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00304]

Non-alcoholic fatty liver disease (NAFLD) is one of the most frequent causes of abnormal liver function and correlates with central adiposity, obesity, insulin resistance, the metabolic syndrome and type 2 diabetes mellitus. The pathological spectrum of NAFLD ranges from fatty liver to non-alcoholic steatohepatitis (NASH), advanced fibrosis, cirrhosis, and even hepatocellular carcinoma. Though NAFLD and NASH are becoming a major public health problem, ethical constraints on obtaining human liver tissue limit the interpretability of the data and the ability to delineate cause and effect from complex, interactive disease pathogenic pathways. Animal models of NASH can provide critical information leading to identify potential drug targets and to understand their molecular mechanisms, and are platforms for compound screening in drug development and for the assessment of novel therapeutic strategies. This review is aimed to offer an updated overview of the nutritional, genetic and pharmacologic animal models of NASH. Though the information derived from these models has clear relevance for the comprehension of the molecular basis of human disease, most of them fail to reproduce the full spectrum of liver pathology and the metabolic context that characterizes human NASH. Consequently, it is necessary to establish animal models that can best mimic the actual etiology, progression, and pathogenesis of the disease, and prove effectiveness for examining and selecting compounds with potential therapeutic benefit in NASH.
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Update on the Slow Delayed Rectifier Potassium Current (IKs): Role in Modulating Cardiac Function
Zhenzhen Liu, Lupei Du and Minyong Li
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00305]

The slow delayed rectifier current (I_Ks) is the slow component of cardiac delayed rectifier current and is critical for the late phase repolarization of cardiac action potential. This current is also an important target for Sympathetic Nervous System (SNS) to regulate the cardiac electivity to accommodate to heart rate alterations in response to exercise or emotional stress and can be up-regulated by β- adrenergic or other signal molecules. I_Ks channel is originated by the co-assembly of pore-forming KCNQ1 β-subunit and accessory KCNE1 β-subunit. Mutations in any subunit can bring about severe long QT syndrome (LQT-1, LQT-5) as characterized by deliquium, seizures and sudden death. This review summarizes the normal physiological functions and molecular basis of I_Ks channels, as well as illustrates up-to-date development on its blockers and activators. Therefore, the current extensive survey should generate fundamental understanding of the role of I_Ks channel in modulating cardiac function and donate some instructions to the progression of I_Ks blockers and activators as potential antiarrhythmic agents or pharmacological tools to determine the physiological and pathological function of I_Ks.
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Plant Polyphenols and Oral Health: Old Phytochemicals for New Fields
E.M. Varoni, G. Lodi, A. Sardella, A. Carrassi and M. Iriti
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00306]

Despite the protective role of diets rich in fruit plant polyphenols against some cancers and chronic degenerative and inflammatory diseases, insufficient emphasis has been placed on oral health. Numerous studies have aimed to ascertain the role of polyphenols in the prevention and treatment of oral diseases; however, even when in vitro evidence appears convincing, the same is not true for in vivo studies, and thus there is a general paucity of solid evidence based on animal and clinical trials. To the best of our knowledge, only two reviews of polyphenols and oral health have been published; however, neither considered the potential role of whole plant extracts, which contain mixtures of many polyphenols that are often not completely identified. In the present study, our main aim was to review the current state of knowledge (search period: January 1965 to March 2011) on the effects of plant extracts/polyphenols on oral health. We found data on grapes, berries, tea, cocoa, coffee, myrtle, chamomile, honey/propolis, aloe extracts and the three main groups of polyphenols (stilbenes, flavonoids and proanthocyanidins). Their effects on caries, gingivitis, periodontal disease, candidiasis, oral aphtae, oral mucositis, oral lichen planus, leukoplakia and oral cancer were investigated. The data suggest that there is a lack of strong evidence, in particular regarding randomized clinical trials. However, a fascinating starting point hasbeen provided by pre-clinical studies that have shown interesting activities of polyphenols against the most common oral diseases (caries,periodontitis and candidiasis), as well as in oral cancer prevention.
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Converting Peptides into Drug Leads by Lipidation
L. Zhang and G. Bulaj
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00307]

Lipidation is a posttranslational modification of proteins that has also found its use in designing peptide drugs. The presence of a lipid group in peptides modulates their hydrophobicity, secondary structures and self-assembling propensities while retaining their abilities to bind to target receptors. Lipidation improves peptides’ metabolic stability, membrane permeability, bioavailability, and changes peptides’ pharmacokinetic and pharmacodynamic properties. Herein, we review the applications of various lipidation strategies in peptide drug design, the effects of the chain length and anchor position of fatty acids in peptide lipidation, the physicochemical and biological properties of selected lipidated peptides and the synthesis strategies for peptide lipidation.
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Privileged Structures – Dream or Reality: Preferential Organization Of Azanaphthalene Scaffold
Jaroslaw Polanski, Agata Kurczyk, Andrzej Bak and Robert Musiol
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00308]

The concept of privileged structures/substructures (PS) is the idea that certain structural features produce biological effects more often than others.The PS method can be seen as an offspring of fragonomics, which is based on recent experimental measurements of protein-ligand interactions. If PS prove to be true, then chemical motives that enrich biological activity can be used when designing new drugs. However, PS remains controversial because we cannot be sure whether the excess of active structures does not result from an abundance in chemical libraries. In this review, we will focus, in particular, on the preferential organization of azanaphthalene scaffolds (AN) in drugs and natural products (NP), which are preferred by Nature in evolution. We will show that knowledge discovery in molecular databases can reveal interesting time-trends profiles for important classes of potentially privileged scaffolds. The chemical library of AN is dominated by monoaza-compounds, among which quinoline appears to be the most frequently investigated scaffold; however; more sophisticated database mining seems to indicate different PS patterns within the AN scaffold family.
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Role of Ligand-Based Drug Design Methodologies toward the Discovery of New Anti-Alzheimer Agents: Futures Perspectives in Fragment-Based Ligand Design
Alejandro Speck-Planche, Feng Luan and M. Natália D.S. Cordeiro
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00309]

Alzheimer’s disease (AD), a degenerative disease affecting the brain, is the single most common source of dementia in adults. The cause and the progression of AD still remains a mystery among medical experts. As a result, a cure has not yet been discovered, even after decade’s worth of research that started since 1906, when the disease was first identified. Despite the efforts of the scientific community, several of the biological receptors associated with AD have not been sufficiently studied to date, limiting in turn the design of new and more potent anti-AD agents. Thus, the search for new drug candidates as inhibitors of different targets associated with AD constitutes an essential part towards the discovery of new and more efficient anti-AD therapies. The present work is focused on the role of the Ligand-Based Drug Design (LBDD) methodologies which have been applied for the elucidation of new molecular entities with high inhibitory activity against targets related with AD. Particular emphasis is given also to the current state of fragment-based ligand approaches as alternatives of the Fragment-Based Drug Discovery (FBDD) methodologies. Finally, several guidelines are offered to show how the use of fragment-based descriptors can be determinant for the design of multi-target inhibitors of proteins associated with AD.
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Molecular Property Filters Describing Pharmacokinetics and Drug Binding
A.T. García-Sosa, U. Maran and C. Hetényi
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00310]

Drug-target binding affinity and pharmacokinetics are equally important factors of drug design. Simple molecular properties such as molecular size have been used as pharmacokinetic and/or drug-likeness filters during chemical library design and also correlated with binding affinity. In the present study, current property filters are reviewed, a collection of their optimal values is provided, and a statistical framework is introduced allowing calibration of their selectivity and sensitivity for drugs. The role of ligand efficiency indices in drug design is also described. It is concluded that the usefulness of property filters of molecular size and lipophilicity is limited as predictors of general drug-likeness. However, they demonstrate increased performance in specific cases, e.g. in central nervous system diseases, emphasizing their future importance in specific, disease-focused library design instead of general drug-likeness filtering.
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Molecular docking of opiates and opioid peptides, a tool for the design of selective agonists and antagonists, and for the investigation of atypical ligand-receptor interactions
Luca Gentilucci, Alessandra Tolomelli, Rossella De Marco and Roberto Artali
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00311]

In the last years, molecular docking emerged as a powerful tool to investigate the interactions between opioid ligands and their receptors, thus drivingthe design and development of new selective agonists or antagonists of therapeutic interest. This review especially covers the most representative and recent comparative molecular docking analysis of structurally related compounds, as well as of agonists and antagonists within the active and inactive states of the receptors. The comparative analyses gave important information on the structural determinants responsible for the affinity and selectivity of the ligands, and defined the features responsible for the activation of the receptors. A special section is dedicated to the analyses of recently discovered, unusual agonists lacking of the tyramine pharmacophore, such as Salvinorin A, and the cyclopeptides including the D-Trp-Phe pharmacophoric motif. For the atypical structure of these compounds, the docking proved to be essential to disclose how they interact with and activate the receptors.
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Ion Pore Formation in Lipid Bilayers and Related Energetic Considerations
Ashrafuzzaman and J. Tuszynski
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00312]

Interactions between membrane proteins (MPs)/antimicrobial peptides (AMPs) and lipids play important roles in the creation and function of membrane transport events like ion channels, defects, etc. Energetics based on these interactions have been found to explain various aspects of general drug effects on cell membranes. We have used various membrane active agents (MAAs) such as peptides, chemotherapy drugs, amphipathic molecules, amphiphiles, etc. to observe the complexes created between them and lipids in bilayers that often serve as membrane transport events in order to better understand the underlying mechanism(s). We find that the structures and functions of MAAs-lipids complexes are very specific to the respective MAAs. However, the underlying mechanisms originating from some common types of interactions are found to depend on physical properties of both MAAs and lipids. Specifically, the stability and functions of MAAs-lipid complexes depend primarily on the electrostatic energy coupling between MAAs and lipids. The mechanical energy coupling between MAAs and lipids, depending mainly on the bilayer elastic profiles, contributes just secondary effects into the stability and functions of the complexes. Both of these electrostatic and mechanical energetic couplings emerge from a unique interaction energy expression appearing from screened Coulomb interaction treatment between MAAs and lipids, mainly depending on the localized charge profiles and on other physical properties of both MAAs and lipids. This review will address the functions and underlying molecular mechanisms of membrane transport events, membrane effects of general drugs, etc. and thus will open up avenues leading to novel drug discovery.
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Possible Involvement of Angiogenesis in Chronic Liver Disease: Interaction among Renin-Angiotensin-Aldosterone System, Insulin Resistance and Oxidative Stress
K. Kaji, H. Yoshiji, Y. Ikenaka, R. Noguchi, Y. Aihara, Y. Shirai, A. Douhara and H. Fukui
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00313]

Angiogenesis plays a pivotal role in many pathological processes including chronic liver diseases. Various factors, such as renin-angiotensin-aldosterone system (RAAS), insulin resistance (IR), and reactive oxygen species (ROS) contribute reciprocally topromote angiogenesis. Blockade of RAAS by angiotensin-converting enzyme inhibitor (ACE-I) or angiotensin II (AngII) receptor blocker (ARB) markedly attenuates liver fibrosis and hepatocellular carcinoma (HCC) along with suppression of angiogenesis, IR, and ROS. Aldosterone (Ald), a downstream component of AngII, is also involved in these processes, and a selective Ald blocker (SAB) significantly suppressed the progression of chronic liver diseases. The IR status itself has shown to directly accelerate the progression of chronic liver diseases whereas inhibition of ROS by iron chelator suppressed it through augmentation and inhibition of neovascularization. The combination therapy of ACE-I/ARB/SAB with other clinically used agents, such as interferon, imatinib mesylate, vitamin K, iron chelator, and branched-chain amino acids (BCAA) exerted more potent inhibitory effects on the development of liver fibrosis and HCC than the treatment using a single agent alone. Collectively, the anti-angiogenic treatment targeting RAAS, IR, ROS with clinically available agents may become a new therapeutic strategy against the progression of chronic liver diseases.
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The Protective Effects of Natural Products on Blood-Brain Barrier Breakdown
A. Kam, K.M. Li, V. Razmovski-Naumovski, S. Nammi, K. Chan, Y. Li and G.Q. Li
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00314]

The blood-brain barrier (BBB) is a protective fence between the central nervous system and the systemic circulation, and is essential for maintaining the normal homeostasis of the central nervous system. BBB breakdown is instigated in many neurological disorders such as Alzheimer’s disease and multiple sclerosis. Recent literature has advanced the knowledge on the physiology and pathophysiology of BBB breakdown, including the attribution of detrimental inducers and signalling transduction cascades. Natural products, such as flavonoids, phenolic compounds, terpenes, alkaloids, lipids and phthalides have been reported to attenuate many neurological diseases by modulating the signalling transduction cascades associated with BBB breakdown. Understanding the activities of these natural products through the molecular mechanisms associated with BBB breakdown will offer considerable scope in the discovery and development of novel agents for preventing BBB breakdown and thus, the progression of neurological disorders.
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Cognitive, Psychological and Psychiatric Effects of Ionizing Radiation Exposure
D. Marazziti, S. Baroni, M. Catena-Dell’Osso, D. Ceresoli, L. Dell’Osso, C. Conversano and E. Picano
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00315]

Radiation exposure leads to an increased risk for cancer and, possibly, additional ill-defined non-cancer risk, including atherosclerotic, cardiovascular, cerebro-vascular and neurodegenerative effects. Studies of brain irradiation in animals and humans provide evidence of apoptosis, neuro-inflammation, loss of oligo-dendrocytes precursors and myelin sheaths, and irreversible damage to the neural stem compartment with long-term impairment of adult neurogenesis. With the present paper we aim to present a comprehensive review on brain effects of radiation exposure, with a special focus on its impact on cognitive processes and psychological functions, as well as on their possible role in the pathophysiology of different psychiatric disorders.
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Selective Serotonin Reuptake Inhibitors (SSRIs): Therapeutic Drug Monitoring and Pharmacological Interactions
R. Mandrioli, L. Mercolini, M.A. Saracino and M.A. Raggi
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00316]

New-generation antidepressants are a heterogeneous class of drugs used in the treatment of depression and related disorders. This review deals with the first new-generation antidepressant class to enter the pharmaceutical market, i.e., selective serotonin reuptake inhibitors (SSRIs), which are still the most prescribed and widely used ones. Their common characteristics are the comparable clinical efficacy, good tolerability and relative safety in comparison to "first generation antidepressants", i.e. classic tricyclic antidepressants and monoamine oxidase inhibitors. This class of drugs includes fluoxetine, citalopram, paroxetine, sertraline, fluvoxamine and, since 2011, vilazodone. In this review, the main pharmacodynamic and pharmacokinetic properties of the six commercially available SSRIs are described, focusing on side and toxic effects, chemical-clinical correlations, interactions with other drugs, the role of therapeutic drug monitoring (TDM) and related bioanalytical methodologies.
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UDP-3-O-(R-3-hydroxymyristoyl)-N-Acetylglucosamine Deacetylase (LpxC) Inhibitors: A New Class of Antibacterial Agents
J. Zhang, L. Zhang, X. Li and W. Xu
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00317]

The rapid increase of health-threatening infections by Gram-negative pathogens along with the emergence of multidrugresistant bacterial strains demands the development of novel antibiotics directed against the previously unexploited targets. One of the promising targets in Gram-negative bacteria is the zinc-dependent metalloamidase, UDP-3-O-(R-3-hydroxymyristoyl)-Nacetylglucosamine deacetylase (LpxC). LpxC catalyzes the first committed, second overall step in the biosynthetic pathway of lipid A. Thus, research on LpxC inhibitors as antibacterial agents has become an attractive field in the development of the novel antibiotic therapy of Gram-negative bacteria. In this review, we will summarize the recent progress in the studies on the structure, catalytic mechanism and regulation of LpxC and the current development of LpxC inhibitors.
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How is Gene Transfection Able to Improve Current Chemotherapy? The Role of Combined Therapy in Cancer Treatment
J. Prados, P.J. Álvarez, C. Melguizo, F. Rodriguez-Serrano, E. Carrillo, H. Boulaiz, C. Vélez, J.A. Marchal, O. Caba, R. Ortiz, A. Rama and A. Aranega
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00318]

Despite advances in cancer treatment, a large number of patients eventually develop metastatic disease that is generally incurable. Systemic chemotherapy remains the standard treatment for these patients. Several chemotherapeutic combinations have proven effective in the management of cancer. Paradoxically, although the purpose of polychemotherapy is to improve the prognosis and prolong the survival of patients, it often carries considerable toxicity that causes substantial adverse symptoms. For this reason, a major goal of cancer research is to improve the effectiveness of these cytotoxic agents and reduce their adverse effects. Gene transfer has been proposed as a new strategy to enhance the efficacy of anti-tumor drugs in the treatment of intractable or metastatic cancers. In fact, the association of gene therapy and drugs (combined therapy) has been reported to increase the anti-proliferative effect of classical treatments in lung, bladder, pancreatic, colorectal and breast cancers, among others. Various especially promising therapies have been proposed in this context, including the use of suicide genes, antisense oligonucleotides, ribozymes and RNA interference. In this chapter, we review recent progress in the development of novel anti-cancer strategies that associate cytotoxic agents with gene transfer to enhance their antitumor effect.
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Novel Patented Src Kinase Inhibitor
Xiao-Ling Lu, Xiao-Yu Liu, Xin Cao and Bing-Hua Jiao
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00319]

Src family of protein tyrosine kinases (SFKs) plays key roles in the regulation of signal transductions in cellular processes. However, hyper-activated SFKs lead to uncontrolled cell proliferation and cancers. Src-targeted compounds were developed to block the cell proliferation signal transductions for cancer therapy. Src kinase domain inhibitors were designed, synthesized and evaluated as anticancer agents, while the patents applied at the same time. Great progress has been made in the Src kinase inhibitor area. Herein, some predominant patents about Src kinase inhibitors of the recent years are reviewed.
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Modulation of Inflammatory Immune Reactions by Low-Dose Ionizing Radiation: Molecular Mechanisms and Clinical Application
F. Rödel, B. Frey, U. Gaipl, L. Keilholz, C. Fournier, K. Manda, H. Schöllnberger, G. Hildebrandt and C. Rödel
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00320]

During the last decade, a multitude of experimental evidence has accumulated showing that low-dose radiation therapy (single dose 0.5–1 Gy) functionally modulates a variety of inflammatory processes and cellular compounds including endothelial (EC), mononuclear (PBMC) and polymorphonuclear (PMN) cells, respectively. These modulations comprise a hampered leukocyte adhesion to EC, induction of apoptosis, a reduced activity of the inducible nitric oxide synthase, and a lowered oxidative burst in macrophages. Moreover, irradiation with a single dose between 0.5–0.7 Gy has been shown to induce the expression of X-chromosome linked inhibitor of apoptosis and transforming growth factor beta 1, to reduce the expression of E-selectin and L-selectin from EC and PBMC, and to hamper secretion of Interleukin-1, or chemokine CCL20 from macrophages and PMN. Notably, a common feature of most of these responses is that they display discontinuous or biphasic dose dependencies, shared with “non-targeted” effects of low-dose irradiation exposure like the bystander response and hyper-radiosensitivity. Thus, the purpose of the present review is to discuss recent developments in the understanding of low-dose irradiation immune modulating properties with special emphasis on discontinuous dose response relationships.
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Induction of Abscopal Anti-Tumor Immunity and Immunogenic Tumor Cell Death by Ionizing Irradiation – Implications for Cancer Therapies
B. Frey, Y. Rubner, R. Wunderlich, E.-M. Weiss, A.G. Pockley, R. Fietkau and U.S. Gaipl
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00321]

Although cancer progression is primarily driven by the expansion of tumor cells, the tumor microenvironment and anti-tumor immunity also play important roles. Herein, we consider how tumors can become established by escaping immune surveillance and also how cancer cells can be rendered visible to the immune system by standard therapies such as radiotherapy or chemotherapy, either alone or in combination with additional immune stimulators. Although local radiotherapy results in DNA damage (targeted effects), it is also capable of inducing immunogenic forms of tumor cell death which are associated with a release of immune activating danger signals (non-targeted effects), such as necrosis. Necrotic tumor cells may result from continued exposure to death stimuli and/or an impaired phosphatidylserine (PS) dependent clearance of the dying tumor cells. In such circumstances, mature dendritic cells take up tumor antigen and mediate the induction of adaptive and innate anti-tumor immunity. Locally-triggered, systemic immune activation can also lead to a spontaneous regression of tumors or metastases that are outside the radiation field - an effect which is termed abscopal. Preclinical studies have demonstrated that combining radiotherapy with immune stimulation can induce anti-tumor immunity. Given that it takes time for immunity to develop following exposure to immunogenic tumor cells, we propose practical combination therapies that should be considered as a basis for future research and clinical practice. It is essential that radiation oncologists become more aware of the importance of the immune system to the success of cancer therapy.
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The Effect of Chemotherapy/Radiotherapy on Cancerous Pattern Recognition by NK Cells
B. Rosental, M.Y. Appel, R. Yossef, U. Hadad, M. Brusilovsky and A. Porgador
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00322]

In recent years, the effects of cancer chemotherapy and radiotherapy (CT/RT) regimens as they apply to the immune system have been explored. NK cells represent the main cytotoxic arm of the innate immune system, and their functionality is vital to establishing an effective anti tumor immune response. This review examines current CT/RT interventions in light of their effects on NK cell functionality. The effects of CT/RT on the expression of the various ligands for activating and inhibitory NK cell receptors are discussed. Expression of ligands for the activating NKG2D receptor is enhanced by cell stress; accordingly there are numerous reports of their higher expression in cells exposed to various CT/RT agents. In contrast, some agents have been reported to cause ligand shedding, which can serve to inhibit NK cell activity. Reported effects of CT/RT on tumor expression of ligands for the activating Natural Cytotoxicity Receptors, and of HLA class I ligands for NK cell inhibitory receptors are also noted. Additionally, we describe reports concerning the direct effects of CT/RT on NK cell function. Many treatments adversely affect NK cell function directly, but observations made through in vitro systems may differ from those obtained utilizing clinical samples. The effects of CT/RT on both direct NK cell cytotoxicity and on NK cell-mediated Antibody Dependent Cellular Cytotoxicity are explored. Taken together, CT/RT affects NK cell anti-tumor immunity from multiple angles. The interplay is complex, and future work is needed to achieve the optimal synergy between CT/RT and innate as well as adaptive immunity in the treatment of cancer.
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Radiation-Induced Stress Proteins – the Role of Heat Shock Proteins (HSP) in Anti-Tumor Responses
T.E. Schmid and G. Multhoff
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00323]

Together with surgery and chemotherapy, ionizing irradiation is one of the key therapeutic approaches to treat cancer. More than 50 percent of all cancer patients will receive radiotherapeutic intervention at some stage of their disease. The more precise instrumentation for delivery of radiotherapy and the emphasis on hypofractionation technologies have drastically improved loco-regional tumor control within the last decades. However, the appearance of distant metastases often requires additional systemic treatment modalities such as chemotherapy. High dose chemotherapy is generally considered as immunosuppressive and can cause severe adverse effects. Therefore, we want to elucidate the effects of ionizing irradiation on the immune system and provide immunological treatment strategies which are induced by the host’s stress response. Similar to other stressors, ionizing irradiation is known to enhance the synthesis of a variety of immune-stimulatory and -modulating molecules such as heat shock proteins (HSP), high mobility group box 1 (HMGB1) and survivin. Herein, we focus on HSP that exhibit an unusual cell membrane localization and release mechanism in tumor cells. These tumor-specific characteristics render HSP as ideal targets for therapeutic interventions. Depending on their intra/membrane and extracellular localization HSP have the ability to protect tumor cells from stress-induced lethal damage by interfering with antiapoptotic pathways or to elicit anti-cancer immunity.
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The Interaction of NK Cells and Dendritic Cells in the Tumor Environment: How to Enforce NK Cell & DC Action Under Immunosuppressive Conditions?
B. Jacobs and E. Ullrich
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00324]

The crosstalk of natural killer (NK) and dendritic cells (DCs) plays an important role in the induction of the tumor-specific immune response against cancer. During the last decade, our advanced understanding of the immune system led to the development of new therapeutic strategies in the field of immunotherapy and cellular immunology. However, these immunotherapeutic concepts have not been as successful as initially expected because of their inability to counteract cancer-induced immunosuppressive pathways. Some of the major difficulties of effective cellular immunotherapy are the highly immunosuppressive factors induced by tumor cells themselves or by their microenvironment. Therefore, one major challenge in immunotherapy is the question: “How to enforce NK cell & DC action under immunosuppressive conditions?” This review focuses on the current knowledge on the tumor microenvironment, the crosstalk of NK cells and DCs, as well as their deregulation in the complex interplay with the immunosuppressive tumor microenvironment. We further discuss possible strategies to minimize the negative impact of the tumor microenvironment on the immune system.
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ChemoImmunoModulation: Immune Regulation by the Antineoplastic Chemotherapeutic Agents
M.R. Shurin, H. Naiditch, D.W. Gutkin, V. Umansky and G.V. Shurin
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00325]

Since 1948, when Farber et al. introduced aminopterin, the first chemotherapeutic agent, more than 100 such agents have come into use. Initially, antitumor chemotherapies were thought to produce only antiproliferative or cytotoxic effects on dividing tumor cells as it was often associated with the damage to healthy tissues and the development of resistant tumor clones. However, that view has been changing as a consequence of recent demonstrations that several antineoplastic drugs, even at low doses, have antiangiogenic and sometimes immunomodulating effects. In addition, new studies indicate that lowering the dose of conventional cytotoxic agents and combining chemotherapy with other modalities may not only decrease the toxicity of conventional chemotherapy, but also up-regulate the efficacy of different anticancer therapies. Giving chemotherapy in this manner has several potential advantages, including impediment of the onset of mutation-dependent mechanisms of acquired drug resistance and increase in the efficacy and durability of combinatorial therapeutic modalities. Certain “immunogenic” forms of cancer chemotherapy may cause indirect activation of immune cells due to the accessibility of tumor antigens and certain “danger” signals. Furthermore, new findings indicate that several chemotherapeutic agents can directly activate immune cells when used in ultra low noncytotoxic concentrations, the new phenomenon that was termed chemoimmunomodulation. The goal of this review is to analyze the immune modulating properties of antineoplastic chemotherapeutic agents and present new evidence of the immunostimulating potentials of several agents used in low and ultra low nontoxic doses. Therapeutic potentials of combined chemo-immunotherapeutic regimens have been extensively reviewed in a variety of recent publications and will not be discussed.
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In Vitro – In Vivo Correlation of Gene Expression Alterations Induced by Liver Carcinogens
T. Heise, M. Schug, D. Storm, H. Ellinger-Ziegelbauer, H.J. Ahr, B. Hellwig, J. Rahnenführer, A. Ghallab, G. Guenther, J. Sisnaiske, R. Reif, P. Godoy, H. Mielke, U. Gundert-Remy, A. Lampen, A. Oberemm and J.G. Hengstler
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00326]

Although cultivated hepatocytes are widely used in the studies of drug metabolism, their application in toxicogenomics is considered as problematic, because previous studies have reported only little overlap between chemically induced gene expression alterations in liver in vivo and in cultivated hepatocytes. Here, we identified 22 genes that were altered in livers of rats after oral administration of the liver carcinogens aflatoxin B1 (AB1), 2-nitrofluorene (2-NF), methapyrilene (MP) or piperonyl-butoxide (PBO). The functions of the 22 genes have been classified into two groups. Genes related to stress response, DNA repair or metabolism and genes associated with cell proliferation, respectively. Next, rat hepatocyte sandwich cultures were exposed to AB1, 2-NF, MP or PBO for 24h and expression of the above mentioned genes was determined by RT-qPCR. Significant correlations between the degree of gene expression alterations in vivo and in vitro were obtained for the stress, DNA repair and metabolism associated genes at concentrations covering a range from cytotoxic concentrations to non-toxic/in vivo relevant concentrations. In contrast to the stress associated genes, no significant in vivo/in vitro correlation was obtained for the genes associated with cell proliferation. To understand the reason of this discrepancy, we compared replacement proliferation in vivo and in vitro. While hepatocytes in vivo, killed after administration of hepatotoxic compounds, are rapidly replaced by proliferating surviving cells, in vitro no replacement proliferation as evidenced by BrdU incorporation was observed after washing out hepatotoxic concentrations of MP. In conclusion, there is a good correlation between gene expression alterations induced by liver carcinogens in vivo and in cultivated hepatocytes. However, it should be considered that cultivated primary hepatocytes do not show replacement proliferation explaining the in vivo/in vitro discrepancy concerning proliferation associated genes.
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Chemical Metabolism of Medicinal Compounds from Natural Botanicals
Q. Lu and J.-G. Jiang
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00327]

Traditional Chinese medicine (TCM) and its natural products are complex mixtures containing hundreds of chemically different constituents but only a few components are responsible for the pharmacological effects and bioactivities. In order to clarify the functional mechanism of active compounds, the studies on metabolism are of great significance and necessity. Previously, research mainly focused on the aspect of pharmacokinetics, however in recent years, chemical metabolism of active compounds has drawn increasing attention. Researches on the chemical metabolism of single phytochemicals help to understand the transformation process in vivo and mechanism of action, also contribute to pharmacodynamics and toxicology studies and new drug development. In the present paper, the chemical metabolism of nine categories of phytochemicals was reviewed. This review focused on pharmacological action, metabolic characteristics, metabolic pathways, metabolites and assay method of alkaloids, flavonoids, saponins, terpenoids, stilbenes, phenols, quinones, lignans and esters. The parent drugs, perhaps the metabolites, or they together play a role in pharmacological effects. And different routes of administration may lead to different results of transformation pathways and metabolites. Moreover, high-tech assay methods, particularly the combined use of modern instrument analytical techniques, are beneficial to the research of drug metabolism.
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Bcl-2 Inhibitors: Emerging Drugs in Cancer Therapy
C. Bodur and H. Basaga
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00328]

Dose-limiting toxicity to healthy tissues is among the major hurdles in anticancer treatment along with intrinsic or acquired multi-drug resistance. Development of small molecule inhibitors (SMI) specific for antiapoptotic Bcl-2 proteins is a novel approach in a way that these antagonists are aimed to interfere with specific protein-protein interactions unlike conventional chemo-/radiotherapies. SMIs of antiapoptotic Bcl-2 proteins are assumed to compete with proapoptotic Bcl-2s to occupy BH3 docking grooves on the surfaces of antiapoptotic family members. Instead of directly initiating cell death, these inhibitors are intended to decrease apoptotic threshold in tumor cells that were already primed to death. In this regard, antiapoptotic Bcl-2 protein SMIs have the advantage of lower normal tissue toxicity relative to conventional anticancer therapies that interfere with general mechanisms including DNA synthesis, mitosis and tyrosine kinase activity. Besides, Bcl-2 antagonists were shown to potentiate efficacies of established drugs in several hematological malignancies and solid tumors which render them promising candidates for combination anticancer therapy. Utilizing these SMIs in such a way may prove to decrease the patient drug load by diminishing the required chemo-/radiotherapy dose. This review summarizes and compares BH3 mimetics on the basis of specificity, mode of action and efficacy, as well as providing remarks on their therapeutical potential and routes of development in near future.
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Power from the Garden: Plant Compounds as Inhibitors of the Hallmarks of Cancer
B. Orlikova and M. Diederich
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00331]

On December 23rd, 1971, President Richard Nixon signed the National Cancer Act and invested more than $ 100 million “to launch an intensive campaign to find a cure for cancer”. Today, despite these considerable efforts, cancer still remains a very aggressive silent killer all over the world. Moreover, over the last decade, novel synthetic chemotherapeutic agents currently in use in the clinics did not succeed in fulfilling their expectations even though they are very cost-intensive. In parallel, there is increasing evidence for the potential of plant-derived compounds on the inhibition of different steps of tumor genesis and associated inflammatory processes, underlining the importance of these products in cancer prevention and therapy. This review summarizes the impact of selected natural compounds on the eight major alterations, known as the cancer hallmarks, and also on their two enabling characteristics that were coined by Hanahan and Weinberg earlier. Altogether these ten alterations are responsible for the progressive transition of healthy cells into neoplastic ones and their further dissemination in the body. With this review, we try to highlight molecular mechanisms by which plant extracts and their purified active components fight and overcome these pathological variations of the cell signaling pathways for the improvement of prevention and therapy. We truly believe that all diseases can be found in Nature and that Nature also provides the efficient cures.
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Anti-Inflammatory Agents from Plants: Progress and Potential
M.C. Recio, I. Andújar and J.L. Ríos
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00332]

The identification of substances that can promote the resolution of inflammation in a way that is homeostatic, modulatory, efficient, and well-tolerated by the body is of fundamental importance. Traditional medicines have long provided front-line pharmacotherapy for many millions of people worldwide. Medicinal extracts are a rich source of therapeutic leads for the pharmaceutical industry. The use of medicinal plant therapies to treat chronic illness, including rheumatoid arthritis (RA) and inflammatory bowel disease (IBD), is thus widespread and on the rise.The aim of this review is to present recent progress in clinical anti-inflammatory studies of plant extracts and compound leads such as green tea polyphenols, curcumin, resveratrol, boswellic acid, and cucurbitacins, among others, against chronic inflammatory diseases, mainly RA and IBD. In this context, the present paper also highlights the most promising experimental data on those plant extracts and pure compounds active in animal models of the aforementioned diseases.
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Anti-Inflammatory Iridoids of Botanical Origin
A. Viljoen, N. Mncwangi and I. Vermaak
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00333]

Inflammation is a manifestation of a wide range of disorders which include; arthritis, atherosclerosis, Alzheimer’s disease, inflammatory bowel syndrome, physical injury and infection amongst many others. Common treatment modalities are usually nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, paracetamol, indomethacin and ibuprofen as well as corticosteroids such as prednisone. These however, may be associated with a host of side effects due to non-selectivity for cyclooxygenase (COX) enzymes involved in inflammation and those with selectivity may be highly priced. Thus, there is a continuing search for safe and effective anti-inflammatory molecules from natural sources. Research has confirmed that iridoids exhibit promising anti-inflammatory activity which may be beneficial in the treatment of inflammation. Iridoids are secondary metabolites present in various plants, especially in species belonging to the Apocynaceae, Lamiaceae, Loganiaceae, Rubiaceae, Scrophulariaceae and Verbenaceae families. Many of these ethnobotanicals have an illustrious history of traditional use alluding to their use to treat inflammation. Although iridoids exhibit a wide range of pharmacological activities such as cardiovascular, hepatoprotection, hypoglycaemic, antimutagenic, antispasmodic, anti-tumour, antiviral, immunomodulation and purgative effects this review will acutely focus on their anti-inflammatory properties. The paper aims to present a summary for the most prominent iridoid-containing plants for which anti-inflammatory activity has been demonstrated in vitro and / or in vivo.
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The Potential of Secondary Metabolites from Plants as Drugs or Leads Against Protozoan Neglected Diseases – Part I
T.J. Schmidt, S.A. Khalid, A.J. Romanha, T.M.A. Alves, M.W. Biavatti, R. Brun, F.B. Da Costa, S.L. de Castro, V.F. Ferreira, M.V.G. de Lacerda, J.H.G. Lago, L.L. Leon, N.P. Lopes, R.C. das Neves Amorim, M. Niehues, I.V. Ogungbe, A.M. Pohlit, M.T. Scotti, W.N. Setzer, M. de N.C. Soeiro, M. Steindel and A.G. Tempone
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00334]

Infections with protozoan parasites are a major cause of disease and mortality in many tropical countries of the world. Diseases caused by species of the genera Trypanosoma (Human African Trypanosomiasis and Chagas Disease) and Leishmania (various forms of Leishmaniasis) are among the seventeen “Neglected Tropical Diseases” (NTDs) defined as such by WHO due to the neglect of financial investment into research and development of new drugs by a large part of pharmaceutical industry and neglect of public awareness in high income countries. Another major tropical protozoan disease is malaria (caused by various Plasmodium species), which -although not mentioned currently by the WHO as a neglected disease- still represents a major problem, especially to people living under poor circumstances in tropical countries. Malaria causes by far the highest number of deaths of all protozoan infections and is often (as in this review) included in the NTDs. The mentioned diseases threaten many millions of lives world-wide and they are mostly associated with poor socioeconomic and hygienic environment. Existing therapies suffer from various shortcomings, namely, a high degree of toxicity and unwanted effects, lack of availability and/or problematic application under the life conditions of affected populations. Development of new, safe and affordable drugs is therefore an urgent need. Nature has provided an innumerable number of drugs for the treatment of many serious diseases. Among the natural sources for new bioactive chemicals, plants are still predominant. Their secondary metabolism yields an immeasurable wealth of chemical structures which has been and will continue to be a source of new drugs, directly in their native form and after optimization by synthetic medicinal chemistry. The current review, published in two parts, attempts to give an overview on the potential of such plant-derived natural products as antiprotozoal leads and/or drugs in the fight against NTDs.
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The Potential of Secondary Metabolites from Plants as Drugs or Leads Against Protozoan Neglected Diseases - Part II
T.J. Schmidt, S.A. Khalid, A.J. Romanha, T.M.A. Alves, M.W. Biavatti, R. Brun, F.B. Da Costa, S.L. de Castro, V.F. Ferreira, M.V.G. de Lacerda, J.H.G. Lago, L.L. Leon, N.P. Lopes, R.C. das Neves Amorim, M. Niehues, I.V. Ogungbe, A.M. Pohlit, M.T. Scotti, W.N. Setzer, M. de N.C. Soeiro, M. Steindel and A.G. Tempone
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00335]

Infections with protozoan parasites are a major cause of disease and mortality in many tropical countries of the world. Diseases caused by species of the genera Trypanosoma (Human African Trypanosomiasis and Chagas Disease) and Leishmania (various forms of Leishmaniasis) are among the seventeen “Neglected Tropical Diseases” (NTDs) defined by the WHO. Furthermore, malaria (caused by various Plasmodium species) can be considered a neglected disease in certain countries and with regard to availability and affordability of the antimalarials. Living organisms, especially plants, provide an innumerable number of molecules with potential for the treatment of many serious diseases. The current review attempts to give an overview on the potential of such plant-derived natural products as antiprotozoal leads and/or drugs in the fight against NTDs. In part I, a general description of the diseases, the current state of therapy and need for new therapeuticals, assay methods and strategies applied in the search for new plant derived natural products against these diseases and an overview on natural products of terpenoid origin with antiprotozoal potential were given. The present part II compiles the current knowledge on natural products with antiprotozoal activity that are derived from the shikimate pathway (lignans, coumarins, caffeic acid derivatives), quinones of various structural classes, compounds formed via the polyketide pathways (flavonoids and related compounds, chromenes and related benzopyrans and benzofurans, xanthones, acetogenins from Annonaceae and polyacetylenes) as well as the diverse classes of alkaloids. In total, both parts compile the literature on almost 900 different plant-derived natural products and their activity data, taken from over 800 references. These data, as the result of enormous efforts of numerous research groups world-wide, illustrate that plant secondarymetabolites represent an immensely rich source of chemical diversity with an extremely high potential to yield a wealth of lead structures towards new therapies for NTDs. Only a small percentage, however, of the roughly 200,000 plant species on earth have been studied chemically and only a small percentage of these plants or their constituents has been investigated for antiprotozoal activity. The repository of plant-derived natural products hence deserves to be investigated even more intensely than it has been up to present.
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Nature Against Depression
A.T. El-Alfy, E.A. Abourashed and R.R. Matsumoto
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00336]

Depression is a major health problem currently recognized as a leading cause of morbidity worldwide. In the United States alone, depression affects approximately 20% of the population. With current medications suffering from major shortcomings that include slow onset of action, poor efficacy, and unwanted side effects, the search for new and improved antidepressants is ever increasing. In an effort to evade side effects, people have been resorting to popular traditional herbal medicines to relieve the symptoms of depression, and there is a need for more empirical knowledge about their use and effectiveness. This review provides an overview of the current knowledge state regarding a variety of natural plant products commonly used in depression. Herbal medicines discussed that have been used in clinical trials for the treatment of mild to moderate depression states include the popular St. John’s wort, saffron, Rhodiola, lavender, Echium, and the Chinese formula banxia houpu. In addition, new emerging herbal products that have been studied in different animal models are discussed including Polygala tenuifolia, the traditional Chinese herbal SYJN formula, gan mai da zao, and Cannabis sativa constituents. A comprehensive review of the chemical, pharmacological, and clinical aspects of each of the reviewed products is provided. Finally, recent preclinical studies reporting the antidepressant action of marine-derived natural products are discussed at the end of the review.
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Phytochemicals from Plants to Combat Cardiovascular Disease
H.R. Vasanthi, N. ShriShriMal and D.K. Das
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00337]

For many decades, the use of synthetic chemicals as drugs has been effective in the treatment of most diseases. Moreover, from ancient to modern history, many traditional plant based medicines are playing an important role in health care. Phytochemicals are natural bioactive compounds found in vegetables, fruits, medicinal plants, aromatic plants, leaves, flowers and roots which act as a defense system to combat against diseases. The phytochemicals from natural products cover a diverse range of chemical entities such as polyphenols, flavonoids, steroidal saponins, organosulphur compounds and vitamins. A number of bioactive compounds generally obtained from terrestrial plants such as isoflavones, diosgenin, resveratrol, quercetin, catechin, sulforaphane, tocotrienols and carotenoids are proven to reduce the risk of cardiovascular diseases and aid in cardioprotection which is the leading cause of death globally. The cardioprotective effects of the various phytochemicals are perhaps due to their antioxidative, antihypercholesteroemic, antiangiogenic, anti-ischemic, inhibition of platelet aggregation and anti inflammatory activities that reduce the risk of cardiovascular disorders. The multi-faceted role of the phytochemicals is mediated by its structure-function relationship and can be considered as leads for cardiovascular drug design in future. This review summarizes the findings of recent studies on selected phytochemicals as prophylactic and therapeutic agents in cardioprotection.
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Current Concepts on Selected Plant Secondary Metabolites With Promising Inhibitory Effects Against Enzymes Linked to Alzheimer’s Disease
I.E. Orhan
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00338]

Alzheimer’s disease (AD) has become one of the deadliest diseases for human beings with special incidence in elderly population. It is a progressive neurodegenerative disease and the most prevalent cause of dementia. The neuropathology of AD has not been fully elucidated yet, however, cholinergic hypothesis is the most accepted theory nowadays, resulting from the cholinergic deficit emerging in the brains of AD patients. Shortage of the neurotransmitters, acetylcholine and butyrylcholine has been demonstrated, and therefore, inhibition of the enzymes; acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) that break down acetylcholine and butyrylcholine has become a standard approach for AD treatment. However, cholinesterase inhibitors are only effective in symptomatic treatment and have no ability to impede the disease. The pathogenesis of AD is highly complex and another hypothesis is the formation of amyloid plaques containing beta-amyloid peptide, which causes neurolesions in the brains of AD patients. Beta-amyloid peptide is generated after the sequential cleavage of amyloid precursor protein, especially by the beta- and gamma-secretase in the amyloidogenic pathway. The secretases involved in the processing of amyloid precursor protein are of particular interest and, consequently, the inhibition of secretase enzyme family of protease type has become another desired treatment strategy for AD. On the other hand, medicinal plants are attractive sources for drug research and development as they produce chemically-varying molecules with preferred biological activities. The aim of this article is to review the available data on selected inhibitors from plant secondary metabolites with emphasis on cholinesterase, prolyl endopeptidase, and secretase enzyme families as being the current treatments of AD.
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Novel Tyrosinase Inhibitors From Natural Resources – Their Computational Studies
M.T.H. Khan
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00339]

Tyrosinase is a multi-copper enzyme widely distributed in different organisms, including plants & mammals, etc., which is responsible for pigmentations, undesired browning of fruits and vegetables. This is the key enzyme in the melanogenesis in human and molting process of insects. Therefore the inhibitors of the enzyme may lead to novel skin whitening agents, anti-browning substances or compounds for insect control. A large numbers of moderate to potent tyrosinase inhibitors have been reported during the last decade. From our group, we reported a number of potent inhibitors from synthetic, semi-synthetic and natural origins. The compounds are from several chemical classes, like phenolics, terpenes, steroids, chalcones, flavonoids, alkaloids, long-chain fatty acids, coumarins, sildenafil analogs, bipiperidines, biscoumarins, oxadiazole, tetraketones, etc. More recently, the crystal structure of mushroom and couple of other tyrosinases has been published and more recently the crystal structure of mushroom tyrosinase complexes with a highly potent inhibitor tropolone has been reported. Yet there is a lack of information of inhibitor-tyrosinase intermolecular interactions. To overcome such issues, some researchers started utilizing in silico tools, like molecular docking simulations, for such purposes. There are also few papers published about the successful utilization of computational tools like QSAR-based and ligand-based virtual screening to identify novel and potent inhibitors of the enzyme. In our group, we are using all possible computational tools, like ligand-based as well structure-based approaches, to identify new inhibitors. In this review, some of such examples are briefly described.
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Modulation of k-Ras Signaling by Natural Products
S.B. Bharate, B. Singh and R.A. Vishwakarma
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00340]

Ras proteins regulate diverse cellular pathways that are important in the growth and spread of malignancies, including cell proliferation, cell cycle regulation, cell survival, angiogenesis and cell migration. These proteins lack the conventional transmembrane or hydrophobic domain typical of membrane associated proteins. Being small and hydrophilic in nature, these proteins undergo four-stage post-translational lipid modifications viz. prenylation, AAX proteolysis, carboxymethylation and palmitoylation for membrane localization which is important for their function. Therefore, enzymes involved in these modifications viz. farnesyl transferase (FTase), geranylgeranyl transferase-I (GGTase-I), geranylgeranyl transferase-II (GGTase-II), Ras converting enzyme-1 (Rce-1) and isoprenyl cysteine methyl transferase (ICMT) are emerging as potential therapeutic targets for the discovery of newer anticancer therapeutics. Several natural products have shown modulation of these post-translational enzymes. In the present review, natural products isolated from terrestrial as well as marine sources showing ability to modulate these k-Ras post-translational targets and their promise as potential anticancer agents have been discussed. A total of 157 natural products with 141 corresponding references have been covered.
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Chios Gum Mastic: A Review of its Biological Activities
S. Paraschos, S. Mitakou and A.-L. Skaltsounis
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00341]

The resin of Pistacia lentiscus (L.) var. chia (Duham), an evergreen shrub belonging to the family Anacardiaceae and uniquely cultivated in southern Chios, is known as mastic. It has been used for more than 2500 years in traditional Greek medicine for treating several diseases such as gastralgia and peptic ulcers, while the actions of the gum are mentioned in the works of Herodotus, Dioscorides and Galen. Several Roman, Byzantine, Arab and European authors make extensive references to mastic’s healing properties. Modern scientific research has justified the beneficial action of mastic to gastric diseases, by revealing its in vivo and in vitro activity against Helicobacter pylori, which is considered as the main cause for gastric ulcers. Furthermore, studies of the antimicrobial, antifungal, antioxidant, hypolipidemic, anti-inflammatory, anti-Crohn and anticancer activities of mastic have characterized it as a wide-range therapeutic agent and a potential source of nature-originated treatments.
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An Artificial Neural Network Model for Predicting the Subcellular Localization of Photosensitisers for Photodynamic Therapy of Solid Tumours
R. Tejedor-Estrada, S. Nonell, J. Teixidó, M.L. Sagristá, M. Mora, A. Villanueva, M. Cañete and J.C. Stockert
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00342]

Photodynamic therapy (PDT) is a promising modality for the treatment of tumours based on the combined action of a photosensitiser (PS), visible light and molecular oxygen, which generates a local oxidative damage that leads to cell death. The site where the primary photodynamic effect takes place depends on the subcellular localization of the PS and affects the mode of action and efficacy of PDT. It is therefore of prime interest to develop structure-subcellular localization prediction models for a PS from its molecular structure and physicochemical properties. Here we describe such a prediction method for the localization of macrocyclic PSs into cell organelles based on a wide set of physicochemical properties and processed through an artificial neural network (ANN). 128 2Dmolecular descriptors related to lipophilicity/hydrophilicity, charge and structural features were calculated, then reduced to 76 by using Pearson’s correlation coefficient, and finally to 5 using Guyon and Elisseeff’s algorithm. The localization of 61 PSs was compiled from literature and distributed into 3 possible cell structures (mitochondria, lysosomes and “other organelles”). A non-linear ANN algorithm was used to process the information as a decision tree in order to solve PS-organelle assignment: first to identify PSs with mitochondrial and/or lysosomal localization from the rest, and to classify them in a second stage. This sequential ANN classification method has permitted to distinguish PSs located into two of the most important cell targets: lysosomes and mitochondria. The absence of false negatives in this assignation, combined with the rate of success in predicting PS localization in these organelles, permits the use of this ANN method to perform virtual screenings of drug candidates for PDT.
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Activity of Epiisopiloturine Against Schistosoma mansoni
L.M. Veras, M.A. Guimarães, Y.D. Campelo, M.M. Vieira, C. Nascimento, D. F. Lima, L. Vasconcelos, E. Nakano, S.S. Kuckelhaus, M.C. Batista, J.R. Leite and J. Moraes
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00343]

Schistosomiasis, caused by blood flukes of the genus Schistosoma, still imposes a considerable public health burden on large parts of the world. The control of this disease depends almost exclusively on the drug praziquantel, and there are no alternative drugs in sight. Natural compounds have recently attracted significant attention due to their relevance to parasitic infection and potential development into new therapeutic agents. Epiisopiloturine is an imidazole alkaloid isolated from the leaves of Pilocarpus microphyllus (Rutaceae), a native plant from Brazil. Here, we report the in vitro effect of this drug on the survival time of Schistosoma mansoni of different ages, such as 3 h old and 1, 3, 5, and 7 days old schistosomula, 49-day-old adults, and on egg output by adult worms. Epiisopiloturine at a concentration of 300 μg/mL caused the death of all schistosomula within 120 h. Extensive tegumental alterations and death were observed when adult schistosomes had been exposed to 150 μg/mL of the epiisopiloturine. At the highest sub-lethal dose of alkaloid (100 μg/mL), a 100% reduction in egg laying of paired adult worms was observed. Additionally, epiisopiloturine showed selective antischistosomal activity and exhibited no cytotoxicity to mammalian cells. This report provides the first evidence that epiisopiloturine is able to kill S. mansoni of different ages and inhibit worm egg laying.
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Mitochondrial Disturbances, Tryptophan Metabolites and Neurodegeneration: Medicinal Chemistry Aspects
L. Szalárdy, P. Klivényi, D. Zádori, F. Fülöp, J. Toldi and L. Vécsei
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00344]

Neurodegenerative disorders, e.g. Parkinson’s, Huntington’s and Alzheimer’s diseases are distinct clinical and pathological entities sharing a number of leading features in their underlying processes. These common features involve the disturbances in the normal functioning of the mitochondria and the alterations in the delicate balance of tryptophan metabolism. The development of agents capable of halting the progression of these diseases is in the limelight of neuroscience research. This review highlights the role of mitochondria in the development of neurodegenerative processes with special focus on the involvement of neuroactive kynurenines both as pathological agents and potential targets and tools for future therapeutic approaches by providing a comprehensive summary of the main streams of rational drug design and giving an insight into present clinical achievements.
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Syntheses and In-vitro Evaluation of Novel Adamantane Based γ-Secretase Inhibitors
Adegoke O. Adeniji, Ryan M. Wells and Adeboye Adejare
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00345]

Abnormal processing of amyloid precursor protein (APP) by β- and γ-secretases to produce excess amyloid-β-peptide is believed to contribute to the pathophysiological cascade that results in Alzheimer’s disease.  γ-Secretase inhibition or modulation therefore represents a rational approach to the prevention and/or management of AD.  Here, we present the discovery and SAR of a class of novel adamantanyl sulfonamide based γ-secretase inhibitors. Activity evaluation was conducted on cell lines overexpressing APP (wild type and Swedish mutation).  Our results suggest size threshold and hydrogen bond formation are necessary for inhibitory activity. There was no correlation between compound activity, Log P, and the electronic effect of substituents on the aromatic ring.These compounds possess desirable drug like properties and results of the study can guide a pharmacophore based design of γ-secretase inhibitors.
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Recent Advances in the Research of 2,3-Diaryl-1,3-thiazolidin-4-one Derivatives as Potent HIV-1 Non-nucleoside Reverse Transcriptase Inhibitors
Ye Tian, Peng Zhan, Diwakar Rai, Jiyan Zhang, Erik De Clercq and Xinyong Liu
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00346]

Derived from the structure of 1H,3H-thiazolo[3,4-a]benzimidazoles (TBZs), 2,3-diaryl-1,3-thiazolidin-4-one derivatives became a novel class of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Under the guidance of continuous structureactivity relationship (SAR) analysis and molecular modeling, various structural modifications were carried out on nearly all the positions of the thiazolidin-4-one nucleus. Some of the derivatives proved to be highly effective against HIV-1 replication at 10–40 nanomolar concentration ranges with minimal cytotoxicities. In this article, the whole development of 2,3-diaryl-1,3-thiazolidin-4-one series from the discoveries to recent advances, their panoramic SAR studies and binding modes based on molecular modeling were reviewed, and also some enlightenments for further investigation were presented.
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Bifunctional Chelators in the Design and Application of Radiopharmaceuticals for Oncological Diseases
Dikran Sarko, Michael Eisenhut, Uwe Haberkorn and Walter Mier
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00347]

Radiopharmaceuticals constitute diagnostic and therapeutic tools for both clinical and preclinical applications. They are a blend of a tracer moiety that mediates a site specific accumulation and an effector: a radioisotope whose decay enables either molecular imaging or exhibits cytotoxic effects. Radioactive halogens and lanthanides are the most commonly used isotopes for radiopharmaceuticals. Due to their ready availability and the facile labeling metallic radionuclides offer ideal characteristics for applications in nuclear medicine. A stable link between the radionuclide and the carrier molecule is the primary prerequisite for in vivo applications. The radionuclide is selected according to its physical and chemical properties i.e. half-life, the type of decay, the energy emitted and its availability. Bifunctional chelating agents are used to stably link the radiometal to the carrier moiety of the radiopharmaceutical. The design of the bifunctional chelator has to consider the impact of the radiometal chelate on the biological properties of the target-specific pharmaceutical. Here, with an emphasis on oncology, we review applications of radiopharmaceuticals that contain bifunctional chelators, while highlighting successes and identifying the key challenges that need to be addressed for the successful translation of target binding molecules into tracers for molecular imaging and endoradiotherapy.
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Iron Chelators for the Treatment of Cancer
Yu Yu, Elaine Gutierrez, Zaklina Kovacevic, Federica Saletta, Peyman Obeidy, Yohan Suryo Rahmanto and Des R. Richardson
[Purchase Article] [BSP/CMC/E-Pub/00348]

The study of iron chelators as anti-tumor agents is still in its infancy. Iron is important for cellular proliferation and this is demonstrated by observations that iron-depletion results in cell cycle arrest and also apoptosis. In addition, many iron chelators are known to inhibit ribonucleotide reductase, the iron-containing enzyme that is the rate-limiting step for DNA synthesis. Desferrioxamine is a well known chelator used for the treatment of iron-overload disease, but it has also been shown to possess anti-cancer activity. Another class of chelators, namely the thiosemicarbazones, have been shown to possess anti-cancer activity since the 1950’s, although their mechanism(s) of action have only recently been more comprehensively elucidated. In fact, the redox activity of thiosemicarbazone iron complexes is thought to be important in mediating their potent cytotoxicity. Moreover, unlike typical iron chelators which simply act to deplete tumors of iron, several thiosemicarbazones (i.e., Bp44mT and Dp44mT) do not induce this effect, their anti-cancer efficacy being due to other mechanisms e.g., redox activity. Other reports have also shown that some thiosemicarbazones inhibit topoisomerase IIα, demonstrating that this class of agents have multiple molecular targets and act by various mechanisms. The most well characterized thiosemicarbazone iron chelator in terms of its assessment in humans is 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP). Observations from these clinical trials highlight the less than optimal activity of this ligand and several side effects related to its use, including myelo-suppression, hypoxia and methemoglobinemia. The mechanisms responsible for these latter effects must be elucidated and the design of the ligand altered to minimise these problems and increase efficacy. This review discusses the development of chelators as unique agents for cancer treatment.
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Deciphering the Antimicrobial Activity of Phenanthroline Chelators
Malachy McCann, Andrew Kellett, Kevin Kavanagh, Michael Devereux and André L. S. Santos
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00349]

The opportunistic fungal pathogen, Candida albicans, causes a range of diseases in susceptible individuals. The adverse side-effects of many of the current anti-fungal prescription drugs and the emergence of C. albicans isolates and other Candida species which are resistant to these compounds have accelerated the search for new drug candidates which have different modes of action. A family of metal chelators, which are based on the 1,10-phenanthroline core, exhibit excellent growth inhibitory effects in vitro against a number of Candida species, including clinical isolates. The compounds sequester transition metal ions, damage mitochondrial function and uncouple cell respiration. Additionally, fungal cell morphology undergoes dramatic changes and there is evidence of apoptotic cell death. Importantly, in vivo studies have confirmed that the compounds have an acceptably low toxicity profile.
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Antimicrobial Action of Chelating Agents: Repercussions on the Microorganism Development, Virulence and Pathogenesis
André L.S. Santos, Cátia L. Sodré , Roberta S. Valle , Bianca A. Silva , Érika A. Abi-chacra , Lívia V. Silva , Ana Luiza Souza-Gonçalves , Leandro S. Sangenito , Diego S. Gonçalves , Lucieri O.P. Souza , Vanila F. Palmeira, Claudia M. d’Avila-Levy , Lucimar F. Kneipp , Andrew Kellett , Malachy McCann and Marta H. Branquinha
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00350]

Infections caused by resistant microorganisms often fail to respond to conventional therapy, resulting in prolonged illness, increased treatment costs and greater risk of death. Consequently, the development of novel antimicrobial drugs is becoming more demanding every day since the existing drugs either have too many side-effects or they tend to lose effectiveness due to the selection of resistant strains.In view of these facts, a number of new strategies to obstruct vital biological processes of a microbial cell have emerged; one of these is focused on the use of metal-chelating agents, which are able to selectively disturb the essential metal metabolism of the microorganism by interfering with metal acquisition and bioavailability for crucial reactions. The chelation activity is able to inhibit the biological role of metal-dependent proteins (e.g., metalloproteases and transcription factors), disturbing the microbial cell homeostasis and culminating in the blockageof microbial nutrition, growth and development, cellular differentiation, adhesion to biotic (e.g., extracellular matrix components, cell and/or tissue) and abiotic (e.g., plastic, silicone and acrylic) structures as well as controlling the in vivo infection progression. Interestingly, chelating agents also potentiate the activity of classical antimicrobial compounds. The differences between the microorganism and host in terms of the behavior displayed in the presence of chelating agents could provide exploitable targets for the development of an effective chemotherapy for these diseases. Consequently, metal chelators represent a novel group of antimicrobial agents with potential therapeutic applications. This review will focus on the anti-fungal and anti-protozoan action of the most common chelating agents, deciphering and discussing their mode of action.
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Metal transport and homeostasis within the human body. Toxicity associated with transport abnormalities
Slawomir Potocki, Magdalena Rowinska-Zyrek, Danuta Witkowska, Monika Pyrkosz, Agnieszka Szebesczyk, Karolina Krzywoszynska and Henryk Kozlowski
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00351]

In this work, latest reports about metal toxicity, transport and homeostasis have been thoroughly described and discussed. Although diseases associated with transport and homeostasis abnormalities are those of great interest, still a variety of the phenomena associated with these processes are under debate.  In this paper, we try to summarize the newest theses on this topic, presenting contradictory points of view. We focus on toxic and essential metal pathways crossing and try to follow the exact metal binding molecules within the body and provide insight into the transport mechanism. Special attention is given to the mechanism of action of lately investigated metal transporters.
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Hydroxypyri(mi)dine-based chelators as antidotes of toxicity due to Aluminium and Actinides
M Amélia Santos,M Alexandra Esteves and Sílvia Chaves
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00352]

This review is focused on recent developments on hydroxypyri(mi)dines, as aluminium and actinide chelating agents to combat the toxicity due to accumulations of these metal ions  in human body resulting from excessive metal exposure. After a brief update revision of the most common processes of aluminum (Al) exposure, as well as the associated toxicities and pathologies, we will focus on the current available Al chelators and future perspective as potential antidotes of Al toxicity. Due to the similarity between Al and Fe, a major emphasis is given to the hydroxypyridinone and hydroxypyrimidinone chelators, since they are analogues of the current iron chelators in clinical use (DFP and DFO). This review includes issues such as molecular design strategies and corresponding effects on the associated physico-chemical properties, lipo-hydrophilic balance, toxicity, in vivo bioassays and current clinical applications. The hydroxypyri(mi)dine chelators are also suitable for other hard metal ions, such as the radiotoxic actinides, and so a brief review  is included on the applications of these chelators in scavenging actinides.
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Chelating agents for metal intoxication
Guido Crisponi, Valeria Marina Nurchi Miriam Crespo Alonso and Leonardo Toso
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00353]

In this paper we took into examination the use of chelation therapy for treating metal intoxication in humans. We divided this paper in four main parts: before all the principal causes of toxicity are exposed; second the chemical requirements (thermodynamic and kinetic), the interactions with the endogenous molecules and the target organs, as well as the biomedical restraints;as a third step the classes of chelators in use along with the specific treatments allowed are treated and as a final step the principal toxic metal ions are presented.Based on the presented material some conclusion are drawn on the state of art of metal chelation, and the basis are given for a rationale development of metal chelation, founded on chemical, biological and medical considerations.
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Chelating agents for the treatment of systemic iron overload
Yongmin Ma, Tao Zhou, Xiaole Kong and Robert C Hider
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00354]

The first successful therapeutic iron chelator was desferrioxamine which was introduced in the late 1960’s by Ciba (now Novartis). Desferrioxamine has been an extremely successful compound having received the MMW “Pharmaceutical of the year” award for 1991. It is a life saving and a life – prolonging drug which improves the quality of life. However it is not orally active and its administration is both uncomfortable and expensive.

Over the past twenty years there has been a growing interest in the orally active iron chelators, deferiprone and exjade, both having been extensively studied. The ability of these compounds to mobilize iron from the heart and endocrine tissue has presented the clinician with some advantages over desferrioxamine. Other orally active iron chelators are currently under development and one, FBS0701 is in clinical trial.

The critical features necessary for the design of therapeutically useful iron chelators is presented in this review, together with recent studies devoted to the design of such chelators. This newly emerging range of iron chelators will enable clinicians to apply iron chelation methodology to other disease states and to begin to design personalised chelation regimes.
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Selective Divalent Copper Chelation for the Treatment of Diabetes Mellitus
Garth J S Cooper
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00355]

Oxidative stress and mitochondrial dysfunction have been identified by many workers as key pathogenic mechanisms in ageing-related metabolic, cardiovascular and neurodegenerative diseases (for example diabetes mellitus, heart failure and Alzheimer’s disease). However, although numerous molecular mechanisms have been advanced to account for these processes, their precise nature remains obscure. This author has previously suggested that, in such diseases, these two mechanisms are likely to occur as manifestations of a single underlying disturbance of copper regulation. Copper is an essential but highly-toxic trace metal that is closely regulated in biological systems. Several rare genetic disorders of copper homeostasis are known in humans: these primarily affect various proteins that mediate intracellular copper transport processes, and can lead either to tissue copper deficiency or overload states. These examples illustrate how impaired regulation of copper transport pathways can cause organ damage and provide important insights into the impact of defects in specific molecular processes, including those catalyzed by the copper-transporting ATPases, ATP7A (mutated in Menkes disease), ATP7B (Wilson’s disease), and the copper chaperones such as those for cytochrome c oxidase, SCO1 and SCO2. In diabetes, impaired copper regulation manifests as elevations in urinary CuII excretion, systemic chelatable-CuII and full copper balance, in increased pro-oxidant stress and defective antioxidant defenses, and in progressive damage to the blood vessels, heart, kidneys, retina and nerves. Linkages between dysregulated copper and organ damage can be demonstrated by Cu^II-selective chelation, which simultaneously prevents/reverses both copper dysregulation and organ damage. Pathogenic structures in blood vessels that contribute to binding and localization of catalytically-active Cu^II probably include advanced glycation endproducts (AGEs), as well as atherosclerotic plaque: the latter probably undergoes AGE-modification itself. Defective copper regulation mediates organ damage through two general processes that occur simultaneously in the same individual: elevation of Cu^II-mediated pro-oxidant stress and impairment of copper-catalyzed antioxidant defence mechanisms. This author has proposed that diabetes-evoked copper dysregulation is an important new target for therapeutic intervention to prevent/reverse organ damage in diabetes, heart failure, and neurodegenerative diseases, and that triethylenetetramine (TETA) is the first in a new class of anti-diabetic molecules, which function by targetting these copper-mediated pathogenic mechanisms. TETA prevents tissue damage and causes organ regeneration by acting as a highly-selective CuII chelator which suppresses copper-mediated oxidative stress and restores anti-oxidant defenses. My group has employed TETA in a comprehensive programme of nonclinical studies and proof-of-principle clinical trials, thereby characterizing copper dysregulation in diabetes and identifying numerous linked cellular and molecular mechanisms though which TETA exerts its therapeutic actions. Many of the results obtained in nonclinical models with respect to the molecular mechanisms of diabetic organ damage have not yet been replicated in patients’ tissues so their applicability to the human disease must be considered as inferential until the results of informative clinical studies become available. Based on evidence from the studies reviewed herein, trientine is now proceeding into the later stages of pharmaceutical development for the treatment of heart failure and other diabetic complications.
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Sirtuin Modulators: Mechanisms and Potential Clinical Implications
S. Sánchez-Fidalgo, I.V. Lama, M. Sánchez-Hidalgo and C.A. de la Lastra
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00356]

In the last years, studies about longevity have highlighted that caloric restriction can be linked with a less normal agingassociated damage, and in the same way, with the activity of the Silent Information Regulator 2 (SIR2) gene. Sir2-like genes, known as sirtuins (SIRTs), have been found in organisms ranging from bacteria to mammals promoting health and survival. At the moment, it has been identified seven classes of SIRTs in mammalian and the understanding of many of them remains still rudimentary. However, they are in the spotlight by their potential protection against aging-associated diseases and have emerged as key mediators of longevity in evolutionarily distant organisms models. SIRTs are proteins found in numerous compartments within the cell, which are NAD(+)-dependent protein deacetylases and adenosine diphosphate (ADP)-ribosyltransferases. They catalyse a reaction in which NAD(+) and an acetylated substrate are converted into a deacetylated substrate, nicotinamide and a novel metabolite O-acetyl ADP ribose. Therefore, its enzymatic activity requires NAD(+), whichis a crucial molecule intermediary of many metabolic reactions in cells. Basically, SIRTs are mediators of aging process, they have the potential of ameliorating and taking part in important cellular processesassociated, such as metabolic homeostasis, tumorigenesis and cancer cell proliferation, inflammatory disorders, cardiovascular diseasesand neurodegeneration. This background opens up new lines of investigation into the modulation of SIRTs activity in order to develop novel therapeutic targets to these age-related diseases. Current experiments using molecule activators or inhibitors and genetically engineered animals havefacilitated new insights into the role of these enzymes and contributed to highlight some of the potentially relevant targets.This review is intended to provide an appreciation of the possible protection against aging-associated diseases by these enzymes,summarize novel underlying mechanisms and evaluate potential clinical applications.
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CuAAC Click Chemistry Accelerates the Discovery of Novel Chemical Scaffolds as Promising Protein Tyrosine Phosphatases Inhibitors
X.-P. He, J. Xie, Y. Tang, J. Li and G.-R. Chen
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00357]

Protein tyrosine phosphatases (PTPs) are crucial regulators for numerous biological processes in nature. The dysfunction and overexpression of many PTP members have been demonstrated to cause fatal human diseases such as cancers, diabetes, obesity, neurodegenerative diseases and autoimmune disorders. In the past decade, considerable efforts have been devoted to the production of PTPs inhibitors by both academia and the pharmaceutical industry. However, there are only limited drug candidates in clinical trials and no commercial drugs have been approved, implying that further efficient discovery of novel chemical entities competent for inhibition of the specific PTP target in vivo remains yet a challenge. In light of the click-chemistry paradigm which advocates the utilization of concise and selective carbon-heteroatom ligation reactions for the modular construction of useful compound libraries, the Cu(I)-catalyzed azidealkyne 1,3-dipolar cycloaddition reaction (CuAAC) has fueled enormous energy into the modern drug discovery. Recently, this ingenious chemical ligation tool has also revealed efficacious and expeditious in establishing large combinatorial libraries for the acquisition of novel PTPs inhibitors with promising pharmacological profiles. We thus offer here a comprehensive review highlighting the development of PTPs inhibitors accelerated by the CuAAC click chemistry.
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Supramolecular Approaches for Drug Development
K. Kawakami, M. Ebara, H. Izawa, N.M. Sanchez-Ballester, J.P. Hill and K. Ariga
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00358]

Various supramolecular systems can be used as drug carriers to alter physicochemical and pharmacokinetic characteristics of drugs. Representative supramolecular systems that can be used for this purpose include surfactant/polymer micelles, (micro)emulsions, liposomes, layer-by-layer assemblies, and various molecular conjugates. Notably, liposomes are established supramolecular drug carriers, which have already been marketed in formulations including AmBisome® (for treatment of fungal infection), Doxil® (for Kaposi’s sarcoma), and Visudyne® (for age-related macular degeneration and choroidal neovascularization). Microemulsions have been used oral drug delivery of poorly soluble drugs due to improvements in bioavailability and predictable of absorption behavior. Neoral®, an immunosuppressant used after transplant operations, is one of the most famous microemulsion-based drugs. Polymer micelles are being increasingly investigated as novel drug carriers and some formulations have already been tested in clinical trials. Supramolecular systems can be functionalized by designing the constituent molecules to achieve efficient delivery of drugs to desired sites in the body. In this review, representative supramolecular drug delivery systems, that may improve usability of candidate drugs or add value to existing drugs, are introduced.
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Recent Advances in the Development of 14-Alkoxy Substituted Morphinans as Potent and Safer Opioid Analgesics
M. Spetea and H. Schmidhammer
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00359]

Morphine and other opioid morphinans produce analgesia primarily through μ opioid receptors (MORs), which mediate beneficial but also the non-beneficial actions. There is a continued search for efficacious opioid analgesics with reduced complications. The cornerstone in the development of 14-alkoxymorphinans as novel analgesic drugs was the synthesis of the highly potent MOR agonist 14-O-methyloxymorphone. This opioid showed high antinociceptive potency but also the adverse effects associated with morphine type compounds. Further developments represent the introduction of a methyl and benzyl group at position 5 of 14-Omethyloxymorphone leading to the strong opioid analgesics 14-methoxymetopon and its 5-benzyl analogue, which exhibited less pronounced side effects than morphine although interacting selectively with MORs. Introduction of arylalkyl substituents such as phenylpropoxy in position 14 led to a series of extremely potent antinociceptive agents with enhanced affinities at all three opioid receptor types. During the past years, medicinal chemistry and opioid research focused increasingly on exploring the therapeutic potential of peripheral opioid receptors by peripheralization of opioids in order to minimize the occurrence of centrally-mediated side effects. Strategies to reduce penetration to the central nervous system (CNS) include chemical modifications that increase hydrophilicity. Zwitterionic 6-amino acid conjugates of 14-O-alkyloxymorphones were developed in an effort to obtain opioid agonists that have limited access to the CNS. These compounds show high antinociceptive potency by interacting with peripheral MORs. Opioid drugs with peripheral site of action represent an important target for the treatment of severe and chronic pain without the adverse actions of centrally acting opioids.
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Role of microRNAs in Gynecological Pathology
J. Gilabert-Estellés, A. Braza-Boïls, L.A. Ramón, E. Zorio, P. Medina, F. España and A. Estellés
[Purchase Article] [BSP/CMC/E-Pub/00360]

microRNAs (miRNAs) are 21-22 nucleotide non-coding RNAs that regulate gene expression and play fundamental roles inbiological processes. These small molecules bind to target mRNAs, leading to translational repression and/or mRNA degradation.Aberrant miRNA expression is associated with several human diseases such as cancer, cardiovascular disorders, inflammatory diseases and gynecological pathology. The present article reviews the role of miRNAs in four gynecological disorders that affect the ovary or the uterus, one benign and frequent disease (endometriosis) that is classified as a tumor-like lesion and three malignant gynecological diseases (endometrial, cervical and ovarian cancers). Endometriosis, defined as the presence of endometrium outside the uterus, is one of the most frequent benign gynecological diseases.Similarly to tumor metastasis, endometriotic implants require neovascularization to proliferate, invade the extracellular matrix and establish an endometriotic lesion. Despite its high prevalence and incapacitating symptoms, the exact pathogenic mechanism of endometriosis remains unsolved. A relationship between endometriosis and gynecological cancer, especially ovarian cancer, has beenreported. Endometriosis is a multifactorial and polygenic disease, and emerging data provide evidence that a dysregulation of miRNA expression may be involved. miRNAs appear to be potent regulators of gene expression in endometriosis, raising the prospect of usingmiRNAs as biomarkers and therapeutic tools in this disease.In cancer, miRNAs have an important role as regulatory molecules, acting as oncogenes (oncomiRs) or tumor suppressors. Endometrialcancer is one of the most frequent gynecological malignancies in the developed countries. Cervical cancer, also one of the most common cancers in women, is associated with high-risk human papillomaviruses although this infection alone may not be enough to induce themalignant transformation. Ovarian cancer is the fifth leading cause of all cancer-related deaths among women. Over 80% of cases arediagnosed at an advanced stage, with a reduced five-year survival rate. Recent studies have shown that miRNAs are aberrantly expressed in different human cancer types, including endometrial, cervical and ovarian cancer, and that specific dysregulated miRNAs may act as biomarkers of patients’ outcome. Recently, miRNAs have been detected in serum and plasma, and circulating miRNA expression profiles have now been associated with a range of different tumor types. Their accessibility in peripheral blood and stability given the fact that miRNAs circulate confined within exosomes, make researchers foster hope in their role as emerging biomarkers of cancer and other disorders. The development of therapies that might block the expression or mimic the functions of miRNAs could represent new therapeutic strategies for any of the aforementioned gynecological disorders.
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The Quinoline Imidoselenocarbamate EI201 Blocks AKT/mTOR Pathway and Targets Cancer Stem Cells Leading to a Strong Antitumor Activity
E. Ibáñez, A. Agliano, C. Prior, P. Nguewa, M. Redrado, I. González, D. Plano, J.A. Palop, C. Sanmartín and A. Calvo
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00361]

Methylimidoselenocarbamates have previously proven to display potent antitumor activities. In the present study we show that these compounds act as multikinase inhibitors. We found that the most effective compound, quinoline imidoselenocarbamate EI201, inhibits the PI3K/AKT/mTOR pathway, which is persistently activated and contributes to malignant progression in various cancers. EI201 blocked the phosphorylation of AKT, mTOR and several of its downstream regulators (p70S6K and 4E-BP1) and ERK1/2 in PC-3, HT-29 and MCF-7 cells in vitro, inducing both autophagy and apoptosis. EI201 also contributes to the loss of maintenance of the selfrenewal and tumorigenic capacity of cancer stem cells (CSCs). 0.1 μmol/L EI201 triggered a reduction in size and number of tumorspheres in PC-3, HT-29 and MCF-7 cells and 4 μmol/L induced the elimination of almost all the tumorspheres in the three studied cell lines. In addition, EI201 suppressed almost 80% prostate tumor growth in vivo (p < 0.01) compared to controls at a relatively low dose (10 mg/kg) in a mouse xenograft model. There was a significant decrease in the subcutaneous primary tumor [18F]-FDG uptake (76.5% reduction, p < 0.05) and in the total tumor burden (76.8% reduction, p < 0.05) after EI201 treatment compared to vehicle control, without causing toxicity in mice. Taken together, our results support further development of EI201 as a novel multi-kinase inhibitor that may be useful against cancers with aberrant upregulation of PI3K/AKT and MAPK signaling pathways.
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Cadmium and Its Epigenetic Effects
B. Wang, Y. Li, C. Shao, Y. Tan and L. Cai
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00362]

Cadmium (Cd) is a toxic, nonessential transition metal and contributes a health risk to humans, including various cancers and cardiovascular diseases; however, underlying molecular mechanisms remain largely unknown. Cells transmit information to the next generation via two distinct ways: genetic and epigenetic. Chemical modifications to DNA or histone that alters the structure of chromatin without change of DNA nucleotide sequence are known as epigenetics. These heritable epigenetic changes include DNA methylation, post-translational modifications of histone tails (acetylation, methylation, phosphorylation, etc), and higher order packaging of DNA around nucleosomes. Apart from DNA methyltransferases, histone modification enzymes such as histone acetyltransferase, histone deacetylase, and methyltransferase, and microRNAs (miRNAs) all involve in these epigenetic changes. Recent studies indicate that Cd is able to induce various epigenetic changes in plant and mammalian cells in vitro and in vivo. Since aberrant epigenetics plays a critical role in the development of various cancers and chronic diseases, Cd may cause the above-mentioned pathogenic risks via epigenetic mechanisms. Here we review the in vitro and in vivo evidence of epigenetic effects of Cd. The available findings indicate that epigenetics occurred in association with Cd induction of malignant transformation of cells and pathological proliferation of tissues, suggesting that epigenetic effects may play a role in Cd toxic, particularly carcinogenic effects. The future of environmental epigenomic research on Cd should include the role of epigenetics in determining long-term and late-onset health effects following Cd exposure.
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Diagnosis and Therapeutic Approaches to Transthyretin Amyloidosis
Y. Ando and M. Ueda
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00364]

Hereditary amyloidogenic transthyretin (TTR) (ATTR) amyloidosis is an autosomal dominant form of fatal hereditary amyloidosis. Owing to progress in biochemical and molecular genetic analyses, this disease is now believed to occur worldwide. As of today, reports of about 120 different points of single or double mutations, or a deletion in the TTR gene have been reported, and several different phenotypes of ATTR amyloidosis have been documented. In addition, since liver transplantation has been established to halt the progression of hereditary ATTR amyloidosis in the early stage, rapid and reliable diagnostic system for ATTR amyloidosis is needed. On the other hand, senile systemic amyloidosis (SSA) derived from wild-type (WT) TTR affects primarily in the heart and lungs and occasionally in carpal ligaments in the elderly. To perform accurate diagnosis and effective treatments, we should distinguish between hereditary ATTR amyloidosis and SSA by means of genetic and proteomic analyses. The liver transplantation for hereditary ATTR amyloidosis has become a well-established treatment, because the main source of serum variant TTR is shut out. However, this treatment has several problems, such as expensive medical costs, lifelong administration of immunosuppressants, non-indication for the mutated-TTR gene carriers without clinical symptoms, shortage of liver donors, and further development of cardiac and ocular disorders. Therefore, we and other ATTR amyloidosis research groups have been investigating the possibility of stabilization of variant TTR, gene therapy, and immunotherapy for ATTR amyloidosis on the basis of TTR amyloid formation mechanism.
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Nearly 200 X-Ray Crystal Structures of Transthyretin: What Do They Tell Us About This Protein and the Design of Drugs for TTR Amyloidoses?
S.K. Palaninathan
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00365]

Transthyretin (TTR), a β-strand rich tetrameric protein present in human serum and cerebrospinal fluid is involved in the transport of thyroxine and retinol binding protein:retinol complex (holo-RBP). TTR forms two T4 binding sites at the center of the dimer-dimer interface and contains holo-RBP binding sites on both faces of the tetramer. Dissociation of TTR tetramers followed by misfolding and misassembly results in amyloid fibril formation, the causative agent of four neurodegenerative diseases. Misfolding of wild type TTR in humans over 60 years of age is linked to a sporadic amyloid disease called senile systemic amyloidosis. Single point mutations enhance the amyloidogenicity of TTR, causing familial amyloid cardiomyopathy, familial amyloid polyneuropathy, and central nervous system selective amyloidosis. To date, nearly 200 X-ray crystal structures of TTR and their complexes have been solved. They have provided potential insights into its structure-function relationships with molecular partners, and its interactions with small molecule ligands that inhibit tetramer destabilization and amyloid formation. This review will focus on the key findings of the structural studies of TTR that provided atomic level description of its architecture, the mechanistic role of structural components involved in its function and misfolding, and the progress and limitations towards the design of selective inhibitors for TTR amyloidoses.
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Transthyretin Deposition in Familial Amyloidotic Polyneuropathy
M.J. Saraiva, J. Magalhães, N. Ferreira and M. R. Almeida
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00366]

The subject of the review is on hereditary transthyretin (TTR) amyloidosis which is a genetically transmitted disease that results from a mutation in the gene encoding the plasma TTR protein. TTR is a transport protein for thyroid hormones and vitamin A and is predominantly synthesised in the liver. Although originally regarded as a rare disease, it is now becoming clear that many kindreds exist worldwide. Current knowledge and hypotheses on the biology of TTR, mechanisms of TTR amyloid fibril formation, phenotypic consequences TTR amyloid deposition and pre-clinical models of the disease will be discussed.
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Methods to Evaluate the Inhibition of TTR Fibrillogenesis Induced by Small Ligands
G. Arsequell and A. Planas
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00367]

Transthyretin is an amyloidogenic protein associated with several amyloidosis, namely familial amyloidotic polyneuropathy, familial amyloidotic cardiomyopathy, and central nervous system selective amyloidosis, familial rare diseases caused by single point mutants, and senile systemic amyloidosis associated with wild-type TTR. The current model for amyloid fibril formation involves initial dissociation of the native TTR tetramer into non-native monomers which associate into soluble oligomers and protofibrils that evolve to mature amyloid deposits. A number of efforts are addressed to identify small molecules targeting the formation, clearance, or assembly of toxic aggregates as a promising therapeutic strategy to treat amyloidosis. This review classifies and summarizes the different strategies and assays that have been developed in vitro, ex vivo, and in vivo as tools to screen libraries of compounds or to test compounds from rational design in the search of drug candidates for the treatment of TTR-associated amyloidosis. Depending on the property they measure, the assays are classified as: a) in vitro assays that monitor protein aggregation and/or fibril formation, b) in vitro assays that monitor binding to native protein, c) ex vivo TTR plasma selectivity assays, d) in vitro assays for tetrameric TTR stabilization, e) cellular assays, and f) animal models to evaluate amyloidosis inhibitors.
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TTR Fibril Formation Inhibitors: Is there a SAR?
S. Nencetti and E. Orlandini
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00368]

Transthyretin is a homotetrameric protein that carries thyroxine and retinol binding protein in plasma and is associated with a variety of amyloid diseases. One approach to the potential treatment of TTR amyloidosis is the stabilization of the native tetramer, over the dissociative transition state, through the binding of small molecules; this increases the kinetic barrier for tetramer dissociation and prevents protein misfolding. Several molecules discovered through focused screening, or created utilizing the structure-based design, were studied to identify the structural features that could make up for a good candidate drug. In this review, we examine several different chemical classes of TTR fibril formation inhibitors, highlighting the structural modifications that have led to an improvement or to a decrease of their potency and/or selectivity.
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Computational Studies on Transthyretin
G. Ortore and A. Martinelli
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00369]

Among the 23 different fibril proteins described in human amyloidosis, transthyretin is associated with the most common hereditary form of the disease and its knowledge is corroborated through about 150 crystal structures in addition to thousands of small ligands tested as fibril formation inhibitors. In spite of the large amount of available data, the mechanism of transthyretin aggregation and its inhibition through binding with small ligands is not clear. In the last decade, many groups of researchers have attempted to apply computational procedures to simulate these phenomena, with the aim of understanding them in depth and in order to rationalize the design of new promising inhibitors. A summary of the main molecular dynamics, docking, and structure-activity relationship studies carried out on transthyretin are reviewed here, and the most successful results and new trends are described in detail.
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Clinical utility of biomarkers in premature atherosclerosis
Anna-Maria Kampoli, Dimitris Tousoulis, Nikolaos Papageorgiou, Zoi Pallatza, Georgia Vogiatzi, Alexandros Briasoulis, Emmanouel Androulakis, Costas Toutouzas, Pavlos Stougianos, Costas Tentolouris and Christodoulos Stefanadis
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00370]

Atherosclerosis is a very complex procedure responsible for the development of coronary artery disease which is the leading cause of death in the civilized world. The obvious pandemic character of atherosclerosis augments the need to discover an ideal biomarker, which will be able to facilitate the clinical diagnosis of the atherosclerosis from the physicians especially in the early stages of the atherosclerotic process. Among the biomarkers that are already used there are classical ones, such as c-reactive protein, interleukins, tumour necrosis factor, apolipoproteins, fibrinogen, homocysteine, and novel promising ones such as lipoprotein-associated phospholipase, asymmetric dimethylarginine, myeloperoxidase, cathepsins and cystatin C. The possibility of combining circulating biomarkers with other methods such as non-invasive and invasive imaging is clinically attractive because this could contribute to improved diagnosis and understanding of premature atherosclerosis pathogenesis.
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Evaluating oxidative stress in human cardiovascular disease: Methodological aspects and considerations
Regent Lee, Marios Margaritis, Keith M Channon and Charalambos Antoniades
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00371]

Oxidative stress is a key feature in atherogenesis, since reactive oxygen species (ROS) are involved in all stages of the disease, from endothelial dysfunction to atheromatic plaque formation and rupture. It is therefore important to identify reliable biomarkers allowing us to monitor vascular oxidative stress status. These may lead to improved understanding of disease pathogenesis and development of new therapeutic strategies. Measurement of circulating biomarkers of oxidative stress is challenging, since circulation usually behaves as a separate compartment than the individual structures of the vascular wall. However, measurement of stable products released by the reaction of ROS and vascular/circulating molecular structures is a particularly popular approach. Serum lipid hydroperoxides , plasma malondialdehyde or urine F2-isoprostanes are widely used and have a prognostic value in cardiovascular disease. Quantification of oxidative stress at a tissue level is much more accurate. Various chemiluminescence and high performance liquid chromatography assays have been developed over the last few years, and some of them are extremely accurate and specific. Electron spin resonance spectroscopy and micro-electrode assays able to detect ROS directly, are also widely used. In conclusion, measurement of circulating biomarkers of oxidative stress is valuable, and some of them appear to have predictive value in cardiovascular disease. However, these biomarkers do not reflect intravascular oxidative stress and therefore cannot be used as therapeutic targets or markers to monitor pharmacological treatments in clinical settings. Measurement of vascular oxidative stress status is still the only reliable way to evaluate the involvement of oxidative stress in atherogenesis.
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Assessment of Acute Coronary Syndromes: Focus on Novel Biomarkers
Dimitris Tousoulis, George Hatzis, Nikolaos Papageorgiou, Emmanuel Androulakis, George Bouras, Anastasios Giolis, Konstantinos Bakogiannis, Gerasimos Siasos, George Latsios, Charalambos Antoniades and Christodoulos Stefanadis
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00372]

Coronary artery disease (CAD) is the leading cause of mortality in Western Societies and several developing countries. Recent evidence suggests that most detrimental clinical manifestations of CAD, such as acute coronary syndromes (ACS), are the outcome of inflammatory processes that lead to plaque formation and rupture and eventually to ischemia and potentially myocardial necrosis. Neither of the traditionally used biomarkers is thought to be the gold standard in detection of myocardial ischemia or necrosis. A biomarker that could detect quite early the ischemic myocardium as well as define the risk of a future event with high sensitivity and specificity is still lacking. Several biomarkers, implicated in the pathogenesis and clinical evolution of atherosclerosis, have emerged as potent biomarkers for early detection of myocardial ischemia. In the current review, we summarize recent evidence of the most promising biomarkers and discuss their potential role in clinical practice in patients suffering from ACSs.
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Predictive Value of Biomarkers in Patients with Heart Failure
Dimitris Tousoulis, Evangelos Oikonomou, Gerasimos Siasos, Evangelos D. Papadimitriou, Maria Limperi, Christina Chrysohoou, Marietta Charakida, Athanasios Trikas, Athanasios G. Papavassiliou and Christodoulos Stefanadis
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00373]

Heart failure (HF) is a complex syndrome with high morbidity and mortality while, myocardial injury, hemodynamic overload, genetic, neurohormonal, inflammatory and biochemical factors are implicated in the development and progression of the disease. Interestingly, despite the development of several diagnostic tests, HF diagnosis remains clinical, based on symptoms and signs, while there is a poor relationship between symptoms and the prognosis of HF. Several biomarkers have recently been examined for their efficacy to predict outcome and assess prognosis of HF patients. The best study sub-group is the neurohormones including the natriuretic peptides, the components of the renin-angiotensin-aldosterone system and the catecholamines. Others sub-groups of biomarkers include inflammatory and oxidative stress markers, extracellular matrix remodeling markers and myocardial injury markers (such as troponins I and T). Nevertheless, it is difficult to access a single biomarker fulfilling our need to evaluate prognosis and guiding treatment in acute or chronic HF patients, thus the predictive ability of combined biomarkers is recently under research. Therefore, further studies are needed to elucidate the clinical significance of these biomarkers.
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Monitoring Calcific Aortic Valve Disease: The Role of Biomarkers
George Latsios, Dimitris Tousoulis, Emmanuel Androulakis, Nikolaos Papageorgiou, Andreas Synetos, Costas Tsioufis,  Kostas Toutouzas and Christodoulos Stefanadis
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00374]

Calcific aortic valve disease is a common disease in the elderly associated with significant morbidity and mortality. It was once described as a passive degenerative process during which serum calcium attaches to the valve surface and binds to the leaflet. However, during the last decade mounting evidence demonstrated that this disease has an active biologic process with numerous signaling pathways. The histological hallmarks seem to be inflammation, oxidized lipids-also detectable in aortic valve lesions-and a remodeling of the extracellular matrix leading to bone formation. Over the years, growing evidence has indicated the risk factors for calcific aortic stenosis including lipids, hypertension, male gender, renal failure, and diabetes. Additional monitoring tools, such as molecular imaging, could improve risk stratification, while assessment of severity and prognosis of patients with chronic aortic regurgitation, is desirable. Also, several studies have investigated the role of biomarkers regarding their utility in the screening of calcific aortic valve disease and their putative clinical value, though their role still remains undetermined.
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Biomarkers Determining Cardiovascular Risk in Patients with Kidney Disease
Gerasimos Siasos, Dimitris Tousoulis, Stavroula Michalea, Evangelos Oikonomou, Christina Kolia, Stamatis Kioufis, Andreas Synetos, Athanasios G. Papavassiliou and Christodoulos Stefanadis
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00375]

Cardiovascular disease (CVD) remains the leading cause of premature death in patients with chronic kidney disease (CKD). Recent evidence suggests that the interaction of ‘‘classic’’ and ‘‘non-classic” cardiovascular risk factors is an important contributor in excessive and accelerated CVD in patients with CKD. Indeed, the imposing cardiovascular morbidity and mortality of CKD patients corresponds to a significant extent in endothelial dysfunction, inflammation, oxidative stress, vascular calcification and volume overload. In addition, the kidney’s function decline is independently associated with CVD in patients with kidney disease. Currently, there is a growing interest in the role of new biomarkers that are closely correlated with the aforementioned novel risk factors in CKD population. In current review, we summarize the so far acquired knowledge of the most promising biomarkers and we discuss the major clinical correlations of novel risk factors and new biomarkers of CVD in CKD patients, their predictive value for future cardiovascular events and their use in the treatment monitoring of this population.
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Circulating endothelial progenitor cells as biomarkers for prediction of cardiovascular outcomes
Konstantinos Bakogianis, Dimitris Tousoulis, Emmanuel Androulakis, Alexandros Briasoulis, Nikolaos Papageorgiou, Georgia Vogiatzi, Anna-Maria Kampoli, Marietta Charakida, Gerasimos Siasos, George Latsios, Charalambos Antoniades and Christodoulos Stefanadis
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00376]

Experimental studies suggest that bone marrow-derived endothelial progenitor cells (EPCs) play an important role in the maintenance of endothelial integrity and hemostasis. The number of circulating EPC has been shown to be inversely correlated with cardiovascular risk factors and vascular function and to predict cardiovascular events independent of both traditional and non-traditional risk factors. Thus, EPCs provide a clinical advantage over the use of other biomarkers as their measurement is directly associated with endothelial function, and available evidence suggests that they are consistently and significantly associated with a spectrum of cardiovascular complications, such as acute coronary syndromes and coronary artery disease.  However, many issues in the field of EPC isolation and identification, particularly in regards to the effective and unequivocal molecular characterization of these cells still remain unresolved. In addition, simple EPC counts do not adequately describe cardiovascular disease risk. This limitation is attributable to variation in the definition of EPCs, the number of existing cardiovascular risk factors in different patients as well as a difference in the interaction between EPCs and other hematopoietic progenitor, inflammatory cells or platelets.
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Biomarkers as a guide of medical treatment in cardiovascular diseases
Vavuranakis M, Kariori M, Kalogeras K, Vrachatis D, Moldovan C, Tousoulis D and Stefanadis C
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00377]

There is increasing interest in utilizing novel markers of cardiovascular disease risk, and consequently, there is a need to assess the value of their use. In this paper, we will review the role of biomarkers in acute coronary syndromes, heart failure and risk stratification for cardiovascular events as guide for treatment scribing. In particular, high sensitivity assays for troponin evaluation detect with greater precision patients with elevated troponin. Therefore, direct and appropriate management is succeeded in these patients with reduction of complications due to later treatment, as well. Regarding heart failure, randomized trials that have evaluated biomarker guided treatment approach have not succeeded in establishing specific results for natriuretic peptides (BNP, NT-proBNP) use in terms of therapy guidance. Apart from them, a variety of novel or already used biomarkers, have been tested by small trials for heart failure management, without however, managing to dominate in every day care. Finally, as far as risk stratification for cardiovascular events is concerned, hsCRP has proved to be a strong but doubted biomarker. Therefore, lifestyle and behavioral modification remain the cornerstone of primary prevention.
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Functional, Genetic and Biochemical Biomarkers of Peripheral Arterial DiseaseMarietta Charakida, Stefano Masi and Dimitris Tousoulis
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00378]

Patients with peripheral arterial disease (PAD) suffer from increased cardiovascular morbidity and mortality. The ankle brachial index has been widely used as an easy tool to identify and stratify patients with PAD, however its predictive value remains limited. Higher levels of inflammatory and prothrombotic biomarkers have been associated with the development and progression of PAD and recent data suggest that may provide additional information for cardiovascular risk stratification of these patients. The current review will present available information on functional, genetic and biochemical biomarkers which have been associated with PAD in cross sectional and large prospective studies and highlight their additive value for risk stratification of these patients.
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The Role of microRNAs in Cardiovascular Disease
Nikolaos Papageorgiou, Dimitris Tousoulis, Emmanuel Androulakis, Gerasimos Siasos, Alexandros Briasoulis, Georgia Vogiatzi, Anna-Maria Kampoli, Eleftherios Tsiamis, Costas Tentolouris and Christodoulos Stefanadis
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00379]

Cardiovascular disease, which is multifactorial and can be influenced by a multitude of environmental and heritable risk factors, remains a  major health problem, even though its pathophysiology is far from been elucidated.  Discovered just over a decade ago, microRNAs comprise short, non-coding RNAs, which have evoked a great deal of interest, due to their importance for many aspects of homeostasis and disease. Hundreds of different microRNAs are constantly being reported in various organisms. According to a growing body of literature, they have been implicated in the regulation of human physiological processes. More specifically, miRNAs are expressed in the cardiovascular system and could have crucial roles in normal development and physiology, as well as in disease development. Furthermore, they have been shown to participate in cardiovascular disease pathogenesis including atherosclerosis, coronary artery disease, myocardial infarction, heart failure and cardiac arrhythmias. In contrast to our original thought, miRNAs exist in circulating blood and are relatively stable, thus, they could be proved useful as biomarkers in that state. Understanding the underlying mechanisms, in which these major regulatory gene families are implicated, will provide novel opportunities for diagnostics and therapy of cardiovascular diseases.
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Biomarkers associated with vulnerable atheromatous plaque
Toshio Imanishi and Takashi Akasaka
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00380]

Atherogenesis progresses through lipid core expansion and macrophage accumulation at the plaque, leading to fibrous cap rupture. Plaque rupture occurs in the plaque fissuring at one point, which ultimately brings the platelets into contact with the content of the lipid core, and the blood coagulation factors together with tissue factor. The transition from stable atherosclerotic plaques to vulnerable plaques finally resulting in the plaque rupture is the consequence of an inflammatory reaction. This process involves complex cellular interactions engaging many mediators, chemokines, and cytokines which can be measured in serum and plasma and thus serve as biomarkers that differentiate the pathophysiologic phases of disease progression. Pathological studies support the risk of inflammation in high-risk patients to a greater extent than the degree of vessel stenosis. It is therefore important to identify reliable biomarkers allowing us to monitor vascular inflammatory state.

In clinical investigations, several new biomarkers have been identified that provide increasing diagnostic and prognostic significance. However, more confirmatory studies are required to clinical use. Furthermore, assays for automated use need to be developed, and cut-off levels need to be defined. Further technological advances will likely facilitate the use of multimarker profiling to identify with coronary vulnerable plaque.
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Chelating agents for neurodegenerative diseases
Roberta J Ward, David T Dexter and Robert R Crichton
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00382]

It has become apparent in the last years that metal ion homeostasis and its dysfunction which results in increased accumulation in brain, notably of copper, iron and zinc, may be associated with a number of neurodegenerative diseases, such that chelation therapy may be one therapeutic option. We briefly outline chelators currently available together with strategies to develop new chelators capable of crossing the blood-brain-barrier. The homeostasis of iron in brain together with changes in brain iron with ageing are reviewed as well as the role of iron in Parkinson’s disease, and the potential of chelation therapy in PD. Copper and zinc homeostasis in brain and age associated changes are then outlined, along with a discussion of the possible involvement of Zn, Cu and Fe in Alzheimer’s disease. We conclude with a brief summary of chelation therapy in AD.
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Compounds derived from endophytes: A review of phytochemistry and pharmacology
Rosa Martha Perez Gutierrez, Adriana Maria Neira Gonzalez and Alethia Muñiz Ramirez
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00383]

Objective: Endophytes, microorganisms that reside in the tissues of living plants, are a promising source of novel compounds with biological activity, or an alternative source of compounds originally isolated from higher plants. The intent of this review is to provide insights into their occurrence in nature, the products that they make, and how some of these organisms are beginning to show some potential for human use.

Methods: Information for analysis of endophytic microorganisms was obtained from libraries and Internet scientific databases such as Scirus, Google Scholar, CAB-Abstracts, MedlinePlus, PubMed, SciFinder, Scopus and Web of Science.

Results: Many of the compounds reported here were isolated exclusively from endophytes in culture, while other compounds had been previously reported as chemical constituents of higher plants. A survey of the literature shows endophytic microorganisms are mainly known for their alkaloids with cytotoxic, chemopreventive, anti-metastatic and antitumor properties used in the treatment of several types of cancer. The studies of these alkaloids highlight the existence of various potential leads for the development of novel anti-cancer agents. Modern pharmacology studies demonstrated that their crude extracts and active compounds possess wide pharmacological actions, especially for anti-microbial drug discovery, with neuroprotective, antioxidant, nematicidal, antiplasmodium, anti-inflammatory activities.

Aim of the review: This review summarizes the up-to-date and comprehensive information on compounds from endophytes fungi from 1995 to 2011 that relates to 313 compounds isolated from endophytic microorganisms, together with the botany, phytochemistry, pharmacology and toxicology, and discusses possible trends and the scope for future research of endophytes.
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New therapeutic approaches by using microorganism-derived compounds
Amedeo Amedei and Mario Milco D'Elios
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00384]

It has become apparent in the last years that metal ion homeostasis and its dysfunction which results in increased accumulation in brain, notably of copper, iron and zinc, may be associated with a number of neurodegenerative diseases, such that chelation therapy may be one therapeutic option. We briefly outline chelators currently available together with strategies to develop new chelators capable of crossing the blood-brain-barrier. The homeostasis of iron in brain together with changes in brain iron with ageing are reviewed as well as the role of iron in Parkinson’s disease, and the potential of chelation therapy in PD. Copper and zinc homeostasis in brain and age associated changes are then outlined, along with a discussion of the possible involvement of Zn, Cu and Fe in Alzheimer’s disease. We conclude with a brief summary of chelation therapy in AD.
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Pitfalls in Lung Cancer Molecular Pathology: How to Limit them in Routine Practice?
M. Ilie and P. Hofman
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00385]

New treatment options in advanced non-small cell lung carcinoma (NSCLC) targeting activating epidermal growth factor receptor (EGFR) gene mutations and other genetic alterations demonstrated the clinical significance of the molecular features of specific subsets of tumors. Therefore, the development of personalized medicine has stimulated the routine integration into pathology departments of somatic mutation testing. However, clinical mutation testing must be optimized and standardized with regard to histological profile, type of samples, pre-analytical steps, methodology and result reporting. Routine molecular testing in NSCLC is currently moving beyond EGFR mutational analysis. Recent progress of targeted therapies will require molecular testing for a wide panel of mutations for a personalized molecular diagnosis. As a consequence, efficient testing of multiple molecular abnormalities is an urgent requirement in thoracic oncology. Moreover, increasingly limited tumor sample becomes a major challenge for molecular pathology. Continuous efforts should be made for safe, effective and specific molecular analyses. This must be based on close collaboration between the departments involved in the management of lung cancer. In this review we explored the practical issues and pitfalls surrounding the routine implementation of molecular testing in NSCLC in a pathology laboratory.
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The Progress of Selective Fluorescent Chemosensors by Boronic Acid
S. Huang, M. Jia, Y. Xie, J. Wang, W. Xu and H. Fang
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00386]

As a cutting-edge scientific research field, the detection of biological active substance is very important for the prevention, diagnosis and treatment of diseases. Boronic acid interacts with cis-1,2-or 1,3-diol to form five- or six-membered ring which could be used as the reporter of fluorescent sensors to probe carbohydrates and bioactive substance. This review summarizes the recent progress of boronic acid sensors for carbohydrates, L-dopamine, fluoride, copper ion, mercury ion and hydrogen peroxide. In this article, we will briefly introduce the chemistry of boronic acid, and then give a description of the fluorescence properties of each boronic acid sensor, such as fluorescence intensity change, excitation and emission wavelengths, quantum yields and water solubility. In addition, we summarize the mechanisms of fluorescent signal output for some representative sensors and discuss the strategies for developing new fluorescent probes.
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The Chemistry and Biology of the Bryostatins: Potential PKC Inhibitors in Clinical Development
B.-F. Ruan and H.-L. Zhu
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00387]

The bryostatins, powerful protein kinase C (PKC) agonists, are a family of complex macrolactone natural products. They are originally isolated from the marine bryozoan Bugula neritina. So far tweenty bryostatins have been obtained naturally and exhibit a remarkable range of biological activities, including antineoplastic activity, synergistic chemotheoreputic activity, cognition and memory enhancement, etc. Of the 20 known members, the most extensively studied is bryostatin 1. The effects of bryostatin 1 are mainly linked to its ability of selectively modulating the function of various individual protein kinase C (PKC) isozymes. Moreover, bryostatin 1, or in combination with other agents, has been proposed for phase I and phase II clinical trials. The bryostatins have excellent biological properties, but are scarce in nature. Therefore, it has attracted considerable interests in structural modification over the past two decades. In this review, we will attempt to summarize the main developments that have occurred in the structure-activity relationship and biology of bryostatins over the period 1982–2011.
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Some Recent Approaches of Biologically Active Substituted Pyridazine and Phthalazine Drugs
M. Asif
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00388]

Nitrogen atom containing heterocyclic compounds, pyridazines, pyridazinones and phthalazines are important structural feature of many biologically active compounds and show diverse pharmacological properties. Pyridazines and phthalazines hold considerable interest relative to the preparation of organic intermediates and physiologically active compounds. On the basis of literature, pyridazines, pyridazinone and phthalazines further focus our attention because of their easy fictionalization at various ring positions, which makes them attractive synthetic compounds for designing and development of the novel pyridazines and phthalazines drugs in future.
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Disulfide Linkage: A Potent Strategy in Tumor-Targeting Drug Discovery
J. Wang, S. Li, T. Luo, C. Wang and J. Zhao
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00389]

Targeted drug delivery has attracted much attention in improving the curative effect of existing chemotherapy drugs, and many published studies have suggested the disulfide linkage for key unit in constructing a targeting conjugate. An appropriate disulfide bond, through which cytotoxic agents and drug carriers were linked together, would guarantee the conjugate stable during circulation in vivo and, readily cleavable to release the drug. The aim of this article is to review various design strategies based on disulfide linkage which have been used to assemble a tumor-targeting conjugate, with the goal of presenting a promising avenue in the field of targeted drug delivery.
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Protocatechuic Acid and Human Disease Prevention: Biological Activities and Molecular Mechanisms
R. Masella, C. Santangelo, M. D’Archivio, G. LiVolti, C. Giovannini and F. Galvano
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00390]

Epidemiological evidence has shown that a high dietary intake of vegetables and fruit rich in polyphenols is associated with a reduction of cancer incidence and mortality from coronary heart disease. The healthy effects associated with polyphenol consumption have made the study of the mechanisms of action a matter of great importance. In particular, the hydroxybenzoic acid protocatechuic acid (PCA) has been eliciting a growing interest for several reasons. Firstly, PCA is one of the main metabolites of complex polyphenols such as anthocyanins and procyanidins that are normally found at high concentrations in vegetables and fruit, and are absorbed by animals and humans. Since the daily intake of anthocyanins has been estimated to be much higher than that of other polyphenols, the nutritional value of PCA is increasingly recognized. Secondly, a growing body of evidence supports the concept that PCA can exert a variety of biological effects by acting on different molecular targets. It has been shown that PCA possesses antioxidant, anti-inflammatory as well as antihyperglycemic and neuroprotective activities. Furthermore, PCA seems to have chemopreventive potential because it inhibits the in vitro chemical carcinogenesis and exerts pro-apoptotic and anti-proliferative effects in different tissues. This review is aimed at providing an up-dated and comprehensive report on PCA giving a special emphasis on its biological activities and the molecular mechanisms of action most likely responsible for a beneficial role in human disease prevention.
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Discovery of Selective Small Molecular TACE Inhibitors for the Treatment of Rheumatoid Arthritis
N.-G. Li, Z.-H. Shi, Y.-P. Tang, Wei-Li, Lian-Yin and J.-A. Duan
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00391]

Rheumatoid arthritis (RA) is a chronic, inflammatory disease that afflicts 1-2% of the world population, characterized by an immune mediated inflammatory synovitis that leads to joint destruction, functional impairment, and reduced quality of life. The treatment goals of RA should be longterm substantial relief of pain, arrested joint inflammation and damage, and improved function. Current treatment can be divided into four classes, namely general analgesics and non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, disease modifying anti-rheumatic drugs (DMARDs) and biological agents (tumor-necrosis factor modifiers). However, gastrointestinal (GI) side effects of NSAIDs cannot be neglected, direct joint injections of glucocorticoids cannot be injected more than once every 3 months, synthetic DMARDs is far from optimal and only minority of patients achieved longterm remission, the biologics are very expensive to manufacture, need to be injected, and can cause allergic reactions. An alternative and good approach to the treatment of this disease is to lower the levels of tumour necrosis factor-α (TNF-α) in RA, which can be achieved by selectively inhibiting the tumour necrosis factor-α converting enzyme (TACE) that generate these cytokines using cheaper small molecules. This review focuses on the current status of selective small molecule inhibitors of TACE, with respect to lead compound search, inhibitors design approach, structure-activity relationship (SAR) and pharmacological studies in animals and humans. Through these methods, new hope is emerging for the treatment of RA through selective inhibition of TACE.
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Mechanisms Involved in the Protective Effects of Metformin Against Nonalcoholic Fatty Liver Disease
V.J. Barbero-Becerra, J.J. Santiago-Hernandez, F.A. Villegas-Lopez, N. Mendez-Sanchez, M. Uribe and N.C. Chavez-Tapia
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00392]

Metformin is an antidiabetic drug used widely in clinical practice. Its main clinical effect is to reduce blood glucose levels by improving insulin resistance. Nonalcoholic fatty liver disease is characterized by chronic liver damage and can develop into liver cirrhosis. Nonalcoholic fatty liver disease is associated with obesity and contributes to insulin resistance, and metformin is used to treat individuals with these conditions. The mechanisms underlying the clinical effects of metformin in treating nonalcoholic fatty liver disease are unclear. This article summarizes the literature on the mechanisms associated with liver glucose metabolism and the beneficial effects of metformin on this common liver disease.
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Intracellular Signaling Pathways Modulated by Phenolic Compounds: Application for New Anti-Inflammatory Drugs Discovery
G. Costa, V. Francisco, M.C. Lopes, M.T. Cruz and M.T. Batista
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00393]

Extensive research within the last two decades revealed that most chronic illnesses, including cancer, neurological, autoimmune and cardiovascular diseases are mediated through chronic inflammation. Thus, suppressing chronic inflammation has the potential to delay, prevent, and treat those diseases. However, side effects and high costs of current anti-inflammatory drugs force the development of new drugs. Natural products represent an important source of new bioactive compounds. Among them, phenolic compounds, which are widely distributed in plants, have been described as having many therapeutic effects. Several reviews have addressed the anti-inflammatory activity of phenols, attributing their properties not only to the antioxidant capacity, but also to inflammatory mediators’ modulation, namely cytokines and pro-inflammatory proteins, such as inducible nitric oxide synthase and cyclooxygenase-2. Signal transduction pathways precede changes in inflammatory mediators’ expression. However, only a restricted number of studies have addressed the effect of phenols on a specific signal transduction pathway. The present review attempts to summarize and highlight a broad range of inflammation-associated signaling pathways modulated by phenols namely: nuclear factor (NF)-κB, activator protein (AP)-1, peroxisome proliferator-activated receptor (PPAR) and nuclear factor erythroid 2-related factor 2 (Nrf2) transcription factors; mitogen-activated protein kinases (MAPKs); protein tyrosine kinases (PTKs); tyrosine phosphatidylinositol 3-kinase (PI3K)/Akt and ubiquitin-proteasome system. As a consequence of phenols effect on signaling pathways, described above, their action on inflammatory mediators’ production is mentioned. Finally, it is established that the structure-activity relationships of phenolic compounds are a valuable information source on the development of new anti-inflammatory drugs from natural products.
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Recent Advances in the Medicinal Chemistry of Aurones
R. Haudecoeur and A. Boumendjel
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00394]

The first review regarding the potential of aurones as promising drug candidates was reported in 2003. Since, considerable efforts have been made to explore the pharmacological and therapeutical activities of aurones. In this regard, many biological areas were concerned, including major pathological, such as cancer and neurodegenerative disorders. The aim of the present report is to highlight the progress made during the last ten years on the medicinal chemistry of aurones. A special focus will be made on the structure-activity relationship aspects among aurones and especially in case where aurones were found highly active than the corresponding flavones and chalcones.
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Recent Progress and Future Potential for Metal Complexes as Anticancer Drugs Targeting G-quadruplex DNA
J. Zhang, F. Zhang, H. Li, C. Liu, J. Xia, L. Ma, W. Chu, Z. Zhang, C. Chen, S. Li and S. Wang
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00395]

Now cisplatin and its analogs are some of the most effective chemotherapeutic agents in clinical use as the first line of treatment in testicular and ovarian cancers. Unfortunately, they have several major drawbacks, such as cumulative toxicities of nephrotoxicity and ototoxicity, inherent or treatment-induced resistance. This has provided the motivation for developing novel metal complexes as anticancer agents with different mechanism of action. In recent years, significant attention has been devoted to the role of G-quadruplexes in cancer. It was found that the stabilization of G-quadruplexes by small molecules has been shown to inhibit the transcriptional activity of some oncogenes. Thus, the G-quadruplex motif has emerged as a promising target for the design of selective anticancer drugs. Apart from the purely organic heteroaromatic compounds reported as G-quadruplex binders, it has recently been shown that metal complexes can also interact strongly and selectively with quadruplex DNA and have potential anticancer activity. This review will highlight recent progress of the metal complexes as anticancer drugs targeting G-quadruplex DNA, and discuss their future potential in the medical fields. Considering the significant roles of the metal ions, the metal complexes will be discussed as follows:

(1) Ruthenium(II) complexes; (2) Nickel(II) complexes; (3) Zinc(II) complexes; (4) Manganese(III) complexes; (5) Copper(II) complexes; (6) Palladium(II)/Platinum(II); (7) Other metal complexes.
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Extraction, Characterization and In Vivo Neuromodulatory Activity of Phytosterols from Microalga Dunaliella Tertiolecta
M. Francavilla, M. Colaianna, M. Zotti, M.G. Morgese, P. Trotta, P. Tucci, S. Schiavone, V. Cuomo and L. Trabace
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00396]

In recent years, a great deal of research has been devoted to identify new natural sources of phytosterols and to improve methods for their recovery and purification. In this regard, unexplored natural sources of bioactive ingredients are gaining much attention since they can lead to the isolation of new compounds or bioactivities. The field of available natural sources has been further increased by including algae and, even more interestingly, microalgae. In the present study, a multidisciplinary approach has been used considering, in an integrated view, extraction, chemical composition and bioactivity of phytosterols from the microalga Dunaliella tertiolecta. A novel methodology to extract, separate and characterize microalgal-derived phytosterols has been developed. In addition, recoverable and reusable eluents have been selected in order to reduce the quantities of employed organic solvents. Finally, we addressed the question whether orally administered phytosterols reach the brain and if those interfere with the major neurotransmitter systems, such as the dopaminergic, serotoninergic and noradrenergic ones, in several brain areas of rats. Flash Liquid Chromatography has been used to separate the Total Sterol (TS) fraction, composed of twelve sterols, with a purity of 97.87% and a recovery percentage of 98%, while the “flash version” of Silver Ion Liquid Chromatography has been used to purify the most abundant phytosterols in TS, (22E,24R)-methylcholesta-5,7,22-trien-3β-ol (ergosterol) and (22E,24R)-ethylcholesta-5,7,22-trien-3β-ol (7-dehydroporiferasterol), with a purity of 97.4%. These two combined methods did not need sophisticated technologies but only cheap laboratory supplies. Moreover, the possibility of recovering and recycling the solvents used as eluents made it a cleaner process. Finally, for the first time, a neuromodulatory action of Dunaliella tertiolecta-derived phytosterols has been found in selective brain areas of rats.
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Screening of 64 Tryptamines at NMDA, 5-HT1A, and 5-HT2A Receptors: A Comparative Binding and Modeling Study
M.L. Berger, R. Palangsuntikul, P. Rebernik, P. Wolschann and H. Berner
[FULL-TEXT INQUIRY] [BSP/CMC/E-Pub/00397]

Tryptamine (T) and several T derivatives (Ts) inhibit in a voltage-dependent manner the NMDA receptor (NR). This effect is influenced by substituents at various positions, but has not yet been subjected to a detailed SAR study. Here, 64 Ts have been tested as inhibitors of [3H]MK-801 binding to NRs on rat brain membranes. For comparison, they were also tested as inhibitors of [3H]8-OHDPAT binding to 5-HT1A and of [3H]ketanserin binding to 5-HT2A receptors. Since most of these Ts have not been tested before at any of these receptors, we start with a review of the effects of Ts on 5-HT1A and 5-HT2A binding sites. NRs were inhibited with IC50s from 2 to 7 μM by Ts with alkyl or halogen at positions 2, 5, and/or 7. Inhibition by some Ts was attenuated more than 10-fold by 30 μM spermine. The most potent inhibitors at 5-HT1A receptors were 5-carboxamido-T (IC50 0.00015 μM) and serotonin (0.0016 μM), at 5-HT2A receptors 2-Me-4,7-Cl2-T (1.2 μM) and 2,7-Me2-4-Cl-T (2.0 μM). Fujita-Ban modified Free-Wilson analyses pointed to the individual significance of particular substituents. Also QSARs based on molecular operating environment descriptors resulted in sound correlations at all 4 targets. No similarities between the NR and 5-HT receptors could be found. At the NR, only L-Trp-NH2 bound 10 times better than at both 5-HT receptors studied. L-Trp-NH2 may be a structural lead to endogenous non-competitive NR antagonists.
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