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Class III β -Tubulin (TUBB3): More than a Biomarker in Solid Tumors?
M. Mariani, S. Shahabi, S. Sieber, G. Scambia and C. Ferlini
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21999149 PubMed - indexed for MEDLINE] [BSP/CMM/E-Pub/00004]
Involvement of IL-1R/TLR Signalling in Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis
Vito Ruggiero
[Abstract] [FULL-TEXT INQUIRY] [PMID: 22082484 PubMed - indexed for MEDLINE] [BSP/CMM/E-Pub/00015]
DNA Repair Mechanisms in Colorectal Carcinogenesis
Christina Michailidi, Athanasios G. Papavassiliou and Constantinos Troungos
[Abstract] [FULL-TEXT INQUIRY] [PMID: 22082485 PubMed - indexed for MEDLINE] [BSP/CMM/E-Pub/00016]
The impact of the activated stroma on pancreatic ductal adenocarcinoma biology and therapy resistance
Mert Erkan, Carolin Reiser-Erkan, Christoph W. Michalski, Bo Kong, Irene Esposito, Helmut Friess and Jörg Kleeff
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00018]
Cellular prion and its catabolites in the brain: production and function
Guillot-Sestier M-V and Checler, F
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00019]
Possible pathogenic role of the transmembrane isoform of CD160 NK lymphocyte receptor in paroxysmal nocturnal hemoglobinuria
Jérôme Giustiniani, Sanaa Sabour Alaoui, Anne Marie-Cardine, Jacky Bernard, Daniel Olive, Christophe Bos, Alain Razafindratsita, Anna Petropoulou, Régis Peffault de Latour, Philippe Le Bouteiller, Martine Bagot, Gérard Socié and Armand Bensussan
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00022]
Xanthohumol, a Prenylated Chalcone Derived from Hops, Suppresses Cancer Cell Invasion through Inhibiting the Expression of CXCR4 Chemokine Receptor
Yang Wang, Yihua Chen, Jieqiong Wang, Jing Chen, Bharat B. Aggarwal, Xiufeng Pang and Mingyao Liu
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00023]
Combination of Valproic acid and ATRA Restores RARβ2 Expression and Induces Differentiation in Cervical Cancer through the PI3K/Akt Pathway
Dingqing Feng, Zhenping Cao, Cairong Li, Lina Zhang, Ying Zhou, Jie Ma, Ran Liu, Hu Zhou, Weidong Zhao, Haiming Wei and Bin Ling
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00024]
BCR/ABL1 Fusion Transcripts Generated from Alternative Splicing: Implications for Future Targeted Therapies in Ph+ Leukamias
Pieranna Chiarella, Valentina Summa, Stefania De Santis, Emanuela Signori, Ernesto Picardi, Graziano Pesole, Giuseppe Saglio and Vito M. Fazio
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00025]
Recent advances in GNAS epigenetic research of pseudohypoparathyroidism
Benedetta Izzi, Chris Van Geet and Kathleen Freson
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00026]
AAV-mediated gene therapy in mouse models of recessive retinal degeneration
Ji-jing Pang, Lei Lei, Xufeng Dai, Wei Shi, Xuan Liu, Astra Dinculescu and J. Hugh McDowell
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00027]
The PD-1/PD-L1 Pathway in Human Pathology
Marina Saresella, Veronica Rainone, Nasser M. Al-Daghri, Mario Clerici and Daria Trabattoni
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00028]
Emerging Roles of MicroRNA-22 in Human Disease and Normal Physiology
Jianhua Xiong
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00029]
The Role and Therapeutic Potential of Ser/Thr Phosphatase PP2A in Apoptotic Signalling Networks in Human Cancer Cells
Veerle Janssens and Angelita Rebollo
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00030]
Oxidatively generated DNA lesions as potential biomarkers of in vivo oxidative stress
Jean-Luc Ravanat, Jean Cadet and Thierry Douki
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00031]
The interplay between inflammation and oxidative stress in carcinogenesis
Somaira Nowsheen, Khaled Aziz, Thomas B. Kryston, Nicholas F. Ferguson and Alexandros Georgakilas
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00032]
Biomarkers of protein oxidation in human disease
Aracely-Garcia-Garcia Humberto Rodriguez-Rocha Nandakumar Madayiputhiya, Aglaia Pappa Mihalis I. Panagiotidis and Rodrigo Franco
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00033]
Oxidative Stress Based-Biomarkers In Oral Carcinogenesis: How Far Have We Gone?
Rania Hanafi, Ioannis Anestopoulos, Georgia Pershefoni Voulgaridou, Rodrigo Franco, Alexandros G. Georgakilas, Dominique Ziech, Vasiliki Malamou-Mitsi, Aglaia Pappa and Mihalis I. Panagiotidis
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00034]
The tumor suppressor gene ARF as a sensor of oxidative stress
Michalis Liontos, Ioannis S. Pateras, Konstantinos Evangelou and Vassilios G. Gorgoulis
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00035]
Monitoring Oxidative Stress Biomarkers in the Lipidome: Is There A Roadmap For “Human Inspection”?
Harald Jungnickel, Jutta Tentschert and Andreas Luch
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00036]
Oxidative stress generated damage to DNA by gastrointestinal exposure to insoluble particles
Peter Møller, Janne Kjærsgaard Folkmann, Pernille Høgh Danielsen, Kim Jantzen and Steffen Loft
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00037]
Tumor invasion and oxidative stress: biomarkers and therapeutic strategies
Laura Muinelo-Romay, Lorena Alonso-Alconada, Marta Alonso-Nocelo, Jorge Barbazan and Miguel Abal
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00038]
Current and Proposed Biomarkers of Anthracycline Cardiotoxicity in Cancer: Emerging Opportunities in Oxidative Damage and Autophagy
Jennifer S. Dickey and V. Ashutosh Rao
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00039]
Tissue Biomarkers for Prostate Cancer Radiation Therapy
Phuoc T. Tran, Russell K. Hales, Jing Zeng, Khaled Aziz, Tarek Salih, Rajendra P. Gajula, Sivarajan Chettair, Rachit Kumar, Danny Song and Theodore L. DeWeese
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00040]
Biomarkers to assess the targeting of DNA repair pathways to augment tumor response to therapy
Somaira Nowsheen, Alexander C Whitley and Eddy S. Yang
[Abstract] [Purchase Article] [BSP/CMM/E-Pub/00041]
Anti-inflammatory role of Fetuin-A in Injury and Infection
Haichao Wang and Andrew E. Sama
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00042]
IL-10 producing regulatory B cells in mice and humans: state of the art
Jean-David Bouaziz, Hélène Le Buanec, Anne Saussine, Armand Bensussan and Martine Bagot
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00043]
Editorial: Biomarkers of Oxidative Stress and Cancer. From Chemistry, Biology to Clinical Applications and Personalized Therapy
Alexandros G. Georgakilas and Mihalis Panayiotidis
[BSP/CMM/E-Pub/00044]
Editorial: The Physiology and Pharmacology of the mitochondrial 18-Kd Translocator Protein (TSPO): an Emerging Molecular Target for Diagnosis and Therapy
Michelangelo Campanella
[BSP/CMM/E-Pub/00045]
Is there any correlation between binding and functional effects at the translocator protein (TSPO) (18 kDa)?
Alana M Scarf, Kylee M Auman and Michael Kassiou
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00046]
The role of 18 kDa mitochondrial Translocator Protein (TSPO) in programmed cell death, and effects of steroids on TSPO expression
Leo Veenman and Moshe Gavish
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00047]
Translocator Protein (TSPO) and neurosteroids: implications in psychiatric disorders
Eleonora Da Pozzo, Barbara Costa and Claudia Martini
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00048]
Translocator protein (TSPO) in Breast Cancer
Shyamali Mukherjee and Salil K. Das
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00049]
Preclinical Molecular Imaging of the Translocator Protein (TSPO) in a Metastases Model Based on Breast Cancer Xenografts Propagated in the Murine Brain
Shelby K. Wyatt, H. Charles Manning, Mingfeng Bai, Moneeb Ehtesham, Khubaib Y. Mapara, Reid C. Thompson and Darryl J. Bornhop
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00050]
Developmental expression of the Translocator protein 18 kDa (TSPO) in testicular germ cells
Gurpreet Manku, Yan Wang, Raphael Thuillier, Corinne Rhodes and Martine Culty
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00051]
PK11195 inhibits mitophagy targeting the F1Fo-ATPsynthase in Bcl-2 knock-down cells
Michael SD Seneviratne, Danilo Faccenda, Valerio De Biase and Michelangelo Campanella
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00052]
Role of Translocator Protein (18 kDa) in adult separation anxiety and attachment style in patients with depression
Barbara Costa, Stefano Pini, Marianna Abelli, Pamela Gabelloni, Eleonora Da Pozzo, Beatrice Chelli, Simona Calugi, Lisa Lari, Alessandra Cardini, Antonio Lucacchini, Giovanni B Cassano and Claudia Martini
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00053]
Evidence for Complex Binding Profiles and Species Differences at the Translocator Protein (TSPO) (18 kDa)
Alana M Scarf, Christopher Luus, Eleonora Da Pozzo, Silvia Selleri, Chiara Guarino, Claudia Martini, Lars M. Ittner and Michael Kassiou
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00054]
Structural and functional evolution of the translocator protein (18 kDa)
Jinjiang Fan, Peter Lindemann, Marc G. J. Feuilloley and Vassilios Papadopoulos
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00055]
The 18Kda Translocator Protein (TSPO): a New Perspective in Mitochondrial Biology
Jemma Gatliff and Michelangelo Campanella
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00056]
Role of Translocator Protein in renal ischemia reperfusion, renal preservation and acute kidney injury
Raphael Thuillier and Thierry Hauet
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00057]
Evaluation of early regenerative processes in a preclinical pig model of acute kidney injury
Ludivine Rossard, Frederic Favreau, Julie Demars, René Robert, Cédric Nadeau, Jérome Cau, Raphael Thuillier and Thierry Hauet
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00058]
MicroRNAs as Regulators in Normal Hematopoietic and Leukemia Stem Cells: Current Concepts and Clinical Implications
Ke Fang, Feng Qian and Yue-Qin Chen
[Abstract] [Purchase Article] [BSP/CMM/E-Pub/00059]
The radiation bystander effect and its potential implications for human health
M. Mancuso, E. Pasquali, P. Giardullo, S. Leonardi, M. Tanori, V. Di Majo, S. Pazzaglia and A. Saran
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00060]
Neuroprotective Strategies for the Treatment of Inherited Photoreceptor Degeneration
Dragana Trifunović, Ayşe Sahaboglu, Jasvir Kaur, Stine Mencl, Eberhart Zrenner, Marius Ueffing, Blanca Arango-Gonzalez and François Paquet-Durand
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00061]
Th17-related cytokines in inflammatory bowel diseases: friends or foes?
Ivan Monteleone, Massimiliano Sarra, Francesco Pallone and Giovanni Monteleone
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00062]
Immunosuppressive properties of mesenchymal stem cells: advances and applications
De Miguel MP, Fuentes-Julián S, Blázquez-Martínez A, Pascual CY Aller MA, Arias J and Arnalich-Montiel F
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00063]
Beyond the Cardiac Myofilament: Hypertrophic Cardiomyopathy-Associated Mutations in Genes that Encode Calcium-Handling Proteins
Andrew P. Landstrom and Michael J. Ackerman
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00064]
GADD45 proteins: central players in tumorigenesis
Rodrigo Esaki Tamura, Jaíra Ferreira de Vasconcellos, Devanand Sarkar, Towia A Libermann, Paul B Fisher and Luiz Fernando Zerbini
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00065]
Spinophilin: a new tumor suppressor at 17q21
Amancio Carnero
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00066]
Plumbagin Inhibits Breast Tumor Bone Metastasis and Osteolysis by Modulating the Tumor-Bone Microenvironment
Zhenxi Li , Jianru Xiao, Xian Wu, Wenjun Li, Zhengfeng Yang, Juan Xie, Leqin Xu, Xiaopan Cai, Zaijun Lin, Wen Guo, Jian Luo and Mingyao Liu
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00067]
Abstracts
Class III β -Tubulin (TUBB3): More than a Biomarker in Solid Tumors?
M. Mariani, S. Shahabi, S. Sieber, G. Scambia and C. Ferlini
[FULL-TEXT INQUIRY] [PMID: 21999149 PubMed - indexed for MEDLINE] [BSP/CMM/E-Pub/00004]
Class III β-tubulin (TUBB3) is a prominent mechanism of drug resistance expressed in a variety of solid tumors and particularly in lung and ovarian cancer. In the classical view, TUBB3 expression and drug resistance have been linked, and together they have been associated with a perturbation in microtubule dynamics. In keeping with this observation, TUBB3 was associated with drug resistance only when chemotherapy included a taxane in its chemical composition. In this review, we demonstrate that the classical supposition about TUBB3 is not correct, and that instead TUBB3 expression is linked to drug resistance as a complex survival mechanism activated by microenvironmental conditions such as poor nutrient supply and hypoxia.
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Involvement of IL-1R/TLR Signalling in Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis
Vito Ruggiero
[FULL-TEXT INQUIRY] [PMID: 22082484 PubMed - indexed for MEDLINE] [BSP/CMM/E-Pub/00015]
Multiple sclerosis is a complex disease characterised by chronic inflammation, demyelination and axonal pathology resulting in progressive neurological disabilities. Multiple sclerosis is generally considered to be an autoimmune disease, even though the primary cause of the underlying autoimmune response is unknown. Epidemiological evidence suggests that both genetic and environmental factors play a key role in susceptibility to multiple sclerosis; however, the relative contributions of these factors in triggering the onset of the disease remain unclear. Several studies indicate that receptors belonging to the Interleukin-1 and Toll-like receptor families are crucially involved in the mechanisms underlying the development of experimental autoimmune encephalomyelitis, an animal model that mimics multiple sclerosis. Moreover, recent evidence highlights the importance of downstream signalling proteins in the Interleukin-1 and Toll-like receptor signalling pathways, namely, myeloid differentiation primary response protein 88 and Interleukin-1-receptor-associated kinase. This review summarises the current knowledge concerning the involvement of Interleukin-1/Toll-like receptor signalling in the development of experimental autoimmune encephalomyelitis and multiple sclerosis. A deeper understanding of the role of these important pathways in the pathogenesis of experimental autoimmune encephalomyelitis may eventually yield clinical benefits in the treatment of central nervous system-based inflammatory disorders.
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DNA Repair Mechanisms in Colorectal Carcinogenesis
Christina Michailidi, Athanasios G. Papavassiliou and Constantinos Troungos
[FULL-TEXT INQUIRY] [PMID: 22082485 PubMed - indexed for MEDLINE] [BSP/CMM/E-Pub/00016]
Colon cancer is among the most common cancers and the third cause of cancer deaths worldwide. If detected at an early stage, treatment might often lead to cure. The present review adduces the so far studied alterations in the expression of genes, as well as polymorphisms of genes engaged in DNA repair systems, with particular emphasis on indirect ones that are correlated with colorectal cancer. Such aberrations could be linked to an increased risk for the development of colorectal cancer and might serve as potential targets in the areas of prevention and therapy.
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The impact of the activated stroma on pancreatic ductal adenocarcinoma biology and therapy resistance
Mert Erkan, Carolin Reiser-Erkan, Christoph W. Michalski, Bo Kong, Irene Esposito, Helmut Friess and Jörg Kleeff
[FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00018]
Around 95% of patients diagnosed with pancreatic cancer will die of their disease within 5 years, three quarters within a year. The major hurdle in improving prognosis is the lack of a therapeutic time window. Early cancerous lesions are far beneath our threshold of detection. Therefore, at the time of diagnosis even early (T1) tumors can be metastatic and resistant to conventional treatments.
Several therapies targeting epithelial tumor cells—all showing impressive results in vitro and in animal experiments—have failed to show relevant effects in clinical trials. This discrepancy between experimental data and clinical reality results mostly from the inefficiency of our current experimental setups in recreating the tumor microenvironment. Forming more than 80% of the tumor mass, the fibrotic stroma of pancreatic ductal adenocarcinoma is not a passive scaffold for the malignant cells but an active player in carcinogenesis. This component is mostly missing in the xeno-/allograft- mouse models. Although tumors are bigger if stellate cells are co-implanted, due to the disproportionate cancer/stromal cell ratio and –possibly- too rapid tumor growth, the stromal reaction is much smaller than in human pancreatic cancer. One the other hand, desmoplasia is present only in some of the genetically engineered mouse models. Clinically, stromal activity of the pancreatic ductal adenocarcinoma has as great an impact on patient prognosis as the lymph node status of the tumor. The exact molecular mechanisms behind this observation remain obscure. However, one possible fundamental biologic explanation could be that selective pressure applied by the stroma leads to the evolution of cancer cells. Consequently, somatic evolution of invasive cancer could be viewed as a sequence of phenotypical adaptations to this barrier, highlighting the importance of the fibrotic tumor microenvironment in the behavior of pancreatic cancer.
In this review, the interaction of the epithelial tumor cells with the stroma in humans and in various animal models is scrutinized, and novel therapeutic options for uncoupling cancer-stroma interactions are discussed.
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Cellular prion and its catabolites in the brain: production and function
Guillot-Sestier M-V and Checler, F
[FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00019]
During the last thirty years, part of the scientific community focused on the mechanisms by which a naturally occurring protein called cellular prion (PrPc) converts into a protease-resistant isoform (PrPsc) responsible for fatal Transmissible Spongiform Encephalopathies (TSE). Concomitantly, the physiology of PrPc has also been studied. PrPc undergoes proteolytic attacks leading to both membrane-attached and secreted fragments, the nature of which differs in normal and TSE-affected human brains. Does proteolysis of PrPc correspond to an inactivating mechanism impairing the biological function of the protein, or alternatively, does it represent a maturation process allowing the produced fragments to trigger their own physiological function? Here we review the mechanisms involved in the production of PrPc catabolites and we focus on the function of PrPc and its derived fragments in the cell death/ survival regulation in the nervous system.
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Possible pathogenic role of the transmembrane isoform of CD160 NK lymphocyte receptor in paroxysmal nocturnal hemoglobinuria
Jérôme Giustiniani, Sanaa Sabour Alaoui, Anne Marie-Cardine, Jacky Bernard, Daniel Olive, Christophe Bos, Alain Razafindratsita, Anna Petropoulou, Régis Peffault de Latour, Philippe Le Bouteiller, Martine Bagot, Gérard Socié and Armand Bensussan
[FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00022]
PIGA mutations in paroxysmal nocturnal hemoglobinuria (PNH) patients lead to a glycosylphosphatidylinositol (GPI)-linked membrane proteins expression deficiency. Herein, we report the constitutive expression of the transmembrane CD160 (CD160-TM) activating receptor on non PIGA-mutated PNH patients circulating NK cells. In healthy individuals, only the GPI-anchored isoform of CD160 receptors is expressed on the circulating NK lymphocytes, while the transmembrane isoform appears after ex vivo activation. Similarly to CD160-GPI, we identified CD160-TM as a receptor for the MHC class I molecules. We demonstrate that PNH patients NK lymphocytes spontaneously produce significant amounts of IFN-γ that is inhibited by anti-CD160-TM or anti-MHC class I mAbs. These results indicate that circulating NK cells from PNH patients exhibit a self-MHC class I molecule reactive effector function, which could be mediated through the recruitment of CD160-TM receptor. Our data provide new insights regarding the possible role of CD160-TM on PNH patients NK lymphocytes and in the pathogenesis of the disease.
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Xanthohumol, a Prenylated Chalcone Derived from Hops, Suppresses Cancer Cell Invasion through Inhibiting the Expression of CXCR4 Chemokine Receptor
Yang Wang, Yihua Chen, Jieqiong Wang, Jing Chen, Bharat B. Aggarwal, Xiufeng Pang and Mingyao Liu
[FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00023]
Cancer metastasis is the main cause of death (90%), and only recently we have gained some insight into the mechanisms by which metastatic cells arise from primary tumors and target to specific organs. Cysteine X Cysteine (CXC) chemokine receptor 4 (CXCR4), initially linked with leukocyte trafficking, is overexpressed in various tumors and mediates homing of tumor cells to distant sites expressing its cognate ligand CXCL12. Therefore, identification of CXCR4 inhibitors has great potential to abrogate tumor metastasis. In this study, we demonstrated that xanthohumol (XN), a prenylflavonoid derived from the female flowers of the hops plant (Humulus lupulus. L), suppressed CXCR4 expression in various cancer cell types in a concentration- and time-dependent manner. Both proteasome and lysosomal inhibitors had no effect to prevent the XN-induced downregulation of CXCR4, suggesting that the inhibitory effect of XN was not due to proteolytic degradation but occurred at the transcriptional level. Electrophoretic mobility shift assay and chromatin immunoprecipitation assay further confirmed that XN could block endogenous activation of nuclear factor kappa B, a key transcription factor regulates the expression of CXCR4 in cancer cells. Consistent with the above molecular basis, XN abolished cell invasion induced by CXCL12 in both breast and colon cancer cells. Interestingly, although co-exist in hops, XN is the only isoform that exhibited the inhibitory effect on the expression of CXCR4 compared with other isomers, isoxanthohumol and 8-prenylnaringenin. Together, our results suggested that XN, as a novel inhibitor of CXCR4, could be a promising therapeutic agent contributed to cancer treatment.
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Combination of Valproic acid and ATRA Restores RARβ2 Expression and Induces Differentiation in Cervical Cancer through the PI3K/Akt Pathway
Dingqing Feng, Zhenping Cao, Cairong Li, Lina Zhang, Ying Zhou, Jie Ma, Ran Liu, Hu Zhou, Weidong Zhao, Haiming Wei and Bin Ling
[FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00024]
Epigenetic silencing of the tumor suppressor gene, RARβ2, through histone deacetylation has been established as an important process of cervical carcinogenesis. This pivotal role has led to the suggestion that a combination of retinoids selective for RARβ2 with histone deacetylase (HDAC) inhibitors may have therapeutic potential. Valproic acid (VPA), a HDAC inhibitor, has a critical role in the regulation of gene expression through histone acetylation and causes transformed cells to undergo growth arrest, differentiation, and apoptosis. Therefore, we hypothesized that the combination of VPA and ATRA could restore RARβ2 expression, thus resulting in enhanced anti-neoplastic activity in cervical cancer. Here, we show that VPA combined with ATRA led to hyperacetylation of histone H3 and a significant alteration of gene expression in cervical cancer cells, including RARβ2 gene expression, which was upregulated 50- to 90-fold. The combination therapy effectively inhibited the growth of cervical cancer cells more than the single agent treatment both in vitro and in vivo. The additive effects were associated with a significant upregulation of P21CIP1 and P53 as well as a pronounced decrease in p-Stat3. Furthermore, the combined treatment led to cell cycle arrest predominantly at the G1 phase, and it preferentially induced cell differentiation rather than apoptosis in cervical cancer cells. The differentiation program was determined by the presence of E-cadherin-mediated adhesion and activation of the PI3K/Akt pathway. Taken together, these results provide new insight into the mechanisms of enhanced antitumor activity of the HDAC inhibitor and ATRA regimen, thus offering a new therapeutic strategy for cervical cancer patients.
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BCR/ABL1 Fusion Transcripts Generated from Alternative Splicing: Implications for Future Targeted Therapies in Ph+ Leukamias
Pieranna Chiarella, Valentina Summa, Stefania De Santis, Emanuela Signori, Ernesto Picardi, Graziano Pesole, Giuseppe Saglio and Vito M. Fazio
[FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00025]
Philadelphia (Ph+) positive leukaemias are an example of haematological malignant diseases where different chromosomal rearrangements involving both BCR and ABL1 genes generate a variety of chimeric proteins (BCR/ABL1 p210, p190 and p230) which are considered pathological “biomarkers”. In addition to these three, there is a variety of fusion transcripts whose origin may depend either on diverse genetic rearrangement or on alternative/atypical splicing of the main mRNAs or on the occurrence of single-point mutations. Although the therapy of Philadelphia+ leukaemias based on Imatinib represents a triumph of medicine, not all patients benefit from such drug and may show resistance and intolerance. Furthermore, interruption of Imatinib administration is often followed by clinical relapse, suggesting a failure in the eradication of residual leukaemic stem cells. Therefore, while the targeted therapy is searching for new and implemented pharmacological inhibitors covering all the possible mutations in the kinase domain, there is urge to identify alternative molecular targets to develop other specific and effective therapeutic approaches.
In this review we discuss the importance of recent advances based on the discovery of novel BCR/ABL1 variants and their potential role as new targets/biomarkers of Ph+ leukaemias in the light of the current therapeutic trends. The limits of the pharmacological inhibitors used for treating the disease can be overcome by considering other targets than the kinase enzyme. Our evaluations highlight the potential of alternative perspectives in the therapy of Ph+ leukaemias.
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Recent advances in GNAS epigenetic research of pseudohypoparathyroidism
Benedetta Izzi, Chris Van Geet and Kathleen Freson
[FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00026]
Endocrinopathies in patients with hypocalcemia and hyperphosphatemia that share resistance to parathyroid hormone (PTH) are grouped under the term pseudohypoparathyroidism (PHP). Patients with PHP type Ia (PHP-Ia) often present with additional hormonal resistance and show characteristic physical features that are jointly termed as having an Albright's hereditary osteodystrophy (AHO) phenotype. Alternatively, PHP-Ib patients predominantly have PTH and sometimes TSH resistance but don’t present with AHO features. Most of these PHP forms are caused by defects in GNAS, an imprinted gene locus consisting of maternal, paternal and biallelic transcripts. PHP-Ia is caused by heterozygous inactivating mutations in those exons of GNAS encoding the alpha subunit of the stimulatory guanine nucleotide-binding protein (Gsalpha) while PHP-Ib results from epigenetic GNAS defects. Familial and sporadic forms of PHP-Ib have distinct GNAS imprinting patterns: familial PHP-Ib patients have an exon A/B-only imprinting defect whereas sporadic PHP-Ib cases have abnormal imprinting of the three differentially methylated regions (DMRs) in GNAS. This classification of PHP was made years ago but was recently questioned since different studies showed GNAS epigenetic defects in PHP-Ia patients. In this review, we focus on the epigenetic description and screening methods of GNAS, the associated pathology and the recent need for a PHP reclassification.
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AAV-mediated gene therapy in mouse models of recessive retinal degeneration
Ji-jing Pang, Lei Lei, Xufeng Dai, Wei Shi, Xuan Liu, Astra Dinculescu and J. Hugh McDowell
[FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00027]
In recent years, more and more mutant genes that cause retinal diseases have been detected. At the same time, many naturally occurring mouse models of retinal degeneration have also been found, which show similar changes to human retinal diseases. These, together with improved viral vector quality allow more and more traditionally incurable inherited retinal disorders to become potential candidates for gene therapy. Currently, the most common vehicle to deliver the therapeutic gene into target retinal cells is the adeno-associated viral vector (AAV). Following delivery to the immuno-priviledged subretinal space, AAV-vectors can efficiently target both retinal pigment epithelium and photoreceptor cells, the origin of most retinal degenerations. This review focuses on the AAV-based gene therapy in mouse models of recessive retinal degenerations, especially those in which delivery of the correct copy of the wild-type gene has led to significant beneficial effects on visual function, as determined by morphological, biochemical, electroretinographic and behavioral analysis. The past studies in animal models and ongoing successful LCA2 clinical trials, predict a bright future for AAV gene replacement treatment for inherited recessive retinal diseases.
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The PD-1/PD-L1 Pathway in Human Pathology
Marina Saresella, Veronica Rainone, Nasser M. Al-Daghri, Mario Clerici and Daria Trabattoni
[FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00028]
T-cell activation is dependent on signals delivered through the antigen-specific T-cell receptor and accessory receptors on T-cells. Integration of signals through this family of costimulatory and inhibitory receptors and their ligands regulates the balance between T-cell activation, tolerance, and immunopathology. Programmed death 1 (PD-1) and its ligands, PD-L1 and PD-L2, deliver inhibitory signals and exert a vital and diverse range of immunoregulatory roles in T-cell activation, tolerance, and immune-mediated tissue damage. In this review, we revisit current understanding of the immunoregulatory functions of PD-1 and its ligands and their involvement in immune-mediated diseases.
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Emerging Roles of MicroRNA-22 in Human Disease and Normal Physiology
Jianhua Xiong
[FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00029]
MicroRNAs (miRNAs) are an abundant class of small noncoding RNAs that have critical regulatory functions in various biological processes. MicroRNA-22 (miR-22) is a highly-conserved 22-nt miRNA, whose roles in human diseases and normal physiology are just beginning to emerge. Recently, miR-22 has been connected to a great number of activities that encompass tumorigenesis, epigenetic modification, embryonic development, skeletal metabolism, panic disorder, and cardiomyocyte hypertrophy. Aberrant expression of miR-22 has been identified in multiple human diseases. Here, we describe our current understanding of the roles of miR-22 and its signaling circuitry in pathology and physiology, and discuss important advances that set the scene for applying miR-22 to the prevention and treatment of a wide range of human diseases.
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The Role and Therapeutic Potential of Ser/Thr Phosphatase PP2A in Apoptotic Signalling Networks in Human Cancer Cells
Veerle Janssens and Angelita Rebollo
[FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00030]
A block in apoptotic cell death is a likely requirement for cancer maintenance. Likewise, drug resistance, one of the key clinical problems in oncology, can often be explained by apoptotic resistance following drug administration. Several signalling pathways can commit cells to death, including intrinsic mitochondrial pathways controlled by the Bcl-2-like proteins, extrinsic Death Receptor-triggered pathways, and Dependence Receptor-initiated pathways. In addition, depending on the cell type, external stimulus and context, various other pro- or anti-survival signalling pathways may become repressed or activated. Proper coordination and conversion into a common cellular response is ensured by various ways of inter-pathway crosstalk. As for most signalling cascades, post-translational control of the signalling proteins involved is mainly achieved by reversible phosphorylation and thus by the coordinated actions of protein kinases and phosphatases. Despite increasing interest in phosphatases as potential tumour suppressors, their role in controlling apoptotic signalling remains poorly understood. Here we review current knowledge about the regulatory functions of Protein Phosphatase type 2A (PP2A) phosphatases in these apoptotic signalling networks. PP2A represents an abundant class of structurally complex Ser/Thr phosphatases which are of particular interest in this context because of their recently established role as genuine tumour suppressors. In line with these tumour suppressive characteristics, PP2A predominantly displays pro-apoptotic functions, although some PP2A complexes also clearly counteract apoptotic cell death. Finally, we speculate how this knowledge might be exploited for therapeutic purposes, in light of pre-clinical pharmacological approaches, currently demonstrated to target PP2A in cancer cells.
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Oxidatively generated DNA lesions as potential biomarkers of in vivo oxidative stress
Jean-Luc Ravanat, Jean Cadet and Thierry Douki
[FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00031]
During the last three decades there was an increasing interest for developing biomarkers of oxidative stress. Therefore, efforts have been made to develop sensitive methods aimed at measuring cellular levels of oxidatively generated DNA lesions. Initially, most attention had focused on 8-oxo-7,8-dihydro-2’-deoxyguanosine (8-oxodGuo) probably because reliable analytical methods (mostly HPLC coupled to electrochemical detection) were available since mid-eighties to detect that lesion at the cellular level. With the recent development of more versatile analytical (using mass spectrometric detection) and biochemical assays (such as the comet assay) efforts are currently made to measure simultaneously several DNA lesions. The main degradation pathways of the four main pyrimidine (thymine, cytosine) and purine (adenine, guanine) bases mediated by hydroxyl radical (•OH), one-electron oxidants and singlet oxygen (1O2) have been also studied in detail and results indicate that other DNA modification than 8-oxodGuo could represent suitable biomarkers of oxidative stress. In this review article, the main degradation products of DNA will be presented together with their mechanisms of formation. Then the developed methods aimed at measuring cellular levels of oxidatively generated DNA lesions will be critically reviewed based on their specificity, versatility and sensitivity. Illustration of the powerfulness of the described methods will be demonstrated using quantification of DNA lesions in cells exposed to ionizing radiations. In addition, recent work highlighting the possible formation of complex DNA lesions will be reported and commented regarding the possibility of using such complex damage as potential biomarkers of oxidative stress.
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The interplay between inflammation and oxidative stress in carcinogenesis
Somaira Nowsheen, Khaled Aziz, Thomas B. Kryston, Nicholas F. Ferguson and Alexandros Georgakilas
[FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00032]
Emerging data suggest that primary dysfunction in the tumor microenvironment is crucial for carcinogenesis. These recent findings make a compelling case for targeting the milieu for cancer chemoprevention as well as therapy. The stroma is an integral part of its physiology, and functionally, one cannot totally dissociate the tumor surrounding from the tumor cells. A thorough understanding of the tumor and stroma will aid us in developing new treatment targets. In this review, we shed light at the key aspects of the carcinogenic process and how oxidative stress and inflammation contribute to this process. We dissect the connection between metastasis and oxidative stress and focus on the key players in the tumor microenvironment that leads to inflammation, oxidative stress and DNA damage. Moreover, we consider the role of inflammation in disease, specifically cancer and metastasis. Finally, we discuss the potential applications in prognosis and cancer treatment.
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Biomarkers of protein oxidation in human disease
Aracely-Garcia-Garcia Humberto Rodriguez-Rocha Nandakumar Madayiputhiya, Aglaia Pappa Mihalis I. Panagiotidis and Rodrigo Franco
[FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00033]
Oxidative stress is caused by an imbalance between the production of RS and the ability to either detoxify the reactive intermediates produced, or repair the resulting damage. Ultimately, oxidative stress conveys the alteration in cellular function caused by the reaction of RS with cellular constituents. Oxidative stress has been extensively reported to participate in the progression of a variety of human diseases including cancer, neurodegenerative disorders and diabetes. Oxidation of proteins is thought to be one of the major mechanisms by which oxidative stress is integrated into cellular signal transduction pathways. Thus, recent research efforts have been aimed to identifying the role of specific oxidative protein modifications in the signal transduction events mediating the etiology of human diseases progression. The identification of theses oxidative modifications has also raised the possibility of using this knowledge to develop new methods to diagnose diseases before they are clinically evident. In this work, we summarize the mechanisms by which RS generate distinct oxidative modifications. Furthermore, we also review the potential of these oxidative modifications to be used early biomarkers of disease in human disease.
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Oxidative Stress Based-Biomarkers In Oral Carcinogenesis: How Far Have We Gone?
Rania Hanafi, Ioannis Anestopoulos, Georgia Pershefoni Voulgaridou, Rodrigo Franco, Alexandros G. Georgakilas, Dominique Ziech, Vasiliki Malamou-Mitsi, Aglaia Pappa and Mihalis I. Panagiotidis
[FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00034]
Oral cancer accounts for 2-3% of all malignancies and according to the World Health Organization (WHO) is the fifth most common cancer worldwide. On the other hand, “oxidative stress” implies a cellular state whereby reactive oxygen species (ROS) production exceeds its metabolism resulting in excessive ROS accumulation and overwhelmed cellular defenses. Such a state has been shown to be involved in the multistage process of human carcinogenesis (including oral cancer) via many different mechanisms. Amongst them are ROS-induced oxidative modifications on major cellular macromolecules like DNA, proteins and lipids with the resulting byproducts being involved in the pathophysiology of human oral malignant and pre-malignant lesions. Throughout this manuscript, we review the current state of knowledge on the role of these oxidative-modified cellular byproducts in serving as reliable biomarkers for oral cancer detection, prognosis and diagnosis.
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The tumor suppressor gene ARF as a sensor of oxidative stress
Michalis Liontos, Ioannis S. Pateras, Konstantinos Evangelou and Vassilios G. Gorgoulis
[FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00035]
Oxidative stress as a result of either exogenous stimuli or cellular metabolism affects several cellular processes such as proliferation, apoptosis, cell death and senescence. Consequently, it is implicated in the pathogenesis of various human diseases like cancer, diabetes mellitus, atherosclerosis, neurodegenerative diseases and aging. Oxidative stress is implicated in carcinogenesis either by directly provoking DNA damage or through the regulation of intracellular signaling cascades. In both cases the cellular response to oxidative stress is determined by the cellular context. ARF, the alternative protein product of the CDKN2A locus has been recently recognized as a novel sensor of oxidative stress, in a β-catenin and Hsp70-mediated manner. Since, improved understanding of cellular responses to oxidative stress may facilitate the design of novel antineoplastic regimens, we herein review the mechanisms by which oxidative stress promotes carcinogenesis, focusing on the role of ARF as a sensor of oxidative stress.
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Monitoring Oxidative Stress Biomarkers in the Lipidome: Is There A Roadmap For “Human Inspection”?
Harald Jungnickel, Jutta Tentschert and Andreas Luch
[FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00036]
Oxidative stress is more and more recognized as the underlying motif for a broad variety of diseases including cancer. Medicine faces the paramount task to develop better diagnostic tools and drug treatment prediction models in the future to significantly enhance the quality of life. Special interest will focus on early-stage disease biomarkers and biomarkers that could predict healing success at the earliest time point after the treatment started. The accelerated formation of so-called reactive oxygen species (ROS) is becoming widely regarded as the underlying process associated with many diseases like myocardial infarction, Alzheimer’s, Parkinson’s and kidney disease, etc. Once generated within cells and tissues, ROS can react with a variety of cellular metabolites like fatty acids, proteins or DNA. This review investigates the possibilities for various oxidized metabolites as well as proteomics, genomics and bioimaging biomarkers to serve as early-stage disease biomarkers or biomarkers for drug treatment success. We also assess the value of a step-by-step or cascade biomarker approach as a new paradigm in medical diagnostics. Examples are given for possible analytical methodology and tools as well as statistical methods that could be applied. Such an approach may straighten the road toward new medical diagnostics and treatment regimes, which ultimatively could lead to a significantly enhanced medical service for patients suffering from chronic and debilitating or deadly diseases including cancer. Examples from recent research are given to show the progress and possibilities for the proposed model.
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Oxidative stress generated damage to DNA by gastrointestinal exposure to insoluble particles
Peter Møller, Janne Kjærsgaard Folkmann, Pernille Høgh Danielsen, Kim Jantzen and Steffen Loft
[FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00037]
There is growing concern that gastrointestinal exposure to particles is associated with increased risk of toxicity to internal organs and carcinogenicity. The mechanism of action is related to particle-induced oxidative stress and oxidation of DNA. Observations from animal models indicate that gastrointestinal exposure to single-walled carbon nanotubes (SWCNT), fullerenes C60, carbon black, titanium dioxide and diesel exhaust particles generate oxidized DNA base lesions in organs such as the bone marrow, liver and lung. Oral exposure to nanosized carbon black has also been associated with increased level of lipid peroxidation derived exocyclic DNA adducts in the liver, suggesting multiple pathways of oxidative stress for particle-generated damage to DNA. At equal dose, diesel exhaust particles (SRM2975) generated larger levels of 8-oxo-7,8-dihydro-2'-deoxyguanosine in rat liver than carbon black (Printex 90) did, whereas exposure to fullerenes C60 and SWCNT were the least potent. This ranking of samples was also observed for oxidatively damaged DNA in cultured cells. The extent of translocation from the gut is largely unresolved. However, there is evidence indicating that gastrointestinal exposure to particulate matter is associated with oxidative damage to DNA and this might be associated with increased risk of cancer.
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Tumor invasion and oxidative stress: biomarkers and therapeutic strategies
Laura Muinelo-Romay, Lorena Alonso-Alconada, Marta Alonso-Nocelo, Jorge Barbazan and Miguel Abal
[FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00038]
Tumor invasion is paradigmatic of the complex interactions connecting a carcinoma with its environment, and a reflex of the cellular and molecular heterogeneity that defines the initiation of dissemination and metastasis. The hostile situation generated by a growing carcinoma and a reactive stroma is at the basis of the promotion of carcinoma invasion and metastasis, with oxidative stress emerging as a main player in the acquisition of an aggressive tumor phenotype. In this review, we present this complex scenario with a focus on the contribution of the reactive environment and the oxidative stress to the cellular and molecular events associated with carcinoma invasion and metastasis. We also discuss the potential of oxidative stress as a source of biomarkers of advance disease, and as supplier of a therapeutic armamentarium against the initial steps of metastatic dissemination.
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Current and Proposed Biomarkers of Anthracycline Cardiotoxicity in Cancer: Emerging Opportunities in Oxidative Damage and Autophagy
Jennifer S. Dickey and V. Ashutosh Rao
[FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00039]
A biomarker is defined as “a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or biological responses to a therapeutic intervention.” Biomarkers can be utilized to detect disease, evaluate treatment risks, or determine treatment effectiveness. In the case of cancer, anthracyclines such as doxorubicin are front-line therapy to treat a number of different malignancies including breast cancer. However, a significant fraction of patients experience drug-induced cardiotoxicity. This toxicity is dose-limiting and can cause long-term morbidity or mortality. There is an unmet medical need to identify patients who are at risk for doxorubicin-induced cardiotoxicity, to detect cardiac damage early so that patient risk can be minimized, and to monitor the success of cardioprotective strategies. Therefore, doxorubicin treatment of cancer is an excellent example of the need for biomarkers to indicate drug safety in addition to drug efficacy. In this review we will discuss the mechanism of doxorubicin-associated cardiotoxicity, as well as other cancer therapies that induce cardiac toxicity by causing oxidative damage. We will also evaluate established and proposed biomarkers for cardiotoxicity based on our evolving knowledge of oxidative damage and subsequent autophagy. Finally, we will discuss advantages of combining oxidative damage- and autophagy-based protein biomarkers with current biomarkers such as troponins to facilitate early detection and mitigation of cardiotoxicity induced by cancer therapeutic agents.
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Tissue Biomarkers for Prostate Cancer Radiation Therapy
Phuoc T. Tran, Russell K. Hales, Jing Zeng, Khaled Aziz, Tarek Salih, Rajendra P. Gajula, Sivarajan Chettair, Rachit Kumar, Danny Song and Theodore L. DeWeese
[FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00040]
Prostate cancer is the most common cancer and second leading cause of cancer deaths among men in the United States. Most men have localized disease diagnosed following an elevated serum prostate specific antigen test for cancer screening purposes. Standard treatment options consist of surgery or definitive radiation therapy directed by clinical factors that are organized into risk stratification groups. Current clinical risk stratification systems are still insufficient to differentiate lethal from indolent disease. Similarly, a subset of men in poor risk groups need to be identified for more aggressive treatment and enrollment into clinical trials. Furthermore, these clinical tools are very limited in revealing information about the biologic pathways driving these different disease phenotypes and do not offer insights for novel treatments which are needed in men with poor-risk disease. We believe molecular biomarkers may serve to bridge these inadequacies of traditional clinical factors opening the door for personalized treatment approaches that would allow tailoring of treatment options to maximize therapeutic outcome. We review the current state of prognostic and predictive tissue-based molecular biomarkers which can be used to direct localized prostate cancer treatment decisions, specifically those implicated with definitive and salvage radiation therapy.
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Biomarkers to assess the targeting of DNA repair pathways to augment tumor response to therapy
Somaira Nowsheen, Alexander C Whitley and Eddy S. Yang
[Purchase Article] [BSP/CMM/E-Pub/00041]
Hyper-activation of DNA repair pathways can enable tumor cells to survive DNA damage. Therefore, targeting specific DNA repair pathways might prove efficacious for cancer therapy. The advent of personalized therapy necessitates novel biomarkers to assess tumor response to therapy. Biological indicators are vital in the field of cancer research and treatment. The focus of this review is on the DNA repair machinery as an emerging target for enhancement of therapy. Additionally, DNA damage and repair biomarkers for prognosis in different types of cancer will be discussed. The application of biomarkers to assess tumor response to therapy based on targeting DNA repair pathways can potentially improve patient quality of life and aid in treatment design.
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Anti-inflammatory role of Fetuin-A in Injury and Infection
Haichao Wang and Andrew E. Sama
[FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00042]
Infection and injury are two seemingly unrelated processes that often converge on common innate inflammatory responses mediated by pathogen- or damage-associated molecular patterns (PAMPs or DAMPs). If dysregulated, an excessive inflammation menifested by the overproduction and release of proinflammatory mediators (e.g., TNF, IFN-γ, and HMGB1) may adversely lead to many pathogenic consequences. As a counter-regulatory mechanism, the liver strategically re-prioritizes the synthesis and systemic release of acute phase proteins (APP) including the fetuin-A (also termed alpha-2-HS-glycoprotein for the human homologue). Fetuin-A is divergently regulated by different proinflammatory mediators, and functions as a positive or negative APP in injury and infection. It not only facilitates anti-inflammatory actions of cationic polyamines (e.g., spermine), but also directly inhibits PAMP-induced HMGB1 release by innate immune cells. Peripheral administration of fetuin-A promotes a short-term reduction of cerebral ischemic injury, but confers a long-lasting protection against lethal endotoxemia. Furthermore, delayed administration of fetuin-A rescues mice from lethal sepsis even when the first dose is given 24 hours post the onset of disease. Collectively, these findings have reinforced an essential role for fetuin-A in counter-regulating injury- or infection-elicited inflammatory responses.
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IL-10 producing regulatory B cells in mice and humans: state of the art
Jean-David Bouaziz, Hélène Le Buanec, Anne Saussine, Armand Bensussan and Martine Bagot
[FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00043]
IL-10-producing regulatory B cells have been undoubtedly identified in mice and shown to downregulate inflammation, making them potentially important for maintenance of tolerance. Several recent works have also identified IL-10 producing regulatory B cells in humans and have begun to unravel their phenotype and mode of suppression. Cell surface phenotype of human Bregs includes CD38, CD27, CD24 and CD5. Mechanisms of suppression may imply inhibition of CD4+ T proliferation, inhibition of Th1 differentiation, induction of regulatory T cells and suppression of monocytes activation. These recent findings imply that manipulating IL-10 production by human B cells could be a useful therapeutic strategy for modulating immune responses in humans.
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Editorial: Biomarkers of Oxidative Stress and Cancer. From Chemistry, Biology to Clinical Applications and Personalized Therapy
Alexandros G. Georgakilas and Mihalis Panayiotidis
[BSP/CMM/E-Pub/00044]
The philosophy of this Special Issue was based on the fact that biomarkers change the way in which we diagnose, classify and monitor disease and/or therapy progression. In addition, biomarkers provide new insights into mechanisms of disease as well as new therapeutic targets like in the case of elevated oxidative stress and cancer development. It is therefore of outmost importance to present the current state of oxidative stress-based (and others) biomarker development and their use to human carcinogenesis, prognosis and treatment. In addition, knowledge of the redox status or other key molecular markers can lead to the development of therapeutic strategies by the use, for example, of radiosensitizers and personalized therapy especially in the case of solid tumors where hypoxia and anoxia limit the effectiveness of current radio- or chemotherapies. The interaction of human cells or tissues with sources of oxidative stress (intra- or extracellular) like byproducts of endogenous metabolism and ionizing radiations can result in a variety of DNA lesions. This pool of DNA lesions usually consists of oxidized purines and pyrimidines often called as apurinic/apyrimidinic (abasic) DNA sites, single stranded (SSBs) and double stranded (DSBs) DNA breaks. These lesions may appear in an isolated or complex (clustered) synthesis of several damage points within 1-15 base pairs. Although the basic chemistry for the induction of DNA damage by reactive oxygen/nitrogen species (ROS/RNS) has been known for decades new insights and new lesions emerge every year. In addition, new repair pathways involved in the processing of these lesions in vivo or in vitro are discovered on a regular basis suggesting the overlap and cooperation between for example base excision repair (BER) and DSB repair pathways. Knowledge of the chemistry behind induction of DNA damage and repair mechanisms is considered crucial not only for the understanding of the biological importance of DNA damage but also for clinical applications.
In this Special Issue, we have compiled a significant number of concise reviews and original research articles, by top and well-established experts in their fields. The articles present with unique originality the current status of knowledge and explore new advances in the chemical or molecular biological pathways related to the induction of oxidatively-induced DNA damage and shed light to the potential applications of this knowledge towards the improvement of life and treatment of pathophysiological conditions like cancer. Specifically, we investigate the chemical and biological components regarding oxidative stress induction, for example: (1) Dr. Jean-Luc Ravanat and colleagues review the main methodologies that are currently available for monitoring single and complex oxidatively generated damage to cellular DNA and use of oxidatively-generated DNA lesions as potential biomarkers of in vivo oxidative stress; (2) Dr. Alex Georgakilas’s group provides new insights into the interplay between inflammation and oxidative stress in carcinogenesis, (3) Dr. Rodrigo Franco and colleagues in their review discuss biomarkers of protein oxidation in human disease while (4) Drs. Mihalis Panagiotidis and Aglaia Pappa discuss the great potential of oxidative stress based-biomarkers in oral carcinogenesis and how far we have really gone? Towards the development of reliable tools for the measurement of DNA damage markers, (5) Dr. Vassilis Gorgoulis and colleagues investigate thoroughly the prospect of the tumor suppressor gene ARF as a sensor of oxidative stress while (6) Dr. Andreas Luch’s group discuss the potential biomonitoring of oxidative stress biomarkers in the lipidome and if there is a roadmap for “human inspection”? To the same direction, (7) Dr. Peter Møller’s group review the oxidative stress generated damage to DNA by gastrointestinal exposure to insoluble particles. In addition, in this Special Issue, we discuss new advances in the potential application of oxidative stress-related biomarkers in cancer detection and treatment. Specifically, (8) Dr. Miguel Abal and colleagues discuss the association of tumor invasion and oxidative stress and the potential outcome for reliable biomarkers and therapeutic strategies, (9) Drs. Jennifer Dickey and Ashutosh Rao critically review current and proposed biomarkers of anthracycline cardiotoxicity in cancer and emerging opportunities in oxidative damage and autophagy, (10) Dr. Phuoc Tran and colleagues present recent insights into the use of tissue biomarkers for prostate cancer radiation therapy and finally (11) Dr. Eddy Yang’s group discuss thoroughly the utilization of new biomarkers to assess the targeting of DNA repair pathways and to augment tumor response to therapy.
The critical goals of this Special Issue was to first, indentify and bring up to the scientific community new advances on the chemistry, detection of oxidatively-induced DNA lesions and explore the new roadmaps to using this knowledge towards the development of accurate and reliable biomarkers for tumor diagnosis and personalized therapy. Concluding, we would like to express our sincere gratitude and appreciation to all authors contributing their expertise to this Special Issue of Current Molecular Medicine entitled “Biomarkers of oxidative stress and cancer. From chemistry, biology to clinical applications and personalized therapy”. Last, but certainly not least, we would like to sincerely thank Ms. Samina Khan (Coordinating Editor for Special Issues) for the opportunity she has given me as well as for her guidance and support towards the completion of this Special Issue.
Corresponding author:
Alexandros Georgakilas
DNA Damage and Repair Laboratory
Biology Department, East Carolina University
Greenville NC 27858
USA
Email: georgakilas@ecu.edu
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Editorial: The Physiology and Pharmacology of the mitochondrial 18-Kd Translocator Protein (TSPO): an Emerging Molecular Target for Diagnosis and Therapy
Michelangelo Campanella
[BSP/CMM/E-Pub/00045]
The need for a focused issue covering the physiology and pharmacology of the Translocator Protein (TSPO) was in demand for quite some time in biomedical literature to summarize the current knowledge on this fascinating molecule and provide an overview useful to a broader community thereby boosting interest by experimental biologists, pharmacologists and clinicians.
To achieve this, the leading and most representative figures on the subject have contributed with enthusiasm to its realization thus generating a memorable editorial occasion that not only summarizes the most exploited features but also shares original data to inspire future research angles on TSPO.
TSPO -formerly known as the Peripheral Benzodiazepine Receptor (PBR) - is a ubiquitous 18kDa molecule on which the synthesis of steroids depends. Located on the outer mitochondrial membrane (OMM), it is critical for the modulation of mitochondrial pathophysiology by standing -and possibly interacting with- the ‘putative’ molecules composing the mitochondrial permeability transition pore, with the Voltage Dependent Anion Channel (VDAC) as foreseeable principal target.
TSPO binds cholesterol and with similar affinity endozapine as well as synthetic ligands such as a) the benzodiazepine 4'-chlorodiazepam Ro5-4864 and b) the isoquinoline carboxamide PK11195; although the latter, as you will learn in the pages of the issue, affects mitochondrial biology independently from this most acknowledged target.
Hitherto, have been the pharmacologically based approaches to corroborate a role for TSPO in the genesis of neurosteroids and outline those in: i) cell proliferation, ii) apoptotic cell death and iii) mitochondrial coupling.
TSPO is associated with the inflammatory states of the Central Nervous System (CNS) and positively correlated with tumor progression and malignancy besides playing a part in the pathophysiology of the kidney for which defines the response to ischemia and reperfusion.
Physiological and pathological processes linked to this protein range therefore from metabolism to inflammation, to cell death, making TSPO a prime element in cellular and systemic homeostasis. Unsurprisingly, since envisaged as logical target for novel diagnostics and therapeutics quite substantial has been the development of chemicals designed to bind and modulate TSPO.
This issue holds the promise to provide the reader with an organic overview on the most relevant findings surrounding TSPO, considering the evolution of the gene, its involvement in organ pathology, and the diagnostic/therapeutic applications likewise the functional role of its ligands.
I therefore warmly recommend this selection of articles that besides pinpointing the past work concomitantly inform on future avenues to improve the understanding of this pleiotropic molecule.
Corresponding author:
Michelangelo Campanella
Royal Veterinary College,
University of London,
Royal College Street,
NW1 0TU, London
mcampanella@rvc.ac.uk
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Is there any correlation between binding and functional effects at the translocator protein (TSPO) (18 kDa)?
Alana M Scarf, Kylee M Auman and Michael Kassiou
[FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00046]
The translocator protein (TSPO) is a potential drug target for the treatment of CNS diseases, with TSPO ligands being able to modulate steroidogenesis, apoptosis, and cell proliferation. While there exist multiple TSPO binding sites, the nature of these sites – either overlapping or allosterically linked – remains largely uncharacterized. Furthermore, while evidence suggests that microglial activation and polymerization result in changes to TSPO binding sites, these changes are poorly understood. While current pharmacophoric models can be used to synthesize TSPO ligands with high affinity and selectivity, these models are unable to predict ligands with desirable functional effects. Better characterization of TSPO binding sites in health and disease may provide insight into particular sites which mediate promising therapeutic profiles, thus refining the TSPO pharmacophore.
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The role of 18 kDa mitochondrial Translocator Protein (TSPO) in programmed cell death, and effects of steroids on TSPO expression
Leo Veenman and Moshe Gavish
[FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00047]
The mitochondrial 18 kDa Translocator Protein (TSPO) was first detected by its capability to bind benzodiazepines in peripheral tissues and later also in glial cells in the brain, hence it previous most common name peripheral benzodiazepine receptor (PBR). TSPO has been implicated in various functions, including apoptosis and steroidogenesis, among others. Various endogenous TSPO ligands have been proposed, for example: diazepam Binding Inhibitor (DBI), triakontatetraneuropeptide (TTN), phospholipase A2 (PLA2), and protoporphyrin IX. However, the functional implications of interactions between the TSPO and its putative endogenous ligands still have to be firmly established. The TSPO has been suggested to interact with a mitochondrial protein complex, summarized as mitochondrial membrane permeability transition pore (MPTP), which is considered to regulate the mitochondrial membrane potential (Δψm). In addition, the TSPO is associated with several other proteins. The associations of the TSPO with these various proteins at the mitochondrial membranes have been attributed to functions such as apoptosis, steroidogenesis, phosphorylation, reactive oxygen species (ROS) generation, ATP production, and collapse of the Δψm. Interestingly, while TSPO is known to play a role in the modulation of steroid production, in turn, steroids are also known to affect TSPO expression. As with the putative endogenous TSPO ligands, the effects of steroids on TSPO functions still have to be established. In any case, steroid – TSPO interactions occur in organs and tissues as diverse as the reproductive system, kidney, and brain. In general, the steroid – TSPO interactions are thought to be part of stress responses, but may also be essential for reproductive events, embryonic development, and responses to injury, including brain injury. The present review focuses on the role of TSPO in cell death i.e. the notion that enhanced expression and / or activation of the TSPO leads to cell death, and the potential of steroids to regulate TSPO expression and activation.
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Translocator Protein (TSPO) and neurosteroids: implications in psychiatric disorders
Eleonora Da Pozzo, Barbara Costa and Claudia Martini
[FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00048]
The translocator protein (TSPO) is a five transmembrane domain protein localised primarily in the outer mitochondrial membrane of steroid-synthesizing tissues, including the brain. The TSPO mediates the rate-limiting step of steroidogenesis, consisting of the translocation of the substrate cholesterol from the outer to the inner mitochondrial membrane. In the recent years TSPO function has received attention in several psychiatric disorders since these diseases have been associated with unbalanced steroid levels. Accordingly, an alteration in the levels of TSPO has been found in various psychiatric disorders, including social phobia, post-traumatic stress disorder, adult separation anxiety and schizophrenia. The discovery that TSPO drug ligands are able to stimulate neurosteroid production in the brain, independently of peripheral endocrine sources, and restore neurosteroid-mediated neurotransmission, has made the TSPO an attractive drug target for treating a number of psychiatric disorders. In anxiety TSPO drug ligands have shown in vivo efficacy in pharmacologically induced anxiety models in both animals and humans.
The focus of this review is to illustrate the currently available literature regarding the role of TSPO in psychiatric disorders.
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Translocator protein (TSPO) in Breast Cancer
Shyamali Mukherjee and Salil K. Das
[FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00049]
Several molecular and cellular markers are currently used as prognostic indicators for diagnosis and therapeutic intervention of breast cancer. Although some of these markers have helped clinicians provide an earlier diagnosis (or prognosis), they have failed to provide adequate information about the mechanisms responsible for different stages of tumor malignancy so that more effective anticancer therapies can be developed. Recently translocator protein (TSPO), formerly known as the peripheral benzodiazepine receptor (PBR), has received attention as a potential target for anticancer drug development. It is a well-conserved protein, located at outer-inner mitochondrial membrane contact sites, and is expressed in almost all tissues, although the level of expression varies. TSPO is closely associated with the 32 kDa voltage-dependent anion channel (VDAC) and the 30 kDa adenine nucleotide translocase (ANT), considered to form the core of a mitochondria multiprotein complex [named the mitochondrial permeability transition pore (MPTP)] and plays a role in apoptotic cell death. As the major role of TSPO is steroid biosynthesis, TSPO expression is particularly high in organs involved in steroidogenesis such as the adrenals, testes, ovaries, placenta, prostate, colon, kidney, and cardiovascular system. It is well known that TSPO is over-expressed in highly aggressive tumors, especially those of the breast, and that expression correlates with advancing stages of this malignancy. TSPO expression, nuclear localization, and TSPO-mediated cholesterol transport into the nucleus are involved in breast cancer cell proliferation and aggressive phenotype expression. Hence, it can be used as a biomarker in the stage-dependent diagnosis of this cancer.
In addition, cell proliferation, invasion and migration appears to be decreased when treated with high doses of TSPO ligand PK-11195, a compound that may represent a therapeutic agent for the control of breast cancer progression. Control of breast cancer development by consumption of dietary soy protein has been linked to down-regulation of the expression of TSPO-mediated angiogenic signaling molecules. This chapter provides insight into the potential of TSPO as a rational target for the development of novel therapeutics for breast cancer.
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Preclinical Molecular Imaging of the Translocator Protein (TSPO) in a Metastases Model Based on Breast Cancer Xenografts Propagated in the Murine Brain
Shelby K. Wyatt, H. Charles Manning, Mingfeng Bai, Moneeb Ehtesham, Khubaib Y. Mapara, Reid C. Thompson and Darryl J. Bornhop
[FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00050]
Previous studies have demonstrated the feasibility of translocator protein (TSPO) imaging to visualize and quantify human breast adenocarcinoma (MDA-MB-231) cells in vivo using a TSPO-targeted near-infrared (NIR) probe (NIR-conPK11195). This study aimed to extend the use of the TSPO-targeted probe to a more biologically relevant and clinically important tumor microenvironment as well as to assess our ability to longitudinally detect the presence and progression of breast cancer cells in the brain. The in vivo biodistribution and accumulation of NIR-conPK11195 and free (unconjugated) NIR dye were quantitatively evaluated in intracranial MDA-MB-231-bearing mice and non-tumor-bearing control mice longitudinally once a week from two to five weeks post-inoculation. The in vivo time-activity curves illustrate distinct clearance profiles for NIR-conPK11195 and free NIR dye, resulting in preferential accumulation of the TSPO-targeted probe in the intracranial tumor bearing hemisphere (TBH) with significant tumor contrast over normal muscle tissue (p<0.005 at five weeks; p<0.01 at four weeks). In addition, the TSPO-labeled TBHs demonstrated significant contrast over the TBHs of mice injected with free NIR dye (p<0.001 at four and five weeks) as well as over the TSPO-labeled non-tumor-bearing hemispheres (NTBHs) of control mice (p<0.005 at four and five weeks). Overall, TSPO-targeted molecular imaging appears useful for visualizing and quantifying breast cancer xenografts propagated in the murine brain and may assist in preclinical detection, diagnosis and monitoring of metastatic disease as well as drug discovery. Furthermore, these results indicate it should be possible to perform TSPO-imaging of breast cancer cells in the brain using radiolabeled TSPO-targeted agents, particularly in light of the fact that [11C]-labeled TSPO probes such as [11C]-PK 11195 have been successfully used to image gliomas in the clinic.
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Developmental expression of the Translocator protein 18 kDa (TSPO) in testicular germ cells
Gurpreet Manku, Yan Wang, Raphael Thuillier, Corinne Rhodes and Martine Culty
[FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00051]
Translocator protein (TSPO) is a high affinity 18 kDa drug- and cholesterol-binding protein strongly expressed in steroidogenic tissues where it mediates cholesterol transport into mitochondria and steroid formation. Testosterone formation by Leydig cells in the testis is critical for the regulation of spermatogenesis and male fertility. Male germ cell development comprises two main phases, the pre-spermatogenesis phase occurring from fetal life to infancy and leading to spermatogonial stem cell (SSC) formation, and spermatogenesis, which consists of repetitive cycles of germ cell mitosis, meiosis and differentiation, starting with SSC differentiation and ending with spermiogenesis and spermatozoa formation. Little is known about the molecular mechanisms controlling the progression from one germ cell phenotype to the next. Here, we report that testicular germ cells express TSPO from neonatal to adult phases, although at lower levels than Leydig cells. TSPO mRNA and protein were found at specific steps of germ cell development. In fetal and neonatal gonocytes, the precursors of SSCs, TSPO appears to be mainly nuclear. In the prepubertal testis, TSPO is present in pachytene spermatocytes and dividing spermatogonia. In adult testes, it is found in a stage-dependent manner in pachytene spermatocyte and round spermatid nuclei, and in mitotic spermatogonia. In search of TSPO function, the TSPO drug ligand PK 11195 was added to isolated gonocytes with or without the proliferative factors PDGF and 17β-estradiol, and was found to have no effect on gonocyte proliferation. However, TSPO strong expression in dividing spermatogonia suggests that it might play a role in spermatogonial mitosis. Taken together, these results suggest that TSPO plays a role in specific phases of germ cell development.
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PK11195 inhibits mitophagy targeting the F1Fo-ATPsynthase in Bcl-2 knock-down cells
Michael SD Seneviratne, Danilo Faccenda, Valerio De Biase and Michelangelo Campanella
[FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00052]
The pharmacological agent 1-(2-Chlorophenyl-N-methylpropyl)-3-isoquinolinecarboxamide (PK11195) is the prototypical ligand of the 18-KDa Translocator Protein (TSPO) but at μM concentrations deactivates the oncoprotein Bcl-2 increasing the efficiency of chemotherapeutic agents and promoting the Ca2+-dependent macro-autophagy (or autophagy).
In this paper, we report that PK11195, in HeLa cells, modifies the mitochondria-targeted type of autophagy -hereafter referred to as mitophagy- and the associated resizing of the mitochondrial network but does so exclusively in absence of the oncoprotein Bcl-2 (Bcl-2 Kd cells).
This is consequence of a “side” targeting of the mitochondrial F1Fo-ATPsynthase enzyme, since identical outcome is mimicked by the antibiotic Oligomycin, of which PK11195 matches the effect on: i) mitochondrial membrane potential (Δψm), ii) ATP homeostasis and iii) Reactive Oxygen Species (ROS) generation.
Taken together, these data highlight a novel TSPO-independent biological effect for PK11195 and provide evidences for a hitherto uncovered Bcl-2-dependent role of the F1Fo-ATPsynthase in mitochondrial quality control.
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Role of Translocator Protein (18 kDa) in adult separation anxiety and attachment style in patients with depression
Barbara Costa, Stefano Pini, Marianna Abelli, Pamela Gabelloni, Eleonora Da Pozzo, Beatrice Chelli, Simona Calugi, Lisa Lari, Alessandra Cardini, Antonio Lucacchini, Giovanni B Cassano and Claudia Martini
[FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00053]
Background: and Objectives: A role for the protein that mediates the rate-limiting step of steroidogenesis, the 18 kDa Translocator Protein (TSPO), has been suggested in the pathophysiology of Adult Separation Anxiety Disorder (ASAD). It has been shown that ASAD patients have 1) low TSPO expression levels and 2) a high frequency of the allele that substitutes Ala with Thr at position 147 of TSPO. The Thr147 ASAD-associated allele has been recently related with a low pregnenolone production. The aim of the present work was to evaluate the relationship between TSPO expression levels and Ala147Thr single nucleotide polymorphism (SNP), which are the two TSPO biological parameters that we have previously examined separately. A further aim was to confirm the genetic association of Ala147Thr SNP with ASAD in an extended case-control sample and to investigate whether this SNP was related to an anxious attachment style that is thought to be connected to ASAD.
Methods: TSPO expression levels were compared among patients with ASAD (n=26), without ASAD (n=26) and control samples (n=10) stratified into the two genotype groups: those with the Ala147 genotype (named “normal pregnenolone production”) and those with the Thr147 genotype (named “reduced pregnenolone production”). The case-control genetic study included patients with (n=87) or without (n=101) ASAD and 236 controls. In the patient group, the association between the Ala147Thr SNP and an anxious attachment style was analysed by stepwise logistic regression analysis.
Results: The genotype with the lowest TSPO expression levels was the “normal pregnenolone production” genotype in the ASAD group. The genetic Ala147Thr SNP confirmed an excess of the Thr147 allele in ASAD patients. Stepwise logistic regression analysis did not show an association with an anxious attachment style.
Conclusions: ASAD individuals who expressed normal TSPO levels exhibited the “reduced pregnenolone production” genotype. In contrast, the ASAD individuals with the “normal pregnenolone production” genotype expressed low TSPO levels. It is possible that low TSPO expression levels could compromise normal pregnenolone production. Such evidence may have therapeutic implications because it has been documented that drugs targeting TSPO increased pregnenolone production and have anxiolytic effects.
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Evidence for Complex Binding Profiles and Species Differences at the Translocator Protein (TSPO) (18 kDa)
Alana M Scarf, Christopher Luus, Eleonora Da Pozzo, Silvia Selleri, Chiara Guarino, Claudia Martini, Lars M. Ittner and Michael Kassiou
[FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00054]
The translocator protein (TSPO) (18 kDa) is an emerging drug target for the treatment of numerous pathologies including cancer and neurodegenerative disease. However, our limited knowledge of TSPO binding site(s) has hindered the development of TSPO ligands with potential therapeutic effects. We have synthesized a series of pyrrolobenzoxazepines (1-10) to better characterize the interaction of ligands with the TSPO across species, and to determine their functional profiles. All ligands 1-10 displaced the binding of [3H]PK 11195 to the TSPO at nanomolar concentrations, with discrepancies in binding affinity between rat and human TSPO. Interestingly, non-linear regression analysis revealed that some ligands bound to the protein with a Hill slope not equal to 1.0, suggesting possible additional TSPO binding sites with allosteric effects. However, this trend was not conserved between rat and human. When tested for their effects on pregnenolone production in rat C6 glioma cells, nitric oxide release in murine microglia, and cell proliferation in human MCF-7 breast cancer cells, the pyrrolobenzoxazepines (40 μM) displayed functional effects which did not correlate to the binding trend observed in competition assays. We propose that consideration of species differences and binding site cooperativity, plus optimization of currently accepted functional assays, will aid in the development of drugs targeting TSPO that can be used as therapeutics for human disease.
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Structural and functional evolution of the translocator protein (18 kDa)
Jinjiang Fan, Peter Lindemann, Marc G. J. Feuilloley and Vassilios Papadopoulos
[FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00055]
Translocator proteins (TSPO) are the products of a family of genes that is evolutionarily conserved from bacteria to humans and expressed in most mammalian tissues and cells. Human TSPO (18 kDa) is expressed at high levels in steroid synthesizing endocrine tissues where it localizes to mitochondria and functions in the first step of steroid formation, the transport of cholesterol into the mitochondria. TSPO expression is elevated in cancerous tissues and during tissue injury, which has lead to the hypothesis that TSPO has roles in apoptosis and the maintenance of mitochondrial integrity. We recently identified a new paralog of Tspo in both the human and mouse. This paralog arose from an ancient gene duplication event before the divergence of the classes aves and mammals, and appears to have specialized tissue-, cell-, and organelle-specific functions. Evidence from the study of TSPO homologs in mammals, bacteria, and plants supports the conclusion that the TSPO family of proteins regulates specialized functions related to oxygen-mediated metabolism. In this review, we provide a comprehensive overview of the divergent function and evolutionary origin of Tspo genes in Bacteria, Archaea, and Eukarya domains.
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The 18Kda Translocator Protein (TSPO): a New Perspective in Mitochondrial Biology
Jemma Gatliff and Michelangelo Campanella
[FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00056]
In mammals, mitochondria are central in maintaining normal cell function and dissecting the pathways that govern their physiology and pathology is therefore of utmost importance. For a long time, the science world has acknowledged the Translocator Protein (TSPO), an intriguing molecule that, through its position and association with biological processes, stands as one of the hidden regulatory pathways in mitochondrial homeostasis. Here we aim to review the literature and highlight what links TSPO to mitochondrial homeostasis in order to delineate its contribution in the functioning and malfunctioning of this critical organelle. In detail, we will discuss: 1) TSPO localization and interplay with controlling phenomena of mitochondria (e.g. mPTP); 2) TSPO interaction with the prominent mitochondrial player VDAC; consider evidence on how TSPO relates to 3) mitochondrial energy production; 4) Ca2+ signalling and 5) the generation of Reactive Oxygen Species (ROS) before finally describing 6) its part in apoptotic cell death. In essence, we hope to demonstrate the intimate involvement TSPO has in the regulation of mitochondrial homeostasis and muster attention towards this molecule, which is equally central for both cellular and mitochondrial biology.
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Role of Translocator Protein in renal ischemia reperfusion, renal preservation and acute kidney injury
Raphael Thuillier and Thierry Hauet
[FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00057]
Translocator protein (TSPO), formerly known as peripheral-type benzodiazepine receptor (PBR), has been described in several tissues and characterized as one of the main elements of steroidogenesis. However, TSPO is also involved in other pathways and cell functions, such as apoptosis regulation, protein import, membrane biogenesis, cell cycle regulation, oxygen homeostasis and mitochondrial membrane fluidity regulation.
In the kidney, TSPO is normally located in the distal parts of the nephron from the thick ascending limb of the loop of Henle to the medullary collecting ducts. However when the kidney is submitted to a stress such as ischemia reperfusion injury there is a defined change in TSPO expression towards more proximal areas of the nephron, and the protein can be detected as high as proximal tubular cells and the Bowman Capsule. As the injury persists, TSPO is also located in invading mononucleated cells, in a pattern reproducing invasion by CD4+ helper Tcells, and in the damaged vessels where TSPO is expressed both in endothelial and smooth muscle cells.
Herein we review the potential use of TSPO-directed treatment for ischemia reperfusion injury, particularly regarding pre-conditioning of the organ. We also detail the relationship of proximal TSPO staining with the intensity of the injury, particularly the implication of monomeric (18kDa) TSPO and its role in hypoxia-reoxygenation and apoptosis prevention. The potential implications of the protein with regeneration processes activated in response to injury and their relation with embryogenesis pathways are discussed.
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Evaluation of early regenerative processes in a preclinical pig model of acute kidney injury
Ludivine Rossard, Frederic Favreau, Julie Demars, René Robert, Cédric Nadeau, Jérome Cau, Raphael Thuillier and Thierry Hauet
[FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00058]
Renal failure due to ischemic injury is a common denominator of various clinical situations in critically ill patients. This study was designed to characterize the TPSO/Cholesterol synthesis and cell division pathways in response to different levels of ischemia. Porcine kidneys were subjected to either 60min-warm ischemia (WI) or auto-transplanted after cold storage for 24h at 4°C (CS), or both conditions (WI+CS), pathway activation and function were evaluated at 3h, 3 and 7 days after reperfusion.
CS combined to WI affects renal functions indicating a high degree of injury. During the first week of reperfusion, renal levels of free and esterified cholesterol, major cellular components, increased in CS group with an attenuated production when WI was associated. CS and WI+CS groups exhibited an elevated expression of cell cycle induction markers such as PCNA and stathmin. TSPO expression was highest in groups with the lowest injury, and correlated with kidney outcome, revealing its potential for diagnosis.
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MicroRNAs as Regulators in Normal Hematopoietic and Leukemia Stem Cells: Current Concepts and Clinical Implications
Ke Fang, Feng Qian and Yue-Qin Chen
[Purchase Article] [BSP/CMM/E-Pub/00059]
Relapse after current treatment is one of the main limitations to the complete cure of leukemia, and a concept that leukemia stem cell (LSC) is the major cause of relapse has been proposed. LSCs are derived from normal hematopoietic stem cells (HSCs), residing at the apex of leukemia cells and hiding in the bone marrow (BM) niche to evade chemotherapy. Novel therapy is strongly needed based on the unique features of LSCs to directly target these cells. MicroRNAs (miRNAs), a class of small non-coding RNAs, are now known to play important roles on cancer stem cell maintenance and differentiation. Because of the ability of miRNAs to inactivate either specific genes or entire gene families, strategies based on differential expression levels of miRNAs in LSCs as dominant activators or suppressors of gene activity have emerged as promising new candidate approaches for eradicating LSCs. In this review, we highlight new findings regarding the roles of miRNAs in LSC maintenance of quiescence repression, self-renewal, surface marker targeting, and the LSC-BM niche interaction. We also discuss recent advances and future challenges to use LSC specific miRNAs as potential therapeutic molecules in eradicating LSCs.
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The radiation bystander effect and its potential implications for human health
M. Mancuso, E. Pasquali, P. Giardullo, S. Leonardi, M. Tanori, V. Di Majo, S. Pazzaglia and A. Saran
[FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00060]
A long-held dogma in radiation biology has been that the biological effects of exposure to ionizing radiation occur as a result of damage in directly irradiated cells and that no effect would occur in neighboring unirradiated cells. This paradigm has been frequently challenged by reports of radiation effects in unirradiated or ‘bystander’ cells receiving signals from directly irradiated cells, an issue that may have substantial impact on radiation risk assessment and development of radiation-based therapies. Radiation-induced bystander effects have been shown in single-cell systems in vitro for an array of cancer relevant endpoints, and may trigger damage in more complex 3-D tissue systems. They may be mediated by soluble factors released by irradiated cells into the extracellular environment and/or by the passage of mediator molecules through gap-junction intercellular communication. To date, evidence that radiation-associated bystander or abscopal responses are effectual in vivo has been limited, but new data suggest that they may significantly affect tumor development in susceptible mouse models. Further understanding of how the signal/s is transmitted to unirradiated cells and tissues and how it provokes long-range and significant responses is crucial. By summarizing the existing evidence of radiation induced bystander-like effects in various systems with emphasis on in vivo findings, we will discuss the potential mechanisms involved in these observations and how effects in bystander cells contribute to uncertainties in assessing cancer risks associated with radiation exposure.
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Neuroprotective Strategies for the Treatment of Inherited Photoreceptor Degeneration
Dragana Trifunović, Ayşe Sahaboglu, Jasvir Kaur, Stine Mencl, Eberhart Zrenner, Marius Ueffing, Blanca Arango-Gonzalez and François Paquet-Durand
[FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00061]
Photoreceptor degeneration is the hallmark of several groups of inherited neurodegenerative diseases causing blindness in humans. These diseases are a major cause of visual handicap and to date no satisfactory treatment is available. Here, we briefly review different approaches for the treatment of photoreceptor degeneration, to then focus on neuroprotection.
Up to date, translation of experimental neuroprotection into a clinical setting has faced major obstacles, which are in part due to an incomplete understanding of the regulation of pro-survival as well as neurodegenerative mechanisms. Previous approaches were often based on the hypothesis that photoreceptor cell death was governed by a single, apoptotic cell death mechanism. This perception has turned out too simple as recent work has demonstrated that photoreceptor cell death is governed by non-apoptotic mechanisms as well. Moreover, there is evidence, that several different destructive processes are executed in parallel. Briefly reviewing the complexity of degenerative mechanisms, this review discusses relevant pathways, options to target signaling cascades, final common denominators of cell death, and the interplay of events executing cell death. In particular, we focus on cGMP-signaling, epigenetic and proteolytic processes and the corresponding enzymatic activities that were recently shown to be causally related to retinal degeneration. Finally, we illustrate how a better understanding of destructive mechanisms may enable identification and validation of novel targets for neuroprotection, and allow development of next generation neuroprotective treatments as well as combination therapy.
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Th17-related cytokines in inflammatory bowel diseases: friends or foes?
Ivan Monteleone, Massimiliano Sarra, Francesco Pallone and Giovanni Monteleone
[FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00062]
T helper (Th)17 cells and other interleukin (IL)-17-producing cells are supposed to play critical roles in several human immune-mediated diseases, including Crohn’s disease (CD) and ulcerative colitis (UC), the main forms of inflammatory bowel diseases (IBD) in man. Th17 cells infiltrate massively the inflamed intestine of IBD patients and in vitro and in vivo studies have shown that Th17-type cytokines may trigger and amplify multiple inflammatory pathways. Nonetheless, some Th17-related cytokines, such as interleukin (IL)-17A and IL-22 , may gut target epithelial cells and promote the activation of counter-regulatory mechanisms. This observation together with the demonstration that Th17 cells are not stable and can be converted into either regulatory T cells or Th1 cells if stimulated by immune-suppressive (e.g. TGF-1) or inflammatory (e.g. IL-12, IL-23) cytokines have contributed to advance our understanding of mechanisms that regulate mucosal homeostasis and inflammation in the gut.
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Immunosuppressive properties of mesenchymal stem cells: advances and applications
De Miguel MP, Fuentes-Julián S, Blázquez-Martínez A, Pascual CY Aller MA, Arias J and Arnalich-Montiel F
[FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00063]
Mesenchymal stem cells (MSCs) have been isolated from a variety of tissues, such as bone marrow, skeletal muscle, dental pulp, bone, umbilical cord and adipose tissue. MSCs are used in regenerative medicine mainly based on their capacity to differentiate into specific cell types and also as bioreactors of soluble factors that will promote tissue regeneration from the damaged tissue cellular progenitors.
In addition to these regenerative properties, MSCs hold an immunoregulatory capacity, and elicit immunosuppressive effects in a number of situations. Not only are they immunoprivileged cells, due to the low expression of class II Major Histocompatibilty Complex (MHC-II) and costimulatory molecules in their cell surface, but they also interfere with different pathways of the immune response by means of direct cell-to-cell interactions and soluble factor secretion. In vitro, MSCs inhibit cell proliferation of T cells, B-cells, natural killer cells (NK) and dendritic cells (DC), producing what is known as division arrest anergy. Moreover, MSCs can stop a variety of immune cell functions: cytokine secretion and cytotoxicity of T and NK cells; B cell maturation and antibody secretion; DC maturation and activation; as well as antigen presentation. It is thought that MSCs need to be activated to exert their immunomodulation skills. In this scenario, an inflammatory environment seems to be necessary to promote their effect and some inflammation-related molecules such as tumor necrosis factor-α and interferon-γ might be implicated. It has been observed that MSCs recruit T-regulatory lymphocytes (Tregs) to both lymphoid organs and graft. There is great controversy concerning the mechanisms and molecules involved in the immunosuppressive effect of MSCs. Prostaglandin E2, transforming growth factor-β, interleukins- 6 and 10, human leukocyte antigen-G5, matrix metalloproteinases, indoleamine-2,3-dioxygenase and nitric oxide are all candidates under investigation.
In vivo studies have shown many discrepancies regarding the immunomodulatory properties of MSCs. These studies have been designed to test the efficacy of MSC therapy in two different immune settings: the prevention or treatment of allograft rejection episodes, and the ability to suppress abnormal immune response in autoimmune and inflammatory diseases. Preclinical studies have been conducted in rodents, rabbits and baboon monkeys among others for bone marrow, skin, heart, and corneal transplantation, graft versus host disease, hepatic and renal failure, lung injury, multiple sclerosis, rheumatoid arthritis, diabetes and lupus diseases. Preliminary results from some of these studies have led to human clinical trials that are currently being carried out. These include treatment of autoimmune diseases such as Crohn’s disease, ulcerative colitis, multiple sclerosis and type 1 diabetes mellitus; prevention of allograft rejection and enhancement of the survival of bone marrow and kidney grafts; and treatment of resistant graft versus host disease. We will try to shed light on all these studies, and analyze why the results are so contradictory.
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Beyond the Cardiac Myofilament: Hypertrophic Cardiomyopathy-Associated Mutations in Genes that Encode Calcium-Handling Proteins
Andrew P. Landstrom and Michael J. Ackerman
[FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00064]
Traditionally regarded as a genetic disease of the cardiac sarcomere, hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disease and a significant cause of sudden cardiac death. While the most common etiologies of this phenotypically diverse disease lie in a handful of genes encoding critical contractile myofilament proteins, approximately 50% of patients diagnosed with HCM worldwide do not host sarcomeric gene mutations. Recently, mutations in genes encoding calcium-sensitive and calcium-handling proteins have been implicated in the pathogenesis of HCM. Among these are mutations in TNNC1-encoded cardiac troponin C, PLN-encoded phospholamban, and JPH2-encoded junctophilin 2 which have each been associated with HCM in multiple studies. In addition, mutations in RYR2-encoded ryanodine receptor 2, CASQ2-encoded calsequestrin 2, CALR3-encoded calreticulin 3, and SRI-encoded sorcin have been associated with HCM, although more studies are required to validate initial findings. While a relatively uncommon cause of HCM, mutations in genes that encode calcium-handling proteins represent an emerging genetic subset of HCM. Furthermore, these naturally occurring disease-associated mutations have provided useful molecular tools for uncovering novel mechanisms of disease pathogenesis, increasing our understanding of basic cardiac physiology, and dissecting important structure-function relationships within these proteins.
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GADD45 proteins: central players in tumorigenesis
Rodrigo Esaki Tamura, Jaíra Ferreira de Vasconcellos, Devanand Sarkar, Towia A Libermann, Paul B Fisher and Luiz Fernando Zerbini
[FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00065]
The Growth Arrest and DNA Damage-inducible 45 (GADD45) proteins have been implicated in regulation of many cellular functions including DNA repair, cell cycle control, senescence and genotoxic stress. However, the pro-apoptotic activities have also positioned GADD45 as an essential player in oncogenesis. Emerging functional evidence implies that GADD45 proteins serve as tumor suppressors in response to diverse stimuli, connecting multiple cell signaling modules. Defects in the GADD45 pathway can be related to the initiation and progression of malignancies. Moreover, induction of GADD45 expression is an essential step for mediating anti-cancer activity of multiple chemotherapeutic drugs and the absence of GADD45 might abrogate their effects in cancer cells. In this review, we present a comprehensive discussion of the functions of GADD45 proteins, linking their regulation to effectors of cell cycle arrest, DNA repair and apoptosis. The ramifications regarding their roles as essential and central players in tumor growth suppression are also examined. We also extensively review recent literature to clarify how different chemotherapeutic drugs induce GADD45 gene expression and how its up-regulation and interaction with different molecular partners may benefit cancer chemotherapy and facilitate novel drug discovery.
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Spinophilin: a new tumor suppressor at 17q21
Amancio Carnero
[FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00066]
The scaffold protein spinophilin (SPN) is a regulatory subunit of phosphatase 1a (PP1a) located at 17q21.33. This region is frequently associated with microsatellite instability and LOH and contains a relatively high density of known tumor suppressor genes, and several unidentified candidate tumor suppressor genes located distal to BRCA1. Spn is located in this locus and proposed to be a new tumor suppressor. Loss of Spn induces a proliferative response by increasing pRb phosphorylation, which in turn activates p53, thereby, neutralizing the proliferative response. The absence of p53 bypasses this barrier and enhances the malignant phenotype. Furthermore, the ectopic expression of SPN in human tumor cells from different types of malignancies greatly reduced cell growth. Spn knock-out mice had decreased lifespan with increased cellular proliferation in tissues such as the mammary ducts and early appearance of tumors. Furthermore, the combined loss of Spn and mutant p53 activity led to increased mammary carcinomas, confirming the functional relationship between p53 and Spn. In human tumors, Spn is absent in 20% and reduced in another 37% of human lung tumors. Spn reduction correlates with malignant grade and p53 mutations. Furthermore, Spn mRNA is lost in a percentage of renal carcinomas and lung adenocarcinomas. Finally, lower levels of Spn mRNA correlate with higher grade of ovarian carcinoma and chronic myelogenous leukemia. Therefore, Spn may be the tumor suppressor gene that is located at 17q21.33 and that its tumor suppressive function is dependent on the absence of p53.
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Plumbagin Inhibits Breast Tumor Bone Metastasis and Osteolysis by Modulating the Tumor-Bone Microenvironment
Zhenxi Li , Jianru Xiao, Xian Wu, Wenjun Li, Zhengfeng Yang, Juan Xie, Leqin Xu, Xiaopan Cai, Zaijun Lin, Wen Guo, Jian Luo and Mingyao Liu
[FULL-TEXT INQUIRY] [BSP/CMM/E-Pub/00067]
Bone metastasis is a common and serious consequence of breast cancer. Bidirectional interaction between tumor cells and the bone marrow microenvironment drives a so-called ‘vicious cycle’ that promotes tumor cell malignancy and stimulates osteolysis. Targeting these interactions and pathways in the tumor-bone microenvironment has been an encouraging strategy for bone metastasis therapy. In the present study, we examined the effects of plumbagin on breast cancer bone metastasis. Our data indicated that plumbagin inhibited cancer cell migration and invasion, suppressed the expression of osteoclast-activating factors, altered the cancer cell induced RANKL/OPG ratio in osteoblasts, and blocked both cancer cell- and RANKL-stimulated osteoclastogenesis. In mouse model of bone metastasis, we further demonstrated that plumbagin significantly repressed breast cancer cell metastasis and osteolysis, inhibited cancer cell induced-osteoclastogenesis and the secretion of osteoclast-activating factors in vivo. At the molecular level, we found that plumbagin abrogated RANKL-induced NF-κB and MAPK pathways by blocking RANK association with TRAF6 in osteoclastogenesis, and by inhibiting the expression of osteoclast-activating factors through the suppression of NF-κB activity in breast cancer cells. Taken together, our data demonstrate that plumbagin inhibits breast tumor bone metastasis and osteolysis by modulating the tumor-bone microenvironment and that plumbagin may serve as a novel agent in the treatment of tumor bone metastasis.
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