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      Sensitization of Radioresistant Prostate Cancer Cells by Resveratrol Isolated from Arachis hypogaea Stems

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          Abstract

          Resveratrol (RV, 3,4ʹ,5-trihydroxystilbene) is naturally produced by a wide variety of plants including grapes and peanuts ( Arachis hypogaea). However, the yield of RV from peanut stem and its potential radiosensitizing effects in prostate cancer (PCa) have not been well investigated. In this study, we characterized RV in peanut stem extract (PSE) for the first time and showed that both RV and PSE dose-dependently induced cell death in DOC-2/DAB2 interactive protein (DAB2IP)-deficient PCa cells with the radioresistant phenotype. Furthermore, the combination of radiation with either RV or PSE induced the death of radioresistant PCa cells through delayed repair of radiation-induced DNA double-strand break (DSB) and prolonged G2/M arrest, which induced apoptosis. The administration of RV and PSE effectively enhanced radiation therapy in the shDAB2IP PCa xenograft mouse model. These results demonstrate the promising synergistic effect of RV and PSE combined with radiation in the treatment of radioresistant PCa.

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          DNA damage signalling guards against activated oncogenes and tumour progression.

          DNA damage response (DDR), the guardian of genomic integrity, emerges as an oncogene-inducible biological barrier against progression of cancer beyond its early stages. Recent evidence from both cell culture and animal models as well as analyses of clinical specimens show that activation of numerous oncogenes and loss of some tumour suppressors result in DNA replication stress and DNA damage that alarm the cellular DDR machinery, a multifaceted response orchestrated by the ATR-Chk1 and ATM-Chk2 kinase signalling pathways. Such activation of the DDR network leads to cellular senescence or death of oncogene-transformed cells, resulting in delay or prevention of tumorigenesis. At the same time, the ongoing chronic DDR activation creates selective pressure that eventually favours outgrowth of malignant clones with genetic or epigenetic defects in the genome maintenance machinery, such as aberrations in the ATM-Chk2-p53 cascade and other DDR components. Furthermore, the executive DDR machinery is shared by at least two anticancer barriers, as both the oncogene-induced DNA replication stress and telomere shortening impact the cell fate decisions through convergence on DNA damage signalling. In this study, we highlight recent advances in this rapidly evolving area of cancer research, with particular emphasis on mechanistic insights, emerging issues of special conceptual significance and discussion of major remaining challenges and implications of the concept of DDR as a tumorigenesis barrier for experimental and clinical oncology.
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            Resveratrol as an anti-inflammatory and anti-aging agent: mechanisms and clinical implications.

            Resveratrol is a phytoalexin polyphenolic compound found in various plants, including grapes, berries, and peanuts. Multiple lines of compelling evidence indicate its beneficial effects on neurological, hepatic, and cardiovascular systems. Also one of the most striking biological activities of resveratrol soundly investigated during the late years has been its cancer-chemopreventive potential. In fact, recently it has been demonstrated that this stilbene blocks the multistep process of carcinogenesis at various stages: tumor initiation, promotion, and progression. One of the possible mechanisms for its biological activities involves downregulation of the inflammatory response through inhibition of synthesis and release of pro-inflammatory mediators, modification of eicosanoid synthesis, inhibition of activated immune cells, or inhibiting such as inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) via its inhibitory effects on nuclear factor (kappa)B (NF-(kappa)B) or the activator protein-1 (AP-1). More recent data provide interesting insights into the effect of this compound on the lifespan of yeast and flies, implicating the potential of resveratrol as an anti-aging agent in treating age-related human diseases. It is worthy to note that the phenolic compound possesses a low bioavailability and rapid clearance from the plasma. As the positive effects of resveratrol on inflammatory response regulation may comprise relevant clinical implications, the purpose of this article is to review its strong anti-inflammatory activity and the plausible mechanisms of these effects. Also, this review is intended to provide the reader an up-date of the bioavailability and pharmacokinetics of resveratrol and its impact on lifespan.
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              Resveratrol and health--a comprehensive review of human clinical trials.

              In the past decade, the small polyphenol resveratrol has received widespread attention as either a potential therapy or as a preventive agent for numerous diseases. Studies using purified enzymes, cultured cells, and laboratory animals have suggested that resveratrol has anti-aging, anti-carcinogenic, anti-inflammatory, and anti-oxidant properties that might be relevant to chronic diseases and/or longevity in humans. Although the supporting research in laboratory models is quite substantial, only recently data has emerged to describe the effects of resveratrol supplementation on physiological responses in humans. The limited number of human clinical trials that are available has largely described various aspects of resveratrol's safety and bioavailability, reaching a consensus that it is generally well-tolerated, but have poor bioavailability. Very few published human studies have explored the ability of resveratrol to achieve the physiological benefits that have been observed in laboratory models, although many clinical trials have recently been initiated. This review aims to examine the current state of knowledge on the effects of resveratrol on humans and to utilize this information to develop further guidelines for the implementation of human clinical trials. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                12 January 2017
                2017
                : 12
                : 1
                : e0169204
                Affiliations
                [1 ]Graduate Institute of Basic Medical Science, School of Medicine, China Medical University, Taichung, Taiwan
                [2 ]Research Institute of Biotechnology, Hungkuang University, Taichung, Taiwan
                [3 ]Department of Microbiology and Immunology, Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
                [4 ]Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America
                [5 ]Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan
                [6 ]Department of Rehabilitation, Dachien General Hospital, Miaoli, Taiwan
                [7 ]School of Management, Feng Chia University, Taichung, Taiwan
                [8 ]Department of Nursing, Asia University, Taichung, Taiwan
                [9 ]Molecular Infectious Disease Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan
                Taipei Medical University, TAIWAN
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                • Conceptualization: CHT HL JTH CHL.

                • Data curation: SJC CCC.

                • Formal analysis: UGL LCL CJL.

                • Funding acquisition: HL CHL.

                • Investigation: YAC HML MCK UGL LCL CJL.

                • Methodology: JTH CHL.

                • Project administration: HL JTH CHL.

                • Resources: HL CHL.

                • Software: YAC.

                • Supervision: CHT HL JTH CHL.

                • Validation: YAC HML MCK.

                • Visualization: CHT HL JTH CHL.

                • Writing – original draft: YAC HML CHL.

                • Writing – review & editing: CHT HL JTH CHL.

                Article
                PONE-D-16-33223
                10.1371/journal.pone.0169204
                5231355
                28081154
                892cae69-3b99-42bb-b9ce-36ce76df40a7
                © 2017 Chen et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 19 August 2016
                : 14 December 2016
                Page count
                Figures: 7, Tables: 0, Pages: 15
                Funding
                Funded by: Central Taiwan Science Park
                Award ID: 103-RB04
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100004663, Ministry of Science and Technology, Taiwan;
                Award ID: 104-2320-B-182-040, and 105-2313-B-182-001
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100004663, Ministry of Science and Technology, Taiwan;
                Award ID: 104-2911-I-005-501
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100005795, Chang Gung Memorial Hospital, Linkou;
                Award ID: CMRPD1F0011-3, CMRPD1F0431-3, and BMRPE90
                Award Recipient :
                This study was supported by grants from Central Taiwan Science Park (103-RB04), Ministry of Science and Technology (104-2911-I-005-501, 104-2320-B-182-040, and 105-2313-B-182-001), Chang Gung Memorial Hospital (CMRPD1F0011-3, CMRPD1F0431-3, and BMRPE90), and the Tomorrow Medical Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Medicine and Health Sciences
                Oncology
                Cancers and Neoplasms
                Genitourinary Tract Tumors
                Prostate Cancer
                Medicine and Health Sciences
                Urology
                Prostate Diseases
                Prostate Cancer
                Biology and Life Sciences
                Cell Biology
                Cell Processes
                Cell Death
                Apoptosis
                Biology and Life Sciences
                Organisms
                Plants
                Legumes
                Peanut
                Medicine and Health Sciences
                Oncology
                Cancer Treatment
                Biology and Life Sciences
                Cell Biology
                Cell Processes
                Cell Cycle and Cell Division
                Research and Analysis Methods
                Chromatographic Techniques
                Liquid Chromatography
                High Performance Liquid Chromatography
                Medicine and Health Sciences
                Oncology
                Cancer Treatment
                Radiation Therapy
                Medicine and Health Sciences
                Clinical Medicine
                Clinical Oncology
                Radiation Therapy
                Medicine and Health Sciences
                Oncology
                Clinical Oncology
                Radiation Therapy
                Research and Analysis Methods
                Experimental Organism Systems
                Model Organisms
                Mouse Models
                Research and Analysis Methods
                Model Organisms
                Mouse Models
                Research and Analysis Methods
                Experimental Organism Systems
                Animal Models
                Mouse Models
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                All relevant data are within the paper and its Supporting Information files.

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