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      Systems pharmacology-based investigation of Sanwei Ganjiang Prescription: related mechanisms in liver injury

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          Abstract

          Liver injury remains a significant global health problem and has a variety of causes, including oxidative stress (OS), inflammation, and apoptosis of liver cells. There is currently no curative therapy for this disorder. Sanwei Ganjiang Prescription (SWGJP), derived from traditional Chinese medicine (TCM), has shown its effectiveness in long-term liver damage therapy, although the underlying molecular mechanisms are still not fully understood. To explore the underlining mechanisms of action for SWGJP in liver injury from a holistic view, in the present study, a systems pharmacology approach was developed, which involved drug target identification and multilevel data integration analysis. Using a comprehensive systems approach, we identified 43 candidate compounds in SWGJP and 408 corresponding potential targets. We further deciphered the mechanisms of SWGJP in treating liver injury, including compound-target network analysis, target-function network analysis, and integrated pathways analysis. We deduced that SWGJP may protect hepatocytes through several functional modules involved in liver injury integrated-pathway, such as Nrf2-dependent anti-oxidative stress module. Notably, systems pharmacology provides an alternative way to investigate the complex action mode of TCM.

          Most cited references31

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          Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked.

          Bcl-2 is an integral membrane protein located mainly on the outer membrane of mitochondria. Overexpression of Bcl-2 prevents cells from undergoing apoptosis in response to a variety of stimuli. Cytosolic cytochrome c is necessary for the initiation of the apoptotic program, suggesting a possible connection between Bcl-2 and cytochrome c, which is normally located in the mitochondrial intermembrane space. Cells undergoing apoptosis were found to have an elevation of cytochrome c in the cytosol and a corresponding decrease in the mitochondria. Overexpression of Bcl-2 prevented the efflux of cytochrome c from the mitochondria and the initiation of apoptosis. Thus, one possible role of Bcl-2 in prevention of apoptosis is to block cytochrome c release from mitochondria.
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            An essential role for NF-kappaB in preventing TNF-alpha-induced cell death.

            Studies on mice deficient in nuclear factor kappa B (NF-kappaB) subunits have shown that this transcription factor is important for lymphocyte responses to antigens and cytokine-inducible gene expression. In particular, the RelA (p65) subunit is required for induction of tumor necrosis factor-alpha (TNF-alpha)-dependent genes. Treatment of RelA-deficient (RelA-/-) mouse fibroblasts and macrophages with TNF-alpha resulted in a significant reduction in viability, whereas RelA+/+ cells were unaffected. Cytotoxicity to both cell types was mediated by TNF receptor 1. Reintroduction of RelA into RelA-/- fibroblasts resulted in enhanced survival, demonstrating that the presence of RelA is required for protection from TNF-alpha. These results have implications for the treatment of inflammatory and proliferative diseases.
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              Is Open Access

              Antioxidant responses and cellular adjustments to oxidative stress

              Redox biological reactions are now accepted to bear the Janus faceted feature of promoting both physiological signaling responses and pathophysiological cues. Endogenous antioxidant molecules participate in both scenarios. This review focuses on the role of crucial cellular nucleophiles, such as glutathione, and their capacity to interact with oxidants and to establish networks with other critical enzymes such as peroxiredoxins. We discuss the importance of the Nrf2-Keap1 pathway as an example of a transcriptional antioxidant response and we summarize transcriptional routes related to redox activation. As examples of pathophysiological cellular and tissular settings where antioxidant responses are major players we highlight endoplasmic reticulum stress and ischemia reperfusion. Topologically confined redox-mediated post-translational modifications of thiols are considered important molecular mechanisms mediating many antioxidant responses, whereas redox-sensitive microRNAs have emerged as key players in the posttranscriptional regulation of redox-mediated gene expression. Understanding such mechanisms may provide the basis for antioxidant-based therapeutic interventions in redox-related diseases.
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                Author and article information

                Journal
                CJNM
                Chinese Journal of Natural Medicines
                Elsevier
                1875-5364
                20 October 2018
                : 16
                : 10
                : 756-765
                Affiliations
                [1] 1Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
                [2] 2Cancer Center, Sun Yat-sen University, Guangzhou 510060, China
                [3] 3School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, SAR, China
                Author notes
                Corresponding author: WANG Qi, E-mail: wangqi@ 123456gzucm.edu.cn ; FANG Jian-Song, fangjs@ 123456gzucm.edu.cn

                ΔThese authors contributed equally to this work.

                These authors have no conflict of interest to declare.

                Article
                S1875-5364(18)30115-8
                10.1016/S1875-5364(18)30115-8
                30322609
                e6f7249e-bd00-4810-b35b-03935f2916bb
                Copyright © 2018 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.
                History
                : 10 May 2018
                Funding
                Funded by: National Natural Science Foundation of China
                Award ID: 81603318
                Award ID: 81473740
                Award ID: 81673627
                Funded by: Guangdong Provincial Major Science and Technology for Special Program of China
                Award ID: 2015A030302072
                Funded by: Guangzhou Science Technology and Innovation Commission Technology Research Projects
                Award ID: 201805010005
                Funded by: Guangdong Provincial Major Science and Technology for Special Program of China
                Award ID: 2015A030302071
                Funded by: Guangzhou Science Technology and Innovation Commission Technology Research Projects
                Award ID: 201607010333
                This work was supported by the National Natural Science Foundation of China (Nos. 81603318, 81473740, and 81673627), Guangdong Provincial Major Science and Technology for Special Program of China (No. 2015A030302072), and the Guangzhou Science Technology and Innovation Commission Technology Research Projects (No. 201805010005), Guangdong Provincial Major Science and Technology for Special Program of China (No. 2015A030302071) and the Guangzhou Science Technology and Innovation Commission Technology Research Projects (No. 201607010333).

                Medicine,Pharmaceutical chemistry,Pharmacology & Pharmaceutical medicine,Complementary & Alternative medicine
                Systems pharmacology,Liver injury,Oxidative stress,Traditional Chinese Medicine,Sanwei Ganjiang Prescription

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