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      Schisandrin B elicits the Keap1-Nrf2 defense system via carbene reactive metabolite which is less harmful to mice liver

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          Abstract

          Background

          Schisandrin B (Sch B) a main active component of Schisandra chinensis, has been shown to act as a liver protectant via activation of the Nrf2 pathway. Nevertheless, it remains unclear whether its reactive metabolite is responsible for Nrf2 activation; also, the effects of its reactive metabolite on liver function are still unknown.

          Methods

          The present study determined and identifed the carbene reactive metabolite of Sch B in human and mice liver microsomes. Its roles in activating Nrf2 pathway and modifying macromolecules were further explored in human liver microsomes. Moreover the potential cytotoxicity and hepatoxicity of carbene on HepG-2 and mice were also investigated.

          Results

          In the present study, cytochromes P450 (CYP450s) metabolized Sch B to carbene reactive metabolite, which, with the potential to modify peptides, were identifed and observed in human and mice liver microsomes. Moreover, the relevance of carbene in Nrf2 activation was verifed by co-incubation in the presence of CYP450 inhibitors in HepG-2 cells, as well as by molecular docking study of carbene and Keap1. Additionally, the cytotoxicity of Sch B on HepG-2 cells was signifcantly aggravated by CYP450 inducer (with LD 50 decreasing from 63 to 21 µM) and signifcantly alleviated by CYP450 inhibitor and glutathione (with LD 50 increasing from 63 µM to 200 µM). Besides, after oral administration of mice with Sch B (25–100 mg/kg) for 21 days, only the highest dose induced mild hepatotoxicity, which was accompanied by increasing the aminotransferase activity and centrilobular hepatocellular infltration of lymphocytes. In addition, upregulation of CYP450 activity; Nrf2, NQO-1, and GST expression; and glutathione level was observed in Sch B treatment groups.

          Conclusion

          The present study revealed that CYP450s mediate the conversion of Sch B to carbene, which subsequently binds to Keap1 and elicits Nrf2 pathway, which could further increase the elimination of carbene and thus exhibit a less harmful effect on mice liver.

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          Most cited references 28

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          Oral medications with significant hepatic metabolism at higher risk for hepatic adverse events.

          Reactive metabolites generated by hepatic metabolism are thought to play an important role in the pathogenesis of drug-induced liver injury (DILI), but supporting data are limited. If this is true, then compounds with significant hepatic metabolism should cause more DILI than those without it. We conducted a study to examine the relationship between hepatic metabolism and DILI of prescription medications. We systematically extracted the metabolism characteristics of 207 of the most widely prescribed oral medications in the United States. Compounds with >50% hepatic metabolism were characterized as those with significant hepatic metabolism (n = 149). Hepatic adverse events of interest were alanine aminotransferase >3 times the upper limit of normal, jaundice, liver failure, liver transplantation, or fatal DILI. Compared with compounds with lesser hepatic metabolism, compounds belonging to the significant hepatic metabolism group had significantly higher frequency of alanine aminotransferase >3 times the upper limit of normal (35% versus 11%, P = 0.001), liver failure (28% versus 9%, P = 0.004), and fatal DILI (23% versus 4%, P = 0.001), but not jaundice (46% versus 35%, P = 0.2) or liver transplantation (9% versus 2%, P = 0.11). Twelve compounds with no hepatic metabolism had no reports of liver failure, liver transplantation, or fatal DILI. When the relationship between hepatic adverse events and combination of hepatic metabolism and daily dose was examined, compounds with both significant hepatic metabolism and daily dose >50 mg (n = 50) were significantly more hepatotoxic than compounds belonging to other groups. Compared with medications without biliary excretion, compounds with biliary excretion (n = 50) had significantly higher frequency of jaundice (74% versus 40%, P = 0.0001). Our study finds an important relationship between a compound's metabolism profile and reports of hepatic adverse events.
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            The protective effects of Schisandra chinensis fruit extract and its lignans against cardiovascular disease: a review of the molecular mechanisms.

            Schisandra chinensis fruit extract (SCE) has traditionally been used as an oriental medicine for the treatment of various human diseases, including cardiovascular disease. Advances in scientific knowledge and analytical technologies provide opportunities for translational research involving S. chinensis; such research may contribute to future drug discovery. To date, emerging experimental evidence supports the therapeutic effects of the SCE or its bioactive lignan ingredients in cardiovascular disease, unraveling the mechanistic basis for their pharmacological actions. In the present review, we highlight SCE and its lignans as promising resources for the development of safe, effective, and multi-targeted agents against cardiovascular disease. Moreover, we offer novel insight into future challenges and perspective on S. chinensis research to future clinical investigations and healthcare strategies.
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              Schisandrin B exhibits anti-inflammatory activity through modulation of the redox-sensitive transcription factors Nrf2 and NF-κB.

              Schisandrin B (SB), a dibenzocyclooctadiene derivative isolated from Schisandra chinensis and used commonly in traditional Chinese medicine for the treatment of hepatitis and myocardial disorders, has been recently shown to modulate cellular redox balance. Since we have shown that cellular redox plays an important role in the modulation of immune responses, the present studies were undertaken to study the effects of SB on activation and effector functions of lymphocytes. SB altered the redox status of lymphocytes by enhancing the basal reactive oxygen species levels and altering the GSH/GSSG ratio in lymphocytes. It also induced nuclear translocation of redox sensitive transcription factor Nrf2 and increased the transcription of its dependent genes. SB inhibited mitogen-induced proliferation and cytokine secretion by lymphocytes. SB also significantly inhibited mitogen-induced upregulation of T cell costimulatory molecules and activation markers. It was observed that SB inhibited mitogen-induced phosphorylation of c-Raf, MEK, ERK, JNK, and p38. It suppressed IκBα degradation and nuclear translocation of NF-κB in activated lymphocytes. Anti-inflammatory effects of SB were significantly abrogated by the inhibitors of Nrf2 and HO-1, suggesting the involvement of this pathway. Similar anti-inflammatory effects of SB on lymphocyte proliferation and cytokine secretion were also observed in vivo. To our knowledge, this is the first report showing that the anti-inflammatory effects of SB are mediated via modulation of Nrf2 and NF-κB in lymphocytes. Copyright © 2012 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2018
                23 November 2018
                : 12
                : 4033-4046
                Affiliations
                College of Pharmaceutical Sciences and Chinese Medicine, Southwest University, Beibei, Chongqing 400715, China, xuxiaoyu@ 123456swu.edu.cn ; zhfbsci@ 123456126.com
                Author notes
                Correspondence: Xiaoyu Xu; Huifeng Zhu, College of Pharmaceutical Sciences and Chinese Medicine, Southwest University, Beibei, 2 Tiansheng Road, Chongqing 400715, China, Tel/fax +86 23 6825 1225, Email xuxiaoyu@ 123456swu.edu.cn ; zhfbsci@ 123456126.com
                [*]

                These authors contributed equally to this work

                Article
                dddt-12-4033
                10.2147/DDDT.S176561
                6267698
                © 2018 Feng et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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                Original Research

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