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      Chinese medicine in the treatment of autoimmune hepatitis: Progress and future opportunities

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          Abstract

          Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease occurring in individuals of all ages with a higher incidence in females and characterized by hypergammaglobulinemia, elevated serum autoantibodies and histological features of interface hepatitis. AIH pathogenesis remains obscure and still needs in‐depth study, which is likely associated with genetic susceptibility and the loss of immune homeostasis. Steroids alone and in combination with other immunosuppressant agents are the primary choices of AIH treatment in the clinic, whereas, in some cases, severe adverse effects and disease relapse may occur. Chinese medicine used for the treatment of AIH has proven its merits over many years and is well tolerated. To better understand the pathogenesis of AIH and to evaluate the efficacy of novel therapies, several animal models have been generated to recapitulate the immune microenvironment of patients with AIH. In the current review, we summarize recent advances in the study of animal models for AIH and their application in pharmacological research of Chinese medicine‐based therapies and also discuss current limitations. This review aims to provide novel insights into the discovery of Chinese medicine‐originated therapies for AIH using cutting‐edge animal models.

          Abstract

          Generalized relations between traditional Chinese medicines and different animal models for AIH.

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          Most cited references117

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          Mitochondria as multifaceted regulators of cell death

          Through their many and varied metabolic functions, mitochondria power life. Paradoxically, mitochondria also have a central role in apoptotic cell death. Upon induction of mitochondrial apoptosis, mitochondrial outer membrane permeabilization (MOMP) usually commits a cell to die. Apoptotic signalling downstream of MOMP involves cytochrome c release from mitochondria and subsequent caspase activation. As such, targeting MOMP in order to manipulate cell death holds tremendous therapeutic potential across different diseases, including neurodegenerative diseases, autoimmune disorders and cancer. In this Review, we discuss new insights into how mitochondria regulate apoptotic cell death. Surprisingly, recent data demonstrate that besides eliciting caspase activation, MOMP engages various pro-inflammatory signalling functions. As we highlight, together with new findings demonstrating cell survival following MOMP, this pro-inflammatory role suggests that mitochondria-derived signalling downstream of pro-apoptotic cues may also have non-lethal functions. Finally, we discuss the importance and roles of mitochondria in other forms of regulated cell death, including necroptosis, ferroptosis and pyroptosis. Collectively, these new findings offer exciting, unexplored opportunities to target mitochondrial regulation of cell death for clinical benefit.
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            Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase.

            NF-kappaB is responsible for upregulating gene products that control cell survival. In this study, we demonstrate that SIRT1, a nicotinamide adenosine dinucleotide-dependent histone deacetylase, regulates the transcriptional activity of NF-kappaB. SIRT1, the mammalian ortholog of the yeast SIR2 (Silencing Information Regulator) and a member of the Sirtuin family, has been implicated in modulating transcriptional silencing and cell survival. SIRT1 physically interacts with the RelA/p65 subunit of NF-kappaB and inhibits transcription by deacetylating RelA/p65 at lysine 310. Treatment of cells with resveratrol, a small-molecule agonist of Sirtuin activity, potentiates chromatin-associated SIRT1 protein on the cIAP-2 promoter region, an effect that correlates with a loss of NF-kappaB-regulated gene expression and sensitization of cells to TNFalpha-induced apoptosis. While SIRT1 is capable of protecting cells from p53-induced apoptosis, our work provides evidence that SIRT1 activity augments apoptosis in response to TNFalpha by the ability of the deacetylase to inhibit the transactivation potential of the RelA/p65 protein.
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              Metabolic coordination of T cell quiescence and activation

              Naive T cells are actively maintained in a quiescent state that promotes their survival and persistence. On antigen stimulation, T cells exit quiescence to initiate clonal expansion and effector differentiation. Initial studies focused on the immune receptors and transcriptional regulators involved in T cell quiescence and activation, but recent findings highlight cell metabolism as a crucial regulator of these processes. Here we summarize these intrinsic metabolic programmes and also describe how cell-extrinsic factors, such as nutrients and regulatory T cells, directly and indirectly balance quiescence and activation programmes in conventional T cells. We propose that immunological cues and nutrients license and tune metabolic programmes and signalling networks that communicate in a bidirectional manner to promote quiescence exit. Understanding the programmes that regulate T cell quiescence will be key for developing novel approaches to modulate protective and pathological T cell responses in human diseases.
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                Author and article information

                Contributors
                xiaojiaoyang.li@bucm.edu.cn
                Journal
                Animal Model Exp Med
                Animal Model Exp Med
                10.1002/(ISSN)2576-2095
                AME2
                Animal Models and Experimental Medicine
                John Wiley and Sons Inc. (Hoboken )
                2096-5451
                2576-2095
                19 January 2022
                April 2022
                : 5
                : 2 , Themed Section: Traditional Chinese Medicines and Natural Medicines Research ( doiID: 10.1002/ame2.v5.2 )
                : 95-107
                Affiliations
                [ 1 ] ringgold 47839; School of Life Sciences Beijing University of Chinese Medicine Beijing China
                Author notes
                [*] [* ] Correspondence

                Xiaojiaoyang Li, School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China.

                Email: xiaojiaoyang.li@ 123456bucm.edu.cn

                Author information
                https://orcid.org/0000-0002-8997-9651
                Article
                AME212201
                10.1002/ame2.12201
                9043711
                35263512
                eba346e7-2065-4483-8f06-d2e8c05785de
                © 2022 The Authors. Animal Models and Experimental Medicine published by John Wiley & Sons Australia, Ltd on behalf of The Chinese Association for Laboratory Animal Sciences.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 31 December 2021
                : 30 November 2021
                : 06 January 2022
                Page count
                Figures: 2, Tables: 1, Pages: 13, Words: 10742
                Funding
                Funded by: Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine
                Award ID: ZYYCXTD‐C‐202006
                Funded by: Beijing Municipal Science & Technology Commission
                Award ID: 7212174
                Funded by: National Natural Science Foundation of China , doi 10.13039/501100001809;
                Award ID: 82004045
                Funded by: Beijing Nova Program of Science & Technology
                Award ID: Z191100001119088
                Award ID: Z201100006820025
                Funded by: Young Talents Promotion Project of China Association of Trad
                Award ID: 2020‐QNRC2‐01
                Funded by: itional Chinese Medicine
                Award ID: 2020‐QNRC2‐01
                Categories
                Review
                Themed Section: Traditional Chinese Medicines and Natural Medicines Research
                Themed Section: Reviews
                Custom metadata
                2.0
                April 2022
                Converter:WILEY_ML3GV2_TO_JATSPMC version:6.1.4 mode:remove_FC converted:27.04.2022

                animal models,autoimmune hepatitis,immune regulation,traditional chinese medicine

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