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      Ginkgo biloba extract mitigates liver fibrosis and apoptosis by regulating p38 MAPK, NF-κB/IκBα, and Bcl-2/Bax signaling

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          Abstract

          Background

          Liver fibrosis is the consequence of diverse liver injuries and can eventually develop into liver cirrhosis. Ginkgo biloba extract (GBE) is an extract from dried ginkgo leaves that has many pharmacological effects because of its various ingredients and has been shown to be hepatoprotective.

          Purpose and methods

          Aimed to investigate the underlying protective mechanisms of GBE on carbon tetrachloride (CCl 4)-induced liver fibrosis in rats. Male Sprague Dawley rats were randomly divided into four groups: control group (C), model group (M), low-dose group (L), and high-dose group (H). Liver fibrosis was induced by CCl 4 groups M, L, and H: group C was administered saline. In addition, GBE at different doses was used to treat groups L and H.

          Results

          The results of hematoxylin and eosin staining, Masson’s trichrome staining, a liver function index, and a liver fibrosis index showed that GBE application noticeably mitigated fibrosis and improved the function of the liver. The western blotting and immunohistochemistry analyses indicated that GBE reduced liver fibrosis not only by inhibiting p38 MAPK and NF-κBp65 via inhibition of IκBα degradation but also by inhibiting hepatocyte apoptosis via downregulation of Bax, upregulation of Bcl-2, and subsequent inhibition of caspase-3 activation. Inflammation-associated factors and hepatic stellate cell (HSC)-activation markers further demonstrated that GBE could effectively inhibit HSC activation and inflammation as a result of its regulation of p38 MAPK and nuclear factor-kappa B/IκBα signaling.

          Conclusion

          Our findings indicated a novel role for GBE in the treatment of liver fibrosis. The potential mechanisms may be associated with the following signaling pathways: 1) the p38 MAPK and nuclear factor-kappa B/IκBα signaling pathways (inhibiting inflammation and HSCs activation) and 2) the Bcl-2/Bax signaling pathway (inhibiting the apoptosis of hepatocytes).

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          Most cited references 48

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          Hepatic fibrosis -- overview.

          The study of hepatic fibrosis, or scarring in response to chronic liver injury, has witnessed tremendous progress in the past two decades. Clarification of the cellular sources of scar, and emergence of hepatic stellate cells not only as a fibrogenic cell type, but also as a critical immunomodulatory and homeostatic regulator are among the most salient advances. Activation of hepatic stellate cells remains a central event in fibrosis, complemented by evidence of additional sources of matrix-producing cells including bone marrow, portal fibroblasts, and epithelial-mesenchymal transition from both hepatocytes and cholangiocytes. A growing range of cytokines and their receptors and inflammatory cell subsets have further expanded our knowledge about this dynamic process. Collectively, these findings have laid the foundation for continued elucidation of underlying mechanisms, and more importantly for the implementation of rationally based approaches to limit fibrosis, accelerate repair and enhance liver regeneration in patients with chronic liver disease.
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            Liver fibrosis: cellular mechanisms of progression and resolution.

            Liver fibrosis represents a major worldwide health care burden. The last 15 years have seen a rapid growth in our understanding of the pathogenesis of this clinically relevant model of inflammation and repair. This work is likely to inform the design of effective antifibrotic therapies in the near future. In this review, we examine how the innate and adaptive immune response interacts with other key cell types in the liver, such as the myofibroblast, regulating the process of hepatic fibrosis and, where relevant, resolution of fibrosis with remodelling. Emphasis is placed on the increasing knowledge that has been generated by the use of transgenic animals and animals in which specific cell lines have been deleted. Additionally, we review the increasing evidence that, although significant numbers of wound-healing myofibroblasts are derived from the hepatic stellate cell, significant contributions may occur from other cell lineages, including those from distant sites such as bone marrow stem cells.
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              Activation of hepatic stellate cells by TGF alpha and collagen type I is mediated by oxidative stress through c-myb expression.

              Excessive production of collagen type I is a major contributor to hepatic fibrosis. Activated (myofibroblastic), but not quiescent, hepatic stellate cells (lipocytes) have a high level of collagen type I and alpha-smooth muscle actin expression. Therefore, stellate cell activation is a critical step in hepatic fibrosis. Here we show that quiescent stellate cells were activated by the generation of free radicals with ascorbate/FeSO4 and by malondialdehyde, a product of lipid peroxidation. In addition, stellate cell activation by collagen type I matrix and TGF alpha was blocked by antioxidants, such as d-alpha-tocopherol and butylated hydroxytoluene. Moreover, oxidative stress, TGF alpha and collagen type I markedly stimulated stellate cell entry into S-phase, NFkB activity, and c-myb expression, which were prevented by antioxidants. c-myb antisense oligonucleotide blocked the activation and proliferation of stellate cells induced by TGF alpha. Nuclear extracts from activated, but not from quiescent, stellate cells formed a complex with the critical promoter E box of the alpha-smooth muscle actin gene, which was disrupted by c-myb and NFkB65 antibodies, and competed by c-myb and NFkB cognate DNA. c-Myb expression was also stimulated in activated stellate cells in carbon tetrachloride-induced hepatic injury and fibrogenesis. This study indicates that oxidative stress plays an essential role, through the induction of c-myb and NFkB, on stellate cell activation.
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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
                2015
                03 December 2015
                : 9
                : 6303-6317
                Affiliations
                Department of Pharmacy, Shanghai 9th People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China
                Author notes
                Correspondence: Yongfang Yuan, Department of Pharmacy, Shanghai 9th People’s Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhi Zao Ju Road, Shanghai 200011, People’s Republic of China, Tel +86 136 2167 6746, Fax +86 21 5678 6907, Email nmxyyf@ 123456126.com
                Article
                dddt-9-6303
                10.2147/DDDT.S93732
                4671772
                © 2015 Wang et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Categories
                Original Research

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