Modulation of the cannabinoid receptors by andrographolide attenuates hepatic apoptosis following bile duct ligation in rats with fibrosis |
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Authors: | Tzung-Yan Lee Ko-Chen Lee Hen-Hong Chang |
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Institution: | (1) Graduate Institute of Traditional Chinese Medicine, Chang Gung University, No. 259, Wen-Hwa 1st Road, Kwei-Shan Tao-Yuan, 333, Taiwan, ROC;(2) School of Traditional Chinese Medicine, Chang Gung University, Kwei-Shan Tao-Yuan, Taiwan, ROC;(3) Center for Traditional Chinese Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan; |
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Abstract: | Bile acid-induced apoptosis plays an important role in the pathogenesis of cholestatic liver disease, and its prevention is
of therapeutic interest. The aim of this study was to test whether the andrographolide limits the evolution of apoptosis in
a murine model of bile duct ligation (BDL)-induced hepatic fibrosis. Male Sprague–Dawley rats were divided into four groups
and hepatic apoptosis was induced by BDL for 2 weeks. The BDL animals were also treated with andrographolide (50, 100, and
200 mg/kg, i.p.) during the same time period. BDL-induced liver injury was associated with apoptosis and fibrosis, and the
latter was significantly reduced in animals receiving andrographolide. The increase in serum alanine aminotransferase, asparate
aminotransferase, tumor necrosis factor-α and IL-1β levels caused by BDL were also significantly reduced by treatment with
andrographolide. Andrographolide decreased the intrahepatic protein levels of cannabinoid receptor 1 (CB1), Bax, and cytochrome
c, along with of α-smooth muscle actin (α-SMA) and transforming growth factor-β (TGF-β), two markers of fibrogenesis. This
effect was mediated by the inactivation of the c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK1/2)
phosphorylation cascade, but it did not affect the p38 mitogen-activated protein kinase pathway. Additionally, andrographolide
reduced the generation of hepatic lipid peroxidation and enhance senescence marker protein-30 levels to resist the hepatic
oxidative stress in the presence of BDL. In conclusion, this study has identified AP as a potent protector against cholestasis-induced
apoptosis in vivo. Its anti-apoptotic action largely relies on the inhibition of the oxidative stress pathway. |
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