Hepatic fibrosis is concomitant with liver inflammation, which has been highlighted as significant treatment of chronic liver disease. We previously demonstrated that tetramethylpyrazine (TMP), the effective component of Ligusticum chuanxiong Hort, can inhibit the activation of HSCs and consequential anti-hepatic fibrosis. In this study, our work demonstrated that TMP improved liver histological architecture, decreased hepatic enzyme levels and attenuated collagen deposition in the rat fibrotic liver. In addition, TMP significantly protected the liver from CCl4-caused injury and fibrogenesis by suppressing inflammation with reducing levels of inflammatory cytokines, including tumor necrosis factor-α (TNF-α), NLRP3, nuclear factor-kappa B (NF-κB) and interleukin-1β (IL-1β). Experiments in vitro showed that TMP inhibited inflammatory cytokine expression in HSCs associated with disrupting platelet-derived growth factor-b receptor (PDGF-βR)/NLRP3/caspase1 pathway. These data collectively indicate that TMP can attenuate liver inflammation in liver fibrosis and possibly by targeting HSCs via PDGF-βR/NLRP3/caspase1 pathway. It provides novel mechanistic insights into TMP as a potential therapeutic remedy for hepatic fibrosis.
Alcoholic liver disease (ALD) is a common health problem worldwide, characterized by aberrant accumulation of lipid in hepatocytes. Inhibition of lipid accumulation has been well recognized as a promising strategy for ALD. Previous studies showed that curcumin has potential effect on ALD by regulating oxidative stress and ethanol metabolism. However, the effects of curcumin on lipid accumulation and its mechanism remain unclear. Recent researches have indicated that farnesoid X receptor (FXR) and nuclear factor (erythroid-derived 2)-like 2 (Nrf2) have excellent effects on reducing lipid deposition. This study demonstrated that curcumin alleviated ethanol-induced liver injury by ameliorating activities of serum marker enzymes and inflammation. Moreover, curcumin alleviated the symptom of hyperlipidemia and hepatic steatosis via modulating the expression of sterol regulatory elementbinding protein-1c, fatty acid synthase, and peroxisome proliferator-activated receptor-alpha as well as the activity of carnitine palmitoyltransferase 1. Additionally, curcumin induced the expression of Nrf2 and FXR in liver, strongly implying close relationship between inhibitory effect of curcumin on hepatic steatosis and the above two genes. The following in vitro experiments further verified the protective effects of curcumin against hepatotoxicity and lipid accumulation in hepatocytes induced by ethanol. Gain-or loss-of-function analyses revealed Nrf2 and FXR mediated the effect of curcumin on lipid deposition in hepatocytes, and curcumin modulated Additional Supporting Information may be found in the online version of this article.Abbreviations: ALD, alcoholic liver disease; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CPT1, carnitine palmitoyltransferase 1; DMEM, Dulbecco's modified eagle medium; DMSO, dimethylsulfoxide; FAS, fatty acid synthase; FBS, fetal bovine serum; FXR, farnesoid X receptor; GAPDH, glyceraldehyde phosphate dehydrogenase; H&E, haematoxylin-eosin; HDL-C, high-density lipoprotein-cholesterol; LDH, lactate dehydrogenase; LDL-C, low-density lipoprotein-cholesterol; MTT, 3-(4,5-dimethylthiazol-2-yl)22,5-diphenyltetrazolium bromide; NF-jB, nuclear factor-kappa B; Nrf2, nuclear factor (erythroid-derived 2)-like 2; PPAR-a, peroxisome proliferator-activated receptor-alpha; SREBP-1c, sterol regulatory element-binding protein-1c; TC, total cholesterol; TG, triglyceride; TNF-a, tumor necrosis factor-alpha. 645the expression of FXR mediated by Nrf2. Collectively, we drew a conclusion that curcumin attenuated ALD by modulating lipid deposition in hepatocytes via a Nrf2/FXR activationdependent mechanism. The findings make curcumin a potential agent for ALD and broaden the horizon of the molecular mechanism involved. V C 2015 IUBMB Life, 67(8):645-658, 2015
Accumulating evidence indicates that Hedgehog (Hh) signaling becomes activated in chronic liver injury and plays a role in the pathogenesis of hepatic fibrosis. Hepatic stellate cells (HSCs) are Hh-responsive cells and activation of the Hh pathway promotes transdifferentiation of HSCs into myofibroblasts. Targeting Hh signaling may be a novel therapeutic strategy for treatment of liver fibrosis. We previously reported that curcumin has potent antifibrotic effects in vivo and in vitro, but the underlying mechanisms are not fully elucidated. This study shows that curcumin downregulated Patched and Smoothened, two key elements in Hh signaling, but restored Hhip expression in rat liver with carbon tetrachlorideinduced fibrosis and in cultured HSCs. Curcumin also halted the nuclear translocation, DNA binding, and transcription activity of Gli1. Moreover, the Hh signaling inhibitor cyclopamine, like curcumin, arrested the cell cycle, induced mitochondrial apoptosis, reduced fibrotic gene expression, restored lipid accumulation, and inhibited invasion and migration in HSCs. However, curcumin's effects on cell fate and fibrogenic properties of HSCs were abolished by the Hh pathway agonist SAG. Furthermore, curcumin and cyclopamine decreased intracellular levels of adenosine triphosphate and lactate, and inhibited the expression and/or function of several key molecules controlling glycolysis. However, SAG abrogated the curcumin effects on these parameters of glycolysis. Animal data also showed that curcumin downregulated glycolysis-regulatory proteins in rat fibrotic liver. These aggregated data therefore indicate that curcumin modulated cell fate and metabolism by disrupting the Hh pathway in HSCs, providing novel molecular insights into curcumin reduction of HSC activation.
Liver fibrosis represents a frequent event following chronic insult to trigger wound healing responses in the liver. Activation of hepatic stellate cells (HSCs) is a pivotal event during liver fibrogenesis. Compelling evidence indicates that the renin-angiotensin system (RAS) takes part in the pathogenesis of liver fibrosis. Angiotensin II (Ang II), the primary effector peptide of the RAS, has been demonstrated to be a potent pro-fibrogenic molecule for HSC activation. In this study we investigated the effects of tetramethylpyrazine (TMP) on HSC activation induced by Ang II in order to elucidate the underlying mechanisms. Our results demonstrated that Ang II significantly promoted cell growth, upregulated the expression of the fibrotic markers a-smooth muscle actin (a-SMA) and a1(I) procollagen, and enhanced the invasion capacity in HSCs. TMP inhibited proliferation and arrested the cell cycle at the G2/M checkpoint associated with altering several cell cycle regulatory proteins in Ang II-treated HSCs. TMP also modulated Bcl-2 family proteins and activated the caspase cascade leading to apoptosis in Ang II-treated HSCs. Moreover, TMP reduced the expression of a-SMA and a1(I) procollagen at mRNA and protein levels, and these effects were associated with interference of the platelet-derived growth factor b receptor (PDGF-bR) mediated PI3K/AKT/mTOR pathway in HSCs exposed to Ang II. Furthermore, Ang II-enhanced HSC invasion capacity was diminished by TMP, which was associated with interference of PDGFbR/FAK signaling. These data collectively indicated that interference of PDGF-bR-mediated fibrotic pathways was involved in TMP inhibition of HSC activation caused by Ang II, providing novel mechanistic insights into TMP as a potential therapeutic remedy for hepatic fibrosis. AbbreviationsAng II, angiotensin II; AT 1 R, Ang II type-1 receptor; CDK, cyclin-dependent kinases; DMSO, dimethylsulfoxide; FAK, focal adhesion kinase; GAPDH, glyceraldehyde phosphate dehydrogenase; HSC, hepatic stellate cell; mTOR, mammalian target of rapamycin; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide; PDGF-bR, platelet-derived growth factor b receptor; PI3K, phosphatidylinositol-3-kinase; RAS, renin-angiotensin system; TMP, tetramethylpyrazine; a-SMA, a-smooth muscle actin.
As a frequent event following chronic insult, liver fibrosis triggers wound healing reactions, with extracellular matrix components accumulated in the liver. During liver fibrogenesis, activation of hepatic stellate cells (HSCs) is the pivotal event. Fibrosis regression can feasibly be treated through pharmacological induction of HSC apoptosis. Herein we showed that dihydroartemisinin (DHA) improved liver histological architecture, decreased hepatic enzyme levels, and inhibited HSCs activation in the fibrotic rat liver. DHA also induced apoptosis of HSCs in such liver, as demonstrated by reduced distribution of a-SMA-positive cells and the presence of high number of cleaved-caspase-3-positive cells in vivo, as well as by downregulation of Bcl-2 and up-regulation of Bax. In addition, in vitro experiments showed that DHA significantly inhibited HSC proliferation and led to dramatic morphological alterations in HSCs. we found that DHA disrupted mitochondrial functions and led to activation of caspase cascades in HSCs. Mechanistic investigations revealed that DHA induced HSC apoptosis through disrupting the phosphoinositide 3-kinase (PI3K)/Akt pathway and that PI3K specific inhibitor LY294002 mimicked the pro-apoptotic effect of DHA. DHA is a promising candidate for the prevention and treatment of liver fibrosis. V C 2016 IUBMB Life, 68(3): [220][221][222][223][224][225][226][227][228][229][230][231] 2016
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