科研之友
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摘要
Many patients with chronic viral or alcoholic hepatitis,or non-alcoholic steatohepatitis are in the state of chronic liver injury and inflammation and may lead to hepatic fibrosis.The major culprit of liver fibrosis is activation of hepatic stellate cells(HSCs),characterized by transformation from a quiescent phenotype to a proliferative,contractile and secretory phenotype.In a series of study,we use:(1)in vitro cell assays(HSCs)and(2)in vivo rat models of hepatic fibrosis induced by(a)bile duct ligation,and(b)repeated administration of thioacetamide to investigate the anti-hepato-fibrotic effects of potential herbs or their active compounds and illuminate their mechanisms of action.An immortalized cell line of rat HSCs(HSC-T6)is stimulated by transforming growth factor-1(TGF-1),tumor necrosis factor-α(TNF-α)or platelet-derived growth factor(PDGF),and to evaluate the inhibitory effects of herbs on activated HSCs.The possibilities of HSC inhibition via signaling cascades and networks of apoptosis,migration,inflammation,or oxidative stress are examined by standard assays.The in vitro and in vivo anti-fibrotic effects of both salvianolic acids A and B(active hydrophilic compounds from Salvia miltiorrhiza)have been demonstrated in thioacetamide-intoxicated rats,with mechanisms related to reduction of oxidative stress via inhibiting NADPH oxidase in HSCs.Of note is that salvianolic acids A and B exerted both″common″and″different″effects in terms of phosphorylations of various kinases.We also demonstrated that tanshinone ⅡA(C19H18O3,a lipophilic diterpene from S.miltiorrhiza)inhibited lipopolysaccharide-induced HSC chemotaxis and NF-κB activity.The in vivo antihepato-fibrotic effects of a new 3-herb formula including S.miltiorrhiza,Ligusticum chuanxiong and Glycyrrhiza glabra in rats.For studies with anti-inflammatory approach,we demonstrated anti-fibrotic effects of triptolide(from Tripterygium wilfordii)and armepavine(from Nelumbo nucifera),respectively,on hepatic stellate cells and rat models of hepatic fibrosis,with both″common″and″different″anti-inflammatory effects in terms of transcription factors and phosphorylations of mitogen-activated protein(MAP)kinases.We have shown de-activating effects on rat HSCs via mechanisms of cell-migration inhibition(rhubarb,Rheum palmatum extracts)or apoptosis induction(curcumin).Moreover,we observed with bioactivity-directed fractionation approach that Bupleurum scorzonerifolium extracts and kaerophyllin(a lignin thereof)inhibited HSC activation and migration after engulfing hepatocyte apoptotic bodies.The protective effects of kaerophyllin against liver fibrogenesis were demonstrated in rats with upregulation of PPAR-γexpression in the liver.
