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Inhibitory effects of armepavine against hepatic fibrosis in rats.

ABSTRACT: Activation of hepatic stellate cells (HSCs) plays a crucial role in liver fibrogenesis. armepavine (Arm, C19H23O3N), an active compound from Nelumbo nucifera, has been shown to exert immunosuppressive effects on T lymphocytes and on lupus nephritic mice. The aim of this study was to investigate whether Arm could exert anti-hepatic fibrogenic effects in vitro and in vivo. A cell line of rat HSCs (HSC-T6) was stimulated with tumor necrosis factor-alpha (TNF-alpha) or lipopolysaccharide (LPS) to evaluate the inhibitory effects of Arm. An in vivo therapeutic study was conducted in bile duct-ligated (BDL) rats. BDL rats were given Arm (3 or 10 mg/kg) by gavage twice daily for 3 weeks starting from the onset of BDL. Liver sections were taken for fibrosis scoring, immuno-fluorescence staining and quantitative real-time mRNA measurements. In vitro, Arm (1-10 microM) concentration-dependently attenuated TNF-alpha- and LPS-stimulated alpha-SMA protein expression and AP-1 activation by HSC-T6 cells without adverse cytotoxicity. Arm also suppressed TNF-alpha-induced collagen collagen deposition, NFkappaB activation and MAPK (p38, ERK1/2, and JNK) phosphorylations. In vivo, Arm treatment significantly reduced plasma AST and ALT levels, hepatic alpha-SMA expression and collagen contents, and fibrosis scores of BDL rats as compared with vehicle treatment. Moreover, Arm attenuated the mRNA expression levels of col 1alpha2, TGF-beta1, TIMP-1, ICAM-1, iNOS, and IL-6 genes, but up-regulated metallothionein genes. Our study results showed that Arm exerted both in vitro and in vivo antifibrotic effects in rats, possibly through anti-NF-kappaB activation pathways.

SUBMITTER: Weng TC

PROVIDER: S-EPMC2741443 | biostudies-literature | 2009

REPOSITORIES: biostudies-literature

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Inhibitory effects of armepavine against hepatic fibrosis in rats.

Weng Ting-Chun TC Shen Chien-Chang CC Chiu Yung-Tsung YT Lin Yun-Lian YL Kuo Cheng-Deng CD Huang Yi-Tsau YT

Journal of biomedical science 20090902

Activation of hepatic stellate cells (HSCs) plays a crucial role in liver fibrogenesis. armepavine (Arm, C19H23O3N), an active compound from Nelumbo nucifera, has been shown to exert immunosuppressive effects on T lymphocytes and on lupus nephritic mice. The aim of this study was to investigate whether Arm could exert anti-hepatic fibrogenic effects in vitro and in vivo. A cell line of rat HSCs (HSC-T6) was stimulated with tumor necrosis factor-alpha (TNF-alpha) or lipopolysaccharide (LPS) to ev ...[more]

PMID: 19723340

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Project description:BackgroundCistanche tubulosa is a traditional Chinese herbal medicine that is widely used for regulating immunity. Phenyl ethanol glycosides (CPhGs) from this plant are the primarily efficacious materials. This aim of this study was to evaluate the preventive and therapeutic effects of CPhGs on BSA-induced hepatic fibrosis in rats and related molecular mechanisms involving hepatic stellate cells. Biejiarangan (BJRG), another traditional Chinese herbal medicine, was used as a positive control.MethodsIn in vivo experiments, 75 SD rats were randomly divided into 6 groups: normal (distilled water-treated), model (BSA-treated), positive drug (BSA-treated?+?BJRG 600 mg/kg/day), and BSA-treated?+?CPhGs (125, 250, and 500 mg/kg/day) groups. The liver and spleen indices, serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), hexadecenoic acid (HA), laminin (LN), type III procollagen (PCIII), type IV collagen (IV-C), hydroxyproline (Hyp), and transforming growth factor ? 1 (TGF-? 1) were measured in rat livers. Histopathological grades for liver fibrosis were assessed for each group using H&E and Masson's trichrome staining. The expression of TGF-? 1, collagen I (Col-I) and collagen III (Col-III) were determined by an immunohistochemical staining method. These effects were further evaluated in vitro by determining expression levels of NF-?B p65 and Col-I by quantitative real-time PCR analyses. Col-I protein expression was also examined by western blotting.ResultsAll dose groups (125, 250, and 500 mg/kg/day) of CPhGs significantly reduced the liver and spleen index, decreased ALT, AST, HA, LN, PCIII, IV-C serum levels, TGF-? 1 content (P?<?0.01, P?<?0.01, and P?<?0.01), and Hyp content. CPhGs also markedly alleviated the swelling of liver cells and effectively prevented hepatocyte necrosis and inflammatory cell infiltration. Immunohistochemical results showed that CPhGs significantly reduced the expression of TGF-? 1 (P?<?0.01, P?<?0.01, and P?<?0.01), Col- I, and Col-III. The in vitro effects of CPhGs (100, 75, 50, and 25 ug/ml) on HSC-T6 showed that CPhGs significantly reduced mRNA expression of NF-?B p65 and Col-I, and CPhGs also downregulated Col-I protein expression.ConclusionsCPhGs have a significant anti-hepatic fibrosis effect, and may be used as hepatoprotective agents for treatment of hepatic fibrosis.

Project description:BackgroundIncreased intra-hepatic resistance to portal blood flow is the primary factor leading to portal hypertension in cirrhosis. Up-regulated expression of cyclooxygenase-2 (COX-2) in the cirrhotic liver might be a potential target to ameliorate portal hypertension.ObjectiveTo verify the effect of celecoxib, a selective inhibitor of COX-2, on portal hypertension and the mechanisms behind it.MethodsCirrhotic liver model of rat was established by peritoneal injection of thiacetamide (TAA). 36 rats were randomly assigned to control, TAA and TAA+celecoxib groups. Portal pressures were measured by introduction of catheters into portal vein. Hepatic fibrosis was assessed by the visible hepatic fibrotic areas and mRNAs for collagen III and ?-SMA. The neovasculature was determined by hepatic vascular areas, vascular casts and CD31 expression. Expressions of COX-2, vascular endothelial growth factor (VEGF), VEGF receptor-2 (VEGFR-2) and related signal molecules were quantitated.ResultsCompared with TAA group, the portal pressure in TAA+celecoxib group was significantly decreased by 17.8%, p<0.01. Celecoxib treatment greatly reduced the tortuous hepatic portal venules. The data of fibrotic areas, CD31expression, mRNA levels of ?-SMA and collagen III in TAA+celecoxib group were much lower than those in TAA group, p<0.01. Furthermore, the up-regulation of hepatic mRNA and protein levels of VEGF, VEGFR-2 and COX-2 induced by TAA was significantly inhibited after celecoxib treatment. The expressions of prostaglandin E2 (PGE2), phosphorylated extracellular signal-regulated kinase (p-ERK), hypoxia-inducible factor-1? (HIF-1?), and c-fos were also down-regulated after celecoxib treatment.ConclusionsLong term administration of celecoxib can efficiently ameliorate portal hypertension in TAA rat model by its dual inhibitory effects on the intrahepatic fibrosis and angiogenesis. The anti-angiogenesis effect afforded by celecoxib may attribute to its modulation on VEGF/VEGFR-2 through the down-regulation of integrated signal pathways involving PGE2- HIF-1?- VEGF and p-ERK- c-fos- VEGFR-2.

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Inhibitory effects of armepavine against hepatic fibrosis in rats.

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Inhibitory effects of armepavine against hepatic fibrosis in rats.

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