Inhibitory effects of armepavine against hepatic fibrosis in rats.
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.
Weng
Ting-Chun
TC
Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan, Republic of China. apa9394@yahoo.com.tw
Shen
Chien-Chang
CC
Chiu
Yung-Tsung
YT
Lin
Yun-Lian
YL
Kuo
Cheng-Deng
CD
Huang
Yi-Tsau
YT
D000199:Actins / Q000096:biosynthesis; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D044182:Benzylisoquinolines / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D002460:Cell Line / Q000187:drug effects / Q000648:ultrastructure; D003094:Collagen / Q000096:biosynthesis; D004353:Drug Evaluation, Preclinical; D005786:Gene Expression Regulation / Q000187:drug effects; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000648:ultrastructure; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D008070:Lipopolysaccharides / Q000494:pharmacology; D008105:Liver Cirrhosis, Biliary / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D031653:Nelumbo / Q000737:chemistry; D010766:Phosphorylation; D008517:Phytotherapy; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000199:Actins; D000894:Anti-Inflammatory Agents, Non-Steroidal; D044182:Benzylisoquinolines; D007166:Immunosuppressive Agents; D008070:Lipopolysaccharides; D016328:NF-kappa B; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D003094:Collagen; C064689:armepavine