morin and Liver-Cirrhosis

Despite great progress in understanding the activation of hepatic stellate cells (HSCs) during liver fibrosis, therapeutic approaches to inhibit HSC activation remain very limited. Recent reports highlight Yes-associated protein (Yap) and transforming growth factor-β1 (TGF-β1) as critical regulators of HSC activation and henceforth a compound targeting Hippo/Yap and TGF-β1/Smad pathways would be a potential anti-fibrotic candidate. Morin, a dietary flavonoid, was earlier reported to inhibit HSC proliferation and induction of apoptosis of cultured HSCs, mainly by suppressing Wnt/β-catenin and NF-κB signaling, but its effect on Hippo/Yap and TGF-β1/Smad pathways was not determined. To address this concern, this study was carried out in cultured LX-2 cells and diethylnitrosamine-induced fibrotic rats. Morin activated hippo signaling through significantly increased expression of Mst1 and Lats1 with decreased expression of transcriptional effectors Yap/TAZ, thereby prevented HSC activation and also suppressed the expression of exacerbated TGF-β/Smad signaling molecules such as TGF-β1, p-Smad2/3, collagen-I, MMP-2, MMP-9 and TIMP-1 in cultured LX-2 and DEN induced fibrotic rats. Both the in vitro and in vivo results clearly showed that, morin by acting on Hippo/Yap and TGF-β1/Smad pathways, ameliorated experimental liver fibrosis, indicating that morin has potential for effective treatment of liver fibrosis.

Topics: Animals; Apoptosis Regulatory Proteins; Diethylnitrosamine; Flavonoids; Hepatic Stellate Cells; Humans; Liver Cirrhosis; Male; Protein Serine-Threonine Kinases; Rats; Rats, Wistar; Signal Transduction; Smad2 Protein; Smad3 Protein; Transforming Growth Factor beta1; YAP-Signaling Proteins

In experimental liver fibrosis, activated hepatic stellate cells (HSCs) play a central role and thus, induction of apoptosis of activated HSCs is a promising therapeutic strategy for liver fibrosis. The present study was designed to elucidate the molecular mechanisms of the pro-apoptotic effects of morin, a dietary flavonoid, in vitro and in vivo. Culture-activated human HSCs (LX-2 cells) were treated with morin (50 μM) for 24 and 48 h, and the mechanism of cell death induced by morin was evaluated. Also, the anti-fibrotic and pro-apoptotic effect of morin in diethylnitrosamine (DEN)-induced fibrotic rats were determined. Morin induced apoptosis in cultured LX-2 cells by preventing the nuclear translocation of nuclear factor-κBp65 (NF-κBp65) by inhibiting NF-κB activation via inhibition of IκBα degradation and thereby suppressing anti-apoptotic proteins and activating caspases. In fibrotic rats, morin treatment resulted in inhibition of canonical NF-κB signaling and induction of apoptosis, mainly by downregulating Bcl-2, upregulating Bax and cyt c and by activation of caspase-9 and caspase-3. Translocation of phosphatidylserine to the outer membrane, altered nuclear morphology and DNA fragmentation confirmed the induction of apoptosis by morin. Overall, morin treatment ameliorated experimental liver fibrosis, most likely through induction of apoptosis by inhibiting canonical NF-κB signaling in activated HSCs. It is therefore postulated that morin is a potential therapeutic candidate for liver fibrosis.

Topics: Animals; Apoptosis; Cell Line; Diet; Flavonoids; Hepatic Stellate Cells; Humans; Liver Cirrhosis; Male; NF-kappa B; Rats; Rats, Wistar; Signal Transduction

Therapeutic potential of morin, a member of flavonoid family, against carbon tetrachloride (CCl4)-induced liver fibrosis in rats was investigated and compared with that of silymarin. Results show that treatment with morin (30 mg/kg/day) revealed attenuation in liver index and serum biomarkers of liver function that were enhanced by chronic CCl4 intoxication. Further, morin inhibited the elevated levels of malondialdehyde and nitric oxide and restored hepatic reduced glutathione to its normal level. The increased production of hepatic hydroxyproline content by CCl4 was markedly decreased by administration of morin. In addition, treatment with morin significantly attenuated the inflammatory responses caused by CCl4 as evident by the decreased hepatic tumor necrosis factor-alpha (TNF-α) level, immunohistochemical expressions of inducible nitric oxide synthase and nuclear factor kappa B. Collectively, this study indicates that morin possesses antifibrotic effect in the CCl4 model of fibrosis via reducing oxidative stress, inflammatory responses and fibrogenic markers.

Topics: Alanine Transaminase; Alkaline Phosphatase; Animals; Aspartate Aminotransferases; Bilirubin; Carbon Tetrachloride; Flavonoids; Hydroxyproline; Liver; Liver Cirrhosis; Male; NF-kappa B; Nitric Oxide Synthase Type II; Oxidative Stress; Protective Agents; Rats; Silymarin; Tumor Necrosis Factor-alpha

Morin, a plant-derived flavonoid, has been reported to exhibit a wide range of pharmacological properties. In this study, we investigated the protective effect of morin on hepatic fibrosis induced by dimethylnitrosamine (DMN) in rats. Oral administration of morin remarkably prevented weight loss in the body and liver from DMN and inhibited the elevation of serum alanine transaminase (ALT), aspartate transaminase (AST), and total bilirubin levels. For the evaluation of hepatic fibrosis-related factors, we investigated expressions of collagen type I, transforming growth factor beta(1) (TGF-beta(1)), and alpha-smooth muscle actin (alpha-SMA) in mRNA and protein levels. We observed that morin significantly reduced the expression of collagen type I, TGF-beta(1), and alpha-SMA on hepatic fibrosis induced by DMN. Taken together, this study demonstrated that morin showed hepatoprotective and antifibrogenic effects against DMN-induced hepatic injury. This suggests that morin may be useful in preventing the development of hepatic fibrosis and cirrhosis.

Topics: Actins; Animals; Antioxidants; Body Weight; Collagen Type I; Dimethylnitrosamine; Flavonoids; Liver; Liver Cirrhosis; Liver Function Tests; Male; Organ Size; Phytotherapy; Rats; Rats, Sprague-Dawley; RNA, Messenger; Transforming Growth Factor beta1