title: Morin, a dietary flavonoid, exhibits anti-fibrotic effect and induces apoptosis of activated hepatic stellate cells by suppressing canonical NF-κB signaling.
abstract: 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.
authors.affiliation: Department of Biochemistry, University of Madras, Guindy Campus, Chennai, 600 025, Tamil Nadu, India.
authors.forename: Perumal
authors.initials: P
authors.lastname: MadanKumar
authors.affiliation: Department of Biochemistry, University of Madras, Guindy Campus, Chennai, 600 025, Tamil Nadu, India.
authors.forename: Perumal
authors.initials: P
authors.lastname: NaveenKumar
authors.affiliation: Department of Zoology, University of Madras, Guindy Campus, Chennai, 600 025, Tamil Nadu, India.
authors.forename: Halagowder
authors.initials: H
authors.lastname: Devaraj
authors.affiliation: Department of Biochemistry, University of Madras, Guindy Campus, Chennai, 600 025, Tamil Nadu, India. Electronic address: niranjali@yahoo.com.
authors.forename: Sivasithamparam
authors.initials: S
authors.lastname: NiranjaliDevaraj
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D004032:Diet; D005419:Flavonoids / Q000494:pharmacology* / Q000627:therapeutic use; D055166:Hepatic Stellate Cells / Q000166:cytology* / Q000187:drug effects / Q000473:pathology; D006801:Humans; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects*; D047309:Flavones
chemical_list: D005419:Flavonoids; D016328:NF-kappa B; C008548:morin; D047309:Flavones
keywords: Apoptosis; Diethylnitrosamine; Hepatic stellate cells; NF-κB; α-SMA