title: Inhibitory effects of quercetin on the progression of liver fibrosis through the regulation of NF-кB/IкBα, p38 MAPK, and Bcl-2/Bax signaling.
abstract: Quercetin, a natural flavonoid, has been used as a nutritional supplement for its anti-inflammatory and antioxidative properties. Quercetin was reported to exhibit a wide range of pharmacological properties, including its effect on anti-hepatic fibrosis. However, the anti-fibrotic mechanisms of quercetin have not been well-characterized to date. This study aimed to investigate the protective effects of quercetin on carbon tetrachloride (CCl4)-induced liver fibrosis in rats and to clarify its anti-hepatofibrotic mechanisms. We demonstrated that quercetin exhibited in-vivo hepatoprotective and anti-fibrogenic effects against CCl4-induced liver injury by improving the pathological manifestations, thereby reducing the activities of serum total bilirubin (TBIL), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and decreasing the serum levels of hyaluronic acid (HA), laminin (LN), type IV collagen (IV-C) and procollagen III peptide (PIIIP). Furthermore, treatment with quercetin 5-15mg/kg inhibited the activation of NF-κB in a dose-dependent manner via inhibition of IкBα degradation and decreased the expression of p38 MAPK by inhibiting its phosphorylation. Additionally, in a dose-dependent manner, quercetin down-regulated Bax, up-regulated Bcl-2, and subsequently inhibited caspase-3 activation. Moreover, quercetin regulated inflammation factors and hepatic stellate cells (HSCs)-activation markers, such as TNF-α, IL-6, IL-1β, Cox-2, TGF-β, α-SMA, Colla1, Colla2, TIMP-1, MMP-1, and desmin. Taken together, quercetin prevented the progression of liver fibrosis in SD rats. The anti-fibrotic mechanisms of quercetin might be associated with its ability to regulate NF-кB/IкBα, p38 MAPK anti-inflammation signaling pathways to inhibit inflammation, and regulate Bcl-2/Bax anti-apoptosis signaling pathway to prevent liver cell apoptosis.
authors.affiliation: Department of Pharmacy, Shanghai 9th People's Hospital, Shanghai Jiao Tong University School of Medicine, 280 Mo He Rd, Shanghai 201999, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Wang
authors.affiliation: Department of Pharmacy, Shanghai First Maternity and Infant Hospital, Tong Ji University School of Medicine, 536 Changle Road, Shanghai 200080, China.
authors.forename: Hai
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Pharmacy, Shanghai 9th People's Hospital, Shanghai Jiao Tong University School of Medicine, 280 Mo He Rd, Shanghai 201999, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pharmacy, Shanghai 9th People's Hospital, Shanghai Jiao Tong University School of Medicine, 280 Mo He Rd, Shanghai 201999, China.
authors.forename: Fuxing
authors.initials: F
authors.lastname: Song
authors.affiliation: Department of Pharmacy, Shanghai 9th People's Hospital, Shanghai Jiao Tong University School of Medicine, 280 Mo He Rd, Shanghai 201999, China. Electronic address: nmxyyf@126.com.
authors.forename: Yongfang
authors.initials: Y
authors.lastname: Yuan
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D001219:Aspartate Aminotransferases / Q000097:blood; D001663:Bilirubin / Q000097:blood; D002251:Carbon Tetrachloride / Q000633:toxicity; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000473:pathology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000188:drug therapy*; D000072000:NF-KappaB Inhibitor alpha / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011794:Quercetin / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000975:Antioxidants; D016207:Cytokines; D018836:Inflammation Mediators; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D000072000:NF-KappaB Inhibitor alpha; D011794:Quercetin; D002251:Carbon Tetrachloride; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D048051:p38 Mitogen-Activated Protein Kinases; D001663:Bilirubin
keywords: Liver fibrosis; NF-кB; Quercetin; p38 MAPK, apoptosis pathway