title: Antiproliferative mechanisms of quercetin in rat activated hepatic stellate cells.
abstract: Quercetin, rich in fruits and vegetables, has been used as a nutritional supplement because of its anti-inflammatory and antioxidative properties. Its positive effects on anti-hepatic fibrosis have also been suggested. However the anti-hepatofibrotic mechanisms upon which quercetin acts have yet to be well characterized. In the present study, we investigated the anti-proliferative effect of quercetin on activated hepatic stellate cells (aHSCs), the central role of hepatofibrosis, and evaluated the proteins involved in growth inhibition by a 2D gel electrophoretic analysis. Activated HSCs were isolated from Sprague Dawley rats and were spontaneously activated in vitro. Quercetin restrained the proliferation of aHSCs rather than quiescent HSCs and heptotcytes by inducing a G(1) arrest as examined by cell cycle analysis and evidenced by increased levels of p53, p21(CIP1/WAF1), as well as p27(KIP1), and decreased abundance of cyclins (D(1), D(2), A, E). An apoptosis through extrinsic pathway as demonstrated by elevated expression of Fas/Fas ligand (FasL), annexin V labeling, chromatin condensation, sub-G(1) fraction (7.39%), caspase-3 activity, was also observed. The 2D electrophoresis analysis revealed that quercetin negatively regulated protein molecules associated with metabolism (α-enolase, phosphoglycerate kinase), survival, cytokinesis (tubulin), and protein folding (protein disulfide isomerase A3) leading to cell growth retardation. Furthermore, quercetin might restrain HSC activation through reducing the levels of inflammatory cytokines (CXCL10, Midkine). Taken together, quercetin exerted diverse mechanisms to inhibit the growth of aHSCs. Proper consumption of quercetin could be beneficial to control the progression of heptofibrosis.
authors.affiliation: Department of Applied Chemistry, National Chi Nan University, Puli, Nantou 545, Taiwan. lw25@ncnu.edu.tw
authors.forename: Li-Chen
authors.initials: LC
authors.lastname: Wu
authors.forename: In-Wei
authors.initials: IW
authors.lastname: Lu
authors.forename: Chi-Fu
authors.initials: CF
authors.lastname: Chung
authors.forename: Hsing-Yu
authors.initials: HY
authors.lastname: Wu
authors.forename: Yi-Ting
authors.initials: YT
authors.lastname: Liu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D054357:Chemokine CXCL10 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000032:analysis / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000032:analysis / Q000378:metabolism; D015180:Electrophoresis, Gel, Two-Dimensional; D053222:Fas Ligand Protein / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D055166:Hepatic Stellate Cells / Q000187:drug effects*; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D011794:Quercetin / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C493958:Cdkn1a protein, rat; C493962:Cdkn1b protein, rat; D054357:Chemokine CXCL10; C091326:Cxcl10 protein, rat; D050759:Cyclin-Dependent Kinase Inhibitor p21; D053222:Fas Ligand Protein; D050760:Cyclin-Dependent Kinase Inhibitor p27; D011794:Quercetin; C505410:Casp3 protein, rat; D053148:Caspase 3; D010751:Phosphopyruvate Hydratase