title: Anti-fibrotic effect of thymoquinone on hepatic stellate cells.
abstract: Hepatic stellate cells (HSCs) are the major cell type involved in the production of extracellular matrix in liver. After liver injury, HSCs undergo transdifferentiation process from quiescent state to activated state, which plays an important role in liver fibrosis. Previous studies have shown that thymoquinone (TQ) might have protective effect against liver fibrosis in animal models; however, the underlying mechanism of action is not fully understood. The aim of this study is to examine whether TQ has any direct effect on HSCs. Our results showed that pretreatment of mice with TQ has protective effect against CCl4-induced liver injury compared to control group (untreated), which is consistent with previous studies. Moreover, our in vivo study showed that COL1A1 and α-SMA mRNA levels were significantly downregulated by TQ treatment. Similarly, in vitro study confirmed that TQ downregulated COL1A1, COL3A1 and α-SMA mRNA levels in activated rat HSCs and LX2 cells, an immortalized human hepatic stellate cell line. Pretreatment with TQ also inhibited the LPS-induced proinflammatory response in LX2 cells as demonstrated by reduced mRNA expression of IL-6 and MCP-1. Mechanistically, inactivation of NF-κB pathway is likely to play a role in the TQ-mediated inhibition of proinflammatory response in HSCs. Finally, we have shown that TQ inhibited the culture-triggered transdifferentiation of freshly isolated rat HSCs as shown by significant downregulation of mRNA expression of several fibrosis-related genes. In conclusion, our study suggests that TQ has a direct effect on HSCs, which may contribute to its overall antifibrotic effect.
authors.affiliation: Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Ghazwani
authors.affiliation: Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors.forename: Yifei
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors.forename: Xiang
authors.initials: X
authors.lastname: Gao
authors.affiliation: Department of Surgery, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Fan
authors.affiliation: Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA. Electronic address: jil35@pitt.edu.
authors.forename: Jiang
authors.initials: J
authors.lastname: Li
authors.affiliation: Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA. Electronic address: sol4@pitt.edu.
authors.forename: Song
authors.initials: S
authors.lastname: Li
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D016227:Benzoquinones / Q000494:pharmacology* / Q000627:therapeutic use; D054338:Cell Transdifferentiation / Q000187:drug effects*; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism / Q000517:prevention & control; D018932:Chemokine CCL2 / Q000378:metabolism; D024042:Collagen Type I / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D024061:Collagen Type III / Q000378:metabolism; D005355:Fibrosis; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008103:Liver Cirrhosis / Q000378:metabolism / Q000517:prevention & control; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D031881:Nigella sativa / Q000737:chemistry*; D008517:Phytotherapy; D010936:Plant Extracts / Q000494:pharmacology / Q000627:therapeutic use; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000199:Actins; D000893:Anti-Inflammatory Agents; D016227:Benzoquinones; D018932:Chemokine CCL2; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D024061:Collagen Type III; D015850:Interleukin-6; D008070:Lipopolysaccharides; D016328:NF-kappa B; D010936:Plant Extracts; D012333:RNA, Messenger; C439971:COL3A1 protein, human; C491766:Ccl2 protein, rat; C498862:Acta2 protein, rat; C003466:thymoquinone
keywords: Carbon tetrachloride; Hepatic stellate cells; Lipopolysaccharide; Liver fibrosis; NF-κB; Thymoquinone