Hydroxysafflor yellow A protects against thioacetamide-induced liver fibrosis in rats via suppressing proinflammatory/fibrogenic mediators and promoting hepatic stellate cell senescence and apoptosis

Abstract

Objective: To evaluate the effect of hydroxysafflor yellow A (HSYA) on thioacetamide-induced liver fibrosis. Methods: Thioacetamide was administered to rats intraperitoneally in doses of 200 mg/kg twice a week for 12 weeks. Thioacetamide-intoxicated rats were given silymarin (50 mg/kg) or HSYA (5 mg/kg) orally every day for 8 weeks. Liver enzymes, fibrosis markers, histological changes as well as immunohistochemistry of TNF-α, IL-6, p21, α-SMA, and caspase-3 were examined. The effect of HSYA on HSC-T6 activation/proliferation and apoptosis was also determined in vitro. Results: HSYA decreased liver enzymes, TNF-α, IL-6, and p21 expressions, hepatic PDGF-B, TIMP-1, TGF-β1, and hydroxyproline levels, as well as fibrosis score (S2 vs. S4) compared to the thioacetamide group. HSYA also downregulated α-SMA while increasing caspase-3 expression. Surprisingly, at 500 µg/mL, HSYA had only a slightly suppressive effect on HSC proliferation, with a 9.5% reduction. However, it significantly reduced TGF-β1, inhibited α-SMA expression, induced caspase-3 expression, and promoted cell senescence. Conclusions: HSYA may be a potential therapeutic agent for delaying and reversing the progression of liver fibrosis. More research on HSYA at higher doses and for a longer period is warranted.

Keywords

Hydroxysafflor yellow A / Thioacetamide / Hepatic stellate cells / Inflammatory markers / Liver fibrosis / p21 / α-SMA / Apoptosis

Acknowledgments

The authors would like to thank Prof. S.L. Friedman, Mount Sinai School of Medicine, NY, for his gracious gift of HSC-T6 cells.

Conflict of interest statement

The authors declare that they have no conflicts of interest.

Funding

This investigation is part of a project funded by Theodore Bilharz Research Institute (grant number: ID-MS-99/A, Principal investigator: Naglaa M. El-Lakkany).

Authors’ contributions

SHS contributed to the study’s conceptualization and design, data analysis and interpretation, and critical revision of the manuscript. OAH contributed to histological and immunohistochemistry investigations. SME carried out isolation, extraction, and identification of HSYA. MMS helped with data curation and formal analysis. SS supervised the study and contributed to the final version of the manuscript. WHE contributed to the study’s conceptualization, investigation of in vitro and in vivo studies, data curation and formal analysis. NME contributed to the study’s conceptualization and design, funding acquisition, project administration, validation, data analysis and interpretation, drafting and critical editing/revision of the manuscript.

Publisher’s note

The Publisher of the Journal remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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