Diosmin attenuates radiation-induced hepatic fibrosis by boosting PPAR-gamma expression and hampering miR-17-5p-activated canonical Wnt-beta-catenin signaling

作者：Hasan Hesham Farouk; Abdel Rafei Mohamed Khairy; Galal Shereen Mohamed

来源：Biochemistry and Cell Biology, 2017, 95(3): 400-414.

DOI：10.1139/bcb-2016-0142

<jats:p>Background: Liver fibrosis is one of the major complications from upper right quadrant radiotherapy. MicroRNA-17-5p (miR-17-5p) is hypothesized to act as a regulator of hepatic stellate cell (HSCs) activation by activation of the canonical Wnt–β-catenin pathway. Diosmin (Dios), a citrus bioflavonoid, is known to possess potent antioxidant, anti-inflammatory, and anti-apoptotic properties. Purpose: To explore the molecular mechanisms that underlie radiation-induced liver fibrosis, and to evaluate the possible influence of Dios on the miR-17-5p–Wnt–β-catenin signaling axis during fibrogenesis provoked by irradiation (IRR) in rats. Also, the effect of Dios on hepatic peroxisome proliferator activated receptor-γ (PPAR-γ) expression as a regulator for HSC activation was considered. Methods: We administered 100 mg·(kg body mass)<jats:sup>–1</jats:sup>·day<jats:sup>–1</jats:sup>(per oral) of Dios were administered to IRR-exposed rats (overall dose of 12 Gy on 6 fractions of 2 Gy each) for 6 successive weeks. Results: Data analysis revealed that Dios treatment mitigated oxidative stress, enhanced antioxidant defenses, alleviated hepatic inflammatory responses, abrogated pro-fibrogenic cytokines, and stimulated PPAR-γ expression. Dios treatment repressed the miR-17-5p activated Wnt–β-catenin signaling induced by IRR. Moreover, Dios treatment restored the normal hepatic architecture and reversed pathological alterations induced by IRR. Conclusion: We hypothesize that the stimulation of PPAR-γ expression and interference with miR-17-5p activated Wnt–β-catenin signaling mediates the antifibrotic properties of Dios.</jats:p>

• 出版日期2017-6