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



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.



We administered 100 mg·(kg body mass)-1·day-1(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.



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.



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.
a Radiation Biology Department, National Center for Radiation Research and Technology (NCRRT), Atomic Energy Authority, PO Box 29, Nasr City, Cairo, Egypt.
Hesham Farouk
HF
Hasan
a Radiation Biology Department, National Center for Radiation Research and Technology (NCRRT), Atomic Energy Authority, PO Box 29, Nasr City, Cairo, Egypt.
Mohamed Khairy
MK
Abdel-Rafei
b Health Radiation Research Department, National Center for Radiation Research and Technology (NCRRT), Atomic Energy Authority, PO Box 29, Nasr City, Cairo, Egypt.
Shereen Mohamed
SM
Galal
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D002478:Cells, Cultured; D004145:Diosmin / Q000494:pharmacology*; D005720:Gamma Rays / Q000009:adverse effects*; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000528:radiation effects; D008103:Liver Cirrhosis / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051155:Wnt1 Protein / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
C000601368:MIRN17 microRNA, rat; D035683:MicroRNAs; D047495:PPAR gamma; C000613696:PPAR gamma, rat; D012333:RNA, Messenger; D051155:Wnt1 Protein; C495245:Wnt1 protein, rat; D051176:beta Catenin; D004145:Diosmin
Wnt–β-catenin; Wnt–β-caténine; diosmin; diosmine; fibrose hépatique; liver fibrosis; miR-17-5p; radiation-γ; γ-radiation