Inflammatory Modulation of miR-155 Inhibits Doxorubicin‑Induced Testicular Dysfunction Via Sirt1/Foxo1 Pathway: Insight to the Role of Acacetin and Bacillus Cereus Protease

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Abstract Purpose Doxorubicin (DOX), a chemotherapeutic agent, can disrupt testicular function leading to male infertility. The present study aimed to explore the possible protective effect of natural flavone, acacetin (ACA), and protease of Bacillus Cereus bacteria (B. Cereus) as well as the potential role of miR-155/SIRT1/FOXO1 network in DOX-induced testicular toxicity. Methods Twenty-eight male Wistar rats were randomly allocated into four groups and treated as follows: Control (1% DMSO 1 mL/kg/day; p.o), DOX (1mg/kg, i.p) on every other day for 21 days with a cumulative dose equal to 10 mg/kg throughout the experimental period, pre-treated groups received ACA (5 mg/kg/day, p.o) or B. Cereus protease (36 mg/kg/day, p.o) for a week prior DOX administration. Results DOX challenge reduced serum testosterone, and testicular 17β-hydroxysteroid dehydrogenase (17β-HSD). DOX exhibited a significant increase in testicular oxidative stress, inflammatory and apoptotic markers. Aberrant testicular miR-34c, a germ-specific miRNA, and miR-155 expressions were observed, along with decreased protein expression of sirtuin1 (SIRT1) dependent forkhead box 1 (FOXO1) acetylation inducing apoptosis. Besides, abnormal histopathological architecture and a marked reduction in the testicular expression of proliferating cell nuclear antigen (PCNA) were detected. ACA or protease administration significantly improves the histopathological and immunohistochemical pictures compared to DOX alone and renovated testicular functions. Nevertheless, treatment with protease was more effective than treatment with ACA in ameliorating DOX-induced testicular toxicity. Conclusion This study reveals the prophylactic role of these two regimens on male fertility by exhibiting antioxidant, anti-inflammatory, and anti-apoptotic effects against DOX-elicited testicular toxicity, possibly via modulating miR-155/SIRT1/FOXO1 network.

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