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Effect of troxerutin on the expression of genes regulating mitochondrial biogenesis and microRNA-140 in doxorubicin-induced testicular toxicity
Behnaz Mokhtari1, Arezou Abdi2, Seyed Zanyar Athari3, Hojjatollah Nozad-Charoudeh4, Alireza Alihemmati5, Reza Badalzadeh6
1 Molecular Medicine Research Center, Tabriz University of Medical Sciences; Department of Physiology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
2 Department of Physiology, Faculty of Medicine, Tabriz University of Medical Sciences; Student Research Committee, Tabriz University of Medical Sciences; Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
3 Department of Physiology, Faculty of Medicine, Tabriz University of Medical Sciences; Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
4 Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
5 Molecular Medicine Research Center, Tabriz University of Medical Sciences; Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
6 Stem Cell Research Center, Tabriz University of Medical Sciences; Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
Correspondence Address:
Prof. Reza Badalzadeh
Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz
Iran
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/jrms.jrms_120_22
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Background: Application of doxorubicin (DOX) in cancer patients is limited due to its dose-dependent toxicity to nontarget tissues such as testis and subsequent infertility. Due to limitation of our knowledge about the mechanisms of DOX toxicity in the reproductive system, reduction of DOX-induced testicular toxicity remains an actual and primary clinical challenge. Considering the potentials of troxerutin (TXR) in generating a protective phenotype in many tissues, we aimed to examine the effect of TXR on DOX-induced testicular toxicity by evaluating the histological changes and the expression of mitochondrial biogenesis genes and microRNA-140 (miR-140). Materials and Methods: Twenty-four adult male Wistar rats (250–300 g) were divided in groups with/without DOX and/or TXR. DOX was injected intraperitoneally at 6 consecutive doses over 12 days (cumulative dose: 12 mg/kg). TXR (150 mg/kg/day; orally) was administered for 4 weeks before DOX challenge. One week after the last injection of DOX, testicular histopathological changes, spermatogenesis activity, and expression of mitochondrial biogenesis genes and miR-140 were determined. Results: DOX challenge significantly increased testicular histopathological changes, decreased testicular expression profiles of sirtuin 1 (SIRT-1) and nuclear respiratory factor-2 (NRF-2), and increased expression of miR-140 (P < 0.05 to P < 0.01). Pretreatment of DOX-received rats with TXR significantly reversed testicular histopathological changes, spermatogenesis activity index, and the expression levels of SIRT-1, peroxisome proliferator-activated receptor-γ coactivator 1-alpha (PGC-1α), NRF-2, and miR-140 (P < 0.05 to P < 0.01). Conclusion: Reduction of DOX-induced testicular toxicity following TXR pretreatment was associated with upregulation of SIRT-1/PGC-1α/NRF-2 profiles and better regulation of miR-140 expression. It seems that improving microRNA-mitochondrial biogenesis network can play a role in the beneficial effect of TXR on DOX-induced testicular toxicity.
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