Quercetin ameliorates testosterone secretion disorder by inhibiting endoplasmic reticulum stress through the miR-1306-5p/HSD17B7 axis in diabetic rats

Abstract

Testicular damage and testosterone secretion disorder are associated with diabetes mellitus. Quercetin, a common flavonoid, has antioxidant, anti-cancer, and blood sugar lowering effects. Therefore, this study aims to investigate the effect of quercetin on the reproductive system of male rats with diabetes in vivo and in vitro and elucidate its mechanism. Streptozotocin (STZ) induction was used to establish a diabetes model in forty male Sprague Dawley (SD) rats, which were subsequently administered with 20 or 50 mg/kg of quercetin. Leydig cells of rat testes were treated by high glucose (HG) followed by 5 or 10 μM quercetin. Two doses of quercetin increased rat body weight and testicular weight, decreased blood glucose,and inhibited oxidative stress. RT-qPCR and Western blotting revealed that quercetin alleviated STZ-induced testicular damage and promoted testosterone synthesis. Both doses of quercetin reduced ROS and MDA levels, and increased SOD level in HG-treated cells. Both, in vivo and in vitro results confirmed that a high dose of quercetin was more effective. MiR-1306-5p was upregulated in testicular tissue of diabetic rats and HG-treated cells. 17β-hydroxysteroid dehydrogenase (HSD17B7) was a target of miR-1306-5p and HSD17B7 was downregulated in STZ-induced rat tissues and HG-treated cells. HSD17B7 overexpression reversed the increase of C/EBP homologous protein (CHOP) and glucose-regulated protein 78 (Grp78) protein levels as well as eIF2α phosphorylation level and promotion of cell apoptosis caused by miR-1306-5p overexpression. Moreover, overexpression of HSD17B7 activated the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) axis in HG-treated cells. In conclusion, quercetin inhibits ER stress and improves testosterone secretion disorder through the miR-1306-5p/HSD17B7 axis in diabetic rats.

Quercetin Ameliorates Testicular Damage in Zucker Diabetic Fatty Rats through Its Antioxidant, Anti-Inflammatory and Anti-Apoptotic Properties

“…In the meantime, the testicular weights were increased following QUE supplementation in both experimental groups. A similar phenomenon was reported by Khaki et al [27] and Wang et al [28] hypothesizing that QUE was able to improve the hypothalamic-pituitary-testicular function and ameliorate structural changes to the seminal epithelium caused by chronic hyperglycemia.…”

JAK Inhibition Prevents DNA Damage and Apoptosis in Testicular Ischemia-Reperfusion Injury via Modulation of the ATM/ATR/Chk Pathway

“…Increased ROS levels activate the JAK2/NFκB pathway in the testis, which triggers apoptosis and results in dysfunctional testicles, while JAK2 inhibition reduces oxidative damage and cell apoptosis in the testis [21,22]. In vitro, JAK/STAT phosphorylation was increased in high glucose, and quercetin treated Sertoli cells, implicating JAK's role in diabetes-induced testicular damage [23]. Upon activation by JAK2, the roles of STAT1 and STAT3 in cell proliferation and apoptosis is still controversial, with some studies associating the two STATs with either function depending on the type of tissue and the nature of the injury [24].…”

Quercetin Attenuates Osteoporosis in Orchiectomy Mice by Regulating Glucose and Lipid Metabolism via the GPRC6A/AMPK/mTOR Signaling Pathway

“…The potential pharmacological effects of quercetin have been extensively explored as dietary constituents. Due to its antioxidative, anti-inflammatory, and anti-apoptotic effects, it has been clinically applied for the treatment of various diseases ( 11 – 15 ). In this study, we found that quercetin increased bone mass and improved bone strength in orchiectomy mice, indicating that quercetin has therapeutic effects on osteoporosis induced by testosterone deficiency.…”

“…In the testes, 95% of testosterone is produced, with the remaining 5% secreted by the adrenal glands. Recent research has shown that the main mechanism by which quercetin increases testosterone is by promoting its synthesis in the Leydig cells ( 15 ). Notably, quercetin significantly increased the serum levels of testosterone, OCN, and uOCN after orchiectomy.…”

“…Quercetin possesses various pharmacological benefits, including antioxidative, anti-inflammatory, and antiapoptotic effects ( 10 , 11 ). Recent studies have also shown that quercetin can promote testosterone secretion and ameliorate ovariectomy-induced osteoporosis in vitro and in vivo ( 12 – 15 ). Furthermore, it can decrease blood pressure, hyperlipidemia, and hyperglycemia, thus addressing the key problematics of testosterone therapy.…”