Ameliorating immune-dependent inflammation and apoptosis by targeting TLR4/MYD88/NF-κB pathway by celastrol mitigates the diabetic reproductive dysfunction

This study aimed to examine the protective effect of celastrol on testicular dysfunction in diabetic rats and the potential underlying mechanisms. All rats included in the study were divided into four groups: a control group treated with sodium citrate buffer and vehicle), a celastrol-treated control group, a streptozotocin (STZ)-induced diabetic group following insulin resistance, and a celastrol-treated diabetic group. Serum glucose, triglyceride, total cholesterol, high-density lipoprotein cholesterol, interleukin (IL)-1β, tumor necrosis factor-α, and testosterone levels were measured. In addition, the levels of testicular homogenate superoxide dismutase and malondialdehyde were assessed. Furthermore, testicular tissue relative toll-like receptor 4 (<i>TLR4</i>), nuclear factor kappa B (<i>NF-κB</i>), and myeloid differentiation factor 88 (<i>MYD88</i>) expressions were quantitatively measured using polymerase chain reaction. Histopathological and immunohistochemical studies were also conducted. The results revealed that treatment with celastrol significantly reduced <i>TLR4</i>, <i>MyD88</i>, and <i>NF-κB</i> expressions, and the levels of inflammatory mediators such as tumor necrosis factor-α and IL-1β in the testicular tissue of treated rats. These findings suggest that celastrol has the potential to be effective in the treatment of diabetes-induced testicular injury by inhibiting testicular inflammation, apoptosis, and oxidative stress.<b>NEW & NOTEWORTHY</b> Celastrol inhibits the production of proinflammatory cytokines in the testicular tissue by specifically targeting the TLR4/MyD88/NF-<i>κ</i>B signaling cascade pathways. This indicates that celastrol may serve as a promising new therapeutic target for treating diabetic reproductive dysfunction.