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Ameliorating immune-dependent inflammation and apoptosis by targeting TLR4/MYD88/NF-κB pathway by celastrol mitigates
Heba Faheem1, Rana Alawadhi2, Eman H Basha1,3
1Department of Physiology, Faculty of Medicine, Tanta University, Tanta, Egypt.
Abstract:
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 (TLR4), nuclear factor kappa B (NF-κB), and myeloid differentiation factor 88 (MYD88) expressions were quantitatively measured using polymerase chain reaction. Histopathological and immunohistochemical studies were also conducted. The results revealed that treatment with celastrol significantly reduced TLR4, MyD88, and NF-κB 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.NEW & NOTEWORTHY Celastrol inhibits the production of proinflammatory cytokines in the testicular tissue by specifically targeting the TLR4/MyD88/NF-κB signaling cascade pathways. This indicates that celastrol may serve as a promising new therapeutic target for treating diabetic reproductive dysfunction.
Insights
Celastrol protects against diabetes-induced testicular injury by inhibiting inflammation and oxidative stress. It targets the Toll-like receptor 4 (TLR4)/MyD88/NF-κB pathway, offering a potential treatment for diabetic reproductive dysfunction.
Area of Science:
- Endocrinology
- Reproductive Biology
- Pharmacology
Background:
- Diabetes mellitus can lead to testicular dysfunction and reproductive issues.
- Inflammation, oxidative stress, and apoptosis are key factors in diabetes-induced testicular injury.
- The Toll-like receptor 4 (TLR4) signaling pathway is implicated in diabetic complications.
Purpose of the Study:
- To investigate the protective effects of celastrol on testicular dysfunction in diabetic rats.
- To elucidate the underlying mechanisms of celastrol's action, focusing on the TLR4/MyD88/NF-κB pathway.
Main Methods:
- Streptozotocin (STZ)-induced diabetic rat model.
- Administration of celastrol to diabetic and control groups.
- Measurement of serum biochemical markers, inflammatory cytokines (IL-1β, TNF-α), and testosterone levels.
- Assessment of testicular oxidative stress markers (superoxide dismutase, malondialdehyde).
- Quantitative analysis of testicular TLR4, MyD88, and NF-κB gene expression via PCR.
- Histopathological and immunohistochemical examination of testicular tissues.
Main Results:
- Celastrol treatment significantly reduced serum glucose, triglyceride, and total cholesterol levels in diabetic rats.
- Celastrol administration decreased testicular levels of inflammatory mediators (IL-1β, TNF-α) and oxidative stress markers.
- Celastrol significantly downregulated the expression of TLR4, MyD88, and NF-κB in the testicular tissue of diabetic rats.
- Histopathological analysis showed reduced testicular damage in celastrol-treated diabetic rats.
Conclusions:
- Celastrol exhibits significant protective effects against diabetes-induced testicular injury.
- Celastrol ameliorates testicular dysfunction by inhibiting inflammation, apoptosis, and oxidative stress.
- The therapeutic potential of celastrol lies in its ability to target and inhibit the TLR4/MyD88/NF-κB signaling pathway, making it a promising candidate for treating diabetic reproductive dysfunction.
