Mechanistic Protective Effect of Cilostazol in Cisplatin-Induced Testicular Damage via Regulation of Oxidative Stress and TNF-α/NF-κB/Caspase-3 Pathways.

Despite being a potent anticancer drug, cisplatin has limited applicability due to its adverse effects, such as testicular damage. Consequently, reducing its toxicity becomes necessary. In this study, a selective phosphodiesterase-3 inhibitor, cilostazol, which is used to treat intermittent claudication, was examined for its ability to abrogate cisplatin-induced testicular toxicity. Its ameliorative effect was compared to that of two phosphodiesterase inhibitors, tadalafil and pentoxifylline. The study also focused on the possible mechanisms involved in the proposed protective effect. Cisplatin-treated rats showed a significant decrease in sperm number and motility, serum testosterone, and testicular glutathione levels, as well as a significant elevation in malondialdehyde, total nitrite levels, and the protein expression of tumor necrosis factor-alpha, nuclear factor-kappa ß, and caspase-3. These outcomes were confirmed by marked testicular architecture deterioration. Contrary to this, cilostazol, in a dose-dependent manner, showed potential protection against testicular toxicity, reversed the disrupted testicular function, and improved histological alterations through rebalancing of oxidative stress, inflammation, and apoptosis. In addition, cilostazol exerted a more pronounced protective effect in comparison to tadalafil and pentoxifylline. In conclusion, cilostazol ameliorates cisplatin-induced testicular impairment through alteration of oxidative stress, inflammation, and apoptotic pathways, offering a promising treatment for cisplatin-induced testicular damage.

Protective effects of menthol against sepsis-induced hepatic injury: Role of mediators of hepatic inflammation, apoptosis, and regeneration.

Liver dysfunction in sepsis is a major complication that amplifies multiple organ failure and increases the risk of death. Inflammation and oxidative stress are the main mediators in the pathophysiology of sepsis. Therefore, we investigated the role of menthol, a natural antioxidant, against sepsis-induced liver injury in female Wistar rats. Sepsis was induced by cecal ligation and puncture (CLP). Menthol (100 mg/kg) was given intragastric 2 h after CLP. Blood samples and liver tissues were collected 24 h after surgery. Menthol significantly (p < 0.05) attenuated the sepsis-induced elevation in serum liver enzymes and improved the hepatic histopathological changes. Menthol treatment significantly (p < 0.05) decreased hepatic levels of tumor necrosis factor-alpha, malondialdehyde, total nitrite, and cleaved caspase-3. It restored the hepatic levels of superoxide dismutase and reduced glutathione. Additionally, menthol significantly (p < 0.05) increased hepatic levels of B-cell lymphoma 2 (Bcl-2); an anti-apoptotic factor, and proliferating cell nuclear antigen (PCNA), a biomarker of regeneration and survival. Our results showed the therapeutic potential of menthol against liver injury induced by sepsis.

Comparative effects of incretin-based therapy on early-onset diabetic nephropathy in rats: Role of TNF-α, TGF-ß and c-caspase-3.

AIMS: Diabetic nephropathy, a major threat to diabetic patients, is considered as the main reason for end-stage renal disease. Fortunately, incretin-based therapy has been aroused as considerable source to attenuate diabetic renal damage. This study aimed to investigate whether superior protective effects on the progression of diabetic kidney are exerted by glucagon-like peptide-1 analog, exenatide, or dipeptidyl peptidase-4 inhibitor, sitagliptin. MATERIALS AND METHODS: Male Wistar rats were fed high-fat diet for 2 weeks followed by injection of low dose streptozotocin to induce type 2 diabetes mellitus. Four weeks after induction of diabetes, diabetic rats were administered vehicle, exenatide (5 µg/kg/day, SC) or sitagliptin (10 mg/kg/day, orally) for 4 weeks. KEY FINDINGS: Different incretin mimetic agents improved renal function as evident by significant decreases in serum creatinine and urea levels with decline in urinary microalbuminuria and marked improvement in histological alterations. Both treated diabetic rats also exhibited a significant improvement in metabolic intolerance with more pronounced effect of exenatide on glucose regulation. Ameliorated renal oxidative stress alongside significant downregulation in transforming growth factor-beta, tumor necrosis factor-alpha and cleaved-caspase-3 protein expressions in renal tissues were recorded in treated diabetic rats. SIGNIFICANCE: Administration of either exenatide or sitagliptin showed ameliorative effects on early diabetic nephropathy without notable differences between their renal protective effects. However, further clinical studies are still required to ensure their comparative promising effects on the management of renal complication of diabetes.

Effect of combined therapy of mesenchymal stem cells with GLP-1 receptor agonist, exenatide, on early-onset nephropathy induced in diabetic rats.

Diabetic nephropathy is the principal cause of end-stage renal failure and current interventions for its recession remains unsatisfactory. Mesenchymal stem cells (MSCs) hold an attractive source for renovating injured tissues. Unfortunately, limited self-renewal and migration capacity of MSCs after transplantation hinder their clinical applicability which demands a new policy for enhancing their biological functions. This study aimed to investigate whether the renoprotective potential of adipose-derived MSCs (ADMSCs) in diabetic rats could be promoted by exenatide, a glucagon-like peptide-1 (GLP-1) analogue. These effects were studied in type 2 diabetes mellitus rats which were administrated ADMSCs, exenatide or their combination four weeks post-induction. Four weeks later, renal function parameters were evaluated. To address the possible underlying mechanisms, parameters indicating glycolipid metabolism tolerance and oxidative stress biomarkers were assessed in renal tissues alongside evaluation of protein expression of tumor necrosis factor-alpha, transforming growth factor-beta1 and cleaved caspase-3. The results showed that the combined therapy had superior renoprotective effect as evident by significant improvement in kidney function and renal architecture changes through rebalancing of inflammatory, fibrotic and apoptotic markers. Based on these outcomes, ADMSCs with exenatide were supposed to effectively ameliorate diabetic renal dysfunction compared to ADMSCs solely, presenting a promise therapy for diabetic nephropathy with further clinical studies warranted to validate this effect.