Ginkgolide A downregulates transient receptor potential (melastatin) 2 to protect cisplatin-induced acute kidney injury in rats through the TWEAK/Fn14 pathway: Ginkgolide A improve acute renal injury.

PURPOSE: In order to seek effective drugs for treating cisplatin-induced acute renal injury and explore the corresponding potential mechanism. METHODS: Mouse kidney injury model was established by intraperitoneal injection of 20 mg/kg cisplatin. The temporal expression of TRPM2 and the regulation of Ginkgolide A on its expression were analyzed by western blot. In order to perform the mechanical analysis, we used TRPM2-KO knockout mice. In this study, we evaluated the repair effect of GA on acute kidney injury through renal function factors, inflammatory factors and calcium and potassium content. Pathological injury and cell apoptosis were detected by H&E and TUNEL, respectively. RESULT: Ginkgolide A inhibited inflammatory reaction and excessive oxidative stress, reduced renal function parameters, and improved pathological injury. Meanwhile, we also found that the repair effect of Ginkgolide A on renal injury is related to TRPM2, and Ginkgolide A downregulated TRPM2 expression and inactivated TWEAK/Fn14 pathway in cisplatin-induced renal injury model. We also found that inhibition of TWEAK/Fn14 pathway was more effective in TRPM2-KO mice than TRPM2-WT mice. CONCLUSION: Ginkgolide A was the effective therapeutic drug for cisplatin-induced renal injury through acting on TRPM2, and TWEAK/Fn14 pathway was the downstream pathway of Ginkgolide A in acute renal injury, and Ginkgolide A inhibited TWEAK/Fn14 pathway in cisplatin-induced renal injury model.

Protective role of crocin against sepsis-induced injury in the liver, kidney and lungs via inhibition of p38 MAPK/NF-κB and Bax/Bcl-2 signalling pathways.

CONTEXT: Crocin has been reported to have multiple bioactivities. However, the effect of crocin administration on caecal ligation and puncture (CLP)-induced sepsis remains unknown. OBJECTIVE: We investigated the effects of crocin on CLP-induced sepsis in mice and the underlying mechanism of action. MATERIALS AND METHODS: Five experimental groups (n = 10) of BALB/c mice were used: control, CLP (normal saline) and CLP + crocin (50, 100 and 250 mg/kg, 30 min prior to CLP). Mice were sacrificed 24 h after CLP. Liver, kidney and lung histopathology, indicator levels, apoptotic status, pro-inflammatory cytokines and relative protein levels were evaluated. RESULTS: Compared to the CLP group, crocin treatment significantly increased the survival rate (70%, 80%, 90% vs. 30%). Crocin groups exhibited protection against liver, kidney and lung damage with mild-to-moderate morphological changes and lower indicator levels: liver (2.80 ± 0.45, 2.60 ± 0.55, 1.60 ± 0.55 vs. 5.60 ± 0.55), kidney (3.00 ± 0.71, 2.60 ± 0.55, 1.40 ± 0.55 vs. 6.20 ± 0.84) and lungs (8.00 ± 1.59, 6.80 ± 1.64, 2.80 ± 0.84 vs. 14.80 ± 1.79). The proinflammatory cytokines (IL-1ß, TNF-α, IL-6 and IL-10 levels in the crocin groups) were distinctly lower and the apoptotic index showed a significant decrease. Crocin administration significantly suppressed p38 MAPK phosphorylation and inhibited NF-κB/IκBα and Bcl-2/Bax activation. DISCUSSION AND CONCLUSIONS: Pre-treatment with crocin confers protective effects against CLP-induced liver, kidney and lung injury, implying it to be a potential therapeutic agent.