Melatonin alleviates cadmium‐induced liver injury by inhibiting the TXNIP‐NLRP3 inflammasome

Abstract

Cadmium (Cd) is a persistent environmental and occupational contaminant that accumulates in the liver and induces oxidative stress and inflammation. Melatonin possesses potent hepatoprotective properties against the development and progression of acute and chronic liver injury. Nevertheless, the molecular mechanism underlying the protective effects of melatonin against Cd-induced hepatotoxicity remains obscure. In this study, we aimed to investigate the effects of melatonin on Cd-induced liver inflammation and hepatocyte death. Male C57BL/6 mice were intraperitoneally injected with melatonin (10 mg/kg) once a day for 3 days before exposure to CdCl (2.0 mg/kg). We found that Cd induced hepatocellular damage and inflammatory infiltration as well as increased serum ALT/AST enzymes. In addition, we showed that Cd triggered an inflammatory cell death, which is mediated by the NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome. Moreover, melatonin treatment significantly alleviated Cd-induced liver injury by decreasing serum ALT/AST levels, suppressing pro-inflammatory cytokine production, inhibiting NLRP3 inflammasome activation, ameliorating oxidative stress, and attenuating hepatocyte death. Most importantly, melatonin markedly abrogated Cd-induced TXNIP overexpression and decreased the interaction between TXNIP and NLRP3 in vivo and in vitro. However, treatment with siRNA targeting TXNIP blocked the protective effects of melatonin in Cd-treated primary hepatocytes. Collectively, our results suggest that melatonin confers protection against Cd-induced liver inflammation and hepatocyte death via inhibition of the TXNIP-NLRP3 inflammasome pathway.

Melatonin administration to wild‐type mice and nontreated NLRP3 mutant mice share similar inhibition of the inflammatory response during sepsis

“…These effects of melatonin against sepsis in mice lead to an increased survival rate of animals . The beneficial effects due the inhibition of the NLRP3 inflammasome by melatonin are receiving increased attention because it is related to the improvement of diseases such as cadmium‐induced liver injury, acute lung injury, and subarachnoid hemorrhage‐induced brain injury . However, the specific interaction of melatonin with the NLRP3 inflammasome during sepsis in cardiac tissue remains to be identified.…”

Effects of Melatonin on Liver Injuries and Diseases

“…Melatonin reduced liver injury and inflammation through decreasing serum ALT/AST levels, inhibiting pro-inflammatory cytokine production, preventing NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome activation, ameliorating oxidative stress, and attenuating hepatocyte death. In vivo and in vitro, Cd-induced TXNIP overexpression was markedly abrogated and the interaction between TXNIP and NLRP3 was decreased by melatonin [29]. In addition, melatonin increased hepatic GSH levels and improved histopathological changes after Cd 2+ exposure.…”

Melatonin ameliorates spinal cord injury by suppressing the activation of inflammasomes in rats

“…15,16 It was reported that the reduction in inflammasome activation could significantly decrease the level of inflammatory responses in neurons as a result of decreased caspase-1 activity and reduced production of IL-1. [20][21][22] In this study, we established a rat model of SCI and treated SCI rats with MT to explore the molecular mechanisms underlying the therapeutic effect of MT in the treatment of SCI. 18 Although the reduction in inflammatory responses is transient in nature, it can lead to significant improvements in terms of functional and histopathological properties of neurons.…”