Melatonin ameliorates trimethyltin chloride‐induced cardiotoxicity: The role of nuclear xenobiotic metabolism and Keap1‐Nrf2/ARE axis‐mediated pyroptosis

Abstract

Trimethyltin chloride (TMT) is a stabilizer for polyvinyl chloride plastics that causes serious health hazards in nontarget organisms. Melatonin (MT) exhibits powerful protective effects in cardiac diseases. As a new environmental pollutant, TMT‐induced cardiotoxicity and the protective effects of MT remain unclear. To explore this, the mice were treated with TMT (2.8 mg/kg) and/or MT (10 mg/kg) for 7 days. Firstly, the histopathological and ultrastructural evaluation showed that TMT induced cardiac damage, tumescent rupture and nuclear pyknosis. Moreover, TMT elevated the expressions of pyroptosis genes NLRP3, ASC and Cas1 and inflammation factors IL‐6, IL‐17 and TNFα. Secondly, TMT reduced antioxidant enzymes (GSH, CAT and T‐AOC) via decreasing the expression of genes associated with the Keap1‐Nrf2/ARE pathway to increase oxidative stress. Thirdly, TMT decreased the expression of genes associated with the ARE‐driven drug metabolizing enzymes (DMEs), including Akr7a3, Akr1b8, and Akr1b10. Besides, TMT upregulated the mRNA expression of nuclear Xenobiotic metabolism on cytochrome P450s enzymes via increasing the expression of CAR, PXP, and AHR genes. Furthermore, MT treatment mitigated the aforementioned adverse changes induced by TMT. Overall, these results demonstrated that TMT caused pyroptosis and inflammation to aggravate cardiac damage via inducing excessive oxidative stress, imbalance of DMEs homeostasis, and nuclear Xenobiotic metabolism disorder, which could be alleviated by MT.

Dietary Selenium Alleviated Mouse Liver Oxidative Stress and NAFLD Induced by Obesity by Regulating the KEAP1/NRF2 Pathway

“…NRF2 is closely related to the function of mitochondria [ 46 ]. At present, research has proved that melatonin can ameliorate trimethyltin chloride-induced cardiotoxicity through KEAP1/NRF2, and that Cimicifugae Rhizoma extract attenuates oxidative stress via the regulation of NRF2 [ 9 , 19 ]. These have shown that promoting NRF2 activity with some beneficial drugs can protect organs from oxidative damage.…”

“…Some studies have shown that promoting NRF2 activity with some beneficial drugs can protect animals from oxidative damage [ 7 , 17 , 18 ]. Under normal circumstances, NRF2 and KEAP1 bind to each other in the cytoplasm and then degrade through the ubiquitous protein-prosthetic pathway in a way on which KEAP1 relies [ 19 ]. However, in the presence of ROS, NRF2 is isolated from KEAP1; the degradation is stopped; and then accumulates in the nucleus and becomes heterogeneous with small Musculoaponeurotic fibrosarcoma oncogene (Maf) family proteins, which can be activated by antioxidant reaction elements (ARE) to protect the target gene of cells [ 7 , 19 ].…”

“…Under normal circumstances, NRF2 and KEAP1 bind to each other in the cytoplasm and then degrade through the ubiquitous protein-prosthetic pathway in a way on which KEAP1 relies [ 19 ]. However, in the presence of ROS, NRF2 is isolated from KEAP1; the degradation is stopped; and then accumulates in the nucleus and becomes heterogeneous with small Musculoaponeurotic fibrosarcoma oncogene (Maf) family proteins, which can be activated by antioxidant reaction elements (ARE) to protect the target gene of cells [ 7 , 19 ]. Therefore, the level of NRF2 protein is regulated by the degradation process, and the stability of NRF2 is the key to the response of cells to oxidative stress.…”

Effectiveness of melatonin in preventing vancomycin-induced nephrotoxicity: an experimental study

“…Melatonin is one of the hormones secreted by the pineal gland, which has immunomodulatory activity and an antioxidant ability to scavenge free radicals 25,26 . Besides being a chief hormone of the pineal gland, melatonin is a pleiotropic molecule that plays a role in regulation of the circadian system, seasonal reproduction, and regulation of sleep, exhibiting significant immunoregulatory, antiinflammatory, and antioxidant properties 11 .…”

Empagliflozin protects diabetic pancreatic tissue from damage by inhibiting the activation of the NLRP3/caspase-1/GSDMD pathway in pancreatic β cells: in vitro and in vivo studies

“…Previous studies have shown that NLRP3 is expressed in a variety of cells and its mediated signaling pathway plays an important role in the progression of diabetes [ 35 , 36 ]. Several studies have shown that activation of NLRP3 can stimulate inflammatory formation and pyroptosis of cells [ 37 , 38 ]. These findings prompted us to detect NLRP3 expression in db/db mice and analyze its association with pancreatic β cells.…”