title: 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 CdCl2(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.
authors.affiliation: Department of Occupational Health, Third Military Medical University, Chongqing, China.
authors.forename: Zhengwang
authors.identifier: http://orcid.org/0000-0001-5698-8044
authors.initials: Z
authors.lastname: Cao
authors.affiliation: Department of Occupational Health, Third Military Medical University, Chongqing, China.
authors.forename: Yiliang
authors.initials: Y
authors.lastname: Fang
authors.affiliation: Department of Occupational Health, Third Military Medical University, Chongqing, China.
authors.forename: Yonghui
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: Dunxian
authors.initials: D
authors.lastname: Tan
authors.affiliation: State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, Third Military Medical University, Chongqing, China.
authors.forename: Changhong
authors.initials: C
authors.lastname: Du
authors.affiliation: Institute of Hepatobiliary Surgery, XinQiao Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Yuming
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Occupational Health, Third Military Medical University, Chongqing, China.
authors.forename: Qinlong
authors.initials: Q
authors.lastname: Ma
authors.affiliation: Department of Occupational Health, Third Military Medical University, Chongqing, China.
authors.forename: Junmei
authors.initials: J
authors.lastname: Yu
authors.affiliation: Department of Occupational Health, Third Military Medical University, Chongqing, China.
authors.forename: Mengyan
authors.initials: M
authors.lastname: Chen
authors.affiliation: Department of Occupational Health, Third Military Medical University, Chongqing, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Zhou
authors.affiliation: Department of Occupational Health, Third Military Medical University, Chongqing, China.
authors.forename: Liping
authors.initials: L
authors.lastname: Pei
authors.affiliation: Department of Occupational Health, Third Military Medical University, Chongqing, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Biomedical Analysis Center, Third Military Medical University, Chongqing, China.
authors.forename: Haiying
authors.initials: H
authors.lastname: Ran
authors.affiliation: Department of Occupational Health, Third Military Medical University, Chongqing, China.
authors.forename: Mindi
authors.initials: M
authors.lastname: He
authors.affiliation: Department of Occupational Health, Third Military Medical University, Chongqing, China.
authors.forename: Zhengping
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Department of Occupational Health, Third Military Medical University, Chongqing, China.|Department of Occupational Health, School of Medicine, Guangxi University, Nanning, China.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Zhou
mesh_terms: D000818:Animals; D002104:Cadmium / Q000633:toxicity*; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics; D016923:Cell Death / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D058847:Inflammasomes / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D008297:Male; D008550:Melatonin / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000096:biosynthesis / Q000235:genetics; D013879:Thioredoxins / Q000096:biosynthesis / Q000235:genetics
chemical_list: D002352:Carrier Proteins; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C445672:Txnip protein, mouse; D002104:Cadmium; D013879:Thioredoxins; D008550:Melatonin
keywords: NLRP3 inflammasome; TXNIP; cadmium; liver injury; melatonin