College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China.
College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China; Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, Northeast Agricultural University, Harbin 150030, PR China.
Life Sci. 2022 Jul 15;301:120622. doi: 10.1016/j.lfs.2022.120622. Epub 2022 May 7.
Nickel(Ni) accumulates in the environment due to human activities such as electroplating, alloy production, stainless steel, Ni‑cadmium batteries and industrial production. Ni enriched in humans and animals through food chains, poses a serious health threat. Txnrd3, as a member of the thioredoxin reductase family, has long been thought to be testicular specific and involved in sperm maturation. However, its role in liver diseases still unknown. Melatonin exerts its antioxidant effects directly through its ability to clear free radicals and protects the liver from oxidative damage. Hepatic fibrosis with an ever-increasing incidence year by year, is correlating with outcome and risk of hepatocellular carcinoma.
In this study, 60 8-week-old male C57BL/6 wild-type mice and 60 Txnrd3-/- mice were randomly divided into three groups, respectively. Control group was gavaged with distilled water, 10 mg/kg NiCl in Ni group, Ni + Mel group treated with 2 mg/kg melatonin in the morning, 10 mg/kg NiCl in the afternoon, serum and tissue was extracted after 21 days.
Results showed that liver function was significantly worse after Ni exposure, morphological and masson staining showed more significant liver fibrosis in Txnrd3-/- mice, damage of organelles in hepatocytes was observed. qPCR and WB results showed activation of the IRE1/Nuclear factor-kappa B/NLRP3 axis during Ni exposure lead to hepatocyte pyroptosis, while upregulation of PERK/TGF-β promoted liver fibrosis process and Txnrd3 knockout exacerbated liver damage during Ni exposure.
The above results will lay the theoretical foundation for the monitoring and clinical treatment of Ni exposure.
由于电镀、合金生产、不锈钢、镍镉电池和工业生产等人类活动，镍（Ni）在环境中积累。Ni 通过食物链在人类和动物中富集，对健康构成严重威胁。Txnrd3 作为硫氧还蛋白还原酶家族的一员，长期以来被认为是睾丸特异性的，参与精子成熟。然而，其在肝脏疾病中的作用尚不清楚。褪黑素通过清除自由基的能力直接发挥抗氧化作用，保护肝脏免受氧化损伤。肝纤维化的发病率逐年增加，与肝癌的预后和风险相关。
在这项研究中，将 60 只 8 周龄雄性 C57BL/6 野生型小鼠和 60 只 Txnrd3-/- 小鼠随机分为三组，对照组灌胃蒸馏水，Ni 组灌胃 10mg/kg NiCl2，Ni+Mel 组在早上给予 2mg/kg 褪黑素，下午给予 10mg/kg NiCl2，21 天后提取血清和组织。
结果表明，Ni 暴露后肝功能明显恶化，形态学和 Masson 染色显示 Txnrd3-/- 小鼠肝纤维化更明显，肝细胞细胞器损伤。qPCR 和 WB 结果表明，Ni 暴露激活 IRE1/Nuclear factor-kappa B/NLRP3 轴导致肝细胞焦亡，而 PERK/TGF-β 的上调促进了肝纤维化过程，Txnrd3 敲除加剧了 Ni 暴露时的肝损伤。
上述结果将为 Ni 暴露的监测和临床治疗奠定理论基础。
