尼克罗米胺调节环孢素 A 诱导的小鼠模型肝毒性：PPAR-γ 和 Wnt/β-连环蛋白的串扰。
Niclosamide modulates cyclosporin A-induced hepatotoxicity in a mouse model: PPAR-γ and Wnt/β-catenin crosstalk.
机构信息
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Egyptian Russian University, Cairo, Egypt.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt.
出版信息
Int Immunopharmacol. 2023 Apr;117:109941. doi: 10.1016/j.intimp.2023.109941. Epub 2023 Feb 28.
OBJECTIVES
The aim of this study was to evaluate whether: 1) Wnt/β-catenin signaling is involved in cyclosporin A (CsA)-induced hepatotoxicity, and 2) knockdown of this pathway by niclosamide (NCL) attenuate CsA-induced hepatotoxicity.
METHODS
The experiment was accomplished in 21 days. Adult male mice were randomly distributed into five groups: control group, CsA (25 mg/kg/day) group, CsA + NCL (2.5 mg/kg/day) group, CsA + NCL (5 mg/kg/day) group, and NCL (5 mg/kg/day) group.
RESULTS
NCL showed marked hepatoprotection by significantly decreasing liver enzymes activities and ameliorating the histopathological alterations induced by CsA. Besides, NCL alleviated oxidative stress and inflammation. NCL-treated groups (2.5 and 5 mg/kg) displayed rise in the expression of hepatic peroxisome proliferator-activated receptor-γ (PPAR-γ) by 2.1- and 2.5-fold, respectively. Notably, NCL (2.5 and 5 mg/kg) significantly inhibited Wnt/β-catenin signaling, evidenced by a marked decrease in the hepatic expression of Wnt3a by 54 % and 50 %, frizzled-7 receptor by 50 % and 50 %, β-catenin by 22 % and 49 %, and c-myc by 50 % and 50 %, respectively.
CONCLUSIONS
NCL can be regarded as a potential agent to mitigate CsA-induced hepatotoxicity.
目的
本研究旨在评估：1）Wnt/β-连环蛋白信号通路是否参与环孢素 A（CsA）诱导的肝毒性，以及 2）用尼氯柳胺（NCL）阻断该通路是否减轻 CsA 诱导的肝毒性。
方法
实验在 21 天内完成。成年雄性小鼠随机分为五组：对照组、CsA（25mg/kg/天）组、CsA+NCL（2.5mg/kg/天）组、CsA+NCL（5mg/kg/天）组和 NCL（5mg/kg/天）组。
结果
NCL 通过显著降低肝酶活性和改善 CsA 诱导的组织病理学改变，表现出明显的肝保护作用。此外，NCL 还减轻了氧化应激和炎症。NCL 治疗组（2.5 和 5mg/kg）分别使肝过氧化物酶体增殖物激活受体-γ（PPAR-γ）的表达增加了 2.1 倍和 2.5 倍。值得注意的是，NCL（2.5 和 5mg/kg）显著抑制了 Wnt/β-连环蛋白信号通路，肝组织中 Wnt3a 的表达分别降低了 54%和 50%，frizzled-7 受体的表达分别降低了 50%和 50%，β-catenin 的表达分别降低了 22%和 49%，c-myc 的表达分别降低了 50%和 50%。
结论
NCL 可作为减轻 CsA 诱导肝毒性的潜在药物。
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