Zhong Haoran, Dong Bowen, Zhu Danlin, Li Hao, Lu Ke, Fu Zhiqiang, Liu Jinming, Jin Yamei
National Reference Laboratory for Animal Schistosomiasis, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai 200241, China.
Key Laboratory of Animal Parasitology of Ministry of Agriculture and Rural Affairs, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai 200241, China.
Biology (Basel). 2023 Nov 24;12(12):1465. doi: 10.3390/biology12121465.
Liver fibrosis (LF) is a chronic progressive disease with no definitive treatment. The aim of this study was to assess helminth-derived molecules as potential therapeutic targets to prevent or reverse LF. A mouse model of carbon tetrachloride (CCL)-induced LF was established and sja-let-7 was overexpressed by treatment with a miRNA agomir once per week. After four weeks, serum biochemistry, hepatic hydroxyproline content measurements, liver histology, mRNA expression profiling of fibrotic markers, the dual-luciferase reporter assay, and fluorescence in situ hybridization (FISH) were performed. Administration of the sja-let-7 agomir markedly ameliorated hepatosplenomegaly and reduced the liver hydroxyproline content. Liver histological analysis showed significant reductions in collagen deposition in the sja-let-7 agomir-treated mice. Additionally, the mRNA levels of both pro-fibrotic markers and pro-inflammatory cytokines were diminished after treatment. Furthermore, the dual-luciferase reporter assay and FISH identified the α2 chain of collagen type 1 (Col1α2) as the direct target of sja-let-7. Accordingly, the progression of LF was attenuated by targeting Col1α2 and the TGF-β/Smad signaling pathway.
肝纤维化(LF)是一种尚无确切治疗方法的慢性进行性疾病。本研究的目的是评估源自蠕虫的分子作为预防或逆转肝纤维化的潜在治疗靶点。建立了四氯化碳(CCL)诱导的肝纤维化小鼠模型,并通过每周一次用miRNA激动剂处理使sja-let-7过表达。四周后,进行了血清生化分析、肝脏羟脯氨酸含量测定、肝脏组织学检查、纤维化标志物的mRNA表达谱分析、双荧光素酶报告基因检测以及荧光原位杂交(FISH)。给予sja-let-7激动剂可显著改善肝脾肿大,并降低肝脏羟脯氨酸含量。肝脏组织学分析显示,经sja-let-7激动剂处理的小鼠胶原沉积明显减少。此外,治疗后促纤维化标志物和促炎细胞因子的mRNA水平均降低。此外,双荧光素酶报告基因检测和FISH确定Ⅰ型胶原α2链(Col1α2)为sja-let-7的直接靶点。因此,通过靶向Col1α2和TGF-β/Smad信号通路可减轻肝纤维化的进展。