一种新型合成α-乳清蛋白衍生肽治疗肝纤维化的治疗潜力和机制见解。

IF 3.3 Q2 GASTROENTEROLOGY & HEPATOLOGY
Sara Maher , Shimaa Atta , Manal Kamel , Olfat A. Hammam , Hend Okasha
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引用次数: 0

摘要

背景:肝纤维化是一个严重的全球性健康问题,但由于缺乏能够预防或逆转已建立的纤维化的批准疗法,目前的治疗选择有限。目的:研究α-乳清蛋白合成肽对硫代乙酰胺(TAA)致小鼠肝纤维化模型的抗纤维化作用。方法:采用计算机分析方法对该肽的理化性质、药效团特征和对接相互作用进行评价。诱导纤维化小鼠用三种不同剂量的合成肽(2.5、5或10 μg/kg,每周两次,连续8周)治疗。评估免疫组织化学、抗氧化酶水平、IGF-1水平和纤维化相关基因的表达。结果:肽与人凝血酶原的许多位点相互作用,并具有不同的结合亲和力。此外,配体相似性分析鉴定出26种凝血酶抑制剂具有高谷本评分。多肽表现出抗纤维化作用,且呈剂量依赖性改善。与病理未治疗组相比,所有治疗组IGF-1表达上调。相反,纤维化标志物TIMP、PDGF-α和TGF-β在未治疗的病理组中上调,而在肽治疗组中下调。血清中IGF-1浓度的评估表明,肽处理组表现出IGF-1水平的增加。肽处理组的组织病理学检查显示肝脏结构正常,肝细胞排列在薄板上。高剂量肽处理组免疫组化结果显示少量α - sma阳性,增殖细胞核抗原轻度表达。结论:人工合成的α-乳清蛋白肽具有抗纤维化的作用。其安全性和有效性得到了芯片和体内分析的支持。该肽的药效团特性和作为凝血酶抑制剂的潜力,结合其下调纤维化标志物和维持肝组织完整性的能力。这些发现总结了该肽作为肝纤维化的有希望的治疗候选物的潜力,值得进一步研究。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Therapeutic Potential and Mechanistic Insights of a Novel Synthetic α-Lactalbumin-Derived Peptide for the Treatment of Liver Fibrosis

Background

Liver fibrosis is a serious global health issue, but current treatment options are limited due to a lack of approved therapies capable of preventing or reversing established fibrosis.

Aim

This study investigated the antifibrotic effects of a synthetic peptide derived from α-lactalbumin in a mouse model of thioacetamide (TAA)-induced liver fibrosis.

Methods

In silico analyses were conducted to assess the physicochemical properties, pharmacophore features, and docking interactions of the peptide. Mice with induced fibrosis were treated with three different doses of the synthetic peptide (2.5, 5, or 10 μg/kg, twice weekly for 8 weeks). Immunohistochemistry, antioxidant enzyme levels, IGF-1 levels, and expression of fibrosis-related genes were assessed.

Results

Peptide interacted with human prothrombin's many sites with varying binding affinities. Besides, ligand similarity analysis identified 26 thrombin inhibitors with high Tanimoto scores. The peptide exhibited antifibrotic effects with dose-dependent improvements. The upregulated expression of IGF-1 in all treated groups compared with the pathological untreated group. In contrast, fibrotic markers such as TIMP, PDGF-α, and TGF-β were upregulated in the untreated pathological group but downregulated in the peptide-treated groups. The assessment of IGF-1 concentration in sera demonstrated that the peptide-treated groups exhibited an increase in IGF-1 levels. Histopathological examination of peptide-treated groups showed normal hepatic architecture with hepatocytes arranged in thin plates. Immunohistochemical results of high dose peptide-treated group showed a few numbers of positive αSMA with mild proliferating cell nuclear antigen expression.

Conclusion

The synthetic α-lactalbumin peptide shows promise as an antifibrotic therapy. Its safety and effectiveness are supported by in silico and in vivo analyses. The peptide's pharmacophore characteristics and potential as a thrombin inhibitor combine with its ability to downregulate fibrotic markers and maintain liver tissue integrity. These findings concluded the potential of this peptide as a promising therapeutic candidate for liver fibrosis, warranting further investigation.
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来源期刊
Journal of Clinical and Experimental Hepatology
Journal of Clinical and Experimental Hepatology GASTROENTEROLOGY & HEPATOLOGY-
CiteScore
4.90
自引率
16.70%
发文量
537
审稿时长
64 days
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