Exploring the Therapeutic Potential and Underlying Mechanism of Bergapten in Renal Fibrosis: Network Pharmacology, Molecular Docking, and Experimental Validation.

IF 6.1 2区 医学 Q1 CHEMISTRY, MEDICINAL
Phytotherapy Research Pub Date : 2025-05-01 Epub Date: 2025-03-15 DOI:10.1002/ptr.8460
Shobhit Gairola, Montu Saini, Archana Bhatta, Ravinder K Kaundal
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引用次数: 0

Abstract

Chronic kidney disease (CKD) is characterized by progressive interstitial fibrosis, contributing to high global mortality due to limited treatment options. Contemporary findings highlight the potential of natural compounds for CKD treatment. Bergapten (BGT), a bioactive furocoumarin, is recognized for its antioxidant and anti-inflammatory properties but remains unexplored as an antifibrotic agent. The potential targets of BGT were identified using network pharmacology and in silico approaches. The antifibrotic effects of BGT were evaluated in transforming growth factor (TGF)-β1-induced normal rat kidney fibroblast (NRK-49F) cells. For in vivo validation, CKD was induced in mice using unilateral ureteral obstruction (UUO). Immunocytochemistry, histopathological analysis, and immunoblotting were conducted to assess the effects of BGT on fibroblast activation, renal microstructural changes, and expression of profibrotic markers. Network pharmacology analysis revealed 119 BGT-target genes involved in renal fibrosis, including those in the TGF-β1 signaling pathway. Molecular docking confirmed the interaction of BGT with TGF-β receptor 1 (TGFR1). In vitro studies demonstrated that BGT (30 μM) inhibited TGF-β1-induced fibrotic response in NRK-49F cells by inhibiting TGF-β1/Smad signaling. In vivo, oral administration of BGT (20 mg/kg) improved kidney function and alleviated histological damage, and pathological collagen deposition while mitigating renal inflammation. BGT suppressed the TGF-β1/Smad signaling pathway, reduced the expression of extracellular matrix (ECM) proteins, and mitigated oxidative stress by activating the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme-oxygenase-I (HO-I) signaling pathway. This study demonstrated the therapeutic potential of BGT in alleviating renal fibrosis in experimental models of CKD. The observed effects were attributed to the inhibition of TGF-β1/Smad signaling and activation of the Nrf2 pathway.

探索Bergapten在肾纤维化中的治疗潜力和潜在机制:网络药理学,分子对接和实验验证。
慢性肾脏疾病(CKD)以进行性间质纤维化为特征,由于治疗选择有限,导致全球死亡率高。当代研究结果强调了天然化合物治疗慢性肾病的潜力。Bergapten (BGT)是一种生物活性呋喃香豆素,因其抗氧化和抗炎特性而被公认,但作为抗纤维化剂仍未被探索。利用网络药理学和计算机方法确定了BGT的潜在靶点。用转化生长因子(TGF)-β1诱导的正常大鼠肾成纤维细胞(NRK-49F)观察BGT的抗纤维化作用。为了在体内验证,使用单侧输尿管梗阻(UUO)诱导小鼠CKD。通过免疫细胞化学、组织病理学和免疫印迹分析来评估BGT对成纤维细胞活化、肾脏微结构改变和纤维化标志物表达的影响。网络药理学分析发现119个bgt靶基因参与肾纤维化,包括TGF-β1信号通路。分子对接证实了BGT与TGF-β受体1 (TGFR1)的相互作用。体外研究表明,BGT (30 μM)通过抑制TGF-β1/Smad信号通路抑制TGF-β1诱导的NRK-49F细胞纤维化反应。在体内,口服BGT (20 mg/kg)可改善肾功能,减轻组织损伤和病理性胶原沉积,同时减轻肾脏炎症。BGT可抑制TGF-β1/Smad信号通路,降低细胞外基质(extracellular matrix, ECM)蛋白表达,并通过激活核因子红细胞2相关因子2 (Nrf2)/血红素加氧酶- i (HO-I)信号通路,减轻氧化应激。本研究证实了BGT在缓解CKD实验模型肾纤维化方面的治疗潜力。观察到的效果归因于抑制TGF-β1/Smad信号和激活Nrf2通路。
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来源期刊
Phytotherapy Research
Phytotherapy Research 医学-药学
CiteScore
12.80
自引率
5.60%
发文量
325
审稿时长
2.6 months
期刊介绍: Phytotherapy Research is an internationally recognized pharmacological journal that serves as a trailblazing resource for biochemists, pharmacologists, and toxicologists. We strive to disseminate groundbreaking research on medicinal plants, pushing the boundaries of knowledge and understanding in this field. Our primary focus areas encompass pharmacology, toxicology, and the clinical applications of herbs and natural products in medicine. We actively encourage submissions on the effects of commonly consumed food ingredients and standardized plant extracts. We welcome a range of contributions including original research papers, review articles, and letters. By providing a platform for the latest developments and discoveries in phytotherapy, we aim to support the advancement of scientific knowledge and contribute to the improvement of modern medicine.
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