Vaccarin Ameliorates Renal Fibrosis by Inhibiting Ferroptosis via Nrf2/SLC7A11/GPX4 Signaling Pathway.

IF 4.7 2区医学 Q1 CHEMISTRY, MEDICINAL Drug Design, Development and Therapy Pub Date : 2025-03-06 eCollection Date: 2025-01-01 DOI:10.2147/DDDT.S509357

Mengjiao Cui, Qiming Xu, Lianxiang Duan, Jianrao Lu, Jing Hu

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Abstract

Purpose: Vaccarin is a natural flavonoid glycoside with anti-inflammatory, antioxidant and nephroprotective effects. However, the effects of vaccarin on renal fibrosis (RF) and its molecular mechanisms remain unclear. This study aimed to investigate the effects of vaccarin on RF and its molecular mechanisms.

Methods: Network pharmacology was used to analyze the effect of vaccarin on RF, and molecular docking and molecular dynamics simulations were performed to assess the binding of nuclear factor erythroid 2-related factor 2 (Nrf2) to vaccarin. A mouse model of unilateral ureteral obstruction (UUO) was established in vivo, and human renal tubular epithelial (HK2) cells were induced with transforming growth factor-β (TGF-β) and RSL3, respectively, as an in vitro model. The anti-fibrotic effect of vaccarin was observed by histopathological staining and determination of fibrous markers. Changes in oxidative stress and ferroptosis-related markers were detected by kits, Western blot (WB), qRT-PCR and immunofluorescence (IF). Finally, Nrf2 inhibitors were added to the in vitro model to observe the effects on fibrosis and ferroptosis.

Results: Vaccarin and RF cross genes are enriched for oxidative stress. Nrf2 binds stably to vaccarin. Both in vivo and in vitro experiments showed that vaccarin treatment reduced the expression of fibrosis markers, decreased the levels of reactive oxygen species (ROS), malondialdehyde (MDA), lipid peroxidation (LPO) and Fe²⁺, and increased glutathione (GSH) secretion. In addition, vaccarin down-regulated the expression of Long-chain acyl-CoA synthetase 4 (ACSL4), prostaglandin-endoperoxide synthase 2 (PTGS2) and NADPH oxidase 1 (NOX1), and up-regulated Nrf2 and its downstream solute transport family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) expression. Mechanistic studies indicated that vaccarin activated the Nrf2/SLC7A11/GPX4 pathway to inhibit ferroptosis, and this inhibition was effectively reversed by the Nrf2 inhibitor.

Conclusion: Vaccarin ameliorates RF by inhibiting ferroptosis via Nrf2/SLC7A11/GPX4 pathway.

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目的：空洞素是一种天然黄酮苷，具有抗炎、抗氧化和保护肾脏的作用。然而，空泡素对肾脏纤维化（RF）的影响及其分子机制仍不清楚。本研究旨在探讨空泡素对肾纤维化的影响及其分子机制：方法：采用网络药理学分析空泡素对RF的影响，并进行分子对接和分子动力学模拟，评估核因子红细胞2相关因子2（Nrf2）与空泡素的结合。在体内建立了单侧输尿管梗阻（UUO）小鼠模型，并分别用转化生长因子-β（TGF-β）和RSL3诱导人肾小管上皮细胞（HK2）作为体外模型。通过组织病理学染色和纤维标记物的测定，观察了空泡素的抗纤维化作用。通过试剂盒、Western 印迹（WB）、qRT-PCR 和免疫荧光（IF）检测了氧化应激和铁突变相关标记物的变化。最后，在体外模型中加入 Nrf2 抑制剂，观察其对纤维化和铁蛋白沉积的影响：结果：Vaccarin和RF交叉基因富含氧化应激。Nrf2与空泡素稳定结合。体内和体外实验均表明，空泡素处理可减少纤维化标志物的表达，降低活性氧（ROS）、丙二醛（MDA）、脂质过氧化（LPO）和Fe2+的水平，并增加谷胱甘肽（GSH）的分泌。此外，空泡素还能下调长链酰基-CoA 合成酶 4（ACSL4）、前列腺素内过氧化物合成酶 2（PTGS2）和 NADPH 氧化酶 1（NOX1）的表达，上调 Nrf2 及其下游溶质转运家族 7 成员 11（SLC7A11）和谷胱甘肽过氧化物酶 4（GPX4）的表达。机理研究表明，空泡素激活了Nrf2/SLC7A11/GPX4通路，从而抑制了铁突变，Nrf2抑制剂可有效逆转这种抑制作用：结论：空泡素通过Nrf2/SLC7A11/GPX4途径抑制铁跃迁，从而改善射频。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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IF 4.6 2区工程技术Physics of FluidsPub Date : 2024-01-24 DOI: 10.1063/5.0188386

Jun-Xue Leng, Yuan Feng, Wei Huang, Yang Shen, Zhen-Guo Wang

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来源期刊

Drug Design, Development and Therapy CHEMISTRY, MEDICINAL-PHARMACOLOGY & PHARMACY

CiteScore

9.00

自引率

0.00%

发文量

382

审稿时长

>12 weeks

期刊介绍： Drug Design, Development and Therapy is an international, peer-reviewed, open access journal that spans the spectrum of drug design, discovery and development through to clinical applications. The journal is characterized by the rapid reporting of high-quality original research, reviews, expert opinions, commentary and clinical studies in all therapeutic areas. Specific topics covered by the journal include: Drug target identification and validation Phenotypic screening and target deconvolution Biochemical analyses of drug targets and their pathways New methods or relevant applications in molecular/drug design and computer-aided drug discovery* Design, synthesis, and biological evaluation of novel biologically active compounds (including diagnostics or chemical probes) Structural or molecular biological studies elucidating molecular recognition processes Fragment-based drug discovery Pharmaceutical/red biotechnology Isolation, structural characterization, (bio)synthesis, bioengineering and pharmacological evaluation of natural products** Distribution, pharmacokinetics and metabolic transformations of drugs or biologically active compounds in drug development Drug delivery and formulation (design and characterization of dosage forms, release mechanisms and in vivo testing) Preclinical development studies Translational animal models Mechanisms of action and signalling pathways Toxicology Gene therapy, cell therapy and immunotherapy Personalized medicine and pharmacogenomics Clinical drug evaluation Patient safety and sustained use of medicines.