Chemico-Biological Interactions最新文献_第7页

Cigarette smoke exposure diminishes ovarian reserve in mice by regulating granulosa cells redox homeostasis imbalance through Wnt10b-ERβ feedback loop 香烟烟雾暴露通过Wnt10b-ERβ反馈回路调节颗粒细胞氧化还原稳态失衡，从而减少小鼠卵巢储备

IF 5.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemico-Biological Interactions

Pub Date : 2025-11-05 DOI: 10.1016/j.cbi.2025.111811

Fang Li , Mengting Xu , Yanhui Zhao , Ying Wang , Nengyin Hu , Sailing Ji , Jianing Miao , Li Wang , Lili Wang

Oxidative stress induced by cigarette smoke (CS) exposure can cause ovarian follicle damage and diminishes reserve in women. Our previous study showed CS exposure caused premature ovarian insufficiency (POI) in mice through oxidative stress and senescence in granulosa cells (GCs) via suppressing the expression of Wnt10b, GPX1/GPX4 and FDX1. However, their roles and molecular relationships in oxidative stress and senescence in GCs after CS exposure as well as their diagnostic value for POI remains unclear. In this study, we found that CS exposure resulted in increased ROS production, reduced antioxidant function, mitochondrial dysfunction, cell cycle arrest and cellular senescence in GCs. And the levels of GPX4, GPX1, FDX1 and Wnt10b were also reduced in GCs of pre-POI patients. Over-expression of Wnt10b or application of diarylpropionitrile (DPN, an ERβ agonist) could alleviate above phenotypic changes caused by CSE exposure, however, over-expression of FDX1 only could partially alleviate. Additionally, the serum FDX1 levels exhibit an association with POI progression and serum follicle stimulating hormone (FSH) levels, yet its diagnostic potential for POI alone remains limited. Moreover, ChIP results demonstrated a feedback regulatory relationship between Wnt10b and ERβ, and ERβ is involved in regulating the expression of GPX1, GPX4 and FDX1. The current study demonstrated the regulatory role of the Wnt10b-ERβ feedback loop on GCs redox homeostasis. Our findings provide a theoretical basis for revealing the molecular mechanism of reduced ovarian reserve in women induced by CS exposure, and may provide potential new targets and ideas for the early clinical prediction and diagnosis of human POI.

吸烟引起的氧化应激（CS）暴露会导致卵巢卵泡损伤并减少女性的储备。我们之前的研究表明，CS暴露通过抑制Wnt10b、GPX1/GPX4和FDX1的表达，通过氧化应激和颗粒细胞（GCs）衰老导致小鼠卵巢功能不全（POI）。然而，它们在CS暴露后GCs氧化应激和衰老中的作用和分子关系以及它们对POI的诊断价值尚不清楚。在本研究中，我们发现CS暴露导致GCs中ROS生成增加，抗氧化功能降低，线粒体功能障碍，细胞周期阻滞和细胞衰老。poi前期患者GCs中GPX4、GPX1、FDX1、Wnt10b水平也均降低。过表达Wnt10b或应用ERβ激动剂二芳基丙腈（DPN）可缓解CSE暴露引起的上述表型变化，而过表达FDX1仅能部分缓解。此外，血清FDX1水平与POI进展和血清促卵泡激素（FSH）水平相关，但其单独诊断POI的潜力仍然有限。此外，ChIP结果表明Wnt10b与ERβ之间存在反馈调节关系，ERβ参与调节GPX1、GPX4和FDX1的表达。目前的研究证明了Wnt10b-ERβ反馈回路对GCs氧化还原稳态的调节作用。本研究结果为揭示CS暴露导致女性卵巢储备减少的分子机制提供了理论基础，并可能为人类POI的早期临床预测和诊断提供潜在的新靶点和思路。

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引用次数: 0

Novel senescence inducer ICA-11c, a derivative of icaritin, YAP-dependently suppresses hepatocellular carcinoma cells 新型衰老诱导剂ICA-11c，一种伊卡蒿素衍生物，yap依赖性地抑制肝癌细胞。

IF 5.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemico-Biological Interactions

Pub Date : 2025-11-05 DOI: 10.1016/j.cbi.2025.111814

Hong-fei Chen , Shuai Shen , Shuang-li Wang , Li Ye , Ji-chong Li , Wen-li Cao , Zi-lin Hou , Jian-huan Jia , Qing-bo Liu , Guo-dong Yao , Shao-jiang Song

The Hippo/YAP signaling pathway has been implicated in promoting cancer development in liver cancer. YAP serves as its core effector to promote the expression of downstream oncogenes, exacerbating the difficulty in treatment and prognosis. ICA-11c, a derivative of icaritin (ICT), which was designed and synthesized in our previous study, inhibited the proliferation of HepG2 and Huh-7 cells in a concentration-dependent manner. Moreover, ICA-11c promoted G0/G1 cell cycle arrest and cellular senescence by regulating the p53/p21 and p16/RB pathways. Mechanistically, the cellular thermal shift assay (CETSA) and molecular docking assay confirmed the combination between ICA-11c and YAP, which inhibited YAP nuclear translocation, eventually promoted its phosphorylation and reduction in the cytoplasm. Particularly, YAP overexpression attenuated the effect of ICA-11c on cellular senescence as well as its anti-proliferative activity. Our findings not only show that ICA-11c served as a potential YAP regulator for the treatment of hepatocellular carcinoma, but also explore the relationship between YAP and cellular senescence. This study suggests that ICA-11c may be a potential novel inducer of cellular senescence in hepatocellular carcinoma cells.

Hippo/YAP信号通路与肝癌的发展有关。YAP作为其核心效应物，促进下游癌基因的表达，增加了治疗和预后的难度。ICA-11c是我们前期设计合成的icaritin （ICT）衍生物，对HepG2和Huh-7细胞的增殖具有浓度依赖性。此外，ICA-11c通过调控p53/p21和p16/RB通路促进G0/G1细胞周期阻滞和细胞衰老。在机制上，细胞热移实验（CETSA）和分子对接实验证实了ICA-11c与YAP的结合，抑制了YAP的核易位，最终促进了YAP在细胞质中的磷酸化和还原。特别是，YAP过表达减弱了ICA-11c对细胞衰老的作用及其抗增殖活性。我们的研究结果不仅表明ICA-11c作为一种潜在的YAP调节剂治疗肝细胞癌，而且还探讨了YAP与细胞衰老的关系。本研究提示ICA-11c可能是一种潜在的新型肝癌细胞衰老诱导剂。

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引用次数: 0

Comments on: “Formoterol, a clinically approved drug, inhibits ferroptosis by suppressing lipid peroxidation and attenuates APAP-induced acute liver injury” 点评：“福莫特罗是临床批准的药物，通过抑制脂质过氧化抑制铁下垂，减轻apap引起的急性肝损伤”。

IF 5.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemico-Biological Interactions

Pub Date : 2025-11-04 DOI: 10.1016/j.cbi.2025.111806

Hartmut Jaeschke, Anup Ramachandran

引用次数: 0

Reactivation screening of A-234-inhibited human recombinant acetylcholinesterase in vitro a -234抑制人重组乙酰胆碱酯酶体外再激活筛选。

IF 5.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemico-Biological Interactions

Pub Date : 2025-11-04 DOI: 10.1016/j.cbi.2025.111810

Jakub Opravil , Jaroslav Pejchal , Martina Hrabinova , Lubica Muckova , Lukas Prchal , Jan Korabecny , Tomas Rozsypal , Lukas Gorecki , Jakub Fibigar , Ondrej Soukup , Kamil Musilek , Daniel Jun

The nerve agent A-234, classified among the so-called A-series agents or “Novichoks”, represents a significant challenge in the treatment of nerve agent poisoning due to its potent and irreversible inhibition of human recombinant acetylcholinesterase (HssAChE). In this study, we screened 22 structurally diverse oxime reactivators for their efficacy against A-234-inhibited HssAChE in vitro after a 10-min incubation. The initial screening was extended to GB- and VX-inhibited enzymes under the same conditions for comparison. Then, the 22 oximes were tested against A-234-inhibited HssAChE for up to 24 h. Finally, we evaluated the reactivation kinetics of the two most effective oximes over a 240-min period. While most reactivators demonstrated considerable reactivation against GB- and VX-inhibited enzymes within 10 min, none showed efficacy against A-234 in this time frame. Extended incubation over 24 h revealed that only HLö-7, MMB-4, HI-6, K027, K868, TMB-4, GM415, and LüH-6 achieved efficient reactivation (set at a 10 % threshold for a 24-h interval), with HLö-7 and methoxime (MMB-4) being the most effective. Kinetic analysis indicated that HLö-7 exhibited a superior second-order reactivation rate constant compared to MMB-4, highlighting differences in binding affinity and catalytic efficacy. In the case of A-234 poisonings, our findings indicate the most effective oxime antidotes and emphasize the need for prolonged therapy to improve clinical outcomes.

神经毒剂a -234被归类为所谓的a系列毒剂或“诺维乔克”，由于其对人类重组乙酰胆碱酯酶（HssAChE）的有效和不可逆的抑制，代表了神经毒剂中毒治疗的重大挑战。在这项研究中，我们筛选了22种结构不同的肟再激活剂，在体外培养10分钟后对a -234抑制的HssAChE的疗效进行了研究。在相同条件下，将初始筛选扩展到GB-和vx -抑制酶进行比较。然后，将22种肟对a -234抑制的HssAChE进行长达24小时的测试。最后，我们在240分钟的时间内评估了两种最有效的肟的再激活动力学。虽然大多数再激活剂在10分钟内对GB-和vx -抑制酶表现出相当大的再激活作用，但在这个时间框架内没有一种对A-234有效。延长24小时的培养时间表明，只有HLö-7、MMB-4、HI-6、K027、K868、TMB-4、GM415和l h -6实现了有效的再激活（设定为24小时间隔10%的阈值），HLö-7和甲氧基肟（MMB-4）是最有效的。动力学分析表明，与MMB-4相比，HLö-7具有更好的二级再激活速率常数，突出了结合亲和力和催化效果的差异。在A-234中毒的情况下，我们的研究结果指出了最有效的肟解毒剂，并强调需要延长治疗以改善临床结果。

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引用次数: 0

Retraction notice to “An in vitro investigation of the induction of apoptosis and modulation of cell cycle events in human cancer cells by bisphenanthroline-coumarin-6,7-dioxacetatocopper(II) complex” [Chem. Biol. Interact. 168 (2007) 143–158] “双菲罗啉-香豆素-6,7-二氧乙酸铜（II）复合物诱导人癌细胞凋亡和调节细胞周期事件的体外研究”[化学]。医学杂志。[j].科学通报，2007(5):387 - 398。

IF 5.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemico-Biological Interactions

Pub Date : 2025-11-04 DOI: 10.1016/j.cbi.2025.111804

Bhumika Thati , Andy Noble , Bernadette S. Creaven , Maureen Walsh , Kevin Kavanagh , Denise A. Egan

引用次数: 0

Antimycin A: From mitochondrial poison to multifaceted biological probe and therapeutic agent 抗霉素A：从线粒体毒素到多方面的生物探针和治疗剂。

IF 5.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemico-Biological Interactions

Pub Date : 2025-11-03 DOI: 10.1016/j.cbi.2025.111805

Woo Hyun Park

Antimycin A is a member of a large family of depsipeptide natural products produced primarily by Streptomyces bacteria. First identified for its potent antifungal properties, it has become one of the most widely used and best-characterized inhibitors of cellular respiration. The canonical mechanism of Antimycin A involves high-affinity binding to the Qi site of the cytochrome bc1 complex (Complex III) in the mitochondrial electron transport chain, effectively blocking electron flow and halting ATP synthesis via oxidative phosphorylation. This inhibition leads to a cascade of profound cellular consequences, most notably the massive production of superoxide radicals from the Complex III Qo site, induction of oxidative stress, and the initiation of cell death pathways such as apoptosis. However, decades of research have revealed that the biological activities of Antimycin A extend far beyond its role as a simple mitochondrial poison. It is a key modulator of complex cellular processes including autophagy and mitophagy, and a molecule with a surprisingly diverse and potent range of bioactivities. Recent studies have highlighted its potential as an anticancer agent that selectively targets tumor cells, a potential antifungal and antiviral therapy, and an indispensable chemical probe for investigating mitochondrial function and retrograde signaling. This review synthesizes the current understanding of Antimycin A, covering its biosynthesis and chemical diversity, its detailed molecular mechanism of action, its multifaceted impacts on cellular physiology in organisms from yeast to humans, and its expanding applications in both basic research and as a potential therapeutic agent.

抗霉素A是主要由链霉菌细菌产生的一大家族的天然产物。首先发现其有效的抗真菌特性，它已成为最广泛使用和最具特征的细胞呼吸抑制剂之一。抗霉素A的典型机制是与线粒体电子传递链中细胞色素bc1复合体（复合体III）的Qi位点高亲和力结合，有效阻断电子流动，并通过氧化磷酸化阻止ATP合成。这种抑制导致一系列深刻的细胞后果，最显著的是复合物III Qo位点的超氧自由基的大量产生，氧化应激的诱导，以及细胞凋亡等细胞死亡途径的启动。然而，几十年的研究表明，抗霉素A的生物活性远远超出了它作为一种简单的线粒体毒药的作用。它是包括自噬和有丝自噬在内的复杂细胞过程的关键调节剂，是一种具有惊人多样性和强大生物活性范围的分子。最近的研究强调了其作为选择性靶向肿瘤细胞的抗癌药物，潜在的抗真菌和抗病毒治疗以及研究线粒体功能和逆行信号不可缺少的化学探针的潜力。本文综述了目前对抗霉素A的认识，包括其生物合成和化学多样性，其详细的分子作用机制，其对从酵母到人类的生物细胞生理的多方面影响，以及其在基础研究和潜在治疗剂中的广泛应用。

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引用次数: 0

Comprehensive insights into DEHP neurotoxicity across the lifespan: Behavioral effects, mechanisms, and preventive strategies DEHP终身神经毒性的综合研究：行为影响、机制和预防策略。

IF 5.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemico-Biological Interactions

Pub Date : 2025-11-03 DOI: 10.1016/j.cbi.2025.111807

Jing Bai , Xin Zhang , Lei Hu , Xiaoyan Chen , Ruimin Wang

Di(2-ethylhexyl) phthalate (DEHP) is a widely used plasticizer, and accumulating evidence indicates that its exposure can harm the nervous system. This review integrates findings from animal and human epidemiological studies, focusing on DEHP-induced neurotoxic effects spanning different life stages from the embryonic period to adulthood. It analyzes the stage-specific characteristics of neurotoxicity across the lifespan and explores sex-specific differences in response to DEHP. In addition, the review summarizes the cellular and molecular mechanisms underlying these effects, including oxidative stress, neuroinflammation, neurotransmitter imbalance, apoptosis, estrogen signaling disruption,mitochondrial dysfunction, and blood-brain barrier dysfunction. Furthermore, emerging protective strategies such as antioxidant intervention, γ-aminobutyric acid (GABA) and its derivatives, as well as exercise are outlined. The current limitations of the field and future research directions are also discussed. These syntheses are expected to deepen our understanding of DEHP neurotoxicity and provide valuable references to environmental health protection.

邻苯二甲酸二（2-乙基己基）酯（DEHP）是一种广泛使用的增塑剂，越来越多的证据表明，接触它会损害神经系统。这篇综述整合了动物和人类流行病学研究的结果，重点关注dehp诱导的神经毒性效应跨越从胚胎期到成年期的不同生命阶段。它分析了整个生命周期中神经毒性的阶段特异性特征，并探讨了DEHP反应的性别特异性差异。此外，本文还综述了这些影响的细胞和分子机制，包括氧化应激、线粒体功能障碍、神经炎症、神经递质失衡、细胞凋亡、雌激素信号干扰和血脑屏障功能障碍。此外，还概述了新兴的保护策略，如抗氧化干预、γ-氨基丁酸（GABA）及其衍生物以及运动。讨论了该领域目前的局限性和未来的研究方向。这些合成有望加深我们对DEHP神经毒性的认识，并为环境健康保护提供有价值的参考。

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引用次数: 0

Platinum(IV) oxaliplatin analog containing axial benzoate ligands induces mitochondrial hyperpolarization and caspase-dependent apoptosis in pancreatic cancer cell models 含轴向苯甲酸配体的铂（IV）奥沙利铂类似物在胰腺癌细胞模型中诱导线粒体超极化和caspase依赖性凋亡

IF 5.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemico-Biological Interactions

Pub Date : 2025-11-03 DOI: 10.1016/j.cbi.2025.111792

Michal Berecka , Jitka Pracharova , Nicola Margiotta , Alessandra Barbanente , Nicoletta Ditaranto , Jana Kasparkova , Viktor Brabec

This study investigates the molecular mechanisms underlying the antiproliferative effects of the platinum(IV) complex trans-[Pt(OBz)₂(O,C-10-BzODA)(1R,2R-DACH)] (complex 1; OBz = benzoate, 10-BzODA = 10-benzoyloxy-2-decenoate, DACH = diaminocyclohexane) in pancreatic cancer cell models. Initial findings revealed that complex 1 exhibits substantial antiproliferative activity, positioning it as a promising therapeutic agent for pancreatic cancer, where effective treatment options remain limited. Notably, complex 1 demonstrates significantly greater efficacy compared to platinum(II) drugs, such as cisplatin and oxaliplatin, with IC₅₀ values in the low micromolar range across various pancreatic cancer cell lines. Mechanistic studies suggest that complex 1's enhanced activity is attributed to the axial benzoate ligands, which differentiate it from its platinum(II) analog. Complex 1 accumulates intracellular platinum without undergoing reduction in the extracellular environment, and it induces mitochondrial hyperpolarization. This effect is reminiscent of free sodium benzoate but occurs at a much lower extracellular concentration, indicating the crucial role of the benzoate ligands in modulating mitochondrial function. Furthermore, complex 1 triggers caspase-dependent apoptosis in cancer cells and is also effective in 3D tumor cell models, highlighting its potential as an effective anticancer agent. Thus, this work presents a Pt(IV) prodrug bearing benzoate axial ligands that exhibit distinctive chemical and biological behavior compared with previously reported Pt(IV) prodrugs.

In conclusion, the unique properties of complex 1, driven by its benzoate ligands, suggest that Pt(IV) complexes represent a promising approach for the development of targeted chemotherapeutic agents for the treatment of pancreatic cancer.

本研究探讨了铂（IV）配合物反式-[Pt(OBz)2(O,C-10-BzODA)(1R,2R-DACH)]（配合物1；OBz =苯甲酸酯，10-BzODA = 10-苯甲酰氧基-2-十烯酸，DACH =二氨基环己烷）在胰腺癌细胞模型中抗增殖作用的分子机制。初步研究结果显示，复合物1具有显著的抗增殖活性，使其成为一种有前景的治疗胰腺癌的药物，而胰腺癌的有效治疗方案仍然有限。值得注意的是，与铂（II）药物（如顺铂和奥沙利铂）相比，复合物1的疗效显著提高，在各种胰腺癌细胞系中的IC50值在低微摩尔范围内。机理研究表明配合物1的活性增强归因于轴向苯甲酸酯配体，这与它的铂（II）类似物不同。复合物1在细胞内积累铂而不经过细胞外环境的还原，并诱导线粒体超极化。这种作用让人想起游离苯甲酸钠，但发生在细胞外浓度低得多，表明苯甲酸钠配体在调节线粒体功能中的关键作用。此外，复合物1在癌细胞中触发caspase依赖性凋亡，并且在3D肿瘤细胞模型中也有效，这突出了其作为有效抗癌药物的潜力。因此，本研究提出了一种含Pt（IV）前药的苯甲酸酯轴向配体，与先前报道的Pt（IV）前药相比，它表现出独特的化学和生物学行为。综上所述，由苯甲酸酯配体驱动的配合物1的独特性质表明，Pt（IV）配合物代表了开发用于治疗胰腺癌的靶向化疗药物的有希望的方法。

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引用次数: 0

Oxidative stress and mitochondrial dysfunction in neuronal cells induced by commercial CBD products 商业CBD产品诱导的神经细胞氧化应激和线粒体功能障碍。

IF 5.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemico-Biological Interactions

Pub Date : 2025-11-01 DOI: 10.1016/j.cbi.2025.111785

A. Sanz-Pérez , B.J. Anaya , A.I. Fraguas-Sánchez , D.R. Serrano , T. Pérez , M. Spineli , P. Basilicata , M. Pieri , E. González-Burgos

The global cannabis market is rapidly expanding, but safety concerns are rising due to inconsistent CBD product labelling and contamination, driven by rapid commercialization and weak regulation. Studies show significant discrepancies in CBD concentrations, with many products either over- or under-labelled, and some contaminated with THC, pesticides, or heavy metals. This study investigates the neurotoxic effects of commercial CBD formulations, focusing on oxidative stress and redox imbalance in neurons. The analysis of two commercially available CBD samples (white and pink powder) revealed the presence of cannabidiol (CBD) in a content of 51.8 % and 51.4 %, respectively. Elemental analysis revealed notable contamination, with predominant metals including boron, lead, silicon, and zinc in the white sample, and boron, iron, silicon, and chromium in the pink sample. Treatment of SH-SY5Y neuroblastoma cells with these samples for 48 h resulted in a concentration-dependent reduction in cell viability, particularly at 10 and 50 μg/mL, accompanied by morphological changes. Both samples significantly increased reactive oxygen species (ROS) production and induced oxidative stress, evidenced by a reduced GSH/GSSG ratio and elevated lipid peroxidation at 50 μg/mL. Additionally, the activity of key antioxidant enzymes including catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione reductase (GR), was markedly inhibited. Mitochondrial function was also impaired, as indicated by decreased mitochondrial content and signal intensity. These findings underscore the potential neurotoxic effects of commercially available CBD products, particularly due to heavy metal contamination, and highlight the urgent need for comprehensive regulatory measures to ensure consumer safety amidst growing market availability.

全球大麻市场正在迅速扩大，但由于快速商业化和监管不力，CBD产品标签和污染不一致，安全问题正在加剧。研究表明，CBD浓度存在显著差异，许多产品的标签要么过高，要么过低，有些产品还被四氢大麻酚、杀虫剂或重金属污染。本研究探讨了商业CBD配方的神经毒性作用，重点关注神经元的氧化应激和氧化还原失衡。对两种市售CBD样品（白色和粉红色粉末）的分析显示，大麻二酚（CBD）的含量分别为51.8%和51.4%。元素分析显示出明显的污染，白色样品中的主要金属包括硼、铅、硅和锌，粉红色样品中的主要金属包括硼、铁、硅和铬。SH-SY5Y神经母细胞瘤细胞用这些样品处理48小时，导致细胞活力呈浓度依赖性降低，特别是在10和50 μg/mL时，并伴有形态学改变。两种样品均显著增加活性氧（ROS）的产生，诱导氧化应激，在50 μg/mL浓度下，GSH/GSSG比例降低，脂质过氧化水平升高。过氧化氢酶（CAT）、超氧化物歧化酶（SOD）、谷胱甘肽过氧化物酶（GPx）和谷胱甘肽还原酶（GR）等关键抗氧化酶活性均受到显著抑制。线粒体功能也受损，线粒体含量和信号强度下降。这些发现强调了商用CBD产品的潜在神经毒性作用，特别是由于重金属污染，并强调了迫切需要采取全面的监管措施，以确保消费者在日益增长的市场供应中安全。

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引用次数: 0

Oxidative stress and inflammation in renal fibrosis: Novel molecular mechanisms and therapeutic targets 氧化应激和炎症在肾纤维化：新的分子机制和治疗靶点。

IF 5.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemico-Biological Interactions

Pub Date : 2025-11-01 DOI: 10.1016/j.cbi.2025.111784

Haojie Liu , Xiadan Xiang , Chengqian Shi , Jiaowei Guo , Ting Ran , Jinglian Lin , Futing Dong , Jie Yang , Hua Miao

Renal fibrosis, a hallmark of acute kidney injury (AKI), chronic kidney disease (CKD) and AKI-to-CKD transition, is characterized by the excessive accumulation and deposition of extracellular matrix components, tubular atrophy, tubulointerstitial fibrosis and glomerulosclerosis, that ultimately lead to renal failure. Oxidative stress and inflammation play pivotal roles in renal pathogenesis that form a vicious cycle of cellular injury and fibrotic progression. Accumulating evidence has revealed key molecular mechanisms involved in the fibrotic processes, such as inhibitor of kappa B/nuclear factor kappa B (NF-κB) and Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2), nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4), transforming growth factor-β (TGF-β)/Suppressor of Mothers against Decapentaplegic (Smad) and aryl hydrocarbon receptor (AHR) pathways. Novel therapeutic strategies targeting IκB/NF-κB, Keap1/Nrf2, NOX4, TGF-β/Smad and AHR pathways, such as small-molecule inhibitors, antioxidant agents, and antiinflammatory cytokines, show promise in mitigating renal fibrosis. Emerging approaches by targeting epigenetic regulation, non-coding RNAs, gut microbiota and metabolic disorders by chemical drugs (dapagliflozin) and natural compounds (polydatin, dihydromyricetin, baicalin, diosmin, gentiopicroside, hyocholic acid and natural polysaccharides) further expand therapeutic landscape. This review synthesizes recent advances in understanding molecular mechanisms of renal fibrosis and highlights potential therapeutic targets, offering insights into innovative strategies for managing CKD and improving patient outcomes.

肾纤维化是急性肾损伤（AKI）、慢性肾脏疾病（CKD）和AKI向CKD过渡的标志，其特征是细胞外基质（ECM）成分的过度积累和沉积、小管萎缩、小管间质纤维化（TIF）和肾小球硬化，最终导致肾功能衰竭。氧化应激和炎症在肾脏发病中起关键作用，使细胞损伤和纤维化进展的循环永久化。越来越多的证据揭示了参与纤维化过程的关键分子机制，如κB /核因子κB （NF-κB）和kelch样ech相关蛋白1 (Keap1)/核因子红系2相关因子2 （Nrf2）抑制剂、烟酰胺腺嘌呤二核苷酸磷酸氧化酶4 （NOX4）、转化生长因子-β (TGF-β)和芳烃受体（AHR）途径。针对NF-κB、Nrf2、NOX4、TGF-β和AHR通路的新治疗策略，如小分子抑制剂、抗氧化剂和抗炎细胞因子，有望缓解肾纤维化。以表观遗传调控、非编码rna、肠道微生物群和代谢紊乱为靶点的化学药物（达格列净）和天然化合物（多甙、二氢杨梅素、黄芩苷、薯蓣皂苷、龙胆苷、蛇胆酸和天然多糖）的新方法进一步拓展了治疗领域。本综述综合了肾纤维化分子机制的最新进展，强调了潜在的治疗靶点，为CKD治疗和改善患者预后的创新策略提供了见解。

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引用次数: 0