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金丝桃苷通过调节生物能量和氧化应激减轻两性霉素B诱导的HK-2细胞肾毒性。

Hyperoside mitigates amphotericin B-induced nephrotoxicity in HK-2 cells via bioenergetic and oxidative stress modulation.

作者信息

Elmorsy Ekramy M, Al Doghaither Huda A, Al-Ghafari Ayat B, Hifni Badriah Abdullah, Jawad Najlaa M M, Hakim Noor A, Fawzy Manal S, Aly Nagwa M

机构信息

Center for Health Research, Northern Border University, Arar, 73213, Saudi Arabia.

Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, 21589, Saudi Arabia.

出版信息

BMC Pharmacol Toxicol. 2025 Aug 12;26(1):149. doi: 10.1186/s40360-025-00985-1.

DOI:10.1186/s40360-025-00985-1
PMID:40797341
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12341085/
Abstract

Amphotericin B (Amp-B/FZ), a first-line antifungal, is limited by dose-dependent nephrotoxicity. This study investigated the protective effects of hyperoside (HP), a dietary flavonoid, against FZ-induced renal toxicity in human proximal tubular (HK-2) cells. Molecular docking revealed strong binding affinities of HP with mitophagy (PINK1/PARKIN) and antioxidant (Nrf2/HO-1) regulators, contrasting with FZ's preferential binding to mitochondrial complex I. FZ (30-60 µM) induced cytotoxicity (MTT/LDH), genotoxicity (comet assay), and bioenergetic disruption: ATP depletion (58%), mitochondrial complex I/III inhibition (42-67%), and PINK1/PARKIN dysregulation. FZ elevated reactive species (3.2-fold) and lipid peroxidation (2.8-fold) while suppressing catalase (64%) and superoxide dismutase (51%) activities. qPCR confirmed FZ-induced downregulation of NDUFS1, CYC1, CAT, and SOD2, alongside impaired Nrf2/HO-1 antioxidant signaling. Co-treatment with HP (20-40 µM) attenuated FZ toxicity, restoring ATP (1.8-fold), mitochondrial complex activities (35-49%), and antioxidant defenses (CAT:2.1-fold, SOD:1.7-fold). HP also normalized Nrf2/HO-1 expression and mitigated oxidative/genotoxic damage. These findings highlight HP's dual role in countering FZ-induced mitochondrial dysfunction and oxidative stress, positioning it as a promising nephroprotective adjuvant. Further in vivo validation could advance HP's clinical application in reducing antifungal-associated renal injury.

摘要

两性霉素B(Amp - B/FZ)作为一线抗真菌药物,受剂量依赖性肾毒性的限制。本研究调查了一种膳食类黄酮金丝桃苷(HP)对FZ诱导的人近端肾小管(HK - 2)细胞肾毒性的保护作用。分子对接显示HP与线粒体自噬(PINK1/PARKIN)和抗氧化(Nrf2/HO - 1)调节因子具有很强的结合亲和力,而FZ则优先与线粒体复合体I结合。FZ(30 - 60 μM)诱导细胞毒性(MTT/LDH)、遗传毒性(彗星试验)和生物能量紊乱:ATP耗竭(58%)、线粒体复合体I/III抑制(42 - 67%)以及PINK1/PARKIN失调。FZ使活性物质升高(3.2倍)和脂质过氧化增加(2.8倍),同时抑制过氧化氢酶(64%)和超氧化物歧化酶(51%)的活性。qPCR证实FZ诱导NDUFS1、CYC1、CAT和SOD2下调,同时Nrf2/HO - 1抗氧化信号受损。与HP(20 - 40 μM)联合处理可减轻FZ毒性,恢复ATP(1.8倍)、线粒体复合体活性(35 - 49%)和抗氧化防御(CAT:2.1倍,SOD:1.7倍)。HP还使Nrf2/HO - 1表达正常化并减轻氧化/遗传毒性损伤。这些发现突出了HP在对抗FZ诱导的线粒体功能障碍和氧化应激方面的双重作用,使其成为一种有前景的肾保护佐剂。进一步的体内验证可能会推动HP在减少抗真菌相关肾损伤方面的临床应用。

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本文引用的文献

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The multiple biological activities of hyperoside: from molecular mechanisms to therapeutic perspectives in neoplastic and non-neoplastic diseases.金丝桃苷的多种生物学活性:从分子机制到肿瘤和非肿瘤疾病的治疗前景
Front Pharmacol. 2025 Mar 3;16:1538601. doi: 10.3389/fphar.2025.1538601. eCollection 2025.
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A Promising Amphotericin B Derivative Induces Morphological Alterations, Mitochondrial Damage, and Oxidative Stress In Vitro and Prevents Mice from Death Produced by a Virulent Strain of .一种有前景的两性霉素B衍生物在体外可诱导形态学改变、线粒体损伤和氧化应激,并能保护小鼠免受一种强毒株所致的死亡。
Microorganisms. 2024 May 24;12(6):1064. doi: 10.3390/microorganisms12061064.
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SwissDock 2024: major enhancements for small-molecule docking with Attracting Cavities and AutoDock Vina.
SwissDock 2024:小分子对接的重大增强,具有吸引腔和 AutoDock Vina。
Nucleic Acids Res. 2024 Jul 5;52(W1):W324-W332. doi: 10.1093/nar/gkae300.
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The Art and Science of Molecular Docking.分子对接的艺术与科学。
Annu Rev Biochem. 2024 Aug;93(1):389-410. doi: 10.1146/annurev-biochem-030222-120000. Epub 2024 Jul 2.
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Comprehensive overview of the role of mitochondrial dysfunction in the pathogenesis of acute kidney ischemia-reperfusion injury: a narrative review.线粒体功能障碍在急性肾缺血再灌注损伤发病机制中的作用综述:一篇叙述性综述
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Arsenic Exposure-Induced Acute Kidney Injury by Regulating SIRT1/PINK1/Mitophagy Axis in Mice and in HK-2 Cells.砷暴露通过调节 SIRT1/PINK1/线粒体自噬轴导致小鼠和 HK-2 细胞急性肾损伤。
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Hyperoside mediates protection from diabetes kidney disease by regulating ROS-ERK signaling pathway and pyroptosis.金丝桃苷通过调节ROS-ERK信号通路和细胞焦亡介导对糖尿病肾病的保护作用。
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