Redox homeostasis in human renal cells that had been treated with amphotericin B in combination with selected 1,3,4-thiadiazole derivatives

IF 3.6 3区医学 Q2 PHARMACOLOGY & PHARMACY

Pharmacological Reports Pub Date : 2024-04-08 DOI:10.1007/s43440-024-00592-7

Magdalena Kimsa-Dudek, Celina Kruszniewska-Rajs, Jolanta Adamska, Barbara Strzałka-Mrozik, Arkadiusz Matwijczuk, Dariusz Karcz, Mariusz Gagoś, Joanna Magdalena Gola

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Abstract

Background

The use of amphotericin B (AmB) in the therapy of systemic mycosis is associated with strong side effects, including nephrotoxicity, and hepatotoxicity. Therefore, agents that can reduce the toxic effects of AmB while acting synergistically as antifungal agents are currently being sought. 1,3,4-thiadiazole derivatives are promising compounds that have an antifungal activity and act synergically with AmB. Such combinations might allow the dose of AmB, which is essential for preventing patients from having serious side effects, to be decreased. This might result from the antioxidant properties of 1,3,4-thiadiazoles. Thus, the aim of the study was to investigate redox homeostasis in human renal proximal tubule epithelial cells (RPTEC) after they had been treated with AmB in combination with 1,3,4-thiadiazole derivatives.

Methods

Cellular redox homeostasis was assessed by investigating the total antioxidant capacity (TAC) of cells, the malondialdehyde (MDA) concentration, and the activity of antioxidant enzymes such as superoxide dismutase (SOD), glutathione peroxidase (GPX), and catalase (CAT). TAC was measured using an ABTS method. The MDA concentration, and the activity of SOD, GPX, and CAT were determined spectrophotometrically using commercially available assays. Additionally, the antioxidant defense system-related gene expression profile was determined using oligonucleotide microarrays (HG-U133A 2.0). Quantitative reverse transcription polymerase chain reaction (RT-qPCR) was used to confirm the microarray results.

Results

Amphotericin B and selected 1,3,4-thiadiazole derivatives had a significant effect on the total antioxidant capacity of the RPTEC cells, and the activity of the antioxidant enzymes. We also revealed that the effect of thiadiazoles on the SOD and CAT activities is dependent on the treatment of RPTEC cells with AmB. At the transcriptional level, the expression of several genes was affected by the studied compounds and their combinations.

Conclusions

The results confirmed that thiadiazoles can stimulate the RPTEC cells to defend against the oxidative stress that is generated by AmB. In addition, together with the previously demonstrated synergistic antifungal activity, and low nephrotoxicity, these compounds have the potential to be used in new therapeutic strategies in the treatment of fungal infections.

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经两性霉素 B 与特定 1,3,4-噻二唑衍生物联合处理的人类肾脏细胞的氧化还原稳态

背景使用两性霉素 B（AmB）治疗全身性真菌病会产生强烈的副作用，包括肾毒性和肝毒性。因此，目前正在寻找既能降低两性霉素 B 毒性作用，又能发挥协同抗真菌作用的药物。1,3,4-噻二唑衍生物是一种很有前景的化合物，它具有抗真菌活性并能与 AmB 起协同作用。这种复方制剂可以减少 AmB 的剂量，而 AmB 对防止患者出现严重副作用至关重要。这可能源于 1,3,4-噻二唑的抗氧化特性。因此，本研究的目的是调查人类肾近曲小管上皮细胞（RPTEC）在接受 AmB 与 1,3,4-噻二唑衍生物联合治疗后的氧化还原稳态。方法通过研究细胞的总抗氧化能力（TAC）、丙二醛（MDA）浓度以及超氧化物歧化酶（SOD）、谷胱甘肽过氧化物酶（GPX）和过氧化氢酶（CAT）等抗氧化酶的活性来评估细胞的氧化还原稳态。使用 ABTS 法测量 TAC。MDA 浓度以及 SOD、GPX 和 CAT 的活性则使用市售的测定仪进行分光光度测定。此外，还使用寡核苷酸芯片（HG-U133A 2.0）测定了抗氧化防御系统相关基因的表达谱。结果两性霉素 B 和选定的 1,3,4-噻二唑衍生物对 RPTEC 细胞的总抗氧化能力和抗氧化酶的活性有显著影响。我们还发现，噻二唑对 SOD 和 CAT 活性的影响取决于用 AmB 处理 RPTEC 细胞。在转录水平上，所研究的化合物及其组合影响了多个基因的表达。此外，由于这些化合物具有协同抗真菌活性和低肾毒性，因此有望用于治疗真菌感染的新疗法。

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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来源期刊

Pharmacological Reports 医学-药学

CiteScore

8.40

自引率

0.00%

发文量

审稿时长

6 months

期刊介绍： Pharmacological Reports publishes articles concerning all aspects of pharmacology, dealing with the action of drugs at a cellular and molecular level, and papers on the relationship between molecular structure and biological activity as well as reports on compounds with well-defined chemical structures. Pharmacological Reports is an open forum to disseminate recent developments in: pharmacology, behavioural brain research, evidence-based complementary biochemical pharmacology, medicinal chemistry and biochemistry, drug discovery, neuro-psychopharmacology and biological psychiatry, neuroscience and neuropharmacology, cellular and molecular neuroscience, molecular biology, cell biology, toxicology. Studies of plant extracts are not suitable for Pharmacological Reports.