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

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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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Data availability

The data presented in this study are available upon request from the corresponding author.

Abbreviations

ABTS:

diammonium 2,2'azinobis[3-ethyl-2,3-dihydrobenzothiazole-6-sulphonate

AmB:

amphotericin B

C1:

1,3,4-thiadiazole derivative

CAT:

catalase

CYP1B1:

cytochrome P450 Family 1 Subfamily B Member 1

DEGs:

differentially expressed genes

DMSO:

dimethyl sulfoxide

ERCC8:

ERCC Excision Repair 8, CSA Ubiquitin Ligase Complex Subunit

GDF15:

growth differentiation 15

GPX:

glutathione peroxidase

GPX3:

glutathione peroxidase 3

GPX7:

glutathione peroxidase 7

MDA:

malondialdehyde

N:

1,3,4-thiadiazole derivative

ROS:

reactive oxygen species

RPTEC:

renal proximal tubule epithelial cells

RT-qPCR:

quantitative reverse transcription polymerase chain reaction

SEPP1:

selenoprotein P

SIK1:

salt inducible kinase 1

SOD:

superoxide dismutase

SOD2:

superoxide dismutase 2, mitochondrial

TAC:

total antioxidant capacity

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Funding

This research was funded by the Polish National Science Centre grant 2019/35/B/NZ7/02756.

Author information

Authors and Affiliations

  1. Department of Nutrigenomics, and Bromatology, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, Katowice, 40-055, Poland

    Magdalena Kimsa-Dudek

  2. Department of Molecular Biology, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, Katowice, 40-055, Poland

    Celina Kruszniewska-Rajs, Jolanta Adamska, Barbara Strzałka-Mrozik & Joanna Magdalena Gola

  3. Department of Biophysics, University of Life Sciences, Akademicka 13, Lublin, 20-950, Poland

    Arkadiusz Matwijczuk

  4. Department of Chemical Technology, and Environmental Analytics, Cracow University of Technology, Cracow, 31-155, Poland

    Dariusz Karcz

  5. ECOTECH-COMPLEX—Analytical, and Programme Centre for Advanced Environmentally- Friendly Technologies, Maria Curie-Sklodowska University, Głęboka 39, Lublin, 20-033, Poland

    Arkadiusz Matwijczuk & Dariusz Karcz

  6. Department of Cell Biology, Maria Curie-Sklodowska University, Akademicka 19, Lublin, 20-033, Poland

    Mariusz Gagoś

  7. Department of Biochemistry, and Molecular Biology, Medical University of Lublin, Lublin, 20-093, Poland

    Mariusz Gagoś

Authors
  1. Magdalena Kimsa-Dudek
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Contributions

Conceptualization, J.M.G., M.K.-D. A.M., and M.G.; methodology, M.K.-D., C.K.-R., and J.A.; software, M.K.-D.; validation, C.K.-R.; formal analysis, M.K.-D., and B.S.-M.; investigation, M.K.-D., C.K.-R., A.M., D.K., and J.A.; resources, M.K.-D.; data curation, M.K.-D., C.K.-R., and J.A.; writing—original draft preparation, M.K.-D.; writing—review and editing, J.M.G., A.M., D.K., and B.S.-M.; visualization, M.K.-D. and C.K.-R.; supervision, J.M.G.; project administration, M.G. and J.M.G.; funding acquisition, M.G. All of the authors have read and agreed to the published version of the manuscript.

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Correspondence to Magdalena Kimsa-Dudek.

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Kimsa-Dudek, M., Kruszniewska-Rajs, C., Adamska, J. et al. Redox homeostasis in human renal cells that had been treated with amphotericin B in combination with selected 1,3,4-thiadiazole derivatives. Pharmacol. Rep (2024). https://doi.org/10.1007/s43440-024-00592-7

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