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The Beneficial Influence of Testosterone in Hepatic Ischemia/Reperfusion Injury and Its Possible Mechanisms

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Abstract

Most studies have indicated that the sex hormone estrogen is hepatoprotective, but little attention has been paid to investigating the effect of testosterone on hepatic ischemia/reperfusion (I/R) injury. Our study aimed to the evaluation of the effect of testosterone on the liver’s functional and structural responses to hepatic I/R. To achieve this, 65 male Wistar albino-rats were divided into 5 groups: sham-operated control group (Sham), hepatic ischemia/reperfusion group (hepatic I/R), orchidectomized hepatic ischemia/reperfusion group (Orch+I/R), Testosterone-treated hepatic ischemia/reperfusion group (T+I/R) and orchidectomized testosterone-treated hepatic ischemia/reperfusion group (Orch+T+I/R). All rats were subjected to determination of serum levels of alanine transaminase (ALT), aspartate transaminase (AST), testosterone and estradiol, and hepatic tissue level of malondialdehyde (MDA), superoxide dismutase (SOD), tumor necrosis factor-alpha (TNF-α), and gene expression of nuclear factor-kappa B (NF-κB) and nuclear factor erythroid 2-related factor 2 (Nrf2). Also, hepatic tissues were histopathologically assessed. The data obtained demonstrated that hepatic I/R significantly increased serum ALT, AST, hepatic tissue MDA, TNF-α, and NF-κB, and significantly decreased serum testosterone, estradiol, hepatic tissue SOD and Nrf2. Histopathological examination revealed cytoplasmic vacuolization, sinusoidal dilatation, inflammatory cell infiltration, and increased collagen fibers with a significant increase in apoptotic cell death (increased caspase-3). Orchidectomy worsened the effect of hepatic I/R while testosterone treatment improved the hepatic I/R-induced functional and morphological disruption in both intact and testosterone-depleted rats, owing to its antioxidant, anti-inflammatory, and anti-apoptotic properties, which were exerted partly via its direct action, and via being converted to estradiol.

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Abbreviations

I/R:

ischemia/reperfusion

Sham:

Sham-operated control group

hepatic I/R:

hepatic ischemia/reperfusion group

Orch+I/R:

orchidectomized hepatic ischemia/reperfusion group

T+I/R:

Testosterone-treated hepatic ischemia/reperfusion group

Orch+T+I/R:

orchidectomized testosterone-treated hepatic ischemia/reperfusion group

ALT:

alanine aminotransferase

AST:

aspartate aminotransferase

MDA:

malondialdehyde

SOD:

superoxide dismutase

TNF-α:

tumor necrosis factor-alpha

NF-κB:

nuclear factor-kappa B

Nrf2:

nuclear factor erythroid 2-related factor 2

IQR:

interquartile range

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ACKNOWLEDGMENTS

We are very grateful to Laila Ahmed Rashed, Professor of Medical Biochemistry and Molecular Biology at the Faculty of Medicine of Cairo University, for her help with the biochemical measurements.

Funding

No funding was received.

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Authors and Affiliations

  1. Faculty of Medicine, Ain Shams University, Cairo, Egypt

    Y. M. Khaled, M. H. ElSayed, D. M. Abdel-Wahed, L. A. Elkhateb & M. A. Ahmed

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  1. Y. M. Khaled
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  2. M. H. ElSayed
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  3. D. M. Abdel-Wahed
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  4. L. A. Elkhateb
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  5. M. A. Ahmed
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Contributions

Khaled YM: conducting the experiments, acquisition, and analysis of the data, and writing the manuscript; Ahmed MA: design of the experimental protocol and revision of the manuscript; ElSayed MH: practical work supervision and revision of the manuscript; Abdel-Wahed DM: practical work supervision and revision of the manuscript; ElKhateb LA: histopathological examination.

Corresponding author

Correspondence to Y. M. Khaled.

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ETHIC STATEMENT

The study protocol, the methods for euthanasia and anesthesia, and all the methods were carried out under relevant guidelines and regulations by the Research Ethical Committee, Faculty of Medicine, Ain Shams University (FMASU REC) which is operated according to the guidelines of the International Council on Harmonization (ICH) anesthesiology, the United States Office for Human Research Protections and the United States Code of Federal Regulations and operates under Federal Wide Assurance No. FWA000017585.

CONFLICT OF INTEREST

The authors declare no competing interests.

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Khaled, Y.M., ElSayed, M.H., Abdel-Wahed, D.M. et al. The Beneficial Influence of Testosterone in Hepatic Ischemia/Reperfusion Injury and Its Possible Mechanisms. J Evol Biochem Phys 59, 1150–1166 (2023). https://doi.org/10.1134/S0022093023040117

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  • DOI: https://doi.org/10.1134/S0022093023040117

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