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Epigallocatechin-3-gallate modulates germ cell apoptosis through the SAFE/Nrf2 signaling pathway

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Abstract

To examine the role of the transcription factor nuclear factor-erythroid 2 (NF-E2)–related factor 2 (Nrf2) and the SAFE pathway (JAK/STAT) in the induction of germ cell apoptosis (GCA) and the protective role of epigallocatechin-3-gallate (EGCG) during testicular ischemia reperfusion injury (tIRI). Male Sprague-Dawley rats (n = 18) were divided into three groups: sham, unilateral tIRI, tIRI + epigallocatechin-3-gallate (EGCG, 50 mg/Kg). Unilateral tIRI was induced by 1-h ischemia followed by 4-h reperfusion, and EGCG was injected i.p. 30-min post ischemia. Immuno-histological analyses were used to detect spermatogenesis, oxidative DNA damage, and the immuno-expression of the JAK2, STAT3, and STAT1. Biochemical assays were used to investigate the oxidative, apoptosis proteins and enzymes, while Western blot was used to detect the expression of NOX and Nrf2. Expression of apoptosis-related genes was measured by real-time PCR. During tIRI, there was a clear damage to spermatogenesis associated with decreased activities of SOD, CAT, and GPx and increased levels of lipid peroxidation and oxidative DNA damage. In addition, GCA was indicated by the activation of caspase1, PARP, decreased gene expression of survivin and increased Bax to Bcl2 ratio. In contrast to lowered Nrf2 levels, NOX levels were augmented and phosphorylation of JAK2, STAT3, and STAT1 was increased. Pre-perfusion treatment with EGCG prevented the above modulations. The coordinated activation of the SAFE pathway and suppression of Nrf2 contribute to the tIRI-induced oxidative damages and GCA, which were modulated by EGCG.

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Acknowledgments

The authors thank Prof. Suad AlFadhli and Mrs. Shabeeba Pattillath for their excellent support. The authors ASA and AI have contributed equally to the study.

Funding

This study was supported by Kuwait University Research Grant SRU02/13.

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Authors and Affiliations

  1. Department of Biochemistry, Faculty of Medicine, Kuwait University, 24923, Safat, 13110, Jabriyah, Kuwait

    May Al-Maghrebi, Abdullah S. Alnajem & Ali Esmaeil

Authors
  1. May Al-Maghrebi
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  2. Abdullah S. Alnajem
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  3. Ali Esmaeil
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Contributions

MA: devising the concept and assumptions of the study, research methodology used, and manuscript preparation (writing, reviewing, and final approval).

ASA and AI: conducting research, statistical analysis and calculations, and manuscript preparation (reviewing and final approval).

All authors read and approved the manuscript.

Corresponding author

Correspondence to May Al-Maghrebi.

Ethics declarations

The maintenance and experimental protocols were approved by Kuwait university ethical committee (SRU02/13) that conforms to the norms of the International Council for Laboratory Animal Sciences (ICLAS).

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The authors declare that they have no conflicts of interest.

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Al-Maghrebi, M., Alnajem, A.S. & Esmaeil, A. Epigallocatechin-3-gallate modulates germ cell apoptosis through the SAFE/Nrf2 signaling pathway. Naunyn-Schmiedeberg's Arch Pharmacol 393, 663–671 (2020). https://doi.org/10.1007/s00210-019-01776-2

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  • DOI: https://doi.org/10.1007/s00210-019-01776-2

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