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Intermittent fasting restores fertility dysfunction caused by a high-fat diet in male rats: role of SIRT-1/NRF2/P38 MAPK/NLRP3

Hemead, Dalia A., El-Malkey, Nanees F., Aref, Mohamed, Mahran, Nievin Ahmed, ElSheikh, Esraa, Nassan, Mohamed A., Gadelmawla, Mohamed H. A., Salem, Gamal A., Ahmed, Amira F. A., El-Sayed, Sahar M., Elsheikh, Eman H., Hendy, Nehal I.·2025·Reproduction, Fertility and Development
DOI 10.1071/rd24187
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Abstract

Context: Intermittent fasting (IF) is a dietary approach against obesity; however, investigations on its role in male fertility showed contradictory results. Aims: As nuclear factor erythroid 2-related factor 2 (NRF2)/mitogen-activated protein kinase p38 (MAPK)/nucleotide-binding oligomerization domain-like receptor with a pyrin domain 3 (NLRP3) signaling pathways regulate inflammation and pyrotosis, this study aimed to elucidate whether these pathways are involved in the underlying molecular mechanisms and to investigate the prophylactic effects of IF on male reproduction dysfunction in obese rats. Methods: Twenty-four adult rats were divided as follows: Control lean (CL), control positive (CP), which were fed standard diet for four non-consecutive days/week, with alternate fasting on the other 3 days (24 h fasting), high-fat diet group (HFD), and the HFD-fasting group (HFD-IF), which was fed a HFD, followed by fasting protocol as in CP group. Serum testosterone, inflammatory markers, semen analysis, testicular malondialdehyde (MDA) concentration, and superoxide dismutase (SOD) activity were measured. Also, testicular and epididymal histological study, immunohistochemical analysis of NLRP3 and NRF2 and reverse-transcription quantitative polymerase chain reaction (RT-qPCR) for mRNA expression of SIRT1, NRF2, p38AMPK and NLRP3 were performed. Key results: Combining IF with HFD limited rats’ testicular spermatic and steroidogenesis impairment, histopathological alterations, by upregulating SIRT1/NRF2 and downregulating p38 MAPK/NLRP3 signaling pathways versus the HFD group. In the HFD-IF group, oxidative and inflammatory markers had a significant decrease versus in the HFD group. Conclusions: IF has a beneficial effect on male reproductive health and emphasizes the significance of customized dietary strategies for addressing male fertility issues. Implications: Further investigation is required to clarify more prophylactic mechanisms of IF.

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Metadata

Authors
Hemead, D. A., El-Malkey, N. F., Aref, M., Mahran, N. A., ElSheikh, E., Nassan, M. A., Gadelmawla, M. H. A., Salem, G. A., Ahmed, A. F. A., El-Sayed, S. M., Elsheikh, E. H., & Hendy, N. I.
Affiliations
  • AMedical Physiology Department, Faculty of medicine, Zagazig University, El-Sharkia, Egypt.
  • BAnatomy and Embryology Department, Faculty of Veterinary Medicine, Zagazig University, El-Sharkia 44519, Egypt.
  • CBiochemistry Department, Faculty of Dentistry, Sinai University – Kantara Campus, Egypt.
  • DDepartment of Clinical Laboratory Sciences, Turabah University College, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia.
  • EHistology Department, Faculty of Dentistry, Sinai University, Kantara Campus, Egypt.
  • FDepartment of Pharmacology, Faculty of Veterinary Medicine, Zagazig University, El-Sharkia 44519, Egypt.
  • GHuman Anatomy and Embryology, Faculty of Medicine, Zagazig University, El-Sharkia, Egypt.
  • HComparative Anatomy Department, Faculty of Science, Zagazig University, El-Sharkia, Egypt.
ORCID
Aref, Mohamed
Venue
Reproduction, Fertility and Development
Publisher
CSIRO Publishing
Published
2025-08-26
Volume
37
Issue
14
ISSN
  • 1031-3613
  • 1448-5990
DOI
10.1071/rd24187
Cited by
4
References
5
Language
en
Licence
creativecommons.org/licenses/by-nc-nd/4.0/ (vor, 15 d)

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Hemead, D. A., El-Malkey, N. F., Aref, M., Mahran, N. A., ElSheikh, E., Nassan, M. A., Gadelmawla, M. H. A., Salem, G. A., Ahmed, A. F. A., El-Sayed, S. M., Elsheikh, E. H., & Hendy, N. I. (2025). Intermittent fasting restores fertility dysfunction caused by a high-fat diet in male rats: role of SIRT-1/NRF2/P38 MAPK/NLRP3. Reproduction, Fertility and Development. https://doi.org/10.1071/rd24187

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