Involvement of Hypoxia-Inducible Factor 1-α in Experimental Testicular Ischemia and Reperfusion: Effects of Polydeoxyribonucleotide and Selenium

Abstract

Polydeoxyribonucleotide (PDRN) is an agonist of the A2A adenosine receptor derived from salmon trout sperm. Selenium (Se) is a trace element normally present in the diet. We aimed to investigate the long-term role of PDRN and Se, alone or in association, after ischemia-reperfusion (I/R) in rats. The animals underwent 1 h testicular ischemia followed by 30 days of reperfusion or a sham I/R and were treated with PDRN or Se alone or in association for 30 days. I/R significantly increased hypoxia-inducible factor 1-α (HIF-1α) in Leydig cells, malondialdehyde (MDA), phosphorylated extracellular signal-regulated kinases 1/2 (pErk 1/2), and apoptosis decreased testis weight, glutathione (GSH), testosterone, nuclear factor erythroid 2-related factor 2 (Nrf2), induced testicular structural changes, and eliminated HIF-1α spermatozoa positivity. The treatment with either PDRN or Se significantly decreased MDA, apoptosis, and HIF-1α positivity of Leydig cells, increased testis weight, GSH, testosterone, and Nrf2, and improved the structural organization of the testes. PDRN and Se association showed a higher protective effect on all biochemical, structural, and immunohistochemical parameters. Our data suggest that HIF-1α could play important roles in late testis I/R and that this transcriptional factor could be modulated by PDRN and Se association, which, together with surgery, could be considered a tool to improve varicocele-induced damages.

Integrative analysis of transcriptomics and metabolomics reveals the protective effect and mechanism of salidroside on testicular ischemia-reperfusion injury

“…Nrf2 can also induce and regulate the composition and expression of antioxidant proteins (including CAT, SOD, and GSH), reduce the production of ROS, and maintain the redox stability of the body ( Sang et al, 2024 ; Zhang et al, 2024 ). Studies have shown that testicular I/R damage is related to the decrease in antioxidant enzymes regulated by Nrf2 ( Antonuccio et al, 2022 ). Indeed, the use of some antioxidants (including SAL) has been extensively discussed for preventing testicular injury ( Matzkin et al, 2021 ; Cai et al, 2023 ).…”

Role of nuclear factor erythroid 2-related factor 2 (Nrf2) in female and male fertility

“…The use of an antioxidant, e.g., Zinc, can lead to the activation of the Nrf2 pathway in rats with testicular I/R damage by reducing the expression of miR-101-3p [ 122 ]. The findings show that the use of antioxidants such as Idebenone (IDE), selenium (Se), and MitoQ, in spermatic cord torsion/detorsion models can improve Nrf2/Keap1 signaling translocation from the cytoplasm to the nucleus and regulate the Nrf2 levels to counteract with oxidative stress [ [123] , [124] , [125] ]( Fig. 5 )( Table 2 ).…”

Positive Effects of the Nutraceutical Association of Lycopene and Selenium in Experimental Varicocele

“…In particular, HIF-1α, the active subunit of HIF-1, regulates the physiological activity and the expression of this factor. In testis, HIF-1α is present under both normoxia and ischemia [7]. An evident increase in its expression was shown in experimental models of ischemia/reperfusion [7,8], even if its role has not yet been completely elucidated.…”

“…In testis, HIF-1α is present under both normoxia and ischemia [7]. An evident increase in its expression was shown in experimental models of ischemia/reperfusion [7,8], even if its role has not yet been completely elucidated.…”

“…The outcomes of different substances on the biochemical and morphological damages induced in testes by experimental varicocele were studied in the last years [7,[9][10][11][12][13][14][15]. In particular, the effects of lycopene and selenium (Se) were evaluated.…”