title: Genistein alleviates testicular ischemia and reperfusion injury-induced spermatogenic damage and oxidative stress by suppressing abnormal testicular matrix metalloproteinase system via the Notch 2/Jagged 1/Hes-1 and caspase-8 pathways.
abstract: The aim of the study is to examine the role of matrix metalloproteinases (MMPs) and their inhibitors (TIMP) during testicular ischemia/reperfusion (t I/R). The involvement of the Notch pathway, and their modulation by the antioxidant genistein is also studied. Three groups of male Sprague-Dawley rats were used: sham rats, t I/R rats, and genistein-treated rats (10 mg/kg). The t I/R rat model underwent testicular artery occlusion of the left testis and was subjected to 60 min ischemia followed by 4 h reperfusion. Protein expression of MMP-2, MMP-9, TIMP-1, and TIMP-2 were measured in testicular tissue. Histological examination was performed to assess spermatogenesis. Protein levels of Notch 2, Jagged 1, and hairy/enhancer of split 1 (hes-1) was quantified. The degree of testicular oxidative stress, DNA damage and germ cell apoptosis were also evaluated. T I/R induced severe tubular damage, a significant increase in MMP- 2 and MMP-9 expression and decreased expression TIMP-1 and TIMP-2. Genistein treatment normalized the MMP-TIMP imbalance. Rats subjected to t I/R had low total antioxidant capacity of the testis, decreased superoxide dismutase activity, and increased oxidative DNA damage. Enhanced activities of caspase 8, caspase 3 and PARP were also observed during t I/R. Genistein reversed the t I/R-induced suppression of the Notch 2/Jagged 1/hes-1 pathway. Genistein was also able to salvage the testicular structure and function through restoring the MMP-TIMP anti-proteolytic balance, suppressing spermatogenic damage, alleviating oxidative stress and apoptosis. The Notch pathway is partly involved in inhibiting the t I/R-induced testicular impairment.
authors.affiliation: Department of Biochemistry, Faculty of Medicine-Kuwait University, Jabriyah, Kuwait. malmaghrebi@hsc.edu.kw.
authors.forename: M
authors.initials: M
authors.lastname: Al-Maghrebi
authors.affiliation: Department of Anatomy, Faculty of Medicine-Kuwait University, Jabriyah, Kuwait.
authors.forename: W M
authors.initials: WM
authors.lastname: Renno
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D053181:Caspase 8 / Q000378:metabolism; D019833:Genistein / Q000494:pharmacology*; D000072100:Jagged-1 Protein / Q000378:metabolism; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000071656:Receptor, Notch3 / Q000378:metabolism; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013091:Spermatogenesis / Q000187:drug effects*; D013737:Testis / Q000187:drug effects* / Q000378:metabolism; D000072056:Transcription Factor HES-1 / Q000378:metabolism*
chemical_list: D000975:Antioxidants; C489735:Hes1 protein, rat; C000606275:Jag1 protein, rat; D000072100:Jagged-1 Protein; D000071656:Receptor, Notch3; D000072056:Transcription Factor HES-1; D019833:Genistein; C505528:Casp8 protein, rat; D053181:Caspase 8; D020782:Matrix Metalloproteinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9