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Title: Mitochondrial Dysfunction Contributes to Germ Cell Apoptosis via the JNK/p53/Survivin Pathway in Testicular Ischemia Reperfusion Injury
Authors: Fatemah Fadel Mohammad 
Supervisor: Dr. May Al-Maghrebi
Degree Awarded: Degree in: Molecular Biology
Keywords: Testicular Ischemia Reperfusion Injury; JNK; Mitochondrial Dysfunction; Germ Cell Apoptosis
Issue Date: 2019
Publisher:  Kuwait university - college of graduate studies
Abstract: Testicular ischemia reperfusion injury (tIRI) is the underlying mechanism of testicular torsion and detorsion (TTD), a urological emergengy in adolescents. TTD/tIRI are characterized by testicular oxidative stress (OS) and germ cell apoptosis (GCA). The c-Jun N-terminal kinases (JNK) pathway is activated in response to cell stress and DNA damage. Objective: The aim is to study whether JNK signaling and mitochondrial dysfunction contribute to the pathophysiology of tIRIinduced GCA and oxidative DNA damage using the JNK inhibitor SP600125. Methodolgy: Male Sprague-Dawley rats (n=36) were equally divided into three groups: sham, tIRI only and tIRI + SP600125 (15 mg/kg, i.p., 30 min post ischemia). Testicular ischemia was induced for 1 hour followed by four hours reperfusion prior to animal sacrifice. Spermatogenesis was evaluated by H&E staining using the Johnsen’s scoring system and the mean seminiferous tubules diameter. The expression of oxidative stress induced-GCA genes and proteins were evaluated by real-time PCR and immunofluorescence (IF) staining, respectively. Mitochondrial stress was examined by western blot and colorimetric assays. Results: Significantly decreased superoxide dismutase (SOD) antioxidant activity was associated with a 2-fold increase in both protein and lipid peroxidation products during tIRI. Additionally, oxidative DNA damage was augmented by a 24.3-fold increase in the number of TUNEL stained nuclei and a 1.5-fold increase in the concentration of 8-OHdG. During tIRI, induction of GCA was confirmed by elevated Bax to Bcl-2 ratio and activation of the initiator caspase 9 and the executioner caspase 3 by 1.3-fold and 2.3-folds, respectively. This was also accompanied by a significantly heightened IF expression of phosphorylated JNK and p53 and survivin down-regulation. During tIRI, mitochondrial dysfunction was reflected by depletion of ATP and NADH, overexpression of uncoupling protein 2 and increased cytochrome c protein levels. All the results were compared to sham group as control group. These tIRI-induced damages were all attenuated by SP600125 treatment prior to reperfusion
Appears in Programs:2050 Molecular Biology

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