JAK Inhibition Prevents DNA Damage and Apoptosis in Testicular Ischemia-Reperfusion Injury via Modulation of the ATM/ATR/Chk Pathway

Abstract

Testicular ischemia reperfusion injury (tIRI) causes oxidative stress-induced DNA damage leading to germ cell apoptosis (GCA). The aim of the study is to establish a direct link between JAK2 activation and the DNA damage response (DDR) signaling pathways and their role in tIRI-induced GCA using AG490, a JAK2 specific inhibitor. Male Sprague Dawley rats (n = 36) were divided into three groups: sham, unilateral tIRI and tIRI + AG490 (40 mg/kg). During tIRI, augmentation in the phosphorylation levels of the JAK2/STAT1/STAT3 was measured by immunohistochemistry. Observed spermatogenic arrest was explained by the presence of considerable levels of DSB, AP sites and 8OHdG and activation of caspase 9, caspase 3 and PARP, which were measured by colorimetric assays and TUNEL. The ATM/Chk2/H2AX and ATR/Chk1 pathways were also activated as judged by their increased phosphorylation using Western blot. These observations were all prevented by AG490 inhibition of JAK2 activity. Our findings demonstrate that JAK2 regulates tIRI-induced GCA, oxidative DNA damage and activation of the ATM/Chk2/H2AX and ATR/Chk1 DDR pathways, but the cell made the apoptosis decision despite DDR efforts.

Helicobacter pylori Thioredoxin1 May Play a Highly Pathogenic Role via the IL6/STAT3 Pathway

“…Previous studies have shown that the expression of STAT3 was closely related to DNA damage [ 12 ]. In the above results, we found that the high-Trx1 HP can induce higher expression of p-STAT3, so we speculated that the high-Trx1 HP may result in stronger DNA damage.…”

“…The STAT3 signaling pathway is involved in regulating DNA transcription and gene expression and affects biological processes such as cell proliferation, differentiation, and apoptosis [ 11 ]. Besides, the previous studies have shown that the downregulation of STAT3 activity was related to the reduction of DNA damage, to maintain genome stability and protect against cell death [ 12 ]. It has been reported that as many as 70% of human tumors have abnormal enhancement of STAT3 activity, including gastric cancer, esophageal cancer, liver cancer, and other tumors [ 13 , 14 ].…”

Inhibition of PLK3 Attenuates Tubular Epithelial Cell Apoptosis after Renal Ischemia–Reperfusion Injury by Blocking the ATM/P53-Mediated DNA Damage Response

“…To better characterize the molecular and 14 Oxidative Medicine and Cellular Longevity cellular events related to AKI, we used the TRAP-seq results in the GEO database to examine PLK3 expression in the translation profile of nephrons (tubules) exposed to IRI for 24 h. GO analysis showed that PLK3 was mainly involved in oxidative stress and DNA damage after renal I/R injury. DNA damage has been reported to be involved in I/R injury in a variety of vital organs, including the testicular, brain, liver, and heart [33][34][35][36]. During renal I/R injury, DNA fragmentation in the renal tubules after DNA damage occurs as early as 12 h after reperfusion and increases within 24 h [37].…”

New Strategies Protecting from Ischemia/Reperfusion

“…Differently, myocardial infarction, stroke or testicular torsion are sudden, and the management can only occur during ischemia [ 7 ] and during blood reflow [ 8 ]. Despite the identification of many protective treatments in experimental models of I/R, their translation to the clinic has shown very disappointing benefits for patients, especially for stroke and infarct [ 9 , 10 ].…”

“…The multiplicity of these processes involves numerous cellular mechanisms and pathways, which are all potential therapeutic targets. In this Special Issue, original approaches targeting various ubiquitous kinase pathways are proposed for testicular torsion and kidney transplantation [ 3 , 4 , 7 ], which could be extended to other ischemic events, as well as specific combinatory treatment using hormones in the case of uterus transplantation [ 5 ]. In the majority of ischemic situations, mitochondria play a central role as depletion in oxygen supply leads to the impairment of mitochondrial function and loss of energy metabolites, mainly following at the time of reperfusion by oxidative stress and disturbance of Ca 2+ homeostasis crucial for cell viability [ 1 , 13 ].…”