Oxidative stress and DNA damage after cerebral ischemia: Potential therapeutic targets to repair the genome and improve stroke recovery.

Glia scar is a pathological marker in late phase of brain ischemia disease, which constitutes a major physical biochemical barrier to impede axonal regrowth. Astrocytes are known to be critically involved in the formation of glial scar. However, their response to ischemia and their role in neuroprotection after central nervous system (CNS) injury are not completely clear. Recently, we have demonstrated for the first time that Ski was up-regulated in reactive astrocytes after spinal cord injury in vivo and in vitro, which indicates Ski may be a new molecule that control astrocytes biologic properties after CNS injury. However, its role in the process of reactive astrogliosis after cerebral ischemia and its definite mechanism still remains unknown. This study is to elucidate the role of Ski in reactive astrocytes induced by oxygen-glucose deprivation/reoxygenation (OGD/R) model in vitro. The expression of Ski was proved to be up-regulated in OGD/R model. Meanwhile, Up-regulation of Ski was accompanied with high ratio of EdU (+) cells and up-expression of related proteins including GFAP, PCNA, CDK4, and CyclinD1, which demonstrated the distinct activation and proliferation of astrocytes after stimulation by OGD/R. Astrocytes were transfected with Ski-specific siRNA to knockdown Ski expression and subsequently attenuated OGD-induced astrocyte proliferation. Our results also showed that Ski down-regulation could suppress the activity of the Ras-Raf-ERK1/2 signaling pathway. Together, knockdown of Ski can effectively inhibit the proliferation of reactive astrogliosis via suppressing the Ras-Raf-ERK1/2 pathway. These findings indicated that maybe Ski is a promising therapeutic target for cerebral ischemic injury.

Knockdown of Ski decreased the reactive astrocytes proliferation in vitro induced by oxygen-glucose deprivation/reoxygenation.

Excision repair cross-complementing 1 (ERCC1) gene encodes ERCC1 protein, which is mainly responsible for the repair of DNA damage in different diseases including coronary artery atherosclerosis by acting as a rate-limiting element in nucleotide excision repair (NER). Using a three-stage case-control study with 3037 coronary artery disease (CAD) patients and 3002 controls, we investigated associations of three single nucleotide polymorphisms (SNPs) with CAD risk and severity of coronary artery atherosclerosis in Chinese Han population. In the discovery set, the variant allele T of rs11615 was significantly associated with higher CAD risk (adjusted OR = 1.27, P = 0.006) and severity of coronary artery atherosclerosis (adjusted OR = 1.54, P = 0.003). These associations were more remarkable in the merged set (adjusted OR = 1.23, P = 8 × 10−6 for CAD risk; adjusted OR = 1.36, P = 4.3 × 10−5 for severity of coronary artery atherosclerosis). And the expression level of ERCC1 was significantly higher in CAD cases than controls. Multiplicative interactions among SNP rs11615, alcohol drinking, history of T2DM, and history of hyperlipidemia could increase 5.06-fold risk of CAD (P = 1.59 × 10−9). No significant association of rs2298881 and rs3212986 with CAD risk was identified. Taken together, SNP rs11615 in ERCC1 gene might confer susceptibility to CAD and severity of coronary atherosclerosis in a Chinese Han population.

/pdf/polymorphism-in-ercc1-confers-susceptibility-of-coronary-5ergzkg390.pdf

Polymorphism in ERCC1 confers susceptibility of coronary artery disease and severity of coronary artery atherosclerosis in a Chinese Han population

The xeroderma pigmentosum group F (XPF) gene participates in the pathophysiological process of ischemic stroke, and XPF polymorphisms might be associated with ischemic stroke susceptibility. This study aimed to investigate XPF messenger RNA (mRNA) levels in peripheral blood mononuclear cells and protein levels in plasma and to analyze the 30028T/C polymorphism (rs1799801) in ischemic stroke patients and controls. Levels of both mRNA and protein in ischemic stroke patients were significantly lower than in controls (P < 0.05). The C allele of the 30028T/C polymorphism significantly increased the risk of ischemic stroke (OR = 1.512, 95 % CI = 1.219–1.875). The CT and CC/CT genotypes of 30028T/C were observed significantly more frequently in ischemic stroke patients than in controls (CT: OR = 1.916, 95 % CI = 1.446–2.539; CC/CT: OR = 1.877, 95 % CI = 1.427–2.468). Similar results were obtained after adjusting for age, gender, and smoking status. Additionally, XPF plasma protein levels were significantly decreased in the CC/CT genotype compared with the TT genotype (P = 0.025). These data indicate that XPF might play an important role in the pathophysiological process of ischemic stroke, and the 30028T/C polymorphism might be associated with ischemic stroke susceptibility in a Chinese Han population.

Association of XPF Levels and Genetic Polymorphism with Susceptibility to Ischemic Stroke

Tea polyphenols increase X-ray repair cross-complementing protein 1 and apurinic/apyrimidinic endonuclease/redox factor-1 expression in the hippocampus of rats during cerebral ischemia/reperfusion injury.

To study the effects of excision repair cross-complementing 1 (ERCC1) on the pathophysiological process of brain ischemia, we examined the changes in ERCC1 expression, as well as the functional significance of ERCC1 in the rat brain following middle cerebral artery occlusion (MCAO). The results were as follows: (1) ERCC1 immunopositive cells were widely distributed in various brain regions. ERCC1 expression was localized to the nuclei of neurons and astrocytes. (2) ERCC1 expression, as determined by western blot, increased at 3 days, remaining until 14 days, in the ipsilateral cortex and striatum following MCAO. Immunohistochemical analysis demonstrated that ischemia induced increased ERCC1 expression within the periinfarct core, with increasingly less expression toward the core. (3) Knockdown of ERCC1 expression by intraventricular injection of antisense plasmids increased DNA damage and infarct volume in the ischemic brain. (4) ERCC1 overproduction, by injection of expression plasmids, significantly reduced infarct volume and the accumulation of DNA-damaged neurons. Taken together, these results indicate that both endogenous ERCC1 and exogenous ERCC1 have an important neuroprotective function in the brain. In addition, administration of ERCC1 to the brain could prove to be a successful strategy for neuronal protection against ischemic injury.

Excision repair cross-complementing 1 expression protects against ischemic injury following middle cerebral artery occlusion in the rat brain.

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Excision repair cross-complementing 1 expression protects against ischemic injury following middle cerebral artery occlusion in the rat brain.