Background: Inflammation and apoptosis are considered to be two main factors affecting ischemic brain injury and the subsequent reperfusion damage. MiR-19a-3p has been reported to be a possible novel biomarker in ischemic stroke. However, the function and molecular mechanisms of miR-19a-3p remain unclear in cerebral ischemia/reperfusion (I/R) injury. Methods: The I/R injury model was established in vivo by middle cerebral artery occlusion/reperfusion (MCAO/R) in rats and in vitro by oxygen-glucose deprivation and reperfusion (OGD/R) induced SH-SY5Y cells. The expression of miR-19a-3p was determined by reverse transcription quantitative PCR. The infarction volumes, Neurological deficit scores, apoptosis, cell viability, pro-inflammatory cytokines and apoptosis were evaluated using Longa score, Bederson score, TTC, TUNEL staining, CCK-8, ELISA, flow cytometry assays. Luciferase reporter assay was utilized to validate the target gene of miR-19a-3p. Results: We first found miR-19a-3p was significantly up-regulated in rat I/R brain tissues and OGD/R induced SH-SY5Y cells. Using the in vivo and in vitro I/R injury model, we further demonstrated that miR-19a-3p inhibitor exerted protective role against injury to cerebral I/R, which was reflected by reduced infarct volume, improved neurological outcomes, increased cell viability, inhibited inflammation and apoptosis. Mechanistically, miR-19a-3p binds to 3′UTR region of IGFBP3 mRNA. Inhibition of miR-19a-3p caused the increased expression of IGFBP3 in OGD/R induced SH-SY5Y cells. Furthermore, we showed that IGFBP3 overexpression imitated, while knockdown reversed the protective effects of miR-19a-3p inhibitor against OGD/R-induced injury. Conclusions: In summary, our findings showed miR-19a-3p regulated I/R-induced inflammation and apoptosis through targeting IGFBP3, which might provide a potential therapeutic target for cerebral I/R injury.
DNA replication fidelity is a critical issue in molecular biology. Biochemical experiments have provided key insights on the mechanism of fidelity control by DNAP in the past decades, whereas systematic theoretical studies on this issue began only recently. Because of the underlying difficulties of mathematical treatment, comprehensive surveys on the template-specific replication kinetics are still rare. Here we proposed a first-passage approach to address this problem, in particular the positional fidelity, for complicated processes with high-order neighbor effects. Under biologicallyrelevant conditions, we derived approximate analytical expressions of the positional fidelity which shows intuitively how some key kinetic pathways are coordinated to guarantee the high fidelity, as well as the high velocity, of the replication processes. It was also shown that the fidelity at any template position is dominantly determined by the nearest-neighbor template sequences, which is consistent with the idea that replication mutations are randomly distributed in the genome.
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