Understanding the molecular mechanism of cerebral hypoxic preconditioning (HPC)-induced endogenous neuroprotection may provide potential therapeutic targets for ischemic stroke. By using bioinformatics analysis, we found that miR-181b, one of 19 differentially expressed miRNAs, may target aconitate hydratase (ACO2), heat shock protein A5 (HSPA5), and ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL1) among 26 changed protein kinase C isoform-specific interacting proteins in HPC mouse brain. In this study, the role of miR-181b in oxygen-glucose deprivation (OGD)-induced N2A cell ischemic injury in vitro and mouse middle cerebral artery occlusion (MCAO)-induced cerebral ischemic injury in vivo, and its regulation of ACO2, HSPA5, and UCHL1 were further determined. We found that miR-181b expression levels significantly decreased in mouse brain following MCAO and in OGD-treated N2A cells. Up- and downregulation of miR-181b by transfection of pre- or anti-miR-181b could negatively regulate HSPA5 and UCHL1 (but not ACO2) protein levels as well as N2A cell death and programmed cell death in OGD-treated N2A cells. By using a T7 promoter-driven control dual luciferase assay, we confirmed that miR-181b could bind to the 3'-untranslated rergions of HSPA5 and UCHL1 mRNAs and repress their translations. miR-181b antagomir reduced caspase-3 cleavage and neural cell loss in cerebral ischemic cortex and improved neurological deficit of mice after MCAO. In addition, HSPA5 and UCHL1 short interfering RNAs (siRNAs) blocked anti-miR-181b-mediated neuroprotection against OGD-induced N2A cell injury in vitro. These results suggest that the downregulated miR-181b induces neuroprotection against ischemic injury through negatively regulating HSPA5 and UCHL1 protein levels, providing a potential therapeutic target for ischemic stroke.
Background/Aims: To explore the relationship between hydrogen sulfide (H2S) and uremic accelerated atherosclerosis (UAAS) in chronic hemodialysis patients with diabetic nephropathy (CHD/DN). Methods: A total of 36 CHD/DN and 32 chronic hemodialyzed non-diabetic patients with chronic glomerulonephritis (CHD/non-DN) were studied. Plasma H2S was measured with a sulfide sensitive electrode. Results: Plasma H2S in CHD/DN was significantly lower than that in CHD/non-DN patients. Plasma H2S was positively correlated with plasma TGF-β1, and negatively correlated with MMP-12 in CHD/DN patients. CHD/DN patients exhibited higher CCA-IMT, hsCRP, and lower H2S levels than in CHD/non-DN patients. Moreover, in CHD/DN patients, CCA-IMT was negatively correlated with plasma H2S, and positively correlated with hsCRP and LDL. On multiple regression analysis, H2S levels exhibited independent association with IMT in CHD/DN patients. Conclusions: These findings suggest possible linkage between H2S metabolism and TGF-β/Smad signaling pathway modulation abnormalities that may contribute to the development of UAAS in CHD/DN patients.
Prostate cancer (PCa) is a common malignant tumor and the second leading cause of morbidity and mortality in men worldwide. Considering the prevalence and effects of PCa in males, an understanding of the molecular mechanisms underlying PCa tumorigenesis are essential and may provide novel therapeutic strategies for treating PCa. Bloom syndrome protein (BLM) is a member of the RecQ helicase family. The major function of BLM is to uncoil the double-stranded DNA structure. It has previously been demonstrated that BLM acts as a ‘genome caretaker’, and dysregulation of BLM function has been implicated in the development of multiple tumor types; however, its potential for inducing PCa tumorigenesis remains undetermined. The present study aimed to explore the function of BLM in PCa progression. Reverse transcription-polymerase chain reaction, immunohistochemistry and western blot analyses were performed to detect the BLM expression pattern in PCa patients and cell lines. The proliferation, and migration and invasion capacities of prostate cells were determined by EdU and Transwell assays following transfection with BLM-targeting short hairpin RNA (shRNA). The expression of BLM was significantly increased in PCa tissues and PC3 cells compared with non-PCa tissues and benign prostatic hyperplasia cells. Knockdown of BLM via shRNA inhibited PCa cell proliferation, and promoted PCa cell apoptosis. Notably, reducing the expression of BLM had no effect on the migration or invasive abilities of PCa cells. These results suggest that downregulation of BLM may alleviate PCa development, providing a novel perspective for PCa tumorigenesis and a potential therapeutic target for PCa.
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