BackgroundLimb remote ischemic preconditioning (RIPC) protects against brain injury induced by stroke, but the underlying protective mechanisms remain unknown. As hypoxia inducible factor 1α (HIF‐1α) is neuroprotective in stroke and mediates neuroinflammation, we tested the hypothesis that HIF‐1α is a key factor of RIPC against stroke by mediating inflammation.Methods and ResultsStroke was induced by transient middle cerebral artery occlusion in rats, and RIPC was conducted in both hind limbs. The HIF‐1α mRNA was examined by quantitative reverse transcription polymerase chain reaction after RIPC. In addition, inflammatory cytokines in the peripheral blood and brain were measured using the AimPlex multiplex immunoassays. Data showed that RIPC reduced the infarct size, improved neurological functions, and increased HIF‐1α mRNA levels, interleukin (IL)‐4, and IL‐10 protein levels in the peripheral blood. Intraperitoneal injection of the HIF activator, dimethyloxaloylglycine, reduced the infarct size and inhibited interferon‐γ protein levels, while promoting IL‐4 and IL‐10 protein levels, while decreasing interferon‐γ protein levels in both the peripheral blood and ischemic brain. In addition, injection of dimethyloxaloylglycine had a synergistic effect with RIPC on reducing infarction and improving neurological functions, as well as decreasing interferon‐γ in the peripheral blood and ischemic brain. In contrast, injection of the HIF inhibitor, acriflavine hydrochloride, abolished the protective effects of RIPC on infarction, and reduced IL‐4 and IL‐10 protein levels in both the peripheral blood and ischemic brain.ConclusionsWe conclude that HIF‐1α plays a key role in RIPC, likely mediated by a systemic modulation of the inflammatory response.
Circular RNAs (circRNAs) have been demonstrated to act as microRNA (miRNA) sponges and they play important roles in regulating gene expression through a circRNA-miRNA-gene pathway. The specific roles of circRNAs in the pathogenesis of cerebral ischemia, however, are still unclear. Thus, the aim of this study is to determine circRNA expression profiles in the ischemic brain after stroke, which was induced by 45 min of transient middle cerebral artery occlusion (MCAO). The results from the circRNA microarrays revealed that 1027 circRNAs were significantly altered 48 hours after reperfusion in the ischemic brain compared with the sham group. Among them, 914 circRNAs were significantly upregulated, and the remaining 113 were significantly downregulated. In addition, the expressions of the three selected circRNAs, mmu_circRNA_40001, mmu_circRNA_013120, and mmu_circRNA_40806, were verified using quantitative real-time polymerase chain reaction (qRT-PCR). After predicting their target genes, the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses were further used to predict the associated significant cell signaling pathways and functions. The results show that the most enriched pathways are associated with the Rap1 signaling pathway and the Hippo signaling pathway, which regulate cell survival and death. Finally, we constructed an interaction network of circRNA-miRNA-target genes, including 13 miRNAs and their corresponding genes, indicating that changes in circRNA are associated with genes related with brain injury and recovery. In conclusion, circRNAs are complicated in the pathological development of brain injury after stroke, suggesting novel diagnostic and therapeutic targets for stroke therapy.
Macrophages that differentiate from precursor monocytes can be polarized into a classically activated (M1) or alternatively activated (M2) status depending on different stimuli. Generally, interferon (IFN)-γ and lipopolysaccharide (LPS) are considered the classical stimuli with which to establish M1 polarization. IFN regulatory factor (IRF)1 and IFN-β are two crucial molecules involved in IFN-γ- and LPS-initialed signaling. However, the association between IRF1 and IFN-β in the context of the M1 polarization of macrophages is not yet fully understood. In this study, we demonstrate that U937-derived macrophages, in response to IFN-γ and LPS stimulation, readily acquire an M1 status, indicated by the increased expression of interleukin (IL)-12, IL-6, IL-23, tumor necrosis factor (TNF)-α and the M1-specific cell surface antigen, CD86, and the decreased expression of the M2-specific mannose receptor, CD206. However, the knockdown of IRF1 in U937-derived macrophages led to an impaired M1 status, as indicated by the decreased expression of the above-mentioned M1 markers, and the increased expression of the M2 markers, CD206 and IL-10. A similar phenomenon was observed in the M1 macrophages in which IFN-β was inhibited. Furthermore, we demonstrated that IRF1 and IFN-β may interact with each other in the IFN-γ- and LPS-initiated signaling pathway, and contribute to the IRF5 regulation of M1 macrophages. In addition, the conditioned medium collected from the M1 macrophages in which IRF1 or IFN-β were inhibited, exerted pro-tumor effects on the HepG2 and SMMC-7721 cells, as indicated by an increase in proliferation, the inhibition of apoptosis and an enhanced invasion capability. The findings of our study suggest that the interactions of IRF1, IFN-β and IRF5 are involved in the M1 polarization of macro phages and have antitumor functions. These data may provide a novel antitumor strategy for targeted cancer therapy.
J. Neurochem. (2012) 120, 830–841. Abstract We previously reported the involvement of conventional protein kinase C (cPKC) βII, γ, novel PKC (nPKC) ε and their interacting proteins in hypoxic pre‐conditioning (HPC)‐induced neuroprotection. In this study, the large‐scale miRNA microarrays and bioinformatics analysis were used to determine the differentially expressed miRNAs and their PKC‐isoform specific gene network in mouse brain after HPC and 6 h middle cerebral artery occlusion (MCAO). We found 4 up‐regulated and 13 down‐regulated miRNAs in the cortex of HPC mice, 26 increased and 39 decreased gene expressions of miRNAs in the peri‐infarct region of 6 h MCAO mice, and 11 up‐regulated and 22 down‐regulated miRNAs in the peri‐infarct region of HPC and 6 h MCAO mice. Based on Diff Score, 19 differentially expressed miRNAs were identified in HPC and 6 h MCAO mouse brain. Then the miRNA‐gene‐network of 19 specified miRNAs target genes of cPKCβII, γ and nPKCε‐interacting protein was predicted by using bioinformatics analysis of genome databases. Furthermore, the down‐regulated miR‐615‐3p during HPC had a detrimental effect on the oxygen‐glucose deprivation (OGD)‐induced N2A cell injury. These results suggested that the identified 19 miRNAs, notably miR‐615‐3p, might target these genes of cPKCβII, γ and nPKCε‐interacting proteins involved in HPC‐induced neuroprotection.
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