Search Results (3)

Background and Objective: Stroke poses a critical health issue without effective neuroprotection. We explore ischemic postconditioning’s (IPostC) potential to mitigate stroke-induced brain injury, focusing on its interaction with disulfidptosis, a novel cell death pathway marked by protein disulfide accumulation. We aim to clarify IPostC’s protective mechanisms against stroke through gene sequencing and experimental analysis in mice. Methods: Through our initial investigation, we identified 27 disulfidptosis-related genes (DRGs) and uncovered their interactions. Additionally, differential gene analysis revealed 11 potential candidate genes that are linked to disulfidptosis, stroke, and IPostC. Our comprehensive study employed various analytical approaches, including machine learning, functional enrichment analysis, immune analysis, drug sensitivity analysis, and qPCR experiments, to gain insights into the molecular mechanisms underlying these processes. Results: Our study identified and expanded the list of disulfidptosis-related genes (DRGs) critical to stroke, revealing key genes and their interactions. Through bioinformatics analyses, including PCA, UMAP, and differential gene expression, we were able to differentiate the effects of stroke from those of postconditioning, identifying Peroxiredoxin 1 (PRDX1) as a key gene of interest. GSEA highlighted PRDX1’s involvement in protective pathways against ischemic damage, while its correlations with various proteins suggest a broad impact on stroke pathology. Constructing a ceRNA network and analyzing drug sensitivities, we explored PRDX1’s regulatory mechanisms, proposing novel therapeutic avenues. Additionally, our immune infiltration analysis linked PRDX1 to key immune cells, underscoring its dual role in stroke progression and recovery. PRDX1 is identified as a key target in ischemic stroke based on colocalization analysis, which revealed that PRDX1 and ischemic stroke share the causal variant rs17522918. The causal relationship between PRDX1-related methylation sites (cg02631906 and cg08483560) and the risk of ischemic stroke further validates PRDX1 as a crucial target. Conclusions: These results suggest that the DRGs are interconnected with various cell death pathways and immune processes, potentially contributing to IPostC regulating cell death mechanisms in stroke. Full article

Although the application of cardioprotective ischaemia/reperfusion (I/R) stimuli after myocardial infarction (MI) is a promising concept for salvaging the myocardium, translation to a clinical scenario has not fulfilled expectations. We have previously shown that in pigs, ischaemic postconditioning (IPostC) reduces myocardial oedema and microvascular obstruction (MVO), without influencing myocardial infarct size. In the present study, we analyzed the mechanisms underlying the IPostC-induced microvascular protection by transcriptomic analysis, followed by pathway analysis. Closed-chest reperfused MI was induced by 90 min percutaneous balloon occlusion of the left anterior descending coronary artery, followed by balloon deflation in anaesthetised pigs. Animals were randomised to IPostC (n = 8), MI (non-conditioned, n = 8), or Control (sham-operated, n = 4) groups. After three hours or three days follow-up, myocardial tissue samples were harvested and subjected to RNA-seq analysis. Although the transcriptome analysis revealed similar expression between IPostC and MI in transcripts involved in cardioprotective pathways, we identified gene expression changes responding to IPostC at the three days follow-up. Focal adhesion signaling, downregulated genes participating in cardiomyopathy and activation of blood cells may have critical consequences for microvascular protection. Specific analyses of the gene subsets enriched in the endothelium of the infarcted area, revealed strong deregulation of transcriptional functional clusters, DNA processing, replication and repair, cell proliferation, and focal adhesion, suggesting sustentative function in the endothelial cell layer protection and integrity. The spatial and time-dependent transcriptome analysis of porcine myocardium supports a protective effect of IPostC on coronary microvasculature post-MI. Full article

Autophagy participates in the progression of many diseases, comprising ischemia/ reperfusion (I/R). It is reported that it is involved in the protective mechanism of ischemic postconditioning (IPostC). According to research, neuronal nitric oxide synthase (nNOS) is also involved in the condition of I/R and IPostC. However, the relationship between nNOS, autophagy and IPostC has not been previously investigated. We hypothesize that IPostC promotes autophagy activity against I/R injury partially through nNOS-mediated pathways. Mouse hearts were subjected to I/R injury through the ligation of the left anterior descending coronary artery. H9c2 cells were subjected to hypoxia/reoxygenation (H/R) in vitro. IPostC, compared with I/R, restored nNOS activity, increased the formation of autophagosome and restored the impaired autophagic flux, thus autophagic activity was raised markedly. IPostC increased adenosine monophosphate-activated protein kinase (AMPK) phosphorylation and suppressed mammalian target of rapamycin (mTOR), but a selective nNOS inhibitor abolished those effects. Similar effects of IPostC were demonstrated in H9c2 cells in vitro. IPostC decreased infarct size and preserved most of the normal structure. The level of reactive oxygen species (ROS) and cell apoptosis were reduced by IPostC with improved cell viability and mitochondrial membrane potential. However, an autophagy inhibitor suppressed the protective effects. These results suggest that IPostC promoted autophagy against I/R injury at least partially via the activation of nNOS/AMPK/mTOR pathway. Full article