Postconditioning inhibits myocardial apoptosis during prolonged reperfusion via a JAK2-STAT3-Bcl-2 pathway

<p>Abstract</p> <p>Background</p> <p>Postconditioning (PostC) inhibits myocardial apoptosis after ischemia-reperfusion (I/R) injury. The JAK2-STAT3 pathway has anti-apoptotic effects and plays an essential role in the late protection of preconditioning. Our aim was to investigate the anti-apoptotic effect of PostC after prolonged reperfusion and the role of the JAK2-STAT3 pathway in the anti-apoptotic effect of PostC.</p> <p>Methods</p> <p>Wistar rats were subjected to 30 minutes ischemia and 2 or 24 hours (h) reperfusion, with or without PostC (three cycles of 10 seconds reperfusion and 10 seconds reocclusion at the onset of reperfusion). Separate groups of rats were treated with a JAK2 inhibitor (AG490) or a PI3K inhibitor (wortmannin) 5 minutes before PostC. Immunohistochemistry was used to analyze Bcl-2 protein levels after reperfusion. mRNA levels of Bcl-2 were detected by qRT-PCR. TTC staining was used to detect myocardial infarction size. Myocardial apoptosis was evaluated by TUNEL staining. Western-blot was used to detect p-STAT3 and p-Akt levels after reperfusion.</p> <p>Results</p> <p>There was more myocardial apoptosis at 24 h <it>vs </it>2 h after reperfusion in all groups. PostC significantly reduced myocardial apoptosis and elevated Bcl-2 levels at both 2 and 24 hours after reperfusion. PostC increased p-STAT3 and p-Akt levels after reperfusion. Administration of AG490 reduced p-STAT3 and p-Akt levels and attenuated the anti-apoptotic effect of PostC. Wortmannin also reduced p-Akt levels and attenuated the anti-apoptotic effect of PostC but had no effect on p-STAT3 levels. AG490 abrogated the up-regulation of Bcl-2 by PostC.</p> <p>Conclusion</p> <p>PostC may reduce myocardial apoptosis during prolonged reperfusion via a JAK2-STAT3-Bcl-2 pathway. As a downstream target of JAK2 signaling, activation of PI3K/Akt pathway may be necessary in the protection of PostC.</p

An Advancing GCT-Inception-ResNet-V3 Model for Arboreal Pest Identification

The significance of environmental considerations has been highlighted by the substantial impact of plant pests on ecosystems. Addressing the urgent demand for sophisticated pest management solutions in arboreal environments, this study leverages advanced deep learning technologies to accurately detect and classify common tree pests, such as “mole cricket”, “aphids”, and “Therioaphis maculata (Buckton)”. Through comparative analysis with the baseline model ResNet-18 model, this research not only enhances the SE-RegNetY and SE-RegNet models but also introduces innovative frameworks, including GCT-Inception-ResNet-V3, SE-Inception-ResNet-V3, and SE-Inception-RegNetY-V3 models. Notably, the GCT-Inception-ResNet-V3 model demonstrates exceptional performance, achieving a remarkable average overall accuracy of 94.59%, average kappa coefficient of 91.90%, average mAcc of 94.60%, and average mIoU of 89.80%. These results signify substantial progress over conventional methods, outperforming the baseline model’s results by margins of 9.1%, nearly 13.7%, 9.1%, and almost 15% in overall accuracy, kappa coefficient, mAcc, and mIoU, respectively. This study signifies a considerable step forward in blending sustainable agricultural practices with environmental conservation, setting new benchmarks in agricultural pest management. By enhancing the accuracy of pest identification and classification in agriculture, it lays the groundwork for more sustainable and eco-friendly pest control approaches, offering valuable contributions to the future of agricultural protection

Therapeutic Efficacy of Alpha-Lipoic Acid against Acute Myocardial Infarction and Chronic Left Ventricular Remodeling in Mice

Background. We hypothesized that daily administration of a potent antioxidant (α-lipoic acid: ALA) would protect the heart against both acute myocardial infarction (AMI) and left ventricular remodeling (LVR) post-AMI. Methods and Results. Two separate studies were conducted. In the AMI study, C57Bl/6 mice were fed ALA daily for 7 d prior to a 45-minute occlusion of the left coronary artery (LCA). Mean infarct size in control mice (fed water) was 60 ± 2%. Mean infarct size in ALA-treated mice was 42 ± 3% in the 15 mg/kg·d group and 39 ± 3% in the 75 mg/kg·d group (both P<0.05 vs. control). In the LVR study, AMI increased LV end-systolic volume (LVESV) and reduced LV ejection fraction (LVEF) to a similar extent in both groups when assessed by cardiac MRI 1 day after a 2-hour LCA occlusion. Treatment with ALA (75 mg/kg·d) or H2O was initiated 1 day post-AMI and continued until study’s end. Both LVESV and LVEF in ALA-treated mice were significantly improved over control when assessed 28 or 56 days post-AMI. Furthermore, the survival rate in ALA-treated mice was 63% better than in control mice by 56 days post-AMI. Conclusions. Daily oral ingestion of ALA not only protects mice against AMI but also attenuates LVR and preserves contractile function in the months that follow

Atorvastatin at Reperfusion Reduces Myocardial Infarct Size in Mice by Activating eNOS in Bone Marrow-Derived Cells

<div><p>Background</p><p>The current study was designed to test our hypothesis that atorvastatin could reduce infarct size in intact mice by activating eNOS, specifically the eNOS in bone marrow-derived cells. C57BL/6J mice (B6) and congenic eNOS knockout (KO) mice underwent 45 min LAD occlusion and 60 min reperfusion. Chimeric mice, created by bone marrow transplantation between B6 and eNOS KO mice, underwent 40 min LAD occlusion and 60 min reperfusion. Mice were treated either with vehicle or atorvastatin in 5% ethanol at a dose of 10 mg/kg IV 5 min before initiating reperfusion. Infarct size was evaluated by TTC and Phthalo blue staining.</p><p>Results</p><p>Atorvastatin treatment reduced infarct size in B6 mice by 19% (p<0.05). In eNOS KO vehicle-control mice, infarct size was comparable to that of B6 vehicle-control mice (p = NS). Atorvastatin treatment had no effect on infarct size in eNOS KO mice (p = NS). In chimeras, atorvastatin significantly reduced infarct size in B6/B6 (donor/recipient) mice and B6/KO mice (p<0.05), but not in KO/KO mice or KO/B6 mice (p = NS).</p><p>Conclusions</p><p>The results demonstrate that acute administration of atorvastatin significantly reduces myocardial ischemia/reperfusion injury in an eNOS-dependent manner, probably through the post-transcriptional activation of eNOS in bone marrow-derived cells.</p></div

Adenosine 2B Receptor Activation Reduces Myocardial Reperfusion Injury by Promoting Anti-Inflammatory Macrophages Differentiation via PI3K/Akt Pathway

Background. Activation of the adenosine A2B receptor (A2BR) can reduce myocardial ischemia/reperfusion (IR) injury. However, the mechanism underlying the A2BR-mediated cardioprotection is less clear. The present study was designed to investigate the potential mechanisms of cardioprotection mediated by A2BR. Methods and Results. C57BL/6 mice underwent 40-minute ischemia and 60-minute reperfusion. ATL-801, a potent selective A2BR antagonist, could not block ischemic preconditioning induced protection. BAY 60-6583, a highly selective A2BR agonist, significantly reduced myocardial infarct size, and its protective effect could be blocked by either ATL-801 or wortmannin. BAY 60-6583 increased phosphorylated Akt (p-Akt) levels in the heart at 10 min of reperfusion, and this phosphorylation could also be blocked by ATL-801 or wortmannin. Furthermore, BAY 60-6583 significantly increased M2 macrophages and decreased M1 macrophage and neutrophils infiltration in reperfused hearts, which also could be blocked by wortmannin. Meanwhile, confocal imaging studies showed that the majority of Akt phosphorylation in the heart was colocalized to CD206+ cells in both control and BAY 60-6583 pretreated hearts. Conclusion. Our results indicated that pretreatment with BAY 60-6583 protects the heart against myocardial IR injury by its anti-inflammatory effects, probably by modulating macrophages phenotype switching via a PI3K/Akt pathway

Blood cell differentials in B6 (Panel A) and eNOS KO (Panel B) mice.

<p>Blood samples were acquired before ischemia (open bar) and after 45 min of LAD occlusion and 60 min of reperfusion (black or shaded bars). At baseline, hemoglobin, WBC and platelets were comparable between B6 and eNOS KO mice; however, the white cell differentials showed significantly higher lymphocytes in eNOS KO mice. In B6 mice, LAD occlusion and reperfusion caused a 40–50% reduction in total circulating white blood cells and a 50–60% reduction in circulating lymphocytes. In contrast, the neutrophil count nearly doubled after ischemia/reperfusion in B6 mice, but this negative effect was essentially abolished atorvastatin when administered just prior to the onset of reperfusion.</p

Acute Hyperglycemia Abolishes Ischemic Preconditioning by Inhibiting Akt Phosphorylation: Normalizing Blood Glucose before Ischemia Restores Ischemic Preconditioning

This study examined the hypothesis that acute hyperglycemia (HG) blocks ischemic preconditioning (IPC) by inhibiting Akt phosphorylation. Brief HG of approximately 400 mg/dL was induced in C57BL/6 mice via intraperitoneal injection of 20% dextrose (2 g/kg). All mice underwent 40 min LAD occlusion and 60 min reperfusion. The IPC protocol was 2 cycles of 5 min ischemia and 5 min reperfusion prior to index ischemia. Results. In control mice, infarct size (IF) was 51.7 ± 2.0 (% risk region). Preconditioning reduced IF by 50% to 25.8 ± 3.2 ( versus control). In HG mice, IF was significantly exacerbated to 58.1 ± 2.3. However, the effect of IPC completely disappeared in HG mice. Normalization of blood glucose with insulin 5 min before IPC recovered the cardioprotective effect. Administration of CCPA before index ischemia mimicked IPC effect. The cardioprotective effect of CCPA, not its chronotropic effect, completely disappeared in HG mice. Phosphorylation of cardiac tissue Akt before index ischemia was enhanced by IPC or CCPA but was significantly inhibited by HG in both groups. Normalization of glucose with insulin reversed the inhibition of Akt phosphorylation by HG. Conclusion. HG abolishes the cardioprotective effect of preconditioning by inhibiting Akt phosphorylation. Normalization of blood glucose with insulin suffices to recover the cardioprotective effect of preconditioning

Myocardial infarct size in wild type and congenic eNOS KO mice.

<p>Myocardial infarct size (as percentage of risk region) was measured after 45 min of LAD occlusion and 60 min of reperfusion. Vehicle or atorvastatin was administered 5 min prior to the onset of reperfusion. Infarct size was significantly smaller in atorvastatin-treated B6 mice than in vehicle-treated B6 controls or either group of eNOS KO mice (p<0.05).</p

Animal groups and protocols.

<p>I/R: ischemia/reperfusion, B6: C57BL/6, KO: eNOS knockout, CBC: complete blood count, IF: infarct size, IHC: immunohistochemistry. Atorvastatin was given intravenously 5 min before reperfusion at a dose of 10 mg/Kg.</p><p>Animal groups and protocols.</p