Exploring anesthetic-induced gene expression changes and immune cell dynamics in atrial tissue post-coronary artery bypass graft surgery.

Background: This study leverages the GSE4386 dataset, obtained from atrial tissue samples post-coronary artery bypass graft (CABG) surgery, to investigate the impact of anesthetic agents (sevoflurane and propofol) on gene expression and immune cell infiltration. Methods: Hierarchical clustering and box plots were employed for dataset preprocessing, highlighting a significant outlier (sample GSM99282), subsequently removed to ensure data integrity. Differentially expressed genes (DEGs) were identified using volcano plots based on specific log-fold-change and P-value thresholds. Additional analyses included the Friends approach, Spearman's correlation, and gene set enrichment analysis (GSEA), exploring functional annotations and pathways. Results: Heatmaps and bubble plots depicted DEGs, revealing distinct expression patterns between the sevoflurane and propofol groups. Friends analysis identified top genes based on log fold changes, further correlated using Spearman's method. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses illustrated functional annotations of DEGs, while GSEA highlighted enriched biological categories. Immune cell infiltration analysis showcased varied cellular presence post-CABG. ESTIMATE algorithm scores demonstrated differences in immune, stroma, and estimate scores. Microenvironment Cell Populations-counter (MCPcounter) revealed an increased abundance of cytotoxic lymphocytes in the sevoflurane group, confirmed by a single sample GSEA. CIBERSORT algorithm identified distinct immune cell compositions, highlighting differences in macrophage M0 prevalence between sevoflurane and propofol groups. Conclusions: This comprehensive analysis provides insights into anesthetic-induced gene expression changes and immune cell dynamics in atrial tissue post-CABG surgery. The identified DEGs and immune cell compositions offer potential biomarkers and therapeutic targets for refining anesthetic strategies in cardiac surgeries.

Understanding the heterogeneity in liver hepatocellular carcinoma with a special focus on malignant cell through single-cell analysis.

INTRODUCTION: Hepatocellular carcinoma (HCC) is the most common form of liver cancer globally and remains a major cause of cancer-related deaths. HCC exhibits significant intra-tumoral and interpatient heterogeneity, impacting treatment efficacy and patient prognosis. METHODS: We acquired transcriptome data from the TCGA and ICGC databases, as well as liver cancer chip data from the GEO database, and processed the data for subsequent analysis. We also obtained single cell data from the GEO database and performed data analysis using the Seurat package. To further investigate epithelial cell subgroups and their copy number variations, we used the Seurat workflow for subgroup classification and the InferCNV software for CNV analysis, utilizing endothelial cells as a reference. Pseudo-time analysis and transcription factor analysis of epithelial cells were performed using the monocle2 and SCENIC software, respectively. To assess intercellular communication, we employed the CellChat package to identify potential ligand-receptor interactions. We also analyzed gene expression differences and conducted enrichment analysis using the limma and clusterProfiler packages. Additionally, we established tumor-related risk characteristics using Cox analysis and Lasso regression, and predicted immunotherapy response using various datasets. RESULTS: The samples were classified into 23 clusters, with malignant epithelial cells being the majority. Trajectory analysis revealed the differentiation states of the malignant epithelial cells, with cluster 1 being in the terminal state. Functional analysis revealed higher aggressiveness and epithelial-mesenchymal transition (EMT) scores in cluster 1, indicating a higher propensity for metastasis. RBP4+ tumor cells were highly enriched with hypoxia process and intensive cell-to-cell communication. A prognostic model was established, and immune infiltration analysis showed increased infiltration in the high-risk group. TP53 demonstrated significant differences in mutation rate between the two risk groups. Validation analysis confirmed the up-regulation of model genes, including AKR1B10, ARL6IP4, ATP6V0B, and BSG in tumor tissues. CONCLUSION: A prognostic model was established based on HCC malignant cell associated gene signature, displaying decent prognosis guiding effectiveness in the multiple cohorts. The study provided comprehensive insights into the heterogeneity and potential therapeutic targets of LIHC.

Cardiac injury activates STING signaling via upregulating SIRT6 in macrophages after myocardial infarction.

AIMS: This work sought to investigate the mechanism underlying the STING signaling pathway during myocardial infarction (MI), and explore the involvement and the role of SIRT6 in the process. MAIN METHODS: Mice underwent the surgery of permanent left anterior descending (LAD) artery constriction. Primary cardiomyocytes (CMs) and fibroblasts were subjected to hypoxia to mimic MI in vitro. STING expression was assessed in the infarct heart, and the effect of STING inhibition on cardiac fibrosis was explored. This study also evaluated the regulatory effect of STING by SIRT6 in macrophages. KEY FINDINGS: STING protein was increased in the infarct heart tissue, highlighting its involvement in the post-MI inflammatory response. Hypoxia-induced death of CMs and fibroblasts contributed to the upregulation of STING in macrophages, establishing the involvement of STING in the intercellular signaling during MI. Inhibition of STING resulted in a significant reduction of cardiac fibrosis at day 14 after MI. Additionally, this study identified SIRT6 as a key regulator of STING via influencing its acetylation and ubiquitination in macrophages, providing novel insights into the posttranscriptional modification and expression of STING at the acute phase after myocardial infarction. SIGNIFICANCE: This work shows the key role of SIRT6/STING signaling in the pathogenesis of cardiac injury after MI, suggesting that targeting this regulatory pathway could be a promising strategy to attenuate cardiac fibrosis after MI.

Akt2 deficiency alleviates oxidative stress in the heart and liver via up-regulating SIRT6 during high-fat diet-induced obesity.

The present study aims to investigate the role of AKT2 in the pathogenesis of hepatic and cardiac lipotoxicity induced by lipid overload-induced obesity and identify its downstream targets. WT and Akt2 KO mice were fed either normal diet, or high-fat diet (HFD) to induce obesity model in vivo. Human hepatic cell line (L02 cells) and neonatal rat cardiomyocytes (NRCMs) were used as in vitro models. We observed that during HFD-induced obesity, Akt2 loss-of-function mitigated lipid accumulation and oxidative stress in the liver and heart tissue. Mechanistically, down-regulation of Akt2 promotes SIRT6 expression in L02 cells and NRCMs, the latter deacetylates SOD2, which promotes SOD2 activity and therefore alleviates oxidative stress-induced injury of hepatocytes and cardiomyocytes. Furthermore, we also proved that AKT2 inhibitor protects hepatocytes and cardiomyocytes from HFD-induced oxidative stress. Therefore, our work prove that AKT2 plays an important role in the regulation of obesity-induced lipid metabolic disorder in the liver and heart. Our study also indicates AKT2 inhibitor as a potential therapy for obesity-induced hepatic and cardiac injury.

Plerixafor may treat intractable post-herpetic neuralgia.

Varicella-zoster virus (VZV) causes varicella (chicken pox) and establishes latency in ganglia. A reactivation of latent VZV leads to herpes zoster (shingles). Herpes zoster often causes herpetic pain that can last for months or years after the rash has healed. Prolonged herpetic pain is defined as post-herpetic neuralgia (PHN). There is an unmet need to explore novel therapeutic approaches for intractable PHN. Postmortem studies have shown that VZV induces neuro-inflammation and damage to the ganglia and spinal cord. These pathological changes may be critical factors resulting in PHN. Accumulated evidence suggests that stem cells may alleviate neuropathic pain in animal models through immunomodulatory actions and neuronal repair. Unfortunately, exogenous stem cell transplantation has limited clinical use due to safety concerns, immune rejection, and complications. Pharmacological mobilization of endogenous bone marrow stem cells may overcome these obstacles. Plerixafor is a SDF-1/CXCR4 axis blocker which can stimulate the release of stem cells from the bone marrow into blood circulation. We propose a hypothesis that endogenous stem cells mobilized by plerixafor may relieve the symptoms of PHN. If so, it may represent a novel approach for the treatment of intractable PHN.