Korean Journal of Physiology & Pharmacology最新文献

BIS (Bcl-2-interacting cell death suppressor, or BAG-3), is a multifunctional co-chaperone that maintains protein quality control via autophagy and proteostasis. Following the central nervous system (CNS) injury, BIS expression is markedly upregulated in reactive astrocytes, suggesting a regulatory role of reactive astrogliosis. To investigate this, we generated astrocyte-specific BIS knockout (BIS-aKO) mice for the first time. While BIS-aKO mice exhibited normal growth and survival, the injury-induced upregulation of BIS expression was abolished in reactive astrocytes following excitotoxic injury. Using a photothrombotic stroke model, we found that astrocytic BIS deficiency resulted in significantly increased GFAP expression in scar-forming astrocytes at the infarct border and altered morphology in the peri-infarct region. Furthermore, we observed increased infiltration of amoeboid Iba1-positive cells in the astroglial scar, indicating enhanced neuroinflammation. Correlative light-and electron-microscopy following both stroke and stab wound injury revealed BIS-aKO astrocytes exhibited a greater density of intermediate filament filling in their soma and processes, along with relatively fewer cytoplasmic organelles, such as mitochondria. Collectively, these findings highlight a previously unrecognized role of BIS in modulating reactive gliosis during brain injury and our model provides a valuable tool for investigating the astrocyte-specific functions of BIS in CNS pathophysiology.

Recent interest in metabolically healthy obesity highlights the need to evaluate the relationship between adiposity and hematologic and metabolic biomarkers. With the increasing use of bioelectrical impedance analysis (BIA), measuring body composition, including percent body fat (PBF), has become more accessible. This study aimed to investigate the associations between PBF and hematologic and metabolic biomarkers related to cardiometabolic health. We conducted a retrospective, cross-sectional analysis using data from the 2023 Korea National Health and Nutrition Examination Survey (KNHANES-IX), which included BIA-based body composition metrics. A total of 5,518 adults with complete records and no predefined outliers were analyzed. Survey-weighted Pearson correlation coefficients were calculated by sex and age groups, followed by multiple linear regression adjusting for sex, age, and body weight. PBF was significantly associated with alanine transaminase (β = 1.06 per % PBF), hemoglobin (β = 0.02), hematocrit (β = 0.06), total cholesterol (β = 0.48), high-density lipoprotein cholesterol (β = -0.50), low-density lipoprotein cholesterol (β = 0.62), and triglyceride (β = 2.93). No significant association was found between PBF and aspartate transaminase. Notably, the associations of PBF with alanine transaminase and triglycerides varied by sex and age group. These findings suggest that PBF may be a useful non-invasive marker for assessing cardiometabolic risk, warranting further investigation in diverse populations.

Pulmonary fibrosis is a progressive and irreversible lung disease characterized by excessive fibroblast activation and extracellular matrix (ECM) deposition, leading to respiratory failure. Despite recent advances in understanding its molecular mechanisms, effective therapies remain limited. Circular RNAs have emerged as key regulators of gene expression, yet their role in pulmonary fibrosis is poorly understood. Here, we investigated circSmad4 and its therapeutic potential. Our results demonstrate that circSmad4 expression was markedly upregulated in bleomycininduced pulmonary fibrosis, suggesting a role in fibrotic progression. Silencing circ- Smad4 by siRNA significantly alleviated lung fibrosis, reducing lung weight, collagen deposition, and inflammatory cytokine expression. Mechanistically, we identified that circSmad4 exerted its pro-fibrotic effects through the miR-671-5p/Fgfr2 axis, suppressing miR-671-5p and increasing Fgfr2 expression, thereby enhancing fibroblast activation. Additionally, si-circSmad4 treatment also downregulated pro-inflammatory cytokines (IL-6, TNF-α, and TGF-β1) and inhibited ECM protein expression. Furthermore, in vitro experiments using TGF-β1-induced fibroblast activation models showed that circSmad4 knockdown mitigated fibroblast activation by lowering the expression of fibrosis-related genes (Acta2, Col1a1, Col3a1, Ctgf) and collagen secretion. Consistently, pharmacological inhibition of Fgfr2 with FGFR2-IN-1 also suppressed the pro-fibrotic effects of TGF-β1, mimicking si-circSmad4. These findings suggest that circSmad4 functions as a central regulator of pulmonary fibrosis by modulating fibroblast activation, ECM deposition, and inflammation. In conclusion, circSmad4 represents a novel driver of pulmonary fibrosis, and targeting circSmad4 may offer a promising therapeutic strategy.

Pro-inflammatory cytokine-induced chondrocyte death contributes to various types of arthritis, including osteoarthritis and rheumatoid arthritis. Recent studies have indicated that oxysterols induce oxiapoptophagy, a form of cell death characterized by oxidative stress, apoptosis, and autophagy. This study aimed to determine whether interleukin-1β (IL-1β)-induced articular cartilage degeneration is associated with chondrocyte oxiapoptophagy. Intra-articular injection of IL-1β into the knee joints of experimental animals induced progressive articular cartilage degeneration and promoted the expression of cholesterol-25-hydroxylase (CH25H), 25-hydroxycholesterol 7α-hydroxylase (CYP7B1), caspase-3, cyclooxygenase-2 (COX-2), and beclin-1. Consistently, IL-1β-stimulated cartilage explants showed proteoglycan loss, and chondrocytes exhibited increased expression and activation of matrix metalloproteinases (MMP-1, MMP-3, MMP-13). IL-1β upregulated the expression of CH25H and CYP7B1, thereby increasing 25-HC production in chondrocytes. Sequentially, IL-1β promoted chondrocyte apoptosis by triggering the caspase cascade, while levels of oxidative stress-related molecules, including reactive oxygen species (ROS), inducible nitric oxide synthase, COX-2, nitric oxide, and prostaglandin E₂, were elevated in chondrocytes. Additionally, IL-1β increased autophagosome formation and the expression of autophagy biomarkers, including beclin-1 and microtubule-associated protein 1A/1B-light chain 3, by increasing p53 and decreasing the phosphorylation of Akt and mTOR in chondrocytes. Furthermore, IL-1β increased the phosphorylation of NF-κB, which subsequently translocated from the cytosol to the nucleus in chondrocytes. CDDO-Me, an inhibitor of the NF-κB pathway, suppressed the IL-1β-induced expression of CH25H, CYP7B1, caspase-3, and beclin-1, as well as ROS production in chondrocytes. Collectively, these findings consistently indicate that IL-1β-induced articular cartilage degeneration is associated with chondrocyte oxiapoptophagy via the NF-κB signaling pathway.

This study focused on discussing the mechanism of lncRNA KCNQ1OT1 mediating histone methylase enhancer of zeste homolog 2 (EZH2) to repress tissue inhibitor of metalloproteinase-3 (TIMP-3) expression in myocardial ischemia/reperfusion injury (MI/RI). Ischemia-hypoxia hypoxia/reoxygenation (H/R) models were successfully constructed by utilizing primary cardiomyocytes. KCNQ1OT1 and TIMP-3 expression in cardiomyocytes was tested. The proliferative capacity of the cells was assessed. The changes of lactate dehydrogenase (LDH), superoxide dismutase (SOD), and malondialdehyde (MDA) contents in the supernatant of primary cardiomyocytes and Caspase-3 activity were measured. The apoptosis of primary cardiomyocytes was tested. The interactions of KCNQ1OT1, EZH2 and TIMP-3 were verified. Compared to the control group, KCNQ1OT1 expression levels, supernatant LDH and MDA levels, Caspase-3 activity, and cardiomyocyte apoptosis rate in the H/R group were elevated, and cell viability, TIMP-3 expression, and supernatant SOD levels were decreased. After KCNQ1OT1 interference or TIMP-3 overexpression, LDH and MDA levels, Caspase-3 activity, and cardiomyocyte apoptosis rate were reduced, while cell viability, TIMP-3 expression, and SOD levels were raised. Interfering TIMP-3 reversed the ameliorative effects of KCNQ1OT1 downregulation on MI/RI. Mechanistically, KCNQ1OT1 inhibited TIMP-3 expression by recruiting EZH2 to the TIMP-3 promoter region. Interference with KCNQ1OT1 could block EZH2 to the TIMP-3 promoter region and thereby up-regulate TIMP-3 expression, which possesses an ameliorative impact on MI/RI.

Ischemic cardiomyopathy (ICM) is characterized by impaired myocardial function resulting from reduced coronary blood flow, resulting in heart failure. Emerging evidence from proteomic studies indicates that ischemic preconditioning confers cardioprotection against ICM through the regulation of mitochondrial proteins. Proteomic analyses have identified phosphorylation in mitochondrial proteins, including malate dehydrogenase 2 (MDH2), as mediators of cardioprotective mechanisms. However, the mechanism by which MDH2 phosphorylation contributes to cardioprotection in cardiovascular diseases remains poorly understood. This study investigates the role of MDH2 phosphorylation, particularly at S246, in regulating cardiac function. Analysis of patients with dilated cardiomyopathy indicated no significant change in MDH2 expression, similar to a trend observed in ischemic patient data. Considering that a previous proteomic analysis of ischemic preconditioned rat hearts indicated phosphorylation at S246, we analyzed the functional role of this phosphorylation by introducing S246A phosphomutation. S246A phosphomutation significantly decreased MDH2 activity, accompanied by an increased accumulation of acetate and lactate as demonstrated by metabolomics. S246A phosphomutation also lowers mitochondrial membrane potential and ATP production. Under hypoxia/reoxygenation (H/R) conditions, S246A phosphomutation downregulates mitochondrial biogenesis and fusion proteins such as PGC1α and OPA1. Overall, these findings suggest that MDH2 phosphorylation at S246 is important in protecting against H/R injury through mitochondrial function regulation and activation of metabolic pathways. This discovery establishes a potential therapeutic strategy and a clear direction for drug development to specifically address conditions such as ICM.

Arterial atherosclerosis is a common cardiovascular disease with serious health impact. Growing evidence suggests that serum hydroxyvitamin D may influence its progression. Investigating the causal relationship and underlying mechanisms between vitamin D and atherosclerosis is essential for developing effective prevention and treatment strategies. We conducted Mendelian randomization analysis with stringent single-nucleotide polymorphism selection to assess causal relationships. We analyzed transcriptomic datasets to identify differentially expressed genes (DEGs) and genes related to vitamin D metabolism. Feature selection was performed using Least Absolute Shrinkage and Selection Operator regression, Support Vector Machine-Recursive Feature Elimination, and random forest algorithms. Receiver operating characteristic (ROC) curves were used to evaluate diagnostic performance, and a nomogram was constructed for predictive modeling. Immune cell infiltration was assessed via CIBERSORT, while Gene Set Enrichment Analysis (GSEA) was employed to explore key pathways. Quantitative real-time PCR validated gene expression. Mendelian randomization analysis confirmed that 25-hydroxyvitamin D acted a protective factor against coronary atherosclerosis. We identified 1,195 DEGs and 33 vitamin D-related genes, with four key genes demonstrating strong diagnostic accuracy in ROC curve analysis. Immune profiling revealed significant differences in nine immune cell types, and GSEA highlighted critical biological pathways involved in disease progression. The nomogram model showed high predictive performance. This multi-omics study establishes a causal relationship between serum hydroxyvitamin D levels and atherosclerosis while uncovering potential biomarkers and pathogenic mechanisms through analyses of gene expression, immune infiltration, and signaling pathways. These findings provide valuable insights into atherosclerosis research and may help guide future therapeutic strategies.

Lung adenocarcinoma (LUAD) displays significant biological heterogeneity, with matrisome-related genes (MRGs) playing key roles in tumor progression and immune regulation. Understanding the interplay between MRGs, the tumor microenvironment, and host immunity is critical for mechanistic insights. LUAD transcriptomic and clinical data were sourced from TCGA, GEO (GSE31210), and single-cell data (GSE189357). MRGs were analyzed via limma, with prognostic genes identified using univariate Cox. A LASSO-multivariate Cox model was built and validated using Kaplan-Meier, receiver operating characteristic, and external datasets. Functional enrichment (GO/KEGG/GSEA), immune infiltration (ssGSEA/ESTIMATE/CIBERSORT), tumor mutational burden, immunotherapy response, and drug sensitivity were assessed. Consensus clustering defined molecular subtypes. Single-cell analysis (Seurat/SCISSOR) identified risk-associated cells, with AUCell and CellChat evaluating activity and cell communication. A 7-gene risk model (ANGPTL4, C1QTNF6, CCL20, CLEC3B, FCN1, LAMA3, PRELP) stratified LUAD patients into distinct survival groups (area under the curve > 0.7). Low-risk patients showed higher immune infiltration, lower TIDE scores (suggesting better immunotherapy response), and reduced sensitivity to Axitinib/Gefitinib. Single-cell analysis implicated fibroblasts and myeloid cells in high-risk profiles, with activated MIF/TGF-β pathways. This integrated transcriptomic and single-cell model predicts LUAD prognosis and immune landscape, guiding personalized therapy.

Aloe vera extracts, particularly aloin, have been widely used in traditional Chinese medicine for their anti-inflammatory and detoxifying properties. Recent studies suggest that aloin may also exert neuroprotective effects, though its specific mechanisms remain unclear. Glutamate excitotoxicity, a critical factor in neurodegenerative and pain-related disorders, is mediated primarily by N-methyl-D-aspartic acid (NMDA) receptors, which regulate calcium influx and neuronal excitability. Meanwhile, substantia gelatinosa (SG) of the trigeminal subnucleus caudalis (Vc) plays a central role in processing orofacial pain, where glutamate is a key excitatory neurotransmitter. Using whole-cell patch-clamp electrophysiology and calcium imaging techniques in mice SG neurons of the Vc, we examined aloin's effects on glutamate receptor-mediated responses. Aloin selectively inhibited NMDA-induced responses without affecting AMPA or kainate receptor activity. The suppression of NMDA-mediated currents by aloin was linked to changes in Ca²⁺ influx but occurred independently of voltage-gated sodium channels and action potential generation. Calcium imaging revealed that aloin reduced NMDA-induced intracellular calcium influx, supporting its role in mitigating NMDA-mediated excitotoxicity. Furthermore, aloin significantly suppressed the spontaneous firing activity of SG neurons, suggesting its broader regulatory effects on neuronal excitability. Our findings demonstrate that aloin attenuates NMDA receptor-induced excitatory signaling by regulating calcium response. This specificity highlights aloin's potential as a therapeutic candidate for conditions involving glutamate excitotoxicity and orofacial pain regulation.

Aldosterone plays a central role in regulating blood pressure and electrolyte balance, and emerging evidence implicates its involvement in metabolic disorders. This study evaluated the metabolic effects of CS-3150, a novel nonsteroidal and selective mineralocorticoid receptor (MR) antagonist, in genetically obese db/db mice. Mice were administered CS-3150 (3 mg/kg/day) for 8 weeks while maintained on a normal chow diet. Metabolic parameters, tissue morphology, inflammatory gene expression, and insulin signaling-assessed via Akt phosphorylation-were examined using standard biochemical and molecular techniques. CS-3150 treatment significantly improved insulin sensitivity (p < 0.05) without notable changes in fasting blood glucose or lipid profiles. However, CS-3150 markedly reduced adipocyte size, visceral fat accumulation, and hepatic lipid deposition (p < 0.01). These changes were accompanied by decreased macrophage infiltration (p < 0.01) and reduced expression of inflammatory markers, including Vcam1, Sele, and Il6 in white adipose tissue (p < 0.05). In vitro, aldosterone impaired insulin-induced Akt phosphorylation in 3T3-L1 adipocytes, HepG2 hepatocytes, and C2C12 myotubes. CS-3150 treatment reversed this effect, whereas the traditional MR antagonist eplerenone failed to do so at equivalent concentrations. In conclusion, CS-3150 improved insulin sensitivity in obese diabetic mice, likely through attenuation of adipose inflammation, reduction in fat accumulation, and enhancement of insulin signaling. These findings support the potential of CS-3150 as a therapeutic agent for obesity-associated metabolic dysfunction.