The Kaohsiung journal of medical sciences最新文献

Traumatic brain injury (TBI) causes a high level of blood glutamate, which triggers host defense by activating oxidative stress and inflammation response. However, the concrete mechanism underlying its exacerbating effects on acute lung injury (ALI) severity remains unknown. In the present study, we aim to demonstrate the special role of N-methyl-D-aspartate receptor (NMDAR) in regulating glutamate-related inflammation signaling to facilitate the sustaining injury. After the interventions, blood glutamate concentration was measured using HPLC-MS/MS. The level of pro-inflammation cytokines, wet/dry weight ratio, protein concentration, and lung injury score were measured to examine the severity of lung damage. The oxidative status was evaluated by measuring the levels of reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD) activity, and intracellular Ca²⁺ concentration. Endothelial cell dysfunction was assessed through dye extravasation assay and quantification of p-NFAT, p-p65, ICAM-1, and VCAM-1 expression levels. Results showed that glutamate activated the NMDAR pathway, inducing endothelial barrier dysfunction via ROS/MDA elevation and SOD suppression. This cascade promoted the concentration of Ca²⁺, activating both nuclear factor of activated T cells (NFAT) and nuclear factor kappa-B (NF-κB) pathway. Glutamate administration exacerbated NMDAR activation, leading to persistent lung injury following TBI. Memantine-mediated NMDAR blockade effectively attenuated this injury. Our findings indicate that blood glutamate elevation may trigger TBI-associated acute lung injury (TBI-ALI) through endothelial NMDAR/ROS/Ca²⁺ signaling.

Acute coronary syndrome (ACS) is a clinical syndrome involving myocardial ischemia. This study aimed to elucidate the mechanism of TET3 in ACS-induced CMEC damage, thereby identifying a new target for ACS treatment. The expression of TET3 in ACS patients and healthy subjects was analyzed. CMECs were stimulated with ox-LDL and transfected with si-TET3 for the detection of TET3 RNA and protein levels. Cell proliferation, apoptosis, and angiogenesis were evaluated. Subsequently, m5C modification and TET3 enrichment on CCAT2 were assessed, and CCAT2 stability was measured. The binding relationships between CCAT2 and FUS and between FUS and TRIM14 mRNA were analyzed. Additionally, lncRNA CCAT2 inhibition or TRIM14 overexpression in combination with si-TET3 treatment was conducted to verify the underlying mechanism. TET3 was strongly expressed in serum from ACS patients and ox-LDL-stimulated CMECs, and silencing TET3 reduced ox-LDL-induced CMEC damage. TET3 removed m5C modification on CCAT2 to decrease CCAT2 stability and expression. With TRIM14, CCAT2 competes to bind to FUS to suppress TRIM14 expression. CCAT2 knockdown or TRIM14 overexpression partially reversed the protective effect of si-TET3 on CMEC damage. In conclusion, TET3 removed m5C modification to inhibit CCAT2 expression and reduced the binding relationship between CCAT2 and FUS to upregulate TRIM14, thereby exacerbating CMEC damage in ACS.

Hepatocellular carcinoma (HCC) is a heterogeneous malignancy characterized by high mortality rates. This article presents a discussion of the role of ZNF652 in HCC cell proliferation and apoptosis, thereby identifying a new target for HCC treatment. The expression levels of ZNF652, circRHOT1, and SLC38A6 in HCC and healthy cells were analyzed. Cell proliferation and apoptosis were subsequently validated. The binding relationships between ZNF652 and the circRHOT1 promoter and between circRHOT1 and KAT5 were validated. The recruitment of KAT5 and H3K27ac to the SLC38A6 promoter was assessed via ChIP. Combined experiments were carried out to verify the role of the circRHOT1/SLC38A6 pathway in HCC cell proliferation and apoptosis. ZNF652, circRHOT1, and SLC38A6 were upregulated in HCC cells. ZNF652 silencing inhibited HCC cell proliferation but promoted apoptosis. Mechanistically, ZNF652 increased circRHOT1 expression at the transcriptional level and recruited KAT5 to the SLC38A6 promoter to increase H3K27ac enrichment and activate SLC38A6 expression. Combined experiments revealed that overexpression of circRHOT1 or SLC38A6 could alleviate the effects of ZNF652 silencing on HCC cell proliferation and apoptosis. In conclusion, ZNF652 transcriptionally activated circRHOT1 expression, recruited KAT5 to the SLC38A6 promoter, increased H3K27ac enrichment, and activated SLC38A6 expression, thus promoting HCC cell proliferation and inhibiting apoptosis.

Glioblastoma (GBM) is an aggressive brain tumor with poor prognosis owing to its high invasiveness and resistance to therapy. RTA-408, a synthetic triterpenoid and nuclear factor erythroid 2-related factor 2 activator, exhibits anti-inflammatory and anti-cancer properties; however, its effects on GBM remain unclear. This study investigated the therapeutic potential of RTA-408 in GBM, focusing on its role in the activation of the JNK pathway. GBM8401 and A172 cells were treated with RTA-408, and cell viability, apoptosis, migration, and radiosensitivity were assessed. Western blot analysis was used to evaluate the epithelial-mesenchymal transition markers, cyclin D1, and JNK signaling. Intracranial xenograft models were used to assess tumor growth suppression by RTA-408 alone or in combination with radiotherapy. RTA-408 significantly reduced cell viability, induced apoptosis, and inhibited the migration of GBM cells, correlating with the activation of the JNK pathway. JNK inhibition reversed these effects, confirming its role in RTA-408-mediated tumor suppression. RTA-408 also enhanced radiosensitivity and reduced clonogenic survival. RTA-408 suppressed GBM tumor growth in vivo, with the greatest effect observed in combination with radiotherapy. RTA-408 exerts antitumour and radiosensitizing effects via activation of the JNK pathway and inhibits GBM progression. These findings highlight its potential as a novel therapeutic strategy for the treatment of GBM.

IgA nephropathy (IgAN), the most common form of glomerulonephritis, is a major and growing public health issue. It results from intestinal barrier dysfunction that leads to mesangial deposition of pathogenic galactose-deficient IgA1 (Gd-IgA1) and renal inflammation. This study aimed to investigate the therapeutic effects and associated mechanisms of forsythiaside A on intestinal barrier injury in IgAN in animal models. Rats were treated with bovine serum albumin (BSA), carbon tetrachloride (CCl₄), and lipopolysaccharide (LPS) to induce IgAN, followed by intragastric administration of forsythiaside A once daily from weeks 15 to 20 after model establishment. Biochemical markers, including 24-h urinary protein, blood urea nitrogen (BUN), serum creatinine (SCr), renal and intestinal tissue pathology, and levels of pro-inflammatory cytokines in the serum, kidney, and intestine, intestinal tight junction proteins, and TLR4/NF-κB pathway components were examined. The results showed that forsythiaside A decreased 24-h urinary protein, BUN, and SCr levels, alleviated renal damage, and attenuated glomerular and tubular lesions, collagen deposition, and glomerular IgA deposition in IgAN rats. Forsythiaside A treatment inhibited CD68-positive macrophage infiltration in renal tissues and downregulated serum and renal levels of IL-1β, IL-6, and TNF-α, while also alleviating intestinal barrier injury and intestinal inflammation, as shown by reduced levels of IL-1β, IL-6, and TNF-α and increased expression of the intestinal tight junction proteins occludin and ZO-1. Lastly, forsythiaside A treatment lowered serum LPS concentrations, as well as renal and intestinal levels of TLR4, p-NF-κB p65, and p-IκBα, and raised both renal and intestinal levels of IκBα. Collectively, forsythiaside A was found to ameliorate the progression of IgAN in rats by alleviating inflammation and intestinal barrier injury by suppression of TLR4/NF-κB signaling.

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, with a 5-year survival rate of less than 20% and a high risk of recurrence despite advances in treatment. This study aimed to identify new therapeutic targets to increase the effectiveness of NSCLC treatments. We examined the role of USP54 in ferroptosis using an MTT assay and assessed the levels of reactive oxygen species (ROS), ferrous iron (Fe²⁺), and malondialdehyde (MDA). To explore the underlying molecular mechanism, the intermolecular interactions was assessed using coimmunoprecipitation (Co-IP), chromatin immunoprecipitation (ChIP), and dual-luciferase reporter assays. We found that USP54 expression was reduced in NSCLC and that its overexpression inhibited NSCLC cell proliferation while inducing ferroptosis, as indicated by increased ROS, Fe²⁺, and MDA levels, along with changes in SLC7A11, GPX4, and ACSL4 expression. Additionally, USP54 mediated the deubiquitination of FOXA2, decreasing its degradation. And FOXA2 promoted ACSL4 transcription, which further induced ferroptosis in NSCLC cells. In conclusion, USP54 promotes ferroptosis and inhibits NSCLC progression by stabilizing FOXA2, which in turn activates ACSL4 transcription. This study provides a theoretical foundation for the development of therapies targeting USP54 or ACSL4 for NSCLC treatment.

Pediatric asthma is a common chronic airway inflammatory disease, where accurate assessment of disease severity and prognosis prediction is crucial for treatment decisions. Currently, there is a lack of precise and effective biomarkers. This study aimed to investigate the association between serum levels of lipocalin-2 (LCN2), soluble suppression of tumorigenicity 2 (sST2), and fibroblast growth factor 21 (FGF21) with asthma severity and to evaluate their predictive value for prognosis. A total of 110 asthmatic children (asthma group) were enrolled and stratified by severity into mild (n = 50), moderate (n = 34), and severe (n = 26) subgroups. After 4 weeks of treatment, the asthma group was further divided into good prognosis (n = 48) and poor prognosis (n = 64) subgroups based on Childhood Asthma Control Test (C-ACT) scores. Additionally, 110 healthy children were randomly selected as controls. Serum LCN2, sST2, and FGF21 levels were measured using enzyme-linked immunosorbent assay. Clinical data and pulmonary function parameters were collected. Spearman correlation analysis assessed the relationship between biomarker levels and C-ACT scores. Multivariate logistic regression identified risk factors for poor prognosis. Receiver operating characteristic (ROC) curve analysis evaluated the predictive performance of LCN2, sST2, and FGF21 for poor prognosis. Serum LCN2, sST2, and FGF21 levels were significantly higher in asthmatic children than in controls (p < 0.05), with levels progressively elevating as disease severity increased (p < 0.05). The good prognosis group exhibited lower levels of all three biomarkers compared to the poor prognosis group (p < 0.05). Spearman analysis revealed negative correlations between biomarker levels and C-ACT scores (p < 0.05). Multivariate logistic regression confirmed LCN2, sST2, and FGF21 as independent risk factors for poor prognosis (p < 0.05). ROC analysis demonstrated moderate predictive efficacy for individual biomarkers, while their combination achieved an area under the curve of 0.938, with 93.33% sensitivity and 90.00% specificity, suggesting potential clinical utility for severity assessment and prognosis prediction. Serum LCN2, sST2, and FGF21 levels increase with asthma severity and demonstrate high predictive value for poor prognosis when combined. These biomarkers may serve as early prognostic indicators in pediatric asthma management.