The Kaohsiung journal of medical sciences最新文献

This study investigated the effects of histone lactylation on ferroptosis in hypoxia-induced cardiomyocytes. A hypoxia model was established in AC16 cells treated with 2-Deoxy-D-glucose (2-DG, a glucose analogue), ferrostatin-1 (Fer-1, a selective ferroptosis inhibitor), lactate (LA), sh-β-catenin (shRNA of β-catenin), or SKL2001 (an agonist of the Wnt/β-catenin pathway) for subsequent experiments. Hypoxia increased glycolysis ability, HK2, PDK1, and LDHA mRNA expression, HK and LDH activities, and LA levels in AC16 cells, decreased SLC7A11 and GPX4 protein levels and GSH levels, and elevated iron ion, MDA, and ROS levels, Wnt3 and nuclear β-catenin protein levels, β-catenin nucleus entry, the overall level of lactylation, the lactylation of β-catenin, and β-catenin protein stability. 2-DG or Fer-1 treatment reduced iron ion, MDA, and ROS levels but increased SLC7A11 and GPX4 protein levels and GSH levels in hypoxia-treated cells. 2-DG treatment decreased Wnt3 and nuclear β-catenin protein levels, β-catenin nucleus entry, the overall level of lactylation, the lactylation of β-catenin, and β-catenin protein stability, whereas LA treatment produced the opposite effects. Wnt/β-catenin pathway repression attenuated hypoxia-induced ferroptosis in cardiomyocytes. Collectively, hypoxia enhances histone lactylation, activates the Wnt/β-catenin pathway, and increases β-catenin stability, thereby promoting ferroptosis in cardiomyocytes.

Liver transplantation (LT) is the standard treatment for end-stage liver disease, yet the gap between the demand for organs and their availability is widening. In Taiwan, the scarcity of deceased donor organs highlights the need for optimized utilization strategies. The donor risk index (DRI) has emerged as a predictive tool for transplant outcomes, but existing models are not well-suited for Taiwan's unique demographic and clinical context. This retrospective cohort study analyzed a total of 118 deceased donor liver transplantation (DDLT) cases from Chang Gung Memorial Hospital between January 2020 and October 2023. Key demographic and clinical data were collected, focusing on one-year mortality and associated outcomes. Additionally, a retrospective validation cohort of 60 patients from January 2018 to December 2019 and a prospective validation cohort of 41 patients from November 2023 to August 2024 were included to assess the robustness of the CGMH-DRI model. Statistical analyses included univariate and multivariate logistic regression to identify independent risk factors. The study identified MELD 3.0 score, donor total bilirubin, and cold ischemia time (CIT) as independent predictors of one-year mortality. The CGMH-DRI model demonstrated good predictive performance (AUC = 0.778) for mortality, early allograft dysfunction (EAD), and major complications. Validation results showed consistent performance, with AUROC values of 0.716 in the retrospective cohort and 0.694 in the prospective cohort for one-year mortality; 0.781 and 0.676 for EAD; and 0.727 and 0.705 for major complications, respectively. The CGMH-DRI model offers a simple yet helpful tool for risk stratification in DDLT. It enables clinicians to identify high-risk patients and improve decision-making in liver transplantation. Further validation in diverse populations is warranted to enhance its applicability.

Doxorubicin (DOX), a potent anthracycline chemotherapeutic, exhibits dose-dependent cardiotoxicity that limits its clinical utility. Although miR-145-5p demonstrates cardioprotective properties in cardiovascular diseases, its role in DOX-induced cardiomyopathy remains undefined. This study investigated the therapeutic potential of miR-145-5p against DOX-induced cardiotoxicity and its underlying mechanism. Wistar rats received cumulative DOX dosing (15 mg/kg total) to establish cardiotoxicity, with miR-145-5p overexpression achieved via adeno-associated virus serotype 9 (AAV9) delivery. Cardiac function was assessed by echocardiography and serum biomarkers, including creatine kinase-MB isoenzyme (CK-MB), cardiac troponin T (c-TnT), C-reactive protein (CRP), and N-terminal pro-B-type natriuretic peptide (NT-proBNP). Histopathology (Hematoxylin & Eosin/Masson's Trichrome staining), apoptosis (TUNEL), oxidative stress (dihydroethidium staining/malondialdehyde/glutathione), and NLRP3 inflammasome activation (ELISA/Western blot/immunohistochemistry) were evaluated. Clinical relevance was determined by quantifying serum miR-145-5p and SOX9 mRNA in healthy controls and breast cancer patients before and after DOX treatment. DOX significantly downregulated miR-145-5p and upregulated SOX9 in rat myocardium and H9C2 cells. DOX-treated patients displayed reduced serum miR-145-5p and increased SOX9 mRNA compared with pre-chemotherapy baselines. AAV9-miR-145-5p attenuated DOX-induced systolic dysfunction, reduced serum biomarkers, ameliorated histopathological injury and fibrosis, suppressed apoptosis and oxidative stress, and inhibited NLRP3 inflammasome activation (decreased NLRP3, ASC, caspase-1, IL-1β, and IL-18). miR-145-5p directly targeted the SOX9 3'UTR, and SOX9 overexpression reversed miR-145-5p-mediated reductions in CK release, ROS production, apoptosis, and NLRP3 expression in H9C2 cells. These findings demonstrate that miR-145-5p protects against DOX cardiotoxicity by targeting SOX9 to inhibit NLRP3 inflammasome-mediated pyroptosis, offering a potential therapeutic strategy.

The long-term cumulative impact of metabolic syndrome (MS) on cognitive decline remains uncertain. This study investigated how changes in MS status over 10 years relate to cognition and whether sex modifies this relationship. A total of 766 participants (mean baseline age: 54 years) from the Kaohsiung Atherosclerosis Longitudinal Study were enrolled. MS was defined using the modified National Cholesterol Education Program Adult Treatment Panel III criteria for Asian populations. Participants were categorized into four groups based on changes in MS status over the 10-year follow-up: never MS, ever MS, new MS, and persistent MS. Cognition was assessed using the Chinese version of the Montreal Cognitive Assessment (MoCA). Multivariate regression models were adjusted for age, sex, education, smoking status, physical activity, alcohol consumption, anxiety and depression. The results showed that participants with persistent MS had lower MoCA scores (β = -0.08, adjusted p = 0.020) compared to those who never had MS, with impairments primarily in the memory and language domains. This adverse effect was observed only in women (β = -0.12, adjusted p = 0.004), while no significant association was found in men (β = -0.03, adjusted p = 0.628). Individuals with nonpersistent MS (either ever or new MS) did not show significant cognitive decline compared to those who never had MS. This study demonstrates that persistent MS over a decade is linked to cognitive decline, with a more pronounced effect in women. These findings highlight the importance of early MS intervention in midlife, particularly for women, to reduce the risk of cognitive deterioration later in life.

Spinal cord injury (SCI) is a severe trauma to the central nervous system that often leads to motor and sensory dysfunction in patients, severely affecting their quality of life. Autophagy plays a role in the pathological process of SCI, but the specific mechanism of autophagy in this case is unknown. COL1A1 and CD44, as potentially important genes in the autophagic process, may regulate the signaling pathway and thus affect the autophagic process through protein interactions. The aim of this study was to investigate the interaction between COL1A1 and CD44 and its mechanism of regulating autophagy through the JAK1/STAT3 pathway, providing new targets for SCI treatment. An SCI rat model was established, along with a PC12 cell model induced by oxygen-glucose deprivation (OGD). COL1A1 and CD44 in rat spinal cord tissues and cells were assessed using RT-qPCR and Western blot. Motor function in rats was assessed by BBB score, and the pathological conditions of the rat spinal cord tissues and neuronal numbers were observed by HE staining and Nissl staining. COL1A1 and CD44 localization in PC12 cells was confirmed via immunofluorescence analysis, and their targeting binding was verified by Co-IP. In the cell model, apoptosis, proliferation, and autophagy were evaluated through flow cytometry, CCK-8, and mRFP-GFP-LC3 transfection, respectively. The activation of the JAK1/STAT3 cascade in spinal cord tissues and PC12 cells was assessed, along with its function in the cell model. COL1A1 and CD44 were significantly overexpressed in spinal cord tissues of SCI rats and OGD-treated PC12 cells. COL1A1 silencing promoted functional recovery and autophagy after SCI in rats, ameliorated OGD-induced PC12 cell injury, upregulated autophagy proteins, and increased the number of autophagosomes and autolysosomes. COL1A1 was able to bind to CD44 in a targeting fashion and regulated the JAK1/STAT3 cascade. CD44 overexpression counteracted the positive effects of COL1A1 silencing on both the functional recovery of SCI rats and OGD-induced PC12 cell injury. COL1A1 targets and binds to CD44 to activate autophagy mediated by the JAK1/STAT3 signaling pathway, inhibiting functional recovery after SCI.

Osteoarthritis (OA) is a prevalent degenerative joint disease. This study combines bioinformatics analysis with in vivo and in vitro experiments to elucidate the molecular mechanisms through which melatonin (MT) regulates mitophagy to alleviate OA. Rat and chondrocyte OA models were established via anterior cruciate ligament transection or interleukin (IL)-1β induction, followed by treatment with MT, Cyclosporine A (a mitophagy inhibitor), and 740Y-P (a phosphatidylinositol-3 kinase [PI3K] activator). Pathological changes in cartilage, histological scores, and cell apoptosis were evaluated alongside chondrocyte viability, apoptosis, mitochondrial morphology, mitochondrial membrane potential, and mitophagy using H&E and Safranin O-fast green staining, Osteoarthritis Research Society International scoring (OARSI), TUNEL staining, CCK-8, flow cytometry, transmission electron microscopy, JC-1 staining, and immunofluorescence. Levels of inflammatory factors and mitophagy-related protein levels were determined by ELISA and western blot. Bioinformatics analysis was applied to investigate the regulatory mechanisms of MT on mitophagy in OA. In vivo, MT mitigated OA by enhancing mitophagy and reducing apoptosis of cartilage cells. In vitro, MT attenuated IL-1β-induced chondrocyte apoptosis through mitophagy activation, and this effect was partially reversed by mitophagy inhibition. Mechanistically, the PI3K/protein kinase B (AKT)/forkhead box O3 (FoxO3) axis appeared to play a central role. MT suppressed PI3K/AKT signaling, thereby upregulating FoxO3 expression and promoting mitophagy, ultimately reducing chondrocyte apoptosis. Collectively, these findings suggest that MT enhances mitophagy via inhibition of the PI3K/AKT pathway, and subsequent upregulation of FoxO3, leading to reduced apoptosis of cartilage cells and attenuation of OA progression in rats.

Cervical cancer (CC) remains a major global health concern, particularly due to its aggressive nature and limited treatment options in advanced stages. Long noncoding RNA (lncRNA) TOB1-AS1 has been proposed as a tumor suppressor, yet its regulatory mechanism in CC remains unclear. This study aimed to elucidate the role of TOB1-AS1 in CC progression through the miR-27a-3p/thioredoxin-interacting protein (TXNIP) molecular axis. Functional gain- and loss-of-function assays were conducted to assess the effects of TOB1-AS1, miR-27a-3p, and TXNIP on cell proliferation, invasion, migration, and apoptosis. RT-qPCR, Western blotting, dual-luciferase reporter assays, and in vivo xenograft models were used to validate interactions and phenotypic outcomes. TOB1-AS1 was found to be downregulated in CC cells. Its overexpression suppressed proliferation, invasion, and migration, while enhancing apoptosis. Mechanistically, TOB1-AS1 functioned as a competing endogenous RNA (ceRNA) by sponging miR-27a-3p, thereby restoring TXNIP expression. Modulating miR-27a-3p or TXNIP levels partially reversed the effects of TOB1-AS1. In vivo, TOB1-AS1 overexpression significantly inhibited tumor growth and altered miR-27a-3p and TXNIP expression profiles. These findings suggest that lncRNA TOB1-AS1 acted as a ceRNA of miR-27a-3p to upregulate TXNIP, thereby suppressing CC cell proliferation, invasion and migration.

Non-small cell lung cancer (NSCLC) is a common and fatal malignancy. This study aimed to elucidate the mechanism of Kruppel-like factor (KLF1) in NSCLC progression. Clinical samples were collected, after which the expression levels of KLF1, LINC02159, and dynein cytoplasmic 1 heavy chain 1 (DYNC1H1) in tissues and cells were initially detected, and NSCLC cell proliferation and invasion were measured when KLF1 was up- or downregulated. The binding relationships among KLF1, the LINC02159 promoter, DYNC1H1, and serine and arginine-rich splicing factor 1 (SRSF1) were analyzed. The colocalization of LINC02159 and SRSF1 was verified. DYNC1H1 stability upon actinomycin D treatment was assessed. Combined experiments were designed to confirm the interaction of the LINC02159/DYNC1H1 pathway in NSCLC development. Finally, xenograft tumors were generated in nude mice to validate the mechanism involved. KLF1, LINC02159, and DYNC1H1 were upregulated in NSCLC tissues and cells. KLF1 overexpression promoted NSCLC cell proliferation and invasion, whereas KLF1 knockdown inhibited NSCLC cell proliferation and invasion. Mechanistically, KLF1 transcriptionally activated LINC02159, which could recruit the SRSF1 protein and increase DYNC1H1 mRNA stability in the cytoplasm. Combined experiments revealed that LINC02159 and DYNC1H1 overexpression could counteract the inhibitory effect of KLF1 silencing on NSCLC cell proliferation and invasion. KLF1 silencing inhibited tumor growth in vivo by downregulating the LINC02159DYNC1H1 pathway.

Ulcerative colitis (UC) has become a prevalent global health concern. This study scrutinized the influence of Astragaloside IV (ASI) on DSS-induced UC, with particular emphasis on the role of WDR5 in mediating ENO1 expression. The therapeutic efficacy of ASI was assessed in a mouse model of UC by evaluating disease activity index, pathology, colon length, and inflammatory factor contents. Through bioinformatics analysis, the UC-related differentially expressed genes were predicted using the GSE38713 database and intersected with the lists of ASI targets and transcription factors, and the protein-protein network was constructed to screen the key target transcription factors. ASI inhibited the shortening of colon length, reduced histological damage scores, ameliorated pathology, and the overproduction of pro-inflammatory cytokines. After ASI treatment, DSS-stimulated human NCM460 cells showed increased cell viability, decreased levels of pro-inflammatory cytokines and cleaved-Caspase-3, and enhanced ZO-1 and claudin-3 expression. WDR5 was a target of ASI in UC, and overexpression of WDR5 compromised the effects of ASI. WDR5 promoted the H3K4me3 modification of the ENO1 promoter and thereby regulated ENO1 transcriptional activation. Silencing of ENO1, again, repressed NCM460 cell apoptosis and alleviated UC-like symptoms in mice. In conclusion, ASI mitigated UC by inhibiting WDR5 and reducing H3K4me3-mediated ENO1 activation.