The Kaohsiung journal of medical sciences最新文献

Osimertinib (OSI) resistance in non-small cell lung cancer (NSCLC) remains a significant challenge. This report explored the precise role of USP28 on OSI resistance in NSCLC and identified a functional downstream effector. OSI-resistant H1975 cells (H1975/OSI) were established by long-term OSI exposure. USP28 and SIRT1 expression levels were analyzed by quantitative PCR, immunoblotting, and immunohistochemistry. Functional assays included cell viability, colony formation, EdU incorporation, apoptosis analysis, and glycolysis assays. The interaction between USP28 and SIRT1 was confirmed by co-immunoprecipitation (Co-IP) assay and SIRT1 protein stability analysis. In vivo validation was performed using H1975/OSI xenograft models. USP28 and SIRT1 were upregulated in H1975/OSI cells and OSI-resistant NSCLC tissues. USP28 overexpression enhanced cell proliferation and glycolysis, suppressed apoptosis, and conferred OSI resistance in H1975 cells, while its depletion exerted opposite effects in H1975/OSI cells. Mechanistically, USP28 stabilized SIRT1 by deubiquitination. SIRT1 knockdown attenuated the effects of USP28 overexpression, while SIRT1 restoration reversed the phenotype alterations upon USP28 depletion. In vivo, USP28 depletion sensitized H1975/OSI xenografts to OSI treatment. Our study indicates that USP28 promotes OSI resistance in NSCLC by deubiquitinating SIRT1. Targeting the USP28/SIRT1 axis may represent a novel therapeutic approach to overcome OSI resistance in EGFR-mutant NSCLC.

Spontaneous pneumomediastinum (SPM) with pneumorrhachis is rare but generally benign and self-limiting. However, the impact of environmental and seasonal factors on SPM remains unclear. This study investigated their association with SPM onset and clinical outcomes. We conducted a 12-year retrospective review of SPM cases, comparing clinical characteristics and outcomes between patients with and without pneumorrhachis. A case-crossover design was used to assess short-term associations between environmental exposures and SPM incidence, analyzed via conditional logistic regression. A total of 70 consecutive patients were identified, with 9 classified as SPM with pneumorrhachis and 61 as SPM without pneumorrhachis. While both groups were predominantly managed with hospitalization, those with pneumorrhachis had longer hospital stays (median: 7 vs. 3 days, p = 0.002) and were more often associated with severe-grade SPM and identifiable triggers (p < 0.001 and p = 0.009, respectively). No significant environmental exposure differences were observed between groups. Seasonally, SPM incidence was significantly higher in autumn and winter (p < 0.001), consistent with elevated air pollutant levels. Linear regression showed that standardized β coefficients for PM_2.5 were higher in autumn and winter (β = 1.15 and β = 1.18), indicating a seasonal association between PM_2.5 and SPM onset. Despite experiencing more triggers and longer hospitalization, patients with pneumorrhachis had similarly favorable clinical courses. The seasonal clustering of SPM and its association with elevated PM_2.5 levels suggest that air pollution may be a contributing factor, warranting further investigation.

Airway epithelial injury plays a critical role in the pathogenesis of chronic obstructive pulmonary disease (COPD). Mitochondrial dysfunction is implicated in this injury, while the underlying mechanism remains incompletely understood. RNA sequencing was conducted to identify key genes involved in mitochondrial dysfunction in airway epithelial injury induced by cigarette smoke extract (CSE). We identified 1981 significantly up-regulated and 4952 down-regulated differentially expressed genes (DEGs) in CSE-treated airway epithelial cells. A protein-protein interaction network constructed from the DEGs revealed that several key genes were involved in CSE-induced airway epithelial injury. Additionally, PDCD5 was identified as a hub gene potentially linked to mitochondrial dysfunction. PDCD5 expression was significantly increased in the airway epithelium of COPD patients and the corresponding experimental mice. The mRNA and protein expression levels of PDCD5 were significantly increased in concentration- and time-dependent manners in airway epithelial cells treated with CSE. PDCD5 silencing significantly attenuated CSE-induced mitochondrial reactive oxygen species (ROS) accumulation, mitochondrial membrane potential loss, and intracellular ATP depletion. Transmission electron microscopy revealed that PDCD5 siRNA treatment ameliorated CSE-induced mitochondrial structural damage. Moreover, PDCD5 knockdown significantly reduced intracellular ROS accumulation, attenuated apoptosis increases, and inhibited cell viability decline in airway epithelial cells treated with CSE. Our findings demonstrate that PDCD5 contributes to airway epithelial cell damage through the mitochondrial pathway and participates in the pathogenesis of COPD, implicating it as a potential diagnostic biomarker and therapeutic target for COPD.

Radiotherapy effectively eradicates tumor cells but can also trigger pyroptotic damage in vascular endothelial cells. This study investigates the role of interferon regulatory factor 1 (IRF1) in radiation-induced endothelial injury, aiming to provide mechanistic insights for optimizing radiotherapy. Human umbilical vein endothelial cells (HUVECs) were exposed to x-ray irradiation, after which cell viability, lactate dehydrogenase (LDH) release, γ-H2AX foci formation, and the expression of pyroptosis-associated proteins (NLRP3, Cleaved Caspase-1, GSDMD-N, IL-1β, IL-18) were assessed. Expression levels of IRF1, NFE2L1-DT, PELP1, ALKBH5, and Cx43 were quantified. Chromatin enrichment of IRF1 at the NFE2L1-DT promoter and IRF1-NFE2L1-DT interactions were examined, along with NFE2L1-DT or ALKBH5 binding to PELP1. The enrichment of m⁶A modifications on Cx43 transcripts was also evaluated. X-ray exposure reduced HUVEC viability, elevated LDH release, increased γ-H2AX foci, and upregulated IRF1, along with pyroptosis markers. Silencing IRF1 reversed these changes. Mechanistically, IRF1 directly bound to and increased NFE2L1-DT expression. NFE2L1-DT interacted with PELP1 to enhance the binding of PELP1 to and ALKBH5 mRNA, thus upregulating ALKBH5 expression. ALKBH5-mediated m⁶A demethylation subsequently downregulated Cx43 expression. Overexpression of NFE2L1-DT or ALKBH5, or silencing Cx43, attenuated the protective effects of IRF1 silencing against radiation-induced damage. These findings indicate that radiation-induced IRF1 upregulation leads to endothelial injury by promoting pyroptosis through the NFE2L1-DT/ALKBH5/Cx43 axis.