The Kaohsiung journal of medical sciences最新文献

Sepsis-associated acute kidney injury (SA-AKI) is associated with morbidity and mortality. Ferroptosis is associated with the pathophysiology of SA-AKI. Here, we investigated the role of LIM and cysteine-rich domain 1 (LMCD1) in the regulation of ferroptosis during SA-AKI progression. SA-AKI models were established by CLP and LPS treatments. Hematoxylin and eosin (HE) and (PAS) staining were conducted to examine renal pathological changes. ELISA was used to measure serum creatinine and BUN levels. Lipid ROS levels in cells were examined using flow cytometry. MDA, GSH, SOD, and Fe²⁺ levels in the cells were measured using appropriate kits. Molecular interactions were analyzed using ChIP, a dual-luciferase reporter gene, and Co-IP assays. GATA1 knockdown inhibits LPS-induced cell injury, oxidative stress, and ferroptosis in HK-2 cells by transcriptionally inhibiting LMCD1 expression. Moreover, LMCD1 activates the Hippo/YAP pathway by promoting CUL3-mediated Nrf2 ubiquitination degradation. LMCD1 knockdown alleviates CLP-induced AKI in mice by inhibiting ferroptosis. Taken together, LMCD1 transcriptionally activated by GATA1 promotes ferroptosis during SA-AKI progression by activating the Hippo/YAP pathway and facilitating CUL3-mediated Nrf2 ubiquitination degradation.

This study investigated whether Ginsenoside Rg1 (Rg1) alleviates autism-like behaviors in mice prenatally exposed to valproic acid (VPA) via Sirt2/Foxo1 signaling. Pregnant C57BL/6J mice received a single intraperitoneal injection of VPA (600 mg/kg) on embryonic Day 12.5 to establish an autism model. At 8 weeks of age, male offspring were randomly divided into four groups: Normal, VPA, VPA + Rg1 (5 mg/kg), and VPA + Rg1 (10 mg/kg). Rg1 was administered once daily for 28 days. Behavioral assessments included grooming, rearing, locomotor activity, social interaction, novel object recognition, open field, and marble-burying tests. Molecular assays measured Sirt2/Foxo1 expression, inflammatory cytokines, oxidative stress markers in the hippocampus and prefrontal cortex. Nissl staining was performed to evaluate neuronal integrity in the prefrontal cortex and hippocampus. Rg1 administration significantly ameliorated core autism-like behaviors in VPA-exposed mice, including deficits in social interaction, recognition memory, and anxiety- and compulsive-like behaviors, as well as excessive grooming and marble-burying. VPA reduced Sirt2/Foxo1 expression, increased levels of interleukin (IL)-1β, IL-6, tumor necrosis factor-α (TNF-α), and malondialdehyde (MDA), and decreased superoxide dismutase (SOD) activity in both brain regions. Rg1 treatment reversed these alterations in a dose-responsive manner, with the 10 mg/kg dose yielding more pronounced behavioral and molecular improvements than the 5 mg/kg dose. Nissl staining revealed significant neuronal loss in VPA-exposed mice, which was partially restored by Rg1 treatment. These findings suggest that Rg1 alleviates VPA-induced behavioral and neuropathological abnormalities, potentially via Sirt2/Foxo1-mediated regulation of neuroinflammation and oxidative stress, and may represent a promising therapeutic strategy for autism spectrum disorder.

Colorectal cancer (CRC) ranks as the third most prevalent malignancy and the second leading cause of cancer-related mortality worldwide. This study explored the role of lysine-specific histone demethylase 5C (KDM5C) in CRC progression. Expression levels of KDM5C, HOXC-AS3, and discs large MAGUK scaffold protein 4 (DLG4) were evaluated. Following the KDM5C knockdown, cell proliferation assays were conducted. The recruitment of KDM5C and histone H3 lysine 4 tri-methylation (H3K4me3) to the HOXC-AS3 promoter region was investigated. Furthermore, the subcellular distribution of HOXC-AS3 was assessed using nuclear-cytoplasmic fractionation and RNA fluorescence in situ hybridization (RNA-FISH). The interactions between HOXC-AS3, YTH domain-containing protein 1 (YTHDC1), and DLG4 were detected. The stability of DLG4 mRNA was evaluated, and the functional roles of HOXC-AS3 and DLG4 in CRC cells were examined through combined experimental analyses. KDM5C expression was elevated in CRC cells, whereas HOXC-AS3 and DLG4 levels were notably reduced. Silencing KDM5C resulted in suppressed cell proliferation. Mechanistically, KDM5C inhibited HOXC-AS3 expression by demethylating H3K4me3 at its promoter. HOXC-AS3 promoted DLG4 mRNA stability by recruiting the RNA-binding protein YTHDC1. Combined experimental results indicated that overexpression of HOXC-AS3 or DLG4 reduced the inhibitory effect of KDM5C downregulation on CRC cells. In conclusion, KDM5C promotes CRC cell proliferation by demethylating H3K4me3, repressing HOXC-AS3 expression. The reduced HOXC-AS3 levels impair the recruitment of YTHDC1, leading to decreased DLG4 expression.

Rhaponitin (Rha) possesses anti-tumor activity and mediates the transcriptional activity of hypoxia-inducible factor (HIF)-1α that affects cisplatin (Cis) resistance. However, whether Rha can lessen Cis resistance in tongue squamous cell carcinoma (TSCC) by mediating HIF-1α activity is unclear. Cis-resistant SCC9 (SCC9-CisR) cells were treated with Cis, Rha, or Cis plus Rha to explore the effect of Rha on Cis resistance using a cell counting kit-8, flow cytometry, and tumor sphere formation assays. Stemness markers CD44 and SOX2 and HIF-1α mRNA levels were detected by quantitative PCR. The GSE115119 database and plugin iRegulon were employed to select target genes mediated by HIF-1α. Protein levels of HIF-1α, monocarboxylate transporter 4 (MCT4), and the Wnt/β-catenin pathway were measured by western blot. Subcutaneous xenograft models were constructed to explore the efficacy of Rha in combating Cis resistance. Rha repressed the growth and stemness of SCC9-CisR cells in vitro and in vivo. HIF-1α protein levels were markedly elevated in SCC9-CisR cells, yet Rha treatment attenuated the transcriptional activity of HIF-1α but not HIF-1α mRNA levels. Rha plus Cis repressed the viability and stemness of SCC9-CisR cells, but not HIF-1α-knockdown SCC9-CisR cells, compared with Cis alone. Rha-induced stemness inhibition and apoptosis in SCC9-CisR cells were overridden after HIF-1α overexpression. Rha inhibited the Wnt/β-catenin signaling by regulating the HIF-1α/MCT4 axis. In conclusion, Rha reduced cell stemness and enhanced Cis sensitivity in TSCC, which was achieved possibly via suppressing the Wnt/β-catenin signaling through mediation of the HIF-1α/MCT4 axis.

This study examines the impact of hepatitis C virus (HCV) eradication through sofosbuvir/velpatasvir (SOF/VEL) treatment on glycated hemoglobin (HbA1c) levels in patients with chronic hepatitis C and type 2 diabetes mellitus (T2DM). Utilizing data from the Taiwan HCV Registry, a retrospective analysis was conducted on 2180 patients who met the inclusion criteria, 695 of whom had T2DM. HbA1c levels significantly decreased in the diabetes group from 7.32% ± 1.72% at baseline to 6.87% ± 1.34% after achieving sustained virological response (SVR12). Patients with higher baseline HbA1c levels and cirrhosis experienced more pronounced HbA1c reductions. Among diabetic patients with HbA1c levels ≥ 6.5, 24.6% achieved levels < 6.5 following HCV elimination, while 24.4% of prediabetic patients observed HbA1c reductions < 5.7. Multivariate analysis identified fasting glucose levels and diabetes status as significant factors associated with HbA1c decline. These findings suggest that successful HCV treatment can improve glycemic control, highlighting the need for collaboration between hepatology and non-hepatology specialists in patient care.

Sepsis is typified by organ failure due to an unchecked host reaction to infection. This study aims to explore the mechanism of ubiquitin-specific peptidase 7 (USP7) in sepsis with the involvement of intercellular adhesion molecule-1 (ICAM-1). A sepsis model was established using lipopolysaccharide (LPS) induction in WT and USP7^-/- mice, and various assays were conducted to evaluate survival rates, organ damage, inflammatory markers, and protein interactions. The results revealed that USP7 expression increased in LPS-treated WT mice, and its interaction with ICAM-1 stabilized ICAM-1 through deubiquitination. USP7 knockout significantly elevated survival rates of septic mice. USP7 knockout reduced pulmonary inflammation, neutrophil extracellular trap (NET) formation, and myeloperoxidase and Cit-H3 levels in septic mice. Moreover, USP7 knockout lowered the levels of organ injury markers (creatine kinase-MB [CK-MB], troponin-I, and blood urea nitrogen [BUN]), liver enzymes (ALT and AST), and inflammatory markers (TNF-α, IL-1β, IL-6, and IL-8). Co-culture of bone marrow-derived macrophages (BMDMs) from WT mice with ICAM-1+ neutrophils elevated levels of TNF-α, IL-1β, and IL-6. These findings suggest that USP7 plays a critical role in driving sepsis-induced NET formation and inflammation by stabilizing ICAM-1. Targeting USP7 may represent a potential therapeutic approach to mitigate sepsis-related inflammation and organ damage.

The age-related decline in accommodative function after the age of 50 years corresponds with an increasing incidence of primary angle-closure disease (PACD); however, the interaction between this decline and PACD remains unexamined. Additionally, refractive error-accommodation associations in elderly individuals, which are critical for PACD pathophysiology, remain unclear, despite a prior pediatric focus. This study evaluated visual functions (including binocular vision, vergence function, and accommodation function) in patients diagnosed with PACD. A total of 51 patients (102 eyes) were included in this prospective study. The subjects were categorized into the following three groups: primary angle-closure/primary angle-closure glaucoma (PAC/PACG), primary angle-closure suspect (PACS), and a control group. Various parameters, including best-corrected near visual acuity, refractive error, Worth's 4 Dot test results, stereoacuity, vergence facility, accommodative facility (AF), and amplitude of accommodation (AMP), were measured and compared across the groups. A negative correlation was noted between AMP and refractive error (p < 0.001). After controlling for age and refractive error, no significant difference in AMP was detected; however, a statistically significant difference in AF was noted among the groups. PACS (p = 0.002) and PAC/PACG (p = 0.048) emerged as independent predictors of strong AF compared with normal controls. No significant differences in best-corrected near visual acuity, binocular vision, or vergence facility were observed between the groups. This research demonstrated that patients diagnosed with PACS and PAC/PACG exhibited stronger AF compared with the control group. Furthermore, a negative correlation between AMP and refractive error was observed within the elderly population. This research characterizes the correlation between refractive status and accommodative function, while establishing a link between accommodative function and PACD. Future studies on PACD pathogenesis and clinical management should prioritize accommodative function as a key research focus.