The Kaohsiung journal of medical sciences最新文献

Preeclampsia (PE) is an obstetric disease that is characterized by reduced migration and invasion of placental trophoblast cells. Here, the effects of the E3 ubiquitin ligase UBE3A on the migration and invasion of trophoblast cells were evaluated. RT-qPCR and Western blotting were used to measure the expression of genes and proteins. Immunohistochemical (IHC) staining was used to determine UBE3A and ITGB1 levels in the placental tissues of PE patients. Cell viability was evaluated with a CCK-8 assay. Wound healing and Transwell assays were used to evaluate cell migration and invasion, respectively. Cell cycle progression and apoptosis were analyzed by flow cytometry. Co-immunoprecipitation (Co-IP) was used to verify molecular interactions. Our results revealed that the mRNA and protein levels of UBE3A were upregulated, whereas ITGB1 expression was downregulated in the placental tissues of PE patients. Depletion of UBE3A promoted the migration and invasion of HTR-8/SVneo cells while inhibiting apoptosis. The phosphorylation of PI3K and AKT increased after UBE3A was silenced. Mechanistically, UBE3A induced the ubiquitination and degradation of ITGB1. Functionally, UBE3A reduced cell migration and invasion, as well as induced apoptosis by negatively regulating ITGB1 mediating PI3K/AKT signaling. In summary, our results revealed that UBE3A hindered the migration and invasion of trophoblast cells by facilitating ITGB1 degradation and affecting PI3K/AKT signaling, providing a new therapeutic target for PE treatment.

Unhealthy alcohol use (UAU) screening facilitates identification of patients with alcohol use problems for intervention. This study evaluates the usefulness of gamma-glutamyl transferase (GGT) and sequential percentage of carbohydrate-deficient transferrin (%CDT) in community screening for UAU. In two indigenous communities (A and B), liver disease screening data including GGT, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alcohol use disorders identification test (AUDIT) were reviewed. In Community B, residents with high GGT were invited for sequential evaluation including %CDT, AUDIT, ultrasonography, and liver stiffness measurement. With AUDIT score ≥ 8 and ≥ 4 as UAU criteria for male and female genders, we determined the diagnostic performances and validities of GGT and sequential %CDT in detecting UAU. A total of 1755 residents with available GGT, AST, ALT, and AUDIT were reviewed. UAU prevalence ranged from 7.4% to 44% between communities. For sequential evaluation, 79 residents were enrolled in which 57 (72.2%) were classified as UAU. The performances of GGT, AST, ALT, and AST/ALT ratios in detecting UAU were 0.767, 0.66, 0.597, and 0.549, respectively. With a cutoff of GGT ≥ upper normal limit in detecting UAU, the sensitivity, specificity, accuracy, positive (PPV), and negative predictive value (NPV) were 62.5%, 75.5%, 72.1%, 47.4%, and 85.0%. In Community B, among residents with high GGT, %CDT had a performance of 0.684. With a cutoff of 1.72, the sensitivity, specificity, accuracy, PPV, and NPV were 59.6%, 81.8%, 65.8%, 89.5%, and 43.9%, respectively. GGT and sequential %CDT are useful for screening UAU in indigenous communities with high negative and positive predictive values, respectively.

The 5-hydroxytryptamine type 4 receptor agonist mosapride is known to modulate esophageal peristalsis and enhance lower esophageal sphincter compliance. However, its impact on oropharyngeal swallowing physiology remains insufficiently characterized. This study aimed to investigate the acute effects of mosapride on oropharyngeal swallowing dynamics in adults. Participants received either oral mosapride (40 mg) or placebo 1 h prior to testing in a randomized, crossover design. High-resolution impedance manometry was performed using a solid-state catheter to measure pressure and impedance within the oropharyngeal segment. Each participant underwent at least three swallows of 5, 10, and 20 mL thin and thick liquids administered by syringe. Manometric data were analyzed using the Swallow Gateway web-based platform. Twenty-four volunteers (13 male, mean age, 33 years; range, 24-56 years) completed the study. During thick swallows, mosapride significantly increased upper esophageal sphincter (UES) maximal opening admittance compared to placebo (5 mL: p = 0.017; 10 mL: p = 0.008) and reduced UES integrated relaxation pressure (10 mL: p = 0.018; 20 mL: p = 0.017). No significant effects were observed during thin liquid swallows. A marginal reduction in pre-deglutitive UES basal pressure was noted during 5 mL thick swallows (p = 0.050). Following adjustment using repeated measures ANOVA, only the reduction in UES basal pressure remained statistically significant (p = 0.040). Acute administration of oral mosapride results in reduced UES basal tone in adults. These findings provide novel physiological evidence suggesting that mosapride may modulate neuroregulatory mechanisms controlling UES contractility.

Type 2 diabetes mellitus (T2DM) is associated with an increased risk of osteoporosis and fractures, and denosumab, a non-kidney-excreted antiresorptive medication, represents a viable alternative to bisphosphonates for osteoporosis treatment in patients with T2DM. This study aimed to investigate the association among denosumab adherence, renal function, and all-cause mortality in patients with T2DM and osteoporosis. New denosumab users between 2010 and 2017 were identified from an electronic health record database, and after exclusion, 536 participants were screened and analyzed based on their 2-year drug adherence: high adherence (HA) defined as three or four doses, and low adherence (LA) defined as one or two doses. The 1-year average estimated glomerular filtration rate (eGFR) was calculated, and all-cause mortality was analyzed using Kaplan-Meier curves and Cox regression models. The study included 286 and 250 subjects in the HA and LA groups, respectively, and although eGFR declined in both groups, renal function remained comparable between the groups. The all-cause mortality rate was significantly lower in the HA group compared to the LA group (adjusted hazard ratio: 0.52, 95% confidence interval: 0.29-0.92). High denosumab adherence was found to be associated with a lower risk of all-cause mortality among patients with T2DM and osteoporosis without significantly impacting renal function, highlighting the potential benefits of maintaining regular denosumab treatment in this high-risk population. Nevertheless, this observational study design indicates association rather than causation, and further prospective research is warranted to validate these results and elucidate the mechanisms underlying the relationships observed in this study.

Myocardial infarction (MI), the most prevalent form of acute coronary syndrome, is often accompanied by cardiomyocyte apoptosis. In addition to apoptosis, autophagy plays a critical role in determining cardiomyocyte survival during MI. This study aimed to elucidate the regulatory role of miR-499a-5p in cardiomyocyte apoptosis and autophagy under hypoxic conditions. An MI mouse model was established via ligation of the left anterior descending coronary artery, and RT-qPCR was used to assess miR-499a-5p expression levels in cardiac tissues from MI and sham-operated mice. Masson's trichrome staining was employed to evaluate cardiac fibrosis, and echocardiography was conducted to assess cardiac functional parameters. For in vitro experiments, TUNEL assays and flow cytometry analyses were used to measure apoptosis and autophagy. A luciferase reporter assay confirmed the direct binding between miR-499a-5p and arginine and glutamate rich 1 (ARGLU1). Western blot analysis was used to quantify protein levels of apoptotic markers, autophagy-related proteins, and ARGLU1. The results demonstrated that MI mice developed significant cardiac fibrosis and functional impairment, along with increased miR-499a-5p expression. In H9c2 cells, knockdown of miR-499a-5p significantly reduced hypoxia-induced apoptosis and autophagy, whereas miR-499a-5p overexpression exacerbated these processes. Moreover, ARGLU1 was identified as a direct target of miR-499a-5p and was negatively regulated by it. Silencing ARGLU1 enhanced hypoxia-induced apoptosis and autophagy and reversed the protective effects observed with miR-499a-5p knockdown. In summary, miR-499a-5p inhibition mitigates hypoxia-induced injury in H9c2 cells by reducing apoptosis and autophagy through the upregulation of ARGLU1, suggesting a potential therapeutic target for MI.

After total thyroidectomy for pediatric differentiated thyroid cancer (DTC), the subsequent radioactive iodine (RAI) treatment is a robust therapy, the dosing of which is a major concern. This study was designed to evaluate the "as high as safe administration" (AHASA) principle of RAI treatment in pediatric DTC patients based on the maximum tolerance activity (MTA) of blood to certify dosimetry via a simple algorithm method. Twenty pediatric DTC patients were enrolled and received RAI treatment empirical dosing based on risk stratification after total thyroidectomy. The MTA concentration in the blood was estimated by the modified Hänscheid equation. About 6 (30%) patients had tumors larger than 4 cm, 10 (50%) patients had lateral cervical lymph node metastasis, and 4 (20%) patients had recurrent/persistent thyroid cancer and received more than two RAIs. Five (25%) pediatric patients who had higher serum thyroglobulin antibodies levels at initial diagnosis exhibited aggressive clinical manifestations. Body weight-based doses showed wide variability, and the Dutch recommended dose showed underdosing. In addition, lower body weight was associated with a significantly higher blood absorption dose (R ² = 0.3849, p = 0.014). No severe adverse effects were observed in patients who received empirical RAI dosage according to the AHASA principle. The presentation of pediatric DTC can be advanced and aggressive. Empirical RAI dosing based on risk stratification is a simple, safe and effective method. In compliance with the AHASA principle, for prepubertal patients with very low body weight, it is necessary to calculate the blood MTA for RAI dose adjustment.

Timely and efficient diagnosis of hepatitis C virus (HCV) infection remains the effective approach for the subsequent care cascade of HCV treatment. It is of importance in under-resourced areas. The study aimed to assess the feasibility of a point-of-care (POC) model by a rapid diagnostic test and subsequent confirmational HCV RNA test in remote islands where traffic is an additional hurdle for health care. We conducted a mass POC screening program in 3 outlying islands, including Liuqiu (6.8 km², 12,000 residents), Green (15.1 km², 4280 residents), and Orchid (48.4 km², 5230 residents) islands. We used immunochromatography-based finger-tip assays for HCV antibody detection. Serum HCV RNA was measured among patients seropositive for the rapid anti-HCV test. There were 1055, 268, and 276 adult residents receiving rapid tests in Liuqiu, Green, and Orchid, respectively, yielding response rates of 47.0%, 41.1%, and 24.4%, respectively. The prevalence of anti-HCV-positive were 1.3% (n = 14), 1.1% (n = 3), and 0, respectively. Nine (52.9%) of the 17 anti-HCV-positive patients were HCV RNA-negative. The HCV RNA-positive patients then received anti-viral treatment. The average turnaround time for overall POC HCV test results was 11.8 ± 3.2 min, and the sampling time was completed within 10-30 s. Meanwhile, the labor cost of HCV RNA screening was 156.3 USD, which was a 28.6% decrease compared to traditional methods. The study demonstrated the feasibility and effectiveness of the POC model for HCV elimination in remote islands with limited resources.

Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma and is an aggressive and highly heterogeneous tumor. Kaempferitrin (KPF) is a natural flavonoid glycoside that exerts a protective role in multiple human tumors. However, the impact of KPF on DLBCL remains unclear. In this study, we discovered that 240 μM KPF had a toxic effect on GM12878 cells. KPF inhibited DLBCL cell proliferation while promoting apoptosis in these cells. Additionally, KPF induced ferroptosis in DLBCL cells by elevating intracellular Fe²⁺ levels and reactive oxygen species (ROS) levels, alongside reducing the protein levels of GPX4 and SLC7A11. Moreover, KPF suppressed the activation of NF-κB in DLBCL cells. Building upon this finding, we further validated that KPF reduced DLBCL cell malignant growth through the inhibition of NF-κB activation. Meanwhile, animal studies further suggested that KPF inhibited DLBCL proliferation in vivo, mainly through reduced subcutaneous tumor volume, tumor weight, and increased apoptosis levels in mice. Furthermore, KPF suppressed the disorder of DLBCL cancer tissue arrangement and decreased p-NF-κB and p-IKB-α protein levels in DLBCL subcutaneous tumor tissues. In summary, our findings suggested that KPF enhanced apoptosis and ferroptosis in DLBCL cells via the deactivation of the NF-κB signaling pathway.

Pancreatic cancer (PC) is a highly aggressive malignancy of the digestive system. Recent studies have indicated that the long noncoding RNA SOX21-AS1 is significantly upregulated in PC tissue samples. This study aims to elucidate the biological role and underlying molecular mechanisms of SOX21-AS1 in PC progression. Quantitative real-time PCR (qRT-PCR) and western blot analyses were employed to assess RNA and protein expression levels, respectively. The subcellular localization of SOX21-AS1 was determined using subcellular fractionation assays. PC cell viability, migratory capacity, and apoptosis were evaluated through CCK-8 assays, wound healing assays, and flow cytometry. Dual-luciferase reporter and RNA pull-down assays were conducted to confirm the interactions between miR-9-3p and either SOX21-AS1 or YOD1. Additionally, a xenograft mouse model was established to investigate the in vivo effects of SOX21-AS1. The findings revealed that SOX21-AS1 is highly expressed in PC tissues and cell lines, with its upregulation correlating with poor patient prognosis. Functional assays demonstrated that knockdown of SOX21-AS1 suppressed PC cell proliferation and migration, induced apoptosis in vitro, and reduced tumor growth in vivo. Mechanistically, SOX21-AS1 competitively interacted with miR-9-3p to upregulate YOD1, consequently activating the TGF-β/Smad signaling pathway. Furthermore, overexpression of YOD1 reversed the tumor-suppressive effects observed after SOX21-AS1 knockdown. In conclusion, SOX21-AS1 promotes PC cell malignancy through the miR-9-3p/YOD1 axis and subsequent activation of TGF-β/Smad signaling.