The Kaohsiung journal of medical sciences最新文献

Triple-negative breast cancer (TNBC) is characterized as an aggressive malignancy with limited therapeutic options. The circular RNA circ_0006174 has been implicated in oncogenic processes across various cancers; however, its specific role in the pathogenesis of TNBC remains unclear. This study employed a range of in vitro assays, including cell counting kit-8, transwell invasion, ELISA, flow cytometry, RNA pull-down, dual-luciferase reporter, RNA immunoprecipitation, and western blotting, to investigate the function of circ_0006174 in TNBC. In vivo validation was conducted using xenograft models, with HE staining and immunohistochemistry. The results showed that overexpression of circ_0006174 was associated with poor prognosis in TNBC patients. Silencing circ_0006174 genetically resulted in reduced proliferation, invasion, and PD-L1-mediated immune-moderation in TNBC cells. At the molecular level, circ_0006174 was found to sequester miR-3139, leading to the upregulation of PD-L1. Furthermore, the regulation of circ_0006174 by METTL3 was shown to be dependent on m6A methylation, with the primary m6A methylation site identified at position 315. In vivo interference led to a reduction in tumor burden and the decreased expression of ki-67 and PD-L1, while increasing the levels of miR-3139 and IFN-γ. Therefore, circ_0006174, regulated by METTL3-mediated m6A methylation, promoted the progression of TNBC through the miR-3139/PD-L1 axis. This study was the first to validate the circ_0006174 as a novel m6A-modified circRNA as well as the circ_0006174/miR-3139/PD-L1 axis as a potential target for TNBC.

Diabetic cardiomyopathy (DCM) is a common complication of diabetes mellitus. This study investigated the effects of alogliptin on DCM and its underlying mechanisms. A DCM model was constructed and treated with alogliptin. Downstream targets of alogliptin were screened using bioinformatics analysis. An in vitro DCM model was constructed using mouse cardiomyocytes with a high concentration of glucose. Echocardiography was performed to measure the heart function parameters. Myocardial damage, collagenous fibrosis, and apoptosis of cardiomyocytes in mouse heart tissues were assessed using cardiac histological staining. AURKB and NLGN2 levels, ROS levels, MDA levels, SOD activity, and cardiomyocyte viability were determined. Alogliptin ameliorated DCM in mice. Bioinformatics analysis revealed that the target of alogliptin was AURKB, and the downstream target of AURKB was NLGN2. AURKB and NLGN2 levels were reduced in the heart tissues of streptozotocin-induced mice. Combined knockdown of AURKB and NLGN2 inhibited the therapeutic effect of alogliptin in DCM mice. Alogliptin attenuated oxidative stress, increased viability, and decreased apoptosis in cardiomyocytes treated with high glucose, which were reversed by combined knockdown of AURKB and NLGN2. Overall, alogliptin ameliorated oxidative stress in cardiomyocytes and DCM in mice by promoting AURKB expression to transcriptionally activate NLGN2.

A high percentage of women who undergo the transition to postmenopause experience both menopausal symptoms and genitourinary syndrome of menopause (GSM). However, GSM is often underdiagnosed. This research aims to identify risk factors that may influence the number of GSM symptoms and whether they cause distress in Taiwanese women > 45 years of age who experienced at least one GSM symptom. Data were collected using a self-developed questionnaire, the Taiwanese Greene Climacteric Scale, and the Genitourinary Symptoms Scale. Participants reported a low frequency and low level of distress related to menopause symptoms (14.33 ± 9.12; 10.75 ± 10.01, respectively) with an average of 3.64 genitourinary symptoms experienced. The majority of participants (59.7%) reported experiencing distress regarding GSM. Multivariate analyses indicated that the distress level of menopause symptoms (p < 0.001), distress caused by genitourinary symptoms (p < 0.001), BMI > 24.0 kg/m² (p = 0.034) and seeking medical consultation for incontinence (p < 0.001) were significantly associated with the number of genitourinary symptoms. Notably, a higher level of distress regarding menopause symptoms (p = 0.022), a greater number of genitourinary symptoms (p < 0.001), and having sought medical consultation due to genitourinary symptoms (p = 0.007) were significantly associated with experiencing distress caused by genitourinary symptoms. This study highlights the importance of patient education, proactive discussions, and addressing barriers to healthcare and cultural factors in GSM management. Healthcare professionals might consider providing additional assessments for GSM in older women who are admitted to the hospital for other diseases and highlight the distress caused by genitourinary symptoms, as GSM is frequently underreported yet treatable.

Diabetic retinopathy (DR) is a leading cause of vision impairment in patients diagnosed with Type 2 diabetes mellitus (T2DM). Awareness of risk factors is necessary to reduce or prevent harmful effects of DR such as irreversible vision loss, and to help ensure early treatment. This study aimed to evaluate associations between initial HbA1c at diabetes diagnosis, longitudinal changes, and medication adherence (MR), and the severity and progression of sight-threatening diabetic retinopathy (STDR). From July 2022 to January 2024, 300 patients with T2DM aged ≥ 20 years were recruited, and the data of 178 patients with complete data were analyzed, focusing on initial HbA1c levels at DM diagnosis, subsequent HbA1c changes at ophthalmologic visits, and MR using the Taiwanese version of the Morisky Medication Adherence Scale-8 (MMAS-8). Patients with persistently high or fluctuating HbA1c levels had a higher risk of severe DR compared to those with consistently low HbA1c. High initial HbA1c was more strongly associated with DR severity in females, patients aged < 65 years, and those without diet or exercise control. Poor or moderate MR was associated with higher HbA1c at follow-up and increased STDR risk. In contrast, patients aged ≥ 65 years were less likely to develop severe DR. Findings of this study accentuate the importance of initial glycemic control and HbA1c trends during ophthalmologic care in managing DR progression, suggesting that patients with high initial HbA1c may benefit from closer early ophthalmic monitoring.

Intracerebral hemorrhage (ICH) is a life-threatening stroke subtype that lacks effective drug therapy. In the context of ICH, neuroinflammation, and ferroptosis are key contributors to secondary brain injury. In this study, we assessed the neuroprotective effects of matrine (MAT) and its mechanism of action involving the HMGB1/RAGE axis in an ICH mouse model. ICH was induced in mice by autologous blood injection. MAT (1.5 or 20 mg/kg) was administered orally 5 min postinduction. ICH significantly upregulated RAGE and its associated proteins (HMGB1, protein kinase C [PKC], phospholipase C [PLC], and β-amyloid), confirming pathway activation. Molecular docking revealed a specific hydrogen bond interaction between MAT and RAGE but not with PKC or PLC. MAT improved neurological performance, reduced hematoma volume and brain edema, and restored blood-brain barrier integrity through upregulation of tight junction proteins (ZO-1, Occludin, Claudin-4). MAT suppressed activation of the HMGB1/RAGE pathway and downstream kinases JNK, p38, ERK1/2, and NF-κB p65. It also decreased IL-1β, IL-6, and TNF-α levels, reduced Bax, increased Bcl-2, and mitigated neuronal apoptosis. Additionally, MAT lowered Fe²⁺ accumulation, inhibited ACSL4, and restored GPX4 levels, indicating ferroptosis suppression. RAGE knockdown mimicked the effects of MAT and negated its therapeutic benefits. MAT induced no detectable liver or kidney toxicity. This study is the first to demonstrate that MAT alleviates ICH-induced neurological deficits by targeting the HMGB1/RAGE axis-mediated ferroptosis, thereby extending the current understanding of the neuroprotective mechanisms of MAT beyond its known anti-inflammatory and antioxidant actions.

Schwann cells (SCs) support axonal function and promote nerve regeneration. This study investigated how various glucose concentrations influence SC viability, oxidative stress, and autophagy, which contribute to diabetic neuropathy. RSC96 SCs were cultured under five glucose conditions (0, 2.5, 5.5, 50, or 100 mM) for 24, 48, and 72 h. Cell viability was assessed by MTT; ROS levels were determined by DCFDA staining, and apoptosis and ER stress markers, as well as autophagy-related proteins were assessed by Western blotting. Autophagic flux was also analyzed using bafilomycin A1 and Cyto-ID. The results revealed time-dependent increases in cell death across all glucose conditions, especially under deprivation and low glucose (LG) conditions. ROS, CHOP, Bax, and cleaved caspase-3 levels increased from 24 to 72 h. The initial increase in the LC3B-II/I ratio indicated that autophagy was overactivated under glucose deprivation or LG conditions but impaired by 72 h, as indicated by reduced Lamp-2 expression. High glucose conditions led to early and persistent autophagy suppression, with minimal autophagic flux and vacuole formation. These findings demonstrate that SCs are sensitive to glucose levels and undergo distinct autophagic impairments through different mechanisms under persistent low or high glucose environments.

Hepatitis C virus (HCV) infection is an infectious disease carrying a high risk of metabolic disorders. Chronic HCV (CHC) patients can possess extrahepatic manifestations such as diabetes, steatotic liver disease (SLD), and other metabolic alterations. Hepatic steatosis, which is triggered by insulin resistance or the direct insult of a specific genotype, is commonly observed in CHC. The changes in SLD after HCV eradication by direct-acting antivirals (DAAs) present a significant impact on patient outcomes. We reviewed the changes in cardiometabolic risk factors (CMRFs) and the evolution of CMRFs items in CHC patients with SLD after HCV cure. The reassessment of CMRFs after the successful eradication of HCV is an essential task for primary care providers. CHC patients could benefit from appropriate management of both infectious and metabolic disorders in terms of liver and nonliver related outcomes.

This study evaluated the prognostic value of the C-PLAN index in advanced esophageal squamous cell carcinoma (ESCC) patients receiving immune checkpoint inhibitor (ICI) therapy. A retrospective analysis of 241 eligible patients treated during February 2020 to January 2023 was conducted. Based on the C-PLAN index, calculated from lactate dehydrogenase (LDH), C-reactive protein (CRP), performance status (PS), albumin (ALB), and derived neutrophil-to-lymphocyte ratio (dNLR), patients were categorized into Good (0-1 points) and Poor (2-5 points) groups. The Poor group exhibited more advanced clinical stages and larger tumor diameters (both p < 0.05). The Good group demonstrated a significantly higher objective response rate and disease control rate (both p < 0.05), lower progression/death incidence (both p < 0.001), and longer progression-free survival and overall survival (p < 0.001). Multifactorial Cox regression analysis revealed that PD-L1 CPS < 10%, clinical stage IV, and high C-PLAN score (2-5 points) were independent risk factors for disease progression or death following ICI therapy in patients with advanced ESCC. The C-PLAN index effectively stratifies prognosis and optimizes therapeutic decision-making for advanced ESCC. The C-PLAN index serves as a prognostic factor, providing an objective basis for survival assessment and treatment plan optimization in advanced ESCC patients.

Steroid-induced osteonecrosis of the femoral head (SIONFH) is a debilitating orthopedic condition. This study investigated the mechanism of Tanshinone I (TsI) in SIONFH modulating apoptosis in SIONFH via the PI3K/AKT/mTOR pathway. A SIONFH rat model was treated with TsI and a PI3K activator. Bone mineral density (BMD), bone volume/total volume (BV/TV), trabecular number (Tb.N), trabecular thickness (Tb.Th), and trabecular separation (Tb.Sp) were determined by microCT. Empty lacunae count, Osteopontin, and apoptosis of the femoral head tissues were assessed. Levels of Bax, cleaved-caspase-3, Bcl-2, and AKT, PI3K, and mTOR phosphorylation in femoral head tissues were determined by Western blot. SIONFH rats exhibited decreased BMD, BV/TV, Tb.N, and Tb.Th, increased Tb.Sp, reduced Osteopontin-positive cells, increased empty lacunae rate, and TUNEL and Osteopontin co-positive cells, elevated Bax and cleaved-caspase-3 protein levels, and diminished Bcl-2 protein expression. TsI promoted osteogenesis, attenuated SIONFH, and reduced apoptosis in SIONFH rats. TsI inhibited AKT, PI3K, and mTOR phosphorylation levels in the femoral head tissues of SIONFH rats, thereby repressing the PI3K/AKT/mTOR pathway activation. Activating the PI3K/AKT/mTOR pathway partially reversed TsI's effect in rats. Collectively, TsI limited the PI3K/AKT/mTOR pathway activation to reduce osteocyte apoptosis in SIONFH rats, which provided potential therapeutic insights for SIONFH treatment.