Search Results (26,375)

Background: Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by both motor and non-motor symptoms, including autonomic dysfunction. Structural alterations in the vagus nerve (VN) may contribute to PD pathophysiology, though existing data remain inconsistent. Objective: This study aimed to evaluate morphological changes in the VN using high-resolution ultrasound (USVN) and to investigate associations with autonomic symptoms, heart rate variability (HRV), and clinical characteristics in PD patients. Methods: A cross-sectional study was conducted involving 60 PD patients and 60 age- and sex-matched healthy controls. USVN was performed to assess VN cross-sectional area (CSA), echogenicity, and homogeneity bilaterally. Autonomic symptoms were measured using the Composite Autonomic Symptom Scale 31 (COMPASS-31). HRV parameters—SDNN, RMSSD, and pNN50—were obtained via 24 h Holter monitoring. Additional clinical data included Unified Parkinson’s Disease Rating Scale (UPDRS) scores, transcranial sonography findings, and third ventricle width. Results: PD patients showed significantly reduced VN CSA compared to controls (right: 1.90 ± 0.19 mm² vs. 2.07 ± 0.18 mm²; left: 1.74 ± 0.21 mm² vs. 1.87 ± 0.22 mm²; p < 0.001 and p < 0.02). Altered echogenicity and decreased homogeneity were also observed. Right VN CSA correlated with body weight, third ventricle size, and COMPASS-31 scores. Left VN CSA was associated with body size parameters and negatively correlated with RMSSD (p = 0.025, r = −0.21), indicating reduced vagal tone. Conclusions: USVN detects structural VN changes in PD, correlating with autonomic dysfunction. These findings support its potential as a non-invasive biomarker for early autonomic involvement in PD. Full article

Background: Meniere’s disease (MD) is a rare inner ear disorder characterized by endolymphatic hydrops and symptoms such as vertigo and hearing loss, with no curative treatment currently available. XuanYunNing tablets (XYN) have been clinically used to treat MD, but their molecular mechanisms remain unclear. Objective: This study aimed to systematically evaluate the pharmacological effects of XYN in a guinea pig model of MD and to elucidate the underlying molecular mechanisms of both MD pathogenesis and XYN intervention through integrated multi-omics analyses, including transcriptomics, proteomics, and bioinformatics. Methods: A guinea pig model of endolymphatic hydrops was induced by intraperitoneal injection of desmopressin acetate (dDAVP). Pharmacodynamic efficacy was evaluated via behavioral scoring and histopathological analysis. The differentially expressed genes (DEGs) and differentially expressed proteins (DEPs) modulated by XYN treatment were identified using high-throughput transcriptomic and proteomic sequencing. These data were integrated through multi-omics bioinformatic analysis. Key molecular targets and signaling pathways were further validated using RT-qPCR and Western blotting. Results: Pharmacological evaluations showed that guinea pigs in the model group exhibited a 26% increase in endolymphatic hydrops area, while high-dose XYN treatment reduced this area by 19% and significantly improved functional parameters, including overall physiological condition (e.g., weight and general appearance), auricular reflexes to low-, medium-, and high-frequency sound stimuli, nystagmus, and the righting reflex. High-throughput sequencing combined with integrative omics analysis identified 513 potential molecular targets of XYN. Subsequent network and module analyses pinpointed the JAK-STAT signaling pathway as the central axis. Mendelian randomization (MR) analysis further supported a causal relationship between MD and metabolic, immune, and inflammatory traits, reinforcing the central role of JAK-STAT signaling in both MD progression and XYN-mediated intervention. Mechanistic studies confirmed that XYN downregulated IFNG, IFNGR1, JAK1, p-STAT3/STAT3, and AOX at both mRNA and protein levels, thereby inhibiting aberrant JAK-STAT pathway activation in MD model animals. In addition, a total of 125 chemical constituents were identified in XYN by UHPLC-MS analysis. ZBTB20 and other molecules were identified as potential blood-based biomarkers for MD. Conclusions: This study reveals that XYN alleviates MD symptoms by disrupting a pathological cycle driven by JAK-STAT signaling, inflammation, and metabolic dysfunction. These findings support the clinical potential of XYN in the treatment of Meniere’s disease and may inform the development of novel therapeutic strategies. Full article

Coronavirus disease 2019 (COVID-19) in adults is well characterized and associated with multisystem dysfunction. A subset of patients develop post-acute sequelae of SARS-CoV-2 infection (PASC, or long COVID), marked by persistent and fluctuating organ system abnormalities. In children, distinct clinical and pathophysiological features of COVID-19 and long COVID are increasingly recognized, though knowledge remains limited relative to adults. The exponential expansion of the COVID-19 literature has made comprehensive appraisal by individual researchers increasingly unfeasible, highlighting the need for new approaches to evidence synthesis. Large language models (LLMs) such as the Generative Pre-trained Transformer (GPT) can process vast amounts of text, offering potential utility in this domain. Earlier versions of GPT, however, have been prone to generating fabricated references or misrepresentations of primary data. To evaluate the potential of more advanced models, we systematically applied GPT-4 to summarize studies on pediatric long COVID published between January 2022 and January 2025. Articles were identified in PubMed, and full-text PDFs were retrieved from publishers. GPT-4-generated summaries were cross-checked against the results sections of the original reports to ensure accuracy before incorporation into a structured review framework. This methodology demonstrates how LLMs may augment traditional literature review by improving efficiency and coverage in rapidly evolving fields, provided that outputs are subjected to rigorous human verification. Full article

Background and Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) is now widely acknowledged as belonging to the broader category of metabolic disorders, being closely associated with obesity, insulin resistance, and chronic systemic inflammation. Recent evidence indicates that in MASLD, alterations in the gut–liver axis—particularly increased intestinal permeability may serve as a crucial mechanistic link between metabolic dysfunction and hepatic steatosis. Zonulin, a physiological modulator of intestinal tight junctions, has been suggested as an indicator of compromised barrier integrity; however, its specific role in MASLD remains to be fully elucidated. Materials and Methods: We conducted a prospective observational study including 52 adult patients diagnosed with MASLD. Hepatic steatosis was evaluated using the SteatoTest (FibroMax panel), while fecal zonulin levels were measured by ELISA at baseline. Clinical, anthropometric, and metabolic parameters were assessed. We used ROC curve analysis to explore zonulin’s predictive value for moderate-to-severe steatosis (≥S2). Results: Elevated fecal zonulin (>107 ng/mL) occurred in 26.9% of participants. In a binary logistic model with SteatoTest ≥ S2 as outcome, zonulin was independently associated with clinically significant steatosis (OR per 1 ng/mL = 1.017; 95% CI 1.002–1.032; p = 0.029). Discrimination for ≥S2 was AUC = 0.680 (95% CI 0.535–0.825; p = 0.015). The Youden-optimal cut-off was 57.0 ng/mL (sensitivity 68.2%, specificity 63.3%) versus 40.9%/83.3% at the manufacturer’s 107 ng/mL threshold. Conclusions: Fecal zonulin shows modest discriminatory ability for steatosis and is best used as an adjunct to non-invasive assessment; cohort-specific calibration (57.0 ng/mL) outperformed the generic 107 ng/mL threshold. Full article

Diabetic cardiomyopathy (DCM) is a serious complication of type 2 diabetes mellitus (T2DM), characterized by cardiac dysfunction, inflammation, and fibrosis. In this study, a T2DM mouse model was established by administering a high-fat diet (60% fat) in combination with streptozotocin injection in male C57BL/6J mice. The mice subsequently underwent an eight-week exercise intervention consisting of swimming training, resistance training, or high-intensity interval training (HIIT). The results showed that all three forms of exercise improved cardiac function and attenuated myocardial hypertrophy in DCM mice. Exercise training further downregulated the expression of pro-inflammatory cytokines, including interleukin-6, tumor necrosis factor-α, nuclear factor κB, and monocyte chemoattractant protein-1, and mitigated myocardial fibrosis by suppressing fibronectin, α-SMA, collagen type I alpha 1 chain, collagen type III alpha 1 chain, and the TGF-β1/Smad signaling pathway. Moreover, exercise inhibited the expression of PANoptosis-related genes and proteins in cardiomyocytes of DCM mice. Notably, HIIT produced the most pronounced improvements across these pathological markers. In addition, all three exercise modalities effectively suppressed the aberrant activation of the cGAS–STING signaling pathway in the myocardium. In conclusion, exercise training exerts beneficial effects against DCM by improving cardiac function and reducing inflammation, PANoptosis, and fibrosis, and HIIT emerged as the most effective strategy. Full article

Excessive stress disrupts cardiac homeostasis via complex and multifactorial mechanisms, resulting in cardiac dysfunction, cardiovascular disease, or even sudden cardiac death, yet the underlying molecular mechanisms remain poorly understood. Accordingly, we aimed to elucidate how stress induces calcium dysregulation and contributes to cardiac dysfunction and injury through the nuclear receptor subfamily 3 group c member 1 (NR3C1)/Glomulin (GLMN)/FK506-binding protein 12.6 (FKBP12.6) signaling pathway. Using mouse models of acute and chronic restraint stress, we observed that stress-exposed mice exhibited reduced left ventricular ejection fraction, ventricular wall thickening, elevated serum and myocardial cTnI levels, along with pathological features of myocardial ischemia and hypoxia, through morphological, functional, and hormonal assessments. Using transmission electron microscopy and Western blotting, we found that stress disrupted mitochondrial quality control in cardiomyocytes, evidenced by progressive mitochondrial swelling, cristae rupture, decreased expression of fusion proteins (MFN1/OPA1) and biogenesis regulator PGC-1α, along with aberrant accumulation of fission protein (FIS1) and autophagy marker LC3. At the cellular level, ChIP-qPCR and siRNA knockdown confirmed that stress activates the glucocorticoid receptor NR3C1 to repress its downstream target GLMN, thereby preventing FKBP12.6 ubiquitination and degradation, resulting in calcium leakage and overload, which ultimately impairs mitochondrial quality control and damages cardiomyocytes. In conclusion, our findings reveal that stress induces myocardial damage through NR3C1/GLMN-mediated FKBP12.6 ubiquitination, disrupting calcium homeostasis and mitochondrial quality control, and lay a theoretical foundation for dissecting the intricate molecular network of stress-induced cardiomyopathy. Full article

In addition to its role in angiotensin II (Ang II) production, chymase exhibits various functions, including activation of latent transforming growth factor beta 1 (TGF-β1) and pro-matrix metalloproteinases (MMPs). However, the extent to which these Ang II-independent functions contribute to pathological conditions remains unclear. In this study, we investigated the Ang II-independent roles of chymase in cardiac remodeling and dysfunction. Eighteen male Syrian hamsters, aged 6 weeks and weighing 90–110 g, were used. Exogenous Ang II was administered to a hamster model that mirrors the human chymase-dependent Ang II production pathway, via subcutaneous osmotic mini pumps (2 mg/kg/day) for 4 weeks. A chymase-specific inhibitor, TY-51469 (10 mg/kg/day), was given daily starting 1 day after commencement of Ang II infusion. Evaluation showed that while systolic blood pressure increased significantly, only diastolic dysfunction developed over time. Ang II treatment led to elevated cardiac expression of chymase, TGF-β1, and MMP-2, and increased the number of chymase-positive mast cells, resulting in notable cardiac hypertrophy and fibrosis. TY-51469 effectively suppressed these molecular changes and improved both cardiac structure and diastolic dysfunction, despite continued Ang II exposure. These results suggest that chymase promotes cardiac remodeling and dysfunction not only through Ang II generation but also by activating profibrotic and matrix-degrading factors, such as TGF-β1 and MMP-2. Full article

Preeclampsia (PE) is not merely a pregnancy complication but a clinical manifestation of underlying vascular dysfunction with long-term health implications. It is diagnosed after 20 weeks of gestation as new-onset hypertension with proteinuria or organ involvement. The condition arises from impaired placental development, particularly defective spiral artery remodeling, which leads to placental ischemia and the release of antiangiogenic factors such as soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng). These circulating factors contribute to systemic endothelial dysfunction, resulting in hypertension, inflammation, and multiorgan stress. Histopathological findings, including acute atherosis and abnormal vascular remodeling, further reflect the cardiovascular damage underlying PE. This review synthesizes emerging evidence on the vascular and histological mechanisms of PE, highlighting novel biomarkers such as microRNAs and neprilysin, and the potential of advanced diagnostic tools, including machine learning. Importantly, PE is now recognized not only as an obstetric disorder but also as an early marker of future cardiovascular disease. This paradigm shift emphasizes the need for personalized prevention strategies, close surveillance of high-risk women, and long-term cardiovascular follow-up. Pregnancy thus represents a critical window for early detection and intervention in women’s cardiovascular health. Full article

Background/Objectives: Cervicodorsal lipodystrophy, commonly referred to as “buffalo hump,” has traditionally been associated with Human Immunodeficiency Virus (HIV)-related antiretroviral therapy. However, similar deformities may also occur independently of HIV treatment. This study aimed to investigate non HIV-associated buffalo hump as a potential clinical marker of underlying metabolic or endocrine disorders. Methods: We retrospectively reviewed 12 HIV-negative patients who presented with cervicodorsal lipodystrophy between 2012 and 2022. Patient demographics, laboratory values, and imaging findings were analyzed. All patients underwent surgical resection of a hypertrophic fat pad. Exploratory statistical analyses were performed using Mann–Whitney U and Fisher’s exact tests and Spearman’s correlation analysis. Results: These 12 patients had a mean age of 56.92 ± 16.69 years and a mean Body Mass Index (BMI) of 30.15 ± 4.59 kg/m². Hypertension and diabetes were each present in 66.7% of patients, and hyperlipidemia in 75%. Three patients were newly diagnosed with metabolic disease. No significant differences were found between newly diagnosed and previously diagnosed patients in age (45.67 ± 21.46 vs. 60.67 ± 14.31 years, p = 0.194) or BMI (32.44 ± 2.39 vs. 29.39 ± 4.99 kg/m², p = 0.145). Group differences in hypertension, diabetes, hyperlipidemia, or liver dysfunction were also not significant (all p > 0.49). No correlation was observed between age and BMI (ρ = −0.158, p = 0.624). Conclusions: Although the small sample size precludes definitive conclusions, the prevalence of obesity, hypertension, and diabetes in this cohort was notably higher than reported in Korean population-based surveys. These findings suggest that non HIV-associated buffalo hump may serve as an externally visible marker of systemic metabolic burden. Metabolic screening should be considered even in the absence of overt systemic disease. Full article

Background/Objectives: Immune checkpoint inhibitors targeting the PD-1/PD-L1 axis have become a standard in the treatment of all stages of non-small lung cancer. Beyond tumor-intrinsic biomarkers like PD-L1 expression, evidence points to the role of patient-related factors, such as body mass index, sarcopenia, and cachexia. These body composition parameters may reflect metabolic reserve or even immune competence and could help stratify outcomes in patients treated with PD-1 and PD-L1. This systematic review aims to evaluate the impact of body composition—specifically BMI, pretreatment weight loss, sarcopenia, and cachexia—on clinical outcomes such as progression-free and overall survival in NSCLC patients treated with immune checkpoint inhibitors. Methods: A systematic literature search was conducted across multiple databases including PubMed, Google Scholar, and Science Direct. We included full-text original research articles (1 January 2020–1 May 2025) reporting clinical outcomes of NSCLC patients treated with PD-1 or PD-L1 inhibitors, in relation to body composition factors (BMI, pretreatment weight loss, sarcopenia, cachexia). Eligible studies involved adults (>18 years) and included observational cohorts or controlled trials; animal or in vitro studies were excluded. Data extraction and risk of bias assessments were performed independently by two reviewers, with discrepancies being resolved through a third one. Results: From 12,358 records identified, 21 studies met the inclusion criteria. Most were retrospective cohorts assessing the impact of pre-treatment weight loss, cachexia, and sarcopenia on ICI outcomes in NSCLC. These factors consistently predicted poorer survival and response, while BMI alone showed limited prognostic value. Considerable heterogeneity in body composition definitions and outcome reporting was observed. Conclusions: Body composition—particularly weight loss, cachexia, and sarcopenia—significantly impacts survival and response in NSCLC patients treated with ICIs. These factors reflect immune–metabolic dysfunction that may impair treatment efficacy. BMI alone is insufficient; routine assessment of muscle mass and cachexia could improve risk stratification. Full article

Gestational complications, such as preeclampsia and gestational diabetes mellitus (GDM), pose significant risks to maternal and fetal health and increase long-term cardiovascular disease risk in offspring. This review aims to synthesize current knowledge on the roles of ferroptosis and neutrophil extracellular trap formation (NETosis)—two regulated cell death pathways—in these pregnancy-related conditions. We performed a comprehensive analysis of preclinical and clinical studies that investigate the involvement of dysregulated iron metabolism, oxidative stress, inflammation, and endothelial dysfunction mediated by ferroptosis and NETosis in gestational pathologies. Evidence indicates that disturbances in maternal iron homeostasis and enhanced formation of lipid peroxides and NETs contribute to placental dysfunction and systemic inflammation, exacerbating disease severity. Therapeutic strategies targeting these pathways are emerging but require further validation. Our review also identifies key gaps in mechanistic understanding, biomarker development, and translational research needs. We conclude that modulation of ferroptosis and NETosis offers promising avenues for improving diagnosis and treatment of pregnancy complications, though carefully designed clinical studies are essential to confirm their clinical utility and safety. Full article

Background and Objectives: Postoperative physical recovery, particularly the acquisition of independent ambulation, is a critical milestone in rehabilitation following living donor liver transplantation (LDLT). Although liver function markers are conventionally used to assess hepatic physiology, emerging evidence has suggested their potential role as prognostic indicators of physical performance. Materials and Methods: This study investigated the association between liver function parameters at the initiation of postoperative physical therapy (total bilirubin [T-Bil], aspartate aminotransferase [AST], and alanine aminotransferase [ALT]) and the independent walking ability of 63 patients who underwent LDLT. A logistic regression model was constructed using these variables, and a receiver-operating characteristic (ROC) curve analysis was performed to evaluate its discriminative performance. Predicted probabilities of each patient were calculated, and the optimal cutoff value was determined based on the Youden Index. Results: The multivariate logistic regression model demonstrated a statistically significant association between liver function markers and the ambulation status of a cohort of 63 patients. The ROC curve analysis yielded an area under the ROC curve (AUC) of 0.8416 (95% confidence interval [CI]: 0.715–0.968), indicating strong predictive performance. The optimal cutoff value was 0.865, with sensitivity and specificity of 74.1% and 88.9%, respectively. The bootstrap CI for sensitivity at this threshold ranged from 0.6111 to 0.8519. The Hosmer–Lemeshow test indicated good model fit (p = 0.363), and the correct classification rate was 87.3%. Conclusions: Liver function test results may be indicators of hepatic dysfunction as well as functional biomarkers that could predict ambulatory outcomes following LDLT. This predictive model may enhance early clinical decision-making regarding rehabilitation and discharge planning. Future prospective studies should be performed to validate the generalizability of these results to broader clinical contexts. Full article

Cirrhotic cardiomyopathy (CCM) is a cardiac dysfunction in patients with cirrhosis, occurring in the absence of structural heart disease. It increases perioperative risk, especially in liver transplantation, and may contribute to hepatorenal syndrome. Despite its clinical significance, CCM remains poorly understood and lacks effective treatments. This review aims to summarize recent findings on the pathogenesis of CCM and highlight potential therapeutic targets. A focused literature review was conducted using PubMed, Scopus, and Clarivate databases, selecting studies from the last five years. Included studies investigated molecular, cellular, and receptor-mediated mechanisms involved in CCM. Results: CCM results from neurohumoral, inflammatory, and electrophysiological disturbances. Key mechanisms involve dysfunction of β-adrenergic and muscarinic receptors, altered ion channels (potassium, L-type calcium), impaired sodium–calcium exchange, and suppression of the P2X7 receptor (P2X7R). Dysregulation of the CD73 (5’-nucleotidase, ecto-5’-nucleotidase)–A2 adenosine axis, along with effects from endocannabinoids, nitric oxide (NO) inhibition by tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6), carbon monoxide (CO), and elevated galectin-3 (Gal-3), further contribute to myocardial dysfunction. Conclusions: CCM is a multifactorial condition linked to systemic and myocardial effects of cirrhosis. A deeper understanding of its mechanisms is essential for developing targeted therapies. Further research is needed to improve patient outcomes. Full article

Background/Objectives: Fecal peritonitis following penetrating abdominal trauma is a serious condition that often results in sepsis and organ failure. The aim of our study was to develop a novel conscious porcine model of sepsis and organ dysfunction caused by multiple penetrating injuries to the small and large intestines. Methods: Twelve female Yorkshire pigs (average weight 50.6 ± 6.5 kg) were divided into two groups: Penetrating Abdominal Trauma (PAT) (n = 8) and Control (n = 4). All surgical procedures were performed under anesthesia with adequate analgesia. In the PAT group, the small and large intestines were punctured, and feces mixed with saline were introduced into the abdominal cavity to induce peritonitis. The Control group received sham surgery with only saline solution. The animals were observed in a conscious state over a period of 72 h, vital parameters were recorded, and blood samples were taken regularly. We adapted a pig-specific SOFA score and developed pig-specific SIRS criteria and NEWS2 score to assess organ function. The model was validated by independent investigators. Results: The survival rate in the PAT group was 75%, with an average survival time of 58.5 h, while all animals in the Control group survived to euthanasia. Monitoring showed pathophysiological changes, such as tachycardia, leucopenia, and thrombocytopenia, indicative of sepsis and organ dysfunction. Blinded investigators independently confirmed the model’s validity. Conclusions: A new swine model of penetrating abdominal trauma and sepsis has been successfully developed that demonstrates significant physiological and immunologic changes comparable to human sepsis. This new model provides a realistic platform for future research into sepsis, its diagnostics, and the evaluation of therapeutic strategies. Full article

Background: Hereditary transthyretin amyloidosis (ATTRv) is a rare, autosomal dominant multisystem disease caused by pathogenic variants in the transthyretin (TTR) gene. Although ATTRv is classically categorized into “cardiac” and “neurologic” phenotypes, recent evidence suggests a more complex and overlapping disease spectrum. Objectives: This study investigates the relationship between neurological staging and cardiac involvement through an integrated assessment of patients with confirmed TTR mutations. Methods and Results: Fifty-eight patients with genetically confirmed ATTRv (41% female, mean age 60 ± 15 years) were evaluated. Genotypes included Phe64Leu, Val30Met, Val122Ile, and others. Patients were stratified by neurological stage: G0 (asymptomatic carriers), G1 (symptomatic but ambulatory), and G2 (requiring walking support). Cardiac assessment included clinical evaluation, echocardiography with tissue Doppler, global longitudinal strain (GLS), and NT-proBNP levels. Cardiac markers worsened with neurological stage. NT-proBNP, left ventricular mass index, maximal wall thickness, and E/E′ ratio increased progressively, while GLS declined (G0: –19%, G1: –14%, G2: –13%; p < 0.001), indicating a progressive structural and functional myocardial disease. Ejection fraction remained preserved. Neurological stage independently predicted cardiac dysfunction after age adjustment. Conclusions: This is the first study to assess cardiac abnormalities across neurological stages in a well-characterized cohort of ATTRv patients. Cardiac involvement in ATTRv begins early, even in asymptomatic carriers, and progresses with neurological deterioration. GLS and diastolic parameters are sensitive indicators of early myocardial dysfunction, highlighting the need for integrated neurologic and cardiac monitoring in all patients with ATTRv, regardless of initial phenotype. Full article