Background The triglyceride-glucose-HDL-BMI (TyHGB) index combines triglycerides, HDL cholesterol, fasting glucose and BMI, which overlap with components used in cardiovascular-kidney-metabolic (CKM) staging. We examined its cross-sectional association with advanced CKM syndrome in two population-based cohorts. Methods We analysed adults aged 45 years or older in two population-based cohorts. Advanced CKM syndrome was defined as stages 3–4. Missing covariates were imputed using random forests. Associations were estimated with multivariable logistic regression, restricted cubic splines and subgroup analyses. Results The analytic sample included 12,286 US participants and 17,562 Chinese participants. In the extended clinical-adjustment model (Model 4), each one-unit increase in TyHGB was associated with higher odds of advanced CKM syndrome in the US cohort (OR, 1.18; 95% CI, 1.13–1.22) and Chinese cohort (OR, 1.26; 95% CI, 1.22–1.30). Participants in the highest TyHGB quartile also had higher odds in both cohorts. Spline analyses showed positive, approximately monotonic associations without significant non-linearity. Conclusions Higher TyHGB was consistently associated with advanced CKM syndrome in two population-based cohorts. Because TyHGB and CKM staging share metabolic components, the findings describe an epidemiological association rather than independent prediction or additional clinical utility.
Background Cardiovascular–kidney–metabolic (CKM) syndrome integrates metabolic risk, kidney dysfunction and cardiovascular disease. The C-reactive protein–triglyceride–glucose index (CTI) combines inflammatory, lipid and glycaemic measures, but its association with advanced CKM across populations remains unclear. Methods Cross-sectional analyses included adults aged ≥45 years from NHANES 2001–2010 and the 2011 and 2015 CHARLS waves. NHANES included 6290 participants from five consecutive two-year cycles with positive fasting-subsample weights. CHARLS included 19,347 observations from 13,867 participants; models adjusted for survey wave, with standard errors clustered by participant. CTI was examined continuously, per cohort-specific SD, by quartiles and with three-knot restricted cubic splines. Analyses included core and expanded models, sensitivity analyses and comparisons of concurrent discrimination. Results Core-model odds ratios per one-unit higher CTI were 1.76 (95% CI, 1.57–1.98) in NHANES and 2.90 (2.72–3.10) in CHARLS, attenuating to 1.50 (1.30–1.72) and 1.37 (1.26–1.49), respectively, after expanded adjustment. Sensitivity estimates remained positive. Overall spline associations were significant; non-linearity was absent in NHANES (P = 0.384) but present in CHARLS (P = 0.0039). Conclusions Higher CTI was cross-sectionally associated with prevalent advanced CKM. Shared measurement domains and contemporaneous assessment limit causal and prospective interpretation, and the clinical value of CTI remains uncertain.
Background The immunometabolic mechanisms behind the protective association between physical activity and reduced sepsis risk remain poorly understood. Methods We combined global epidemiological data, Mendelian randomization, bulk and single-cell transcriptomics, machine learning, clinical analyses and macrophage functional experiments to explore how physical activity modulates sepsis susceptibility. Results Physical inactivity, metabolic dysfunction and high BMI substantially contribute to global sepsis burden. Mendelian randomization indicated a causal protective effect of physical activity partially mediated by metabolic pathways. The renin-angiotensin system (RAS), represented by the ACE/ACE2 ratio, acts as a core regulatory network linking physical activity to sepsis. Macrophages are key effector cells, with ACE, ACE2, GLUT4, TLR4, CHPT1 and LBP identified as core immunometabolic regulators. Asparagine alleviated inflammasome-triggered macrophage injury in an LBP-dependent manner. Clinical data showed RAS inhibitor use was associated with improved 28-day survival in sepsis patients. Conclusion Physical activity reduces sepsis risk through renin-angiotensin system and LBP-centered immunometabolic regulation, providing potential preventive and therapeutic targets.
Background Ovarian cancer (OC) is characterized by tumor microenvironment remodeling and immune dysregulation. Methods We integrated bulk, single-cell, and spatial transcriptomic data with co-expression, immunotherapy-response, pan-cancer, and exploratory machine-learning analyses. FXYD5 was examined in ovarian cancer cells using silencing, overexpression, phenotypic assays, and captopril or losartan treatment. Results FXYD5 was upregulated in OC and showed opposite patterns in ovarian cancer- and exercise-responsive datasets. Higher expression was associated with shorter overall survival, ACE-AGTR1-TGFB1-related transcription, and inflammatory, stromal, angiogenic, epithelial-mesenchymal transition (EMT), and immune-checkpoint signatures. In a 32-patient anti-PD-1 cohort, FXYD5 expression differed between responders and non-responders, without independent validation. Single-cell and spatial analyses linked FXYD5 to malignant epithelial and myeloid compartments and macrophage- and fibroblast-enriched regions. FXYD5 silencing reduced cell viability and colony formation, whereas overexpression produced opposite effects and altered the expression of genes related to the renin–angiotensin system (RAS) and EMT. Captopril and losartan reduced viability in FXYD5-overexpressing cells, but missing matched drug controls precluded attribution to FXYD5-specific RAS dependence. Pan-cancer associations were context dependent. Conclusions FXYD5 is associated with adverse clinical and microenvironmental features and RAS/TGFB1-related programs in OC, but its mechanistic and therapeutic roles require further validation.
Cardiac hypertrophy is a dynamic adaptive response of the heart to physiological and pathological stimuli. Physiological hypertrophy, such as that induced by exercise training and pregnancy, is generally associated with preserved cardiac function and reversible remodeling. In contrast, pathological hypertrophy is characterized by fibrosis, oxidative stress, inflammation, and progression to heart failure. Among the major regulatory systems involved in cardiac remodeling, the renin–angiotensin system (RAS) plays a central role in both adaptive and maladaptive cardiac growth. While activation of the classical ACE/Ang II/AT1 receptor axis promotes pathological remodeling, the counter-regulatory ACE2/Ang-(1–7)/Mas axis exerts important cardioprotective effects by attenuating pathological cardiac hypertrophy and fibrosis. In addition, growing evidence indicates that this protective axis also contributes to the appropriate development of physiological hypertrophy, particularly during exercise training and pregnancy, supporting adaptive cardiac growth and remodeling. In this review, we provide an overview of the RAS and the general characteristics of physiological and pathological cardiac hypertrophy, highlighting the role of the ACE2/Ang-(1–7)/Mas axis as a key regulator of cardiomyocyte growth, myocardial remodeling, and cardiac adaptation under physiological and pathological conditions.
