Cardiovascular-kidney-metabolic (CKM) syndrome reflects the overlap of cardiovascular, kidney, and metabolic dysfunction and is associated with increased cardiovascular disease (CVD) risk. Whether cardiovascular health, assessed by Life’s Essential 8 (LE8), is associated with adverse outcomes in early-stage CKM remains insufficiently characterized, and the related metabolomic profiles are unclear. We conducted an observational dual-cohort study including adults with early-stage CKM (stages 0–2) from the UK Biobank and the National Health and Nutrition Examination Survey (NHANES). LE8 total, lifestyle, and biological scores were categorized as low, medium, or high according to American Heart Association criteria. Cox proportional hazards models were used to examine associations with incident CVD and mortality in the UK Biobank and all-cause mortality in NHANES. Exploratory metabolomic mediation analyses were performed in the UK Biobank using 168 non-derived nuclear magnetic resonance biomarkers. During a median follow-up of 14.4 years in the UK Biobank, participants with high LE8 scores (80–100) had a significantly lower risk of incident CVD (HR = 0.50, 95
Type 2 diabetes mellitus (T2DM) is a major risk factor for fibrosis progression in metabolic dysfunction-associated steatotic liver disease (MASLD), but the underlying mechanisms remain incompletely understood. The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) is a key regulator of immune and metabolic pathways, and has been implicated in liver fibrogenesis. This study aims to elucidate the role of the cGAS-STING pathway in T2DM-associated MASLD fibrosis and its underlying mechanisms. A T2DMmouse model was established in male C57BL/6J mice by a high-fat diet (HFD) with a low-dose intraperitoneal streptozotocin (STZ) injection, followed by assessment of hepatic biochemical parameters. For the in vitro model, mouse hepatic stellate cells (mHSCs) were treated with high glucose and palmitic acid (HGPA) to mimic the glucolipotoxic microenvironment of T2DM. The cGAS-STING pathway was markedly activated in the liver of T2DM conditions. Pharmacologic inhibition of STING with C176 attenuated liver fibrosis in vivo and suppressed HSC activation in vitro. Mechanistically, cGAS-STING inhibition reduced the expression of key glycolytic enzymes, decreased intracellular pyruvate and lactate accumulation, and downregulated the fibrotic markers αSMA and COL1A1. Moreover, exogenous sodium lactate partially reversed the inhibitory effect of C176 on HSC activation, supporting a role for the glycolysis-lactate axis downstream of cGAS-STING signaling. These findings suggest that the cGAS-STING pathway promotes HSC activation and liver fibrosis in T2DM-associated MASLD, at least in part by enhancing glycolytic reprogramming and lactate production. Targeting the cGAS-STING-lactate axis may therefore represent a potential therapeutic strategy for fibrosis in the setting of T2DM-associated MASLD.
Obesity is a global health crisis and a major modifiable risk factor for cardiometabolic disorders, with prevalence continuing to rise worldwide. Saffron (Crocus sativus) has shown promise for managing obesity indices, but evidence remains inconsistent. This updated systematic review and meta-analysis aimed to evaluate the effects of saffron supplementation on obesity indices in adults. A comprehensive search was conducted in the Scopus, PubMed, and Web of Science databases through February 2026. Randomized controlled trials (RCTs) examining the effects of saffron on obesity indices in adults aged ≥18 years were included. Data extraction and quality assessment using the Cochrane Risk of Bias tool were performed independently by two reviewers. Statistical analyses were conducted in Stata 14, and weighted mean differences (WMD) and 95
Thermogenic adipose tissue, including classical brown adipose tissue (BAT) and inducible beige adipocytes, has re-emerged as a promising therapeutic target in the obesity field. Because BAT can convert chemical energy into heat while also playing a role in regulating systemic glucose and lipids. However, transforming a laboratory breakthrough into a practical treatment has proven to be more of a marathon than a sprint. Two main obstacles keep hindering progress. First, we still primarily “see” human BAT through imaging surrogates rather than directly measuring its actual thermogenic output. More importantly, we have learned the hard way that mechanistic insights from inbred rodents often do not translate well to the complex, varied fat depots in humans. In this review, we argue that it is time to move beyond relying solely on 18 F-fluorodeoxyglucose ([^18F]FDG) uptake. We propose a multimodal framework that carefully distinguishes three different states: whether the tissue is present, whether it has been acutely recruited, and whether it is actively functioning. We also explore recent atlas-scale data, which shows that these thermogenic depots are far from uniform. They heavily depend on their specific microenvironment and vary widely from person to person. This inherent “patchiness” helps explain why some individuals respond to certain triggers while others do not. Additionally, the mechanistic landscape has expanded well beyond the traditional uncoupling protein 1 (UCP1)-driven model. We now need to consider UCP1-independent energy pathways, mitochondrial quality-control loops, and the complex “crosstalk” between different organs. Ultimately, turning BAT into a viable clinical tool requires a much stronger alignment between basic mechanisms and the clinical setting. We won’t see real progress until our study designs focus more on endpoints and are far more sensitive to human diversity. The goal isn’t just to see if we can activate the tissue, but to determine what truly constitutes a meaningful functional benefit for a patient.
We investigated the associations of sarcopenia, handgrip strength (HGS), appendicular skeletal muscle mass index (ASMI), and longitudinal changes in sarcopenia status with all-cause mortality among middle-aged and older adults aged ≥ 50 years with cardiovascular-kidney-metabolic (CKM) syndrome. This prospective cohort study included 6,601 participants with CKM syndrome from the China Health and Retirement Longitudinal Study (CHARLS), of whom 454 had sarcopenia at baseline. Sarcopenia was defined according to the Asian Working Group for Sarcopenia 2025 criteria. Cox proportional hazards models and restricted cubic splines were used to examine the associations of sarcopenia, HGS, and ASMI with all-cause mortality. Joint associations across CKM stages were further evaluated. Longitudinal analyses of changes in sarcopenia status were conducted among 4,842 participants with repeated assessments. During a mean follow-up of 8.75 ± 1.34 years, 251 deaths occurred. Sarcopenia was associated with an increased risk of all-cause mortality (HR, 2.098; 95
The ketogenic diet is a high-fat, low-carbohydrate diet. Its role in metabolic regulation has been widely studied. However, its metabolic impact in individuals with hyperlipidemia remains debated, with inconsistent evidence regarding lipid profiles, glycemic control, and inflammatory status. Whether this diet is associated with lower urinary tract symptoms (LUTS) in hyperlipidemic individuals remains unclear. Therefore, this study investigated the association between the ketogenic ratio (KDR) and overactive bladder and nocturia. It also examined whether albumin-corrected anion gap, depressive symptoms, and frailty index mediate this relationship in individuals with hyperlipidemia. A total of 17,633 adults with hyperlipidemia were selected from the National Health and Nutrition Examination Survey (NHANES) database, spanning 2005–2018. The KDR was calculated as (0.9 × fat + 0.46 × protein) / (0.1 × fat + 0.58 × protein + carbohydrates). Weighted multivariable logistic regression models evaluated associations between KDR and overactive bladder (OAB) or nocturia. Restricted cubic spline (RCS) and threshold effect analyses assessed nonlinear relationships. Mediation analyses examined the roles of depressive symptoms, frailty index (FI), and albumin-corrected anion gap (ACAG). Subgroup and interaction analyses identified potential effect modifiers. Among 17,633 individuals with hyperlipidemia, higher KDR was inversely associated with the odds of both OAB and nocturia. When analyzed as a standardized continuous variable, each standard deviation increase in KDR was associated with lower odds of OAB (OR = 0.93, 95
Diet and gut microbiota alterations are key contributors to metabolic syndrome (MetS). As the Dietary Index for Gut Microbiota (DI-GM) captures diet–microbiome interplay, we examined the associations of DI-GM and its components with MetS. A total of 13,684 participants aged 20 years or older from the National Health and Nutrition Examination Survey 2007–2018 were included. DI-GM scores were calculated based on the mean dietary intake from two 24-h dietary recalls. Survey-weighted logistic regression, restricted cubic splines, and stratified analyses were used to assess associations, nonlinear dose–response patterns, and susceptible subgroups. Furthermore, weighted quantile sum (WQS) regression was employed to evaluate the collective impact of DI-GM components on MetS risk. Higher DI-GM scores were associated with a lower odds of MetS, particularly for the unfavorable gut microbiota component (DI-GM: OR = 0.90, 95
Plant-based diets have been garnering increasing attention for their ability to reshape gut microbiota, reduce systemic inflammation, and alleviate joint pain in rheumatoid arthritis (RA). However, dietary responses are not uniform, as substantial inter-individual variability arises from genetic polymorphisms, metabolic diversity, and immune heterogeneity. In some patients, specific foods may exacerbate disease activity, emphasizing the need to identify personal dietary triggers and implement individualized nutritional strategies. Nutrigenomics, which integrates nutrition with genetic profiling, provides a valuable framework for understanding the influence of genetic variants on nutrient absorption, metabolism, inflammatory signaling, and immune regulation. Notably, dietary bioactive compounds can also modulate RA pathogenesis through epigenetic mechanisms, including DNA methylation, histone modifications, and microRNA-mediated regulation, thereby altering gene expression programs associated with autoimmunity and chronic inflammation. Diet-derived metabolites and microbial products further interact with host genomic and epigenomic networks, creating a dynamic nutrient–gene–microbiome axis that shapes RA susceptibility, disease severity, and therapeutic responsiveness. Recent advances in multi-omics technologies, including genomics, epigenomics, transcriptomics, proteomics, metabolomics, and microbiome profiling, have offered deeper insights into nutrient-driven molecular pathways and immune dysregulation in RA. These findings enable precision dietary interventions enriched with anti-inflammatory nutrients and functional bioactive to improve symptom control and long-term outcomes. Artificial intelligence (AI) offers an emerging strategy by integrating multi-omics, clinical, and dietary data to generate actionable personalized nutrition approaches. This review highlights current evidence on nutrigenomic and epigenetic regulation in RA and discusses AI-driven precision nutrition as a future strategy to enhance disease management and patient wellbeing. Nutrigenomics uses genetic differences to tailor specific dietary interventions for individuals. Plant-based foods lower RA inflammation by boosting antioxidants, improving gut health, and cutting saturated fats. Bioactive compounds in food directly modulate immune responses and inflammatory pathways in RA. Nutrition alters gene expression through epigenetic mechanisms, directly influencing how the disease progresses. Combining multi-omics data with AI enables precise nutrition strategies to improve RA management.
An elevation in circulating free fatty acid (FFA) levels due to dysregulated adipose lipolysis is a major factor in the development of metabolic dysfunction-associated steatotic liver disease (MASLD) as a consequence of obesity. Hepatic lipid content also increases in response to trans-10,cis-12 conjugated linoleic acid (t10,c12 CLA), but this can occur independent of obesity. T10,c12 CLA treatment also stimulates adipose lipolysis, thus increasing FFA levels, but whether FFAs contribute indirectly to CLA-induced hepatic lipid accumulation has not been previously investigated. To address this issue, changes in triglyceride accumulation, lipid droplets and regulatory pathways (mTOR, AMPK, PPARα, JNK) related to hepatic lipid uptake (CD36, FABP1), synthesis (ACC, FAS) and secretion (MTP) were compared in lean and obese db/db mice fed control diet or diet containing t10,c12 CLA (0.4
High body mass index (BMI) drives diabetes, but evidence linking population burden and individual risk across settings is limited. To characterize high-BMI-attributable diabetes burden (1990–2023) and BMI-associated incident diabetes risk across diverse cohorts. Using GBD 2023, we quantified high-BMI-attributable deaths and disability-adjusted life years (DALYs) from 1990 to 2023 in six countries. We analyzed 42,280 diabetes-free adults aged ≥ 45 years from six cohorts (CHARLS, HRS, ELSA, KLoSA, MHAS, CRELES; follow-up 3.5–12.0 years). Cox models estimated hazard ratios (HRs) per 1 kg/m² BMI increase with adjustment; restricted cubic splines assessed dose-response. Absolute DALY counts rose 60.6
Metabolic dysfunction-associated fatty liver disease (MAFLD) is increasingly diagnosed in children with overweight or obesity. Diet is a key modifiable factor, yet the role of obesity-preventive dietary patterns in pediatric MAFLD remains unclear. The Dietary Obesity-Prevention Score (DOS) is a food-based index reflecting adherence to a diet favoring obesity prevention, but its association with MAFLD in youth has not been investigated. In this cross-sectional analysis, 505 children and adolescents with overweight or obesity were included. MAFLD was defined as hepatic steatosis on ultrasonography plus BMI-for-age Z-score ≥ 1, consistent with international pediatric consensus criteria. Usual dietary intake was assessed using a validated 147-item food frequency questionnaire, and DOS was calculated from 13 energy-adjusted food groups, including fruits, vegetables, legumes, yogurt, nuts, fish, plant-to-animal protein ratio (protective components), and red meat, processed meats, refined grains, saturated animal fats, ultra-processed products, and sugar-sweetened beverages (adverse components). Multivariable logistic regression estimated odds ratios (ORs) and 95
Sarcopenia and anemia co-occur frequently among middle-aged and older adults, yet the relationship between anemia status transitions and sarcopenia remains poorly characterized. Drawing on data from the China Health and Retirement Longitudinal Study (CHARLS), we conducted an analysis of 2,507 participants aged 45 years and older who were free of sarcopenia at baseline. Anemia was defined according to World Health Organization criteria as hemoglobin levels < 13 g/dL for men and < 12 g/dL for women. Anemia status transitions between 2011 and 2015 were classified as persistent non-anemia, incident anemia, resolved anemia, and persistent anemia. Sarcopenia and its components were ascertained in 2015 according to the Asian Working Group for Sarcopenia 2019 criteria. Multivariable logistic regression, restricted cubic spline analysis, subgroup analyses, and multiple sensitivity analyses were performed. Persistent anemia was significantly associated with higher odds of sarcopenia compared with persistent non-anemia (OR = 1.85, 95
Astaxanthin, a marine-derived carotenoid, has shown antioxidant and anti-inflammatory properties in studies. However, its effects on cardiometabolic risk factors in overweight and obese populations remain inconclusive. Therefore, this systematic review and meta-analysis aimed to evaluate the efficacy of astaxanthin on cardiometabolic risk factors in overweight and obese adults. A comprehensive literature search was conducted to identify relevant studies published up to May 2026, using databases including PubMed, Scopus, Embase, Cochrane, and Web of Science. Standard mean differences (SMDs) or weighted mean differences (WMDs) were analyzed using a random-effects model. Risk of bias was assessed using RoB 2.0, and the certainty of evidence was rated using the GRADE approach. A total of 16 trials comprising 694 participants (346 in the intervention group and 348 in the control group) were included in this meta-analysis. Astaxanthin supplementation was associated with a significant reduction in MDA (SMD: -1.75), CRP (SMD: -0.35), IL-6 (SMD: -0.69), TG (WMD: -2.90 mg/dL), TC (WMD: -2.73 mg/dL), and LDL-C (WMD: -1.09 mg/dL), while increasing SOD (SMD: 1.37) TAC (SMD: 2.31), and HDL-C (1.04 mg/dL). No significant changes were observed in weight, BMI, TNF-α or blood pressure. Subgroup analyses revealed that longer intervention durations (≥ 12 weeks) and higher dosages (≥ 12 mg/day) yielded more pronounced lipid improvements. Astaxanthin supplementation improves oxidative stress, inflammation, and lipid profile in overweight and obese adults, supporting its potential as an adjunctive nutritional strategy for managing cardiometabolic risk factors. However, the low to very low certainty of evidence for several outcomes underscores the need for larger, well-designed trials with standardized formulations.
Gastric signet ring cell carcinoma (GSRCC) is an aggressive subtype of gastric cancer with poor prognosis. Sarcopenia and systemic inflammation have been linked to adverse outcomes in malignancies. This study aimed to evaluate the prognostic value of sarcopenia combined with systemic inflammatory indices in patients with GSRCC. Patients with GSRCC who underwent curative gastrectomy between 2014 and 2018 were retrospectively analyzed and randomly divided into a training cohort (n = 392) and an internal validation cohort (n = 165). Sarcopenia was defined using sex-specific L3 skeletal muscle index (SMI) cutoffs on preoperative CT images. Prognostic factors for overall survival (OS) were identified using univariable Cox, LASSO, and multivariable Cox analyses. Kaplan-Meier analysis was applied to ascertain the prognostic value. A nomogram was constructed and evaluated by concordance index (C-index), calibration curve, and decision curve analysis (DCA). Among 557 patients, 264 (47.4
Cardiovascular-kidney-metabolic (CKM) syndrome is a global health challenge. However, few studies have explored the associations between muscle health and CKM syndrome. This study aimed to investigate the associations between appendicular skeletal muscle mass (ASM), grip strength, and fat-to-muscle ratio (FMR) and advanced CKM syndrome in a Chinese community-based population. We conducted an observational study involving 7,330 Chinese adults. CKM syndrome is categorized into five stages, with stages 3–4 defined as advanced CKM syndrome. An electronic dynamometer and bioelectrical impedance analysis were used to measure grip strength, ASM, and FMR. The FMR was calculated as fat mass divided by muscle mass, and ASM/BMI as ASM divided by body mass index (BMI). Associations of grip strength, ASM/BMI, and FMR with advanced CKM syndrome were assessed using multivariable logistic regression, with subgroup analyses by age and sex. Subgroup analyses were further conducted to explore potential interactions. Advanced CKM syndrome was identified in 8.57
Dietary patterns may influence survival among individuals with sarcopenia, but evidence comparing different dietary indices remains limited. This study examined the associations of six commonly used dietary pattern indices with all-cause and cardiovascular disease mortality among U.S. adults with sarcopenia. This nationally representative cohort study included 1,774 adults with sarcopenia from the National Health and Nutrition Examination Survey with linked mortality data. Sarcopenia was defined according to the Foundation for the National Institutes of Health criteria using DXA-derived appendicular skeletal muscle mass adjusted for body mass index. Dietary patterns were assessed using the alternate Mediterranean diet score (aMED), Healthy Eating Index-2020 (HEI-2020), Dietary Approaches to Stop Hypertension score (DASH), Planetary Health Diet Index (PHDI), Dietary Inflammatory Index (DII), and Ketogenic Diet Ratio (KDR). Survey-weighted Cox proportional hazards models were used to estimate associations with mortality. Restricted cubic spline analyses were performed to assess dose–response patterns. False discovery rate correction and multiple sensitivity analyses were conducted to evaluate robustness. Among 1,774 adults with sarcopenia, 545 all-cause deaths and 183 cardiovascular deaths occurred during follow-up. In fully adjusted survey-weighted Cox models, compared with the lowest quartile, higher aMED adherence was associated with lower all-cause mortality in Q3 (HR = 0.57, 95
Cognitive dysfunction, driven by psychiatric and functional factors, toxic factors, neurodegenerative diseases and cerebrovascular diseases, metabolic diseases, and other systemic diseases, represents a significant global health challenge with limited pharmacological interventions. Emerging evidence highlights Urolithin A (UroA)-a gut microbiota-derived polyphenol of dietary ellagitannins (ETs) and ellagic acid (EA) -as a highly promising neuroprotective candidate. Current research has found that UroA and its derivatives have an effect against cognitive dysfunction. However, there is currently a lack of comprehensive reviews. This review provides a comprehensive insight of aetiology and pathogenesis of cognitive dysfunction, with a specific focus on how UroA and its precursors intercept these pathological trajectories, while evaluating the source and metabolism of Urolithin A. And we deeply dissect its mechanisms against cognitive dysfunction, particularly its capacity to mitigate neuroinflammation, restore autophagy, modulate the gur-brain axis and so on. Moreover, we address current knowledge gaps and focus on future perspectives.
Dietary patterns represent a major modifiable risk factor contributing to metabolic dysfunction-associated steatotic liver disease (MASLD), which can lead to insulin resistance, inflammation, gut dysfunction and hepatic steatosis. Diet-induced animal models have become essential preclinical tools for investigating the underlying pathological mechanisms of MASLD and for identifying potential therapeutic strategies. However, the complex and multifactorial interactions among diet, host metabolism, genetic predisposition, and environmental factors have limited the ability of conventional approaches to accurately predict disease progression. In recent years, artificial intelligence (AI) has emerged as a powerful tool for deciphering the complex diet-related factors involved in the progression from MASLD to hepatocellular carcinoma (HCC). Although these technologies have demonstrated potential in promoting risk stratification for personalized nutritional interventions, most applications remain at the research stage and require further clinical validation. To the best of our knowledge, no review articles are available on the role of AI in understanding diet-related mechanisms involved in MASLD-HCC disease progression. In the present review, we highlight the implications of AI-enabled methodologies in elucidating the role of dietary factors in MASLD-to-HCC progression.
The purpose of this study was to investigate the relationship among physical activity (PA), metabolic syndrome (MetS) and dementia based on UK Biobank. A total of 220,372 dementia-free participants over the age of 50 had available data for outcomes and exposures components were included. Four PA groups [High, Medium, Low and No Moderate-to-vigorous PA (MVPA)], two MetS groups (MetS and No MetS) and eight joint groups were categorized to explore the effects of PA level and MetS status on dementia outcomes. Multivariate Cox proportional hazards regression model was used to explore the associations between PA, MetS and new-onset dementia. During a median follow-up of 13 years, 4778 all-cause dementia [ACD, including 2997 Alzheimer’s disease (AD) and 960 vascular dementia (VD) events] were recorded. In multivariate models adjusting for genetic and biological factors, lifestyle factors and socioeconomic factors, participants with MetS had a 25
Vitamins are essential micronutrients that play crucial roles in human health, including immune function, cell development, energy metabolism, and the function of the nervous system. Within the body, vitamins can activate and modulate various biological pathways by acting as cofactors for enzymes. The objective of this study was to identify microRNAs (miRNAs) associated with the serum concentration of specific vitamins in the general population, and subsequently identifying vitamin associated biological systems and diseases potentially influenced by post-transcriptional regulation of these miRNAs. Data from the population-based Study of Health in Pomerania (SHIP-TREND-0, N = 792) were utilized to examine the associations between vitamin B12 and folic acid (vitamin B9) and 181 miRNAs. Multivariate linear models were employed, adjusting for potential confounders such as age, sex, platelet count, BMI, hemolysis, batch effects, and seasonality. Publicly available databases were used to identify biological pathways influenced by those significant miRNAs. After correction for multiple comparisons, eight miRNAs were found to be positively associated with folic acid, and six miRNAs were positively associated with vitamin B12. The miRNAs significantly associated with folic acid were predominantly found in red blood cells, while those associated with vitamin B12 were associated with red blood cells and T-cells according to the miR-Blood database. Analyses of over-represented miRNAs revealed enrichment in processes related to cell-cycle regulation, DNA synthesis, metabolic processes, and erythropoiesis. In accordance to the known positive role of folic acid and vitamin B12 in pregnancy, nearly all significant miRNAs have been identified to be associated with pregnancy outcomes based on previous research. The analyses revealed that several miRNAs are related to vitamin levels and that these miRNAs are associated with processes such as cell proliferation and human fertility. These miRNAs could be interesting targets for further clinical applications.
