ER carboxylesterase 1A (CES1A) is an important metabolic enzyme involved in lipid metabolism. Targeting the CES1A is a promising approach for diseases associated with disorders of lipid metabolism therapy. In this study, screening of 26 natural lignans, three of them were found displaying potent inhibition on CES1A and high specificity over other serine hydrolases. Inhibition kinetic analyses demonstrated that Schisandrin C and Anwuligan were mixed-type inhibitors, while Magnolol acts as a competitive inhibitor. Further investigation showed that they were cell permeable and exhibited minimal cytotoxicity and mitochondrial toxicity, as well as capable of inhibiting intracellular CES1A in living cells. Further investigation found that three Schisandras decreased the number of lipid droplets (LDs) in free fatty acid (FFA)-treated HepG2 cells. Collectively, our findings suggest that Schisandrin C is a potent and highly selective inhibitor of CES1A, which can be served as a promising lead compound.

Precision diabetology is increasingly becoming diabetes phenotype-driven, whereby the specific hormonal imbalances involved are taken into consideration. Concomitantly, body weight-favorable therapeutic approaches are being dictated by the obesity pandemic, which extends to all diabetes subpopulations. Amylin, an anorexic neuroendocrine hormone co-secreted with insulin, is deficient in individuals with diabetes and plays an important role in postprandial glucose homeostasis, with additional potential cardiovascular and neuroprotective functions. Its actions include suppressing glucagon secretion, delaying gastric emptying, increasing energy expenditure and promoting satiety. While amylin holds promise as a therapeutic agent, its translation into clinical practice is hampered by complex receptor biology, the limitations of animal models, its amyloidogenic properties and pharmacokinetic challenges. In individuals with advanced β-cell dysfunction, supplementing insulin therapy with pramlintide, the first and currently only approved injectable short-acting selective analog of amylin, has demonstrated efficacy in enhancing both postprandial and overall glycemic control in both type 2 diabetes (T2D) and type 1 diabetes (T1D) without increasing the risk of hypoglycemia or weight gain. Current research focuses on several key strategies, from enhancing amylin stability by attaching polyethylene glycol or carbohydrate molecules to amylin, to developing oral amylin formulations to improve patients' convenience, as well as developing various combination therapies to enhance weight loss and glucose regulation by targeting multiple receptors in metabolic pathways. The novel synergistically acting glucagon-like peptide-1 (GLP-1) receptor agonist combined with the amylin agonist, CagriSema, shows promising results in both glucose regulation and weight management. As such, amylin agonists (combined with other members of the incretin class) could represent the elusive drug candidate to address the multi-hormonal dysregulations of diabetes subtypes and qualify as a precision medicine approach that surpasses the long overdue division into T1DM and T2DM. Further development of amylin-based therapies or delivery systems is crucial to fully unlock the therapeutic potential of this intriguing hormone.Graphical abstract available for this article.

This meta-analysis investigates the sex differences in mortality risk between the acute coronary syndrome (ACS) population without standard modifiable risk factors (SMuRF-less) and those with at least one standard modifiable risk factor (SMuRF), and analyses mortality rates between males and females within the SMuRF-less cohort.

The MEDLINE and Embase databases were searched for cohort studies with sex-stratified outcomes for SMuRF-less versus SMuRF patients with ACS till 15 December 2023. The analysis of variables reported in proportions was carried out by utilizing a meta-analysis with a generalized linear mixed model while continuous variables were analyzed by a meta-analysis of means, using an inverse variance method.

Eight studies were included in the current paper, with 82,395 SMuRF-less ACS patients and 607,558 SMuRF ACS patients. Excess in-hospital mortality found in SMuRF-less ACS, compared to those with SMuRFs, were only observed in females (RR 1.56, 95%CI 1.08-2.25, p = 0.029), but not in males (RR 1.59, 95%CI 0.90-2.80, p = 0.088). On longer follow-up, the 1- and 2-year post-ACS mortality rates were similar across the SMuRF-less and SMuRF cohorts, for both sexes. The subgroup analysis of SMuRF-less ACS individuals revealed that SMuRF-less females had higher in-hospital (RR 1.52, 95%CI 1.30-1.78, p = 0.002), 1-year (RR 1.51, 95%CI 1.34-1.71, p = 0.005) and 2-year mortality risks (RR 1.40, 95%CI 1.13-1.75, p = 0.016) compared to the SMuRF-less male counterparts.

Paradoxical excess mortality in SMuRF-less ACS, compared to those with SMuRFs, was only observed in females. Females without cardiovascular risk factors are at the highest risk of short- and medium-term mortality following ACS.

The objective is to evaluate the temporal trends in the burden of cardiovascular diseases attributable to metabolic risk factors from 1990 to 2021 and to project the burden over the subsequent 30 years.

A joinpoint regression model was employed to estimate the annual percentage change in cardiovascular disease mortality attributable to metabolic risk factors, utilizing data from the Global Burden of Disease (GBD) 2021. An age-period-cohort analysis was conducted to evaluate the effects of age, period, and cohort. A frontier analysis was employed to investigate the correlation between the prevalence of cardiovascular disease attributable to metabolic risk factors and socio-demographic trends. An autoregressive integrated moving average (ARIMA) model was subsequently constructed to forecast future cardiovascular disease burden.

Between 1990 and 2021, the global age-standardized mortality rate (ASMR) of cardiovascular diseases attributable to metabolic factors exhibited a consistent decline (Average Annual Percent Change (AAPC) = -1.28, 95% CI [-1.42, -1.14], P < 0.01). However, the absolute number of deaths increased from 8.326 million to 13.595 million. The most substantial reduction in ASMR was observed in the High Socio-Demographic Index (SDI) region (AAPC = -2.98, 95% CI [-3.10, -2.86], P < 0.01), whereas the reductions were relatively smaller in the Low-middle SDI and Low SDI regions. The ARIMA model predicts a decline in global cardiovascular disease mortality over the next three decades, with the most pronounced decrease anticipated in the high-middle SDI region and smaller declines expected in the middle SDI and low SDI regions.

Notwithstanding a global decline in age-standardized mortality and disability-adjusted life year (DALY) rates, the burden of cardiovascular diseases attributable to metabolic factors remains significant worldwide. Targeted interventions must be implemented without delay, particularly for males and populations in low and middle SDI regions, to mitigate the impact of metabolic factors on public health.

The association between visceral adiposity index (VAI) and metabolic dysfunction-associated steatotic liver disease (MASLD) remains unestablished. Our study sought to investigate the potential relationship between VAI and MASLD risk.

This study employed data from the 2017-2018 National Health and Nutrition Examination Survey (NHANES). Weighted multivariable regression models, subgroup analyses, and machine learning algorithms were used to evaluate associations and predictive performance.

Higher VAI tertiles correlated with increased MASLD risk (adjusted OR for T3 vs. T1: 7.08, 95% CI: 4.35-11.5; P-trend=0.003). Machine learning models demonstrated robust predictive accuracy, with random forest (AUC=0.869) and gradient boosting machine (AUC=0.868) outperforming non-invasive scores. However, lipid accumulation product (LAP, AUC=0.834) and fatty liver index (FLI, AUC=0.833) achieved superior diagnostic performance compared to VAI (AUC=0.736), while maintaining clinical interpretability through simplicity and routine parameter availability.

While VAI demonstrated significant positive associations with MASLD risk, non-invasive scores like LAP and FLI emerged as superior diagnostic tools, balancing accuracy with clinical practicality.

Elevated blood pressure (BP) during childhood and adolescence is increasingly being recognized as a precursor to adult hypertension and cardiovascular disease (CVD). This review examines the existing evidence of the relationship between early BP elevations and long-term cardiovascular (CV) outcomes. Previous studies demonstrated a moderate association between childhood BP and adult hypertension, with early BP elevations contributing to subclinical CV changes such as left ventricular hypertrophy and increased carotid intima-media thickness as well as major premature CVD events in adulthood. However, evidence also indicates that BP normalization before adulthood may mitigate these risks, suggesting a critical interventional window before irreversible CV changes occur. Multiple modifiable and nonmodifiable factors contribute to early-life BP elevations, including genetic predisposition, a high sodium intake, obesity, sedentary behavior, and sleep disturbances. Although establishing a direct causal association between childhood BP and adult hypertension or CVD remains challenging owing to the need for longterm follow-up and large sample sizes, further research is essential to addressing the existing knowledge gaps in pediatric hypertension prevention, detection, impact, and treatment. This review highlights the importance of preventing BP elevations early in life to reduce the longterm burden of hypertension and CVD. Promoting healthy behaviors, such as maintaining a healthy weight, reducing one's sodium intake, engaging in physical activity, and ensuring adequate sleep, is essential for managing BP at an early age. These efforts reduce individual CV risk and help alleviate the broader future public health burden of hypertension and CVD.

Defective insulin secretion is a hallmark of diabetes mellitus. Glucose-induced Ca2+ oscillations are critical for the stimulation of insulin secretion, though the mechanisms through which these propagate across the islet are poorly understood. Here, we use beta cell-targeted GCaMP6f to explore the role of endoplasmic reticulum (ER) Ca2+ mobilization in response to submaximal (11mM) and hyperglycemic (25mM) glucose concentrations. Inhibition of inositol 1,4,5 trisphosphate (IP3) receptors, and other ion channels, with 2-aminoethoxydiphenyl borate (2-APB) had minimal effects on the initial peak or intercellular connectivity provoked by 11mM glucose. However, 2-APB lowered subsequent glucose-induced cytosolic Ca2+ increases and connectivity at both 11 and 25mM glucose. Unexpectedly, the activation of IP3 receptors with the muscarinic acetylcholine receptor agonist carbachol had minimal impact on the initial peak elicited by 11 mM glucose, but Ca2+ waves at 11 and 25 mM glucose were more poorly coordinated. To determine whether ER calcium mobilization was sufficient to initiate Ca2+ waves we next blocked sarco(endo)plasmic Ca2+ ATPase (SERCA) pumps with thapsigargin, whilst preventing plasma membrane depolarization with the KATP-channel opener, diazoxide. Under these conditions, an initial cytosolic Ca2+ increase was followed by secondary Ca2+ waves that slowly subsided. The application of carbachol alongside diazoxide still enhanced Ca2+ dynamics, though this activity was uncoordinated and beta cells were poorly connected. Our results show that ER Ca2+ mobilization plays a relatively minor role in the initiation and propagation of Ca2+ waves in response to glucose. On the other hand, ER stores are required to transition to sustained Ca2+ waves.

Metabolic diseases (MDs), exemplified by diabetes, hypertension, and dyslipidemia, have become increasingly prevalent with rising living standards, posing significant public health challenges. The MDs are influenced by a complex interplay of genetic factors, lifestyle choices, and socioeconomic conditions. Additionally, environmental pollutants, particularly air pollutants (APs), have attracted increasing attention for their potential role in exacerbating these MDs. However, the impact of APs on the MDs remains unclear. This study introduces a novel machine learning (ML) pipeline, an Algorithm for Spatial Relationships Analysis between Exposome and Metabolic Diseases (ASEMD), to analyze spatial associations between APs and MDs at the prefecture-level city scale in China.

The ASEMD pipeline comprises three main steps: (i) Spatial autocorrelation between APs and MDs is evaluated using Moran's I statistic and Local Indicators of Spatial Association (LISA) maps. (ii) dimensionality reduction and spatial similarities identification between APs and MDs clusters using Principal Component Analysis (PCA), k-means clustering, and Jaccard index calculations, further validated through spatial maps. (iii) AP exposure is adjusted by demographic and lifestyle confounders to predict MDs using machine learning models (e.g., eXtreme Gradient Boosting (XGBoost), Random Forest (RF), Decision Tree (DT), LightGBM, and Multi-Layer Perceptron (MLP)). SHAP values are employed to identify key adjusted APs that are linked to MDs. Model performance is evaluated through 10-fold cross-validation using five different metrics. The data utilized include CHARLS (2015) and meteorological data (2013-2015).

Significant spatial correlations were found between APs and the prevalence of diabetes, dyslipidemia, and hypertension, with higher prevalence rates observed in alignment with elevated APs concentrations. By adjusting for demographic and lifestyle confounders, APs effectively predicted the risk of developing MDs (AUROC=0.890, 0.877, 0.710 for diabetes, dyslipidemia, and hypertension, respectively). The results showed that C O , P M 2.5 , and A Q I were strongly correlated with diabetes, whereas N O 2 , P M 2.5 , and P M 10 were significantly associated with dyslipidemia. For hypertension, C O , O 3 , and A Q I were mostly correlated. Sensitivity analyses across different regions and different types of APs underscored the robustness of our conclusions.

The ASEMD pipeline successfully integrates ML models, epidemiological methods, and spatial analysis techniques, providing a robust framework for understanding the complex interactions between APs and MDs. We also identified specific APs, including P M 10 , C O , and S O 2 , as being strongly linked to higher rates of diabetes, dyslipidemia, and hypertension in central and northern cities. Future region-specific public health strategies or interventions, especially in those areas with high pollutant levels, are needed to mitigate air pollution's impact on metabolic health.

Exercise is an effective non-pharmacological strategy for ameliorating metabolic dysfunction-associated steatotic liver disease (MASLD). Neuregulin-4 (Nrg4) is an adipokine with a potential role in metabolic homeostasis. Previous findings have shown that Nrg4 is upregulated by exercise and that Nrg4 reduces hepatic steatosis, but the underlying mechanism is not fully understood. Here, we show that adipose Nrg4 is transactivated by Pparγ in response to exercise in mice. Adeno-associated virus (AAV)-mediated knockdown of adipose Nrg4 as well as hepatocyte-specific knockout of Erbb4 (Nrg4 receptor) impair exercise-mediated alleviation of MASLD in mice. Conversely, AAV-mediated overexpression of adipose Nrg4 mitigates MASLD in mice in synergy with exercise. Mechanistically, Nrg4/Erbb4/AKT signaling promotes cyclic guanosine monophosphate-AMP synthase (cGAS) phosphorylation to blunt its enzyme activity, thereby inhibiting cGAS-STING pathway-mediated inflammation and steatosis in hepatocytes. Thus, Nrg4 functions as an exercise-induced adipokine that participates in adipose-liver tissue communication to counteract MASLD.

Cardiovascular disease affects millions of people worldwide and often presents with other conditions including metabolic, renal and neurological disorders. A variety of secreted factors from multiple organs/tissues (proteins, nucleic acids and lipids) have been implicated in facilitating organ cross-talk that may contribute to the development of multimorbidity. Secreted proteins have received the most attention, with the greatest body of research related to factors released from adipose tissue (adipokines), followed by skeletal muscle (myokines). To date, there have been fewer studies on proteins released from the heart (cardiokines) implicated with organ cross-talk. Early evidence for the secretion of cardiac-specific factors facilitating organ cross-talk came in the form of natriuretic peptides which are secreted via the classical endoplasmic reticulum-Golgi pathway. More recently, studies in cardiomyocyte-specific genetic mouse models have revealed cardiac-initiated organ cross-talk. Cardiomyocyte-specific modulation of microRNAs (miR-208a and miR-23-27-24 cluster) and proteins such as the mediator complex subunit 13 (MED13), G-protein-coupled receptor kinase 2 (GRK2), mutant α-myosin heavy-chain (αMHC), ubiquitin-like modifier-activating enzyme (ATG7), oestrogen receptor alpha (ERα) and fibroblast growth factor 21 (FGF21) have resulted in metabolic and renal phenotypes. These studies have implicated a variety of factors which can be secreted via the classical pathway or via non-classical mechanisms including the release of extracellular vesicles. Cross-talk between the heart and the brain has also been described (e.g. via miR-1 and an emerging concept, interoception: detection of internal neural signals). Here we summarize these studies taking into consideration that factors may be secreted in both settings of health and in disease.

Hyperlipidemia is a lipid metabolism disorder and a risk factor for obesity, diabetes, and coronary heart disease. It occurs mostly in the old adults; however, its incidence rate is increasing annually and there is a trend towards younger adults. Current clinical drugs for treating hyperlipidemia have multiple side effects. Therefore, it is necessary to develop safe and effective drugs from natural products to prevent and treat hyperlipidemia. Simiao Wan (SMW) is a classic Chinese medicine prescription first recorded in the Cheng Fang Bian Du of the Qing Dynasty. Studies have shown that SMW has excellent efficacy in metabolic diseases, which can effectively improve hyperlipidemia combined with other metabolic diseases. However, its underlying mechanism in hyperlipidemia treatment is yet to be clarified.

To investigate the hypolipidemic effect of SMW on hyperlipidemic mice and explore whether the gut microbiota-bile acid (BA) axis is the potential mechanism.

A hyperlipidemic mouse model was established using a high-fat diet (HFD), and the hypolipidemic effect of SMW was detected in vivo. We performed 16S ribosomal RNA sequencing and BA metabolism analysis to explore the hypolipidemic mechanisms of SMW. Western blotting was conducted to detect the expression of proteins involved in the gut microbiota-BA axis to determine the potential lipid-lowering pathway.

Excessive obesity in hyperlipidemic mice was alleviated after 8 weeks of SMW treatment. The total cholesterol and low-density lipoprotein cholesterol levels decreased significantly, whereas high-density lipoprotein cholesterol levels increased. SMW also reduced hepatic lipid and inguinal white adipose tissue accumulation in HFD-induced hyperlipidemic mice. Furthermore, intestinal bile saline hydrolase (BSH) level, associated with BA excretion, decreased. Meanwhile, SMW decreased the abundance of BSH-enriched microbes in hyperlipidemic mice. SMW increased the intestinal conjugated-BAs contents in hyperlipidemic mice, especially tauro-β-muricholic acid and tauro-ursodeoxycholic acid, which are ileac farnesoid X receptor (FXR) antagonists. Inhibited intestinal FXR signaling with SMW was accompanied by a decreased expression of intestinal fibroblast growth factor 15 and the activation of hepatic FXR, which promoted hepatic cholesterol conversion to BA.

SMW indirectly attenuated HFD-induced hyperlipidemia in mice by regulating the gut microbiota-BA axis. Our results provide a pharmacological basis for SMW treating hyperlipidemia and suggest a new idea for developing lipid-lowering drugs.

There is a new awareness of the widespread nature of metabolic dysfunction-associated steatotic liver disease (MASLD) and its connection to cardiovascular disease (CVD). This has catalyzed collaboration between cardiologists, hepatologists, endocrinologists, and the wider multidisciplinary team to address the need for earlier identification of those with MASLD who are at increased risk for CVD. The overlap in the pathophysiologic processes and parallel prevalence of CVD, metabolic syndrome, and MASLD highlight the multisystem consequences of poor cardiovascular-liver-metabolic health. Metabolic dysfunction and associated insulin resistance, together with the predilection for ectopic fat deposition in the liver and surrounding tissues, are associated with elevated risk of endothelial dysfunction, systemic inflammatory response, and ectopic fat deposition in the epicardium. This complex pathophysiology can accelerate atherogenic dyslipidemia, atherogenesis, diastolic dysfunction, valvular calcification, and cardiac arrhythmias. Despite the mounting evidence of mechanistic pathways underpinning MASLD and CVD, current recommendations have not clearly focused upon MASLD as a risk factor or target for intervention in CVD. We have brought together a diverse range of international experts committed to promoting cardiovascular-liver-metabolic health and related outcomes across the globe. The overarching goal of this document is to offer a construct for clinicians in the cardiovascular field with regards to (1) diagnosis and screening of MASLD through the use of noninvasive serum and imaging tests; (2) screening for CVD in all individuals with MASLD regardless of established atherosclerotic risk factors; and (3) the approach to management of MASLD with respect to prevention of CVD through lifestyle, as well as pharmacologic and surgical strategies. To achieve this, the modified Delphi method was applied and a series of evidence-based quality standard recommendations have been identified.

The incidence of cancer and the prevalence of metabolic disease and metabolic dysfunction-associated steatotic liver disease is increasing in young adults. However, updated global data on metabolic dysfunction-associated steatohepatitis (MASH)-associated primary liver cancer (PLC) in young adults remains scarce.

This study analyzed data from the Global Burden of Disease study between 2000 and 2021 to assess the age-standardized incidence, mortality, and disability-adjusted life years rates from MASH-associated PLC in young adults (15-49 y).

In 2021, there were 4300 incidence cases, 3550 deaths, and 179,340 disability-adjusted life years from MASH-associated PLC in young adults. Among various etiologies of PLC in young adults, only MASH-associated PLC had increased incidence rates (annual percent change: +0.26, 95% CI: 0.16%-0.35%), with the Eastern Mediterranean region having the largest observed increase (annual percent change: 1.46%, 95% CI: 1.40%-1.51%). In 2021, MASH-associated PLC in young adults made up 6% (+1% from 2000) incident cases, 6% (+2% from 2000) deaths, and 6% (+2% from 2000) disability-adjusted life years of all PLC in this age group. Over half of the countries exhibited an increase in age-standardized incidence rate from MASH-associated PLC in young adults from 2000 to 2021.

The incidence of MASH-associated PLC in young adults is significantly increasing, signaling likely future increases in PLC incidence among older adults as this cohort ages. This trend necessitates urgent strategies worldwide to mitigate the epidemics of MASH-associated PLC in young adults.

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), is a leading cause of morbidity and mortality, and health disparities have been shown to influence disease burden.

In this review, we aim to characterize disparities in prevalence, diagnosis, treatment, and outcomes of MASLD, and to make recommendations for next steps to minimize these disparities.

Literature search on PubMed and Scopus databases was conducted to identify relevant articles published before September 2, 2024.

Relative to women and White populations, MASLD is more common in men and Hispanic populations and less common in Black populations. It is also more prevalent among those with lower SES. Noninvasive clinical scores may perform differently across groups, and screening practices vary both for initial disease and for progression to metabolic dysfunctionassociated steatohepatitis (MASH), formerly called non-alcoholic steatohepatitis (NASH). Women and Black and Hispanic patients suffer worse outcomes including rates of progression to MASH and mortality.

Health disparities related to race, ethnicity, gender, and socioeconomic factors impact multiple stages of care for patients with MASLD.

Obesity is a major contributor to metabolic and cardiovascular disease. Although senescent cells have been shown to accumulate in adipose tissue, the role of senescence in obesity-induced metabolic disorders and in cardiac dysfunction is not yet clear; therefore, the therapeutic potential of managing senescence in obesity-related metabolic and cardiac disorders remains to be fully defined.

We investigated the beneficial effects of a senolytic cocktail (dasatinib and quercetin) on senescence and its influence on obesity-related parameters.

We found that the increase in body weight and adiposity, glucose intolerance, insulin resistance, dyslipidemia, hyperleptinemia, and hepatic disorders which were induced by an obesogenic diet were alleviated by senolytic cocktail treatment in mice. Treatment with senolytic compounds eliminated senescent cells, counteracting the activation of the senescence program and DNA damage in white adipose tissue (WAT) observed with an obesogenic diet. Moreover, the senolytic cocktail prevented the brown adipose tissue (BAT) whitening and increased the expression of the thermogenic gene profile in BAT and pWAT. In the hearts of obese mice, senolytic combination abolished myocardial maladaptation, reducing the senescence-associated secretory phenotype (SASP) and DNA damage, repressing cardiac hypertrophy, and improving diastolic dysfunction. Additionally, we showed that treatment with the senolytic cocktail corrected gene expression programs associated with fatty acid metabolism, oxidative phosphorylation, the P53 pathway, and DNA repair, which were all downregulated in obese mice.

Collectively, these data suggest that a senolytic cocktail can prevent the activation of the senescence program in the heart and WAT and activate the thermogenic program in BAT. Our results suggest that targeting senescent cells may be a novel therapeutic strategy for alleviating obesity-related metabolic and cardiac disorders.

Metabolic disorders (type 2 diabetes, insulin resistance, hyperglycaemia, obesity, hyperlipidaemia, hypertension, non-alcoholic fatty liver disease and metabolic syndrome) are leading causes of mortality and disability worldwide. These disorders disproportionately affect older adults relative to those younger. Digital health technologies (DHTs), such as patient monitoring, digital diagnostics and digital therapeutics, emerge as promising tools for health promotion in day-to-day life. However, their role in targeting metabolic disorders, particularly among a key demographic of older adults, is not yet fully understood. Thus, this study aims to scope the use of DHTs in managing metabolic health disorders among older adults. To our knowledge, this is the first review to categorise DHTs for older adults with metabolic disorders, contributing to the growing literature in the intersection of metabolic disorders and DHTs.

We will conduct a scoping review following the recommended framework by Arksey and O'Malley. Our search will focus on three primary concepts: metabolic disorders, DHTs and older adults. We plan to search five online databases (Cochrane, ScienceDirect, PubMed, Scopus and Web of Science) to identify original research articles published between January 2014 and January 2024. Two independent reviewers will screen articles based on predefined eligibility criteria, with a third reviewer resolving conflicts. Data will be extracted using a standardised form, and results will be synthesised qualitatively and quantitatively. The database searches, data collection and analysis are planned and have not been conducted.

No ethics approval is required for this protocol and scoping review. Data will be used only from published studies with appropriate ethics approval. Results will be disseminated in a peer-reviewed publication.

Metabolic disorders are a global health concern, necessitating the development of drugs with fewer side effects and more efficacy. Traditional Indian medicine uses Tinospora cordifolia and Tinospora sinensis, but their metabolite fingerprints and impact on geographical location remains unknown.

The present study aimed to identify metabolite fingerprints from T. cordifolia and T. sinensis species from different geographic locations and also to identify potential quality markers for treating metabolic disorders.

Non-targeted metabolite fingerprinting of T. cordifolia and T. sinensis was performed using HPLC-QTOF-MS/MS analysis. Network pharmacology, molecular docking and molecular dynamics simulation analysis were performed to identify potential quality markers, hub targets, and key pathways associated with metabolic disorders.

In this study, six potential marker compounds and twenty-five differential compounds were identified between T. cordifolia and T. sinensis. Based on geography, five and one metabolite marker compounds were identified in T. cordifolia and T. sinensis respectively. Network pharmacology, molecular docking, and molecular dynamics simulation analysis revealed trans piceid, crustecdysone in T. cordifolia, and gallic acid in T. sinensis as potential quality markers against metabolic disorder related hub targets.

Integration of non-targeted metabolomics and network pharmacology approach deciphers the pharmacological mechanism of action in terms of identifying potential quality markers from Tinospora species that can be used against metabolic disorders. However, further research is required to validate these findings in in vitro and in vivo studies for better assertion.

Although glucose, as a secretagogue of intestinal hormone, can stimulate glucagon-like peptide 1 (GLP-1) release, it has not been fully elucidated how glucose triggers GLP-1 release from enteroendocrine cells (EECs). Here, we investigated the regulatory mechanisms of glucose-induced Ca2+-dependent GLP-1 release from EECs. STC-1 cells that possess many features of native intestinal EECs were used. The expression of TRPV4 channels and Na+/Ca2+ exchanger 1 (NCX1) in STC-1 was analysed by immunocytochemistry. Calcium and sodium imaging, and patch clamp were applied, and GLP-1 was detected using quantitative PCR, western blot and enzyme-linked immunosorbent assays. Glucose markedly induced Na+ and Ca2+ signalling in STC-1 cells. The glucose-induced Ca2+ signalling was significantly attenuated by selective blockers of the voltage-gated Ca2+ channels (VGCC), ryanodine receptors and InsP3 receptors. Most importantly, glucose-induced Ca2+ signalling was significantly attenuated by the selective blockers of TRPV4 and NCX1. Moreover, the physical and functional couplings of TRPV4 and NCX1 were demonstrated in STC-1 cells, and they promoted glucose-mediated Ca2+ signalling to upregulate expression and release of GLP-1 via Ca2+-sensitive PKCα. Finally, the selective TRPV4 activator improved glucose tolerance in an oral glucose tolerance test in mice, but the selective blockers of TRPV4 and NCX1 attenuated glucose-induced intestinal GLP-1 release. We demonstrate a coupling of TRPV4 and NCX1 in EECs to regulate glucose-stimulated intestinal GLP-1 release via a novel TRPV4/NCX1/Ca2+/PKCα axis. Targeting this axis may provide new therapeutic potentials for glycometabolic diseases. KEY POINTS: Glucagon-like peptide 1 (GLP-1) secreted primarily from intestinal L cells in response to meals plays a critical role in maintaining glucose homeostasis. Physical and functional couplings of TRPV4 and NCX1 are pivotal in glucose-stimulated GLP-1 release via a novel TRPV4/NCX1/Ca2+/PKCα axis. Since this axis is involved in glucose homeostasis, our findings may provide new potential drug targets for prevention/treatment of glycometabolic diseases.

Metabolic risk factors are a significant cause of global burden among adolescents and young adults, but there is a lack of attention to the burden attributable to these metabolic risk factors globally.

This study aims to provide comprehensive estimates of five important metabolic risk factors and the attributable disease burden in people aged 15-39 years from 1990 to 2021, based on the Global Burden of Disease Study (GBD) database.

Global total deaths and disability-adjusted life years (DALYs) were used to describe the burden attributable to five common metabolic risk factors, including high fasting plasma glucose (FPG), high low-density lipoprotein cholesterol (LDL-C), high systolic blood pressure (SBP), high body mass index (BMI), and kidney dysfunction, in adolescents and young adults. The estimated annual percentage changes (EAPC) of DALYs were utilized to depict the trends from 1990 to 2021.

From 1990 to 2021, the DALY rates attributable to all metabolic risk factors showed a globally significant upward trend, with EAPC reaching 33.0 % (27.4-38.7). Compared to females, males had a heavier burden and a more significant increase in deaths and DALYs attributable to metabolic risk factors. High BMI and high FPG have become the top two metabolic risk factors in 2021, with summary exposure variables (SEV) rising by 84.2 % and 53.6 %, respectively. Low-middle socio-demographic index (SDI), middle SDI, and high SDI regions experienced upward regional trends in DALY rates, while low SDI regions remained stable. Among 204 countries and territories, 101 (49.5 %) showed a significant increase in DALY rates, as indicated by the EAPC.

There is a substantial global burden attributable to metabolic risk factors in adolescents and young adults in 2021, especially high BMI and high FPG. This calls for further investigation and intervention to address this emerging trend.

Gastrointestinal (GI) cancers have heavily burdened public health. Few studies reported GI cancer burden among adolescents and young adults (AYA). To address this gap, we explored the burden of GI cancer among people aged 15-39.

We retrieved data from the Global Burden of Disease Study 2019 Data Resources. The average annual percent change (AAPC) of rates was calculated by linear regression analysis of the natural logarithm. Bayesian age-period-cohort model was applied to predict the future burden.

In 2019, there were 171,857 (95% uncertain interval [95% UI]: 157,092-187,974) new GI cancer cases with a rate of 5.79/100,000 (95% UI: 5.29-6.33) and 91,033 (95% UI: 83,156-99,399) deaths at a rate of 3.07/100,000 (95% UI: 2.80-3.35) among AYA. The number of prevalent cases and disability-adjusted life years (DALYs) were 722,573 (95% UI: 660,806-789,476) and 5,151,294 (95% UI: 4,706,065-56,188,77), with rates of 24.35/100,000 (95% UI: 22.27-26.60) and 173.57/100,000 (95% UI: 158.57-189.32) respectively. The overall rates of mortality (AAPC = -1.281, p < 0.001) and DALY (AAPC = -1.283, p < 0.001) of GI cancers declined during the past 30 years, while the incidence rate (AAPC = -0.270, p = 0.074) remained stable and the prevalence rate (AAPC = 1.066, p < 0.001) increased. The burden of colorectal cancer (CRC) and pancreatic cancer increased, while those of stomach cancer (SC) and liver cancer (LC) declined. Among the 21 GBD regions, East Asia exhibited the highest burden, while within the five SDI regions, high-middle SDI locations showed the highest rates across all four indicators. CRC, SC, and LC emerged as the primary culprits, attaining a position within the top ten absolute DALYs for all AYA cancers. There were predicted to be 315,792 new cases and 174,068 deaths of GI cancers among AYA in 2040.

Despite the decrease in mortality and DALY rates of GI cancers among AYA, they remain prevalent. The burden varied with locations, SDI levels, sexes, and cancer types. Sufficient attention and multi-party cooperation are needed to control the widespread public health issue.

Sleeve gastrectomy (SG) is considered the standard bariatric surgery due to its excellent outcomes. However, in patients with obesity and type 2 diabetes mellitus (T2DM), SG alone carries a high risk of metabolic failure. To achieve better metabolic results, SG can be combined with either foregut- or hindgut-based procedures, although a direct comparison between these approaches is lacking. In this retrospective study, we compared the bariatric and metabolic effects of SG (n = 20 patients) with SG associated with duodenal diversion and ileal interposition (SG-DD-II) (n = 20), SG associated with duodenal-ileal anastomosis (SADI-S) (n = 20), and SG associated with single gastro-ileal anastomosis (SASI-S) (n = 20). Patient data, including anthropometric measurements and T2DM characteristics, were extracted from our database. The evaluation criteria included weight loss (% excess weight loss), fasting glycemia (FGL), glycated hemoglobin (HbA1C) percentage, and T2DM remission rates. Our statistical analysis (p < 0.05) revealed that shortly after surgery, all procedures demonstrated acceptable outcomes in terms of weight loss and T2DM remission. However, after 3 and 5 years post-surgery, the T2DM relapse rate was significantly higher following SG alone compared to hindgut-based operations. In patients with obesity and T2DM, we recommend combining SG with a hindgut-based procedure to reduce the long-term relapse rate.

The present study aimed to explore the associations between Mediterranean diet trajectories (MDTs) and cardiovascular disease-related risk factors in Chinese adults.

A total of 4,332 participants from the China Health and Nutrition Survey (CHNS) were included in this study. A group-based trajectory model (GBTM) was used to explore Mediterranean diet trajectories (MDTs). Linear regression analyses were conducted to assess the association between Mediterranean diet trajectories and cardiovascular disease-related risk factors. Stratified analyses by gender were also performed.

The following four groups were identified in the total population: Group 1 (Persistently low MDT, n = 292, 6.74%), Group 2 (Descent MDT, n = 537, 12.40%), Group 3 (Ascent MDT, n = 454, 10.48%), and Group 4 (Persistently high MDT, n = 3,049, 70.38%). Compared to the persistently low MDT (Group 1), both Group 2 and Group 4 were negatively related to low-density lipoprotein cholesterol (LDL-C) (Group 2: β = -0.23, 95% CI: -0.36 to -0.09, p = 0.001; Group 4: β = -0.25, 95% CI: -0.37 to -0.14, p < 0.001), total cholesterol (TC) (Group 2: β = -0.18, 95% CI: -0.32 to -0.04, p = 0.010; Group 4: β = -0.31, 95% CI: -0.43 to -0.19, p < 0.001), and uric acid (UA) (Group 2: β = -15.16, 95% CI: -28.66 to -2.56, p = 0.019; Group 4: β = -27.51, 95% CI: -38.77 to -16.25, p < 0.001) after adjusting for potential risk factors. Only Group 4 exhibited a negative relationship with triglycerides (TG) (β = -0.18, 95% CI: -0.34 to -0.02, p = 0.028) and blood glucose (β = -0.19, 95% CI: -0.37 to -0.02, p = 0.032).

Four MDTs were identified among the total participants, including men and women. These trajectories were summarized as persistently low MDT, ascent MDT, descent MDT, and persistently high MDT. Adherence to high MDTs could reduce the level of some CVD-related risk factors. The impact of the remote MD on CVD-related risk factors may be greater than that of the proximal MD.

Polyphenols are plant-based compounds with potential anti-inflammatory, antioxidant, and anti-obesogenic properties. However, their effects on health outcomes remain unclear.

To evaluate the effects of polyphenols on anthropometric and cardiometabolic markers.

Six electronic databases-namely, EMBASE, CINAHL, PubMed, Scopus, The Cochrane Library (reviews only), and Web of Science-were searched for relevant systematic reviews with meta-analyses (SRMAs).

Three reviewers performed the data extraction via a data-extraction Microsoft Excel spreadsheet.

An umbrella review and meta-analysis of existing SRMAs was conducted. Eighteen SRMAs published from 2015 to 2023, representing 445 primary studies and 838 unique effect sizes, were identified. Meta-analyses were conducted using random-effects models with general inverse variance. Polyphenol-containing foods were found to significantly improve weight (-0.36 kg; 95% confidence interval [CI]: -0.62, 0.77 kg; P < 0.01, I2 = 64.9%), body mass index (-0.25 kg/m2; 95% CI: -0.34, -0.17 kg/m2; P < 0.001, I2 = 82.4%), waist circumference (-0.74 cm; 95% CI: -1.34, -0.15 cm; P < 0.01, I2 = 99.3%), low-density-lipoprotein cholesterol (-1.75 mg/dL; 95% CI: -2.56, -0.94; P < 0.001, I2 = 98.6%), total cholesterol (-1.23 mg/dL; 95% CI: -2.00, -0.46; P = 0.002, I2 = 94.6%), systolic blood pressure (-1.77 mmHg; 95% CI: -1.77, -0.93 mmHg; P < 0.001, I2 = 72.4%), diastolic blood pressure (-1.45 mmHg; 95% CI: -2.09, -0.80 mmHg; P < 0.001, I2 = 61.0%), fat percentage (-0.70%; 95% CI: -1.03, -0.36%; P < 0.001, I2 = 52.6%), fasting blood glucose (-0.18 mg/dL; 95% CI: -0.35, -0.01 mg/dL; P = 0.04, I2 = 62.0%), and C-reactive protein (CRP; including high-sensitivity-CRP [hs-CRP]) (-0.2972 mg/dL; 95% CI: -0.52, -0.08 mg/dL; P = 0.01, I2 = 87.9%). No significant changes were found for high-density-lipoprotein cholesterol (-0.12 mg/dL; 95% CI: -1.44, 0.69; P = 0.67, I2 = 89.4%) and triglycerides (-1.29 mg/dL; 95% CI: -2.74, 0.16; P = 0.08, I2 = 85.4%). Between-study heterogeneity could be explained by polyphenol subclass differences.

The findings of this umbrella review support the beneficial effects of polyphenols on anthropometric and metabolic markers, but discretion is warranted to determine the clinical significance of the magnitude of the biomarker improvements.

International Prospective Register of Systematic Reviews no. CRD42023420206.

Type 2 diabetes mellitus (T2DM) poses a major global health burden, yet epidemiological research on low physical activity's (LPA) impact is limited. This study examines LPA's global effect on T2DM.

Analyzing Global Burden of Disease Database (GBD) 2019, we explored LPA-attributable T2DM deaths and Disability-Adjusted Life Years (DALYs) from 1990 to 2019, stratified by year, gender, country, and SDI regions. Estimated Annual Percentage Change (EAPC) assessed trends, and Bayesian models predicted future patterns.

In 2019, LPA accounted for a substantial 8.5% of T2DM deaths and 6.9% of DALYs, representing a noticeable rise since 1990. Age-standardized mortality rates (ASMR) and disability-adjusted life years rates (ASDR) increased globally, particularly in low Socio-Demographic Index (SDI) regions. High and high-middle SDI regions saw a decrease in ASMR, while all regions generally saw an upward trend in ASDR. Projections for 2050 suggest a declining ASMR but an increasing ASDR, indicating a continuing burden of T2DM despite potential mortality reductions.

LPA significantly impacts T2DM, particularly in low SDI regions. Promotion of physical activity is crucial to reduce this burden, particularly in regions where the disease's impact is most severe.

Common metabolic diseases, such as type 2 diabetes mellitus (T2DM), hypertension, obesity, hypercholesterolemia, and metabolic dysfunction-associated steatotic liver disease (MASLD), have become a global health burden in the last three decades. The Global Burden of Disease, Injuries, and Risk Factors Study (GBD) data enables the first insights into the trends and burdens of these metabolic diseases from 1990 to 2021, highlighting regional, temporal and differences by sex.

Global estimates of disability-adjusted life years (DALYs) and deaths from GBD 2021 were analyzed for common metabolic diseases (T2DM, hypertension, obesity, hypercholesterolemia, and MASLD). Age-standardized DALYs (mortality) per 100,000 population and annual percentage change (APC) between 1990 and 2021 were estimated for trend analyses. Estimates are reported with uncertainty intervals (UI).

In 2021, among five common metabolic diseases, hypertension had the greatest burden (226 million [95 % UI: 190-259] DALYs), whilst T2DM (75 million [95 % UI: 63-90] DALYs) conferred much greater disability than MASLD (3.67 million [95 % UI: 2.90-4.61]). The highest absolute burden continues to be found in the most populous countries of the world, particularly India, China, and the United States, whilst the highest relative burden was mostly concentrated in Oceania Island states. The burden of these metabolic diseases has continued to increase over the past three decades but has varied in the rate of increase (1.6-fold to 3-fold increase). The burden of T2DM (0.42 % [95 % UI: 0.34-0.51]) and obesity (0.26 % [95 % UI: 0.17-0.34]) has increased at an accelerated rate, while the rate of increase for the burden of hypertension (-0.30 % [95 % UI: -0.34 to -0.25]) and hypercholesterolemia (-0.33 % [95 % UI: -0.37 to -0.30]) is slowing. There is no significant change in MASLD over time (0.05 % [95 % UI: -0.06 to 0.17]).

In the 21st century, common metabolic diseases are presenting a significant global health challenge. There is a concerning surge in DALYs and mortality associated with these conditions, underscoring the necessity for a coordinated global health initiative to stem the tide of these debilitating diseases and improve population health outcomes worldwide.

Vaccinium uliginosum L. (VU), rich in polyphenols, is an important wild berry resource primarily distributed in extremely cold regions. However, the detailed composition of Vaccinium uliginosum L. polyphenols (VUPs) has not been reported, which limits the development and utilization of VU. In this study, VU-free polyphenols (VUFPs) and VU-bound polyphenols (VUBPs) were, respectively, extracted using an ultrasonic, complex enzyme and alkali extraction method; the compositions were identified using ultra-performance liquid chromatography-electrospray ionization mass spectrometry, and lipid-lowering activity in vitro was evaluated. The results showed that 885 polyphenols and 47 anthocyanins were detected in the VUFPs and VUBPs, and 30 anthocyanin monomers were firstly detected in VU. Compared with the model group, the accumulation of lipid droplets and the total cholesterol and triglyceride contents in the high-concentration VUP group reduced by 36.95%, 65.82%, and 62.43%, respectively, and liver damage was also alleviated. It was also found that VUP can regulate the level of Asialoglycoprotein receptor 1, a new target for lipid lowering. In summary, this study provides a detailed report on VUP for the first time, confirming that VUP has lipid-lowering potential in vitro. These findings suggest new strategies and theoretical support for the development and utilization of VU, especially in the field of functional foods.

The prevalence of cardiometabolic diseases is escalating in sub-Saharan Africa (SSA) alongside the prevailing high burden of communicable diseases. Although many countries in SSA, including Rwanda, have existing data on the prevalence of individual components of the MetS, many SSA countries have insufficient data to guide policy makers on the magnitude of MetS. This study sought to determine the magnitude of MetS and its associated risk factors by sex at a referral teaching hospital in Rwanda.

A cross-sectional, study was conducted among adults aged 35 to 65 years presenting at Ruhengeri Referral Teaching Hospital, Rwanda. We collected socio-clinicodemographic data using the World Health Organization (WHO) STEPwise tool for non-communicable diseases. We used the National Cholesterol Education Program Adult Treatment Panel III criteria for MetS.

Overall, 99 (23.5%) males and 322 (76.5%) female participants with mean ± SD age 47.5 ± 8.2 years were enrolled. The overall frequency of MetS was 51.9% (95% CI: 47.0-56.8) and was significantly higher (p < 0.001) in females 193 (59.4%) compared to males 26 (26.3%). Significant differences by sex were also noted in the proportions of visceral obesity; 70.4% vs 7.1% (p < 0.001), hypoalphalipoproteinaemia 36.1% vs 69.7% (p < 0.0001), type 2 diabetes mellitus; 18.4% vs 31.6% (p = 0.020) and body mass index 25.9 ± 15.6 vs 28.2 ± 6.4 (p = 0.032). On multivariate logistic regression, older age (odds ratio (OR) 1.05; 95% confidence interval ((CI) 1.01-1.10)), higher body weight (OR 1.06; 95% CI 1.04-1.08) and higher total cholesterol (1.25; 95% CI 1.05 -1.74) were significantly associated with MetS in females; whereas only higher body weight (OR1.10; 95% CI 1.04-1.18) was significantly associated with MetS in males.

A high frequency of MetS was observed in the present study, which was higher among females. Our findings emphasize the need for tailored prevention and intervention strategies to mitigate the long-term impact of MetS.

Obesity remains a global epidemic. The effect of obesity on the risk of complications after acetabular fracture is unknown. Here, we evaluate the effect of BMI on early complications and mortality after acetabular fracture. We hypothesize that the risk of inpatient complications and mortality will be greater in patients with high BMI when compared to those with normal BMI.

Adult patients with acetabular fracture were identified via the Trauma Quality Improvement Program data from 2015 to 2019. The primary outcome was overall complication rate with reference to normal-weight patients (BMI = 25-30 kg/m2). The secondary outcome was rates of death. The association of obesity class on the primary and secondary outcomes was assessed using Bonferroni-corrected multiple logistic regression models considering patient, injury, and treatment covariates.

A total of 99,721 patients with acetabular fracture were identified. Class I obesity (BMI = 30-35 kg/m2) was associated with 1.2 greater adjusted relative risk (aRR; 95% confidence interval (CI) 1.1-1.3) of any adverse event, without significant increases in adjusted risk of death. Class II obesity (BMI = 35-40 kg/m2) was associated with aRR = 1.2 (95% CI 1.1-1.3) of any adverse event and aRR = 1.5 (95% CI 1.2-2.0) of death. Class III obesity (BMI ≥ 40 kg/m2) was associated with aRR = 1.3 (95% CI 1.2-1.4) of any adverse event and aRR = 2.3 (95% CI 1.8-2.9) of death.

Obesity is associated greater risk of adverse events and death following acetabular fracture. Obesity severity classification scales with these risks.

The worldwide burden of cancer is increasing in younger populations. However, the epidemiology of primary liver cancer remains understudied in young adults compared to other cancer forms.

This study analyzed data from the Global Burden of Disease study between 2010 and 2019 to assess the age-standardized incidence, mortality, and disability-adjusted life years associated with primary liver cancer in the young (15-49 y), stratified by region, nation, sociodemographic index, and sex. The study found a global estimate of 78,299 primary liver cancer cases, 60,602 deaths, and 2.90 million disability-adjusted life years in the young population. The Western Pacific region exhibited the highest burden in 2019, showing the most significant increase compared to other regions between 2010 and 2019. More than half of the countries worldwide have undergone an increase in primary liver cancer incidence rates in young adults. Around 12.51% of deaths due to primary liver cancer occur in young individuals. Throughout the study period, there was a significant decline in primary liver cancer mortality due to most etiologies, except for metabolic dysfunction-associated steatotic liver disease-attributable primary liver cancer (annual percentage change + 0.87%, 95% CI: 0.70%-1.05%) and alcohol-attributable primary liver cancer (annual percentage change + 0.21%, 95% CI: 0.01%-0.42%). The limitations of the Global Burden of Disease database include reliance on the quality of primary data and possible underestimation of alcohol consumption.

Over the past decade, there has been a marked increase in the burden of primary liver cancer, especially that originating from steatotic liver disease. This trend calls for the development of urgent and comprehensive strategies to mitigate this rising burden globally.

To quantify the burden of metabolic dysfunction-associated steatotic liver disease (MASLD) and related metabolic disorders in premenopausal women.

Between 2010 and 2019, global evaluations of prevalence, mortality, disability-adjusted life years (DALYs), and their age-standardized rate (ASR) were conducted for metabolic conditions such as MASLD, type 2 diabetes mellitus, dyslipidemia, hypertension (HTN), obesity, and polycystic ovarian syndrome. Subgroup assessments were conducted according to geographical regions and the sociodemographic index. The predictive models were established to estimate mortality and DALYs through 2040.

In 2019, the most significant ASR of deaths was found in HTN (11.37; 9.52 to 13.45), followed by obesity (10.49; 7.57 to 13.64). In contrast, the greatest ASR of DALYs was attributed to obesity (816.13; 581.41 to 1073.32), followed by HTN (634.73; 536.75 to 744.77). The mortality rates for dyslipidemia (-0.55%) and HTN (-0.72%) have been decreasing over time, but there has been an increase in obesity (+0.58%), type 2 diabetes mellitus (+0.85%), and MASLD (+0.51%). Lower sociodemographic index countries exhibit a higher disability-to-prevalence ratio. In 2040, obesity is predicted to cause the most deaths (+41.59% from 2019).

The escalating impact of metabolic syndrome, the rising trends in death rates linked to obesity, and the disparities based on region and socioeconomic status in premenopausal women underscore the alarming increase in the global burden of metabolic syndrome.