Obesity is a global health concern that promotes chronic low-grade inflammation, leading to insulin resistance, a key factor in many metabolic diseases. Angiotensin 1-7 (Ang 1-7), a component of the renin-angiotensin system (RAS), exhibits anti-inflammatory effects in obesity and related disorders, though its mechanisms remain unclear. In this study, we examined the effect of Ang 1-7 on inflammation of white adipose tissue (WAT) in dietary-induced obese mice. Monocyte chemoattractant protein-1 (MCP-1) produced by white adipocytes and tumour necrosis factor-α (TNF-α) produced by macrophages are pro-inflammatory cytokines and interact to form a pathogenic loop to exacerbate obesity-induced inflammation. We found that Ang 1-7 reduced MCP-1 and TNF-α gene expressions and the number of crown-like structures, which are histological hallmarks of the pro-inflammatory process, in visceral epididymal WAT (eWAT) and reduced circulating MCP-1 and TNF-α levels, accompanied by improvement in insulin resistance, in dietary-induced obese mice. Furthermore, Ang 1-7 reduced MCP-1 and TNF-α secretions in 3T3-L1 white adipocytes and RAW 264.7 macrophages, respectively, which are in vitro experimental models mimicking obesity condition. Our results suggest that Ang 1-7 directly acts on WAT to mitigate obesity-induced inflammation. Thus, this study provides novel insights into the underlying mechanism of anti-obesity effects of Ang 1-7.

The global obesity epidemic highlights the need to understand the molecular mechanisms that regulate energy metabolism. Among emerging research areas, fat browning-the transformation of white adipose tissue into beige fat-has gained significant attention. This review explores the molecular pathways involved in fat browning triggered by fasting, physical exercise, and cold exposure, emphasizing both shared and distinct regulatory mechanisms. These stimuli consistently induce physiological responses such as lipolysis, mitochondrial biogenesis, and improved insulin sensitivity. Notably, PGC-1α and SIRT3 are upregulated across all three conditions, underscoring their central roles in mitochondrial function and energy metabolism and identifying them as promising therapeutic targets. In contrast, UCP1 and PRDM16 exhibit condition-specific regulation, suggesting they may not be universally essential for fat browning. In addition, the review discusses species-specific differences in brown adipose tissue (BAT) activation, particularly between rodents and humans, highlighting the challenges of translating animal model findings to human therapies. Future research should aim to develop selective pharmacological activators of PGC-1α and SIRT3 to enhance therapeutic outcomes while minimizing adverse effects. This review also proposes that integrating fasting, exercise, and cold exposure could provide innovative strategies to promote metabolic health.

Individuals with low sexual frequency often experience comorbidities that exacerbate mortality. This article evaluates the predictive value of five body fat anthropometric indicators for all-cause mortality and explores the interaction between obesity and depression in mortality among young and middle-aged individuals with sexual frequency <12 times per year.

This study included participants with a sexual frequency of <12 times per year from the 2015-2016 National Health and Nutrition Examination Survey (NHANES). We assessed the impact of anthropometric indicators and depression on mortality, as well as their synergistic interactions, and further developed an accessible predictive survival model.

A total of 4978 participants aged 20-59 were included, with 215 deaths (4.3 %) over 15 years of follow-up. A Body Shape Index (ABSI) showed the strongest association with all-cause mortality, with an AUC of 0.67. Participants with ABSI ≥0.082 had a significantly higher risk of death (HR: 1.87, 95%CI: 1.31-2.68), as did those with depression (HR: 1.86, 95%CI: 1.19-2.92). Interaction analysis revealed a synergistic effect between depression and ABSI, increasing death risk by 293 % when both were present. Significant survival differences were observed between men and women with these risk factors, with median survival rates of 76.3 % and 90.8 %, respectively. The model based on ABSI and depression provided valuable mortality predictions, with AUC of 0.78, 0.77, and 0.77 for 3-year, 5-year, and 10-year survival.

ABSI and depression are associated with all-cause mortality in individuals with low sexual frequency, potentially creating a synergistic effect on mortality risk.

Epithelial V-like antigen 1 (Eva1) is a highly specific marker for brown adipose tissue (BAT) in both mice and humans, but its metabolic function remains unclear. We investigated the impact of Eva1 deletion on the development of obesity.

To assess the metabolic role of Eva1, we generated whole-body and adipocyte-specific Eva1knockout (KO) mice, which were subjected to a high-fat diet (HFD) for 12 weeks and characterized metabolic phenotypes. To further elucidate the depot-dependent impact of Eva1 deficiency, we performed histological analysis and 3' mRNA-seq of BAT and epididymal visceral white adipose tissue (eWAT). To investigate the role of macrophage-derived Eva1 in obesity development, we transplanted wild-type (WT) or Eva1KO macrophages into Eva1KO mice fed an HFD.

We found that whole-body Eva1KO mice are resistant to HFD-induced obesity, insulin resistance and visceral adipose inflammation. However, Eva1 deletion in adipocytes, both brown and white, did not phenocopy these protective effects. Notably, whole-body Eva1 deficiency triggers functional changes in eWAT, but not in BAT. These results led us to investigate a possible involvement of macrophages in Eva1-mediated obesity regulation. We found that Eva1 is expressed in macrophages and plays a role in lipopolysaccharide (LPS)-induced inflammatory responses, possibly through the direct interaction with toll-like receptor 4 (TLR4). Moreover, Eva1KO mice exhibited improved survival rates in the face of severe sepsis induced by LPS. Importantly, transplantation of WT macrophages to Eva1KO mice abolished the beneficial effects of whole-body Eva1 deletion against obesity and visceral adipose inflammation.

Our findings highlight macrophage-derived Eva1 as an important mediator in obesity-induced eWAT remodeling, suggesting that targeting Eva1 could offer a novel therapeutic strategy for obesity-related metabolic disorders.

This study endeavors to unveil the association between the Metabolic Score for Insulin Resistance (METS-IR) and stroke among adults utilizing data of the National Health and Nutrition Examination Survey (NHANES) and the China Health and Retirement Longitudinal Study (CHARLS), and whether oxidative stress (OS) mediates their association.

Our study cohort comprised 101,316 individuals from NHANES and 17,708 individuals from CHARLS. The intricate relationships among the METS-IR, stroke, and OS biomarkers were evaluated via logistic regression, restricted cubic splines (RCS), as well as mediation analysis.

The final analysis included 22,542 American and 9521 Chinese participants, among whom 844 and 887 were diagnosed with stroke, respectively. Regression analysis indicated a positive association of METS-IR with stroke [NHANES: OR = 1.01, 95 % CI (1.01, 1.02), p < 0.001; CHARLS: OR = 1.02, 95 % CI (1.02, 1.03), p < 0.001], with higher METS-IR quartiles being associated with elevated stroke incidence [NHANES: OR = 1.39, 95 % CI (1.11, 1.73), p = 0.004; CHARLS: OR = 1.74, 95 % CI (1.39, 2.17), p < 0.001]. Participants with elevated METS-IR and serum uric acid (SUA) exhibited the greatest probability of stroke. Mediation analysis proved that OS partially mediated this association [Mediation effect: NHANES β = -8.45e-5, 95 % CI (-1.41e-4, -4.01e-5), p < 0.001; CHARLS β = -4.02e-5, 95 % CI (-8.14e-5, -7.76e-6), p = 0.012].

The METS-IR was positively associated with stroke in NHANES and CHARLS cohorts, and OS partially mediated this association.

Mitochondria, as central regulators of cellular processes such as energy production, apoptosis, and metabolic homeostasis, are essential to cellular function and health. The maintenance of mitochondrial integrity, especially through mitophagy-the selective removal of impaired mitochondria-is crucial for cellular homeostasis. Dysregulation of mitochondrial function, dynamics, and biogenesis is linked to neurodegenerative and metabolic diseases, notably Alzheimer's disease (AD), which is increasingly recognized as a metabolic disorder due to its shared pathophysiologic features: insulin resistance, oxidative stress, and chronic inflammation. In this review, we highlight recent advancements in pharmacological interventions, focusing on agents that modulate mitophagy, mitochondrial uncouplers that reduce oxidative phosphorylation, compounds that directly scavenge reactive oxygen species to alleviate oxidative stress, and molecules that ameliorate amyloid beta plaque accumulation and phosphorylated tau pathology. Additionally, we explore dietary and lifestyle interventions-MIND and ketogenic diets, caloric restriction, physical activity, hormone modulation, and stress management-that complement pharmacological approaches and support mitochondrial health. Our review underscores mitochondria's central role in the pathogenesis and potential treatment of neurodegenerative and metabolic diseases, particularly AD. By advocating for an integrated therapeutic model that combines pharmacological and lifestyle interventions, we propose a comprehensive approach aimed at mitigating mitochondrial dysfunction and improving clinical outcomes in these complex, interrelated diseases.

This review aims to provide a comprehensive overview to understand the role of pollution in the development of noncommunicable diseases (NCDs), with a focus on metabolic diseases.

In the context of NCDs, the incidence of metabolic diseases such as obesity and diabetes are increasing at an alarming rate. In addition to the well-known role of the so-called "obesogenic" environment, characterized by unhealthy diet and physical inactivity, great attention has been paid in recent years to the effects of pollution. Indeed, progressive urbanization has been associated with increased exposure to pollutants. The harmful effects of some pollutants on the endocrine system have been known for decades, but data on the metabolic impact of pollution are rather recent. Pollution in its various forms promotes a systemic inflammatory state, insulin resistance, and oxidative stress, which appear to be closely associated with increased risk of NCD, particularly obesity and diabetes.

In conclusion, urbanization has so far had a predominantly negative impact on collective health, but a better understanding of the mechanisms linking pollution to metabolic health is crucial to implement preventive strategies, including careful urban planning to improve community health, understood not only as the absence of disease but also as psychological and social well-being, overcoming the risks associated with urbanization.

To determine the associations of body mass index (BMI) and waist circumference (WC) with severe diabetic complications in patients with type 2 diabetes.

In total, 114 254 participants with type 2 diabetes (82% male; mean age, 52.52 ± 8.27 years; median follow-up, 4.64 years) were enrolled from a nationwide Japanese medical claims database. Cox proportional models with multivariate adjustment were used to assess the associations of BMI and WC with treatment-requiring diabetic eye disease (TRDED), initiation of dialysis, coronary artery disease (CAD), cerebrovascular disease (CVD), heart failure (HF) and amputation.

BMI was inversely associated with TRDED, especially in women. Men with WC ≥ 95 cm had a significantly lower risk of TRDED (hazard ratio [HR] = 0.79, 95% CI = 0.69-0.91). Dialysis initiation displayed L-shaped associations with BMI and WC. The risk of CAD was significantly reduced among men with BMI < 20.0 kg/m2 (HR = 0.68, 95% CI = 0.49-0.94). HF had U-shaped associations with BMI and WC. Abdominal obesity increased CVD risk (HR = 1.36, 95% CI = 1.08-1.70). BMI ≥ 25 kg/m2/WC ≥ 90 cm significantly reduced the risk of dialysis (HR = 0.42, 95% CI = 0.29-0.62) and increased the risk of HF (HR = 1.33, 95% CI = 1.03-1.72).

BMI/WC had both positive and negative associations with diabetic complications. Therefore, each patient's BMI/WC target should be carefully determined for each diabetic complication, considering the risk of developing other diseases.

The treatment landscape of non-small-cell lung cancer (NSCLC) is evolving rapidly, driven by advances in the development of targeted agents and immunotherapies. Despite this progress, some patients have suboptimal responses to treatment, highlighting the need for new therapeutic strategies. In the past decade, the important role of the tumour microenvironment (TME) in NSCLC progression, metastatic dissemination and response to treatment has become increasingly evident. Understanding the complexity of the TME and its interactions with NSCLC can propel efforts to improve current treatment modalities, overcome resistance and develop new treatments, which will ultimately improve the outcomes of patients. In this Review, we provide a comprehensive view of the NSCLC TME, examining its components and highlighting distinct archetypes characterized by spatial niches within and surrounding tumour nests, which form complex neighbourhoods. Next, we explore the interactions within these components, focusing on how inflammation and immunosuppression shape the dynamics of the NSCLC TME. We also address the emerging influences of patient-related factors, such as ageing, sex and health disparities, on the NSCLC-TME crosstalk. Finally, we discuss how various therapeutic strategies interact with and are influenced by the TME in NSCLC. Overall, we emphasize the interconnectedness of these elements and how they influence therapeutic outcomes and tumour progression.

Most forms of obesity are associated with chronic diseases that remain a global public health challenge.

Despite significant advancements in understanding its pathophysiology, effective management of obesity is hindered by the persistence of knowledge gaps in epidemiology, phenotypic heterogeneity and policy implementation.

This consensus statement by the European Society for Clinical Investigation identifies eight critical areas requiring urgent attention. Key gaps include insufficient long-term data on obesity trends, the inadequacy of body mass index (BMI) as a sole diagnostic measure, and insufficient recognition of phenotypic diversity in obesity-related cardiometabolic risks. Moreover, the socio-economic drivers of obesity and its transition across phenotypes remain poorly understood.

The syndemic nature of obesity, exacerbated by globalization and environmental changes, necessitates a holistic approach integrating global frameworks and community-level interventions. This statement advocates for leveraging emerging technologies, such as artificial intelligence, to refine predictive models and address phenotypic variability. It underscores the importance of collaborative efforts among scientists, policymakers, and stakeholders to create tailored interventions and enduring policies.

The consensus highlights the need for harmonizing anthropometric and biochemical markers, fostering inclusive public health narratives and combating stigma associated with obesity. By addressing these gaps, this initiative aims to advance research, improve prevention strategies and optimize care delivery for people living with obesity.

This collaborative effort marks a decisive step towards mitigating the obesity epidemic and its profound impact on global health systems. Ultimately, obesity should be considered as being largely the consequence of a socio-economic model not compatible with optimal human health.

Emerging studies suggest obesity may improve PD-1/PD-L1 inhibitor efficacy, correlating with prolonged survival, known as the 'obesity paradox'. However, the impact of this paradox and obesity-related chronic inflammation on immunotherapy for advanced gastric cancer (AGC) has not received sufficient research.

Between January 2018 and December 2021, patients receiving neoadjuvant therapy were categorized into two groups: combined immunotherapy (ICIs, n = 173) and neoadjuvant chemotherapy (NAC, n = 126). Visceral (VATI) and subcutaneous adipose tissue index (SATI) were obtained from pre-treatment CT images. The systemic immune-inflammation index (SII) was calculated as platelet count multiplied by the neutrophil-to-lymphocyte ratio.

The median age of patients was 64 years (IQR 56-69), with 219 (73.2%) males and 80 (26.8%) females. In the ICIs group, the VATI-High group showed significantly higher 3-year overall survival (OS) (p = 0.010) and disease-free survival (DFS) (p = 0.029). Similar results were observed in the SATI analysis (p < 0.05). Conversely, OS (p = 0.040) and DFS (p = 0.039) were significantly lower in the SII-High group. Both VATI and SATI were independent protective factors for OS and DFS, but the effect disappeared after adjustment for SII. SII was associated with poorer OS and DFS, even after adjustment for VATI and SATI. No significant differences were observed in the analysis of the NAC group.

Elevated adiposity indices (VATI/SATI) and low SII correlate with survival benefit in ICI-treated AGC patients, and importantly, this paradoxical survival benefit is dependent on SII status. In contrast, no such benefit is observed in chemotherapy-alone cohorts.

We assessed the associations of visceral adiposity indexes such as Chinese Visceral Adiposity Index (CVAI), Visceral Adiposity Index (VAI), Lipid Accumulation Product (LAP), waist circumference (WC), and waist-hip ratio (WHR) with overall and specific cancer incidence in a Chinese population.

332,297 individuals from the Taiwan MJ cohort (1996-2007) were included. We utilized multivariable Cox proportional hazards models to examine associations of baseline visceral adiposity indexes and cancer incidences. Sex-specific CVAI, VAI, and LAP were calculated, incorporating WC and triglycerides levels. CVAI and VAI also included body mass index and high-density lipoprotein, with CVAI further incorporating age.

Higher CVAI was consistently associated with higher overall cancer incidence, with HRs of 1.45 (95% CI: 1.2-1.76) and 2.03 (95% CI: 1.52-2.72) for males and females, respectively, comparing the fifth quintile to the first. The HRs for WC were 1.27 (95% CI: 1.08-1.49) and 1.19 (95% CI: 1.01-1.40) for males and females, WHR was significantly associated with cancer risk in males (HR:1.28; 95% CI: 1.13-1.45), and LAP was significantly associated with cancer risk in females (HR: 1.25; 95% CI: 1.04-1.5). VAI was not associated with overall cancer incidence.

CVAI is a superior clinical biomarker for predicting cancer incidence in the Chinese population compared to traditional visceral obesity indices.

Major depressive disorder (MDD) is a leading cause of disability, and chronic inflammation is a contributing factor to its onset and progression. This study examined the relationship between genetic predisposition to inflammation and MDD risk in a nationally representative sample of U.S. military veterans, as well as psychosocial moderators of this association.

A composite polygenic risk score (PRS) for inflammatory biomarkers was derived from the UK Biobank and examined in relation to a positive MDD screen in 1,660 European-American veterans. The analysis adjusted for known correlates of inflammation and MDD, including medical conditions and cumulative trauma burden.

Each standard deviation increase in the inflammatory PRS was associated with more than two-fold increased odds of screening positive for MDD (OR = 2.51, 95% CI = 1.39-4.54). Interaction analyses revealed that optimism moderated this association; among those in the highest PRS tertile, individuals with high optimism were more than 30 times less likely to screen positive for MDD compared to those with low optimism (0.7% vs. 22.6%). Pathway-based analyses identified enrichment of immune- and brain-related gene sets, highlighting potential biological mechanisms linking inflammation and MDD.

Findings suggest genetic risk for inflammation contributes to MDD vulnerability and that optimism may buffer this risk.

Aneurysmal subarachnoid hemorrhage (aSAH) is a life-threatening disease with high morbidity and mortality. The triglyceride-glucose (TyG) index, a marker of insulin resistance (IR), has been linked to adverse outcomes in cerebrovascular conditions; however, its influence on functional prognosis in aSAH remains unclear. This study aimed to elucidate the relationship between the TyG index and functional outcomes in aSAH patients.

A retrospective cohort study included consecutive aSAH patients. Functional outcomes were assessed using the modified Rankin Scale (mRS) at 3 months and categorized as favorable (mRS 0-2) or unfavorable (mRS 3-6). Univariate and multivariate logistic regression analyzed the association between the TyG index and functional outcomes. Propensity score matching (PSM) was used to mitigate confounding. Non-linear relationships were explored with restricted cubic splines (RCS), and subgroup analyses were performed. A nomogram integrating the TyG index and traditional prognostic scales was developed, and model predictive performance was compared using the area under the curve (AUC) on a test set.

A total of 470 patients (61.7% female) were enrolled, with 154 experiencing unfavorable outcomes. Multivariate logistic regression showed a significant association between the TyG index and adverse outcomes (OR: 1.86, 95% CI 1.12-3.1, P = 0.017). An optimal TyG index cutoff of 8.83 was identified. Patients with TyG index ≥ 8.83 had a higher risk of poor outcomes (48.7% vs. 24.8%; P = 0.015). PSM confirmed these findings. RCS indicated a progressive association between elevated TyG index and increased risk of adverse functional outcome. Subgroup analyses showed consistent relationships. The enhanced model with the TyG index had a higher AUC (0.899) than the traditional model (0.889, DeLong test P = 0.048).

A high TyG index is significantly associated with an increased risk of unfavorable functional outcomes in patients with aSAH.

The gut microbiome influences physiological responses to exercise by modulating inflammatory markers and metabolite production. Athletes typically exhibit greater microbial diversity, which may be associated with improved performance, but the mechanisms linking different exercise modalities to the gut microbiome are not fully understood. In this study, blood and stool samples were collected from endurance athletes, strength athletes, and non-athletic controls performing two maximal exercise tests (the anaerobic Wingate test and the aerobic Bruce Treadmill Test) to integrate serum biomarker data with gut bacterial metagenomic profiles. While most biochemical markers showed similar post-exercise trends across groups, SPARC (secreted protein acidic and rich in cysteine) and adiponectin levels showed modality-specific responses. Strength-trained participants showed unique microbiome-biomarker associations after the Wingate test. In addition, baseline enrichment of certain bacterial taxa, including Clostridium phoceensis and Catenibacterium spp., correlated with reduced Bruce Treadmill test response in strength-trained individuals. These findings, while requiring further validation, indicate the complex interplay between exercise type, training background, and the gut microbiome, and suggest that specific microbial species may help shape recovery and adaptation.

Metabolic syndrome (MetS) is a disease with complex and diverse etiologies. Extrinsic factors such as diet and lifestyle can induce dysbiosis of gut microbes, compromising intestinal barrier integrity and leading to inflammation and insulin resistance, thereby advancing MetS. Probiotic interventions have shown potential in ameliorating gut microbiota dysbiosis and regulating host metabolism by assimilating lipids, metabolizing carbohydrates, and producing short-chain fatty acids (SCFA), indole compounds, secondary bile acids, conjugated linoleic acid (CLA), and other active ingredients. An increasing number of new strains are being isolated and validated for their effective roles intervening on MetS in animal and population studies. This review aims to provide updated insights into the pathogenic mechanisms of MetS, highlight the newly identified probiotic strains that have demonstrated improvements in MetS, and elucidate their mechanisms of action, with the aim of offering contemporary perspectives for the future use of probiotics in mitigating MetS.

Ischemic stroke(IS) is the second leading cause of mortality and disability worldwide and neuroimmunity plays an important role in its occurrence and development. The pathogenesis of IS is associated with various metabolic disorders. Yet reports on the amelioration of neuroinflammation by modulating metabolic disorders in clinical practice are scarce. By screening drugs targeting the inflammatory cytokine pro IL-1β in the metabolism-related compound library, we first found that clofibrate, an antihyperlipidemic drug, has an anti-neuroinflammatory effect. However, the role of clofibrate in exerting anti-inflammatory effects in IS and its underlying mechanisms remain unclear. To further investigate the role of clofibrate, we administered clofibrate in an LPS-stimulated microglial cell model and in mice with transient middle cerebral artery occlusion. Notably, clofibrate lowered IL-1β expression, both in vivo and in vitro. Simultaneously, clofibrate reduced infarct volume after ischemia and reperfusion. Moreover, clofibrate affected IS by regulating the expression of NF-κB p65 and NLRP3, thus suppressing the expression of inflammatory factors. These findings suggest that clofibrate could be a prospective medication to alleviate neuroinflammation in IS.

Obesity and insulin resistance are well-established risk factors for atherosclerosis and cardiovascular disease (CVD). Although some obesity- and insulin resistance-related indices (OIRIs) have been linked to CVD, their associations with subclinical carotid atherosclerosis (SCA) in individuals with type 1 diabetes (T1D) remain unclear. This study aims to systematically explore and compare the associations of various common OIRIs with SCA in T1D population.

A total of 418 adult inpatients with classic T1D admitted from October 2008 to June 2021 to the First Affiliated Hospital of Air Force Medical University in Xi'an, China were included in this study. Demographic, anthropometric, and laboratory data were collected. Studied OIRIs comprised body mass index, waist-to-height ratio, waist-to-hip ratio (WHR), a body shape index, abdominal volume index, body adiposity index, body roundness index, conicity index, triglyceride-glucose index, visceral adiposity index, Chinese visceral adiposity index (CVAI), lipid accumulation product, estimated glucose disposal rate (eGDR), triglyceride-to-HDL ratio, and cardiometabolic index. Binary logistic regression, restricted cubic spline (RCS), and receiver operating characteristic curves were used to examine the associations of these indices with SCA.

In multivariable logistic regression analyses, after adjusting for potential confounders, per 1.0-standard deviation (SD) increase in CVAI (OR, 95% CI: 1.68, 1.16-2.47), eGDRWHR (eGDR calculated with WHR; OR, 95% CI: 0.44, 0.22-0.82), and eGDRWC (eGDR calculated with waist circumference; OR, 95% CI: 0.49, 0.24-0.93) were significantly associated with SCA. CVAI exhibited the highest area under the curve (AUC) in diagnosing SCA, with a value of 0.73 (95% CI: 0.69-0.77). RCS analyses indicated a linear and positive association between CVAI and SCA in the overall population and the females. Subgroup analyses and sensitivity analyses further supported the association between CVAI and SCA. Additionally, adding CVAI to the Steno Type 1 Risk Engine (ST1RE) improved the reclassification, but did not enhance the overall discriminative ability of ST1RE to identify SCA.

Among various OIRIs, CVAI shows the strongest association with SCA in adults with T1D. These findings suggest that CVAI may merit further longitudinal investigation as a potential marker for SCA assessment in this population.

Little is known about the effect of bronchoscopic lung volume reduction using endobronchial valves (BLVR-EBV) on extrapulmonary manifestations like body composition, muscle function or metabolism. Pulmonary rehabilitation (PR) clearly addresses extrapulmonary manifestations of COPD, including physical inactivity and low muscle mass. However, the added impact of BLVR-EBV+PR remains unknown. Therefore, this study aimed to assess the effect of BLVR-EBV on body composition, muscle function and metabolic markers and whether PR has an additional impact on these outcomes.

Subjects with severe COPD eligible for both PR and BLVR-EBV were randomized into three groups: PR+BLVR-EBV, BLVR-EBV+PR, or only BLVR-EBV (n=97). Assessments included Dual Energy X-ray Absorptiometry, thigh muscle Computed Tomography, muscle strength measurements, accelerometry, and plasma (leptin, adiponectin, insulin, and triglycerides) at baseline and six months after the last intervention.

A total of 74 participants completed the study. At follow-up, there were significant increases in the groups combined and both groups separated in total weight, lean mass, fat mass, muscle strength, daily physical activity, and triglyceride levels while leptin/fat mass ratio levels were significantly reduced. No differences were found between groups who underwent BLVR-EVR alone or BLVR-EBV with PR.

BLVR-EBV results in significant increases in body weight, lean and fat mass, muscle strength and daily physical activity level, and impacts on adipokine profile, irrespective of PR. This underscores the systemic benefits of addressing lung hyperinflation in patients with severe COPD.

Diabetes-associated cognitive impairment (DACI) is a common complication of Type 2 diabetes mellitus (T2DM), with its mechanisms and treatments for DACI remaining incompletely clarified. This study investigated the protective efficacy of the novel lipid S-enantiomer of 9-palmitic acid esters of hydroxy stearic acids (S-9-PAHSA, S9P) in a high-fat diet-induced DACI mouse model.

Mice were randomly assigned to three groups: normal diet (ND), high-fat diet (HFD), and HFD + 30 mg/kg/day S9P (HFD + S9P). Fasting blood glucose (FBG), intraperitoneal glucose tolerance test (IPGTT), and insulin tolerance test (ITT) were conducted to assess blood glucose homeostasis. Morris Water Maze and Y maze tests evaluated cognitive function, and neuronal status was examined through pathological analysis, Golgi staining, and transmission electron microscopy (TEM). Colonic barrier integrity was assessed using periodic acid-Schiff and Alcian blue staining (AB-PAS) and immunohistochemistry (IHC) staining. Intestinal microbiota composition was analyzed by 16S rDNA sequencing, and serum metabolic characteristics were determined by metabolomics sequencing.

S9P improved glucose homeostasis and alleviated cognitive decline in DACI mice. It also mitigated neuronal damage, dendritic degeneration, and synaptic damage, while restoring colonic barrier integrity and ameliorating gut microbiome imbalances, insulin resistance, and lipid imbalance. Additionally, S9P regulated metabolite profiles and the PI3K/AKT/mTOR signaling pathways, and reduced astrocyte activation and neuroinflammatory responses in the hippocampus of HFD-induced DACI mice.

S9P had a protective effect against HFD-induced diabetic cognitive impairment closely related to the modulation of the gut-brain axis, suggesting that S9P has the potential to become a new therapeutic approach for DACI.

The increase in sugar consumption has been associated with current metabolic disease epidemics. This study aimed to investigate the pancreatic molecular mechanisms involved in cellular stress, inflammation, mitogenesis, and apoptosis in metabolic disease induced by high-fructose diet. Here, we used biochemical, histopathological, Western blot, and immunohistochemistry methods to determine the metabolic and pancreatic alterations in male Wistar rats fed 20% fructose in drinking water for 15 weeks. High-fructose consumption in rats increased the immunopositivity and protein expression of glucose transporter 2 (GLUT2) and insulin in the pancreatic tissue, in association with abdominal adiposity, hyperglycemia, and hypertriglyceridemia. The expressions of cellular stress markers, glucose-regulated protein-78 (GRP78) and PTEN-induced putative kinase 1 (PINK1), were increased in the pancreas. The levels of interleukin (IL)-6, nuclear factor kappa B (NFκB), tumor necrosis factor α (TNFα), and IL-1β and components of the Nod-like receptor protein 3 (NLRP3) inflammasome were elevated. Excess fructose intake stimulated the activation of mitogenic extracellular signal-regulated kinases 1/2 (ERK1/2), p38, and c-Jun N-terminal kinase (JNK)1 as well as the apoptotic p53 and Fas pathways in the pancreas of rats. There was also an increase in caspase-8 and caspase-3 cleavage. Our findings revealed that dietary high-fructose in the pancreas causes hyperinsulinemia due to the upregulation of GLUT2 together with cellular stress and inflammatory markers, thereby stimulates mitogenic mitogen-activated protein kinase (MAPK) and apoptosis pathways, resulting in a complex pathological situation.

Obesity treatment requires an individualized approach, emphasizing the need to identify metabolic pathways of diagnostic relevance. Toll-like receptors (TLRs), particularly TLR2 and TLR4, play a crucial role in metabolic disorders, as receptor deficiencies improves insulin sensitivity and reduces obesity-related inflammation. Additionally, hydrogen sulfide (H2S) influences lipolysis, adipogenesis, and adipose tissue browning through persulfidation. This study investigates the impact of a high-fat diet (HFD) on low molecular weight sulfur compounds in the visceral adipose tissue (VAT) of C57BL/6 and TLR2-deficient mice. It focuses on key enzymes involved in H2S metabolism: cystathionine beta-synthase (CBS), cystathionine gamma-lyase (CGL), 3-mercaptopyruvate sulfurtransferase (MPST), and thiosulfate sulfurtransferase (TST). In C57BL/6 mice on HFD, MPST activity decreased, while CBS level increased, potentially compensating for H2S production. In contrast, TLR2-deficient mice on HFD exhibited higher MPST activity but reduced level of CBS and CGL activity, suggesting that TLR2 deficiency mitigates HFD-induced changes in sulfur metabolism. TST activity was lower in TLR2-deficient mice, indicating an independent regulatory role of TLR2 in TST activity. Elevated oxidative stress, reflected by increased glutathione levels, was observed in wild-type mice. Interestingly, cysteine and cystine were detectable only in the VAT of the C57BL/6 ND group and were absent in all other groups. The capacity for hydrogen sulfide production in tissues from TLR2-/-B6 HFD group was significantly lower than in the C57BL/6 HFD group. In conclusion, TLR2 modulates sulfur metabolism, oxidative stress, and inflammation in obesity. TLR2 deficiency disrupts H2S production and redox balance, potentially contributing to metabolic dysfunction, highlighting TLR2 as a potential therapeutic target for obesity-related metabolic disorders.

In recent years, the prevalence of metabolic diseases has increased significantly, posing a serious threat to global health. Chronic low-grade inflammation is implicated in the development of most metabolic diseases, such as type 2 diabetes mellitus (T2DM), obesity, dyslipidemia, and cardiovascular disease, serving as a link between diet and these conditions. Increasing attention has been directly toward dietary inflammatory patterns that may prevent or ameliorate metabolic diseases. The Dietary Inflammatory Index (DII) was developed to assess the inflammatory potential of dietary intake. Consequently, a growing body of research has examined the associations between the DII and the risk of several metabolic diseases. In this review, we explore the current scientific literature on the relationships between the DII, T2DM, obesity, and dyslipidemia. It summarizes recent findings and explore potential underlying mechanisms from two aspects: the interaction between diet and inflammation, and the link between inflammation and metabolic diseases. Furthermore, this review discusses the therapeutic strategies, including dietary modifications, prebiotics, and probiotics, and discusses the application of the DII in metabolic diseases, as well as future research directions.

The widespread prevalence of NCDs calls for an improvement in their prevention and treatment. Wearable technologies can be an important asset in the development of precision nutrition strategies, for both health professionals and patients. However, their clinical use is hindered by a lack of validation against current methodologies or appropriate tools to deliver nutritional strategies based on their data. Our study includes manual and automatic data capture methods within a weight loss intervention with the aim to create an essential asset for the implementation, validation, and benchmarking of AI-based tools in nutritional clinical practice.

This is a feasibility prospective and crossover controlled trial for weight loss in overweight and obese participants, randomized into two groups: Group 1 used manual data collection methods based on validated questionnaires for the first two weeks; while Group 2 started with automatic data collection methods consisting of wearable sensors. After two weeks, the two groups switched data collection methods. Lifestyle data, anthropometric measurements and biological samples were collected from all participants.

A total of 93 participants completed the nutritional intervention designed for weight loss, achieving a mean reduction of 2 kg (V1: 84.99 SD ± 13.69, V3: 82.72 SD ± 13.32, p < 0.001). Significant reductions were observed in body mass index, visceral fat, waist circumference, total cholesterol, and HbA1c levels. The use of electronic devices proved satisfactory among the participants (System Usability Scale score 78.27 ± 12.86). We also report the presence of distinct patient groups based on continuous glucose measurements.

This study has yielded a large amount of data and has showcased how automatic data collection devices can be employed to gather data in the context of a nutritional intervention. This will enable the implementation of AI-based tools in nutritional clinical practice.

ClinicalTrials.gov, NCT05807243.

Chronic metabolic inflammation is a common mechanism linked to the development of metabolic disorders such as obesity, diabetes, and cardiovascular disease (CVD). Chronic metabolic inflammation often related to alterations in gut homeostasis, and pathological processes involve the activation of endotoxin receptors, metabolic reprogramming, mitochondrial dysfunction, and disruption of intestinal nuclear receptor activity. Recent investigations into homeostasis and chronic metabolic inflammation have revealed a novel mechanism which is characterized by a timing interaction involving multiple components and targets. This article explores the positive impact of tea consumption on metabolic health of populations, with a special focus on the improvement of inflammatory indicators and the regulation of gut microbiota. Studies showed that tea consumption is related to the enrichment of gut microbiota. The relative proportion of Firmicutes/Bacteroidetes (F/B) is altered, while the abundance of Lactobacillus, Bifidobacterium, and A. muciniphila increased significantly in most of the studies. Thus, tea consumption could provide potential protection from the development of chronic diseases by improving gut homeostasis and reducing chronic metabolic inflammation. The direct impact of tea on intestinal homeostasis primarily targets lipopolysaccharide (LPS)-related pathways. This includes reducing the synthesis of intestinal LPS, inhibiting LPS translocation, and preventing the binding of LPS to TLR4 receptors to block downstream inflammatory pathways. The TLR4/MyD88/NF-κB p65 pathway is crucial for anti-metaflammatory responses. The antioxidant properties of tea are linked to enhancing mitochondrial function and mitigating mitochondria-related inflammation by eliminating free radicals, inhibiting NLRP3 inflammasomes, and modulating Nrf2/ARE activity. Tea also contributes to safeguarding the intestinal barrier through various mechanisms, such as promoting the synthesis of short-chain fatty acids in the intestine, activating intestinal aryl hydrocarbon receptor (AhR) and farnesoid X receptor (FXR), and improving enteritis. Functional components that improve chronic metabolic inflammation include tea polyphenols, tea pigments, TPS, etc. Tea metabolites such as 4-Hydroxyphenylacetic acid and 3,4-Dihydroxyflavan derivatives, etc., also contribute to anti-chronic metabolic inflammation effects of tea consumption. The raw materials and processing technologies affect the functional component compositions of tea; therefore, consuming different types of tea may result in varying action characteristics and mechanisms. However, there is currently limited elaboration on this aspect. Future research should conduct in-depth studies on the mechanism of tea and its functional components in improving chronic metabolic inflammation. Researchers should pay attention to whether there are interactions between tea and other foods or drugs, explore safe and effective usage and dosage, and investigate whether there are individual differences in the tea-drinking population leading to different effects of tea intervention. Ultimately, the application of tea drinking could be a universal therapy for regulating intestinal homeostasis, anti-chronic metabolic inflammatory responses, and promoting metabolic health.

a series of 6-substituted dihydrobenzophenanthridine alkaloids were synthesized by introduction of different functional groups to C-6 of dihydrobenzophenanthridine backbone. The preliminary anti-inflammatory activities of all compounds were screened by investigating the inhibitory ability on NO production in LPS-stimulated RAW 264.7 cells. Among synthesized compounds, 6-(N-phenyl)-aminocarbonyl methyl dihydrochelerythrine (compound 12b) showed increased anti-inflammatory ability and decreased cytotoxicity and could inhibit the expression of pro-inflammatory factors TNF-α and IL-6 in RAW 264.7 macrophages. The anti-inflammatory ability of compound 12b was further evaluated using DSS-induced mice colitis models based on colonic tissue damage assessment, histopathological assessment and immunohistochemical analysis. In vivoexperiment revealed that compound 12b had good alleviating effect on acute colitis in mice. In conclusion, compound 12b may be a promising anti-inflammatory lead compound.

Adipose-derived stem cells (ADSCs) are mesenchymal stem cells (MSCs) derived from adipose tissue with mesenchymal lineage differentiation potential and remarkable potential in regenerative medicine. ADSCs are easily sourced from adipose tissue, share regenerative characteristics akin to other MSCs. Their convenient adherence to plastic culture flasks, coupled with their capacity for in vitro expansion and multi-lineage differentiation, underscores their promise as a robust tool for tissue repair and enhancement. The accessibility of human adipose tissue and the development of minimally invasive isolation protocols have further propelled the autologous use of ADSCs, fueling excitement in both organ repair and regenerative medicine. Consequently, research in ADSCsis experiencing rapid growth. A detailed overview of the current landscape of ADSCs isolation and differentiation capacity including the latest advancements in ADSCs usage, encompassing ongoing clinical investigations are important considerations to understand their potential to shape the landscape of regenerative medicine.

This systematic review investigates gut bacterial diversity and composition in patients with Obstructive Sleep Apnea-Hypopnea Syndrome (OSAHS) and examines how these changes may contribute to cardiovascular complications.

A comprehensive search was conducted in PubMed, Web of Science, and Scopus up to March 2025. After removing duplicates, titles and abstracts were screened by two reviewers, and full texts were assessed for inclusion. Data extraction on study characteristics and outcomes was performed. Methodological quality was evaluated using the Joanna Briggs Institute checklist. α-diversity was assessed using richness and diversity indices, while β-diversity examined community structure differences. Meta-analysis was conducted using standardized mean differences (SMD) and confidence intervals (CIs), and heterogeneity was assessed with the Cochrane I2 test.

The review included 18 studies (16 adults, 2 pediatrics) examining the gut microbiome in OSAHS. Meta-analysis revealed significant reductions in α-diversity indices (Shannon, Chao1, observed species, ACE) in OSAHS patients, while Simpson's index showed no difference. β-diversity analyses showed distinct gut microbiome differences in OSA. Key differential bacteria included Bacteroides, Proteobacteria, Faecalibacterium, Ruminococcaceae, Megamonas, Oscillibacter, Dialister, Roseburia, and Lachnospira. Study quality was medium to high.

OSAHS is associated with significant gut microbiome alterations, including a reduction in beneficial bacteria and an increase in LPS-producing bacteria, leading to intestinal barrier dysfunction. These changes may contribute to systemic inflammation and elevate the risk of cardiovascular diseases.

The JAK pathway is central to mammalian cell communication, characterized by rapid responses, receptor versatility, and fine-tuned regulation. It involves Janus kinases (JAK1, JAK2, JAK3, TYK2), which are activated when natural ligands bind to receptors, leading to autophosphorylation and activation of STAT transcription factors [1, 2]. JAK-dependent signaling plays a pivotal role in coordinating cell communication networks across a broad spectrum of biological systems including development, immune responses, cell growth, and differentiation. JAKs are frequently mutated in the aging hematopoietic system [3, 4] and in hematopoietic cancers [5]. Thus, dysregulation of the pathway results in various diseases, including cancers and immune disorders. The binding of extracellular ligands to class I and II cytokine receptors initiates a critical signaling cascade through the activation of Janus kinases (JAKs). Upon ligand engagement, JAKs become activated and phosphorylate specific tyrosine residues on the receptor, creating docking sites for signal transducer and activator of transcription (STAT) proteins. Subsequent JAK-mediated phosphorylation of STATs enables their dimerization and nuclear translocation, where they function as transcription factors to modulate gene expression. Under physiological conditions, JAK-signaling is a tightly regulated mechanism that governs cellular responses to external cues, such as cytokines and growth factors, ensuring homeostasis and maintaining the functional integrity of tissues and organs. Highly defined regulation of JAK-signaling is essential for balancing cellular responses to inflammatory stimuli and growth signals, thus safeguarding tissue health. In contrast, dysregulated JAK-signaling results in chronic inflammation and unrestrained cellular proliferation associated with various diseases. Understanding the qualitative and quantitative differences at the interface of physiologic JAK-signaling and its aberrant activation in disease is crucial for the development of targeted therapies that precisely tune this pathway to target pathologic activation patterns while leaving homeostatic processes largely unaffected. Consequently, pharmaceutical research has targeted this pathway for drug development leading to the approval of several substances with different selectivity profiles towards individual JAKs. Yet, the precise impact of inhibitor selectivity and the complex interplay of different functional modules within normal and malignant cells remains incompletely understood. In this review, we summarize the current knowledge on JAK-signaling in health and disease and highlight recent advances and future directions in the field.

Metabolic syndrome (MetS) poses a significant global health challenge, closely associated with cardiovascular diseases, diabetes, and other conditions. With the global prevalence of MetS steadily rising, the potential role of gut microbiota in its development has garnered increasing attention. Against this backdrop, the present study aims to explore the association between the dietary index for gut microbiota (DI-GM) score and MetS. This cross-sectional study utilized data from the 2007-2018 U.S. National Health and Nutrition Examination Survey (NHANES), including 339,242 adults aged ≥ 18 years. The DI-GM score, constructed based on 14 food or nutrient components, served as the exposure variable. MetS was defined according to the Adult Treatment Panel III (ATP III) criteria, including abdominal obesity (waist circumference ≥ 102 cm in men and ≥ 88 cm in women), elevated triglycerides (≥ 150 mg/dL), reduced HDL cholesterol (< 40 mg/dL in men and < 50 mg/dL in women), elevated blood pressure (≥ 130/85 mmHg), and elevated fasting glucose (≥ 100 mg/dL). Multivariable logistic regression analyses were performed to adjust for demographic characteristics, lifestyle factors, and other potential confounders. Higher DI-GM scores were significantly associated with a reduced risk of MetS. After adjusting for all confounders, individuals in the highest quartile (Q4) of DI-GM scores had a 16% lower risk of MetS compared to those in the lowest quartile (Q1) (OR: 0.84; 95%CI: 0.70-1.01). Mediation analyses revealed that systemic immune-inflammation index (SII) and neutrophil-to-lymphocyte ratio (NLR) mediated 4.63% and 3.83% of the association between DI-GM and MetS, respectively. There is an inverse association between DI-GM scores and the risk of MetS, potentially mediated in part by inflammatory markers. These findings provide new evidence supporting dietary interventions aimed at improving gut microbiota to prevent MetS.

Nanomedicines offer a means to overcome the limitations associated with traditional drug dosage formulations by affording drug protection, enhanced drug bioavailability, and targeted drug delivery to affected sites. Inflamed tissues possess unique microenvironmental characteristics (including excessive reactive oxygen species, low pH levels, and hypoxia) that stimuli-responsive nanoparticles can employ as triggers to support on-demand delivery, enhanced accumulation, controlled release, and activation of anti-inflammatory drugs. Stimuli-responsive nanomedicines respond to physicochemical and pathological factors associated with diseased tissues to improve the specificity of drug delivery, overcome multidrug resistance, ensure accurate diagnosis and precision therapy, and control drug release to improve efficacy and safety. Current stimuli-responsive nanoparticles react to intracellular/microenvironmental stimuli such as pH, redox, hypoxia, or specific enzymes and exogenous stimuli such as temperature, magnetic fields, light, and ultrasound via bioresponsive moieties. This review summarizes the general strategies employed to produce stimuli-responsive nanoparticles tailored for inflammatory diseases and all recent advances, reports their applications in drug delivery, and illustrates the progress made toward clinical translation.

To investigate the association between rs402007 polymorphism in the ADAMTS-1 gene and carotid atherosclerotic plaque vulnerability, as well as the lipid-lowering efficacy of atorvastatin in cerebral infarction patients. Clinical data from 684 cerebral infarction patients admitted to The First Hospital of Hebei Medical University (2016-2019) were analyzed. Patients were stratified into stable plaque (n = 338) and vulnerable plaque (n = 346) groups based on carotid ultrasound. General information, biochemical markers, rs402007 (G/C) genotypes (dominant model), and allele frequencies were compared. Polymorphism genotyping was performed using TaqMan SNP assays (Applied Biosystems) on an ABI 7500 Fast Real-Time PCR system. Logistic regression evaluated plaque vulnerability risk factors and gene-risk factor interactions. Atorvastatin's lipid-lowering efficacy was compared across genotypes. Diabetes prevalence, LDL-C, TC, HCY, and FIB levels differed significantly between groups (P < 0.05). Genotypic distribution analysis revealed a higher frequency of the GG genotype in the stable plaque group (29.59% vs. 21.68%, χ2 = 5.618, P = 0.018). Diabetes, LDL-C, HCY, and FIB were independent risk factors for plaque vulnerability (P < 0.05). A significant interaction between rs402007 polymorphism and LDL-C was observed (P < 0.05). Atorvastatin efficacy rates were 82.29% (GG), 84.27% (GC), and 89.27% (CC), with significant post-treatment lipid improvements in all genotypes (P < 0.05). The CC genotype exhibited superior efficacy compared to GG (P < 0.05). The rs402007 polymorphism influences carotid plaque vulnerability and modulates atorvastatin efficacy, underscoring its potential role in genotype-guided therapeutic strategies.

Obesity is defined as abnormal or excessive accumulation of body fat and contributes to several metabolic disorders. White adipose tissue (WAT) releases energy as free fatty acids and glycerol from triglycerides through a process called lipolysis. People with obesity have impaired catecholamine-stimulated lipolysis, but comprehensive understanding of this lipolysis is still unclear. We previously showed that expression of WW domain-containing E3 ubiquitin ligase 1 (WWP1), a member of the HECT-type E3 family of ubiquitin ligases, was increased in WAT of obese mice. In this study, we generated Wwp1 knockout (KO) mice to evaluate the effect of WWP1 in WAT of obese mice. The mRNA levels of beta-3 adrenergic receptor (Adrb3), which were decreased with a high-fat diet, were increased by Wwp1 KO in WAT. Moreover, Wwp1 KO mice showed increased phosphorylated hormone-sensitive lipase levels in WAT. In contrast, noradrenaline and its metabolism were not altered in WAT of obese Wwp1 KO mice. These findings indicate that WWP1, which is increased in adipocytes because of obesity, is a candidate for suppressing lipolysis independently of noradrenaline metabolism. We anticipate that inhibition of WWP1 is a promising approach for a new treatment of obesity and type-2 diabetes using Adrb3 agonists.

Intestinal inflammation significantly impairs intestinal function and is closely associated with various health complications. Understanding its molecular mechanisms is crucial for developing effective therapeutic strategies. Galnt3, a member of the polypeptide N-acetylgalactosaminyltransferase family, participates in multiple biological processes, yet its specific role in intestinal inflammation remains poorly understood. In this study, we observed a significant downregulation of zebrafish galnt3 in response to GCRV virus or poly(I:C) infection. Galnt3 knockout (galnt3-/-) zebrafish exhibited reduced survival rates, particularly following GCRV virus inoculation, accompanied by severe ascites and abdominal hemorrhage. Histopathological examination of intestinal tissues revealed thinning of intestinal walls, shortened villi, and increased acidic mucus secretion, all indicative of aggravated intestinal inflammation. Furthermore, galnt3 deficiency was found to trigger the upregulation of numerous pro-inflammatory cytokine genes. Through cell scratch assays and p38 MAPK phosphorylation analysis, we demonstrated that Galnt3 inhibits p38 MAPK phosphorylation and macrophage migration, thereby reducing the production of pro-inflammatory factors. Our findings highlight the pivotal role of Galnt3 in maintaining intestinal homeostasis and regulating inflammatory responses, providing valuable insights into the molecular mechanisms underlying intestinal inflammation and identifying potential therapeutic targets.

Acrylamide, advanced glycation end products (AGEs), and alpha-dicarbonyls are formed during the thermal processing of foods. Their dietary intake raises potential health concerns. Using food frequency questionnaires on acrylamide-rich Slovak foods, we estimated dietary acrylamide intake in 107 students aged 19-to-30 years and correlated it with salivary, plasma, skin autofluorescence; plasma levels of soluble receptor for advanced glycated end-products, and oxidative status markers (thiobarbituric acid reacting substances, ferric-reducing ability of plasma). No significant relationship was revealed between estimated daily acrylamide intake and analyzed biomarkers. As the extent of exposure to alpha-dicarbonyls and AGEs when consuming acrylamide-rich food remains unknown, we aligned acrylamide intake with that of glyoxal, methylglyoxal, 3-deoxyglucosone, and Nε-carboxymethyllysine, Nε-carboxyethyllysine, or methylglyoxal-derived hydroimidazolone. Correlation coefficients between intakes of acrylamide and alpha-dicarbonyls or AGEs reached 0.7-to-0.8 (p < 0.001, all), but, at individual levels, high intake of acrylamide was not unequivocally associated with high intake of AGEs or alpha-dicarbonyls. Our data suggest that the restriction of dietary AGEs recommended to patients with chronic non-communicable diseases must not simultaneously mitigate acrylamide intake. Nutritional research should explore the potential cumulative or synergistic adverse health effects of concurrent dietary intakes of acrylamide, AGEs, and alpha-dicarbonyls.

Cinnamomi Ramulus (CR) is the dried bark of Cinnamomum cassia Presl, Lauraceae. Puerariae Lobatae Radix (PLR) is the dried root of the Pueraria lobata (Wild.) Ohwi, Leguminosae. This Chinese herb couple come from the classic formula "Gui Zhi Ge Gen Tang," which is included in the TCM classic "Treatise on Febrile Diseases." Our previous studies have found that CR related herbal compound and PLR related herbal compound are useful in improving type 2 diabetes mellitus (T2DM), which is expected to be an antidiabetic candidate with fewer side effects. However the mechanism of action of CR-PLR on T2DM has not yet been fully elucidated.

The decoction of CR-PLR was prepared by aqueous extraction method and the composition of it was analyzed using UPLC-Q-TOF-MS and HPLC. The T2DM model was established by intraperitoneal injection of streptozotocin, and the groups of drug administration were metformin, CR, PLR and CR-PLR groups, with continuous gastric gavage for 6 weeks, and the serological indexes were detected by ELISA. The abundance of rats' gut flora was detected by 16s rDNA sequencing, and changes in the content of short-chain fatty acids (SCFAs) in feces of rats were detected by GC-MS; and the expression of G protein-coupled receptor43 (GPR43) and glucagon-like peptide-1 (GLP-1) proteins in colonic tissues of rats were detected by Western Blot. The pharmacokinetic behavior of CR-PLR was investigated in both normal and T2DM model rats. Caco-2/HT29 co-culture cell model was established in vitro, transepithelial electrical resistance (TEER) and ALP activity of epithelial cells were measured to evaluate cell model integrity and cell polarization, Alcian blue staining was used to verify the presence of mucus production, and CCK-8 was used to screen drug safe concentration. The bidirectional transport of puerarin was studied to investigate the transport mechanism of puerarin and the effect of leuric acid on puerarin transport.

The results indicated that CR-PLR can stimulate intestinal flora, increase the content of SCFAs, activate intestinal GPR43 protein, and promote the secretion of GLP-1 in intestinal L cells, which plays a therapeutic role in the treatment of T2DM. Additionally, cytology and pharmacokinetics experiments have proved that cinnamic acid (CA) can enhance the absorption and transport of puerarin (PUR) by inhibiting the efflux effects mediated by P-gp and MRP efflux transporters. The present study exhibites the scientific and reasonable menaning of this novel Chinese herb couple treating T2DM from the perspecives of pharmacodynamics and pharmacokinetics.