Understanding the Role of Gut Microbial Enzyme in CMD.

Dpp4 inhibition as a therapeutic strategy in cardiometabolic disease: Incretin-dependent and -independent function

Visceral adiposity is considered to have a key role in cardiometabolic diseases. The purpose of this study is to investigate cross-sectionally the association between intra-abdominal fat area (IAFA) measured by computed tomography (CT) and high blood pressure independent of abdominal subcutaneous fat area (ASFA) and insulin resistance. Study participants included 624 Japanese men not taking oral hypoglycemic medications or insulin. Abdominal, thoracic and thigh fat areas were measured by CT. Total fat area (TFA) was calculated as the sum of abdominal, thoracic and thigh fat area. Total subcutaneous fat area (TSFA) was defined as TFA minus IAFA. Hypertension and high normal blood pressure were defined using the 1999 criteria of the World Health Organization. Multiple-adjusted odds ratios of hypertension for tertiles of IAFA were 2.64 (95% confidence interval, 1.35-5.16) for tertile 2, and 5.08 (2.48-10.39) for tertile 3, compared with tertile 1 after adjusting for age, fasting immunoreactive insulin, diabetes status, ASFA, alcohol consumption, regular physical exercise and smoking habit. IAFA remained significantly associated with hypertension even after adjustment for ASFA, TSFA, TFA, body mass index or waist circumference, and no other measure of regional or total adiposity was associated with the odds of hypertension in models, which included IAFA. Similar results were obtained for the association between IAFA and the prevalence of high normal blood pressure or hypertension. In conclusion, greater visceral adiposity was associated with a higher odds of high blood pressure in Japanese men.

Lipoprotein(a) [Lp(a)] is a significant player in cardiovascular disease (CVD) and type 2 diabetes (T2D). While Lp(a) contributes to residual cardiovascular risk in T2D, lower levels paradoxically increase the risk of developing T2D. This review explores Lp(a)'s dual role in cardiometabolic disease, its association with T2D, and emerging Lp(a)-lowering therapies. Large-scale studies confirm Lp(a) as a potent risk factor for cardiovascular events in T2D, with lower Lp(a) thresholds increasing risk compared to nondiabetic individuals. Observational and genetic studies reveal an inverse relationship between Lp(a) and T2D risk, linked to insulin dynamics, Kringle IV-type-2 repeat variants, and metabolic pathways. Emerging evidence suggests a connection between Lp(a), nonalcoholic fatty liver disease, and statin use. However, Mendelian randomization analyses have yielded conflicting results, leaving key mechanistic questions unresolved. Lp(a) plays a complex role in cardiometabolic health, acting as both a cardiovascular hazard and a potential metabolic marker in T2D. The paradoxical association of low Lp(a) with increased T2D risk challenges conventional perspectives and raises concerns regarding Lp(a)-lowering interventions. Further research is needed to clarify causality, refine risk stratification, and guide clinical decisions for Lp(a) modulation in T2D patients.

This article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc.

The transcription factor Nrf2 is a master regulator of multiple cytoprotective genes that maintain redox homeostasis and exert anti-inflammatory functions. The Nrf2-Keap1 signaling pathway is a paramount target of many cardioprotective strategies, because redox homeostasis is essential in cardiovascular health. Nrf2 gene variations, including single nucleotide polymorphisms (SNPs), are correlated with cardiometabolic diseases and drug responses. SNPs of Nrf2, KEAP1, and other related genes can impair the transcriptional activation or the activity of the resulting protein, exerting differential susceptibility to cardiometabolic disease progression and prevalence. Further understanding of the implications of Nrf2 polymorphisms on basic cellular processes involved in cardiometabolic diseases progression and prevalence will be helpful to establish more accurate protective strategies. This review provides insight into the association between the polymorphisms of Nrf2-related genes with cardiometabolic diseases. We also briefly describe that SNPs of Nrf2-related genes are potential modifiers of the pharmacokinetics that contribute to the inter-individual variability.

Cell behavior is influenced by substrate stiffness and cell-cell and cell-environment interactions. The limitations of 2D culture, such as its inability to fully capture the complexity of cell interactions and tissue structure, underscore the necessity of 3D cell culture. While still in its infancy, 3D cell culture helps overcome these caveats of 2D culture systems and provides information of significant physiological relevance. This explicitly applies to ‘disease modeling in a dish’ platforms for pre-clinical and reverse-translation studies. 3D bioprinting has demonstrated significant potential in replicating the intricate physiological environments of human tissues associated with both healthy and pathological states. This allows for improved recapitulation of the complex biochemical interactions and physiological environment vital for understanding the pathophysiology and drug responses. Our study used the state-of-the-art 3D bioprinting technology to understand the response of 3D matrix-embedded human cardiac fibroblasts (HCFs) and 2D cultures to a ‘high-fat diet’ mimic. We hypothesized that 3D-embedded HCFs would closely mimic human myocardium more than the 2D-HCFs, both in uninjured state as well as in response to stressors such as high-caloric nutritional load. It is well established that overnutrition can contribute to cardiometabolic disease. To capture this in vitro, HCFs in 2D were exposed to fatty-acid (FA) rich medium for 48 hours and processed for assay for transpose accessible chromatin with sequencing (ATAC-seq) to identify chromatin accessibility and regulatory genes. These signatures were validated by gene and protein expression assays. HCFs in 3D matrix proliferated slower than in 2D cultures, with substrate stiffness ranging from low kilopascal (3D) to gigapascals (2D). The transcriptional profiles of both 2D and 3D cultured cells varied dramatically, including fibroblast activation markers and mechanosensing-responsive genes. To investigate this mechanical signaling further, we performed mitogen-activated protein kinase (MAPK) protein arrays. Extracellular matrix (ECM) homeostasis, critical for maintaining healthy tissue structure and function, is deregulated in response to excess FA in the cellular microenvironment. The pro-fibrotic agent transforming growth factor β (TGF-β) orchestrates the upregulation of ECM genes via canonical (Smad-dependent) and non-canonical (MAPK-dependent) pathways. Compared to 2D cultures, reduced activation of MAPK pathway members in 3D cultures closely mimicked the in vivo healthy microenvironment of the human heart and physiological response to FA overload. The significance of our findings is two-fold. Firstly, we establish that 3D matrix embedded HCFs have striking resemblance in form and function to the human heart tissue. Secondly, 3D-cultured HCFs accurately capture the response to acute stressors such as overnutrition, which may be insufficiently estimated by already activated 2D-HCFs. Our study, therefore, identifies key mechanisms of nutritional stress response in cardiac fibroblasts, and provides the foundation for a robust and physiologically relevant drug-screening platform with high translational capability for cardiometabolic diseases. This work is supported by UAMS/ABI Faculty Start-up funds and the American Heart Association Career Development Award to RAB. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

The development of safe and efficacious enzyme-based human therapies has increased greatly in the last decades, thanks to remarkable advances in the understanding of the molecular mechanisms responsible for different diseases, and the characterization of the catalytic activity of relevant exogenous enzymes that may play a remedial effect in the treatment of such pathologies. Several enzyme-based biotherapeutics have been approved by FDA (the U.S. Food and Drug Administration) and EMA (the European Medicines Agency) and many are undergoing clinical trials. Apart from enzyme replacement therapy in human genetic diseases, which is not discussed in this review, approved enzymes for human therapy find applications in several fields, from cancer therapy to thrombolysis and the treatment, e.g., of clotting disorders, cystic fibrosis, lactose intolerance and collagen-based disorders. The majority of therapeutic enzymes are of microbial origin, the most convenient source due to fast, simple and cost-effective production and manipulation. The use of microbial recombinant enzymes has broadened prospects for human therapy but some hurdles such as high immunogenicity, protein instability, short half-life and low substrate affinity, still need to be tackled. Alternative sources of enzymes, with reduced side effects and improved activity, as well as genetic modification of the enzymes and novel delivery systems are constantly searched. Chemical modification strategies, targeted-and/or nanocarrier-mediated delivery, directed evolution and site-specific mutagenesis, fusion proteins generated by genetic manipulation are the most explored tools to reduce toxicity and improve bioavailability and cellular targeting. This review provides a description of exogenous enzymes that are presently employed for the therapeutic management of human diseases with their current FDA/EMA-approved status, along with those already experimented at the clinical level and potential promising candidates.

Cell aging processes (senescence) in the development of cardiometabolic diseases, including type 2 diabetes mellitus (T2DM), remain poorly understood. Research on the effect of dietary interventions on cell aging is of undoubted importance for scientific and practical medicine.The purpose of the review was to assess the effect of dietary interventions on senescence processes in cardiometabolic diseases. Literature data were collected and analyzed using the RINTS, Pubmed, and Google Scholar databases using the keywords «senescence», «chronic noncommunicable diseases», «systemic chronic inflammation», «T2DM».Results. Senescence has been shown to be a key factor in aging and contributes to tissue dysfunction and the development of many diseases. Dietary interventions with anti-inflammatory and antioxidant effects may become an important additional option for maintaining metabolic health during cellular aging and are of great interest in terms of prevention and management of chronic non-communicable diseases. Restriction of caloric intake, reduction of simple carbohydrates, inclusion of foods enriched with vitamins and minerals, polyphenolic compounds, and other strategies may provide additional information to deepen our understanding of the potential role of senescence in the development and progression of nutrition-related diseases.Conclusions. The search for new strategies for dietary intervention. Cells that affect senescence processes play a key role in the development and progression of cardiometabolic diseases, which opens up broad prospects for influencing senescent cells, providing support for dietary interventions to achieve healthy longevity.

ObjectivesTo examine the impact of demographic, socioeconomic, and behavioral factors on the development of cardiometabolic multimorbidity and mortality in Chinese elders.MethodsData from the Chinese Longitudinal Healthy Longevity Survey (CLHLS) 2002–2018 was used in the study. Cardiometabolic multimorbidity was defined as the presence of two or more cardiometabolic disorders, such as hypertension, diabetes, cardiovascular disease (CVD), heart disease, or stroke. Cox regression model and multi-state Markov model were developed to evaluate the association of the study factors with the progression of cardiometabolic conditions and mortality. The outcomes included three states (first cardiometabolic disease, cardiometabolic multimorbidity, and all-cause mortality) and five possible transitions among the three states.ResultsOf the 13,933 eligible individuals, 7,917 (56.8%) were female, and 9,540 (68.50%) were over 80 years old. 2,766 (19.9%) participants had their first cardiometabolic disease, 975 (7.0%) participants suffered from cardiometabolic multimorbidity, and 9,365 (67.2%) participants died. The progression to cardiometabolic multimorbidity was positively associated with being female (HR = 1.42; 95%CI, 1.10 − 1.85), living in the city (HR = 1.41; 95%CI, 1.04 − 1.93), overweight (HR = 1.43; 95%CI, 1.08 − 1.90), and obesity (HR = 1.75; 95% CI, 1.03 − 2.98). A higher risk for the first cardiometabolic disease was associated with being female (HR = 1.26; 95% CI, 1.15 − 1.39), higher socioeconomic status (SES, HR = 1.17; 95%CI, 1.07 − 1.28), lack of regular physical activity (HR = 1.13; 95%CI, 1.04 − 1.23), smoking (HR = 1.20; 95%CI, 1.08 − 1.33), ≤ 5 h sleep time (HR = 1.15; 95%CI, 1.02 − 1.30), overweight (HR = 1.48; 95% CI, 1.32 − 1.66), and obesity (HR = 1.34; 95%CI, 1.06 − 1.69). It also should be noted that not in marriage, lower SES and unhealthy behavioral patterns were risk factors for mortality.ConclusionThis study emphasized the importance of lifestyle and SES in tackling the development of cardiometabolic conditions among Chinese elders and provided a reference for policy-makers to develop a tailored stage-specific intervention strategy.

The constitutive androstane receptor (CAR), a member of the NR1I group of nuclear hormone receptors, has been implicated in regulating the expression of genes that are critical in xenobiotic and endobiotic metabolism, uptake and elimination as well as genes involved in various other physiological processes. Hence, functional variation in CAR associated with its expression and/or activity can influence the transcriptional activation of its target genes and could contribute to the observed variation in drug response and toxicity. Moreover, coadministration of agents that are also CAR activators contributes to clinically relevant drug-drug interactions in patients receiving certain combination therapies. This review will discuss the functional significance of known genetic variants in CAR and the most common alternatively spliced isoforms of CAR. We will also discuss the influence of gender and ethnicity on CAR and its target genes. Although genetic polymorphisms in CAR may have an indirect effect on drug disposition, understanding the association of genetic polymorphisms in CAR with the expression of its target genes might help us to better understand the molecular mechanisms underlying the interindividual variation in drug disposition in addition to drug-drug interactions.

Bamboo charcoal enhances cellulase and urease activities during chicken manure composting: Roles of the bacterial community and metabolic functions

Major adverse cardiovascular events among Black and White Veterans receiving androgen deprivation therapy for prostate cancer: a retrospective cohort study

Assessing underlying illnesses can inform health stakeholders about chronic conditions for targeted enhanced prevention and treatment strategies. Since the Eastern Cape Province has a high disease burden, this study aimed to assess the prevalence of human immunodeficiency virus (HIV) infection and selected disease burden of outpatients from primary health care (PHC) facilities in the districts. From February 2019 to February 2021, a cross-sectional study was conducted. Research Electronic Data Capture (REDCap)-enabled tablets were used to collect data from consenting outpatients over the age of 18 years using an interviewer-administered WHO core and expanded stepwise questionnaire. The statistical analysis was mainly descriptive with the use of counts, frequencies, and summary measures. The study population was predominantly female (86.5%). Prevalent diseases included HIV, hepatitis B virus (HBV) infection, and cardiometabolic diseases. HIV prevalence was 52% and highest in the age group of 30–59 years. In people living with HIV, the nonsuppressed viral load (VL 1000 copies/mL) was highest in the age group of 40–49 years (34.6%). Prevalence of diabetes was highest at the Mhlontlo subdistrict (42.3%), while the King Sabata Dalindyebo (KSD) subdistrict had the highest prevalence of HBV infections (39.1%). Based on the findings, we advocate for intermittent assessments of disease burden in certain settings, such as rural areas, to improve PHC practice and outcomes, especially in the wake of the coronavirus disease (COVID-19) pandemic.

Much information has been collected over the past few years on the main features of neuroadrenergic abnormalities that characterize cardiovascular disease. We learned, eg, that in a number of pathological states adrenergic influences lose their homeostatic regulatory function and become “less sympathetic,” not only favoring the development of the disease itself but also contributing to its clinical progression. We also learned that elevated circulating plasma norepinephrine levels do not invariably reflect sympathetic activation and that complex but accurate methodologic approaches to quantify neuroadrenergic drive should be of help in dissecting the peripheral (reduced clearance and or reuptake of norepinephrine) versus the central (increased in central sympathetic outflow) origin of the sympathetic activation characterizing a given physiological or pathophysiological condition. Other key findings of recent investigations in the field of neural cardiovascular control should not be forgotten. They include, eg, the evidence that sympathetic influences on cardiac, renal, thermoregulatory, and metabolic function are not independent entities but rather complex phenomena integrating each other in a “neurally exchanging network.” They also include the evidence that, in several cardiovascular and noncardiovascular diseases, therapeutic counterbalance of adrenergic overdrive may be clinically relevant for reducing cardiovascular risk, improving cardiovascular function, and possibly retarding the progression and favoring the regression of the end-organ damage. This therapeutic goal is based on a well-documented rationale, namely the evidence that in a number of diseases (heart failure, acute myocardial infarction, stroke, and renal failure) sympathetic activation has proven clinical and prognostic relevance.1 In …

Lignocellulosic biomass is a renewable raw material. Industrial interest with new technology has grown to take advantage of this raw material. Different microbial enzymes are treated with biomass to produce the desired products under ideal industrial conditions. Xylanases are the key enzymes that degrade the xylosidic linkages in the xylan backbone of the biomass, and commercial enzymes are categorized into different glycoside hydrolase families. Thermophilic microorganisms are an excellent source of thermostable enzymes that can tolerate the extreme conditions of industrial processing. Thermostability of xylanases from thermophilic microorganisms has given the importance for a specific activity at elevated temperatures and distinction due to biochemical properties, structure, and mode of action. Optimized xylanases can be produced through genetic engineering: a novel xylanase is isolated from an extreme environment and then genetically modified to improve suitability for industrial contexts. Recombinant protein techniques have made it possible to engineer and express thermostable xylanases in bacteria, yeasts, and filamentous fungi. We will discuss the biotechnological potential of xylanases from thermophilic microorganism and the ways they are being optimized and expressed for industrial applications.