T-2 toxin induces cardiac fibrosis by causing metabolic disorders and up-regulating Sirt3/FoxO3α/MnSOD signaling pathway-mediated oxidative stress.

T-2 toxin, an omnipresent environmental contaminant, poses a serious risk to the health of humans and animals due to its pronounced cardiotoxicity. This study aimed to elucidate the molecular mechanism of cardiac tissue damage by T-2 toxin. Twenty-four male Sprague-Dawley rats were orally administered T-2 toxin through gavage for 12 weeks at the dose of 0, 10, and 100 nanograms per gram body weight per day (ng/(g·day)), respectively. Morphological, pathological, and ultrastructural alterations in cardiac tissue were meticulously examined. Non-targeted metabolomics analysis was employed to analyze alterations in cardiac metabolites. The expression of the Sirt3/FoxO3α/MnSOD signaling pathway and the level of oxidative stress markers were detected. The results showed that exposure to T-2 toxin elicited myocardial tissue disorders, interstitial hemorrhage, capillary dilation, and fibrotic damage. Mitochondria were markedly impaired, including swelling, fusion, matrix degradation, and membrane damage. Metabonomics analysis unveiled that T-2 toxin could cause alterations in cardiac metabolic profiles as well as in the Sirt3/FoxO3α/MnSOD signaling pathway. T-2 toxin could inhibit the expressions of the signaling pathway and elevate the level of oxidative stress. In conclusion, the T-2 toxin probably induces cardiac fibrotic impairment by affecting amino acid and choline metabolism as well as up-regulating oxidative stress mediated by the Sirt3/FoxO3α/MnSOD signaling pathway. This study is expected to provide targets for preventing and treating T-2 toxin-induced cardiac fibrotic injury.

Overview of the therapeutic efficacy of marine fish oil in managing obesity and associated metabolic disorders.

In the present scenario, obesity is a challenging health problem and its prevalence along with comorbidities are on the rise around the world. Ingestion of fish becomes trendy in daily meals. Recent research has shown that marine fish oil (FO) (found in tuna, sardines, and mackerel) may offer an alternative method for reducing obesity and problems associated with it. Marine FO rich in long-chain omega-3 polyunsaturated fatty acids (LC n-3 PUFA) and long-chain omega-6 polyunsaturated fatty acids (LC n-6 PUFA) plays an important role in reducing abnormalities associated with the metabolic syndrome and has a variety of disease-fighting properties, including cardioprotective activity, anti-atherosclerotic, anti-obesity, anti-cancer, anti-inflammatory activity. Studies in rodents and humans have indicated that LC n-3 PUFA potentially elicit a number of effects which might be useful for reducing obesity, including suppression of appetite, improvements in circulation, enhanced fat oxidation, energy expenditure, and reduced fat deposition. This review discusses the interplay between inflammation and obesity, and their subsequent regulation via the beneficial role of marine FO, suggesting an alternative dietary strategy to ameliorate obesity and obesity-associated chronic diseases.

Directly targeting PRDM16 in thermogenic adipose tissue to treat obesity and its related metabolic diseases.

Obesity is increasing globally and is closely associated with a range of metabolic disorders, including metabolic associated fatty liver disease, diabetes, and cardiovascular diseases. An effective strategy to combat obesity involves stimulating brown and beige adipocyte thermogenesis, which significantly enhances energy expenditure. Recent research has underscored the vital role of PRDM16 in the development and functionality of thermogenic adipocytes. Consequently, PRDM16 has been identified as a potential therapeutic target for obesity and its related metabolic disorders. This review comprehensively examines various studies that focus on combating obesity by directly targeting PRDM16 in adipose tissue.

Effect of low muscle mass on total mortality related to metabolic disease in chronic kidney disease patients.

Low muscle mass is a risk factor for mortality in patients with chronic kidney disease (CKD). However, it is not clear to what extent low muscle mass contributes to this risk, either independently or in combination with metabolic abnormalities and frailty. This study used data from the National Health and Nutrition Examination Survey 1999-2006 and 2011-2018. Low muscle mass was defined as Appendicular Skeletal Mass Index < 7 kg/m2 in men or < 5.5 kg/m2 in women. The follow-up duration was from the first anthropometric and clinical measurements to death or the last follow-up. This study enrolled 2072 patients with CKD. Low muscle mass was associated with a lower risk of metabolic abnormalities, but was associated with an elevated mortality risk. Conversely, central obesity was associated with a higher likelihood of metabolic abnormalities and frailty, yet showed no significant association with mortality risk. Subsequently conducted mediation analysis indicated that the effect of low muscle mass on mortality was direct, not mediated by frailty and metabolic abnormalities. In spite of the inverse relationship between low muscle mass and metabolic abnormalities, low muscle mass are directly associated with an increased risk of all-cause mortality. Low muscle mass may directly contribute to mortality in patients with CKD, independent of metabolic abnormalities and frailty in these patients.

Association between metabolic disorders and clinicopathologic features in endometrial cancer.

Background: In recent years, the incidence of Endometrial cancer (EC) has been on the rise due to high-fat, high-calorie diets and low-exercise lifestyles. However, the relationships between metabolic disorders and the progression of EC remain uncertain. The purpose of our study was to explore the potential association between obesity, hypertension, hyperglycemia and clinicopathologic characteristics in EC patients. Methods: In categorical variables, Chi-square tests were used to calculate P values. Univariate logistic regression and multivariate logistic regression were used to identify the risk factors of myometrial invasion>1/2 and lymph node metastasis. Overall survival (OS) was estimated using the Kaplan-Meier method. Results: The study included 406 individuals with EC, 62.6% had type I and 37.4% had type II. Hypertension was seen in 132 (32.5%), hyperglycemia in 75 (18.5%), and overweight or obesity in 217 (53.4%). Hypertension, hyperglycemia, and obesity are strongly associated with the clinicopathologic features of EC. Multivariate logistic regression revealed that hyperglycemia (OR=2.439,95% CI: 1.025-5.804, P = 0.044) was a risk factor for myometrial invasion depth >1/2 in patients with type I EC, and hypertension (OR=32.124,95% CI: 3.287-313.992, P = 0.003) was a risk factor for lymph node metastasis in patients with type I EC. Survival analysis found that hyperglycemia (P < 0.001) and hypertension (P = 0.002) were associated with OS in type I EC. Neither hyperglycemia, hypertension, nor obesity were associated with the prognosis in type II EC. Conclusion: Hyperglycemia was a risk factor for myometrial invasion depth >1/2 in patients with type I EC and hypertension was a risk factor for lymph node metastasis in patients with type I EC. Hypertension and hyperglycemia were associated with poor prognosis in patients with type I EC.

Genetic interactions and pleiotropy in metabolic diseases: Insights from a comprehensive GWAS analysis.

This study offers insights into the genetic and biological connections between nine common metabolic diseases using data from genome-wide association studies. Our goal is to unravel the genetic interactions and biological pathways of these complex diseases, enhancing our understanding of their genetic architecture. We employed a range of advanced analytical techniques to explore the genetic correlations and shared genetic variants of these diseases. These methods include Linked Disequilibrium Score Regression, High-Definition Likelihood (HDL), genetic analysis combining multiplicity and annotation (GPA), two-sample Mendelian randomization analyses, analysis under the multiplicity-complex null hypothesis (PLACO), and Functional mapping and annotation of genetic associations (FUMA). Additionally, Bayesian co-localization analyses were used to examine associations of specific loci across traits. Our study discovered significant genomic correlations and shared loci, indicating complex genetic interactions among these metabolic diseases. We found several shared single nucleotide variants and risk loci, notably highlighting the role of the immune system and endocrine pathways in these diseases. Particularly, rs2476601 and its associated gene PTPN22 appear to play a crucial role in the connection between type 2 diabetes mellitus, hypothyroidism/mucous oedema and hypoglycaemia. These findings enhance our understanding of the genetic underpinnings of these diseases and open new potential avenues for targeted therapeutic and preventive strategies. The results underscore the importance of considering pleiotropic effects in deciphering the genetic architecture of complex diseases, especially metabolic ones.

A new perspective in intestinal microecology: lifting the veil of exercise regulation of cardiometabolic diseases.

Cardiometabolic diseases (CMDs), encompassing cardiovascular and metabolic dysfunctions, characterized by insulin resistance, dyslipidemia, hepatic steatosis, and inflammation, have been identified with boosting morbidity and mortality due to the dearth of efficacious therapeutic interventions. In recent years, studies have shown that variations in gut microbiota and its own metabolites can influence the occurrence of CMDs. Intriguingly, the composition and function of the gut microbiota are susceptible to exercise patterns, thus affecting inflammatory, immune, and metabolic responses within the host. In this review, we introduce the key mechanisms of intestinal microecology involved in the onset and development of CMDs, discuss the relationship between exercise and intestinal microecology, and then analyze the role of intestinal microecology in the beneficial effects of exercise on CMDs, aiming at elucidating the gut-heart axis mechanisms of exercise mediated protective effect on CMDs, building avenues for the application of exercise in the management of CMDs.

Ecnomotopic olfactory receptors in metabolic regulation.

Olfactory receptors are seven-transmembrane G-protein-coupled receptors on the cell surface. Over the past few decades, evidence has been mounting that olfactory receptors are not unique to the nose and that their ectopic existence plays an integral role in extranasal diseases. Coupled with the discovery of many natural or synthetic odor-compound ligands, new roles of ecnomotopic olfactory receptors regulating blood glucose, obesity, blood pressure, and other metabolism-related diseases are emerging. Many well-known scientific journals have called for attention to extranasal functions of ecnomotopic olfactory receptors. Thus, the prospect of ecnomotopic olfactory receptors in drug target research has been greatly underestimated. Here, we have provided an overview for the role of ecnomotopic olfactory receptors in metabolic diseases, focusing on their effects on various metabolic tissues, and discussed the possible molecular biological and pathophysiological mechanisms, which provide the basis for drug development and clinical application targeting the function of ecnomotopic olfactory receptors via literature machine learning and screening.

Associations between co-exposure to per- and polyfluoroalkyl substances and metabolic diseases: The mediating roles of inflammation and oxidative stress.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) pose potential risks to human health. In real-world settings, humans are exposed to various PFAS through numerous pathways. OBJECTIVES: This study evaluated the associations between co-exposure to PFAS and obesity and its comorbidities, along with the mediating roles of inflammation and oxidative stress. METHODS: We analyzed 11,090 participants from National Health and Nutrition Examination Survey (NHANES), 2003-2018. Linear regression, logistic regression, and generalized additive models were used to assess the individual effects of PFAS exposure on obesity and its comorbidities. The environmental risk score (ERS) was calculated using the adaptive elastic-net model to assess the co-exposure effects. Linear and logistic regression models explored the associations between ERS and obesity and its comorbidities. Mediation analyses explored the roles of inflammatory (neutrophils, lymphocytes, and alkaline phosphatase) and oxidative stress (gamma-glutamyl transferase, total bilirubin, and uric acid) markers in the associations between ERS and obesity and its comorbidities. RESULTS: For each unit increase in ERS, the odds of obesity and type 2 diabetes mellitus (T2DM) increased 3.60-fold (95 % CI: 2.03, 6.38) and 1.91-fold (95 % CI: 1.28, 2.86), respectively. For each unit increase in ERS, BMI increased by 2.36 (95 % CI: 1.24, 3.48) kg/m2, waist circumference increased by 6.47 (95 % CI: 3.56, 9.37) cm, and waist-to-height ratio increased by 0.04 (95 % CI: 0.02, 0.06). Lymphocytes, alkaline phosphatase, and total bilirubin were significantly associated with both ERS and obesity, with mediation proportions of 4.17 %, 3.62 %, and 7.37 %, respectively. Lymphocytes, alkaline phosphatase, total bilirubin, and uric acid were significantly associated with both ERS and T2DM, with the mediation proportions of 8.90 %, 8.74 %, 29.73 %, and 38.19 %, respectively. CONCLUSIONS: Co-exposure to PFAS was associated with obesity and T2DM, and these associations may be mediated by inflammation and oxidative stress. Further mechanistic and prospective studies are required to verify these associations.

Chios Mastic Gum: A Promising Phytotherapeutic for Cardiometabolic Health.

Chios mastic gum (CMG) is a resin obtained from the Pistacia lentiscus var. Chia tree that grows in the Mediterranean. For millennia, it has been renowned for its medicinal properties, but recently, CMG has gained attention due to its pronounced anti-inflammatory and antioxidative properties and its use in oral health, inflammatory bowel disease, cancer, and risk factors related to cardiovascular and metabolic diseases. This narrative review seeks to briefly overview its bioactive constituents and examine and describe its potential as a cardiometabolic disease (CMD) phytotherapeutic. The results of clinical trials and in vivo, in vitro, and in silico studies provide accumulating evidence of the mechanisms underlying CMG's impacts on lipid and glucose metabolism, cardiovascular and hepatic health, inflammation, oxidative stress, body composition, and microbiota. Despite the relatively limited studies with mixed results, they have provided the foundation to understand the strengths, weaknesses, and opportunities moving forward that may help to establish CMG and its bioactives as viable therapeutics for CMD.

Pharmacological Features and Therapeutic Implications of Plumbagin in Cancer and Metabolic Disorders: A Narrative Review.

Plumbagin (PLB) is a naphthoquinone extracted from Plumbago indica. In recent times, there has been a growing body of evidence suggesting the potential importance of naphthoquinones, both natural and artificial, in the pharmacological world. Numerous studies have indicated that PLB plays a vital role in combating cancers and other disorders. There is substantial evidence indicating that PLB may have a significant role in the treatment of breast cancer, brain tumours, lung cancer, hepatocellular carcinoma, and other conditions. Moreover, its potent anti-oxidant and anti-inflammatory properties offer promising avenues for the treatment of neurodegenerative and cardiovascular diseases. A number of studies have identified various pathways that may be responsible for the therapeutic efficacy of PLB. These include cell cycle regulation, apoptotic pathways, ROS induction pathways, inflammatory pathways, and signal transduction pathways such as PI3K/AKT/mTOR, STAT3/PLK1/AKT, and others. This review aims to provide a comprehensive analysis of the diverse pharmacological roles of PLB, examining the mechanisms through which it operates and exploring its potential applications in various medical conditions. In addition, we have conducted a review of the various formulations that have been reported in the literature with the objective of enhancing the efficacy of the compound. However, the majority of the reviewed data are based on in vitro and in vivo studies. To gain a comprehensive understanding of the safety and efficacy of PLB in humans and to ascertain its potential integration into therapeutic regimens for cancer and chronic diseases, rigorous clinical trials are essential. Finally, by synthesizing current research and identifying gaps in knowledge, this review seeks to enhance our understanding of PLB and its therapeutic prospects, paving the way for future studies and clinical applications.

The use of capsicum oleoresin microparticles to mitigate hepatic damage and metabolic disorders induced by obesity.

Capsicum oleoresin has potential health benefits, particularly against obesity markers. Due to its high pungency, few studies have been done to explore the intake of this ingredient. The objective of this study was to use the Capsicum oleoresin (CO) microencapsulated into a high-fat diet to evaluate its metabolic effect on mice. Two formulation containing 15 % solids were prepared: the first (F1) with 5% CO and 95% emulsifier, and the second (F2) with 2.5% corn oil, 2.5% CO, and 95% emulsifier. These formulation were atomized in a spray dryer. Ultra-Performance Liquid Chromatography determined the capsaicin content for both formulations. Mice were divided into two groups: lean control (normocaloric AIN diet, n = 10) and high fat (HF diet: hypercaloric, n = 30), which were subdivided into three subgroups: HF control diet (n = 10); diet F1: HF + 20 % CO oleoresin microparticles (n = 10); and diet F2: HF + 20 % CO microparticles containing corn oil (n = 10). The animals treated with the microparticles showed lower glucose levels than the HF control. Mice fed with HF-containing CO microparticles had cholesterol blood levels similar to that of the lean group and lower (<100 mg/dL) than that of the HF control group (150 mg/dL). Capsicum oleoresin microparticles added to high-fat diets promoted lower weight gain and protected the liver against hepatic steatosis. Leptin levels for mice fed with HF diet plus CO microparticles averaged between 2 and 5 ng/ml, whereas the fat control group developed leptin resistance. Capsicum microparticles evidenced a protective effect against dyslipidemia compared to the fat control group, which suggests their use as a potential ingredient for the control of obesity.

Small Bowel Therapies for Metabolic Disease and Obesity.

The small bowel has a crucial role in metabolic homeostasis. Small bowel endoscopic bariatric metabolic treatments (EBMTs) include several devices aimed at providing minimally invasive approaches for the management of metabolic disorders. The aim of this review is to provide an updated and exhaustive overview of the EBMTs targeting the small bowel developed to date, including the duodenal mucosa resurfacing, the duodenal-jejunal bypass liners, gastro-jejunal bypass sleeve, and the incisioneless magnetic anastomosis system, as well as to mention the future perspectives in the field.

Ferroptosis at the nexus of metabolism and metabolic diseases.

Ferroptosis, an iron-dependent form of regulated cell death, is emerging as a crucial regulator of human physiology and pathology. Increasing evidence showcases a reciprocal relationship between ferroptosis and dysregulated metabolism, propagating a pathogenic vicious cycle that exacerbates pathology and human diseases, particularly metabolic disorders. Consequently, there is a rapidly growing interest in developing ferroptosis-based therapeutics. Therefore, a comprehensive understanding of the intricate interplay between ferroptosis and metabolism could provide an invaluable resource for mechanistic insight and therapeutic development. In this review, we summarize the important metabolic substances and associated pathways in ferroptosis initiation and progression, outline the cascade responses of ferroptosis in disease development, overview the roles and mechanisms of ferroptosis in metabolic diseases, introduce the methods for ferroptosis detection, and discuss the therapeutic perspectives of ferroptosis, which collectively aim to illustrate a comprehensive view of ferroptosis in basic, translational, and clinical science.

PDIA3 defines a novel subset of adipose macrophages to exacerbate the development of obesity and metabolic disorders.

Adipose tissue macrophages (ATMs) play important roles in maintaining adipose tissue homeostasis and orchestrating metabolic inflammation. Given the extensive functional heterogeneity and phenotypic plasticity of ATMs, identification of the authentically pathogenic ATM subpopulation under obese setting is thus necessitated. Herein, we performed single-nucleus RNA sequencing (snRNA-seq) and unraveled a unique maladaptive ATM subpopulation defined as ATF4hiPDIA3hiACSL4hiCCL2hi inflammatory and metabolically activated macrophages (iMAMs), in which PDIA3 is required for the maintenance of their migratory and pro-inflammatory properties. Mechanistically, ATF4 serves as a metabolic stress sensor to transcribe PDIA3, which then imposes a redox control on RhoA activity and strengthens the pro-inflammatory and migratory properties of iMAMs through RhoA-YAP signaling. Administration of Pdia3 small interfering RNA (siRNA)-loaded liposomes effectively repressed adipose inflammation and high-fat diet (HFD)-induced obesity. Together, our data support that strategies aimed at targeting iMAMs by suppressing PDIA3 expression or activity could be a viable approach against obesity and metabolic disorders in clinical settings.

Progress in the Study of Animal Models of Metabolic Dysfunction-Associated Steatotic Liver Disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD) has recently been proposed as an alternative term to NAFLD. MASLD is a globally recognized chronic liver disease that poses significant health concerns and is frequently associated with obesity, insulin resistance, and hyperlipidemia. To better understand its pathogenesis and to develop effective treatments, it is essential to establish suitable animal models. Therefore, attempts have been made to establish modelling approaches that are highly similar to human diet, physiology, and pathology to better replicate disease progression. Here, we reviewed the pathogenesis of MASLD disease and summarised the used animal models of MASLD in the last 7 years through the PubMed database. In addition, we have summarised the commonly used animal models of MASLD and describe the advantages and disadvantages of various models of MASLD induction, including genetic models, diet, and chemically induced models, to provide directions for research on the pathogenesis and treatment of MASLD.

Citrus reticulata Olive Oil: Production and Nutraceutical Effects on the Cardiovascular System in an In Vivo Rat Model of Metabolic Disorder.

Recently, there has been significant exploration into the utilization of food by-products as natural reservoirs of bioactive substances, particularly in the creation of functional foods naturally enriched with antioxidants. Citrus peels represent a viable option for formulating enhanced olive oils that contribute to a healthier diet, due to their bioactive compound content. This study aimed to (i) ascertain the compositional characteristics of Citrus reticulata olive oil (CrOO) and (ii) assess its nutraceutical properties in rats with metabolic disorder induced by 3 weeks of feeding with a high-fat diet (HFD). The results showed a peculiar phytochemical composition, thanks to the contribution of citrus peels, which are excellent bio-products. In addition, it demonstrated HFD-induced weight gain (18 ± 2% for HFD vs. 13 ± 0.9% for CrOO) and showed protective effects on fasting blood glucose levels (90.2 ± 3.8 mg/dL for HFD vs. 72.3 ± 2.6 for CrOO). Furthermore, a reduction in cardiovascular risk (total cholesterol/HDL cholesterol = 5.0 ± 0.3 for HFD vs. 3.8 ± 0.3 for CrOO) and an improvement in myocardial tissue function were observed, as well as a significant reduction in inflammatory mediators such as iNOS, COX-2, and mPGES-1 in aortic vessel tissues, thus preserving endothelial function at the vascular level.

A clinical decision support tool for metabolic dysfunction-associated steatohepatitis in real-world clinical settings: a mixed-method implementation research study protocol.

Aim: A clinical decision support (CDS) tool for metabolic dysfunction-associated steatohepatitis (MASH) was developed to align health systems with clinical guidelines detailed in the MASH Clinical Care Pathway and improve patients' proactive self-management of their disease. The tool includes a provider-facing web-based application and a mobile application (app) for patients. This protocol outlines a pilot study that will systematically evaluate the implementation of the tool in real-world clinical practice settings. Materials & methods: This implementation research study will use a simultaneous mixed-methods design and is guided by the Consolidated Framework for Implementation Research. The CDS tool for MASH will be piloted for ≥3 months at multiple US-based sites with eligible gastroenterologists and hepatologists (n = 5-10 per site) and their patients (n = 50-100 per site) with MASH or suspected MASH. Each pilot site may choose one or all focus areas within the tool (i.e., risk stratification, screening and referral, or patient care management), based on on-site capabilities. Prior to and at the end of the pilot period, providers and patients will complete quantitative surveys and partake in semi-structured interviews. Outcomes will include understanding the feasibility of implementing the tool in real-world clinical settings, its effectiveness in increasing patient screenings and risk stratification for MASH, its ability to improve provider and patient knowledge of MASH, barriers to adoption of the tool and the tool's capacity to enhance patient engagement and satisfaction with their care. Conclusion: Findings will inform the scalable implementation of the tool to ensure patients at risk for MASH are identified early, referred to specialty care when necessary and managed appropriately. Successful integration of the patient app can contribute to better health outcomes for patients by facilitating their active participation in the management of their condition.