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Parasites and obesity are health problems worldwide. Rabbits are production animals yielding one of the healthiest meats, also taking advantage of skin, hair, limbs and excreta. It is among the most frequent pets in some countries and widely used as animal model in research. Psoroptes cuniculi is a mite of high transmission rate, affecting welfare and production and obesity causes multiple metabolic, endocrine and immunological disorders, being an emerging problem in domestic animals. Obesity and acarosis are prolonged stressors, modifying the activity of the hypothalamic-pituitary-adrenal axis that can induce metabolic and behavioral disorders. Alterations caused by comorbidities could be similar to or different from those induced by each morbidity separately. We analyzed the influence of obesity on the infection degree with P. cuniculi and on behavior and production. Rabbit does induced to obesity were infected and mated; behaviors in the open field test, obesity estimation indices and productive parameters at delivery and weaning were analyzed. The acarosis induced a decrease in feed intake and a decrease in body weight, a decrease in locomotor, exploratory and chinning behaviors in normal weight and obese does. The infection induced 23% mortality at birth, obesity 45% and comorbidity 74%, while in normal weight rabbits a 6.5% was observed. Weight gain from birth to weaning was lower in the comorbid group, reaching a litter weight of 4.5±0.13 kg in healthy normal weight does and 2.6±0.67 kg in comorbid does. The disturbances induced by the comorbidity were magnified in both behavioral and productive parameters. [ABSTRACT FROM AUTHOR]

Laboratory animal research with nonhuman primates (NHPs) requires anesthesia for most procedures to ensure safety and consistency in sample collection. However, anesthesia drugs can have adverse effects on the physiological measures of interest. Alfaxalone, most notably used in dogs and cats, offers rapid onset, short duration of action, and has a high safety margin. Here, we compared our current anesthesia protocol using Telazol, to three different doses of alfaxalone during a one-hour intravenous glucose tolerance test, the standard evaluation of glucose metabolism in NHPs. Results indicate there are no differences in the rate of glucose metabolism, anesthesia depth measurements, or total duration of sedation, but induction, number of supplemental doses required, and recovery time to eating were affected by the different doses of alfaxalone. Cardiovascular measures showed variability between the four protocols in respiratory rate and systolic blood pressure rates only. These results indicate that alfaxalone can produce a reliable state of anesthesia, similar to our current protocol, and confers minimal cardiovascular or metabolic disturbance, as well as enhanced recovery characteristics. As such, alfaxalone is a promising anesthetic for use in laboratory animals and further investigation is warranted. [ABSTRACT FROM AUTHOR]

Background: The prevention of obesity represents a major health and socio-economic challenge. Nutraceuticals are regularly highlighted for their beneficial effects in preventing the metabolic disturbances associated with obesity. However, few studies have described the combined action of nutraceutical mixtures combining polyphenols with alkaloids. Objective: The aim of this study was to evaluate the effects of long-term dietary supplementation with a mixture of Berberine, Citrus and Apple extracts (BCA) in the primary prevention of obesity and its metabolic and vascular complications in the obese Zucker rat, a spontaneous model of genetic obesity and insulin resistance. Methods: Sixteen 8-week-old obese Zucker male rats were randomly divided into two groups: all rats received oral gavage daily either with water, untreated obese (U-ObZ) or BCA (BCA-ObZ) mixture for thirteen weeks. Morphological and metabolic parameters were measured along the study. Cumulative concentration-response curves to insulin, acetylcholine and phenylephrine were determined on isolated thoracic aorta. Colon permeability measurements were performed using the Ussing chamber technique. Fecal samples collected at the beginning and the end of the protocol were used as a template for amplification of the V3-V4 region of the 16S rDNA genes. Results: BCA supplementation reduced weight gain (p<0.05) and food intake (p<0.05) in the BCA-ObZ group rats compared to the U-ObZ group rats. It also improved glucose tolerance (p<0.001) and decreased fasting insulin and Homeostasis model assessment index (p<0.05). Through ex vivo experiments, the BCA mixture enhanced significantly aortic insulin relaxation (p<0.01), reduced α1-adrenoceptor-mediated vasoconstriction (p<0.01), and decreased distal colon permeability. Moreover, short-chain fatty acid producers such as Bacteroides, Blautia, and Akkermansia were found to be increased by the BCA mixture supplementation. Conclusion: The results showed that a 13-week-supplementation with BCA mixture prevented weight gain and improved glucose metabolism in obese Zucker rats. We also demonstrated that BCA supplementation improved vascular function, colonic barrier permeability and gut microbiota profile. [ABSTRACT FROM AUTHOR]

Introduction: Previous studies have extensively examined the relationship between social support and various health outcomes. However, little is known about the distinct longitudinal associations between perceived social support and the development of cardiovascular events in patients with metabolic syndrome. In this cohort study, we investigated whether the levels of perceived social support in patients with metabolic syndrome were associated with an increased risk of cerebrovascular and cardiovascular events. Methods: The level of social support was assessed using the Medical Outcomes Study-Social Support Survey (MOS-SSS) in 2,721 individuals living in Wonju and Pyeongchang, South Korea. The presence of metabolic syndrome was determined by physical measurements and blood tests, and the occurrence of cerebral cardiovascular disease in relation to the presence of metabolic syndrome and the level of social support was analyzed using Cox proportional-hazards models. Results: The median follow-up period was 2,345 days (2,192–2,618). Overall, in the group with metabolic syndrome and low social support, low social support was associated with an increased risk of later cerebral cardiovascular events; in this group, the hazard ratio after adjusting for confounding variables was 1.97 times (95% confidence interval, 1.01–3.85) higher than that in the group without metabolic syndrome and low social support. Conclusion: This study shows, for the first time, that the level of social support is a risk factor for preventing cerebral cardiovascular disease in patients with metabolic syndrome and suggests that social support status should be incorporated into multifactorial risk assessment and intervention procedures to prevent metabolic syndrome and cerebral cardiovascular disease. [ABSTRACT FROM AUTHOR]

Excessive body weight may disrupt hepatic enzymes that may be aggravated by obesity-related comorbidities. The current case-control study was designed to evaluate the extent of liver enzyme alteration in obesity-related metabolic disorders. Obese females with BMI ≥ 30 suffering from metabolic disorders were grouped according to existing co-morbidity and their hepatic enzymes were compared with non-obese healthy females. The resultant data was subjected to analysis of variance and mean difference in liver enzymes were calculated at P = 0.05. Analysis of variance indicated that obese diabetic and obese hypertensive females had almost 96% and 67% increase in the concentration of gamma-glutamyl transferase than control, respectively (P<0.0001). The obese females suffering from diabetes and hypertension exhibited nearly 54% enhancement in alanine transaminase level (P<0.0001) and a 17% increase in aspartate aminotransferase concentration (P = 0.0028). Obesity along with infertility decline liver enzyme production and a 31% significant decline in aspartate aminotransferase was observed while other enzyme concentrations were not significantly altered. Regression analysis was performed on the resultant data to understand the association between liver enzyme alteration and the development of metabolic diseases. Regression analysis indicated that obese diabetic and obese diabetic hypertensive women had 20% production of normal liver enzymes and 80% enzymes produced abnormally. Obese hypertensive and obese infertile females had only 5% and 6% normal production of liver enzymes, respectively. This research leads to the conclusion that the ability of the liver to function normally is reduced in obesity-related diabetes and hypertension. This may be due to inflamed and injured liver and poses a serious threat to developing fatty liver disease and ultimately liver cirrhosis. [ABSTRACT FROM AUTHOR]

Introduction: Adequate hydration is essential for maintaining the health and functionality of the human body. This study aimed to examine the association between selected socioeconomic, lifestyle, and health factors and the hydration status of adults with metabolic disorders by analyzing their urine osmolality. Methods: The study involved 290 adults aged 18–70 years with metabolic disorders. Separate multivariate logistic regression models were conducted to evaluate the factors associated with urine osmolality in tertiles for women and men. Odds Ratios (OR) and 95% Confidence Intervals (95% CI) were calculated. Results: In women, the following factors of urine osmolality were identified in 1st tertile: age (OR:1.04), physical activity (moderate/high vs. no/low; OR:0.38), and headaches (no vs. yes; OR:1.55), in 2nd tertile: physical activity (moderate/high vs. no/low; OR:2.46) and fatigue during the day (sometimes vs. never/very rarely; OR:0.45), and in 3rd tertile: age (OR:0.94), professional status ('I work part-time/I study and I work' vs. 'I do not work/I study'; OR:0.27), fatigue during the day (very often vs. never/very rarely; OR:2.55), and headaches (no vs. yes; OR:0.44). In men, the following factors of urine osmolality were identified in 1st tertile: place of residence (city vs. village; OR:2.72) and health assessment (average vs. poor; OR:0.32). Conclusion: Different factors affecting urine osmolality have been identified in women and men. These results highlight the need to implement studies to clarify the relationship between socioeconomic, lifestyle and health factors, and hydration status in adults with metabolic disorders. [ABSTRACT FROM AUTHOR]

Diabetes Mellitus is one of the oldest diseases known to humankind, dating back to ancient Egypt. The disease is a chronic metabolic disorder that heavily burdens healthcare providers worldwide due to the steady increment of patients yearly. Worryingly, diabetes affects not only the aging population but also children. It is prevalent to control this problem, as diabetes can lead to many health complications. As evolution happens, humankind starts integrating computer technology with the healthcare system. The utilization of artificial intelligence assists healthcare to be more efficient in diagnosing diabetes patients, better healthcare delivery, and more patient eccentric. Among the advanced data mining techniques in artificial intelligence, stacking is among the most prominent methods applied in the diabetes domain. Hence, this study opts to investigate the potential of stacking ensembles. The aim of this study is to reduce the high complexity inherent in stacking, as this problem contributes to longer training time and reduces the outliers in the diabetes data to improve the classification performance. In addressing this concern, a novel machine learning method called the Stacking Recursive Feature Elimination-Isolation Forest was introduced for diabetes prediction. The application of stacking with Recursive Feature Elimination is to design an efficient model for diabetes diagnosis while using fewer features as resources. This method also incorporates the utilization of Isolation Forest as an outlier removal method. The study uses accuracy, precision, recall, F1 measure, training time, and standard deviation metrics to identify the classification performances. The proposed method acquired an accuracy of 79.077% for PIMA Indians Diabetes and 97.446% for the Diabetes Prediction dataset, outperforming many existing methods and demonstrating effectiveness in the diabetes domain. [ABSTRACT FROM AUTHOR]

Fatty acid esters of hydroxy fatty acid (FAHFA) are anti-diabetic and anti-inflammatory lipokines. Recently FAHFAs were also found to predict cardiorespiratory fitness in a cross-sectional study of recreationally trained runners. Here we report the influences of body composition and gender on static FAHFA abundances in circulation. We compared the association between circulating FAHFA concentrations and body composition, determined by dual x-ray absorptiometry, in female recreational runners who were lean (BMI < 25 kg/m2, n = 6), to those who were overweight (BMI ≥ 25 kg/m2, n = 7). To characterize the effect of gender we also compared circulating FAHFAs in lean male recreational runners (n = 8) to recreationally trained lean female (n = 6) runner group. Circulating FAHFAs were increased in females in a manner that was modulated by specific adipose depot sizes, blood glucose, and lean body mass. As expected, circulating FAHFAs were diminished in the overweight group, but strikingly, within the lean cohort, increases in circulating FAHFAs were promoted by increased fat mass, relative to lean mass, while the overweight group showed a significantly attenuated relationship. These studies suggest multimodal regulation of circulating FAHFAs and raise hypotheses to test endogenous FAHFA dynamic sources and sinks in health and disease, which will be essential for therapeutic target development. Baseline circulating FAHFA concentrations could signal sub-clinical metabolic dysfunction in metabolically healthy obesity. [ABSTRACT FROM AUTHOR]

Discrepancies between the measurement of body mass index (BMI) and metabolic health status have been described for the onset of metabolic diseases. Studying novel biomarkers, some of which are associated with metabolic syndrome, can help us to understand the differences between metabolic health (MetH) and BMI. A group of 1469 young adults with pre-specified anthropometric and blood biochemical parameters were selected. Of these, 80 subjects were included in the downstream analysis that considered their BMI and MetH parameters for selection as follows: norm weight metabolically healthy (MHNW) or metabolically unhealthy (MUNW); overweight/obese metabolically healthy (MHOW) or metabolically unhealthy (MUOW). Our results showed for the first time the differences when the MetH status and the BMI are considered as global MetH statures. First, all the evaluated miRNAs presented a higher expression in the metabolically unhealthy group than the metabolically healthy group. The higher levels of leptin, IL-1b, IL-8, IL-17A, miR-221, miR-21, and miR-29 are directly associated with metabolic unhealthy and OW/OB phenotypes (MUOW group). In contrast, high levels of miR34 were detected only in the MUNW group. We found differences in the SIRT1-PGC1α pathway with increased levels of SIRT1+ cells and diminished mRNA levels of PGCa in the metabolically unhealthy compared to metabolically healthy subjects. Our results demonstrate that even when metabolic diseases are not apparent in young adult populations, MetH and BMI have a distinguishable phenotype print that signals the potential to develop major metabolic diseases. [ABSTRACT FROM AUTHOR]

Obesity leads to insulin resistance (IR) and type 2 diabetes. In humans, low levels of the hormone prolactin (PRL) correlate with IR, adipose tissue (AT) dysfunction, and increased prevalence of T2D. In obese rats, PRL treatment promotes insulin sensitivity and reduces visceral AT adipocyte hypertrophy. Here, we tested whether elevating PRL levels with the prokinetic and antipsychotic drug sulpiride, an antagonist of dopamine D2 receptors, improves metabolism in high fat diet (HFD)-induced obese male mice. Sulpiride treatment (30 days) reduced hyperglycemia, IR, and the serum and pancreatic levels of triglycerides in obese mice, reduced visceral and subcutaneous AT adipocyte hypertrophy, normalized markers of visceral AT function (PRL receptor, Glut4, insulin receptor and Hif-1α), and increased glycogen stores in skeletal muscle. However, the effects of sulpiride reducing hyperglycemia were also observed in obese prolactin receptor null mice. We conclude that sulpiride reduces obesity-induced hyperglycemia by mechanisms that are independent of prolactin/prolactin receptor activity. These findings support the therapeutic potential of sulpiride against metabolic dysfunction in obesity. [ABSTRACT FROM AUTHOR]

Background and aims: Metabolic dysfunction associated steatotic liver disease (MASLD) increases the risk of incident chronic kidney disease (CKD). However, the relative risk of CKD associated with increasing hepatic fibrosis, and consequent mortality risk, remains underexplored in real-world cohorts. In this study, we sought to establish whether hepatic fibrosis is associated with increased CKD risk and explore differences in mortality risk in a cohort of people living with MASLD, contingent on liver fibrosis and CKD status. Methods: This was an observational study of people who underwent routine liver function testing in Tayside, Scotland. MASLD was defined as: elevated ALT (>30 U/L) or GGT (>73 U/L); presence of diabetes, and/or hypertension, and/or obesity; weekly alcohol consumption <14 units (112g (+/-8g) alcohol); and negative screen for other aetiologies. Data was collected from digital health records. We used log-binomial models to quantify the risk of CKD among those with and without fibrosis, and Cox regression models to estimate differences in mortality risk dependent on fibrosis and CKD. Results: In our cohort (n = 2,046), 1,448 (70.8%) people had MASLD without fibrosis and 598 (29.2%) with fibrosis; 161 (11.1%) and 117 (19.6%) respectively also had CKD. After excluding individuals with structural, autoimmune, or malignant CKD (n = 22), liver fibrosis (n = 593; 18.9% with CKD) was associated with increased CKD risk (aRR = 1.31, 1.04–1.64, p = 0.021). Increased mortality risk was observed for those with liver fibrosis (aHR = 2.30, 1.49–3.56, p = <0.001) and was higher again among people with both fibrosis and CKD (aHR = 5.07, 3.07–8.39, p = <0.014). Conclusions: Liver fibrosis was an independent risk factor for CKD in this cohort of people living with MASLD. Furthermore, those with MASLD with liver fibrosis had higher risk for mortality and this risk was further elevated among those with co-morbid CKD. Given the increased risk of CKD, and consequent mortality risk, among people living with MASLD fibrosis, renal function screening should be considered within liver health surveillance programmes and guidelines. [ABSTRACT FROM AUTHOR]

Background & aims: A new nomenclature, Steatotic Liver Disease (SLD), has been proposed by consensus with sub-classifications and requires evidence-based validation. We assessed whether the presence and severity of SLD, as well as its sub-classifications, are associated with the progression of coronary atherosclerosis. Methods: This longitudinal cohort study included 13,811 adults who participated in repeated regular health screening examinations between January 1, 2004 and December 31, 2021 that included assessments of their coronary artery calcium (CAC) scores. SLD was defined using abdominal ultrasonography and classified as metabolic dysfunction associated steatotic liver disease (MASLD), MASLD with increased alcohol intake (MetALD), and cryptogenic SLD. SLD severity was assessed using fibrosis-4 (FIB-4) scores. The progression of CAC scores was measured using multidetector CT scans. Results: The average duration of follow-up was 5.8 years. During follow-up, the annual rate of CAC progression in participants with and without SLD was 18% (95% CI 17%–19%) and 14% (95% CI 13%–14%) (p < 0.01), respectively. The multivariable ratios of progression rates when we compared participants with cryptogenic SLD, MASLD, or MetALD with those without SLD were 0.98 (95% CI 0.95–1.01), 1.03 (95% CI 1.03–1.04), and 1.07 (95% CI 1.04–1.09), respectively. The multivariable ratios of progression rates when we compared participants with SLD with FIB-4 score <1.3 and SLD with FIB-4 score ≥1.3 with those without SLD were 1.03 (95% CI 1.02–1.04), and 1.05 (95% CI 1.04–1.06), respectively. Conclusions: SLD was associated with a higher risk of coronary atherosclerosis, and the risk differed by sub-classifications and severity. These findings suggest that the newly proposed definition has clinical relevance in terms of stratifying cardiovascular disease risk. [ABSTRACT FROM AUTHOR]

Chronic intermittent hypoxia (CIH) may play an important role in the development of diabetic cardiomyopathy (DCM). However, the exact mechanism of CIH-induced myocardial injury in DCM remains unclear. In vivo, the db/db mice exposed to CIH were established, and in vitro, the H9C2 cells were exposed to high glucose (HG) combined with intermittent hypoxia (IH). The body weight (BW), fasting blood glucose (FBG) and food intake were measured every two weeks. The glycolipid metabolism was assessed with the oral glucose tolerance test (OGTT) and insulin resistance (IR). Cardiac function was detected by echocardiography. Cardiac pathology was detected by HE staining, Masson staining, and transmission electron microscopy. The level of reactive oxygen species (ROS) in myocardial tissue was detected by dihydroethidium (DHE). The apoptosis was detected by TUNEL staining. The cell viability, ROS, and the mitochondrial membrane potential were detected by the cell counting kit-8 (CCK-8) assay and related kits. Western blotting was used to analyze the liver kinase B1/AMP-activated protein kinase/ nuclear factor-erythroid 2-related factor 2 (LKB1/AMPK/Nrf2) signaling pathway. CIH exposure accelerated glycolipid metabolism disorders and cardiac injury, and increased the level of cardiac oxidative stress and the number of positive apoptotic cells in db/db mice. IH and HG decreased the cell viability and the level of mitochondrial membrane potential, and increased ROS expression in H9C2 cells. These findings indicate that CIH exposure promotes glycolipid metabolism disorders and myocardial apoptosis, aggravating myocardial injury via the LKB1/AMPK/Nrf2 pathway in vitro and in vivo. [ABSTRACT FROM AUTHOR]

Aims: Metabolic dysfunction Associated Steatotic Liver Disease (MASLD) outcomes such as MASH (metabolic dysfunction associated steatohepatitis), fibrosis and cirrhosis are ordinarily determined by resource-intensive and invasive biopsies. We aim to show that routine clinical tests offer sufficient information to predict these endpoints. Methods: Using the LITMUS Metacohort derived from the European NAFLD Registry, the largest MASLD dataset in Europe, we create three combinations of features which vary in degree of procurement including a 19-variable feature set that are attained through a routine clinical appointment or blood test. This data was used to train predictive models using supervised machine learning (ML) algorithm XGBoost, alongside missing imputation technique MICE and class balancing algorithm SMOTE. Shapley Additive exPlanations (SHAP) were added to determine relative importance for each clinical variable. Results: Analysing nine biopsy-derived MASLD outcomes of cohort size ranging between 5385 and 6673 subjects, we were able to predict individuals at training set AUCs ranging from 0.719-0.994, including classifying individuals who are At-Risk MASH at an AUC = 0.899. Using two further feature combinations of 26-variables and 35-variables, which included composite scores known to be good indicators for MASLD endpoints and advanced specialist tests, we found predictive performance did not sufficiently improve. We are also able to present local and global explanations for each ML model, offering clinicians interpretability without the expense of worsening predictive performance. Conclusions: This study developed a series of ML models of accuracy ranging from 71.9—99.4% using only easily extractable and readily available information in predicting MASLD outcomes which are usually determined through highly invasive means. [ABSTRACT FROM AUTHOR]

Thioredoxin-interacting protein (TXNIP) has emerged as a key player in cancer and diabetes since it targets thioredoxin (TRX)-mediated redox regulation and glucose transporter (GLUT)-mediated metabolism. TXNIP consists of two arrestin (ARR, N-ARR and C-ARR) domains at its amino-terminus and two PPxY (PY) motifs and a di-leucine (LL) motif for endocytosis at its carboxyl-terminus. Here, we report that TXNIP shuffles between TRX and GLUTs to regulate homeostasis of intracellular oxidative stress and glucose metabolism. While TXNIP functions as a gatekeeper of TRX by default, it robustly interacted with class I GLUTs through its C-ARR domain upon increase of intracellular reactive oxygen species. This interaction prompted the surface expression downregulation and lysosomal degradation of GLUTs by its carboxyl-terminal LL endocytic signaling motif to attenuate glucose uptake. Consequently, TXNIP expression significantly limited glucose uptake, leading to the suppression of glycolysis, hexosamine biosynthesis, and the pentose phosphate pathway. Our findings establish a fundamental link between ROS and glucose metabolism through TXNIP and provide a promising target for the drug development against GLUT-related metabolic disorders. [ABSTRACT FROM AUTHOR]

Introduction: Increased plasma trimethylamine oxide (TMAO) is observed in cardiovascular and metabolic diseases, originating from the gut microbiota product, trimethylamine (TMA), via flavin-containing monooxygenases (FMOs)-dependent oxidation. Numerous studies have investigated the association between plasma TMAO and various pathologies, yet limited knowledge exists regarding tissue concentrations of TMAO, TMAO precursors, and interspecies variability. Methods: Chromatography coupled with mass spectrometry was employed to evaluate tissue concentrations of TMAO and its precursors in adult male mice, rats, and guinea pigs. FMO mRNA and protein levels were assessed through PCR and Western blot, respectively. Results: Plasma TMAO levels were similar among the studied species. However, significant differences in tissue concentrations of TMAO were observed between mice, rats, and guinea pigs. The rat renal medulla exhibited the highest TMAO concentration, while the lowest was found in the mouse liver. Mice demonstrated significantly higher plasma TMA concentrations compared to rats and guinea pigs, with the highest TMA concentration found in the mouse renal medulla and the lowest in the rat lungs. FMO5 exhibited the highest expression in mouse liver, while FMO3 was highly expressed in rats. Guinea pigs displayed low expression of FMOs in this tissue. Conclusion: Despite similar plasma TMAO levels, mice, rats, and guinea pigs exhibited significant differences in tissue concentrations of TMA, TMAO, and FMO expression. These interspecies variations should be considered in the design and interpretation of experimental studies. Furthermore, these findings may suggest a diverse importance of the TMAO pathway in the physiology of the evaluated species. [ABSTRACT FROM AUTHOR]

Background: Recurrent spontaneous abortion (RSA) is characterized by the occurrence of two or more consecutive spontaneous abortions, with a rising prevalence among pregnant women and significant implications for their physical and mental well-being. The multifaceted etiology of RSA has posed challenges in unraveling the molecular mechanisms underlying that underlie its pathogenesis. Oxidative stress and immune response have been identified as pivotal factors in the development of its condition. Methods: Eleven serum samples from healthy pregnant women and 17 from RSA were subjected to liquid chromatography/mass spectrometry (LC-MS) analysis. Multivariate statistical analysis was employed to excavate system-level characterization of the serum metabolome. The measurement of seven oxidative stress products, namely superoxide dismutase (SOD), catalase (CAT), malonaldehyde (MDA), glutathione (GPx), glutathione peroxidase (GSH), oxidized glutathione (GSSG), heme oxygenase (HO-1), was carried out using ELISA. Results: Through the monitoring of metabolic and lipid alternations during RSA events, we have identified 816 biomarkers that were implicated in various metabolic pathways, including glutathione metabolism, phosphonate and phosphinate metabolism, nucleotide metabolism, sphingolipid metabolism, lysine degradation and purine metabolism, etc. These pathways have been found to be closely associated with the progression of the disease. Our finding indicated that the levels of MDA and HO-1 were elevated in the RSA group compared to the control group, whereas SOD, CAT and GPx exhibited a contrary pattern. However, no slight difference was observed in GSH and GSSG levels between the RSA group and the control group. Conclusion: The manifestation of RSA elicited discernible temporal alternations in the serum metabolome and biochemical markers linked to the metabolic pathways of oxidative stress and immune response. Our investigation furnished a more comprehensive analytical framework encompassing metabolites and enzymes associated with oxidative stress. This inquiry furnished a more nuanced comprehension of the pathogenesis of RSA and established the ground work for prognostication and prophylaxis. [ABSTRACT FROM AUTHOR]

The relaxin-3/RXFP3 system has been implicated in the modulation of depressive- and anxiety-like behaviour in the animal literature; however, there is a lack of human studies investigating this signalling system. We seek to bridge this gap by leveraging the large UK Biobank study to retrospectively assess genetic risk variants linked with this neuropeptidergic system. Specifically, we conducted a candidate gene study in the UK Biobank to test for potential associations between a set of functional, candidate single nucleotide polymorphisms (SNPs) pertinent to relaxin-3 signalling, determined using in silico tools, and several outcomes, including depression, atypical depression, anxiety and metabolic syndrome. For each outcome, we used several rigorously defined phenotypes, culminating in subsample sizes ranging from 85,881 to 386,769 participants. Across all outcomes, there were no associations between any candidate SNP and any outcome phenotype, following corrections for multiple testing burden. Regression models comprising several SNPs per relevant candidate gene as exploratory variables further exhibited no prediction of outcome. Our findings corroborate conclusions from previous literature about the limitations of candidate gene approaches, even when based on firm biological hypotheses, in the domain of genetic research for neuropsychiatric disorders. [ABSTRACT FROM AUTHOR]

Plasma of COVID-19 patients contains a strong metabolomic/lipoproteomic signature, revealed by the NMR analysis of a cohort of >500 patients sampled during various waves of COVID-19 infection, corresponding to the spread of different variants, and having different vaccination status. This composite signature highlights common traits of the SARS-CoV-2 infection. The most dysregulated molecules display concentration trends that scale with disease severity and might serve as prognostic markers for fatal events. Metabolomics evidence is then used as input data for a sex-specific multi-organ metabolic model. This reconstruction provides a comprehensive view of the impact of COVID-19 on the entire human metabolism. The human (male and female) metabolic network is strongly impacted by the disease to an extent dictated by its severity. A marked metabolic reprogramming at the level of many organs indicates an increase in the generic energetic demand of the organism following infection. Sex-specific modulation of immune response is also suggested. Author summary: Metabolites and lipoproteins are the main components of human plasma and their concentration can be determined by nuclear magnetic resonance. In COVID-19 patients there are significant alterations in the concentration of several of these molecules. Using the plasma of more than 600 subjects (510 patients sampled in the acute phase of the infection plus 95 independent recovered subjects), we demonstrate that the dysregulation of these molecules is a function of the disease severity but it is not affected by either the SARS-CoV-2 variants or the vaccination status. The disease signature is particularly evident in those cases that subsequently evolve towards a fatal outcome, and could have prognostic value. Building on this large amount of data, we propose a metabolic reconstruction of the disease using a sex-specific multi-organ metabolic model. [ABSTRACT FROM AUTHOR]

Introduction: Insulin resistance (IR) could be regarded as a therapeutic target for metabolic diseases. Therefore, multiple therapeutic strategies that target IR should be applied to provide a more effective means of treatment. It aims to determine Tuina's efficacy and safety for IR through this systematic review and meta-analysis. Methods: From the inception to July 31, 2023, we will search four English databases (Pubmed, Embase, Cochrane Central Register of Controlled Trials, Web of Science) and two Chinese databases (China National Knowledge Infrastructure and the Chinese Science and Technology Periodical Database). We will search and include studies of both human and animal models that evaluate Tuina's effects on insulin sensitivity or resistance. Data selection, data extraction, and risk of bias assessment will be made by two independent reviewers. We will evaluate the methodological quality of all included studies and conduct meta-analyses using Review Manager Software 5.4.1. Discussion: In both animal and human studies, the effects and safety of Tuina for IR will be evaluated. The evidence generated bythis study will validate effects and safety of Tuinain treating IR and inform future research and clinical decision-making. Trail registration: PROSPERO Registration ID: CRD42022360128. [ABSTRACT FROM AUTHOR]

Paracoccidioidomycosis (PCM) is caused by Paracoccidioides spp.; during infection, some host mechanisms limit the availability of iron, thereby reducing its reproduction. However, Paracoccidioides spp. can evade the immune defense and, even under limited iron conditions, use this mineral for growth and dissemination. This study evaluated the iron metabolism of 39 patients who were diagnosed with chronic PCM from 2013 to 2021. The forms of iron before treatment and at the time of clinical cure were evaluated based on the following: serum ferritin levels (storage iron); total iron-binding capacity (TIBC) and transferrin saturation (TSAT) level (transport iron); red blood cell (RBC), hemoglobin (Hb), hematocrit (HCT), and soluble transferrin receptor (sTfR) levels; and sTfR/log ferritin ratio (functional iron). The mean age of the patients was 54.5 years (±6.7 years). Most patients were men (97.4%), rural workers (92.1%), and smokers (84.6%); furthermore, most had moderate disease severity (66.7%). After achieving clinical cure, we observed that serum ferritin levels decreased, and parameters of functional iron increased. The extent of alteration in these parameters were more pronounced in severe cases than in to mild or moderate cases. Furthermore, moderate correlations were observed between C-reactive protein and the Hb (r = -0.500; p = 0.002), RBC (r = -0.461; p = 0.005), HCT (r = -0.514; p = 0.001), and iron levels (r = -0.491; p = 0.002). However, it is possible to infer that PCM interferes with functional and storage iron because improvements in these parameters after treatment as well as associations with disease severity were observed. PCM can lead to anemia of inflammation, which can be differentiated from iron deficiency anemia by a careful investigation of the iron form parameters. [ABSTRACT FROM AUTHOR]

Introduction: The demographics of those developing severe coronavirus disease (COVID-19) outcomes are shifting to younger patients. In an observational study utilizing electronic health records from a Massachusetts group medical practice, we identified 5025 patients with confirmed COVID-19 from March 1 to December 18, 2020. Of these, 3870 were under 65 years of age. We investigated the hypothesis that pre-infection metabolic or immunologic dysregulation including polycystic ovary syndrome (PCOS) increased risk of serious COVID-19 outcomes in patients under 65 years of age. Materials and methods: We compared those with COVID-19 related hospitalization or mortality to all other COVID-19 patients, using a case control approach. Using logistic regression and propensity score modeling, we evaluated risk of developing severe COVID-19 outcomes (hospitalization or death) in those with pre-infection comorbidities, metabolic risk factors, or PCOS. Results: Overall, propensity score matched analyses demonstrated pre-infection elevated liver enzymes alanine aminotransferase (ALT) >40, aspartate aminotransferase (AST) >40 and blood glucose ≥215 mg/dL were associated with more severe COVID-19 outcomes, OR = 1.74 (95% CI 1.31, 2.31); OR = 1.98 (95% CI 1.52, 2.57), and OR = 1.55 (95% CI 1.08, 2.23) respectively. Elevated hemoglobin A1C or blood glucose levels were even stronger risk factors for severe COVID-19 outcomes among those aged < 65, OR = 2.31 (95% CI 1.14, 4.66) and OR = 2.42 (95% CI 1.29, 4.56), respectively. In logistic regression models, women aged < 65 with PCOS demonstrated more than a four-fold increased risk of severe COVID-19, OR 4.64 (95% CI 1.98, 10.88). Conclusion: Increased risk of severe COVID-19 outcomes in those < age 65 with pre-infection indicators of metabolic dysfunction heightens the importance of monitoring pre-infection indicators in younger patients for prevention and early treatment. The PCOS finding deserves further investigation. Meanwhile women who suffer from PCOS should be carefully evaluated and prioritized for earlier COVID-19 treatment and vaccination. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus (T2DM) is a challenging and progressive metabolic disease caused by insulin resistance. Skeletal muscle is the major insulin-sensitive tissue that plays a pivotal role in blood sugar homeostasis. Dysfunction of muscle metabolism is implicated in the disturbance of glucose homeostasis, the development of insulin resistance, and T2DM. Understanding metabolism reprogramming in newly diagnosed patients provides opportunities for early diagnosis and treatment of T2DM as a challenging disease to manage. Here, we applied a system biology approach to investigate metabolic dysregulations associated with the early stage of T2DM. We first reconstructed a human muscle-specific metabolic model. The model was applied for personalized metabolic modeling and analyses in newly diagnosed patients. We found that several pathways and metabolites, mainly implicating in amino acids and lipids metabolisms, were dysregulated. Our results indicated the significance of perturbation of pathways implicated in building membrane and extracellular matrix (ECM). Dysfunctional metabolism in these pathways possibly interrupts the signaling process and develops insulin resistance. We also applied a machine learning method to predict potential metabolite markers of insulin resistance in skeletal muscle. 13 exchange metabolites were predicted as the potential markers. The efficiency of these markers in discriminating insulin-resistant muscle was successfully validated. [ABSTRACT FROM AUTHOR]

Background: Life-style metabolic diseases are steadily rising, not only in developed countries, but also in low- and middle-income countries, presenting a global health problem. Metabolic disorders like type 2 diabetes and cardiovascular diseases are among the ten leading causes of death defined by the WHO in 2019. Results from animal and observational human studies suggest a connection between the decline in human helminth infections and rise of life-style-associated metabolic diseases in developing regions. This trial was designed to investigate filarial infections and their impact on metabolic diseases in Cameroon. We hypothesize that the induction of regulatory immune responses during filarial infection reduces obesity-induced low-grade inflammatory immune responses and thereby improves metabolic parameters, whereas anthelmintic treatment abolishes this protective effect. Methods/design: Participants infected with Mansonella perstans, Onchocerca volvulus and/or Loa loa being lean (BMI <25), overweight (BMI >25 and <30) or clinically obese (BMI ≥30) from Littoral regions of Cameroon will be evaluated for their parasitological, immunological, metabolic and biochemical profile before and after treatment of their parasitic infections. Anthropomorphic measurements and a detailed questionnaire will complement our analysis. The investigation will assess blood immune cell populations, serum adipokines and cytokines that could be influenced by the parasite infection and/or metabolic diseases. Further, parameters like blood glucose, homeostatic model assessment of insulin resistance (HOMA-IR), circulating lipids and circulating makers of liver function will be monitored. Parameters will be assessed before treatment, 12 and 18 months after treatment. Conclusion: The focus of this study is to obtain a comprehensive metabolic profile of the participants in rural areas of Cameroon and to investigate the relationship between filarial immunomodulation and metabolic diseases. This study will elucidate the effect of anti-filarial treatment on the metabolic and immunological parameters that partake in the development of insulin resistance, narrowing in on a potential protective effect of filarial infections on metabolic diseases. Trial registration: doi.org/10.1186/ISRCTN43845142, ISRCTN43845142 February 2020 Trial title Effects of filarial parasite infection on type 2 diabetes Issue date: 27.10.22, V.1. [ABSTRACT FROM AUTHOR]

Palmitic acid (PA) is considered a major contributor to the inflammation in many metabolic diseases; however, this role has been questioned recently for the complicated procedures in preparing PA-bovine serum albumin (BSA) complex. This study is aimed to evaluate the effect of PA-BSA complexing methods on cell viability and inflammatory responses of BV-2 cells. Three commercially available BSA brands and two types of solvents were compared for their effects on the expression of inflammatory cytokines. Three commonly used proportions of PA-BSA were tested for cell viability and inflammatory responses. We found that all the three types of BSA were proinflammatory. Both ethanol and isopropanol dampened inflammation except that 1% isopropanol treatment increased the IL-1β level by 26%. When reducing the BSA content in PA-BSA solutions from 3:1 to 5:1, a marked increase in cell viability (11%) was seen. To our surprise, reducing BSA content in PA-BSA solutions from 5:1 to 10:1 decreased cell viability by 11%. The 5:1 group exhibited the lowest inflammatory profile. Either PA-BSA or BSA alone increased the entry of LPS to the cytosol, which further caused pyroptosis. In summary, we found 5:1 (PA:BSA) to be the best binding ratio for studying inflammation in BV-2 microglia. The presence of LPS in the cytosol in the context of BSA might be the reason for confounding results from palmitate studies. [ABSTRACT FROM AUTHOR]

Pre-existing and gestationally-developed diabetes mellitus have been linked with impairments in placental villous trophoblast cell metabolic function, that are thought to underlie the development of metabolic diseases early in the lives of the exposed offspring. Previous research using placental cell lines and ex vivo trophoblast preparations have highlighted hyperglycemia is an important independent regulator of placental function. However, it is poorly understood if hyperglycemia directly influences aspects of placental metabolic function, including nutrient storage and mitochondrial respiration, that are altered in term diabetic placentae. The current study examined metabolic and mitochondrial function as well as nutrient storage in both undifferentiated cytotrophoblast and differentiated syncytiotrophoblast BeWo cells cultured under hyperglycemia conditions (25 mM glucose) for 72 hours to further characterize the direct impacts of placental hyperglycemic exposure. Hyperglycemic-exposed BeWo trophoblasts displayed increased glycogen and triglyceride nutrient stores, but real-time functional readouts of metabolic enzyme activity and mitochondrial respiratory activity were not altered. However, specific investigation into mitochondrial dynamics highlighted increased expression of markers associated with mitochondrial fission that could indicate high glucose-exposed trophoblasts are transitioning towards mitochondrial dysfunction. To further characterize the impacts of independent hyperglycemia, the current study subsequently utilized a multi-omics approach and evaluated the transcriptomic and metabolomic signatures of BeWo cytotrophoblasts. BeWo cytotrophoblasts exposed to hyperglycemia displayed increased mRNA expression of ACSL1, HSD11B2, RPS6KA5, and LAP3 and reduced mRNA expression of CYP2F1, and HK2, concomitant with increased levels of: lactate, malonate, and riboflavin metabolites. These changes highlighted important underlying alterations to glucose, glutathione, fatty acid, and glucocorticoid metabolism in BeWo trophoblasts exposed to hyperglycemia. Overall, these results demonstrate that hyperglycemia is an important independent regulator of key areas of placental metabolism, nutrient storage, and mitochondrial function, and these data continue to expand our knowledge on mechanisms governing the development of placental dysfunction. [ABSTRACT FROM AUTHOR]

Introduction: Ursus americanus Pallas 1780 is the largest carnivore and the only ursid in Mexico. It is considered an endangered species in the country because its distribution and population have been reduced by up to 80% because of habitat loss or furtive hunting. These problems can lead to a diet change, which could result in metabolic disorders, such as fatty acid β-oxidation defects or organic acid metabolism disorders. In our study, a free amino acid and acylcarnitine profile was characterized. Methods: Peripheral blood samples were drawn from nine free-ranging black bears in a period of five months, from June to October of 2019 in Northeastern Mexico, and 12 amino acids and 30 acylcarnitines were determined and quantified. Age differences were observed in the samples through ANOVA and post-hoc Tukey test. Results: Only three metabolites showed a significant difference with age: alanine (Ala) [cubs vs juvenile], free-carnitine (C0) [juvenile vs cubs] and acetylcarnitine (C2) [cubs vs adults and juvenile vs cubs]. Conclusion: Metabolites with variability due to age were identified, making them potential biomarkers to monitor metabolic status as early diagnosis in endangered species. This is the first study of black bear amino acid and acylcarnitine profiles, and the values found could be used as reference for free amino acid and acylcarnitine concentrations in further studies of the species. [ABSTRACT FROM AUTHOR]

Background: Cardiovascular disease is the leading cause of morbidity and mortality in postmenopausal women. Early menarche may be associated with an increased risk of metabolic diseases such as diabetes and cardiovascular disease. This study aimed to investigate the effect of menarche age and the risk of diabetes and metabolic syndrome in Korean postmenopausal women. Methods: We analyzed 4,933 postmenopausal women (mean age: 64.7 years) using the Korean National Health and Nutritional Examination Survey 2016–2018. Subjects were divided into three groups according to menarche age (early menarche: ≤ 12 years (n = 451), reference: 13–16 years (n = 3,421), and late menarche: ≥ 17 years (n = 1,061)). Logistic regression analysis was used to estimate the odds ratio (OR) for diabetes and metabolic syndrome. Results: Women with an early menarche age were younger, more educated, and had higher income than the other groups (p-value < 0.001). There were no differences in body mass index, blood pressure, fasting glucose, HbA1c, and cholesterol levels among the three groups. After adjusting for potential confounding factors, early menarche age was significantly associated with the risk of diabetes (OR 1.435, 95% confidence interval (CI): 1.069–1.928). The prevalence of metabolic syndrome in all subjects was 41.1%. After adjusting for potential confounding factors, the OR of metabolic syndrome in the early menarche group was 1.213 (95% CI: 0.971–1.515) Conclusion: The risk of diabetes was 1.43 times higher in postmenopausal Korean women with early menarche. Although the risk of metabolic syndrome was not statistically significant, it showed a tendency to increase in the early menarche group. Our results suggest that age at menarche may be helpful in diabetes risk stratification and early interventions for postmenopausal women. [ABSTRACT FROM AUTHOR]

Niemann-Pick Type C is a rare metabolic disorder characterized by the cellular accumulation of cholesterol within endosomal and lysosomal compartments. 2-Hydroxypropyl-β-cyclodextrin (HP-β-CD) containing polyrotaxanes represent an attractive approach for treating this disease due to their ability to circulate in the blood stream for longer periods of time as a prodrug form of HP-β-CD. Once inside the cell, the macromolecular structure is thought to break down into the Pluronic precursor and the active cyclodextrin agent that promotes cholesterol mobilization from the aberrant accumulations within NPC-deficient cells. We now report that both cholesterol and decaarginine (R10) endcapped polyrotaxanes are able to remove cholesterol from NPC1 patient fibroblasts. R10 endcapped materials enter these cells and are localized within endosomes after 16 h. The cholesterol mobilization from endo-lysosomal compartments of NPC1 cells by the polyrotaxanes was directly related to their extent of endcapping and their threading efficiency. Incorporation of 4-sulfobutylether-β-cyclodextrin (SBE-β-CD) significantly improved cholesterol mobilization due to the improved solubility of the compounds. Additionally, in our efforts to scale-up the synthesis for preclinical studies, we prepared a library of polyrotaxanes using a solid phase synthesis method. These compounds also led to significant cholesterol mobilization from the cells, however, cytotoxicity studies showed that they were substantially more toxic than those prepared by the solvent-assisted method, thus limiting the therapeutic utility of agents prepared by this expedited method. Our findings demonstrate that complete endcapping of the polyrotaxanes and improved solubility are important design features for delivering high copy numbers of therapeutic β-CD to promote enhanced sterol clearance in human NPC1-deficient cells. [ABSTRACT FROM AUTHOR]

Diabetes mellitus (DM) patients are prone to osteoporosis, and high glucose (HG) can affect bone metabolism. In the present study, we investigated the protective effects of traditional Chinese herbal formulation Xianling Gubao (XLGB) on HG-treated MG63 osteoblast-like cells. MG63 cells were incubated with control (mannitol), HG (20 mM glucose) or HG + XLGB (20 mM glucose+200 mg/L XLGB) mediums. Cell proliferation, apoptosis, migration and invasion were examined using CCK8, colony-formation, flow cytometry, Hoechst/PI staining, wound-healing and transwell assays, respectively. ELISA, RT-PCR and western blot analysis were used to detect the levels of osteogenesis differentiation-associated markers such as ALP, OCN, OPN, RUNX2, OPG, and OPGL in MG63 cells. The levels of the PI3K/Akt signaling pathway related proteins, cell cycle-related proteins, and mitochondrial apoptosis-related proteins were detected using western blot analysis. In HG-treated MG63 cells, XLGB significantly attenuated the suppression on the proliferation, migration and invasion of MG63 cells caused by HG. HG downregulated the activation of the PI3K/Akt signaling pathway and the expressions of cell cycle-related proteins, while XLGB reversed the inhibition of HG on MG63 cells. Moreover, XLGB significantly reduced the promotion on the apoptosis of MG63 cells induced by HG, the expressions of mitochondrial apoptosis-related proteins were suppressed by XLGB treatment. In addition, the expressions of osteogenesis differentiation-associated proteins were also rescued by XLGB in HG-treated MG63 cells. Our data suggest that XLGB rescues the MG63 osteoblasts against the effect of HG. The potential therapeutic mechanism of XLGB partially attributes to inhibiting the osteoblast apoptosis and promoting the bone formation of osteoblasts. [ABSTRACT FROM AUTHOR]

Background: Diabetes, one of the major metabolic disorders, is rising in Bangladesh. Studies indicate there is inequality in prevalence and care-seeking behavior, which requires further exploration to understand the socioeconomic disparities in the pathophysiology of diabetes. This study examined the latest nationally representative estimates of diabetes prevalence, awareness, and management among adults aged 18 years and above in Bangladesh and its association with socioeconomic status in 2017–18. Methods: We used the 2017–18 Bangladesh Demographic and Health Survey data. Diabetic status of 12,092 adults aged 18 years and above was measured in the survey using fasting plasma glucose levels. We applied multivariate logistic regressions to examine the role of socioeconomic status on diabetes prevalence, awareness, and management, after controlling for relevant covariates. Results: Overall, 10% of adults had diabetes in Bangladesh in 2017–18, with the highest prevalence of 16% in the age group 55−64 years. Our analyses found statistically significant disparities by socioeconomic status in the prevalence of diabetes as well as the person's awareness of his/her diabetic condition. However, the effect of socioeconomic status on receiving anti-diabetic medication only approached significance (p = 0.07), and we found no significant association between socioeconomic status and control of diabetes. Conclusions: We expect to see an 'accumulation' of the number of people with diabetes to continue in the coming years. The rising prevalence of diabetes is only the tip of an iceberg; a large number of people with uncontrolled diabetes and a lack of awareness of their condition will lead to increased morbidity and mortality, and that could be the real threat. Immediate measures to increase screening coverage and exploration of poor control of diabetes are required to mitigate the situation. [ABSTRACT FROM AUTHOR]

Glucocorticoids (GC) replacement are the mainstay treatment for 21-hydroxylase deficiency (21-OHD), the most common cause of congenital adrenal hyperplasia (CAH), in its classical form. There are novel insights into the genetic basis of the GC action diversity that point to an important role for GC receptor (GR) gene polymorphisms, suggesting a possible modulation in occurrence of metabolic disorders, what may be relevant to clinical management of 21-OHD. The aim of this study was to investigate whether the five GR gene polymorphisms Tth111I, ER22, 23EK, BclI, 9β (rs10052957, rs6189, rs6190, rs41423247, rs6198) and their combination into haplotypes are associated to different GC response in a cohort of classic 21-OHD subjects. GR genotype-phenotype associations were explored after a dexamethasone suppression test using very low-doses (VLD-DST), 20 and 40 μg/m². The final sample (n = 28) was selected based on the 102 individuals' previous genotypes classification, according to literature data of GC sensitivity or resistance. Thus, only patients with GC increased resistance (n = 18) or increased sensitivity (n = 10) profiles were selected. Out of 28 subjects aged 12 (2–34) years enrolled in this study, 75% were females, 75% presented the salt-wasting form (SW) and 25% the simple virilizing form (SV). Subjects who carried Tth111I and 9β, associated or not to the ER22/23EK variants, showed an impaired DST response. Results did not differ significantly according to gender or body mass index. SV subjects with GC hypersensitivity-genotypes showed decreased average cortisol levels compared to those with GC resistance-genotypes (p = 0.0023). The Tth111I + 9β/ Wild or Tth111I + ER22/23EK + 9β/ Wild genotypes were associated to GC resistance in this population. This finding may be relevant given the challenges posed by therapeutic management with GC in CAH. [ABSTRACT FROM AUTHOR]

Background: Although low-middle income countries have been disproportionately affected by the COVID-19 pandemic, there is scarce information about the impact of long COVID on their population. This study aimed to evaluate long COVID symptomatology, complications (hospital readmission and metabolic disorders), and main clinical features that impact Quality of Life (QoL). Methods: This cross-sectional study provides a detailed clinical and laboratory picture of individuals who presented residual symptoms after mild to severe acute COVID-19. Between Aug-2020 to Sep-2021, long COVID patients were evaluated in a reference center for long COVID in Bahia State, Brazil. The EQ-5D-5L questionnaire accessed QoL. Results: A total of 1164 (52 ±13.4 years, 57% female, 88% black/mixed-race) were evaluated 2.3 [IQR = 1.6–3.7] months after mild (n = 351, 30.2%), moderate (338, 29.0%) or severe (475, 40.8%) acute illness. Dyspnea (790, 67.9%), fatigue (738, 63.5%), and chest pain (525, 42.9%) were the most frequent residual symptoms regardless of acute severity, affecting the QoL of 88.9% of patients (n/N—826/925), mainly the domains of anxiety/depression and pain/discomfort. High levels of HbA1c were detected for 175 out of 664 patients (26.6%), 40% of them without a previous diagnosis of diabetes mellitus. Of note, hospital admission one-to-three months after the acute phase of disease was required for 51 (4.4%) patients. Conclusion: In this majority-black/mixed-race population, long COVID was associated with post-acute hospitalization, newly diagnosed diabetes mellitus, and decreased QoL, particularly in women and regardless of disease severity of acute infection, suggesting important implications for health care system. [ABSTRACT FROM AUTHOR]

Introduction: Diabetes mellitus is a chronic metabolic disorder with an increasing prevalence worldwide. Reduction in blood insulin level alters brain function by inducing oxidative stress with changes in dopamine and norepinephrine neurotransmission, ultimately leading to neuropsychological symptoms. The efficacy of currently available psychotropic drugs is not satisfactory. Therefore, this study was conducted to explore the beneficial effects of a combination of the natural herbs, saffron and chamomile, in treating diabetes and its resultant neuropsychological effects using a rodent model of diabetes mellitus. Method: The rats were randomly divided in to eight groups (n = 10), healthy control (HC), diabetic control (DC) and six groups of diabetic rats treated with various concentrations and combinations of saffron and chamomile. Diabetic treatment groups individually received methanolic extract and water decoction of chamomile (30 mg/kg) and saffron (10mg/kg) and their combined half doses (saffron 5mg/kg and chamomile 15mg/kg) for two weeks. Open field test (OFT) and forced swim test (FST) were used to measure the anxiolytic and antidepressant effects of herbs, respectively. Finally, biochemical, and neurochemical estimations were made. Results: The present study suggests the therapeutic effects of herbs especially in co-administrated decoction, against diabetes with improved antioxidant profile and enhanced levels of dopamine and norepinephrine. Anxiolytic and antidepressant effects were evident with improvements in the OFT and FST. Examination of the cortex of the diabetic group revealed cellular damage and tangle formation, which indicates advanced stages of dementia. Conclusion: This study shows that the use of a combination of saffron and chamomile improves diabetes control and reduces its related psychiatric effects. [ABSTRACT FROM AUTHOR]

Microphysiological systems (MPS) are powerful tools for emulating human physiology and replicating disease progression in vitro. MPS could be better predictors of human outcome than current animal models, but mechanistic interpretation and in vivo extrapolation of the experimental results remain significant challenges. Here, we address these challenges using an integrated experimental-computational approach. This approach allows for in silico representation and predictions of glucose metabolism in a previously reported MPS with two organ compartments (liver and pancreas) connected in a closed loop with circulating medium. We developed a computational model describing glucose metabolism over 15 days of culture in the MPS. The model was calibrated on an experiment-specific basis using data from seven experiments, where HepaRG single-liver or liver-islet cultures were exposed to both normal and hyperglycemic conditions resembling high blood glucose levels in diabetes. The calibrated models reproduced the fast (i.e. hourly) variations in glucose and insulin observed in the MPS experiments, as well as the long-term (i.e. over weeks) decline in both glucose tolerance and insulin secretion. We also investigated the behaviour of the system under hypoglycemia by simulating this condition in silico, and the model could correctly predict the glucose and insulin responses measured in new MPS experiments. Last, we used the computational model to translate the experimental results to humans, showing good agreement with published data of the glucose response to a meal in healthy subjects. The integrated experimental-computational framework opens new avenues for future investigations toward disease mechanisms and the development of new therapies for metabolic disorders. Author summary: Microphysiological systems (MPS) are powerful tools to unravel biological knowledge underlying disease. MPS provide a physiologically relevant, human-based in vitro setting, which can potentially yield better translatability to humans than current animal models and traditional cell cultures. However, mechanistic interpretation and extrapolation of the experimental results to human outcome remain significant challenges. In this study, we confront these challenges using an integrated experimental-computational approach. We present a computational model describing glucose metabolism in a previously reported MPS integrating liver and pancreas. This MPS supports a homeostatic feedback loop between HepaRG/HHSteC spheroids and pancreatic islets, and allows for detailed investigations of mechanisms underlying type 2 diabetes in humans. We show that the computational model captures the complex dynamics of glucose-insulin regulation observed in the system, and can provide mechanistic insight into disease progression features, such as insulin resistance and β-cell dynamics. Furthermore, the computational model can explain key differences in temporal dynamics between MPS and human responses, and thus provides a tool for translating experimental insights into human outcome. The integrated experimental-computational framework opens new avenues for future investigations toward disease mechanisms and the development of new therapies for metabolic disorders. [ABSTRACT FROM AUTHOR]

Around 60% of in vitro fertilized (IVF) human embryos irreversibly arrest before compaction between the 3- to 8-cell stage, posing a significant clinical problem. The mechanisms behind this arrest are unclear. Here, we show that the arrested embryos enter a senescent-like state, marked by cell cycle arrest, the down-regulation of ribosomes and histones and down-regulation of MYC and p53 activity. The arrested embryos can be divided into 3 types. Type I embryos fail to complete the maternal-zygotic transition, and Type II/III embryos have low levels of glycolysis and either high (Type II) or low (Type III) levels of oxidative phosphorylation. Treatment with the SIRT agonist resveratrol or nicotinamide riboside (NR) can partially rescue the arrested phenotype, which is accompanied by changes in metabolic activity. Overall, our data suggests metabolic and epigenetic dysfunctions underlie the arrest of human embryos. Human embryos develop poorly in vitro, and as much as 60% of embryos will irreversibly arrest. This study shows that the arrested embryos enter a senescent-like state, and reveals that several mechanisms related to zygotic genome activation problems and erroneous metabolism can at least partly explain some of the reasons behind this arrest. [ABSTRACT FROM AUTHOR]

Familial Hypercholesterolemia (FH) is an inherited disorder of cholesterol metabolism. Current criteria for FH diagnosis, like Simon Broome (SB) criteria, lead to high false positive rates. The aim of this work was to explore alternative classification procedures for FH diagnosis, based on different biological and biochemical indicators. For this purpose, logistic regression (LR), naive Bayes classifier (NB), random forest (RF) and extreme gradient boosting (XGB) algorithms were combined with Synthetic Minority Oversampling Technique (SMOTE), or threshold adjustment by maximizing Youden index (YI), and compared. Data was tested through a 10 × 10 repeated k-fold cross validation design. The LR model presented an overall better performance, as assessed by the areas under the receiver operating characteristics (AUROC) and precision-recall (AUPRC) curves, and several operating characteristics (OC), regardless of the strategy to cope with class imbalance. When adopting either data processing technique, significantly higher accuracy (Acc), G-mean and F1 score values were found for all classification algorithms, compared to SB criteria (p < 0.01), revealing a more balanced predictive ability for both classes, and higher effectiveness in classifying FH patients. Adjustment of the cut-off values through pre or post-processing methods revealed a considerable gain in sensitivity (Sens) values (p < 0.01). Although the performance of pre and post-processing strategies was similar, SMOTE does not cause model's parameters to loose interpretability. These results suggest a LR model combined with SMOTE can be an optimal approach to be used as a widespread screening tool. [ABSTRACT FROM AUTHOR]

Decline of ovarian function in menopausal women increases metabolic disease risk. Curcuma comosa extract and its major compound, (3R)-1,7-diphenyl-(4E,6E)-4,6-heptadien-3-ol (DPHD), improved estrogen-deficient ovariectomized (OVX) rat metabolic disturbances. However, information on their effects on metabolites is limited. Here, we investigated the impacts of C. comosa ethanol extract and DPHD on 12-week-old OVX rat metabolic disturbances, emphasizing the less hydrophobic metabolites. Metabolomics analysis of OVX rat serum showed a marked increase compared to sham-operated rat (SHAM) in levels of lysophosphatidylcholines (lysoPCs), particularly lysoPC (18:0) and lysoPC (16:0), and of arachidonic acid (AA), metabolites associated with inflammation. OVX rat elevated lysoPCs and AA levels reverted to SHAM levels following treatments with C. comosa ethanol extract and DPHD. Overall, our studies demonstrate the effect of C. comosa extract in ameliorating the metabolic disturbances caused by ovariectomy, and the elevated levels of bioactive lipid metabolites, lysoPCs and AA, may serve as potential biomarkers of menopausal metabolic disturbances. [ABSTRACT FROM AUTHOR]

Background: Overweight/obesity is a well-defined risk factor for a variety of chronic cardiovascular and metabolic diseases. Sleep duration has been associated with overweight/obesity and other cardio metabolic and neurocognitive problems. Notably, overweight/obesity and many of the associated comorbidities are prevalent in Indigenous Australians. Generally, sleep duration has been associated with BMI for Australian adults but information about Australian Indigenous adults' sleep is scant. A recent report established that sleep is a weak predictor of obesity for Indigenous Australian adults. Aim: To determine whether sleep remains a predictor of obesity when physical activity, diet and smoking status are accounted for; and to determine whether sleep duration plays a mediating role in the relationship between Indigenous status and BMI. Methods: Statistical analyses of 5,886 Australian adults: 5236 non-Indigenous and 650 Indigenous people aged over 18 years who participated in the Australian Health Survey 2011–2013. Demographic and lifestyle characteristics were described by χ2 and t-tests. ANOVA was used to determine the variables that significantly predicted BMI and sleep duration. Stepwise regression analyses were performed to determine the strongest significant predictors of BMI. Sleep duration was self-reported; BMI was calculated from measurement. Results: The study revealed two main findings: (i) short sleep duration was an independent predictor of obesity (adjusted-R2 = 0.056, p <0.0001); and (ii) controlling for sleep duration and other possible confounders, Indigenous status was a significant predictor of BMI overweight/obesity. Sleep duration played a weak, partial mediator role in this relationship. Increased BMI was associated with lower socioeconomic status and level of disadvantage of household locality for non-remote Indigenous and non-Indigenous people. Conclusion: Indigenous status strongly predicted increased BMI. The effect was not mediated by the socioeconomic indicators but was partially mediated by sleep duration. [ABSTRACT FROM AUTHOR]

Hibernating bears remain in their dens for 5–7 months during winter and survive without eating or drinking while staying inactive. However, they maintain their physical functions with minimal skeletal muscle atrophy and metabolic dysfunction. In bears, resistance to skeletal muscle atrophy during hibernation is likely mediated by seasonally altered systemic factors that are independent of neuromuscular activity. To determine whether there are components in bear serum that regulate protein and energy metabolism, differentiated human skeletal muscle cells were treated with bear serum (5% in DMEM/Ham's F-12, 24 h) collected during active summer (July) and hibernating winter (February) periods. The serum samples were collected from the same individual bears (Ursus thibetanus japonicus, n = 7 in each season). Total protein content in cultured skeletal muscle cells was significantly increased following a 24 h treatment with hibernating bear serum. Although the protein synthesis rate was not altered, the expression of MuRF1 protein, a muscle-specific E3 ubiquitin ligase was significantly decreased along with a concomitant activation of Akt/FOXO3a signaling. Increased levels of insulin-like growth factor-1 (IGF-1) were also observed in hibernating bear serum. These observations suggest that protein metabolism in cultured human myotubes may be altered when incubated with hibernating bear serum, with a significant increase in serum IGF-1 and diminished MuRF1 expression, a potential target of Akt/FOXO3a signaling. A protein sparing phenotype in cultured muscle cells by treatment with hibernating bear serum holds potential for the development of methods to prevent human muscle atrophy and related disorders. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) is a major cause of death and disability, particularly amongst young people. Current intensive care management of TBI patients is targeted at maintaining normal brain physiology and preventing secondary injury. Microdialysis is an invasive monitor that permits real-time assessment of derangements in cerebral metabolism and responses to treatment. We examined the prognostic value of microdialysis parameters, and the inter-relationships with other neuromonitoring modalities to identify interventions that improve metabolism. This was an analysis of prospective data in 619 adult TBI patients requiring intensive care treatment and invasive neuromonitoring at a tertiary UK neurosciences unit. Patients had continuous measurement of intracranial pressure (ICP), arterial blood pressure (ABP), brain tissue oxygenation (PbtO2), and cerebral metabolism and were managed according to a standardized therapeutic protocol. Microdialysate was assayed hourly for metabolites including glucose, pyruvate, and lactate. Cerebral perfusion pressure (CPP) and cerebral autoregulation (PRx) were derived from the ICP and ABP. Outcome was assessed with the Glasgow Outcome Score (GOS) at 6 months. Relationships between monitoring variables was examined with generalized additive mixed models (GAMM). Lactate/Pyruvate Ratio (LPR) over the first 3 to 7 days following injury was elevated amongst patients with poor outcome and was an independent predictor of ordinal GOS (p<0.05). Significant non-linear associations were observed between LPR and cerebral glucose, CPP, and PRx (p<0.001 to p<0.05). GAMM models suggested improved cerebral metabolism (i.e. reduced LPR with CPP >70mmHg, PRx <0.1, PbtO2 >18mmHg, and brain glucose >1mM. Deranged cerebral metabolism is an important determinant of patient outcome following TBI. Variations in cerebral perfusion, oxygenation and glucose supply are associated with changes in cerebral LPR and suggest therapeutic interventions to improve cerebral metabolism. Future prospective studies are required to determine the efficacy of these strategies. [ABSTRACT FROM AUTHOR]

Since long-chain fatty acids work as the primary energy source for the myocardium, radiolabeled long-chain fatty acids play an important role as imaging agents to diagnose metabolic heart dysfunction and heart diseases. With the aim of developing radiogallium-labeled fatty acids, herein four fatty acid-based tracers, [67Ga]Ga-HBED-CC-PDA, [67Ga]Ga-HBED-CC-MHDA, [67Ga]Ga-DOTA-PDA, and [67Ga]Ga-DOTA-MHDA, which are [67Ga]Ga-HBED-CC and [67Ga]Ga-DOTA conjugated with pentadecanoic acid (PDA) and 3-methylhexadecanoic acid (MHDA), were synthesized, and their potential for myocardial metabolic imaging was evaluated. Those tracers were found to be chemically stable in 0.1 M phosphate buffered saline. Initial [67Ga]Ga-HBED-CC-PDA, [67Ga]Ga-HBED-CC-MHDA, [67Ga]Ga-DOTA-PDA, and [67Ga]Ga-DOTA-MHDA uptakes in the heart at 0.5 min postinjection were 5.01 ± 0.30%ID/g, 5.74 ± 1.02%ID/g, 5.67 ± 0.22%ID/g, and 5.29 ± 0.10%ID/g, respectively. These values were significantly lower than that of [123I]BMIPP (21.36 ± 2.73%ID/g). For their clinical application as myocardial metabolic imaging agents, further structural modifications are required to increase their uptake in the heart. [ABSTRACT FROM AUTHOR]

Objectives: Studies concerning the risk of metabolic syndrome associated with night work have shown inconsistent findings, due to imprecise working time data and cross-sectional design. We used register-based daily working time data to examine the risk of incident metabolic syndrome associated with night shift work. Methods: Working time data collected between 2010 and 2018 of 5775 Taiwanese hospital workers were used to identify night shift workers and to calculate the number of night shifts. Metabolic syndrome was identified by annual occupational health examination results, which were linked to the working time data. Logistic regression models and generalized estimating equations were used to examine the association between night shift work and metabolic syndrome and the 5 components of metabolic syndrome. Results: Night shift work is associated with a higher risk of developing metabolic syndrome (adjusted OR = 1.36, 95% CI = 1.04 to 1.78) and high waist circumference (adjusted OR = 1.27, 95% CI = 1.07 to 1.78) compared to day work. Among night shift workers, increased number of night shifts was associated with high blood pressure (adjusted OR = 1.15, 95% CI = 1.01 to 1.31). Conclusions: Night shift work is associated with metabolic risk factors. Long-term effects of circadian rhythm disruption on metabolic disturbances needs to be further studied. [ABSTRACT FROM AUTHOR]

Persistent destruction of pancreatic β-cells in type 1 diabetes (T1D) results from multifaceted pancreatic cellular interactions in various phase progressions. Owing to the inherent heterogeneity of coupled nonlinear systems, computational modeling based on T1D etiology help achieve a systematic understanding of biological processes and T1D health outcomes. The main challenge is to design such a reliable framework to analyze the highly orchestrated biology of T1D based on the knowledge of cellular networks and biological parameters. We constructed a novel hybrid in-silico computational model to unravel T1D onset, progression, and prevention in a non-obese-diabetic mouse model. The computational approach that integrates mathematical modeling, agent-based modeling, and advanced statistical methods allows for modeling key biological parameters and time-dependent spatial networks of cell behaviors. By integrating interactions between multiple cell types, model results captured the individual-specific dynamics of T1D progression and were validated against experimental data for the number of infiltrating CD8+T-cells. Our simulation results uncovered the correlation between five auto-destructive mechanisms identifying a combination of potential therapeutic strategies: the average lifespan of cytotoxic CD8+T-cells in islets; the initial number of apoptotic β-cells; recruitment rate of dendritic-cells (DCs); binding sites on DCs for naïve CD8+T-cells; and time required for DCs movement. Results from therapy-directed simulations further suggest the efficacy of proposed therapeutic strategies depends upon the type and time of administering therapy interventions and the administered amount of therapeutic dose. Our findings show modeling immunogenicity that underlies autoimmune T1D and identifying autoantigens that serve as potential biomarkers are two pressing parameters to predict disease onset and progression. Author summary: Pancreatic β-cells secreting insulin upon metabolic demand are the core to regulate glucose concentration for healthy states. Type 1 diabetes (T1D) is a group of metabolic disorders in which β-cells are targeted by biased decisions of the immune system. The barrier in sampling experimental data from pancreatic tissues in high-risk T1D subjects and the complexity of the mechanisms regulating T1D makes the use of quantitative modeling approaches an intriguing opportunity to analyze this disease. To decipher complex system behaviors resulting from inter- and intra-cellular and signaling networks linking the immune system and metabolism during T1D progression, we developed a hybrid computational framework to unravel high computational complexity levels for individual-specific T1D development in non-obese diabetic mice. We also discovered non-intuitive biological parameters, the potential for therapeutic strategies. These effective strategies associated with hybrid agent-based modeling can serve as a prototype for in- silico experiments of therapy-directed trials potentially regulating T1D progression. We expect that the proposed methods will play an important role in the quest for standardized applications of agent-based modeling to simulating complex disease progression. [ABSTRACT FROM AUTHOR]

Isocitrate dehydrogenase 1 and 2 (IDH1/2) mutations and their key effector 2-hydroxyglutarate (2-HG) have been reported to promote oncogenesis in various human cancers. To elucidate molecular mechanism(s) associated with IDH1/2 mutations, we established mouse embryonic fibroblasts (MEF) cells and human colorectal cancer cells stably expressing cancer-associated IDH1R132C or IDH2R172S, and analyzed the change in metabolic characteristics of the these cells. We found that IDH1/2 mutants induced intracellular 2-HG accumulation and inhibited cell proliferation. Expression profile analysis by RNA-seq unveiled that glucose transporter 1 (Glut1) was induced by the IDH1/2 mutants or treatment with 2-HG in the MEF cells. Consistently, glucose uptake and lactate production were increased by the mutants, suggesting the deregulation of glucose metabolism. Furthermore, PI3K/Akt/mTOR pathway and Hif1α expression were involved in the up-regulation of Glut1. Together, these results suggest that Glut1 is a potential target regulated by cancer-associated IDH1/2 mutations. [ABSTRACT FROM AUTHOR]

Background: Diabetes mellitus is a complex metabolic disorder characterized by hyperglycemia that results from defects in insulin secretion, insulin action, or both. Glaucoma is the ocular complication of diabetic illness. In addition to this, retinopathy, maculopathy, ischemic optic neuropathy, extra-ocular muscle palsy, iridocyclitis, and rubeosis iridis were other complications. This study aims to determine the impact of diabetes on visual impairment and blindness among diabetic patients in Ethiopia. Methods: This hospital-based cross-sectional study includes 401 samples of diabetic patients in the University of Gondar Comprehensive Specialized Hospital from January 2017 to January 2019. The multinomial logistic regression model was employed to identify significant differences among the factor variables. Results: The magnitude of blindness was 32.17%, and the burden of severe visual impairment was 12.46%. Of the total patients, 120(29.9%) were have diabetic retinopathy of whom, 113(94.2%) were blind either in the right, left, or both eyes and 3 (2.5%) had severe visual impairment. One hundred twenty-six (31.42%) patients developed diabetic maculopathy of whom, 117 (92.85%) were blind either in the right or left eye, and one (0.8%) had severe visual impairment. From the whole diabetic patients, the magnitude of glaucoma was 186(46.38%), and from the patients who developed glaucoma was blind visual impairment 127(68.27%) either in the right or left eye. Thirty-eight (20.34%) had severe visual impairment. Glaucoma was significantly associated with severe visual impairment and blindness (p<0.001). Glaucoma, diabetic retinopathy, maculopathy, and type of diabetes are factors for visual impairment. Conclusion: We found that visual impairment in the category of severe and blindness are frequent in Ethiopian diabetic patients. Glaucoma, diabetic retinopathy, maculopathy are the main predictive factors that determine the occurrence of blindness. [ABSTRACT FROM AUTHOR]

Background: Polycystic ovary syndrome (PCOS) is a common gynecological disease that is often accompanied by some metabolic abnormality such as insulin resistance and dyslipidemia. As a non-pharmacological therapy, acupuncture is widely used for the treatment of PCOS, but the effectiveness for insulin resistance and lipid metabolic disorder remains controversial. Objectives: To assess the effectiveness and safety of acupuncture for insulin resistance and lipid metabolic disorder of women with PCOS. Search methods: Eight databases will be searched from inception to June 2021, three clinical trial registration platforms will be searched for relevant trials. Selection criteria: Randomized controlled trials (RCTs) of acupuncture therapy for insulin resistance and lipid metabolic of PCOS will be included. Data collection and analysis: Study screening, data collection, and analysis will be performed by two or more reviewers independently. We will calculate mean difference (MD), standard mean difference (SMD) with 95% confidence intervals (CIs). Data synthesis will be performed with RevMan V.5.3 software and with Stata V.15.0 software when necessary. PROSPERO registration number: CRD42020177846 [ABSTRACT FROM AUTHOR]

Objective: Diagnostic ratios calculated from urinary steroid hormone metabolites are used as a measure for the relative activity of steroidogenic enzymes or pathways in the clinical investigation of steroid metabolism disorders. However, population-based sex- and age-specific reference intervals and day-night differences in adults are lacking. Methods: Sixty-five diagnostic ratios were calculated from steroid metabolites measured by GC-MS in day- and night-time and in 24-hour urine from 1128 adults recruited within the Swiss Kidney Project on Genes in Hypertension (SKIPOGH), a population-based, multicenter cohort study. Differences related to sex, age and day- and night-time were evaluated and reference curves in function of age and sex were modelled by multivariable linear mixed regression for diagnostic ratios and were compared to values from the literature. Results: Most ratios had sex- and age-specific relationships. For each ratio, percentiles were plotted in function of age and sex in order to create reference curves and sex- and age-specific reference intervals derived from 2.5th and 97.5th percentiles were obtained. Most ratios reflected a higher enzyme activity during the day compared to the night. Conclusions: Sex- and age-specific references for 24 hours, day and night urine steroid metabolite ratios may help distinguishing between health and disease when investigating human disorders affecting steroid synthesis and metabolism. The day-night differences observed for most of the diagnostic ratios suggest a circadian rhythm for enzymes involved in human steroid hormones metabolism. [ABSTRACT FROM AUTHOR]

Aging is associated with functional decline in the immune system and increases the risk of chronic diseases owing to smoldering inflammation. In the present study, we demonstrated an age-related increase in the accumulation of Programmed Death-1 (PD-1)+ memory-phenotype T cells that are considered "senescence-associated T cells" in both the visceral adipose tissue and spleen. As caloric restriction is an established intervention scientifically proven to exert anti-aging effects and greatly affects physiological and pathophysiological alterations with advanced age, we evaluated the effect of caloric restriction on the increase in this T-cell subpopulation and glucose tolerance in aged mice. Long-term caloric restriction significantly decreased the number of PD-1+ memory-phenotype cluster of differentiation (CD) 4+ and CD8+ T cells in the spleen and visceral adipose tissue, decreased M1-type macrophage accumulation in visceral adipose tissue, and improved insulin resistance in aged mice. Furthermore, the immunological depletion of PD-1+ T cells reduced adipose inflammation and improved insulin resistance in aged mice. Taken together with our previous report, these results indicate that senescence-related T-cell subpopulations are involved in the development of chronic inflammation and insulin resistance in the context of chronological aging and obesity. Thus, long-term caloric restriction and specific deletion of senescence-related T cells are promising interventions to regulate age-related chronic diseases. [ABSTRACT FROM AUTHOR]

Background: While the use of combination antiretroviral therapy (cART) has conferred significant reduction in morbidity and mortality, there are growing concerns about the metabolic complications of antiretroviral regimens in HIV-infected patients. The aim of this study was to estimate the prevalence of metabolic syndrome (MetS) among people living with HIV (PLHIV) in Singapore. Methods: We conducted a retrospective study using the clinical database maintained by the Clinical HIV Programme at the National Centre for Infectious Diseases, Singapore. Treatment-experienced PLHIV on follow-up during 2015–2017 were included. MetS was defined as having three or more of the following five abnormalities: hypertriglyceridemia, HDL hypocholesterolemia, hypertension, obesity, and diabetes. Results: A total of 2,231 PLHIV were included in this study. 93.9% were men, and the median age at latest follow-up was 48 years. The median duration of HIV infection and duration of exposure to cART was 6.8 years and 5.7 years, respectively. All had been exposed to nucleoside reverse transcriptase inhibitors (NRTIs) as the first line of treatment, 93.9% to non-NRTIs, 28.6% to protease inhibitors (PIs) and 12.8% to integrase strand transfer inhibitors. The most common metabolic abnormality among PLHIV was HDL hypocholesterolemia (60.2%) followed by hypertriglyceridemia (45.5%). Of all the 2,231 individuals, 68.8% had at least one component of MetS. The overall prevalence of MetS was 23.6% (95% confidence interval 21.9%–25.4%). Of the 526 with MetS, the most common combination was HDL hypocholesterolemia, hypertriglyceridemia and hypertension (51.0%), followed by HDL hypocholesterolemia, hypertriglyceridemia, hypertension and diabetes (25.1%). Compared with PLHIV without MetS, a significantly higher proportion of those with MetS were ever on protease inhibitors (33.5% vs. 27.1%). Conclusion: MetS is common in PLHIV. In view of the progressive aging of HIV-infected population and long-term use of cART, regular monitoring for metabolic abnormalities, surveillance of drug effects and behavioural interventions are needed to optimize management and prevention of metabolic disorders in PLHIV. [ABSTRACT FROM AUTHOR]