Search

Visual Abstract, Highlights • PON-1 is an HDL-associated cardioprotective enzyme that prevents oxidized-LDL formation and has not previously been studied in cardio-oncology. • To determine the associations between PON-1 and the development of CTRCD, the Pon and Aryl serum enzymatic activity levels of PON-1 were quantified in a cohort of 225 patients with breast cancer receiving doxorubicin with or without trastuzumab. • After doxorubicin completion, the activity levels of both Pon and Aryl were significantly decreased. • Early increases in the Pon enzymatic activity of PON-1 were associated with increased risk of CTRCD. • With further study, PON-1 activity may provide insight into mechanistic risk prediction of CTRCD with doxorubicin chemotherapy., Summary The objective of this study was to determine associations of paraoxonase-1 (PON-1) with development of cancer therapy–related cardiac dysfunction (CTRCD). PON-1 is a cardioprotective enzyme associated with high-density lipoprotein that prevents oxidized low-density lipoprotein formation. Given the role of oxidative stress in doxorubicin-induced cardiotoxicity, PON-1 activity may have relevance for the prediction of CTRCD. In 225 patients with breast cancer receiving doxorubicin with or without trastuzumab, we quantified PON-1 activity through its paraoxonase (Pon) and arylesterase (Aryl) enzymatic activity at baseline, during, and after doxorubicin completion. Echocardiograms were performed at baseline, during therapy, and annually. CTRCD was defined as a decrease in left ventricular ejection fraction by ≥10% from baseline to

Dioxin-like molecules have been associated with endocrine disruption and liver disease. To better understand aryl hydrocarbon receptor (AHR) biology, metabolic phenotyping and liver proteomics were performed in mice following ligand-activation or whole-body genetic ablation of this receptor. Male wild type (WT) and Ahr–/– mice (Taconic) were fed a control diet and exposed to 3,3′,4,4′,5-pentachlorobiphenyl (PCB126) (61 nmol/kg by gavage) or vehicle for two weeks. PCB126 increased expression of canonical AHR targets (Cyp1a1 and Cyp1a2) in WT but not Ahr–/–. Knockouts had increased adiposity with decreased glucose tolerance; smaller livers with increased steatosis and perilipin-2; and paradoxically decreased blood lipids. PCB126 was associated with increased hepatic triglycerides in Ahr–/–. The liver proteome was impacted more so by Ahr–/– genotype than ligand-activation, but top gene ontology (GO) processes were similar. The PCB126-associated liver proteome was Ahr-dependent. Ahr principally regulated liver metabolism (e.g., lipids, xenobiotics, organic acids) and bioenergetics, but it also impacted liver endocrine response (e.g., the insulin receptor) and function, including the production of steroids, hepatokines, and pheromone binding proteins. These effects could have been indirectly mediated by interacting transcription factors or microRNAs. The biologic roles of the AHR and its ligands warrant more research in liver metabolic health and disease., Graphical abstract The aryl hydrocarbon receptor regulated liver metabolism and endocrine function impacting systemic energy homeostasis and body composition. This regulation appeared to involve both direct and indirect mechanisms.Image 1

Analysis through logistic regression explored to investigate the relationship between binary or multivariable ordinal response probability and in one or more explanatory variables. The main objectives of this study to investigate advanced prediction risk factor of Coronary Heart Disease (CHD) using a logit model. Attempts made to reduce risk factors, increase public or professional awareness. Logit model used to evaluate the probability of a person develop CHD, considering any factors such as age, gender, high low-density lipoprotein (LDL) cholesterol, low high-density lipoprotein (HDL) cholesterol, high blood pressure, family history of CHD younger than 45, diabetes, smoking, being post-menopausal for women and being older than 45 for men. Logit concept of brief statistics described with slight modification to estimate the parameters testing for the significance of the coefficients, confidence interval fits the simple, multiple logit models. Besides, interpretation of the fitted logit regression model introduced. Variables showing best results within the scientific context, good explanation data assessed to fit an estimated logit model containing chosen variables, this present experiment used the statistical inference procedure; chi-square distribution, likelihood ratio, Score, or Wald test and goodness-of-fit. Health promotion started with increased public or professional awareness improved for early detection of CHD, to reduce the risk of mortality, aimed to be Saudi vision by 2030.

Central Illustration, Highlights • Neointimal hyperplasia is the major factor contributing to restenosis after angioplasty procedures. • Multiple animal models exist to study basic and translational aspects of restenosis formation. • Animal models differ substantially, and species-specific differences have major impact on the pathophysiology of the model. • Genetic, dietary, and mechanical interventions determine the translational potential of the animal model used and have to be considered when choosing the model., Summary The process of restenosis is based on the interplay of various mechanical and biological processes triggered by angioplasty-induced vascular trauma. Early arterial recoil, negative vascular remodeling, and neointimal formation therefore limit the long-term patency of interventional recanalization procedures. The most serious of these processes is neointimal hyperplasia, which can be traced back to 4 main mechanisms: endothelial damage and activation; monocyte accumulation in the subintimal space; fibroblast migration; and the transformation of vascular smooth muscle cells. A wide variety of animal models exists to investigate the underlying pathophysiology. Although mouse models, with their ease of genetic manipulation, enable cell- and molecular-focused fundamental research, and rats provide the opportunity to use stent and balloon models with high throughput, both rodents lack a lipid metabolism comparable to humans. Rabbits instead build a bridge to close the gap between basic and clinical research due to their human-like lipid metabolism, as well as their size being accessible for clinical angioplasty procedures. Every different combination of animal, dietary, and injury model has various advantages and disadvantages, and the decision for a proper model requires awareness of species-specific biological properties reaching from vessel morphology to distinct cellular and molecular features.

Coronavirus disease-2019 (COVID-19) is associated with systemic inflammation, endothelial activation, and multiorgan manifestations. Lipid-modulating agents may be useful in treating patients with COVID-19. These agents may inhibit viral entry by lipid raft disruption or ameliorate the inflammatory response and endothelial activation. In addition, dyslipidemia with lower high-density lipoprotein cholesterol and higher triglyceride levels portend worse outcomes in patients with COVID-19. Upon a systematic search, 40 randomized controlled trials (RCTs) with lipid-modulating agents were identified, including 17 statin trials, 14 omega-3 fatty acids RCTs, 3 fibrate RCTs, 5 niacin RCTs, and 1 dalcetrapib RCT for the management or prevention of COVID-19. From these 40 RCTs, only 2 have reported preliminary results, and most others are ongoing. This paper summarizes the ongoing or completed RCTs of lipid-modulating agents in COVID-19 and the implications of these trials for patient management., Central Illustration

Purpose The impact of the adherence to dietary guidelines of early-stage breast cancer (EBC) patients on body composition changes during treatment is not entirely defined. This study aimed to evaluate the role of an evidence-based nutrition educational intervention, according to adherence to dietary guidelines, in EBC patients. Methods This prospective study included EBC patients, candidates for neoadjuvant/adjuvant therapy. Patients received an evidence-based tailored nutrition educational intervention. The adherence to dietary guidelines, anthropometric and dietary assessments, and blood glucose and lipid profile tests were evaluated at baseline and after a 12-months nutritional intervention. Results Two hundred and forty-three patients were enrolled. At baseline, 38.3% and 23.9% of patients were overweight and obese, weight gain ≥5% (compared to 6-months before enrollment) and central obesity were observed in 47.3% and 52.7% of patients, respectively. Adherence to dietary guidelines was low (median Med-Diet score: 6 [IQR 4–8]). After the nutritional intervention (median follow-up: 22 months [range 12–45]), adherence to dietary guidelines significantly increased (median Med-Diet score: 12 [IQR 8–13]), p, Highlights • A nutritional intervention improves adherence to dietary guidelines among patients with early-stage breast cancer. • High adherence to dietary guidelines enhances anthropometric measures. • Serum metabolic profile improves with high adherence to dietary guidelines. • Early-stage breast cancer patients should receive a nutritional assessment immediately after diagnosis. • Dietary intervention, to control body weight, could enhance the disease outcome.

Objective: To evaluate the magnitude of the association between risk factors and premature myocardial infarction (MI) (men aged 18-55 years; women aged 18-65 years). Patients and Methods: We searched MEDLINE and other databases from inception through April 30, 2020, as well as bibliography of articles selected for data extraction. We selected observational studies reporting the magnitude of the association of at least 1 risk factor (demographic characteristics, lifestyle factors, clinical risk factors, or biomarkers) with premature MI and a control group. Pooled risk estimates (random effects) from all studies unadjusted and adjusted for risk factors were reported as summary odds ratios (ORs) with 95% CIs. Results: From 35,320 articles of 12.7 million participants, we extracted data on 19 risk factors from 77 studies across 58 countries. Men had a higher risk of premature MI (OR, 2.39; 95% CI, 1.71 to 3.35) than did women. Family history of cardiac disease was associated with a higher risk of premature MI (OR, 2.67; 95% CI, 2.29 to 3.27). Major modifiable risk factors associated with higher risk were current smoking (OR, 4.34; 95% CI, 3.68 to 5.12 vs no/former), diabetes mellitus (OR, 3.54; 95% CI, 2.69 to 4.65), dyslipidemia (OR, 2.94; 95% CI, 1.76 to 4.91), and hypertension (OR, 2.85; 95% CI, 2.48 to 3.27). Higher body mass index carried higher risk (OR, 1.46; 95% CI, 1.24 to 1.71 for ≥25 kg/m2 vs

Highlights • Obesity contributes to male infertility. • Can lycopene or moringa improve male infertility? • Tested in a rodent model of diet-induced obesity. • Lycopene was superior to Moringa in improving male fertility parameters., Obesity is a condition of chronic tissue inflammation and oxidative stress that poses as a risk factor for male infertility. Moringa oleifera oil extract is known to have cholesterol-lowering properties and a potential to treat obesity, while lycopene is a potent antioxidant. We hypothesize that Moringa or lycopene may improve male fertility markers in an animal model of diet-induced obesity. Male Albino rats (n = 60) were randomized to receive regular chow (RC) or high-fat diet (HFD) for 12 weeks (n = 30 each). Animals in each arm were further randomized to receive gavage treatment with corn oil (vehicle), lycopene (10 mg/kg), or Moringa (400 mg/kg) for four weeks starting on week 9 (n = 10 each). Animals were sacrificed at 12 weeks, and blood was collected to assess lipid profile, serum testosterone, and gonadotropin levels. The testes and epididymides were removed for sperm analysis, oxidative stress and inflammatory markers, and histopathological assessment. In comparison to their RC littermates, animals on HFD showed an increase in body weights, serum lipids, testosterone and gonadotrophin levels, testicular oxidative stress and inflammatory markers, as well as sperm abnormalities and disrupted testicular histology. Moringa or lycopene reduced body weight, improved oxidative stress, and male fertility markers in HFD-fed animals with lycopene exhibiting better anti-antioxidant and anti-lipidemic effects. Lycopene is superior to Moringa in improving male fertility parameters, possibly by attenuating oxidative stress.

Background and aim Metabolic disease encompasses most contemporary non-communicable diseases, especially cardiovascular and fatty liver disease. Mulberry fruits of Morus alba L. are a favoured food and a traditional medicine. While they are anti-atherosclerotic and reduce hyperlipidemic risk factors, studies need wider scope that include ameliorating cardiovascular and liver pathologies if they are to become clinically effective treatments. Therefore, the present study sought to show that freshly dried mulberry fruits (dMF) might counteract the metabolic/cardiovascular pathologies in mice made hyperlipidemic by high-fat diet (HF). Experimental procedure C57BL/6J mice were fed for 3 months with either: i) control diet, ii) HF, iii) HF+100 mg/kg dMF, or iv) HF+300 mg/kg dMF. Body weight gain, food intake, visceral fat accumulation, fasting blood glucose, plasma lipids, and aortic, heart, and liver histopathologies were evaluated. Adipocyte lipid accumulation, autophagy, and bile acid binding were also investigated. Results and conclusion HF increased food intake, body weight, visceral fat, plasma total cholesterol (TC) and low-density lipoprotein (LDL), TC/HDL ratio, blood glucose, aortic collagen, arterial and cardiac wall thickness, and liver lipid. Both dMF doses prevented hyperphagia, body weight gain, and visceral fat accumulation, lowered blood glucose, plasma TG and unfavourable TC/HDL and elevated plasma HDL beyond baseline. Arterial and cardiac wall hypertrophy, aortic collagen fibre accumulation and liver lipid deposition ameliorated in dMF-fed mice. Clinical trials on dMF are worthwhile but outcomes should be holistic commensurate with the constellation of disease risks. Here, dMF should supplement the switch to nutrient-rich from current energy-dense diets that are progressively crippling national health systems., Graphical abstract Image 1, Highlights • Uses modest amounts of whole unextracted mulberries as in traditional medicine. • Studies important pathologies found in metabolic syndrome, the number one challenge to modern medicine. • dMF reduces risk factors associated with dyslipidemia. • dMF prevents weight gain, visceral fat and hepatic fat accumulation with fatty diets. • dMF ameliorates vascular fibrosis and cardiac hypertrophy, thereby preventing myocardial infarction risk.

Visual Abstract, Highlights • A large animal model that recapitulates the clinical heterogeneity of HFpEF has been developed. • Multiple comorbidities, including obesity, hypercholesterolemia, pre-diabetic phenotype, as well as pulmonary and systemic arterial hypertension, were induced in adult female Göttingen minipigs by mineralocorticoid excess and a diet high in cholesterol, fat, fructose, and salt. • Severity of each comorbidity was titrated, such that marked left ventricular and left atrial diastolic dysfunction, profound left ventricular concentric remodeling, impaired coronary vasorelaxation, and extensive multiorgan fibrosis were achieved over a relatively short time. • This novel heart failure model was generated in Göttingen minipigs to allow for translational studies of novel pharmacological agents and for human-sized device testing in adult-aged animals. • This novel “multihit” minipig heart failure model enabled investigations into the pathology of HFpEF without the confounding effects inherent with invasive surgical procedures or the administration of agents that induce hypertension and end-organ damage in an artificial manner., Summary A lack of preclinical large animal models of heart failure with preserved ejection fraction (HFpEF) that recapitulate this comorbid-laden syndrome has led to the inability to tease out mechanistic insights and to test novel therapeutic strategies. This study developed a large animal model that integrated multiple comorbid determinants of HFpEF in a miniswine breed that exhibited sensitivity to obesity, metabolic syndrome, and vascular disease with overt clinical signs of heart failure. The combination of a Western diet and 11-deoxycorticosterone acetate salt−induced hypertension in the Göttingen miniswine led to the development of a novel large animal model of HFpEF that exhibited multiorgan involvement and a full spectrum of comorbidities associated with human HFpEF.

Background & Aims Nonalcoholic fatty liver disease (NAFLD) is considered a health epidemic with potential devastating effects on the patients and the healthcare systems. Current preclinical models of NAFLD are invariably imperfect and generally take a long time to develop. A mouse model of survival motor neuron (SMN) depletion (Smn2B/- mice) was recently shown to develop significant hepatic steatosis in less than 2 weeks from birth. The rapid onset of fatty liver in Smn2B/- mice provides an opportunity to identify molecular markers of NAFLD. Here, we investigated whether Smn2B/- mice display typical features of NAFLD/nonalcoholic steatohepatitis (NASH). Methods Biochemical, histologic, electron microscopy, proteomic, and high-resolution respirometry were used. Results The Smn2B/- mice develop microvesicular steatohepatitis within 2 weeks, a feature prevented by AAV9-SMN gene therapy. Although fibrosis is not overtly apparent in histologic sections of the liver, there is molecular evidence of fibrogenesis and presence of stellate cell activation. The consequent liver damage arises from mitochondrial reactive oxygen species production and results in hepatic dysfunction in protein output, complement, coagulation, iron homeostasis, and insulin-like growth factor-1 metabolism. The NAFLD phenotype is likely due to non-esterified fatty acid overload from peripheral lipolysis subsequent to hyperglucagonemia compounded by reduced muscle use and insulin resistance. Despite the low hepatic mitochondrial content, isolated mitochondria show enhanced β-oxidation, likely as a compensatory response, resulting in the production of reactive oxygen species. In contrast to typical NAFLD/NASH, the Smn2B/- mice lose weight because of their associated neurological condition (spinal muscular atrophy) and develop hypoglycemia. Conclusions The Smn2B/- mice represent a good model of microvesicular steatohepatitis. Like other models, it is not representative of the complete NAFLD/NASH spectrum. Nevertheless, it offers a reliable, low-cost, early-onset model that is not dependent on diet to identify molecular players in NAFLD pathogenesis and can serve as one of the very few models of microvesicular steatohepatitis for both adult and pediatric populations., Graphical abstract

Background and aims The Hepatitis E virus hijacks the endosomal system for its release. These structures are highly dependent on cholesterol. Hence, this study investigates the impact of HEV on cholesterol-metabolism, the effect of intracellular cholesterol content on HEV-release and the potential of cholesterol-modulators to serve as antivirals. Methods Intracellular cholesterol-content of cells was modulated and impacts on HEV were monitored using qPCR, Western blot, microscopy, virus-titration and density-gradient centrifugation. Blood-lipids and HEV-RNA were routinely quantified in chronically infected patients during follow-up visits. Results In HEV-infected cells, decreased levels of cholesterol are found. In patients, HEV infection decreases serum-lipid concentrations. Importantly, statin treatment herein increases viral titers. Similarly, reduction of intracellular cholesterol via simvastatin treatment increases viral release in vitro. On the contrary, elevating intracellular cholesterol via LDL or 25-hydroxycholesterol strongly reduces viral release due to enhanced lysosomal degradation of HEV. Drug-induced elevation of intracellular cholesterol via fenofibrate or PSC833 impairs HEV release via the same mechanism. Conclusions This study analyses the crosstalk between HEV and intracellular cholesterol. The results highlight the importance of an intact cholesterol homeostasis for HEV-release and thereby identify a potential target for antiviral strategies. Especially fenofibrate is considered a promising novel antiviral against HEV. Beyond this, the study may help clinicians evaluating co-treatments of HEV-infected patients with statins, as this may be counter indicated., Graphical abstract

Graphical abstract, Highlights • Heavy metals effects fishes when its concentration arises from its normal. • Bioaccumulation of manganese and chromium was studied in Cyprinus carpio on hematological and biochemical parameters. • In organ, bioaccumulation is highest in the gills followed by intestine > muscles > skin > bones. • It is concluded that heavy metal can readily bio accumulate in the organs of fish., The present research work was carried out to determine the bioaccumulation of manganese and chromium in the gills, intestine, muscles, skin and bones, as well as its acute toxicity and effects on hematological and biochemical parameters in Common carp (Cyprinus carpio). Adult carps were exposed for 96 h to manganese sulphate and chromium chloride solution, a sub lethal concentration was used in the experiment. Bioaccumulation was highest in the gills followed by intestine > muscles > skin > bones. The concentration of hematocrit (HCT) (37.3 ± 0.36), hemoglobin (HGB) (9.0 ± 0.04), Red Blood Cells (RBCs) (3.7 ± 0.025), mean corpuscular volume (MCV) (121.2 ± 0.36), mean corpuscular hemoglobin (MCH) (41.3 ± 0.3) and mean corpuscular hemoglobin concentration (MCHC) (41.06 ± 0.072) was significantly higher at 96 h (P

Nonalcoholic fatty liver disease comprises a wide spectrum of liver injuries from simple steatosis to steatohepatitis and cirrhosis. Nonalcoholic steatohepatitis (NASH) is defined when liver steatosis is associated with inflammation, hepatocyte damage, and fibrosis. A genetic predisposition and environmental insults (ie, dietary habits, obesity) are putatively responsible for NASH progression. Here, we present the impact of the lipid-sensing nuclear receptors in the pathogenesis and treatment of NASH. In detail, we discuss the pros and cons of the putative transcriptional action of the fatty acid sensors (peroxisome proliferator-activated receptors), the bile acid sensor (farnesoid X receptor), and the oxysterol sensor (liver X receptors) in the pathogenesis and bona fide treatment of NASH.

Hypertension is the most common chronic disease of older adults and an important modifiable cause of mortality and morbidity. In this cross-sectional study, we gathered information about the demographic profile and biochemical parameters associated with hypertension in 897 study subjects above 50 years by structured questionnaires and various laboratory investigations. Higher body mass index, sedentary lifestyle, male sex, living alone, diabetes mellitus, alcohol consumption, medication non-compliance, and a higher serum cholesterol level were associated significantly with uncontrolled hypertension in our study. Hence, weight reduction, adopting an active lifestyle, improving social support, and strict compliance with anti-hypertensives are the cornerstones of blood pressure control.

Background & Aims The etiology of nonalcoholic fatty liver disease (NAFLD) is poorly understood, with males and certain populations exhibiting markedly increased susceptibility. Using a systems genetics approach involving multi-omic analysis of ∼100 diverse inbred strains of mice, we recently identified several candidate genes driving NAFLD. We investigated the role of one of these, liver pyruvate kinase (L-PK or Pklr), in NAFLD by using patient samples and mouse models. Methods We examined L-PK expression in mice of both sexes and in a cohort of bariatric surgery patients. We used liver-specific loss- and gain-of-function strategies in independent animal models of diet-induced steatosis and fibrosis. After treatment, we measured several metabolic phenotypes including obesity, insulin resistance, dyslipidemia, liver steatosis, and fibrosis. Liver tissues were used for gene expression and immunoblotting, and liver mitochondria bioenergetics was characterized. Results In both mice and humans, L-PK expression is up-regulated in males via testosterone and is strongly associated with NAFLD severity. In a steatosis model, L-PK silencing in male mice improved glucose tolerance, insulin sensitivity, and lactate/pyruvate tolerance compared with controls. Furthermore, these animals had reduced plasma cholesterol levels and intrahepatic triglyceride accumulation. Conversely, L-PK overexpression in male mice resulted in augmented disease phenotypes. In contrast, female mice overexpressing L-PK were unaffected. Mechanistically, L-PK altered mitochondrial pyruvate flux and its incorporation into citrate, and this, in turn, increased liver triglycerides via up-regulated de novo lipogenesis and increased PNPLA3 levels accompanied by mitochondrial dysfunction. Also, L-PK increased plasma cholesterol levels via increased PCSK9 levels. On the other hand, L-PK silencing reduced de novo lipogenesis and PNPLA3 and PCSK9 levels and improved mitochondrial function. Finally, in fibrosis model, we demonstrate that L-PK silencing in male mice reduced both liver steatosis and fibrosis, accompanied by reduced de novo lipogenesis and improved mitochondrial function. Conclusions L-PK acts in a male-specific manner in the development of liver steatosis and fibrosis. Because NAFLD/nonalcoholic steatohepatitis exhibit sexual dimorphism, our results have important implications for the development of personalized therapeutics., Graphical abstract

Understanding of the nephrotoxicity induced by drug candidates is vital to drug discovery and development. Herein, an in situ metabolomics method based on air flow-assisted desorption electrospray ionization mass spectrometry imaging (AFADESI-MSI) was established for direct analysis of metabolites in renal tissue sections. This method was subsequently applied to investigate spatially resolved metabolic profile changes in rat kidney after the administration of aristolochic acid I, a known nephrotoxic drug, aimed to discover metabolites associated with nephrotoxicity. As a result, 38 metabolites related to the arginine–creatinine metabolic pathway, the urea cycle, the serine synthesis pathway, metabolism of lipids, choline, histamine, lysine, and adenosine triphosphate were significantly changed in the group treated with aristolochic acid I. These metabolites exhibited a unique distribution in rat kidney and a good spatial match with histopathological renal lesions. This study provides new insights into the mechanisms underlying aristolochic acids nephrotoxicity and demonstrates that AFADESI-MSI-based in situ metabolomics is a promising technique for investigation of the molecular mechanism of drug toxicity., Graphical abstract This study investigated the spatially resolved metabolic profile changes in rat kidney after the administration of aristolochic acid I (AAI) by an in situ metabolomics method based on air flow-assisted desorption electrospray ionization mass spectrometry imaging (AFADESI-MSI), providing new insights into the mechanisms underlying aristolochic acids nephrotoxicity.Image 1

Graphical abstract, Highlights • Hypothyroidism is the most frequent toxic effect of a large variety of chemical compounds. • The polyherbal bioactive fraction exhibited a pro-thyroid effect in hypothyroidic rats. • The polyherbal fraction restored the propylthiouracil-depleted thyroid hormone levels significantly. • The polyherbal fraction may act through multiple mechanisms to exhibit a pro-thyroid effect., Hypothyroidism is the most frequent consequence of the interaction of a large variety of drugs, environmental pollutants and industrial chemicals with the thyroid gland. It is associated with diminished endocrine function which may lead to hyperlipidemia, diabetes, Alzheimer’s disease, weight gain, and other metabolic disorders. The present study evaluates the pro-thyroid activity of a bioactive fraction from a polyherbal teabag in rats with hypothyroidism induced by propylthiouracil. The teabag was formulated to stimulate synthesis and/or release of T4 and affectthe conversion of T4 to T3. Phytoconstituents of the polyherbal teabag are potent antioxidants that may be responsible for the pro-thyroid activity. The tea-extract (1000 mg) was found to contain 1076 μg of gallic acid and 1131 μg of rutin from HPTLC analysis. Rats received propylthiouracil (8 mg/kg) for the first 15days followed by the polyherbal tea-extract (500, 1000 and 1500 mg/kg), the standard drug levothyroxine (0.1 mg/kg), aerobic exercise, and a combination of tea-extract (1000 mg/kg) and aerobic exercise daily along with propylthiouracil for the next 30 days. Finally, rats received their respective treatments alone without propylthiouracil for 15 more days. Lipid profile and levels of glucose, insulin, T3, T4, TSH, cortisol, homocysteine, creatinine, uric acid, malondialdehyde, glucose-6 phosphatase, and endogenous antioxidants were determined. All treatments attenuated significantly the propylthiouracil-elevated TSH, homocysteine, creatinine, uric acid, glucose-6-phosphatase, insulin, and malondialdehyde levels, and restored favorably the propylthiouracil-altered lipid profile, T3, T4, and endogenous antioxidant levels. The polyherbal tea-extract (1000 and 1500 mg/kg) treatment and thecombination treatment of tea-extract (1000 mg/kg) with aerobic exercise displayed significant restoration of the suboptimalthyroid function. This may be due to a favorablemodulation ofthe hypothalamic-pituitary–thyroid and the hypothalamic–pituitary–adrenal axes.

Background: Dietary fat has been suggested to be the cause of various health issues. Obesity, hypertension, cardiovascular disease, diabetes, dyslipidemia, and kidney disease are known to be associated with a high-fat diet (HFD). Obesity and associated conditions, such as type 2 diabetes mellitus and nonalcoholic fatty liver disease (NAFLD), are currently a worldwide health problem. Few prospective pharmaceutical therapies that directly target NAFLD are available at present. A Traditional Chinese Medicine, ginseng-plus-Bai-Hu-Tang (GBHT), is widely used by diabetic patients to control glucose level or thirst. However, whether it has therapeutic effects on fat-induced hepatic steatosis and metabolic syndrome remains unclear. Methods: This study was conducted to examine the therapeutic effect of GBHT on fat-induced obesity, hepatic steatosis, and insulin resistance in mice. Results: GBHT protected mice against HFD-induced body weight gain, hyperlipidemia, and hyperglycemia compared with mice that were not treated. GBHT inhibited the expansion of adipose tissue and adipocyte hypertrophy. No ectopic fat deposition was found in the livers of HFD mice treated with GBHT. In addition, glucose intolerance and insulin sensitivity in HFD mice was also improved by GBHT. Conclusion: GBHT prevents changes in lipid and carbohydrate metabolism in a HFD mouse model. Our findings provide evidence for the traditional use of GBHT as therapy for the management of metabolic syndrome. Keywords: diet-induced obesity, ginseng-plus-Bai-Hu-Tang, hepatic steatosis, insulin resistance, Panax ginseng

We report a case of a woman with primary hypertriglyceridemia caused by acquired glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1 (GPIHBP1) autoantibody. This case highlights the necessity of detecting GPIHBP1 autoantibody in patients with acquired hypertriglyceridemia. (Level of Difficulty: Intermediate.), Graphical abstract, We report a case of a woman with primary hypertriglyceridemia caused by acquired glycosylphosphatidylinositol-anchored high-density lipoprotein…

Background Traditional hookah smoking has grown quickly to become a global tobacco epidemic. More recently, electronic hookahs (e-hookahs)—vaped through traditional water pipes—were introduced as healthier alternatives to combustible hookah. With combustible tobacco smoking, oxidative stress, inflammation, and vascular stiffness are key components in the development and progression of atherosclerosis. The comparable effects of hookah are unknown. Research Question What is the differential acute effect of e-hookah vaping vs combustible hookah smoking on oxidation, inflammation, and arterial stiffness? Study Design and Methods In a randomized crossover design study, among a cohort of 17 healthy young adult chronic hookah smokers, we investigated the effect of e-hookah vaping and hookah smoking on measures of conduit arterial stiffness, including carotid-femoral pulse wave velocity (PWV), augmentation index-corrected for heart rate before and after a 30-min exposure session. We assessed a panel of circulating biomarkers indicative of inflammation and oxidants and measured plasma nicotine and exhaled carbon monoxide (CO) levels before and after the sessions. Results e-Hookah vaping tended to lead to a larger acute increase in PWV than hookah smoking (mean ± SE: e-hookah, +0.74 ± 0.12 m/s; combustible hookah, +0.57 ± 0.14 m/s [P < .05 for both]), indicative of large artery stiffening. Compared with baseline, only e-hookah vaping induced an acute increase in augmentation index (e-hookah, +5.58 ± 1.54% [P = .004]; combustible hookah, +2.87 ± 2.12% [P = not significant]). These vascular changes were accompanied by elevation of the proinflammatory biomarkers high-sensitivity C-reactive protein, fibrinogen, and tumor necrosis factor α after vaping (all P < .05). No changes in biomarkers of inflammation and oxidants were observed after smoking. Compared with baseline, exhaled CO levels were higher after smoking than after vaping (+36.81 ± 6.70 parts per million vs –0.38 ± 0.22 parts per million; P < .001), whereas plasma nicotine concentrations were comparable (+6.14 ± 1.03 ng/mL vs +5.24 ± 0.96 ng/mL; P = .478). Interpretation Although advertised to be “safe,” flavored e-hookah vaping exerts injurious effects on the vasculature that are, at least in part, mediated by inflammation. Trial Registry ClinicalTrials.gov; No.: NCT03690427; URL: www.clinicaltrials.gov, Graphical Abstract

Introduction High-fat diet (HFD)-induced obesity impairs clearance of cholesterol through the Reverse Cholesterol Transport (RCT) pathway, with downregulation in hepatic expression of cholesterol and bile acid transporters, namely ABCG5/8 and ABCB11, and reduced high-density lipoprotein (HDL) cholesterol efflux capacity (CEC). In the current study, we hypothesized that the development of hepatosteatosis, secondary to adipose-tissue dysfunction, contributes to obesity-impaired RCT and that such effects could be mitigated using the anti-inflammatory drug sodium salicylate (NaS). Materials and methods C57BL/6J mice, fed HFD ± NaS or low-fat diet (LFD) for 24 weeks, underwent glucose and insulin tolerance testing. The 3H-cholesterol movement from macrophage-to-feces was assessed in vivo. HDL-CEC was determined ex vivo. Cytokine secretion from adipose-derived stromal vascular fraction (SVF) cells was measured ex vivo. Liver and HDL proteins were determined by mass spectrometry and analyzed using Ingenuity Pathway Analysis. Results NaS delayed HFD-induced weight gain, abrogated priming of pro-IL-1β in SVFs, attenuated insulin resistance, and prevented steatohepatitis (ectopic fat accumulation in the liver). Prevention of hepatosteatosis coincided with increased expression of PPAR-alpha/beta-oxidation proteins with NaS and reduced expression of LXR/RXR-induced proteins including apolipoproteins. The latter effects were mirrored within the HDL proteome in circulation. Despite remarkable protection shown against steatosis, HFD-induced hypercholesterolemia and repression of the liver-to-bile cholesterol transporter, ABCG5/8, could not be rescued with NaS. Discussions and conclusions The cardiometabolic health benefits of NaS may be attributed to the reprogramming of hepatic metabolic pathways to increase fatty acid utilization in the settings of nutritional overabundance. Reduced hepatic cholesterol levels, coupled with reduced LXR/RXR-induced proteins, may underlie the lack of rescue of ABCG5/8 expression with NaS. This remarkable protection against HFD-induced hepatosteatosis did not translate to improvements in cholesterol homeostasis., Graphical abstract Image 1, Highlights • Sodium salicylate (NaS) initially delays weight-gain in mice fed high-fat diet (HFD) - catch-up evident in weeks 12–24. • NaS prevents HFD-induced insulin resistance, hepatosteatosis and pro-IL-1β priming in adipose tissue even upon weight-gain. • Hepatic expression of proteins involved in beta oxidation, oxidative phosphorylation and TCA cycle upregulated with NaS. • Hepatic expression of LXR/RXR proteins eg. apolipoproteins reduced with NaS; these effects were mirrored in HDL proteome. • NaS failed to improve HFD-impaired Reverse Cholesterol Transport or hypercholesterolemia despite preventing hepatosteatosis.

The risk of severe coronavirus disease-2019 (COVID-19) disease seems to be higher in individuals with solid organ transplantation. Therefore, the purpose of the present research is to investigate the incidence of COVID-19 and laboratory data and epidemiologic factors in liver transplant recipients and the patients on the waiting list for liver transplantation. In this study, we evaluated the records of patients on the waiting list for liver transplantation and of recipients of a liver transplant. Demographic data, underlying disease, history of drug use and participants' outcomes were collected. The diagnosis of SARS-CoV-2 infection for all patients was confirmed using a nasopharyngeal swab specimen with real-time RT-PCR. During the study period, 172 patients were enrolled, among whom 85 patients (49.4%) were on the waiting list for liver transplantation, and 87 patients (50.6%) were recipients of a liver transplant. Out of them, 10 (5.8%) had a positive result for SARS-CoV-2. Of these patients, 7.05% (6/85) and 4.6% (4/87) of patients on the waiting list and recipients of liver transplants were positive for SARS-CoV-2, respectively. Patients on the waiting list with COVID-19 infection had a higher median of albumin, ALT, AST, TBIL, DBIL, HDL and LDL value. In summary, the incidence of COVID-19 in liver transplant patients was slightly higher. The existence of underlying liver diseases should be well known as one of the poor predictive factors for worse outcomes in patients with COVID-19. So, comparative studies are recommended to identify risk factors for COVID-19 in patients with liver injury.

Background & Aims cAMP responsive element-binding protein 3 like 3 (CREB3L3) is a membrane-bound transcription factor involved in the maintenance of lipid metabolism in the liver and small intestine. CREB3L3 controls hepatic triglyceride and glucose metabolism by activating plasma fibroblast growth factor 21 (FGF21) and lipoprotein lipase. In this study, we intended to clarify its effect on atherosclerosis. Methods CREB3L3-deficifient, liver-specific CREB3L3 knockout, intestine-specific CREB3L3 knockout, both liver- and intestine-specific CREB3L3 knockout, and liver CREB3L3 transgenic mice were crossed with LDLR−/− mice. These mice were fed with a Western diet to develop atherosclerosis. Results CREB3L3 ablation in LDLR−/− mice exacerbated hyperlipidemia with accumulation of remnant APOB-containing lipoprotein. This led to the development of enhanced aortic atheroma formation, the extent of which was additive between liver- and intestine-specific deletion. Conversely, hepatic nuclear CREB3L3 overexpression markedly suppressed atherosclerosis with amelioration of hyperlipidemia. CREB3L3 directly up-regulates anti-atherogenic FGF21 and APOA4. In contrast, it antagonizes hepatic sterol regulatory element-binding protein (SREBP)–mediated lipogenic and cholesterogenic genes and regulates intestinal liver X receptor–regulated genes involved in the transport of cholesterol. CREB3L3 deficiency results in the accumulation of nuclear SREBP proteins. Because both transcriptional factors share the cleavage system for nuclear transactivation, full-length CREB3L3 and SREBPs in the endoplasmic reticulum (ER) functionally inhibit each other. CREB3L3 promotes the formation of the SREBP-insulin induced gene 1 complex to suppress SREBPs for ER-Golgi transport, resulting in ER retention and inhibition of proteolytic activation at the Golgi and vice versa. Conclusions CREB3L3 has multi-potent protective effects against atherosclerosis owing to new mechanistic interaction between CREB3L3 and SREBPs under atherogenic conditions., Graphical abstract

International audience; The correct balance between collagen synthesis and degradation is essential for almost every aspect of life, from development to healthy aging, reproduction and wound healing. When this balance is compromised by external or internal stress signals, it very often leads to disease as is the case in fibrotic conditions. Fibrosis occurs in the context of defective tissue repair and is characterized by the excessive, aberrant and debilitating deposition of fibril-forming collagens. Therefore, the numerous proteins involved in the biosynthesis of fibrillar collagens represent a potential and still underexploited source of therapeutic targets to prevent fibrosis. One such target is procollagen C-proteinase enhancer-1 (PCPE-1) which has the unique ability to accelerate procollagen maturation by BMP-1/tolloid-like proteinases (BTPs) and contributes to trigger collagen fibrillogenesis, without interfering with other BTP functions or the activities of other extracellular metalloproteinases. This role is achieved through a fine-tuned mechanism of action that is close to being elucidated and offers promising perspectives for drug design. Finally, the in vivo data accumulated in recent years also confirm that PCPE-1 overexpression is a general feature and early marker of fibrosis. In this review, we describe the results which presently support the driving role of PCPE-1 in fibrosis and discuss the questions that remain to be solved to validate its use as a biomarker or therapeutic target.

Introduction Amyotrophic lateral sclerosis (ALS) is an intractable and incurable neurological disease. It is a progressive disease characterized by muscle atrophy and weakness caused by selective vulnerability of upper and lower motor neurons. In disease research, it has been common to use mouse models carrying mutations in responsible genes for familial ALS as pathological models of ALS. However, there is no model that has reproduced the actual conditions of human spinal cord pathology. Thus, we developed a method of producing human spinal motor neurons using human induced pluripotent stem cells (iPSCs) and an innovative experimental technique for drug screening. As a result, ropinirole hydrochloride was eventually discovered after considering such results as its preferable transitivity in the brain and tolerability, including possible adverse reactions. Therefore, we explore the safety, tolerability and efficacy of ropinirole hydrochloride as an ALS treatment in this clinical trial. Methods The ROPALS trial is a single-center double-blind randomized parallel group-controlled trial of the safety, tolerability, and efficacy of the ropinirole hydrochloride extended-release tablet (Requip CR) at 2- to 16-mg doses in patients with ALS. Twenty patients will be recruited for the active drug group (fifteen patients) and placebo group (five patients). All patients will be able to receive the standard ALS treatment of riluzole if not changed the dosage during this trial. The primary outcome will be safety and tolerability at 24 weeks, defined from the date of randomization. Secondary outcome will be the efficacy, including any change in the ALS Functional Rating Scale-Revised (ALSFRS-R), change in the Combined Assessment of Function and Survival (CAFS), and the composite endpoint as a sum of Z-transformed scores on various clinical items. Notably, we will perform an explorative search for a drug effect evaluation using the patient-derived iPSCs to prove this trial concept. Eligible patients will have El Escorial Possible, clinically possible and laboratory-supported, clinically probable, or clinically definite amyotrophic lateral sclerosis with disease duration less than 60 months (inclusive), an ALSFRS-R score ≥2 points on all items and age from 20 to 80 years. Conclusion Patient recruitment began in December 2018 and the last patient is expected to complete the trial protocol in November 2020. Trial registration Current controlled trials UMIN000034954 and JMA-IIA00397 Protocol version version 1.6 (Date; 5/Apr/2019)., Highlights • ALS is a progressive neurodegenerative disease caused by selective vulnerability of upper and lower motor neurons. • ALS patients have no radical treatment. • The ROPALS trial reveals the safety, tolerability, and efficacy of the ropinirole hydrochloride in patients with ALS. • This trial is the pioneering clinical trial for ALS based on iPSCs-drug discovery in Japan.

Objective Human blood metabolites are influenced by a number of lifestyle and environmental factors. Identification of these factors and the proper quantification of their relevance provides insights into human biological and metabolic disease processes, is key for standardized translation of metabolite biomarkers into clinical applications, and is a prerequisite for comparability of data between studies. However, so far only limited data exist from large and well-phenotyped human cohorts and current methods for analysis do not fully account for the characteristics of these data. The primary aim of this study was to identify, quantify and compare the impact of a comprehensive set of clinical and lifestyle related factors on metabolite levels in three large human cohorts. To achieve this goal, we improve current methodology by developing a principled analysis approach, which could be translated to other cohorts and metabolite panels. Methods 63 Metabolites (amino acids, acylcarnitines) were quantified by liquid chromatography tandem mass spectrometry in three cohorts (total N = 16,222). Supported by a simulation study evaluating various analytical approaches, we developed an analysis pipeline including preprocessing, identification, and quantification of factors affecting metabolite levels. We comprehensively identified uni- and multivariable metabolite associations considering 29 environmental and clinical factors and performed metabolic pathway enrichment and network analyses. Results Inverse normal transformation of batch corrected and outlier removed metabolite levels accompanied by linear regression analysis proved to be the best suited method to deal with the metabolite data. Association analyses revealed numerous uni- and multivariable significant associations. 15 of the analyzed 29 factors explained >1% of variance for at least one of the metabolites. Strongest factors are application of steroid hormones, reticulocytes, waist-to-hip ratio, sex, haematocrit, and age. Effect sizes of factors are comparable across studies. Conclusions We introduced a principled approach for the analysis of MS data allowing identification, and quantification of effects of clinical and lifestyle factors with metabolite levels. We detected a number of known and novel associations broadening our understanding of the regulation of the human metabolome. The large heterogeneity observed between cohorts could almost completely be explained by differences in the distribution of influencing factors emphasizing the necessity of a proper confounder analysis when interpreting metabolite associations., Graphical abstract Image 1, Highlights • Amino-acids and acylcarnitines analyzed in three studies with >16,000 individuals. • Develop a generic and adaptable bioinformatics workflow. • Analysis of the impact of 29 clinical and life-style factors on blood metabolites. • Analysis of network between factors and metabolites. • Comparison of results between studies.

Objective To clarify the role of dietary carbohydrate, glycemic index (GI), and glycemic load (GL) in progression from health to coronary heart disease (CHD) by determining disease-nutrient risk relation (RR) values needed for intake ranges within jurisdictions and across the globe. Methods We performed a literature search of MEDLINE and EMBASE for prospective cohort studies that used truly valid dietary instruments in heathy adults published from January 1, 2000, to June 5, 2018. Relevant observations were extracted by 2 reviewers independently. We used dose-response meta-analysis accounting for nonindependence of results within studies. Bradford-Hill criteria were used to assess causality. Results Eligible studies had a mean follow-up of 11 years (range, 5-19 years), were conducted in North America, Europe, and East Asia, and yielded combined RRs of 1.44 (95% CI, 1.25-1.65) per 65 g/d GL (11 studies) and 1.24 (95% CI, 1.12-1.38) per 10 U GI (10 studies) (glucose scale). The CHD-carbohydrate RR on GI was 1.66 (95% CI, 1.23-2.25) per 98 g/d of carbohydrates per 10 units GI. The 65 g/d GL, 10 U GI, and 98 g/d carbohydrate values corresponded to oral intakes from the 10th to the 90th percentiles within sampled populations. Inconsistencies were minor (I2≤20%), as were small-study effects (P=.61 for GL and P=.26 for GI). Funnel plots were symmetric. Cubic spline dose-response meta-analysis yielded RRs as follows: across the global range for GL (55-290 g/d), 5.5 (95% CI, 3.1-9.8) (I2=0); for GI (47-82 U), 2.71 (95% CI, 1.47-4.40) (I2=0); and for the CHD-carbohydrate dependence on GI (50-80 U), 4.57 (95% CI, 1.86-11.4) (I2=16%). Bradford-Hill criteria indicated that these relations were probably causal. Conclusion Strong and probably causal CHD-GL and GI RRs exist within populations. The RRs were remarkably higher across global exposures. The results support the consideration of these markers of carbohydrate food quality in dietary guidelines for general populations. Trial Registration PROSPERO Identifier: CRD42013004504

Purpose To examine associations between retinal vessel morphometry and cardiometabolic risk factors in older British men and women. Design Retinal imaging examination as part of the European Prospective Investigation into Cancer—Norfolk Eye Study. Participants Retinal imaging and clinical assessments were carried out in 7411 participants. Retinal images were analyzed using a fully automated validated computerized system that provides novel measures of vessel morphometry. Methods Associations between cardiometabolic risk factors, chronic disease, and retinal markers were analyzed using multilevel linear regression, adjusted for age, gender, and within-person clustering, to provide percentage differences in tortuosity and absolute differences in width. Main Outcomes Measures Retinal arteriolar and venular tortuosity and width. Results In all, 279 802 arterioles and 285 791 venules from 5947 participants (mean age, 67.6 years; standard deviation [SD], 7.6 years; 57% female) were analyzed. Increased venular tortuosity was associated with higher body mass index (BMI; 2.5%; 95% confidence interval [CI], 1.7%–3.3% per 5 kg/m 2 ), hemoglobin A1c (HbA1c) level (2.2%; 95% CI, 1.0%–3.5% per 1%), and prevalent type 2 diabetes (6.5%; 95% CI, 2.8%–10.4%); wider venules were associated with older age (2.6 μm; 95% CI, 2.2–2.9 μm per decade), higher triglyceride levels (0.6 μm; 95% CI, 0.3–0.9 μm per 1 mmol/l), BMI (0.7 μm; 95% CI, 0.4–1.0 per 5 kg/m 2 ), HbA1c level (0.4 μm; 95% CI, –0.1 to 0.9 per 1%), and being a current smoker (3.0 μm; 95% CI, 1.7–4.3 μm); smoking also was associated with wider arterioles (2.1 μm; 95% CI, 1.3–2.9 μm). Thinner venules were associated with high-density lipoprotein (HDL) (1.4 μm; 95% CI, 0.7–2.2 per 1 mmol/l). Arteriolar tortuosity increased with age (5.4%; 95% CI, 3.8%–7.1% per decade), higher systolic blood pressure (1.2%; 95% CI, 0.5%–1.9% per 10 mmHg), in females (3.8%; 95% CI, 1.4%–6.4%), and in those with prevalent stroke (8.3%; 95% CI, –0.6% to 18%); no association was observed with prevalent myocardial infarction. Narrower arterioles were associated with age (0.8 μm; 95% CI, 0.6–1.0 μm per decade), higher systolic blood pressure (0.5 μm; 95% CI, 0.4–0.6 μm per 10 mmHg), total cholesterol level (0.2 μm; 95% CI, 0.0–0.3 μm per 1 mmol/l), and HDL (1.2 μm; 95% CI, 0.7–1.6 μm per 1 mmol/l). Conclusions Metabolic risk factors showed a graded association with both tortuosity and width of retinal venules, even among people without clinical diabetes, whereas atherosclerotic risk factors correlated more closely with arteriolar width, even excluding those with hypertension and cardiovascular disease. These noninvasive microvasculature measures should be evaluated further as predictors of future cardiometabolic disease.

The prevalence and diagnosis of nonalcoholic fatty liver disease (NAFLD) is on the rise worldwide and currently has no FDA-approved pharmacotherapy. The increase in disease burden of NAFLD and a more severe form of this progressive liver disease, nonalcoholic steatohepatitis (NASH), largely mirrors the increase in obesity and type 2 diabetes (T2D) and reflects the hepatic manifestation of an altered metabolic state. Indeed, metabolic syndrome, defined as a constellation of obesity, insulin resistance, hyperglycemia, dyslipidemia and hypertension, is the major risk factor predisposing the NAFLD and NASH. There are multiple potential pharmacologic strategies to rebalance aspects of disordered metabolism in NAFLD. These include therapies aimed at reducing hepatic steatosis by directly modulating lipid metabolism within the liver, inhibiting fructose metabolism, altering delivery of free fatty acids from the adipose to the liver by targeting insulin resistance and/or adipose metabolism, modulating glycemia, and altering pleiotropic metabolic pathways simultaneously. Emerging data from human genetics also supports a role for metabolic drivers in NAFLD and risk for progression to NASH. In this review, we highlight the prominent metabolic drivers of NAFLD pathogenesis and discuss the major metabolic targets of NASH pharmacotherapy.

This patient guideline is intended for all patients at risk of or living with non-alcoholic fatty liver disease (NAFLD). NAFLD is the most frequent chronic liver disease worldwide and comes with a high disease burden. Yet, there is a lot of unawareness. Furthermore, many aspects of the disease are still to be unravelled, which has an important impact on the information that is given (or not) to patients. Its management requires a close interaction between patients and their many healthcare providers. It is important for patients to develop a full understanding of NAFLD in order to enable them to take an active role in their disease management. This guide summarises the current knowledge relevant to NAFLD and its management. It has been developed by patients, patient representatives, clinicians and scientists and is based on current scientific recommendations, intended to support patients in making informed decisions. (C) 2021 The Authors. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL).

The human apolipoprotein L gene family encodes the apolipoprotein L1–6 (APOL1–6) proteins, which are effectors of the innate immune response to viruses, bacteria and protozoan parasites. Due to a high degree of similarity between APOL proteins, it is often assumed that they have similar functions to APOL1, which forms cation channels in planar lipid bilayers and membranes resulting in cytolytic activity. However, the channel properties of the remaining APOL proteins have not been reported. Here, we used transient overexpression and a planar lipid bilayer system to study the function of APOL proteins. By measuring lactate dehydrogenase release, we found that APOL1, APOL3, and APOL6 were cytolytic, whereas APOL2, APOL4, and APOL5 were not. Cells expressing APOL1 or APOL3, but not APOL6, developed a distinctive swollen morphology. In planar lipid bilayers, recombinant APOL1 and APOL2 required an acidic environment for the insertion of each protein into the membrane bilayer to form an ion conductance channel. In contrast, recombinant APOL3, APOL4, and APOL5 readily inserted into bilayers to form ion conductance at neutral pH, but required a positive voltage on the side of insertion. Despite these differences in membrane insertion properties, the ion conductances formed by APOL1-4 were similarly pH-dependent and cation-selective, consistent with conservation of the pore-lining region in each protein. Thus, despite structural conservation, the APOL proteins are functionally different. We propose that these proteins interact with different membranes and under different voltage and pH conditions within a cell to effect innate immunity to different microbial pathogens.

Highlights • Skipping breakfast was associated with metabolic syndrome in men. • Short sleep duration was also associated with metabolic syndrome in men. • There was no association with metabolic syndrome in women. • The interaction of the two factors on metabolic syndrome was not significant., The purpose of the study was to investigate sex-specific associations of skipping breakfast and short sleep duration with metabolic syndrome (MetS) and their interaction. We analyzed baseline data of 14,907 men and 14,873 women aged 35–69 years, who participated in the Japan Multi-Institutional Collaborative Cohort Study from 2005. MetS was diagnosed using a modification of the National Cholesterol Education Program Adult Treatment Panel III revised definition (NCEP-R 2005), using body mass index instead of waist circumference. Breakfast consumption was classified into two categories: ≥6 days/week (consumers) or

Hyperhomocysteinemia (HHcy) is considered as a risk factor for several complications, including cardiovascular and neurological disorders. A high methionine low folate (HMLF) diet chronically causes HHcy by accumulating homocysteine in the systemic circulation. Elevated Hcy level is also associated with the incidence of diabetes mellitus. However, very few studies focus on the impact of HMLF diet on glucose homeostasis, and that on gut microbiome profile. HHcy was induced by feeding C57BL/6 mice a HMLF diet for 8 weeks. The HMLF diet feeding resulted in a progressive body weight loss, and development of slight glucose intolerance and insulin resistance in HHcy mice. Notably, the HMLF diet alters the gut microbiome profile and increases the relative abundance of porphyromonadaceae family of bacteria in HHcy mice. These findings provide new insights into the roles of dysregulated glucose homeostasis and gut flora in the pathogenesis of HHcy-related complications., Highlights • A high methionine low folate (HMLF) diet induces hyperhomocysteinemia in mice. • HMLF diet slightly but significantly induces glucose intolerance and insulin resistance in mice. • HMLF diet alters gut microbiome profile in mice. • HMLF diet increases the abundance of porphyromonadaceae family of bacteria.

The process of restenosis is based on the interplay of various mechanical and biological processes triggered by angioplasty-induced vascular trauma. Early arterial recoil, negative vascular remodeling, and neointimal formation therefore limit the long-term patency of interventional recanalization procedures. The most serious of these processes is neointimal hyperplasia, which can be traced back to 4 main mechanisms: endothelial damage and activation; monocyte accumulation in the subintimal space; fibroblast migration; and the transformation of vascular smooth muscle cells. A wide variety of animal models exists to investigate the underlying pathophysiology. Although mouse models, with their ease of genetic manipulation, enable cell- and molecular-focused fundamental research, and rats provide the opportunity to use stent and balloon models with high throughput, both rodents lack a lipid metabolism comparable to humans. Rabbits instead build a bridge to close the gap between basic and clinical research due to their human-like lipid metabolism, as well as their size being accessible for clinical angioplasty procedures. Every different combination of animal, dietary, and injury model has various advantages and disadvantages, and the decision for a proper model requires awareness of species-specific biological properties reaching from vessel morphology to distinct cellular and molecular features.

Type-1 diabetes mellitus (T1DM) is associated with metabolic changes leading to alterations in glucose and lipid handling. While T1DM-associated effects on many major plasma lipids have been characterised, such effects on plasma free fatty acids (FFA) have not been fully examined. Using gas chromatography–mass spectrometry, we measured the plasma concentrations of FFA species in individuals with T1DM (n = 44) and age/sex-matched healthy controls (n = 44). Relationships between FFA species and various parameters were evaluated. Plasma concentrations of myristate (14:0), palmitoleate (16:1), palmitate (16:0), linoleate (18:2), oleate (18:1c9), cis-vaccenate (18:1c11), eicosapentaenoate (20:5), arachidonate (20:4) and docosahexanoate (22:6) were reduced in the T1DM group (p, Graphical abstract Unlabelled Image, Highlights • Plasma concentrations of major FFA species are lower in T1DM compared to controls. • Plasma FFA concentrations negatively correlates with HbA1c in T1DM. • The SCD1 index is reduced in T1DM. • Lipogenesis, elongase, n3/n6, saturated/unsaturated indices are increased in T1DM. • Collectively, the data highlight specific changes in lipid metabolism in T1DM

Although the intake of specific flavonoid-rich foods may reduce C-reactive protein (CRP) levels, the association between dietary flavonoid intakes and CRP is inconsistent. We aim to describe dietary flavonoid intakes in a Taiwanese nationally representative sample and to investigate the association between flavonoid intakes and CRP. We conducted a cross-sectional study based on 2592 adults from the Nutrition and Health Survey in Taiwan 2005–8. Flavonoid intakes were estimated by linking the 24-h dietary recall with the U.S. Department of Agriculture flavonoid database and divided into quartiles. Adjusted estimates of the flavonoid intakes for the continuous and binary (elevated CRP: >0⋅3 mg/dl) variables were performed by using general linear and logistic regression. We found that tea, orange, tofu and sweet potato leaves/water spinach constituted the major food items of the total flavonoid intake. The total flavonoid intake was lower among women and elderly. Compared with the lowest total flavonoid intake quartile, participants in higher quartiles were associated with a lower CRP status (adjusted odds ratio (OR): 0⋅61, 95 % confidence interval (CI): 0⋅44–0⋅86 for the highest quartiles). The trends were similar for flavonol and flavan-3-ol intakes. Compared with non-consumers, tea consumers were likely to have a lower CRP status (adjusted OR: 0⋅74, 95 % CI: 0⋅57–0⋅97). In brief, a higher total flavonoid intake and tea consumption were inversely associated with CRP levels, indicating that a high-flavonoid diet may contribute to anti-inflammatory effects. A Taiwanese flavonoid content table is necessary for conducting further studies related to flavonoids in Taiwan.

Although acute psychotic symptoms are often reduced by antipsychotic treatment, many patients with schizophrenia are impaired in daily functioning due to the persistence of negative and cognitive symptoms. Raloxifene, a Selective Estrogen Receptor Modulator (SERM) has been shown to be an effective adjunctive treatment in schizophrenia. Yet, there is a paucity in evidence for raloxifene efficacy in men and premenopausal women. We report the design of a study that aims to replicate earlier findings concerning the efficacy of raloxifene augmentation in reducing persisting symptoms and cognitive impairment in postmenopausal women, and to extend these findings to a male and peri/premenopausal population of patients with schizophrenia. The study is a multisite, placebo-controlled, double-blind, randomised clinical trial in approximately 110 adult men and women with schizophrenia. Participants are randomised 1:1 to adjunctive raloxifene 120 mg or placebo daily during 12 weeks. The treatment phase includes measurements at three time points (week 0, 6 and 12), followed by a follow-up period of two years. The primary outcome measure is change in symptom severity, as measured with the Positive and Negative Syndrome Scale (PANSS), and cognition, as measured with the Brief Assessment of Cognition in Schizophrenia (BACS). Secondary outcome measures include social functioning and quality of life. Genetic, hormonal and inflammatory biomarkers are measured to assess potential associations with treatment effects. If it becomes apparent that raloxifene reduces psychotic symptoms and/or improves cognition, social functioning and/or quality of life as compared to placebo, implementation of raloxifene in clinical psychiatric practice can be considered.

Objective: This systematic review and meta-analysis aimed to evaluate whether dyslipidemia affects the mortality and severity of COVID-19, we also aimed to evaluate whether other comorbidities influence the association. Methods: A systematic literature search using PubMed, Embase, and EuropePMC was performed on 8 October 2020. This study’s main outcome is a poor composite outcome, comprising of mortality and severe COVID-19. Results: There were 9 studies with 3663 patients. The prevalence of dyslipidemia in this pooled analysis was 18% (4%-32%). Dyslipidemia was associated with increased composite poor outcome (RR 1.39 [1.02, 1.88], P = .010; I2: 56.7%, P = .018). Subgroup analysis showed that dyslipidemia was associated with severe COVID-19 (RR 1.39 [1.03, 1.87], P = .008; I2: 57.4%, P = .029). Meta-regression showed that the association between dyslipidemia and poor outcome varies by age (coefficient: −0.04, P = .033), male gender (coefficient: −0.03, P = .042), and hypertension (coefficient: −0.02, P = .033), but not diabetes (coefficient: −0.24, P = .135) and cardiovascular diseases (coefficient: −0.01, P = .506). Inverted funnel-plot was relatively symmetrical. Egger’s test indicates that the pooled analysis was not statistically significant for small-study effects ( P = .206). Conclusion: Dyslipidemia potentially increases mortality and severity of COVID-19. The association was stronger in patients with older age, male, and hypertension. PROSPERO Registration Number: CRD42020213491

Normal human cells can either synthesize cholesterol or take it up from lipoproteins to meet their metabolic requirements. In some malignant cells, de novo cholesterol synthesis genes are transcriptionally silent or mutated, meaning that cholesterol uptake from lipoproteins is required for survival. Recent data suggest that lymphoma cells dependent upon lipoprotein-mediated cholesterol uptake are also subject to ferroptosis, an oxygen- and iron-dependent cell death mechanism triggered by accumulation of oxidized lipids in cell membranes unless the lipid hydroperoxidase, glutathione peroxidase 4 (GPX4), reduces these toxic lipid species. To study mechanisms linking cholesterol uptake with ferroptosis and determine the potential role of the high-density lipoprotein (HDL) receptor as a target for cholesterol depleting therapy, we treated lymphoma cell lines known to be sensitive to the reduction of cholesterol uptake with HDL-like nanoparticles (HDL NPs). HDL NPs are a cholesterol-poor ligand that binds to the receptor for cholesterol-rich HDLs, scavenger receptor type B1 (SCARB1). Our data reveal that HDL NP treatment activates a compensatory metabolic response in treated cells toward increased de novo cholesterol synthesis, which is accompanied by nearly complete reduction in expression of GPX4. As a result, oxidized membrane lipids accumulate, leading to cell death through a mechanism consistent with ferroptosis. We obtained similar results in vivo after systemic administration of HDL NPs in mouse lymphoma xenografts and in primary samples obtained from patients with lymphoma. In summary, targeting SCARB1 with HDL NPs in cholesterol uptake–addicted lymphoma cells abolishes GPX4, resulting in cancer cell death by a mechanism consistent with ferroptosis.

We have previously shown that multimers of plasma pentraxin-3 (PTX3) were predictive of survival in patients with sepsis. To characterize the release kinetics and cellular source of plasma protein changes in sepsis, serial samples were obtained from healthy volunteers (n = 10; three time points) injected with low-dose endotoxin (lipopolysaccharide [LPS]) and analyzed using data-independent acquisition MS. The human plasma proteome response was compared with an LPS-induced endotoxemia model in mice. Proteomic analysis of human plasma revealed a rapid neutrophil degranulation signature, followed by a rise in acute phase proteins. Changes in circulating PTX3 correlated with increases in neutrophil-derived proteins following LPS injection. Time course analysis of the plasma proteome in mice showed a time-dependent increase in multimeric PTX3, alongside increases in neutrophil-derived myeloperoxidase (MPO) upon LPS treatment. The mechanisms of oxidation-induced multimerization of PTX3 were explored in two genetic mouse models: MPO global knock-out (KO) mice and LysM Cre Nox2 KO mice, in which NADPH oxidase 2 (Nox2) is only deficient in myeloid cells. Nox2 is the enzyme responsible for the oxidative burst in neutrophils. Increases in plasma multimeric PTX3 were not significantly different between wildtype and MPO or LysM Cre Nox2 KO mice. Thus, PTX3 may already be stored and released in a multimeric form. Through in vivo neutrophil depletion and multiplexed vascular proteomics, PTX3 multimer deposition within the aorta was confirmed to be neutrophil dependent. Proteomic analysis of aortas from LPS-injected mice returned PTX3 as the most upregulated protein, where multimeric PTX3 was deposited as early as 2 h post-LPS along with other neutrophil-derived proteins. In conclusion, the rise in multimeric PTX3 upon LPS injection correlates with neutrophil-related protein changes in plasma and aortas. MPO and myeloid Nox2 are not required for the multimerization of PTX3; instead, neutrophil extravasation is responsible for the LPS-induced deposition of multimeric PTX3 in the aorta., Graphical Abstract, Highlights • Multimer formation of pentraxin-3 (PTX3) has been linked to outcome in sepsis. • PTX3 plasma levels have been correlated to increases in neutrophil-derived proteins. • Neutrophil-derived myeloperoxidase and NADPH oxidase 2 are not responsible for PTX3 oxidation. • PTX3 multimer deposition within the aorta is neutrophil dependent., In Brief Circulating proteome alterations, in both humans and mice, in response to endotoxin were mapped utilizing proteomic approaches. Multimeric pentraxin-3 (PTX3) plasma and aortic levels mimicked changes observed in proteins of known neutrophil origin in response to endotoxin. Genetic mouse models ruled out myeloperoxidase and NADPH oxidase 2 as drivers of PTX3 oxidation; however, neutrophil extravasation promotes PTX3 deposition within the vasculature. The results reveal a link between the systemic inflammatory response and the neutrophil-dependent vascular deposition of multimeric PTX3.

Background Birthweight reflects in utero exposures and later health evolution. Despite existing studies employing high-dimensional molecular measurements, the understanding of underlying mechanisms of birthweight remains limited. Methods To investigate the systems biology of birthweight, we cross-sectionally integrated the methylome, the transcriptome, the metabolome and a set of inflammatory proteins measured in cord blood samples, collected from four birth-cohorts (n = 489). We focused on two sets of 68 metabolites and 903 CpGs previously related to birthweight and investigated the correlation structures existing between these two sets and all other omic features via bipartite Pearson correlations. Results This dataset revealed that the set of metabolome and methylome signatures of birthweight have seven signals in common, including three metabolites [PC(34:2), plasmalogen PC(36:4)/PC(O-36:5), and a compound with m/z of 781.0545], two CpGs (on the DHCR24 and SC4MOL gene), and two proteins (periostin and CCL22). CCL22, a macrophage-derived chemokine has not been previously identified in relation to birthweight. Since the results of the omics integration indicated the central role of cholesterol metabolism, we explored the association of cholesterol levels in cord blood with birthweight in the ENVIRONAGE cohort (n = 1097), finding that higher birthweight was associated with increased high-density lipoprotein cholesterol and that high-density lipoprotein cholesterol was lower in small versus large for gestational age newborns. Conclusions Our data suggests that an integration of different omic-layers in addition to single omics studies is a useful approach to generate new hypotheses regarding biological mechanisms. CCL22 and cholesterol metabolism in cord blood play a mechanistic role in birthweight., Highlights • Using multiple omics, we provide an unprecedented window into the biological processes underlying birthweight. • We identified molecular signals never previously linked to birthweight, e.g. gene expression of JAK3 and chemokine CCL22. • Our data suggested that cholesterol and related metabolic pathways are related to birthweight. • The identified signals may create a molecular basis for the onset of health outcomes associated with birthweight variation.

Metabolic syndrome (MS) refers to a clustering of at least three of the following medical conditions: high blood pressure, abdominal obesity, hyperglycemia, low high-density lipoprotein level, and high serum triglycerides. MS is related to a wide range of diseases which includes obesity, diabetes, insulin resistance, cardiovascular disease, dyslipidemia, or non-alcoholic fatty liver disease. There remains an ongoing need for improved treatment strategies for MS. The most important risk factors are dietary pattern, genetics, old age, lack of exercise, disrupted biology, medication usage, and excessive alcohol consumption, but pathophysiology of MS has not been completely identified. Korean Red Ginseng (KRG) refers to steamed/dried ginseng, traditionally associated with beneficial effects such as anti-inflammation, anti-fatigue, anti-obesity, anti-oxidant, and anti-cancer effects. KRG has been often used in traditional medicine to treat multiple metabolic conditions. This paper summarizes the effects of KRG in MS and related diseases such as obesity, cardiovascular disease, insulin resistance, diabetes, dyslipidemia, or non-alcoholic fatty liver disease based on experimental research and clinical studies., Graphical abstract Image 1

Visual Abstract, Highlights • This study shows that apoA-I may be an alternative strategy to improve the biocompatibility of stents. • Systemic infusions of apoA-I reduce in-stent neointimal hyperplasia in a murine model of stenting. • The cellular phenotype of the neointima post-stenting is altered by apoA-I infusions such that the smooth muscle cell phenotype is preserved, and there are fewer macrophages. • There was an increase in endothelial cell content of the arteries post-stenting in the mice infused with apoA-I, indicating an enhancement of endothelialization. • Systemic infusions of apoA-I inhibit platelet activation., Summary Even the most advanced drug-eluting stents evoke unresolved issues, including chronic inflammation, late thrombosis, and neoatherosclerosis. This highlights the need for novel strategies that improve stent biocompatibility. Our studies show that apolipoprotein A-I (apoA-I) reduces in-stent restenosis and platelet activation, and enhances endothelialization. These findings have therapeutic implications for improving stent biocompatibility.