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Background: Supernutrition of selenium (Se) in an effort to produce Se-enriched meat may inadvertently cause lipid accumulation. Se-enriched Cardamine violifolia (SeCv) contains >80% of Se in organic forms.Objectives: This study was to determine whether feeding chickens a high dose of SeCv could produce Se-biofortified muscle without altering their lipid metabolism.Methods: Day-old male broilers were allocated to 4 groups (6 cages/group and 6 chicks/cage) and were fed either a corn-soy base diet (BD, 0.13-0.15 mg Se/kg), the BD plus 0.5 mg Se/kg as sodium selenite (SeNa) or as SeCv, or the BD plus a low-Se Cardamine violifolia (Cv, 0.20-0.21mg Se/kg). At week 6, concentrations of Se and lipid and expression of selenoprotein and lipid metabolism-related genes were determined in the pectoral muscle and liver.Results: The 4 diets showed no effects on growth performance of broilers. Compared with the other 3 diets, SeCv elevated (P < 0.05) Se concentrations in the pectoral muscle and liver by 14.4-127% and decreased (P < 0.05) total cholesterol concentrations by 12.5-46.7% and/or triglyceride concentrations by 28.8-31.1% in the pectoral muscle and/or liver, respectively. Meanwhile, SeCv enhanced (P < 0.05) muscular α-linolenic acid (80.0%) and hepatic arachidonic acid (58.3%) concentrations compared with SeNa and BD, respectively. SeCv downregulated (P < 0.05) the cholesterol and triglyceride synthesis-related proteins (sterol regulatory element binding transcription factor 2 and diacylglycerol O-acyltransferase 2) and upregulated (P < 0.05) hydrolysis and β-oxidation of fatty acid-related proteins (lipoprotein lipase, fatty acid binding protein 1, and carnitine palmitoyltransferase 1A), as well as selenoprotein P1 and thioredoxin reductase activity in the pectoral muscle and/or liver compared with SeNa.Conclusions: Compared with SeNa, SeCv effectively raised Se and reduced lipids in the liver and muscle of broilers. The effect was mediated through the regulation of the cholesterol and triglyceride biosynthesis and utilization-related genes. [ABSTRACT FROM AUTHOR]

Recent studies indicated potential importance of membrane contact sites (MCS) between the endoplasmic reticulum (ER) and other cellular organelles. These MCS have unique protein and lipid composition and serve as hubs for inter-organelle communication and signaling. Despite extensive investigation of MCS protein composition and functional roles, little is known about the process of MCS formation. In this perspective, we propose a hypothesis that MCS are formed not as a result of random interactions between membranes of ER and other organelles but on the basis of pre-existing cholesterol-enriched ER microdomains. [ABSTRACT FROM AUTHOR]

Background and Purpose: Many drugs and environmental contaminants induce hypercholesterolemia and promote the risk of atherosclerotic cardiovascular disease. We tested the hypothesis that pregnane X receptor (PXR), a xenobiotic-sensing nuclear receptor, regulates the level of circulating atherogenic lipids in humans and utilized mouse experiments to identify the mechanisms involved.Experimental Approach: We performed serum NMR metabolomics in healthy volunteers administered rifampicin, a prototypical human PXR ligand or placebo in a crossover setting. We used high-fat diet fed wild-type and PXR knockout mice to investigate the mechanisms mediating the PXR-induced alterations in cholesterol homeostasis.Key Results: Activation of PXR induced cholesterogenesis both in pre-clinical and clinical settings. In human volunteers, rifampicin increased intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL) and total cholesterol and lathosterol-cholesterol ratio, a marker of cholesterol synthesis, suggesting increased cholesterol synthesis. Experiments in mice indicated that PXR activation causes widespread induction of the cholesterol synthesis genes including the rate-limiting Hmgcr and upregulates the intermediates in the Kandutsch-Russell cholesterol synthesis pathway in the liver. Additionally, PXR activation induced plasma proprotein convertase subtilisin/kexin type 9 (PCSK9), a negative regulator of hepatic LDL uptake, in both mice and humans. We propose that these effects were mediated through increased proteolytic activation of sterol regulatory element-binding protein 2 (SREBP2) in response to PXR activation.Conclusion and Implications: PXR activation induces cholesterol synthesis, elevating LDL and total cholesterol in humans. The PXR-SREBP2 pathway is a novel regulator of the cholesterol and PCSK9 synthesis and a molecular mechanism for drug- and chemical-induced hypercholesterolemia. [ABSTRACT FROM AUTHOR]

Avocado pear pulp (Persea americana) is indigenous to Mexico. It is widely cultivated and consumed all over the world. Its oil is rich in monounsaturated fatty acids (SFAs) and can be used to replace SFAs in a diet to lower low-density lipoprotein (LDL) and raise high-density lipoprotein (HDL). Consumers seek healthy foods that aid in reducing metabolic syndrome. The aim of this study is to evaluate the effects of the best acceptable cakes supplemented with 0%, 10%, 30%, and 50% avocado on the serum lipid profile and plasma protein in rats. Twenty-five rats separated into five groups of four test groups and one control group were fed individually for 14 days, after which blood samples were withdrawn and subjected to biochemical analysis. Intake of cake supplemented with avocado pear pulp resulted in significant (P < .05) increment in the body weight, total cholesterol, triglycerides and HDL, and serum protein and decrement in LDL of the rats. The group fed 50% supplemented cake showed highest increase in HDL and least decrease in LDL. Cake supplemented with 50% avocado pear pulp proved to be a better supplementation in reducing serum LDL and increasing serum HDL and serum protein in rats, indicating to be a promising nutraceutical for the management of cardiovascular diseases and its associated complications. [ABSTRACT FROM AUTHOR]

Background: We investigated the effects of spirulina under high-intensity interval training (HIIT) on levels of nesfatin-1, omentin-1, and lipid profiles in overweight and obese females. Materials and Methods: This is a randomized, quasi-experimental controlled, single-blind with a pre- and post-test design, in which twenty overweight and obese women (body mass index = 29.32 ± 3.01 kg/m2, age = 21.55 ± 1.76 years), were randomly divided into the following groups: HIIT + spirulina (n = 10) and HIIT + placebo (n = 10). Running anaerobic sprint test was used for HIIT protocol consisting of six intervals at 35 m maximal speed runs, with a rest of 10 s in each trial (3 times/week, 4 weeks). HIIT + spirulina group received 500 mg of the spirulina pills twice daily for 4 weeks and the second group took placebo. Results: There was a significant increase in serum levels of nesfatin-1 in HIIT + spirulina (P < 0.0001) but not in HIIT + placebo (P = 0.61) group. Furthermore, results indicated a significant difference between two groups with respect to serum levels of nesfatin-1 (P = 0.04). Serum levels of omentin-1 significantly increased in both groups (P < 0.05). However, there was no significant difference between two groups (P = 0.49). In addition, results showed no significant inter- and intra-group differences in total cholesterol levels, triglycerides, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol between groups (P > 0.05). Conclusion: The spirulina under HIIT increased levels of nesfatin-1 and omentin-1 with no effects on the levels of lipid profiles in overweight and obese females. [ABSTRACT FROM AUTHOR]

Background: Type 2 diabetes mellitus (T2DM) patients are predisposed to several diabetes-related complications. Dysregulation of the haemostatic mechanisms have been implicated. There are however no current studies assessing the levels and activity of protein C (PC), protein S (PS), and antithrombin III (AT III), which are essential in haemostatic regulation, in a single cohort of T2DM patients. This study evaluated the effect of poorly-managed T2DM on the levels and activity of PC, PS, and AT III. Methods: This cross-sectional study was conducted at the Diabetes Clinic, Cocoa Clinic in Kumasi, Ghana. A total of 242 T2DM patients, comprising 152 patients with poorly-managed diabetes and 90 well-managed diabetes patients, were recruited for the study. Fasting blood glucose, liver function tests and lipid profile were performed for each respondent. Glycated haemoglobin (HbA1c) was estimated by turbidimetric inhibition immunoassay. The levels and activity of PC, PS and AT III were measured by solid phase sandwich ELISA method. Results: There was a negative correlation between HbA1c and the levels and activity of PC, PS and AT III. The levels and activity of PC [(5.78 vs 4.64 μg/ml, p<0.0001) and (42.22 vs 36.21 U/ml, p = 0.01) respectively], PS [(22.55 vs 20.29 μg/ml, p = 0.010) and (235.94 vs 211.67 U/ml, p<0.0001) respectively] and AT III [(16.28 vs 14.41μg/ml, p<0.0001) and (176.01 vs 160.09 U/ml, p = 0.03) respectively] were significantly increased in patients with well-managed T2DM compared to the poorly-managed diabetes patients. Likewise, the levels and activity of PC, PS, and AT III was higher among T2DM patients using statins than patients who were statin-naïve. Among patients with well-managed T2DM, those who were on statins had significantly higher levels and activities of PC, PS, and AT III compared to well-managed T2DM patients not on statins. However, there no statistically significant differences between the level and activity of PC, PS, and AT III among poorly-managed T2DM patients with respect to statin status. Conclusion: Poorly-managed type 2 diabetes mellitus is associated with reduced levels and activity of PC, PS and AT III compared to well-managed T2DM. Though use of statins may improve the levels and activity of the PC, PS and AT III in T2DM, their effect is limited in the presence of poorly-controlled T2DM. Proper management of diabetes is essential to reduce the likelihood of thrombotic events among T2DM patients. [ABSTRACT FROM AUTHOR]

The osmotic stability of the erythrocyte membrane (OSEM) has been associated with changes in lipid profile, blood glucose and blood pressure. Changes in these parameters are very frequent in shift workers, possibly because of the lack of synchronization of biological rhythms, which results in the social jetlag. However, the existence of association between OSEM and circadian misalignment has not been investigated in this population. Therefore, this study investigated whether shift work, sleep time and social jetlag (SJL) are associated with biochemical and hematological variables. A population consisting of 79 men working at night (n = 37) or during the day (n = 42), aged between 21 and 65 years and with a mean BMI of 27.56 ± 4.0 kg/m2, was investigated cross-sectionally in relation to sleep time, SJL, anthropometric (height, weight and waist circumference) and blood variables, with emphasis on the OSEM. SJL was calculated by the absolute difference between the midpoint of sleep on work and rest days. The Generalized Linear Model (GzLM) was used to investigate the existence of associations between SJL and average sleep time in relation to the analyzed variables. Workers without SJL presented lower baseline lysis values of erythrocytes in isotonic medium in relation to workers with SJL. In addition, workers who slept on average less than 6 hours had higher OSEM, and higher total and LDL-cholesterol in relation to those who slept more than 6 hours, regardless of the shift. It is possible that the association of sleep deprivation and SJL with erythrocyte membrane stability is mediated through changes in the lipid profile. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus (EBV) causes infectious mononucleosis and is associated with multiple human malignancies. EBV drives B-cell proliferation, which contributes to the pathogenesis of multiple lymphomas. Yet, knowledge of how EBV subverts host biosynthetic pathways to transform resting lymphocytes into activated lymphoblasts remains incomplete. Using a temporal proteomic dataset of EBV primary human B-cell infection, we identified that cholesterol and fatty acid biosynthetic pathways were amongst the most highly EBV induced. Epstein-Barr nuclear antigen 2 (EBNA2), sterol response element binding protein (SREBP) and MYC each had important roles in cholesterol and fatty acid pathway induction. Unexpectedly, HMG-CoA reductase inhibitor chemical epistasis experiments revealed that mevalonate pathway production of geranylgeranyl pyrophosphate (GGPP), rather than cholesterol, was necessary for EBV-driven B-cell outgrowth, perhaps because EBV upregulated the low-density lipoprotein receptor in newly infected cells for cholesterol uptake. Chemical and CRISPR genetic analyses highlighted downstream GGPP roles in EBV-infected cell small G protein Rab activation. Rab13 was highly EBV-induced in an EBNA3-dependent manner and served as a chaperone critical for latent membrane protein (LMP) 1 and 2A trafficking and target gene activation in newly infected and in lymphoblastoid B-cells. Collectively, these studies identify highlight multiple potential therapeutic targets for prevention of EBV-transformed B-cell growth and survival. [ABSTRACT FROM AUTHOR]

Background: Frequency of insulin pen use, despite its higher costs, is increasing to substitute the traditional use of insulin vials. This study aims to report insulin pen use frequency and its associated factors among participants of the STEPS survey 2016 in Iran, which was conducted based on the World Health Organization (WHO) STEPS methodology. Methods: In this cross-sectional study, 19,503 (mean age of 46.03±0.13) out of 30,541 participants of the Iran STEPS survey were included (Inclusion criteria: aged >25 years old and availability of their demographic, clinical, and laboratory results for serum glucose, HbA1c, and lipid profile). Clinical and demographic characteristics, a frequency of use of each diabetes mellitus treatment type, and the association of insulin pen use with health outcomes are reported using descriptive analysis and propensity score modeling. Results: There were 1,999(10.85%) individuals diagnosed with diabetes in the population, while 1,160(56.87%) cases were taking antihyperglycemic treatments. In this subset, 240(21.14%) individuals administered insulin with or without using oral agents at the same time. 52.28% of participants who were under insulin therapy used insulin pens. None of the socioeconomic determinants, including gender (p-value = 0.11), type of residential areas (p-value = 0.52), years of schooling (p-value = 0.27), wealth index (p-value = 0.19), marital status (p-value = 0.37), and insurance types (p-value = 0.72) were significantly different among groups using insulin pens and insulin vials. Moreover, in the propensity score modeling, pen usage was not associated with a lower heart attack and ischemic stroke histories, systolic blood pressure, serum lipid profile, blood glucose, or HbA1c levels. Conclusion: Results showed that the use of the higher-costing insulin pens compared to traditional vials and syringes is not associated with improved glycemic control and better lipid profile in our sample. Future studies are needed to confirm these findings and to compare other aspects of insulin pen use, including adherence to treatment and cost-effectiveness. [ABSTRACT FROM AUTHOR]

Objective: Previous studies indicate a role for Oncostatin M (OSM) in atherosclerosis and other chronic inflammatory diseases for which inhibitory antibodies are in development. However, to date no intervention studies with OSM have been performed, and its relation to coronary heart disease (CHD) has not been studied. Approach and results: Gene expression analysis on human normal arteries (n = 10) and late stage/advanced carotid atherosclerotic arteries (n = 127) and in situ hybridization on early human plaques (n = 9) showed that OSM, and its receptors, OSM receptor (OSMR) and Leukemia Inhibitory Factor Receptor (LIFR) are expressed in normal arteries and atherosclerotic plaques. Chronic OSM administration in APOE*3Leiden.CETP mice (n = 15/group) increased plasma E-selectin levels and monocyte adhesion to the activated endothelium independently of cholesterol but reduced the amount of inflammatory Ly-6CHigh monocytes and atherosclerotic lesion size and severity. Using aptamer-based proteomics profiling assays high circulating OSM levels were shown to correlate with post incident CHD survival probability in the AGES-Reykjavik study (n = 5457). Conclusions: Chronic OSM administration in APOE*3Leiden.CETP mice reduced atherosclerosis development. In line, higher serum OSM levels were correlated with improved post incident CHD survival probability in patients, suggesting a protective cardiovascular effect. [ABSTRACT FROM AUTHOR]

Gene set analysis (GSA) has become the common methodology for analyzing transcriptomics data. However, self-contained GSA techniques are rarely, if ever, used for proteomics data analysis. Here we present a self-contained proteome level GSA of four consensus molecular subtypes (CMSs) previously established by transcriptome dissection of colon carcinoma specimens. Despite notable difference in structure of proteomics and transcriptomics data, many pathway-wide characteristic features of CMSs found at the mRNA level were reproduced at the protein level. In particular, CMS1 features show heavy involvement of immune system as well as the pathways related to mismatch repair, DNA replication and functioning of proteasome, while CMS4 tumors upregulate complement pathway and proteins participating in epithelial-to-mesenchymal transition (EMT). In addition, protein level GSA yielded a set of novel observations visible at the proteome, but not at the transcriptome level, including possible involvement of major histocompatibility complex II (MHC-II) antigens in the known immunogenicity of CMS1 and a connection between cholesterol trafficking and the regulation of Integrin-linked kinase (ILK) in CMS3. Overall, this study proves utility of self-contained GSA approaches as a critical tool for analyzing proteomics data in general and dissecting protein-level molecular portraits of human tumors in particular. [ABSTRACT FROM AUTHOR]

Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a hepatic enzyme that regulates circulating low-density lipoprotein (LDL) cholesterol levels by binding to LDL receptors (LDLR) and promoting their degradation. Although PCSK9 inhibitors were shown to reduce the risk of cardiovascular disease, a warning was issued concerning their possible impact on cognitive functions. In Alzheimer’s disease (AD), it is believed that cognitive impairment is associated with cholesterol metabolism alterations, which could involve PCSK9. The main objective of this study is to determine if PCSK9 plays a significant role in the pre-symptomatic phase of the disease when the pathophysiological markers of AD unfolds and, later, when cognitive symptoms emerge. Methods and findings: To test if PCSK9 is associated with AD pathology, we measured its expression levels in 65 autopsy confirmed AD brains and 45 age and gender matched controls. Messenger ribonucleic acid (mRNA) were quantified using real-time polymerase chain reaction (RT-PCR) and protein levels were quantified using enzyme-linked immunosorbent assay (ELISA). PCSK9 was elevated in frontal cortices of AD subjects compared to controls, both at the mRNA and protein levels. LDLR protein levels were unchanged in AD frontal cortices, despite and upregulation at the mRNA level. To verify if PCSK9 dysregulation was observable before the onset of AD, we measured its expression in the cerebrospinal fluid (CSF) of 104 “at-risk” subjects and contrasted it with known apolipoproteins levels and specific AD biomarkers using ELISAs. Positive correlations were found between CSF PCSK9 and apolipoprotein E (APOE), apolipoprotein J (APOJ or CLU), apolipoprotein B (APOB), phospho Tau (pTau) and total Tau. To investigate if PCSK9 levels were driven by genetic variants, we conducted an expression quantitative trait loci (eQTL) study using bioinformatic tools and found two polymorphisms in strong association. Further investigation of these variants in two independent cohorts showed a female specific association with AD risk and with CSF Tau levels in cognitively impaired individuals. Conclusions: PCSK9 levels differ between control and AD brains and its protein levels correlate with those of other lipoproteins and AD biomarkers even before the onset of the disease. PCSK9 regulation seems to be under tight genetic control in females only, with specific variants that could predispose to increased AD risk. [ABSTRACT FROM AUTHOR]

Objective: To investigate cardiometabolic risk factor levels in a group of Norwegian 10-year-old children compared to international values and examine the association between cardiorespiratory fitness (CRF) and the reference-standardized clustered risk score. Methods: 913 children (49% girls) were included from the Active Smarter Kids (ASK) study. Body mass index (BMI), waist circumference (WC), systolic blood pressure (SBP), diastolic blood pressure (DBP), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC) to HDL-C ratio, triglyceride (TG), glucose, insulin, homeostatic model assessment (HOMA) score and CRF, were standardized according to international age-and sex-specific reference values. Results: The Norwegian children had significantly more favorable WC, DBP, glucose, HDL-C and CRF levels compared to the international reference values, but similar or less favorable levels of other cardiometabolic risk factors. CRF was the variable that differed the most from the international values (mean (95% CI) 1.20 (1.16 to 1.24) SD). The clustered risk score (excluding CRF) was higher in the Norwegian children, but decreased to below international levels when including CRF (mean (95% CI) - 0.08 (- 0.12 to –0.05) SD). CRF had a significant inverse association with the clustered risk score (excluding CRF) (β - 0.37 SD, 95% CI –0.43 to –0.31). Conclusions: Norwegian children have substantially higher CRF levels than international standards, and including CRF in clustered risk scores reduces overall risk in Norwegian children below that of international levels. CRF is associated with improved cardiometabolic health in children. [ABSTRACT FROM AUTHOR]

The glucagon-like peptide-1 receptor (GLP-1R), a key pharmacological target in type 2 diabetes (T2D) and obesity, undergoes rapid endocytosis after stimulation by endogenous and therapeutic agonists. We have previously highlighted the relevance of this process in fine-tuning GLP-1R responses in pancreatic beta cells to control insulin secretion. In the present study, we demonstrate an important role for the translocation of active GLP-1Rs into liquid-ordered plasma membrane nanodomains, which act as hotspots for optimal coordination of intracellular signaling and clathrin-mediated endocytosis. This process is dynamically regulated by agonist binding through palmitoylation of the GLP-1R at its carboxyl-terminal tail. Biased GLP-1R agonists and small molecule allosteric modulation both influence GLP-1R palmitoylation, clustering, nanodomain signaling, and internalization. Downstream effects on insulin secretion from pancreatic beta cells indicate that these processes are relevant to GLP-1R physiological actions and might be therapeutically targetable. [ABSTRACT FROM AUTHOR]

Background: Extra-gastric manifestation of Helicobacter pylori infection involves systemic inflammation, which results in the production of several cytokines. Only a few clinical trials have investigated the effect of H. pylori eradication therapy on lipid metabolism in the infected patients with chronic gastritis. We aimed to evaluate the effect of H. pylori eradication therapy on lipid metabolism in a Japanese population with chronic gastritis. Methods: One hundred and sixty-three patients with H. pylori-associated chronic gastritis were enrolled in this study between June 2015 and March 2017. They underwent H. pylori eradication therapy; the effects of the therapy were assessed by the urea breath test performed at least 4 weeks after the therapy. After confirming H. pylori eradication, the health screening examination was repeated between May 2016 and August 2018. The clinical parameters were compared before and after the administration of the eradication therapy. Results: The mean age of the enrolled patients was 56.7 years, and the mean follow-up duration was 514.7 days. Weight, body mass index, and obesity index were significantly increased post-eradication therapy compared to those pre-eradication therapy. White blood cell and platelet counts were significantly decreased, and high density lipoprotein cholesterol (HDL) level was significantly increased (P = 0.001), while low density lipoprotein cholesterol (LDL), total cholesterol, and triglycerides levels were not altered significantly. Hence, the LDL/HDL ratio was significantly decreased. Conclusions: This study reported that H. pylori eradication therapy increase the HDL levels in the infected patients with chronic gastritis. Hence, the LDL/HDL ratio, which is used to evaluate the risk of atherosclerosis, was significantly decreased post-eradication therapy compared to that pre-eradication therapy. [ABSTRACT FROM AUTHOR]

Background: In Asian countries, many patients with type 2 diabetes fail to achieve controlled glycated hemoglobin (HbA1c) levels while taking several classes of oral hypoglycemic agents (OHAs). Traditional Chinese medicine could be an alternative therapeutic option for poorly controlled type 2 diabetes. YH1 is a concentrated Chinese herbal extract formula that combines Rhizoma Coptidis and Shen-Ling-Bai-Zhu-San. This randomized, double-blind, placebo-controlled pilot study evaluated YH1 as an add-on medication for poorly controlled type 2 diabetes. Methods: Forty-six patients with poorly controlled type 2 diabetes were randomly assigned 1:1 to the YH1 or placebo group. Before the trial, all subjects had received three or more classes of OHAs with HbA1c > 7.0% (53 mmol/mol) and a body mass index ≥ 23 kg/m2. During the 12-week trial, participants continued to take OHAs without any dose or medication changes. The primary endpoint was the percentage change in HbA1c level. Per-protocol analysis was applied to the final evaluation. Results: At week 12, there was an 11.1% reduction in HbA1c from baseline and a 68.9% increase in homeostatic model assessment (HOMA) of β cell function in the YH1 group, which also exhibited significant reductions in two-hour postprandial glucose (-26.2%), triglycerides (-29.5%), total cholesterol (-21.6%), low-density lipoprotein cholesterol (-17.4%), body weight (-0.5%), and waist circumference (-1.1%). The changes in fasting plasma glucose, HOMA insulin resistance and symptom scores were not significantly different between the YH1 and placebo groups. No serious adverse events occurred during this clinical trial. Conclusions: This pilot study indicates that YH1 together with OHAs can improve hypoglycemic action and β-cell function in overweight/obese patients with poorly controlled type 2 diabetes. YH1 is a safe add-on medication for OHAs and has beneficial effects on weight control and lipid metabolism. A larger study population with longer treatment and follow-up periods is required for further verification. [ABSTRACT FROM AUTHOR]

There is no cure or beneficial management option for Limb-Girdle muscular dystrophy (MD) type 2B (LGMD2B). Losartan, a blood pressure (BP) lowering angiotensin II (AngII) receptor type 1 (ATR1) blocker (ARB) with unique anti-transforming growth factor-β (TGF-β) properties, can protect muscles in various types of MD such as Duchenne MD, suggesting a potential benefit for LGMD2B patients. Herein, we show in a mild, dysferlin-null mouse model of LGMD2B that losartan increased quadriceps muscle fibrosis (142%; P<0.0001). In a severe, atherogenic diet-fed model of LGMD2B recently described by our group, losartan further exacerbated dysferlin-null mouse muscle wasting in quadriceps and triceps brachii, two muscles typically affected by LGMD2B, by 40% and 51%, respectively (P<0.05). Lower TGF-β signalling was not observed with losartan, therefore plasma levels of atherogenic lipids known to aggravate LGMD2B severity were investigated. We report that losartan increased both plasma triglycerides and cholesterol concentrations in dysferlin-null mice. Other protective properties of losartan, such as increased nitric oxide release and BP lowering, were also reduced in the absence of dysferlin expression. Our data suggest that LGMD2B patients may show some resistance to the primary BP-lowering effects of losartan along with accelerated muscle wasting and dyslipidemia. Hence, we urge caution on the use of ARBs in this population as their ATR1 pathway may be dysfunctional. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD) is featured by increased plasma very low density lipoproteins (VLDL). The extent to which plasma apolipoprotein E (ApoE) levels are elevated in NAFLD is unclear. We determined whether plasma ApoE is elevated in subjects with suspected NAFLD. Plasma ApoE and genotypes were determined in 6,762 participants of the Prevention of Renal and Vascular End-Stage Disease (PREVEND) cohort. A Fatty Liver Index (FLI) ≥ 60 was used as a proxy of NAFLD. A total of 1,834 participants had a FLI ≥ 60, which coincided with increased triglycerides, non-HDL cholesterol, ApoB and ApoE (all P<0.001). In multivariable linear regression analysis, plasma ApoE levels were positively associated with an elevated FLI when taking account of ApoE genotypes and other clinical and laboratory covariates (fully adjusted model: β = 0.201, P<0.001). Stratified analysis for ApoE genotypes (ApoE ε3ε3 homozygotes, ApoE ε2 carriers, and ApoE ε3ε4 and ε4ε4 carriers combined), also showed positive associations of plasma ApoE levels with an elevated FLI in each group (all P<0.001). In conclusion, it is suggested that NAFLD is characterized by increased plasma ApoE levels, even when taking account of the various ApoE genotypes. Increased plasma ApoE may contribute to altered VLDL metabolism and to increased atherosclerosis susceptibility in NAFLD. [ABSTRACT FROM AUTHOR]

Background: Low-grade albuminuria has been considered a predictor of cardiovascular mortality. We investigated the relationship between high-normal albuminuria and subclinical atherosclerosis in non-diabetic men with estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2. Methods: In this cross-sectional study, 1,756 men with eGFR ≥60 mL/min/1.73 m2 and urine albumin-to-creatinine ratio (UACR) <30 mg/g, who attended general health checkups between April 2012 and March 2015, underwent blood sampling, urinalysis, and carotid ultrasonography. We excluded the subjects who were diabetic and/or received an anti-hypertensive drug. Carotid intima-media thickness (IMT) and the number of focal atheromatous plaques were used as indicators of subclinical atherosclerosis. Multiple linear regression analysis was performed to identify clinical factors associated with carotid IMT. Poisson regression analysis was used to assess the determinants of the carotid plaque number. Results: Median UACR was 4.8 mg/g (interquartile range, 3.6–6.9 mg/g). Compared with subjects with low-normal UACR (<10.0 mg/g), subjects with high-normal UACR (10.0–29.8 mg/g) had greater IMT and higher carotid plaque number. High-normal UACR was independently associated with thickened IMT in the model adjusted for conventional cardiovascular disease risk factors. Moreover, participants with high-normal UACR were also more likely to be associated with increased plaque count (prevalence ratio: 1.06; 95% confidence interval: 1.01–1.14) after adjustment for conventional cardiovascular disease risk factors. Conclusions: Our results indicate that high-normal albuminuria is associated with both carotid IMT and plaque formation in the non-diabetic male population with eGFR ≥60 mL/min/1.73 m2. [ABSTRACT FROM AUTHOR]

We aimed to investigate the clinical factors affecting the therapeutic effectiveness of the sodium–glucose cotransporter-2 inhibitor empagliflozin in patients with type 2 diabetes mellitus (T2DM). We reviewed the medical records of 374 T2DM patients aged between 20 and 75 years who were prescribed empagliflozin 10 mg or 25 mg as add-on therapy for more than 90 consecutive days. Changes in hemoglobin A1c (HbA1c) from baseline levels and the reduction in body weights of the study participants were assessed. We found that younger patients (≤ 50 years), patients with the highest levels of HbA1c (>9%) at baseline, patients with an estimated glomerular filtration rate (eGFR) of >90 mL/min/1.73 m2, and patients with a shorter duration of T2DM (< 10 years) were more likely to exhibit a better glycemic response. Multivariate linear regression analysis revealed that a shorter duration of T2DM, higher baseline levels of HbA1c, and higher eGFR were positively associated with HbA1c reduction. Higher BMI and lower HbA1c levels were predictors of a more significant reduction in body weight among patients taking empagliflozin. The glucose-lowering effect of empagliflozin was more evident in T2DM patients with higher baseline HbA1c levels, better renal function, and shorter duration of T2DM. [ABSTRACT FROM AUTHOR]

Background: The complement system is involved in pathogenesis of cardiovascular disease, and might play a role in accelerated atherogenesis in spondylarthropathies (SpA). Hence, we examined complement activation in SpA, and its relationship to antirheumatic treatment, inflammatory and cardiovascular markers. Methods: From PSARA, a prospective observational study, we examined 51 SpA patients (31 psoriatic arthritis (PsA), and 20 ankylosing spondylitis (AS)), starting tumor necrosis factor (TNF) inhibitor alone (n = 25), combined with methotrexate (MTX) (n = 10), or MTX monotherapy (n = 16). Complement activation was determined by the soluble terminal complement complex (sC5b-9), inflammation by erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), and endothelial function by finger plethysmography (Endopat) at baseline, after 6 weeks and 6 months of treatment. Results: SpA patients had sC5b-9 levels at (PsA) or above (AS) the upper limit of the estimated reference range. Median sC5b-9 levels decreased significantly from baseline to 6 weeks, with no significant difference between the AS and PsA group. Notably, a significant reduction in sC5b-9 was observed after administration of TNF inhibitor ± MTX, whereas no significant changes were observed in patients treated with MTX alone. Between 6 weeks and 6 months, sC5b-9 remained stable across all subgroups. Reduction in sC5b-9 was independently related to decreased ESR and CRP, and to increased high density cholesterol and total cholesterol. Reduction in sC5b-9 from baseline to 6 weeks was associated with improved EF in age and gender adjusted analyses. Conclusion: TNF-inhibition, but not MTX monotherapy, led to rapid and sustained reduction of complement activation in SpA. Thus, the observed decrease in cardiovascular morbidity in patients treated with TNF-inhibitors might be partly due to its beneficial effect on complement. Trial registration: Clinical Trials (), retrospectively registered on the 14th of May 2009. [ABSTRACT FROM AUTHOR]

Schnyder corneal dystrophy (SCD) is a rare genetic eye disease characterized by corneal opacification resulted from deposition of excess free cholesterol. UbiA prenyltransferase domain-containing protein-1 (UBIAD1) is an enzyme catalyzing biosynthesis of coenzyme Q10 and vitamin K2. More than 20 UBIAD1 mutations have been found to associate with human SCD. How these mutants contribute to SCD development is not fully understood. Here, we identified HMGCR as a binding partner of UBIAD1 using mass spectrometry. In contrast to the Golgi localization of wild-type UBIAD1, SCD-associated mutants mainly resided in the endoplasmic reticulum (ER) and competed with Insig-1 for HMGCR binding, thereby preventing HMGCR from degradation and increasing cholesterol biosynthesis. The heterozygous Ubiad1 G184R knock-in (Ubiad1G184R/+) mice expressed elevated levels of HMGCR protein in various tissues. The aged Ubiad1G184R/+ mice exhibited corneal opacification and free cholesterol accumulation, phenocopying clinical manifestations of SCD patients. In summary, these results demonstrate that SCD-associated mutations of UBIAD1 impair its ER-to-Golgi transportation and enhance its interaction with HMGCR. The stabilization of HMGCR by UBIAD1 increases cholesterol biosynthesis and eventually causes cholesterol accumulation in the cornea. [ABSTRACT FROM AUTHOR]

Background: Childhood obesity is a world-wide concern due to its growing prevalence and association with cardiometabolic risk factors in childhood and subsequent adult cardiovascular disease. In young pre-school children, there is uncertainty regarding which of the commonly used anthropometric measures of childhood obesity is best associated with cardiometabolic risk factors. This study compared the utility of common measures used in identifying obesity in these young children. Methods: The four commonly used metrics for identifying obesity in children: body fat percentage ≥ 90th percentile, waist circumference ≥ 90th percentile, BMI z score > 2 SD and waist-to-height ratio (WHtR) ≥ 0.5, were measured in a cohort of children born singleton, at full term and followed from birth (n = 761) to 5 years of age (n = 513). The utility of each in identifying cardiometabolic risk factors (fasting lipid profile, fasting blood glucose and blood pressure) was examined. Results: At age 5 years, children with percent body fat ≥ 90th percentile or waist circumference ≥ 90th percentile, were associated with higher levels of triglycerides, glucose, and systolic and diastolic blood pressures than those < 90th percentile, respectively. Such differences were not obvious at age 3 years or at birth. A BMI z-score > 2 SD was associated with higher levels of triglycerides and systolic and diastolic blood pressure but not glucose at age 5 years. Differences in HDL cholesterol, fasting glucose and systolic blood pressure were observed in children with BMI z score > 2 SD at age 3 years but not with the other indices of obesity. As almost all children had WHtR ≥ 0.5 at birth, ages 1 and 3 years, this measure could not differentiate increased cardiometabolic risk. At age 5 years, the differences were much more obvious, with significant differences in triglycerides and systolic and diastolic blood pressures between those with WHtR ≥ 0.5 and those with < 0.5. Conclusion: Each of the four commonly used measures of childhood obesity shows moderate associations with cardiometabolic risk factors at 5 years, with no advantage of one measure over the other. These associations were less consistent at 3 years of age or younger. These observations have not been reported previously. [ABSTRACT FROM AUTHOR]

Background: The incidence of type 2 diabetes (T2DM) in children has increased dramatically. However, limited published information is known about the glycemic control and lipid outcomes in pediatric T2DM outside of clinical trials. Objectives: To determine the glycemic control and lipid measure outcomes at one and three- year follow-up in children with T2DM. Methods: A retrospective electronic medical record review of children with T2DM at the Children’s Hospital of Alabama over a 12-year period. Results: There were 301 patients with a diagnosis of T2DM who had a 1-year follow-up visit, of which 184 also had a 3-year follow-up. Most patients (78%) received either insulin with metformin or insulin alone at diagnosis. At one year, 37% of the cohort achieved ‘optimal glycemic control’ (HbA1C ≤6.5%) and 58% of patients achieved durable glycemic control (HbA1C ≤8%). Optimal glycemic control was seen in 48 patients at 3 years. The patients treated with insulin (alone or in combination with metformin) tended to have higher HbA1C at diagnosis, but had improved lipid and glycemic outcomes at follow-up. The group treated with insulin along with metformin had significant improvements in non-HDL, HDL and TC/HDL ratios. The effects of insulin treatment on glycemic control at 3 years were not statistically significant. Conclusion: With the current modality of treatment, only a minority of patients achieve optimal glycemic control at 1 and 3 years of follow-up. Studies are warranted to further elucidate the optimal therapies in the management of pediatric T2DM. [ABSTRACT FROM AUTHOR]

Background: High-density lipoprotein (HDL) functionality and low-density lipoprotein (LDL) atherogenic traits can describe the role of both particles on cardiovascular diseases more accurately than HDL- or LDL-cholesterol levels. However, it is unclear how these lipoprotein properties are particularly affected by different cardiovascular risk factors. Objective: To determine which lipoprotein properties are associated with greater cardiovascular risk scores and each cardiovascular risk factor. Methods: In two cross-sectional baseline samples of PREDIMED trial volunteers, we assessed the associations of HDL functionality (N = 296) and LDL atherogenicity traits (N = 210) with: 1) the 10-year predicted coronary risk (according to the Framingham-REGICOR score), and 2) classical cardiovascular risk factors. Results: Greater cardiovascular risk scores were associated with low cholesterol efflux values; oxidized, triglyceride-rich, small HDL particles; and small LDLs with low resistance against oxidation (P-trend<0.05, all). After adjusting for the rest of risk factors; 1) type-2 diabetic individuals presented smaller and more oxidized LDLs (P<0.026, all); 2) dyslipidemic participants had smaller HDLs with an impaired capacity to metabolize cholesterol (P<0.035, all); 3) high body mass index values were associated to lower HDL and LDL size and a lower HDL capacity to esterify cholesterol (P<0.037, all); 4) men presented a greater HDL oxidation and lower HDL vasodilatory capacity (P<0.046, all); and 5) greater ages were related to small, oxidized, cytotoxic LDL particles (P<0.037, all). Conclusions: Dysfunctional HDL and atherogenic LDL particles are present in high cardiovascular risk patients. Dyslipidemia and male sex are predominantly linked to HDL dysfunctionality, whilst diabetes and advanced age are associated with LDL atherogenicity. [ABSTRACT FROM AUTHOR]

The regulation of cholesterol, an essential brain lipid, ensures proper neuronal development and function, as demonstrated by links between perturbations of cholesterol metabolism and neurodegenerative diseases, including Alzheimer’s disease. The central nervous system (CNS) acquires cholesterol via de novo synthesis, where glial cells provide cholesterol to neurons. Both lipoproteins and lipoprotein receptors are key elements in this intercellular transport, where the latter recognize, bind and endocytose cholesterol containing glia-produced lipoproteins. CNS lipoprotein receptors are like those in the periphery, among which include the ApoB, E binding lipolysis stimulated lipoprotein receptor (LSR). LSR is a multimeric protein complex that has multiple isoforms including α and α’, which are seen as a doublet at 68 kDa, and β at 56 kDa. While complete inactivation of murine lsr gene is embryonic lethal, studies on lsr +/- mice revealed altered brain cholesterol distribution and cognitive functions. In the present study, LSR profiling in different CNS regions revealed regiospecific expression of LSR at both RNA and protein levels. At the RNA level, the hippocampus, hypothalamus, cerebellum, and olfactory bulb, all showed high levels of total lsr compared to whole brain tissues, whereas at the protein level, only the hypothalamus, olfactory bulb, and retina showed the highest levels of total LSR. Interestingly, major regional changes in LSR expression were observed in aged mice which suggests changes in cholesterol homeostasis in specific structures in the aging brain. Immunocytostaining of primary cultures of mature murine neurons and glial cells isolated from different CNS regions showed that LSR is expressed in both neurons and glial cells. However, lsr RNA expression in the cerebellum was predominantly higher in glial cells, which was confirmed by the immunocytostaining profile of cerebellar neurons and glia. Based on this observation, we would propose that LSR in glial cells may play a key role in glia-neuron cross talk, particularly in the feedback control of cholesterol synthesis to avoid cholesterol overload in neurons and to maintain proper functioning of the brain throughout life. [ABSTRACT FROM AUTHOR]

Background: There is ongoing debate about whether education or socioeconomic status (SES) should be inputs into cardiovascular disease (CVD) prediction algorithms and clinical risk adjustment models. It is also unclear whether intervening on education will affect CVD, in part because there is controversy regarding whether education is a determinant of CVD or merely correlated due to confounding or reverse causation. We took advantage of a natural experiment to estimate the population-level effects of educational attainment on CVD and related risk factors.Methods and Findings: We took advantage of variation in United States state-level compulsory schooling laws (CSLs), a natural experiment that was associated with geographic and temporal differences in the minimum number of years that children were required to attend school. We linked census data on educational attainment (N = approximately 5.4 million) during childhood with outcomes in adulthood, using cohort data from the 1992-2012 waves of the Health and Retirement Study (HRS; N = 30,853) and serial cross-sectional data from 1971-2012 waves of the National Health and Nutrition Examination Survey (NHANES; N = 44,732). We examined self-reported CVD outcomes and related risk factors, as well as relevant serum biomarkers. Using instrumental variables (IV) analysis, we found that increased educational attainment was associated with reduced smoking (HRS β -0.036, 95%CI: -0.06, -0.02, p < 0.01; NHANES β -0.032, 95%CI: -0.05, -0.02, p < 0.01), depression (HRS β -0.049, 95%CI: -0.07, -0.03, p < 0.01), triglycerides (NHANES β -0.039, 95%CI: -0.06, -0.01, p < 0.01), and heart disease (HRS β -0.025, 95%CI: -0.04, -0.002, p = 0.01), and improvements in high-density lipoprotein (HDL) cholesterol (HRS β 1.50, 95%CI: 0.34, 2.49, p < 0.01; NHANES β 0.86, 95%CI: 0.32, 1.48, p < 0.01), but increased BMI (HRS β 0.20, 95%CI: 0.002, 0.40, p = 0.05; NHANES β 0.13, 95%CI: 0.01, 0.32, p = 0.05) and total cholesterol (HRS β 2.73, 95%CI: 0.09, 4.97, p = 0.03). While most findings were cross-validated across both data sets, they were not robust to the inclusion of state fixed effects. Limitations included residual confounding, use of self-reported outcomes for some analyses, and possibly limited generalizability to more recent cohorts.Conclusions: This study provides rigorous population-level estimates of the association of educational attainment with CVD. These findings may guide future implementation of interventions to address the social determinants of CVD and strengthen the argument for including educational attainment in prediction algorithms and primary prevention guidelines for CVD. [ABSTRACT FROM AUTHOR]

Protein kinase B (AKT) is a serine/threonine kinase that functions as an important downstream effector of phosphoinositide 3-kinase. We have recently shown that MK-2206 and triciribine, two highly selective AKT inhibitors increase the level of low density lipoprotein receptor (LDLR) mRNA which leads to increased amount of cell-surface LDLRs. However, whereas MK-2206 induces transcription of the LDLR gene, triciribine stabilizes LDLR mRNA, raising the possibility that the two inhibitors may actually affect other kinases than AKT. In this study, we aimed to ascertain the role of AKT in regulation of LDLR mRNA expression by examining the effect of five additional AKT inhibitors on LDLR mRNA levels. Here we show that in cultured HepG2 cells, AKT inhibitors ARQ-092, AKT inhibitor VIII, perifosine, AT7867 and CCT128930 increase LDLR mRNA levels by inducing the activity of LDLR promoter. CCT128930 also increased the stability of LDLR mRNA. To study the role of AKT isoforms on LDLR mRNA levels, we examined the effect of siRNA-mediated knockdown of AKT1 or AKT2 on LDLR promoter activity and LDLR mRNA stability. Whereas knockdown of either AKT1 or AKT2 led to upregulation of LDLR promoter activity, only knockdown of AKT2 had a stabilizing effect on LDLR mRNA. Taken together, these results provide strong evidence for involvement of AKT in regulation of LDLR mRNA expression, and point towards the AKT isoform specificity for upregulation of LDLR mRNA expression. [ABSTRACT FROM AUTHOR]

This study investigated how camp management and tourist activities affect body condition, adrenocortical function, lipid profiles and metabolic status in female tourist elephants. We compared twice monthly serum insulin, glucose, fructosamine, total cholesterol (TC), triglyceride (TG), low density lipoprotein (LDL), high density lipoprotein (HDL), and fecal glucocorticoid metabolite (FGM) concentrations to body condition scores (BCS) at five camps with different management styles (e.g., tourist activities, work type, diet) between the High (November–February) and Low (March–October) tourist seasons. There were significant camp effects on health parameters, with BCS, TC, HDL, insulin and glucose being among the highest, and G:I being the lowest (less heathy) in elephants at an observation camp compared to those at camps where elephants received exercise by providing rides to tourists. Differences between High and Low tourist season months also were found for all measures, except TG and FGM concentrations. Both work time and walking distance were negatively correlated to glucose, fructosamine and insulin, while walking distance was negatively related to FGM concentrations. By contrast, positive associations were found between tourist number and BCS, TG, and insulin, perhaps related to tourists feeding elephants. Quantity of supplementary diet items (e.g., bananas, sugar cane, pumpkin) were positively correlated with FGM concentrations, glucose, fructosamine, and insulin. This study provides evidence that body condition, adrenal activity, metabolic markers, and lipid profiles in captive elephants may be affected by visitor numbers, work activities, and the amount of supplementary foods offered by tourists. Some activities appear to have negative (e.g., feeding), while others (e.g., exercise) may have positive effects on health and welfare. We conclude that camps adopting a more hands-off approach to tourism need to ensure elephants remain healthy by providing environments that encourage activity and rely on more natural diets or foraging. [ABSTRACT FROM AUTHOR]

G protein-coupled receptors (GPCRs) control cellular signaling and responses. Many of these GPCRs are modulated by cholesterol and polyunsaturated fatty acids (PUFAs) which have been shown to co-exist with saturated lipids in ordered membrane domains. However, the lipid compositions of such domains extracted from the brain cortex tissue of individuals suffering from GPCR-associated neurological disorders show drastically lowered levels of PUFAs. Here, using free energy techniques and multiscale simulations of numerous membrane proteins, we show that the presence of the PUFA DHA helps helical multi-pass proteins such as GPCRs partition into ordered membrane domains. The mechanism is based on hybrid lipids, whose PUFA chains coat the rough protein surface, while the saturated chains face the raft environment, thus minimizing perturbations therein. Our findings suggest that the reduction of GPCR partitioning to their native ordered environments due to PUFA depletion might affect the function of these receptors in numerous neurodegenerative diseases, where the membrane PUFA levels in the brain are decreased. We hope that this work inspires experimental studies on the connection between membrane PUFA levels and GPCR signaling. [ABSTRACT FROM AUTHOR]

Context: While the role of overt hypothyroidism in lipid disorders is clear, the association between dyslipidemia and subclinical thyroid diseases remains unclarified. Objective: To examine lipid trends based on thyroid function over a 10-year period. Design: This is a prospective population based cohort study. Setting: General community. Participants: 2383 euthyroid participants, as well as those with subclinical thyroid diseases, in all residents of district 13 of Tehran were examined. Subjects who were on levothyroxine, anti-hyperthyroid drugs, and glucocorticoids, those with a history of thyroid surgery or RAI and pregnant women were excluded. Main outcome measures: Lipid trends in Model 1 were adjusted for age and follow up duration, and in Model 2 gender-specific multivariate adjustments were performed for thyroid status, diabetes mellitus, smoking status, education, BMI, lipid lowering medications, age and follow up duration by using generalized estimating equations. Results: In every four years of assessments, there were significant decreases in levels of all lipid parameters (all Ps <0.001) except for HDL-C, in which a decrescendo-crescendo trend was observed. The results did not change after adjusting for thyroid status, consumption of lipid lowering drugs during the follow-up period, or other variables. There were significant decreases in the prevalence of hypercholesterolemia and hypertriglyceridemia (all Ps <0.001) during the follow-up period. Conclusion: During a 10 year follow-up, decrescendo trends were observed in levels of total cholesterol, triglycerides, which were not be accounted for by the consumption of lipid lowering drugs and thyroid status. [ABSTRACT FROM AUTHOR]

Background: Dietary intake of polyunsaturated fatty acids (PUFAs), e.g., linoleic acid and n-3 (ω-3) long-chain PUFAs, has been shown in adults to affect plasma cholesterol and triglycerides (TGs), respectively. Little is known about the effects of PUFAs on plasma lipids in early life.Objective: The aim of this study was to explore the associations between plasma concentrations of total, LDL, and HDL cholesterol and TGs in infants and 2 single nucleotide polymorphisms (SNPs) in the fatty acid desaturase genes (FADS) oppositely associated with docosahexaenoic acid (rs1535 and rs174448) and potential effect modification by a functional peroxisome proliferator-activated receptor-γ2 gene variant (PPARG2 Pro12Ala).Methods: In 9-mo-old infants (n = 561) from 3 Danish cohorts, we analyzed associations between plasma lipids, erythrocyte PUFAs, and FADS SNPs, and interactions with PPARG2 Pro12Ala genotype, by multiple linear regression. We also examined potential effect modification by breastfeeding, as 46% of the infants were still being breastfed.Results: Minor allele carriage of rs174448 was associated with lower total cholesterol (difference: -0.22 mmol/L; 95% CI: -0.37, -0.06 mmol/L; P = 0.006) and LDL cholesterol (difference: -0.15 mmol/L; 95% CI: -0.29, -0.01 mmol/L; P = 0.035), but no associations were observed with TGs or for rs1535. Minor allele carriage of both FADS SNPs was associated with 1 SD lower HDL cholesterol, but only in currently breastfed infants (rs174448 × breastfeeding, P = 0.080; rs1535 × breastfeeding, P = 0.030) and PPARG2 minor allele carriers (rs174448 × PPARG2, P = 0.001; rs1535 × PPARG2, P = 0.004). Erythrocyte arachidonic acid and eicosapentaenoic acid were inversely associated with LDL cholesterol [estimated effect (β): -0.3 mmol/L; 95% CI: -0.06, -0.00 mmol/L per percentage of fatty acids (FA%); P = 0.035] and TGs (β: -0.23 mmol/L; 95% CI: -0.41, -0.05 mmol/L per FA%; P = 0.015), respectively.Conclusions: The observed associations with FADS variants indicate that PUFAs are involved in plasma lipid regulation in 9-mo-old infants. Observed FADS SNP differences and interactions with breastfeeding and PPARG2 warrant additional studies to explore the effects of individual FADS SNPs on PUFA status and potential genetic modification of dietary PUFA effects. [ABSTRACT FROM AUTHOR]

For most complex traits, the majority of SNPs identified through genome-wide association studies (GWAS) reside within noncoding regions that have no known function. However, these regions are enriched for the regulatory enhancers specific to the cells relevant to the specific trait. Indeed, many of the GWAS loci that have been functionally characterized lie within enhancers that regulate expression levels of key genes. In order to identify polymorphisms with potential allele-specific regulatory effects, we developed a bioinformatics pipeline that harnesses epigenetic signatures as well as transcription factor (TF) binding motifs to identify putative enhancers containing a SNP with potential allele-specific TF binding in linkage disequilibrium (LD) with a GWAS-identified SNP. We applied the approach to GWAS findings for blood lipids, revealing 7 putative enhancers harboring associated SNPs, 3 of which lie within the introns of LCAT and ABCA1, genes that play crucial roles in cholesterol biogenesis and lipoprotein metabolism. All 3 enhancers demonstrated allele-specific in vitro regulatory activity in liver-derived cell lines. We demonstrated that these putative enhancers are in close physical proximity to the promoters of their respective genes, in situ, likely through chromatin looping. In addition, the associated alleles altered the likelihood of transcription activator STAT3 binding. Our results demonstrate that through our approach, the LD blocks that contain GWAS signals, often hundreds of kilobases in size with multiple SNPs serving as statistical proxies to the true functional site, can provide an experimentally testable hypothesis for the underlying regulatory mechanism linking genetic variants to complex traits. [ABSTRACT FROM AUTHOR]

Background & aims: The offspring of patients with premature coronary artery disease (P-CAD) are at higher risk for cardiovascular disease, compared with subjects without a family history (FH) of P-CAD. The increased risk for cardiovascular disease in subjects with FH of early-onset CAD results from unfavorable genetic variants as well as social, behavioral and environmental factors, which are more prevalent in this group. Previous studies have shown that specific sex hormone levels may be associated with the risk of cardiovascular disease. The aim of this study was to compare wide range of biochemical marker levels including i.e. the levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), progesterone, estradiol, testosterone and sex-hormone binding globulin (SHBG) between young healthy male adults with and without FH of P-CAD. Methods: The study group consisted of young healthy Polish male adults enrolled in a MAGNETIC case-control study, who were recruited between July 2015 and October 2017. The inclusion criteria were as follows: male sex, age ≥18 and ≤35 years old, FH of P-CAD (cases) or no P-CAD in first-degree relatives (controls). The comparison of continuous and categorical variables was performed using the Student’s t-test or the U-Mann–Whitney test, and Fisher’s exact test, respectively. The correlations between FSH, LH, testosterone, progesterone, SHBG and other laboratory parameters were assessed using the Spearman rank correlation test. Both univariable and multivariable logistic regression analyses were performed to assess the association between analyzed variables and FH of P-CAD. Results: A total of 411 subjects (223 cases and 188 controls) were included in the study. There was a higher prevalence of major cardiovascular risk factors in subjects with FH of P-CAD (smoking, higher total and LDL cholesterol levels, higher body mass index and lower HDL cholesterol level). Moreover, the offspring of patients with P-CAD had lower SHBG level, and higher LH and progesterone levels in the crude comparison, compared with individuals without FH of P-CAD. After adjustment for confounding variables, progesterone and LH were determined to be independently associated with FH of P-CAD. Conclusion: Progesterone and LH levels are significantly associated with FH of P-CAD, independent of traditional risk factors for CAD. [ABSTRACT FROM AUTHOR]

Introduction: Adipose tissue is considered an important metabolic tissue, in charge of energy storage as well as being able to act in systemic homeostasis and inflammation. Epigenetics involves a series of factors that are important for gene regulation or for chromatin structure, mostly DNA methylation and histone-tail modifications, which can be modified by environmental conditions (nutrition, lifestyle, smoking…). Since metabolic diseases like obesity and diabetes are closely related to lifestyle and nutrition, epigenetic deregulation could play an important role in the onset of these diseases and vice versa. However, little is known about histone marks in human adipose tissue. In a previous work, we developed a protocol for chromatin immunoprecipitation (ChIP) of frozen human adipose tissue. By using this method, this study investigates, for the first time, the H3K4 trimethylation (H3K4me3) mark (open chromatin) on the promoter of several factors involved in adipogenesis, lipid metabolism and inflammation in visceral adipose tissue (VAT) from human subjects with different degrees of body mass index (BMI) and metabolic disease. Methodology: VAT was collected and frozen at -80°C. 100 mg VAT samples were fixed in 0.5% formaldehyde and homogenized. After sonication, the sheared chromatin was immune-precipitated with an anti-H3K4me3 antibody linked to magnetic beads and purified. H3K4me3 enrichment was analyzed by qPCR for LEP, LPL, SREBF2, SCD1, PPARG, IL6, TNF and E2F1 promoters. mRNA extraction on the same samples was performed to quantify gene expression of these genes. Results: H3K4me3 was enriched at the promoter of E2F1, LPL, SREBF2, SCD1, PPARG and IL6 in lean normoglycemic compared to morbid obese subjects with prediabetes. Accordingly H3K4me3 mark enrichment at E2F1, LPL, SREBF2, SCD1, PPARG and IL6 promoters was positively correlated with the BMI and the HOMA-IR. Regression analysis showed a strong relationship between the BMI with H3K4me3 at the promoter of E2F1 and LPL, and with mRNA levels of LEP and SCD. In the case of HOMA-IR, the regression analysis showed associations with H3K4me3 enrichment at the promoter of SCD1 and IL6, and with the mRNA of LEP and SCD1. Moreover H3K4me3 at the E2F1 promoter was positively associated to E2F1 mRNA levels. Conclusions: H3K4me3 enrichment in the promoter of LEP, LPL, SREBF2, SCD1, PPARG, IL6, TNF and E2F1 is directly associated with increasing BMI and metabolic deterioration. The H3k4me3 mark could be regulating E3F1 mRNA levels in adipose tissue, while no associations between the promoter enrichment of this mark and mRNA levels existed for the other genes studied. [ABSTRACT FROM AUTHOR]

Objective: Patients with persistent poorly-controlled diabetes mellitus (PPDM) despite engagement in clinic-based care are at particularly high risk for diabetes complications and costs. Understanding this population’s demographics, comorbidities and care utilization could guide strategies to address PPDM. We characterized factors associated with PPDM in a large sample of Veterans with type 2 diabetes. Methods: We identified a cohort of Veterans with medically treated type 2 diabetes, who received Veterans Health Administration primary care during fiscal years 2012 and 2013. PPDM was defined by hemoglobin A1c levels uniformly >8.5% during fiscal year (FY) 2012, despite engagement with care during this period. We used FY 2012 demographic, comorbidity and medication data to describe PPDM in relation to better-controlled diabetes patients and created multivariable models to examine associations between clinical factors and PPDM. We also constructed multivariable models to explore the association between PPDM and FY 2013 care utilization. Results: In our cohort of diabetes patients (n = 435,820), 12% met criteria for PPDM. Patients with PPDM were younger than better-controlled patients, less often married, and more often Black/African-American and Hispanic or Latino/Latina. Of included comorbidities, only retinopathy (OR 1.68, 95% confidence interval (CI): 1.63,1.73) and nephropathy (OR 1.26, 95% CI: 1.19,1.34) demonstrated clinically significant associations with PPDM. Complex insulin regimens such as premixed (OR 10.80, 95% CI: 10.11,11.54) and prandial-containing regimens (OR 18.74, 95% CI: 17.73,19.81) were strongly associated with PPDM. Patients with PPDM had higher care utilization, particularly endocrinology care (RR 3.56, 95% CI: 3.47,3.66); although only 26.4% of patients saw endocrinology overall. Conclusion: PPDM is strongly associated with complex diabetes regimens, although heterogeneity in care utilization exists. While there is evidence of underutilization, inadequacy of available care may also contribute to PPDM. Our findings should inform tailored approaches to meet the needs of PPDM, who are among the highest-risk, highest-cost patients with diabetes. [ABSTRACT FROM AUTHOR]

The family of oxysterol binding protein (OSBP) and OSBP-related proteins (ORPs) mediate sterol and phospholipid transfer and signaling at membrane contact sites (MCS). The activity of OSBP at MCS is regulated by phosphorylation, but whether this applies to ORPs is unknown. Here we report the functional characterization of a unique proline/serine-rich phosphorylation motif (S762SPSSPSS769) in the lipid binding OSBP-related domain of full-length ORP4L and a truncated variant ORP4S. Phosphorylation was confirmed by mass spectrometry and [32P]PO4 incorporation, and in silico and in vitro assays using purified ORP4L identified putative proline-directed kinases that phosphorylate the site. The functional significance of the phospho-site was assessed by mutating serine 762, S763, S766 and S768 to aspartate or alanine to produce phosphomimetic (S4D) and phosphorylation-deficient (S4A) mutants, respectively. Solution binding of 25-hydroxycholesterol and cholesterol by recombinant ORP4L-S4D and -S4A was similar to wild-type but ORP4L-S4D more effectively extracted cholesterol from liposomes. ORP4L homo-dimerization was unaffected by phosphorylation but gel filtration of ORP4L-S4D indicated that the native conformation was affected. Confocal microscopy revealed that ORP4L-S4D also strongly associated with bundled vimentin filaments, a feature shared with ORP4S which lacks the PH and dimerization domains. We conclude that phosphorylation of a unique serine/proline motif in the ORD induces a conformation change in ORP4L that enhances interaction with vimentin and cholesterol extraction from membranes. [ABSTRACT FROM AUTHOR]

Background: Protein energy wasting (PEW) is a risk factor for death. However, the cutoff vales for PEW are not optimized for early identification of hemodialysis patients with malnutrition. We evaluated the prognosis of Japanese maintenance hemodialysis patients using nutritional indices optimized for them. Materials and methods: We analyzed data from a nation-wide prospective cohort study of the Japanese Society for Dialysis Therapy Renal Data Registry to develop and validate a nutritional risk index (n = 48349, 48349, respectively). The association of nutritional factors with one-year death was tested using Cox proportional hazards models. Their cutoff levels were determined from the hazard ratios or receiver operating characteristic curves. Then, risk index was developed using scoring models. Results: Male was 61.4%; average age, 65.7±12.2 years; and diabetes mellitus, 32.8%. Four clinical factors were retained in the final model: low BMI (<20kg/m2), yes = 3, no = 0; low serum albumin level (young <3.7g/dL; old <3.5g/dL), yes = 4, no = 0; abnormal serum total cholesterol level, low (<130mg/dL) = 1, high (220≥mg/dL) = 2, no = 0; low serum creatinine level (young female, <9.7mg/dL; old female, <8.0mg/dL; young male, <11.6mg/dL; old male, <9.7mg/dL), yes = 4, no = 0. In the validation dataset, medium- and high-risk groups (total score 8 to 10; 11 or more) showed a higher risk of all-cause death than the low-risk group (0 to 7): medium-risk group (10.5%), hazard ratio adjusted for baseline characteristics 1.96 (95% confidence interval 1.77, 2.16); high-risk group (8.2%), 3.91 (3.57, 4.29). The medium- and high-risk groups also showed a higher risk of cardiovascular disease- and infection-caused deaths than the low-risk group. Conclusion: We developed a new nutritional risk index for hemodialysis patients, which may detect patients with malnutrition with a high-risk of death. [ABSTRACT FROM AUTHOR]

Background: Assessment of infection-related mortality remains inadequate in patients undergoing peritoneal dialysis. This study was performed to develop a risk model for predicting the 2-year infection-related mortality risk in patients undergoing peritoneal dialysis. Methods: The study cohort comprised 606 patients who started and continued peritoneal dialysis for 90 at least days and was drawn from the Fukuoka Peritoneal Dialysis Database Registry Study in Japan. The patients were registered from 1 January 2006 to 31 December 2016 and followed up until 31 December 2017. To generate a prediction rule, the score for each variable was weighted by the regression coefficients calculated using a Cox proportional hazard model adjusted by risk factors for infection-related mortality, including patient characteristics, comorbidities, and laboratory data. Results: During the follow-up period (median, 2.2 years), 138 patients died; 58 of them of infectious disease. The final model for infection-related mortality comprises six factors: age, sex, serum albumin, serum creatinine, total cholesterol, and weekly renal Kt/V. The incidence of infection-related mortality increased linearly with increasing total risk score (P for trend <0.001). Furthermore, the prediction model showed adequate discrimination (c-statistic = 0.79 [0.72–0.86]) and calibration (Hosmer–Lemeshow test, P = 0.47). Conclusion: In this study, we developed a new model using clinical measures for predicting infection-related mortality in patients undergoing peritoneal dialysis. [ABSTRACT FROM AUTHOR]

Introduction: The triggering of severe dengue has been associated with an exacerbated inflammatory process characterized by the production of pro-inflammatory cytokines such as IL-1β/IL-18, which are the product of inflammasome activation. Furthermore, alteration in the levels of high-density (HDL) and low-density lipoproteins (LDL) has been observed; and HDL are known to have immunomodulatory properties, including the regulation of inflammasomes. While HDL would be expected to counteract hyperactivation of the inflammasome, the relationship between HDL and dengue severity, has not previously been explored. Methodology: We conducted a cross-sectional study of 30 patients with dengue and 39 healthy controls matched by sex and age. Lipid profile and levels of C-reactive protein were quantified. Serum levels of IL-1β, IL-6, IL-10, IL-18, and TNF-α, were assessed by ELISA. Expression of inflammasome-related genes in PBMC was quantified by qPCR. Results: Dengue patients presented an alteration in the parameters of the lipid profile, with a significant decrease in HDL levels, which was more pronounced in dengue patients with warning signs. Moreover, a decrease in the expression of the inflammasome-related genes NLRP1, NLRC4, caspase-1, IL-1β and IL-18 was observed, as well as an increase in serum levels of C-reactive protein and IL-10 in dengue patients versus healthy donors. Significant positive correlations between LDL levels and the relative expression of NLRP3, NLRC4, IL-1β and IL-18, were found. Conclusion: The results suggest that there is a relationship between the alteration of LDL and HDL with the imbalance in the inflammatory response, which could be associated with the severity of dengue. [ABSTRACT FROM AUTHOR]

Background: Adiponectin protein and some variations in its gene, ADIPOQ have recently been associated with cancer because they regulate glucose and lipid metabolism as well as anti-apoptotic and anti-inflammatory proteins. Aim: The aim of this study was to analyse the relationship between selected biochemical markers, anthropometric indices and ADIPOQ rs2241766 and rs1501299 SNPs in ductal infiltrating breast cancer (DIBC) in a Mexican population. Methods: This cross-sectional study included 64 DIBC patients and 167 healthy women. Polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) analysis was performed to identify the genotypes of the rs2241766 (exon 2) and rs1501299 (intron 2) ADIPOQ polymorphisms. Corporal composition and biochemical markers included body mass index (BMI), waist circumference (WC), hip circumference (HC), waist-hip ratio (WHR), glucose, cholesterol, triglycerides and high- and low-density lipoprotein cholesterol. Results: Patients with DIBC had higher serum glucose, WC and WHR than controls. Intergroup differences in allele and genotype frequencies were found for both polymorphisms (P < 0.05). Patients carrying the rs2241766 TT and TG genotypes had higher values of WC, HC and WHR, but only TG carriers had higher levels of glucose. For the SNP rs1501299, carriers of the GG genotype in the DIBC group had higher values of glucose, WC, HC and WHR than the respective control group. Conclusions: These results suggest that WC, HC and WHR are better predictors of DIBC than BMI. The ADIPOQ SNP rs2241766 emerges as a protective factor, whereas rs1501299 is a risk factor for DIBC development in a Mexican population. [ABSTRACT FROM AUTHOR]

Background/Purpose: Few studies have examined the risk factors for gallbladder (GB) disease in young adults. This study aimed to evaluate risk factors for GB disease in young adults based on big data in Korea. Methods: All participants underwent routine checkup at the Korea Medical Institute from June 2014 to May 2015. After excluding 677 individuals with missing information in records, 724,114 individuals (435,635 men, 288,479 women) were finally included. The definition of abnormal GB finding included stones, sludge, polyps, and adenomyomatosis detected using ultrasonography. All statistical analyses were performed using SAS software version 9.2. Results: Overall, 27,130 (17.5%) individuals were diagnosed as having abnormal GB finding in the young age group (N = 154,463, aged 20–39 years). In men, significant differences in low-density lipoprotein (LDL) and cholesterol levels were observed between the abnormal GB finding group and normal GB group (p < 0.05). In women, a significant difference in smoking history was noted between the abnormal GB finding group and normal GB group (p < 0.05). The prevalence rate of GB stones was 1.9% (27,979/154,463) in the young age group. High body mass index (BMI), large thigh circumference, and low high-density lipoprotein (HDL) level in women and low HDL level in men were independent risk factors for the presence of GB stones (p < 0.05). Conclusion: In this study, obesity-related factors (BMI, waist size, thigh circumference, and cholesterol, LDL, and HDL levels) correlated with GB disease in the young generation of Korea. [ABSTRACT FROM AUTHOR]

Objective: To determine the relationship between plaque composition and low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), apolipoprotein B (Apo-B), and Apo-A1 using virtual-histology intravascular ultrasound (VH-IVUS). Methods: We assessed plaque composition in patients with stable coronary artery disease (SCD) admitted to our hospital for percutaneous coronary intervention (PCI) between November 1, 2012, and March 10, 2015. Before PCI, fibrous (FI), fibrofatty (FF), necrotic core (NC), and dense calcium (DC) regions were evaluated using VH-IVUS, and the contributions of each to the culprit lesion volume were recorded. Plasma LDL-C, HDL-C, Apo-B, and Apo-A1 levels were assessed before PCI. The relationship between the regions on VH-IVUS and plasma lipid levels was assessed. Patients were categorized into low Apo-B (LAB) and high Apo-B (HAB) groups, based on the overall cohort median Apo-B level. Results: We enrolled 115 patients (median Apo-B, 91 mg/dL, male n = 88) with 57 and 58 patients in the LAB (Apo-B ≤ 90 mg/dL) and HAB (Apo-B ≥ 91 mg/dL) groups, respectively. Vessel, plaque, and %NC volumes were significantly greater in the HAB group than in the LAB group. The %FI, %FF, and %DC volumes were similar in both groups. In all 115 patients, the %NC volume correlated with LDL-C (r = 0.2353, P = 0.0114) and Apo-B (r = 0.2487, P = 0.0074) but not with HDL-C and Apo A-1. The high-sensitivity C-reactive protein level tended to be higher in the HAB group than in the LAB group. Multiple regression analysis showed that being male, Apo-A1, and Apo-B were significant predictors of %NC volume extent. Conclusions: Elevated Apo-B level was related to the %NC in target coronary artery lesions in SCD patients, suggesting a role of Apo-B as a biomarker of unstable plaque in this population. [ABSTRACT FROM AUTHOR]

Spot 14 (S14) protein is primarily expressed in adipogenic tissues. Compared to wild type, S14 knockout mice had better resistance to diet-induced obesity and glucose tolerance. However, the association between serum S14 level and metabolic variables in humans has never been investigated. The objectives of this study were to evaluate the associations between serum S14 concentrations with components of metabolic syndrome (MetS). A total of 327 subjects were recruited in this cross-sectional study and categorized by presence of MetS. The mean serum levels of S14 were significantly lower in subjects with MetS than those without (87.1±26.3 μg/L vs. 107.3±40.2 μg/L, p<0.001). In addition, the subjects with central obesity, low high density lipoprotein-C (HDL-C) or hypertriglyceridemia also had significantly lower S14 levels in comparison to those without. Adjusted with age and sex, diagnosis of MetS (β = -0.227, p<0.001), central obesity (β = -0.176, p = 0.001), low HDL-C (β = -0.149, p = 0.005), and high triglyceride (TG) (β = -0.198, p<0.001) were negatively associated with log transformation of serum S14 levels (logS14). With 25% logS14 increased, the risk of MetS (OR 0.65, 95% CI, 0.51–0.82, p<0.001), central obesity (OR 0.72, 95% CI, 0.58–0.89, p = 0.002), low HDL-C (OR 0.76, 95% CI, 0.61–0.95, p = 0.015) or high TG (OR 0.65, 95% CI, 0.51–0.83, p = 0.001) was reduced with a dose response trend. Our analysis revealed that patients with MetS had lower serum S14 levels than those without. Negative associations existed between MetS, central obesity, high TG, low HDL-C and logS14. [ABSTRACT FROM AUTHOR]

Cholesterol oxidase is a bifunctional bacterial flavoenzyme which catalyzes oxidation and isomerization of cholesterol. This valuable enzyme has attracted a great deal of attention because of its wide application in the clinical laboratory, synthesis of steroid derived drugs, food industries, and its potentially insecticidal activity. Therefore, development of an efficient protocol for overproduction of cholesterol oxidase could be valuable and beneficial in this regard. The present study examined the role of various parameters (host strain, culture media, induction time, isopropyl ß-D-1-thiogalactopyranoside concentration, as well as post-induction incubation time and temperature) on over-expression of cholesterol oxidase from Chromobacterium sp. DS1. Applying the optimized protocol, the yield of recombinant cholesterol oxidase significantly increased from 92 U/L to 2115 U/L. Under the optimized conditions, the enzyme was produced on a large-scale, and overexpressed cholesterol oxidase was purified from cell lysate by column nickel affinity chromatography. Km and Vmax values of the purified enzyme for cholesterol were estimated using Lineweaver-Burk plot. Further, the optimum pH and optimum temperature for the enzyme activity were determined. This study reports a straightforward protocol for cholesterol oxidase production which can be performed in any laboratory. [ABSTRACT FROM AUTHOR]

Liposomes are versatile and well-proven as a means to deliver nucleic acids into cells. Most of the formulation procedures used are labour intensive and result in unstable end products. We have previously reported on the development of a simple, yet efficient, hydration-of-freeze-dried-matrix (HFDM) method to entrap siRNA within lipid particles. Here we show that the particles are stable up to 12 months after storage at room temperature (RT), 4°C or -20°C. While RT storage results in changes in particle size and polydispersity, gene silencing of all particles was similar to freshly prepared particles following storage for 3, 6, 9 or 12 months at all temperatures. This is the first report of such long-term stability in siRNA-loaded liposomes. [ABSTRACT FROM AUTHOR]

Objective: Shift work has been linked to cardio-metabolic diseases, but insight into different shift work-related aspects and chronotype of shift workers and their relation with metabolic risk factors is limited. This study examined the association between current shift work status, frequency and duration of night shift work, chronotype, and metabolic risk factors in a population of health care workers. Methods: Anthropometrics, questionnaires, and blood samples were collected from 503 shift working and 93 non-shift working health care workers employed in hospitals. Body mass index, waist circumference, cholesterol (total, HDL, LDL), triglycerides, and high-sensitivity C-reactive protein were measured. Associations of current shift work, frequency (non-night shift worker, 1–2, 3–4, ≥5 night shifts/month) and duration of night shift work (non-night shift workers, <10, 10–19, ≥20 years), and shift workers’ chronotype, with metabolic risk factors were studied using linear regression analysis. Results: Compared to non-shift workers, shift workers’ total cholesterol level was 0.38 mmol/L lower (95%-CI = -0.73 –-0.04) and LDL cholesterol was 0.34 mmol/L lower (95%-CI = -0.60 –-0.08). For all other metabolic risk factors, no differences were found. The association between shift work and LDL cholesterol was especially found among shift workers working night shifts for ≥20 years (B = -0.49 (95%-CI = -0.78 –-0.19)). No differences were found for night shift frequency and chronotype. Conclusion: In this population of health care workers employed in hospitals, no evidence for differences in metabolic risk factors was observed that could underlie a link between shift work and cardio-metabolic diseases. Further research using different aspects of shift work to study the association with metabolic risk factors is recommended. [ABSTRACT FROM AUTHOR]

People who develop type 2 diabetes (T2D) are known to have a higher mortality risk. We estimated all-cause, cardiovascular, and cancer mortality-risks in our patient cohort according to categories of impaired glucose metabolism. This 18-year retrospective analysis included a region-wide, representative sample of a population aged 30–75 years. Age- and sex-stratified hazard ratios (HRs) were calculated for 48 participants with diagnosed T2D, 83 with undiagnosed T2D (HbA1c ≥6.5%, fasting glycemia ≥126 mg/dL, or glycemia after 75 g glucose load ≥200 mg/dL); 296 with prediabetes (HbA1c 5.7%-6.4%, fasting glycemia 100–125 mg/dL, or glycemia after 75 g glucose load 140–199 mg/dL), and 607 with normoglycemia. Over 18,612 person-years, 32 individuals with undiagnosed T2D, 30 with diagnosed T2D, 62 with prediabetes, and 80 with normoglycemia died. Total sample crude mortality rate (MR) was 10.96 deaths per 1,000 person-years of follow-up. MR of the diagnosed T2D group was more than 3-times higher and that of newly diagnosed T2D was 2-times higher (34.72 and 21.42, respectively) than total sample MR. Adjusted HR for all-cause mortality was 2.02 (95% confidence interval 1.29–3.16) and 1.57 (95% CI 1.00–2.28) in the diagnosed T2D group and the newly diagnosed T2D group, respectively. Adjusted HR for cardiovascular mortality in the T2D group was 2.79 (95% CI 1.35–5.75); this risk was greatly increased in women with T2D: 6.72 (95% CI 2.50–18.07). In Asturias, age- and sex-standardized all-cause mortality is more than 2-times higher for adults with T2D than for adults without T2D. The HR for cardiovascular mortality is considerably higher in T2D women than in normoglycemic women. [ABSTRACT FROM AUTHOR]

It remains widely perceived that early-onset Type 2 Diabetes (T2D) in children and adolescents is rare and clinically distinct from Type 1 Diabetes (T1D). We studied the challenges of classifying subtypes of early-onset diabetes using clinical features and biomarkers, and management of these patients. We reviewed retrospectively the record of patients < 25 years old who attended the diabetes clinic in Penang General Hospital, Malaysia between 1st December 2012 and 30th June 2015. We examined their clinical features, C-peptide and pancreatic autoantibodies. Comparisons were made between T1D and T2D for magnitude, demographics, metabolic status and complications. We studied 176 patients with a mean age of 20 ± 3.7 years, 43.2% had T1D, 13.6% had T2D, and 13.6% had mixed features of both. When tested, pancreatic autoantibodies were positive in 59.4% of the T1D. T2D presented two years later than T1D at 14.3 years, 20% were asymptomatic at presentation, and 50% required insulin supplementation despite fasting c-peptide of > 250 pmol/L. HbA1C of ≤ 8.0% (64 mmol/mol) was achieved in 30.3% of T1D, 58.3% of T2D on OAD and 16.7% of T2D on insulin. The T2D had greater cardiovascular risk with higher body mass index, more dyslipidaemia, higher blood pressure and earlier onset of nephropathy. The overlapping clinical features, variable autoimmunity, and beta-cell loss complicate classification of young diabetes. Pancreatic autoantibodies and C-peptide did not always predict diabetes subtypes nor respond to insulin. The poor metabolic control and high cardiovascular risk burden among the T2D highlight the need for population-based study and focused intervention. [ABSTRACT FROM AUTHOR]

Cell penetrating peptides (CPPs) are able to transport hydrophilic molecules inside cells. To reach the cytosol, the peptide associated with a cargo must cross the plasma or the endosomal membrane. Different molecular mechanisms for peptide internalisation into cells have been proposed and it is becoming clear that the cellular internalisation mechanisms are different depending on the peptide sequence and structure and the target membrane. Herein, the penetration of three peptides into large unilamellar vesicles were studied: the homeodomain derived 16-residues penetratin, nona-arginine (R9), and a small peptide containing 6 arginine and 3 tryptophan residues (RW9). The membrane models were composed of phospholipids from natural sources containing different molecular species. We observed that among the three peptides, only the amphipathic peptide RW9 was able to cross the membrane vesicles in the liquid disordered state. The changes in the distribution of the previously characterized cholesterol-pyrene probe show that cholesterol-pyrene molecules dissociate from clusters upon membrane interaction with the three peptides and that the cholesterol environment becomes more disordered in the presence of RW9. Finally, we studied the effect of the peptides on lipid ordering on giant plasma membrane vesicles. The amphipathic peptides RW9 and its longer homologue RW16 induced lipid de-packing in plasma membrane vesicles. Overall, the data suggest that a disordered membrane favours the translocation of RW9, that the membrane cholesterol is redistributed during peptide interaction, and that the peptide amphipathic character is important to increase membrane fluidity and peptide membrane translocation. [ABSTRACT FROM AUTHOR]