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The HERMES (HEart failure Molecular Epidemiology for Therapeutic targetS) consortium aims to identify the genomic and molecular basis of heart failure. The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome-wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow-up following heart failure diagnosis ranged from 2 to 116 months. Forty-nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34-90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of ≥1.10 for common variants (allele frequency ≥ 0.05) and ≥1.20 for low-frequency variants (allele frequency 0.01-0.05) at P < 5 × 10 HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction. Show less

Cardiovascular disease is the number one cause of death globally. Lowering cholesterol levels in plasma is the mainstay therapy; however lifelong treatment and adverse effects call for improved therapeutic interventions. We developed a trivalent vaccine candidate targeting proprotein convertase subtilisin/kexin-9 (PCSK9), apolipoprotein B (ApoB), and cholesteryl ester transfer protein (CETP). Vaccine candidates were developed using bacteriophage Qβ-based virus-like particles (VLPs) displaying antigens of PCKS9, ApoB, and CETP, respectively. Vaccine candidate mixtures were formulated as slow-release PLGA:VLP implants using hot-melt extrusion. The delivery of the trivalent vaccine candidate via the implant produced antibodies against the cholesterol checkpoint proteins at levels comparable to a three-dose injection schedule with soluble mixtures. The reduction in PCSK9 and ApoB levels in plasma, inhibition of CETP ( Show less

Development of cholesteryl ester transfer protein (CETP) inhibitors for coronary heart disease (CHD) has yet to deliver licensed medicines. To distinguish compound from drug target failure, we compared evidence from clinical trials and drug target Mendelian randomization of CETP protein concentration, comparing this to Mendelian randomization of proprotein convertase subtilisin/kexin type 9 (PCSK9). We show that previous failures of CETP inhibitors are likely compound related, as illustrated by significant degrees of between-compound heterogeneity in effects on lipids, blood pressure, and clinical outcomes observed in trials. On-target CETP inhibition, assessed through Mendelian randomization, is expected to reduce the risk of CHD, heart failure, diabetes, and chronic kidney disease, while increasing the risk of age-related macular degeneration. In contrast, lower PCSK9 concentration is anticipated to decrease the risk of CHD, heart failure, atrial fibrillation, chronic kidney disease, multiple sclerosis, and stroke, while potentially increasing the risk of Alzheimer's disease and asthma. Due to distinct effects on lipoprotein metabolite profiles, joint inhibition of CETP and PCSK9 may provide added benefit. In conclusion, we provide genetic evidence that CETP is an effective target for CHD prevention but with a potential on-target adverse effect on age-related macular degeneration. Show less

Dyslipidemia is highly prevalent in youth with type 2 diabetes (T2D), yet the pathogenic components of dyslipidemia in youth with T2D are poorly understood. To evaluate the genetic determinants of lipid traits in youth with T2D through a genome-wide association study. We genotyped 206 928 variants and imputed 17 642 824 variants in 1076 youth (mean age 15.0 ± 2.48 years) with T2D from the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) and SEARCH for Diabetes in Youth (SEARCH) studies as part of the Progress in Diabetes Genetics in Youth (ProDiGY) consortium. We performed association testing for triglyceride and low-density lipoprotein cholesterol and high-density lipoprotein cholesterol (HDL-c) concentrations adjusted for the genetic relationship matrix within each substudy followed by meta-analyses for each trait. We identified a novel association between a deletion on chromosome 3 (3:67817380_AT/A_Deletion:RP11-81N13.1) and triglyceride levels at genome-wide level of significance ( Our genetic analyses of lipid traits in youth with T2D have identified 1 novel and 1 previously known locus. Additional studies are needed to further characterize the genetic architecture of dyslipidemia in youth with T2D. Show less

Murine atherosclerosis models are key for investigation of atherosclerosis pathophysiology and drug development. However, they do not feature spontaneous atherothrombosis as a final stage of atherosclerosis. Transgenic mice expressing both the human mutant apolipoprotein E form APOE*3-Leiden and human cholesteryl ester transfer protein (CETP), i.e. APOE*3-Leiden.CETP mice, feature a moderate hyperlipoproteinemia and atherosclerosis phenotype. In contrast to apolipoprotein E deficient (Apoe- Show less

Resource acquisition and allocation impacts individual fitness. Using pellet analysis of breeding adults and stable isotopes of carbon and nitrogen of down feathers of Kelp Gull (Larus dominicanus) nestlings, we evaluated the relationship between urban refuse (beef and chicken) and natural food (fish) consumption of individual females during the pre-incubation period, with fecundity and young nesting's success in the Río de la Plata Estuary in Uruguay. Assimilated urban refuse positively correlated with egg weight and negatively with young nestling's success. This suggests a possible impact of urban refuse foraged by females during the pre-incubation period on their immediate fecundity (positively) and young nestling's survival (negatively). Differences between studies at the individual and colony levels are also discussed in light of an "ecological fallacy" of interpretation and we thus argue for the need of additional research to evaluate this relationship further, considering potential confounding factors. Show less

Although the associations between serum lipid levels and aneurysms have been investigated in epidemiological studies, causality remains unknown. Thus, this study aimed to investigate the causal relationships of serum high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglyceride (TG) levels on five types of aneurysms, using genetic variants associated with four lipid traits as instrumental variables in a Mendelian randomization (MR) analysis. We performed two-sample Mendelian randomization (MR) analyses to evaluate the associations of HDL-C, LDL-C, TC, and TG levels with risks for five types of aneurysms and those of LDL-C- ( The sample sizes of the included studies ranged from nearly 80,000 to 410,000. We found inverse associations between genetically predicted HDL-C levels and aortic (OR = 0.74, 95% CI = 0.65-0.85) and abdominal aortic aneurysms (0.58, 0.45-0.75). A 1-SD increase in LDL-C and TC levels was associated with increased risks for aortic (1.41, 1.26-1.58 and 1.36, 1.18-1.56, respectively) and abdominal aortic aneurysms (1.82, 1.48-2.22 and 1.55, 1.25-1.93, respectively). TG levels were significantly associated with aortic (1.36, 1.18-1.56) and lower extremity artery aneurysms (2.76, 1.48-5.14), but limited to cerebral aneurysm (1.23, 1.06-1.42). Secondary analyses revealed a relationship between genetically proxied LDL-C-lowering targets and all types of aneurysms; however, the drug targets remained heterogeneous. We found a weak association between TG-lowering therapies and aortic ( According to genetic evidence, lipid dysfunction is a causal risk factor for aneurysms. Lipid-lowering drugs may be a potential effective strategy in preventing and managing aneurysms. Show less

Understanding whether a person has consumed alcohol or not, as well as quantitative assessment of alcohol use, are often based on self-reported measures, which may be subject to recall bias, among other challenges. Although not without limitations, blood biomarkers may complement self-reported assessments to provide a more accurate determination of the presence and quantity of alcohol use. The aim of this review is to provide a critical overview of the current knowledge and research on biomarkers of alcohol use, with a particular focus on blood tests. This scoping review summarizes the published work on blood tests currently used in clinical practice, including phosphatidyl ethanol (PEth), fatty acid ethyl ester (FAEE), carbohydrate-deficient transferrin (CDT), total serum sialic acid (TSA), mean corpuscular volume (MCV), alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl transpeptidase (GGT), and cholesteryl ester transfer protein (CETP). Emerging blood biomarkers with a potential use to assess alcohol drinking are also briefly reviewed, including N-Acetyl-β-Hexosaminidase (Beta-Hex), macrophage migration inhibitory factor (MIF), and D-dopachrome tautomerase (DDT). We discuss the aforementioned biomarkers in the context of their clinical implications, characteristics, strengths, and limitations. The available blood biomarkers considerably vary in the time period in which they detect alcohol use and the amount of alcohol they are sensitive to. While currently available biomarkers provide useful information, especially in combination with self-reported measures, future work is needed to identify more sensitive and specific blood biomarkers for different levels and patterns of alcohol use. Integration of such biomarkers into clinical practice and research will increase the accuracy and richness of the data and may guide more effective and targeted strategies for prevention, diagnosis, and treatment of excessive alcohol use. Show less

One SNP in exon 9 (r5883) has been involved with high risk of cardiovascular disease in hypertensive subjects. The goal of the present study was to test the role of this genetic variant on lipid levels and Metabolic Syndrome (MS) in menopausal obese females. The study enrolled a sample of 112 menopausal obese females. Measurements of adiposity parameters, blood pressure, fasting blood glucose, insulin concentration, insulin resistance (HOMA-IR), lipid profile, C reactive protein and prevalence of MS were recorded. Genotype of CETP gene polymorphism (rs5883) was studied. The distribution of the rs5883 polymorphism in this menopausal obese population was 83.9% (n=94) (CC), 15.2% (n=17) (CT) and 0.9% (n=1) (TT). Adiposity parameters, blood pressure, fasting glucose levels, insulin levels, HOMA-IR, C reactive protein, total cholesterol, LDL-cholesterol and triglycerides were similar in both genotype groups (CC vs. CT+TT). Moreover, HDL cholesterol (8.5+1.2 mg/dl; p=0.01) and ratio total cholesterol/HDL-cholesterol (0.5±0.2; p=0.04) were higher in T allele carriers (dominant model). MS percentage was similar in both genotypes (37.6% vs. 27.2%; p=0.43). Logistic regression analysis showed a decreased risk of low-HDL cholesterol in T allele carriers (OR=0.18, 95% CI=0.02-0.77, p=0.03) after adjusting by dietary fatty acid intakes, body mass index and age. The results reported here support that CETP variant rs5883 is related with HDL-cholesterol levels and ratio total cholesterol/HDL-cholesterol. Show less

Atherosclerosis has been effectively avoided with many therapies that lower low-density lipoprotein cholesterol. However, significant cardiovascular burden remains. The effect of raising high-density lipoprotein (HDL) has been confounded by other factors (such as lowering triglycerides or LDL) and unsuccessful when attempting to solely increase HDL. Reviewing the available data, the failures of previous strategies may reflect the complexity of HDL in human metabolism and the heterogeneity of human genetics. dal-GenE (NCT02525939) represents the first large cardiovascular outcomes study to use a selective genomic test to identify the target population most likely to receive therapeutic benefit and uses a cholesterol ester transfer protein inhibitor, dalcetrapib. Both the cholesterol ester transfer protein target and the ADCY9 polymorphism identified by the diagnostic test are based on inheritance and an evolving understanding of inborn risk. Selective treatment of subpopulations may be the key to the conundrum of HDL as an actionable risk factor. Show less

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. Show less

Monoclonal anti-proprotein convertase subtilisin/kexin type 9 (PSCK9) neutralizing antibodies effectively lower plasma cholesterol levels and decrease cardiovascular events but also raised some concern that cognitive function could worsen as a side effect. Here, we performed experiments in mice to characterize the effect of anti-PCSK9 antibodies on behavior and cognitive function in detail. APOE*3Leiden.CETP mice and B6129SF1/J wildtype mice were fed a Western type diet and treated with the fully human anti-PCSK9 antibody CmAb1 (PL-45134; 10mg*kg Show less

Gene-diet interactions may play an important role in the inter individual diversity observed in on cardiovascular disease (CVD) risk factors. Therefore, in the current study, we examined the interaction of CETP TaqB1 polymorphism with dietary insulin index and load (DII and DIL), in altering on CVD risk factors among type 2 diabetes mellitus (T2DM). In this cross-sectional study, blood samples were collected from 220 type 2 diabetic patients (134 females and 86 male) with a mean age of 52.24 years in Tehran, Iran. DIL and DII were obtained via validated food-frequency questionnaire (FFQ). Taq1B polymorphism was genotyped by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Biochemical markers including total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglyceride (TG), superoxide dismutase (SOD), C-reactive protein (CRP), total antioxidant capacity (TAC), pentraxin-3 (PTX3), isoprostaneF2α (PGF2α). interleukin 18 (IL18), leptin and ghrelin were measured by standard protocol. Patients with B1B1 genotype had lower lipid profiles include LDL/HDL (P < 0.001) and TG (P = 0.04) when they consumed diets higher on the DIL and DII index. Moreover, carriers of B2B2 genotype who were in the last tertile of DIL had higher antioxidant and inflammatory markers include SOD (P = 0.01), PGF2α (P = 0.04) and CRP (P = 0.02). Further, a significant interaction between CETP TaqB1 and DII was shown in terms of WC (P = 0.01), where the highest WC were observed in B2B2 genotype carriers following a DII score. However, the highest inflammatory and antioxidant markers include CRP (P = 0.04), TAC (P = 0.01), SOD (P = 0.02), and PGF2α (P = 0.02) were observed in B2B2 genotype carriers when they consumed diets higher on the DII index. Based on the current study, it could be proposed that CETP polymorphism may be associated with CVD risk factors in T2DM patients with high following insulin indices, including DII and DIL. It seems that CETP Taq1B polymorphism can invert the result produced by insulin. This conclusion illustrates that the CETP Taq1B B1 allele could counteract the CVD risk induced by high DII and DIL. Show less

Depression is a common symptom of many mental disorders, especially major depressive disorder (MDD) and bipolar disorder (BD). Previous studies have reported that these diseases share common pathophysiological pathways; therefore, this study elucidated whether the plasma levels of protein markers related to common depressive symptoms differed between patients with BD and those with MDD. Plasma samples of 71 patients with mood disorders and clinical manifestations were analyzed in this study. After depleting the abundant proteins, liquid chromatography-tandem mass spectrometry and label-free quantification were performed. Five proteins, viz., cholesteryl ester transfer protein (CETP), apolipoprotein D (APOD), mannan-binding lectin serine protease 2 (MASP2), Ig lambda chain V-II region BO (IGLV2-8) and Ig kappa chain V-III region NG9 (IGKV3-20) were negatively associated with the total scores of the Hamilton depression rating scale (HAM-D), after adjusting for the covariates. CETP and APOD also showed significant negative correlations with the anhedonia/retardation and guilt/agitation scores of the HAM-D. Four proteins, namely, Ig kappa chain V-II region TEW (IGKC; IGKV2D-28), Ig lambda variable 5-45 (IGLV5-45), complement factor H (CFH) and attractin (ATRN), showed significant associations with anhedonia/retardation after adjusting for covariates. Proteins that significantly correlated with the symptoms could predict the remission state of depression (area under the curve [AUC], 0.83) and anhedonia/retardation (AUC, 0.80). Bioinformatics analysis revealed that complement activation, immune response, and lipid metabolism were significantly enriched pathways. Although our study design was cross-sectional and no controls were included, protein markers identified in this preliminary study will be further investigated in our subsequent longitudinal study. Show less

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) 3CL protease is a promising target for inhibition of viral replication by interaction with a cysteine residue (Cys145) at its catalytic site. Dalcetrapib exerts its lipid-modulating effect by binding covalently to cysteine 13 of a cholesteryl ester transfer protein. Because 12 free cysteine residues are present in the 3CL protease, we investigated the potential of dalcetrapib to inhibit 3CL protease activity and SARS-CoV-2 replication. Molecular docking investigations suggested that dalcetrapib-thiol binds to the catalytic site of the 3CL protease with a delta Show less

Low high-density lipoprotein (HDL)-cholesterol is frequent in patients with peripheral artery disease (PAD) and also in type 2 diabetes mellitus (T2DM), the major risk factor for PAD. The transfer of cholesterol from the other lipoproteins to HDL is an important aspect of HDL metabolism and function, and may contribute to atherogenic mechanisms that lead to PAD development. The aim of this study was to investigate the status of cholesterol transfers in patients with PAD without or with T2DM. Patients with PAD ( Low-density lipoprotein (LDL)-cholesterol and triglycerides were similar in the three groups. Compared to controls, HDL-C was lower in PAD + DM ( Deficient cholesterol transfer to HDL may play a role in PAD pathogenesis. Since UC transfer to HDL was lower in PAD + DM compared to PAD alone, it is possible that defective HDL metabolism may contribute to the higher PAD incidence in patients with T2DM.Keywords. Show less

Omega-3 (ω-3) fatty acids have been extensively studied for primary and secondary prevention of cardiovascular health, but their ability to modulate HDL functionality remains unclear. The purpose of this study was to investigate the role of ω-3, rich in eicosapentaenoic (EPA) and docosahexaenoic (DHA), on HDL functionality. For that, 147 individuals with high cardiovascular risk were randomized in ω-3 (1 g of fish oil each - 370 mg of EPA and 230 mg of DHA, 3 times per day total EPA+DHA = 1,800 mg) or ω-6 groups (1 g of sunflower oil each - 760 mg of linoleic acid, 3 times per day; total linoleic acid = 2,280 mg). Fasting blood samples were collected at baseline time and after 8 weeks of follow-up and, and the lipid profile and glucose metabolism were evaluated from plasma. From HDL, the fatty acid profile, apolipoproteins (Apo AI, CII and CIII), paraoxonase-1 (PON1), cholesteryl ester transfer protein (CETP), subfractions and antioxidant activity were investigated. Omega-3 improved large HDL (HDL = 28.7%) and reduced small HDL (HDL10 = -10.6%) and the non-esterified fatty acids in HDL (NEFAs-HDL) level (-16.2%). A significant reduction in CETP activity was observed in the ω-3group (Δ ω-6 = 3.60 pmol/ul/h and Δ ω-3 = -1.99 pmol/ul/h; Show less

Hyperalphalipoproteinemia (HALP) is a lipid disorder characterized by elevated plasma high-density lipoprotein cholesterol (HDL-C) levels above the 90th percentile of the distribution of HDL-C values in the general population. Secondary non-genetic factors such as drugs, pregnancy, alcohol intake, and liver diseases might induce HDL increases. Primary forms of HALP are caused by mutations in the genes coding for cholesteryl ester transfer protein (CETP), hepatic lipase (HL), apolipoprotein C-III (apo C-III), scavenger receptor class B type I (SR-BI) and endothelial lipase (EL). However, in the last decades, genome-wide association studies (GWAS) have also suggested a polygenic inheritance of hyperalphalipoproteinemia. Epidemiological studies have suggested that HDL-C is inversely correlated with cardiovascular (CV) risk, but recent Mendelian randomization data have shown a lack of atheroprotective causal effects of HDL-C. This review will focus on primary forms of HALP, the role of polygenic inheritance on HDL-C, associated risk for cardiovascular diseases and possible treatment options. Show less

Lipoprotein(a) forms a subfraction of the lipid profile and is characterized by the addition of apolipprotein(a) (apo(a)) to apoB100 derived particles. Its levels are mostly genetically determined inversely related to the number of protein domain (kringle) repeats in apo(a). In epidemiological studies, it shows consistent association with cardiovascular disease (CVD) and most recently with extent of aortic stenosis. Issues with standardizing the measurement of Lp(a) are being resolved and consensus statements favor its measurement in patients at high risk of, or with family histories of CVD events. Major lipid-lowering therapies such as statin, fibrates, and ezetimibe have little effect on Lp(a) levels. Therapies such as niacin or cholesterol ester transfer protein (CETP) inhibitors lower Lp(a) as well as reducing other lipid-related risk factors but have failed to clearly reduce CVD events. Proprotein convertase subtilisin kexin-9 (PCSK9) inhibitors reduce cholesterol and Lp(a) as well as reducing CVD events. New antisense therapies specifically targeting apo(a) and hence Lp(a) have greater and more specific effects and will help clarify the extent to which intervention in Lp(a) levels will reduce CVD events. Show less

The high-density lipoprotein hypothesis of atherosclerosis has been challenged by clinical trials of cholesteryl ester transfer protein (CETP) inhibitors, which failed to show significant reductions in cardiovascular events. Plasma levels of high-density lipoprotein cholesterol (HDL-C) decline drastically during sepsis, and this phenomenon is explained, in part, by the activity of CETP, a major determinant of plasma HDL-C levels. We tested the hypothesis that genetic or pharmacological inhibition of CETP would preserve high-density lipoprotein levels and decrease mortality in clinical cohorts and animal models of sepsis. We examined the effect of a gain-of-function variant in A fixed-effect meta-analysis of all 7 cohorts found that the Clinical genetics and humanized mouse models suggest that inhibiting CETP may preserve high-density lipoprotein levels and improve outcomes for individuals with sepsis. Show less

Low HDL-C (high-density lipoprotein cholesterol) is the most frequent dyslipidemia in Mexicans, but few studies have examined the underlying genetic basis. Our purpose was to identify genetic variants associated with HDL-C levels and cardiovascular risk in the Mexican population. A genome-wide association studies for HDL-C levels in 2335 Mexicans, identified four loci associated with genome-wide significance: CETP, ABCA1, LIPC, and SIDT2. The SIDT2 missense Val636Ile variant was associated with HDL-C levels and was replicated in 3 independent cohorts (P=5.9×10−18 in the conjoint analysis). The SIDT2/Val636Ile variant is more frequent in Native American and derived populations than in other ethnic groups. This variant was also associated with increased ApoA1 and glycerophospholipid serum levels, decreased LDL-C (low-density lipoprotein cholesterol) and ApoB levels, and a lower risk of premature CAD. Because SIDT2 was previously identified as a protein involved in sterol transport, we tested whether the SIDT2/Ile636 protein affected this function using an in vitro site-directed mutagenesis approach. The SIDT2/Ile636 protein showed increased uptake of the cholesterol analog dehydroergosterol, suggesting this variant affects function. Finally, liver transcriptome data from humans and the Hybrid Mouse Diversity Panel are consistent with the involvement of SIDT2 in lipid and lipoprotein metabolism. This is the first genome-wide association study for HDL-C levels seeking associations with coronary artery disease in the Mexican population. Our findings provide new insight into the genetic architecture of HDL-C and highlight SIDT2 as a new player in cholesterol and lipoprotein metabolism in humans. Show less

Green tea is associated with decreased risk for cardiovascular disease and stroke. Matcha is a special kind of powdered green tea known for its use in the Japanese tea ceremony. Due to its influence on lipoprotein parameters, it has been postulated to exert antiatherogenic effects. This study investigates whether it modulates the high-density lipoprotein (HDL) function and thereby influences the atherogenic process in an animal model with a strong influence on humans' situation. After a pretreatment phase based on a standard diet, 10 female New Zealand White (NZW) rabbits are fed a high-fat diet for 20 weeks. The treatment group is additionally administered 1% matcha during the whole experiment. Long-term matcha treatment leads to lowered HDL cholesterol, impaired cholesterol transport manifested by reduced in vitro cholesterol efflux capacity, reduced cholesteryl ester transfer protein (CETP)-mediated cholesterol ester (CE) transfer between HDL and triglyceride-rich particles, and reduced macrophage-specific in vivo transfer, where ian increased absorption of cholesterol in the liver but a decreased secretion into bile is observed. Pulse wave velocity, assessed by nuclear magnetic resonance, is increased in matcha-treated animals, and a similar trend is observed for atherosclerotic lesion formation. Long-term matcha green tea treatment of hypercholesterolemic rabbits cause impaired reverse cholesterol transport and increased vascular stiffness, and susceptibility for atherosclerotic lesion development. Show less

The complex pathophysiology of sepsis makes it a syndrome with limited therapeutic options and a high mortality rate. Gram-negative bacteria containing lipopolysaccharides (LPS) in their outer membrane correspond to the most common cause of sepsis. Since the gut is considered an important source of LPS, intestinal damage has been considered a cause and a consequence of sepsis. Although important in the maintenance of the intestinal epithelial cell homeostasis, the microbiota has been considered a source of LPS. Recent studies have started to shed light on how sepsis is triggered by dysbiosis, and an increased inflammatory state of the intestinal epithelial cells, expanding the understanding of the gut-liver axis in sepsis. Here, we review the gut-liver interaction in Gram-negative sepsis, exploring the mechanisms of LPS inactivation, including the recently described contribution of an isoform of the cholesteryl-ester transfer protein (CETPI). Although several key questions remain to be answered when the pathophysiology of sepsis is reviewed, new contributions coming to light exploring the way LPS might be inactivated in vivo, suggest that new applications might soon reach the clinical setting. Show less

We investigated the effects of chronic oral administration of mineral oil, versus corn oil as control, on intestinal permeability, inflammatory markers, and plasma lipids in APOE*3-Leiden.CETP mice. Mice received mineral oil or corn oil 15 or 30 μL/mouse/day for 16 weeks (15 mice/group). Intestinal permeability was increased with mineral versus corn oil 30 µL/day, shown by increased mean plasma FITC-dextran concentrations 2 h post-administration (11 weeks: 1.5 versus 1.1 μg/ml, Show less

Inhibitors of cholesteryl ester transfer protein (CETP) elevate HDL levels human clinical trials. However, the first CETP inhibitors proved toxic in pivotal trials or showed minimal therapeutic benefit. Anacetrapib showed some clinical benefit but is high lipophilic. This Viewpoint highlights efforts to optimize anacetrapib to a best-in-class CETP inhibitor. Show less

Cholesteryl ester transfer protein (CETP) represents one of the key regulators of the homeostasis of lipid particles, including high-density lipoprotein (HDL) and low-density lipoprotein (LDL) particles. Epidemiological evidence correlates increased HDL and decreased LDL to coronary heart disease (CHD) risk reduction. This relationship is consistent with a clinical outcomes trial of a CETP inhibitor (anacetrapib) combined with standard of care (statin), which led to a 9% additional risk reduction compared to standard of care alone. We discuss here the discovery of MK-8262, a CETP inhibitor with the potential for being the best-in-class molecule. Novel in vitro and in vivo paradigms were integrated to drug discovery to guide optimization informed by a critical understanding of key clinical adverse effect profiles. We present preclinical and clinical evidence of MK-8262 safety and efficacy by means of HDL increase and LDL reduction as biomarkers for reduced CHD risk. Show less

In this article, monomers (tannic acid (TA) and m- phenylenediamine (MPD)) were used in the fabrication of a novel PES based thin-film composite nanofiltration (TFC-NF) membrane for the treatment of a common effluent treatment plant (CETP) of textile industrial wastewater. PES support sheets and TFC layers were fabricated via non-solvent induced phase inversion and in-situ interfacial polymerization (IP) process. The ultra-thin active layer was synthesized via the IP process with monomers such as tannic acid (TA) and m- phenylenediamine (MPD). T and M series membranes correspond to (PES/x wt% TA, x = 2, 4, 6) as T1, T2, T3 -TA and (PES/x wt% MPD, x = 2, 4, 6) as M1, M2, M3-MPD respectively. M0 corresponds to PES which is the virgin membrane. The chemical structure, surface morphology, surface roughness and surface properties were explored using fourier transform infrared (FTIR) spectroscopy, field emission scanning electron microscopy (FESEM), atomic force microscopy (AFM) and contact angle, respectively. The filtration performance of the thin-film composite nanofiltration (TFC-NF) membranes was investigated by various properties like pure water flux, salt rejection, porosity, mean pore radius and antifouling analysis. T1-TA membrane showed better water permeability, high salt rejection and better industrial effluent rejection with 94.4% of TDS that are suitable for industrial reuse and agricultural irrigation. Moreover, for T1-TA membrane, the water flux, porosity, mean pore radius, salt rejection, surface roughness and contact angle of 43.5lm The online version contains supplementary material available at 10.1007/s40201-021-00624-x. Show less