Pharmacoinformatics and UPLC-QTOF/ESI-MS-Based Phytochemical Screening of Combretum indicum against Oxidative Stress and Alloxan-Induced Diabetes in Long-Evans Rats.

This research investigated a UPLC-QTOF/ESI-MS-based phytochemical profiling of Combretum indicum leaf extract (CILEx), and explored its in vitro antioxidant and in vivo antidiabetic effects in a Long-Evans rat model. After a one-week intervention, the animals' blood glucose, lipid profile, and pancreatic architectures were evaluated. UPLC-QTOF/ESI-MS fragmentation of CILEx and its eight docking-guided compounds were further dissected to evaluate their roles using bioinformatics-based network pharmacological tools. Results showed a very promising antioxidative effect of CILEx. Both doses of CILEx were found to significantly (p < 0.05) reduce blood glucose, low-density lipoprotein (LDL), and total cholesterol (TC), and increase high-density lipoprotein (HDL). Pancreatic tissue architectures were much improved compared to the diabetic control group. A computational approach revealed that schizonepetoside E, melianol, leucodelphinidin, and arbutin were highly suitable for further therapeutic assessment. Arbutin, in a Gene Ontology and PPI network study, evolved as the most prospective constituent for 203 target proteins of 48 KEGG pathways regulating immune modulation and insulin secretion to control diabetes. The fragmentation mechanisms of the compounds are consistent with the obtained effects for CILEx. Results show that the natural compounds from CILEx could exert potential antidiabetic effects through in vivo and computational study.

Baricitinib induces LDL-C and HDL-C increases in rheumatoid arthritis: a meta-analysis of randomized controlled trials.

BACKGROUND: Baricitinib, an oral-administrated selective inhibitor of the JAK1 and JAK2, is recently approved for rheumatoid arthritis (RA) treatment. With the aim to provide some insights on the clinical safety, the current study mainly focused on the effect of baricitinib on low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) levels and cardiovascular risk. METHODS: The net change scores [least squares mean (LSM) and mean change] of LDL-C and HDL-C levels from baseline with the comparison of baricitinib versus placebo were pooled, respectively. Risk rations (RR) of major cardiovascular events (MACEs) and differences of cardiovascular risk scores at the end of treatment across groups were compared. RESULTS: Six trials with randomized 3552 patients were finally included in summary analysis. Results showed that baricitinib significantly increased LDL-C levels, the net mean change was 13.15 mg/dl with 95% CI 8.89~17.42 (I2 = 0) and the net LSM was 11.94 mg/dl with 95% CI 7.52~16.37 (I2 = 84%). HDL-C also increased obviously with the net LSM change was 7.19 mg/dl (95% CI, 6.05~8.33, I2 = 47%) and net mean change was 5.40 mg/dl (95% CI, 3.07~7.74, I2 = 10%). Subgroup and meta-regression analysis demonstrated baricitinib induced LDL-C and HDL-C increases in a dose-response manner. However, both the pooled RRs of MACEs and differences of cardiovascular risk scores were not statistically significant across groups. CONCLUSION: This study confirmed that baricitinib induced a stable dose-response increase in LDL-C and HDL-C levels. Since the causality association between altered lipids and cardiovascular risk was not identified yet, this issue cannot be completely dismissed. Future research is needed to fully dissect the implications of these lipid changes.

The effect of oat ß-glucan on LDL-cholesterol, non-HDL-cholesterol and apoB for CVD risk reduction: a systematic review and meta-analysis of randomised-controlled trials.

Oats are a rich source of ß-glucan, a viscous, soluble fibre recognised for its cholesterol-lowering properties, and are associated with reduced risk of CVD. Our objective was to conduct a systematic review and meta-analysis of randomised-controlled trials (RCT) investigating the cholesterol-lowering potential of oat ß-glucan on LDL-cholesterol, non-HDL-cholesterol and apoB for the risk reduction of CVD. MEDLINE, Embase, CINAHL and Cochrane CENTRAL were searched. We included RCT of ≥3 weeks of follow-up, assessing the effect of diets enriched with oat ß-glucan compared with controlled diets on LDL-cholesterol, non-HDL-cholesterol or apoB. Two independent reviewers extracted data and assessed study quality and risk of bias. Data were pooled using the generic inverse-variance method with random effects models and expressed as mean differences with 95 % CI. Heterogeneity was assessed by the Cochran's Q statistic and quantified by the I 2-statistic. In total, fifty-eight trials (n 3974) were included. A median dose of 3·5 g/d of oat ß-glucan significantly lowered LDL-cholesterol (-0·19; 95 % CI -0·23, -0·14 mmol/l, P<0·00001), non-HDL-cholesterol (-0·20; 95 % CI -0·26, -0·15 mmol/l, P<0·00001) and apoB (-0·03; 95 % CI -0·05, -0·02 g/l, P<0·0001) compared with control interventions. There was evidence for considerable unexplained heterogeneity in the analysis of LDL-cholesterol (I 2=79 %) and non-HDL-cholesterol (I 2=99 %). Pooled analyses showed that oat ß-glucan has a lowering effect on LDL-cholesterol, non-HDL-cholesterol and apoB. Inclusion of oat-containing foods may be a strategy for achieving targets in CVD reduction.

Acute Cocoa Supplementation Increases Postprandial HDL Cholesterol and Insulin in Obese Adults with Type 2 Diabetes after Consumption of a High-Fat Breakfast.

BACKGROUND: Dietary cocoa is an important source of flavonoids and is associated with favorable cardiovascular disease effects, such as improvements in vascular function and lipid profiles, in nondiabetic adults. Type 2 diabetes (T2D) is associated with adverse effects on postprandial serum glucose, lipids, inflammation, and vascular function. OBJECTIVE: We examined the hypothesis that cocoa reduces metabolic stress in obese T2D adults after a high-fat fast-food-style meal. METHODS: Adults with T2D [n = 18; age (mean ± SE): 56 ± 3 y; BMI (in kg/m(2)): 35.3 ± 2.0; 14 women; 4 men] were randomly assigned to receive cocoa beverage (960 mg total polyphenols; 480 mg flavanols) or flavanol-free placebo (110 mg total polyphenols; <0.1 mg flavanols) with a high-fat fast-food-style breakfast [766 kcal, 50 g fat (59% energy)] in a crossover trial. After an overnight fast (10-12 h), participants consumed the breakfast with cocoa or placebo, and blood sample collection [glucose, insulin, lipids, and high-sensitivity C-reactive protein (hsCRP)] and vascular measurements were conducted at 0.5, 1, 2, 4, and 6 h postprandially on each study day. Insulin resistance was evaluated by homeostasis model assessment. RESULTS: Over the 6-h study, and specifically at 1 and 4 h, cocoa increased HDL cholesterol vs. placebo (overall Δ: 1.5 ± 0.8 mg/dL; P ≤ 0.01) but had no effect on total and LDL cholesterol, triglycerides, glucose, and hsCRP. Cocoa increased serum insulin concentrations overall (Δ: 5.2 ± 3.2 mU/L; P < 0.05) and specifically at 4 h but had no overall effects on insulin resistance (except at 4 h, P < 0.05), systolic or diastolic blood pressure, or small artery elasticity. However, large artery elasticity was overall lower after cocoa vs. placebo (Δ: -1.6 ± 0.7 mL/mm Hg; P < 0.05), with the difference significant only at 2 h. CONCLUSION: Acute cocoa supplementation showed no clear overall benefit in T2D patients after a high-fat fast-food-style meal challenge. Although HDL cholesterol and insulin remained higher throughout the 6-h postprandial period, an overall decrease in large artery elasticity was found after cocoa consumption. This trial was registered at clinicaltrials.gov as NCT01886989.

Dietary Almonds Increase Serum HDL Cholesterol in Coronary Artery Disease Patients in a Randomized Controlled Trial.

BACKGROUND: More than one-half of coronary artery disease (CAD) patients have low HDL cholesterol despite having well-managed LDL cholesterol. Almond supplementation has not been shown to elevate circulating HDL cholesterol concentrations in clinical trials, perhaps because the baseline HDL cholesterol of trial subjects was not low. OBJECTIVE: This clinical trial was designed to test the effect of almond supplementation on low HDL cholesterol in CAD patients. METHODS: A total of 150 CAD patients (50 per group), with serum LDL cholesterol ≤100 mg/dL and HDL cholesterol ≤40 mg/dL in men and ≤50 mg/dL in women, were recruited from the Aga Khan University Hospital. After recording vital signs and completing a dietary and physical activity questionnaire, patients were randomly assigned to 1 of the following 3 groups: the no-intervention group (NI), the Pakistani almonds group (PA), and the American almonds group (AA). The respective almond varieties (10 g/d) were given to patients with instructions to soak them overnight, remove the skin, and eat them before breakfast. Blood samples for lipid profiling, body weight, and blood pressure were collected, and assessment of dietary patterns was done at baseline, week 6, and week 12. RESULTS: Almonds significantly increased HDL cholesterol. At weeks 6 and 12, HDL cholesterol was 12-14% and 14-16% higher, respectively, in the PA and AA than their respective baselines. In line with previous reports, serum concentrations of total cholesterol, triglycerides, LDL cholesterol, and VLDL cholesterol; total-to-HDL and LDL-to-HDL cholesterol ratios, and the atherogenic index were reduced in both the PA and AA at weeks 6 and 12 compared with baseline (P < 0.05). Effects on serum lipids did not differ between the 2 almond groups. Dietary patterns, body weight, and blood pressure did not change in any of the 3 groups during the trial. CONCLUSION: A low dose of almonds (10 g/d) consumed before breakfast can increase HDL cholesterol, in addition to improving other markers of abnormal lipid metabolism in CAD patients with low initial HDL cholesterol. This trial was registered at the Australian New Zealand Clinical Trial Registry as ACTRN12614000036617.

Effects of alcohol and polyphenols from beer on atherosclerotic biomarkers in high cardiovascular risk men: a randomized feeding trial.

BACKGROUND AND AIMS: Moderate alcohol consumption exerts a cardioprotective effect, but no studies have evaluated the alcohol-independent cardiovascular effects of the non-alcoholic components of beer. We aimed to evaluate the effects of ethanol and the phenolic compounds of beer on classical and novel cardiovascular risk factors. METHODS AND RESULTS: Thirty-three high risk male volunteers were included in a randomized, crossover feeding trial. After a washout period, all subjects received beer (30 g alcohol/d, 660 mL), the equivalent amount of polyphenols as non-alcoholic beer (990 mL), and gin (30 g alcohol/d, 100 mL) for 4 weeks. All outcomes were evaluated before and after each intervention period. Moderate alcohol consumption increased serum HDL-cholesterol (∼5%), ApoA-I (∼6%), ApoA-II (∼7%) and adiponectin (∼7%), and decreased serum fibrinogen (∼8%), and interleukin (IL)-5 (∼14%) concentrations, whereas the non-alcoholic fraction of beer (mainly polyphenols) increased the receptor antagonist of IL-1 (∼24%), and decreased lymphocyte expression of lymphocyte function-associated antigen-1 (∼11%), lymphocyte and monocyte expression of Sialil-Lewis X (∼16%) and monocyte expression of CCR2 (∼31%), and tumor necrosis factor (TNF)-ß (∼14%) and IL-15 (∼22%) plasma concentrations. No changes were observed in glucose metabolism parameters or in body weight and adiposity parameters. CONCLUSION: The phenolic content of beer reduces leukocyte adhesion molecules and inflammatory biomarkers, whereas alcohol mainly improves the lipid profile and reduces some plasma inflammatory biomarkers related to atherosclerosis.

Statins and lipid metabolism: an update.

PURPOSE OF REVIEW: The reduction in cardiovascular disease risk by statins is well established. This risk reduction has mostly been attributed to decreases in plasma LDL cholesterol and other pleiotropic effects of statins. Emerging evidence indicates that statins exert multiple effects on lipoprotein metabolism, including chylomicrons and HDLs. RECENT FINDINGS: Kinetic and in-vitro studies have documented that the effects of statins on the metabolism of different lipoproteins are for the most part the direct consequence of cholesterol biosynthesis inhibition and the subsequent change in transcription factors and cell signaling, regulating different aspects of lipoprotein metabolism. Differences in pharmacokinetics and pharmacodynamics among statins lead to diverse biological outcomes. SUMMARY: The current review summarizes recent experimental evidence highlighting the different effects of statins on cellular pathways regulating gene expression. Understanding the basic mechanisms by which different statins regulate lipoprotein metabolism will lead to improved strategies for the prevention and treatment of specific lipoprotein disorders.

Recent advances in niacin and lipid metabolism.

PURPOSE OF REVIEW: This review focuses on the current understanding of the physiological mechanisms of action of niacin on lipid metabolism and atherosclerosis. RECENT FINDINGS: Emerging findings indicate that niacin decreases hepatic triglyceride synthesis and subsequent VLDL/LDL secretion by directly and noncompetitively inhibiting hepatocyte diacylglycerol acyltransferase 2. Recent studies in mice lacking niacin receptor GPR109A and human clinical trials with GPR109A agonists disproved the long believed hypothesis of adipocyte triglyceride lipolysis as the mechanism for niacin's effect on serum lipids. Niacin, through inhibiting hepatocyte surface expression of ß-chain ATP synthase, inhibits the removal of HDL-apolipoprotein (apo) AI resulting in increased apoAI-containing HDL particles. Additional recent findings suggest that niacin by increasing hepatic ATP-binding cassette transporter A1-mediated apoAI lipidation increases HDL biogenesis, thus stabilizing circulation of newly secreted apoAI. New concepts have also emerged on lipid-independent actions of niacin on vascular endothelial oxidative and inflammatory events, myeloperoxidase release from neutrophils and its impact on HDL function, and GPR109A-mediated macrophage inflammatory events involved in atherosclerosis. SUMMARY: Recent advances have provided physiological mechanisms of action of niacin on lipid metabolism and atherosclerosis. Better understanding of niacin's actions on multiple tissues and targets may be helpful in designing combination therapy and new treatment strategies for atherosclerosis.

Assessment of exopolysaccharides, bacteriocins and in vitro and in vivo hypocholesterolemic potential of some Egyptian Lactobacillus spp.

Lactobacilli probiotics have been suggested to reduce cholesterol with low side effects to host. Bacteriocins and exopolysaccharides (EPSs) production are two meaningful examples of functional applications of lactobacilli in the food industry. Eight Lactobacillus strains were isolated from some Egyptian fermented food and tested for their probiotic properties. Analysis of the monosaccharide composition by thin layer chromatography showed the presence of glucose, galactose and unknown sugar. The main functional groups of EPSs were elucidated by Fourier-Transform Infrared Spectroscopy. Their fermentation cultures displayed powerful antioxidant activities extending from 97.5 to 99%, 40-75% for their EPSs and free cells, respectively, and exhibited in vitro cholesterol downgrading from 48 to 82% and 72 to 91% after 48 and 120 h, respectively. Their EPSs showed good anticancer activities against carcinoma cells with low IC50 values for HCT-116, PC-3 and HepG-2 cells. To the best of our knowledge, there have been no previous reports on the potential of Lactobacillus EPSs activity against PC-3. The selected strains, L. plantarum KU985433 and L. rhamnosus KU985436 produced two different bacteriocins as detected by gel permeation chromatography with good antimicrobial activities. In vivo study demonstrated that feeding Westar rats with fermented milk exhibited greater cholesterol, LDL and blood triglyceride reduction for both strains. Whereas, HDL was increased by about 43 and 38%, respectively, and the atherogenic indices decreased.

Cholesterol absorption and synthesis markers in individuals with and without a CHD event during pravastatin therapy: insights from the PROSPER trial.

Cholesterol homeostasis, defined as the balance between absorption and synthesis, influences circulating cholesterol concentrations and subsequent coronary heart disease (CHD) risk. Statin therapy targets the rate-limiting enzyme in cholesterol biosynthesis and is efficacious in lowering CHD events and mortality. Nonetheless, CHD events still occur in some treated patients. To address differences in outcome during pravastatin therapy (40 mg/day), plasma markers of cholesterol synthesis (desmosterol, lathosterol) and fractional cholesterol absorption (campesterol, sitosterol) were measured, baseline and on treatment, in the Prospective Study of Pravastatin in the Elderly at Risk trial participants with (cases, n = 223) and without (controls, n = 257) a CHD event. Pravastatin therapy decreased plasma LDL-cholesterol and triglycerides and increased HDL-cholesterol concentrations to a similar extent in cases and controls. Decreased concentrations of the cholesterol synthesis markers desmosterol (-12% and -11%) and lathosterol (-50% and -56%) and increased concentrations of the cholesterol absorption markers campesterol (48% and 51%) and sitosterol (25% and 26%) were observed on treatment, but the magnitude of change was similar between cases and controls. These data suggest that decreases in cholesterol synthesis in response to pravastatin treatment were accompanied by modest compensatory increases in fractional cholesterol absorption. The magnitude of these alterations were similar between cases and controls and do not explain differences in outcomes with pravastatin treatment.

Real-world use of PCSK9 inhibitors: A single-center experience.

OBJECTIVE: Hyperlipidemia is an important risk factor for atherosclerotic cardiovascular disease. Many patients are intolerant to or have limited benefit from statins. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been approved for treating hyperlipidemia in these patients. We sought to investigate the impact of these medications in a real-world cardiology practice. METHODS: This was a retrospective study of 17 patients with either heterozygous familial hypercholesterolemia or established atherosclerotic cardiovascular disease with low-density lipoprotein cholesterol (LDL-C) levels above the treatment target despite maximally tolerated statins. Baseline lipid profile was compared with a repeat lipid profile obtained 4 to 6 weeks after initiating treatment with a PCSK9 inhibitor. RESULTS: The average duration of PCSK9 inhibitor treatment was 10.7 months. Lipid profile comparison showed that total cholesterol decreased from 243 ± 72 to 148 ± 39 (mg/dL) (39% reduction), triglycerides decreased from 185 ± 86 to 149 ± 62 (mg/dL) (19.5% reduction), high-density lipoprotein cholesterol increased from 56 ± 20 to 62 ± 26 (mg/dL) (10.7% increase), and LDL-C decreased from 154 ± 30 to 57 ± 32 (mg/dL) (63% reduction) from baseline. CONCLUSIONS: PCSK9 inhibitors as add-on therapy to maximally tolerated statins resulted in an approximately 63% reduction in LDL-C.

Akkermansia muciniphila can reduce the damage of gluco/lipotoxicity, oxidative stress and inflammation, and normalize intestine microbiota in streptozotocin-induced diabetic rats.

This study aimed to investigate how Akkermansia muciniphila can implicate type 2 diabetes mellitus and the mechanisms underlying the effects A. muciniphila on type 2 diabetes mellitus. Normal and streptozotocin-induced diabetic Sprague-Dawley rats were orally administered with A. muciniphila and solvent. After 4 weeks of treatment, diabetic rats orally administered with live or pasteurized A. muciniphila exhibited significant increase in the blood concentration of high-density lipoprotein, and decrease in the hepatic glycogen, serum plasminogen activator inhibitor-1, tumor necrosis factor-α, lipopolysaccharide, malondialdehyde and total glucagon-like peptide-1. Moreover, diabetic rats orally administered with A. muciniphila showed significantly increased species alpha diversity and gene function in gut microbes. These results indicated that A. muciniphila can improve liver function, reduce gluco/lipotoxicity, alleviate oxidative stress, suppress inflammation and normalize intestine microbiota of the host animal, thereby ameliorating type 2 diabetes mellitus. Akkermansia muciniphila might be considered as one of the ideal new probiotics used in the management of type 2 diabetes mellitus in future.

Lipidomic and Antioxidant Response to Grape Seed, Corn and Coconut Oils in Healthy Wistar Rats.

Specialty oils differ in fatty acid, phytosterol and antioxidant content, impacting their benefits for cardiovascular health. The lipid (fatty acid, phytosterol) and antioxidant (total phenolics, radical scavenging capacity) profiles of grapeseed (GSO), corn (CO) and coconut (CNO) oils and their physiological (triacylglycerides, total and HDL-cholesterol and antioxidant capacity (FRAP) in serum and fatty acid and phytosterol hepatic deposition) and genomic (HL, LCAT, ApoA-1 and SR-BP1 mRNA hepatic levels) responses after their sub-chronic intake (10% diet for 28 days) was examined in healthy albino rats. Fatty acid, phytosterol and antioxidant profiles differed between oils (p ≤ 0.01). Serum and hepatic triacylglycerides and total cholesterol increased (p ≤ 0.01); serum HDL-Cholesterol decreased (p < 0.05); but serum FRAP did not differ (p > 0.05) in CNO-fed rats as compared to CO or GSO groups. Hepatic phytosterol deposition was higher (+2.2 mg/g; p ≤ 0.001) in CO- than GSO-fed rats, but their fatty acid deposition was similar. All but ApoA-1 mRNA level increased in GSO-fed rats as compared to other groups (p ≤ 0.01). Hepatic fatty acid handling, but not antioxidant response, nor hepatic phytosterol deposition, could be related to a more efficient reverse-cholesterol transport in GSO-fed rats as compared to CO or CNO.

Protective and therapeutic effects of Crataegus aronia in non-alcoholic fatty liver disease.

AIM: We evaluated the potential preventive and therapeutic effects of Crataegus aronia (C. aronia) in NAFLD induced by high-fat diet (HFD) in rat models. METHODS: Protective effect of Crataegus aronia or simvastatin was investigated in Wistar rats fed either low-fat diet (LFD) or HFD. RESULTS: Liver histopathological examinations confirmed the development of NAFLD in rats fed HFD. In both protective and therapeutic treatments, C. aronia significantly reduced liver index (3.85 ± 0.21% in HFD plus aronia group versus 6.22 ± 0.58% in HFD model group), increased the HDL-cholesterol and reduced the LDL-cholesterol in blood. The hawthorn plant also significantly ameliorated oxidative stress biomarker (p < 0.002) and liver enzymes (p < 0.0001) that indicate liver damage. CONCLUSION: C. aronia exhibits therapeutic and protective effects on NAFLD in an animal model possibly by its lipid lowering and antioxidant effects; thus, may offer therapeutic potential in humans.

Increasing high-density lipoprotein cholesterol in dyslipidemia by cholesteryl ester transfer protein inhibition: an update for clinicians.

Reduced HDL cholesterol may be a risk factor comparable in importance to increased LDL cholesterol. Interventions that raise HDL are antiatherosclerotic, presumably through acceleration of reverse cholesterol transport and by antioxidant and antiinflammatory effects. In the hypercholesterolemic rabbit, HDL levels can be increased by >50% by inhibition of cholesteryl ester transfer protein (CETP), a molecule that plays a central role in HDL metabolism. This HDL-raising effect is antiatherosclerotic in moderately severe hyperlipidemia but appears to be ineffective in the presence of severe hypertriglyceridemia. In humans, mutations resulting in CETP inhibition have been associated with both reduced and increased risk of atherosclerosis. Proposed explanations for these apparently disparate observations are that the antiatherosclerotic effect of CETP inhibition varies with either the metabolic milieu or the degree of CETP inhibition. We now have pharmacological inhibitors of CETP that are capable of increasing HDL by as much as 50% to 100% in humans. The importance of this development is that reduced HDL is a risk factor independent of LDL and that these new agents alter HDL by a magnitude comparable to that of statins on LDL. Clinical trials, now beginning, will need to identify the patient subsets in which CETP inhibition may be more or less effective.

New approaches to raising the HDL cholesterol level.

Not only a high level of low-density lipoprotein (LDL) cholesterol, but also a low level of high-density lipoprotein (HDL) cholesterol, is a critical risk factor for atherosclerosis and coronary heart disease. Although fibrates and niacin can be used to improve low HDL cholesterol levels, their effect is not wholly satisfactory, so better drugs for the elevation of HDL cholesterol are desired. Among the many methods that may be used to raise HDL cholesterol levels, this review focuses on inhibitors of cholesteryl ester transfer protein (CETP) and on nuclear orphan receptor agonists that mediate the expression of ATP-binding cassette transporter 1 (ABC1).

Chronic inflammatory disorders and accelerated atherosclerosis: chronic kidney disease.

Increasing evidence points to the fact that plasma HDL cholesterol levels do not always accurately predict HDL function including reverse cholesterol transport and modulation of inflammation. These functions appear to have evolved as part of our innate immune system. HDL is anti inflammatory in healthy individuals in the absence of systemic oxidative stress and inflammation. In those with chronic illnesses such as renal failure however, HDL may become dysfunctional and actually promote inflammation. HDL may be thought of as a shuttle whose size can be estimated by HDL cholesterol levels. The content of the shuttle however, is what determines the anti inflammatory potential of HDL and can change from one, supporting reverse cholesterol transport to one that is less efficient in carrying out this function. Chronic kidney disease (CKD), and inflammatory disorder, is associated with development of accelerated atherosclerosis and premature death from coronary artery disease (CAD). Patients with CKD present with dyslipidemia, oxidative stress and systemic inflammation. Among the abnormalities in lipid metabolism in these patients is reduced levels and protective capacity of HDL. Recent studies have shown that HDL from patients with end stage renal disease is not capable of preventing LDL oxidation and that it induces monocyte migration in artery wall model systems. Treatment of plasma from these patients, with an HDL mimetic peptide improved the anti inflammatory properties of patient's HDL and made LDL more resistant to oxidative modification. Animal models of kidney disease also had proinflammatory HDL and treatment with the peptide mimetic improved markers of inflammation and anti inflammatory capacity of HDL. Whether HDL mimetic peptides will have therapeutic benefit in patients with renal failure will have to be determined in clinical studies.

S-(2-(acylamino)phenyl) 2,2-dimethylpropanethioates as CETP inhibitors.

Studies on the relationship between the structure of the benzene moiety of S-(2-(acylamino)phenyl) 2,2-dimethylpropanethioates and CETP inhibitory activity were performed. Substituents on the benzene moiety influenced CETP inhibitory activity in a type and position dependent manner, and electron-withdrawing groups at the 4- or 5-position increased the activity. The most potent compound showed 50% inhibition of CETP activity in human plasma at a concentration of 2 microM.