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Adults with vascular disease were treated with a statin to lower LDL cholesterol and were assigned to receive either extended-release niacin plus laropiprant or placebo. Niacin–laropiprant did not significantly reduce the risk of major vascular events and increased the risk of serious adverse events. Patients with cardiovascular disease remain at substantial risk for major vascular events despite current approaches to treatment of risk factors. 1 Observational data indicate that the low-density lipoprotein (LDL) cholesterol level is strongly positively associated with the risk of coronary heart disease and that the high-density lipoprotein (HDL) cholesterol level is strongly inversely associated. 2 High-dose niacin decreases the LDL cholesterol level and increases the HDL cholesterol level, as well as lowering triglyceride and lipoprotein(a) levels and blood pressure. 3 , 4 Current guidelines recommend that niacin therapy be considered for reducing cardiovascular risk, 5 , 6 and its use in the United States has been . . .

In this clinical trial involving patients with established cardiovascular disease, the addition of niacin to intensive statin therapy provided no additional clinical benefit over a period of 3 years, despite favorable changes in lipid levels. More than 18 million North Americans have coronary heart disease, and despite profound advances in both pharmacologic and interventional management, both morbidity and mortality remain appreciable. 1 , 2 Elevated low-density lipoprotein (LDL) cholesterol levels are an established predictor of the risk of coronary heart disease. Multiple primary and secondary prevention trials have shown a significant reduction of 25 to 35% in the risk of cardiovascular events with statin therapy 3 ; however, residual risk persists despite the achievement of target LDL cholesterol levels. Epidemiologic studies have shown that, in addition to elevated LDL cholesterol levels, low levels of high-density lipoprotein (HDL) cholesterol . . .

Background. Low levels of high-density lipoprotein cholesterol (HDL-C) are common in individuals with human immunodeficiency virus (HIV) infection, persist during antiretroviral therapy (ART), and are associated with increased cardiovascular disease (CVD) risk. Methods. Virologically controlled participants without CVD on stable ART with low HDL-C (men <40 mg/dL, women <50 mg/dL) and triglycerides >150 mg/dL were randomized to receive open-label extended-release niacin 1500 mg/day with aspirin 325 mg/day or fenofibrate 200 mg/day for 24 weeks. The primary endpoint was the week 24 within-arm change in brachial artery flow-mediated dilation (FMD) in participants with complete follow-up scans. Results. Of 99 participants, 74 had complete data (35 niacin, 39 fenofibrate). Median age was 45 years, 77% were male, median CD4+ count was 561 cells/μL, and brachial FMD was 4.2%. Median HDL-C was 32 mg/dL for men and 38 mg/dL for women, low-density lipoprotein cholesterol was 103 mg/dL, and triglycerides were 232 mg/dL. In men, HDL-C increased a median of 3 mg/dL with niacin and 6.5 mg/dL with fenofibrate (P < .001 for both). In women, HDL-C increased a median of 16 mg/dL with niacin and 8 mg/dL with fenofibrate (P = .08 for both). After 24 weeks, there was no significant change in FMD in either arm; the median (interquartile range) change was +0.6% (−1.6 to 2.3) with niacin (P = .28) and +0.5% (−1.0 to 3.0) with fenofibrate (P = .19). Neither treatment significantly affected C-reactive protein, interleukin 6, or D-dimer levels. Conclusions. Despite improvements in lipids, niacin or fenofibrate treatment for 24 weeks did not improve endothelial function or inflammatory markers in participants with well-controlled HIV infection and low HDL-C. Clinical Trials Registration. NCT01426438.

The use of lower concentrations and fewer applications of herbicides is one of the prime objectives of the sustainable agriculture as it decreases the toxicity to non-targeted organisms and the risk of wider environmental contamination. In the present work, nanoparticles were developed for encapsulation of the herbicides imazapic and imazapyr. Alginate/chitosan and chitosan/tripolyphosphate nanoparticles were manufactured and their physicochemical stability was evaluated. Determinations were made of the encapsulation efficiency and release kinetics and the toxicity of the nanoparticles was evaluated using cytotoxicity and genotoxicity assays. The effects of herbicides and herbicide-loaded nanoparticles on soil microorganisms were studied in detail using real-time polymerase chain reactions. The nanoparticles showed an average size of 400 nm and remained stable during 30 days of storage at ambient temperature. Satisfactory encapsulation efficiencies of between 50 and 70% were achieved for both types of particles. Cytotoxicity assays showed that the encapsulated herbicides were less toxic, compared to the free compounds and genotoxicity was decreased. Analyses of soil microbiota revealed changes in the bacteria of the soils exposed to the different treatments. Our study proves that encapsulation of the herbicides improved their mode of action and reduced their toxicity, indicating their suitability for use in future practical applications.

In patients who have, or are at risk for, coronary artery disease, niacin added to statin therapy resulted in regression of the carotid intima–media thickness. In contrast, ezetimibe added to statin therapy paradoxically resulted in progression of the carotid intima–media thickness. Treatment with 3-hydroxy-3-methylglutaryl–coenzyme A reductase inhibitors reduces low-density lipoprotein (LDL) cholesterol levels and results in clinically significant reductions in the relative risk of major cardiovascular events. 1 However, because of the residual cardiovascular risk seen with statin monotherapy, treatment may be intensified with the use of combination therapy, aimed at either further reducing the LDL cholesterol level or at altering levels of other lipids, such as high-density lipoprotein (HDL) cholesterol. Progressive lowering of the LDL cholesterol level through intensification of statin therapy leads to a 16% reduction in the odds of cardiovascular events and death from cardiovascular causes. 2 This approach has . . .

The objective of this study was to observe the antihypertensive effect of losartan and levamlodipine besylate on insulin resistance in patients with essential hypertension (EH) combined with isolated impaired fasting glucose (i-IFG). Patients (n=244) were randomly assigned to losartan potassium tablets (50-100 mg per day) or levamlodipine besylate tablets (2.5-5.0 mg per day) for intensive antihypertensive treatment with no lifestyle interventions for 3 years. The changes in fasting plasma glucose, fasting insulin (FINS) and insulin sensitivity index (ISI) from before to after treatment were observed. Blood pressure (BP) in each group was significantly reduced by treatment (P<0.05). After 12 months of treatment, the FINS level in the losartan potassium group was significantly decreased and ISI was significantly increased compared with before treatment (P<0.05) and compared with the levamlodipine besylate group (P<0.05). After 24 and 36 months of treatment, FINS was significantly decreased and ISI was significantly improved in both groups compared with baseline (P<0.05), and there was no difference between the groups (P>0.05). The incidence of new-onset diabetes mellitus was not significantly different between two groups. The antihypertensive effect of losartan and levamlodipine besylate could amoliorate insulin resistance in patients with EH combined with i-IFG. The improvement of insulin resistance by losartan potassium at 12 months might be better than that by levamlodipine besylate; however, after 24 and 36 months of follow-up, both agents significantly alleviated insulin resistance. These results suggest that the effects of these two drugs on insulin resistance are not significantly different.

In this study, we used macrophage RAW264.7 cells to elucidate the molecular mechanism underlying the anti-inflammatory actions of niacin. Anti-inflammatory actions of niacin and a possible role of its receptor GPR109A have been studied previously. However, the precise molecular mechanism of niacin’s action in reducing inflammation through GPR109A is unknown. Here we observed that niacin reduced the translocation of phosphorylated nuclear kappa B (p-NF-κB) induced by lipopolysaccharide (LPS) in the nucleus of RAW264.7 cells. The reduction in the nuclear translocation in turn decreased the expression of pro-inflammatory cytokines IL-1β, IL-6 in RAW264.7 cells. We observed a decrease in the nuclear translocation of p-NF-κB and the expression of inflammatory cytokines after knockdown of GPR109A in RAW264.7 cells. Our results suggest that these molecular actions of niacin are mediated via its receptor GPR109A (also known as HCAR2) by controlling the translocation of p-NF-κB to the nucleus. Overall, our findings suggest that niacin treatment may have potential in reducing inflammation by targeting GPR109A.

The X-ray crystal structure of the human P2Y 12 receptor, which regulates platelet activation and thrombus formation, is solved in complex with an antithrombotic drug, providing insights for the development of new drugs. Key platelet aggregation GPCR structures Two papers in this issue of Nature present the crystal structures of the human P2Y 12 receptor, first in complex with the antithrombotic drug AZD1283, and second, bound to a full agonist (a close analogue of endogenous agonist ADP) and to a partial agonist. P2Y receptors are a family of purinergic G-protein-coupled receptors (GPCRs) that are activated by extracellular nucleotides. The P2Y 12 receptor is found mainly on the surface of platelets, where it regulates platelet activation and thrombus formation, and it is the target of several important antithrombotic drugs. In overall structure, P2Y 12 receptor is found to be similar to other GPCRs, although both the shape and location of the ligand-binding pocket are unusual. Comparisons of the three newly determined structures reveal that agonist binding induces a large-scale rearrangement of the extracellular domains of the GPCR. P2Y receptors (P2YRs), a family of purinergic G-protein-coupled receptors (GPCRs), are activated by extracellular nucleotides. There are a total of eight distinct functional P2YRs expressed in human, which are subdivided into P2Y 1 -like receptors and P2Y 12 -like receptors 1 . Their ligands are generally charged molecules with relatively low bioavailability and stability in vivo 2 , which limits our understanding of this receptor family. P2Y 12 R regulates platelet activation and thrombus formation 3 , 4 , and several antithrombotic drugs targeting P2Y 12 R—including the prodrugs clopidogrel (Plavix) and prasugrel (Effient) that are metabolized and bind covalently, and the nucleoside analogue ticagrelor (Brilinta) that acts directly on the receptor—have been approved for the prevention of stroke and myocardial infarction. However, limitations of these drugs (for example, a very long half-life of clopidogrel action and a characteristic adverse effect profile of ticagrelor) 5 , 6 suggest that there is an unfulfilled medical need for developing a new generation of P2Y 12 R inhibitors 7 , 8 . Here we report the 2.6 Å resolution crystal structure of human P2Y 12 R in complex with a non-nucleotide reversible antagonist, AZD1283. The structure reveals a distinct straight conformation of helix V, which sets P2Y 12 R apart from all other known class A GPCR structures. With AZD1283 bound, the highly conserved disulphide bridge in GPCRs between helix III and extracellular loop 2 is not observed and appears to be dynamic. Along with the details of the AZD1283-binding site, analysis of the extracellular interface reveals an adjacent ligand-binding region and suggests that both pockets could be required for dinucleotide binding. The structure provides essential insights for the development of improved P2Y 12 R ligands and allosteric modulators as drug candidates.

Purpose We determined the effect of suppressing lipolysis via administration of Nicotinic acid (NA) and pre-exercise feeding on rates of whole-body substrate utilisation and cycling time trial (TT) performance. Methods In a randomised, single-blind, crossover design, eight trained male cyclists/triathletes completed two series of TTs in which they performed a predetermined amount of work calculated to last ~60, 90 and 120 min. TTs were undertaken after a standardised breakfast (2 g kg −1 BM of carbohydrate (CHO)) and ingestion of capsules containing either NA or placebo (PL). Results Plasma [free fatty acids] were suppressed with NA, but increased in the later stages of TT90 and TT120 with PL ( p  < 0.05). There was no treatment effect on time to complete TT60 (60.4 ± 4.1 vs. 59.3 ± 3.4 min) or TT90 (90.4 ± 9.1 vs. 89.5 ± 6.6 min) for NA and PL, respectively. However, TT120 was slower with NA (123.1 ± 5.7 vs. 120.1 ± 8.7 min, p  < 0.001), which coincided with a decline in plasma [glucose] during the later stages of this ride ( p  < 0.05). For TTs of the same duration, the rates of whole-body CHO oxidation were unaffected by NA, but decreased with increasing TT time ( p  < 0.05). CHO was the predominant substrate for all TTs contributing between 83 and 94 % to total energy expenditure, although there was a small use of lipid-based fuels for all rides. Conclusion (1) NA impaired cycling TT performance lasting 120 min, (2) cycling TTs lasting from 60 to 120 min are CHO dependent, and (3) there is an obligatory use of lipid-based fuels in TTs lasting 1–2 h.

Cachexia is a debilitating wasting syndrome and highly prevalent comorbidity in cancer patients. It manifests especially with energy and mitochondrial metabolism aberrations that promote tissue wasting. We recently identified nicotinamide adenine dinucleotide (NAD + ) loss to associate with muscle mitochondrial dysfunction in cancer hosts. In this study we confirm that depletion of NAD + and downregulation of Nrk2 , an NAD + biosynthetic enzyme, are common features of severe cachexia in different mouse models. Testing NAD + repletion therapy in cachectic mice reveals that NAD + precursor, vitamin B3 niacin, efficiently corrects tissue NAD + levels, improves mitochondrial metabolism and ameliorates cancer- and chemotherapy-induced cachexia. In a clinical setting, we show that muscle NRK2 is downregulated in cancer patients. The low expression of NRK2 correlates with metabolic abnormalities underscoring the significance of NAD + in the pathophysiology of human cancer cachexia. Overall, our results propose NAD + metabolism as a therapy target for cachectic cancer patients. The loss of nicotinamide adenine dinucleotide is reported to be associated with muscle mitochondrial dysfunction in murine cancer models. Here the authors show that niacin supplementation improves mitochondrial metabolism and reduces muscle wasting in mouse models of cachexia.