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Niacin is a broad-spectrum lipid-regulating drug used for clinical therapy of chronic high-grade inflammatory diseases. However, the mechanisms by which either niacin or the byproducts of its catabolism ameliorate these inflammatory diseases are not clear yet. Human circulating monocytes and mature macrophages were used to analyze the effects of niacin and its metabolites (NAM, NUA and 2-Pyr) on oxidative stress, plasticity and inflammatory response by using biochemical, flow cytometry, quantitative real-time PCR and Western blot technologies. Niacin, NAM and 2-Pyr significantly decreased ROS, NO and NOS2 expression in LPS-treated human mature macrophages. Niacin and NAM skewed macrophage polarization toward antiinflammatory M2 macrophage whereas a trend toward proinflammatory M1 macrophage was noted following treatment with NUA. Niacin and NAM also reduced the inflammatory competence of LPS-treated human mature macrophages and promoted bias toward antiinflammatory CD14 + CD16 ++ nonclassical human primary monocytes. This study reveals for the first time that niacin and its metabolites possess antioxidant, reprogramming and antiinflammatory properties on human primary monocytes and monocyte-derived macrophages. Our findings imply a new understanding of the mechanisms by which niacin and its metabolites favor a continuous and gradual plasticity process in the human monocyte/macrophage system., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Long and short QT syndromes associated with loss and gain of human ether-a-go-go-related gene (hERG) channel activity, respectively, can cause life-threatening arrhythmias. As such, modulation of hERG channel activity is an important consideration in the development of all new therapeutic agents. In the present study, we investigated the mechanisms of action of 2-[2-(3,4-dichloro-phenyl)-2,3-dihydro-1H-isoindol-5-ylamino]-nicotinic acid (PD-307243), a known hERG channel activator, on hERG channels stably expressed in Chinese hamster ovary (CHO) cells using the patch-clamp technique. In the whole-cell recordings, the extracellular application of PD-307243 concentration-dependently increased the hERG current and markedly slowed hERG channel deactivation and inactivation. PD-307243 had no effect on the selectivity filter of hERG channels. The activity of PD-307243 was use-dependent. PD-307243 (3 and 10 muM) induced instantaneous hERG current with little decay at membrane potentials from -120 to -40 mV. At more positive voltages, PD-307243 induced an I(to)-like upstroke of hERG current. The actions of PD-307243 on the rapid component of delayed rectifier K(+) current (I(Kr)) in rabbit ventricular myocytes were similar to those observed in hERG channel-transfected CHO cells. Inside-out patch experiments revealed that PD-307243 increased hERG tail currents by 2.1 +/- 0.6 (n = 7) and 3.4 +/- 0.3-fold (n = 4) at 3 and 10 muM, respectively, by slowing the channel deactivation but had no effect on channel activation. During a voltage-clamp protocol using a prerecorded cardiac action potential, 3 muM PD-307243 increased the total potassium ions passed through hERG channels by 8.8 +/- 1.0-fold (n = 5). Docking studies suggest that PD-307243 interacts with residues in the S5-P region of the channel.

We investigated the relative activity of N-(beta-D-glucopyranosyl)-nicotinic acid as a niacin nutrient in rats and in Lactobacillus plantarum ATCC 8014. N-(beta-D-Glucopyranosyl)-nicotinic acid is a detoxified product or storage form of nicotinic acid that is found in plants. The relative activity of N-(beta-D-glucopyranosyl)nicotinic acid to nicotinic acid in rats was 1/2.3, 1/2.2, 1/1.0, and 1/1.7 as indices of the body weight gain, food intake, blood NAD content, and the increased urinary excretion of niacin and its metabolites, respectively. N-(beta-D-Glucopyranosyl)nicotinic acid had no niacin activity in Lactobacillus plantarum ATCC 8014.

A series of pyridines and other six-membered ring heterocycles connected to a biphenyltetrazole with a -CH2-NR'-link (1) were discovered to be potent angiotensin II antagonists. In the pyrimidine carboxylic acid series (W = CR, X = N, Y = CH, Z = COOH), compounds with an alkyl group (R') on the exocyclic nitrogen were much more potent than compounds with an alkyl group (R) on the heterocyclic ring. The corresponding pyridine, pyridazine, pyrazine, and 1,2,4-triazine carboxylic acids also showed potent in vitro angiotensin II antagonism. The pyridine (W, X, Y = CH, Z = COOH, R' = n-C3H7) demonstrated potent in vitro activity (pA2 = 10.10, rabbit aorta, and Ki = 0.61 nM, receptor binding in rat liver) as well as exceptional oral antihypertensive activity and bioavailability. Any nonacidic replacement for the carboxylic acid was detrimental for activity.

A hypolipidemic agent, pentaerythritol tetranicotinate (niceritrol) yields nicotinic acid upon hydrolysis in vivo, but niceritrol is hardly soluble in distilled water, so that the effects of nicotinic acid on platelet aggregation in vitro were studied. Nicotinic acid inhibited in vitro platelet aggregation induced by ADP, collagen and adrenaline. Twenty patients (61.4 +/- 2.4 years (mean +/- S.E.)) with ischemic heart disease, cerebral infarction, transient cerebral ischemic attack and hypercholesterolemia were given niceritrol orally at 750 mg per day for 8 weeks. Significant decreases in ADP-, collagen- and adrenaline-induced platelet aggregation were observed at 4 and 8 weeks after niceritrol treatment. There was a significant correlation between the rates of changes in platelet aggregation and those in plasma total cholesterol or plasma LDL-cholesterol before treatment and 8 weeks following treatment. The results indicate that niceritrol has inhibitory effects on platelet aggregation not only caused by its direct action on platelet but mediated by its secondary action due to decrease in blood lipids.