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Abstract: A series of fifteen new compounds related to pyrazinamide (PZA) were synthesized, characterized with analytical data and screened for antimycobacterial, antifungal and antibacterial activity. The series consists of 6-chloro-5-cyanopyrazine-2-carboxamide and N-substituted 6-amino-5-cyanopyrazine-2-carboxamides, derived from the previous by nucleophilic substitution with various non-aromatic amines (alkylamines, cycloalkylamines, heterocyclic amines). Some of the compounds exerted antimycobacterial activity against Mycobacterium tuberculosis equal to pyrazinamide (12.5–25μg/mL). More importantly, 6-chloro-5-cyanopyrazine-2-carboxamide and 5-cyano-6-(heptylamino)pyrazine-2-carboxamide were active against Mycobacterium kansasii and Mycobacterium avium, which are unsusceptible to PZA. Basic structure–activity relationships are presented. Only weak antifungal and no antibacterial activity was detected. [Copyright &y& Elsevier]

Introduction: Epicardial adipose tissue (EAT) may serve as a transducer of metabolic influences on the heart. The determinants of EAT gene expression in advanced heart failure (HF) are not known. Hypothesis: HF and associated clinical factors affect EAT gene expression profile. Methods: We examined EAT from 54 advanced HF patients undergoing heart transplantation (age: 49±7y, 83% males, 37% ischemic, LVEF: 20±5.9%, NYHA 3.3±0.5, BMI 25±4.0 kg.m-2) and 20 controls (HF-free organ donors, LVEF 57±8.9%) of similar BMI, age and gender. EAT from anterior interventricular area was harvested at TX. After RNA isolation (RNeasy Lipid Tissue MiniKit, Qiagen), gene expression analysis (qPCR) was performed (LightCycler, Roche Diagnostics) and normalized to the mean of GAPDH and EF-1A genes. Results: Compared to controls, EAT of HF patients displayed profound upregulation of metabolic transcription factors PGC1a and PPARa, upregulation of adipokines (leptin, adiponectin) and enhanced prolipolytic signalling (upregulated natriuretic peptide receptors A and C, hormone sensitive lipase, perilipin, ATGL) that correlated (p<0.05) with neurohumoral activation (log-BNP). PRDM16, marker of adipocyte browning, was not different between HF and controls. HF patients had higher expression of IL-6. Enhanced expression of lipolytic genes was coupled with enhanced lipogenesis (FAS, ACSL1) and triacyglycerol synthesis (DGAT1, 2). From studied clinical factors (DM, age, HF etiology, BMI) within HF group, EAT gene expression was most strongly influenced by cardiac cachexia (body weight-BW loss ≥5% in 6m, present in 46%). Cachectic HF patients markedly reduced expression of NP-C receptor (p<0.001). NPR-C expression in EAT of HF subjects correlated with BMI (r=0.43, p=0.001), log-BNP (r=-0.44, p=0.001). BW loss (%) correlated (p<0.05) with enhanced EAT expression of PGC-1a (r: -0.27), PPARa (r:-0.32) and reduced expression of NPR-C (r: 0.29) and leptin (r: 0.38). Conclusions: EAT in advanced HF is characterized by enhanced lipolysis and compensatory increase in lipogenesis. HF-related cachexia affects EAT transcription profile, is associated with loss of clearance receptor for natriuretic peptides (NPR-C) leading to more profound EAT metabolic activation. [ABSTRACT FROM AUTHOR]

n-3 polyunsaturated fatty acids ( n-3 PUFA ) might regulate metabolism by lowering endocannabinoid levels. We examined time-dependent changes in adipose tissue levels of endocannabinoids as well as in parameters of glucose homeostasis induced by n-3 PUFA in dietary-obese mice, and compared these results with the effect of n-3 PUFA intervention in type 2 diabetic (T2DM) subjects. Male C57BL/6J mice were fed for 8, 16 or 24 weeks a high-fat diet alone (cHF) or supplemented with n-3 PUFA (cHF + F). Overweight/obese, T2DM patients on metformin therapy were given for 24 weeks corn oil (Placebo; 5 g/day) or n-3 PUFA concentrate as above (Omega-3; 5 g/day). Endocannabinoids were measured by liquid chromatography-tandem mass-spectrometry. Compared to cHF-fed controls, the cHF + F mice consistently reduced 2-arachidonoylglycerol (up to ~2-fold at week 24) and anandamide (~2-fold) in adipose tissue, while the levels of endocannabinoid-related anti-inflammatory molecules N -eicosapentaenoyl ethanolamine (EPEA) and N -docosahexaenoyl ethanolamine (DHEA) increased more than ~10-fold and ~8-fold, respectively. At week 24, the cHF + F mice improved glucose tolerance and fasting blood glucose, the latter being positively correlated with adipose 2-arachidonoylglycerol levels only in obese cHF-fed controls, like fasting insulin and HOMA-IR. In the patients, n-3 PUFA failed to reduce 2-arachidonoylglycerol and anandamide levels in adipose tissue and serum, but they increased both adipose tissue and serum levels of EPEA and DHEA. In conclusion, the inability of n-3 PUFA to reduce adipose tissue and serum levels of classical endocannabinoids might contribute to a lack of beneficial effects of these lipids on glucose homeostasis in T2DM patients. [ABSTRACT FROM AUTHOR]

Combining pharmacological treatments and life style interventions is necessary for effective therapy of major diseases associated with obesity, which are clustered in the metabolic syndrome. Acting via multiple mechanisms, combination treatments may reduce dose requirements and, therefore, lower the risk of adverse side effects, which are usually associated with long-term pharmacological interventions. Our previous study in mice fed high-fat diet indicated additivity in preservation of insulin sensitivity and in amelioration of major metabolic syndrome phenotypes by the combination treatment using n-3 long-chain polyunsaturated fatty acids (n-3 LC-PUFA) and rosiglitazone, i.e. an anti-diabetic drug of the thiazolidinedione (TZD) family. We investigated here whether pioglitazone, a TZD-drug in clinical use, could elicit the additive beneficial effects when combined with n-3 LC-PUFA. Adult male mice (C57BL/6N) were fed an obesogenic corn oil-based high-fat diet (cHF) for 8 weeks, or randomly assigned to various dietary treatments (i) cHF+F, cHF with n-3 LC-PUFA concentrate replacing 15% of dietary lipids; (ii) cHF+ROSI, cHF with 10 mg rosiglitazone/kg diet; (iii) cHF+F+ROSI; (iv) cHF+PIO, cHF with 50 mg pioglitazone/kg diet; and (v) cHF+F+PIO, or chow-fed. Plasma concentrations of 163 metabolites were evaluated using a targeted metabolomics approach. Both TZDs preserved glucose homeostasis and normal plasma lipid levels while inducing adiponectin, with pioglitazone showing better effectiveness. The beneficial effects of TZDs were further augmented by the combination treatments. cHF+F+ROSI but not cHF+F+PIO counteracted development of obesity, in correlation with inducibility of fatty acid β-oxidation, as revealed by the metabolomic analysis. By contrast, only cHF+F+PIO eliminated hepatic steatosis and this treatment also reversed insulin resistance in dietary obese mice. Our results reveal differential effects of rosiglitazone and pioglitazone, unmasked in the combination treatment with n-3 LC-PUFA, and support the notion that n-3 LC-PUFA could be used as add-on treatment to TZDs in order to improve diabetic patient's therapy. [ABSTRACT FROM AUTHOR]