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Background and objective: Microbial resistance to antibiotics continues to emerge as a significant global health concern. The misuse of antibiotics is an important factor contributing to the development of antibiotic resistance by bacteria. Urinary tract infection is among the most common bacterial infections, being Escherichia coli the main etiological agent.

The antihyperglycaemic effect of eight standard flavonoids, previously identified in the ethanol extract of the claimed antidiabetic plant Genista tenera, was evaluated on streptozotocin (STZ)-induced diabetic Wistar rats. The aglycones apigenin, chrysoeriol and genistein, the monoglucosides apigenin 7-O-glucoside, luteolin 7-O-glucoside and genistein 7-O-glucoside and the diglycosides rutin and luteolin 7,3′-di-O-glucoside were administered i.p. for 7 days (4 mg/kg b.w./day). The protective effect of these compounds over liver and kidneys of STZ–diabetic models was also evaluated by the determination of seric AST, ALT and urea levels. After 7 days of treatment, apigenin, chrysoeriol and genistein significantly lowered the blood glucose levels of diabetic animals; this effect was more pronounced (P < 0.01) in the oral glucose tolerance test. Glucose tolerance was also significantly improved in the rutin (P < 0.01) and in the genistein 7–O–glucoside (P < 0.05) treated groups. In addition, almost all the tested compounds effectively protected the liver and kidneys against STZ-induced damage in rats FCT

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Background/Aims: Oxidative and nitrosative stress plays important roles in the pathogenesis of renal ischemia/reperfusion (I/R) injury. Here we investigate the effect of EUK-134, a synthetic superoxide dismutase and catalase mimetic, (i) on renal dysfunction and injury caused by I/R in vivo and (ii) on proximal tubular cell (PTC) injury and death caused by oxidative and nitrosative stress. Methods: Rats, subjected to bilateral renal ischemia (45 min) followed by reperfusion (6 h), were administered EUK-134 (0.3 and 3 mg/kg, i.v.) prior to and during reperfusion, after which biochemical and histological indicators of renal dysfunction and injury were measured. The expression of poly(ADP-ribose) (PAR) and inducible nitric oxide (NO) synthase (iNOS) and nitrotyrosine formation were determined immunohistochemically and used as indicators of oxidative and nitrosative stress. Primary cultures of rat PTCs, isolated and cultured from the kidney cortex, were incubated with hydrogen peroxide (H2O2; 1 mM for 2 h) in the presence of increasing concentrations of EUK-134 (1–100 µM) after which PTC injury and death were measured. The effects of EUK-134 on serum levels of NO in rats subjected to renal I/R or on NO production by PTCs incubated with interferon-γ (IFN-γ, 100 IU/ml) and bacterial lipopolysaccharide (LPS, 10 µg/ml) in combination for 24 h were also measured. Results: EUK-134 produced a significant reduction in renal dysfunction and injury caused by I/R. Specifically, serum creatinine levels, an indicator of renal dysfunction, were reduced from 227 ± 11 (n = 12, I/R only) to 146 ± 9 µM (n = 12, I/R +3 mg/kg EUK-134). Urinary N-acetyl-β-D-glucosaminidase activity, an indicator of tubular damage, was reduced from 42 ± 5 (n = 12, I/R only) to 22 ± 3 IU/l (n = 12, I/R +3 mg/kg EUK-134). EUK-134 significantly reduced renal injury caused by oxidative stress in vivo (reduction in PAR formation), and in vitro EUK-134 reduced PTC injury and death caused by H2O2. However, EUK-134 also reduced nitrosative stress caused by I/R in vivo (reduction of iNOS expression and nitrotyrosine formation), which was reflected by a significant reduction in serum NO levels in rats subjected to renal I/R. Specifically, serum NO levels were reduced from 57 ± 12 (n = 12, I/R only) to 23 ± 3 mM (n = 12, I/R +3 mg/kg EUK-134). In vitro, EUK-134 significantly reduced NO production by PTCs incubated with IFN-γ/LPS. Conclusion: We propose that EUK-134 reduces renal I/R injury not only via reduction of oxidative stress, but also by reducing nitrosative stress caused by renal I/R.

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This study was designed to investigate the effects of various chemically distinct activators of PPAR-gamma and PPAR-alpha in a rat model of acute myocardial infarction. Using Northern blot analysis and RT-PCR in samples of rat heart, we document the expression of the mRNA for PPAR-gamma (isoform 1 but not isoform 2) as well as PPAR-beta and PPAR-alpha in freshly isolated cardiac myocytes and cardiac fibroblasts and in the left and right ventricles of the heart. Using a rat model of regional myocardial ischemia and reperfusion (in vivo), we have discovered that various chemically distinct ligands of PPAR-gamma (including the TZDs rosiglitazone, ciglitazone, and pioglitazone, as well as the cyclopentanone prostaglandins 15D-PGJ(2) and PGA(1)) cause a substantial reduction of myocardial infarct size in the rat. We demonstrate that two distinct ligands of PPAR-gamma (including clofibrate and WY 14643) also cause a substantial reduction of myocardial infarct size in the rat. The most pronounced reduction in infarct size was observed with the endogenous PPAR-gamma ligand, 15-deoxyDelta(12,14)-prostagalndin J(2) (15D- PGJ(2)). The mechanisms of the cardioprotective effects of 15D- PGJ(2) may include 1) activation of PPAR-alpha, 2) activation of PPAR-gamma, 3) expression of HO-1, and 4) inhibition of the activation of NF-kappaB in the ischemic-reperfused heart. Inhibition by 15D- PGJ2 of the activation of NF-kappaB in turn results in a reduction of the 1) expression of inducible nitric oxide synthase and the nitration of proteins by peroxynitrite, 2) formation of the chemokine MCP-1, and 3) expression of the adhesion molecule ICAM-1. We speculate that ligands of PPAR-gamma and PPAR-alpha may be useful in the therapy of conditions associated with ischemia-reperfusion of the heart and other organs. Our findings also imply that TZDs and fibrates may help protect the heart against ischemia-reperfusion injury. This beneficial effect of 15D- PGJ(2) was associated with a reduction in the expression of the 1) adhesion molecules ICAM-1 and P-selectin, 2) chemokine macrophage chemotactic protein 1, and 3) inducible isoform of nitric oxide synthase. 15D- PGJ(2) reduced the nitration of proteins (immunohistological analysis of nitrotyrosine formation) caused by ischemia-reperfusion, likely due to the generation of peroxynitrite. Not all of the effects of 15D-PGJ(2), however, are due to the activation of PPAR-gamma. For instance, exposure of rat cardiac myocytes to 15D-PGJ(2), but not to rosiglitazone, results in an up-regulation of the expression of the mRNA for heme-oxygenase-1 (HO-1). Taken together, these results provide convincing evidence that several, chemically distinct ligands of PPAR-gamma reduce the tissue necrosis associated with acute myocardial infarction.

The involvement of the nitric oxide synthase/soluble guanylate cyclase pathway on the modulation of phenylephrine-induced contractility in the rat vas deferens was investigated. Phenlylephrine-concentration response curves were obtained in absence and in presence of inhibitors, N-G-Nitro-L-arginine (L-NOARG), N-G-Nitro-L-arginine methyl esther (L-NAME) or N-G-monomethyl-L-arginine (L-NMMA) or GC inhibitior, 1H-(1,2,4)-oxadiaziol-(4,3-a)quinoxalin-1-one (ODQ) or nitric oxide donor, 3-morpholinosydnonimine hydrochloride (SIN-1) alone or together with L-NMMA or ODQ. Both nitric oxide synthase and GC inhibitors reduced the Phe-E-max SIN-1 alone did not change phenylephrine-induced responses and it could reverse the L-NMMA effect but not ODQ effect. The reduction of the phenylephrine-induced contractility obtained in consequence of the inhibition of the nitric oxide/GC pathway suggest that, in the rat vas deferens, despite its well identified relaxant properties, nitric oxide potentiates the contractility induced by adrenergic stimulation.

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