Synthesis and cytotoxicity of a ruthenium nitrosyl nitric oxide donor with isonicotinic acid and a cell penetrating peptide

The syntheses and properties of trans-[Ru(NH3) 4(L)(NO)](BF4)3 (L = isonicotinic acid (inaH) (I) or ina-Tat48-60 (II)) are described. Tat48-60, a cell penetrating peptide fragment of the Tat regulatory protein of the HIV virus, was linked to the ruthenium nitrosyl through inaH. I and II release NO after reduction forming trans-[Ru(NH3)4(L)(H2O)]3 +. The IC50 values against B16-F10 melanoma cells of I and II (21 μmol L- 1 and 23 μmol L- 1, respectively) are close to that of the commercially available cisplatin (33 μmol L- 1) and smaller than similar complexes. The cytotoxicity is assigned to the NO released from I and II. © 2012 Elsevier B.V.

Increase nitric oxide and oxidative stress in dogs experimentally infected by Ehrlichia canis: Effect on the pathogenesis of the disease

The aim of this study was to evaluate nitric oxide levels, lipid peroxidation, protein oxidation and glutathione reductase activity in serum of dogs experimentally infected by Ehrlichia canis. Banked serum samples of dogs divided into two groups were used: negative control (n=5) and infected by E. canis (n=5). The concentration of nitrite/nitrate (NOx), lipid peroxidation (TBARS), advanced oxidation protein products (AOPP), and glutathione reductase (GR) activity in sera were evaluated. Samples were collected on days 0, 3, 6, 18 and 30 post-infection (PI). NOx and TBARS levels were significantly (P<0.05) higher in the infected group at 18 and 30 days PI, as well as AOPP levels at 30 days PI when compared to samples from control group. The GR activity was significant (P<0.05) increased in serum of dogs infected by E. canis on days 18 and 30 PI. Based on the increased levels of NOx, TBARS, AOPP and GR activity we concluded that dogs experimentally infected by E. canis develop a state of redox imbalance and that these changes might be involved in the pathophysiology of the disease. © 2013 Elsevier B.V.

Role of brain nitric oxide in the cardiovascular control of bullfrogs

The goal of the present study was to determine if nitric oxide (NO) acting on the brain of bullfrog (Lithobates catesbeianus) is involved in arterial pressure and heart rate (HR) control by influencing sympathetic activity. We investigated the effect of intracerebroventricular injections of l-NMMA (a nonselective NO synthase inhibitor) on mean arterial blood pressure (MAP), HR and cutaneous vascular conductance (CVC) of pelvic skin after intravenous injection of α or β adrenergic blockers, prazosin or sotalol, respectively. Arterial pressure was directly measured by a telemetry sensor inserted in the aortic arch of animals. l-NMMA increased MAP, but did not change HR. This hypertensive response was inhibited by the pre-treatment with prazosin, but accentuated by sotalol. The effect of l-NMMA on MAP was also inhibited by i.v. injections of the ganglionic blocker, hexamethonium. Thus, NO acting on the brain of bullfrog seems to present a hypotensive effect influencing the sympathetic activity dependent on α and β adrenergic receptors in the periphery. © 2013 Elsevier Inc.

Elevated Plasma Hemoglobin Levels Increase Nitric Oxide Consumption in Experimental and Clinical Acute Pulmonary Thromboembolism

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Type 2 Diabetes Elicits Lower Nitric Oxide, Bradykinin Concentration and Kallikrein Activity Together with Higher DesArg(9)-BK and Reduced Post-Exercise Hypotension Compared to Non-Diabetic Condition

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Effects of exercise training on stress-induced vascular reactivity alterations: role of nitric oxide and prostanoids

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Nitric oxide and brazilian propolis combined accelerates tissue repair by modulating cell migration, cytokine production and collagen deposition in experimental leishmaniasis

The fact that drugs currently used in the treatment of Leishmania are highly toxic and associated with acquired resistance has promoted the search for new therapies for treating American tegumentary leishmaniasis (ATL). In this study, BALB/c mice were injected in the hind paw with Leishmania (Leishmania) amazonensis and subsequently treated with a combination of nitric oxide (NO) donor (cis-[Ru(bpy)(2)imN(NO)](PF6)(3)) (Ru-NO), given by intraperitoneal injection, and oral Brazilian propolis for 30 days. Ru-NO reached the center of the lesion and increased the NO level in the injured hind paw without lesion exacerbation. Histological and immunological parameters of chronic inflammation showed that this combined treatment increased the efficacy of macrophages, determined by the decrease in the number of parasitized cells, leading to reduced expression of proinflammatory and tissue damage markers. In addition, these drugs in combination fostered wound healing, enhanced the number of fibroblasts, pro-healing cytokines and induced collagen synthesis at the lesion site. Overall, our findings suggest that the combination of the NO donor Ru-NO and Brazilian propolis alleviates experimental ATL lesions, highlighting a new therapeutic option that can be considered for further in vivo investigations as a candidate for the treatment of cutaneous leishmaniasis.

Contrasting effects of nitric oxide and corticotropin-releasing factor within the dorsal periaqueductal gray on defensive behavior and nociception in mice

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Gastric cancer is associated with NOS2-954G/C polymorphism and environmental factors in a Brazilian population

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Influence of Th1/Th2 cytokines and nitric oxide in murine systemic infection induced by Sporothrix schenckii

In an attempt to elucidate the effects of Sporothrix schenckii infection on the immune response, our laboratory has developed a murine model of disseminated sporotrichosis. Helper T cells can be further subdivided into Th1 and Th2 phenotypes. The differentiation of two subsets of T lymphocytes is driven by IL-12 and IL-4 cytokines, respectively. Th1 cells produce IFN-gamma that activate macrophages and promote cell-mediated immunity. In addition, we found low levels of iNOS and NO production in the initial (1st and 2nd weeks) and final (9th and 10th weeks) periods of the infection, in contrast with the period of week 4 to 7 of elevated values. The determination of IFN-gamma and IL-12 are in agreement with NO/iNOS detection, showing the presence of cellular immune response throughout the infectious process. However, the production of IL-4 shows an increase in levels after the 5th and 6th weeks suggesting a participation of Th2 response in this period as well. Regarding these results, the study demonstrated that in experimental sporotrichosis infection the cellular immune response participated throughout the period analyzed as a nitric oxide dependent mechanism. In contrast, the presence of Th2 response began in the 5th week, suggesting the participation of humoral immune response in advanced stages of sporotrichosis.

Influence of Yersinia pseudotuberculosis outer proteins (Yops) on interleukin-12, tumor necrosis factor alpha and nitric oxide production by peritoneal macrophages

An essential key to pathogenicity in Yersinia is the presence of a 70 kb plasmid (pYV) which encodes a type-III secretion system and several virulence outer proteins whose main function is to enable the bacteria to survive in the host. Thus, a specific immune response is needed in which cytokines are engaged. The aim of this study was to assess the influence of Yersinia outer proteins (Yops) released by Yersinia pseudotuberculosis on the production of the proinflammatory cytokines, interleukin-12 (IL-12), and tumor necrosis factor alpha (TNF-alpha), and nitric oxide (NO) by murine peritoneal macrophages. To this end, female Swiss mice were infected intravenously with wild-type Y pseudotuberculosis or with mutant strains unable to secrete specific Yops (YopE, YopH, YopJ, YopM, and YpkA). on the 7th, 14th, 21st, and 28th days after infection, the animals were sacrificed and the cytokines and NO were assayed in the peritoneal macrophages culture supernatants. A fall in NO production was observed during the course of infection with all the strains tested, though during the infection with the strains that did not secrete YopE and YopH, the suppression occurred later. There was, in general, an unchanged or sometimes increased production of TNF-alpha between the 7th and the 21st day after infection, compared to the control group, followed by an abrupt decrease on the last day of infection. The IL-12 production was also suppressed during the infection, with most of the strains tested, except with those that did not secrete YopJ and YopE. The results suggest that Yops may suppress IL-12, TNF-alpha, and NO production and that the most important proteins involved in this suppression are YopE and YopH. (C) 2004 Elsevier B.V. All rights reserved.

Morphological and physiological alterations induced by lactofen in soybean leaves are reduced with nitric oxide

O lactofen é um herbicida difeniléter recomendado para controlar plantas daninhas de folhas largas em campos de soja (Glycine max) e seu mecanismo de ação é a inibição da protoporfirinogênio-IX oxidase (Protox), que atua na biossíntese de clorofilas. Essa inibição resulta em um acúmulo de protoporfirina-IX, o que leva à produção de espécies reativas de oxigênio (ROS), causando estresse oxidativo. Conseqüentemente, podem ocorrer manchas, enrugamento e queima das folhas, o que leva à paralisação temporária do crescimento da cultura. Porém, o óxido nítrico (NO) atua como um antioxidante na eliminação direta das ROS. Assim, o objetivo deste trabalho foi verificar, por meio de avaliações fitométricas e bioquímicas, o efeito protetor do NO em plantas de soja tratadas com o herbicida lactofen. Plantas de soja foram pré-tratadas com diferentes doses de Nitroprussiato de Sódio (SNP), substância doadora de NO, e então pulverizadas com 168 g a.i. ha-1 lactofen. O pré-tratamento com SNP foi benéfico, pois o NO reduziu os sintomas de injúria causados pelo lactofen nos folíolos jovens e manteve baixos teores de açúcares solúveis. Porém, o NO proporcionou crescimento mais lento das plantas. Desta forma, posteriores estudos são necessários para elucidar os mecanismos de ação do NO na sinalização do estresse promovido pelo lactofen na cultura da soja.

eNOS T-786C polymorphism affects atorvastatin-induced changes in erythrocyte membrane fluidity

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