RESUMO
Although nitrite improves vascular function and lowers blood pressure, its cardiac effects are not completely known. We investigated whether nitrite improves the cardiac function in normotensive and in hypertensive rats. Two-kidney, one-clip hypertension model (2K1C) was induced in Wistar rats. Blood pressure was evaluated by tail-cuff plethysmography over 6â¯weeks. By the end of week 2, hypertensive and normotensive rats received nitrite (daily dose of 1 or 15â¯mg/kg) by gavage for 4â¯weeks. Cardiac morphology and function were performed by transthoracic echocardiography. Intrinsic heart function was evaluated using the isolated heart model (Langendorff's preparation). Starling curves were generated under nitrite (1⯵mol/L) and/or ascorbate (1â¯mmol/L) or vehicle. Cardiac tissue was collected and snap frozen for biochemical analysis. Nitrite treatment (15â¯mg/kg) lowered both systolic blood pressure and the increases in left ventricular (LV) mass found in 2K1C rats (Pâ¯<â¯.05). In addition, nitrite treatment restored the decreased cardiac output in 2K1C rats (Pâ¯<â¯.05) and improved the cardiac function. These findings were associated with increased nitrite, S-nitrosothiols, and protein S-nitrosylation (all Pâ¯<â¯.05) assessed in heart tissue. The cardiac effects of nitrite were further investigated in the isolated heart model, and nitrite infusion (1⯵mol/L) enhanced cardiac contractility and relaxation. This infusion increased S-nitrosothiols concentrations and protein S-nitrosylation in the heart. Ascorbate completely blunted all nitrite-induced effects. These findings show that treatment with oral nitrite improves cardiac function by mechanisms involving increased S-nitrosothiols generation and S-nitrosylation of cardiac proteins. Pharmacological strategies promoting cardiac S-nitrosylation may be useful to improve myocardial function in heart diseases.
Assuntos
Cardiomiopatias/etiologia , Cardiomiopatias/prevenção & controle , Hipertensão/complicações , Miocárdio/metabolismo , Nitratos/metabolismo , Nitrito de Sódio/farmacologia , Animais , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Cardiomiopatias/metabolismo , Coração/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Masculino , Miocárdio/patologia , Nitrosação/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Nitrito de Sódio/uso terapêuticoRESUMO
Bactris setosa Mart. is a Brazilian tree from the palm family (Arecaceae), whose fruits are scientifically underexploited. Here, we report, for the first time, the identification and quantification of phenolic compounds and carotenoids in the pulp, seed, and peel extracts of B. setosa fruits and their in vitro biological activity. The anthocyanins cyanidin deoxyhexose hexoside and cyanidin hexoside and other phenolic compounds were detected mainly in the peel but also in the pulp extracts. All-trans-lutein was the unique carotenoid identified and quantified, and only in the peel extract. All extracts were able to scavenge reactive oxygen and nitrogen species (ROS and RNS, respectively), to modulate human neutrophils' oxidative burst and to protect Caco-2 cells against oxidative damage, the peel extract being the most efficient. This study indicates that extracts from B. setosa fruits, especially the peel extract, are a source of bioactive compounds with promising antioxidant and anti-inflammatory properties.
Assuntos
Arecaceae/química , Carotenoides/análise , Frutas/química , Nitrosação/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Fenóis/análise , Extratos Vegetais/farmacologia , Substâncias Protetoras/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Brasil , Células CACO-2 , Proliferação de Células/efeitos dos fármacos , Humanos , Extratos Vegetais/química , Substâncias Protetoras/química , Espécies Reativas de Nitrogênio/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Sementes/químicaRESUMO
Several studies report that (+)-usnic acid, a lichen secondary metabolite, inhibits growth of different bacteria and fungi; however, the mechanism of its antimicrobial activity remains unknown. In this study, we explored the ability of usnic acid, obtained from Usnea amblyoclada, as an antibiofilm agent against azole-resistant and azole-sensitive Candida albicans strains by studying the cellular stress and antioxidant response in biofilms. The biofilm inhibitory concentration of usnic acid (4 µg/mL) exhibited a significant biofilm inhibition, 71.08â% for azole-resistant and 87.84â% for azole-sensitive C. albicans strains. Confocal scanning laser microscopy showed that the morphology of mature biofilm was altered (reduced the biomass and thickness) in the presence of usnic acid. The antifungal effect was mediated by an oxidative and nitrosative stress, with a significant accumulation of intracellular and extracellular reactive oxygen species detected by confocal scanning laser microscopy and by nitro blue tetrazolium, respectively. In fact, azole-resistant and azole-sensitive C. albicans biofilms treated at the biofilm inhibitory concentration of usnic acid presented 30-fold and 10-fold increased reactive oxygen species measurements compared to basal levels, respectively, and important nitric oxide generation, showing 25-fold and 60-fold increased reactive nitrogen intermediates levels with respect to the controls, respectively. Nonenzymatic and enzymatic antioxidant defenses were increased in both strains compared to biofilm basal levels as response to the increase of oxidant metabolites. The present study shows for the first time that usnic acid can alter the prooxidant-antioxidant balance, which may be the cause of the irreversible cell damage and lead to cell death. Our results suggest that usnic acid could be an alternative for the treatment of Candida infections, which deserves further investigation.
Assuntos
Azóis/farmacologia , Benzofuranos/farmacologia , Biofilmes/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Candida albicans/fisiologia , Antifúngicos/isolamento & purificação , Antifúngicos/farmacologia , Antioxidantes/farmacologia , Bactérias/efeitos dos fármacos , Benzofuranos/química , Benzofuranos/isolamento & purificação , Biomassa , Farmacorresistência Fúngica , Líquens/química , Líquens/metabolismo , Testes de Sensibilidade Microbiana , Microscopia Confocal , Nitrosação/efeitos dos fármacos , Oxirredução/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Usnea/químicaRESUMO
Two decades ago, it was hypothesized that antidepressants could alter the course of neoplastic diseases. However, contradictory findings indicated that antidepressants could either have carcinogenic properties or improve the disease outcome. Intriguingly, controversial results were reported on the action of antidepressant drugs on immune function. Further hypotheses proposed that antidepressants could indirectly affect the cancer prognosis through the modulation of antitumor activity. Here we review the literature in order to elucidate the influence of antidepressants on cancer and immunity.
Assuntos
Antidepressivos/efeitos adversos , Antidepressivos/imunologia , Antidepressivos/metabolismo , Imunidade Celular/efeitos dos fármacos , Metástase Neoplásica , Neoplasias/induzido quimicamente , Neoplasias/epidemiologia , Transdução de Sinais/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Humanos , Modelos Biológicos , Nitrosação/efeitos dos fármacos , Oxirredução/efeitos dos fármacos , Fatores de Risco , Transdução de Sinais/imunologia , Células Tumorais Cultivadas/efeitos dos fármacosRESUMO
The activation of the transient receptor potential vanilloid type 1 channel (TRPV1) has been correlated with oxidative and nitrosative stress and cell death in the nervous system. Our previous results indicate that TRPV1 activation in the adult retina can lead to constitutive and inducible nitric oxide synthase-dependent protein nitration and apoptosis. In this report, we have investigated the potential effects of TRPV1 channel activation on nitric oxide synthase (NOS) expression and function, and the putative participation of ionotropic glutamate receptors in retinal TRPV1-induced protein nitration, lipid peroxidation, and DNA fragmentation. Intravitreal injections of the classical TRPV1 agonist capsaicin up-regulated the protein expression of the inducible and endothelial NOS isoforms. Using 4,5-diaminofluorescein diacetate for nitric oxide (NO) imaging, we found that capsaicin also increased the production of NO in retinal blood vessels. Processes and perikarya of TRPV1-expressing neurons in the inner nuclear layer of the retina were found in the vicinity of nNOS-positive neurons, but those two proteins did not colocalize. Retinal explants exposed to capsaicin presented high protein nitration, lipid peroxidation, and cell death, which were observed in the inner nuclear and plexiform layers and in ganglion cells. This effect was partially blocked by AP-5, a NMDA glutamate receptor antagonist, but not by CNQX, an AMPA/kainate receptor antagonist. These data support a potential role for TRPV1 channels in physiopathological retinal processes mediated by NO, which at least in part involve glutamate release.
Assuntos
N-Metilaspartato/metabolismo , Óxido Nítrico Sintase/metabolismo , Retina/enzimologia , Retina/patologia , Transdução de Sinais , Canais de Cátion TRPV/metabolismo , Regulação para Cima , Aldeídos/farmacologia , Animais , Morte Celular/efeitos dos fármacos , Fragmentação do DNA/efeitos dos fármacos , Ativação do Canal Iônico/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Óxido Nítrico Sintase Tipo I/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Nitrosação/efeitos dos fármacos , Ratos , Ratos Wistar , Receptores de N-Metil-D-Aspartato/metabolismo , Retina/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Tirosina/análogos & derivados , Tirosina/farmacologia , Regulação para Cima/efeitos dos fármacosRESUMO
Stem cell therapy has been considered a promise for damaged myocardial tissue. We have previously shown that S-nitroso-N-acetyl-D,L-penicillamine (SNAP) increases the expression of several muscular markers and VEGF in mesenchymal stem cells, indicating that transplantation of SNAP-treated cells could provide better functional outcomes. Here, we transplanted SNAP-treated adipose tissue-derived stem cells (ADSCs) in rat infarcted myocardium. After 30days, we observed a significant improvement of the ejection fraction in rats that received SNAP-treated ADSCs, compared with those that received untreated cells (p=0.008). Immunohistochemical reactions showed an increased expression of troponin T-C and von Willebrand factor, and organized vascular units in the infarcted area of tissue transplanted with treated ADSCs. SNAP exposure induced intracellular S-nitrosation, a decreased GSH/GSSG ratio, but did not increase cGMP levels. Collectively, these results indicate that SNAP alters the redox environment of ADSCs, possibly associated with a pre-differentiation state, which may improve cardiac function after transplantation.
Assuntos
Tecido Adiposo/citologia , Coração/fisiopatologia , Infarto do Miocárdio/terapia , Neovascularização Fisiológica/efeitos dos fármacos , S-Nitroso-N-Acetilpenicilamina/farmacologia , Transplante de Células-Tronco , Células-Tronco/citologia , Animais , Glutationa/metabolismo , Proteínas de Fluorescência Verde/metabolismo , Coração/efeitos dos fármacos , Testes de Função Cardíaca/efeitos dos fármacos , Espaço Intracelular/efeitos dos fármacos , Espaço Intracelular/metabolismo , Masculino , Infarto do Miocárdio/fisiopatologia , Nitrosação/efeitos dos fármacos , Ratos , Ratos Wistar , Células-Tronco/efeitos dos fármacos , Células-Tronco/metabolismo , Volume Sistólico/efeitos dos fármacos , Troponina/metabolismo , Fator de von Willebrand/metabolismoRESUMO
We have previously demonstrated that the insulin resistance associated with inducible nitric oxide synthase (iNOS) induction in two different models of obesity, diet-induced obesity and the ob/ob mice, is mediated by S-nitrosation of proteins involved in insulin signal transduction: insulin receptor beta-subunit (IRbeta), insulin receptor substrate 1(IRS-1), and Akt. S-nitrosation of IRbeta and Akt impairs their kinase activities, and S-nitrosation of IRS-1 reduces its tissue expression. In this study, we observed that LPS-induced insulin resistance in the muscle of wild-type mice, as demonstrated by reduced insulin-induced tyrosine phosphorylation of IRbeta and IRS-1, reduced IRS-1 expression and reduced insulin-induced serine phosphorylation of Akt. This resistance occurred in parallel with enhanced iNOS expression, which was accompanied by S-nitrosation of IRbeta/IRS-1 and Akt. In the muscle of iNOS(-/-) mice, we did not observe enhanced iNOS expression or any S-nitrosation of IRbeta/IRS-1 and Akt after LPS treatment. Moreover, insulin resistance was not present. The preservation of insulin-induced tyrosine phosphorylation of IRbeta and IRS-1, of IRS-1 protein expression, and of insulin-induced serine phosphorylation of Akt observed in LPS-treated iNOS(-/-) mice strongly suggests that the insulin resistance induced by LPS is iNOS mediated, probably through S-nitrosation of proteins of early steps of insulin signaling.