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Int. j. cardiovasc. sci. (Impr.) ; 35(2): 253-264, Mar.-Apr. 2022. tab, graf
Article in English | LILACS-Express | LILACS | ID: biblio-1364973


Abstract The regular practice of physical exercise as a non-pharmacological treatment of arterial hypertension (AH) has been encouraged due to causing a series of physiological responses in the cardiovascular system, such as the production of vasoactive substances, including nitric oxide (NO). NO is a relaxation factor released by the endothelium, and the decrease in its bioavailability is related to coronary and arterial diseases, such as AH. This study aimed to perform an integrative literature review to elucidate the effect of physical training on NO levels in patients with AH and to establish a relationship between these levels and blood pressure (BP) control. A literature review was was performed by searching PubMed / MEDLINE, Lilacs, Scielo, Cinahl and Embase databases. The search string used was ("arterial hypertension" OR hypertension) AND (exercise OR "physical exercise" OR "aerobic exercise" OR "exercise training" or "physical activity") AND ("nitric oxide"). We included fully available controlled and uncontrolled clinical trials published in English and Portuguese languages in the last 10 years. The review consisted of 16 articles, of which 13 reported an increase in NO production after the physical training intervention, and three studies found no change. In addition, 15 studies observed a reduction in BP after the intervention. In conclusion, regular practice of physical exercises, advocating moderate intensity, can improve NO bioavailability in pre-hypertensive and hypertensive individuals, which seems to be one of the mechanisms responsible for BP reduction.

Rev. bras. cir. cardiovasc ; 37(1): 20-28, Jan.-Feb. 2022. tab, graf
Article in English | LILACS-Express | LILACS | ID: biblio-1365538


Abstract Introduction: There are many reasons to believe that the nitric oxide/guanosine 3'5' - cyclic monophosphate (or NO/cGMP) pathway on vasoplegic states is underestimated. To study indigo carmine (IC) as an alternative to methylene blue was the investigation rationale. Methods: The IC (3mg/kg intravenous infusion) study protocol included five experimental groups; 1) Control group — saline was injected at 0 and 10 minutes; 2) IC group — IC was injected at 0 and saline at 10 minutes; 3) compound 48/80 (C48/80) group — C48/80 was injected at 0 minute and saline at 10 minutes; 4) C48/80 + IC group — C48/80 was injected at 0 minute and IC at 10 minutes; and 5) IC + C48/80 group — IC was injected at 0 minute and C48/80 at 10 minutes. The studies were carried out by registering and measuring hemodynamic and blood gasometric parameters, including continuous cardiac output. Results: 1) The effects of the drugs (IC and C48/80) were more evident in the first 20 minutes of recording; 2) hypotensive responses were more pronounced in the C48/80 groups; 3) IC isolated or applied before C48/80 caused transient pulmonary hypertension; and 4) after the first 20 minutes, the pressure responses showed stability with apparent hypotension more pronounced in the C48/80 groups. Clinical observations showed significant hemodynamic instability and catastrophic anaphylactic reactions (agitation, pulmonary hypertension, severe bronchospasm, urticaria, high-intensity cyanosis, violent gastric hypersecretion, and ascites). Conclusion: A global results analysis showed differences between groups only in the first 20 minutes of the experiments.

Article in English | LILACS | ID: biblio-1368946


ABSTRACT: Objectives: The objective of this study was to review data from randomized controlled trials to assess whether or not the supplementation of L-Arginine (L-Arg) is effective in reducing the incidence of preeclampsia (PE) in pregnancies at risk of developing the disorder. Methods: We aimed to systematic review randomized controlled trials, including those which compared L-Arg supplementation with placebo in pregnant women at high risk of PE development, analyzing PE incidence as the main outcome. Data were collected from MEDLINE/ Pubmed, EMBASE/ Elsevier, LILACS/ BVS and Cochrane. Results: A total of 46 papers were identified in the primary search. After analysis of eligibility, inclusion and exclusion criteria, two articles (which respected in detail all the stages of evaluation) were included in the present review. A risk of bias assessment was performed. Data analysis revealed that the incidence of PE was significantly lower in both studies, and no major adverse effects were reported. The limitations of this study were the lack of standardization between the trials analyzed and the relative low number of studies included. Conclusions: The supplementation with L-Arg appears to reduce the incidence of PE in pregnant women with high risk for its development. (AU)

RESUMO: Objetivo: O objetivo deste estudo foi revisar dados de ensaios clínicos randomizados para avaliar se a suplementação de L-Arginina é efetiva para reduzir a incidência de pré-eclâmpsia em gestantes com alto risco de desenvolver a doença. Métodos: Realizamos uma revisão sistemática de ensaios clínicos randomizados, incluindo aqueles que compararam a suplementação de L-Arginina com placebo em gestantes de alto risco de desenvolvimento de pré-eclâmpsia, analisando a incidência de pré-eclâmpsia como desfecho principal. Os estudos foram selecionados do MEDLINE/ Pubmed, EMBASE/ Elsevier, LILACS/ BVS e Cochrane. Resultados: Um total de 46 estudos foram identificados na busca primária. Após análise da elegibilidade, dos critérios de inclusão e de exclusão, dois artigos (que respeitaram em detalhes todas etapas de avaliação) foram incluídos na presente revisão. Foi realizada uma avaliação de risco de viés. A análise dos dados revelou que a incidência de pré-eclâmpsia foi significativamente menor em ambos os estudos, e nenhum efeito adverso importante foi relatado. As limitações deste estudo foram a falta de padronização entre os ensaios clínicos analisados e o número relativamente baixo de estudos incluídos. Conclusão: A suplementação com L-Arginina parece reduzir a incidência de pré-eclâmpsia em gestantes de alto risco para seu desenvolvimento. (AU)

Humans , Female , Pregnancy , Arginine/therapeutic use , Pre-Eclampsia/epidemiology , Pregnancy, High-Risk , Nitric Oxide/therapeutic use
Braz. j. med. biol. res ; 55: e11612, 2022. graf
Article in English | LILACS-Express | LILACS | ID: biblio-1360231


Anoikis is a type of apoptosis that occurs in response to the loss of adhesion to the extracellular matrix (ECM). Anoikis resistance is a critical mechanism in cancer and contributes to tumor metastasis. Nitric oxide (NO) is frequently upregulated in the tumor area and is considered an important player in cancer metastasis. The aim of this study was to evaluate the effect of NO on adhesiveness, invasiveness, and migration of anoikis-resistant endothelial cells. Here, we report that anoikis-resistant endothelial cells overexpress endothelial nitric oxide synthase. The inhibition of NO release in anoikis-resistant endothelial cells was able to decrease adhesiveness to fibronectin, laminin, and collagen IV. This was accompanied by an increase in cell invasiveness and migration. Furthermore, anoikis-resistant cell lines displayed a decrease in fibronectin and collagen IV protein expression after L-NAME treatment. These alterations in adhesiveness and invasiveness were the consequence of MMP-2 up-regulation observed after NO release inhibition. The decrease in NO levels was able to down-regulate the activating transcription factor 3 (ATF3) protein expression. ATF3 represses MMP-2 gene expression by antagonizing p53-dependent trans-activation of the MMP-2 promoter. We speculate that the increased release of NO by anoikis-resistant endothelial cells acted as a response to restrict the MMP-2 action, interfering in MMP-2 gene expression via ATF3 regulation. The up-regulation of nitric oxide by anoikis-resistant endothelial cells is an important response to restrict tumorigenic behavior. Without this mechanism, invasiveness and migration potential would be even higher, as shown after L-NAME treatment.

Braz. j. oral sci ; 20: e211512, jan.-dez. 2021. ilus
Article in English | LILACS, BBO | ID: biblio-1254424


Aim: Several systemic diseases, such as periodontitis and apical periodontitis, can cause extensive bone resorption. Host defense peptides may have the potential for the development of novel therapies for the bone resorption process. This study evaluated the potential of host defense peptides clavanins A, MO, and LL-37 in in vitro osteoclastogenesis. Methods: RAW 264.7 cultures were stimulated with recombinant of receptor activator of nuclear factor kappa B ligand in the presence of different tested concentrations of host defense peptides, besides calcium hydroxide and doxycycline. Cellular viability, nitric oxide production, and a number of differentiated osteoclast-like cells were also evaluated. Results: Results showed that none of the substances were cytotoxic, except for 128 µg.mL-1 of doxycycline after 3 days. Host defense peptides, calcium hydroxide, and doxycycline did not interfere in nitric oxide production or downregulated it. An exception was observed in the presence of 2 µg.mL-1 of doxycycline, in which nitric oxide production was up-regulated. All host defense peptides were capable of reducing osteoclast-like cell differentiation. Conclusion: Host defense peptides clavanins A and MO demonstrated to be potential suppressors of osteoclastogenesis in vitro without interfering in cellular viability and nitric oxide production. These promising results need to be further analyzed in in vivo models of bone resorption

Osteogenesis , Bone Resorption , Antimicrobial Cationic Peptides , Nitric Oxide
Saude e pesqui. (Impr.) ; 14(Supl. 1): e8410, Dez. 2021.
Article in Portuguese | LILACS-Express | LILACS | ID: biblio-1367910


Objetivou-se avaliar a suplementação com acetil-L-carnitina (ALC) sobre os neurônios mioentéricos do íleo de ratos após a indução de diabetes. Foram usados animais diabéticos suplementados com ALC (DC), diabéticos (D), normoglicêmicos suplementados com ALC (CC) e normoglicêmicos (C). Neurônios NADPH-d foram quantificados e mensurados. Observou-se redução na glicemia e na ingestão de água no grupo DC. A densidade neuronal em 12,72mm² de íleo foi semelhante nos quatro grupos (p>0,05): DC (558,8 ± 220,2), D (513,4 ± 72,01), CC (645,2 ± 144,9) e C (934 ± 248,5). A área média do corpo celular dos neurônios (µm²) nos animais diabéticos, DC (303,9 ± 114,2) e D (285,4 ± 111,8), foram maiores que nos grupos normoglicêmicos, CC (173,6 ± 53,78) e C (158,4 ± 53,73). A área do íleo (mm²) também mostrou-se maior nos animais dos grupos diabéticos, DC (190,96) e D (171,62) quando comparados aos normoglicêmicos: CC (138,04) e C (130,06). Entretanto no grupo DC, ambas as áreas foram maiores que no D (P<0,05). Assim, pode se inferir discreto incremento na população neuronal. Os dados indicaram que a ALC não interferiu nos mecanismos que promovem aumento na produção de óxido nítrico (NO) pelos neurônios mioentéricos do íleo e que a maior dilatação do íleo no grupo DC poderia ser resultante de efeito colateral da dose de carnitina empregada.

The objective was to evaluate supplementation with acetyl-L-carnitine (ALC) on myenteric neurons of the ileum of rats after induction of diabetes. Diabetic animals supplemented with ALC (DC), diabetic (D), normoglycemic animals supplemented with ALC (CC) and normoglycemic (C) were used. NADPH-d neurons were quantified and measured. There was a reduction in blood glucose and water intake in the DC group. The neuronal density in 12.72mm² of ileum was similar in the four groups (p>0.05): DC (558.8 ± 220.2), D (513.4 ± 72.01), CC (645.2 ± 144.9) and C (934 ± 248.5). The mean cell body area of neurons (µm²) in diabetic animals, DC (303.9 ± 114.2) and D (285.4 ± 111.8), were greater than in the normoglycemic groups, CC (173.6 ± 53.78) and C (158.4 ± 53.73). The ileum area (mm²) was larger in animals of the diabetic groups, CD (190.96) and D (171.62) compared to the normoglycemic groups: CC (138.04) and C (130.04). However, in the DC group, both areas were larger than in D (p<0.05). Thus, a slight increase in neuronal population can be inferred. The data indicated that ALC did not interfere with mechanisms that promote an increase in the production of nitric oxide (NO) by myenteric neurons of the ileum and that the greater dilation of the ileum in the DC group could be the result of a side effect of the dose of carnitine used.

Arq. bras. cardiol ; 117(1): 108-117, July. 2021. tab, graf
Article in English, Portuguese | LILACS | ID: biblio-1285219


Resumo Fundamento As células progenitoras endoteliais (CPEs) desempenham um papel importante na manutenção da função endotelial. A síndrome metabólica (SM) está associada à disfunção das CPEs. Embora o exercício físico tenha um impacto benéfico na atividade das CPEs, seu mecanismo ainda não está completamente esclarecido. Objetivo O objetivo deste estudo é investigar os efeitos do exercício físico nas funções das CPEs e os mecanismos subjacentes em pacientes com SM. Métodos Os voluntários com SM foram divididos em grupo exercício (n=15) e grupo controle (n=15). Antes e após 8 semanas de treinamento físico, as CPEs foram isoladas do sangue periférico. Foram feitos o ensaio de unidades formadoras de colônias (UFC), o ensaio de formação de tubos, a expressão proteica do óxido nítrico sintase endotelial (eNOS), da fosfatidilinositol-3-quinase (PI3-K) e da proteína quinase B (AKT). Considerou-se um valor de probabilidade <0,05 para indicar significância estatística. Resultados Após 8 semanas, o número de UFCs aumentou significativamente no grupo exercício em comparação com o grupo controle (p<0,05). Além disso, observamos uma diminuição significativa do modelo de avaliação da homeostase da resistência à insulina (HOMA-IR), endotelina-1, proteína C reativa de alta sensibilidade e dos níveis de homocisteína no grupo exercício. A intervenção com exercícios também pode aumentar a capacidade de formação de tubos de CPEs e aumentar o nível de fosforilação de eNOS, PI3-K e AKT. Conclusão O exercício físico aprimorou as funções das CPEs. O mecanismo pode estar relacionado ao exercício, ativando a via PI3-K/AKT/eNOS.

Abstract Background Endothelial progenitor cells (EPCs) play an important role in maintaining endothelial function. Metabolic syndrome (MetS) is associated with EPC dysfunction. Although physical exercise has a beneficial impact on EPC activity, its mechanism is not completely clear yet. Objective The purpose of this study is to investigate the effects of physical exercise on the functions of EPCs and the underlying mechanisms in patients with MetS. Methods Volunteers with MetS were divided into exercise group (n=15) and control group (n=15). Before and after 8 weeks exercise training, EPCs were isolated from peripheral blood. Colony forming unit (CFU) assay, tube-formation assay, the protein expression of endothelial nitric oxide synthase (eNOS), phosphatidylinositol-3-kinase (PI3-K) and protein kinase B (AKT) were determined. A probability value <0.05 was considered to indicate statistical significance. Results After 8 weeks, the number of CFUs was significantly increased in the exercise group compared to the control group (p<0.05). In addition, we observed a significant decrease of homeostasis model assessment for insulin resistance (HOMA-IR), endothelin-1, high-sensitive C-reactive protein, and homocysteine levels in the exercise group. Exercise intervention could also enhance tube-formation capacity of EPCs and increase phosphorylation level of eNOS, PI3-K and AKT. Conclusion Physical exercise enhanced the functions of EPCs. The mechanism may be related to exercise, activating the PI3-K/AKT/eNOS pathway.

Humans , Metabolic Syndrome/therapy , Endothelial Progenitor Cells , Phosphorylation , Exercise , Cells, Cultured , Nitric Oxide Synthase Type III/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Nitric Oxide
Braz. dent. j ; 32(3): 10-20, May-June 2021. tab, graf
Article in English | LILACS, BBO | ID: biblio-1345504


Abstract The host defense response to microbial challenge emerging from the root canal system leads to apical periodontitis. The aim of this study was to evaluate the expression of inflammatory cytokines and Nitric Oxide (NO) by macrophages after interaction with Enterococcus faecalis in the: plankton and dislodged biofilm mode; intact biofilm mode stimulated by calcium hydroxide (CH), CH and chlorhexidine (CHX) or Triple Antibiotic Paste (TAP). For this purpose, culture of macrophages from monocytes in human peripheral blood (N=8) were exposed to the different modes of bacteria for 24 hours. Subsequently, the cytokines, such as, Tumor Necrotic Factor- alfa (TNF-α), interleukin (IL)-1β, IL-6, IL-10; and NO were quantified by Luminex xMAP and Greiss reaction, respectively. In addition to the potential therapeutic effects of the intracanal medication, their antimicrobial activity against Enterococcus faecalis biofilm were also tested in vitro by confocal microscopy. The experiments` data were analyzed by the Kruskal-Wallis test with the Dunn post hoc test (α < 0.05). Bacteria in dislodged biofilm mode were shown to be more aggressive to the immune system than bacteria in plankton mode and negative control, inducing greater expression of NO and TNF-α. Relative to bacteria in intact biofilm mode, the weakest antimicrobial activity occurred in Group CH. In Groups CH/CHX and TAP the percentage of dead bacteria was significantly increased to the same extent. Interestingly, the biofilm itself did not induce the release of pro-inflammatory cytokines - except for NO - while the biofilm treated with TAP and CH based pastes enhanced the levels of IL-6 and TNF-α; and IL-1 β, respectively. In contrast, the levels of a potent anti-inflammatory (IL-10) were increased in Group TAP.

Resumo A resposta de defesa do hospedeiro ao desafio microbiano que emerge do sistema de canais radiculares leva à periodontite apical. Os objetivos deste estudo foram avaliar a expressão de citocinas pró e anti-inflamatórias e Óxido Nítrico (NO) por macrófagos após interação com Enterococcus faecalis no modo: planctônio e de biofilme desalojado; biofilme intacto estimulado por hidróxido de cálcio (CH), CH e clorexidina ou Pasta Tri Antibiótica (TAP). Para isto, a cultura de macrófagos originados de monócitos do sangue periférico de humanos (N=8) foi exposta aos diferentes tipos de bactéria por 24 horas. Então, a quantificação da produção de of Fator de Necrose Tumoral- alfa (TNF-α), interleucina (IL)-1β, IL-6, IL-10 e NO por macrófagos se deu por meio do Luminex xMAP e reação de Greiss, respectivamente. Além dos potenciais efeitos terapêuticos desses compostos, sua atividade antimicrobiana contra E. faecalis também foi testada através microscopia confocal. Os dados dos experimentos foram analisados através do teste de Kruskal-Wallis com Dunn`s post hoc (α < 0.05). Bactéria em modo de biofilme desalojado se mostrou mais agressivo ao sistema imune que as bactérias planctônicas e controle negativo induzindo a maior excreção de NO e TNF-α. Em relação ao biofilme intacto, a atividade antimicrobiana mais fraca ocorreu no grupo de CH. Os grupos CHX e TAP aumentaram significativamente a porcentagem de bactérias mortas na mesma extensão. Interessantemente, o biofilme por ele mesmo não induziu a liberação de citocinas pro-inflamatórias - exceto por NO - enquanto que o biofilme tratado com TAP ou pastas a base de CH aumentaram os níveis de IL-6; e TNF-α e IL-1 β respectivamente. Em contraste, os níveis da potente citocina anti-inflamatória (IL-10) foram aumentados pelo grupo TAP.

Humans , Plankton , Biofilms , Root Canal Irrigants , Bacteria , Calcium Hydroxide , Chlorhexidine , Enterococcus faecalis , Anti-Bacterial Agents
Rev. bras. cir. cardiovasc ; 36(3): 406-411, May-June 2021. tab, graf
Article in English | LILACS-Express | LILACS | ID: biblio-1288253


Abstract Vasoplegic syndrome (VS) comprises a constellation of concurrent signs and symptoms: hypotension, high cardiac index, low systemic vascular resistance, low filling pressures, the tendency to occur diffuse bleeding, and sustained hypotension. All of these parameters may persist even despite the use of high doses of vasoconstrictor amines. VS arises from vasoplegic endothelial dysfunction with excessive release of nitric oxide by polymorphonuclear leukocytes mediated by the nitric oxide synthase's inducible form and is associated with systemic inflammatory reaction and high morbimortality. The achievements regarding the treatment of VS with methylene blue (MB) are a valuable Brazilian contribution to cardiac surgery. The present text review was designed to deliver the accumulated knowledge in the past ten years of employing MB to treat VS after cardiac surgery. Considering that we have already published two papers describing acquired experiences and concepts after 15 and 20 years, now, as we achieve the 30-year mark, we compose a trilogy.

Vitae (Medellín) ; 28(2): 1-14, 2021-05-18. Ilustraciones
Article in English | LILACS, COLNAL | ID: biblio-1362619


Background: Ayanin (3,7,4'-Tri-O-methylquercetin) and 3,7-Di-O-methylquercetin (DMQ) are the main active metabolites isolated by bioguided fractionation from Croton schiedeanus, species known popularly in Colombia as "almizclillo", which has been studied in experimental models in rats, exerting vasodilator and antihypertensive effects. Also, when the effect of these flavonoids was studied separately, important vasodilation was observed. Objective:To evaluate whether flavonoids from Croton schiedeanus have synergistic vasodilator properties when different combinations are used in isolated aorta rings. Methods: Cumulative concentrations of ayanin (10-8 M - 6x10-5 M or 0.01 µM - 60 µM) were assayed in the absence and presence of an increasing concentration of 3,7-Di-O-methylquercetin (DMQ) (10-8 ­ 3x10-5M or 0.01­30 µM) in isolated rings from Wistar rats, pre-contracted with phenylephrine. The concentration-response curve with the maximal effect was compared with that obtained by Croton schiedeanus whole ethanolic extract (10-6 ­ 3x10-4 g/mL). Also, this combination was assayed in the presence of the nitric oxide synthetase inhibitor L-NAME (10-4 M) and the guanylate cyclase inhibitor methylene blue (10-4 M) to assess the role of the NO/cGMP pathway in this interaction. Results: Ayanin and DMQ display a dual interaction in vascular relaxant response: agonism at higher concentration ranges (10-6 ­ 3x10-5 M or 1­30 µM) and antagonism at lower concentration ranges (10-8 ­ 3x10-7 M or 0.01­0.3 µM). The efficacy at the highest concentration was greater than that obtained by the whole extract (Emax: 98.4% vs. 33.9%). This response was decreased but not reverted in the presence of L-NAME and methylene blue. Thus, the vasodilator effect of this combination does not depend entirely on the NO/cGMP cyclic pathway. Conclusion: The combined use of appropriate concentrations of these flavonoids could represent an advantage over Croton schiedeanus whole extract for vasodilator purposes

Antecedentes: Ayanina (3,7,4'-Tri-O-metilquercetina) y 3,7-Di-O-metilquercetina (DMQ) son los principales metabolitos activos aislados mediante fraccionamiento bioguiado, a partir de Croton schiedeanus, especie conocida popularmente en Colombia como "almizclillo", la cual ha sido estudiada en modelos experimentales en ratas, ejerciendo efectos antihipertensivos y vasodilatadores. Además, al estudiar por separado el efecto de los flavonoides, se observó importante vasodilatación. Objetivo:Evaluar si los principales flavonoides de Croton schiedeanus tienen propiedades vasodilatadoras sinérgicas al utilizar diferentes combinaciones de ellos en anillos de aorta aislados. Metodología: Se analizaron concentraciones acumulativas de ayanina (10-8 M - 6x10-5 M o 0,01 µM - 60 µM) en ausencia y en presencia de concentraciones crecientes de DMQ (10-8 M - 3x10-5 M o 0,01 µM ­ 30 µM) en anillos aislados de ratas Wistar, pre-contraídos con fenilefrina. La curva concentración respuesta obtenida con el efecto máximo, fue comparada con la obtenida con el extracto etanólico de Croton schiedeanus (10-6 - 3x10-4 g/mL). Adicionalmente, esta combinación fue ensayada en presencia del inhibidor de óxido nítrico sintetasa L-NAME (10-4 M) y el inhibidor de guanilato ciclasa, azul de metileno (10-4 M) para evaluar el papel de la vía NO/GMPc en esta interacción. Resultados: Ayanina y DMQ muestran una interacción dual en la respuesta vascular relajante: agonismo en el rango más alto (10-6 M ­ 3x10-5 M o 1 µM ­ 30 µM), y antagonismo en el rango más bajo (10-8 M ­ 3x10-7 M o 0.01 µM ­ 0,3 µM). A altas concentraciones, la eficacia de los flavonoides fue mayor que las obtenidas por el extracto completo (Emáx: 98,4% vs 33,9%). Esta respuesta disminuyó, pero no se revirtió en presencia de L-NAME y azul de metileno. Por lo tanto, el efecto vasodilatador de esta combinación no depende enteramente de la vía NO/GMPc. Conclusión: El uso combinado de las concentraciones apropiadas de estos flavonoides podría representar una ventaja sobre el extracto de Croton schiedeanus, con propósitos vasodilatadores

Humans , Flavonoids , Croton , Drug Synergism , Guanylate Cyclase , Nitric Oxide
Rev. argent. cardiol ; 89(2): 92-97, abr. 2021. tab, graf
Article in Spanish | LILACS-Express | LILACS | ID: biblio-1356854


RESUMEN Introducción: Resultados de nuestro laboratorio sugieren que la disfunción mitocondrial en el corazón precede a la falla miocárdica asociada a la hiperglucemia sostenida. Objetivo: Estudiar los eventos tempranos que ocurren en las mitocondrias de corazón en un modelo de diabetes mellitus tipo 1. Materiales y métodos: Ratas Wistar macho fueron inyectadas con estreptozotocina (STZ; 60 mg/kg, ip) y sacrificadas 10 o 14 días posinyección. Se obtuvo la fracción mitocondrial de corazón. Resultados: El consumo de O2 en estado 3 en presencia de malato-glutamato (21%) o succinato (16%) y las actividades de los complejos I-III (27%), II-III (24%) y IV (22%) fueron menores en los animales diabéticos a los 14 días posinyección. Cuando los animales se sacrificaron al día 10, solo el consumo de O2 en estado 3 en presencia de sustratos del complejo I (23%) y su control respiratorio (30%) fueron menores en las ratas inyectadas con STZ, de acuerdo con una reducción en la actividad del complejo I-III (17%). Estos cambios se acompañaron de un aumento en las velocidades de producción de H2O2 (117%), NO (30%) y ONOO- (∼225%), en la expresión de mtNOS (29%) y en la [O2 -]ss (∼150%) y [NO]ss (∼30%), junto con una disminución de la actividad de la Mn-SOD (15%) y la [GSSG+GSH]mitocondrial (28%), sin cambios en la expresión de PGC-1α. Conclusión: La disfunción del complejo I y el aumento en la generación de H2O2, NO y ONOO- pueden considerarse señales subcelulares prodrómicas del deterioro de la función mitocondrial que precede a la disfunción cardíaca en la diabetes.

ABSTRACT Background: Previous results from our laboratory suggest that heart mitochondrial dysfunction precedes myocardial failure associated with sustained hyperglycemia. Purpose: The aim of this study was to analyze the early events that take place in heart mitochondria in a type 1 diabetes mellitus (DM) model. Methods: Male Wistar rats were injected with streptozotocin (STZ; 60 mg/kg, ip.) to induce DM. They were euthanized 10 or 14 days later and the heart mitochondrial fraction was obtained. Results: State 3 O2 consumption in the presence of malate-glutamate (21%) or succinate (16%), and complex I-III (27%), II-III (24%) and IV (22%) activities were lower in diabetic animals 14 days after STZ injection. When animals were euthanized at day 10, only state 3 O2 consumption sustained by complex I substrates (23%) and its corresponding respiratory control (30%) were lower in rats injected with STZ, in agreement with reduced complex I-III activity (17%). These changes were accompanied by increased H2O2 (117%), NO (30%) and ONOO- (~225%) production rates, mtNOS expression (29%) and O2 - (~150%) and NO (~30%) steady-state concentrations, together with a decrease in Mn-SOD activity (15%) and mitochondrial [GSSG+GSH] (28%), without changes in PGC-1α expression. Conclusion: Complex I dysfunction and increased H2O2, NO and ONOO- production rates can be considered subcellular prodromal signals of the mitochondrial damage that precedes myocardial dysfunction in diabetes.

J. health sci. (Londrina) ; 23(1):, 20210330.
Article in English | LILACS-Express | LILACS | ID: biblio-1222915


The aim of this study was to evaluate the effects of citrulline malate (CIT) supplementation on aerobic and muscular endurance in young adult males. Eighteen young adult men (age: 21.5 ± 2.7 years) were randomized into two groups (Citrulline malate - CIT and Placebo - PLA; N = 9/ group ) and received the respective supplements for 7 days. The CIT group was supplemented with 6 g CIT + 6 g dextrose (total: 12 g), while the PLA group received the same amount (12 g) of dextrose. At the pre- and post-supplementation, the following variables were analyzed: aerobic (maximal treadmill test, Tmax) and muscle (repetitions maximum test, Rmax) endurance tests, as well as mean and maximum heart rate (HR) in Tmax and ratings of perceived exertion (PSE) in Rmax. No significant (P > 0.05) differences were found between CIT and PLA groups in time until exhaustion in Tmax, total repetitions in Rmax, maximal HR and PSE from pre- to post-supplementation. The mean HR was statistically lower (P < 0.05) in the CIT group compared to the PLA in the Tmax. In conclusion, supplementation of CIT (6 g / day) does not improve aerobic and muscular endurance, as well as maximal HR or PSE in healthy young adults, despite reducing the mean HR during the maximal incremental test. (AU)

O objetivo deste estudo foi avaliar os efeitos da suplementação de citrulina malato (CIT) sobre a resistência aeróbica e muscular em homens adultos jovens. Em um desenho experimental randomizado, duplo-cego e controlado com placebo, dezoito homens adultos jovens (idade: 21,5 ± 2,7 anos) foram randomizados em dois grupos (Citrulina malato ­ CIT e Placebo ­ PLA; N = 9/grupo) e receberam os respectivos suplementos por um período de 7 dias. O grupo CIT foi suplementado com 6 g de CIT + 6 g de dextrose (total: 12 g), enquanto o grupo PLA recebeu a mesma quantidade (12 g) de dextrose. Nos momentos pré e pós suplementação as seguintes variáveis foram analisadas: resistência aeróbia (teste incremental máximo em esteira rolante, Tmáx) e muscular (teste de repetições máximas, Rmáx), bem como a frequência cardíaca (FC) média e máxima no Tmáx e a análise da percepção subjetiva de esforço (PSE) no Rmáx. Nenhuma diferença significante (P > 0,05) foi encontrada entre os grupos CIT e PLA no tempo até a exaustão no Tmáx, total de repetições no Rmáx, FC máxima e PSE do momento pré para o pós suplementação. A FC média foi estatisticamente (P < 0,05) menor no grupo CIT comparado ao PLA no Tmáx. Em conclusão, a suplementação de CIT (6 g/dia) não melhora a resistência aeróbica e muscular, bem como a FC máxima ou PSE em adultos jovens saudáveis, apesar de reduzir a FC média durante o teste incremental máximo. (AU)

Braz. j. med. biol. res ; 54(6): e10423, 2021. tab, graf
Article in English | LILACS | ID: biblio-1285668


About 3000 tons of beans are not used in human food due to hardening. Several studies on bean-derived bioactive peptides have shown potential to treat some diseases, including those relying on oxidative dysfunctions. We assessed the effects of peptides extracted from hardened bean Phaseolus vulgaris (PV) on reactive oxygen species (ROS) and nitric oxide (NO) production, cytotoxic and cytoprotective effects in endothelial cells, and oxidonitrergic-dependent vasodilating effects. Extract was composed by peptide fraction <3 kDa (PV3) from hardened common bean residue. PV3 sequences were obtained and analyzed with bioinformatics. Human umbilical vein endothelial cells were treated with 10, 20, 30, and 250 µg/mL PV3. Oxidative stress was provoked by 3% H2O2. Cytotoxicity and cytoprotective effects were evaluated by MTT assay, whereas, ROS and NO were quantified using DHE and DAF-FM fluorescent probes by confocal microscopy. NO- and endothelium-dependent vasodilating effects of PV3 were assessed in isolated aortic rings. We found 35 peptides with an average mass of 1.14 kDa. There were no cell deaths with 10 and 20 μg/mL PV3. PV3 at 30 μg/mL increased cell viability, while cytotoxicity was observed only with 250 μg/mL PV3. PV3 at 10 μg/mL was able to protect cells from oxidative stress. PV3 also increased NO release without causing cell death. It also reduced relative ROS production induced by H2O2. PV3 vasodilating effects relied on endothelium-dependent NO release. PV3 obtained from low-commercial-value bean displays little cytotoxicity and exerts antioxidant effects, whereas it increases endothelial NO release.

Humans , Phaseolus , Peptides/pharmacology , Endothelium , Hydrogen Peroxide , Molecular Weight , Antioxidants/pharmacology
Neumol. pediátr. (En línea) ; 16(2): 62-68, 2021. ilus, tab
Article in Spanish | LILACS | ID: biblio-1293286


El asma es la enfermedad respiratoria crónica pediátrica más frecuente. En la mayoría de los niños se caracteriza por inflamación de la vía aérea de tipo eosinofílica alérgica. La fracción espirada de óxido nítrico (FENO) es un biomarcador de inflamación eosinofílica de vía aérea, su medición es no invasiva y fácil de realizar y ha sido evaluado en los últimos años para su aplicación clínica en el diagnóstico y tratamiento del asma en niños y adultos. Esta revisión abordará el origen anatómico y bioquímico del FENO, aspectos prácticos de su medición, valores de referencia y su aplicación clínica en el diagnóstico y tratamiento del asma pediátrico.

Asthma is the most common pediatric chronic disease characterized in most children by allergic eosinophilic airway inflammation. The exhaled fraction of nitric oxide (FENO) is a biomarker of eosinophilic airway inflammation, constituting a non-invasive and easy-to-perform test that has been evaluated in recent years for its clinical application in the diagnosis and treatment of asthma in children and adults. This review will address the anatomical and biochemical origin of FENO, practical aspects of its measurement, reference values and its clinical application in the diagnosis and treatment of pediatric asthma.

Humans , Asthma/diagnosis , Nitric Oxide/analysis , Asthma/metabolism , Breath Tests , Biomarkers , Exhalation , Eosinophilia , Inflammation , Nitric Oxide/metabolism
Mem. Inst. Oswaldo Cruz ; 116: e200417, 2021. tab, graf
Article in English | LILACS | ID: biblio-1154880


BACKGROUND Toxoplasma gondii causes toxoplasmosis and is controlled by activated macrophages. However, infection of macrophages by tachyzoites induces TGF-β signaling (TGF-s) inhibiting nitric oxide (NO) production. NO inhibition may be a general escape mechanism of distinct T. gondii strains. OBJECTIVES To evaluate in activated macrophages the capacity of T. gondii strains of different virulence and genetics (RH, type I; ME-49, type II; VEG, type III; P-Br, recombinant) to evade the NO microbicidal defense system and determine LC3 loading to the parasitophorous vacuole. METHODS Activated peritoneal macrophages were infected with the different T. gondii strains, NO-production was evaluated by the Griess reagent, and inducible nitric oxide synthase expression, TGF-s, and LC3 localisation assayed by immunofluorescence. FINDINGS Only RH persisted in macrophages, while VEG was more resistant than P-Br and ME-49. All strains induced TGF-s, degradation of inducible nitric oxide synthase, and NO-production inhibition from 2 to 24 h of infection, but only RH sustained these alterations for 48 h. By 24 h of infection, TGF-s lowered in macrophages infected by ME-49, and P-Br, and NO-production recovered, while VEG sustained TGF-s and NO-production inhibition longer. LC3 loading to parasitophorous vacuole was strain-dependent: higher for ME-49, P-Br and VEG, lower for RH. All strains inhibited NO-production, but only RH sustained this effect probably because it persisted in macrophages due to additional evasive mechanisms as lower LC3 loading to parasitophorous vacuole. MAIN CONCLUSIONS These results support that T. gondii can escape the NO microbicidal defense system at the initial phase of the infection, but only the virulent strain sustain this evasion mechanism.

Animals , Mice , Toxoplasma/physiology , Macrophages, Peritoneal/parasitology , Nitric Oxide Synthase/metabolism , Macrophages/parasitology , Nitric Oxide/biosynthesis , Toxoplasmosis, Animal/parasitology , Macrophages/metabolism
Braz. J. Pharm. Sci. (Online) ; 57: e19187, 2021. graf
Article in English | LILACS | ID: biblio-1350232


Propolis from stingless bees (Heterotrigona itama) is a resinous compound that exhibits antihyperglycaemia, free radical scavenging, and cardioprotective properties. The effect of propolis on diabetic vessels has not been investigated. Thus, this research aimed to determine the effect of propolis supplementation on the level of antioxidants and its mechanism of action in the aorta of diabetic rats. Male Sprague-Dawley rats were divided into five groups (n=8/group): healthy (control), untreated diabetes (DM), metformin-treated diabetes (DM+M, 300 mg/kg/day metformin), propolis-treated diabetes (DM+P, 300 mg/kg/day propolis extract) and diabetes with combined treatment (DM+M+P, dosage as former). Oral supplementation was conducted for four weeks immediately upon successful induction of diabetes by streptozotocin (60 mg/kg, intraperitoneal injection). At the end of the study, the rats were euthanised, and thoracic aorta was processed into tissue homogenates to determine the levels of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase-1 (GPx-1) and soluble receptor for advanced glycation end-products (sRAGE). Aorta segments were harvested to examine their relaxation response towards graded concentration of acetylcholine (Ach; 10-8-10-4) M following precontraction with phenylephrine (PE; 10-6 M). Vasorelaxation towards a cumulative dose of propolis (0.01-1.00%) using PE-precontracted healthy aorta (n=6/experiments) was investigated under various simulated conditions: physiological buffer, L-NAME (10-4 M), methylene blue (10-5 M), indomethacin (10-5 M) and elevated glucose (25 mM). Propolis maintained antioxidative enzymes and sRAGE decoy molecules in the aortic tissue of the diabetic rats. The amelioration of diabetes-induced impairment of endothelium-dependent relaxation by propolis was mediated through the nitric oxide(NO)-cyclic guanosine monophosphate (cGMP) pathway. This non-clinical study reports vasoprotective property of propolis in diabetes mellitus.

Animals , Male , Rats , Propolis/analysis , Bees/anatomy & histology , Rats, Sprague-Dawley/classification , Diabetes Mellitus/drug therapy , Endothelium/abnormalities , Nitric Oxide/adverse effects , Aorta/abnormalities , Relaxation , Vasodilation , Antioxidants/pharmacology
Braz. J. Pharm. Sci. (Online) ; 57: e19177, 2021. tab, graf
Article in English | LILACS | ID: biblio-1350229


Probiotic consumption promotes numerous health benefits. The aim of this study is 1) to evaluate the antihypertensive effect of kefir in a hypertension rat model caused by the administration of the nitric oxide synthesis inhibitor, L-NAME, and 2) to evaluate the acute angiotensin converting enzyme (ACE) inhibitory activity of the soluble nonbacterial fraction (SNBF) of kefir. To develop the first aim, male rats were separated into three groups: control group (C) treated with 0.3 mL/100 g of milk; L-NAME group (LN) received 10 mg/kg of said inhibitor; and Kefir group (K) treated with 0.3 mL/100 g of kefir plus L-NAME (10 mg/kg of said inhibitor). The treatments were given by oral gavage twice a day for four weeks. For the second aim"instead additionally, male rats received angiotensin I (in bolus) in three doses (Ang I: 0.03, 3 and 300 µg/kg) and were separated into two groups: a) received captopril (30 mg/kg i.v.) and b)received SNBF of kefir (5 mL/kg i.v.). Blood pressure were evaluated before and after Ang I. After treatment, hemodynamic parameters were evaluated, heart weight was recorded, and body weight gain was calculated. SNBF of kefir did not decrease the blood pressure for L-NAMEtreated animals, and no changes were observed in the cardiac parameters. However, the SNBF of kefir demonstrated acute inhibition of ACE in vivo similar to that of captopril. Thus, our results suggest that kefir may improve human cardiovascular systems by using mechanisms independent of nitric oxide syntheses. Additionally, the renin angiotensin system is probably the most important system involved in kefir effect regarding hypertension.

Animals , Male , Rats , Angiotensin-Converting Enzyme Inhibitors , Kefir/adverse effects , Blood Pressure/genetics , Probiotics/pharmacology , Antihypertensive Agents/analysis , Nitric Oxide/adverse effects