RESUMO
Gestational diabetes mellitus (GDM) is characterized by a set of metabolic complications arising from adaptive failures to the pregnancy period. Estimates point to a prevalence of 3 to 15% of pregnancies. Its etiology includes intrinsic and extrinsic aspects of the progenitress, which may contribute to the pathophysiogenesis of GDM. Recently, researchers have identified that inflammation, oxidative stress, and the gut microbiota participate in the development of the disease, with potentially harmful effects on the health of the maternal-fetal binomial, in the short and long terms. In this context, alternative therapies were investigated from two perspectives: the modulation of the intestinal microbiota, with probiotics and prebiotics, and the use of natural products with antioxidant and anti-inflammatory properties, which may mitigate the endogenous processes of the GDM, favoring the health of the mother and her offspring, and in a future perspective, alleviating this critical public health problem.
RESUMO
Reactive oxygen and nitrogen species (RONS) are involved in many biochemical processes, including nitro-oxidative stress that causes cancer cell death, observed in cancer therapies such as photodynamic therapy and cold atmospheric plasma. However, their mechanisms of action and selectivity still remain elusive due to the complexity of biological cells. For example, it is not well known how RONS generated by cancer therapies permeate the cell membrane to cause nitro-oxidative damage. There are many studies dedicated to the permeation of RONS across native and oxidized membranes, but not across nitrated membranes, another lipid product also generated during nitro-oxidative stress. Herein, we performed molecular dynamics (MD) simulations to calculate the free energy barrier of RONS permeation across nitrated membranes. Our results show that hydrophilic RONS, such as hydroperoxyl radical (HO2) and peroxynitrous acid (ONOOH), have relatively low barriers compared to hydrogen peroxide (H2O2) and hydroxyl radical (HO), and are more prone to permeate the membrane than for the native or peroxidized membranes, and similar to aldehyde-oxidized membranes. Hydrophobic RONS like molecular oxygen (O2), nitrogen dioxide (NO2) and nitric oxide (NO) even have insignificant barriers for permeation. Compared to native and peroxidized membranes, nitrated membranes are more permeable, suggesting that we must not only consider oxidized membranes during nitro-oxidative stress, but also nitrated membranes, and their role in cancer therapies.
Assuntos
Peróxido de Hidrogênio , Nitratos , Simulação de Dinâmica Molecular , Espécies Reativas de Nitrogênio , Espécies Reativas de OxigênioRESUMO
Nitric oxide (NO) has been implicated as part of the ripening regulatory network in fleshy fruits. However, very little is known about the simultaneous action of NO on the network of regulatory events and metabolic reactions behind ripening-related changes in fruit color, taste, aroma and nutritional value. Here, we performed an in-depth characterization of the concomitant changes in tomato (Solanum lycopersicum) fruit transcriptome and metabolome associated with the delayed-ripening phenotype caused by NO supplementation at the pre-climacteric stage. Approximately one-third of the fruit transcriptome was altered in response to NO, including a multilevel down-regulation of ripening regulatory genes, which in turn restricted the production and tissue sensitivity to ethylene. NO also repressed hydrogen peroxide-scavenging enzymes, intensifying nitro-oxidative stress and S-nitrosation and nitration events throughout ripening. Carotenoid, tocopherol, flavonoid and ascorbate biosynthesis were differentially affected by NO, resulting in overaccumulation of ascorbate (25%) and flavonoids (60%), and impaired lycopene production. In contrast, the biosynthesis of compounds related to tomato taste (sugars, organic acids, amino acids) and aroma (volatiles) was slightly affected by NO. Our findings indicate that NO triggers extensive transcriptional and metabolic rewiring at the early ripening stage, modifying tomato antioxidant composition with minimal impact on fruit taste and aroma.
Assuntos
Frutas/fisiologia , Óxido Nítrico/fisiologia , Solanum lycopersicum/fisiologia , Etilenos , Regulação da Expressão Gênica de Plantas , FenótipoRESUMO
This study investigated nitro-oxidative stress in patients with systemic lupus erythematosus (SLE) in association with disease activity, immune-inflammatory biomarkers, and adhesion molecules. Two-hundred-four patients with SLE and 256 healthy volunteers were enrolled in this case-control study, which measured nitro-oxidative stress biomarkers, including lipid peroxides (LOOH), advanced oxidation protein products (AOPPs), nitric oxide metabolites (NOx), sulfhydryl (-SH) groups, products of deoxyribonucleic acid (DNA)/ribonucleic acid (RNA) oxidative degradation, and total radical-trapping anti-oxidant parameter (TRAP). Also measured were anti-nuclear antibodies (ANAs), antibodies against double-stranded DNA (dsDNA), plasma levels of diverse cytokines, C-reactive protein, and adhesion molecules. LOOH (p < 0.001) and AOPP (p < 0.001) were significantly higher, while TRAP was significantly lower (p < 0.001) in SLE patients than in controls. AOPP and LOOH were significantly and positively associated with SLE disease activity index (SLEDAI) scores, anti-nuclear antibodies, and antibodies against double-stranded DNA (anti-dsDNA) levels, while TRAP was significantly and inversely correlated with SLEDAI, ANA, and dsDNA antibody levels. There were significant positive associations between AOPP and LOOH and immune-inflammatory markers, indicating T helper (Th)-17 and Th1 bias and Th1 + Th17/Th2 ratio (p = 0.002 and p = 0.001, respectively). AOPP and LOOH (positively) and TRAP (inversely) were associated with adhesion molecule expression. A model predicting SLE was computed showing that, using LOOH, AOPP, NOx, adhesion molecules, and body mass index, 94.2% of the patients were correctly classified with a specificity of 91.5%. Increased nitro-oxidative stress takes part in the (auto)immune pathophysiology of SLE and modulates severity of illness and adhesion molecule expression.
Assuntos
Biomarcadores/metabolismo , Inflamação/metabolismo , Lúpus Eritematoso Sistêmico/metabolismo , Células Th1/imunologia , Células Th17/imunologia , Adulto , Produtos da Oxidação Avançada de Proteínas/metabolismo , Anticorpos Antinucleares/sangue , Moléculas de Adesão Celular/metabolismo , Feminino , Humanos , Peróxidos Lipídicos/metabolismo , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Pessoa de Meia-Idade , Óxido Nítrico/metabolismo , Estresse Nitrosativo , Estresse OxidativoRESUMO
Crotoxin (CTX), the predominant toxin in Crotalus durissus terrificus snake venom (CdtV), has anti-inflammatory and immunomodulatory effects. Despite its inhibitory action on neutrophil migration and phagocytosis, CTX does not directly affect the production of reactive oxygen species (ROS) by the neutrophils. In contrast, it enhances the generation of reactive oxygen and nitrogen intermediates by macrophages. Given the importance of macrophage-neutrophil interactions in innate antimicrobial defense, the aim of this study was to investigate the effect of CTX on neutrophil ROS production and killing activity, either through CTX-treated macrophage co-culture or conditioned medium of CTX-treated macrophages. The results showed an important modulatory action of CTX on the neutrophil function as well as neutrophil-macrophage interactions, as demonstrated by the increased production of hydrogen peroxide, hypochlorous acid, nitric oxide and TNF- a , along with the increased fungicidal activity of neutrophils.
RESUMO
Current Tuberculosis treatment is long and expensive, faces the increasing burden of MDR/XDR strains and lack of effective treatment against latent form, resulting in an urgent need of new anti-TB drugs. Key to TB biology is its capacity to fight the host's RNOS mediated attack. RNOS are known to display a concentration dependent mycobactericidal activity, which leads to the following hypothesis "if we know which proteins are targeted by RNOS and kill TB, we we might be able to inhibit them with drugs resulting in a synergistic bactericidal effect". Based on this idea, we performed an Mtb metabolic network whole proteome analysis of potential RNOS sensitive and relevant targets which includes target druggability and essentiality criteria. Our results, available at http://tuberq.proteinq.com.ar yield new potential TB targets, like I3PS, while also providing and updated view of previous proposals becoming an important tool for researchers looking for new ways of killing TB.
Assuntos
Antituberculosos/uso terapêutico , Proteínas de Bactérias/genética , Biologia Computacional , Descoberta de Drogas/métodos , Genoma Bacteriano , Estudo de Associação Genômica Ampla , Tuberculose Latente/tratamento farmacológico , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/genética , Animais , Proteínas de Bactérias/metabolismo , Bases de Dados Genéticas , Perfilação da Expressão Gênica , Interações Hospedeiro-Patógeno , Humanos , Tuberculose Latente/metabolismo , Tuberculose Latente/microbiologia , Camundongos Endogâmicos C57BL , Viabilidade Microbiana , Terapia de Alvo Molecular , Mycobacterium tuberculosis/metabolismo , Mycobacterium tuberculosis/patogenicidade , Análise de Sequência com Séries de Oligonucleotídeos , Mapas de Interação de Proteínas , Espécies Reativas de Nitrogênio/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de SinaisRESUMO
The purpose of the present study was to evaluate the oxidative status of the brain of arthritic rats, based mainly on the observation that arthritis induces a pronounced oxidative stress in the liver of arthritis rats and that morphological alterations have been reported to occur in patients with rheumatoid arthritis. Rats with adjuvant-induced arthritis were used. These animals presented higher levels of reactive oxygen species (ROS) in the total brain homogenate (25% higher) and in the mitochondria (+55%) when compared to healthy rats. The nitrite plus nitrate contents, nitric oxide (NO) markers, were also increased in both mitochondria (+27%) and cytosol (+14%). Arthritic rats also presented higher levels of protein carbonyl groups in the total homogenate (+43%), mitochondria (+69%) and cytosol (+145%). Arthritis caused a diminution of oxygen consumption in isolated brain mitochondria only when ascorbate was the electron donor. The disease diminished the mitochondrial cytochrome c oxidase activity by 55%, but increased the transmembrane potential by 16%. The pro-oxidant enzyme xanthine oxidase was 150%, 110% and 283% higher, respectively, in the brain homogenate, mitochondria and cytosol of arthritic animals. The same occurred with the calcium-independent NO-synthase activity that was higher in the brain homogenate (90%) and cytosol (122%) of arthritic rats. The catalase activity, on the other hand, was diminished by arthritis in all cellular fractions (between 30 and 40%). It is apparent that the brain of rats with adjuvant-induced arthritis presents a pronounced oxidative stress and a significant injury to lipids and proteins, a situation that possibly contributes to the brain symptoms of the arthritis disease.
Assuntos
Artrite Experimental/metabolismo , Encéfalo/metabolismo , Estresse Oxidativo , Animais , Metabolismo dos Lipídeos , Masculino , Mitocôndrias/metabolismo , Óxido Nítrico Sintase/metabolismo , Ratos , Espécies Reativas de Oxigênio/metabolismo , Xantina Oxidase/metabolismoRESUMO
As células dendríticas são apresentadoras de antígeno mais eficazes para iniciar resposta primaria de linfocitos T. Quando internalizado o antígeno e processado gerando peptideos que serão apresentados por complexos de histocompatibilidade do tipo I em celulas dendriticas, os antigenos proteicos no citoplasma são processados pelo imunoproteassomo. Uma vez que celulas dendriticas estão nativamente expostas a uma serie de agentes estressantes incluindo os pro oxidantes, nosso objetivo neste trabalho foi examinar o efeito de pro oxidantes em celulas dendriticas para posterior avaliacao de linfocitos TCD8+... .
Dendritic cells are the most effect antigen presenting cells in starting sumary response of T lymphocytes. Once internalized, the antigen is processing generating peptides that are be presented the major histocompatibility complex type I, the cytosolic protein antigens must be processed by the imunoproteasome. Since dendritic cells are natively exposed to a variety of stress agents including pro oxidants our goal in this study was to examine the effect of pro oxidants in dendritic cell-induced TCD8 +... .