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1.
Toxicol Lett ; 324: 95-103, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32017979

RESUMO

Sulfur mustard (SM) is a toxicant and chemical warfare agent with strong vesicant properties. The mechanisms behind SM-induced toxicity are not fully understood and no antidote or effective therapy against SM exists. Both, the risk of SM release in asymmetric conflicts or terrorist attacks and the usage of SM-derived nitrogen mustards as cancer chemotherapeutics, render the mechanisms of mustard-induced toxicity a highly relevant research subject. Herein, we review a central role of the abundant cellular molecule nicotinamide adenine dinucleotide (NAD+) in molecular mechanisms underlying SM toxicity. We also discuss the potential beneficial effects of NAD+ precursors in counteracting SM-induced damage.


Assuntos
Substâncias para a Guerra Química/toxicidade , Gás de Mostarda/toxicidade , NAD/fisiologia , Animais , Suplementos Nutricionais , Humanos , NAD/administração & dosagem , Niacinamida/administração & dosagem , Estresse Oxidativo/efeitos dos fármacos , Poli(ADP-Ribose) Polimerases/metabolismo , Espécies Reativas de Nitrogênio/metabolismo , Sirtuínas/antagonistas & inibidores
2.
Biochemistry (Mosc) ; 85(Suppl 1): S56-S78, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32087054

RESUMO

Oxidative stress resulting from accumulation of reactive oxygen, nitrogen, and halogen species (ROS, RNS, and RHS, respectively) causes the damage of cells and biomolecules. However, over the long evolutionary time, living organisms have developed the mechanisms for adaptation to oxidative stress conditions including the activity of the antioxidant system (AOS), which maintains low intracellular levels of RONS (ROS and RNS) and RHS. Moreover, living organisms have adapted to use low concentrations of these electrophiles for the regulation of cell functions through the reversible post-translational chemical modifications of redox-sensitive amino acid residues in intracellular effectors of signal transduction pathways (protein kinases and protein phosphatases), transcription factors, etc. An important fine-tuning mechanism that ensures involvement of RONS and RHS in the regulation of physiological processes is interconversion between different reactive species. This review focuses on the complex networks of interacting RONS and RHS types and their endogenous sources, such as NOX family of NADPH oxidases, complexes I and III of the mitochondrial electron transport chain, NO synthases, cytochrome P450-containing monooxygenase system, xanthine oxidoreductase, and myeloperoxidases. We highlight that kinetic parameters of reactions involving RONS and RHS determine the effects of these reactive species on cell functions. We also describe the functioning of enzymatic and non-enzymatic AOS components and the mechanisms of RONS and RHS scavenging under physiological conditions. We believe that analysis of interactions between RONS and relationships between different endogenous sources of these compounds will contribute to better understanding of their role in the maintenance of cell redox homeostasis as well as initiation and progression of diseases.


Assuntos
Halogênios/metabolismo , Espécies Reativas de Nitrogênio/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/fisiologia , Antioxidantes/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Complexo de Proteínas da Cadeia de Transporte de Elétrons/metabolismo , Radicais Livres/metabolismo , Halogenação , Humanos , Mitocôndrias/enzimologia , NADPH Oxidases/metabolismo , Óxido Nítrico Sintase/metabolismo , Oxirredução , Estresse Oxidativo , Peroxidase/metabolismo , Xantina Desidrogenase/metabolismo
3.
Infect Immun ; 88(3)2020 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-31907194

RESUMO

Yersinia pestis is the causative agent of bubonic, pneumonic, and septicemic plague. We demonstrate that Toll-like receptor 2-deficient (TLR2-/-) mice are resistant to septicemic infection by the KIM5 strain of Y. pestis but not to infection by the CO92 Δpgm strain. This resistance is dependent on TLR2, the route of infection, and the isoform of YopJ. Elevated bacterial burdens were found in the spleens of CO92 Δpgm-infected animals by 24 h postinfection and in the livers by 4 days. The YopJ isoform present contributed directly to cytotoxicity and inflammatory cytokine production of bone marrow-derived macrophages from TLR2-/- mice. Immune cell trafficking is altered in CO92 Δpgm infections, with an increased neutrophil infiltration to the spleen 5 days postinfection. Immune cell infiltration to the liver was greater and earlier in KIM5-infected TLR2-/- mice. The functionality of the immune cells was assessed by the ability to develop reactive oxygen and nitrogen species. Our data suggest an inhibition of granulocytes in forming these species in CO92 Δpgm-infected TLR2-/- mice. These findings suggest that resistance to KIM5 in TLR2-/- mice is dependent on early immune cell trafficking and functionality.


Assuntos
Peste/imunologia , Receptor 2 Toll-Like/deficiência , Yersinia pestis/patogenicidade , Animais , Carga Bacteriana , Proteínas de Bactérias/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Granulócitos/metabolismo , Fígado/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neutrófilos/imunologia , Neutrófilos/metabolismo , Peste/metabolismo , Peste/microbiologia , Espécies Reativas de Nitrogênio/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Baço/imunologia , Baço/microbiologia , Receptor 2 Toll-Like/imunologia , Virulência/genética , Yersinia pestis/genética
4.
Infect Immun ; 88(2)2020 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-31740527

RESUMO

The mechanisms by which interferon gamma (IFN-γ) controls the replication of cytosolic pathogens independent of responses, such as the generation of reactive oxygen species/reactive nitrogen species (ROS/RNS), have not been fully elucidated. In the current study, we developed a model using Francisella tularensis, the causative agent of tularemia, in which pathways triggered by IFN-γ commonly associated with bacterial control were not required. Using this model, we demonstrated that IFN-γ-mediated production of itaconate and its ability to impair host mitochondrial function, independent of activity on the pathogen, were central for the restriction of bacterial replication in vitro and in vivo We then demonstrate that IFN-γ-driven itaconate production was dispensable, as directly targeting complex II using cell membrane-permeable metabolites also controlled infection. Together, these findings show that while reprogramming of mitochondrial metabolism is a key factor in IFN-γ control of intracellular bacteria, the development of antimicrobial strategies based on targeting host mitochondrial metabolism independent of this cytokine may be an effective therapeutic approach.


Assuntos
Francisella tularensis/efeitos dos fármacos , Interferon gama/farmacologia , Mitocôndrias/efeitos dos fármacos , Animais , Membrana Celular/metabolismo , Membrana Celular/microbiologia , Citosol/metabolismo , Citosol/microbiologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Mitocôndrias/microbiologia , Espécies Reativas de Nitrogênio/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Succinatos/farmacologia , Tularemia/tratamento farmacológico , Tularemia/metabolismo , Tularemia/microbiologia
5.
Cell Biochem Biophys ; 78(1): 101-110, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31875278

RESUMO

S.cerevisiae is an industrially important organism known for its ability to produce ethanol as the demand for ethanol is increasing day by day all over the world, the need to find better and alternative ways to increase ethanol production is also rising. In this work we have proposed such alternative but effective method for producing ethanol by S.cerevisiae. Here, we are reporting for the first time the effect of nitrosative stress on ethanol production. Under in vivo condition, nitrosative stress is marked by the modification of macromolecules in the presence of reactive nitrogen species (RNS). Our result showed that treated cells were more capable for ethanol production compared with untreated cells. Our result also showed enhanced alcohol dehydrogenase activity under stressed condition. Further ethanol production was also optimized by using Response Surface Methodology (RSM) with stressed cells. Further, production of ethanol with immobilized beads of stress affected Saccharomyces cerevisiae was also determined. Overall, the obtained data showed that under nitrosative stress, the maximum ethanol production is 34.4 g/l after 24 h and such higher production was observed even after several cycles of fermentation. This is the first report of this kind showing the relation between nitrosative stress and ethanol production in Saccharomyces cerevisiae which may have important industrial application.


Assuntos
Etanol/metabolismo , Estresse Nitrosativo , Saccharomyces cerevisiae/metabolismo , Álcool Desidrogenase/metabolismo , Estresse Nitrosativo/efeitos dos fármacos , Espécies Reativas de Nitrogênio/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Saccharomyces cerevisiae/crescimento & desenvolvimento , Nitrito de Sódio/farmacologia
6.
Int J Mol Sci ; 20(20)2019 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-31600882

RESUMO

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) that involves the autoreactive T-cell attack on axonal myelin sheath. Lesions or plaques formed as a result of repeated damage and repair mechanisms lead to impaired relay of electrical impulses along the nerve, manifesting as clinical symptoms of MS. Evidence from studies in experimental autoimmune encephalomyelitis (EAE) models of MS strongly suggests that mitochondrial dysfunction presents at the onset of disease and throughout the disease course. The aim of this study was to determine if mitochondrial dysfunction occurs before clinical symptoms arise, and whether this is confined to the CNS. EAE was induced in C57B/L6 mice, and citrate synthase and mitochondrial respiratory chain (MRC) complex I-IV activities were assayed at presymptomatic (3 or 10 days post first immunisation (3 or 10 DPI)) and asymptomatic (17 days post first immunisation (17 DPI) time-points in central nervous system (CNS; spinal cord) and peripheral (liver and jaw muscle) tissues. Samples from animals immunised with myelin oligodendrocyte glycoprotein (MOG) as EAE models were compared with control animals immunised with adjuvant (ADJ) only. Significant changes in MOG compared to control ADJ animals in MRC complex I activity occurred only at presymptomatic stages, with an increase in the spinal cord at 10 DPI (87.9%), an increase at 3 DPI (25.6%) and decrease at 10 DPI (22.3%) in the jaw muscle, and an increase in the liver at 10 DPI (71.5%). MRC complex II/III activity changes occurred at presymptomatic and the asymptomatic stages of the disease, with a decrease occurring in the spinal cord at 3 DPI (87.6%) and an increase at 17 DPI (36.7%), increase in the jaw muscle at 10 DPI (25.4%), and an increase at 3 DPI (75.2%) and decrease at 17 DPI (95.7%) in the liver. Citrate synthase activity was also significantly decreased at 10 DPI (27.3%) in the liver. No significant changes were observed in complex IV across all three tissues assayed. Our findings reveal evidence that mitochondrial dysfunction is present at the asymptomatic stages in the EAE model of MS, and that the changes in MRC enzyme activities are tissue-specific and are not confined to the CNS.


Assuntos
Encefalomielite Autoimune Experimental/metabolismo , Mitocôndrias/metabolismo , Esclerose Múltipla/metabolismo , Animais , Biomarcadores , Modelos Animais de Doenças , Suscetibilidade a Doenças , Encefalomielite Autoimune Experimental/diagnóstico , Encefalomielite Autoimune Experimental/etiologia , Feminino , Camundongos , Esclerose Múltipla/diagnóstico , Esclerose Múltipla/etiologia , Músculo Esquelético/metabolismo , Espécies Reativas de Nitrogênio/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Índice de Gravidade de Doença
7.
Redox Biol ; 26: 101282, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31386964

RESUMO

Reactive oxygen and nitrogen species (ROS and RNS, respectively) activate the redox-sensitive Ras small GTPases. The three canonical genes (HRAS, NRAS, and KRAS) are archetypes of the superfamily of small GTPases and are the most common oncogenes in human cancer. Oncogenic Ras is intimately linked to redox biology, mainly in the context of tumorigenesis. The Ras protein structure is highly conserved, especially in effector-binding regions. Ras small GTPases are redox-sensitive proteins thanks to the presence of the NKCD motif (Asn116-Lys 117-Cys118-Asp119). Notably, the ROS- and RNS-based oxidation of Cys118 affects protein stability, activity, and localization, and protein-protein interactions. Cys residues at positions 80, 181, 184, and 186 may also help modulate these actions. Moreover, oncogenic mutations of Gly12Cys and Gly13Cys may introduce additional oxidative centres and represent actionable drug targets. Here, the pathophysiological involvement of Cys-redox regulation of Ras proteins is reviewed in the context of cancer and heart and brain diseases.


Assuntos
Cisteína/metabolismo , Oxirredução , Proteínas ras/metabolismo , Animais , Transformação Celular Neoplásica , Regulação da Expressão Gênica , Humanos , Isoformas de Proteínas , Processamento de Proteína Pós-Traducional , Espécies Reativas de Nitrogênio/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Relação Estrutura-Atividade , Proteínas ras/química , Proteínas ras/genética
8.
Int J Mol Sci ; 20(15)2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31387214

RESUMO

Sarcopenia is characterized by the progressive loss of skeletal muscle mass and strength. In older people, malnutrition and physical inactivity are often associated with sarcopenia, and, therefore, dietary interventions and exercise must be considered to prevent, delay, or treat it. Among the pathophysiological mechanisms leading to sarcopenia, a key role is played by an increase in reactive oxygen and nitrogen species (ROS/RNS) levels and a decrease in enzymatic antioxidant protection leading to oxidative stress. Many studies have evaluated, in addition to the effects of exercise, the effects of antioxidant dietary supplements in limiting age-related muscle mass and performance, but the data which have been reported are conflicting. In skeletal muscle, ROS/RNS have a dual function: at low levels they increase muscle force and adaptation to exercise, while at high levels they lead to a decline of muscle performance. Controversial results obtained with antioxidant supplementation in older persons could in part reflect the lack of univocal effects of ROS on muscle mass and function. The purpose of this review is to examine the molecular mechanisms underlying the dual effects of ROS in skeletal muscle function and the analysis of literature data on dietary antioxidant supplementation associated with exercise in normal and sarcopenic subjects.


Assuntos
Músculo Esquelético/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Adaptação Fisiológica , Envelhecimento/metabolismo , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Suplementos Nutricionais , Exercício Físico , Humanos , Oxirredução , Espécies Reativas de Nitrogênio/metabolismo , Sarcopenia/etiologia , Sarcopenia/metabolismo , Sarcopenia/fisiopatologia , Sarcopenia/prevenção & controle , Transdução de Sinais
9.
Phys Chem Chem Phys ; 21(35): 19327-19341, 2019 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-31453592

RESUMO

The mechanisms of plasma in medicine are broadly attributed to plasma-derived reactive oxygen and nitrogen species (RONS). In order to exert any intracellular effects, these plasma-derived RONS must first traverse a major barrier in the cell membrane. The cell membrane lipid composition, and thereby the magnitude of this barrier, is highly variable between cells depending on type and state (e.g. it is widely accepted that healthy and cancerous cells have different membrane lipid compositions). In this study, we investigate how plasma-derived RONS interactions with lipid membrane components can potentially be exploited in the future for treatment of diseases. We couple phospholipid vesicle experiments, used as simple cell models, with molecular dynamics (MD) simulations of the lipid membrane to provide new insights into how the interplay between phospholipids and cholesterol may influence the response of healthy and diseased cell membranes to plasma-derived RONS. We focus on the (i) lipid tail saturation degree, (ii) lipid head group type, and (iii) membrane cholesterol fraction. Using encapsulated molecular probes, we study the influence of the above membrane components on the ingress of RONS into the vesicles, and subsequent DNA damage. Our results indicate that all of the above membrane components can enhance or suppress RONS uptake, depending on their relative concentration within the membrane. Further, we show that higher RONS uptake into the vesicles does not always correlate with increased DNA damage, which is attributed to ROS reactivity and lifetime. The MD simulations indicate the multifactorial chemical and physical processes at play, including (i) lipid oxidation, (ii) lipid packing, and (iii) lipid rafts formation. The methods and findings presented here provide a platform of knowledge that could be leveraged in the development of therapies relying on the action of plasma, in which the cell membrane and oxidative stress response in cells is targeted.


Assuntos
Dano ao DNA , Lipídeos de Membrana/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Colesterol/química , Lipídeos de Membrana/química , Simulação de Dinâmica Molecular , Fosfolipídeos/química , Espécies Reativas de Nitrogênio/sangue , Espécies Reativas de Nitrogênio/metabolismo , Espécies Reativas de Oxigênio/sangue , Vesículas Transportadoras/química
10.
Med Hypotheses ; 129: 109249, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31371070

RESUMO

Although once considered by biologists almost exclusively for their toxicity, reactive oxygen (ROS) and nitrogen (RNS) species produced within normal cells under baseline physiological conditions are now appreciated as redox regulators of a wide range of protein functions. Two families of enzymes, the NADPH oxidases (NOXs) and nitric oxide synthases (NOSs), are major sources of ROS/RNS from molecular oxygen. Aquaporins (AQPs) are membrane channels capable of transporting some ROS/RNS, in particular hydrogen peroxide and perhaps nitric oxide. The activities of all these enzymes and channels are sensitive to variations in oxygen levels within the physiological range experienced by cells in the human body. Since ROS/RNS have important physiological roles and their endogenous production is affected by oxygen levels, we hypothesize that the synthesis of these proteins is increased at lower oxygen levels within the physiological range of most human cells in vivo, i.e. 2-5%, in order to facilitate the maintenance of ROS/RNS production rates. We further postulate that this is achieved, at least in part, by transcriptional stimulation mediated by the activity of hypoxia inducible factors (HIFs), which are strongly regulated by oxygen levels over the same range of oxygen. Here we survey the evidence supporting this hypothesis, including induction of expression of NOXs, NOSs, and AQPs at lower oxygen levels, presence of hypoxia response elements in the corresponding human genes, and evidence from chromatin immunoprecipitation (ChIP) experiments that HIF-1 and/or HIF-2 bind these regions. We find a significant amount of empirical data supporting the hypothesis that HIFs could function as physiological regulators of ROS/RNS homeostasis in the normoxic range in human cells.


Assuntos
Fator 1 Induzível por Hipóxia/metabolismo , Óxido Nítrico/metabolismo , Oxigênio/metabolismo , Espécies Reativas de Nitrogênio/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Animais , Aquaporinas/metabolismo , Membrana Celular/metabolismo , Imunoprecipitação da Cromatina , Regulação da Expressão Gênica , Homeostase , Humanos , Hipóxia/metabolismo , NADPH Oxidases/metabolismo , Nitrogênio/metabolismo , Oxirredução
11.
Oxid Med Cell Longev ; 2019: 8107265, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31316721

RESUMO

Specialized proresolving mediators (SPMs) are a novel class of endogenous lipids, derived by ω-6 and ω-3 essential polyunsaturated fatty acids such as arachidonic acid (AA), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA) that trigger and orchestrate the resolution of inflammation, which is the series of cellular and molecular events that leads to spontaneous regression of inflammatory processes and restoring of tissue homeostasis. These lipids are emerging as highly effective therapeutic agents that exert their immunoregulatory activity by activating the proresolving pathway, as reported by a consistent bulk of evidences gathered in the last two decades since their discovery. The production of reactive oxygen (ROS) and nitrogen (RNS) species by immune cells plays indeed an important role in the inflammatory mechanisms of host defence, and it is now clear that oxidative stress, viewed as an imbalance between such species and their elimination, can lead to many chronic inflammatory diseases. This review, the first of its kind, is aimed at exploring the manifold effects of SPMs on modulation of reactive species production, along with the mechanisms through which they either inhibit molecular signalling pathways that are activated by oxidative stress or induce the expression of endogenous antioxidant systems. Furthermore, the possible role of SPMs in oxidative stress-mediated chronic disorders is also summarized, suggesting not only that their anti-inflammatory and proresolving properties are strictly associated with their antioxidant role but also that these endogenous lipids might be exploited in the treatment of several pathologies in which uncontrolled production of ROS and RNS or impairment of the antioxidant machinery represents a main pathogenetic mechanism.


Assuntos
Anti-Inflamatórios/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Animais , Ácidos Docosa-Hexaenoicos/farmacologia , Ácido Eicosapentaenoico/farmacologia , Humanos , Espécies Reativas de Nitrogênio/metabolismo , Espécies Reativas de Oxigênio/metabolismo
12.
Free Radic Res ; 53(8): 875-881, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31257950

RESUMO

Peroxiredoxin 1 (PRDX1) is an antioxidant enzyme that, when secreted, can act as a proinflammatory signal. Here we studied the regulation of intracellular PRDX1 by lipopolysaccharide (LPS) and interferon-gamma (IFN-γ) in the RAW 264.7 mouse macrophage cell line. While LPS or IFN-γ alone did not affect PRDX1 protein levels, their combination led to an almost complete loss of the PRDX1 dimer. This was likely mediated by the increased production of nitric oxide (NO) as it was reversed by the NO synthase inhibitor L-N-methylarginine (L-NMMA), while a NO-releasing agent decreased PRDX1 levels. Inhibition of the proteasome with MG132 also prevented the loss of the PRDX1 dimer, suggesting that the decrease is due to a NO-activated proteasomal degradation pathway. By contrast with the decrease in protein levels, LPS increased PRDX1 mRNA and this effect was amplified by IFN-γ. Two other Nrf2 target genes, thioredoxin reductase (TXNRD1) and haem oxygenase (HMOX1), were also induced by LPS but IFN-γ did not increase their expression further. This study shows that inflammation differentially regulates PRDX1 at the levels of protein stability and gene expression, and that NO plays a key role in this mechanism.


Assuntos
Inflamação , Macrófagos/metabolismo , Óxido Nítrico/metabolismo , Peroxirredoxinas/metabolismo , Animais , Regulação da Expressão Gênica , Interferon gama , Lipopolissacarídeos , Macrófagos/enzimologia , Camundongos , Peroxirredoxinas/genética , Proteólise , Células RAW 264.7 , Espécies Reativas de Nitrogênio/metabolismo
13.
Infect Immun ; 87(10)2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31308080

RESUMO

Macrophages are critical mediators of innate immunity and must be overcome for bacterial pathogens to cause disease. The Gram-positive bacterium Staphylococcus aureus produces virulence factors that impede macrophages and other immune cells. We previously determined that production of the metabolic cofactor lipoic acid by the lipoic acid synthetase, LipA, blunts macrophage activation. A ΔlipA mutant was attenuated during infection and was more readily cleared from the host. We hypothesized that bacterial lipoic acid synthesis perturbs macrophage antimicrobial functions and therefore hinders the clearance of S. aureus Here, we found that enhanced innate immune cell activation after infection with a ΔlipA mutant was central to attenuation in vivo, whereas a growth defect imparted by the lipA mutation made a negligible contribution to overall clearance. Macrophages recruited to the site of infection with the ΔlipA mutant produced larger amounts of bactericidal reactive oxygen species (ROS) and reactive nitrogen species (RNS) than those recruited to the site of infection with the wild-type strain or the mutant strain complemented with lipA ROS derived from the NADPH phagocyte oxidase complex and RNS derived from the inducible nitric oxide synthetase, but not mitochondrial ROS, were critical for the restriction of bacterial growth under these conditions. Despite enhanced antimicrobial immunity upon primary infection with the ΔlipA mutant, we found that the host failed to mount an improved recall response to secondary infection. Our data suggest that lipoic acid synthesis in S. aureus promotes bacterial persistence during infection through limitation of ROS and RNS generation by macrophages. Broadly, this work furthers our understanding of the intersections between bacterial metabolism and immune responses to infection.


Assuntos
Proteínas de Bactérias/genética , Regulação Bacteriana da Expressão Gênica , Macrófagos Peritoneais/metabolismo , Infecções Estafilocócicas/metabolismo , Staphylococcus aureus/genética , Ácido Tióctico/biossíntese , Animais , Proteínas de Bactérias/metabolismo , Feminino , Interações Hospedeiro-Patógeno/imunologia , Ativação de Macrófagos , Macrófagos Peritoneais/imunologia , Macrófagos Peritoneais/microbiologia , Masculino , Camundongos , Viabilidade Microbiana , Mutação , NADPH Oxidases/genética , NADPH Oxidases/imunologia , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/imunologia , Espécies Reativas de Nitrogênio/antagonistas & inibidores , Espécies Reativas de Nitrogênio/imunologia , Espécies Reativas de Nitrogênio/metabolismo , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/imunologia , Espécies Reativas de Oxigênio/metabolismo , Infecções Estafilocócicas/imunologia , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/metabolismo , Ácido Tióctico/farmacologia
14.
Redox Biol ; 26: 101261, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31279985

RESUMO

Activated macrophages play a central role in both the development and resolution of inflammation. These immune cells need to be functional in harmful conditions with high levels of reactive oxygen and nitrogen species that can damage their basic cell components, which may alter their metabolism. An excessive accumulation of these cell alterations drives macrophages inexorably to cell death, which has been associated to the development of several inflammatory diseases and even with aging in a process termed as "immunosenescence". Macrophages, however, exhibit a prolonged survival in this hostile environment because they equip themselves with a complex network of protective mechanisms. Here we provide an overview of these self-defense mechanisms with special attention being paid to bioactive lipid mediators, NRF2 signaling and metabolic reprogramming.


Assuntos
Imunossenescência , Macrófagos/metabolismo , Oxirredução , Estresse Oxidativo , Animais , Biomarcadores , Suscetibilidade a Doenças , Humanos , Imunidade Inata , Inflamação/etiologia , Inflamação/metabolismo , Metabolismo dos Lipídeos , Macrófagos/imunologia , Espécies Reativas de Nitrogênio/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais
15.
Asian Pac J Cancer Prev ; 20(7): 2167-2176, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31350981

RESUMO

Background: Smokeless tobacco (SLT) acts as a modifier of erythrocyte and platelet membranes by disrupting antioxidant system with the concomitant increase in free radical production and induction of apoptosis. Methods: The SLT users was that individuals used gutkha and khaini products (Khaleja/mahak chaini brand respectively) habitually, at least >20 times per week consists of 50-60 g during the last 2-4 years. Results: The gutkha and khaini users found to be significantly increased levels of iNOS (Inducible nitric oxide synthase) enzyme in plasma, erythrocytes, and platelet membranes when compared to normal controls. The gutkha and khaini users exhibited that the significant increase in the levels of gene expression of apoptotic proteins (Bcl2-B cell lymphoma gene 2, Bax, caspases 8, caspase 10, and caspase 12), IL-6 (Interleukin-6), and decreased levels of TNF-α (Tumor necrosis factor-alpha) and decreased expression of caspase 12 of khaini users were observed from blood samples. The significant increase in the concentrations of peroxynitrites (ONOO-), nitric oxide (NO) (Nitrates and nitrites), malondialdehyde (MDA), cholesterol, and phospholipids were reported in the smokeless tobacco users of erythrocytes and platelets. The experimental subjects showed that the increased osmotic fragility and decreased membrane fluidity of erythrocytes and platelets in comparison with non-tobacco users. The normal subjects had been exposed that the proper functioning of antioxidant enzymes and decreased enzyme activities of antioxidants were reported by SLT users. Conclusion: The smokeless tobacco products are exerted chronic damage to membranes of erythrocytes and platelets and elevation of apoptosis in the prolonged periods of human male volunteers.


Assuntos
Biomarcadores/metabolismo , Plaquetas/patologia , Eritrócitos/patologia , Uso de Tabaco/epidemiologia , Tabaco sem Fumaça/efeitos adversos , Adulto , Apoptose , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Estudos de Casos e Controles , Membrana Eritrocítica/efeitos dos fármacos , Membrana Eritrocítica/metabolismo , Membrana Eritrocítica/patologia , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Seguimentos , Perfilação da Expressão Gênica , Humanos , Índia/epidemiologia , Masculino , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Estresse Oxidativo , Prognóstico , Espécies Reativas de Nitrogênio/metabolismo , Espécies Reativas de Oxigênio/metabolismo
16.
Oxid Med Cell Longev ; 2019: 2730896, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31191796

RESUMO

Bladder cancer (BC) is one of the most common tumors found in the urinary bladder for both male and female in western countries. In vitro and in vivo studies suggest that high levels of reactive oxygen species (ROS) and reactive nitrogen species (RNS) and oxidative stress play a crucial role in human cancer. Low concentration of ROS and RNS is indispensable for cell survival and proliferation. However, high concentration of ROS and RNS can exert a cytotoxic effect. Increased oxidative stress is a result of either increased ROS/RNS production or a decrease of antioxidant defense mechanisms. A literature search was carried out on PubMed, Medline, and Google Scholar for articles in English published up to May 2018 using the following keywords: oxidative stress, antioxidants, reactive oxygen species, lipid peroxidation, paraoxonase, urinary bladder cancer, and nitric oxide. Literature data demonstrate that BC is associated with oxidative stress and with an imbalance between oxidants and antioxidant enzymes. Markers of lipid peroxidation, protein and nucleic acid oxidation are significantly higher in tissues of patients with BC compared with control groups. A decrease of activity of antioxidant enzymes (superoxide dismutase, catalase, glutathione, and paraoxonase) has also been demonstrated. The imbalance between oxidants and antioxidants could have a potential role in the etiology and progression of bladder cancer.


Assuntos
Antioxidantes/metabolismo , Neoplasias da Bexiga Urinária/metabolismo , Animais , Biomarcadores/metabolismo , Humanos , Estresse Oxidativo/fisiologia , Espécies Reativas de Nitrogênio/metabolismo , Espécies Reativas de Oxigênio/metabolismo
17.
J Exp Clin Cancer Res ; 38(1): 271, 2019 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-31221176

RESUMO

BACKGROUND: Recently, we have reported the characterization of a novel protein named Coiled-coil Helix Tumor and Metabolism 1 (CHTM1). CHTM1 localizes to both cytosol and mitochondria. Sequence corresponding to CHTM1 is also annotated in the database as CHCHD5. CHTM1 is deregulated in human breast and colon cancers and its deficiency in human cancer cells leads to defective lipid metabolism and poor growth under glucose/glutamine starvation. METHODS: Human cancer cell lines and tissue specimens were used. CHTM1 knockdown was done via lentiviral approach. CHTM1-expresssion constructs were developed and mutants were generated via site-directed mutagenesis approach. Western blotting, immunostaining, immunohistochemistry, cell fractionation and luciferase assays were performed. Reactive oxygen species and reactive nitrogen species were also measured. RESULTS: Here we report that CHTM1 deficiency sensitizes human lung cancer cells to metabolic stress-induced cell death mediated by glucose/glutamine deprivation and metformin treatment. CHTM1 interacts with Apoptosis Inducing Factor 1 (AIF1) that is one of the important death inducing molecules. CHTM1 appears to negatively regulate AIF1 by preventing AIF1 translocation to cytosol/nucleus and thereby inhibit AIF1-mediated caspase-independent cell death. Our results also indicate that p38, a stress kinase, plays a critical role in metabolic stress-induced cell death in CHTM1-deficient cells. Furthermore, p38 appears to enhance AIF1 translocation from mitochondria to cytosol particularly in metabolically stressed CHTM1-deficient cells and CHTM1 negatively regulates p38 kinase activity. The expression status of CHTM1 in lung cancer patient samples is also investigated and our results indicate that CHTM1 levels are increased in the majority of lung tumors when compared to their matching normal tissues. CONCLUSION: Thus, CHTM1 appears to be an important metabolic marker that regulates cancer cell survival under metabolic stress conditions, and has the potential to be developed as a predictive tumor marker.


Assuntos
Fator de Indução de Apoptose/metabolismo , Neoplasias Pulmonares/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Estresse Fisiológico , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Células A549 , Linhagem Celular Tumoral , Sobrevivência Celular , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Células HeLa , Humanos , Metabolismo dos Lipídeos , Neoplasias Pulmonares/genética , Células MCF-7 , Metformina/farmacologia , Transporte Proteico , Espécies Reativas de Nitrogênio/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Regulação para Cima
18.
Biofactors ; 45(5): 641-650, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31185139

RESUMO

Epigenetic regulation is attracting much attention because it explains many of the effects that the external environment induces in organisms. Changes in the cellular redox status and even more specifically in its nuclear redox compartment is one of these examples. Redox changes can induce modulation of the epigenetic regulation in cells. Here we present a few cases where reactive oxygen or nitrogen species induces epigenetic marks in histones. Posttranslational modification of these proteins like histone nitrosylation, carbonylation, or glutathionylation together with other mechanisms not reviewed here are the cornerstones of redox-related epigenetic regulation. We currently face a new field of research with potential important consequences for the treatment of many pathologies.


Assuntos
Epigênese Genética , Histonas/metabolismo , Processamento de Proteína Pós-Traducional , Espécies Reativas de Nitrogênio/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Animais , Glutationa/metabolismo , Histonas/genética , Humanos , Camundongos , Compostos Nitrosos/metabolismo , Oxirredução , Estresse Oxidativo , Carbonilação Proteica , Transdução de Sinais , Compostos de Enxofre/metabolismo
19.
Nanoscale ; 11(24): 11605-11616, 2019 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-31173033

RESUMO

Anti-oxidative agents hold great potential in osteoarthritis (OA) therapy. However, most radical scavengers have poor biocompatibility and potential cytotoxicity, which limit their applications. Herein we explore dopamine melanin (DM) nanoparticles as a novel scavenger of reactive oxygen species (ROS) and reactive nitrogen species (RNS). DM nanoparticles show low cytotoxicity and a strong ability to sequester a broad range of ROS and RNS, including superoxides, hydroxyl radicals, and peroxynitrite. This translates to excellent anti-inflammatory and chondro-protective effects by inhibiting intracellular ROS and RNS and promoting antioxidant enzyme activities. With an average diameter of 112.5 nm, DM nanoparticles can be intra-articularly (i.a.) injected into an affected joint and retained at the injection site. When tested in vivo in rodent OA models, DM nanoparticles showed diminished inflammatory cytokine release and reduced proteoglycan loss, which in turn slowed down cartilage degradation. Mechanistic studies suggest that DM nanoparticles also enhance autophagy that benefits OA control. In summary, our study suggests DM nanoparticles as a safe and promising therapeutic for OA.


Assuntos
Dopamina , Depuradores de Radicais Livres , Melaninas , Nanopartículas , Osteoartrite/tratamento farmacológico , Espécies Reativas de Nitrogênio/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Animais , Modelos Animais de Doenças , Dopamina/química , Dopamina/farmacologia , Feminino , Depuradores de Radicais Livres/química , Depuradores de Radicais Livres/farmacologia , Melaninas/química , Melaninas/farmacologia , Nanopartículas/química , Nanopartículas/uso terapêutico , Osteoartrite/metabolismo , Osteoartrite/patologia , Ratos , Ratos Sprague-Dawley
20.
Oxid Med Cell Longev ; 2019: 7838406, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31249650

RESUMO

Detection of free radicals in tissues is challenging. Most approaches rely on incubating excised sections or homogenates with reagents, typically at supraphysiologic oxygen tensions, to finally detect surrogate, nonspecific end products. In the present work, we explored the potential of using intravenously (i.v.) injected dihydroethidine (DHE) to detect superoxide radical (O2 ∙-) abundance in vivo by quantification of the superoxide-specific DHE oxidation product, 2-hydroxyethidium (2-OH-E+), as well as ethidium (E+) and DHE in multiple tissues in a murine model of endotoxemia induced by lipopolysaccharide (LPS). LPS was injected intraperitoneally (i.p.), while DHE was delivered via the tail vein one hour before sacrifice. Tissues (kidney, lung, liver, and brain) were harvested and subjected to HPLC/fluorescent analysis of DHE and its monomeric oxidation products. In parallel, electron spin resonance (EPR) spin trapping was used to measure nitric oxide (∙NO) production in the aorta, lung, and liver isolated from the same mice. Endotoxemic inflammation was validated by analysis of plasma biomarkers. The concentration of 2-OH-E+ varied in the liver, lung, and kidney; however, the ratios of 2-OH-E+/E+ and 2-OH-E+/DHE were increased in the liver and kidney but not in the lung or the brain. An LPS-induced robust level of ∙NO burst was observed in the liver, whereas the lung demonstrated a moderate yet progressive increase in the rate of ∙NO production. Interestingly, endothelial dysfunction was observed in the aorta, as evidenced by decreased ∙NO production 6 hours post-LPS injection that coincided with the inflammatory burden of endotoxemia (e.g. elevated serum amyloid A and prostaglandin E2). Combined, these data demonstrate that systemic delivery of DHE affords the capacity to specifically detect O2 ∙- production in vivo. Furthermore, the ratio of 2-OH-E+/E+ oxidation products in tissues provides a tool for comparative insight into the oxidative environments in various organs. Based on our findings, we demonstrate that the endotoxemic liver is susceptible to both O2 ∙--mediated and nonspecific oxidant stress as well as nitrosative stress. Oxidant stress in the lung was detected to a lesser extent, thus underscoring a differential response of liver and lung to endotoxemic injury induced by intraperitoneal LPS injection.


Assuntos
Dicarbetoxi-Di-Hidrocolidina/análogos & derivados , Endotoxemia/patologia , Lipopolissacarídeos/toxicidade , Fígado/patologia , Pulmão/patologia , Estresse Nitrosativo , Estresse Oxidativo , Animais , Dicarbetoxi-Di-Hidrocolidina/química , Endotoxemia/induzido quimicamente , Endotoxemia/metabolismo , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico/metabolismo , Oxirredução , Espécies Reativas de Nitrogênio/metabolismo , Superóxidos/metabolismo
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