Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 98
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Chemosphere ; 238: 124602, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31545211

RESUMO

Polybrominated diphenyl ethers (PBDEs) have been known to exhibit neurotoxicity in rats; however, the underlying mechanism remains unknown and there is no available intervention. In this study, we aimed to investigate the role of oxidative and nitrosative stress in the neurotoxicity in the cerebral cortex and primary neurons in rats following the BDE-153 treatment. Compared to the untreated group, BDE-153 treatment significantly induced the neurotoxic effects in rats, as manifested by the increased lactate dehydrogenase (LDH) activities and cell apoptosis rates, and the decreased neurotrophic factor contents and cholinergic enzyme activities in rats' cerebral cortices and primary neurons. When compared to the untreated group, the oxidative and nitrosative stress had occurred in the cerebral cortex or primary neurons in rats following the BDE-153 treatment, as manifested by the increments in levels of reactive oxygenspecies (ROS), malondialdehyde (MDA), nitric oxide (NO), and neuronal nitric oxide synthase (nNOS) mRNA and protein expressions, along with the decline in levels of superoxide dismutase (SOD) activity, glutathione (GSH) content, and peroxiredoxin I (Prx I) and Prx II mRNA and protein expressions. In addition, the ROS scavenger N-acetyl-l-cysteine (NAC) or NO scavenger NG-Nitro-l-arginine (L-NNA) significantly rescued the LDH leakage and cell survival, reversed the neurotrophin contents and cholinergic enzymes, mainly via regaining balance between oxidation/nitrosation and antioxidation. Overall, our findings suggested that oxidative and nitrosative stresses are involved in the neurotoxicity induced by BDE-153, and that the antioxidation is a potential targeted intervention.


Assuntos
Córtex Cerebral/patologia , Éteres Difenil Halogenados/toxicidade , Síndromes Neurotóxicas/patologia , Estresse Nitrosativo/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Bifenil Polibromatos/toxicidade , Acetilcisteína/farmacologia , Animais , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Glutationa/metabolismo , Éteres Difenil Halogenados/metabolismo , Masculino , Malondialdeído/metabolismo , Fatores de Crescimento Neural/metabolismo , Neurônios/efeitos dos fármacos , Neurotrofina 3/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo I/metabolismo , Estresse Nitrosativo/fisiologia , Estresse Oxidativo/fisiologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
2.
Eur J Pharmacol ; 855: 192-201, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31075241

RESUMO

Inflammatory bowel disease is an umbrella-term used to describe a set of chronic inflammatory conditions that affect the gastro-intestinal tract. Since most of the inflammatory medications in current use have several undesirable side-effects, stevioside, a naturally occurring, high-intensity sweetener was assessed in our study for its anti-inflammatory properties by in-vitro and in-vivo experiments. Stevioside was observed to significantly inhibit the levels of LPS induced elevation of cytokines, TNF-α (P < 0.05) and IL-6 (P < 0.001) as well as the production of reactive oxygen species (P < 0.01) and nitrites (P < 0.001) in RAW264.7 cells. Stevioside has also been evaluated for its anti-inflammatory effect by using dextran sulfate sodium (DSS)-induced ulcerative colitis model in mice. Stevioside significantly reduced the disease activity index (DAI) score, ameliorated the inflammatory symptoms induced by DSS in mice and exhibited intact colon histo-architecture. Stevioside treatment significantly inhibited the levels of pro-inflammatory cytokines, TNF-α and IL-6, and the protein expressions of pro-inflammatory mediators, COX-2 (P < 0.01) and iNOS (P < 0.01) and restored the levels of endogenous anti-oxidants such as superoxide dismutase (P < 0.01), catalase (P < 0.001), glutathione s-transferase (P < 0.001) and reduced glutathione (P < 0.001) level in colon tissues. It was also observed that stevioside significantly suppressed NF-κB (p65) activation by abrogating IκB phosphorylation and attenuated the phosphorylation of p38, ERK and JNK proteins in colon tissues. The findings of the present study suggest that stevioside exhibits anti-inflammatory property by inhibiting NF-κB (p65) and MAPK pathways and can be employed as an adjunct in nutraceuticals to treat IBD.


Assuntos
Anti-Inflamatórios/farmacologia , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Sulfato de Dextrana/efeitos adversos , Diterpenos de Caurano/farmacologia , Glucosídeos/farmacologia , Animais , Anti-Inflamatórios/uso terapêutico , Antioxidantes/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Colite Ulcerativa/metabolismo , Colite Ulcerativa/patologia , Colo/efeitos dos fármacos , Colo/patologia , Citocinas/metabolismo , Diterpenos de Caurano/uso terapêutico , Glucosídeos/uso terapêutico , Mediadores da Inflamação/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Nitritos/metabolismo , Estresse Nitrosativo/efeitos dos fármacos , Tamanho do Órgão/efeitos dos fármacos , Células RAW 264.7 , Espécies Reativas de Oxigênio/metabolismo
3.
Pharmacol Rep ; 71(3): 517-521, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31009843

RESUMO

BACKGROUND: Cyclic neucleotides are involved in many cellular functions including smooth muscle relaxation, inflammation, and signal transduction. Sildenafil and tadalafil are phosphodiesterase-5 (PDE-5) inhibitors which prevent the degradation of cyclic neucleotide i.e. guanosine 3',5' cyclic monophosphate (cGMP) and increase the levels of cGMP. In this study sildenafil and tadalafil were evaluated for their anti-inflammatory, anti-oxidative and anti-nitrosative stress potential in animal model of bronchial asthma. METHODS: Wistar rats were sensitized with 10 mg intraperitoneal (ip) ovalbumin adsorbed to 10 µg of aluminum hydroxide on day 0. Animals were given sildenafil (1 and 3 mg/kg ip) and tadalafil (1 and 3 mg/kg ip) from day 1 to day 14. Also, on day 14 animals were challenged with ovalbumin (1 mg ip). After 24 h, samples were collected to analyze interleukin-4 (IL-4) and tumour necrosis factor-α (TNF-α), in serum and bronchoalveolar lavage fluid (BALF). The oxidative stress markers malondialdehyde (MDA), reduced glutathione (GSH) and nitric oxide metabolites (NOx) were also measured in serum. RESULTS: Pre-treatment with sildenafil (1 and 3 mg/kg ip) and tadalafil (1 and 3 mg/kg ip) significantly reduced the levels of pro-inflammatory cytokines IL-4 and TNF-α in rat serum and BALF. In addition, pre-treatment with both the drugs decreased the levels of MDA and NOx and increased the levels of GSH in serum. CONCLUSIONS: Sildenafil and tadalafil decreased pro-inflammatory cytokines in serum and BALF. Both drugs inhibit oxidative and nitrosative stress in animal model of bronchial asthma and could have a therapeutic potential in bronchial asthma.


Assuntos
Asma/tratamento farmacológico , Brônquios/efeitos dos fármacos , Inflamação/tratamento farmacológico , Estresse Nitrosativo/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Citrato de Sildenafila/farmacologia , Tadalafila/farmacologia , Animais , Asma/metabolismo , Brônquios/metabolismo , Líquido da Lavagem Broncoalveolar/química , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Glutationa/metabolismo , Inflamação/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Masculino , Malondialdeído/metabolismo , Óxido Nítrico/metabolismo , Ratos , Ratos Wistar
4.
Toxicol Lett ; 310: 39-50, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30980911

RESUMO

This study explored the role of gasotransmitters in lead-induced nephrotoxicity. Long-term exposure of rats to lead resulted in its accumulation in kidney. The accumulated metal impaired kidney function and structure. Lead intoxication resulted in oxidative stress, inflammation and apoptosis in kidney. In addition, it resulted in nitric oxide (NO) overproduction and decrease in hydrogen sulfide (H2S) level and heme oxygenase (HO-1) concentration in kidney. Inhibition of NO overproduction by L-N(G)-nitroarginine methyl ester (L-NAME) and increasing of H2S level by sodium hydrosulfide (NaHS) and CO level by carbon monoxide-releasing molecule-A1 (CORM-A1) inhibited lead-induced impairment of kidney function and structure. These agents inhibited lead-intoxication induced oxidative stress, inflammation, apoptosis, nitrosative stress and reduction of H2S level and HO-1 concentration. Also, concomitant treatment with these agents inhibited lead intoxication-induced increase in protein expressions of inducible NO synthase (iNOS), tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1ß) and caspase-3 as well as decrease in protein expressions of HO-1 and cystathionine- γ-lyase (CSE) in kidney. The NO donor, L-arginine and the H2S and CO biosynthesis inhibitors, trifluoro-DL-alanine and zinc deutroporphyrin, respectively produced opposite effects and aggravated the toxic effects of lead. These results demonstrate, for the first time, that gasotransmitters play an important role in lead-induced nephrotoxicity.


Assuntos
Monóxido de Carbono/metabolismo , Gasotransmissores/metabolismo , Sulfeto de Hidrogênio/metabolismo , Nefropatias/induzido quimicamente , Rim/efeitos dos fármacos , Óxido Nítrico/metabolismo , Compostos Organometálicos/toxicidade , Animais , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Citocinas/metabolismo , Heme Oxigenase (Desciclizante)/metabolismo , Mediadores da Inflamação/metabolismo , Rim/metabolismo , Rim/patologia , Nefropatias/metabolismo , Nefropatias/patologia , Masculino , Estresse Nitrosativo/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos
5.
Mol Neurobiol ; 56(10): 6952-6963, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30945158

RESUMO

Amitriptyline, antidepressant frequently prescribed for treatment of depressive disorders and several neuropathic and inflammatory diseases, has been shown to cause neurotoxic effects. This effect has been partially linked with increased oxidative stress and apoptosis initiation; however, the exact mechanism is still unknown. Klotho protein due to its neuroprotective characteristics seems to be involved in the amitriptyline-mediated neurotoxicity. In this study, we have evaluated the effect of klotho silencing on mouse hippocampal cells exposed to amitriptyline. We show, for the first time, that klotho silencing intensified in hippocampal neurons amitriptyline-induced imbalance in oxido-nitrosative and mineral homeostasis, genomic instability associated with telomere dysfunction what resulted in p16- and p53/p21-mediated cell cycle arrest and activation of autophagy and apoptotic cell death in consequence. Therefore, these results indicate that klotho serves as a part of the cellular defense mechanism engaged in the protection of neurons against amitriptyline-mediated toxicity.


Assuntos
Amitriptilina/toxicidade , Apoptose , Autofagia , Glucuronidase/metabolismo , Hipocampo/patologia , Neurônios/patologia , Proteína 2 de Ligação a Repetições Teloméricas/metabolismo , Animais , Linhagem Celular , Dano ao DNA , Inativação Gênica/efeitos dos fármacos , Instabilidade Genômica , Camundongos , Neurônios/efeitos dos fármacos , Estresse Nitrosativo/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , RNA Interferente Pequeno/metabolismo
6.
Cardiovasc Diabetol ; 18(1): 40, 2019 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-30909895

RESUMO

OBJECTIVE: Diabetic nephropathy (DN) is characterized by glomerular and tubulointerstitial injury, proteinuria and remodeling. Here we examined whether the combination of an inhibitor of neprilysin (sacubitril), a natriuretic peptide-degrading enzyme, and an angiotensin II type 1 receptor blocker (valsartan), suppresses renal injury in a pre-clinical model of early DN more effectively than valsartan monotherapy. METHODS: Sixty-four male Zucker Obese rats (ZO) at 16 weeks of age were distributed into 4 different groups: Group 1: saline control (ZOC); Group 2: sacubitril/valsartan (sac/val) (68 mg kg-1 day-1; ZOSV); and Group 3: valsartan (val) (31 mg kg-1 day-1; ZOV). Group 4 received hydralazine, an anti-hypertensive drug (30 mg kg-1 day-1, ZOH). Six Zucker Lean (ZL) rats received saline (Group 5) and served as lean controls (ZLC). Drugs were administered daily for 10 weeks by oral gavage. RESULTS: Mean arterial pressure (MAP) increased in ZOC (+ 28%), but not in ZOSV (- 4.2%), ZOV (- 3.9%) or ZOH (- 3.7%), during the 10 week-study period. ZOC were mildly hyperglycemic, hyperinsulinemic and hypercholesterolemic. ZOC exhibited proteinuria, hyperfiltration, elevated renal resistivity index (RRI), glomerular mesangial expansion and podocyte foot process flattening and effacement, reduced nephrin and podocin expression, tubulointerstitial and periarterial fibrosis, increased NOX2, NOX4 and AT1R expression, glomerular and tubular nitroso-oxidative stress, with associated increases in urinary markers of tubular injury. None of the drugs reduced fasting glucose or HbA1c. Hypercholesterolemia was reduced in ZOSV (- 43%) and ZOV (- 34%) (p < 0.05), but not in ZOH (- 13%) (ZOSV > ZOV > ZOH). Proteinuria was ameliorated in ZOSV (- 47%; p < 0.05) and ZOV (- 30%; p > 0.05), but was exacerbated in ZOH (+ 28%; p > 0.05) (ZOSV > ZOV > ZOH). Compared to ZOC, hyperfiltration was improved in ZOSV (p < 0.05 vs ZOC), but not in ZOV or ZOH. None of the drugs improved RRI. Mesangial expansion was reduced by all 3 treatments (ZOV > ZOSV > ZOH). Importantly, sac/val was more effective in improving podocyte and tubular mitochondrial ultrastructure than val or hydralazine (ZOSV > ZOV > ZOH) and this was associated with increases in nephrin and podocin gene expression in ZOSV (p < 0.05), but not ZOV or ZOH. Periarterial and tubulointerstitial fibrosis and nitroso-oxidative stress were reduced in all 3 treatment groups to a similar extent. Of the eight urinary proximal tubule cell injury markers examined, five were elevated in ZOC (p < 0.05). Clusterin and KIM-1 were reduced in ZOSV (p < 0.05), clusterin alone was reduced in ZOV and no markers were reduced in ZOH (ZOSV > ZOV > ZOH). CONCLUSIONS: Compared to val monotherapy, sac/val was more effective in reducing proteinuria, renal ultrastructure and tubular injury in a clinically relevant animal model of early DN. More importantly, these renoprotective effects were independent of improvements in blood pressure, glycemia and nitroso-oxidative stress. These novel findings warrant future clinical investigations designed to test whether sac/val may offer renoprotection in the setting of DN.


Assuntos
Aminobutiratos/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Nefropatias Diabéticas/prevenção & controle , Glomérulos Renais/efeitos dos fármacos , Túbulos Renais/efeitos dos fármacos , Inibidores de Proteases/farmacologia , Tetrazóis/farmacologia , Animais , Pressão Arterial/efeitos dos fármacos , Biomarcadores/metabolismo , Glicemia/metabolismo , Nefropatias Diabéticas/sangue , Nefropatias Diabéticas/patologia , Nefropatias Diabéticas/fisiopatologia , Modelos Animais de Doenças , Fibrose , Glomérulos Renais/metabolismo , Glomérulos Renais/fisiopatologia , Glomérulos Renais/ultraestrutura , Túbulos Renais/metabolismo , Túbulos Renais/fisiopatologia , Túbulos Renais/ultraestrutura , Lipídeos/sangue , Masculino , Neprilisina/antagonistas & inibidores , Estresse Nitrosativo/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Proteinúria/fisiopatologia , Proteinúria/prevenção & controle , Ratos Zucker , Fatores de Tempo
7.
Neuroscience ; 406: 1-21, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30825584

RESUMO

The global burden of neurodegenerative disorders has increased substantially over the past 2 decades due to rising rates of population aging. Although neurodegenerative disorders differ in their clinical presentation, the underlying pathobiological processes are largely shared. Oxidative stress, among other mechanisms, is strongly implicated in neurodegenerative disorders and aging, and can potentially be targeted by antioxidative agents. Curcumin, a component of turmeric, is a compound that has received considerable attention for its therapeutic properties, and it is considered to be a powerful antioxidant. In this review, we analyzed the evidence for curcumin as an antioxidant in models of neurodegenerative disorders as well as oxido-nitrosative stress. A total of 1451 articles were found from 3 scientific literature databases (PubMed, Scopus, and Web of Science). After all exclusions, a final total of 64 articles were included in this review. The majority of the studies showed that curcumin, or derivatives thereof, were protective against oxidative and/or nitrosative stress in various cellular and animal models. Overall, curcumin protected against lipid and protein oxidation with a reduction in levels of malondialdehyde, and protein carbonyls, thiols and nitrotyrosines. Furthermore, it stimulated the activities of antioxidant enzymes such as superoxide dismutase and glutathione peroxidase. In conclusion, curcumin appears to be a promising compound for phytomedicine. However, due to some concerns about its efficacy, further targeted experiments are needed to identify its exact molecular targets and pathways responsible for its antioxidant effects.


Assuntos
Envelhecimento/efeitos dos fármacos , Antioxidantes/uso terapêutico , Curcumina/uso terapêutico , Doenças Neurodegenerativas/tratamento farmacológico , Estresse Nitrosativo/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Envelhecimento/metabolismo , Animais , Animais Geneticamente Modificados , Antioxidantes/farmacologia , Linhagem Celular , Curcumina/farmacologia , Humanos , Doenças Neurodegenerativas/metabolismo , Estresse Nitrosativo/fisiologia , Estresse Oxidativo/fisiologia
8.
Int J Mol Sci ; 20(5)2019 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-30871034

RESUMO

Several mechanisms underlying 3,4-Methylenedioxy-N-methylamphetamine (MDMA) neurotoxicity have been proposed, including neurochemical alterations and excitotoxicity mediated by reactive oxygen species (ROS), nitric oxide (NO), and reactive nitrogen species (RNS). However, ROS, NO, and RNS sources in the brain are not fully known. We aimed to investigate possible alterations in the expression of the ROS producer NOX enzymes (NOX2, NOX1, and NOX4), NO generators (iNOS, eNOS, and nNOS), markers of oxidative (8-hydroxy-2'-deoxyguanosine, 8OHdG), and nitrosative (3-nitrotyrosine, NT) stress, as well as the colocalization between cells positive for the dopamine transporter (DT1) and cells expressing the neuronal nuclei (NeuN) marker, in the frontal cortex of rats receiving saline or MDMA, sacrificed 6 h, 16 h, or 24 h after its administration. MDMA did not affect NOX2, NOX1, and NOX4 immunoreactivity, whereas iNOS expression was enhanced. The number of NT-positive cells was increased in MDMA-exposed animals, whereas no differences were detected in 8OHdG expression among experimental groups. MDMA and NT markers colocalized with DT1 positive cells. DT1 immunostaining was found in NeuN-positive stained cells. Virtually no colocalization was observed with microglia and astrocytes. Moreover, MDMA immunostaining was not found in NOX2-positive cells. Our results suggest that iNOS-derived nitrosative stress, but not NOX enzymes, may have a crucial role in the pathogenesis of MDMA-induced neurotoxicity, highlighting the specificity of different enzymatic systems in the development of neuropathological alterations induced by the abuse of this psychoactive compound.


Assuntos
Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , N-Metil-3,4-Metilenodioxianfetamina/farmacologia , Óxido Nítrico Sintase Tipo II/metabolismo , Estresse Nitrosativo/efeitos dos fármacos , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Masculino , Microglia/efeitos dos fármacos , Microglia/metabolismo , Óxido Nítrico/metabolismo , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Espécies Reativas de Nitrogênio/metabolismo , Espécies Reativas de Oxigênio/metabolismo
9.
J Trace Elem Med Biol ; 52: 199-208, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30732883

RESUMO

Excess copper exposure is a risk factor of neurodegeneration related to Alzheimer's disease (AD). Evidence indicates that, besides promoting amyloid ß aggregation, activation of neuroinflammation and oxido-nitrosative stress (two key pathophysiological processes of AD) may also play important roles in Cu(II)-induced neuronal injury. Therefore, the copper-chelating strategy has gained attention in search for new anti-AD drugs. We previously reported a novel multifunctional compound N1,N2-bis(3-(S)-meptazinol-propyl) oxalamide (ZLA), a bis-(-)-nor-meptazinol-oxalamide hybrid with properties of dual binding site acetylcholinesterase (AChE) inhibition and Cu(II)/Zn(II) chelation. The present study was aimed to explore its effect on cognitive deficits caused by intrahippocampal injection of Cu(II) in mice. Results showed that ZLA (2, 5 mg/kg; i.p.) treatment significantly ameliorated the Cu(II)-induced impairment of hippocampus-dependent learning and memory, whereas rivastigmine, an AChE inhibitor showing a similar potency of enzyme inhibition to ZLA, had no obvious effect. Immunohistochemical and Western blot analyses revealed that ZLA attenuated the decrease in hippocampal expression of microtubule-associated protein 2 (MAP2, a dendritic marker) in Cu(II)-challenged mice. Further analysis showed that ZLA suppressed the Cu(II)-evoked microglial activation. Moreover, it inhibited the Cu(II)-evoked production of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and IL-1ß and expression of inducible nitric oxide synthase in the hippocampus. The Cu(II)-induced oxidative and nitrosative stress in the hippocampus was also attenuated after ZLA treatment. Collectively, these results suggest that ZLA ameliorates the Cu(II)-caused cognitive deficits. Inhibition of neuroinflammation and oxido-nitrosative stress, and thus ameliorating neuronal injury, may be the potential mechanism for the anti-amnesic effect of ZLA.


Assuntos
Quelantes/farmacologia , Inflamação/prevenção & controle , Transtornos da Memória/tratamento farmacológico , Estresse Nitrosativo/efeitos dos fármacos , Aprendizagem Espacial/efeitos dos fármacos , Animais , Quelantes/uso terapêutico , Cobre/administração & dosagem , Modelos Animais de Doenças , Inflamação/induzido quimicamente , Inflamação/patologia , Masculino , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/patologia , Camundongos , Camundongos Endogâmicos , Conformação Molecular
10.
Drug Dev Res ; 80(4): 475-480, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30701566

RESUMO

An overdose of acetaminophen (APAP) causes liver injury in experimental animals and humans. The activation step (formation of reactive metabolite, N-acetyl-p-benzoquinone imine by cytochrome P450 system) and the consequent downstream pathway of oxidative stress, nitrosative stress, and inflammation play an important role in APAP-induced hepatotoxicity. Formulation of APAP with an inhibitor of the activation step would be ideal to prevent accidental and intentional APAP toxicity. Dimethyl sulfoxide (DMSO) is a common colorless, inexpensive solvent, and considered safe in human. We hypothesized that a less hepatotoxic APAP if co-formulated with DMSO. To test this hypothesis, C57BL/6 mice were given toxic dose of APAP (250 mg kg-1 , i.p.) mixed with different doses of DMSO (25, 50, 100, and 200 µl kg-1 ). Six hours after APAP treatment, blood and lives were collected for analysis. In DMSO treated groups, there was dose-dependent decrease in markers of liver injury, alanine aminotransferase, and aspartate aminotransferase. Maximum protection was obtained with 200 µl DMSO kg-1 . DMSO was shown to inhibit the activation step by decreasing the rate of GSH depletion in vivo and inhibiting cytochrome P450 system in vitro. Also the levels of lipid peroxides, nitrate/nitrite, tumor necrosis factor-alpha, and interleukin 1ß were decreased significantly. In conclusion, DMSO exerts its protective action by inhibiting the metabolic activation of APAP and thus alleviating the downstream, oxidative stress, nitrosative stress, and inflammation via indirect inhibition. Our findings suggest that replacing the current APAP with APAP/DMSO formulation could prevent accidental and intentional APAP toxicity.


Assuntos
Acetaminofen/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Dimetil Sulfóxido/farmacologia , Fígado/efeitos dos fármacos , Acetaminofen/administração & dosagem , Animais , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Dimetil Sulfóxido/administração & dosagem , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Composição de Medicamentos , Fígado/metabolismo , Testes de Função Hepática , Camundongos Endogâmicos C57BL , Estresse Nitrosativo/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos
11.
Oxid Med Cell Longev ; 2019: 8912768, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30774748

RESUMO

Cardiovascular diseases frequently coexist with chronic kidney disease that constitutes a major determinant of outcome in patients with heart failure. Dysfunction of both organs is related to chronic inflammation, endothelial dysfunction, oxidative stress, and fibrosis. Widespread expression of serine protease DPP4 that degrades varieties of substrates suggests its involvement in numerous physiological processes. In this study, we tested the effects of selective DPP4 inhibition on the progression of renal disease in a nondiabetic model of hypertensive heart disease using Dahl salt-sensitive rats. Chronic DPP4 inhibition positively affected renal function with a significant reduction in albuminuria and serum creatinine. DPP4 inhibition attenuated the inflammatory component by reducing the expression of NF-κB, TNFα, IL-1ß, IL-6, and MCP-1. Kidney macrophages expressed GLP-1R, and DPP4 inhibition promoted macrophage polarization toward the anti-inflammatory M2 phenotype. Finally, high degrees of NADPH oxidase 4 expression and oxidation of nucleic acids, lipids, and proteins were reduced upon DPP4 inhibition. Our study provides evidence of renoprotection by DPP4 inhibition in a nondiabetic hypertension-induced model of chronic cardiorenal syndrome, indicating that DPP4 pathway remains a valid object to study in the context of chronic multiorgan diseases.


Assuntos
Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Hipertensão/complicações , Hipertensão/tratamento farmacológico , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/tratamento farmacológico , Cloreto de Sódio na Dieta/efeitos adversos , Animais , Inibidores da Dipeptidil Peptidase IV/farmacologia , Modelos Animais de Doenças , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Fibrose , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Hipertensão/fisiopatologia , Inflamação/patologia , Rim/efeitos dos fármacos , Rim/fisiopatologia , Testes de Função Renal , Modelos Biológicos , Estresse Nitrosativo/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Fenótipo , Ratos Endogâmicos Dahl , Insuficiência Renal Crônica/fisiopatologia , Transdução de Sinais/efeitos dos fármacos
12.
Artigo em Inglês | MEDLINE | ID: mdl-30684670

RESUMO

There is a need for short-term, reliable and reproducible animal model of chronic pancreatitis (CP) in small animals like mice. This study was aimed to establish the 9 exposures of cerulein-induced CP in mice. Repeated intraperitoneal cerulein injections were performed at 6 consecutive doses (50 µg/kg)/day, 3 days a week for 3 weeks to induce chronic pancreatitis in Swiss albino mice. The severity of damage was assessed by biochemical assays and histopathology. The expression of pro-inflammatory cytokine and fibrotic proteins was assessed by IHC and western blotting. The cerulein treated mice showed significantly elevated plasma amylase (p < .0285) and lipase levels (p < .0022) and resulted in significantly increased pancreatic oxidative (p < .0022) and nitrosative (p < .0022) stress. The hydroxyproline levels were 3.06 fold increased in the cerulein treated mice. The expressions of fibrotic cytokine TGF-ß1 by 1.8 folds and pro-inflammatory cytokines TNF-α by 2.3 fold, IL-6 by 2.2 fold and IL-1ß by 3.7 fold were markedly increased in cerulein treated mice. The histological evaluations indicated increased inflammatory cells infiltration and deposition of collagen. Moreover, the expression of fibrotic markers such as α-SMA increased by 2.5 folds (p < .00014), collagen1a by 1.3 folds (p < .0258) and fibronectin by 3.5 folds (p < .00014) were significantly increased. Our study demonstrates the superiority of 9 exposures of cerulein-induced CP model in mice with the reduction of duration, cerulein exposure, more economical and mortality rate of mice over the available models. Therefore, our model may be suitable to evaluate the pharmacological effects of new drugs in chronic pancreatitis.


Assuntos
Ceruletídeo/farmacologia , Modelos Animais de Doenças , Camundongos , Pancreatite Crônica/induzido quimicamente , Animais , Colágeno/metabolismo , Citocinas/metabolismo , Fibronectinas/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Estresse Nitrosativo/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Pancreatite Crônica/metabolismo , Pancreatite Crônica/patologia , Fator de Crescimento Transformador beta1/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
13.
Psychopharmacology (Berl) ; 236(10): 2867-2880, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30610349

RESUMO

RATIONALE AND OBJECTIVES: Stress-induced alterations in oxidative and inflammatory parameters have been implicated in the pathophysiology of mood disorders. Based on the antioxidant and anti-inflammatory properties of the selenium-containing compound 3-((4-chlorophenyl)selanyl)-1-methyl-1H-indole (CMI), we assessed its ability to reverse depression-like behavioral alterations, neuroinflammation, and oxidative imbalance induced by acute restraint stress. METHODS: Mice submitted to restraint for 240 min received CMI (1 or 10 mg/kg, orally) 10 min after the end of the stress induction. Behavioral and biochemical tests were carried out after further 30 min. RESULTS: Restraint-induced depression-like behavior in the tail suspension test (TST), splash test, and new object exploration test was reversed by CMI. None of the treatments evoked locomotor alteration. In addition, CMI abrogated restraint-induced increases in plasma levels of corticosterone and in markers of oxidative stress and impaired superoxide dismutase and catalase activity in the prefrontal cortex (PFC) and hippocampus (HC). CMI also blocked stress-induced downregulation of mRNA levels of glucocorticoid receptor and brain-derived neurotrophic factor and upregulation of nuclear factor kappa B, inducible nitric oxide synthase, tumor necrosis alpha, indoelamine-2,3-dioxygenase, and glycogen synthase kinase 3 beta in PFC and HC. CONCLUSIONS: These preclinical results indicate that administration of selenium-containing compounds might help to treat depression associated with inflammation and oxidative stress. Graphical abstract ᅟ.


Assuntos
Depressão/tratamento farmacológico , Indóis/uso terapêutico , Estresse Nitrosativo/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Compostos de Selênio/uso terapêutico , Estresse Psicológico/tratamento farmacológico , Animais , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Depressão/metabolismo , Depressão/psicologia , Indóis/química , Indóis/farmacologia , Inflamação/tratamento farmacológico , Inflamação/psicologia , Masculino , Camundongos , Estresse Nitrosativo/fisiologia , Estresse Oxidativo/fisiologia , Distribuição Aleatória , Restrição Física/métodos , Restrição Física/psicologia , Compostos de Selênio/química , Compostos de Selênio/farmacologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Estresse Psicológico/metabolismo , Estresse Psicológico/psicologia
14.
Immunopharmacol Immunotoxicol ; 41(1): 68-75, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30604648

RESUMO

Context: Nephrotoxicity is a highly manifested complication in cancer patients undergoing cisplatin therapy. Oxidative stress, nitrosative stress, and inflammation are the major patho-mechanisms of cisplatin-induced nephrotoxicity. Objective: The purpose of this study was to determine the protective effect of pretreatment and post-treatment of nordihydroguaiarectic acid (NDGA) on cisplatin-induced nephrotoxicity. Material and methods: Cisplatin-induced renal damage was accessed by biochemical estimation of nephrotoxicity markers, oxidative and nitrosative stress whereas inflammatory markers were accessed by ELISA technique. Results and conclusion: Cisplatin administration had resulted in renal injury associated with oxidative stress, nitrosative stress as evident by increased MDA, ROS, and nitrite level with decreased antioxidants such as SOD, catalase and, glutathione. Furthermore, cisplatin treated animals exhibited a noticeable pro-inflammatory response with the substantial increase in renal levels of TNF-α, IL-1ß, and IL-6 and decrease in the renal level of IL-10. NDGA pretreatment did not lead to significantly rise in oxidative stress, nitrosative stress, and inflammation along with restored the level of IL-10 in the kidney and preserved renal function. Moreover, NDGA post-treatment also presented nephroprotective effects, but the effects were not as positive as compared to NDGA pretreatment. In conclusion, these results indicate that NDGA pretreatment is renoprotective while on the other hand NDGA post-treatment is not so effective in cisplatin-induced nephrotoxicity.


Assuntos
Antioxidantes/farmacologia , Cisplatino/toxicidade , Rim/efeitos dos fármacos , Masoprocol/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Animais , Antioxidantes/metabolismo , Peso Corporal/efeitos dos fármacos , Feminino , Rim/metabolismo , Rim/patologia , Testes de Função Renal , Peroxidação de Lipídeos/efeitos dos fármacos , Estresse Nitrosativo/efeitos dos fármacos , Tamanho do Órgão/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
15.
Pharmacology ; 103(1-2): 93-100, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30517939

RESUMO

Depression is a mental disease that causes severe economic and social burdens. The mechanism for the onset of depression remains largely unknown. Recently, more and more attention is being given to the role of neuroinflammation and oxidative stress in depression. Tauroursodeoxycholic acid (TUDCA), a clinically available agent used to treat cholesterol gallstone and protect neurons against neurodegeneration, has been reported to prevent neuroinflammation and oxidative stress. In this study, we investigated the effect of TUDCA on lipopolysaccharide (LPS)-induced depression-like behavior, neuroinflammation, and oxido-nitrosative stress in mice. Results showed that TUDCA pretreatment (once daily for 7 consecutive days) at the dosage of 200 and 400 mg/kg, but not 100 mg/kg, markedly attenuated LPS (0.83 mg/kg)-induced behavioral abnormalities in the tail suspension test, forced swim test, and sucrose preference test. Further analysis showed that the TUDCA pretreatment (200, 400 mg/kg) not only inhibited the production of proinflammatory cytokines induced by LPS stimulation, such as interleukin-6 and tumor necrosis factor-α, but attenuated LPS-triggered oxido-nitrosative stress in the hippocampus and prefrontal cortex. Taken together, our results provide evidence to show that the TUDCA could be a potential antidepressant, and its antidepressive mechanism may be associated with the inhibition of the neuroinflammatory response and oxido-nitrosative stress in the brain.


Assuntos
Antidepressivos/farmacologia , Depressão/induzido quimicamente , Depressão/tratamento farmacológico , Lipopolissacarídeos/farmacologia , Estresse Nitrosativo/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ácido Tauroquenodesoxicólico/farmacologia , Animais , Citocinas/metabolismo , Depressão/metabolismo , Modelos Animais de Doenças , Fluoxetina/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Interleucina-6/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
16.
Mini Rev Med Chem ; 19(3): 178-193, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30324879

RESUMO

Preeclampsia (PE) has a profound effect in increasing both maternal and fetal morbidity and mortality especially in third World. Disturbances of extravillous trophoblast migration toward uterine spiral arteries is characteristic feature of PE, which, in turn, leads to increased uteroplacental vascular resistance and by vascular dysfunction resulting in reduced systemic vasodilatory properties. Underlying pathogenesis appeared to be an altered bioavailability of nitric oxide (NO•) and tissue damage caused by increased levels of reactive oxygen species (ROS) and reactive nitrogen species (RNS). The increase in ROS and RNS production or the decrease in antioxidant mechanisms generates a condition called oxidative and nitrosative stress, respectively, defined as the imbalance between pro- and antioxidants in favor of the oxidants. Additionally, ROS might trigger platelet adhesion and aggregation leading to intravascular coagulopathy. ROS-induced coagulopathy causes placental infarction and impairs the uteroplacental blood flow in PE. As a consequence of these disorders could result in deficiencies in oxygen and nutrients required for normal fetal development resulting in fetal growth restriction. On the one hand, enzymatic and nonenzymatic antioxidants scavenge ROS and protect tissues against oxidative damage. More specifically, placental antioxidant enzymes including catalase, superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) protect the vasculature from ROS, maintaining the vascular function. On the other hand, ischemia in placenta in PE reduces the antioxidant activity. Collectively, the extent of oxidative stress would increase and therefore leads to the development of the pathological findings of PE including hypertension and proteinuria. Our goal in this article is to review current literature about researches demonstrating the interplay between oxidative, nitrosative stresses and PE, about their roles in the pathophysiology of PE and also about the outcomes of current clinical trials aiming to prevent PE with antioxidant supplementation.


Assuntos
Radicais Livres/metabolismo , Estresse Nitrosativo , Estresse Oxidativo , Pré-Eclâmpsia/metabolismo , Feminino , Medicina Herbária , Humanos , Estresse Nitrosativo/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Pré-Eclâmpsia/tratamento farmacológico , Pré-Eclâmpsia/fisiopatologia , Gravidez
17.
Oxid Med Cell Longev ; 2018: 1805354, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30584458

RESUMO

This study is aimed at analysing biochemical and genetic endpoints of toxic effects after administration of adrenaline. For this purpose, the study was carried out on Wistar rats and three doses of adrenaline were used: 0.75 mg/kg, 1.5 mg/kg, and 3 mg/kg body weight. To achieve these aims, we investigated the effects of adrenaline on catalase (CAT), Cu, Zn-superoxide dismutase (SOD), malondialdehyde (MDA), nitrite (NO2-), carbonyl groups (PCC), and nitrotyrosine (3-NT). Total activity of lactate dehydrogenase (LDH), its relative distribution (LDH1-LDH5) activity, level of acute phase proteins (APPs), and genotoxic effect were also evaluated. The obtained results revealed that all doses of adrenaline induced a significant rise in CAT activity, MDA level, PCC, NO2 -, and 3-NT and a significant decrease in SOD activity compared to control. Adrenaline exerted an increase in total activity of LDH, LDH1, and LDH2 isoenzymes. Further study showed that adrenaline significantly decreased serum albumin level and albumin-globulin ratio, while the level of APPs (α 1-acid glycoprotein and haptoglobulin) is increased. The micronucleus test revealed a genotoxic effect of adrenaline at higher concentrations (1.5 mg/kg and 3 mg/kg body weight) compared to untreated rats. It can be concluded that adrenaline exerts oxidative and nitrative stress in rats, increased damage to lipids and proteins, and damage of cardiomyocytes and cytogenetic damage. Obtained results may contribute to better understanding of the toxicity of adrenaline with aims to preventing its harmful effects.


Assuntos
Epinefrina/farmacologia , Estresse Nitrosativo/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Reação de Fase Aguda , Animais , Antioxidantes/metabolismo , Catalase/metabolismo , Dano ao DNA/efeitos dos fármacos , Dano ao DNA/genética , Masculino , Malondialdeído/metabolismo , Oxirredução/efeitos dos fármacos , Ratos , Ratos Wistar , Albumina Sérica/metabolismo , Superóxido Dismutase/metabolismo
18.
Expert Opin Ther Targets ; 22(12): 1049-1061, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30445883

RESUMO

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease associated with disruption of alveolar epithelial cell layer and expansion of fibroblasts/myofibroblasts. Excessive levels of oxidative/nitrosative stress, induction of apoptosis, and insufficient autophagy may be involved in IPF pathogenesis; hence, the targeting of these pathways may ameliorate IPF. Areas covered: We describe the ameliorative effect of melatonin on IPF. We summarize the research on IPF pathogenesis with a focus on oxidative/nitrosative stress, autophagy and apoptosis pathways and discuss the potential effects of melatonin on these pathways. Expert opinion: Oxidative/nitrosative stress, apoptosis and autophagy could be interesting targets for therapeutic intervention in IPF. Melatonin, as a potent antioxidant, induces the expression of antioxidant enzymes, scavenges free radicals and modulates apoptosis and autophagy pathways. The effect of melatonin in the induction of autophagy could be an important mechanism against fibrotic process in IPF lungs. Further clinical studies are necessary to determine if melatonin could be a candidate for treating IPF.


Assuntos
Antioxidantes/farmacologia , Fibrose Pulmonar Idiopática/tratamento farmacológico , Melatonina/farmacologia , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Fibroblastos/patologia , Humanos , Fibrose Pulmonar Idiopática/fisiopatologia , Terapia de Alvo Molecular , Miofibroblastos/patologia , Estresse Nitrosativo/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos
19.
Physiol Int ; 105(3): 233-246, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-30282485

RESUMO

BACKGROUND: Exposure to high altitude in hypobaric hypoxia (HH) is considered to be a physiological oxidative/nitrosative stress. Quercetin (Que) is an effective antioxidant and free radical scavenger against oxidative/nitrosative stress. AIMS: The aim of this study was to investigate the cardioprotective effects of Que in animals exposed to intermittent HH (IHH) and therefore exposed to oxidative/nitrosative stress. MATERIALS AND METHODS: Wistar albino male rats were exposed to short-term (2 days) or long-term (4 weeks; 5 days/week) IHH in a hypobaric chamber (5,500 m, 8 h/day, 380 mmHg, 12% O2, and 88% N2). Half of the animals received natural antioxidant Que (body weight: 30 mg/kg) daily before each IHH exposure and the remaining rats received vehicle (carboxymethylcellulose solution). Control rats were kept under normobaric normoxia (Nx) and treated in a corresponding manner. One day after the last exposure to IHH, we measured the cardiac hypoxia-induced oxidative/nitrosative stress biomarkers: the malondialdehyde (MDA) level and protein carbonyl (PC) content, the activity of some antioxidant enzymes [superoxide dismutase (SOD) and catalase (CAT)], the nitrite plus nitrate (NOx) production, and the inducible nitric oxide synthase (iNOS) protein expression. RESULTS: Heart tissue MDA and PC levels, NOx level, and iNOS expression of IHH-exposed rats had increased, and SOD and CAT activities had decreased compared with those of the Nx-exposed rats (control groups). MDA, CP, NOx, and iNOS levels had decreased in Que-treated IHH-exposed rats compared with IHH-exposed rats (control groups). However, Que administration increased SOD and CAT activities of the heart tissue in the IHH-exposed rats. CONCLUSION: HH exposure increases oxidative/nitrosative stress in heart tissue and Que is an effective cardioprotective agent, which further supports the oxidative cardiac dysfunction induced by hypoxia.


Assuntos
Antioxidantes/farmacologia , Coração/efeitos dos fármacos , Hipóxia/fisiopatologia , Estresse Nitrosativo/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Quercetina/farmacologia , Altitude , Animais , Masculino , Ratos , Ratos Wistar
20.
PLoS Pathog ; 14(10): e1007388, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30365536

RESUMO

The metabolic processes that enable the replication of intracellular Salmonella under nitrosative stress conditions engendered in the innate response of macrophages are poorly understood. A screen of Salmonella transposon mutants identified the ABC-type high-affinity zinc uptake system ZnuABC as a critical determinant of the adaptation of Salmonella to the nitrosative stress generated by the enzymatic activity of inducible nitric oxide (NO) synthase of mononuclear phagocytic cells. NO limits the virulence of a znuB mutant in an acute murine model of salmonellosis. The ZnuABC transporter is crucial for the glycolytic function of fructose bisphosphate aldolase, thereby fueling growth of Salmonella during nitrosative stress produced in the innate response of macrophages. Our investigations demonstrate that glycolysis mediates resistance of Salmonella to the antimicrobial activity of NO produced in an acute model of infection. The ATP synthesized by substrate-level phosphorylation at the payoff phase of glycolysis and acetate fermentation powers the replication of Salmonella experiencing high levels of nitrosative stress. In contrast, despite its high potential for ATP synthesis, oxidative phosphorylation is a major target of inhibition by NO and contributes little to the antinitrosative defenses of intracellular Salmonella. Our investigations have uncovered a previously unsuspected conjunction between zinc homeostasis, glucose metabolism and cellular energetics in the adaptation of intracellular Salmonella to the reactive nitrogen species synthesized in the innate host response.


Assuntos
Imunidade Inata/imunologia , Macrófagos/imunologia , Óxido Nítrico/metabolismo , Infecções por Salmonella/microbiologia , Salmonella/crescimento & desenvolvimento , Zinco/farmacologia , Animais , Homeostase , Imunidade Inata/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Estresse Nitrosativo/efeitos dos fármacos , Fosforilação , Salmonella/efeitos dos fármacos , Salmonella/imunologia , Infecções por Salmonella/tratamento farmacológico , Infecções por Salmonella/imunologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA