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Inflamm Res ; 68(6): 511-523, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31037316


OBJECTIVE: Chicoric acid (CA) is a natural product with promising antioxidant and anti-inflammatory properties; however, its protective effect on methotrexate (MTX)-induced acute kidney injury (AKI) hasn't been reported. We investigated the effect of CA on MTX-induced AKI in rats, pointing to the role of NF-κB/NLRP3 inflammasome and Nrf2/ARE/HO-1 signaling. MATERIALS AND METHODS: Wistar rats received 25 mg/kg and 50 mg/kg CA for 15 days and a single injection of MTX at day 16. At day 19, the rats were killed, and samples were collected for analyses. RESULTS: MTX induced a significant increase in serum creatinine and urea, and kidney Kim-1, reactive oxygen species (ROS), malondialdehyde and nitric oxide levels. In addition, MTX-induced rats exhibited multiple histopathological alterations, diminished antioxidant defenses, and decreased expression of Nrf2, NQO-1 and HO-1. CA prevented histological alterations, ameliorated kidney function markers, attenuated ROS production and lipid peroxidation, and boosted antioxidant defenses. CA suppressed the expression of NF-κB p65, NLRP3, caspase-1 and IL-1ß in the kidney of MTX-induced rats. Furthermore, CA inhibited MTX-induced apoptosis as evidenced by the decreased expression of BAX and caspase-3, and increased Bcl-2 gene expression. CONCLUSIONS: CA prevented MTX-induced AKI through activation of Nrf2/ARE/HO-1 signaling, and attenuation of ROS-induced activation of NF-κB/NLRP3 inflammasome signaling.

Lesão Renal Aguda/tratamento farmacológico , Lesão Renal Aguda/imunologia , Ácidos Cafeicos/farmacologia , Ácidos Cafeicos/uso terapêutico , Succinatos/farmacologia , Succinatos/uso terapêutico , Lesão Renal Aguda/induzido quimicamente , Lesão Renal Aguda/patologia , Animais , Elementos de Resposta Antioxidante/imunologia , Apoptose/efeitos dos fármacos , Antagonistas do Ácido Fólico , Heme Oxigenase (Desciclizante)/imunologia , Rim/efeitos dos fármacos , Rim/imunologia , Rim/patologia , Masculino , Metotrexato , Fator 2 Relacionado a NF-E2/imunologia , NF-kappa B/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Ratos Wistar , Transdução de Sinais , Regulação para Cima/efeitos dos fármacos
Fish Shellfish Immunol ; 90: 173-179, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31059815


It is well documented that diarrhetic shellfish poisoning (DSP) toxins have strong genetic toxicity, cytotoxicity and oxidative damage to bivalve species. However, these toxic effects seem to decrease with the extension of exposure time and the increment of the toxin concentration, the mechanism involved remained unclear, though. In this paper, we found that expression of the genes related to cytoskeleton and Nrf2 signaling pathway displayed different changes over time in the gill of Perna viridis after exposure to DSP toxins-producing microalga Prorocentrum lima. During the short-term exposure (3 h and 6 h), KEAP1 gene expression was significantly up-regulated, coupled with up-regulation of MRP, ABCB1 and CAT transcriptions and down-regulation of GPx1 and NQO1 mRNA. After longer exposure to high density of P. lima, Nrf2 was significantly up-regulated, accompanied with up-regulation of Nrf2 pathway related genes such as NQO1, SOD, GST-ω and ABCB1, whereas KEAP1 was down-regulated. TUBA1C and TUBB1 transcripts were significantly down-regulated after short-term exposure of P. lima, but both of them were up-regulated at 96 h after exposure to high density of P. lima. Paraffin section demonstrated that P. lima had a strong damage on the gill of mussels during the short-term exposure. However, the negative effect to the gill decreased, and the gill restored after longer exposure (96 h). Taking together, we proposed that P. lima had a negative impact on cytoskeleton of mussel gill tissue, could cause oxidative damage to the gills. However, longer exposure of P. lima in high density could activate Nrf2 signaling pathway, thereby reducing the influence of toxin on mussel. Our study might provide a novel clue for the resistance mechanism of shellfish to DSP toxins.

Antioxidantes/metabolismo , Dinoflagelados/fisiologia , Toxinas Marinhas/efeitos adversos , Fator 2 Relacionado a NF-E2/genética , Perna (Organismo)/genética , Animais , Elementos de Resposta Antioxidante/imunologia , Fator 2 Relacionado a NF-E2/metabolismo , Perna (Organismo)/efeitos dos fármacos , Perna (Organismo)/enzimologia , Perna (Organismo)/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/imunologia , Regulação para Cima
J Leukoc Biol ; 102(2): 517-525, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28550120


Respiratory complications occur frequently in individuals living with human immunodeficiency-1 virus (HIV) infection, and there is evidence that HIV-related oxidative stress impairs alveolar macrophage immune function. We hypothesized that nuclear factor (erythroid-derived 2)-like 2 (Nrf2), a master transcription factor that activates the antioxidant response element (ARE) and regulates antioxidant defenses, has an important role in alveolar macrophage (AMs) immune dysfunction in individuals with HIV infections. To test that hypothesis, we analyzed human monocyte-derived macrophages (MDMs) that were either infected with HIV-1 or were exposed to the HIV-related proteins gp120 and Tat ex vivo and determined that either stress affected the expression of Nrf2 and the Nrf2-ARE-dependent genes for NAD(P)H dehydrogenase, quinone 1 (NQO1) and glutamate-cysteine ligase, catalytic subunit (GCLC). We then determined that the expression of Nrf2, NQO1, and GCLC was significantly decreased in primary AMs isolated from HIV-1 transgenic rats. In parallel, treating a rat macrophage cell line (NR8383 cells) with the HIV-related proteins gp120 or Tat similarly decreased the gene and protein expression of Nrf2, NQO1, and GCLC. Further, phagocytic function was decreased in both human MDMs infected with HIV-1 and primary AMs from HIV-1 transgenic rats. Importantly, treating HIV-1-infected human MDMs or AMs from HIV-1 transgenic rats with sulforaphane (SFN, an Nrf2 activator) significantly improved their phagocytic function. The salutary effects of SFN were abrogated by silencing RNA to Nrf2 in wild-type rat macrophages. Our findings demonstrate that HIV-1 infection and exposure to HIV-1-related proteins inhibit Nrf2-ARE activity in the AMs and impair their phagocytic function. Treatments targeted at increasing Nrf2-ARE activity could, therefore, enhance lung innate immunity in people living with HIV-1.

Elementos de Resposta Antioxidante/imunologia , Regulação da Expressão Gênica/imunologia , Infecções por HIV/imunologia , Macrófagos Alveolares/imunologia , Fator 2 Relacionado a NF-E2/imunologia , Animais , Western Blotting , HIV-1/imunologia , Humanos , Macrófagos Alveolares/virologia , Fator 2 Relacionado a NF-E2/metabolismo , Fagocitose/imunologia , Ratos , Ratos Endogâmicos F344 , Ratos Transgênicos , Reação em Cadeia da Polimerase em Tempo Real
Fish Physiol Biochem ; 41(1): 203-17, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25432579


This study aimed to determine the effects of fructooligosaccharide (FOS) on immune response, antioxidant capability and HSP70 and HSP90 mRNA expressions of blunt snout bream (Megalobrama amblycephala) under high ammonia stress. A total of 360 fish were randomly distributed into three groups (each with four replicates) and were fed three levels of FOS (0, 0.4 and 0.8 %) for 8 weeks. After the feeding trial, 24 fish per tank were exposed to ammonia at 10 mg L(-1). After stress, plasma cortisol and glucose levels of fish fed 0.4 % FOS were all significantly lower than that of the control group at 6 and 3 h, respectively. Plasma lysozyme and alternative complement pathway (ACH50) activities as well as nitrogen monoxide (NO) levels all increased significantly with the maximum levels being attained at 6, 6 and 3 h, respectively. Thereafter, these parameters all decreased significantly. In addition, fish fed 0.4 % FOS showed higher immune parameters under stress compared with that of control group. In addition, liver superoxide dismutase and catalase activities of fish fed 0.4 % FOS were both significantly higher than that of the control group before and after stress, while the opposite was true for malondialdehyde content. After stress, the expression of HSP70 and HSP90 of fish fed FOS was significantly higher than that of the control group at 6 and 12 h, respectively. After 12 h stress, the cumulative mortality of fish fed FOS was significantly lower than that of the control. The results indicated that the supplementation of 0.4 % FOS could increase the nonspecific immunity, antioxidant capacity and HSP70 and HSP90 expression of blunt snout bream and enhance its resistance to high ammonia stress.

Elementos de Resposta Antioxidante/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas de Choque Térmico HSP70/metabolismo , Proteínas de Choque Térmico HSP90/metabolismo , Oligossacarídeos/farmacologia , Perciformes/imunologia , Estresse Fisiológico/efeitos dos fármacos , Amônia/toxicidade , Análise de Variância , Animais , Elementos de Resposta Antioxidante/imunologia , Glicemia/metabolismo , Via Alternativa do Complemento/efeitos dos fármacos , Primers do DNA/genética , Relação Dose-Resposta a Droga , Hidrocortisona/sangue , Muramidase/sangue , Óxido Nítrico/sangue , Oligossacarídeos/administração & dosagem , Reação em Cadeia da Polimerase em Tempo Real , Estresse Fisiológico/fisiologia
Inflamm Res ; 63(9): 729-40, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24888323


OBJECTIVE: This study was conducted to evaluate the effect of the synthetic water-soluble phenolic antioxidant TS-13 (sodium 3-(4'-methoxyphenyl)propyl thiosulfonate), an inducer of the redox-dependent Keap1/Nrf2/ARE signaling system, in experimental models of acute and chronic inflammation. METHODS: Acute local inflammation was induced by intraplantar carrageenan injection into rat hind paws, and acute systemic inflammation was modeled by intravenous zymosan injection (in rats) or LPS-induced endotoxic shock (in mice). Chronic inflammation was investigated in rat models of air pouch and collagen-induced arthritis. The effects of TS-13 treatment were estimated by changes in the intensity of inflammation (paw edema, liver infiltration, animal survival, exudation, and clinical score of arthritis) and by the effects on reactive oxygen species (ROS) generation by leukocytes from peripheral blood and inflammatory exudates. RESULTS: We found the significant increase in expression of mRNA, content of protein and activity of a well-characterized Nrf2 target enzyme glutathione S-transferase P1, as well as nuclear extract protein binding to the ARE consensus sequence in liver of mice fed with diet containing TS-13. TS-13 markedly attenuated carrageenan-induced paw edema, reduced blood granulocyte number and volume density of liver infiltrates in the systemic zymosan-induced inflammation model, and increased mice survival after lipopolysaccharide-induced septic shock. However, TS-13 administration did not influence cell and protein exudation into air pouches and suppressed clinical manifestation of collagen-induced polyarthritis only at early stages. Nevertheless, TS-13 inhibited the generation of ROS by leukocytes in all inflammation models. CONCLUSION: The data suggest that the anti-inflammatory effects of Keap1/Nrf2/ARE system are more prominent against acute innate-mediated inflammation than chronic immune inflammation. This narrows the potential therapeutic efficacy of ARE inducers in inflammation treatment.

Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Artrite Experimental/tratamento farmacológico , Edema/tratamento farmacológico , Choque Séptico/tratamento farmacológico , Ácidos Tiossulfônicos/uso terapêutico , Doença Aguda , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Elementos de Resposta Antioxidante/imunologia , Antioxidantes/química , Antioxidantes/farmacologia , Artrite Experimental/imunologia , Artrite Experimental/patologia , Carragenina , Doença Crônica , Edema/induzido quimicamente , Edema/patologia , Pé/patologia , Glutationa S-Transferase pi/genética , Glutationa S-Transferase pi/metabolismo , Granulócitos/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Proteína 1 Associada a ECH Semelhante a Kelch , Contagem de Leucócitos , Lipopolissacarídeos , Masculino , Camundongos Endogâmicos BALB C , Fator 2 Relacionado a NF-E2/imunologia , RNA Mensageiro/metabolismo , Ratos Wistar , Espécies Reativas de Oxigênio/imunologia , Choque Séptico/induzido quimicamente , Solubilidade , Ácidos Tiossulfônicos/química , Ácidos Tiossulfônicos/farmacologia , Água/química , Zimosan