Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 169
Filtrar
Mais filtros










Intervalo de ano de publicação
1.
BMC Complement Altern Med ; 19(1): 310, 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31718640

RESUMO

BACKGROUND: Heracleum moellendorffii roots (HM-R) have been long treated for inflammatory diseases such as arthritis, backache and fever. However, an anti-inflammatory effect and the specific mechanism of HM-R were not yet clear. In this study, we for the first time explored the anti-inflammatory of HM-R. METHODS: The cytotoxicity of HM-R against RAW264.7 cells was evaluated using MTT assay. The inhibition of NO and PGE2 production by HM-R was evaluated using Griess reagent and Prostaglandin E2 ELISA Kit, respectively. The changes in mRNA or protein level following HM-R treatment were assessed by RT-PCR and Western blot analysis, respectively. RESULTS: HM-R dose-dependently blocked LPS-induced NO and PGE2 production. In addition, HM-R inhibited LPS-induced overexpression of iNOS, COX-2, IL-1ß and IL-6 in RAW264.7 cells. HM-R inhibited LPS-induced NF-κB signaling activation through blocking IκB-α degradation and p65 nuclear accumulation. Furthermore, HM-R inhibited MAPK signaling activation by attenuating the phosphorylation of ERK1/2, p38 and JNK. HM-R increased nuclear accumulation of Nrf2 and HO-1 expression. However, NAC reduced the increased nuclear accumulation of Nrf2 and HO-1 expression by HM-R. In HPLC analysis, falcarinol was detected from HM-R as an anti-inflammatory compound. CONCLUSIONS: These results indicate that HM-R may exert anti-inflammatory activity by inhibiting NF-κB and MAPK signaling, and activating ROS/Nrf2/HO-1 signaling. These findings suggest that HM-R has a potential as a natural material for the development of anti-inflammatory drugs.


Assuntos
Anti-Inflamatórios/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Heme Oxigenase-1/imunologia , Heracleum/química , Fator 2 Relacionado a NF-E2/imunologia , NF-kappa B/imunologia , Espécies Reativas de Oxigênio/imunologia , Animais , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/imunologia , Heme Oxigenase-1/genética , Lipopolissacarídeos/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Fator 2 Relacionado a NF-E2/genética , NF-kappa B/genética , Raízes de Plantas/química , Células RAW 264.7
2.
Int Immunopharmacol ; 75: 105825, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31437789

RESUMO

Mechanical ventilation (MV) is a major support for patients with severe clinical disease, surgery and anesthesia. However, complications of mechanical ventilation especially ventilator-induced lung injury(VILI) can make the course and prognosis worse. Resolvin D1(RvD1) is a class of endogenous polyunsaturated fatty acid derivative, which has protective effects on various pulmonary inflammatory diseases. However, the mechanism of RvD1 in the process of VILI has not been fully elucidated. Our study found that RvD1 does have a protective effect on VILI including inhibiting inflammatory responses, reducing tissue damage and improving pulmonary function. The protective effect of RvD1 is positively related to its dose. Our research suggested RvD1 plays a role that increases the expression of heme oxygenase­1 (HO-1) and decreases the expression of the high mobility group chromosomal protein B1 (HMGB-1) in VILI. HO-1 can exert the protective effect of organism through multiple mechanisms such as anti-inflammatory, anti-oxidation, anti-apoptosis, etc. HMGB1 is a potent inflammatory response factor in the body, which can aggravate the inflammatory response of the body. Our study demonstrated that RvD1 can ameliorate lung inflammation and reduce pathological changes in lung tissue in a model of lung injury induced by mechanical ventilation. The protective role of RvD1 is closely linked to the increased expression of HO-1 and the decreased expression of HMGB1. Moreover, we found that RvD1 can increase the expression of Nrf2 and inhibit the expression of NF-κB. We found the specific inhibitor of HO-1, ZnPP, can significantly inhibit the protective role of RvD1 in VILI. When HO-1 is inhibited, pathological damage and inflammatory reaction in the lungs are considerably aggravated, and pulmonary function is significantly weakened. In addition, the expression of HMGB1 is drastically increased. This indicates that the HO-1-HMGB1 pathway plays an important role in the protective effect of RvD1 on mechanical ventilation lung injury.


Assuntos
Ácidos Docosa-Hexaenoicos/farmacologia , Proteína HMGB1/imunologia , Heme Oxigenase-1/imunologia , Proteínas de Membrana/imunologia , Substâncias Protetoras/farmacologia , Lesão Pulmonar Induzida por Ventilação Mecânica/imunologia , Animais , Líquido da Lavagem Broncoalveolar/imunologia , Citocinas/imunologia , Ácidos Docosa-Hexaenoicos/uso terapêutico , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Masculino , Camundongos Endogâmicos C57BL , Substâncias Protetoras/uso terapêutico , Lesão Pulmonar Induzida por Ventilação Mecânica/tratamento farmacológico , Lesão Pulmonar Induzida por Ventilação Mecânica/patologia , Ventiladores Mecânicos/efeitos adversos
3.
Mol Med Rep ; 20(2): 1761-1771, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31257541

RESUMO

Atopic dermatitis (AD), a chronic inflammatory skin disease, is characterized by intense itching and recurrent eczematous lesions. Sulforaphane is known to attenuate oxidative stress, and tissue or cell damage in cerebral ischemia, brain inflammation and intracerebral hemorrhage. In the present study, a 2,4­dinitrochlorobenzene (DNCB)­induced AD mouse model was developed, and ear thickness, dermatitis score, eosinophil count, mast cell infiltration, and serum IgE levels were measured in DNCB­induced AD and sulforaphane­treated groups to demonstrate the therapeutic effects of sulforaphane. AD symptoms of DNCB­induced mice were attenuated by sulforaphane treatment compared with those of negative control mice; furthermore, eosinophil count, mast cell infiltration and serum IgE levels were also reduced by sulforaphane treatment in DNCB­induced AD mice. Western blot assays revealed that the expression levels of nuclear factor­E2­related factor 2 (Nrf2) and heme oxygenase-1 (HO­1), which exhibit oxidation resistance, were increased by sulforaphane treatment in DNCB­induced AD mice. The present study suggested that sulforaphane exerted a therapeutic effect in the AD mouse model through the activation of the Nrf2/HO­1 axis as well as the suppression of Janus kinase 1/STAT3 signaling pathway.


Assuntos
Anti-Inflamatórios/uso terapêutico , Dermatite Atópica/tratamento farmacológico , Heme Oxigenase-1/imunologia , Isotiocianatos/uso terapêutico , Fator 2 Relacionado a NF-E2/imunologia , Animais , Antioxidantes/uso terapêutico , Dermatite Atópica/imunologia , Modelos Animais de Doenças , Feminino , Camundongos Endogâmicos BALB C , Transdução de Sinais/efeitos dos fármacos
4.
Int Immunopharmacol ; 75: 105750, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31330445

RESUMO

Telmisartan, widely prescribed for the treatment of hypertension, has an anti-inflammatory property in addition to being an angiotensin II type 1 receptor antagonist. This study was carried out to explore the influence of telmisartan upon the elaboration of inflammatory mediators in murine macrophages stimulated with lipopolysaccharide (LPS) prepared from Prevotella intermedia, a periodontal pathogen, as well as its molecular mechanisms. Telmisartan significantly inhibited LPS-induced generation of inducible nitric oxide (NO) synthase-derived NO and interleukin-1ß (IL-1ß) as well as their gene expressions in RAW264.7 cells. Telmisartan treatment of LPS-activated cells significantly up-regulated arginase 1 (Arg-1) and chitinase-like 3 (Ym-1), which are specific markers of M2 macrophages. Telmisartan caused a significant increase in heme oxygenase-1 (HO-1) expression in cells stimulated with LPS, and its inhibitory action against NO production was reversed by treatment with SnPP, an HO-1 inhibitor. Phosphorylation of STAT1 and STAT3 induced by LPS was attenuated by telmisartan. Telmisartan inhibited LPS-induced generation of NO and IL-1ß independently of PPAR-γ activation. In addition, activation of NF-κB as well as JNK and p38 signaling induced by LPS was not modulated by telmisartan. In summary, telmisartan is a potent inhibitor of P. intermedia LPS-induced generation of NO and IL-1ß in RAW264.7 cells and promotes macrophage phenotype switching toward the M2 phenotype. Telmisartan may have potential to be developed into host modulatory agent for inflammatory periodontal disease, although additional studies are needed to confirm the therapeutic effect.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Anti-Inflamatórios/farmacologia , Interleucina-1beta/imunologia , Óxido Nítrico/imunologia , Prevotella intermedia , Telmisartan/farmacologia , Animais , Heme Oxigenase-1/genética , Heme Oxigenase-1/imunologia , Interleucina-1beta/genética , Lipopolissacarídeos , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , Camundongos , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/imunologia , Células RAW 264.7
5.
J Agric Food Chem ; 67(19): 5552-5559, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-31042377

RESUMO

The present study was designed to investigate the role of the canonical and noncanonical inflammasome, MAPKs and NRF-2/HO-1, signaling pathways involved in the antioxidant and anti-inflammatory activities of oleocanthal in lipopolysaccharide (LPS)-stimulated murine peritoneal macrophages. Isolated cells were treated with oleocanthal in the presence or absence of LPS (5 µg mL-1) for 18 h. Oleocanthal showed a potent reduction of reactive oxygen species (ROS) (25 µM, 50. 612 ± 0.02; 50 µM, 53. 665 ± 0.09; 100 µM, 52. 839 ± 0.02), nitrites (25 µM, 0.631 ± 0.07; 50 µM, 0.652 ± 0.07; 100 µM, 0.711 ± 0.08), and pro-inflammatory cytokines levels when compared with LPS-DMSO-treated control cells. In terms of enzymes protein expression, oleocanthal was able to downregulate iNOS (25 µM, 0.173 ± 0.02; 50 µM, 0.149 ± 0.01; 100 µM, 0.150 ± 0.01; p < 0.001), COX-2 (25 µM, 0.482 ± 0.08; 50 µM, 0.469 ± 0.05; 100 µM, 0.418 ± 0.06; p < 0.001), and mPGES-1 (25 µM, 0.185 ± 0.11; 50 µM, 0.218 ± 0.13; 100 µM, 0.161 ± 0.15; p < 0.001) as well as p38 (25 µM, 0.366 ± 0.11; 50 µM, 0.403 ± 0.13; 100 µM, 0.362 ± 0.15; p < 0.001), JNK (25 µM, 0.443 ± 0.11; 50 µM, 0.514 ± 0.13; 100 µM, 0.372 ± 0.15; p < 0.001), and ERK (25 µM, 0.294 ± 0.01; 50 µM, 0.323 ± 0.01; 100 µM, 0.274 ± 0.01; p < 0.001) protein phosphorylation, which was accompanied by an upregulation of Nrf-2 (25 µM, 1.57 ± 0.01; 50 µM, 1.54 ± 0.01; 100 µM, 1.63 ± 0.05; p < 0.05) and HO-1(25 µM, 2.12 ± 0,03; 50 µM, 2.24 ± 0.01; 100 µM, 1.92 ± 0.05; p < 0.01) expression in comparison with LPS-DMSO cells. Moreover, oleocanthal inhibited canonical and noncanonical inflammasome signaling pathways. Thus, oleocanthal might be a promising natural agent for future treatment of immune-inflammatory diseases.


Assuntos
Aldeídos/farmacologia , Heme Oxigenase-1/imunologia , Inflamassomos/imunologia , Lipopolissacarídeos/farmacologia , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/imunologia , Fator 2 Relacionado a NF-E2/imunologia , Fenóis/farmacologia , Animais , Células Cultivadas , Feminino , Heme Oxigenase-1/genética , Inflamassomos/efeitos dos fármacos , Inflamassomos/genética , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Ativação de Macrófagos/efeitos dos fármacos , Camundongos , Fator 2 Relacionado a NF-E2/genética , Fosforilação , Espécies Reativas de Oxigênio/imunologia
6.
Immunopharmacol Immunotoxicol ; 41(2): 337-348, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31056974

RESUMO

Objective: The isochroman-type fungal metabolite 3,7-dimethyl-1,8-hydroxy-6-methoxyisochroman (DMHM) was isolated from the extracts of a marine-derived fungal strain of Penicillium sp. SF-6013. In this study, we investigated the effect of DMHM on inflammatory response. Materials and methods: Anti-inflammatory effects of DMHM were examined in lipopolysaccharide (LPS)-stimulated RAW264.7 and BV2 cells. We observed their anti-inflammatory effects by ELISA, qRT-PCR, and western blot analysis. Results: DMHM revealed that it suppressed the production of prostaglandin E2 (PGE2), nitric oxide (NO), cyclooxygenase-2 (COX-2), and inducible NO synthase (iNOS) in LPS-stimulated RAW264.7 and BV2 cells. Furthermore, DMHM decreased the mRNA expression of pro-inflammatory cytokines including interleukin (IL)-1ß and IL-6. Therefore, DMHM was further investigated to elucidate the mechanisms of its anti-inflammatory properties; the results indicated that its effect was mediated by the suppression of the nuclear factor (NF)-κB and c-Jun N-terminal kinase (JNK) MAPK pathways. Furthermore, the anti-inflammatory activity of DMHM correlated with its induction of heme oxygenase-1 (HO)-1 expression via activation of the nuclear factor erythroid 2-like 2 (Nrf2) pathway. Discussion and conclusions: Collectively, the results of this study suggest that DMHM inhibited several inflammatory pathways including the NF-κB and MAPK pathways, and induced Nrf2-mediated HO-1 expression, demonstrating its potential usefulness for treating inflammatory and neuroinflammatory diseases.


Assuntos
Anti-Inflamatórios/farmacologia , Cromanos/farmacologia , Heme Oxigenase-1/imunologia , Lipopolissacarídeos/toxicidade , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas de Membrana/imunologia , Fator 2 Relacionado a NF-E2/imunologia , Animais , Anti-Inflamatórios/química , Cromanos/química , Ciclo-Oxigenase 2/imunologia , Dinoprostona/imunologia , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/patologia , Sistema de Sinalização das MAP Quinases/imunologia , Camundongos , Óxido Nítrico/imunologia , Penicillium/química , Células RAW 264.7
7.
Free Radic Res ; 53(5): 522-534, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31117828

RESUMO

Physical activity, particularly that, exerted by endurance athletes, impacts the immune status of the human body. Prolonged duration and high-intensity endurance training lead to increased production of reactive oxygen species (ROS) and thereby to oxidative stress. Military combat swimmers (O2-divers) are regularly exposed to hyperbaric hyperoxia (HBO) in addition to intensive endurance training intervals. They are, therefore, exposed to extreme levels of oxidative stress. Several studies support that the intensity of oxidative stress essentially determines the effect on immune status. The aim of this study was to comparatively characterise peripheral blood mononuclear cells (PBMCs) of O2-divers (military combat swimmers), endurance athletes (amateur triathletes), and healthy control volunteers with respect to DNA fragmentation, immune status and signs of inflammation. Furthermore, it was investigated how PBMCs from these groups responded acutely to exposure to HBO. We showed that DNA fragmentation was comparable in PBMCs of all three groups under basal conditions directly after HBO exposure. However, significantly higher DNA fragmentation was observed in O2-divers 18 hours after HBO, possibly indicating a slower recovery. O2-divers also exhibited a proinflammatory immune status exemplified by an elevated number of CD4+CD25+ T cells, elevated expression of proinflammatory cytokine IL-12, and diminished expression of anti-inflammatory TGF-ß1 compared to controls. Supported by a decreased basal gene expression and prolonged upregulation of anti-oxidative HO-1, these data suggest that higher oxidative stress levels, as present under intermitted hyperbaric hyperoxia, e.g. through oxygen diving, promote a higher inflammatory immune status than oxidative stress through endurance training alone.


Assuntos
Atletas , Mergulho/fisiologia , Hiperóxia/imunologia , Imunidade Inata/efeitos dos fármacos , Oxigênio/farmacologia , Resistência Física/imunologia , Adulto , Estudos de Casos e Controles , Ensaio Cometa , Fragmentação do DNA , Regulação da Expressão Gênica , Heme Oxigenase-1/genética , Heme Oxigenase-1/imunologia , Humanos , Oxigenação Hiperbárica/métodos , Hiperóxia/genética , Hiperóxia/fisiopatologia , Inflamação , Interleucina-12/genética , Interleucina-12/imunologia , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo/imunologia , Oxigênio/imunologia , Resistência Física/genética , Esforço Físico/genética , Esforço Físico/imunologia , Espécies Reativas de Oxigênio/imunologia , Espécies Reativas de Oxigênio/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/imunologia
8.
Transpl Immunol ; 55: 101203, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30904623

RESUMO

Acute graft-versus-host disease (aGvHD) remains lethal, even after allogeneic hematopoietic stem cell transplantation. Inflammatory responses play an important role in aGvHD. Salvianolic acid B (Sal B) has been widely reported to have a major effect on the anti-inflammatory response, but these effects in an aGvHD model have never been reported. B6 donor splenocytes were transplanted into unirradiated BDF1 recipients and liver and serum were collected on day 14 after transplantation with or without Sal B administration. We measured the expression of pro-inflammatory cytokines and chemokines and other manifestations in aGvHD mice after Sal B treatment. Sal B ameliorated liver injury in aGvHD and promoted survival in mice. Sal B treatment resulted in decreased expression of pro-inflammatory cytokines and chemokines whose expressions in liver are normally elevated by aGvHD. Furthermore, Sal B treatment also enhanced PGC-1α expression in liver tissue and HO-1 expression in nonparenchymal cells. In addition, HO-1 inhibitor abrogated the improvement of survival rate of mice with aGvHD. These results indicated that the protective effect of Sal B relies on suppressing the inflammatory response phase in the aGvHD model, presumably by inducing HO-1. Taken together our data showed that Sal B ameliorates liver injury in aGvHD by decreasing inflammatory responses via upregulation of HO-1. It may provide a novel way to deal with this disease.


Assuntos
Benzofuranos/farmacologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Doença Enxerto-Hospedeiro/imunologia , Heme Oxigenase-1/imunologia , Hepatopatias/imunologia , Fígado/imunologia , Proteínas de Membrana/imunologia , Regulação para Cima/efeitos dos fármacos , Doença Aguda , Animais , Modelos Animais de Doenças , Regulação Enzimológica da Expressão Gênica/imunologia , Doença Enxerto-Hospedeiro/genética , Doença Enxerto-Hospedeiro/patologia , Inflamação/imunologia , Inflamação/patologia , Fígado/lesões , Fígado/patologia , Hepatopatias/patologia , Masculino , Camundongos , Regulação para Cima/imunologia
9.
Food Chem Toxicol ; 126: 67-71, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30769049

RESUMO

Aloin is the major anthraquinone glycoside obtained from the Aloe species and exhibits anti-inflammatory and anti-oxidative activities. Here, we aimed to determine the effects of aloin on heme oxygenase-1 (HO-1) induction and on the expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX) 2 in lipopolysaccharide (LPS)-activated human umbilical vein endothelial cells (HUVECs). To the end, aloin was tested whether aloin reduces iNOS protein expression and inflammatory markers (interleukin (IL)-1ß and tumor necrosis factor (TNF)-α) in LPS-treated mice lung tissue. The results indicated that aloin affected HO-1 induction and reduced LPS-activated NF-κB-luciferase activity showed to preferential inhibition of iNOS/NO and COX-2/PGE2 that was partly related to inhibition of STAT-1 phosphorylation. In particular, aloin induced translocation of Nrf2 from cytosol into the nucleus by an increased Nrf2-ARE binding activity, and reduced IL-1ß production in LPS-activated HUVECs. The reduced expression of iNOS/NO by aloin was reversed by siHO-1RNA-transfection. In LPS-treated mice, aloin significantly reduced iNOS protein in lung tissues, and TNF-α levels in the BALF. We concluded that aloin may be beneficial for treatment of lung injury.


Assuntos
Anti-Inflamatórios/administração & dosagem , Emodina/análogos & derivados , Pneumopatias/tratamento farmacológico , NF-kappa B/imunologia , Óxido Nítrico Sintase Tipo II/genética , Extratos Vegetais/administração & dosagem , Fator de Transcrição STAT1/imunologia , Animais , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/imunologia , Emodina/administração & dosagem , Heme Oxigenase-1/genética , Heme Oxigenase-1/imunologia , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/imunologia , Humanos , Pneumopatias/genética , Pneumopatias/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/genética , Óxido Nítrico Sintase Tipo II/imunologia , Fator de Transcrição STAT1/genética , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
10.
Mol Immunol ; 106: 143-152, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30610999

RESUMO

BACKGROUND: Electroacupuncture (EA) at ST-36 can attenuate acute experimental colitis, but the mechanisms are unclear. We investigated the role of macrophages in the anti-inflammatory effects of EA and its molecular mechanisms. METHODS: Male C57BL/6 mice were randomized into five groups: normal control, dextran sulfate sodium (DSS)-induced acute colitis (DSS), DSS with sham EA (SEA), DSS with high-frequency EA (HEA) and DSS with low-frequency EA (LEA). Body weight, colon length, DAI score and histological score were evaluated during colitis progression. Serum and colonic levels of pro- and anti-inflammatory cytokines were detected with ELISA, cytometric beads array, RT-PCR and western blotting analysis. Colonic macrophage subsets were determined using flow cytometry. Magnetic-activated cell sorting was applied to isolate colonic macrophages, and molecular mechanisms were explored with western blotting, RT-PCR and immunofluorescence. RESULTS: (1) Compared with the DSS group, HEA and LEA attenuated body weight loss and decreased DAI and histological scores. (2) Serum levels and colonic protein and mRNA levels of IL-1ß, TNFα, IL-6, IL-12 and IL17 were markedly decreased with HEA and LEA. IL-10 level was increased with HEA. (3) M1 macrophage percentage increased, while M2 macrophage percentage decreased in the DSS group; HEA and LEA reversed these proportions. (4) NLRP3/IL-1ß protein and mRNA levels in isolated macrophages decreased with HEA and LEA compared with the DSS treatment group; (5) HEA increased Nrf2/HO-1 levels compared with levels in DSS mice. CONCLUSION: The anti-inflammatory effects of EA on DSS-induced acute colitis may rely on regulating macrophage polarization, NLRP3/IL-1ß suppression and Nrf2/HO-1 promotion.


Assuntos
Colite , Sulfato de Dextrana/toxicidade , Eletroacupuntura , Heme Oxigenase-1/imunologia , Interleucina-1beta/imunologia , Macrófagos , Proteínas de Membrana/imunologia , Fator 2 Relacionado a NF-E2/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Doença Aguda , Animais , Colite/induzido quimicamente , Colite/imunologia , Colite/patologia , Colite/terapia , Macrófagos/imunologia , Macrófagos/patologia , Masculino , Camundongos
11.
Transgenic Res ; 28(1): 91-102, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30552552

RESUMO

Herein, we successfully generated transgenic pigs expressing both soluble human tumor necrosis factor receptor I IgG1-Fc (shTNFRI-Fc) and human hemagglutinin (HA)-tagged-human heme oxygenase-1 (hHO-1) without Gal epitope. Healthy cloned pigs were produced by somatic cell nuclear transfer (SCNT) using the genetically modified cells. The genetic disruption of the GGTA1 genes and absence of expression of BS-IB4 lectin in tail-derived fibroblast of the SCNT-generated piglets were successfully confirmed. The expression of shTNFRI-Fc and HAhHO-1 was fully identified with protective effect against oxidative stress and apoptosis stimulation. Antibody-mediated complement-dependent cytotoxicity assay for examining the immuno-reactivity of transgenically derived pig cells showed that pigs lacking GGTA1 with the expression of double genes reduce the humoral barrier to xenotransplantation, more than pigs simply expressing double genes and the wild type. Through this approach, rapid production of a pig strain deficient in various genes may be expected to be applicable for xenotransplantation research without extensive breeding protocols.


Assuntos
Animais Geneticamente Modificados/genética , Galactosiltransferases/genética , Heme Oxigenase-1/genética , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Animais , Apoptose/genética , Epitopos/genética , Epitopos/imunologia , Fibroblastos/metabolismo , Regulação da Expressão Gênica/genética , Técnicas de Inativação de Genes , Heme Oxigenase-1/imunologia , Humanos , Técnicas de Transferência Nuclear , Receptores Tipo I de Fatores de Necrose Tumoral/imunologia , Suínos , Transplante Heterólogo
12.
Mol Immunol ; 105: 205-212, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30553057

RESUMO

Carbon monoxide (CO) is an anti-inflammatory gaseous molecule produced endogenously by heme oxygenases (HOs) HO-1 and HO-2. However, the mechanisms underlying the anti-inflammatory effects of CO in the human bronchial epithelium are still not fully understood. In this study, the cationic peptide poly-l-arginine (PLA) was utilized to induce bronchial epithelial damage and subsequent pro-inflammatory cytokine release in the human bronchial epithelial cell line 16HBE14o-. Expression of both HO-1 and HO-2 after PLA exposure was examined. The polarized secretion of two pro-inflammatory cytokines, interleukin (IL)-6 and IL-8, was determined by ELISA. The anti-inflammatory effects of CO liberated from CO-releasing molecules (CORMs) were examined by both ELISA and western blot analysis. Our results indicate that PLA exposure leads to upregulation of HO-1 expression and p65 NF-κB phosphorylation, as well as IL-6 and IL-8 release. HO-1 induction by hemin or CORMs significantly suppressed IL-6 and IL-8 release. In addition, HO-1 knockdown further increased IL-6 and IL-8 release under basal and PLA-stimulated conditions. Our results thereby demonstrate that the HO-1/CO axis exerts significant anti-inflammatory activity during bronchial epithelial damage caused by cationic protein.


Assuntos
Anti-Inflamatórios/farmacologia , Brônquios/imunologia , Monóxido de Carbono/farmacologia , Heme Oxigenase-1/imunologia , Peptídeos/farmacologia , Mucosa Respiratória/imunologia , Linhagem Celular , Heme Oxigenase (Desciclizante)/genética , Heme Oxigenase (Desciclizante)/imunologia , Heme Oxigenase-1/genética , Humanos , Interleucina-6/genética , Interleucina-6/imunologia , Interleucina-8/genética , Interleucina-8/imunologia
13.
Virology ; 528: 80-88, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30580124

RESUMO

The innate immunity plays an essential role in defending infection of Influenza A virus (IAV). The regulatory effect of heme oxygenase-1 (HO-1), a cytoprotective enzyme, on innate immunity has been revealed. In this study, we aim to confirm the antiviral effect of CoPP (Cobaltic Protoporphyrin IX Chloride), a potent HO-1 inducer on IAV infection and elucidate the possible mechanism of HO-1-mediated host innate immune responses. Our results show that CoPP exhibits broad-spectrum antiviral activities against IAV. Furthermore, CoPP attenuates IAV replication through inducing type I IFNs response, not depending on HO-1 enzymatic activity. We also provide direct evidence that HO-1-mediated type I IFN response activation is largely due to its interaction with IRF3, which then promotes IRF3 phosphorylation and nuclear translocation. These results suggest that HO-1 agonist CoPP suppresses IAV replication through IRF3-mediated generation of IFN-α/ß. Thus, therapeutic induction of HO-1 might be a promising strategy to combat IAV epidemics.


Assuntos
Ativadores de Enzimas/farmacologia , Heme Oxigenase-1/imunologia , Vírus da Influenza A/efeitos dos fármacos , Fator Regulador 3 de Interferon/imunologia , Protoporfirinas/farmacologia , Replicação Viral/efeitos dos fármacos , Animais , Cães , Regulação da Expressão Gênica/imunologia , Heme Oxigenase-1/genética , Imunidade Inata , Interferon-alfa/imunologia , Interferon beta/imunologia , Células Madin Darby de Rim Canino , Camundongos , Células RAW 264.7
14.
Mol Immunol ; 104: 61-68, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30439604

RESUMO

Diabetic nephropathy (DN) contributes to end-stage renal disease and kidney dysfunction with a proverbial feature of podocyte injury. Inflammation and insulin resistance is recently implicated in the pathogenesis of diabetic kidney injury. Celastrol exerts critical roles in inflammatory diseases and injury progression. However, its function and mechanism in DN remains elusive. Here, celastrol dose-dependently restored podocyte viability under high glucose (HG) conditions, but with little cytotoxicity in podocyte. Preconditioning with celastrol counteracted HG-evoked cell apoptosis, LDH release, ROS production and podocyte depletion. Additionally, HG-elevated high transcripts and secretions of pro-inflammatory cytokines were reversed following celastrol treatment, including IL-1ß, TNF-α, IL-6. Simultaneously, the inhibitory effects of HG on insulin-triggered glucose uptake and nephrin expression were overturned after celastrol exposure. Intriguingly, celastrol restored HG-induced deficiency of autophagy pathway. Nevertheless, blocking the autophagy signaling by its antagonist 3-MA muted celastrol-protected against HG-evoked cell injury, inflammation and insulin resistance. Importantly, celastrol enhanced heme oxygenase-1 (HO-1) expression in HG-stimulated podocytes. Notably, HO-1 cessation depressed autophagy pathway activation and subsequently blunted beneficial effects of celastrol on HG-exposed podocytes. These finding suggest that celastrol may protect against HG-induced podocyte injury, inflammation and insulin resistance by restoring HO-1-mediated autophagy pathway, implying a promising therapeutic strategy against DN.


Assuntos
Autofagia/efeitos dos fármacos , Glucose/efeitos adversos , Heme Oxigenase-1/imunologia , Resistência à Insulina/imunologia , Proteínas de Membrana/imunologia , Podócitos/imunologia , Transdução de Sinais/efeitos dos fármacos , Triterpenos/farmacologia , Animais , Autofagia/imunologia , Citocinas/imunologia , Nefropatias Diabéticas/imunologia , Nefropatias Diabéticas/patologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/imunologia , Glucose/farmacologia , Inflamação/induzido quimicamente , Inflamação/imunologia , Inflamação/patologia , Camundongos , Podócitos/patologia , Transdução de Sinais/imunologia
15.
Front Immunol ; 9: 1956, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30258436

RESUMO

Heme Oxygenase 1 (HMOX1) is an enzyme that catalyzes the reaction that degrades the heme group contained in several important proteins, such as hemoglobin, myoglobin, and cytochrome p450. The enzymatic reaction catalyzed by HMOX1 generates Fe2+, biliverdin and CO. It has been shown that HMOX1 activity and the by-product CO can downmodulate the damaging immune response in several models of intestinal inflammation as a result of pharmacological induction of HMOX1 expression and the administration of non-toxic amounts of CO. Inflammatory Bowel Diseases, which includes Crohn's Disease (CD) and Ulcerative Colitis (UC), are one of the most studied ailments associated to HMOX1 effects. However, microbiota imbalances and infections are also important factors influencing the occurrence of acute and chronic intestinal inflammation, where HMOX1 activity may play a major role. As part of this article we discuss the immune modulatory capacity of HMOX1 during IBD, as well during the infections and interactions with the microbiota that contribute to this inflammatory disease.


Assuntos
Colite Ulcerativa/imunologia , Doença de Crohn/imunologia , Microbioma Gastrointestinal/imunologia , Heme Oxigenase-1/imunologia , Intestinos/imunologia , Animais , Colite Ulcerativa/microbiologia , Colite Ulcerativa/patologia , Doença de Crohn/microbiologia , Doença de Crohn/patologia , Humanos , Inflamação/imunologia , Inflamação/microbiologia , Inflamação/patologia , Intestinos/microbiologia , Intestinos/patologia
16.
Food Funct ; 9(10): 5115-5123, 2018 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-30206627

RESUMO

Luteolin and sulforaphane are well-known food bioactives with anti-inflammatory properties. Herein, we determined their combinational effects in inhibiting inflammation in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. Both luteolin and sulforaphane showed dose-dependent inhibition on LPS-induced production of nitric oxide (NO) in the macrophages. The combined treatments led to a stronger inhibition on NO production compared to the singular treatments. Isobologram analysis confirmed that the combined treatments produced a synergy. Western blotting and ELISA showed that the combined treatment reduced the expression levels of pro-inflammatory proteins involving NF-κB pathway, and STAT3 activation, which regulated expression of other inflammatory proteins such as iNOS, COX-2, IL-6, and IL-1ß. Moreover, the combination treatments reduced reactive oxygen species in cells and increased the expression of Nrf2 and HO-1, which are cellular antioxidant proteins. In conclusion, our findings support the notion that certain bioactive food components may act synergistically to produce enhanced health effects such as anti-inflammation.


Assuntos
Anti-Inflamatórios/farmacologia , Inflamação/tratamento farmacológico , Isotiocianatos/administração & dosagem , Luteolina/administração & dosagem , Animais , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/imunologia , Sinergismo Farmacológico , Heme Oxigenase-1/genética , Heme Oxigenase-1/imunologia , Humanos , Inflamação/genética , Inflamação/imunologia , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/imunologia , NF-kappa B/genética , NF-kappa B/imunologia , Células RAW 264.7 , Espécies Reativas de Oxigênio/imunologia
17.
Cell Signal ; 51: 110-118, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30076968

RESUMO

BACKGROUND: Mesenchymal stromal/stem cells (MSCs) are multi-potent non-hematopoietic stem cells, residing in most tissues including the lung. MSCs have been used in therapy of chronic inflammatory lung diseases such as Cystic Fibrosis (CF), asthma, and chronic obstructive pulmonary disease (COPD) but the main beneficial effects reside in the anti-inflammatory potential of the released extracellular vesicles (EVs). Recent reports demonstrate that EVs are effective in animal model of asthma, E.coli pneumonia, lung ischemia-reperfusion, and virus airway infection among others. Despite this growing literature, the EVs effects on CF are largely unexplored. METHODS: We treated IB3-1 cells, an in vitro human model of CF, with EVs derived from human lung MSCs under basal and inflammatory conditions (TNFα stimulation). RESULTS: We demonstrated here that treatment of IB3-1 CF cell line with EVs, down-regulates transcription and protein expression of pro-inflammatory cytokines such as IL-1ß, IL-8, IL-6 under TNFα - stimulated conditions. EVs treatment upregulates the mRNA expression of PPARγ, a transcription factor controlling anti-inflammatory and antioxidant mechanisms via NF-kB and HO-1. Accordingly, NF-kB nuclear translocation is reduced resulting in impairment of the downstream inflammation cascade. In addition, the mRNA of HO-1 is enhanced together with the antioxidant defensive response of the cells. CONCLUSIONS: We conclude that the anti-inflammatory and anti-oxidant efficacy of EVs derived from lung MSCs could be mediated by up-regulation of the PPARγ axis, whose down-stream effectors (NF-kB and HO-1) are well-known modulators of these pathways. GENERAL SIGNIFICANCE: EVs could be a novel strategy to control the hyper-inflamed condition in Cystic Fibrosis.


Assuntos
Fibrose Cística/imunologia , Células Epiteliais/imunologia , Vesículas Extracelulares/fisiologia , Inflamação/imunologia , Células-Tronco Mesenquimais/metabolismo , PPAR gama/imunologia , Células Cultivadas , Fibrose Cística/patologia , Células Epiteliais/patologia , Heme Oxigenase-1/imunologia , Humanos , Interleucina-1beta/imunologia , Interleucina-6/imunologia , Interleucina-8/imunologia , Pulmão/citologia , NF-kappa B/imunologia , Fator de Necrose Tumoral alfa/imunologia
18.
J Cell Mol Med ; 22(9): 4335-4343, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29974998

RESUMO

In vitiligo, cutaneous depigmentation is accompanied by increased T cell cytolytic activity targeting melanocytes, indicating that autoimmune tolerance is disrupted. The inhibited amount and function of Tregs have been indicated to be involved in the autoimmune intolerance in vitiligo, however, with the conclusion still controversial and the involved mechanism unknown. In this study, we explored the molecular and cellular alterations accounting for the impaired Treg response in vitiligo. Our results showed that the amount of Tregs was drastically reduced in peripheral blood of active vitiligo patients. Furthermore, the immunoregulatory function of Tregs was attenuated, with lower expression of CTLA4, IL-10 and TGF-ß. Moreover, the expression of HO-1, a functional modulator of Tregs, was decreased in vitiligo Tregs, and the concentrations of HO-1 metabolites, including bilirubin, CoHb and iron, were correspondingly decreased in serum of vitiligo patients. In addition, we treated the Tregs from vitiligo patients with Hemin, an agonist of HO-1, and found that enhanced HO-1 expression restored the function of Tregs by up-regulating IL-10 expression. Our study demonstrates the essential role of HO-1 in the impaired Treg response in vitiligo and indicates the potential of HO-1 as a therapeutic target in vitiligo management.


Assuntos
Antígeno CTLA-4/genética , Heme Oxigenase-1/genética , Interleucina-10/genética , Melanócitos/imunologia , Linfócitos T Reguladores/imunologia , Vitiligo/genética , Adolescente , Adulto , Idoso , Bilirrubina/sangue , Bilirrubina/imunologia , Antígeno CTLA-4/imunologia , Carboxihemoglobina/imunologia , Carboxihemoglobina/metabolismo , Progressão da Doença , Feminino , Regulação da Expressão Gênica , Heme Oxigenase-1/imunologia , Hemina/farmacologia , Humanos , Tolerância Imunológica , Interleucina-10/imunologia , Ferro/sangue , Ferro/imunologia , Contagem de Linfócitos , Masculino , Melanócitos/patologia , Pessoa de Meia-Idade , Cultura Primária de Células , Índice de Gravidade de Doença , Transdução de Sinais , Pele/imunologia , Pele/patologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/patologia , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/imunologia , Vitiligo/imunologia , Vitiligo/patologia
19.
J Autoimmun ; 94: 33-44, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30025621

RESUMO

Aplastic anemia (AA) is a rare disease characterized by immune-mediated suppression of bone marrow (BM) function resulting in progressive pancytopenia. Stem cell transplant and immunosuppressive therapies remain the major treatment choices for AA patients with limited benefit and undesired side effects. Here, we report for the first time the therapeutic utility of Nrf2-induced metabolically reprogrammed tolerogenic dendritic cells (TolDCs) in the suppression of AA in mice. CDDO-DFPA-induced Nrf2 activation resulted in a TolDC phenotype as evidenced by induction of IL-4, IL-10, and TGF-ß and suppression of TNFα, IFN-γ, and IL-12 levels in Nrf2+/+ but not Nrf2-/- DCs. Cellular metabolism holds the key to determining DC immunogenic or tolerogenic cell fate. Although immature and LPS-induced (mature) Nrf2+/+ and Nrf2-/- DCs exhibited similar patterns of oxidative phosphorylation (OXPHOS) and glycolysis, only Nrf2+/+ DCs partially restored OXPHOS and reduced glycolysis during CDDO-DFPA-induced Nrf2 activation. These results were further confirmed by altered glucose uptake and lactate production. We observed significantly enhanced HO-1 and reduced iNOS/NO production in Nrf2+/+ compared to Nrf2-/- DCs, suggesting Nrf2-dependent TolDC induction is linked to suppression of the inhibitory effect of NO on OXPHOS. Furthermore, Nrf2-/- DCs demonstrated higher antigen-specific T cell proliferation. Lastly, TolDC administration improved hematopoiesis and survival in AA murine model, with decreased Th17 and increased Treg cells. Concomitantly, immunohistochemical analysis of AA patient BM biopsies displayed higher DCs, T cells, and iNOS expression accompanied with lower Nrf2 and HO-1 expression when compared to normal subjects. These results provide new insight into the therapeutic utility of metabolically reprogrammed TolDCs by CDDO-DFPA induced Nrf2 signaling in the treatment of AA.


Assuntos
Anemia Aplástica/terapia , Reprogramação Celular/imunologia , Células Dendríticas/imunologia , Tolerância Imunológica/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/imunologia , Ácido Oleanólico/análogos & derivados , Adolescente , Anemia Aplástica/genética , Anemia Aplástica/imunologia , Anemia Aplástica/patologia , Animais , Criança , Pré-Escolar , Citocinas/genética , Citocinas/imunologia , Células Dendríticas/citologia , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/transplante , Modelos Animais de Doenças , Regulação da Expressão Gênica , Glicólise/efeitos dos fármacos , Heme Oxigenase-1/genética , Heme Oxigenase-1/imunologia , Humanos , Ativação Linfocitária/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 2 Relacionado a NF-E2/deficiência , Fator 2 Relacionado a NF-E2/genética , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/imunologia , Ácido Oleanólico/síntese química , Ácido Oleanólico/farmacologia , Fosforilação Oxidativa/efeitos dos fármacos , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologia , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Células Th17/patologia , Adulto Jovem
20.
Cell Death Dis ; 9(5): 548, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29748538

RESUMO

Mesenchymal stromal cells (MSCs) have been demonstrated to ameliorate allergic contact dermatitis (ACD), a typical T-cell-mediated disorder. However, the underlying mechanisms behind the MSC-based treatment for ACD have not yet been fully elucidated. The stanniocalcins (STCs) comprise a family of secreted glycoprotein hormones that act as important anti-inflammatory proteins. Here, we investigated the roles of STCs in MSC-mediated T-cell suppression and their potential role in the MSC-based treatment for ACD. Gene expression profiling revealed that STC2, but not STC1, was highly expressed in MSCs. STC2 knockdown in MSCs significantly impaired their effects in reducing TNF-α- and IFN-γ-producing CD8+ T cells. Importantly, silencing the STC2 expression in MSCs abated their therapeutic effect on contact hypersensitivity (CHS) in mice, mainly restoring the generation and infiltration of IFN-γ-producing CD8+ T cells (Tc1 cells). Mechanistically, STC2 co-localized with heme oxygenase 1 (HO-1) in MSCs, and contributed to MSC-mediated reduction of CD8+ Tc1 cells via regulating HO-1 activity. Together, these findings newly identify STC2 as the first stanniocalcin responsible for mediating the immunomodulatory effects of MSCs on allogeneic T cells and STC2 contribute to MSC-based treatment for ACD mainly via reducing the CD8+ Tc1 cells.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Dermatite de Contato/imunologia , Glicoproteínas/imunologia , Tolerância Imunológica , Peptídeos e Proteínas de Sinalização Intercelular/imunologia , Células-Tronco Mesenquimais/imunologia , Aloenxertos , Animais , Linfócitos T CD8-Positivos/patologia , Dermatite de Contato/patologia , Dermatite de Contato/terapia , Heme Oxigenase-1/imunologia , Xenoenxertos , Humanos , Interferon gama/imunologia , Peptídeos e Proteínas de Sinalização Intracelular , Proteínas de Membrana/imunologia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/patologia , Camundongos Endogâmicos BALB C , Fator de Necrose Tumoral alfa/imunologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA