RESUMO
BACKGROUND: Sea buckthorn has the functions of antioxidation, antitumor, anti-inflammation and regulating energy metabolism. In order to investigate the effects of sea buckthorn powder and sea buckthorn flavonoids on the antioxidant properties, immune function and muscle fatty acid composition of common carp, an oral feeding experiment was carried out. RESULTS: The administration of glucose significantly reduced the levels of glutathione and the activity of total antioxidant capacity enzyme in serum and hepatopancreas, while concurrently upregulating the level of malondialdehyde (MDA)(P < 0.05). Conversely, oral intake of sea buckthorn powder and flavonoids increased antioxidant enzyme activity and decreased MDA levels. In terms of antioxidant molecular indicators, sea buckthorn powder and sea buckthorn flavonoids significantly increased the mRNA levels of nuclear factor NF-E2-related factor (nrf2) in the hepatopancreas and muscle. Meanwhile, mRNA expression levels of downstream antioxidant-related genes (gr, cat, gpx, and sod) regulated by Nrf2 were also upregulated. In the immune aspects, the mRNA expression levels of proinflammatory cytokines, such as interleukin-6 (il-6), interleukin-1ß (il-1ß) and nuclear factor-κB (nf-κb), were reduced but the expressions of anti-inflammatory cytokines, such as growth factor-ß (tgf-ß) and interleukin-10 (il-10), were enhanced in the head kidney and spleen tissues after oral administration with sea buckthorn. In terms of muscle fatty acid composition, the ratio of n-3 polyunsaturated fatty acid (PUFA)/n-6 PUFA was notably higher after administering sea buckthorn flavonoids than that of the glucose group (P < 0.05). CONCLUSION: This study demonstrated that oral administration of sea buckthorn powder and sea buckthorn flavonoids significantly enhanced the antioxidant capacity and immune response and improved the muscle fatty acid compositions in common carp, and also mitigated the adverse effects of glucose treatment to a certain extent. © 2024 Society of Chemical Industry.
Assuntos
Antioxidantes , Carpas , Hippophae , Estresse Oxidativo , Animais , Carpas/imunologia , Carpas/genética , Carpas/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Hippophae/química , Ração Animal/análise , Malondialdeído/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/imunologia , Flavonoides/administração & dosagem , Proteínas de Peixes/genética , Proteínas de Peixes/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , NF-kappa B/imunologia , Glutationa/metabolismo , Extratos Vegetais/administração & dosagem , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Músculos/metabolismo , Músculos/químicaRESUMO
Reactive oxygen species (ROS) acts as a second messenger to trigger biological responses in low concentrations, while it is implicated to be toxic to biomolecules in high concentrations. Mild inhibition of respiratory chain Complex I by metformin at physiologically relevant concentrations stimulates production of low-level mitochondrial ROS. The ROS seems to induce anti-oxidative stress response via activation of nuclear factor erythroid 2-related factor 2 (Nrf2) and glutathione peroxidase (GPx), which results in not only elimination of ROS but also activation of cellular responses including resistance to apoptosis, metabolic changes, cell proliferation, senescence prevention, lifespan extension, and immune T cell activation against cancers, regardless of its effect controlling blood glucose level and T2DM. Although metformin's effect against T2DM, cancers, and ageing, are believed mostly attributed to the activation of AMP-activated protein kinase (AMPK), the cellular responses involving metformin-ROS-Nrf2 axis might be another natural asset to improve healthspan and lifespan.
Assuntos
Metformina , Fator 2 Relacionado a NF-E2 , Espécies Reativas de Oxigênio , Apoptose , Humanos , Metformina/farmacologia , Fator 2 Relacionado a NF-E2/imunologia , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/imunologia , Espécies Reativas de Oxigênio/imunologia , Espécies Reativas de Oxigênio/metabolismoRESUMO
Ovarian cancer (OC) often presents at an advanced stage and is still one of the most frequent causes of gynecological cancer-related mortality worldwide. The nuclear factor erythroid-2 (NFE2) transcription factors include nuclear factor, erythroid 2 like 1 (NFE2L1), NFE2L2, and NFE2L3. NFE2 members bind to the antioxidant-response element (ARE) region and activate the expression of targeted genes. The distinct functions of NFE2 members in OC remain poorly elucidated. Several online bioinformatics databases were applied to determine gene expression, prognosis, mutations, and immune infiltration correlation in OC patients. NFE2L1 and NFE2L2 were decreased in OC, whereas NFE2L3 was increased. NFE2L2 and NFE2L3 were significantly correlated with the clinical stages of OC. High NFE2L1 level was significantly associated with short progression-free survival (PFS) in patients with OC (HR = 1.18, P = 0.021), while high NFE2L2 expression strongly correlated with long PFS (HR = 0.77, P = 0.00067). High NFE2L3 expression was associated with better overall survival and postprogression survival in OC. Functional analysis showed that NFE2 members mainly focused on transcription coactivator activities. Genetic alterations of NFE2 members were found in 13% of OC patients, and amplification ranked the top. The expression of NFE2 members was significantly correlated with immune infiltration of CD4+ T cells, CD8+ T cells, B cells, macrophages, and neutrophils in OC. Our study provides novel insights into the roles and prognostic potential of NFE2 family members in OC.
Assuntos
Regulação Neoplásica da Expressão Gênica/imunologia , Fator 2 Relacionado a NF-E2 , Proteínas de Neoplasias , Neoplasias Ovarianas , Feminino , Humanos , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/imunologia , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/imunologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/mortalidade , Intervalo Livre de Progressão , Taxa de SobrevidaRESUMO
Nephrotoxicity is an indication for the damage of kidney-specific detoxification and excretion mechanisms by exogenous or endogenous toxicants. Exposure to vancomycin predominantly results in renal damage and losing the control of body homeostasis. Vancomycin-treated rats (200 mg/kg/once daily, for seven consecutive days, i.p.) revealed significant increase in serum pivotal kidney function, oxidative stress, and inflammatory biomarkers. Histologically, vancomycin showed diffuse acute tubular necrosis, denudation of epithelium and infiltration of inflammatory cells in the lining tubular epithelium in cortical portion. In the existing study, the conservative consequences of scopoletin against vancomycin nephrotoxicity was investigated centering on its capacity to alleviate oxidative strain and inflammation through streamlining nuclear factor (erythroid-derived-2) like 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling and prohibiting the nuclear factor kappa B (NF-κB)/mitogen-activated protein kinase (p38 MAPK) pathway. With respect to vancomycin group, scopoletin pretreatment (50 mg/kg/once daily, i.p.) efficiently reduced kidney function, oxidative stress biomarkers and inflammatory mediators. Moreover, histological and immunohistochemical examination of scopoletin-treated group showed remarkable improvement in histological structure and reduced vancomycin-induced renal expression of iNOS, NF-κB and p38 MAPK. In addition, scopoletin downregulated (Kelch Like ECH Associated Protein1) Keap1, P38MAPK and NF-κB expression levels while upregulated renal expression levels of regulatory protein (IκBα), Nrf2 and HO-1. Furthermore, molecular docking and network approach were constructed to study the prospect interaction between scopoletin and the targeted proteins that streamline oxidative stress and inflammatory pathways. The present investigations elucidated that scopoletin co-treatment with vancomycin may be a rational curative protocol for mitigation of vancomycin-induced renal intoxication.
Assuntos
Antibacterianos , Nefropatias/tratamento farmacológico , Substâncias Protetoras/uso terapêutico , Escopoletina/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Vancomicina , Animais , Citocinas/sangue , Heme Oxigenase (Desciclizante)/genética , Heme Oxigenase (Desciclizante)/imunologia , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/imunologia , Rim/efeitos dos fármacos , Rim/imunologia , Rim/patologia , Nefropatias/induzido quimicamente , Nefropatias/imunologia , Nefropatias/patologia , Masculino , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/imunologia , Inibidor de NF-kappaB alfa/genética , Inibidor de NF-kappaB alfa/imunologia , Óxido Nítrico Sintase Tipo II/imunologia , Substâncias Protetoras/farmacologia , Ratos Wistar , Escopoletina/farmacologia , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/imunologia , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/imunologiaRESUMO
Clostridium butyricum (CB) can enhance antioxidant capacity and alleviate oxidative damage, but the molecular mechanism by which this occurs remains unclear. This study used enterotoxigenic Escherichia coli (ETEC) K88 as a pathogenic model, and the p62-Keap1-Nrf2 signaling pathway and intestinal microbiota as the starting point to explore the mechanism through which CB alleviates oxidative damage. After pretreatment with CB for 15 d, mice were challenged with ETEC K88 for 24 h. The results suggest that CB pretreatment can dramatically reduce crypt depth (CD) and significantly increase villus height (VH) and VH/CD in the jejunum of ETEC K88-infected mice and relieve morphological lesions of the liver and jejunum. Additionally, compared with ETEC-infected group, pretreatment with 4.4×106 CFU/mL CB can significantly reduce malondialdehyde (MDA) level and dramatically increase superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) levels in the serum. This pretreatment can also greatly increase the mRNA expression levels of tight junction proteins and genes related to the p62-Keap1-Nrf2 signaling pathway in the liver and jejunum in ETEC K88-infected mice. Meanwhile, 16S rDNA amplicon sequencing revealed that Clostridium disporicum was significantly enriched after ETEC K88 challenge relative to the control group, while Lactobacillus was significantly enriched after 4.4×106 CFU/mL CB treatment. Furthermore, 4.4×106 CFU/mL CB pretreatment increased the short-chain fatty acid (SCFA) contents in the cecum of ETEC K88-infected mice. Moreover, we found that Lachnoclostridium, Roseburia, Lactobacillus, Terrisporobacter, Akkermansia, and Bacteroides are closely related to SCFA contents and oxidative indicators. Taken together, 4.4×106 CFU/mL CB pretreatment can alleviate ETEC K88-induced oxidative damage through activating the p62-Keap1-Nrf2 signaling pathway and remodeling the cecal microbiota community in mice.
Assuntos
Antibiose/imunologia , Infecções Bacterianas/imunologia , Ceco/microbiologia , Clostridium butyricum/imunologia , Escherichia coli Enterotoxigênica/imunologia , Estresse Oxidativo/imunologia , Proteínas/imunologia , Animais , Antibiose/fisiologia , Infecções Bacterianas/genética , Infecções Bacterianas/microbiologia , Ceco/metabolismo , Clostridium butyricum/fisiologia , Escherichia coli Enterotoxigênica/fisiologia , Regulação da Expressão Gênica/imunologia , Heme Oxigenase-1/genética , Heme Oxigenase-1/imunologia , Heme Oxigenase-1/metabolismo , Jejuno/imunologia , Jejuno/metabolismo , Jejuno/microbiologia , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/imunologia , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Masculino , Camundongos , Microbiota/genética , Microbiota/imunologia , Microbiota/fisiologia , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/imunologia , Fator 2 Relacionado a NF-E2/metabolismo , Proteínas/genética , Proteínas/metabolismo , Proteína Sequestossoma-1/genética , Proteína Sequestossoma-1/imunologia , Proteína Sequestossoma-1/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Superóxido Dismutase/genética , Superóxido Dismutase/imunologia , Superóxido Dismutase/metabolismo , SuínosRESUMO
COVID-19 is a pandemic requiring immediate solution for treatment because of its complex pathophysiology. Exploration of novel targets and thus treatment will be life savers which is the need of the hour. 2 host factors- TMPRSS2 and ACE2 are responsible for the way the virus will enter and replicate in the host. Also NRF2 is an important protein responsible for its anti-inflammatory role by multiple mechanisms of action like inhibition of NF-kB, suppression of pro-inflammatory genes, etc. NRF2 is deacetylated by Sirtuins and therefore both have a direct association. Absence of SIRT indicates inhibition of NRF2 expression and thus no anti-oxidative and anti-inflammatory protection for the cell. Therefore, we propose that NRF2 activators and/or SIRT activators can be evaluated to check their efficacy in ameliorating the symptoms of COVID-19.
Assuntos
COVID-19/imunologia , Fator 2 Relacionado a NF-E2/imunologia , SARS-CoV-2/imunologia , Sirtuínas/imunologia , Enzima de Conversão de Angiotensina 2/imunologia , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , COVID-19/metabolismo , COVID-19/virologia , Interações Hospedeiro-Patógeno/imunologia , Humanos , Fator 2 Relacionado a NF-E2/metabolismo , SARS-CoV-2/metabolismo , SARS-CoV-2/fisiologia , Serina Endopeptidases/imunologia , Serina Endopeptidases/metabolismo , Sirtuínas/metabolismo , Ligação ViralRESUMO
This study aimed to evaluate that dietary protein levels and culture salinity levels affect the health status of juvenile genetically improved farmed tilapia (GIFT, Oreochromis niloticus). Graded protein levels of six diets were prepared, ranging from 18.20% to 49.49% (dry basis), and were used in cultured GIFT at two salinity levels (0 and 8) for 8 weeks. The results suggested that appropriate protein levels reduced pro-inflammatory gene expressions in the intestine including interleukin 1ß (IL-1ß), interleukin 8 (IL-8) and tumour necrosis factor-α (TNF-α) mRNA levels at two salinity levels (P < 0.05). 8 salinity significantly decreased the expression levels of IL-1ß, TNF-α and nuclear factor-kappa B (NF-κB) (P < 0.05). The anti-inflammatory factor interleukin 10 (IL-10) was significantly increased by 36.42% protein level (P < 0.05). Regarding antioxidant capacity, appropriate protein levels and 8 salinity significantly improved the antioxidant capacity of fish by regulating the activities of intestinal total superoxide dismutase (T-SOD), glutathione peroxidase (GPx), and the levels of glutathione (GSH) and malondialdehyde (MDA). Furthermore, appropriate protein levels and 8 salinity also significantly enhanced the antioxidant gene expressions associated with the Nrf2/keap1 signaling pathway by regulating the expression levels of heme oxygenase-1 (HO-1), GPx, catalase (CAT) and superoxide dismutase (SOD). According to GPx activities and the mRNA levels of IL-10, the optimum dietary protein levels for GIFT juveniles were 31.12%-32.18% (0) and 34.25-35.38% (8) based on second-degree polynomial regression analysis. The present study found that appropriate protein levels and 8 culture salinity are critical in maintaining the health of GIFT juveniles by improving antioxidant and immune capacity.
Assuntos
Ciclídeos/imunologia , Proteínas Alimentares/administração & dosagem , Proteínas de Peixes/imunologia , Fator 2 Relacionado a NF-E2/imunologia , Salinidade , Animais , Animais Geneticamente Modificados , Aquicultura , Ciclídeos/genética , Citocinas/imunologia , Expressão Gênica , Intestinos/imunologia , NF-kappa B/imunologia , Oxirredutases/genética , Transdução de SinaisRESUMO
Air pollution-related particulate matter (PM) exposure reportedly enhances allergic airway inflammation. Some studies have shown an association between PM exposure and a risk for allergic rhinitis (AR). However, the effect of PM for AR is not fully understood. An AR mouse model was developed by intranasal administration of 100 µg/mouse PM with a less than or equal to 2.5 µm in aerodynamic diameter (PM2.5) solution, and then by intraperitoneal injection of ovalbumin (OVA) with alum and intranasal challenging with 10 mg/mL OVA. The effects of PM2.5 on oxidative stress and inflammatory response via the Nrf2/NF-κB signaling pathway in mice with or without AR indicating by histological, serum, and protein analyses were examined. PM2.5 administration enhanced allergic inflammatory cell expression in the nasal mucosa through increasing the expression of inflammatory cytokine and reducing the release of Treg cytokine in OVA-induced AR mice, although PM2.5 exposure itself induced neither allergic responses nor damage to nasal and lung tissues. Notably, repeated OVA-immunization markedly impaired the nasal mucosa in the septum region. Moreover, AR with PM2.5 exposure reinforced this impairment in OVA-induced AR mice. Long-term PM2.5 exposure strengthened allergic reactions by inducing the oxidative through malondialdehyde production. The present study also provided evidence, for the first time, that activity of the Nrf2 signaling pathway is inhibited in PM2.5 exposed AR mice. Furthermore, PM2.5 exposure increased the histopathological changes of nasal and lung tissues and related the inflammatory cytokine, and clearly enhanced PM2.5 phagocytosis by alveolar macrophages via activating the NF-κB signaling pathway. These obtained results suggest that AR patients may experience exacerbation of allergic responses in areas with prolonged PM2.5 exposure.
Assuntos
Poluição do Ar/efeitos adversos , Inflamação/imunologia , Estresse Oxidativo/efeitos dos fármacos , Material Particulado/toxicidade , Rinite Alérgica/imunologia , Animais , Citocinas/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fator 2 Relacionado a NF-E2/imunologia , NF-kappa B/imunologia , Ovalbumina/imunologiaRESUMO
Trichinella spiralis induced alternative activated macrophages (M2), leading to protect against Crohn's disease, known as Th1 -related inflammation, which enhances oxidative stress in the host. However, the relationship of oxidative stress and T. spiralis -mediated immune response is still unknown. In our study, we showed that nuclear factor erythroid 2-related factor-2 (Nrf2), a key transcription factor in antioxidant, participated in M2 polarization induced by T. spiralis muscle larval excretory/secretory (ES) products in vitro. ES -treated M2 were injected intravenously after TNBS challenge and we demonstrated that ES-M could alleviate the severity of the colitis in mice. Adoptive transfer of ES -treated M2 decreased the level of IFN-γ and increased the levels of IL-4 and IL-10 in vivo. However, the capacity of ES -treated Nrf2 KO macrophages to treat colitis was dramatically impaired. ES -treated Nrf2 KO macrophages was insufficient to result in the elevated levels of IL-4 and IL-10. These findings indicate that Nrf2 was required for M2 polarization induced by T. spiralis ES to alleviate colitis in mice.
Assuntos
Colite/imunologia , Macrófagos/imunologia , Fator 2 Relacionado a NF-E2/imunologia , Triquinelose/imunologia , Animais , Colite/induzido quimicamente , Modelos Animais de Doenças , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Trichinella spiralis/imunologia , Ácido Trinitrobenzenossulfônico/toxicidadeRESUMO
After birth, the alveolar epithelium is exposed to environmental pathogens and high O2 tensions. The alveolar type II cells may protect this epithelium through surfactant production. Surfactant protein, SP-A, an immune modulator, is developmentally upregulated in fetal lung with surfactant phospholipid synthesis. Herein, we observed that the redox-regulated transcription factor, NRF2, and co-regulated C/EBPß and PPARγ, were markedly induced during cAMP-mediated differentiation of cultured human fetal lung (HFL) epithelial cells. This occurred with enhanced expression of immune modulators, SP-A, TDO2, AhR, and NQO1. Like SP-A, cAMP induction of NRF2 was prevented when cells were exposed to hypoxia. NRF2 knockdown inhibited induction of C/EBPß, PPARγ, and immune modulators. Binding of endogenous NRF2 to promoters of SP-A and other immune modulator genes increased during HFL cell differentiation. In mouse fetal lung (MFL), a developmental increase in Nrf2, SP-A, Tdo2, Ahr, and Nqo1 and decrease in Keap1 occurred from 14.5 to 18.5 dpc. Developmental induction of Nrf2 in MFL was associated with increased nuclear localization of NF-κB p65, a decline in p38 MAPK phosphorylation, increase in the MAPK phosphatase, DUSP1, induction of the histone acetylase, CBP, and decline in the histone deacetylase, HDAC4. Thus, together with surfactant production, type II cells protect the alveolar epithelium through increased expression of NRF2 and immune modulators to prevent inflammation and oxidative stress. Our findings further suggest that lung cancer cells have usurped this developmental pathway to promote immune tolerance and enhance survival.
Assuntos
Regulação da Expressão Gênica no Desenvolvimento/imunologia , Pulmão , Fator 2 Relacionado a NF-E2 , Animais , Feminino , Humanos , Pulmão/embriologia , Pulmão/imunologia , Camundongos , Camundongos Endogâmicos ICR , Fator 2 Relacionado a NF-E2/biossíntese , Fator 2 Relacionado a NF-E2/imunologiaRESUMO
Human CD4+CD25hiFOXP3+ regulatory T (Treg) cells are key players in the control of immunological self-tolerance and homeostasis. Here, we report that signals of pseudo-starvation reversed human Treg cell in vitro anergy through an integrated transcriptional response, pertaining to proliferation, metabolism, and transmembrane solute carrier transport. At the molecular level, the Treg cell proliferative response was dependent on the induction of the cystine/glutamate antiporter solute carrier (SLC)7A11, whose expression was controlled by the nuclear factor erythroid 2-related factor 2 (NRF2). SLC7A11 induction in Treg cells was impaired in subjects with relapsing-remitting multiple sclerosis (RRMS), an autoimmune disorder associated with reduced Treg cell proliferative capacity. Treatment of RRMS subjects with dimethyl fumarate (DMF) rescued SLC7A11 induction and fully recovered Treg cell expansion. These results suggest a previously unrecognized mechanism that may account for the progressive loss of Treg cells in autoimmunity and unveil SLC7A11 as major target for the rescue of Treg cell proliferation.
Assuntos
Sistema y+ de Transporte de Aminoácidos/imunologia , Proliferação de Células/fisiologia , Linfócitos T Reguladores/imunologia , Adulto , Autoimunidade/imunologia , Células Cultivadas , Feminino , Homeostase/imunologia , Humanos , Tolerância Imunológica/imunologia , Masculino , Esclerose Múltipla Recidivante-Remitente/imunologia , Fator 2 Relacionado a NF-E2/imunologiaRESUMO
Previous studies showed that interleukin-9 (IL-9) is involved in cardiovascular diseases, including hypertension and cardiac fibrosis. This study aimed to investigate the role of IL-9 in lipopolysaccharide (LPS)-induced myocardial cell (MC) apoptosis. Mice were treated with LPS, and IL-9 expression was measured and the results showed that compared with WT mice, LPS-treated mice exhibited increased cardiac Mø-derived IL-9. Additionally, the effects of IL-9 deficiency (IL-9-/-) on macrophage (Mø)-related oxidative stress and MC apoptosis were evaluated, the results showed that IL-9 knockout significantly exacerbated cardiac dysfunction, inhibited Nrf2 nuclear transfer, promoted an imbalance in M1 and M2 Møs, and exacerbated oxidative stress and MC apoptosis in LPS-treated mice. Treatment with ML385, a specific nuclear factor erythroid-2 related factor 2 (Nrf2) pathway inhibitor significantly alleviated the above effects in LPS-treated IL-9-/- mice. Bone marrow-derived Møs from wild-type (WT) mice and IL-9-/- mice were treated with LPS, and the differentiation and oxidative stress levels of Møs were measured. The effect of Mø differentiation on mouse MC apoptosis was also analyzed in vitro. The results showed that LPS-induced M1 Mø/M2 Mø imbalance and Mø-related oxidative stress were alleviated by IL-9 knockout but were exacerbated by ML385 treatment. The protective effects of IL-9 deficiency on the MC apoptosis mediated by LPS-treated Møs were reversed by ML-385. Our results suggest that deletion of IL-9 decreased the nuclear translocation of Nrf2 in Møs, which further aggravated Mø-related oxidative stress and MC apoptosis. IL-9 may be a target for the prevention of LPS-induced cardiac injury.
Assuntos
Apoptose/genética , Interleucina-9/genética , Macrófagos/patologia , Miocardite/genética , Miócitos Cardíacos/patologia , Fator 2 Relacionado a NF-E2/genética , Animais , Antígenos CD/genética , Antígenos CD/imunologia , Apoptose/imunologia , Núcleo Celular/metabolismo , Citoplasma/metabolismo , Regulação da Expressão Gênica , Interleucina-9/deficiência , Interleucina-9/imunologia , Lipopolissacarídeos/administração & dosagem , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Knockout , Miocardite/induzido quimicamente , Miocardite/imunologia , Miocardite/patologia , Miócitos Cardíacos/imunologia , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Fator 2 Relacionado a NF-E2/imunologia , Estresse Oxidativo , Cultura Primária de Células , Transporte Proteico , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/imunologia , Receptores do Fator Natriurético Atrial/genética , Receptores do Fator Natriurético Atrial/imunologia , Receptores de Interleucina-9/genética , Receptores de Interleucina-9/imunologia , Transdução de Sinais , Tiazóis/farmacologia , Função Ventricular Esquerda/fisiologia , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/imunologiaRESUMO
Dendritic cells (DC) play a central role in the pathogenesis of allergic contact dermatitis (ACD), the most prevalent form of immunotoxicity in humans. However, knowledge on allergy-induced DC maturation is still limited and proteomic studies, allowing to unravel molecular effects of allergens, remain scarce. Therefore, we conducted a global proteomic analysis of human monocyte-derived dendritic cells (MoDC) treated with NiSO4, the most prominent cause of ACD and compared proteomic alterations induced by NiSO4 to the bacterial trigger lipopolysaccharide (LPS). Both substances possess a similar toll-like receptor (TLR) 4 binding capacity, allowing to identify allergy-specific effects compared to bacterial activation. MoDCs treated for 24 h with 2.5 µg/ml LPS displayed a robust immunological response, characterized by upregulation of DC activation markers, secretion of pro-inflammatory cytokines and stimulation of T cell proliferation. Similar immunological reactions were observed after treatment with 400 µM NiSO4 but less pronounced. Both substances triggered TLR4 and triggering receptor expressed on myeloid cells (TREM) 1 signaling. However, NiSO4 also activated hypoxic and apoptotic pathways, which might have overshadowed initial signaling. Moreover, our proteomic data support the importance of nuclear factor erythroid 2-related factor 2 (Nrf2) as a key player in sensitization since many Nrf2 targets genes were strongly upregulated on protein and gene level selectively after treatment with NiSO4. Strikingly, NiSO4 stimulation induced cellular cholesterol depletion which was counteracted by the induction of genes and proteins relevant for cholesterol biosynthesis. Our proteomic study allowed for the first time to better characterize some of the fundamental differences between NiSO4 and LPS-triggered activation of MoDCs, providing an essential contribution to the molecular understanding of contact allergy.
Assuntos
Proliferação de Células/efeitos dos fármacos , Células Dendríticas/imunologia , Dermatite Alérgica de Contato/imunologia , Lipopolissacarídeos/toxicidade , Níquel/toxicidade , Transdução de Sinais/efeitos dos fármacos , Linfócitos T/imunologia , Humanos , Fator 2 Relacionado a NF-E2/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/imunologia , Transdução de Sinais/imunologia , Receptor 4 Toll-Like/imunologia , Receptor Gatilho 1 Expresso em Células Mieloides/imunologia , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/imunologiaRESUMO
The oxidative burst generated by the host immune system can restrict intracellular parasite entry and growth. While this burst leads to the induction of antioxidative enzymes, the molecular mechanisms and the consequences of this counter-response on the life of intracellular human parasites are largely unknown. The transcription factor NF-E2-related factor (NRF2) could be a key mediator of antioxidant signaling during infection due to the entry of parasites. Here, we showed that NRF2 was strongly upregulated in infection with the human Leishmania protozoan parasites, its activation was dependent on a NADPH oxidase 2 (NOX2) and SRC family of protein tyrosine kinases (SFKs) signaling pathway and it reprogrammed host cell metabolism. In inflammatory leishmaniasis caused by a viral endosymbiont inducing TNF-α in chronic leishmaniasis, NRF2 activation promoted parasite persistence but limited TNF-α production and tissue destruction. These data provided evidence of the dual role of NRF2 in protecting both the invading pathogen from reactive oxygen species and the host from an excess of the TNF-α destructive pro-inflammatory cytokine.
Assuntos
Interações Hospedeiro-Parasita/fisiologia , Leishmania/metabolismo , Leishmaniose/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/fisiologia , Animais , Inflamação/imunologia , Inflamação/metabolismo , Leishmania/imunologia , Leishmaniose/imunologia , Camundongos , Fator 2 Relacionado a NF-E2/imunologia , Transdução de Sinais/imunologiaRESUMO
B cells play a major role in regulating disease incidence through various factors, including spleen tyrosine kinase (Syk), which transmits signals to all hematopoietic lineage cells. Hypoxia-inducible factor (HIF)-1α accumulates under hypoxic conditions, which is also oxidative stress to induce nuclear factor (erythroid-derived 2)-like 2 (Nrf2) responsible for gene expression of antioxidant enzymes. In the present study, we investigated whether B cells are regulated by crosstalk of HIF-1α and Nrf2 via reactive oxygen species (ROS)-mediated Syk activation. When B cells were incubated under hypoxic conditions, Syk phosphorylation, HIF-1α, and Nrf2 levels were increased. Hypoxia-inducible results were consistent with CoCl2 treatment, which mimics hypoxic conditions. Cell viability was reduced by the Syk inhibitor BAY 61-3606. Increased Nrf2 levels due to hypoxia or CoCl2 were inhibited by treatment with a HIF inhibitor. Hypoxia- or CoCl2-induced ROS increased HIF-1α and Nrf2 levels, which were attenuated by treatment with N-acetyl-L-cysteine (NAC), a ROS scavenger. HIF-1α levels were reduced in doxycycline-treated shNrf2 cells. Clobetasol propionate, a Nrf2 inhibitor, also inhibited HIF-1α levels induced by hypoxia or CoCl2. ROS-mediated Syk phosphorylation at tyrosine 525/526 was confirmed by treatment with H2O2, hypoxia, and CoCl2, and attenuated with NAC treatment. Inhibition of Syk phosphorylation by BAY 61-3606 is consistent with a decrease in protein HIF-1α and Nrf2 levels. Taken together, HIF-1α levels might control Nrf2 levels and vice versa, and could be associated with Syk phosphorylation in B cells. The results indicate that B cells could be regulated by crosstalk of HIF-1α and Nrf2 through ROS-mediated Syk activation.
Assuntos
Linfócitos B/imunologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/imunologia , Fator 2 Relacionado a NF-E2/imunologia , Quinase Syk/imunologia , Animais , Hipóxia Celular/imunologia , Linhagem Celular , Sobrevivência Celular , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Masculino , Camundongos Endogâmicos C57BL , RNA Interferente Pequeno/genética , Espécies Reativas de Oxigênio/imunologiaRESUMO
In this article, we propose that differences in COVID-19 morbidity may be associated with transient receptor potential ankyrin 1 (TRPA1) and/or transient receptor potential vanilloid 1 (TRPV1) activation as well as desensitization. TRPA1 and TRPV1 induce inflammation and play a key role in the physiology of almost all organs. They may augment sensory or vagal nerve discharges to evoke pain and several symptoms of COVID-19, including cough, nasal obstruction, vomiting, diarrhea, and, at least partly, sudden and severe loss of smell and taste. TRPA1 can be activated by reactive oxygen species and may therefore be up-regulated in COVID-19. TRPA1 and TRPV1 channels can be activated by pungent compounds including many nuclear factor (erythroid-derived 2) (Nrf2)-interacting foods leading to channel desensitization. Interactions between Nrf2-associated nutrients and TRPA1/TRPV1 may be partly responsible for the severity of some of the COVID-19 symptoms. The regulation by Nrf2 of TRPA1/TRPV1 is still unclear, but suggested from very limited clinical evidence. In COVID-19, it is proposed that rapid desensitization of TRAP1/TRPV1 by some ingredients in foods could reduce symptom severity and provide new therapeutic strategies.
Assuntos
COVID-19/dietoterapia , COVID-19/imunologia , Fator 2 Relacionado a NF-E2/imunologia , Nutrientes/imunologia , SARS-CoV-2/imunologia , Canal de Cátion TRPA1/imunologia , Canais de Cátion TRPV/imunologia , Antioxidantes/metabolismo , Biomarcadores/metabolismo , Brassica , COVID-19/complicações , COVID-19/diagnóstico , Teste para COVID-19 , Dessensibilização Imunológica/métodos , Regulação para Baixo , Humanos , Estresse Oxidativo/imunologia , SARS-CoV-2/patogenicidade , Índice de Gravidade de Doença , Regulação para CimaRESUMO
Nrf2 is a redox-sensitive transcription factor that is thought to be important in protection against intracellular pathogens. To determine the protective role of Nrf2 in the host defense against Mycobacterium avium complex (MAC), both wild-type and Nrf2-deficient mice were intranasally infected with MAC bacteria. Nrf2-deficient mice were highly susceptible to MAC bacteria compared with wild-type mice. There were no significant changes in the levels of oxidative stress and Th1 cytokine production between genotypes. Comprehensive transcriptome analysis showed that the expressions of Nramp1 and HO-1 were much lower in the infected lungs, and the expression of Nramp1 was especially lower in alveolar macrophages of Nrf2-deficient mice than of wild-type mice. Electron microscopy showed that many infected alveolar macrophages from Nrf2-deficient mice contained a large number of intracellular MAC bacteria with little formation of phagolysosomes, compared with those from wild-type mice. Treatment with sulforaphane, an activator of Nrf2, increased resistance to MAC with increased lung expression of Nramp1 and HO-1 in wild-type mice. These results indicate that Nramp1 and HO-1, regulated by Nrf2, are essential in defending against MAC infection due to the promotion of phagolysosome fusion and granuloma formation, respectively. Thus, Nrf2 is thought to be a critical determinant of host resistance to MAC infection.IMPORTANCE Nontuberculous mycobacteria (NTM) are an important cause of morbidity and mortality in pulmonary infections. Among them, Mycobacterium avium complex (MAC) is the most common cause of pulmonary NTM disease worldwide. It is thought that both environmental exposure and host susceptibility are required for the establishment of pulmonary MAC disease, because pulmonary MAC diseases are most commonly observed in slender, postmenopausal women without a clearly recognized immunodeficiency. However, host factors that regulate MAC susceptibility have not been elucidated until now. This study shows that Nrf2 is a critical regulator of host susceptibility to pulmonary MAC disease by promoting phagolysosome fusion and granuloma formation via activating Nramp1 and HO-1 genes, respectively. The Nrf2 system is activated in alveolar macrophages, the most important cells during MAC infection, as both the main reservoir of infection and bacillus-killing cells. Thus, augmentation of Nrf2 might be a useful therapeutic approach for protection against pulmonary MAC disease.
Assuntos
Proteínas de Transporte de Cátions/genética , Regulação da Expressão Gênica/imunologia , Granuloma/microbiologia , Heme Oxigenase-1/genética , Interações entre Hospedeiro e Microrganismos , Proteínas de Membrana/genética , Fator 2 Relacionado a NF-E2/genética , Animais , Proteínas de Transporte de Cátions/imunologia , Feminino , Granuloma/imunologia , Heme Oxigenase-1/imunologia , Interações entre Hospedeiro e Microrganismos/genética , Interações entre Hospedeiro e Microrganismos/imunologia , Ativação de Macrófagos/imunologia , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/microbiologia , Proteínas de Membrana/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Complexo Mycobacterium avium/imunologia , Fator 2 Relacionado a NF-E2/imunologia , Estresse OxidativoRESUMO
Inflammatory diseases are caused by excessive inflammation from pro-inflammatory mediators and cytokines produced by macrophages. The Nrf2 signaling pathway protects against inflammatory diseases by inhibiting excessive inflammation via the regulation of antioxidant enzymes, including HO-1 and NQO1. We investigated the anti-inflammatory effect of impressic acid (IPA) isolated from Acanthopanax koreanum on the lipopolysaccharide (LPS)-induced inflammation and the underlying molecular mechanisms in RAW264.7 cells. IPA attenuated the LPS-induced production of pro-inflammatory cytokines and reactive oxygen species, and the activation of the NF-κB signaling pathway. IPA also increased the protein levels of Nrf2, HO-1, and NQO1 by phosphorylating CaMKKß, AMPK, and GSK3ß. Furthermore, ML385, an Nrf2 inhibitor, reversed the inhibitory effect of IPA on LPS-induced production of pro-inflammatory cytokines in RAW264.7 cells. Therefore, IPA exerts an anti-inflammatory effect via the AMPK/GSK3ß/Nrf2 signaling pathway in macrophages. Taken together, the findings suggest that IPA has preventive potential for inflammation-related diseases.
Assuntos
Anti-Inflamatórios/farmacologia , Lipopolissacarídeos/imunologia , Macrófagos/efeitos dos fármacos , Triterpenos/farmacologia , Proteínas Quinases Ativadas por AMP/imunologia , Animais , Anti-Inflamatórios/química , Eleutherococcus/química , Glicogênio Sintase Quinase 3 beta/imunologia , Inflamação/tratamento farmacológico , Inflamação/imunologia , Macrófagos/imunologia , Camundongos , Fator 2 Relacionado a NF-E2/imunologia , Células RAW 264.7 , Transdução de Sinais/efeitos dos fármacos , Triterpenos/químicaRESUMO
Chronic pain, encompassing conditions, such as low back pain, arthritis, persistent post-surgical pain, fibromyalgia, and neuropathic pain disorders, is highly prevalent but remains poorly treated. The vast majority of therapeutics are directed solely at neurons, despite the fact that signaling between immune cells, glia, and neurons is now recognized as indispensable for the initiation and maintenance of chronic pain. This review highlights recent advances in understanding fundamental neuroimmune signaling mechanisms and novel therapeutic targets in rodent models of chronic pain. We further discuss new technological developments to study, diagnose, and quantify neuroimmune contributions to chronic pain in patient populations.
Assuntos
Autoanticorpos/imunologia , Dor Crônica/imunologia , Modelos Animais de Doenças , Neuroglia/imunologia , Neuroimunomodulação/fisiologia , Neurônios/imunologia , Animais , Autoanticorpos/metabolismo , Dor Crônica/metabolismo , Humanos , Fator 2 Relacionado a NF-E2/imunologia , Fator 2 Relacionado a NF-E2/metabolismo , Neuroglia/metabolismo , Neurônios/metabolismo , RoedoresRESUMO
Metabolic pathways and redox reactions are at the core of life. In the past decade(s), numerous discoveries have shed light on how metabolic pathways determine the cellular fate and function of lymphoid and myeloid cells, giving rise to an area of research referred to as immunometabolism. Upon activation, however, immune cells not only engage specific metabolic pathways but also rearrange their oxidation-reduction (redox) system, which in turn supports metabolic reprogramming. In fact, studies addressing the redox metabolism of immune cells are an emerging field in immunology. Here, we summarize recent insights revealing the role of reactive oxygen species (ROS) and the differential requirement of the main cellular antioxidant pathways, including the components of the thioredoxin (TRX) and glutathione (GSH) pathways, as well as their transcriptional regulator NF-E2-related factor 2 (NRF2), for proliferation, survival and function of T cells, B cells and macrophages.