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1.
Gene ; 725: 144163, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31639433

RESUMO

BACKGROUND: Previous studies have established that coronary artery disease is associated with excess inflammation. These studies have shown an elevation of both pro and anti-inflammatory cytokines in sufferers of coronary artery disease. There is increasing interest in the role played by the inflammasome Nod Like Receptor family pyrin domain containing 3 (NLRP3) in the aetiology of coronary artery disease. Increased severity of coronary artery disease correlates with higher levels of expression of NLRP3. Does NLRP3 polymorphisms play a role in the aetiology of coronary artery disease? METHOD: In a cohort of Vietnam War (n-299) veterans who have been previously exposed to trauma, NLRP3 polymorphisms were analysed for association with coronary calcium scores using analyses of variance. Independent t-test was used to analyse genotypes. In samples with a small representation of minor homozygotes, genotypes were combined and analysed using independent t-test. If any of the genotype analysis suggested the potential for a dominant or a recessive model the model was further explored. Hardy-Weinberg Equilibrium was calculated using Hardy-Weinberg equilibrium calculator including analysis for ascertainment bias. RESULTS: The NLRP3 polymorphism, rs10159239 was significantly associated (p = 0.001) with a higher raised coronary calcium score. The Single Nucleotide Polymorphism rs10159239 was examined by logistic regression with known risk factors for Coronary artery disease and remained significant (0.035). This is the first time rs10159239 A-allele has been associated with raised coronary calcium score. CONCLUSIONS: This is the first time rs10159239 A-allele has been associated with raised coronary calcium score. Further research is needed to replicate our results in larger well-characterised cohorts.


Assuntos
Doença da Artéria Coronariana/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Idoso , Idoso de 80 Anos ou mais , Alelos , Proteínas de Transporte/genética , Estudos de Coortes , Doença da Artéria Coronariana/metabolismo , Citocinas/genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Frequência do Gene/genética , Predisposição Genética para Doença/genética , Genótipo , Humanos , Inflamação/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Veteranos , Guerra do Vietnã
2.
Gene ; 725: 144191, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31654705

RESUMO

Caloric restriction (CR) has long been known to increase median and maximal lifespans and to decrease mortality and morbidity in short-lived animal models, likely by altering fundamental biological processes that regulate aging and longevity. However, the detailed mechanisms of immunomodulation by CR remain unclear. In this study, we established a mouse model for CR and analyzed the changes of immune cells in these mice. The CR mice fed a calorie-restricted diet for 4 weeks had lower body weight and fat mass compared with control mice. The proportions of CD4+, CD8+, and naïve CD4+ T cells in spleen cells from CR mice were higher than those in of control mice. Additionally, the proportion of CD8+ T cells was significantly decreased and the mRNA expression of proinflammatory cytokines in the colon of CR mice was significantly decreased compared with those of control mice. To determine the effect of CR on microRNA (miRNA) expression, serum and tissues were collected from mice and the expression level of miRNA was analyzed by real-time RT-PCR. As a result, the expressions of miR-16-5p, miR-196b-5p, and miR-218-5p in serum from CR mice were higher than those in control mice. The expression of miR-16-5p increased in the spleen, thymus, colon, and stomach of CR mice compared with expression in control mice. Furthermore, RAW264 cells transfected with a miR-16-5p mimic significantly decreased the mRNA expression of IL-1ß, IL-6, and TNF-α under LPS stimulation. These results suggested that miR-16-5p might be a critical factor involving the anti-inflammatory effects of calorie-restricted feeding.


Assuntos
Macrófagos/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Envelhecimento/metabolismo , Animais , Restrição Calórica/métodos , Citocinas/genética , Citocinas/metabolismo , Dietoterapia , Inflamação/metabolismo , Interleucina-1beta/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Células RAW 264.7 , Ativação Transcricional , Fator de Necrose Tumoral alfa/genética , Regulação para Cima
3.
Pol J Microbiol ; 68(4): 457-464, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31880890

RESUMO

Unravelling of the interplay between the immune system and non-diphtheria corynebacteria would contribute to understanding their increasing role as medically important microorganisms. We aimed at the analysis of pro- (TNF, IL-1ß, IL-6, IL-8, and IL-12p70) and anti-inflammatory (IL-10) cytokines produced by Jurkat T cells in response to planktonic and biofilm Corynebacterium amycolatum. Two reference strains: C. amycolatum ATCC 700207 (R-CA), Staphylococcus aureus ATCC 25923 (R-SA), and ten clinical strains of C. amycolatum (C-CA) were used in the study. Jurkat T cells were stimulated in vitro by the planktonic-conditioned medium (PCM) and biofilm-conditioned medium (BCM) derived from the relevant cultures of the strains tested. The cytokine concentrations were determined in the cell culture supernatants using the flow cytometry. The levels of the cytokines analyzed were lower after stimulation with the BCM when compared to the PCM derived from the cultures of C-CA; statistical significance (p < 0.05) was observed for IL-1ß, IL-12 p70, and IL-10. Similarly, planktonic R-CA and R-SA stimulated a higher cytokine production than their biofilm counterparts. The highest levels of pro-inflammatory IL-8, IL-1ß, and IL-12p70 were observed after stimulation with planktonic R-SA whereas the strongest stimulation of anti-inflammatory IL-10 was noted for the BCM derived from the mixed culture of both reference species. Our results are indicative of weaker immunostimulatory properties of the biofilm C. amycolatum compared to its planktonic form. It may play a role in the persistence of biofilm-related infections. The extent of the cytokine response can be dependent on the inherent virulence of the infecting microorganism.Unravelling of the interplay between the immune system and non-diphtheria corynebacteria would contribute to understanding their increasing role as medically important microorganisms. We aimed at the analysis of pro- (TNF, IL-1ß, IL-6, IL-8, and IL-12p70) and anti-inflammatory (IL-10) cytokines produced by Jurkat T cells in response to planktonic and biofilm Corynebacterium amycolatum. Two reference strains: C. amycolatum ATCC 700207 (R-CA), Staphylococcus aureus ATCC 25923 (R-SA), and ten clinical strains of C. amycolatum (C-CA) were used in the study. Jurkat T cells were stimulated in vitro by the planktonic-conditioned medium (PCM) and biofilm-conditioned medium (BCM) derived from the relevant cultures of the strains tested. The cytokine concentrations were determined in the cell culture supernatants using the flow cytometry. The levels of the cytokines analyzed were lower after stimulation with the BCM when compared to the PCM derived from the cultures of C-CA; statistical significance (p < 0.05) was observed for IL-1ß, IL-12 p70, and IL-10. Similarly, planktonic R-CA and R-SA stimulated a higher cytokine production than their biofilm counterparts. The highest levels of pro-inflammatory IL-8, IL-1ß, and IL-12p70 were observed after stimulation with planktonic R-SA whereas the strongest stimulation of anti-inflammatory IL-10 was noted for the BCM derived from the mixed culture of both reference species. Our results are indicative of weaker immunostimulatory properties of the biofilm C. amycolatum compared to its planktonic form. It may play a role in the persistence of biofilm-related infections. The extent of the cytokine response can be dependent on the inherent virulence of the infecting microorganism.


Assuntos
Biofilmes , Infecções por Corynebacterium/imunologia , Corynebacterium/fisiologia , Citocinas/imunologia , Linfócitos T/imunologia , Linhagem Celular , Corynebacterium/genética , Corynebacterium/imunologia , Infecções por Corynebacterium/genética , Infecções por Corynebacterium/microbiologia , Citocinas/genética , Humanos , Interleucina-10/genética , Interleucina-10/imunologia , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Interleucina-8/genética , Interleucina-8/imunologia , Plâncton/genética , Plâncton/fisiologia
4.
Cancer Immunol Immunother ; 68(12): 2029-2039, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31709456

RESUMO

Interferon-stimulated gene 15 (ISG15) is a 15 kDa protein induced by type I interferons (IFN-α and IFN-ß) and is a member of the ubiquitin-like superfamily of proteins. The ISG15 pathway is highly expressed in various malignancies, including pancreatic ductal adenocarcinoma (PDAC), suggesting a potential role of the ISG15 pathway (free ISG15 and ISG15 conjugates) in pancreatic carcinogenesis. However, very little is known about how the ISG15 pathway may contribute to pancreatic tumorigenesis. In the current study, we demonstrate that ISG15 pathway knockdown reverses the KRAS-associated phenotypes of PDAC cells such as increased proliferation and colony formation. Furthermore, clustered regularly interspaced short palindromic repeats (CRISPR)-mediated ISG15 knockdown decreased tumor programmed death ligand-1 (PDL-1) expression leading to increased number of CD8+ tumor-infiltrating lymphocytes and decreased pancreatic tumor growth. In addition, the syngeneic subcutaneous mouse model revealed that knocking down the ISG15 pathway significantly decreased the rate of tumor incidence and increased the survival rate. Interestingly, the ISG15 knockdown-mediated PDL-1 downregulation in pancreatic tumors increased the efficacy of anti-programmed cell death protein-1 (PD-1) treatment. ISG15 knockdown in combination with anti-PD-1 treatment synergistically increased the number of CD8+ tumor-infiltrating lymphocytes. Additionally, ISG15 knockdown alone significantly decreased the number of tumor-infiltrating regulatory T cells (Tregs) compared to wild type tumors treated with anti-PD-1 antibody. Overall, these findings suggest that strategies to target the ISG15 pathway by itself or in combination with immunotherapy may lead to improved survival for patients diagnosed with PDAC.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Linfócitos T CD8-Positivos/imunologia , Citocinas/metabolismo , Imunoterapia/métodos , Neoplasias Pancreáticas/metabolismo , Linfócitos T Reguladores/imunologia , Animais , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Linhagem Celular Tumoral , Transformação Celular Neoplásica , Citocinas/genética , Regulação para Baixo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias Experimentais , Neoplasias Pancreáticas/genética , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , RNA Interferente Pequeno/genética , Transdução de Sinais , Ubiquitinas/genética , Ubiquitinas/metabolismo
5.
Mol Biol (Mosk) ; 53(5): 755-773, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31661476

RESUMO

Dysregulated proinflammatory cytokine expression may result in the development of severe pathologies, such as rheumatoid arthritis, psoriasis, and neurodegenerative diseases. Transgenic mice and, in particular, those with controllable systemic overexpression of proinflammatory cytokines have recently become an essential instrument to study the molecular mechanisms underlying disease development. Importantly, many of the models are humanized by introducing a human cytokine gene, while leaving or removing the respective endogenous mouse gene. Humanized mice are especially valuable for biomedical research as they provide a relevant model to develop therapies based on blocking the pathogenic activity of a cytokine or to establish the functional significance of genome polymorphisms. The review discusses the available humanized mouse models with overexpression of key proinflammatory cytokines (TNF, IL-ip, and IL-6) and inflammatory cytokines with more specific functions (IL-8, IL-17, and IL-32) and their significance for basic and clinical research.


Assuntos
Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Mediadores da Inflamação/metabolismo , Regulação para Cima , Animais , Artrite Reumatoide/genética , Citocinas/biossíntese , Humanos , Camundongos , Camundongos Transgênicos , Doenças Neurodegenerativas/genética , Psoríase/genética
6.
Cell Physiol Biochem ; 53(5): 774-793, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31647207

RESUMO

BACKGROUND/AIMS: Deregulation of the complex interaction among host genetics, gut microbiota and environmental factors on one hand and aberrant immune responses on the other hand, are known to be associated with the development of inflammatory bowel disease. Recent studies provided strong evidence that autophagy plays a key role in the etiology of Crohn's disease (CD). Probiotics may exhibit many therapeutic properties, including anti-inflammatory abilities. While successful results have been obtained in ulcerative colitis patients, probiotics remain inefficient in CD for unknown reason. It remains therefore important to better understand their molecular mechanisms of action. METHODS: The activation of autophagy was examined by stimulating bone marrow-derived dendritic cells by the bacteria, followed by confocal microscopy and western blot analysis. The impact of blocking in vitro autophagy was performed in peripheral blood mononuclear cells using 3-methyl adenine or bafilomycin followed by cytokine secretion measurement by ELISA. The role of autophagy in the anti-inflammatory capacities of the bacterial strains was evaluated in vivo using an acute trinitrobenzene sulfonic acid-induced murine model of colitis. The impact of BMDC was evaluated by adoptive transfer, notably using bone marrow cells derived from autophagy-related 16-like 1-deficient mice. RESULTS: We showed that selected lactobacilli and bifidobacteria are able to induce autophagy activation in BMDCs. Blocking in vitro autophagy abolished the capacity of the strains to induce the release of the anti-inflammatory cytokine interleukin-10, while it exacerbated the secretion of the pro-inflammatory cytokine interleukin-1ß. We confirmed in the TNBS-induced mouse model of colitis that autophagy is involved in the protective capacity of these selected strains, and showed that dendritic cells are involved in this process. CONCLUSION: We propose autophagy as a novel mechanism involved in the regulatory capacities of probiotics.


Assuntos
Autofagia , Bifidobacterium/fisiologia , Lactobacillus/fisiologia , Adenina/análogos & derivados , Adenina/farmacologia , Animais , Proteínas Relacionadas à Autofagia , Células da Medula Óssea/citologia , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Quimiocinas/genética , Quimiocinas/metabolismo , Colite/induzido quimicamente , Colite/microbiologia , Colite/patologia , Citocinas/genética , Citocinas/metabolismo , Células Dendríticas/citologia , Células Dendríticas/metabolismo , Células Dendríticas/microbiologia , Feminino , Humanos , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/metabolismo , Macrolídeos/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout
7.
J Med Microbiol ; 68(11): 1629-1640, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31553301

RESUMO

Introduction. ML1899 is conserved in all mycobacterium sp. and is a middle member of mle-ML1898 operon involved in mycolic acid modification.Aim. In the present study attempts were made to characterize ML1899 in detail.Methodology. Bioinformatics tools were used for prediction of active-site residues, antigenic epitopes and a three-dimensional model of protein. The gene was cloned, expressed and purified as His-tagged protein in Escherichia coli for biophysical/biochemical characterization. Recombinant protein was used to treat THP-1 cells to study change in production of nitric oxide (NO), reactive oxygen species (ROS), cytokines and chemokines using flowcytometry/ELISA.Results. In silico analysis predicted ML1899 as a member of α/ß hydrolase family with GXSXG-motif and Ser126, His282, Asp254 as active-site residues that were confirmed by site-directed mutagensis. ML1899 exhibited esterase activity. It hydrolysed pNP-butyrate as optimum substrate at pH 8.0 and 50 °C with 5.56 µM-1 min-1 catalytic efficiency. The enzyme exhibited stability up to 60 °C temperature and between pH 6.0 to 9.0. K m, V max and specific activity of ML1899 were calculated to be 400 µM, 40 µmoles min-1 ml-1 and 27 U mg- 1, respectively. ML1899 also exhibited phospholipase activity. The protein affected the survival of macrophages when treated at higher concentration. ML1899 enhanced ROS/NO production and up-regulated pro-inflammatory cytokines and chemokine including TNF-α, IFN-γ, IL-6 and IL-8 in macrophages. ML1899 was also observed to elicit humoral response in 69 % of leprosy patients.Conclusion. These results suggested that ML1899, an esterase could up-regulate the immune responses in favour of macrophages at a low concentration but kills the THP-1 macrophages cells at a higher concentration.


Assuntos
Proteínas de Bactérias/imunologia , Esterases/imunologia , Hanseníase/microbiologia , Mycobacterium leprae/enzimologia , Sequência de Aminoácidos , Anticorpos Antibacterianos/imunologia , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Citocinas/genética , Citocinas/imunologia , Estabilidade Enzimática , Esterases/química , Esterases/genética , Feminino , Humanos , Concentração de Íons de Hidrogênio , Cinética , Hanseníase/imunologia , Macrófagos/imunologia , Macrófagos/microbiologia , Masculino , Mycobacterium leprae/química , Mycobacterium leprae/genética , Mycobacterium leprae/imunologia , Óxido Nítrico/imunologia , Espécies Reativas de Oxigênio/imunologia , Alinhamento de Sequência
8.
Exp Parasitol ; 206: 107755, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31493393

RESUMO

The aim of the present study was to assess the expression of cytokines and FCεR1A receptor stimulated by Haemonchus placei larval excretory and secretory (ES) products associated with the pathogenesis in calves. Bovine peripheral blood mononuclear cells (PBMC) were stimulated in in vitro assays with H. placei L4 ES product at 8, 12, 16 and 24 h. ES products were collected in in vitro assays at 48 h with molecular weight of 72/60 kDa and isoelectric point of 7.2 pI. Specific IgG for infected and control calves, positive and negative, were employed to recognise H. placei larval ES products by indirect ELISA, showing a mean of 1.8, 0.83 and 0.28 OD, respectively, (p ≤ 0.001). The quantification of relative gene expression was performed using a set of cytokines (IL-2, IFNγ, TGFß, IL-4, IL-5, IL-6, IL-8, IL-10 and IL-13), FCεR1A receptor and housekeeping (GAPDH, ß-actin and ß-2-microglobulin) by RT-qPCR. An early increased expression, 2.2- to 3.4-fold change, of IL-2 (p ≤ 0.001), IL-5 and TGFß (p ≥ 0.05) was determined, followed by TGFß (30.7 and 14.14), IL-8 (102.8 and 1504.4) and IL-10 (60.4 and 1.7) (p ≤ 0.05) after 12 and 16 h, respectively, and reducing the expression level at 24 h. In addition, IL-6, IL-13 and FCεR1A receptor also displayed mild expression level, 2.1 - to 7.60-fold change, at 24 h (p ≥ 0.05). We conclude that ES products of 72/60 kDa collected in vitro from H. placei larvae are recognised by infected hosts and have the ability to induce diverse immune factors to modulate the nematode damage.


Assuntos
Citocinas/metabolismo , Haemonchus/metabolismo , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/imunologia , Receptores de IgE/metabolismo , Animais , Bovinos , Proliferação de Células/efeitos dos fármacos , Citocinas/genética , Haemonchus/genética , Haemonchus/imunologia , Imunoglobulina G/metabolismo , Larva/genética , Larva/imunologia , Larva/metabolismo , Leucócitos Mononucleares/metabolismo , Masculino , RNA Mensageiro/metabolismo , Regulação para Cima
9.
J Agric Food Chem ; 67(41): 11408-11419, 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31556290

RESUMO

In this study, the effects of 2-O-ß-d-glucopyranosyl-l-ascorbic acid (AA-2ßG), a natural ascorbic acid derivative from the fruits of Lycium barbarum, on treating the dextran sulfate sodium (DSS)-induced colitis in mice were investigated. The results revealed that AA-2ßG had palliating effects on DSS-induced inflammatory bowel disease (IBD) in terms of slowing down the trends of body weight and solid fecal mass loss, reducing colitis disease activity index, improving serum physiological and biochemical indicators, increasing colon length, blocking proinflammatory cytokines, and increasing tight junction proteins. Additionally, AA-2ßG treatment could promote the production of short-chain fatty acids and modulate the composition of the gut microbiota. The key bacteria related to IBD were found to be Porphyromonadaceae, Prevotellaceae, Rikenellaceae, Parasutterella, Parabacteroides, and Clostridium. The results indicated that AA-2ßG might treat IBD through the regulation of gut microbiota, suggesting that AA-2ßG has the potential to be used as a dietary supplement in the treatment of IBD.


Assuntos
Ácido Ascórbico/administração & dosagem , Colite/tratamento farmacológico , Microbioma Gastrointestinal/efeitos dos fármacos , Lycium/química , Extratos Vegetais/administração & dosagem , Animais , Ácido Ascórbico/química , Bactérias/classificação , Bactérias/efeitos dos fármacos , Bactérias/genética , Bactérias/isolamento & purificação , Colite/genética , Colite/imunologia , Colite/microbiologia , Citocinas/genética , Citocinas/imunologia , Sulfato de Dextrana/efeitos adversos , Modelos Animais de Doenças , Frutas/química , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação
10.
Aquat Toxicol ; 215: 105269, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31408752

RESUMO

Blooms of the dominant cyanobacterium Aphanizomenon flosaquae are frequently encountered in natural waters, and their secretion of neurotoxic paralytic shellfish toxins called aphantoxins threatens environmental safety and human health worldwide. The liver is the primary detoxification organ in animals, and its pro- and anti-inflammatory responses are important functions in the detoxification of toxins. Therefore, we investigated the response of these inflammatory factors to aphantoxins in the liver of zebrafish (Danio rerio). A. flosaquae DC-1 was sampled during blooms in Dianchi Lake, China and cultured, and the toxin was extracted and analyzed using high performance liquid chromatography. The primary constituents were gonyautoxins 1 (34.04%) and 5 (21.28%) and neosaxitoxin (12.77%). Zebrafish were injected intraperitoneally with 5.3 µg (low dose) or 7.61 µg (high dose) of saxitoxin equivalents [equivalents (eq.)]/kg body weight of A. flosaquae DC-1 aphantoxins. Hyperemia, the hepatosomatic index (HSI), and physiological and molecular responses of pro- and anti-inflammatory cytokines in the zebrafish liver were investigated at different time points 1-24 h post-exposure. Aphantoxins significantly enhanced hepatic hyperemia and altered the HSI 3-24 h post-exposure, suggesting that inflammation caused morphological changes. Subsequent investigations using the enzyme-linked immunosorbent assay showed that the pro-inflammatory cytokines tumor necrosis factor-α, interleukin-1ß (IL-1ß), IL-6, and IL-8 and anti-inflammatory cytokines IL-10 and transforming growth factor ß were higher in the liver of zebrafish exposed to aphantoxins, which indicated physiological inflammatory responses. Further analysis by real-time fluorescence quantitative polymerase chain reaction demonstrated upregulated mRNA expression of these cytokines, suggesting molecular inflammatory responses in the zebrafish liver. These changes showed dose- and time-dependent patterns. These results indicated that aphantoxins induced hyperemia and altered the HSI, and subsequently increased the levels of proinflammatory cytokines TNF-α, IL-1ß, IL-6 and IL-8 to induce physiological inflammatory responses. These changes activated the anti-inflammatory cytokines IL-10 and TGF-ß to suppress inflammatory damage. The induced changes were the result of upregulated mRNA expression of these inflammatory cytokines caused by aphantoxins. Aphantoxins resulted in hepatic immunotoxicity and response by inducing pro-inflammatory cytokines. Zebrafish liver in turn suppressed the inflammatory damage by upregulating the activities of anti-inflammatory cytokines. In the future, these pro- and anti-inflammatory cytokines in the zebrafish liver may be prove to be useful biomarkers of aphantoxins and blooms in nature.


Assuntos
Anti-Inflamatórios/metabolismo , Aphanizomenon/química , Toxinas Bacterianas/toxicidade , Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Fígado/metabolismo , Toxinas Marinhas/toxicidade , Peixe-Zebra/metabolismo , Animais , Citocinas/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Hiperemia/genética , Hiperemia/patologia , Fígado/efeitos dos fármacos , Masculino , Poluentes Químicos da Água/toxicidade
11.
J Agric Food Chem ; 67(34): 9522-9531, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31379161

RESUMO

The imbalance of T lymphocyte subsets substantially conduces to disturbed intestinal immune system and succeeding colonic tissue damage in inflammatory bowel diseases. It is considered that regulation of phytochemicals on cytokine production potentially provides a broad prospect for the exploitation of immunomodulatory agents. Here, we reported that oral administration of feruloylated oligosaccharides (FOs) effectively alleviated mice colitis disease induced by dextran sulfate sodium (DSS). FOs decreased the percentage of T helper (Th)17 cells and downregulated the production of Th17-specific cytokines. In contrast, FOs increased the percentage of regulatory T (Treg) cells and elevated the production of Treg-specific cytokines in colons of DSS-challenged mice. These results indicated that FOs restored the immunologic equilibrium of Th17 and Treg subsets, hereby ameliorating the deterioration of colitis. Furthermore, FOs diminished the secretion of interleukin (IL)-23 and IL-6 but enhanced the transforming growth factor-ß1 (TGF-ß1) in dendritic cells in vitro and in vivo, which contributed to the restoration of Th17 and Treg cells immune balance. The mechanistic analysis showed that the regulation of FOs on IL-23 and IL-6 was associated with the nuclear factor-κ-gene binding signaling pathway and TGF-ß1 with mitogen-activated protein kinase-activator protein 1 signaling pathway. Taken together, oral administration of FOs exerted potent immunomodulatory effects against mice colitis via restoring the immune balance of Th17 and Treg cells.


Assuntos
Colite/tratamento farmacológico , Oligossacarídeos/administração & dosagem , Animais , Colite/induzido quimicamente , Colite/genética , Colite/imunologia , Citocinas/genética , Citocinas/imunologia , Sulfato de Dextrana/efeitos adversos , Modelos Animais de Doenças , Humanos , Interleucina-23/genética , Interleucina-23/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oligossacarídeos/química , Transdução de Sinais/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Células Th17/imunologia
12.
Life Sci ; 234: 116778, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31430454

RESUMO

AIMS: To clarify the role of the gut-brain axis in depression. MAIN METHODS: We used the iTRAQ technique to identify differential proteins in the intestine of the rat model of chronic unpredictable mild stress (CUMS)-induced depression. Significant differential proteins were subjected to Gene Ontology (GO) functional annotations and KEGG pathway enrichment analysis. Key proteins were validated at the mRNA and protein levels. The levels of cytokines in the intestine, serum and hypothalamus were examined by ELISA. HPLC-UV was used to detect the levels of amino acids. KEY FINDINGS: In the rat intestine, 349 differential proteins (209 downregulated, 140 upregulated) were identified. GO analysis indicated that "protein complex assembly" was the first-ranked biological process. SNARE complex components, including SNAP23, VAMP3 and VAMP8, were increased at the mRNA levels, while only VAMP3 and VAMP8 were also upregulated at the protein level. TNFα, IL6 and IL1ß were upregulated in the CUMS rat intestine, while TNFα was decreased in the serum and hypothalamus. IL1ß was decreased in the serum. "Protein digestion and absorption" was the most significantly enriched KEGG pathway, involving 5 differential proteins: SLC9A3, ANPEP, LAT1, ASCT2 and B0AT1. Glutamine, glycine and aspartic acid were perturbed in the CUMS rat intestine. SIGNIFICANCE: Our findings suggest that CUMS enhances the adaptive immune response in the intestine through ER-phagosome pathway mediated by SNARE complex and disturb absorption of amino acids. It advances our understanding of the role of gut-brain axis in depression and provides a potential therapeutic target for the disease.


Assuntos
Aminoácidos/análise , Citocinas/análise , Depressão/patologia , Mucosa Intestinal/metabolismo , Intestinos/patologia , Proteínas SNARE/análise , Aminoácidos/metabolismo , Animais , Citocinas/genética , Depressão/etiologia , Depressão/genética , Modelos Animais de Doenças , Regulação da Expressão Gênica , Absorção Intestinal , Masculino , Proteômica , Ratos , Ratos Sprague-Dawley , Proteínas SNARE/genética , Estresse Psicológico/complicações
13.
Chem Biodivers ; 16(10): e1900174, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31419039

RESUMO

The advanced glycation end products (AGEs) are the compounds produced by non-enzymatic glycation reaction of proteins and sugars, which can induce the generation of free radicals and the expression of inflammatory factors, thereby playing an important role in vascular dysfunction in diabetes. To investigate the effects of caffeic acid (CA) on glycation formed by glucose and protein, various spectroscopic techniques and molecular docking methods were carried out. Furthermore, the protective effects of CA on human umbilical vein endothelial cells (HUVECs) damaged by AGEs were detected. The results indicated that CA inhibited AGEs formation in vitro, decreased the expression of IL-1ß, IL-18, ICAM-1, VCAM-1, NLRP3, Caspase-1 and CRP (C-reactive protein) and reduced the ROS in HUVECs exposed to AGEs. Our findings suggested that the supplementation with dietary CA could prevent and delay the AGEs-induced vascular dysfunction in diabetes.


Assuntos
Ácidos Cafeicos/farmacologia , Produtos Finais de Glicação Avançada/antagonistas & inibidores , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Inflamação/tratamento farmacológico , Ácidos Cafeicos/química , Células Cultivadas , Citocinas/antagonistas & inibidores , Citocinas/genética , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Produtos Finais de Glicação Avançada/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Inflamação/metabolismo , Simulação de Acoplamento Molecular , Estresse Oxidativo/efeitos dos fármacos , RNA Mensageiro/antagonistas & inibidores , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade
14.
Res Vet Sci ; 125: 390-396, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31412308

RESUMO

Cold-stress causes disturbance of the homeostatic regulation of animals, and gradually impairs the immune and antioxidant functions of animals. Therefore, increasing the effectiveness of the immune response and antioxidant function are the most attractive strategies against cold-stress. Kaempferol (KPF) exerts both an anti-inflammatory and antioxidant pharmacological effect. However, nor much is known of the effects of KPF on providing protection from cold-induced intestinal oxidative damage and improving immunity. This study investigated the effects of KPF on immune factors and intestinal antioxidation in the blood of cold-stressed mice. KPF was solubilized in diluted saline before administration. The mice were randomly divided into 4 groups: (1) control, (2) cold-stress, (3) KPF 25 mg/kg, and (4) cinnamon (CAM) 30 mg/kg groups. Groups (2)-(4) were exposed to cold stress once a day for 7 days. Cold-stress was achieved by exposing the mice to a temperature of -15 °C and 70 ±â€¯10% humidity for 60 min, once a day. The histopathological changes in the small intestine of the mice were analyzed. The T lymphocyte populations in blood were measured using flow cytometry. The level of SLC6a4, 5-HT3 and 5-HTT in small intestine tissue was assessed using RT-PCR analysis. Cow blood samples were obtained for the hematological analysis. Kaempferol (KPF) (25 mg/kg) regularized the intestinal antioxidant activity in the cold stress animals. KPF was able to significantly (P < .05) return intestinal SLC6a4, 5-HT3 and 5-HTT levels to normal after it had increased due to cold-stress. KPF treatment prevented the cold stress-induced decrease in blood CD4+T cells and decrease CD8+T cells levels in mice. Improved hematological profiles were additionally observed on treatment cows with KPF. KPF compared favorably with cinnamon in cold stress management, suggesting cold stress disturbs the anti-inflammatory effect of KPF. Thus, KPF contributes to suppress the activated pro-inflammatory cytokines, IL-9, IL-13, CD8+T and neurochemicals, and to increase anti-inflammatory cytokines and CD4+T levels.


Assuntos
Anti-Inflamatórios/farmacologia , Temperatura Baixa/efeitos adversos , Resposta ao Choque Frio/efeitos dos fármacos , Quempferóis/farmacologia , Animais , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Cinnamomum zeylanicum , Citocinas/genética , Citocinas/imunologia , Citocinas/metabolismo , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Homeostase , Intestinos/efeitos dos fármacos , Camundongos , Distribuição Aleatória
15.
Vet Immunol Immunopathol ; 216: 109920, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31446205

RESUMO

Mycoplasma bovis causes chronic arthritis in calves. Mycoplasma arthritis shows severe inflammatory reactions in joints that is commonly treated with antibiotics and results in significant economic losses in the calf industry. A previous study showed that inflammatory cytokines and matrix metalloproteinases (MMPs) produced by synovial cells promote progression of the pathophysiology of bacterial arthritis. However, the mechanism underlying the pathogenesis of bovine Mycoplasma arthritis has not been fully clarified. In this study, we examined the immunologic response of bovine synovial tissue to M. bovis. We observed significant increases in expression of interleukin (IL)-1ß, IL-6, IL-8, MMP-1, and MMP-3 mRNA in synovial tissue from Mycoplasma arthritis calves compared with tissues from normal calves. Expression of IL-6, IL-8, and MMP-1 mRNA was also induced in cultured synovial cells stimulated with M. bovis, but not expression of IL-1ß and MMP-3 mRNA. In contrast, the culture supernatant of peripheral blood mononuclear cells stimulated with M. bovis induced marked increases in the expression of IL-1ß, IL-6, IL-8, MMP-1, and MMP-3 mRNA in synovial cells. Our results indicate that inflammatory cytokines and MMPs produced by synovial cells play a key role in the pathogenesis of Mycoplasma arthritis. We suggest that interactions between synovial cells and mononuclear cells in the presence of M. bovis induce expression of these cytokines and MMPs in synovial cells, resulting in severe inflammatory reactions in the joints.


Assuntos
Artrite Infecciosa/veterinária , Citocinas/metabolismo , Metaloproteases/metabolismo , Mycoplasma bovis , RNA Mensageiro/metabolismo , Membrana Sinovial/citologia , Animais , Apoptose/fisiologia , Bovinos , Doenças dos Bovinos/imunologia , Doenças dos Bovinos/microbiologia , Células Cultivadas , Citocinas/genética , Metaloproteases/genética , Infecções por Mycoplasma/imunologia , Infecções por Mycoplasma/metabolismo , Infecções por Mycoplasma/microbiologia , Infecções por Mycoplasma/veterinária , RNA Mensageiro/genética
16.
Ecotoxicol Environ Saf ; 183: 109588, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31450035

RESUMO

Lead (Pb) is one of the most hazardous metals to human and wildlife and it also has multiple negative impacts on birds. However, its influences on bird gut morphology and intestinal microbiota were still unclear. We used female Japanese quails (Coturnix japonica) to examine the effects of chronic lead exposure (0, 50 ppm and 1000 ppm) on cecal histology, microbial communities and immune function. The results showed 50 ppm lead exposure caused subtle damages of cecum cell structure. However, 1000 ppm lead exposure caused severe cecum histopathological changes characterized by mucosa abscission, Lieberkühn glands destruction and lymphocyte proliferation. Moreover, both lead concentrations induced ultrastructural damages featured by nucleus pyknosis, mitochondrial vacuolation and microvilli contraction. Meanwhile, microbial community structure, species diversity, taxonomic compositions and taxa abundance in the cecum were affected by lead exposure. Furthermore, the mRNA relative expression of immunity-related genes such as interleukin 2 (IL-2) and gamma interferon (IFN-γ) was significantly downregulated while that of interleukin 6 (IL-6), tumor necrosis factor α (TNF-α) and natural killer kappa B (NF-κB) was significantly upregulated in the cecum of 50 and 1000 ppm lead exposure groups. We concluded that lead exposure may cause gut health impairment of female Japanese quails by inducing cecal histopathological changes, microbiota dysbiosis and cecal immune disorder.


Assuntos
Ceco/efeitos dos fármacos , Coturnix/imunologia , Coturnix/microbiologia , Disbiose/induzido quimicamente , Exposição Ambiental , Microbioma Gastrointestinal/efeitos dos fármacos , Chumbo/toxicidade , Animais , Ceco/imunologia , Ceco/microbiologia , Ceco/patologia , Citocinas/genética , Modelos Animais de Doenças , Feminino
17.
Nat Biotechnol ; 37(10): 1163-1173, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31451733

RESUMO

A major limitation of current humanized mouse models is that they primarily enable the analysis of human-specific pathogens that infect hematopoietic cells. However, most human pathogens target other cell types, including epithelial, endothelial and mesenchymal cells. Here, we show that implantation of human lung tissue, which contains up to 40 cell types, including nonhematopoietic cells, into immunodeficient mice (lung-only mice) resulted in the development of a highly vascularized lung implant. We demonstrate that emerging and clinically relevant human pathogens such as Middle East respiratory syndrome coronavirus, Zika virus, respiratory syncytial virus and cytomegalovirus replicate in vivo in these lung implants. When incorporated into bone marrow/liver/thymus humanized mice, lung implants are repopulated with autologous human hematopoietic cells. We show robust antigen-specific humoral and T-cell responses following cytomegalovirus infection that control virus replication. Lung-only mice and bone marrow/liver/thymus-lung humanized mice substantially increase the number of human pathogens that can be studied in vivo, facilitating the in vivo testing of therapeutics.


Assuntos
Infecções por Coronavirus/virologia , Modelos Animais de Doenças , Pulmão/fisiologia , Infecção por Zika virus/virologia , Animais , Anticorpos Antivirais , Células Apresentadoras de Antígenos , Infecções por Coronavirus/imunologia , Citocinas/genética , Citocinas/metabolismo , Citomegalovirus/fisiologia , Feminino , Regulação da Expressão Gênica , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Camundongos SCID , Coronavírus da Síndrome Respiratória do Oriente Médio/imunologia , Tropismo/imunologia , Replicação Viral , Zika virus/imunologia , Infecção por Zika virus/imunologia
18.
Anticancer Res ; 39(8): 4503-4509, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366552

RESUMO

BACKGROUND/AIM: Oral administration of Pantoea agglomerans-derived lipopolysaccharide (LPSp) has been reported to have a preventive effect against various lifestyle-related diseases. Therefore, we examined the preventive effect on high blood pressure, which is a kind of reserve arm for lifestyle-related diseases. MATERIALS AND METHODS: Spontaneous hypertensive rat (SHR) and WKY rat were bred from 6 to 16 weeks of age. SHR were orally administered 100 µg/kg LPSp and 0.1% NaCl, and blood pressure was measured at 6, 10, 13 and 16 weeks. Furthermore, at 16 weeks of age, blood biochemical markers were measured and microbial community composition was analyzed. RESULTS: SHRs developed hypertension with age, which was exacerbated by salt loading. Although there was almost no reduction in blood pressure in SHRs that received LPSp. It was suppressed at 13-16 weeks of age in those with salt loading. CONCLUSION: Oral administration of LPSp showed a preventive effect on salt-loaded hypertension.


Assuntos
Citocinas/genética , Hipertensão/tratamento farmacológico , Lipopolissacarídeos/administração & dosagem , Pantoea/química , Administração Oral , Animais , Pressão Sanguínea/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Hipertensão/genética , Hipertensão/patologia , Lipopolissacarídeos/química , Masculino , Fagocitose/efeitos dos fármacos , Ratos , Ratos Endogâmicos SHR , Sais/toxicidade
19.
Life Sci ; 233: 116685, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31348947

RESUMO

AIMS: The present study aimed to investigate the effects of laser irradiation on the growth factors and cell apoptosis of in vitro cultured infant hemangioma endothelial cells. MAIN METHODS: Endothelial cells of infant hemangioma were cultured in vitro and irradiated using a variable pulse width 1064 nm Nd:YAG laser and intense pulsed light (IPL), the expression of VEGF, VEGFR-2, bFGF and their mRNAs before and after irradiation were measured by ELISA, western blot, RT-PCR and flow cytometry, and changes in the apoptotic rate of endothelial cells in hemangioma were monitored. KEY FINDINGS: The mRNA and protein expressions of VEGF, VEGFR-2, bFGF in hemangioma endothelial cells were inhibited by both Nd:YAG laser and ILP compared to the control cells. The apoptotic rates of hemangioma endothelial cells were also decreased after both laser irradiation treatments in comparison to the blank group. The differences were statistically significant. SIGNIFICANCE: Laser irradiation treats hemangioma not only through a selective photothermal mechanism, but also through cytokine signaling pathways.


Assuntos
Apoptose/efeitos da radiação , Células Endoteliais/efeitos da radiação , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Hemangioma/metabolismo , Hemangioma/patologia , Terapia a Laser/métodos , Proliferação de Células , Citocinas/genética , Citocinas/metabolismo , Fator 2 de Crescimento de Fibroblastos/genética , Fator 2 de Crescimento de Fibroblastos/metabolismo , Hemangioma/radioterapia , Humanos , Técnicas In Vitro , Lactente , Células Tumorais Cultivadas , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
20.
Nat Commun ; 10(1): 2924, 2019 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-31266950

RESUMO

Fas induces apoptosis in activated T cell to maintain immune homeostasis, but the effects of non-apoptotic Fas signaling on T cells remain unclear. Here we show that Fas promotes TH9 cell differentiation by activating NF-κB via Ca2+-dependent PKC-ß activation. In addition, PKC-ß also phosphorylates p38 to inactivate NFAT1 and reduce NFAT1-NF-κB synergy to promote the Fas-induced TH9 transcription program. Fas ligation exacerbates inflammatory bowel disease by increasing TH9 cell differentiation, and promotes antitumor activity in p38 inhibitor-treated TH9 cells. Furthermore, low-dose p38 inhibitor suppresses tumor growth without inducing systemic adverse effects. In patients with tumor, relatively high TH9 cell numbers are associated with good prognosis. Our study thus implicates Fas in CD4+ T cells as a target for inflammatory bowel disease therapy. Furthermore, simultaneous Fas ligation and low-dose p38 inhibition may be an effective approach for TH9 cell induction and cancer therapy.


Assuntos
Diferenciação Celular , Doenças Inflamatórias Intestinais/imunologia , Transdução de Sinais , Linfócitos T Reguladores/citologia , Receptor fas/imunologia , Animais , Citocinas/genética , Citocinas/imunologia , Feminino , Humanos , Doenças Inflamatórias Intestinais/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Nus , NF-kappa B/genética , NF-kappa B/imunologia , Fatores de Transcrição NFATC/genética , Fatores de Transcrição NFATC/imunologia , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/terapia , Proteína Quinase C beta/genética , Proteína Quinase C beta/imunologia , Linfócitos T Reguladores/imunologia , Receptor fas/genética , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/imunologia
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