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1.
Gene ; 722: 144098, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31494241

RESUMO

This study evaluated the possible association between SNPs in cytokines coding genes, namely IL10, IL6 and IFNG, cytokines serum levels and clinical assessment' scores in patients with Rheumatoid Arthritis(RA). SNPs genotyping was performed in 126 RA patients and 177 healthy individuals with Taqman probes specific for IL10 -1082 (T>C, rs1800896);INFG -1616 (A>G, rs2069705) and IL6 -174 (G>C, rs1800795) variants,positioned in regulatory regions. Cytokine Bead Array (CBA) was used to measure cytokine levels. We found association between INFG -1616 G allele(p = 0.0210; OR = 1.605) and INFG -1616 GG genotype (p = 0.0268; OR =2.609) and RA susceptibility. We also observed association between IL10 -1082 TT genotype and high clinical disease activity index (CDAI) values (p = 0.026; OR = 1.906; 95% CI = 1.082 - 3.359), IL10 -1082 CC genotype and low CDAI values (p = 0.016; OR = 0.256) and INFG -1616 AA and high CDAI values (p = 0.025; OR = 2.919). IL10 -1082 CC also exhibited the lowest IL-10 levels than IL10 -1082 TT (p = 0.020) and IL10 -1082 TC (p = 0.032). Finally, we verified higher IL-6 value in the RA patients than healthy control group (p = 0.007) and an association between high IL-6 levels and increased CDAI (r = 0.4648, p = 0.0015); DAS 28 (r = 0.3933, p= 0.0091), presence of bone erosions (r = 0.3170, p = 0.0361), ESR levels(r = 0.3041, p = 0.0448) and IFN-γ levels (r = 0.3049, p = 0.0468).Altogether, we suggest that IL10 -1082 (T>C, rs1800896) and INFG -1616(A>G, rs2069705) polymorphisms as well as IL-6 levels alterations may play a role for prognostic and disease follow-up.


Assuntos
Artrite Reumatoide/genética , Interferon gama/genética , Interleucina-10/genética , Interleucina-6/genética , Polimorfismo de Nucleotídeo Único , Adulto , Artrite Reumatoide/sangue , Artrite Reumatoide/diagnóstico , Feminino , Frequência do Gene , Genótipo , Humanos , Interferon gama/sangue , Interleucina-10/sangue , Interleucina-6/sangue , Masculino , Pessoa de Meia-Idade
2.
Medicine (Baltimore) ; 98(39): e17167, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31574823

RESUMO

BACKGROUND: The association between plasma interleukin-6 (IL-6) levels and the development of febrile seizures (FS) has been reported in multiple previous studies, which showed significantly higher serum IL-6 levels in FS patients than in control patients. However, the mechanism underlying this association remains unclear. One previous study indicated an increased frequency of the -174 GG and -597 GG genotypes in FS patients. Although IL-6 gene polymorphisms may be associated with FS risk, this association remains a matter of debate. OBJECTIVE: Considering the lack of meta-analyses addressing the possible association between IL-6 gene polymorphisms and the risk of FS, we aimed to perform a meta-analysis to determine the association of IL-6 gene polymorphisms (-572, -174, -597) with the risk of FS. METHODS: We conducted a systematic literature search in the PubMed, EMBASE, and WANFANG databases to collect eligible articles. The associations of IL-6 gene polymorphisms with FS risk were evaluated by calculating the pooled odds ratios and 95% confidence intervals. The dominant, recessive, heterozygous, homozygous, and allele genetic models were used to calculate the combined ORs. RESULTS: Our meta-analysis showed that IL-6 (-572, -174, -597) polymorphisms were significantly associated with susceptibility to FS. CONCLUSION: This study provided knowledge regarding the association of IL-6 (572, 174, 597) polymorphisms with susceptibility to FS. The T allele and TT genotype may be associated with an increased risk for FS.


Assuntos
Predisposição Genética para Doença/genética , Interleucina-6/genética , Polimorfismo Genético , Convulsões Febris/genética , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Masculino , Razão de Chances , Fatores de Risco
3.
J Agric Food Chem ; 67(35): 9796-9804, 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31393712

RESUMO

Overactivated microglia and persistent neuroinflammation hold an important role in the pathophysiology of neurodegenerative diseases. The extract of Lycoris chejuensis (CJ) and its active compound, 7-deoxy-trans-dihydronarciclasine (named E144), attenuated expressions of pro-inflammatory factors, including nitric oxide, prostaglandin E2, inducible nitric oxide synthase, cyclooxygenase-2 (COX-2), tumor necrosis factor α (TNF-α), and interleukin 6, secreted by lipopolysaccharide-activated BV-2 microglial cells, as measured by an enzyme-linked immunosorbent assay or western blotting. In contrast, CJ extract and E144 promoted the secretion of the anti-inflammatory cytokine, interleukin 10. Moreover, we found that E144 attenuated the expression of TNF-α and COX-2 in the cerebral cortex of lipopolysaccharide-treated mice and/or T2576 transgenic mice as well as reduced the reactive immune cells visualized by ionized calcium-binding adaptor molecule 1. Our results suggest the possibility of E144 to serve as a potential anti-neuroinflammatory agent by preventing excess production of pro-inflammatory factors.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/imunologia , Isoquinolinas/administração & dosagem , Lycoris/química , Extratos Vegetais/administração & dosagem , Doença de Alzheimer/genética , Animais , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/imunologia , Modelos Animais de Doenças , Humanos , Interleucina-6/genética , Interleucina-6/imunologia , Isoquinolinas/química , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microglia/efeitos dos fármacos , Microglia/metabolismo , NF-kappa B/genética , NF-kappa B/imunologia , Extratos Vegetais/química , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
4.
J Agric Food Chem ; 67(36): 10069-10078, 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31422663

RESUMO

Macrophage polarization has been implicated in the pathogenesis of obesity and type 2 diabetes, which are recognized as chronic proinflammatory diseases. This study investigated that high level of glucose, similar to lipopolysaccharide (LPS), activated macrophages toward M1 phenotypes and 1-20 µM asaronic acid (AA) counteracted diabetic macrophage activation. AA reduced the LPS-promoted secretion of proinflammatory interleukin (IL)-6 and monocyte chemoattractant protein-1. The LPS markedly elevated the macrophage induction of the M1 markers of Toll-like receptor 4 (TLR4), CD36, and CD68, which was attenuated by AA. Also, the LPS significantly enhanced the nuclear factor (NF)-κB transactivation, signal transducers, and activators of transcription 1 (STAT1)/STAT3 activation and suppressor of cytokine signaling 3 (SOCS3) induction in macrophages. However, AA highly suppressed the aforementioned effects of LPS. Glucose-stimulated macrophages expressed advanced glycation end products (AGEs) and receptor for AGE (RAGE). Administration of 20 µM AA to macrophages partly but significantly attenuated such effects (1.65 ± 0.12 vs 0.95 ± 0.25 times glucose control for AGE; 2.33 ± 0.31 vs 1.40 ± 0.22 times glucose control for RAGE). Furthermore, glucose enhanced the macrophage induction of TLR4 and inducible nitric oxide synthase and IL-6 production, while it demoted the production of anti-inflammatory arginase-1 and IL-10. In contrast, AA reversed the induction of these markers in glucose-loaded macrophages. AA dose-dependently and significantly encumbered NF-κB transactivation, Janus kinase 2 (JAK2) and STAT1/STAT3 activation, and SOCS3 induction upregulated in glucose-supplemented macrophages. These results demonstrated for the first time that AA may limit diabetic macrophage activation toward the M1 phenotype through the inhibition of TLR4-/IL-6-mediated NF-κB/JAK2-STAT signaling entailing AGE-RAGE interaction.


Assuntos
Glucose/imunologia , Janus Quinase 2/imunologia , Macrófagos/efeitos dos fármacos , NF-kappa B/imunologia , Extratos Vegetais/farmacologia , Fator de Transcrição STAT1/imunologia , Fator de Transcrição STAT3/imunologia , Animais , Linhagem Celular , Interleucina-6/genética , Interleucina-6/imunologia , Janus Quinase 2/genética , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , NF-kappa B/genética , Perilla/química , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT3/genética
5.
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
6.
Psychiatr Danub ; 31(2): 241-248, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31291232

RESUMO

BACKGROUND: Posttraumatic stress disorder (PTSD) is a disorder that occurs in some people who have experienced a severe traumatic event. Several genetic studies suggest that gene encoding proteins of catechol-O-methyl-transferase (COMT) may be relevant for the pathogenesis of PTSD. Some researchers suggested that the elevation of interleukin-6 (IL6) correlates with major depression and PTSD. The aim of this study was to investigate whether the single nucleotide polymorphisms COMT rs4680 (Val158Met) and IL6 rs1800795 are associated with PTSD and contribute to the severity of PTSD symptoms. SUBJECTS AND METHODS: This study comprised 747 participants that experienced war between 1991 and 1999 in the South Eastern Europe conflicts. COMT rs4680 (Val158Met) and IL6 rs1800795 genotypes were determined in 719 participants (369 with and 350 without PTSD). The Mini International Neuropsychiatric Interview (M.I.N.I.), the Clinician Administrated PTSD Scale (CAPS) questionnaire and the Brief Symptom Inventory (BSI) were used for data collection. RESULTS: Regarding the COMT gene polymorphism, the results of the regression analyses for BSI total score were significant in the lifetime PTSD group in the dominant (P=0.031) and the additive allelic model (P=0.047). Regarding the IL6 gene, a significant difference was found for the recessive model predicting CAPS total score in the lifetime PTSD group (P=0.048), and indicated an association between the C allele and higher CAPS scores. n the allelic, genotypic and rezessive model, the results for BSI total score were significant in the lifetime PTSD group (P=0.033, P=0.028 and P=0.009), suggesting a correlation of the C allele with higher BSI scores. CONCLUSION: Although our nominally significant results did not withstand correction for multiple tests they may support a relevance of the COMT (Val158Met) and IL6 rs1800795 polymorphism for aspects of PTSD in war traumatized individuals.


Assuntos
Catecol O-Metiltransferase/genética , Interleucina-6/genética , Transtornos de Estresse Pós-Traumáticos/genética , Alelos , Conflitos Armados/psicologia , Europa Oriental , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
7.
Environ Health Prev Med ; 24(1): 48, 2019 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-31301734

RESUMO

AIMS: To investigate the association of four single-nucleotide polymorphisms (SNPs) of the IL-6 gene with osteoporosis (OST) susceptibility. METHODS: PCR restriction fragment length polymorphism (PCR-RFLP) was carried out for SNPs detection. Generalized multifactor dimensionality reduction (GMDR) model and logistic regression model were used to examine the interaction between SNP and obesity on OST. RESULTS: Logistic regression model revealed that G allele of rs1800796 and the T allele of rs2069849 were associated with increased OST risk, compared to those with wild genotype. However, no significant correlations were found when analyzing the association of rs1800795 and rs1554606 with OST risk. GMDR analysis suggested that the interaction model composed of the rs1800796 and obesity was the best model with statistical significance (P value from sign test [Psign] = 0.012), indicating a potential gene-environment interaction between rs1800796 and obesity. Overall, the two-locus models had a cross-validation consistency of 10/10 and had the testing accuracy of 0.641. We also conducted stratified analysis for rs1800796 genotype and obesity, and found that obese subjects with CG or GG genotype have the highest OST risk, compared to subjects with CC genotype, and normal BMI OR (95% CI) = 2.21 (1.52-3.49), after adjustment for age, smoke, and alcohol consumption status. CONCLUSIONS: Our results suggested that the C allele of rs1800796 and the C allele of rs2069849 of IL-6 gene interaction between rs1800796 and abdominal obesity were all associated with increased OST risk.


Assuntos
Interleucina-6/genética , Obesidade/genética , Osteoporose/epidemiologia , Polimorfismo de Nucleotídeo Único , Pós-Menopausa/fisiologia , Idoso , Idoso de 80 Anos ou mais , China , Feminino , Interação Gene-Ambiente , Humanos , Interleucina-6/metabolismo , Pessoa de Meia-Idade , Obesidade/epidemiologia , Obesidade/etiologia , Osteoporose/etiologia , Osteoporose/genética , Pós-Menopausa/genética , Fatores de Risco
8.
Nat Commun ; 10(1): 3055, 2019 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-31296870

RESUMO

KRAS mutations are present in over 90% of pancreatic ductal adenocarcinomas (PDAC), and drive their poor outcomes and failure to respond to targeted therapies. Here we show that Leukemia Inhibitory Factor (LIF) expression is induced specifically by oncogenic KRAS in PDAC and that LIF depletion by genetic means or by neutralizing antibodies prevents engraftment in pancreatic xenograft models. Moreover, LIF-neutralizing antibodies synergize with gemcitabine to eradicate established pancreatic tumors in a syngeneic, KrasG12D-driven, PDAC mouse model. The related cytokine IL-6 cannot substitute for LIF, suggesting that LIF mediates KRAS-driven malignancies through a non-STAT-signaling pathway. Unlike IL-6, LIF inhibits the activity of the Hippo-signaling pathway in PDACs. Depletion of YAP inhibits the function of LIF in human PDAC cells. Our data suggest a crucial role of LIF in KRAS-driven pancreatic cancer and that blockade of LIF by neutralizing antibodies represents an attractive approach to improving therapeutic outcomes.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Fator Inibidor de Leucemia/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Desoxicitidina/uso terapêutico , Feminino , Técnicas de Inativação de Genes , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Fator Inibidor de Leucemia/antagonistas & inibidores , Fator Inibidor de Leucemia/genética , Camundongos , Mutação , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais/genética , Ensaios Antitumorais Modelo de Xenoenxerto
9.
J Agric Food Chem ; 67(30): 8361-8369, 2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31339708

RESUMO

The calcium-sensing receptor (CaSR), a G-protein receptor, is well recognized for its role in the regulation of adipocyte proliferation, in modulating adipose tissue dysfunction, and as a potential target for therapeutic intervention. In the present study, we investigate the anti-inflammatory effect of γ-glutamylvaline (γ-EV) on mouse adipocytes and explore the role of γ-EV-activated CaSR in the regulation of cellular homeostasis using the mouse 3T3-L1 cell line in vitro model. Our results indicate that the 3T3-L1 adipocyte-like cells accumulated lipids and expressed CaSR after 2 days of differentiation and 7 days of maturation period. The pretreatment with γ-EV (10 µM) suppressed the production of TNF-α-induced pro-inflammatory cytokines, i.e., IL-6 (23.92 ± 5.45 ng/mL, p < 0.05)) and MCP-1 (101.17 ± 39.93 ng/mL, p < 0.05), while enhancing the expression of PPARγ (1.249 ± 0.109, p < 0.001) and adiponectin (7.37 ± 0.59 ng/mL, p < 0.05). Elevated expression of Wnt5a was detected in γ-EV-treated cells (115.90 ± 45.50, p < 0.001), suggesting the involvement of the Wnt/ß-catenin pathway. Also, phosphorylation of ß-catenin was shown to be significantly inhibited (0.442 ± 0.034) by TNF-α but restored when cells were pretreated with γ-EV (0.765 ± 0.048, p < 0.05). These findings suggest that γ-EV-induced CaSR activation not only prevents TNF-α-induced inflammation in adipocytes but also modulates the cross-talk between Wnt and PPARγ pathways. Concentrations of serine phosphorylated IRS-1 were shown to be lower in γ-EV-treated cells, indicating γ-EV may also prevent inflammation in the context of insulin resistance. Thus, γ-EV-activated CaSR plays a significant role in the cross-talk between adipocyte inflammatory and metabolic pathways through the regulation of extracellular sensing.


Assuntos
Adipócitos/efeitos dos fármacos , Dipeptídeos/farmacologia , Receptores de Detecção de Cálcio/imunologia , Células 3T3-L1 , Adipócitos/imunologia , Animais , Interleucina-6/genética , Interleucina-6/imunologia , Camundongos , PPAR gama/genética , PPAR gama/imunologia , Fosforilação , Receptores de Detecção de Cálcio/genética , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
10.
Korean J Parasitol ; 57(3): 217-223, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31284343

RESUMO

Acanthamoeba castellanii has ubiquitous distribution and causes primary acanthamoebic keratitis (AK). AK is a common disease in contact lens wearers and results in permanent visual impairment or blindness. In this study, we observed the cytopathic effect, in vitro cytotoxicity, and secretion pattern of cytokines in human corneal epithelial cells (HCECs) induced by A. castellanii trophozoites and/or cysts. Morphological observation revealed that panked dendritic HCECs co-cultured with amoeba cysts had changed into round shape and gradually died. Such changes were more severe in co-culture with cyst than those of co-cultivation with trophozoites. In vitro cytotoxicity assay revealed the highest cytotoxicity to HCECs in the co-culture system with amoeba cysts. A. castellanii induced the expression of IL-1α, IL-6, IL-8, and CXCL1 in HCECs. Secreted levels of IL-1α, IL-6, and IL-8 in HCECs co-cultured with both trophozoites and cysts were increased at an early incubation time (3 and 6 hr). These results suggested that cytopathic changes and pro-inflammatory cytokines release of HCECs in response to A. castellanii, especially amoebic cysts, are an important mechanism for AK development.


Assuntos
Ceratite por Acanthamoeba/imunologia , Acanthamoeba castellanii/fisiologia , Córnea/citologia , Células Epiteliais/imunologia , Trofozoítos/fisiologia , Ceratite por Acanthamoeba/parasitologia , Acanthamoeba castellanii/crescimento & desenvolvimento , Células Cultivadas , Córnea/imunologia , Córnea/parasitologia , Células Epiteliais/parasitologia , Humanos , Interleucina-1/genética , Interleucina-1/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Interleucina-8/genética , Interleucina-8/imunologia , Trofozoítos/crescimento & desenvolvimento
11.
Medicine (Baltimore) ; 98(26): e16029, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31261506

RESUMO

BACKGROUND: To study the occurrence and prognosis of acute respiratory distress syndrome (ARDS) using single nucleotide polymorphisms (SNPs) of TNF-α rs1800629, IL-6 rs1800796, and MyD88 rs7744 loci in the TLR4/NF-κB pathway. METHODS: Genotypes were analyzed for TNF-α rs1800629, IL-6 rs1800796, and MyD88 rs7744 loci. Plasma TNF-α and IL-6 levels and MyD88 mRNA expression in peripheral blood mononuclear cells (PBMCs) of 300 ARDS patients and 300 non-ARDS patients (control group) were examined. The patients were followed up for 60 days, and the prognosis outcome was recorded. RESULTS: The TNF-α rs1800629 locus A allele and the IL-6 rs1800796 locus G allele were found to be risk factors for ARDS (adjusted OR = 1.452, 95% CI: 1.211-1.689, P < .001 and adjusted OR = 1.205, 95% CI: 1.058-1.358, P = .005, respectively). The G allele at MyD88 rs7744 locus was a protective factor against ARDS (adjusted OR = 0.748, 95% CI: 0.631-0.876, P < .001). Compared with the other groups, homozygotes for TNF-α rs1800629, IL-6 rs1800796, and MyD88 rs7744 loci had higher expression levels, of which homozygotes for TNF-α rs1800629 and IL-6 rs1800796 loci had lower 60-day survival rates, while MyD88 rs7744 locus homozygotes had a higher 60-day survival rate. CONCLUSION: The effect of TNF-α rs1800629, IL-6 rs1800796, and MyD88 rs7744 SNPs on gene expression level is a likely cause of ARDS occurrence and poor prognosis.


Assuntos
NF-kappa B/genética , Polimorfismo de Nucleotídeo Único , Síndrome do Desconforto Respiratório do Adulto/genética , Receptor 4 Toll-Like/genética , Fator de Necrose Tumoral alfa/genética , Biomarcadores/sangue , Feminino , Expressão Gênica/genética , Humanos , Interleucina-6/sangue , Interleucina-6/genética , Masculino , Pessoa de Meia-Idade , Fator 88 de Diferenciação Mieloide/sangue , Fator 88 de Diferenciação Mieloide/genética , NF-kappa B/sangue , Prognóstico , RNA Mensageiro/sangue , Síndrome do Desconforto Respiratório do Adulto/sangue , Síndrome do Desconforto Respiratório do Adulto/diagnóstico , Síndrome do Desconforto Respiratório do Adulto/mortalidade , Transdução de Sinais , Análise de Sobrevida , Receptor 4 Toll-Like/sangue , Fator de Necrose Tumoral alfa/sangue
12.
Life Sci ; 232: 116601, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31252000

RESUMO

AIMS: Tet1, Tet2, and interleukin-6 (IL-6) have been linked to atherosclerosis. Whether Tet3 has a relationship with atherosclerosis and IL-6 was unknown. This study aims to determine the link between Tet3 and IL-6, and the role of Tet3 in prenatal hypoxia-induced atherosclerosis in offspring rats. MAIN METHODS: Pregnant rats were divided into hypoxia and control group. Their male offspring were tested at 20 months old. Hematoxylin-eosin staining and transmission electron microscopic staining were used. Gene mRNA and protein levels were measured with q-PCR or Western blotting. Cell viability and migration was tested with MTT or cell scratch assay. 5-hmC and 5-mC expression were obtained by qGlucMS-PCR; 5-hmC and 5-mC activity were obtained by dot blotting. KEY FINDINGS: Chronic prenatal hypoxia increased Tet3 and IL-6 expression, and decreased Tet3 activity in offspring rats. GlucMS-qPCR showed the percentage of 5-hmC was significantly up-regulated in the promoter of IL-6 in both the rats and cells. Moreover, 5-hmC percentage also was increased in the A7r5 cells transfected with Tet3. Furthermore, Tet3 promoted proliferation and migration of A7r5 cells. However, Tet3 was not sensitive to acute hypoxia, while influenced by HIF-1α DNA element. SIGNIFICANCE: Tet3 enhanced IL-6 expression though up-regulating 5-hmC percentage in the IL-6 promoter.


Assuntos
Aterosclerose/metabolismo , Desoxicitidina/análogos & derivados , Dioxigenases/metabolismo , Hipóxia/metabolismo , Interleucina-6/biossíntese , Animais , Aterosclerose/genética , Aterosclerose/patologia , Movimento Celular/fisiologia , Sobrevivência Celular/fisiologia , Desoxicitidina/metabolismo , Epigênese Genética , Feminino , Hipóxia/genética , Hipóxia/patologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Oxigenases de Função Mista/metabolismo , Gravidez , Complicações na Gravidez/metabolismo , Complicações na Gravidez/patologia , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ativação Transcricional , Regulação para Cima
13.
DNA Cell Biol ; 38(8): 874-879, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31215797

RESUMO

Microglia-mediated neuroinflammation plays an important role in Alzheimer's disease development. Resveratrol, a natural polyphenol from the Japanese knotweed (Polygonum cuspidatumand), is known to protect against neuroinflammation, but the mechanism remains unclear. To begin to explore potential mechanisms, we created a model of inflammatory injury in BV-2 murine microglial cells based on the induction of amyloid-ß. We found that resveratrol (10 and 50 nM) significantly inhibited Aß-induced proliferation and activation of BV-2 cells, as well as their release of the proinflammatory cytokines, IL-6 and TNF-α. Resveratrol also suppressed the overexpression of cleaved caspase-1 and IL-1ß, and decreased Aß-stimulated degradation of IkBα and phosphorylation of NF-κB phosphorylation. Western blot analysis showed that Aß upregulated the TXNIP/TRX/NLRP3 pathway, while resveratrol treatment inhibited it. We conclude that resveratrol protects microglia from Aß-stimulated inflammation by suppressing the inflammatory response, at least in part by inhibiting the TXNIP/TRX/NLRP3 signaling pathway.


Assuntos
Proteínas de Transporte/metabolismo , Microglia/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Resveratrol/farmacologia , Tiorredoxinas/metabolismo , Peptídeos beta-Amiloides/toxicidade , Animais , Caspase 1/metabolismo , Linhagem Celular , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Camundongos , Microglia/fisiologia , NF-kappa B/metabolismo , Fármacos Neuroprotetores/farmacologia , Fragmentos de Peptídeos/toxicidade , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
14.
J Sci Food Agric ; 99(13): 6076-6083, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31233219

RESUMO

BACKGROUND: This study was conducted to evaluate the health benefits to weaning pigs, raised under low sanitary conditions, of dietary supplementation with a multi-strain yeast fraction product (Cyberlindnera jadinii and Saccharomyces cerevisiae). In total, 160 weaning pigs (7.21 ± 1.05 kg) were randomly allotted to two dietary treatments in a 6-week feeding trial. The dietary treatments included a corn-soybean meal-based basal diet (CON) and CON + 2 g kg-1 multi-strain yeast fraction product (MsYF) during weeks 1-2 and 0.4 g kg-1 MsYF during weeks 3-6. RESULTS: The MsYF supplementation increased (P < 0.05) body weight (BW) at day 42 and average daily gain (ADG) during days 1-14 and days 1-42 (P < 0.05) compared to CON. The total tract digestibility of dry matter (DM), fecal Lactobacillus counts, and serum immunoglobulin G (IgG) concentration at day 42 were higher (P < 0.05) in pigs fed a MsYF supplemented diet. The concentration of serum haptoglobin in pigs receiving a MsYF-supplemented diet was higher (P < 0.05) at days 7, 14, and 42 than those receiving CON. The mRNA expression for INF-γ and TNF-α genes were lower (P < 0.05) at days 14 and 7 respectively and the expression of IL-6 and TLR-2 genes was lower (P < 0.01) at days 7 and 14 in pigs fed an MsFY supplemented diet than those fed CON. CONCLUSION: Supplementation with a multi-strain yeast fraction product had a positive effect on ADG during the early post-weaning period and led to better health in weaning pigs. © 2019 Society of Chemical Industry.


Assuntos
Saccharomyces cerevisiae/química , Suínos/crescimento & desenvolvimento , Leveduras/química , Ração Animal/análise , Fenômenos Fisiológicos da Nutrição Animal , Animais , Suplementos Nutricionais/análise , Fezes/microbiologia , Microbioma Gastrointestinal , Trato Gastrointestinal/metabolismo , Trato Gastrointestinal/microbiologia , Higiene , Interferon-alfa/genética , Interferon-alfa/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Suínos/genética , Suínos/imunologia , Suínos/microbiologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia , Desmame
15.
Mar Drugs ; 17(6)2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-31151271

RESUMO

In our previous study, a synthetic compound, (+)-(R,E)-6a1, that incorporated the key structures of anti-inflammatory algal metabolites and the endogenous peroxisome proliferator-activated receptor γ (PPAR-γ) ligand 15-deoxy-∆12,14-prostaglandin J2 (15d-PGJ2), exerted significant PPAR-γ transcriptional activity. Because PPAR-γ expressed in macrophages has been postulated as a negative regulator of inflammation, this study was designed to investigate the anti-inflammatory effect of the PPAR-γ agonist, (+)-(R,E)-6a1. Compound (+)-(R,E)-6a1 displayed in vitro anti-inflammatory activity in lipopolysaccharides (LPS)-stimulated murine RAW264.7 macrophages. Compound (+)-(R,E)-6a1 suppressed the expression of proinflammatory factors, such as nitric oxide (NO), inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), possibly by the inhibition of the nuclear factor-κB (NF-κB) pathway. In macrophages, (+)-(R,E)-6a1 suppressed LPS-induced phosphorylation of NF-κB, inhibitor of NF-κB α (IκBα), and IκB kinase (IKK). These results indicated that PPAR-γ agonist, (+)-(R,E)-6a1, exerts anti-inflammatory activity via inhibition of the NF-κB pathway.


Assuntos
Anti-Inflamatórios/farmacologia , Macrófagos/efeitos dos fármacos , NF-kappa B/agonistas , PPAR gama/antagonistas & inibidores , Prostaglandinas Sintéticas/farmacologia , Animais , Ciclo-Oxigenase 2/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Inflamação/induzido quimicamente , Interleucina-6/genética , Lipopolissacarídeos , Camundongos , Óxido Nítrico/genética , Óxido Nítrico Sintase Tipo II/genética , Células RAW 264.7 , Rodófitas/química , Fator de Necrose Tumoral alfa/genética
16.
Cell Physiol Biochem ; 53(1): 49-61, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31169991

RESUMO

BACKGROUND/AIMS: The most prevalent infectious disease, chronic periodontitis which leads to alveolar bone destruction and subsequent tooth loss, develops due to proinflammatory cytokine production induced by periodontopathic bacteria. Chronic obstructive pulmonary disease (COPD), a non-infectious disease, is the third leading cause of death globally. This condition exacerbates frequently, and which is attributable to proinflammatory cytokine production induced by infection by respiratory microorganisms such as Streptococcus pneumoniae. Although a positive association has recently been revealed between chronic periodontitis and COPD, how periodontitis contributes to the pathogenesis of COPD remains unclear. Therefore, we hypothesized that some periodontopathic bacteria are involved in the exacerbation of COPD through the induction of proinflammatory cytokine production by respiratory epithelial cells. In this connection, COPD develops in the airways; however, because most periodontopathic bacteria are anaerobic, they are unlikely to exhibit stable virulence in the lower respiratory organs in humans. Hence, we aimed to elucidate whether exposure to heat-inactivated periodontopathic bacteria induces proinflammatory cytokine production by several human respiratory epithelial cell lines and in the lower respiratory organs and serum in mice. METHODS: Real-time polymerase chain reaction and enzyme-linked immunosorbent assay (ELISA) were used to investigate in vitro induction by heat-inactivated periodontopathic bacteria and S. pneumoniae for mRNA expression and protein production of interleukin (IL)-8 and IL-6 by human respiratory epithelial cell lines. ELISA was also used to determine in vivo induction of cytokine production in the lower respiratory organs and serum of intratracheally heat-inactivated Fusobacterium nucleatum-inoculated mice. RESULTS: Some, but not all, periodontopathic bacteria, especially F. nucleatum, strongly induced IL-8 and IL-6 production by BEAS-2B bronchial epithelial cells. In addition, F. nucleatum induced IL-8 production by A549 alveolar epithelial cells as well as IL-8 and IL-6 production by Detroit 562 pharyngeal epithelial cells. Furthermore, F. nucleatum induced considerably higher cytokine production than S. pneumoniae. This was also observed in the entire lower respiratory organs and serum in mice. CONCLUSION: Exposure to increased number of F. nucleatum potentially induces proinflammatory cytokine production by human bronchial and pharyngeal epithelial cells, which may trigger exacerbation of COPD.


Assuntos
Fusobacterium nucleatum/patogenicidade , Interleucina-6/metabolismo , Sistema Respiratório/microbiologia , Animais , Brônquios/citologia , Linhagem Celular , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Células Epiteliais/microbiologia , Humanos , Interleucina-6/sangue , Interleucina-6/genética , Interleucina-8/sangue , Interleucina-8/genética , Interleucina-8/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Sistema Respiratório/metabolismo , Streptococcus pneumoniae/patogenicidade
17.
J Photochem Photobiol B ; 197: 111538, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31247385

RESUMO

The effects of topically administered snake (Deinagkistrodon acutus) oil and its main fatty acid components on skin photodamage were explored. Epidermal thickness, mice body weight, antioxidant enzymes (superoxide dismutase, glutathione peroxidase, catalase), inflammatory cytokines (tumor necrosis factor alpha and interleukin-6), skin histology, collagen content, and metalloproteinase-1 indicators were analyzed. The results show that topical application of both snake oil and its main fatty acids recovered ultraviolet B (UVB) irradiation induced antioxidant enzymes depletion, prevented metalloproteinase-1. Snake oil and its main fatty acids suppressed dermal infiltration of inflammatory cells and reduced inflammatory cytokines levels. Notably, there was no significant difference in the antioxidant activity but a significant difference in the anti-inflammatory activity between fatty acids and snake oil under the same dose. Finally, snake oil and its main fatty acids inhibited UVB-induced histological damage such as epidermal thickening, collagen fiber and elastic fiber destruction. Our study demonstrated for the first time in KM mice that snake oil exhibited prominent photoprotection activity by protecting the activity of antioxidant enzymes and inhibiting inflammatory factors, as well as reducing the generation of MMP-1. What's more, the main fatty acids in snake oil play an important role in preventing photo-damage especially in protecting antioxidant enzyme activity.


Assuntos
Anti-Inflamatórios/farmacologia , Ácidos Graxos/farmacologia , Óleos Voláteis/química , Pele/efeitos dos fármacos , Serpentes/metabolismo , Raios Ultravioleta , Animais , Anti-Inflamatórios/química , Antioxidantes/metabolismo , Catalase/metabolismo , Citocinas/metabolismo , Epiderme/fisiologia , Ácidos Graxos/química , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Glutationa Peroxidase/metabolismo , Hidroxiprolina/análise , Interleucina-6/genética , Interleucina-6/metabolismo , Metaloproteinase 1 da Matriz/metabolismo , Camundongos , Pele/metabolismo , Pele/patologia , Pele/efeitos da radiação , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
18.
Eur J Med Chem ; 177: 457-466, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31181405

RESUMO

Histone deacetylases (HDACs) play an important role in cancer, degenerative diseases and inflammation. The currently applied HDAC inhibitors in the clinic lack selectivity among HDAC isoforms, which limits their application for novel indications such as inflammatory diseases. Recent, literature indicates that HDAC 3 plays an important role among class I HDACs in gene expression in inflammation. In this perspective, the development and understanding of inhibitory selectivity among HDACs 1, 2 and 3 and their respective influence on gene expression need to be characterized to facilitate drug discovery. Towards this aim, we synthesized nine structural analogues of the class I HDAC inhibitor Entinostat and investigated their selectivity profile among HDACs 1, 2 and 3. We found that we can explain the observed structure activity relationships by small structural and conformational differences between HDAC 1 and HDAC 3 in the 'lid' interacting region. Cell-based studies indicated, however, that application of inhibitors with improved HDAC 3 selectivity did not provide an anti-inflammatory response in contrast to expectations from biochemical evidence in literature. Altogether, in this study, we identified structure activity relationships among class I HDACs and we connected isoform selectivity among class I HDACs with pro- and anti-inflammatory gene transcription in macrophages.


Assuntos
Anilidas/farmacologia , Benzamidas/farmacologia , Expressão Gênica/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Macrófagos/efeitos dos fármacos , Anilidas/síntese química , Anilidas/química , Anilidas/metabolismo , Animais , Benzamidas/síntese química , Benzamidas/química , Benzamidas/metabolismo , Domínio Catalítico , Histona Desacetilase 1/química , Histona Desacetilase 1/metabolismo , Histona Desacetilase 2/metabolismo , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/metabolismo , Histona Desacetilases/química , Histona Desacetilases/metabolismo , Humanos , Inflamação/genética , Interleucina-10/genética , Interleucina-6/genética , Camundongos , Simulação de Acoplamento Molecular , Subunidade p50 de NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Ligação Proteica , Células RAW 264.7 , Estereoisomerismo , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/genética
19.
J Exp Clin Cancer Res ; 38(1): 189, 2019 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-31072375

RESUMO

BACKGROUND: Hepatocellular carcinoma (HCC) is still the most common cause of tumor-related death worldwide and accumulating studies report that long non-coding RNAs (LncRNAs) are closely related with HCC development, metastasis and prognosis. Cisplatinum, a well-known chemotherapeutic drug, has been widely used for treatment of numerous human cancers including HCC. This study aimed to investigate the differential expressions of LncRNAs in HCC cells treated with cisplatinum and its underlying mechanism. METHODS: The differential expressions of LncRNAs in HCC cells treated with cisplatinum were determined by RNA-seq. The roles of TPTEP1 in HCC development by applying gene function gain and loss analysis in MHCC97H and QYG-7703 cell lines were detected by quantitative real-time polymerase chain reaction (qRT-PCR), cell proliferation, colony formation, cell invasion and flow cytometry assays. The underlying mechanism of TPTEP1 sensitizing hepatocellular carcinoma cells to cisplatinum was examined by RNA-pull down, western blotting, subcellular fractionation, RNA immunoprecipitation and dual luciferase reporter assays. The effect of TPTEP1 on tumorigenesis in vivo was performed with a subcutaneous xenograft mouse model of HCC. In addition, TPTEP1 expression was detected in clinical tumor tissue samples by qRT-PCR. RESULTS: LncRNA TPTEP1 was highly expressed in cisplatinum-treated HCC cells, which sensitizes hepatocellular carcinoma cell to cisplatinum-induced apoptosis. TPTEP1 overexpression inhibited, while TPTEP1 knockdown promoted HCC cell proliferation, tumorigenicity and invasion. Furthermore, TPTEP1 exerted its tumor suppressing activities by interacting with signal transducer and activator of transcription 3 (STAT3) to inhibit its phosphorylation, homodimerization, nuclear translocation and down-stream genes transcription. Moreover, TPTEP1 overexpression obviously inhibits tumor masses in vivo in a subcutaneous xenograft mouse model of HCC and TPTEP1 is frequently downregulated in HCC tissues, compared to its corresponding pre-tumor tissues. CONCLUSION: LncRNA TPTEP1 inhibits hepatocellular carcinoma cells progression by affecting IL-6/STAT3 signaling. Taken together, our findings suggest a tumor suppressing role of TPTEP1 in HCC progression and provide a novel understanding of TPTEP1 during the chemotherapy for HCC.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Cisplatino/administração & dosagem , Neoplasias Hepáticas/tratamento farmacológico , RNA Longo não Codificante/genética , Fator de Transcrição STAT3/genética , Animais , Apoptose/efeitos dos fármacos , Carcinogênese/efeitos dos fármacos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Progressão da Doença , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Interleucina-6/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Camundongos , Fosforilação , Prognóstico , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Environ Pollut ; 251: 564-572, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31108289

RESUMO

The phenylpyrazole insecticide, fipronil, isused for the eradication of insects in agriculture, which also exposes various non-target groups such as birds and animals. Our aim was to assess the cardiac and pulmonary consequences of sub-acute administration of fipronil (1∕5 LD50; 2.26 mg/kg) in the Japanese quail for fifteen days and to determine the tissue recovery over a period of 60 days. Fipronil exposure led to a significant decrease in the body weight of the treated birds. Its exposure also induced cardiac and pulmonary damage of varying degrees. Fipronil increased the lipid peroxide (LPO) and nitric oxide (NO) contents as well as indices of tissue injury in the serum of exposed birds. Furthermore, it decreased the antioxidant indices in both the organs. Most of these changes gradually reversed and the histological changes, particularly of the heart, reversed completely by day-60 of recovery. Furthermore, alterations in the mRNA gene expressions of Nuclear factor kappa B (NF-κB), Interleukin 6 (IL-6), and Tumor necrosis factor-alpha (TNF-α) were monitored by quantitative polymerase chain reaction (RT-PCR). In both the tissues, a significant up-regulation of the transcripts was recorded after fipronil administration, which was reversed during the recovery period in the heart tissue except for TNF-α, while the transcripts in the lung tissue declined non-significantly. This study showed that the exposure of Japanese quail to fipronil has a profound negative impact on heart and lung including oxidative injury and tissue inflammation. Fipronil can induce the activity of NF-κB inflammatory -signaling pathway that play a role in the associated tissue inflammation. Although most of the cardiac changes could be reversed after a recovery period of sixty days, the pulmonary changes did not reverse much.


Assuntos
Coturnix/genética , Expressão Gênica/efeitos dos fármacos , Coração/efeitos dos fármacos , Inseticidas/toxicidade , Pulmão/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Pirazóis/toxicidade , Animais , Antioxidantes/metabolismo , Inflamação , Interleucina-6/genética , Pulmão/imunologia , Pulmão/metabolismo , Masculino , Miocárdio/imunologia , Miocárdio/metabolismo , NF-kappa B/genética , Estresse Oxidativo/genética , RNA Mensageiro/metabolismo , Transdução de Sinais , Testes de Toxicidade , Fator de Necrose Tumoral alfa/genética
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