Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 9.850
Filtrar
1.
Anticancer Res ; 39(8): 4475-4478, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366547

RESUMO

Chronic inflammation is involved in the development of cancer, lifestyle-related diseases, and autoimmune diseases. It also influences the severity of these diseases. Macrophages that accumulate in tumor tissues and adipose tissues of obesity have been shown to increase expression of inflammatory cytokines, thereby inducing inflammatory changes in these tissues. The macrophage phenotype is believed to be important in mediating inflammatory changes in tissues. Recently, monocytes/macrophages activated with low-dose lipopolysaccharide (LPS) were demonstrated to suppress increased expression of monocyte chemotactic protein (MCP)-1 and inflammatory cytokines (interleukin (IL)-1 ß, IL-8, and tumor necrosis factor (TNF)-α). By suppressing the increased expression of chemotaxis-related and inflammation-related factors, monocytes/macrophages activated with low-dose LPS are considered to suppress the migration of macrophages into tissues and to regulate inflammatory changes in these tissues, respectively. The effects of macrophages activated with low-dose LPS were different from those of macrophages activated with high-dose LPS. In this review, we discuss the usefulness of monocytes/macrophages activation by low-dose LPS.


Assuntos
Inflamação/tratamento farmacológico , Lipopolissacarídeos/uso terapêutico , Neoplasias/tratamento farmacológico , Obesidade/genética , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Quimiocina CCL2/genética , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Inflamação/genética , Interleucina-1beta/genética , Interleucina-8/genética , Macrófagos/efeitos dos fármacos , Monócitos/efeitos dos fármacos , Neoplasias/genética , Obesidade/patologia , Fator de Necrose Tumoral alfa/genética
2.
Anticancer Res ; 39(8): 4491-4494, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366550

RESUMO

BACKGROUND/AIM: High-mobility group box 1 (HMGB1) is a nuclear DNA-binding protein that exerts a range of proinflammatory actions when it is secreted extracellularly. We hypothesized that HMGB1 released from damaged cells in pituitary apoplexy would exacerbate the neurological symptoms due to acute inflammation. PATIENTS AND METHODS: All the patients included in this study suffered from non-functioning pituitary adenoma. Four patients with apoplexy and three patients without apoplexy were included in this study. They underwent endonasal transsphenoidal endoscopic surgery to resect the tumors. We conducted enzyme-linked immunosorbent assay (ELISA) to measure HMGB1 in the surgical specimens. RESULTS: Patients with apoplexy expressed HMGB1 at significantly higher levels than those in the non-apoplexy group (p=0.0478). CONCLUSION: HMGB1 may be involved in subacute inflammation of pituitary apoplexy. Further work is needed to elucidate the detailed biological significance of HMGB1 in this disease.


Assuntos
Proteína HMGB1/genética , Inflamação/genética , Apoplexia Hipofisária/genética , Neoplasias Hipofisárias/genética , Adenoma/genética , Adenoma/patologia , Adenoma/cirurgia , Adulto , Endoscopia , Ensaio de Imunoadsorção Enzimática , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Inflamação/diagnóstico por imagem , Inflamação/patologia , Inflamação/cirurgia , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Apoplexia Hipofisária/diagnóstico por imagem , Apoplexia Hipofisária/patologia , Apoplexia Hipofisária/cirurgia , Neoplasias Hipofisárias/diagnóstico por imagem , Neoplasias Hipofisárias/patologia , Neoplasias Hipofisárias/cirurgia
3.
Life Sci ; 234: 116747, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31408661

RESUMO

AIMS: The present study was aimed to investigate the neuroprotective effect of HSP70 against neuroinflammation in a rotenone-induced Parkinson's disease model. MATERIALS AND METHODS: In the present study, SH-SY5Y cells were treated with HSP70 (5-20 mg/L) for 72 h. Cell viability, reactive oxygen species (ROS) levels, mitochondrial membrane potential (MMP), levels of oxidative markers, mitochondrial fragmentation, apoptosis, and mRNA and protein expressions of signal transducer and activator of transcription (STAT)-3 and nuclear factor-kappa B (NF-κB) were assessed. KEY FINDINGS: Cells treated with 5, 10, 15, and 20 mg/L of HSP70 exhibited increased, by 61.7%, 70.3%, 84.6%, and 96.7%, respectively, in cell viability. ROS and lipid peroxidation levels decreased following treatment with HSP70, and reductions in glutathione (GSH), catalase, glutathione peroxidase (Gpx), and superoxide dismutase (SOD) levels were reversed following treatment with HSP70. Additionally, MMP levels were reduced by 29.7, 46.4, 79.5, and 125.2 relative units following treatment with 5-20 mg/L of HSP70, respectively. HSP70 treatment also decreased levels of fragmented mitochondria and apoptosis, and mRNA and protein expressions of NF-κB and STAT3 were reduced by >25%. SIGNIFICANCE: Taken together, these findings indicate that supplementation with HSP70s recovered cell viability and MMP and reduced levels of ROS, apoptosis, and mitochondrial fragmentation. Additionally, supplementation with HSP70 significantly reduced the expressions of STAT3 and NF-κB.


Assuntos
Regulação para Baixo/efeitos dos fármacos , Proteínas de Choque Térmico HSP70/farmacologia , Inflamação/tratamento farmacológico , NF-kappa B/genética , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson Secundária/tratamento farmacológico , Fator de Transcrição STAT3/genética , Apoptose/efeitos dos fármacos , Linhagem Celular , Humanos , Inflamação/genética , Doença de Parkinson Secundária/genética , RNA Mensageiro/genética , Rotenona
4.
High Blood Press Cardiovasc Prev ; 26(4): 321-329, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31325087

RESUMO

Cardiovascular disease (CVD) remains the leading cause of morbility and mortality worldwide. The identification of common cardiovascular risk factors has led to the development of effective treatments that enabled a significant reduction of the global cardiovascular disease burden. However, a significant proportion of cardiovascular risk remains unexplained by these risk factors leaving many individuals at risk of cardiovascular events despite good control of the risk factors. Recent randomized clinical trials and Mendelian randomization studies have suggested that inflammation explains a significant proportion of the residual cardiovascular risk in subjects with good control of risk factors. An accelerated process of vascular ageing is increasingly recognized as a potential mechanism by which inflammation might increase the risk of CVD. In turn, cellular ageing represents an important source of inflammation within the vascular wall, potentially creating a vicious cycle that might promote progression of atherosclerosis, independently from the individual cardiovascular risk factor burden. In this review, we summarise current evidence suggesting a role for biological ageing in CVD and how inflammation might act as a key mediator of this association.


Assuntos
Envelhecimento/metabolismo , Doenças Cardiovasculares/metabolismo , Mediadores da Inflamação/metabolismo , Inflamação/metabolismo , Telômero/metabolismo , Fatores Etários , Envelhecimento/genética , Envelhecimento/patologia , Animais , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/patologia , Doenças Cardiovasculares/fisiopatologia , Senescência Celular , Humanos , Inflamação/genética , Inflamação/patologia , Inflamação/fisiopatologia , Medição de Risco , Fatores de Risco , Transdução de Sinais , Telômero/genética , Telômero/patologia , Homeostase do Telômero , Encurtamento do Telômero , Fatores de Tempo
5.
J Agric Food Chem ; 67(32): 8794-8809, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31345023

RESUMO

Oxidative stress may play a critical role in the progression of liver disorders. Increasing interest has been given to the associations among diet, oxidative stress, gut-liver axis, and nonalcoholic fatty liver disease. Here, we investigated the effects of processed meat proteins on biomarkers of lipid homeostasis, hepatic metabolism, antioxidant functions, and gut microbiota composition in glutaredoxin1 deficient (Glrx1-/-) mice. The wild-type (WT) and Glrx1-/- mice were fed a soy protein diet (SPD), a dry-cured pork protein diet (DPD), a braised pork protein diet (BPD), and a cooked pork protein diet (CPD) at a dose of 20% of protein for 3 months. Serum and hepatic total cholesterol, serum endotoxin, hepatic liver droplet %, and antioxidant capacity were significantly increased in the CPD fed WT mice. In addition, CPD fed Glrx1-/- mice significantly increased total cholesterol, triacylglycerol, and pro-inflammatory cytokines which are accompanied by higher steatosis scores, intrahepatic lipid accumulation, and altered gene expression associated with lipid metabolism. Furthermore, hepatic gene expression of Nrf2/keap1 signaling pathway and its downstream signaling targets were determined using RT-qPCR. Glrx1 deficiency increased Nrf2 activity and expression of its target genes (GPx, catalase, SOD1, G6pd, and Bbc3), which was exacerbated by intake of CPD. Metagenomic analyses revealed that Glrx1-/- mice fed meat protein diets had higher abundances of Mucispirillum, Oscillibacter, and Mollicutes but lower abundances of Bacteroidales S24-7 group_norank, Blautia, and Anaerotruncus than their wild-type counterparts. In summary, Glrx1 deficiency induced an increase in serum biomarkers for lipid homeostasis, gut microbiota imbalance, and upregulation of Nrf2/Keap1 and antioxidant defense genes, which was aggravated by cooked meat protein diet.


Assuntos
Glutarredoxinas/genética , Inflamação/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Lipogênese , Fígado/metabolismo , Produtos da Carne/efeitos adversos , Fator 2 Relacionado a NF-E2/metabolismo , Animais , Colesterol/sangue , Citocinas/metabolismo , Feminino , Microbioma Gastrointestinal , Glutarredoxinas/deficiência , Humanos , Inflamação/genética , Inflamação/imunologia , Inflamação/microbiologia , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 2 Relacionado a NF-E2/genética , Carne Vermelha , Transdução de Sinais , Triglicerídeos/sangue
6.
Nat Commun ; 10(1): 2955, 2019 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-31273203

RESUMO

Dendritic cells (DCs), a vital component of the innate immune system, are considered to lack antigen specificity and be devoid of immunological memory. Strategies that can induce memory-like responses from innate cells can be utilized to elicit protective immunity in immune deficient persons. Here we utilize an experimental immunization strategy to modulate DC inflammatory and memory-like responses against an opportunistic fungal pathogen that causes significant disease in immunocompromised individuals. Our results show that DCs isolated from protectively immunized mice exhibit enhanced transcriptional activation of interferon and immune signaling pathways. We also show long-term memory-like cytokine responses upon subsequent challenge with the fungal pathogen that are abrogated with inhibitors of specific histone modifications. Altogether, our study demonstrates that immunization strategies can be designed to elicit memory-like DC responses against infectious disease.


Assuntos
Células Dendríticas/imunologia , Memória Imunológica , Animais , Criptococose/imunologia , Criptococose/microbiologia , Cryptococcus/fisiologia , Células Dendríticas/microbiologia , Feminino , Histonas/metabolismo , Imunidade Inata , Inflamação/genética , Inflamação/patologia , Interferon gama/metabolismo , Pulmão/imunologia , Pulmão/microbiologia , Camundongos Endogâmicos BALB C , Fenótipo , Processamento de Proteína Pós-Traducional , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Vacinação
7.
Vet Microbiol ; 235: 53-62, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31282379

RESUMO

Nucleases are ubiquitously recognized as essential proteins in mycoplasmas because these organisms lack most capacities for de novo synthesis of nucleotides. Some of these proteins were proved to be important pathogenic factors during the infection of mycoplasms. In this study, the protein Mhp597 from M. hyopneumoniae was expressed and purified in Escherichia coli. Analysis of nuclease activity showed that recombinant Mhp597 (rMhp597) was a Ca2+ or Mg2+ dependent thermostable nuclease with very high activity and neutrophil extracellular traps (NETs) induced by M. hyopneumoniae were completely degraded by this nuclease. In addition, when PK15 cells were incubated with different concentrations of rMhp597, their viability was reduced and cell apoptosis was observed in a dose-dependent manner. To further investigate the host immune system response, we report that rMhp597 up-regulated the exression of inflammatory genes showing that TLR4/MyD88/NF-κB signal pathway was involved. On the other hand, rMhp597 down-regulated the expression of type I IFN (IFN-α/ß) and promoted the multiplication of porcine reproductive and respiratory syndrome virus (PRRSV). Recombinant rMhp597δ315-377 lacking C-terminal 63 amino acids exhibited all biological functions mentioned above except for nuclease activity. In summary, Mhp597 is a dynamic secreted nuclease involved in cytotoxicity, inflammation and immunosuppression.


Assuntos
Proteínas de Bactérias/imunologia , Inflamação/genética , Nuclease do Micrococo/imunologia , Mycoplasma hyopneumoniae/enzimologia , Mycoplasma hyopneumoniae/imunologia , Animais , Apoptose , Proteínas de Bactérias/genética , Sobrevivência Celular/efeitos dos fármacos , Escherichia coli/genética , Interferon Tipo I/genética , Nuclease do Micrococo/genética , Vírus da Síndrome Respiratória e Reprodutiva Suína/fisiologia , Transdução de Sinais , Suínos , Replicação Viral
8.
Biochimie ; 163: 152-162, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31199942

RESUMO

Extra-cellular signal regulated kinase-5 (Erk-5), a transcriptional activator and regulator of endothelial cells (ECs) homeostasis, has been implicated in shear stress-induced endothelial dysfunction (ED), however its role in oxidized low-density lipoprotein (oxLDL)- induced ED during metabolic stress is not known. Herein, regulation and function of Erk-5 in oxLDL-induced EC death, inflammation and dysfunction has been investigated. Primary Human Umbilical Vein Endothelial Cells (pHUVECs) were stimulated with oxLDL. MTT and Trypan blue exclusion assays to assess cell viability, RT-qPCR and Western blotting assays to determine expression of endothelial and inflammatory markers and ED mediators at mRNA and protein levels, respectively were performed. Monocyte adhesion assay was performed to examine monocytes adherence to oxLDL-stimulated pHUVECs. The exposure of oxLDL induced a dose- and time-dependent decrease in pHUVECs viability, which concurred with decreased Erk-5 expression. Further, oxLDL (100 µg/ml) decreased the expression of endothelial markers eNOS and vWF, and increased the expression of ICAM-1, at both mRNA and protein levels. SiRNA-mediated silencing of Erk-5 or its inhibition showed that changes in eNOS, vWF and ICAM-1 expression could be mediated through Erk-5. Furthermore, oxLDL decreased the levels of Erk-5's upstream regulator MEK5 and downstream regulators Mef2c and KLF2, which were similar to their expressions in Erk-5 silenced cells. Fisetin, a phytochemical and bioflavonoid, could reduce the effect of oxLDL in ECs by upregulating the expression of endothelial markers including Erk-5, and downregulating the expression of inflammation markers. These results suggest that Erk-5 could be a critical regulator of oxLDL-induced EC death, inflammation and dysfunction via downregulation of Erk-5/Mef2c-KLF2 signaling pathway, which can be ameliorated by a bioflavonoid, fisetin.


Assuntos
Flavonoides/farmacologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Lipoproteínas LDL/toxicidade , Proteína Quinase 7 Ativada por Mitógeno/metabolismo , Monócitos/fisiologia , Transdução de Sinais , Aterosclerose/induzido quimicamente , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/prevenção & controle , Células Cultivadas , Regulação da Expressão Gênica , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Inflamação/induzido quimicamente , Inflamação/genética , Inflamação/metabolismo , Inflamação/prevenção & controle , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Lipoproteínas LDL/farmacologia , Fatores de Transcrição MEF2/genética , Fatores de Transcrição MEF2/metabolismo , Óxido Nítrico Sintase Tipo III/genética , Substâncias Protetoras/farmacologia
9.
Environ Pollut ; 246: 963-971, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31159146

RESUMO

Bisphenol S (BPS) has been widely used as a bisphenol alternative in recent few years. However, with mounting evidence suggesting that the presence of BPS in the environment also poses risks to ecosystems and human health, we decided to use the juvenile common carp (Cyprinus carpio) and its primary macrophages as in vivo and in vitro models to examine if BPS is a safe substitute of BPA. The present study evaluated the immune responses of chronic BPS exposure and their mechanisms of action associated with peroxisome proliferator-activated receptor (PPAR) signaling pathway. Potential oxidative stress and pro-inflammatory effects of BPS exposure were identified in fish liver after 60-day exposure, based on the increased reactive oxygen species (ROS) production, antioxidant capacity, NO production, lipid peroxidation, and induction of inflammatory cytokine expression, as well as acute phase protein levels of C-reactive protein, immunoglobulin M, lysozyme, and complement component 3. Moreover, pparγ, PPAR pathway-associated genes retinoid x receptor α (rxrα) and nuclear factor-κb (nfκb) presented a rough concentration-dependent alteration after BPS exposure. An acute BPS exposure to the isolated primary macrophages from juvenile common carp was performed to help elucidate gene expression patterns of pparγ, rxrα, and nfκb in a typical immune cell model, the results were consistent with what we found in vivo experiments for long-term BPS exposure. Furthermore, with coexposure to BPS and a PPARγ antagonist, the restriction of PPAR signaling pathway significantly inhibited the induction of ROS and the mRNA level of interleukin-1ß, confirming the involvement of PPAR pathway in BPS-induced chronic inflammatory stress in liver.


Assuntos
Poluentes Ambientais/toxicidade , Inflamação/metabolismo , Fígado/efeitos dos fármacos , PPAR gama/metabolismo , Fenóis/toxicidade , Sulfonas/toxicidade , Animais , Carpas/imunologia , Carpas/metabolismo , Inflamação/genética , Fígado/imunologia , Fígado/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/imunologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética
10.
Cell Physiol Biochem ; 53(1): 1-18, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31162913

RESUMO

BACKGROUND/AIMS: Innate immune toll-like receptors (TLRs) are emerging as nutrient sensors. Oxidative stress in the adipose tissue in obesity acts as a critical early trigger of altered pathophysiology. TLR2/TLR4 adipose upregulation has been associated with insulin resistance in humans; however, it remains unclear whether oxidative stress can modulate expression of TLR2/4 and related immune-metabolic regulators (IRF3/5) in immune cells. We, therefore, assessed their expression along with proinflammatory cytokines in the human PBMC following induction of oxidative stress. METHODS: PBMC were isolated from blood of healthy donors using Ficoll-Paque method and cells were treated with H2O2 to induce oxidative stress. ROS was measured by DCFH-DA assay. Target gene and protein expression was determined using real-time RT-PCR and flow cytometry/confocal microscopy, respectively. TLR2/4 expression by H2O2 in presence of ROS-inhibitors or leptin/LPS/fatty acids was also assessed. Expression of phosphorylated/total ERK1/2, c-Jun, p38, and NF-κB was determined by western blotting. The data (mean±SEM) were compared using unpaired student's t-test or ANOVA; all P-values <0.05 were considered significant. RESULTS: TLR2/4 mRNA/protein expression was elevated by oxidative stress in PBMC compared to controls (P<0.001). This induction was abrogated by apocynin/N-acetyl cysteine treatments (P<0.01). H2O2-induced TLR2/4 gene expression was further enhanced by leptin, LPS, oleate, or palmitate (P<0.05). Oxidative stress also promoted expression of IRF3/5 and proinflammatory cytokines including IFN-γ, IL-1ß, IL-6, TNF-α, and MCP-1/CCL2. This oxidative stress in PBMC involved MAPK/NF-κB dependent signaling. CONCLUSION: Taken together, oxidative stress upregulates expression of TLR2/4, IRF3/5 and signature proinflammatory cytokines in PBMC, involving MAPK/NF-κB dependent signaling, all of which may have implications for metabolic inflammation.


Assuntos
Inflamação/genética , Estresse Oxidativo , Receptor 2 Toll-Like/genética , Receptor 4 Toll-Like/genética , Regulação para Cima , Células Cultivadas , Humanos , Inflamação/metabolismo , Fator Regulador 3 de Interferon/genética , Fatores Reguladores de Interferon/genética , Leucócitos Mononucleares/metabolismo , Espécies Reativas de Oxigênio/metabolismo
11.
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
12.
Biochim Biophys Acta Rev Cancer ; 1872(1): 89-102, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31202687

RESUMO

Metastasis is a complex systemic disease that develops as a result of interactions between tumor cells and their local and distant microenvironments. Local and systemic immune-related changes play especially critical roles in limiting or enabling the development of metastatic disease. Although anti-tumor immune responses likely eliminate most early primary and metastatic lesions, factors secreted by cancer or stromal cells in the primary tumor can mobilize and activate cells in distant organs in a way that promotes the outgrowth of disseminated cancer cells into macrometastatic lesions. Therefore, the prevention, detection, and effective treatment of metastatic disease require a deeper understanding of the systemic effects of primary tumors as well as predisposing hereditary and acquired host factors including chronic inflammatory conditions. The success of immunotherapy in a subset of cancer patients is an example of how modulating the microenvironment and tumor-immune cell interactions can be exploited for the effective eradiation of even advanced-stage tumors. Here, we highlight emerging insights and clinical implications of cancer as a systemic disease.


Assuntos
Imunoterapia , Inflamação/genética , Metástase Neoplásica/genética , Neoplasias/genética , Comunicação Celular/genética , Comunicação Celular/imunologia , Humanos , Imunidade Inata/genética , Inflamação/imunologia , Inflamação/terapia , Metástase Neoplásica/imunologia , Metástase Neoplásica/terapia , Neoplasias/imunologia , Neoplasias/terapia , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
13.
Nat Commun ; 10(1): 2011, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31043609

RESUMO

TET enzymes oxidize 5-methylcytosine to 5-hydroxymethylcytosine and other oxidized methylcytosines in DNA. Here we examine the role of TET proteins in regulatory T (Treg) cells. Tet2/3fl/flFoxp3Cre mice lacking Tet2 and Tet3 in Treg cells develop inflammatory disease, and Treg cells from these mice show altered expression of Treg signature genes and upregulation of genes involved in cell cycle, DNA damage and cancer. In littermate mice with severe inflammation, both CD4+Foxp3+ and CD4+Foxp3- cells show strong skewing towards Tfh/Th17 phenotypes. Wild-type Treg cells in mixed bone marrow chimeras and in Tet2/3fl/flFoxp3WT/Cre heterozygous female mice are unable to rescue the aberrant properties of Tet2/3fl/flFoxp3Cre Treg cells. Treg cells from Tet2/3fl/flFoxp3Cre mice tend to lose Foxp3 expression, and transfer of total CD4+ T cells isolated from Tet2/3fl/flFoxp3Cre mice could elicit inflammatory disease in fully immunocompetent mice. Together, these data indicate that Tet2 and Tet3 are guardians of Treg cell stability and immune homeostasis.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Inflamação/imunologia , Proteínas Proto-Oncogênicas/metabolismo , Linfócitos T Reguladores/imunologia , Transferência Adotiva , Animais , Transplante de Medula Óssea , Colite , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/imunologia , Modelos Animais de Doenças , Feminino , Humanos , Inflamação/genética , Inflamação/patologia , Masculino , Camundongos , Camundongos Knockout , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/imunologia , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/transplante , Quimeras de Transplante
14.
Int J Mol Sci ; 20(9)2019 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-31075840

RESUMO

Timely and reliable distinction of sepsis from non-infectious systemic inflammatory response syndrome (SIRS) supports adequate antimicrobial therapy and saves lives but is clinically challenging. Blood transcriptional profiling promises to deliver insights into the pathomechanisms of SIRS and sepsis and to accelerate the discovery of urgently sought sepsis biomarkers. However, suitable reference genes for normalizing gene expression in these disease conditions are lacking. In addition, variability in blood leukocyte subtype composition complicates gene profile interpretation. Here, we aimed to identify potential reference genes in natural killer (NK) cells and granulocytes from patients with SIRS and sepsis on intensive care unit (ICU) admission. Discovery by a two-step probabilistic selection from microarray data followed by validation through branched DNA assays in independent patients revealed several candidate reference genes in NK cells including AKIRIN1, PPP6R3, TAX1BP1, and ADRBK1. Initially, no candidate genes could be validated in patient granulocytes. However, we determined highly similar AKIRIN1 expression also in SIRS and sepsis granulocytes and no change by in vitro LPS challenge in granulocytes from healthy donors. Inspection of external neutrophil transcriptome datasets further support unchanged AKIRIN1 expression in human systemic inflammation. As a potential new reference gene in NK cells and granulocytes in infectious and inflammatory diseases, AKIRIN1 may improve our pathomechanistic understanding of SIRS and sepsis and help identifying new sepsis biomarkers.


Assuntos
Proteínas de Ligação a DNA/genética , Granulócitos/metabolismo , Células Matadoras Naturais/metabolismo , Sepse/genética , Sepse/patologia , Feminino , Regulação da Expressão Gênica , Humanos , Inflamação/genética , Inflamação/patologia , Masculino , Pessoa de Meia-Idade , Neutrófilos/metabolismo , Padrões de Referência , Reprodutibilidade dos Testes , Síndrome de Resposta Inflamatória Sistêmica/genética , Síndrome de Resposta Inflamatória Sistêmica/patologia , Doadores de Tecidos , Transcriptoma/genética
15.
Int J Mol Sci ; 20(9)2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-31083375

RESUMO

Geranylgeraniol (GGOH), a natural isoprenoid found in plants, has anti-inflammatory effects via inhibiting the activation of nuclear factor-kappa B (NFκB). However, its detailed mechanism has not yet been elucidated. Recent studies have revealed that isoprenoids can modulate signaling molecules in innate immune responses. We found that GGOH decreased the expression of lipopolysaccharide (LPS)-induced inflammatory genes in human macrophage-like THP-1 cells. Furthermore, we observed that the suppression of NFκB signaling proteins, in particular interleukin-1 receptor-associated kinase 1 (IRAK1) and tumor necrosis factor receptor-associated factor 6 (TRAF6), occurred in GGOH-treated cells prior to LPS stimulation, suggesting an immunomodulatory effect. These results indicate that GGOH may modulate and help prevent excessive NFκB activation that can lead to numerous diseases.


Assuntos
Diterpenos/farmacologia , Inflamação/patologia , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Macrófagos/metabolismo , Macrófagos/patologia , NF-kappa B/metabolismo , Fator 6 Associado a Receptor de TNF/metabolismo , Animais , Linhagem Celular , Humanos , Inflamação/genética , Lipopolissacarídeos , Macrófagos/efeitos dos fármacos , Camundongos , Modelos Biológicos , Fosforilação/efeitos dos fármacos , Células RAW 264.7 , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais/efeitos dos fármacos , Células THP-1
16.
Artif Cells Nanomed Biotechnol ; 47(1): 1808-1814, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31062615

RESUMO

BACKGROUND: Delayed inflammatory response is closely associated with the severity of Spinal cord injury (SCI). Herein, the function and molecular mechanism of notoginsenoside R1 (NGR1) in the in vitro model of SCI inflammation injury were explored. METHODS: PC-12 neuronal cells were subjected with LPS to construct a cell-based model of SCI inflammatory injury. NGR1 was applied in this cell model. miR-132 was silenced by transfection with miR-132 inhibitor. Cell viability and apoptosis were assessed, respectively. Then, the expression changes of pro-inflammatory cytokines and JNK pathway were examined. RESULTS: In this model, LPS was neurotoxic, with inhibiting PC-12 cell viability, inducing apoptosis, and enhancing concentrations of IL-6, IL-8 and TNF-α. However, NGR1 weakened the influence of LPS on PC-12 cells via elevating cell viability, decreasing apoptosis, decreasing pro-inflammatory cytokines expression, and suppressing activation of JNK signalling pathway. miR-132 was up-regulated by NGR1 treatment. Silence of miR-132 eliminated the influence of NGR1 on LPS-stimulated PC-12 cells. CONCLUSION: NGR1 relieved PC-12 cells from LPS-triggered inflammatory damage via elevating miR-132 and hereafter suppressing JNK pathway.


Assuntos
Ginsenosídeos/farmacologia , Lipopolissacarídeos/efeitos adversos , MicroRNAs/metabolismo , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Inflamação/induzido quimicamente , Inflamação/genética , Inflamação/patologia , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/genética , MicroRNAs/genética , Células PC12 , Ratos
17.
Environ Pollut ; 251: 689-698, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31108302

RESUMO

Deoxynivalenol (DON) frequently detected in a wide range of foods and feeds, inducing cytotoxicity to animals and humans. To investigate the underlying mechanism of DON-induced apoptosis and inflammation in porcine small intestinal epithelium, intestinal porcine epithelial cells (IPEC-J2 cells) were chosen as objects, and were treated by different concentrations (0 µg/mL, 0.2 µg/mL, 0.5 µg/mL, 1.0 µg/mL, 2.0 µg/mL, 4.0 µg/mL, 6.0 µg/mL) of DON. The results showed that DON induced cytotoxicity of IPEC-J2 cells in a dose-dependent manner, which is demonstrated by decreasing cell viability. Compared with the control group, DON treatment increased the expressions of genes associated with inflammation and apoptosis, such as interleukin-1 beta (IL-1ß), cyclooxgenase-2 (COX-2), interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-α), caspase-3, caspase-8, caspase-9, and decreased the cell anti-oxidative status. Protein immunofluorescence showed increased expression of caspase-3, nuclear factor kB (NF-κB) and phosphorylated NF-κB in IPEC-J2 cells. DON increased the content of intracellular reactive oxygen species (ROS) of IPEC-J2 cells. N-Acetyl-L-cysteine (NAC), a commonly used antioxidant, blocked DON-induced ROS generation, alleviated the DON-induced apoptosis and inflammation. These results suggested that DON-induced impairment of IPEC-J2 cells is possibly due to increased ROS production, and expressions of genes and proteins associated with apoptosis and inflammation.


Assuntos
Apoptose/efeitos dos fármacos , Inflamação/induzido quimicamente , Mucosa Intestinal/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Tricotecenos/toxicidade , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Apoptose/genética , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Inflamação/genética , Inflamação/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Suínos
18.
Ter Arkh ; 91(4): 21-27, 2019 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-31094472

RESUMO

AIM: A comparative analysis of the complex of clinical and laboratory indicators (including the content of cytokines in blood plasma and the level of expression of TNF and IL6 genes in peripheral leukocytes, as well as the level of biochemical and molecular-genetic indicators of apoptosis, such as the content of tissue polypeptide-specific antigen (TPS) in the blood, the activity of caspases 3, 8 and 9 and the expression level of the encoding genes in peripheral blood leukocytes) in patients with non-alcoholic fatty liver disease (NAFLD) with non-alcoholic steatohepatitis (NASH) of different activity, liver cirrhosis (LC) classes A and B and in the donors of control group. MATERIALS AND METHODS: 158 patients with NAFLD were examined: 116 patients with NASH diagnosed for the first time (NASH of weak, moderate and high activity) and 42 patients with the NAFLD at the stage of liver cirrhosis diagnosed for the first time (classes A and B according to the Child-Pugh classification). The control group consisted of 54 healthy donors. The clinical blood biochemistry, cytokine profile, tissue polypeptide-specific antigen content, the level of the TNF, IL6 gene and caspase gene transcription as well as caspase activity in peripheral blood leukocytes (PBL) were evaluated. RESULTS: In the progression of NASH to LC, together with changes in general clinical parameters, the cytokine profile are changed due to an increase in the level of IL-6 and IL-1ß; in peripheral leukocytes, the activity of caspase 9 increases and the activity of caspase 8 decreases compared to NASH, and the level of the TNF gene expression decreases as compared to NASH of high activity. These parameters can be considered as promising minimally invasive markers of progression of NAFLD to LC. CONCLUSION: In nonalcoholic cirrhosis as an outcome of the progression of non-alcoholic steatohepatitis changes in clinical parameters (indicating the development of hepatocellular deficiency, violation of protein and lipid metabolism, progressive inflammation) are accompanied by specific changes in levels of biochemical and molecular-genetic indicators of apoptosis and inflammation. With the progression of NASH to LC, the cytokine profile changes due to an increase in the level of proinflammatory cytokines, the apoptosis processes triggered by the internal pathway increase and the activity of apoptosis activated via the external pathway decreases in PBL.


Assuntos
Inflamação/genética , Cirrose Hepática/patologia , Fígado/patologia , Hepatopatia Gordurosa não Alcoólica/patologia , Apoptose , Criança , Progressão da Doença , Humanos , Inflamação/metabolismo , Fígado/metabolismo , Cirrose Hepática/sangue , Hepatopatia Gordurosa não Alcoólica/sangue
19.
Cell Physiol Biochem ; 52(6): 1484-1502, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31099508

RESUMO

BACKGROUND/AIMS: The transient receptor potential cation channel subfamily C member 6 (TRPC6) is a Ca2+-permeable nonselective cation channel and has received recent attention because of its capability to promote chronic kidney disease (CKD). The aims of this study were (i) to examine whether deletion of TRPC6 impacts on renal fibrosis and inflammatory cell infiltration in an early CKD model of unilateral ureter obstruction (UUO) in mice; and (ii) whether TRPC6-deficiency as well as UUO affect the regulation of TRPC expression in murine kidneys. METHODS: Wild-type (WT), Trpc6-knockout (Trpc6-/-) and New Zealand obese (NZO) mice underwent sham operation or unilateral ureteral obstruction (UUO). The kidneys were harvested 7 days after surgery. We examined renal fibrosis and inflammatory cell infiltration by histological and immunohistochemical staining. The mRNA expression of TRPC members and markers of fibrosis and inflammation in kidney were assessed by using real-time quantitative reverse transcription PCR. RESULTS: Histological and immunohistochemical analyses revealed less inflammatory cell infiltration (F4/80 and CD3) in UUO kidneys of Trpc6-/- mice compared to UUO kidneys of WT mice as well as less fibrosis. Genomic deletion of TRPC6 also affected the expression of pro-fibrotic genes in UUO Trpc6-/- kidneys compared to UUO WT kidneys while the expression of pro-inflammatory genes did not differ. UUO caused marked up-regulation of Trpc6 and down-regulation of Trpc1 mRNA in kidneys of WT and NZO mice. Trpc3 mRNA expression was significantly elevated in kidneys of Trpc6-/- mice underwent UUO while the levels did not change in kidneys of neither WT nor in NZO mice underwent UUO. CONCLUSION: TRPC6 contributes to renal fibrosis and immune cell infiltration in the UUO mouse model. Therefore, inhibition of TRPC6 emerges as a promising novel therapeutic strategy for treatment of chronic kidney failure in chronic obstructive nephropathy. However, confounding genomic and non-genomic effects of other TRPC channels should be taken into consideration to fully comprehend the renoprotective potential of targeting TRPC6 therapeutically under chronic kidney damaging conditions.


Assuntos
Regulação da Expressão Gênica , Rim/patologia , Canais de Cátion TRPC/genética , Obstrução Ureteral/genética , Animais , Modelos Animais de Doenças , Fibrose , Deleção de Genes , Inflamação/complicações , Inflamação/genética , Inflamação/patologia , Rim/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Obesos , RNA Mensageiro/análise , RNA Mensageiro/genética , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/patologia , Regulação para Cima , Obstrução Ureteral/complicações , Obstrução Ureteral/patologia
20.
J Immunol Res ; 2019: 5298792, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31049358

RESUMO

AIRmax and AIRmin mouse strains phenotypically selected for high and low acute inflammatory responsiveness (AIR) are, respectively, susceptible or resistant to developing hepatocellular carcinoma (HCC) induced by the chemical carcinogens urethane and diethylnitrosamine (DEN). Early production of TNF-α, IL-1ß, and IL-6 in the liver after DEN treatment correlated with tumor development in AIRmax mice. Transcriptome analysis of livers from untreated AIRmax and AIRmin mice showed specific gene expression profiles in each line, which might play a role in their differential susceptibility to HCC. Linkage analysis with SNP markers in F2 (AIRmax×AIRmin) intercross mice revealed two quantitative trait loci (QTL) in chromosomes 2 and 9, which are significantly associated with the number and progression of urethane-induced liver tumors. An independent linkage analysis with an intercross population from A/J and C57BL/6J inbred mice mapped regions in chromosomes 1 and 7 associated with the progression of urethane-induced liver tumors, evidencing the heterogeneity of HCC genetic control.


Assuntos
Animais não Endogâmicos , Carcinoma Hepatocelular/genética , Predisposição Genética para Doença , Inflamação/imunologia , Neoplasias Hepáticas/genética , Alelos , Animais , Carcinogênese/genética , Carcinoma Hepatocelular/imunologia , Modelos Animais de Doenças , Ligação Genética , Endogamia , Inflamação/genética , Interleucina-1beta/genética , Interleucina-6/genética , Neoplasias Hepáticas/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Fenótipo , Locos de Características Quantitativas , Transcriptoma , Fatores de Necrose Tumoral/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA