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1.
Medicine (Baltimore) ; 98(34): e15852, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31441836

RESUMO

BACKGROUND: The purpose of this study was to investigate the benefits and harm of combined administration of tranexamic acid (TXA) and dexamethasone (Dexa) in total knee arthroplasty (TKA). METHODS: A total of 88 consecutive patients undergoing TKA for knee osteoarthritis were stratified in 2 groups. All surgeries were performed under general anesthesia. Brief, patients in the TXA + Dexa group (n = 45) received 10 mg Dexa just after the anesthesia, and repeated at 24 hours after the surgery; and patients in the TXA group (n = 43) received 2 ml of normal saline solution at the same time. The measured outcomes were the C-reactive protein (CRP) and interleukin-6 (IL-6) from preoperatively to postoperatively, and postoperative nausea and vomiting (PONV), fatigue, range of motion (ROM), length of stay (LOS), and the analgesic and antiemetic rescue consumption RESULTS:: The level of CRP and IL-6 in the TXA + Dexa group were lower than that in the TXA group at 24 hours (P < .001, P < .001), 48 hours (P < .001, P < .001), and 72 hours (P < .001, P < .001) after the surgery. The pain scores in the TXA + Dexa group were lower during walking at 24 hours (P < .001), 48 hours (P < .001), and 72 hours (P < .001) and at rest at 24 hours (P = .022) after the surgery. Patients in the TXA + Dexa group had a lower nausea score, the incidence of PONV, fatigue, and the analgesic and antiemetic rescue consumption, and had a greater ROM than that in the TXA group. No significant differences were found in LOS and complications. CONCLUSION: The combined administration of TXA + Dexa significantly reduced the level of postoperative CRP and IL-6, relieve postoperative pain, ameliorate the incidence of POVN, provide additional analgesic and antiemetic effects, reduce postoperative fatigue, and improve ROM, without increasing the risk of complications in primary TKA.


Assuntos
Anti-Inflamatórios/uso terapêutico , Antifibrinolíticos/uso terapêutico , Artroplastia do Joelho/métodos , Dexametasona/uso terapêutico , Ácido Tranexâmico/uso terapêutico , Idoso , Analgésicos/administração & dosagem , Anti-Inflamatórios/administração & dosagem , Antieméticos/administração & dosagem , Perda Sanguínea Cirúrgica/prevenção & controle , Proteína C-Reativa/efeitos dos fármacos , Dexametasona/administração & dosagem , Quimioterapia Combinada , Feminino , Humanos , Mediadores da Inflamação/metabolismo , Interleucina-6/biossíntese , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Dor Pós-Operatória/prevenção & controle , Náusea e Vômito Pós-Operatórios/prevenção & controle , Amplitude de Movimento Articular , Ácido Tranexâmico/administração & dosagem
2.
Artigo em Chinês | MEDLINE | ID: mdl-31315358

RESUMO

Objective: To explore the role of autophagy in PM2.5-induced inflammation in human nasal epithelial cells and related mechanism. Methods: Human nasal epithelial cells were exposed to different concentration of PM2.5 for different times, and the expression levels of microtubule-associated protein-1 light chain-3 Ⅱ (LC3 Ⅱ) and Beclin1 proteins were measured by Western blot. The typical autophagosome and autolysosome were observed by using transmission electron microscopy (TEM). To observe autophagic flux, mRFP-GFP-LC3 plasmid was transfected to nasal epithelial cells and the punctate staining of mRFP-GFP-LC3 were determined by confocal laser scanning microscope. The expression of inflammatory cytokines interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α) in cell culture supernatant were assessed by enzyme-linked immunosorbent assay (ELISA). To assess the role of autophagy in PM2.5-mediated inflammation, autophagy related gene Atg5 and Beclin-1 were silenced by siRNA knockdown, and inflammatory cytokines were analyzed.GraphPad Prism 6.0 was used for statistical analysis. Results: PM2.5 exposure increased the expression of LC3 Ⅱ and Beclin-1 proteins in a dose- (in PM2.5 group with concentration of 0, 15, 30, 60, 120 µg/ml, the expression of LC3 Ⅱ was 0.021±0.001(x±s), 0.037±0.002, 0.058±0.005, 0.075±0.006, 0.085±0.004, respectively, F=126.8, P<0.05; the expression of Beclin-1 was 0.002±0.000, 0.003±0.000, 0.005±0.000, 0.007±0.001, 0.008±0.001, respectively, F=137.3, P<0.05) and time-dependent manner (in PM2.5 group with exposure time of 0, 3, 6, 12, 24 h, the expression of LC3Ⅱ was 0.160±0.007, 0.222±0.003, 0.251±0.015, 0.483±0.029, 0.585±0.035, respectively, F=215.3, P<0.05; the expression of Beclin-1 was 0.059±0.002, 0.080±0.002, 0.087±0.002, 0.183±0.007, 0.228±0.005, respectively, F=137.3, P<0.05) in human nasal epithelial cells. TEM analysis showed typical autophagosome and autolysosome in cells after PM2.5 exposure for 24 h. PM2.5 significantly increased the number of yellow and red dots representing autophagosomes and autolysosomes respectively, indicating autophagic flux was elevated. Moreover, PM2.5 enhanced the secretion of inflammatory cytokines such as IL-6 and TNF-α, which was dramatically prevented by Atg5-siRNA and Beclin-1-siRNA. Conclusion: Autophagy plays an important role in PM2.5-caused inflammation response in nasal epithelial cells, which can induce release of inflammatory factors such as IL-6 and TNF-α and advance the inflammatory reaction.


Assuntos
Autofagia/imunologia , Células Epiteliais/imunologia , Inflamação/imunologia , Mucosa Nasal/imunologia , Material Particulado/imunologia , Proteína Beclina-1/biossíntese , Humanos , Interleucina-6/biossíntese , Proteínas Associadas aos Microtúbulos/biossíntese , Material Particulado/efeitos adversos , Fator de Necrose Tumoral alfa/biossíntese
3.
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
4.
Environ Pollut ; 252(Pt B): 1216-1224, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31252119

RESUMO

The effects of methylamine on human health have been debated for several years, but the exact adverse outcomes and definite signaling cascades have not been elucidated yet. Herein, a NF-κB signal pathway, a positive regulator of inflammation was identified as the main pathway of methylamine exposure induced adverse effects in bronchial airway cells (16HBE) for the first time. The results indicated that methylamine could stimulate the overproduction of reactive oxygen species (ROS) in cytoplasm and mitochondria of 16HBE cells. Moreover, ROS accelerate the translocation and phosphorylation of NF-κB in nucleic and promote the expression of inflammatory, such as IL-8 and IL-6. As a result, methylamine was found to be increased ROS-mediated NF-κB activation in cells, leading to the production of inflammatory cytokine. Furthermore, the results also showed that methylamine could affect the expression of cytokines related genes, p53, STAT3, Bcl2, c-myc, Cyclin D, Hes1, Mcl-1, TGF-ß2. The breakdown of those cell proliferation and apoptosis related genes were leading to a common toxic mechanism of cell death. In summary, our work uncovers a mechanism by which methylamine can induce the formation of inflammation response and demonstrates potential inflammation and carcinogenesis in human airway cell upon the methylamine inhaled.


Assuntos
Poluentes Atmosféricos/toxicidade , Exposição Ambiental/efeitos adversos , Inflamação/patologia , Pneumopatias/induzido quimicamente , Metilaminas/toxicidade , Fator de Transcrição RelA/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Citocinas/metabolismo , Regulação da Expressão Gênica , Humanos , Interleucina-6/biossíntese , Interleucina-8/biossíntese , Mitocôndrias/metabolismo , Fosforilação , Transporte Proteico/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
5.
Medicine (Baltimore) ; 98(23): e15913, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31169706

RESUMO

We aimed to investigate the impact of the single nucleotide polymorphisms of rs34436714 of the NOD-like receptor protein 12 gene on the production of tumor necrosis factor-alpha (TNFα) in patients with inflammatory bowel disease (IBD)In a matched case-control study 90 patients with IBD, 56 with Crohn disease (CD) and 34 with ulcerative colitis, were genotyped and compared to 98 healthy comparators matched for age and gender. Expression level of TNFα, interleukin (IL)-6, IL-12, and soluble triggering receptor expressed on myeloid cells were measured in patients' sera. Peripheral blood mononuclear cells (PBMCs) were isolated and stimulated for TNFα production.Serum TNFα was greater among carriers of GT/TT genotypes than GG genotypes of rs34436714. Stimulated TNFα production was also higher in carriers of GT/TT genotypes. The frequency of CD with fistulizing behavior and with CD involving the small intestine was greater among carriers of GT/TT genotypes than of the GG genotype. Distribution of the GG, GT, and TT genotypes of rs34436714 were in Hardy-Weinberg equilibrium in both groups. The genotype distribution was the same in both groups.Carriage of minor frequency alleles of rs34436714 was accompanied by greater circulating levels of TNFα and by greater capacity for stimulated TNFα production by PBMCs. These alleles had an impact on the phenotype of patients with CD.


Assuntos
Doenças Inflamatórias Intestinais/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Fator de Necrose Tumoral alfa/biossíntese , Adulto , Idoso , Estudos de Casos e Controles , Colite Ulcerativa/genética , Colite Ulcerativa/fisiopatologia , Doença de Crohn/genética , Doença de Crohn/fisiopatologia , Feminino , Frequência do Gene , Predisposição Genética para Doença , Humanos , Doenças Inflamatórias Intestinais/fisiopatologia , Interleucina-12/biossíntese , Interleucina-6/biossíntese , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Receptor Gatilho 1 Expresso em Células Mieloides/biossíntese
6.
Artif Cells Nanomed Biotechnol ; 47(1): 1839-1845, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31066305

RESUMO

Atherosclerosis is the chronic inflammatory disease, and inflammation-elicited endothelial activation is an early event in the development of atherosclerosis. The P2Y11 receptor is a purinergic receptor and a member of the P2 family of G coupled protein which has been shown to modulate vascular function. Progress in the study of purine receptors has been tremendous and these receptors have become pharmacological targets for various diseases. In this study, we show that the P2Y11R antagonist NF157 can mitigate oxidized LDL (ox-LDL)-induced endothelial inflammation. Our study demonstrates that P2Y11R is expressed to a fair degree in human aortic endothelial cells and is induced by treatment with ox-LDL. Blockage of P2Y11R by its selective antagonist NF157 ameliorates ox-LDL-induced adhesion of THP-1 monocytes to endothelial cells. NF157 inhibits ox-LDL-induced expression of adhesion molecules including E-selectin and VCAM-1. NF157 also suppresses ox-LDL-associated ROS production and induction of the NADPH oxidase subunit NOX-4. Moreover, NF157 has an inhibitory effect on the production of major cytokines including IL-6 and TNF-α. Mechanistically, we show that NF157 mitigates ox-LDL-induced phosphorylation of MAPK kinase p38 and NF-κB activation. Our findings indicate that blockage of P2Y11R signalling by its antagonist NF157 may protect endothelial cells from ox-LDL-induced endothelial inflammation. Therefore, NF157 may have therapeutic implications in the modulation of atherosclerosis-associated inflammation.


Assuntos
Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Lipoproteínas LDL/farmacologia , Receptores Purinérgicos P2/metabolismo , Suramina/análogos & derivados , Adesão Celular/efeitos dos fármacos , Selectina E/genética , Ativação Enzimática/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Inflamação/tratamento farmacológico , Interleucina-6/biossíntese , Monócitos/citologia , Monócitos/efeitos dos fármacos , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Suramina/farmacologia , Suramina/uso terapêutico , Fator de Necrose Tumoral alfa/biossíntese , Molécula 1 de Adesão de Célula Vascular/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
7.
Medicine (Baltimore) ; 98(18): e15345, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31045776

RESUMO

The brain has multiple functions, and its structures are very closely related to one another. Thus, the brain areas associated with stress, emotion, and intelligence are closely connected. The purpose of this study was to investigate the multiple associations between stress and emotional intelligence (EI), between EI and intelligence quotient (IQ), between cytokines and stress, and between cytokines and IQ. We measured the stress, EI, cognitive intelligence using IQ, and cytokine levels of 70 healthy subjects. We also analyzed the association of cytokines with IQ according to hemispheric dominance using the brain preference indicator (BPI). We found significant negative correlations between stress and the components of EI, such as emotional awareness and expression, emotional thinking, and emotional regulation. High levels of anger, which is a component of stress, were significantly related to poor emotional regulation. Additionally, emotional application was positively correlated with full-scale IQ scores and scores on the vocabulary, picture arrangement, and block design subtests of the IQ test. High IL-10 levels were significantly associated with low stress levels only in the right-brain-dominant group. High IL-10 and IFN-gamma levels have been associated with high scores of arithmetic intelligence. TNF-alpha and IL-6 were negatively associated with vocabulary scores and full-scale IQ, but IL-10 and IFN-gamma were positively associated with scores on the arithmetic subtest in left-brain-dominant subjects. On the other hand, IL-10 showed positive correlations with scores for vocabulary and for vocabulary and arithmetic in right-brain-dominant subjects. Furthermore, we found significant linear regression models which can show integrative associations and contribution on emotional and cognitive intelligence. Thus, we demonstrated that cytokines, stress, and emotional and cognitive intelligence are closely connected one another related to brain structure and functions. Also, the pro-inflammatory cytokines TNF-alpha and IL-6 had negative effects, whereas the anti-inflammatory cytokines (e.g., IL-10 and IFN-gamma) showed beneficial effects, on stress levels, and multiple dimensions of emotional and cognitive intelligence. Additionally, these relationships among cytokines, stress, and emotional and cognitive intelligence differed depending on right and left hemispheric dominance.


Assuntos
Cognição/fisiologia , Citocinas/biossíntese , Inteligência Emocional/fisiologia , Estresse Psicológico/fisiopatologia , Escalas de Wechsler , Adulto , Ira/fisiologia , Encéfalo/metabolismo , Dominância Cerebral/fisiologia , Feminino , Humanos , Mediadores da Inflamação/metabolismo , Testes de Inteligência , Interferon gama/biossíntese , Interleucina-10 , Interleucina-6/biossíntese , Modelos Lineares , Masculino , República da Coreia , Fator de Necrose Tumoral alfa/biossíntese , Adulto Jovem
8.
Medicine (Baltimore) ; 98(18): e15383, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31045788

RESUMO

BACKGROUND: Neuroprotective effects of dexmedetomidine are reported in preclinical and clinical studies but evidence regarding the postoperative neurocognitive function is still unclear. This study performed a meta-analysis on outcomes of studies which examined neurocognitive performance and inflammatory factors to investigate the effects of dexmedetomidine on postoperative cognitive dysfunction (POCD) and inflammation in patients after general anaesthesia. METHODS: Literatures were searched in several electronic databases and studies were selected by following precise inclusion criteria. We searched PubMed, EMBASE, the Cochrane Library, China Academic Journals full-text database (CNKI), and Google Scholar to find randomized controlled trials (RCTs) of the influence of dexmedetomidine on POCD and inflammation in patients who had undergone general anaesthesia. Two researchers independently screened the literature, extracted data, and evaluated quality of methodology against inclusion and exclusion criteria. Meta-analyses of pooled ORs of POCD incidences and mean differences in neurocognitive assessment scores and inflammation levels were carried out and subgroup analyses were performed. Stata 12.0 was used to conduct our meta-analysis. RESULTS: Twenty-six RCTs were included. Compared with controls, perioperative dexmedetomidine treatment significantly reduced the incidence of POCD (pooled ORs = 0.59, 95% confidence interval (CI) 0.45-2.95) and improved Mini-Mental State Examination (MMSE) score (standardized mean difference (SMD) = 1.74, 95% CI 0.43-3.05) on the first postoperative day. Furthermore, perioperative dexmedetomidine treatment significantly decreased IL-6 (SMD = -1.31, 95% CI -1.87-0.75, P < .001) and TNF-α (SMD = -2.14, 95% CI -3.14-1.14, P < .001) compared to saline/comparators treatment. In the stratified analysis by surgical type, age, type of control, and study region, the differences were also significant between dexmedetomidine- and saline-treated patients. CONCLUSION: Perioperative dexmedetomidine treatment is associated with significantly reduced incidence of POCD and inflammation and better neurocognitive function postoperatively in comparison with both saline controls and comparator anaesthetics.


Assuntos
Agonistas de Receptores Adrenérgicos alfa 2/administração & dosagem , Anestesia Geral/efeitos adversos , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/prevenção & controle , Dexmedetomidina/administração & dosagem , China , Humanos , Inflamação/tratamento farmacológico , Mediadores da Inflamação/metabolismo , Interleucina-6/biossíntese , Testes de Estado Mental e Demência , Razão de Chances , Período Perioperatório , Complicações Pós-Operatórias/induzido quimicamente , Complicações Pós-Operatórias/prevenção & controle , Ensaios Clínicos Controlados Aleatórios como Assunto , Fator de Necrose Tumoral alfa/biossíntese
9.
Immunity ; 50(4): 1007-1023, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30995492

RESUMO

Interleukin-6 (IL-6) is a pleiotropic cytokine with roles in immunity, tissue regeneration, and metabolism. Rapid production of IL-6 contributes to host defense during infection and tissue injury, but excessive synthesis of IL-6 and dysregulation of IL-6 receptor signaling is involved in disease pathology. Therapeutic agents targeting the IL-6 axis are effective in rheumatoid arthritis, and applications are being extended to other settings of acute and chronic inflammation. Recent studies reveal that selective blockade of different modes of IL-6 receptor signaling has different outcomes on disease pathology, suggesting novel strategies for therapeutic intervention. However, some inflammatory diseases do not seem to respond to IL-6 blockade. Here, we review the current state of IL-6-targeting approaches in the clinic and discuss how to apply the growing understanding of the immunobiology of IL-6 to clinical decisions.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Inflamação/tratamento farmacológico , Interleucina-6/antagonistas & inibidores , Terapia de Alvo Molecular , Transdução de Sinais/efeitos dos fármacos , Animais , Anticorpos Monoclonais/imunologia , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/imunologia , Ensaios Clínicos como Assunto , Receptor gp130 de Citocina/antagonistas & inibidores , Receptor gp130 de Citocina/imunologia , Humanos , Inflamação/imunologia , Interleucina-6/biossíntese , Interleucina-6/deficiência , Interleucina-6/imunologia , Janus Quinases/antagonistas & inibidores , Janus Quinases/fisiologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Camundongos Knockout , Receptores de Interleucina-6/imunologia , Ribonucleases/deficiência , Fator de Transcrição STAT3/fisiologia , Proteína 1 Supressora da Sinalização de Citocina/fisiologia , Proteína 3 Supressora da Sinalização de Citocinas/fisiologia
10.
Cancer Invest ; 37(3): 174-184, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30982362

RESUMO

As important factors in the tumor microenvironment, interleukin-6 (IL-6) and integrin ανß6 play significant roles in accumulating mutations that drive the progression and metastatic capacities of cancer. The aim of this study was to investigate the expression of IL-6 and integrin ανß6, their clinical significance, as well as their correlation in the colon cancer tissues of 145 cases using immunohistochemistry. Our results showed that IL-6 and integrin ανß6 are indicators of cancer progression and poor prognosis in patients with colon cancer. Moreover, their relationship may provide clues for further studies on how the tumor microenvironment mediates the development of colon cancer, as well as strategies for the identification of novel therapeutic targets in the prevention and treatment of colon cancer.


Assuntos
Antígenos de Neoplasias/biossíntese , Neoplasias do Colo/metabolismo , Integrinas/biossíntese , Interleucina-6/biossíntese , Microambiente Tumoral , Neoplasias do Colo/patologia , Progressão da Doença , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Invasividade Neoplásica , Estadiamento de Neoplasias , Prognóstico
11.
Artigo em Inglês | MEDLINE | ID: mdl-30961803

RESUMO

Salmonella Typhimurium and S. Stanley are the most prevalent serogroup B serovars to infect humans in Taiwan. The aim was to determine possible factors to influence the prevalence between S. Typhimurium and S. Stanley. Genotypes were determined by pulsed field gel electrophoresis (PFGE) analysis and the intracellular survival, phagocytosis, reactive oxygen species (ROS) production of human monocyte THP-1 cell and tumor necrosis factor-α(TNF-α), interleukin-6 (IL-6), and IL-1ßexpression in peripheral blood CD14+ cells after infection were analyzed. 182 S. Stanley was clonal disseminated with main pulsotypes 2 from 2004 to 2007. Overall S. Typhimurium evolved more genotypes, while S. Stanley conserved in genotypes. Human blood CD14+ monocytes expressed TNF-α, IL-6 and IL-1ß differently among serovars and bacterial conditions (live vs. killed). Live S. Stanley and S. Typhimurium suppressed the TNF-α and IL-6 expression compared to killed bacteria. However, live S. Typhimurium stimulated more IL-1ß expression than the killed bacteria, but S. Stanley expressed similar IL-1ß levels in both conditions. Furthermore, S. Stanley and S. Typhimurium differed in intracellular survival in the THP-1 cells, an early decrease for S. Stanley, not for S. Typhimurium. Additionally, higher reactive oxygen species (ROS) production in THP-1 cells was found agsinst S. Stanley infection, not found in S. Typhimurium. However, some isolates of S. Stanley could recover from early loss to become more in the monocytes than S. Typhimurium. Difference in phagocytized number, intracellular survival, ROS production and IL-1ß expression may contribute to prevalence different between two serovars.


Assuntos
Monócitos/imunologia , Fagocitose/imunologia , Infecções por Salmonella/imunologia , Salmonella typhimurium/imunologia , beta-Lactamases/genética , Linhagem Celular Tumoral , Eletroforese em Gel de Campo Pulsado , Humanos , Interleucina-1beta/biossíntese , Interleucina-6/biossíntese , Espécies Reativas de Oxigênio/metabolismo , Infecções por Salmonella/epidemiologia , Infecções por Salmonella/microbiologia , Salmonella typhimurium/genética , Salmonella typhimurium/isolamento & purificação , Células THP-1 , Taiwan , Fator de Necrose Tumoral alfa/biossíntese
12.
Drug Des Devel Ther ; 13: 681-694, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30858698

RESUMO

Purpose: Budesonide (Bud) is a nonhalogenated glucocorticoid with high anti-inflammatory potency and low systemic side effects. However, the poor water solubility of Bud affects its dissolution and release behavior, thus influencing its anti-inflammatory effect. This study was aimed at synthesizing and evaluating novel conjugates of Bud, hoping to increase the anti-inflammatory activity of Bud by improving its water solubility. Materials and methods: Seven novel Bud conjugates (3a-3g) were designed and synthesized in this study. Besides, the equilibrium solubility, cell viability, in vitro and in vivo anti-inflammatory activity, and the hydrolysis behavior of the conjugates in different pH solutions, rat and human plasma, and rat lung homogenate were studied in detail. Results: As compared to Bud, the equilibrium solubility of 3a, 3c, and 3e was significantly increased; 3a, 3b, and 3c significantly inhibited the interleukin-6 production in lipopolysaccharide-induced A549 cells; 3a and 3e could significantly decrease the xylene-induced ear edema; and 3a and 3c were gradually and slowly hydrolyzed into Bud in the alveolar fluid and lung homogenate and broken down quickly in plasma. Conclusion: The amino acid ester compounds budesonide-21-glycine ester (3a) and budesonide-21-alanine ester (3c) were selected as potential conjugates of Bud. This study would provide a theoretical and an experimental basis for the in vivo process of glucocorticoids and the treatment of inflammatory diseases.


Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/farmacologia , Budesonida/síntese química , Budesonida/farmacologia , Otopatias/tratamento farmacológico , Edema/tratamento farmacológico , Células A549 , Animais , Anti-Inflamatórios não Esteroides/química , Budesonida/química , Sobrevivência Celular/efeitos dos fármacos , Otopatias/induzido quimicamente , Edema/induzido quimicamente , Humanos , Interleucina-6/antagonistas & inibidores , Interleucina-6/biossíntese , Masculino , Camundongos , Camundongos Endogâmicos , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Xilenos
13.
Food Chem Toxicol ; 128: 119-128, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30926436

RESUMO

An immunologically active polysaccharide named as UPP-2 (1035.52 kDa) was isolated from Undaria pinnatifida using traditional water extraction followed by DEAE Sepharose fast flow chromatography. UPP-2 was proven to be a low sulfated polysaccharide with relatively abundant uronic acid (13.08 ±â€¯0.67%). UPP-2 mainly consisted of xylose (64.55%), glucose (23.81%), arabinose (5.90%) and mannose (4.26%), and its main glycosidic linkage types included →2)-α-D-Xylp-(1→, →4)-α-D-Glcp-(1→, α-D-Xylp-(1→ and →2,4)-ß-D-Xylp-(1 → . Results indicated that UPP-2 significantly promoted the proliferation and pinocytic capacity of RAW264.7 cells, and upregulated the mRNA expressions of iNOS, TNF-α, IL-6 and IL-1ß at 100-600 µg/mL with a maximum of 195, 42, 768 and 539 times of those of the negative control, respectively. Moreover, UPP-2 significantly increased the secretions of nitric oxide, TNF-α and IL-6 at 100-600 µg/mL (8.0, 73.1 and 188.7 times compared to those of the negative control, respectively), as well as promoted the production of IL-1ß obviously at 600 µg/mL. Overall, UPP-2 could be served as a potential dietary supplement or functional food based on its immunostimulatory activity.


Assuntos
Adjuvantes Imunológicos/química , Adjuvantes Imunológicos/farmacologia , Polissacarídeos/química , Polissacarídeos/farmacologia , Undaria/química , Animais , Configuração de Carboidratos , Interleucina-1beta/biossíntese , Interleucina-1beta/genética , Interleucina-6/biossíntese , Interleucina-6/genética , Camundongos , Peso Molecular , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/biossíntese , Óxido Nítrico Sintase Tipo II/genética , Pinocitose/efeitos dos fármacos , Células RAW 264.7 , RNA Mensageiro/genética , Análise Espectral/métodos , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/genética , Regulação para Cima/efeitos dos fármacos
14.
Cell Physiol Biochem ; 52(3): 439-454, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30873820

RESUMO

BACKGROUND/AIMS: Cerium oxide nanoparticles (CeO2 NPs) are released from diesel engines that use cerium compounds as a catalytic agent to decrease the diesel exhaust particles, leading to human exposure by inhalation to CeO2 NPs. We have recently demonstrated that pulmonary exposure to CeO2 NPs induces lung inflammation, thrombosis, and oxidative stress in various organs including kidneys. It is well known that particulate air pollution effects are greater in patients with renal diseases. The aim of this study is to investigate the effects of pulmonary exposure to CeO2 NPs in a rat model of acute kidney injury (AKI). METHODS: AKI was induced in rats by a single intraperitoneal injection of cisplatin (CP, 6 mg/kg). Six days later, the rats were intratracheally (i.t.) instilled with either CeO2 NPs (1 mg/kg) or saline (control), and various renal and pulmonary endpoints were assessed 24 h afterward using histological, colorimetric assay, enzyme-linked immunosorbent assay and Comet assay techniques. RESULTS: CP alone decreased body weight, and increased water intake, urine volume and relative kidney weight. CP also increased the plasma concentrations urea and creatinine, and decreased creatinine clearance. In the kidneys, CP significantly increased renal injury molecule-1, interleukin-6 (IL-6), tumor necrosis factor α (TNFα) and glutathione concentrations, and caused renal tubular necrosis, and DNA injury assessed by Comet assay. All these actions were significantly aggravated in rats given both CP and CeO2 NPs. Histopathological changes in lungs of CeO2 NPs-treated rats included marked interstitial cell infiltration and congestion. These were aggravated by the combination of CP + CeO2 NPs. Moreover, this combination exacerbated the increase in the concentrations of TNFα and IL-6, and the decrease in the activity of pulmonary catalase and total nitric oxide concentration, and lung DNA damage. CONCLUSION: We conclude that the presence of CeO2 NPs in the lung exacerbated the renal and lung effects of CP-induced AKI.


Assuntos
Lesão Renal Aguda/patologia , Cério/toxicidade , Rim/patologia , Pulmão/patologia , Nanopartículas/toxicidade , Pneumonia/patologia , Lesão Renal Aguda/induzido quimicamente , Lesão Renal Aguda/metabolismo , Lesão Renal Aguda/fisiopatologia , Administração por Inalação , Animais , Catalase/antagonistas & inibidores , Catalase/metabolismo , Cisplatino/administração & dosagem , Creatinina/sangue , Fragmentação do DNA/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Interleucina-6/biossíntese , Intubação Intratraqueal , Rim/efeitos dos fármacos , Rim/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Masculino , Material Particulado/toxicidade , Pneumonia/induzido quimicamente , Pneumonia/metabolismo , Pneumonia/fisiopatologia , Ratos , Ratos Wistar , Fator de Necrose Tumoral alfa/biossíntese , Ureia/sangue , Emissões de Veículos/toxicidade
15.
J Neuroinflammation ; 16(1): 26, 2019 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-30732627

RESUMO

BACKGROUND: Age-related macular degeneration (AMD) is a leading cause of visual impairment in the elderly. The neovascular (wet) form of AMD can be treated with intravitreal injections of different anti-vascular endothelial growth factor (VEGF) agents. Placental growth factor (PGF) is another member of the VEGF family of cytokines with pro-angiogenic and pro-inflammatory effects. Here, we aimed to compare single and combined inhibition of VEGF-A and PGF in the laser-induced mouse model of choroidal neovascularization (CNV) with a focus on the effects on retinal mononuclear phagocytes. METHODS: CNV was induced in C57BL/6J mice using a YAG-Laser. Immediately after laser damage antibodies against VEGF-A (aVEGF), anti-PGF (aPGF), aVEGF combined with aPGF, aflibercept, or IgG control were injected intravitreally in both eyes. Three and 7 days after laser damage, the vascular leakage was determined by fluorescence angiography. Lectin staining of retinal and RPE/choroidal flat mounts was used to monitor CNV. In situ mRNA co-expression of Iba1, VEGF and PGF were quantified using in situ hybridization. Retinal and RPE/choroidal protein levels of VEGF and PGF as well as the pro-inflammatory cytokines IL-6, IL1-beta, and TNF were determined by ELISA. RESULTS: Early (day 3) and intermediate (day 7) vascular leakage and CNV were significantly inhibited by PGF and VEGF-A co-inhibition, most effectively with the trap molecule aflibercept. While VEGF-A blockage alone had no effects, trapping PGF especially with aflibercept prevented the accumulation of reactive microglia and macrophages in laser lesions. The lesion-related mRNA expression and secretion of VEGF-A and PGF by mononuclear phagocytes were potently suppressed by PGF and partially by VEGF-A inhibition. Protein levels of IL-6 and IL1-beta were strongly reduced in all treatment groups. CONCLUSIONS: Retinal inhibition of PGF in combination with VEGF-A prevents vascular leakage and CNV possibly via modulating their own expression in mononuclear phagocytes. PGF-related, optimized strategies to target inflammation-mediated angiogenesis may help to increase efficacy and reduce non-responders in the treatment of wet AMD patients.


Assuntos
Monócitos/metabolismo , Neovascularização Patológica/prevenção & controle , Fator de Crescimento Placentário/antagonistas & inibidores , Doenças Retinianas/prevenção & controle , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Animais , Plexo Corióideo/patologia , Citocinas/metabolismo , Feminino , Interleucina-1/antagonistas & inibidores , Interleucina-1/biossíntese , Interleucina-6/antagonistas & inibidores , Interleucina-6/biossíntese , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/efeitos dos fármacos , Neovascularização Patológica/patologia , Fator de Crescimento Placentário/biossíntese , RNA Mensageiro/biossíntese , Retina/patologia , Doenças Retinianas/patologia , Fator A de Crescimento do Endotélio Vascular/biossíntese
16.
J Biol Chem ; 294(15): 5867-5878, 2019 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-30760523

RESUMO

Endothelial dysfunction is induced by inflammatory mediators including multiple G protein-coupled receptor (GPCR) agonists. However, the GPCR signaling pathways that promote endothelial dysfunction are incompletely understood. We previously showed that thrombin promotes endothelial barrier disruption through autophosphorylation and activation of p38 mitogen-activated protein kinase (MAPK) via a non-canonical transforming growth factor-ß-activated protein kinase-1-binding protein-1 (TAB1) and TAB2-dependent pathway rather than the canonical three-tiered kinase cascade. Here, we sought to determine whether other GPCR agonists stimulate p38 MAPK activation via this non-canonical pathway in human endothelial cells derived from different vascular beds. Using primary human umbilical vein endothelial cells (HUVECs), HUVEC-derived EA.hy926 cells, and human dermal microvascular endothelial cells (HDMECs), we found that both non-canonical and canonical p38 activation pathways components are expressed in these various endothelial cell types, including TAB3, a structurally-related TAB2 homolog. Moreover, multiple GPCRs agonists, including thrombin, histamine, prostaglandin E2, and ADP, stimulated robust p38 autophosphorylation, whereas phosphorylation of the upstream MAPKs MAP kinase kinase 3 (MKK3) and MKK6, was virtually undetectable, indicating that non-canonical p38 activation may exist for other GPCRs. Indeed, in EA.hy926 cells, thrombin- and histamine-stimulated p38 activation depended on TAB1-TAB2, whereas in primary HUVECs, both TAB1-TAB2 and TAB1-TAB3 were required for p38 activation. In HDMECs, thrombin-induced p38 activation depended on TAB1-TAB3, but histamine-induced p38 activation required TAB1-TAB2. Moreover, thrombin- and histamine-stimulated interleukin-6 production required both TAB1-TAB2 and TAB1-TAB3 in HUVEC. We conclude that multiple GPCR agonists utilize non-canonical TAB1-TAB2 and TAB1-TAB3-dependent p38 activation to promote endothelial inflammatory responses.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Sistema de Sinalização das MAP Quinases , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Difosfato de Adenosina/genética , Difosfato de Adenosina/metabolismo , Linhagem Celular , Dinoprostona/genética , Dinoprostona/metabolismo , Histamina/genética , Histamina/metabolismo , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Interleucina-6/biossíntese , Interleucina-6/genética , MAP Quinase Quinase 3/genética , MAP Quinase Quinase 3/metabolismo , Fosforilação/genética , Trombina/genética , Trombina/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/genética
17.
Cell Mol Biol (Noisy-le-grand) ; 65(1): 52-55, 2019 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-30782294

RESUMO

More and more studies show that inflammation, pain and insomnia have become the main common diseases. Effective treatments of inflammation, pain and insomnia have become an issue of primary concern in clinical practice. Oleuropein (OLE), the main phenolic component of Mediterranean extra virgin olive oil, has shown many pharmacological properties. In the present study, the anti-inflammatory effect of OLE was firstly evaluated using RAW264.7 macrophages subjected to stimulation with lipopolysaccharide (LPSC). The results obtained revealed that OLE caused significant and dose-dependent downregulation of nitric (NO), COX-2, inducible NO synthase iNOS, and the inflammation-associated cytokines IL-6 and TNF-α. From the mechanism, the expression of COX-2, cytokines IL-6 and TNF-α OLE is closely related to analgesic and sedation effect. Further evaluations showed significant analgesic and sedative effects of OLE in tail-flick test and sedation test conducted in SD rats in vivo. All these results indicate that OLE has anti-inflammatory, analgesic and sedative effects both in vitro and in vivo.


Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Hipnóticos e Sedativos/farmacologia , Iridoides/farmacologia , Olea/química , Animais , Sobrevivência Celular/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Interleucina-6/biossíntese , Iridoides/química , Ketamina , Lipopolissacarídeos , Camundongos , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase Tipo II/metabolismo , Células RAW 264.7 , Ratos Sprague-Dawley , Cauda , Fator de Necrose Tumoral alfa/biossíntese , Regulação para Cima/efeitos dos fármacos
18.
Kidney Blood Press Res ; 44(1): 62-71, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30808838

RESUMO

BACKGROUND/AIMS: Dysregulation of interleukin-6 (IL-6) production in residual renal cells may play a pivotal role in the development of glomerulonephritis (GN). Given that Toll-like receptor 3 (TLR3) signaling has been implicated in the pathogenesis of some forms of GN, we examined activated TLR3-mediated IL-6 signaling in cultured normal human glomerular endothelial cells (GECs). METHODS: We treated GECs with polyinosinic-polycytidylic acid (poly IC), an authentic double-stranded RNA, and analyzed the expression of IL-6 and the cytosolic viral RNA sensors retinoic acid-inducible gene-I (RIG-I) and melanoma differentiation associated gene 5 (MDA5) using reverse transcription quantitative real-time polymerase chain reaction, western blotting, and enzyme-linked immunosorbent assays. To further elucidate the effects of poly IC on this signaling pathway, we subjected the cells to small interfering RNA (siRNA) against TLR3, interferon (IFN)-ß, RIG-I, and MDA5. RESULTS: We found that poly IC induced the expression of RIG-I, MDA5 and IL-6 via TLR3/IFN-ß signaling in GECs. siRNA experiments revealed that both MDA5 and RIG-I were involved in the poly IC-induced expression of IL-6, with MDA5 being upstream of RIG-I. CONCLUSION: Interestingly, cytosolic sensors of viral RNA were found to be involved in IL-6 production via TLR3 signaling in GECs. Regional activation of TLR3/IFN-ß/ MDA5/RIG-I/IL-6 axis due to viral and "pseudoviral" infections is involved in innate immunity and inflammatory reactions in GECs. We believe this signaling pathway also plays a pivotal role in the development of some forms of GN.


Assuntos
Interleucina-6/biossíntese , Glomérulos Renais/citologia , Receptor 3 Toll-Like/metabolismo , Células Cultivadas , Proteína DEAD-box 58/metabolismo , Células Endoteliais/metabolismo , Glomerulonefrite/etiologia , Humanos , Inflamação , Helicase IFIH1 Induzida por Interferon/metabolismo , Poli I-C/farmacologia , RNA Viral , Transdução de Sinais
19.
Gen Comp Endocrinol ; 279: 109-113, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-30654022

RESUMO

Interleukin-6 (IL-6) is a pleiotropic cytokine secreted by immune tissues such as monocytes/macrophages and have pro-inflammatory/anti-inflammatory and neuroendocrine actions. In this study, we report the modulatory effects of stress hormones, the cortisol agonist dexamethasone and catecholamines on lipopolysaccharide (LPS) - induced stimulation of head kidney IL-6 in the catfish Heteropneustes fossilis. In the in vivo study, the intraperitoneal administration of LPS stimulated, and dexamethasone time-dependently inhibited IL-6 level. In the in vitro study, the incubation of macrophage cultures with LPS stimulated IL-6 level significantly in all incubation times. Dexamethasone did not alter the basal IL-6 level but inhibited time-dependently the LPS-induced stimulation. Likewise, catecholamines did not alter the basal level of IL-6. Both epinephrine and norepinephrine inhibited the LPS-induced stimulation of IL-6. Dopamine, on the other hand, was ineffective. The results indicate that IL-6 is a useful marker of head kidney macrophage activity for studying endocrine-immune interactions in the catfish.


Assuntos
Catecolaminas/farmacologia , Peixes-Gato/metabolismo , Rim Cefálico/metabolismo , Interleucina-6/biossíntese , Lipopolissacarídeos/farmacologia , Estresse Fisiológico , Animais , Dexametasona/farmacologia , Epinefrina/farmacologia , Rim Cefálico/efeitos dos fármacos , Hidrocortisona/farmacologia , Norepinefrina/farmacologia
20.
Environ Toxicol ; 34(4): 476-485, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30623574

RESUMO

Steroid-insensitive asthma-related airway inflammation is associated with the expression of epidermal growth factor receptor (EGFR) tyrosine kinase in asthmatic bronchial epithelium. Proinflammatory cytokines IL-6 and IL-8 are related to steroid-insensitive asthma. It is currently unknown how EGFR-tyrosine kinase inhibitors (EGFR-TKIs) affects house dust mite (HDM)-induced asthma in terms of inflammatory cytokines related to steroid-resistant asthma and further signaling pathway. Cytokine expressions and EGFR signaling pathway were performed by ELISA, reverse transcriptase PCR, real-time PCR, and Western blot in cell-line models. AMP-activated protein kinase (AMPK) pathway-related inhibitors were applied to confirm the association between EGFR-TKI and AMPK pathway. HDM induced IL-6 and IL-8 in a dose-dependent manner. Both Erlotinib (Tarceva) and Osimertinib (AZD-9291) reduced the levels of HDM-stimulated IL-6 and IL-8 levels in BEAS-2B cells. AZD-9291 was more effective than Erlotinib in inhibiting phospho-EGFR, and downstream phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) and phopho-signal transducer and activator of transcription 3 (p-STAT3) pathway signaling. In addition, AMPK pathway-related inhibitor, Calcium-/calmodulin-dependent protein kinase kinase ß (CaMKKß) inhibitor, down-regulated IL-8, but EGFR-TKI had no effect on AMPK pathway. Our findings highlight EGFR-TKIs, Tarceva, and AZD-9291, attenuate HDM-induced inflammatory IL-6 and IL-8 cytokines via EGFR signaling axis pathway, but not AMPK signaling pathway.


Assuntos
Antígenos de Dermatophagoides/imunologia , Proteínas de Artrópodes/imunologia , Dermatophagoides pteronyssinus/imunologia , Células Epiteliais/efeitos dos fármacos , Receptores ErbB/antagonistas & inibidores , Interleucina-6/biossíntese , Interleucina-8/biossíntese , Acrilamidas/farmacologia , Compostos de Anilina/farmacologia , Animais , Asma/imunologia , Asma/prevenção & controle , Linhagem Celular , Relação Dose-Resposta a Droga , Células Epiteliais/imunologia , Receptores ErbB/metabolismo , Cloridrato de Erlotinib/farmacologia , Humanos , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/imunologia , Transdução de Sinais
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