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1.
Medicine (Baltimore) ; 100(7): e24321, 2021 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-33607766

RESUMO

ABSTRACT: Severe acute respiratory syndrome coronavirus (SARS-CoV)-2 induces severe infection, and it is responsible for a worldwide disease outbreak starting in late 2019. Currently, there are no effective medications against coronavirus. In the present study, we utilized a holistic bioinformatics approach to study gene signatures of SARS-CoV- and SARS-CoV-2-infected Calu-3 lung adenocarcinoma cells. Through the Gene Ontology platform, we determined that several cytokine genes were up-regulated after SARS-CoV-2 infection, including TNF, IL6, CSF2, IFNL1, IL-17C, CXCL10, and CXCL11. Differentially regulated pathways were detected by the Kyoto Encyclopedia of Genes and Genomes, gene ontology, and Hallmark platform, including chemokines, cytokines, cytokine receptors, cytokine metabolism, inflammation, immune responses, and cellular responses to the virus. A Venn diagram was utilized to illustrate common overlapping genes from SARS-CoV- and SARS-CoV-2-infected datasets. An Ingenuity pathway analysis discovered an enrichment of tumor necrosis factor- (TNF-) and interleukin (IL)-17-related signaling in a gene set enrichment analysis. Downstream networks were predicted by the Database for Annotation, Visualization, and Integrated Discovery platform also revealed that TNF and TNF receptor 2 signaling elicited leukocyte recruitment, activation, and survival of host cells after coronavirus infection. Our discovery provides essential evidence for transcript regulation and downstream signaling of SARS-CoV and SARS-CoV-2 infection.


Assuntos
/genética , Quimiocinas/biossíntese , Citocinas/biossíntese , Mediadores da Inflamação/metabolismo , Linhagem Celular Tumoral , Quimiocinas/genética , Citocinas/genética , Perfilação da Expressão Gênica , Ontologia Genética , Interações Hospedeiro-Patógeno , Humanos , Interleucina-17/biossíntese , Receptores Tipo II do Fator de Necrose Tumoral/biossíntese , Fator de Necrose Tumoral alfa/biossíntese , Regulação para Cima
2.
Int J Biol Macromol ; 171: 550-559, 2021 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-33444654

RESUMO

Larch arabinogalactan (AG), extracted from Larix gmelinii sawdust, was depolymerized by H2O2 oxidation and purified by gel column to yield a novel degraded fraction (AGD2). The structural analysis indicated AGD2 had lower arabinose content and molecular weight compared with AG, in which the ratio of galactose and arabinose was changed from 7:3 to 16:1, the molecular weight was decreased from 50.2 kDa to 3.7 kDa, and the chain conformation spread from highly branched structure to flexible strand. It was one kind of ß-D-(1 â†’ 3)-galactan with fewer ß-D-(1 â†’ 6)-Galp side branches at O-6 position. Further, the results of the Gal-3 binding and immunomodulatory assay suggested that the unbinding force of AGD2 onto Gal-3 was as twice as AG to be 76 ± 11 pN at the loading rate of 0.15 µm/s. It could better promote the secretion of pro-inflammatory cytokines (TNF-α, IL-6 and IL-1ß) than AG in a dose-dependent manner.


Assuntos
Galactanos/isolamento & purificação , Larix/química , Madeira/química , Animais , Arabinose/análise , Proteínas Sanguíneas/antagonistas & inibidores , Configuração de Carboidratos , Relação Dose-Resposta a Droga , Galactanos/química , Galactanos/farmacologia , Galactose/análise , Galectinas/antagonistas & inibidores , Fatores Imunológicos/química , Fatores Imunológicos/isolamento & purificação , Fatores Imunológicos/farmacologia , Interleucina-1beta/biossíntese , Interleucina-6/biossíntese , Metilação , Camundongos , Microscopia de Força Atômica , Ressonância Magnética Nuclear Biomolecular , Células RAW 264.7 , Fator de Necrose Tumoral alfa/biossíntese
3.
Int J Mol Sci ; 22(3)2021 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-33513808

RESUMO

There is little known about the effect of the periodontopathogen Filifactor alocis on macrophages as key cells of the innate immune defense in the periodontium. Therefore, the aim of the present study was to investigate the effect of F. alocis and additionally of the pro-inflammatory cytokine tumor necrosis factor-alpha (TNFα) on visfatin and other pro-inflammatory and proteolytic molecules associated with periodontitis in human macrophages. The presence of macrophage markers CD14, CD86, CD68, and CD163 was examined in gingival biopsies from healthy individuals and periodontitis patients. Human macrophages were incubated with F. alocis and TNFα for up to 2 d. The effects of both stimulants on macrophages were determined by real-time PCR, ELISA, immunocytochemistry, and immunofluorescence. F. alocis was able to significantly stimulate the synthesis of visfatin by human macrophages using TLR2 and MAPK pathways. In addition to visfatin, F. alocis was also able to increase the synthesis of cyclooxygenase 2, TNFα, and matrix metalloproteinase 1. Like F. alocis, TNFα was also able to stimulate the production of these proinflammatory and proteolytic molecules. Our results highlight the pathogenetic role of F. alocis in periodontal diseases and also underline the involvement of visfatin in the aetiopathogenesis of periodontitis.


Assuntos
Clostridiales/imunologia , Gengiva/metabolismo , Macrófagos/metabolismo , Nicotinamida Fosforribosiltransferase/biossíntese , Periodontite/imunologia , Receptor 2 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Antígenos CD/genética , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/genética , Antígenos de Diferenciação Mielomonocítica/metabolismo , Antígeno B7-2/genética , Antígeno B7-2/metabolismo , Ciclo-Oxigenase 2/biossíntese , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Gengiva/citologia , Gengiva/patologia , Humanos , Imuno-Histoquímica , Receptores de Lipopolissacarídeos/genética , Receptores de Lipopolissacarídeos/metabolismo , Sistema de Sinalização das MAP Quinases/imunologia , Macrófagos/efeitos dos fármacos , Metaloproteinase 1 da Matriz/biossíntese , Metaloproteinase 1 da Matriz/genética , Metaloproteinase 1 da Matriz/metabolismo , Nicotinamida Fosforribosiltransferase/genética , Nicotinamida Fosforribosiltransferase/metabolismo , Periodontite/metabolismo , Periodontite/microbiologia , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
4.
Methods Mol Biol ; 2248: 271-279, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33185884

RESUMO

Tumor necrosis factor superfamily (TNFSF) ligands and receptors have distinctive structural characters that link them to cell growth, cell survival, or cell death. Some of these can activate both inflammatory and apoptotic pathways, depending on target cell types and other extrinsic stimuli. Many of the TNF receptor superfamily molecules are expressed in cells of the immune system, which may be central to autoimmune and inflammatory diseases as well as cancer. However, the function of TNFSF members is not just restricted to immune cells. Members of TNFSF have been linked to an array of pathophysiologies, including cancer, neurologic, cardiovascular, pulmonary, autoimmune, and metabolic diseases. TNF-α of TNFSF is a pro-inflammatory cytokine produced by macrophages/monocytes, widely implicated in the pathogenesis of inflammatory disorders. In view of these facts, TNF-α has been recommended as an important target for discovering drugs for autoimmune and inflammatory diseases and cancer. Various cell-based assays to understand the role of TNF-α in inflammation and to estimate the concentrations of TNF-α levels in body fluids such as plasma, synovium, etc., are being followed by researchers. In this chapter, methods of cell viability assay, ELISA assay, RT-PCR, and western blot analysis for estimating LPS-induced TNF-α protein expressions are described in detail.


Assuntos
Bioensaio , Fator de Necrose Tumoral alfa/metabolismo , Animais , Bioensaio/métodos , Western Blotting , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Citocinas/genética , Citocinas/metabolismo , Ensaio de Imunoadsorção Enzimática , Expressão Gênica , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Células RAW 264.7 , Reação em Cadeia da Polimerase em Tempo Real , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/genética
5.
Acta Cir Bras ; 35(2): e202000202, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32267288

RESUMO

PURPOSE: To investigate the effects of adalimumab pretreatment on the lipopolysaccharide-mediated myocardial injury. METHODS: Twenty-eight Wistar rats were randomized into four groups (n=7). Control (C) group animals were injected once a day with intraperitoneal (i.p) 0.9 % saline for two days. In the Adalimumab (Ada) group, adalimumab was injected at a dose of 10 mg/kg/ day (i.p) for two days. Lipopolysaccharide (Lps) group rats were injected with a dose of 5 mg/kg (i.p) lipopolysaccharide. Lipopolysaccharide + Adalimumab (Lps+Ada) group rats received adalimumab before the administration of lipopolysaccharide. The animals were sacrificed 24 h after the last injection and blood samples were obtained for determination of biochemical cardiac injury markers and circulating levels of TNF-α and interleukin-6 (IL-6). Hearts were harvested for histological examination. RESULTS: Endotoxin exposure resulted in significant increases in serum cardiac injury markers, serum cytokines and histological myocardial injury scores in the Lps group. The levels of circulating cytokines, cardiac injury markers and histological injury scores for myocardial necrosis, perivascular cell infiltration, and inflammation were significantly reduced in Lps+Ada as compared to Lps group (p<0.05). CONCLUSIONS: Adalimumab pretreatment reduces endotoxin-induced myocardial damage in rats. This beneficial effect is thought to be related to the reduction of cytokine release.


Assuntos
Adalimumab/administração & dosagem , Cardiopatias/tratamento farmacológico , Lipopolissacarídeos/administração & dosagem , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Animais , Modelos Animais de Doenças , Endotoxinas , Feminino , Cardiopatias/induzido quimicamente , Ratos , Ratos Wistar , Fator de Necrose Tumoral alfa/biossíntese
6.
Medicine (Baltimore) ; 99(13): e19430, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32221067

RESUMO

INTRODUCTION: Loss of a dental element can generate several repercussions in the stomatognathic system. According to the latest survey by the Ministry of Health, in 2010, Brazilian adults had, on average, 7 missing teeth. This loss may lead to movement of the adjacent teeth and the antagonist, which would make prosthetic rehabilitation harder to do. Anchoring systems, such as mini-implants, have been increasingly used as a treatment option because they act with heavy but controlled forces and without side effects. Recent studies have shown that photobiomodulation (PBM) can accelerate orthodontic movement in molar intrusion. The objective of this study will be to evaluate the effect of PBM on the acceleration of the orthodontic movement of molar verticalization and its effect on pain and inflammation of the periodontal tissues. PATIENT CONCERNS:: the concerns assessments will be done over the study using anamnesis interviews and specific questionnaire. DIAGNOSIS: verticalization will be evaluated by clinical and radiographic analysis. INTERVENTIONS: Thirty four healthy patients aged 30 to 60 years, who need to recover the prosthetic space for oral rehabilitation after loss of the posterior inferior dental elements and inclination of the adjacent element, will be randomly divided into 2 groups: G1 (control group) - verticalization by mini-implant + PBM simulation (placebo); G2 (experimental group) - verticalization by mini-implant + PBM. The movements will occur with the aid of mini-implants and elastomeric chains ligatures. The PBM will occur with diode laser application, 808 nm, 100 mW, receiving 1J per point, 10 seconds, 10 points (5 per buccal and 5 per lingual) and radiant exposure of 25 J/cm. The orthodontic forces of verticalization (corresponding to any exchange of elastomeric ligation) will be applied every 30 days and the PBM will be applied immediately, 3 and 7 days of each month, for a period of 3 months. The crevicular gingival fluid (CGF) will be collected on the 1st, 3rd, and 7th days after the first activation, and then on the 3rd day of the following 2 months. OUTCOMES: Interleukins IL1ß, IL-6, IL-8, IL-10, and TNF-α will be analyzed by ELISA. Panoramic radiography will be performed at baseline and 90 afterwards to ascertain the amount (in degrees) of verticalization. To evaluate the pain, the Visual Analog Scale (VAS) will be used in all the consultations, and to evaluate the quality of life, the Oral Health Impact Profile (OHIP-14) questionnaire will be applied. Analgesics will be given and the quantity of drugs will be counted. If the data are normal, they will be submitted to Student t test. The data will be presented as means ± SD and the value of p will be defined as <0.05. DISCUSSION: This protocol will determine the effectiveness of photobiomoduation regarding the orthodontic movement of molar verticalization. ETHICS AND DISSEMINATION: This protocol received approval from the Human Research Ethics Committee of Universidade Nove de Julho (certificate number: 3 533 219). The data will be published in a peer-reviewed periodical.


Assuntos
Interleucinas/biossíntese , Terapia com Luz de Baixa Intensidade/métodos , Dente Molar/efeitos da radiação , Técnicas de Movimentação Dentária/métodos , Adulto , Brasil , Método Duplo-Cego , Feminino , Líquido do Sulco Gengival , Humanos , Lasers Semicondutores , Masculino , Pessoa de Meia-Idade , Dor/etiologia , Medição da Dor , Qualidade de Vida , Técnicas de Movimentação Dentária/efeitos adversos , Fator de Necrose Tumoral alfa/biossíntese
7.
Sci Rep ; 10(1): 2886, 2020 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-32076052

RESUMO

A continuing quest for specific inhibitors of proinflammatory cytokines brings promise for effective therapies designed for inflammatory and autoimmune disorders. Cefazolin, a safe, first-generation cephalosporin antibiotic, has been recently shown to specifically interact with interleukin 15 (IL-15) receptor subunit α (IL-15Rα) and to inhibit IL-15-dependent TNF-α and IL-17 synthesis. The aim of this study was to elucidate cefazolin activity against IL-2, IL-4, IL-15 and IL-21, i.e. four cytokines sharing the common cytokine receptor γ chain (γc). In silico, molecular docking unveiled two potential cefazolin binding sites within the IL-2/IL-15Rß subunit and two within the γc subunit. In vitro, cefazolin decreased proliferation of PBMC (peripheral blood mononuclear cells) following IL-2, IL-4 and IL-15 stimulation, reduced production of IFN-γ, IL-17 and TNF-α in IL-2- and IL-15-treated PBMC and in IL-15 stimulated natural killer (NK) cells, attenuated IL-4-dependent expression of CD11c in monocyte-derived dendritic cells and suppressed phosphorylation of JAK3 in response to IL-2 and IL-15 in PBMC, to IL-4 in TF-1 (erythroleukemic cell line) and to IL-21 in NK-92 (NK cell line). The results of the study suggest that cefazolin may exert inhibitory activity against all of the γc receptor-dependent cytokines, i.e. IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21.


Assuntos
Anti-Inflamatórios/farmacologia , Cefazolina/farmacologia , Subunidade gama Comum de Receptores de Interleucina/antagonistas & inibidores , Adulto , Anti-Inflamatórios/química , Sítios de Ligação , Antígeno CD11c/metabolismo , Cefazolina/química , Proliferação de Células/efeitos dos fármacos , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Humanos , Interferon gama/metabolismo , Subunidade gama Comum de Receptores de Interleucina/química , Subunidade gama Comum de Receptores de Interleucina/metabolismo , Interleucina-15/metabolismo , Interleucina-2/metabolismo , Janus Quinase 3/metabolismo , Masculino , Monócitos/patologia , Fosforilação/efeitos dos fármacos , Fator de Necrose Tumoral alfa/biossíntese
8.
Lasers Med Sci ; 35(5): 1205-1212, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32030556

RESUMO

The aim of this study was to assess the effects of IL-6 and IL-8 cytokines on human gingival fibroblasts (HGF) cultured in a 3-D model and the possible photobiomodulation (PBM) of such effects by low-level laser therapy. In complete culture medium (DMEM), HGF from a healthy patient were seeded in a type I collagen matrix inserted into 24-well plates. After 5 days of incubation, the cytokines were added or not to serum-free DMEM, which was applied to the cell-enriched matrices. Then, PBM was performed: three consecutive irradiations using LaserTable diode device (780 nm, 0.025 W) at 0.5 J/cm2 were delivered or not to the cells. Twenty-four hours after the last irradiation, cell viability and morphology, gene expression, and synthesis of inflammatory cytokines and growth factors were assessed. The histological evaluation demonstrated that, for all groups, matrices presented homogeneous distribution of cells with elongated morphology. However, numerous cytokine-exposed cells were rounded. IL-6 and IL-8 decreased cell viability, synthesis of VEGF, and gene expression of collagen type I. PBM enhanced cell density in the matrices and stimulated VEGF expression, even after IL-6 challenge. Reduced TNF-α synthesis occurred in those cells subjected to PBM. In conclusion, PBM can penetrate collagen matrix and stimulate HGF, highlighting the relevance of this research model for further phototherapy studies and in vitro biomodulation of the healing process.


Assuntos
Técnicas de Cultura de Células/métodos , Citocinas/metabolismo , Fibroblastos/patologia , Fibroblastos/efeitos da radiação , Gengiva/patologia , Inflamação/patologia , Terapia com Luz de Baixa Intensidade , Modelos Biológicos , Sobrevivência Celular/efeitos da radiação , Colágeno Tipo I/metabolismo , Regulação da Expressão Gênica/efeitos da radiação , Humanos , Interleucina-1beta/biossíntese , Fator de Necrose Tumoral alfa/biossíntese , Fator A de Crescimento do Endotélio Vascular/biossíntese , Cicatrização/efeitos da radiação
9.
Eur J Pharmacol ; 873: 172979, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32014488

RESUMO

Dialysis requiring renal failure is a silent epidemic. Despite an annual mortality of 24% the dialysis population has increased by 1-4% per annum. Regardless of the initial injury, tubulointerstitial fibrosis is a feature of the renal pathology and it inversely correlates with declining renal function. Current agents display little efficacy against tubulointerstitial fibrosis. Clearly, therapies effective against tubulointerstitial fibrosis and able to preserve kidney function are needed. Vasoactive intestinal peptide (VIP) has been shown to reverse pre-existing cardiac fibrosis. We sought to determine whether VIP is effective in tubulointerstitial fibrosis. Spontaneous hypertensive rats (SHR) on a 2.2% salt diet were randomised to zero time control, 4 week infusion of VIP (5 pmol/kg/min) or vehicle control infusion. A fourth group, to match the blood pressure reduction achieved in the VIP infused group was included. Fibrosis was quantitated by computerised histomorphometry, changes in pro-fibrotic mediators were measured by quantitative rt-PCR and macrophage activation assessed by cyclic adenosine monophosphate (c-AMP) response to incubation with VIP. Tubulointerstitial fibrosis in the VIP treated rats was significantly lower than the zero time control (P < 0.0005), the vehicle infused control (P < 0.0005) and the blood pressure matched group (P < 0.01). Although all six profibrotic mediators increased over the 4 week experimental period VIP infusion only decreased tumour necrosis alpha (TNFα) expression significantly (P < 0.001). Incubation of RAW264 macrophages with VIP significantly increased c-AMP (P < 0.01). We conclude that VIP infusion reversed existing tubulointerstitial fibrosis suggesting a possible therapeutic role for a VIP based therapy in chronic kidney disease.


Assuntos
Pressão Sanguínea/efeitos dos fármacos , Nefrite Intersticial/tratamento farmacológico , Peptídeo Intestinal Vasoativo/uso terapêutico , Animais , AMP Cíclico/farmacologia , Fibrose , Expressão Gênica/efeitos dos fármacos , Infusões Intravenosas , Rim/patologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Camundongos , Nefrite Intersticial/genética , Nefrite Intersticial/patologia , Células RAW 264.7 , Ratos , Ratos Endogâmicos SHR , Sódio na Dieta , Fator de Necrose Tumoral alfa/biossíntese , Peptídeo Intestinal Vasoativo/administração & dosagem
10.
FASEB J ; 34(2): 2024-2040, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31909582

RESUMO

Docosahexaenoic acid (DHA) is a ω-3 fatty acid typically obtained from the diet or endogenously synthesized through the action of elongases (ELOVLs) and desaturases. DHA is a key central nervous system constituent and the precursor of several molecules that regulate the resolution of inflammation. In the present study, we questioned whether the impaired synthesis of DHA affected neural plasticity and inflammatory status in the adult brain. To address this question, we investigated neural and inflammatory markers from mice deficient for ELOVL2 (Elovl2-/- ), the key enzyme in DHA synthesis. From our findings, Elovl2-/- mice showed an altered expression of markers involved in synaptic plasticity, learning, and memory formation such as Egr-1, Arc1, and BDNF specifically in the cerebral cortex, impacting behavioral functions only marginally. In parallel, we also found that DHA-deficient mice were characterized by an increased expression of pro-inflammatory molecules, namely TNF, IL-1ß, iNOS, caspase-1 as well as the activation and morphologic changes of microglia in the absence of any brain injury or disease. Reintroducing DHA in the diet of Elovl2-/- mice reversed such alterations in brain plasticity and inflammation. Hence, impairment of systemic DHA synthesis can modify the brain inflammatory and neural plasticity status, supporting the view that DHA is an essential fatty acid with an important role in keeping inflammation within its physiologic boundary and in shaping neuronal functions in the central nervous system.


Assuntos
Encéfalo/metabolismo , Ácidos Docosa-Hexaenoicos/biossíntese , Regulação da Expressão Gênica , Microglia/metabolismo , Plasticidade Neuronal , Animais , Biomarcadores/metabolismo , Encéfalo/patologia , Fator Neurotrófico Derivado do Encéfalo/biossíntese , Fator Neurotrófico Derivado do Encéfalo/genética , Caspase 1/biossíntese , Caspase 1/genética , Ácidos Docosa-Hexaenoicos/genética , Proteína 1 de Resposta de Crescimento Precoce/biossíntese , Proteína 1 de Resposta de Crescimento Precoce/genética , Elongases de Ácidos Graxos/deficiência , Elongases de Ácidos Graxos/metabolismo , Inflamação/genética , Inflamação/metabolismo , Interleucina-1beta/biossíntese , Interleucina-1beta/genética , Camundongos , Camundongos Knockout , Microglia/patologia , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/genética
11.
J Immunother Cancer ; 8(1)2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31940588

RESUMO

BACKGROUND: Ovarian cancers often contain significant numbers of tumor-infiltrating lymphocytes (TILs) that can be readily harnessed for adoptive T-cell therapy (ACT). However, the immunosuppressive ovarian tumor microenvironment and lack of tumor reactivity in TILs can limit the effectiveness of the therapy. We hypothesized that by using an oncolytic adenovirus (Ad5/3-E2F-D24-hTNFa-IRES-hIL2; TILT-123) to deliver tumor necrosis factor alpha (TNFa) and interleukin-2 (IL-2), we could counteract immunosuppression, and enhance antitumor TIL responses in ovarian cancer (OVCA). METHODS: We established ex vivo tumor cultures freshly derived from patients with advanced OVCA and evaluated the effects of Ad5/3-E2F-D24-hTNFa-IRES-hIL2 or Ad5/3-E2F-D24 (the control virus without TNFa and IL-2) on TILs, cytokine response and tumor viability. Tumor reactivity was assessed by determining interferon gamma (IFNg) response of clinically relevant TILs towards autologous T-cell-depleted ex vivo tumor cultures pretreated with or without the aforementioned oncolytic adenoviruses. RESULTS: Treatment of ex vivo tumor cultures with Ad5/3-E2F-D24-hTNFa-IRES-hIL2 caused a substantial rise in proinflammatory signals: increased secretion of IFNg, CXCL10, TNFa and IL-2, and concomitant activation of CD4+ and CD8+ TILs. Potent tumor reactivity was seen, as clinically relevant TIL secreted high levels of IFNg in response to autologous T-cell-depleted ovarian ex vivo tumor cultures treated with Ad5/3-E2F-D24-hTNFa-IRES-hIL2. This phenomenon was independent of PD-L1 expression in tumor cells, a factor that determined the variability of IFNg responses seen in different patient samples. CONCLUSIONS: Overall, oncolytic adenovirus Ad5/3-E2F-D24-hTNFa-IRES-hIL2 was able to rewire the ovarian tumor microenvironment to accommodate heightened antitumor TIL reactivity. Such effects may improve the clinical effectiveness of ACT with TILs in patients with advanced OVCA.


Assuntos
Interleucina-2/imunologia , Linfócitos do Interstício Tumoral/imunologia , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos/imunologia , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/terapia , Microambiente Tumoral/imunologia , Fator de Necrose Tumoral alfa/imunologia , Células A549 , Feminino , Humanos , Interferon gama/metabolismo , Interleucina-2/biossíntese , Interleucina-2/genética , Vírus Oncolíticos/genética , Neoplasias Ovarianas/metabolismo , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/genética
12.
Org Lett ; 22(1): 257-260, 2020 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-31860319
13.
Curr Diabetes Rev ; 16(8): 889-894, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31733638

RESUMO

BACKGROUND: Obesity-induced chronic inflammation is a key component in the pathogenesis of insulin resistance and type-2 diabetes Objective: This study aimed to evaluate the effect of swimming exercise on pancreatic expression levels of inflammatory cytokines, miR-146a and NF-кB in type-2 diabetic male rats. METHODS: Twenty- eight male Wistar rats were divided into four groups: control (Con), exercise, diabetes and diabetic exercise (n = 7). Diabetes induction performed by the combination of high-fat diet (HFD, 4 weeks) and streptozotocin (35 mg/kg. ip). After induction of diabetes, the rats swam in the exercise groups for 12 weeks. Then, blood and tissue samples were collected. RESULTS: Our results indicated a significant increase in expression levels of miR-146, NF-κB and inflammatory cytokines (IL-6, TNF-α, and IL-1ß) while a significant decrease in pancreatic expression levels of TRAF6 and IRAK1 in diabetic group as compared to the control group. In contrast, swimming exercise resulted in a significant decrease in expression levels of miR-146a, NF-кB and inflammatory cytokines and a significant increase in expression levels of TRAF6 and IRAK1 in the exercise-diabetic group compared to the diabetic group. CONCLUSION: Our results indicated a significant increase in expression levels of miR-146, NF-κB and inflammatory cytokines (IL-6, TNF-α, and IL-1ß) while a significant decrease in pancreatic expression levels of TRAF6 and IRAK1 in diabetic group as compared to the control group. In contrast, swimming exercise resulted in a significant decrease in expression levels of miR-146a, NF-кB and inflammatory cytokines and a significant increase in expression levels of TRAF6 and IRAK1 in the exercise-diabetic group compared to the diabetic group.


Assuntos
Citocinas/biossíntese , Diabetes Mellitus Tipo 2/metabolismo , MicroRNAs/biossíntese , NF-kappa B/biossíntese , Pâncreas/metabolismo , Natação/fisiologia , Animais , Diabetes Mellitus Experimental/metabolismo , Modelos Animais de Doenças , Quinases Associadas a Receptores de Interleucina-1/biossíntese , Interleucina-1beta/biossíntese , Interleucina-6/biossíntese , Masculino , Ratos , Ratos Wistar , Fator 6 Associado a Receptor de TNF/biossíntese , Fator de Necrose Tumoral alfa/biossíntese
14.
J Neuroimmunol ; 338: 577082, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31707103

RESUMO

ß2-adrenoceptors are G-protein coupled receptors expressed on both astrocytes and microglia that play a key role in mediating the anti-inflammatory actions of noradrenaline in the CNS. Here the effect of an inflammatory stimulus (LPS + IFN-γ) was examined on glial ß2-adrenoceptor expression and function. Exposure of glia to LPS + IFN-γ decreased ß2-adrenoceptor mRNA and agonist-stimulated production of the intracellular second messenger cAMP. Pre-treatment with the synthetic glucocorticoid and potent anti-inflammatory agent dexamethasone prevented the LPS + IFN-γ-induced suppression of ß2-adrenoceptor mRNA expression. These results raise the possibility that inflammation-mediated ß2-adrenoceptor downregulation in glia may dampen the innate anti-inflammatory properties of noradrenaline in the CNS.


Assuntos
Dexametasona/farmacologia , Inflamação/metabolismo , Neuroglia/efeitos dos fármacos , Receptores Adrenérgicos beta 2/efeitos dos fármacos , Animais , Células Cultivadas , AMP Cíclico/biossíntese , Interferon beta/farmacologia , Interferon gama/farmacologia , Lipopolissacarídeos/farmacologia , Neuroglia/metabolismo , Ratos , Ratos Wistar , Receptores Adrenérgicos beta 2/genética , Receptores Adrenérgicos beta 2/fisiologia , Fator de Necrose Tumoral alfa/biossíntese
15.
Micron ; 129: 102796, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31821933

RESUMO

Ultra-fine grained biodegradable Mg-based Mg1Zn1Mn0.3 Zr - HA and Mg4Y5.5Dy0.5 Zr - 45S5 Bioglass composites have shown great medical potential. Two types of these Mg-based biomaterials subjected to different treatments were tested and as shown earlier they are biocompatible. The aim of the study is to determine how much culture media incubated with these ultra-fine trained Mg-based composites can cause inflammatory reactions and /or periodontal cell death. The incubation of composites in the medium releases metal ions into the solution. It can be assumed that this process is permanent and also occurs in the human body. The results have shown that the effect of proinflammatory IL-6 and TNF- cytokines results in the strongest production of the acute phase proteins in the first day on the Mg1Zn1Mn0.3 Zr-5 wt.% HA-1 wt. % Ag HF-treated biocomposite after immersion for 2 h in 40 % HF and then the fastest decrease in these processes on the third day. In turn, the inflammatory process induced on the Mg1Zn1Mn0.3 Zr-5 wt.% HA-1 wt. % Ag biomaterial, in BAX / BCL ratio assessment, is the strongest on the third day and maintains a significantly high level on the following day, which, at the same time, confirms its persistence and development. In addition, these results confirm the successively generated necrotic processes. Ions can induce inflammatory reactions, which in the case of the implant may take a long time, which results in the loss of the implant. Even if the material is biocompatible in rapid in-vitro tests, it can induce inflammation in the body after some time due to the release of ions. Not every treatment improves the material's properties in terms of subsequent safety.


Assuntos
Materiais Biocompatíveis/farmacologia , Compostos de Magnésio/farmacologia , Magnésio/farmacologia , Teste de Materiais/métodos , Periodonto/efeitos dos fármacos , Células Cultivadas , Cerâmica/farmacologia , Vidro , Humanos , Inflamação/induzido quimicamente , Interleucina-6/biossíntese , Osteoblastos/efeitos dos fármacos , Periodonto/citologia , Próteses e Implantes , Propriedades de Superfície , Fator de Necrose Tumoral alfa/biossíntese
16.
Neurourol Urodyn ; 39(1): 96-107, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31584215

RESUMO

OBJECTIVE: To evaluate the histological response to and changes in the biomechanical properties of titanized polypropylene lightweight mesh and conventional polypropylene mesh at 1 and 12 weeks following implantation in the sheep vagina. METHODS: We compared a titanized polypropylene lightweight mesh (TiLOOP Mesh) to a conventional polypropylene mesh (Gynemesh PS) in a sheep vagina model. Explants were harvested after 1 and 12 weeks (n = 6/mesh type/time point) for histological observation. After 12 weeks, mesh-tissue complex specimens were biomechanically assessed by a uniaxial tension system. RESULTS: One week after implantation, there was no significant difference in the inflammatory response between the two groups. Twelve weeks after implantation, the TiLOOP light mesh elicited a lower inflammatory response than was observed for the Gynemesh PS (1.44 ± 0.61 vs 2.05 ± 0.80, P = .015). Twelve weeks after implantation, the collagen I/III ratio was lower in the TiLOOP light mesh group than in the Gynemesh PS group (9.41 ± 5.06 vs 15.21 ± 8.21, P = .019). The messenger RNA expression levels of the inflammatory factors interleukin 10 and tumor necrosis factor α were lower in the TiLOOP Mesh group than in the Gynemesh PS group at both 1 and 12 weeks (P < .05). There were no significant differences in any of the evaluated biomechanical characteristics between the two meshes (P > .05). CONCLUSION: Although the titanized polypropylene lightweight mesh induces slightly less tissue reactivity and has better in vivo biocompatibility, further studies should be conducted including the complications and the success rate of pelvic organ prolapse in patients before recommending it in pelvic floor reconstruction.


Assuntos
Materiais Biocompatíveis , Teste de Materiais , Polipropilenos , Telas Cirúrgicas , Titânio , Animais , Fenômenos Biomecânicos , Colágeno/metabolismo , Feminino , Inflamação/etiologia , Interleucina-10/biossíntese , Diafragma da Pelve/cirurgia , Carneiro Doméstico , Fator de Necrose Tumoral alfa/biossíntese , Vagina
17.
J Thromb Thrombolysis ; 49(2): 228-234, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31612355

RESUMO

Antiphospholipid antibodies (aPL) are heterogeneous and there is evidence that binding specificity determines which cellular effects they can trigger. We have therefore hypothesised that the induction of tissue factor (TF) in monocytes and endothelial cells by aPL depends on their binding specificity. To further investigate this, we have analyzed the ability of three human monoclonal aPL with distinctly different binding specificities to induce transcription and cell surface expression of TF in monocytes and endothelial cells. Results with human monoclonal aPL were validated with IgG-fractions obtained from patients with APS. We confirmed previous results that a lipid reactive human monoclonal aPL rapidly induced TF transcription and cell surface expression in monocytes and endothelial cells. A monoclonal aPL reactive against ß2 glycoprotein I (ß2GPI) induced TF with a delayed time course. This was fully dependent on the induction of tumor necrosis factor alpha (TNFα) secretion as capture of TNFα by adalimumab prevented TF induction. This pattern was confirmed with patient IgG fractions. Both lipid reactive and anti-ß2GPI induced TF transcription. Unexpectedly, this activity of anti-ß2GPI was mediated fully by TNFα which was secreted in response to incubation with anti-ß2GPI. The role of TNFα in mediating TF induction by anti-ß2GPI may have wider implications for APS pathogenesis.


Assuntos
Anticorpos Monoclonais/farmacologia , Tromboplastina/biossíntese , Fator de Necrose Tumoral alfa/biossíntese , beta 2-Glicoproteína I/farmacologia , Expressão Gênica , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Tromboplastina/genética , Fator de Necrose Tumoral alfa/genética
18.
J Dig Dis ; 21(1): 38-45, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31714673

RESUMO

OBJECTIVES: The activation of the adenosine A3 receptor (A3AR) can regulate inflammation, but the way that this regulates colonic mucosal inflammation in ulcerative colitis (UC) remains unclear. This study aimed at examining A3AR expression and investigating the effect of A3AR activation on ex vivo cytokine expression and nuclear factor-kappa B (NF-κB) signaling in colonic mucosa. METHODS: Colonic mucosal biopsied tissue from 18 patients with UC and 11 healthy controls was tested for A3AR expression by immunofluorescence, quantitative real-time polymerase chain reaction and Western blot. Following treatment for 24 hours with or without 2-Cl-IB-MECA, an A3AR agonist, TNF-α and IL-1ß secreted by the cultured colonic mucosal tissue were quantified by ELISA. The colonic mucosal epithelia were dissected and treated with, or without 2-Cl-IB-MECA for 24 hours. The NF-κB p65 protein and its distribution in the cultured colonic epithelia were examined by immunofluorescence and Western blot. RESULTS: Compared with the controls, down-regulated A3AR expression and up-regulated TNF-α and IL-1ß production and NF-κB p65 protein were observed in the UC colonic mucosa. The activation of A3AR by 2-Cl-IB-MECA significantly decreased TNF-α and IL-1ß production and attenuated the NF-κB p65 activation in colonic tissues from patients with UC. CONCLUSIONS: A3AR activation inhibited inflammation by mitigating pro-inflammatory cytokine production and the NF-κB signal activation in colonic mucosa of patients with UC. A3AR activation may play a role in the pathogenesis of UC.


Assuntos
Adenosina/análogos & derivados , Colite Ulcerativa/imunologia , Colo/imunologia , NF-kappa B/metabolismo , Agonistas do Receptor Purinérgico P1/farmacologia , Receptor A3 de Adenosina/imunologia , Adenosina/farmacologia , Adenosina/uso terapêutico , Colite Ulcerativa/tratamento farmacológico , Colo/efeitos dos fármacos , Citocinas/antagonistas & inibidores , Citocinas/biossíntese , Citocinas/imunologia , Regulação para Baixo , Humanos , Inflamação/tratamento farmacológico , Inflamação/imunologia , Interleucina-1beta/biossíntese , Interleucina-1beta/imunologia , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/imunologia , NF-kappa B/biossíntese , Fragmentos de Peptídeos/biossíntese , Fragmentos de Peptídeos/imunologia , Agonistas do Receptor Purinérgico P1/uso terapêutico , Receptor A3 de Adenosina/biossíntese , Transdução de Sinais , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/imunologia , Regulação para Cima
19.
Nat Prod Res ; 34(3): 351-358, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30580601

RESUMO

A new sesquiterpene (1) and a new monoterpene (2), together with thirteen known compounds (3-15) were isolated from an ethanol extract of the roots of Aristolochia debilis Sieb. et Zucc. The structures of compounds 1 and 2 were elucidated using HR-ESI-MS, 1D and 2D NMR spectroscopy. Anti-inflammatory effects of the isolated compounds were evaluated in terms of inhibition of nitric oxide, tumour-necrosis factor-α and interleukin-6 production in lipopolysaccharide-stimulated RAW264.7 cells. Compounds 1-9 and 12-15 significantly inhibited the levels of NO, TNF-α and IL-6 in LPS-induced RAW264.7 cells from concentrations of 3 µM to 30 µM.


Assuntos
Anti-Inflamatórios/isolamento & purificação , Aristolochia/química , Monoterpenos/isolamento & purificação , Raízes de Plantas/química , Sesquiterpenos/isolamento & purificação , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Interleucina-6/antagonistas & inibidores , Interleucina-6/biossíntese , Lipopolissacarídeos , Camundongos , Estrutura Molecular , Monoterpenos/química , Monoterpenos/farmacologia , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Células RAW 264.7 , Sesquiterpenos/química , Sesquiterpenos/farmacologia , Análise Espectral/métodos , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/biossíntese
20.
Nat Prod Res ; 34(2): 225-232, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30580619

RESUMO

One new aryldihydronaphthalene-type lignan (1) together with eight known lignans (2-4, 7-11) as well as two caffeic-acid dimers (5, 6) were isolated from an ethanol extract of the whole plant of Corispermum mongolicum Iljin (Chenopodiaceae). The chemical structures of these compounds were determined from 1D and 2D NMR and HR-ESI-MS spectra, and results were compared with data from the literature. This study is the first demonstration of nine compounds (2 and 4-11) isolated from the Chenopodiaceae family, with one of these (3) from the genus Corispermum. Anti-inflammatory effects of the isolated compounds were evaluated in terms of inhibition of production of nitric oxide, tumour necrosis factor-α, and interleukin-6 in lipopolysaccharide-induced RAW 264.7 cells.


Assuntos
Anti-Inflamatórios/isolamento & purificação , Chenopodiaceae/química , Lignanas/isolamento & purificação , Extratos Vegetais/química , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Chenopodiaceae/metabolismo , Interleucina-6/biossíntese , Lignanas/química , Lignanas/farmacologia , Lipopolissacarídeos , Camundongos , Estrutura Molecular , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Células RAW 264.7 , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/efeitos dos fármacos
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