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1.
EBioMedicine ; 44: 516-529, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31130472

RESUMO

BACKGROUND: Zika virus (ZIKV) infection during pregnancy may cause major congenital defects, including microcephaly, ocular, articular and muscle abnormalities, which are collectively defined as Congenital Zika Syndrome. Here, we performed an in-depth characterization of the effects of congenital ZIKV infection (CZI) in immunocompetent mice. METHODS: Pregnant dams were inoculated with ZIKV on embryonic day 5.5 in the presence or absence of a sub-neutralizing dose of a pan-flavivirus monoclonal antibody (4G2) to evaluate the potential role of antibody-dependent enhancement phenomenon (ADE) during short and long outcomes of CZI. FINDINGS: ZIKV infection induced maternal immune activation (MIA), which was associated with occurrence of foetal abnormalities and death. Therapeutic administration of AH-D antiviral peptide during the early stages of pregnancy prevented ZIKV replication and death of offspring. In the post-natal period, CZI was associated with a decrease in whole brain volume, ophthalmologic abnormalities, changes in testicular morphology, and disruption in bone microarchitecture. Some alterations were enhanced in the presence of 4G2 antibody. INTERPRETATION: Our results reveal that early maternal ZIKV infection causes several birth defects in immunocompetent mice, which can be potentiated by ADE phenomenon and are associated with MIA. Additionally, antiviral treatment with AH-D peptide may be beneficial during early maternal ZIKV infection. FUND: This work was supported by the Brazilian National Science Council (CNPq, Brazil), Minas Gerais Foundation for Science (FAPEMIG), Funding Authority for Studies and Projects (FINEP), Coordination of Superior Level Staff Improvement (CAPES), National Research Foundation of Singapore and Centre for Precision Biology at Nanyang Technological University.


Assuntos
Anticorpos Facilitadores/imunologia , Interações Hospedeiro-Patógeno/imunologia , Complicações Infecciosas na Gravidez , Infecção por Zika virus/imunologia , Infecção por Zika virus/virologia , Zika virus/fisiologia , Animais , Anticorpos Antivirais/imunologia , Antivirais/farmacologia , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/patologia , Encéfalo/efeitos dos fármacos , Encéfalo/imunologia , Encéfalo/patologia , Encéfalo/virologia , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Camundongos , Peptídeos/farmacologia , Gravidez , Baço/efeitos dos fármacos , Baço/imunologia , Baço/patologia , Baço/virologia , Síndrome , Resultado do Tratamento , Carga Viral , Infecção por Zika virus/diagnóstico , Infecção por Zika virus/tratamento farmacológico
2.
Future Microbiol ; 14: 1511-1525, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31913059

RESUMO

Aim: Characterize the course of acute Aspergillus fumigatus lung infection in immunocompetent mice, investigating the immunological, pathological and tissue functional modifications. Materials & methods: C57BL/6 mice were intranasally infected with A. fumigatus conidia and euthanized to access inflammatory parameters. Results: Mice infected with A. fumigatus showed an inoculum-dependent lethality and body weight loss. An intense proinflammatory cytokine release, neutrophil infiltrate and pulmonary dysfunction was also observed in the early phase of infection. In the late phase of infection, proresolving mediators release, apoptosis and efferocytosis increased and lung tissue architecture is restored. Conclusion: Our study characterized an immunocompetent model of acute pulmonary Aspergillus infection in mice and opened an array of possibilities for investigations on interactions of A. fumigatus with host-immune system.


Assuntos
Lesão Pulmonar Aguda/microbiologia , Aspergillus fumigatus/patogenicidade , Citocinas/imunologia , Imunocompetência , Pulmão/microbiologia , Lesão Pulmonar Aguda/imunologia , Animais , Apoptose , Aspergillus fumigatus/imunologia , Modelos Animais de Doenças , Interações Hospedeiro-Patógeno/imunologia , Inflamação , Pulmão/imunologia , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/imunologia
3.
Front Immunol ; 9: 975, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29867955

RESUMO

Influenza A virus (IAV) infection causes severe pulmonary disease characterized by intense leukocyte infiltration. Phosphoinositide-3 kinases (PI3Ks) are central signaling enzymes, involved in cell growth, survival, and migration. Class IB PI3K or phosphatidyl inositol 3 kinase-gamma (PI3Kγ), mainly expressed by leukocytes, is involved in cell migration during inflammation. Here, we investigated the contribution of PI3Kγ for the inflammatory and antiviral responses to IAV. PI3Kγ knockout (KO) mice were highly susceptible to lethality following infection with influenza A/WSN/33 H1N1. In the early time points of infection, infiltration of neutrophils was higher than WT mice whereas type-I and type-III IFN expression and p38 activation were reduced in PI3Kγ KO mice resulting in higher viral loads when compared with WT mice. Blockade of p38 in WT macrophages infected with IAV reduced levels of interferon-stimulated gene 15 protein to those induced in PI3Kγ KO macrophages, suggesting that p38 is downstream of antiviral responses mediated by PI3Kγ. PI3Kγ KO-derived fibroblasts or macrophages showed reduced type-I IFN transcription and altered pro-inflammatory cytokines suggesting a cell autonomous imbalance between inflammatory and antiviral responses. Seven days after IAV infection, there were reduced infiltration of natural killer cells and CD8+ T lymphocytes, increased concentration of inflammatory cytokines in bronchoalveolar fluid, reduced numbers of resolving macrophages, and IL-10 levels in PI3Kγ KO. This imbalanced environment in PI3Kγ KO-infected mice culminated in enhanced lung neutrophil infiltration, reactive oxygen species release, and lung damage that together with the increased viral loads, contributed to higher mortality in PI3Kγ KO mice compared with WT mice. In humans, we tested the genetic association of disease severity in influenza A/H1N1pdm09-infected patients with three potentially functional PIK3CG single-nucleotide polymorphisms (SNPs), rs1129293, rs17847825, and rs2230460. We observed that SNPs rs17847825 and rs2230460 (A and T alleles, respectively) were significantly associated with protection from severe disease using the recessive model in patients infected with influenza A(H1N1)pdm09. Altogether, our results suggest that PI3Kγ is crucial in balancing antiviral and inflammatory responses to IAV infection.


Assuntos
Classe Ib de Fosfatidilinositol 3-Quinase/genética , Inflamação , Influenza Humana/imunologia , Infecções por Orthomyxoviridae/imunologia , Adolescente , Adulto , Animais , Antivirais , Linfócitos T CD8-Positivos/imunologia , Classe Ib de Fosfatidilinositol 3-Quinase/imunologia , Citocinas/imunologia , Modelos Animais de Doenças , Feminino , Estudos de Associação Genética , Humanos , Vírus da Influenza A Subtipo H1N1 , Sistema de Sinalização das MAP Quinases , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Infiltração de Neutrófilos , Polimorfismo de Nucleotídeo Único , Adulto Jovem
4.
Front Microbiol ; 8: 1235, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28769876

RESUMO

In its hyphal form, Candida albicans invades epithelial and endothelial cells by two distinct mechanisms: active penetration and induced endocytosis. The latter is dependent on a reorganization of the host cytoskeleton (actin/cortactin recruitment), whilst active penetration does not rely on the host's cellular machinery. The first obstacle for the fungus to reach deep tissues is the epithelial barrier and this interaction is crucial for commensal growth, fungal pathogenicity and host defense. This study aimed to characterize in vitro epithelial HeLa cell invasion by four different isolates of C. albicans with distinct clinical backgrounds, including a C. albicans SC5314 reference strain. All isolates invaded HeLa cells, recruited actin and cortactin, and induced the phosphorylation of both Src-family kinases (SFK) and cortactin. Curiously, L3881 isolated from blood culture of a patient exhibited the highest resistance to oxidative stress, although this isolate showed reduced hyphal length and displayed the lowest cell damage and invasion rates. Collectively, these data suggest that the ability of C. albicans to invade HeLa cells, and to reach and adapt to the host's blood, including resistance to oxidative stress, may be independent of hyphal length.

5.
J Biol Chem ; 292(33): 13758-13773, 2017 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-28655761

RESUMO

Annexin A1 (AnxA1) is a glucocorticoid-regulated protein known for its anti-inflammatory and pro-resolving effects. We have shown previously that the cAMP-enhancing compounds rolipram (ROL; a PDE4 inhibitor) and Bt2cAMP (a cAMP mimetic) drive caspase-dependent resolution of neutrophilic inflammation. In this follow-up study, we investigated whether AnxA1 could be involved in the pro-resolving properties of these compounds using a model of LPS-induced inflammation in BALB/c mice. The treatment with ROL or Bt2cAMP at the peak of inflammation shortened resolution intervals, improved resolution indices, and increased AnxA1 expression. In vitro studies showed that ROL and Bt2cAMP induced AnxA1 expression and phosphorylation, and this effect was prevented by PKA inhibitors, suggesting the involvement of PKA in ROL-induced AnxA1 expression. Akin to these in vitro findings, H89 prevented ROL- and Bt2cAMP-induced resolution of inflammation, and it was associated with decreased levels of intact AnxA1. Moreover, two different strategies to block the AnxA1 pathway (by using N-t-Boc-Met-Leu-Phe, a nonselective AnxA1 receptor antagonist, or by using an anti-AnxA1 neutralizing antiserum) prevented ROL- and Bt2cAMP-induced resolution and neutrophil apoptosis. Likewise, the ability of ROL or Bt2cAMP to induce neutrophil apoptosis was impaired in AnxA-knock-out mice. Finally, in in vitro settings, ROL and Bt2cAMP overrode the survival-inducing effect of LPS in human neutrophils in an AnxA1-dependent manner. Our results show that AnxA1 is at least one of the endogenous determinants mediating the pro-resolving properties of cAMP-elevating agents and cAMP-mimetic drugs.


Assuntos
Anexina A1/agonistas , Bucladesina/uso terapêutico , AMP Cíclico/agonistas , Infiltração de Neutrófilos/efeitos dos fármacos , Inibidores da Fosfodiesterase 4/uso terapêutico , Pleurisia/tratamento farmacológico , Rolipram/uso terapêutico , Animais , Anexina A1/antagonistas & inibidores , Anexina A1/genética , Anexina A1/metabolismo , Apoptose/efeitos dos fármacos , Bucladesina/antagonistas & inibidores , Células Cultivadas , AMP Cíclico/análogos & derivados , AMP Cíclico/antagonistas & inibidores , AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/antagonistas & inibidores , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Humanos , Lipopolissacarídeos/toxicidade , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Neutrófilos/metabolismo , Neutrófilos/patologia , Inibidores da Fosfodiesterase 4/química , Fosforilação/efeitos dos fármacos , Pleurisia/imunologia , Pleurisia/metabolismo , Pleurisia/patologia , Inibidores de Proteínas Quinases/farmacologia , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Células RAW 264.7 , Rolipram/antagonistas & inibidores
6.
J Clin Microbiol ; 55(5): 1516-1525, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28275081

RESUMO

Leprosy is an important cause of disability in the developing world. Early diagnosis is essential to allow for cure and to interrupt transmission of this infection. MicroRNAs (miRNAs) are important factors for host-pathogen interaction and they have been identified as biomarkers for various infectious diseases. The expression profile of 377 microRNAs were analyzed by TaqMan low-density array (TLDA) in skin lesions of tuberculoid and lepromatous leprosy patients as well as skin specimens from healthy controls. In a second step, 16 microRNAs were selected for validation experiments with reverse transcription-quantitative PCR (qRT-PCR) in skin samples from new individuals. Principal-component analysis followed by logistic regression model and receiver operating characteristic (ROC) curve analyses were performed to evaluate the diagnostic potential of selected miRNAs. Four patterns of differential expression were identified in the TLDA experiment, suggesting a diagnostic potential of miRNAs in leprosy. After validation experiments, a combination of four miRNAs (miR-101, miR-196b, miR-27b, and miR-29c) was revealed as able to discriminate between healthy control and leprosy patients with 80% sensitivity and 91% specificity. This set of miRNAs was also able to discriminate between lepromatous and tuberculoid patients with a sensitivity of 83% and 80% specificity. In this work, it was possible to identify a set of miRNAs with good diagnostic potential for leprosy.


Assuntos
Marcadores Genéticos/genética , Hanseníase/diagnóstico , MicroRNAs/genética , Mycobacterium leprae/genética , Adulto , Diagnóstico Precoce , Humanos , Hanseníase/imunologia , Hanseníase/microbiologia , Pessoa de Meia-Idade , Mycobacterium leprae/imunologia , Curva ROC , Reação em Cadeia da Polimerase em Tempo Real , Sensibilidade e Especificidade , Adulto Jovem
7.
s.l; s.n; 2017. 10 p. ilus, graf.
Não convencional em Inglês | Sec. Est. Saúde SP, HANSEN, SESSP-ILSLPROD, Sec. Est. Saúde SP, SESSP-ILSLACERVO, Sec. Est. Saúde SP | ID: biblio-1087560

RESUMO

Leprosy is an important cause of disability in the developing world. Early diagnosis is essential to allow for cure and to interrupt transmission of this infection. MicroRNAs (miRNAs) are important factors for host-pathogen interaction and they have been identified as biomarkers for various infectious diseases. The expression profile of 377 microRNAs were analyzed by TaqMan low-density array (TLDA) in skin lesions of tuberculoid and lepromatous leprosy patients as well as skin specimens from healthy controls. In a second step, 16 microRNAs were selected for validation experiments with reverse transcription-quantitative PCR (qRT-PCR) in skin samples from new individuals. Principal-component analysis followed by logistic regression model and receiver operating characteristic (ROC) curve analyses were performed to evaluate the diagnostic potential of selected miRNAs. Four patterns of differential expression were identified in the TLDA experiment, suggesting a diagnostic potential of miRNAs in leprosy. After validation experiments, a combination of four miRNAs (miR-101, miR-196b, miR-27b, and miR-29c) was revealed as able to discriminate between healthy control and leprosy patients with 80% sensitivity and 91% specificity. This set of miRNAs was also able to discriminate between lepromatous and tuberculoid patients with a sensitivity of 83% and 80% specificity. In this work, it was possible to identify a set of miRNAs with good diagnostic potential for leprosy.


Assuntos
Humanos , Adulto , Pessoa de Meia-Idade , Adulto Jovem , Marcadores Genéticos/genética , Curva ROC , Sensibilidade e Especificidade , MicroRNAs/genética , Diagnóstico Precoce , Reação em Cadeia da Polimerase em Tempo Real , Hanseníase/diagnóstico , Hanseníase/imunologia , Hanseníase/microbiologia , Mycobacterium leprae/genética , Mycobacterium leprae/imunologia
8.
FASEB J ; 30(12): 4033-4041, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27535487

RESUMO

Alveolar bone loss is a result of an aggressive form of periodontal disease (PD) associated with Aggregatibacter actinomycetemcomitans (Aa) infection. PD is often observed with other systemic inflammatory conditions, including arthritis. Melanocortin peptides activate specific receptors to exert antiarthritic properties, avoiding excessing inflammation and modulating macrophage function. Recent work has indicated that melanocortin can control osteoclast development and function, but whether such protection takes place in infection-induced alveolar bone loss has not been investigated. The purpose of this study was to evaluate the role of melanocortin in Aa-induced PD. Mice were orally infected with Aa and treated with the melanocortin analog DTrp8-γMSH or vehicle daily for 30 d. Then, periodontal tissue was collected and analyzed. Aa-infected mice treated with DTrp8-γMSH presented decreased alveolar bone loss and a lower degree of neutrophil infiltration in the periodontium than vehicle-treated animals; these actions were associated with reduced periodontal levels of TNF-α, IFN-γ, and IL-17A. In vitro experiments with cells differentiated into osteoclasts showed that osteoclast formation and resorptive activity were attenuated after treatment with DTrp8-γMSH. Thus, melanocortin agonism could represent an innovative way to tame overexuberant inflammation and, at the same time, preserve bone physiology, as seen after Aa infection.-Madeira, M. F. M., Queiroz-Junior, C. M., Montero-Melendez, T., Werneck, S. M. C., Corrêa, J. D., Soriani, F. M., Garlet, G. P., Souza, D. G., Teixeira, M. M., Silva, T. A., Perretti, M. Melanocortin agonism as a viable strategy to control alveolar bone loss induced by oral infection.


Assuntos
Perda do Osso Alveolar/prevenção & controle , Melanocortinas/agonistas , Osteoclastos/microbiologia , Infecções por Pasteurellaceae/prevenção & controle , Doenças Periodontais/metabolismo , Aggregatibacter actinomycetemcomitans , Perda do Osso Alveolar/etiologia , Animais , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/fisiologia , Macrófagos/imunologia , Camundongos Endogâmicos C57BL , Periodontite/tratamento farmacológico , Periodontite/metabolismo
9.
Pesqui. vet. bras ; 36(1): 13-18, Jan. 2016. tab, graf
Artigo em Inglês | LILACS | ID: lil-777376

RESUMO

With the hypothesis that blocking chemokine signaling can ameliorate acute laminitis, the aim was to evaluate the therapeutic effect of intravenous DF1681B, a selective antagonist for CXCR1 and CXCR2 (chemokine receptors), in an oligofructose equine laminitis model. To twelve mixed breed clinically healthy hoses with no previous history of hoof-related lameness was administered oligofructose (10g/kg given by nasogastric tube) and divided into two groups: treated (intravenous DF1681B at 30mg/kg 6, 12, 18, and 24h after oligofructose) and non-treated groups. Laminar biopsies were performed before and 12, 36, and 72h after administering oligofructose. Samples were stained with periodic acid-Schiff (PAS) and scored from 0 to 6 according to epidermal cell and basal membrane changes. The IL-1β, IL-6, and CXCL1 RNA expressions were determined by RT-PCR. Parametric and non-parametric tests were used to compare times within each group (P<0.05). The PAS grades and IL-1β and IL-6 RNA expression increased in the non-treated group, but remained constant in the treated horses. In conclusion, DF1681B therapy reduced laminar inflammation and epidermal deterioration in treated horses. CXCR1/2 blockage should be considered therapeutically for equine acute laminitis.


A expressão de quimiocinas e a infiltração de leucócitos no tecido laminar são característicos de laminite aguda de equinos. O presente estudo avaliou o efeito terapêutico da administração intravenosa de DF1681B , um antagonista seletivo para CXCR1 e CXCR2 (receptores de quimiocinas), em um modelo de laminite equina por oligofrutose. Utilizaram-se doze cavalos sem raça definida, compreendendo quatro machos e oito fêmeas não gestantes, com idade (média ±SD) 7±3,5 anos, pesando 305±35kg e com uma pontuação média de condição corporal de 5±1/9. Os indivíduos elegíveis eram clinicamente saudáveis, sem história prévia de claudicação relacionados ao casco. Após administração de oligofrutose (10g/kg por sonda nasogástrica), os animais foram divididos em dois grupos: tratado (30mg/kg de DF1681B intravenosa, 6, 12, 18 e 24h após a oligofrutose) e não tratado, que recebeu placebo. Biópsias laminares foram realizadas antes e 12, 36 e 72h após a administração de oligofrutose. As amostras foram coradas com ácido periódico de Schiff (PAS) e classificadas de 0-6 de acordo com alterações nas células epidérmicas e na membrana basal. Também determinaram-se as expressões gênicas de IL-1β, CXCL1 e IL-6 por RT-PCR. Testes paramétricos e não paramétricos foram utilizados para comparar os momentos em cada grupo (P<0,05). Estatisticamente, os graus PAS e as expressões de IL-1β e IL-6 se elevaram após a indução no grupo não tratado, mas se mantiveram constantes nos cavalos tratados. Em conclusão, a terapia por DF1681B reduziu a inflamação laminar e a deterioração epidérmica em equinos submetidos ao modelo de intoxicação por oligofructose. O bloqueio de receptores CXCR1/2 deve ser considerado como uma opção terapêutica para prevenção da laminite aguda de equinos.


Assuntos
Animais , Cavalos/fisiologia , Neutrófilos/patologia , Prebióticos , Quimiocinas/antagonistas & inibidores , Receptores CXCR/antagonistas & inibidores , Biópsia/veterinária , Casco e Garras/patologia , Técnicas Histológicas/veterinária
10.
Eur J Immunol ; 46(1): 204-11, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26449770

RESUMO

Gout manifests as recurrent episodes of acute joint inflammation and pain due to the deposition of monosodium urate (MSU) crystals within the affected tissue in a process dependent on NLRP3 inflammasome activation. The synthesis, activation, and release of IL-1ß are crucial for MSU-induced inflammation. The current study evaluated the mechanism by which TNF-α contributed to MSU-induced inflammation. Male C57BL/6J or transgenic mice were used in this study and inflammation was induced by the injection of MSU crystals into the joint. TNF-α was markedly increased in the joint after the injection of MSU. There was inhibition in the infiltration of neutrophils, production of CXCL1 and IL-1ß, and decreased hypernociception in mice deficient for TNF-α or its receptors. Pharmacological blockade of TNF-α with Etanercept or pentoxyfylline produced similar results. Mechanistically, TNF-α blockade resulted in lower amounts of IL-1ß protein and pro-IL-1ß mRNA transcripts in joints. Gene-modified mice that express only transmembrane TNF-α had an inflammatory response similar to that of WT mice and blockade of soluble TNF-α (XPro™1595) did not decrease MSU-induced inflammation. In conclusion, TNF-α drives expression of pro-IL-1ß mRNA and IL-1ß protein in experimental gout and that its transmembrane form is sufficient to trigger MSU-induced inflammation in mice.


Assuntos
Gota/imunologia , Hiperalgesia/etiologia , Inflamação/imunologia , Fator de Necrose Tumoral alfa/metabolismo , Animais , Modelos Animais de Doenças , Gota/complicações , Gota/metabolismo , Inflamação/metabolismo , Interleucina-1beta/imunologia , Interleucina-1beta/metabolismo , Articulação do Joelho , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Estimulação Física , Reação em Cadeia da Polimerase em Tempo Real , Ácido Úrico/efeitos adversos , Ácido Úrico/imunologia
11.
Am J Pathol ; 185(12): 3338-48, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26598236

RESUMO

The relevance of IL-33 and its receptor ST2 for bone remodeling is not well-defined. Our aim was to assess the role and underlying mechanisms of IL-33/ST2 in mechanically induced bone remodeling. BALB/c (wild type) and ST2 deficient (St2(-/-)) mice were subjected to mechanical loading in alveolar bone. Microtomography, histology, and real-time quantitative PCR were performed to analyze bone parameters, apoptosis and bone cell counts, and expression of bone remodeling markers, respectively. MC3T3-E1 osteoblastic cells and bone marrow cells were used to verify if mechanical force triggered IL-33 and ST2 expression as well as the effects of IL-33 on osteoclast differentiation and activity. Mechanical loading increased the expression of IL-33 and ST2 in alveolar bone in vivo and in osteoblastic cells in vitro. St2(-/-) mice had increased mechanical loading-induced bone resorption, number of osteoclasts, and expression of proresorptive markers. In contrast, St2(-/-) mice exhibited reduced numbers of osteoblasts and apoptotic cells in periodontium and diminished expression of osteoblast signaling molecules. In vitro, IL-33 treatment inhibited osteoclast differentiation and activity even in the presence of receptor activator of NF-κB ligand. IL-33 also increased the expression of pro-apoptotic molecules, including Bcl-2-associated X protein (BAX), cell-surface Fas receptor (FAS), FASL, FAS-associated death domain, tumor necrosis factor-related apoptosis-inducing ligand, and BH3 interacting-domain death (BID). Overall, these findings suggest that IL-33/ST2 have anti-osteoclastogenic effects and reduce osteoclast formation and activity by inducing their apoptosis.


Assuntos
Apoptose/fisiologia , Remodelação Óssea/fisiologia , Interleucina-33/fisiologia , Osteoclastos/fisiologia , Receptores de Interleucina/fisiologia , Animais , Biomarcadores/metabolismo , Densidade Óssea/fisiologia , Reabsorção Óssea/fisiopatologia , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Proteína 1 Semelhante a Receptor de Interleucina-1 , Interleucina-33/biossíntese , Interleucina-33/farmacologia , Camundongos Endogâmicos BALB C , Camundongos Knockout , Osteoclastos/citologia , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Periodonto/metabolismo , Periodonto/patologia , Receptores de Interleucina/biossíntese , Receptores de Interleucina/deficiência , Estresse Mecânico , Suporte de Carga
12.
PLoS One ; 10(9): e0138475, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26398190

RESUMO

BACKGROUND: Preeclampsia (PE) is a pregnancy disease associated with exacerbated inflammatory response. Annexin A1 (AnxA1) is a glucocorticoid-regulated protein endowed with anti-inflammatory and proresolving properties that has been much studied in various animal models of inflammation but poorly studied in the context of human inflammatory diseases. The main objective of this study was to measure AnxA1 levels in PE women and to compare those levels in normotensive pregnant and non-pregnant women. We evaluated the association among AnxA1, ultrasensitive C reactive protein (us-CRP) and soluble tumor necrosis factor alpha receptor type 1 (sTNF-R1) plasma levels of the study participants. METHODS: This study included 40 non-pregnant, 38 normotensive pregnant and 51 PE women. PE women were stratified in early (N = 23) and late (N = 28) subgroups, according to gestational age (GA) at onset of clinical symptoms. Protein AnxA1 and us-CRP plasma levels were determined by ELISA and immunoturbidimetric assays, respectively. Transcript levels of AnxA1 in peripheral blood mononuclear cells (PBMC) were measured by real time RT-PCR. RESULTS: Increased levels of AnxA1 coincided with higher us-CRP levels in the plasma of PE women. Pregnant women with early PE had higher levels of AnxA1 and us-CRP than normotensive pregnant women with GA <34 weeks. No significant difference was found for AnxA1 and us-CRP, comparing late PE and normotensive pregnant women with GA ≥ 34 weeks. AnxA1 mRNA levels in PBMC were similar among the studied groups. AnxA1 was positively correlated with sTNF-R1, but not with us-CRP. CONCLUSIONS: Our data show that increased AnxA1 levels were associated with a systemic inflammatory phenotype in PE, suggesting AnxA1 deregulation in PE pathogenesis. However, more studies are needed to clarify the role of AnxA1 and other proresolving molecules in the context of the systemic inflammatory response in this intriguing disease.


Assuntos
Anexina A1/sangue , Pré-Eclâmpsia/sangue , Adulto , Anexina A1/genética , Proteína C-Reativa/metabolismo , Feminino , Idade Gestacional , Humanos , Gravidez , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores Tipo I de Fatores de Necrose Tumoral/sangue , Adulto Jovem
13.
J Immunol ; 194(10): 4940-50, 2015 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-25876761

RESUMO

Glucocorticoid (GC)-induced leucine zipper (GILZ) has been shown to mediate or mimic several actions of GC. This study assessed the role of GILZ in self-resolving and GC-induced resolution of neutrophilic inflammation induced by LPS in mice. GILZ expression was increased during the resolution phase of LPS-induced pleurisy, especially in macrophages with resolving phenotypes. Pretreating LPS-injected mice with trans-activator of transcription peptide (TAT)-GILZ, a cell-permeable GILZ fusion protein, shortened resolution intervals and improved resolution indices. Therapeutic administration of TAT-GILZ induced inflammation resolution, decreased cytokine levels, and promoted caspase-dependent neutrophil apoptosis. TAT-GILZ also modulated the activation of the survival-controlling proteins ERK1/2, NF-κB and Mcl-1. GILZ deficiency was associated with an early increase of annexin A1 (AnxA1) and did not modify the course of neutrophil influx induced by LPS. Dexamethasone treatment resolved inflammation and induced GILZ expression that was dependent on AnxA1. Dexamethasone-induced resolution was not altered in GILZ(-/-) mice due to compensatory expression and action of AnxA1. Our results show that therapeutic administration of GILZ efficiently induces a proapoptotic program that promotes resolution of neutrophilic inflammation induced by LPS. Alternatively, a lack of endogenous GILZ during the resolution of inflammation is compensated by AnxA1 overexpression.


Assuntos
Inflamação/imunologia , Macrófagos/imunologia , Pleurisia/imunologia , Fatores de Transcrição/imunologia , Animais , Anexina A1/imunologia , Apoptose/imunologia , Western Blotting , Movimento Celular , Modelos Animais de Doenças , Citometria de Fluxo , Lipopolissacarídeos/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Reação em Cadeia da Polimerase em Tempo Real
14.
Fundam Clin Pharmacol ; 29(2): 150-63, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25619310

RESUMO

This study aimed to investigate the modulation of nitric oxide/reactive oxygen species in sodium nitroprusside relaxation in mice aorta. Sodium nitroprusside induced relaxation in endothelium-intact (e+) and endothelium-denuded (e-) aortas with greater potency in e+ than in e-. The nitric oxide synthase inhibitor did not alter the sodium nitroprusside relaxation in both e+ and e- aortas. However, the superoxide anion scavenger abolished the difference in sodium nitroprusside potency between e+ and e-. Sodium nitroprusside reduced dihydroethidium-derived fluorescent products in both groups; however, the difference between intact and denuded mice aorta remains. The glutathione levels and basal antioxidant activity of superoxide dismutase were reduced in e- aorta when compared with e+, and these values were not altered by sodium nitroprusside. Confirming these results, the levels of lipid peroxidation in e+ were significantly lower when compared to e-, and these values were not altered by sodium nitroprusside. The sodium nitroprusside potency in the presence of a nonselective COX inhibitor or the EP/DP prostaglandin receptor antagonist in endothelium denuded was similar to that in intact mice aorta. Based on these results, we performed the COX-1 and COX-2 mRNA level studies, and in denuded mice aorta, there was an upregulation in COX-1 mRNA levels. Taken together, our findings show that in the absence of endothelium, there is an enhancement of superoxide levels, leading to GSH consumption and higher levels of lipid peroxidation, showing an intense redox status. Furthermore, in denuded mice aorta, there was an upregulation of COX-1 mRNA expression, leading to vasoconstrictor prostanoids synthesis. The interaction of vasoconstrictor prostanoids with its receptors EP/DP negatively modulates the vascular relaxation induced by SNP in denuded mice aorta.


Assuntos
Aorta Torácica/metabolismo , Ciclo-Oxigenase 1/biossíntese , Proteínas de Membrana/biossíntese , Nitroprussiato/farmacologia , RNA Mensageiro/biossíntese , Espécies Reativas de Oxigênio/metabolismo , Vasodilatadores/farmacologia , Animais , Aorta Torácica/efeitos dos fármacos , Relação Dose-Resposta a Droga , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Técnicas de Cultura de Órgãos , Vasodilatação/efeitos dos fármacos , Vasodilatação/fisiologia
16.
Metab Brain Dis ; 30(3): 669-78, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25148914

RESUMO

The involvement of TNF-α type 1 receptor (TNFR1) in memory deficits induced by sepsis was explored by using TNFR1 knockout (KO) mice. We reported that wild type (WT) mice presented memory deficits in the novel object recognition test 10 days after sepsis induced by cecum ligation and perforation (CLP). These deficits were not observed in TNFR1 KO mice. The involvement of serum and brain cytokines TNF-α, IL-1ß, IL-6, IFN-γ and IL-10 was then investigated. TNFR1 KO mice had higher serum levels of TNF-α and IL-1ß, and brain levels of TNF-α than WT mice. After CLP, the brain levels of TNF-α, IL-1ß, IL-6 and IFN-γ increased in both WT and KO mice. Our next step was to determine the expression of inflammatory cytokines, BDNF and TrKb in the hippocampus. The absence of TNFR1 in mice subjected to polymicrobial sepsis resulted in higher BDNF expression in the hippocampus. In conclusion, after CLP, memory is preserved in the absence of TNFR1. This finding was associated with increased BDNF expression in the hippocampus.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/biossíntese , Hipocampo/metabolismo , Transtornos da Memória/metabolismo , Transtornos da Memória/prevenção & controle , Receptores Tipo I de Fatores de Necrose Tumoral/deficiência , Sepse/metabolismo , Animais , Regulação da Expressão Gênica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Sepse/complicações
17.
BMC Infect Dis ; 14: 249, 2014 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-24884781

RESUMO

BACKGROUND: The interleukin 32 (IL-32) is a proinflammatory cytokine produced by immune and non-immune cells. It can be induced during bacterial and viral infections, but its production was never investigated in protozoan infections. American Tegumentary Leishmaniasis (ATL) is caused by Leishmania protozoan leading to cutaneous, nasal or oral lesions. The aim of this study was to evaluate the expression of IL-32 in cutaneous and mucosal lesions as well as in peripheral blood mononuclear cells (PBMC) exposed to Leishmania (Viannia) braziliensis. METHODS: IL-32, tumour necrosis factor (TNF) and IL-10 protein expression was evaluated by immunohistochemistry in cutaneous, mucosal lesions and compared to healthy specimens. The isoforms of IL-32α, ß, δ, γ mRNA, TNF mRNA and IL-10 mRNA were assessed by qPCR in tissue biopsies of lesions and healthy skin and mucosa. In addition, PBMC from healthy donors were cultured with amastigotes of L. (V.) braziliensis. In lesions, the parasite subgenus was identified by PCR-RFLP. RESULTS: We showed that the mRNA expression of IL-32, in particular IL-32γ was similarly up-regulated in lesions of cutaneous (CL) or mucosal (ML) leishmaniasis patients. IL-32 protein was produced by epithelial, endothelial, mononuclear cells and giant cells. The IL-32 protein expression was associated with TNF in ML but not in CL. IL-32 was not associated with IL-10 in both CL and ML. Expression of TNF mRNA was higher in ML than in CL lesions, however levels of IL-10 mRNA were similar in both clinical forms. In all lesions in which the parasite was detected, L. (Viannia) subgenus was identified. Interestingly, L. (V.) braziliensis induced only IL-32γ mRNA expression in PBMC from healthy individuals. CONCLUSIONS: These data suggest that IL-32 plays a major role in the inflammatory process caused by L. (Viannia) sp or that IL-32 is crucial for controlling the L. (Viannia) sp infection.


Assuntos
Interleucina-10/biossíntese , Interleucinas/biossíntese , Leishmania braziliensis/imunologia , Leishmaniose Cutânea/metabolismo , Fator de Necrose Tumoral alfa/biossíntese , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Interleucinas/genética , Leishmaniose Cutânea/imunologia , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Membrana Mucosa/metabolismo , Pele/metabolismo , Regulação para Cima , Adulto Jovem
18.
BMC Complement Altern Med ; 14: 177, 2014 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-24886376

RESUMO

BACKGROUND: Chronic inflammatory processes in the peritoneal cavity develop as a result of ischemia, foreign body reaction, and trauma. Brazilian green propolis, a beeswax product, has been shown to exhibit multiple actions on inflammation and tissue repair. Our aim was to investigate the effects of this natural product on the inflammatory, angiogenic, and fibrogenic components of the peritoneal fibroproliferative tissue induced by a synthetic matrix. METHODS: Chronic inflammation was induced by placing polyether-polyurethane sponge discs in the abdominal cavity of anesthetized Swiss mice. Oral administration of propolis (500/mg/kg/day) by gavage started 24 hours after injury for four days. The effect of propolis on peritoneal permeability was evaluated through fluorescein diffusion rate 4 days post implantation. The effects of propolis on the inflammatory (myeloperoxidase and n-acetyl-ß-D-glucosaminidase activities and TNF-α levels), angiogenic (hemoglobin content-Hb), and fibrogenic (TGF-ß1 and collagen deposition) components of the fibrovascular tissue in the implants were determined 5 days after the injury. RESULTS: Propolis was able to decrease intraperitoneal permeability. The time taken for fluorescence to peak in the systemic circulation was 20±1 min in the treated group in contrast with 15±1 min in the control group. In addition, the treatment was shown to down-regulate angiogenesis (Hb content) and fibrosis by decreasing TGF-ß1 levels and collagen deposition in fibroproliferative tissue induced by the synthetic implants. Conversely, the treatment up-regulated inflammatory enzyme activities, TNF-α levels and gene expression of NOS2 and IFN-γ (23 and 7 fold, respectively), and of FIZZ1 and YM1 (8 and 2 fold) when compared with the untreated group. CONCLUSIONS: These observations show for the first time the effects of propolis modulating intraperitoneal inflammatory angiogenesis in mice and disclose important action mechanisms of the compound (downregulation of angiogenic components and activation of murine macrophage pathways).


Assuntos
Inflamação/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Peritonite/tratamento farmacológico , Própole/uso terapêutico , Animais , Brasil , Colágeno/metabolismo , Avaliação Pré-Clínica de Medicamentos , Fibrose , Fluoresceína , Reação a Corpo Estranho/tratamento farmacológico , Reação a Corpo Estranho/imunologia , Hemoglobinas/metabolismo , Inflamação/metabolismo , Masculino , Camundongos , Neovascularização Patológica/metabolismo , Peritonite/imunologia , Peroxidase/metabolismo , Tampões de Gaze Cirúrgicos , Fator de Crescimento Transformador beta1/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Cicatrização
19.
Microbes Infect ; 16(6): 481-90, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24704475

RESUMO

Chagas disease, caused by Trypanosoma cruzi (Tc), is an important cause of heart disease. Resistance to Tc infection is multifactorial and associated with Th1 response. IL-18 plays an important role in regulation of IFN-γ production/development of Th1 response. However, the role of IL-18 in the setting of Tc infection remains unclear. Therefore, we investigated the role of IL-18 in the modulation of immune response and myocarditis in Tc infection. C57BL/6 and IL-18 KO mice were infected with Tc (Y or Colombian strain) and parasitemia, immune response and pathology were evaluated. Y strain infection of IL-18 KO did not alter any parameters when compared with C57BL/6 mice. However, during the acute phase (20 and 40 days post infection-dpi), Colombian strain infected-IL-18 KO mice displayed higher serum levels of IL-12 and IFN-γ, respectively, and at the chronic phase (100 dpi) an increase in splenic IFN-γ-producing CD4(+) and CD8(+) T memory cells. There was an IL-10, FOXP3 and CD4(+)CD25(+) cells reduction during acute infection in spleen. Additionally, there was a significant reduction in leukocyte infiltration and parasite load in myocardium of chronically infected IL-18 KO mice. Collectively, these data indicate that IL-18 contributes to the pathogenesis of Tc-induced myocarditis when infected with Colombian but not Y strain. These observations also underscore that parasite and host strain differences are important in evaluation of experimental Tc infection pathogenesis.


Assuntos
Doença de Chagas/imunologia , Interleucina-18/imunologia , Miocardite/imunologia , Trypanosoma cruzi/patogenicidade , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Células Cultivadas , Doença de Chagas/complicações , Interações Hospedeiro-Parasita , Interferon gama/sangue , Interleucina-12/sangue , Interleucina-18/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miocardite/complicações , Miocardite/parasitologia , Miocárdio/patologia , Baço/citologia , Baço/imunologia , Baço/parasitologia
20.
Obesity (Silver Spring) ; 22(3): 663-72, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24339378

RESUMO

OBJECTIVE: The role of platelet-activating factor (PAF) on diet-induced inflammatory and metabolic dysfunction is unknown. The effects of diet-induced metabolic and inflammatory dysfunction in mice with deletion of the PAF receptor (PAFR(-/-) ) were evaluated in this study. METHODS: Wild-type and PAFR(-/-) mice were fed chow (WT-C and PAFR(-/-) -C) or high-refined carbohydrate-containing diet (WT-HC and PAFR(-/-) -HC). PAFR(-/-) - RESULTS: HC mice gained more weight and adiposity than PAFR(-/-) -C and WT-HC mice. Lipogenesis increased and hormone-sensitive lipase expression decreased in PAFR(-/-) -HC compared to WT-HC mice. WT-HC mice had impaired glucose tolerance and insulin sensitivity compared to WT-C mice. In contrast, glucose tolerance and insulin sensitivity in PAFR(-/-) -HC mice were similar to that of lean littermates. PAFR(-/-) -HC mice expressed significantly more peroxisome proliferator-activator receptor gamma (PPARγ) than PAFR(-/-) -C and WT-C mice. Resistin increased in WT-HC mice compared to WT-C mice. However, the levels of resistin were 35% lower in PAFR(-/-) -HC mice than WT-HC mice. PAFR(-/-) presented with less HC diet-induced adipose tissue inflammation than WT mice. Adipocytes isolated from PAFR(-/-) mice incubated in media containing normal or high levels of glucose secreted less interleukin-6 and tumor necrosis factor alpha and presented lower rate of lipolysis than WT mice. CONCLUSION: PAFR deficiency resulted in less inflammation in adipose tissue and improvement in glucose homeostasis when fed the HC diet. The higher adiposity observed in PAFR(-/-) mice fed HC diet could be owing to the maintenance of insulin sensitivity, decreased adipocyte lipolysis rate, high lipogenesis and PPARγ expression, and lower inflammatory milieu in adipose tissue.


Assuntos
Dieta , Carboidratos da Dieta/efeitos adversos , Inflamação/metabolismo , Glicoproteínas da Membrana de Plaquetas/deficiência , Glicoproteínas da Membrana de Plaquetas/metabolismo , Receptores Acoplados a Proteínas-G/deficiência , Receptores Acoplados a Proteínas-G/metabolismo , Adipócitos/metabolismo , Tecido Adiposo , Adiposidade/fisiologia , Animais , Carboidratos da Dieta/administração & dosagem , Intolerância à Glucose , Resistência à Insulina , Interleucina-6/metabolismo , Lipogênese , Lipólise/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , PPAR gama/genética , PPAR gama/metabolismo , Glicoproteínas da Membrana de Plaquetas/genética , Receptores Acoplados a Proteínas-G/genética , Resistina/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Ganho de Peso
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