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1.
Nat Commun ; 10(1): 4044, 2019 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-31492850

RESUMO

Acute graft-versus-host disease (GVHD) remains a major obstacle for the wider usage of allogeneic hematopoietic stem cell transplantation (allo-HSCT), which is an effective therapy for hematopoietic malignancy. Here we show that caspase-11, the cytosolic receptor for bacterial endotoxin (lipopolysaccharide: LPS), enhances GVHD severity. Allo-HSCT markedly increases the LPS-caspase-11 interaction, leading to the cleavage of gasdermin D (GSDMD). Caspase-11 and GSDMD mediate the release of interleukin-1α (IL-1α) in allo-HSCT. Deletion of Caspase-11 or Gsdmd, inhibition of LPS-caspase-11 interaction, or neutralizing IL-1α uniformly reduces intestinal inflammation, tissue damage, donor T cell expansion and mortality in allo-HSCT. Importantly, Caspase-11 deficiency does not decrease the graft-versus-leukemia (GVL) activity, which is essential to prevent cancer relapse. These findings have major implications for allo-HSCT, as pharmacological interference with the caspase-11 signaling might reduce GVHD while preserving GVL activity.


Assuntos
Caspases/genética , Doença Enxerto-Hospedeiro/genética , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Transdução de Sinais/genética , Animais , Caspases/metabolismo , Doença Enxerto-Hospedeiro/patologia , Neoplasias Hematológicas/metabolismo , Humanos , Interleucina-1alfa/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Lipopolissacarídeos/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas de Ligação a Fosfato/metabolismo , Análise de Sobrevida , Transplante Homólogo
2.
PLoS Pathog ; 15(8): e1007990, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31425553

RESUMO

The granulomatous lesion resulting from infection with the fungus Paracoccidioides brasiliensis is characterized by a compact aggregate of mature cells, surrounded by a fibroblast- and collagen-rich content. Granuloma formation requires signaling elicited by inflammatory molecules such as members of the interleukin-1 family. Two members of this family have been thoroughly studied, namely IL-1α and IL-1ß. In this study, we addressed the mechanisms underlying IL-1α secretion and its functional role on the host resistance to fungal infection. We found that, the expression of caspase-11 triggered by P. brasiliensis infection of macrophages depends on IFN-ß production, because its inhibition reduced procaspase-11 levels. Curiously, caspase-11 deficiency did not impair IL-1ß production, however caspase-11 was required for a rapid pore-mediated cell lysis. The plasma membrane rupture facilitated the release of IL-1α, which was necessary to induce NO production and restrict fungal replication. Furthermore, P. brasiliensis-infected macrophages required IL-1α to produce optimal levels of IL-6, a major component of Th17 lymphocyte differentiation. Indeed, IL-1α deficiency accounted for a significant reduction of Th17 lymphocytes in lungs of infected mice, correlating with diminished neutrophil infiltration in the lungs. Strikingly, we identified that IL-1α directly reprograms the transcriptional profile of Th17-committed lymphocytes, increasing cellular proliferation, as for boosting IL-17 production by these cells. Beyond neutrophil chemotaxis in vivo, IL-17 also amplified IL-1α production by infected macrophages in vitro, endorsing a critical amplification loop of the inflammatory response. Therefore, our data suggest that the IFN-ß/caspase-11/IL-1α pathway shapes a protective antifungal Th17 immunity, revealing a molecular mechanism underlying the cross-talk between innate and adaptive immunity.


Assuntos
Caspases/fisiologia , Imunidade Inata/imunologia , Interleucina-1alfa/metabolismo , Macrófagos/imunologia , Paracoccidioides/imunologia , Paracoccidioidomicose/imunologia , Células Th17/imunologia , Animais , Inflamassomos , Macrófagos/metabolismo , Macrófagos/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Paracoccidioidomicose/metabolismo , Paracoccidioidomicose/microbiologia , Células Th17/metabolismo , Células Th17/microbiologia
3.
Hum Exp Toxicol ; 38(11): 1314-1326, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31303057

RESUMO

Electrolyzed water (EW) is a widely used disinfectant agent with high oxidation-reduction potential (ORP). Although EW has been used in many areas, such as food hygiene, agriculture, and animal husbandry, the studies presented in the literature are not enough to clarify the toxic effects of EW. The aim of this study is, therefore, to produce EWs at different pH, ORP, and chlorine concentrations and to assess their safety in terms of toxicology. At the beginning of the study, the antimicrobial activity of the EW types with respect to bacteria and fungus was investigated. EWs below pH 7 were all effective in inactivating Enterococcus hirae, Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, and Candida albicans completely. In vitro studies of cell cultures revealed that different concentrations of EWs were not cytotoxic for the L929 cells under 10- to 80-fold dilutions. In addition, it has been determined that produced EWs did not have irritation potential, according to the in vitro EpiDerm™, reconstituted skin irritation test in the frames of biocompatibility tests. For the mucous membrane irritation test, the hen's egg test-chorioallantoic membrane experiment was performed, and EWs were found to have no eye irritation. In conclusion, it has been shown that produced EWs with antimicrobial efficacy were found to be safe for skin and eye according to in vitro biocompatibility study studies. Thus, the establishment of a technological infrastructure for the EW production and the use of produced EW as an effective disinfectant in the food, medical, and agricultural areas should be encouraged.


Assuntos
Desinfetantes/farmacologia , Eletrólise , Água/farmacologia , Animais , Bactérias/efeitos dos fármacos , Bactérias/crescimento & desenvolvimento , Candida albicans/efeitos dos fármacos , Candida albicans/crescimento & desenvolvimento , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Embrião de Galinha , Membrana Corioalantoide/efeitos dos fármacos , Desinfetantes/química , Olho/efeitos dos fármacos , Humanos , Interleucina-1alfa/metabolismo , Camundongos , Pele/efeitos dos fármacos , Pele/metabolismo , Testes de Irritação da Pele , Água/química
4.
J Toxicol Sci ; 44(6): 393-403, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31167989

RESUMO

To predict the results of a 24-hr closed human patch test, we previously recommended the use of in vitro test with a reconstructed human epidermis (RhE) model adopted in OECD TG 439, and proposed the margin method, which includes evaluation of twice the concentration to avoid a false positive for surfactants. Therefore, in this study, we used LabCyte EPI-MODEL as a RhE model, and confirmed the reproducibility of this method using five surfactants, including benzalkonium chloride (BC), sodium lauryl sulfate (SLS), and lauryl betaine (LB), for which false negative results have previously been reported, and three different surfactants. For all surfactants, prediction of patch test results using a margin of two revealed that human tests could be performed safely, confirming the utility of the margin method. In addition, we examined the relationship with critical micellar concentration (CMC). The IC50 for cell viability in the RhE model for three types of surfactants (BC, SLS, and LB) was 2.7- to 49.7-times the CMC. Therefore, the range of concentrations in which tests were performed with the present method was within the range of concentrations with high cleansing. Furthermore, we examined the relationship between cell viability and release of the inflammatory mediator interleukin-1α (IL-1α). IL-1α release was associated with cell viability, supporting the results of the human patch test.


Assuntos
Epiderme/efeitos dos fármacos , Testes de Irritação da Pele , Tensoativos/toxicidade , Alternativas aos Testes com Animais , Compostos de Benzalcônio/toxicidade , Betaína/análogos & derivados , Betaína/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Epiderme/metabolismo , Humanos , Interleucina-1alfa/metabolismo , Testes do Emplastro , Reprodutibilidade dos Testes , Dodecilsulfato de Sódio/toxicidade
5.
Pharmacol Rep ; 71(4): 688-694, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31207429

RESUMO

BACKGROUND: The management of nonalcoholic steatohepatitis (NASH) is still a crosstalk so the current study was designed to evaluate the effect of different luteolin doses on an experimental model of NASH and to elucidate novel anti-inflammatory pathways underlying its effect. METHODS: Adult male Wistar rats (200-220 g; n = 60) were used. Rats were fed a high carbohydrate/high fat diet (˜ 30% carbohydrate and 42% fat) daily for 12 weeks to induce NASH. Luteolin (10, 25, 50 or 100 mg/kg/day) was administered as a suspension (10% w/v in 0.9% NaCl) using an oral gavage. Histopathological changes (necrosis, inflammation and steatosis) were evaluated. Biomarkers for liver function, lipid peroxidation, extracellular matrix deposition and anti-oxidant activity were measured. Levels of IFN-γ, TNF-α and IL-1α and IL-18 were measured. RESULTS: Obtained results showed ability of luteolin to reduce activity of ALT and AST and to decrease levels of bilirubin, hyaluronic acid and malondialdehyde significantly (p < 0.05). Also, luteolin showed an anti-oxidant activity as indicated by the significant (p < 0.05) increase in reduced glutathione. Finally, a significant (p < 0.05) decrease in IFN-γ, TNF-α, IL-1α and IL-18 levels was observed most notably in groups that received high doses of luteolin (50 and 100 mg/kg). CONCLUSIONS: Luteolin can protect against non-alcoholic steatohepatitis through targeting the pro-inflammatory IL-1 and Il-18 pathways in addition to an antioxidant effect.


Assuntos
Anti-Inflamatórios/farmacologia , Interleucina-18/metabolismo , Interleucina-1alfa/metabolismo , Fígado/efeitos dos fármacos , Luteolina/farmacologia , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Animais , Dieta Hiperlipídica , Relação Dose-Resposta a Droga , Fígado/imunologia , Fígado/metabolismo , Masculino , Hepatopatia Gordurosa não Alcoólica/imunologia , Ratos Wistar
6.
Nutrients ; 11(5)2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31052183

RESUMO

PURPOSE: Resveratrol (RSV), an antioxidant polyphenol, has demonstrated beneficial effects in various ocular diseases including glaucoma. Our study was designed to evaluate the effects of RSV on nitric oxide synthase (NOS) enzymes, nitric oxide (NO) and interleukin-1 alpha (IL-1 α), in human glaucomatous trabecular meshwork (TM) cells. METHODS: Western blot was utilized to determine endothelial and inducible NOS (eNOS, iNOS) expression. The concentration-related effects of RSV on IL-1 α and NO levels were assessed using the respective ELISA kits. RESULTS: Densitometry data showed concentration-related increases in eNOS, and reduction in iNOS expression at high RSV concentrations. RSV treatment (0.1, 1, 10 and 100 µM) resulted in increased NO levels (6 ± 0.7, 7 ± 0.8, 7.3 ± 0.7 and 9.5 ± 1 nM/mg protein, respectively). The average value obtained for control was 4.8 ± 0.6 nM/mg protein. Significant increases in IL-1α levels were observed with lower concentrations of RSV. However, at higher RSV concentrations (10-100 µM), IL-1 levels decreased. CONCLUSIONS: Resveratrol increased NO in glaucomatous TM cells, possibly by increasing eNOS expression. Thus, RSV-induced NO production supports the beneficial effects of this antioxidant in glaucoma. Furthermore, our results showing a reduction in iNOS, a contributor to oxidative stress expression, further support RSV's antioxidant capabilities in vision.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Antioxidantes/farmacologia , Biomarcadores/metabolismo , Glaucoma/tratamento farmacológico , Óxido Nítrico/metabolismo , Resveratrol/farmacologia , Malha Trabecular/efeitos dos fármacos , Western Blotting , Selectina E/metabolismo , Glaucoma/fisiopatologia , Humanos , Interleucina-1alfa/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Estresse Oxidativo/efeitos dos fármacos
7.
J Clin Lab Anal ; 33(6): e22903, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31102307

RESUMO

BACKGROUND: Interleukin-1 promotes tumor angiogenesis through VEGF production. The interleukin-1 receptor antagonist can suppress tumors by blocking this effect. METHODS: Immunohistochemistry, WB, and gene sequencing were used to analyze the expression of IL-1RA in esophageal cancer patients. WB was used to detect the expression of IL-1RA and interleukin-1α in esophageal cancer cells. Stable ESCC cell models overexpressing the IL-1RA were constructed. Their cell functions were tested, and their effects on VEGF were examined. RESULTS: IL-1RA is downregulated in primary EC tumors, and this downregulation of IL-1RA is closely related to TNM staging and survival prognosis. The overexpression of IL-1RA increased the proliferation of KYSE410 EC cells, which have a high level of IL-1α expression. Overexpression of IL-1RA in KYSE410 cells promotes a decrease in the expression of VEGF-A. However, IL-1RA expression did not cause any changes in EC9706 cells with low IL-1α expression. CONCLUSION: IL-1RA acts as a tumor suppressor, and its deletion promotes tumor progression by increasing VEGF-A expression in ESCC.


Assuntos
Neoplasias Esofágicas/patologia , Proteína Antagonista do Receptor de Interleucina 1/genética , Interleucina-1alfa/metabolismo , Idoso , Linhagem Celular Tumoral , Proliferação de Células/genética , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/mortalidade , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Proteína Antagonista do Receptor de Interleucina 1/metabolismo , Interleucina-1alfa/genética , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Prognóstico , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
8.
J Vet Sci ; 20(2): e11, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30944534

RESUMO

Mammary lesions in sows can prevent suckling piglets from consuming colostrum that provides fundamental nutrients and protective immunity. Although mammary gross lesions are frequently found in sows at farms or slaughterhouses, with the exception of mastitis, they have received little research attention. In this study, we investigated mammary lesions observed in South Korean sows between 2015 and 2016. Mammary tissue samples of 82 sows showing gross lesions during meat inspection were histologically classified and immunohistochemical analysis was conducted to assess the expression of estrogen receptor (ER)-α, ER-ß, and progesterone receptor (PR) for mammary hyperplastic lesions as well as that of cluster of differentiation (CD) 3, CD79a, interleukin (IL)-1α, IL-1ß, IL-6, and IL-8 for mastitis. Furthermore, 20 swab samples were cultured, and the isolated bacteria were identified using polymerase chain reactions for 16S ribosomal RNA genes. The lesions were classified as hyperplasia, mastitis, or hyperplasia with mastitis. Immunohistochemistry results revealed that there was neither expression of ER-α nor of ER-ß, but all examined hyperplastic samples expressed PR. In addition, there was a significant correlation between CD3 and IL-1ß expressions, as well as between IL-1ß and IL-6 expressions. Regarding the identity of the isolated bacteria, Pseudomonas spp. were most frequently detected. The results of this study have revealed the incidence and characteristics of porcine mammary lesions.


Assuntos
Doenças Mamárias/veterinária , Citocinas/metabolismo , Glândulas Mamárias Animais/patologia , Receptores Estrogênicos/metabolismo , Doenças dos Suínos/patologia , Matadouros , Animais , Doenças Mamárias/metabolismo , Doenças Mamárias/microbiologia , Doenças Mamárias/patologia , Complexo CD3/metabolismo , Antígenos CD79/metabolismo , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/metabolismo , Feminino , Interleucina-1alfa/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Glândulas Mamárias Animais/metabolismo , Glândulas Mamárias Animais/microbiologia , Mastite/metabolismo , Mastite/microbiologia , Mastite/patologia , Mastite/veterinária , Pseudomonas , Receptores de Progesterona/metabolismo , Suínos , Doenças dos Suínos/classificação , Doenças dos Suínos/metabolismo , Doenças dos Suínos/microbiologia
9.
J Biol Chem ; 294(21): 8325-8335, 2019 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-30940725

RESUMO

Interleukin (IL)-1 family cytokines potently regulate inflammation, with the majority of the IL-1 family proteins being secreted from immune cells via unconventional pathways. In many cases, secretion of IL-1 cytokines appears to be closely coupled to cell death, yet the secretory mechanisms involved remain poorly understood. Here, we studied the secretion of the three best-characterized members of the IL-1 superfamily, IL-1α, IL-1ß, and IL-18, in a range of conditions and cell types, including murine bone marrow-derived and peritoneal macrophages, human monocyte-derived macrophages, HeLa cells, and mouse embryonic fibroblasts. We discovered that IL-1ß and IL-18 share a common secretory pathway that depends upon membrane permeability and can operate in the absence of complete cell lysis and cell death. We also found that the pathway regulating the trafficking of IL-1α is distinct from the pathway regulating IL-1ß and IL-18. Although the release of IL-1α could also be dissociated from cell death, it was independent of the effects of the membrane-stabilizing agent punicalagin, which inhibited both IL-1ß and IL-18 release. These results reveal that in addition to their role as danger signals released from dead cells, IL-1 family cytokines can be secreted in the absence of cell death. We propose that models used in the study of IL-1 release should be considered context-dependently.


Assuntos
Células da Medula Óssea/metabolismo , Interleucina-18/metabolismo , Interleucina-1alfa/metabolismo , Interleucina-1beta/metabolismo , Macrófagos Peritoneais/metabolismo , Animais , Células da Medula Óssea/citologia , Fibroblastos/citologia , Fibroblastos/metabolismo , Células HeLa , Humanos , Taninos Hidrolisáveis/farmacologia , Macrófagos Peritoneais/citologia , Camundongos , Transporte Proteico/efeitos dos fármacos
10.
Bull Exp Biol Med ; 166(5): 622-625, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30903500

RESUMO

Over many years, tick-borne infections remain one of the most serious threats to human health worldwide. The immune response to these infections in a human after confirmed bite by an infected carrier at the early stages of infection in the absence of clinical symptoms can be the first indicator of the presence of the infectious agent in the body. During viral infection, the concentration of IL-1α, IL-8, IL-10, IL-17A, and IFNγ increases; superoxide dismutase also increases, in contrast to bacterial infections. A slight decrease in the concentration is observed only for receptor antagonist IL-1Ra. During the infection caused by bacterial pathogens, very similar profiles of the innate human immune response are observed: activation of IL-1α, IL-8, and IFNα and suppression of superoxide dismutase, IL-1Ra, and IL-17A production. It has been demonstrated, that the immune response is triggered immediately after infection, and changes in the concentration of the main cytokines in the blood plasma can be detected as early as on days 2-5 after tick bite. These results can be useful in developing new methods of emergency diagnosis and prevention of tick-borne infections.


Assuntos
Citocinas/metabolismo , Doenças Transmitidas por Carrapatos/imunologia , Animais , Infecções Bacterianas/imunologia , Vírus da Encefalite Transmitidos por Carrapatos/imunologia , Vírus da Encefalite Transmitidos por Carrapatos/patogenicidade , Humanos , Interleucina-17/metabolismo , Interleucina-1alfa/metabolismo , Doenças Transmitidas por Carrapatos/metabolismo
11.
Cell ; 176(4): 757-774.e23, 2019 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-30712866

RESUMO

ROCK-Myosin II drives fast rounded-amoeboid migration in cancer cells during metastatic dissemination. Analysis of human melanoma biopsies revealed that amoeboid melanoma cells with high Myosin II activity are predominant in the invasive fronts of primary tumors in proximity to CD206+CD163+ tumor-associated macrophages and vessels. Proteomic analysis shows that ROCK-Myosin II activity in amoeboid cancer cells controls an immunomodulatory secretome, enabling the recruitment of monocytes and their differentiation into tumor-promoting macrophages. Both amoeboid cancer cells and their associated macrophages support an abnormal vasculature, which ultimately facilitates tumor progression. Mechanistically, amoeboid cancer cells perpetuate their behavior via ROCK-Myosin II-driven IL-1α secretion and NF-κB activation. Using an array of tumor models, we show that high Myosin II activity in tumor cells reprograms the innate immune microenvironment to support tumor growth. We describe an unexpected role for Myosin II dynamics in cancer cells controlling myeloid function via secreted factors.


Assuntos
Movimento Celular/fisiologia , Miosina Tipo II/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Adesão Celular , Linhagem Celular Tumoral , Movimento Celular/imunologia , Proteínas do Citoesqueleto , Feminino , Humanos , Interleucina-1alfa/metabolismo , Masculino , Melanoma/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos SCID , Pessoa de Meia-Idade , NF-kappa B/metabolismo , Neoplasias/imunologia , Neoplasias/metabolismo , Fosforilação , Proteômica , Receptor Cross-Talk/fisiologia , Transdução de Sinais , Microambiente Tumoral/imunologia
12.
J Tissue Viability ; 28(2): 87-93, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30799135

RESUMO

The prevention of progression of Category I pressure ulcers (PUs) to Category II or higher is important, as Category II or higher PUs are open wounds and have a higher infection risk. Prognosis prediction of Category I PUs is necessary to provide successful intensive care for PUs with impaired healing. We focused on skin blotting using plasminogen activator inhibitor 1 (PAI1), interleukin-1α (IL-1α), vascular endothelial growth factor C (VEGF-C), and heat shock protein 90α (HSP90α). This pilot study was conducted at long-term-care and general hospitals to examine the applicability of DESIGN-R and thermography; the feasibility of skin blotting technique; the biomarker candidates, PAI1, IL-1α, VEGF-C, and HSP90α; and sample size for prognosis prediction for Category I PUs. Patients aged >65 years underwent skin blotting, scoring for DESIGN-R, and took thermography images of their Category I PU site. Albumin signals were not detected in one out of three participants. PAI1, IL-1α, VEGF-C, and HSP90α were detected in 19 participants, among whom 11 participants could be followed up after one week. There was no difference in DESIGN-R score and skin surface temperature between normal and impaired healing groups, and the sample size was calculated as 16. In conclusion, the feasibility of skin blotting was confirmed. PAI1, IL-1α, VEGF-C, and HSP90α could be biomarker candidates for prognosis prediction for Category I PU and the combination of VEGF-C and HSP90α could be associated with the prognosis of Category I PU. We need to investigate 842 patients in a future study.


Assuntos
Biomarcadores/metabolismo , Lesão por Pressão/metabolismo , Pele/metabolismo , Cicatrização/fisiologia , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/análise , Feminino , Humanos , Interleucina-1alfa/análise , Interleucina-1alfa/metabolismo , Japão , Masculino , Projetos Piloto , Inibidor 1 de Ativador de Plasminogênio/análise , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Lesão por Pressão/fisiopatologia , Pele/fisiopatologia , Estatísticas não Paramétricas , Fator C de Crescimento do Endotélio Vascular/análise , Fator C de Crescimento do Endotélio Vascular/metabolismo
13.
Eur J Obstet Gynecol Reprod Biol ; 235: 71-76, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30807994

RESUMO

OBJECTIVE: Exosomes are extracellular microvesicles that participate in intercellular communication. Seminal plasma (SP) contains very large amounts of exosomes which are deposited in female genital tract after insemination. Although the response of vaginal cells to seminal exosomes (SE) is recently being elucidated, the interaction of uterine cells with SE is still unknown. Here, we aimed to evaluate the effect of SE on cytokine secretion by human endometrial stromal cells (eSC). STUDY DESIGN: Exosomes were isolated from the semen samples of healthy men with proven fertility and characterized using common exosome characterization methods. Human eSC were isolated from endometrial biopsies obtained from healthy premenopausal women. For exosome internalization analysis, SE were labeled with PKH67 green fluorescent dye and incubated with the cells. For investigating the effect of SE on cytokine secretion of eSC, we measured levels of interleukin (IL)-6, IL-8, IL-10, IL-1α, and leukemia inhibitory factor (LIF) in the culture supernatants of control and experimental groups by enzyme-linked immunosorbent assay (ELISA) after 24 h of incubation. RESULTS: Our results demonstrated that SE are internalized by eSC and subsequently induce them to produce IL-6 and IL-8, the cytokines which are involved in the immunology of embryo implantation. CONCLUSION: The findings of the present study suggest that SE contribute to the immunoregulatory functions of SP in the uterus and may participate in embryo implantation process. Therefore dysfunction of intracellular machineries of SE biogenesis and secretion, inadequate production, defective transportation to the uterus and impaired communication with endometrium may play a distinct role in pathophysiology of embryo implantation failure.


Assuntos
Implantação do Embrião/imunologia , Exossomos/fisiologia , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Células Estromais/metabolismo , Adulto , Técnicas de Cultura de Células , Endométrio/citologia , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Interleucina-10/metabolismo , Interleucina-1alfa/metabolismo , Fator Inibidor de Leucemia/metabolismo , Masculino , Sêmen/citologia , Útero/imunologia
14.
Ecotoxicol Environ Saf ; 171: 467-474, 2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-30639873

RESUMO

Ambient particulate matter (PM) poses a great threat to global health and contributes to pulmonary inflammation. However, the potential mechanism of PM-induced inflammation of the lung remains unclear. Osteopontin (OPN) is a multifunctional protein that reportedly regulates inflammatory responses in different diseases. Here, we explored the expression of OPN with PM exposure in vivo and in vitro and attempted to elucidate the regulatory role of OPN in PM-induced airway inflammation. Our results showed that PM exposure increased the expression of OPN in the bronchial epithelium, serum, and bronchoalveolar lavage fluid (BALF) of mice. Moreover, PM induced OPN expression in human bronchial epithelial cells (HBECs) in a dose and time-dependent manner. In vitro, inflammatory cytokines such as IL-1α and IL-1ß were increased in HBECs with PM exposure via the ERK and JNK signaling pathways. Recombinant human OPN could potentiate PM-induced expression of IL-1α and IL-1ß, while OPN siRNA could alleviate PM-induced inflammatory responses in HBECs. Furthermore, we showed that OPN regulated PM-induced inflammatory cytokines via the ERK and JNK pathways in HBECs. This study shows for the first time the positive effect of OPN on PM-induced airway inflammation and contributes to a better understanding of its potential mechanism of action.


Assuntos
Interleucina-1alfa/metabolismo , Interleucina-1beta/metabolismo , Sistema de Sinalização das MAP Quinases , Osteopontina/metabolismo , Material Particulado/toxicidade , Animais , Linhagem Celular , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Regulação da Expressão Gênica , Humanos , Interleucina-1alfa/genética , Interleucina-1beta/genética , Masculino , Camundongos Endogâmicos C57BL , Osteopontina/genética
15.
Arch Oral Biol ; 99: 82-91, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30641295

RESUMO

OBJECTIVE: External inflammatory root resorption (EIRR) is a common complication of traumatic dental injury (TDI) that can be detected radiologically. During EIRR, various proteins are released into gingival sulcus fluid (GCF). The aim of the study was to monitor the levels of selected proteins in GCF in children (8-16 years of age) in order to assess their utility in the early diagnosis of EIRR. DESIGN: Twenty five children who experienced TDI to permanent incisors with ended root development were enrolled. GCF was collected from injured and control teeth with paper strips within seven days after TDI and on three visits during six-month follow-up. Concentrations of IL-1α, IL-1ß, IL-6, IL-8, TNFα, RANKL and MMP-9 in GCF were measured using enzyme-linked immunosorbent assays. EIRR was confirmed by radiological imaging techniques. RESULTS: Of all analyzed proteins, only the levels of IL-1α, Il-1ß and TNFα in GCF from the injured teeth with resorption were higher than in GCF from control teeth on the visit during which the EIRR was diagnosed. In univariate logistic regression model, the concentration of IL-1α in GCF was found as the strongest risk factor for the occurrence of EIRR. CONCLUSIONS: The composition of GCF may be indicative of EIRR after TDI. The monitoring of selected biomarkers in GCF may help to detect EIRR at its early stage and might be useful in reducing radiological exposure in children after TDI. IL-1α can be considered as a potential marker of the EIRR in children after TDI to the permanent teeth.


Assuntos
Biomarcadores/metabolismo , Dentição Permanente , Líquido do Sulco Gengival/química , Reabsorção da Raiz/etiologia , Reabsorção da Raiz/metabolismo , Traumatismos Dentários/complicações , Adolescente , Criança , Citocinas/metabolismo , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Incisivo/lesões , Incisivo/metabolismo , Inflamação , Interleucina-1alfa/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Modelos Logísticos , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Análise Multivariada , Estudos Prospectivos , Ligante RANK/metabolismo , Fatores de Risco , Reabsorção da Raiz/diagnóstico , Perda de Dente/etiologia , Fator de Necrose Tumoral alfa/metabolismo
16.
J Dermatol Sci ; 93(2): 82-91, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30514663

RESUMO

BACKGROUND: Psoriasis is an inflammatory disease associated with aberrant crosstalk between the epidermis and immune system. However, the role of Langerhans cells (LCs) in psoriasis remains controversial. OBJECTIVES: To elucidate whether LCs are functionally involved in the development of psoriasis using a mouse model. METHODS: Two lines of transgenic mice were used and crossed. They included K5.Stat3C, the psoriasis-model mouse and langerin DTR knock-in (KI) mouse. We performed immunofluorescence staining for LCs in psoriatic lesion of human and model mice. Flow cytometric analyses were performed to compare between dendritic cells (DCs) and LCs in the epidermis and skin-draining lymph nodes (sDLNs). To assess cytokine/chemokine expression in the skin lesion or primary cultured keratinocytes, we performed RT-PCR, microarray analysis or intracellular staining on the flow cytometer. RESULTS: LCs were activated in psoriatic lesion of patients with psoriasis and K5.Stat3C mice. Compared with non-transgenic mice, K5.Stat3C mice constitutively showed an increased number of LCs in the sDLNs before psoriasis-like lesion developed. Stat3C transgenic keratinocytes expressed an elevated level of IL-1α. Psoriasis-like lesion in K5.Stat3C mice were attenuated in the absence of LCs, indicating that LCs were essential to the development of psoriasis-like lesion. Furthermore, we also recognized that epidermal LCs in psoriatic lesion of not only K5.Stat3C mice but also psoriasis patients produced IL-23. CONCLUSIONS: Our study suggests that Stat3 activation in keratinocytes may impact on LC activation in situ via IL-1α stimulation, at least in part, and that their presence may be essential for the pathogenesis of psoriasis through producing IL-23.


Assuntos
Interleucina-23/imunologia , Queratinócitos/patologia , Células de Langerhans/imunologia , Psoríase/imunologia , Fator de Transcrição STAT3/metabolismo , Animais , Antígenos de Superfície/genética , Antígenos de Superfície/metabolismo , Biópsia , Células Cultivadas , Modelos Animais de Doenças , Voluntários Saudáveis , Humanos , Interleucina-1alfa/imunologia , Interleucina-1alfa/metabolismo , Interleucina-23/metabolismo , Queratinócitos/imunologia , Lectinas Tipo C/genética , Lectinas Tipo C/metabolismo , Lectinas de Ligação a Manose/genética , Lectinas de Ligação a Manose/metabolismo , Camundongos , Camundongos Transgênicos , Cultura Primária de Células , Psoríase/patologia , Pele/citologia , Pele/patologia
17.
Acta Ophthalmol ; 97(1): e97-e102, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29862656

RESUMO

PURPOSE: To evaluate the inflammation associated with the use of standard silicone oil (polydimethylsiloxane; PDMS) and heavy silicone oil (HSO) Densiron-68™ in patients undergoing vitrectomy for retinal detachment. MATERIALS AND METHODS: A prospective study was performed involving 35 patients scheduled to undergo vitrectomy for retinal detachment. Patients received PDMS or Densiron-68™ HSO according to superior or inferior retinal localization of the tears, respectively. For assessing the inflammation, prostaglandin E2 (PGE2 ) and interleukin-1α (IL-1α) levels were evaluated in the aqueous. RESULTS: Thirty-five eyes of 35 patients completed the study: 20 eyes received HSO, and 15 eyes received PDMS. The mean aqueous PGE2 level was significantly higher in HSO patients than in PDMS patients (869.16 ± 242.83 pg/ml versus 369.38 ± 209.7 pg/ml, respectively; p < 0.0001). The mean aqueous IL-1α level was also significantly higher in HSO patients than in PDMS patients (81.40 ± 36.9 pg/ml versus 40.8 ± 32.5 pg/ml, respectively; p = 0.002). In HSO, a moderate positive correlation between the endotamponade duration and both PGE2 (r = 0.44; p = 0.05) and IL-1α (r = 0.48; p = 0.033) levels was observed. In PDMS, a strong positive correlation between the endotamponade duration and both PGE2 (r = 0.89; p < 0.0001) and IL-1α (r = 0.68; p = 0.006) levels was observed. CONCLUSION: Although both HSO and PDMS yielded favourable success rates in the surgical treatment of complicated retinal detachments, HSO triggered a more severe inflammatory reaction, in a time-dependent manner.


Assuntos
Tamponamento Interno/efeitos adversos , Complicações Pós-Operatórias , Descolamento Retiniano/cirurgia , Óleos de Silicone/efeitos adversos , Uveíte/etiologia , Acuidade Visual , Vitrectomia/efeitos adversos , Humor Aquoso/metabolismo , Biomarcadores/metabolismo , Dinoprostona/metabolismo , Feminino , Seguimentos , Humanos , Interleucina-1alfa/metabolismo , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Óleos de Silicone/administração & dosagem , Uveíte/diagnóstico , Uveíte/metabolismo
18.
Arch Oral Biol ; 98: 92-98, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30468993

RESUMO

OBJECTIVE: To examine the effects of gingival mesenchymal stem cells (GMSCs) on inflammatory macrophages upon oxidized low-density lipoprotein (ox-LDL) stimulation and evaluate therapeutic potential of GMSCs on mouse model of periodontitis associated with hyperlipidemia. METHODS: in vitro, GMSCs were co-cultured with macrophages for 48 h in the absence or presence of M1 polarizing conditions and oxidized low-density lipoprotein in the transwell system. The supernatants were collected for ELISA. M1 and M2 markers of macrophages were analyzed by flow cytometry and PCR, and lipid accumulation was assessed by oil red O staining. in vivo, eighteen mice were divided into three groups (n = 6): Group A (periodontally healthy mice as control), Group B (periodontitis mice with hyperlipidemia), Group C (periodontitis mice with hyperlipidemia with the transplantation of GMSCs). The serum levels of cholesterol and inflammatory factors were measured by automatic analyzer. Bone regeneration was evaluated by Masson staining. RESULTS: When co-cultured with GMSCs, the M1 markers of Tumor Necrosis Factor (TNF) -α, Interleukin (IL) -6, Interleukin (IL) -1ß, CD86, and Human Leukocyte Antigen (HLA) -DR were significantly reduced. In contrast, M2 markers such as Interleukin(IL) -10 and CD206 were moderately increased. Similar results were obtained in the cell culture supernatants. In animal experiment, GMSCs suppressed the expression of sterol regulatory element binding transcription factor 1c (SREBP-1c) and elevated the levels of peroxisome proliferator-activated receptor alpha (PPARα) and peroxisome proliferator activator receptor- coactivator 1(PGC-1α) in the liver, attenuated cholesterol dysfunction via the downregulation of low-density lipoprotein (LDL) and total cholesterol (TC), and the upregulation of high-density lipoprotein (HDL), and decreased the levels of TNF-α and IL-6. Moreover, GMSC treatment improved bone regeneration. CONCLUSION: GMSCs inhibit the activation of M1 macrophages, regulate lipid metabolism and reduce inflammatory response, and promote bone regeneration in mouse model of periodontitis associated with hyperlipidemia.


Assuntos
Gengiva/metabolismo , Hiperlipidemias/metabolismo , Metabolismo dos Lipídeos/fisiologia , Lipoproteínas LDL/farmacologia , Macrófagos/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Adolescente , Adulto , Animais , Antígeno B7-2/metabolismo , Regeneração Óssea , Colesterol/sangue , HDL-Colesterol/sangue , HDL-Colesterol/metabolismo , Técnicas de Cocultura , Antígenos HLA-DR/metabolismo , Humanos , Interleucina-1alfa/metabolismo , Interleucina-6/metabolismo , Lipoproteínas LDL/metabolismo , Fígado/metabolismo , Ativação de Macrófagos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , PPAR alfa/metabolismo , Periodontite , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Tetra-Hidroisoquinolinas , Fator de Necrose Tumoral alfa/metabolismo , Adulto Jovem
19.
Mol Pharm ; 16(2): 595-606, 2019 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-30525661

RESUMO

Many novel vaginal/rectal microbicide formulations failed clinically due to safety concerns, indicating the need for the early investigation of lead microbicide formulations. In this study, the preclinical safety of an HIV-1 gp120 and mannose responsive microbicide delivery system (MRP) is evaluated in C57BL/6 mice. MRP was engineered through the layer-by-layer coating of calcium carbonate (CaCO3) with Canavalia ensiformis lectin (Con A) and glycogen. MRP mean particle diameter and zeta potential were 857.8 ± 93.1 nm and 2.37 ± 4.12 mV, respectively. Tenofovir (TFV) encapsulation and loading efficiencies in MRP were 70.1% and 16.3% w/w, respectively. When exposed to HIV-1 rgp120 (25 µg/mL), MRP released a significant amount of TFV (∼5-fold higher) in vaginal and seminal fluid mixture compared to the control (pre-exposure) level (∼59 µg/mL) in vaginal fluid alone. Unlike the positive control treated groups (e.g., nonoxynol-9), no significant histological damages and CD45+ cells infiltration were observed in the vaginal and major reproductive organ epithelial layers. This was probably due to MRP biocompatibility and its isosmolality (304.33 ± 0.58 mOsm/kg). Furthermore, compared to negative controls, there was no statistically significant increase in pro-inflammatory cytokines such as IL1α, Ilß, IL7, IP10, and TNFα. Collectively, these data suggest that MRP is a relatively safe nanotemplate for HIV-1 gp120 stimuli responsive vaginal microbicide delivery system.


Assuntos
Anti-Infecciosos/uso terapêutico , Proteína gp120 do Envelope de HIV/metabolismo , HIV-1/efeitos dos fármacos , HIV-1/patogenicidade , Administração Intravaginal , Animais , Carbonato de Cálcio/metabolismo , Quimiocinas/metabolismo , Difusão Dinâmica da Luz , Feminino , Infecções por HIV/tratamento farmacológico , Imuno-Histoquímica , Interleucina-1alfa/metabolismo , Interleucina-1beta/metabolismo , Interleucina-7/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Eletrônica de Varredura , Concentração Osmolar , Tenofovir/uso terapêutico , Fator de Necrose Tumoral alfa/metabolismo , Vagina/virologia
20.
J Gastroenterol Hepatol ; 34(3): 544-551, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30378164

RESUMO

BACKGROUND AND AIM: Inflammatory bowel diseases is associated with an increased risk for the development of colorectal cancer. However, the mechanism of immune signaling pathways linked to colitis-associated cancer (CAC) has not been fully elucidated. Tauroursodeoxycholic acid (TUDCA) exhibits anti-inflammatory and anti-cancer activities. The aim of this study is to investigate the role of TUDCA in the pathogenesis of CAC. METHODS: Colitis-associated cancer was induced in mice using azoxymethane and dextran sodium sulfate administration, and TUDCA's effect on tumor development was evaluated. HCT 116 and COLO 205 were treated with TUDCA or vehicle and then stimulated with tumor necrosis factor-α (TNF-α). Expression of interleukin (IL)-8 was determined by real-time reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay, and IκBα phosphorylation and degradation was evaluated by immunoblot assay. The DNA-binding activity of NF-κB was assessed by electrophoretic mobility shift assay. Cell viability assay and real-time reverse transcription-polymerase chain reaction of bcl-xL, MCL1, c-FLIP-L, and VEGF were performed. RESULTS: Tauroursodeoxycholic acid significantly attenuated the development of CAC in mice. Exposure to TUDCA resulted in extensive epithelial apoptosis and reduced levels of phospho-IκB kinase in the colon. In HCT 116 cells stimulated with TNF-α, TUDCA significantly inhibited IL-8 and IL-1α expression and suppressed TNF-α-induced IκBα phosphorylation/degradation and DNA-binding activity of NF-κB. Furthermore, in both HCT 116 and COLO 205 cells, TUDCA reduced cell viability and downregulated the expression of bcl-xL, MCL1, c-FLIP-L, and VEGF. CONCLUSION: These results demonstrated that TUDCA suppresses NF-κB signaling and ameliorates colitis-associated tumorigenesis, suggesting that TUDCA could be a potential treatment for CAC.


Assuntos
Colite/complicações , Neoplasias Colorretais/etiologia , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ácido Tauroquenodesoxicólico/farmacologia , Ácido Tauroquenodesoxicólico/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Colo/metabolismo , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Interleucina-1alfa/metabolismo , Interleucina-8/metabolismo , Masculino , Camundongos Endogâmicos C57BL , NF-kappa B/genética , Transdução de Sinais/genética , Células Tumorais Cultivadas
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