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1.
Adv Exp Med Biol ; 1189: 85-133, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31758532

RESUMO

T-cell receptor (TCR)-mediated antigen-specific stimulation is essential for initiating T-cell activation. However, signaling through the TCR alone is not sufficient for inducing an effective response. In addition to TCR-mediated signaling, signaling through antigen-independent co-stimulatory or co-inhibitory receptors is critically important not only for the full activation and functional differentiation of T cells but also for the termination and suppression of T-cell responses. Many studies have investigated the signaling pathways underlying the function of each molecular component. Co-stimulatory and co-inhibitory receptors have no kinase activity, but their cytoplasmic region contains unique functional motifs and potential phosphorylation sites. Engagement of co-stimulatory receptors leads to recruitment of specific binding partners, such as adaptor molecules, kinases, and phosphatases, via recognition of a specific motif. Consequently, each co-stimulatory receptor transduces a unique pattern of signaling pathways. This review focuses on our current understanding of the intracellular signaling pathways provided by co-stimulatory and co-inhibitory molecules, including B7:CD28 family members, immunoglobulin, and members of the tumor necrosis factor receptor superfamily.


Assuntos
Antígenos CD28/metabolismo , Ativação Linfocitária , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais , Linfócitos T/citologia , Humanos , Imunoglobulinas/metabolismo , Receptores do Fator de Necrose Tumoral/metabolismo
2.
Cell Biochem Funct ; 37(7): 516-524, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31343762

RESUMO

Thyroid cancer has been continuously increasing and extraordinarily prevalent worldwide. The genetic diagnosis has been widely used in fine needle aspiration. IGSF1, an immunoglobulin superfamily member 1, has been shown to be associated with the regulation of thyroid hormone. But the function of IGSF1 in thyroid cancer has not been explored yet. In this article, we will illuminate the correlation between IGSF1 expression and thyroid cancer. We analysed the level of IGSF1 expression in 55 pairs of tissue samples by real-time polymerase chain reaction (PCR) and The Cancer Genome Atlas (TCGA) data portal. After that, we transfected small interfering RNA to silence IGSF1 in thyroid cancer cell lines (KTC-1 and BCPAP) and confirmed the function of IGSF1 by performed colony formation, migration, invasion, cell counting kit-8, and apoptosis assays. IGSF1 was upregulated in thyroid cancer tissues compared with the adjacent normal tissues (t = 5.783, df = 54; P < .0001) and TCGA (T: N = 65.91 ± 3.998, n = 501: 2.824 ± 0.273, n = 58; P < .0001). In thyroid cell lines, experiments showed that downregulated IGSF1 inhibited proliferation, metastasis, and promoted cell apoptosis. Meanwhile, inhibited IGSF1 expression could downregulate N-cadherin, vimentin, and EZH2, which is associated with metastasis. Thyroid cancer cells IGSF1 expression levels are a correlation with its ability to growth, metastasis, and apoptosis.


Assuntos
Imunoglobulinas/metabolismo , Proteínas de Membrana/metabolismo , Neoplasias da Glândula Tireoide/metabolismo , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Progressão da Doença , Humanos , Imunoglobulinas/genética , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/genética , RNA Interferente Pequeno/farmacologia , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/patologia , Células Tumorais Cultivadas
3.
Int J Biol Macromol ; 138: 156-167, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31302124

RESUMO

Protein-nanoparticle (NP) interaction, which inevitably form protein corona (PC), has been the subject of much debate about its role in modern biomedical research. In this regard, PC associated with two different NPs viz., magneto-fluorescent (MF) and chitosan coated MF (CMF) NPs were thoroughly investigated, to analyze the effect of polymer coating on protein adsorption. Bradford assay, along with the spectroscopic and microscopic studies suggested increase in adsorbed protein quantity, though the results varied significantly on moving from bare to polymeric coating and in vitro to ex vivo conditions. Interestingly, polymer coated NPs showed increased protein adsorption and induce minimal changes in protein structural integrity under the same conditions. We predict that the changes in secondary structure of primary corona determine the overall signature of surface binding proteins in PC. Our findings suggested that rapid diagnosis of immunoglobulins is possible using the concept of protein corona formation ex vivo.


Assuntos
Análise Química do Sangue/métodos , Imunoglobulinas/sangue , Imunoglobulinas/química , Nanopartículas/química , Proteômica , Adsorção , Quitosana/química , Humanos , Imunoglobulinas/metabolismo , Imãs/química , Teste de Materiais , Estrutura Secundária de Proteína , Propriedades de Superfície , Fatores de Tempo
4.
J Anim Physiol Anim Nutr (Berl) ; 103(4): 1125-1134, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31155767

RESUMO

Our previous study has shown that high levels of l-arginine (ARG) have reduced serum and mucosal antibody concentrations. In order to provide a better understanding in the application of ARG supplementation in the poultry industry, the study was conducted to investigate the effect of high levels of ARG on performance and B-cell secretion of immunoglobulin M (IgM) and IgG development in broiler chickens. A total of 192 1-day-old male Arbor Acres Plus broilers were randomly allocated into 4 groups (8 replicates per group, 6 birds per replicate) fed diets containing one of four ARG concentrations (analysed): 9.8, 14.7, 19.1 and 23.4 g/kg respectively. Growth performance was measured based on body weight gain (BWG), feed intake (FI) and feed conversion ratio (FCR). Increasing ARG quadratically increased (p < 0.05) BWG and FI with reaching plateau at 14.7 g/kg, while linearly decreased (p < 0.05) FCR, indicating that maximal performance required ARG no more than 14.7 g/kg in diets. Serum IgG and IgM concentrations were linearly reduced (p < 0.05) with increasing ARG. Chickens fed 19.1 g/kg or 23.4 g/kg ARG had lower (p < 0.05) serum IgG or IgM than chickens fed 9.8 g/kg ARG. As for the mRNA expression of bursal IgG and IgM, they were significantly downregulated with increasing ARG (p < 0.05). Chickens on ARG (>19.1 g/kg) had a lower (p < 0.05) IgG and IgM mRNA expression than chickens fed 9.8 g/kg. Activator of transcription 3 (STAT3) mRNA expression was linearly reduced with increasing ARG (p < 0.05), the transcriptional repressor B-cell lymphoma 6 (BCL6) mRNA expression was quadratically (p < 0.05) responded, and these cytokines had the lowest expression at 19.1 g/kg. ARG supplementation (>14.7 g/kg) did not significantly improve the growth performance, while it may have a potential negative regulatory effect on B-cell-mediated humoral immunity in chickens associated with suppression of the STAT3 expression associated with the JAK/STAT3 pathway.


Assuntos
Arginina/administração & dosagem , Linfócitos B/metabolismo , Galinhas/crescimento & desenvolvimento , Dieta/veterinária , Imunoglobulinas/metabolismo , Ração Animal/análise , Fenômenos Fisiológicos da Nutrição Animal , Animais , Apoptose , Ciclo Celular , Suplementos Nutricionais , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino
5.
Vet Immunol Immunopathol ; 211: 75-84, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31084898

RESUMO

The primary function of the mammary gland is to produce milk to feed the suckling young. In ruminants, ingestion of maternal antibodies in mammary secretions facilitates the transfer of passive immunity from mother to young, providing antibody-mediated immunity to protect the neonate against disease while their own immune system develops. Antibodies in mammary secretions also play a role in protecting the gland itself against infection. Here we provide a brief history of studies on immunoglobulins in ruminant mammary secretions and review recent findings describing the mechanisms by which antibody-producing plasmablasts are recruited to the gland and immunoglobulins are transported into ruminant mammary secretions. An improved understanding of the complex interaction of factors which regulate immunoglobulin production and transfer to the ruminant mammary gland may provide opportunities to enhance antibody concentrations in mammary secretions during normal lactation and in response to immunisation. Strategies aimed at increasing antibody concentrations in ruminant mammary secretions have the potential to improve the ability of animals to resist mammary infections, enhance the transfer of passive immunity from mother to young and increase the feasibility of harvesting antibodies from the mammary secretions for use in commercial therapeutic applications for humans and domesticated animals.


Assuntos
Imunoglobulinas/metabolismo , Glândulas Mamárias Animais/imunologia , Ruminantes/imunologia , Animais , Transporte Biológico Ativo , Bovinos , Feminino , Imunoglobulina E/metabolismo , Glândulas Mamárias Animais/metabolismo , Leite/imunologia , Receptores Fc/metabolismo , Ruminantes/metabolismo , Ovinos
6.
Ann Diagn Pathol ; 40: 72-76, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31075666

RESUMO

Primary mediastinal large B-cell lymphoma (PMBL) and classic Hodgkin lymphoma (CHL) are the most common large cell lymphomas arising in the mediastinum and are thought to be closely related histogenetically. Although the distinction between PMBL and CHL is usually straightforward, in some cases it is challenging and rarely these neoplasms have intermediate features and qualify for the diagnosis of mediastinal gray zone lymphoma (GZL). CD83 and fascin are markers of CHL and CD23 is a marker of PMBL. In this study we assess the utility of this combination of these immunohistochemical markers to distinguish CHL from PMBL. We retrospectively collected cases of PMBL, CHL and GZL from three centers. Tissue sections were stained with CD83, fascin and CD23. CD83 was expressed in the neoplastic cells of 100% of CHL (22/22), 93% of GZL (16/18) and 41% of PMBL (9/22). Similarly, fascin was positive in the neoplastic cells of 100% of CHL (22/22), 86% of GZL (18/21) and 32% of PMBL (7/22). CD23 was positive in 95% of PMBL (21/22), 67% of GZL (12/18) and 9% of CHL (2/22). CD83 and fascin are sensitive markers for CHL but not specific whereas CD23 is sensitive for PMBL and uncommon in CHL. The GZL cases in this study had an intermediate immunophenotype, but the results were closer to CHL than PMBL. A large panel of immunohistochemical studies is recommended to distinguish CHL from PMBL entities and we suggest that CD83, fascin and CD23 add value to panels designed for this differential diagnosis.


Assuntos
Biomarcadores Tumorais/metabolismo , Doença de Hodgkin/diagnóstico , Linfoma Difuso de Grandes Células B/diagnóstico , Neoplasias do Mediastino/diagnóstico , Antígenos CD/metabolismo , Proteínas de Transporte/metabolismo , Diagnóstico Diferencial , Doença de Hodgkin/metabolismo , Doença de Hodgkin/patologia , Humanos , Imunoglobulinas/metabolismo , Imuno-Histoquímica , Imunofenotipagem , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Neoplasias do Mediastino/metabolismo , Neoplasias do Mediastino/patologia , Glicoproteínas de Membrana/metabolismo , Proteínas dos Microfilamentos/metabolismo , Receptores de IgE/metabolismo , Estudos Retrospectivos
7.
Dis Markers ; 2019: 5421985, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31089395

RESUMO

Human endogenous retrovirus-H long terminal repeat-associating protein 2 (HHLA2) and transmembrane and immunoglobulin domain containing 2 (TMIGD2) are new immune checkpoint molecules of the B7:CD28 family; however, little research has been performed on these immune checkpoint molecules. In this study, we used oral squamous cells carcinoma (OSCC) tissue microarrays and immunohistochemistry methods to investigate the expression patterns of HHLA2 and TMIGD2 in OSCC. After comparing the HHLA2 and TMIGD2 expression levels in OSCC, dysplasia, and mucosa, we found increased HHLA2 expression in OSCC and dysplasia, while the TMIGD2 expression was decreased in OSCC and dysplasia. Using the Kaplan-Meier method and log-rank test, we found that higher HHLA2 or TMIGD2 expression levels in OSCC indicate poor prognosis. Furthermore, two-tailed Pearson's statistical analysis revealed that the HHLA2 expression levels in OSCC, dysplasia, and mucosa were positively correlated with the T cell immunoglobulin and mucin-domain containing-3 (TIM3), lymphocyte-activation gene 3 (LAG3), B7 homolog 3 protein (B7-H3), B7 homolog 4 protein (B7H4), and V-domain Ig suppressor of T cell activation (VISTA) levels, while the TMIGD2 expression levels in OSCC, dysplasia, and mucosa were inversely correlated with the TIM3, LAG3, and B7H3 levels. Our current study demonstrates that HHLA2 may serve as an immune target for OSCC therapy and that the TMIGD2 expression level in OSCC could forecast patient prognosis.


Assuntos
Biomarcadores Tumorais/genética , Antígenos CD28/genética , Carcinoma de Células Escamosas/genética , Regulação Neoplásica da Expressão Gênica , Imunoglobulinas/genética , Neoplasias Bucais/genética , Biomarcadores Tumorais/metabolismo , Antígenos CD28/metabolismo , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Feminino , Humanos , Imunoglobulinas/metabolismo , Masculino , Neoplasias Bucais/metabolismo , Neoplasias Bucais/patologia
8.
Int J Mol Sci ; 20(10)2019 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-31137528

RESUMO

Atopic dermatitis (AD) is a recurrent allergic skin disease caused by genetic and environmental factors. Patients with AD may experience immune imbalance, increased levels of mast cells, immunoglobulin (Ig) E and pro-inflammatory factors (Cyclooxygenase, COX-2 and inducible NO synthase, iNOS). While spilanthol (SP) has anti-inflammatory and analgesic activities, its effect on AD remains to be explored. To develop a new means of SP, inflammation-related symptoms of AD were alleviated, and 2,4-dinitrochlorobenzene (DNCB) was used to induce AD-like skin lesions in BALB/c mice. Histopathological analysis was used to examine mast cells and eosinophils infiltration in AD-like skin lesions. The levels of IgE, IgG1 and IgG2a were measured by enzyme-linked immunosorbent assay (ELISA) kits. Western blot was used for analysis of the mitogen-activated protein kinase (MAPK) pathways and COX-2 and iNOS protein expression. Topical SP treatment reduced serum IgE and IgG2a levels and suppressed COX-2 and iNOS expression via blocked mitogen-activated protein kinase (MAPK) pathways in DNCB-induced AD-like lesions. Histopathological examination revealed that SP reduced epidermal thickness and collagen accumulation and inhibited mast cells and eosinophils infiltration into the AD-like lesions skin. These results indicate that SP may protect against AD skin lesions through inhibited MAPK signaling pathways and may diminish the infiltration of inflammatory cells to block allergic inflammation.


Assuntos
Antialérgicos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Dermatite Atópica/tratamento farmacológico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Alcamidas Poli-Insaturadas/uso terapêutico , Animais , Antialérgicos/administração & dosagem , Antialérgicos/farmacologia , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacologia , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Dermatite Atópica/etiologia , Dermatite Atópica/metabolismo , Dinitroclorobenzeno/toxicidade , Feminino , Imunoglobulinas/genética , Imunoglobulinas/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Alcamidas Poli-Insaturadas/administração & dosagem , Alcamidas Poli-Insaturadas/farmacologia
9.
Immunol Res ; 67(1): 70-76, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30937729

RESUMO

The CD83 molecule is a known marker of dendritic cell differentiation process, and its soluble form (sCD83) exerts immunosuppressive functions. In our research, we examined whether the sCD83 plasma concentration is impaired in DM1 children and if the expected changes are in line with the disturbed process of monocyte's transformation into mCD83+ monocyte-derived cells. 28 newly diagnosed (ND-DM1) and 30 long-standing (LS-DM1) patients were enrolled into our study. We revealed that the examined cells show a high mCD83 expression level in ND-DM1, which was significantly downregulated by the TNF-α stimulation. The results were in line with those from healthy controls. We also observed that monocyte differentiation process into CD83+ cells was much defective in LS-DM1 children and the mCD83 expression level seems not to be controlled by TNF-α. Moreover, the sCD83 level was significantly decreased in plasma from LS-DM1 children and it was negatively related to HbA1c levels, while no correlations were observed between TNF-α plasma concentration or disease duration. Summarizing, our results suggest that reduced sCD83 levels may correspond with a poor metabolic control in LS-DM1 patients and therapeutic administration of this molecule may indicate a new therapy approach in the chronic phase of diabetes.


Assuntos
Antígenos CD/metabolismo , Células Dendríticas/imunologia , Diabetes Mellitus Tipo 1/imunologia , Imunoglobulinas/metabolismo , Glicoproteínas de Membrana/metabolismo , Adolescente , Antígenos CD/genética , Diferenciação Celular , Células Cultivadas , Criança , Progressão da Doença , Feminino , Regulação da Expressão Gênica , Hemoglobina A Glicada/metabolismo , Humanos , Imunoglobulinas/genética , Imunossupressão , Masculino , Glicoproteínas de Membrana/genética , Fator de Necrose Tumoral alfa/metabolismo
10.
Expert Opin Drug Saf ; 18(5): 369-380, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30983432

RESUMO

INTRODUCTION: The treatment of asthma in older ages follows the recommendations of international guidelines for the management of asthma in younger ages, although older age has always represented an exclusion criterion for eligibility to pharmacological trials. This poses a clinical challenge when deciding whether elderly severe asthmatics are candidates for biological drugs. AREAS COVERED: The current article has a narrative structure to review the current literature on efficacy and safety of novel pharmacological drugs against immunoglobulins and interleukins that mediate and orchestrate the main inflammatory pathways in severe asthma, in order to explore whether older subjects (i.e. > 65 years of age) are included. EXPERT OPINION: Asthma in older ages is not a rare entity, and loss of symptom control is common in most advanced ages. Current evidence from randomized clinical trials (RCTs) on the safety of biological drugs in elderly asthmatics is scarce and does not allow drawing definitive conclusions. An urgent call for studies specifically designed for elderly populations is needed, with the purpose to assess the efficacy and safety of target biological therapies in advanced ages. We envision the design of large multi-center clinical trials to decide whether and when geriatric population could benefit from biological therapies.


Assuntos
Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Produtos Biológicos/uso terapêutico , Fatores Etários , Idoso , Antiasmáticos/efeitos adversos , Asma/fisiopatologia , Produtos Biológicos/efeitos adversos , Humanos , Imunoglobulinas/metabolismo , Interleucinas/metabolismo , Guias de Prática Clínica como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Índice de Gravidade de Doença
11.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 35(2): 162-168, 2019 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-30975282

RESUMO

Objective To detect the levels of cell-bound complement activation product (C4d) and immunoglobulins (IgG and IgM) on T and B lymphocytes in patients with systemic lupus erythematosus (SLE), and to evaluate the relationships between C4d and immunoglobulins (Ig) on lymphocytes, and finally to evaluate their diagnostic value for SLE. Methods A cross-sectional study including 142 SLE patients, 144 patients with other non-SLE autoimmune diseases and 100 healthy individuals was conducted. C4d and immunoglobulins on peripheral T and B lymphocytes (T-C4d, B-C4d, T-Ig and B-Ig) were measured by flow cytometry. In vitro immunobinding experiment was performed to characterize serum Ig from SLE patients to generate T-C4d, B-C4d, T-Ig and B-Ig. ANA, anti-dsDNA, anti-Smith antibody and other biomarkers were measured. Area under the receiver operating characteristic curve (AUC), nonparametric tests, partial correlation analysis, sensitivity and specificity were used for statistical analysis. Results Levels of T-C4d, B-C4d, T-Ig and B-Ig were found to be highest in SLE patients. Levels of T-C4d, B-C4d, T-Ig and B-Ig in non-SLE patients were also significantly higher than those in healthy individuals. T-C4d was positively correlated with T-Ig (r=0.587), as well as B-C4d vs B-Ig (r=0.734). Purified Ig from SLE plasma generated higher levels of T-C4d, B-C4d, T-Ig and B-Ig than Ig-removed SLE plasma. AUC of T-C4d, B-C4d, T-Ig and B-Ig were 0.733, 0.834, 0.707 and 0.825, respectively. Compared with anti-dsDNA antibody (38.7%), the sensitivity for SLE diagnosis increased significantly when the combination of T-C4d, B-C4d, T-Ig and B-Ig (85.2%) was made. Conclusion The autoantibody is a key factor for cell-bound C4d formation, and T-C4d, B-C4d, T-Ig and B-Ig may be reliable indicators for the diagnosis of SLE.


Assuntos
Complexo Antígeno-Anticorpo , Complemento C4b , Imunoglobulinas , Lúpus Eritematoso Sistêmico , Complexo Antígeno-Anticorpo/metabolismo , Linfócitos B/metabolismo , Complemento C4b/metabolismo , Estudos Transversais , Testes Diagnósticos de Rotina/normas , Humanos , Imunoglobulinas/metabolismo , Lúpus Eritematoso Sistêmico/diagnóstico , Sensibilidade e Especificidade , Linfócitos T/metabolismo
12.
Mol Med Rep ; 19(5): 4081-4090, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30896871

RESUMO

The dendritic cell (DC)­regulatory T (Treg) system serves a leading role in the immunosuppression of the tumor microenvironment, which is not conducive to radiotherapy and chemotherapy treatment for lung cancer. The present study aimed to investigate the effect of oxymatrine (OMT) on the DC­Treg system in the tumor microenvironment in vitro and to examine its mechanism. The expressions of CD83 antigen, T­lymphocyte activation antigen CD86, CD11 antigen­like family member C and major histocompatibility complex II in DCs were increased upon treatment with 1 mg/ml OMT, as detected by flow cytometry. Following pretreatment with OMT, the DCs mediated the forkhead box protein P3 overexpression in primitive cluster of differentiation 4+ T cells at the protein and mRNA expression levels. The expression levels of anti­inflammatory factors, including interleukin (IL)­10, tumor growth factor­ß, IL­35, and pro­inflammatory cytokines, including interferon­Î³, IL­12 and IL­2, in the co­culture supernatant were increased as measured by ELISA. When DCs and DC­Tregs were co­cultured with cisplatin­resistant A549 cells, the proportion of apoptosis in the co­culture groups was increased under treatment with cisplatin, which was detected by Annexin V/propidium Iodide staining and western blotting. The present results suggested that OMT may promote the maturation of DCs, mediate the differentiation of T cells into Treg cells, and reverse the resistance of tumor cells to cisplatin in vitro. It was suggested that OMT is an important adjunct to chemotherapy through the regulation of antitumor responses.


Assuntos
Alcaloides/farmacologia , Células Dendríticas/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ativação Linfocitária/efeitos dos fármacos , Quinolizinas/farmacologia , Linfócitos T Reguladores/imunologia , Células A549 , Adulto , Antígenos CD/metabolismo , Apoptose/efeitos dos fármacos , Antígenos CD4/metabolismo , Estudos de Casos e Controles , Células Cultivadas , Cisplatino/farmacologia , Citocinas/metabolismo , Células Dendríticas/citologia , Células Dendríticas/imunologia , Fatores de Transcrição Forkhead/metabolismo , Humanos , Imunoglobulinas/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Glicoproteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/metabolismo
13.
Front Biosci (Landmark Ed) ; 24: 735-749, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30844709

RESUMO

Mammalian fertilization that culminates by fusion of the male and female gametes is intricately regulated within the female reproductive tract. To become competent to fertilize an egg, the mammalian spermatozoa that enter the female reproductive tract must undergo a series of physiological changes, including hyperactivation, and capacitation. For reaching full competency, the acrosome, a specialized membrane-bound organelle that covers the anterior part of the sperm head, must undergo an acrosome reaction. For becoming competent to bind an ovum, and to penetrate the zona pellucida and cumulus, many sperm proteins are released in the course of the acrosome reaction. Ultimately, the acrosome binds to the oolemma and fusion of sperm and egg occurs. In this review, we outline current understanding of the roles and effects of some essential sperm proteins and their functions during fertilization in the female reproductive tract.


Assuntos
Fertilização/fisiologia , Genitália Feminina/fisiologia , Espermatozoides/fisiologia , Reação Acrossômica , Animais , Antígenos/metabolismo , Moléculas de Adesão Celular/metabolismo , Feminino , Fertilinas/metabolismo , Humanos , Hialuronoglucosaminidase/metabolismo , Imunoglobulinas/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Receptores de Superfície Celular/metabolismo , Zona Pelúcida/metabolismo
14.
Nat Med ; 25(4): 656-666, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30833750

RESUMO

Overexpression of the B7-H1 (PD-L1) molecule in the tumor microenvironment (TME) is a major immune evasion mechanism in some patients with cancer, and antibody blockade of the B7-H1/PD-1 interaction can normalize compromised immunity without excessive side-effects. Using a genome-scale T cell activity array, we identified Siglec-15 as a critical immune suppressor. While only expressed on some myeloid cells normally, Siglec-15 is broadly upregulated on human cancer cells and tumor-infiltrating myeloid cells, and its expression is mutually exclusive to B7-H1, partially due to its induction by macrophage colony-stimulating factor and downregulation by IFN-γ. We demonstrate that Siglec-15 suppresses antigen-specific T cell responses in vitro and in vivo. Genetic ablation or antibody blockade of Siglec-15 amplifies anti-tumor immunity in the TME and inhibits tumor growth in some mouse models. Taken together, our results support Siglec-15 as a potential target for normalization cancer immunotherapy.


Assuntos
Imunoglobulinas/metabolismo , Imunoterapia , Proteínas de Membrana/metabolismo , Neoplasias/imunologia , Neoplasias/terapia , Animais , Linhagem Celular Tumoral , Proliferação de Células , Epitopos , Humanos , Macrófagos/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Células Mieloides/metabolismo , Neoplasias/patologia , Proteoma/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Linfócitos T/imunologia
15.
Int J Mol Med ; 43(5): 2118-2132, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30864687

RESUMO

Type 2 diabetes mellitus (T2DM) is a disease associated with a number of metabolic disturbances, including protein metabolism. In the present study, blood samples were obtained from Bahraini subjects, including 6 patients with T2DM and 6 age­ and sex­matched, non­diabetic, healthy controls. Depleted and non­depleted sera were prepared from the collected blood, and the global protein expression changes were evaluated by liquid chromatography tandem mass spectrometry. Only significantly and markedly differentially­expressed proteins (P<0.05, analysis of variance; maximum fold change ≥1.5) were considered as candidate proteins for informatics analysis. Accordingly, a total of 62 proteins were identified to be differentially expressed in T2DM, compared with control subjects, and they were grouped functionally into 16 classes of proteins. The largest class was that of the immune­associated proteins. Additionally, ~25 of these proteins (40%) had previously been associated with DM; however, the association of the other 37 proteins with T2DM was a novel observation. The majority of the identified proteins were upregulated in T2DM. The identified proteins could be involved in the pathogenesis of the disease or serve as disease biomarkers. Further validation of the identified proteins in a large study cohort is required, in order to fully access their potential clinical usefulness.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Imunoglobulinas/metabolismo , Proteômica , Espectrometria de Massas em Tandem , Adulto , Cromatografia Líquida , Análise por Conglomerados , Diabetes Mellitus Tipo 2/sangue , Regulação para Baixo , Feminino , Humanos , Imunoglobulinas/sangue , Masculino , Pessoa de Meia-Idade , Regulação para Cima
16.
J Trace Elem Med Biol ; 52: 89-99, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30732905

RESUMO

This study aimed to evaluate the effects of increasing selenium (Se) supply for heat-stressed or actively cooled sows on sow productivity, colostrum and milk composition, as well as the selenium and antioxidant status and immunoglobulin levels of sows and nursing piglets. The study was a 2 × 2 factorial design, where the first factor was farrowing environment [heat stress vs. actively cooling, temperature: 29.61 ± 0.19 ℃ (27.70-31.60 ℃) vs. 27.90 ± 0.15 ℃ (26.90-30.20 ℃); temperature-humidity index: 72.91 ± 0.26 (70.30-75.70) vs. 70.81 ± 0.22 (69.30-73.80)], and the second factor was dietary Se level during late gestation and lactation [(0.3 vs. 1.2 mg/kg Se as Se-yeast, the basal diet was corn-soybean meal diet formulated according to NRC (2012) except for Se level]. Forty multiparous sows (Landrace × Yorkshire) were randomly allotted to 1 of 4 treatments (10 sows and following 90 piglets per treatment, respectively). The results show that: (1) There were no interactions of farrowing environment with Se treatments with the exceptions of nutrient content of 7-d milk; (2) As for zootechnical measures, piglets of sows receiving increasing Se tended to have greater preweaning survival compared with those of sows receiving control diet without interactions of environment and Se treatments; (3) As to colostrum and milk composition, greater concentrations of protein, lactose, solids-not-fat in colostrum, and greater fat concentration in 7-d and 14-d milk were found for sows fed increasing Se; (4) Regarding Se and antioxidant status, increasing Se supply for sows increased Se content in colostrum and 21-d milk, as well as in plasma of 1-day-old and 21-day-old piglets. Meanwhile, increasing Se supply for sows improved antioxidant status in colostrum (MDA content) and 21-d milk (T-AOC and MDA content), as well as in plasma of 1-day-old and 21-day-old piglets (GSH-Px activity and MDA content); (5) With regard to immunoglobulins, sows fed increasing Se had higher IgM levels in colostrum, and higher IgA in 21-d milk. Also, piglets from sows fed increasing Se had higher plasma IgA at 1 d of age, and higher IgA and IgG levels at 21 d of age. Collectively, increasing selenium supply for heat-stressed or actively cooled sows improved piglet preweaning survival, colostrum and milk composition, as well as maternal selenium, antioxidant status and immunoglobulin transfer irrespective of the climatic conditions, which indicates that Se requirements for sows should be urgently reassessed.


Assuntos
Antioxidantes/metabolismo , Colostro/efeitos dos fármacos , Resposta ao Choque Térmico/efeitos dos fármacos , Imunoglobulinas/metabolismo , Leite/efeitos dos fármacos , Selênio/farmacologia , Ração Animal , Animais , Antioxidantes/análise , Bovinos , Colostro/química , Colostro/metabolismo , Suplementos Nutricionais , Feminino , Leite/química , Leite/metabolismo , Gravidez , Selênio/administração & dosagem , Taxa de Sobrevida
17.
Drug Deliv ; 26(1): 98-106, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-30744432

RESUMO

ENHANZE® drug delivery technology is based on the proprietary recombinant human hyaluronidase PH20 enzyme (rHuPH20; Halozyme Therapeutics, Inc.) that facilitates the subcutaneous (SC) delivery of co-administered therapeutics. rHuPH20 works by degrading the glycosaminoglycan hyaluronan (HA), which plays a role in resistance to bulk fluid flow in the SC space, limiting large volume SC drug delivery, dispersion, and absorption. Co-administration of rHuPH20 with partner therapies can overcome administration time and volume barriers associated with existing SC therapeutic formulations, and has been shown to reduce the burden on patients and healthcare providers compared with intravenous formulations. rHuPH20 (as HYLENEX® recombinant) is currently FDA-approved for subcutaneous fluid administration for achieving hydration, to increase the dispersion and absorption of other injected drugs, and in subcutaneous urography for improving resorption of radiopaque agents. rHuPH20 is also co-formulated with two anticancer therapies, trastuzumab (i.e. Herceptin® SC) and rituximab (i.e. RITUXAN HYCELA®/RITUXAN® SC/MabThera® SC) and dosed sequentially with human immunoglobin to treat primary immunodeficiency (i.e. HyQvia®/HYQVIA®). This article reviews pharmaceutical properties of rHuPH20, its current applications with approved therapeutics, and the potential for future developments.


Assuntos
Antineoplásicos Imunológicos/administração & dosagem , Moléculas de Adesão Celular/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Hialuronoglucosaminidase/administração & dosagem , Imunoglobulinas/administração & dosagem , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/metabolismo , Antígenos de Superfície/administração & dosagem , Antígenos de Superfície/metabolismo , Antineoplásicos Imunológicos/metabolismo , Moléculas de Adesão Celular/metabolismo , Sistemas de Liberação de Medicamentos/tendências , Quimioterapia Combinada , Humanos , Hialuronoglucosaminidase/metabolismo , Imunoglobulinas/metabolismo , Injeções Subcutâneas , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/metabolismo
18.
Proc Natl Acad Sci U S A ; 116(6): 2068-2077, 2019 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-30674679

RESUMO

Nectin-like (Necl) molecules are Ca2+-independent Ig-like transmembrane cell adhesion molecules that participate in junctions between different cell types. The specific cell-cell adhesions mediated by Necl proteins are important in neural development and have been implicated in neurodegenerative diseases. Here, we present the crystal structure of the mouse Necl-4 full ectodomain and the structure of the heterophilic Necl ectodomain complex formed by the mNecl-4 and mNecl-1 ectodomains. We demonstrate that, while the ectodomain of mNecl-4 is monomeric, it forms a stable heterodimer with Ig1 of mNecl-1, with an affinity significantly higher than that observed for self-dimerization of the mNecl-1 ectodomain. We validated our structural characterizations by performing a surface plasmon resonance assay and an Fc fusion protein binding assay in mouse primary dorsal root ganglia neurites and Schwann cells and identified a selection of residues important for heterophilic interactions. Finally, we proposed a model of Necl binding specificity that involves an induced-fit conformational change at the dimerization interface.


Assuntos
Moléculas de Adesão Celular/química , Moléculas de Adesão Celular/metabolismo , Imunoglobulinas/química , Imunoglobulinas/metabolismo , Sequência de Aminoácidos , Animais , Sítios de Ligação , Moléculas de Adesão Celular/genética , Imunoglobulinas/genética , Camundongos , Camundongos Knockout , Modelos Moleculares , Ligação Proteica , Conformação Proteica , Domínios e Motivos de Interação entre Proteínas , Multimerização Proteica , Proteínas Recombinantes de Fusão , Relação Estrutura-Atividade
19.
Dev Comp Immunol ; 94: 59-65, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30668960

RESUMO

The present study was conducted to evaluate the effects of dietary Pediococcus acidilactici (PA) and raffinose (RF) alone or in combination on growth performance, mucosal immune factors and immune related genes expression in common carp (Cyprinus carpio) juveniles. Fish with initial weight of 10.0 ±â€¯2.5 g were fed the following experimental diets for 60 days: control (without supplementation), prebiotic (2 g RF kg-1 diet), probiotic (6 × 108 CFU g-1PA) and synbiotic (2 g RF kg-1+ 6 × 108 CFU g-1PA). Carp fed synbiotic and probiotic diets had the highest (19.53 ±â€¯0.16) and the lowest (18.05 ±â€¯0.65) final body weight, respectively and the other experimental groups showed intermediate values. Singular administration of PA or in combination with 2 g RF kg-1 significantly increased skin mucus total immunoglobulin (Ig) and protein compared other groups, meanwhile, values of skin mucus protease activity enhanced by dietary immunostimulants administration in comparison with the control (P < 0.05). The expression of gene encoding lysozyme in skin pronouncedly increased by supplementing diets with singular or mixture of PA and RF; however, the expression of intestinal lysozyme gene as well as tumor necrosis factor-α genes expression in skin and intestine were not affected by administrating different immunostimulants (P > 0.05). The highest growth performance was noticed in fish fed synbiotic (P < 0.05). Overall, the combination of 2 g RF kg-1 with 6 × 108 CFU g-1PA is recommended for improving immunological responses of C. carpio juveniles.


Assuntos
Carpas/imunologia , Muramidase/metabolismo , Pediococcus acidilactici/imunologia , Rafinose/imunologia , Pele/imunologia , Animais , Carpas/crescimento & desenvolvimento , Dieta , Suplementos Nutricionais , Proteínas de Peixes/metabolismo , Regulação da Expressão Gênica , Imunidade Inata/genética , Imunoglobulinas/metabolismo , Muramidase/genética , Probióticos , Simbióticos
20.
Nat Nanotechnol ; 14(3): 260-268, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30643271

RESUMO

Deposition of complement factors (opsonization) on nanoparticles may promote clearance from the blood by macrophages and trigger proinflammatory responses, but the mechanisms regulating the efficiency of complement activation are poorly understood. We previously demonstrated that opsonization of superparamagnetic iron oxide (SPIO) nanoworms with the third complement protein (C3) was dependent on the biomolecule corona of the nanoparticles. Here we show that natural antibodies play a critical role in C3 opsonization of SPIO nanoworms and a range of clinically approved nanopharmaceuticals. The dependency of C3 opsonization on immunoglobulin binding is almost universal and is observed regardless of the complement activation pathway. Only a few surface-bound immunoglobulin molecules are needed to trigger complement activation and opsonization. Although the total amount of plasma proteins adsorbed on nanoparticles does not determine C3 deposition efficiency, the biomolecule corona per se enhances immunoglobulin binding to all nanoparticle types. We therefore show that natural antibodies represent a link between biomolecule corona and C3 opsonization, and may determine individual complement responses to nanomedicines.


Assuntos
Proteínas do Sistema Complemento/metabolismo , Imunoglobulinas/metabolismo , Nanopartículas/química , Proteínas Opsonizantes/metabolismo , Coroa de Proteína/química , Complemento C3/metabolismo , Feminino , Humanos , Imunoglobulina G/metabolismo , Lipossomos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Ligação Proteica
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