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1.
Biochemistry (Mosc) ; 84(9): 1021-1027, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31693461

RESUMO

Semaphorin 4D (Sema4D) is a multifunctional protein widely expressed in an organism that plays an important role in the control of many physiological and pathological processes, including immunoregulation, neurogenesis, angiogenesis, and tumor progression. It was first described almost 30 years ago and has been actively studied since then. However, with rare exceptions, all studies of the Sema4D activity proceed from the assumption that semaphorin is a ligand that acts through specific receptors (CD72 and plexins) and that the main targets of Sema4D in different tissues are cells that carry these receptors on the membrane. This review analyzes the data indicating the presence of an alternative mechanism for the regulatory activity of Sema4D that involves the functioning of membrane semaphorin as a receptor ensuring the outside-in signaling. Cell signaling pathways mediated by the membrane Sema4D and their contribution to the Sema4D-dependent regulation of cell functions are discussed.


Assuntos
Antígenos CD/metabolismo , Receptores de Superfície Celular/metabolismo , Semaforinas/metabolismo , Animais , Humanos , Transdução de Sinais
2.
Mol Biol (Mosk) ; 53(5): 838-848, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31661482

RESUMO

Lymphocyte phosphatase-associated phosphoprotein (LPAP) is a small transmembrane protein that is found in lymphocytes and is tightly associated with the phosphatase CD45. The function of LPAP is still unknown. Studies of the LPAP interactome may reveal new details of how C45 and lymphocyte signaling in general are regulated. LPAP binding partners were sought using coimmunoprecipitation coupled with mass spectrometry, stabilization of protein complexes with chemical crosslinkers, and Blue Native electrophoresis. In addition to CD45, several proteins were identified as LPAP partners, including CD71, CD98, cytoskeletal proteins, the amino acid transporter SLC1A4, and the cell signaling component HS1. It was confirmed that more than 70% of LPAP molecules were bound with CD45 in a 1 : 1 complex. The effect of CD45 on LPAP was studied in CEM and Jurkat cells with a CD45 knockout. The LPAP levels in the cells were 10% of the level in wild-type cells. In the absence of CD45, LPAP phosphorylation at Ser-153 and Ser-163 was not affected, whereas phosphorylation at Ser-99 and Ser-172 decreased significantly. Based on the results, CD45 was assumed to play a role in regulating LPAP expression and phosphorylation status.


Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Ativação Linfocitária , Proteínas de Membrana/metabolismo , Mapas de Interação de Proteínas , Sistema ASC de Transporte de Aminoácidos/metabolismo , Antígenos CD/metabolismo , Proteína-1 Reguladora de Fusão/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/química , Antígenos Comuns de Leucócito/metabolismo , Proteínas de Membrana/química , Fosforilação , Ligação Proteica , Receptores da Transferrina/metabolismo
3.
Medicine (Baltimore) ; 98(43): e17482, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31651850

RESUMO

The aim of this study was to investigate the correlation between cluster of differentiation 86 (CD86) gene rs1129055 and rs2715267 single nucleotide polymorphisms and sepsis susceptibility.One hundred twenty-five sepsis patients and 120 healthy controls were enrolled in this case-control study. CD86 polymorphisms rs1129055 and rs2715267 were genotyped through polymerase chain reaction-restriction fragment length polymorphism approach. Chi-square test was used to analyze differences in genotype and allele frequencies of the 2 polymorphisms between case and control groups. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to present the association strength of the polymorphisms with sepsis susceptibility.AA genotype and A allele frequencies of CD86 rs1129055 were significantly lower in sepsis patients than in healthy controls (P < .05), revealing their significant associations with decreased disease susceptibility (OR = 0.351, 95% CI = 0.169-0.728; OR = 0.593, 95% CI = 0.415-0.847). Nevertheless, rs2715267 had no significant association with sepsis susceptibility (P > .05).AA genotype and A allele of CD86 polymorphism rs1129055 might be correlated with decreased sepsis susceptibility in Chinese Han population, but not rs2715267. Further study should be performed to verify our findings.


Assuntos
Antígenos CD/sangue , Antígeno B7-2/sangue , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Sepse/genética , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Feminino , Frequência do Gene , Predisposição Genética para Doença/etnologia , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , Adulto Jovem
4.
Medicine (Baltimore) ; 98(42): e17416, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31626097

RESUMO

This study aims to evaluate the clinical value of haptoglobin (Hp) and sCD163 testing for the differential diagnosis of pleural effusion, and investigate the correlation of Hp and sCD163 with the inflammatory response of the body.Pleural effusion samples were collected from 78 patients (38 tuberculous pleural effusions [TPE] and 40 malignant pleural effusions [MPE]). The concentrations of Hp and sCD163 in the pleural effusion were measured by enzyme-linked immunosorbent assay (ELISA).The concentrations of Hp and sCD163 were significantly higher in the TPE group than in the MPE group (P < .05). The sensitivity and specificity of the Hp test for the differential diagnosis of TPE and MPE was 82.4% and 86.1%, respectively (P < .01), while the cut off value was 779.05 ug/mL. Furthermore, the sensitivity and specificity of the sCD163 test for the differential diagnosis of TPE and MPE was 76.3% and 85.0%, respectively (P < .01), while the cut off value was 16,401.11 ng/mL. Moreover, the sensitivity and specificity of the combination of Hp and sCD163 tests for diagnosing TPE was 90.0% and 87.5%, respectively. Hp and IL-1ß, TNF-α, CRP and ESR were positively correlated in both the TPE group and MPE group (P < .05). Hp and sCD163 were positively correlated in the TPE group (r = 0.3735, P = .0209), but not in the MPE group (r = 0.22, P = .1684). However, there was no correlation between sCD163 and TNF-α, CRP and ESR in either the TPE group, or the MPE group (P > .05). Furthermore, sCD163 and IL-1ß were weakly correlated in the TPE group (r = 0.49, P = .0018), but these had no correlation in the MPE group (r = 0.068, P = .6767).Hp and sCD163 can be used as biological markers for the differential diagnosis of pleural effusion in clinic, and the level of Hp in pleural effusion may reflect the intensity of inflammation in the body to some extent.


Assuntos
Antígenos CD/sangue , Antígenos de Diferenciação Mielomonocítica/sangue , Haptoglobinas/análise , Derrame Pleural Maligno/diagnóstico , Receptores de Superfície Celular/sangue , Tuberculose/diagnóstico , Idoso , Biomarcadores/sangue , Sedimentação Sanguínea , Proteína C-Reativa/análise , Diagnóstico Diferencial , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Interleucina-1beta/sangue , Masculino , Pessoa de Meia-Idade , Derrame Pleural Maligno/sangue , Curva ROC , Sensibilidade e Especificidade , Fator de Necrose Tumoral alfa/sangue
5.
Wiad Lek ; 72(9 cz 2): 1791-1794, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31622268

RESUMO

OBJECTIVE: Introduction: At present biocomposite materials are used in the surgical treatment of frontal bone fracture. They improve osteogenesis, reduce the number of complications. Immunologic aspects of application of these materials are studied insufficiently, therefore this report presents the results of immunoassay of patients with frontal bone fracture in the proximate posttraumatic period before implanting preparation "Syntekost". The aim: To define the role of immune mechanisms in the realization of the biocomposite material's positive influence on the development of effective posstraumatic rehabilitation schemes. PATIENTS AND METHODS: Materials and methods: 16 patients with frontal bone fracture (FBF) were examined on admission to the Otolaryngology Clinics of Vinnitsa Region Hospital. Additionally, 10 patients of the similar age were examined as a control group. The content of cells with markers of surface antigens-CD3,14,16,20,25, concentration of immunoglobulins of classes M,G,A,E, С4 complement component and lactoferrin was determined in blood. Immunoenzyme methods were applied. Nonparametric Wilcoxon - Mann - Whitney test, computer programme WIN Pepi were used for statistical measurements. RESULTS: Results: A decrease in the level of IgM in comparison with practically healthy donors and an increase in the concentration of lactoferrin were identified as humoral immunity factors of patients with frontal basilar trauma. The most significant deviation in the peripheral blood cellular makeup in CD-markers was an increase in cells with markers CD14 and CD16. CONCLUSION: Conclusions: The level of cells and prodefensin-lactoferrin that maintain inborn immunity increases and the concentration of coarse defensive protein decreases in the initial period after frontal bone fracture, which must be taken into consideration during post-surgical treatment.


Assuntos
Osso Frontal/lesões , Imunidade Celular , Imunidade Humoral , Antígenos CD/análise , Humanos , Imunoglobulinas/sangue , Lactoferrina/sangue
6.
Cell Host Microbe ; 26(3): 299-300, 2019 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-31513765

RESUMO

In this issue of Cell Host & Microbe, Buffalo et al. describe a cryo-EM structure of SIV Nef complexed with AP-2 and tetherin. The structure helps explain why human tetherin is Nef-resistant and why lentiviruses that successfully emerged in humans (HIV-1 and HIV-2) had to evolve novel anti-tetherin strategies.


Assuntos
HIV-1 , Vírus da Imunodeficiência Símia , Antígenos CD , Antígeno 2 do Estroma da Médula Óssea , Proteínas Ligadas por GPI , Humanos , Produtos do Gene nef do Vírus da Imunodeficiência Humana
7.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 41(4): 506-511, 2019 Aug 30.
Artigo em Chinês | MEDLINE | ID: mdl-31484613

RESUMO

To investigate the expressions of mucosal barrier proteins in colon cell line DLD-1 under hypoxic environment in vitro and its mechanism. Methods After DLD-1 cells were treated separately with hypoxia(l% O2),vitamin D(100 nmol/L),or vitamin D plus hypoxia for 48 hours,the expressions of vitamin D receptor(VDR),tight junction proteins zonula occludens-1(ZO-1),occludin,Claudin-1,and adherent junction protein(E-cadherin)were determined by Western blot.Stable VDR knock-down(Sh-VDR)DLD-1 cell line and control DLD-1 cell line were established by lentivirus package technology and the protein expressions after hypoxia treatment were detected. Results Compared with control group,the expressions of occludin,Claudin-1,and VDR increased significantly after hypoxia treatment(all P<0.001).In addition to the protein expressions of occludin,Claudin-1 and VDR,the expressions of ZO-1 and E-cadherin were also obviously higher in vitamin D plus hypoxia group than in single vitamin D treatment group(all P<0.001).After hypoxia treatment,Sh-VDR cell line showed significantly decreased expressions of ZO-1(P<0.001),occludin(P<0.05),Claudin-1(P<0.01)and E-cadherin(P<0.001)when compared with untreated Sh-VDR cell line. Conclusion VDR acts as a regulator for the expressions of intestinal mucosal barrier proteins under hypoxia environment in DLD-1 colon cell line,indicating that VDR pathway may be another important protective mechanism for gut barrier in low-oxygen environment.


Assuntos
Colo/citologia , Receptores de Calcitriol/metabolismo , Antígenos CD/metabolismo , Caderinas/metabolismo , Hipóxia Celular , Linhagem Celular , Claudina-1/metabolismo , Humanos , Ocludina/metabolismo , Junções Íntimas , Vitamina D/farmacologia , Proteína da Zônula de Oclusão-1/metabolismo
8.
Medicine (Baltimore) ; 98(37): e17006, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31517819

RESUMO

CD200 is an immunoglobulin superfamily membrane protein that binds to a myeloid cell-specific receptor and induces inhibitory signaling. The aim of this study was to investigate the role of CD200 and its receptor (CD200R1) on kidney transplant (KTx) outcome. In a collective of 125 kidney recipients (University hospital, Heidelberg, Germany), CD200 and CD200R1 concentrations were evaluated immediately before transplantation. Recipient baseline and clinical characteristics and KTx outcome, including acute rejection (AR), acute tubular necrosis, delayed graft function, cytomegalovirus (CMV) and human polyomaviridae (BK) virus infections, and graft loss were evaluated during the first post-transplant year. The association of CD200 and CD200R1 concentrations and CD200R1/CD200 ratios with the outcome of KTx was investigated for the first time in a clinical setting in a prospective cohort. There was a positive association between pre-transplant CD200R1 concentrations and CMV (re)activation (P = .041). Also, increased CD200R1 concentration was associated with a longer duration of CMV infection (P = .049). Both the frequency of AR and levels of creatinine (3 and 6 months after KTx) were significantly higher in patients with an increased CD200R1/CD200 ratio (median: 126 vs 78, P = .008). Increased pre-transplant CD200R1/CD200 ratios predict immunocompetence and risk of AR, whereas high CD200R1 concentrations predict immunosuppression and high risk of severe CMV (re)activation after KTx.


Assuntos
Antígenos CD/sangue , Antígenos de Superfície/sangue , Falência Renal Crônica/sangue , Falência Renal Crônica/cirurgia , Transplante de Rim , Complicações Pós-Operatórias/diagnóstico , Receptores de Superfície Celular/sangue , Adulto , Idoso , Biomarcadores/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Período Pré-Operatório , Prognóstico , Estudos Prospectivos , Adulto Jovem
9.
Oncology ; 97(5): 311-318, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31550723

RESUMO

INTRODUCTION: Human epidermal growth factor 2 (HER2) gene overexpression in breast carcinoma cell lines has been shown to drive mammary carcinogenesis and tumor growth and invasion through its effects on mammary stem cells. OBJECTIVE: Therefore, we investigated the mechanism by which HER2 regulates cancer stem cell (CSC) activity in gastric cancer cells. METHODS: HER2 was transfected into MKN28 gastric cancer cells, and its role in regulating CSC activity was determined by characterizing the HER2-overexpressing cells. RESULTS: The sphere formation assay revealed that the sphere sizes and frequency of sphere formation were significantly greater for the HER2-overexpressing cells than for the MKN28 control cells. The CSC markers Oct-4 and BMI1 were more highly expressed in the HER2-overexpressing cells, as were the EMT markers. This was accompanied by a significant enhancement in cellular invasion of the Matrigel and migration. The E-cadherin level was significantly downregulated, and the mesenchymal marker Snail upregulated, in the HER2-transfected cells. HER2 overexpression activated the well-characterized CSC-associated Wnt/ß-catenin signaling pathway, as shown by the luciferase assay. After treatment of these cells with the Wnt signal inhibitor PRI-724, the BMI1 and Oct-4 levels were decreased for 24 h and Snail was also downregulated. Immunofluorescence staining revealed the significant restoration of E-cadherin levels in the HER2-transfected cells after PRI-724 treatment. CONCLUSIONS: These results established a role for HER2 in regulating gastric CSC activity, with Wnt/ß-catenin signaling being mediated via a HER2-dependent pathway. In summary, HER2-overexpressing gastric cancer cells exhibited increased stemness and invasiveness and were regulated by Wnt/ß-catenin signaling.


Assuntos
Células-Tronco Neoplásicas/fisiologia , Receptor ErbB-2/fisiologia , Neoplasias Gástricas/patologia , Via de Sinalização Wnt/fisiologia , Antígenos CD/análise , Caderinas/análise , Linhagem Celular Tumoral , Humanos , Invasividade Neoplásica , Fator 3 de Transcrição de Octâmero/análise , Complexo Repressor Polycomb 1/análise , Receptor ErbB-2/análise , Neoplasias Gástricas/química , beta Catenina/análise
10.
Expert Opin Ther Pat ; 29(9): 689-702, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31402706

RESUMO

Introduction: Protein tyrosine phosphatase 1B (PTP1B) inhibition has been recommended as a crucial strategy to enhance insulin sensitivity in various cells and this fact is supported by human genetic data. PTP1B inhibitors improve the sensitivity of the insulin receptor and have the ability to cure insulin resistance-related diseases. In the latter years, targeting PTP1B inhibitors is being considered an attractive target to treat T2DM and therefore libraries of PTP1B inhibitors are being suggested as potent antidiabetic drugs. Areas covered: This review provides an overview of published patents from January 2015 to December 2018. The review describes the effectiveness of potent PTP1B inhibitors as pharmaceutical agents to treat type 2 diabetes. Expert opinion: Enormous developments have been made in PTP1B drug discovery which describes progress in natural products, synthetic heterocyclic scaffolds or heterocyclic hybrid compounds. Various protocols are being followed to boost the pharmacological effects of PTP1B inhibitors. Moreover these new advancements suggest that it is possible to get small-molecule PTP1B inhibitors with the required potency and selectivity. Furthermore, future endevours via an integrated strategy of using medicinal chemistry and structural biology will hopefully result in potent and selective PTP1B inhibitors as well as safer and more effective orally available drugs.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Antígenos CD/metabolismo , Diabetes Mellitus Tipo 2/enzimologia , Desenho de Drogas , Descoberta de Drogas/métodos , Inibidores Enzimáticos/farmacologia , Humanos , Patentes como Assunto , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Receptor de Insulina/metabolismo
11.
BMC Infect Dis ; 19(1): 698, 2019 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-31387541

RESUMO

BACKGROUND: Candida albicans is an opportunistic pathogen, but since it also belongs to the normal fungal flora, positive sputum culture as the solely basis for the diagnosis of invasive Candida albicans pneumonia can easily lead to excessive antifungal therapy. Therefore, identification of a pneumonia biomarker might improve diagnostic accuracy. METHODS: A rabbit model was established by inoculating 5 × 107 cfu/mL C. albicans into the trachea of 20 rabbits with 20 rabbits as control group. Infection was monitored by chest thin-layer computed tomography (CT). 2 mL blood samples were collected daily during each infection and serum levels of potential biomarkers were measured by enzyme-linked immunosorbent assay (ELISA). Seven-day post-inoculation the rabbits were sacrificed by CO2 asphyxiation and lung tissue was histopathologically examined and blood was brought to culture. Data were statistically analyzed. RESULTS: Infection became evident as early as day 3 post-inoculation. The levels of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1), soluble hemoglobin-haptoglobin scavenger receptor (sCD163), procalcitonin (PCT) and tumor necrosis factor-α (TNF-α) were elevated in the experimental group compared to the control (P < 0.01), whereas the levels of C-reactive protein (CRP), interleukin-6 (IL-6), IL-8 and IL-10 showed no significant differences (P > 0.05). The dynamic curves of the levels of CRP, IL-6, IL-8, IL-10, SCD163 and TNF-α in both groups demonstrated a similar trend during infection but differences between the groups was observed only in the sTREM-1 levels. Receiver-operating characteristics (ROC) curve analysis showed that the sensitivity and specificity were 85 and 80% for sTREM-1 (cut-off value: 45.88 pg/mL) and 80 and 75% for SCD163 (cut-off value: 16.44 U/mL), respectively. The values of the area under the ROC curve (AUCROC) of sTREM-1 and SCD163 were 0.882 (95% CI: 0.922-0.976) and 0.814 (95% CI: 0.678-0.950), respectively. Other markers did not exhibit significant differences. CONCLUSION: sTREM-1 and SCD163 might be suitable biomarkers for pneumonia.


Assuntos
Antígenos CD/sangue , Antígenos de Diferenciação Mielomonocítica/sangue , Biomarcadores/sangue , Pneumonia/sangue , Receptores de Superfície Celular/sangue , Receptor Gatilho 1 Expresso em Células Mieloides/sangue , Animais , Proteína C-Reativa/análise , Candida albicans/patogenicidade , Candidíase/sangue , Candidíase/microbiologia , Modelos Animais de Doenças , Masculino , Pneumonia/diagnóstico , Pneumonia/microbiologia , Curva ROC , Coelhos , Sensibilidade e Especificidade , Fator de Necrose Tumoral alfa/sangue
12.
Int Arch Allergy Immunol ; 180(2): 91-102, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31401630

RESUMO

INTRODUCTION: Pathologic accumulation and activation of mast cells and eosinophils are implicated in allergic and inflammatory diseases. Sialic acid-binding immunoglobulin-like lectin (Siglec)-8 is an inhibitory receptor selectively expressed on mast cells, eosinophils and, at a lower extent, basophils. When engaged with an antibody, Siglec-8 can induce apoptosis of activated eosinophils and inhibit mast cell activation. AK002 is a humanized, non-fucosylated IgG1 anti-Siglec-8 antibody undergoing clinical investigation for treatment of allergic, inflammatory, and proliferative diseases. Here we examine the human tissue selectivity of AK002 and evaluate the in vitro, ex vivo, and in vivo activity of AK002 on eosinophils and mast cells. METHODS: The affinity of AK002 for Siglec-8 and CD16 was determined by biolayer interferometry. Ex vivo activity of AK002 on human eosinophils from blood and dissociated human tissue was tested in apoptosis and antibody-dependent cell-mediated cytotoxicity (ADCC) assays. The in vivo activity of a murine precursor of AK002 (mAK002) was tested in a passive systemic anaphylaxis (PSA) humanized mouse model. RESULTS: AK002 bound selectively to mast cells, eosinophils and, at a lower level, to basophils in human blood and tissue and not to other cell types examined. AK002 induced apoptosis of interleukin-5-activated blood eosinophils and demonstrated potent ADCC activity against blood eosinophils in the presence of natural killer cells. AK002 also significantly reduced eosinophils in dissociated human lung tissue. Furthermore, mAK002 prevented PSA in humanized mice through mast cell inhibition. CONCLUSION: AK002 selectively evokes potent apoptotic and ADCC activity against eosinophils and prevents systemic anaphylaxis through mast cell inhibition.


Assuntos
Anafilaxia/prevenção & controle , Citotoxicidade Celular Dependente de Anticorpos/imunologia , Antígenos CD/imunologia , Antígenos de Diferenciação de Linfócitos B/imunologia , Eosinófilos/imunologia , Lectinas/imunologia , Mastócitos/imunologia , Anafilaxia/imunologia , Animais , Anticorpos/imunologia , Anticorpos/farmacologia , Basófilos/imunologia , Humanos , Camundongos , Ácido N-Acetilneuramínico/imunologia , Receptores de IgG/imunologia
13.
Anticancer Res ; 39(8): 4495-4502, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366551

RESUMO

BACKGROUND/AIM: In mice, fetal liver is the first tissue of definitive erythropoiesis for definitive erythroid expansion and maturation. ZFAT, originally identified as a candidate susceptibility gene for autoimmune thyroid disease, has been reported to be involved in primitive hematopoiesis and T cell development. The aim of this study was to examine whether or not Zfat is involved in definitive erythropoiesis in the fetal liver during mammalian development. MATERIALS AND METHODS: The role of Zfat during mouse fetal erythropoiesis in the fetal liver was examined using tamoxifen-inducible CreERT2 Zfat-deficient mice. RESULTS: Zfat-deficient mice exhibit moderate anemia with small and pale fetal liver through a decreased number of erythroblasts by E12.5. Apoptosis sensitivity in fetal liver erythroid progenitors was enhanced by Zfat-deficiency ex vivo. Moreover, Zfat knockdown partially inhibited CD71-/lowTer119- to CD71highTer119- transition of fetal liver erythroid progenitors with impairment in the elevation of CD71 expression. CONCLUSION: Zfat plays a critical role for erythropoiesis in the fetal liver.


Assuntos
Antígenos CD/genética , Eritropoese/genética , Fígado/crescimento & desenvolvimento , Receptores da Transferrina/genética , Fatores de Transcrição/genética , Animais , Apoptose/genética , Diferenciação Celular/genética , Células Eritroides/metabolismo , Células Eritroides/patologia , Desenvolvimento Fetal/genética , Feto , Regulação da Expressão Gênica no Desenvolvimento , Técnicas de Silenciamento de Genes , Humanos , Fígado/metabolismo , Camundongos , Linfócitos T/citologia , Linfócitos T/metabolismo , Tireoidite Autoimune/genética , Tireoidite Autoimune/patologia
14.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 31(7): 842-846, 2019 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-31441407

RESUMO

OBJECTIVE: To observe the damage of high mobility group box 1 (HMGB1) on human umbilical vein endothelial cell (HUVEC) barrier permeability and the protective effect of unfractionated heparin (UFH), and to explore the down-regulated protection effect mechanism of UFH on HMGB1-mediated vascular endothelial cadherin (VE-cadherin) expression. METHODS: The trypsin-digested HUVEC were subcultured in culture flasks. When the cells were grown to 80%, they were randomly divided into four groups: phosphate buffer (PBS) control group (200 µL PBS), recombinant human high mobility group box 1 (rhHMGB1) treatment group (100 µg/L rhHMGB1), UFH control group (10 kU/L UFH), and UFH pretreatment group (10 kU/L UFH+100 µg/L rhHMGB1). The cells in each group were challenged with different reagent for 24 hours, and the activity of endothelial cells was determined by methyl thiazolyl tetrazolium (MTT) colorimetric assay. The permeability of endothelial cells was measured by Transwell method, and the expression and distribution of VE-cadherin was observed by immunofluorescence. The protein expressions of VE-cadherin and phosphorylated p38 mitogen-activated protein kinase (p-p38MAPK) were determined by Western Blot. RESULTS: After treatment with 100 µg/L rhHMGB1 for 24 hours, the activity of endothelial cells was not significantly different from that of the PBS control group (A value: 0.230±0.004 vs. 0.255±0.006, P > 0.05), but the permeability was significantly increased (glucan FD40 fluorescence intensity: 11.05±0.12 vs. 6.34±0.39, P < 0.05). Compared with PBS control group, the fluorescence microscopy showed that the VE-cadherin membrane localization was reduced, the distribution was loose, and there were obvious fissures between cells in rhHMGB1 treatment group, and quantitative analysis showed the protein expression of VE-cadherin was decreased significantly (VE-cadherin/ß-actin: 0.16±0.04 vs. 0.31±0.03, P < 0.05), and the expression of p-p38MAPK protein was significantly increased (p-p38MAPK/ß-actin: 0.79±0.03 vs. 0.26±0.05, P < 0.05). UFH pretreatment could protect HMGB1-mediated endothelial cell injury, cell permeability was significantly reduced (glucan FD40 fluorescence intensity: 9.11±0.23 vs. 11.05±0.12), fluorescence expression of VE-cadherin was enhanced, membrane localization was significantly increased, quantitative analysis showed that VE-cadherin protein expression was significantly up-regulated (VE-cadherin/ß-actin: 0.24±0.02 vs. 0.16±0.04), and p38MAPK phosphorylation level was significantly decreased (p-p38MAPK/ß-actin: 0.54±0.05 vs. 0.79±0.03), the difference was statistically significant as compared with rhHMGB1 treatment group (all P < 0.05). There was no significant difference in all parameters between PBS control group and UFH control group. CONCLUSIONS: UFH can protect the endothelial cell barrier from the HMGB1 by regulating the expression and distribution of VE-cadherin. The mechanism may be related to the inhibition of p38MAPK phosphorylation by UFH.


Assuntos
Caderinas/metabolismo , Fibrinolíticos/uso terapêutico , Proteína HMGB1/metabolismo , Heparina/uso terapêutico , Antígenos CD/metabolismo , Permeabilidade Capilar , Células Cultivadas , Células Endoteliais , Humanos
15.
Chemotherapy ; 64(2): 62-80, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31387102

RESUMO

BACKGROUND: Immune checkpoints are critical regulatory pathways of the immune system which finely tune the response to biological threats. Among them, the CD-28/CTLA-4 and PD-1/PD-L1 axes play a key role in tumour immune escape and are well-established targets of cancer immunotherapy. SUMMARY: The clinical experience accumulated to date provides unequivocal evidence that anti-CTLA-4, PD-1, or PD-L1 monoclonal antibodies, used as monotherapy or in combination regimes, are effective in a variety of advanced/metastatic types of cancer, with improved clinical outcomes compared to conventional chemotherapy. However, the therapeutic success is currently restricted to a limited subset of patients and reliable predictive biomarkers are still lacking. Key Message: The identification and characterization of additional co-inhibitory pathways as novel pharmacological targets to improve the clinical response in refractory patients has led to the development of different immune checkpoint inhibitors, the activities of which are currently under investigation. In this review, we discuss recent literature data concerning the mechanisms of action of next-generation monoclonal antibodies targeting LAG-3, TIM-3, and TIGIT co-inhibitory molecules that are being explored in clinical trials, as single agents or in combination with other immune-stimulating agents.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Neoplasias/tratamento farmacológico , Antígenos CD/imunologia , Antígenos CD/metabolismo , Antígeno CTLA-4/imunologia , Antígeno CTLA-4/metabolismo , Ensaios Clínicos como Assunto , Receptor Celular 2 do Vírus da Hepatite A/imunologia , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Humanos , Neoplasias/imunologia , Receptor de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Receptores Imunológicos/imunologia , Receptores Imunológicos/metabolismo , Microambiente Tumoral
16.
Immunogenetics ; 71(8-9): 545-559, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31384962

RESUMO

Butyrophilins (BTN), specifically BTN3A, play a central role in the modulation of γδ T cells, which are mainly present in gut and mucosal tissues. BTN3A1 is known, for example, to activate Vγ9Vδ2 T cells by means of a phosphoantigen interaction. In the extended HLA region, three genes are located, designated BTN3A1, BTN3A2 and BTN3A3, which were also defined in rhesus macaques. In contrast to humans, rhesus monkeys have an additional gene, BTN3A3Like, which has the features of a pseudogene. cDNA analysis of 32 Indian rhesus and 16 cynomolgus macaques originating from multiple-generation families revealed that all three genes are oligomorphic, and the deduced amino acids display limited variation. The macaque BTN3A alleles segregated together with MHC alleles, proving their location in the extended (Major Histocompatibility Complex) MHC. BTN3A nearly full-length transcripts of macaques and humans cluster tightly together in the phylogenetic tree, suggesting that the genes represent true orthologs of each other. Despite the limited level of polymorphism, 15 Mamu- and 14 Mafa-BTN3A haplotypes were defined, and, as in humans, all three BTN3A genes are transcribed in PBMCs and colon tissues. In addition to regular full-length transcripts, a high number of various alternative splicing (AS) products were observed for all BTN3A alleles, which may result in different isoforms. The comparable function of certain subsets of γδ T cells in human and non-human primates in concert with high levels of sequence conservation observed for the BTN3A transcripts presents the opportunity to study these not yet well understood molecules in macaques as a model species.


Assuntos
Antígenos CD/genética , Butirofilinas/genética , Antígenos de Histocompatibilidade/genética , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Sequência de Aminoácidos , Animais , Butirofilinas/metabolismo , Sequência Conservada , Feminino , Haplótipos , Humanos , Macaca mulatta , Masculino , Filogenia , Receptores de Antígenos de Linfócitos T gama-delta/genética , Homologia de Sequência , Linfócitos T/metabolismo
17.
Cancer Sci ; 110(9): 3006-3011, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31301084

RESUMO

Decreased cell adhesion has been reported as a significant negative prognostic factor of lung cancer. However, the molecular mechanisms responsible for the cell incohesiveness in lung cancer have not yet been elucidated in detail. We herein describe a rare histological variant of lung adenocarcinoma consisting almost entirely of individual cancer cells spreading in alveolar spaces in an incohesive pattern. A whole exome analysis of this case showed no genomic abnormalities in CDH1 or other genes encoding cell adhesion molecules. However, whole mRNA sequencing revealed that this case had an extremely high expression level of mucin 21 (MUC21), a mucin molecule that was previously shown to inhibit cell-cell and cell-matrix adhesion. The strong membranous expression of MUC21 was found on cancer cells using mAbs recognizing different O-glycosylated forms of MUC21. An immunohistochemical analysis of an unselected series of lung adenocarcinoma confirmed that the strong membranous expression of MUC21 correlated with incohesiveness. Thus, MUC21 could be a promising biomarker with potential diagnostic and therapeutic applications for lung adenocarcinoma showing cell incohesiveness.


Assuntos
Adenocarcinoma de Pulmão/patologia , Neoplasias Pulmonares/patologia , Glicoproteínas de Membrana/metabolismo , Mucinas/metabolismo , Adenocarcinoma de Pulmão/diagnóstico por imagem , Adenocarcinoma de Pulmão/genética , Idoso , Antígenos CD/genética , Caderinas/genética , Feminino , Perfilação da Expressão Gênica , Humanos , Pulmão/diagnóstico por imagem , Pulmão/patologia , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/genética , Tomografia Computadorizada por Raios X , Sequenciamento Completo do Exoma
19.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(7): 672-675, 2019 Jul 10.
Artigo em Chinês | MEDLINE | ID: mdl-31302908

RESUMO

OBJECTIVE: To explore the genetic basis for three patients with development delay and to correlate their clinical phenotypes with genetic findings. METHODS: The karyotypes of the probands and their parents were analyzed by conventional G-banding. Chromosomal microarray analysis (CMA) was used to detect microdeletion and microduplication. RESULTS: No kartotypic abnormality was detected in the patients and their parents. CMA analysis identified a de novo 3.10 Mb deletion on chromosome 15q24.1q24.2 in case 1, a de novo 3.14 Mb deletion at 15q24.1q24.2 in case 2, and a 3.13 Mb deletion at 15q24.1q24.2 in case 3. All deletions have encompassed the CPLX3,SEMA7A and SIN3A genes. CONCLUSION: The three patients were diagnosed with 15q24 microdeletion syndrome. CPLX3,SEMA7A and SIN3A may be the key genes responsible for this syndrome.


Assuntos
Transtornos Cromossômicos/genética , Deficiência Intelectual/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Antígenos CD/genética , Criança , Deleção Cromossômica , Cromossomos Humanos Par 15/genética , Proteínas Ligadas por GPI/genética , Humanos , Proteínas Repressoras/genética , Semaforinas/genética
20.
Cancer Immunol Immunother ; 68(8): 1359-1368, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31332464

RESUMO

Immune checkpoint inhibitors targeting coinhibitory pathways in T cells possess efficacy in combating cancer. In addition to PD-1/PD-L1 and CTLA-4 antibodies which are already established in tumor immunotherapy, immune checkpoints such as LAG-3 or BTLA are emerging, which may have the potential to enhance T-cell responses alone or in combination with PD-1 blockers. CD4+ T cells play a central role in the immune system and contribute to productive immune responses in multiple ways. The effects of immune checkpoint inhibitors on this cell subset may thus critically influence therapeutic outcomes. Here, we have used in vitro responses to tetanus toxoid (TT) as a model system to study the effects of immune checkpoint inhibitors on CD4+ T-cell responses. CFSE-labeled PBMCs of 65 donors were stimulated with TT in the presence of blocking antibodies to PD-L1, CTLA-4, LAG-3, or BTLA for 7 days. We found that the PD-L1 antibody greatly enhanced cytokine production and antigen-specific CD4+ T-cell proliferation, whereas blocking antibodies to BTLA or LAG-3 did not augment responses to TT. Surprisingly, the presence of the therapeutic CTLA-4 antibody ipilimumab resulted in a significant reduction of CD4+ T-cell proliferation and cytokine production. Stimulation experiments with an IgG4 variant of ipilimumab indicated that the inhibitory effect of ipilimumab was dependent on its IgG1 isotype. Our results indicate that the therapeutic CTLA-4 antibody ipilimumab can impair CD4+ effector T-cell responses and that this activity is mediated by its Fc part and CD16-expressing cells.


Assuntos
Anticorpos Monoclonais/farmacologia , Antineoplásicos/farmacologia , Linfócitos T CD4-Positivos/imunologia , Vacinas Anticâncer/imunologia , Imunoterapia/métodos , Ipilimumab/farmacologia , Neoplasias/terapia , Anticorpos Monoclonais/uso terapêutico , Antígenos CD/imunologia , Antineoplásicos/uso terapêutico , Antígeno B7-H1/imunologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Antígeno CTLA-4/imunologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Citocinas/metabolismo , Humanos , Fragmentos Fc das Imunoglobulinas/metabolismo , Ipilimumab/uso terapêutico , Ativação Linfocitária/efeitos dos fármacos , Neoplasias/imunologia , Receptores Imunológicos/imunologia , Toxoide Tetânico/imunologia
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