Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.208
Filtrar
1.
Medicine (Baltimore) ; 100(12): e24669, 2021 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-33761636

RESUMO

ABSTRACT: Neutrophils have crucial roles in defensing against infection and adaptive immune responses. This study aimed to investigate the genetic mechanism in neutrophils in response to sepsis-induced immunosuppression.The GSE64457 dataset was downloaded from the Gene Expression Omnibus database and the neutrophil samples (D3-4 and D6-8 post sepsis shock) were assigned into two groups. The differentially expressed genes (DEGs) were identified. The Short Time-series Expression Miner (STEM) clustering analysis was conducted to select the consistently changed DEGs post sepsis shock. The overlapping genes between the DEGs and the deposited genes associated with immune, sepsis, and immunosuppression in the AmiGO2 and Comparative Toxicogenomics Database were screened out and used for the construction of the protein-protein interaction (PPI) network. The expression of several hub genes in sepsis patients was validated using the PCR analysis. The drugs targeting the hub genes and the therapy strategies for sepsis or immunosuppression were reviewed and used to construct the drug-gene-therapy-cell network to illustrate the potential therapeutic roles of the hub genes.A total of 357 overlapping DEGs between the two groups were identified and were used for the STEM clustering analysis, which generated four significant profiles with 195 upregulated (including annexin A1, ANXA1; matrix metallopeptidase 9, MMP9; and interleukin 15, IL-15) and 151 downregulated DEGs (including, AKT1, IFN-related genes, and HLA antigen genes). Then, a total of 34 of the 151 downregulated DEGs and 39 of the 195 upregulated DEGs were shared between the databases and above DEGs, respectively. The PPI network analysis identified a downregulated module including IFN-related genes. The deregulation of DEGs including AKT1 (down), IFN-inducible protein 6 (IFI6, down), IL-15 (up), and ANXA1 (up) was verified in the neutrophils from patients with sepsis-induced immunosuppression as compared with controls. Literature review focusing on the therapy showed that the upregulation of IL-15, IFN, and HLA antigens are the management targets. Besides, the AKT1 gene was targeted by gemcitabine.These findings provided additional clues for understanding the mechanisms of sepsis-induced immunosuppression. The drugs targeting AKT1 might provide now clues for the management strategy of immunosuppression with the intention to prevent neutrophil infiltration.


Assuntos
Regulação da Expressão Gênica/imunologia , Tolerância Imunológica/genética , Neutrófilos/imunologia , Síndrome de Resposta Inflamatória Sistêmica/imunologia , Idoso , Anexina A1/genética , Anexina A1/metabolismo , Estudos de Casos e Controles , Biologia Computacional , Conjuntos de Dados como Assunto , Feminino , Perfilação da Expressão Gênica , Redes Reguladoras de Genes/imunologia , Humanos , Interleucina-15/genética , Interleucina-15/metabolismo , Masculino , Pessoa de Meia-Idade , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Neutrófilos/metabolismo , Mapeamento de Interação de Proteínas , Mapas de Interação de Proteínas/imunologia , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/imunologia , Síndrome de Resposta Inflamatória Sistêmica/sangue , Síndrome de Resposta Inflamatória Sistêmica/genética
2.
BMC Infect Dis ; 21(1): 219, 2021 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-33632146

RESUMO

BACKGROUND: Human T-lymphotropic virus 1 (HTLV-1) is etiologically associated with the chronic inflammatory neurodegenerative disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) Annexin A1 (AnxA1) is an anti-inflammatory protein with proposed neuroprotective and anti-neuroinflammatory functions. We hypothesized that ANXA1 gene expression may be dysregulated in HTLV-1-infected HAM/TSP patients. METHODS: This study involved 37 individuals infected with HTLV-1, including 21 asymptomatic (AS) carriers and 16 with HAM/TSP, and a control group of 30 individuals negative for HTLV-1 and HTLV-2. For AS HTLV-1-positive and HAM/TSP patients, ANXA1 and formyl peptide receptor (FPR1, FPR2 and FPR3) expression and HTLV-1 proviral load (PVL) in peripheral blood cells were evaluated by real-time quantitative PCR (qPCR), and plasma AnxA1 levels were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: ANXA1 gene expression was increased in the AS group compared with the HAM/TSP and control groups, but the differences were not statistically significant. FPR1 gene expression was higher in patients with HTLV-1 than in controls (AS, p = 0.0032; HAM/TSP, p < 0.0001). Plasma AnxA1 levels were higher in the AS group than in the HAM/TSP group (p = 0.0045), and PVL was higher in patients with HAM/TSP than in AS individuals (p = 0.0162). The use of a combined ROC curve using Annexin 1 levels and proviral load significantly increased the sensitivity and specificity to predict progression to HAM/TSP (AUC = 0.851 and AUC = 0.937, respectively, to AUC = 1000). CONCLUSIONS: Our results suggest that AnxA1 may be dysregulated in HAM/TSP patients. Serological detection of AnxA1 in association with proviral load may provide a prognostic biomarker for HTLV-1-associated neurodegenerative disease.


Assuntos
Anexina A1/sangue , Vírus Linfotrópico T Tipo 1 Humano/isolamento & purificação , Paraparesia Espástica Tropical/diagnóstico , Adulto , Anexina A1/genética , Biomarcadores/sangue , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Paraparesia Espástica Tropical/sangue , Paraparesia Espástica Tropical/virologia , Prognóstico , Curva ROC , Sensibilidade e Especificidade , Carga Viral
3.
PLoS One ; 16(1): e0241157, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33406123

RESUMO

We previously reported that IF7 peptide, which binds to the annexin A1 (ANXA1) N-terminus, functions as a tumor vasculature-targeted drug delivery vehicle after intravenous injection. To enhance IF7 stability in vivo, we undertook mirror-image peptide phage display using a synthetic D-peptide representing the ANXA1 N-terminus as target. We then identified peptide sequences, synthesized them as D-amino acids, and designated the resulting peptide dTIT7, which we showed bound to the ANXA1 N-terminus. Whole body imaging of mouse brain tumor models injected with near infrared fluorescent IRDye-conjugated dTIT7 showed fluorescent signals in brain and kidney. Furthermore, orally-administered dTIT7/geldanamycin (GA) conjugates suppressed brain tumor growth. Ours is a proof-of-concept experiment showing that ANXA1-binding D-peptide can be developed as an orally-administrable tumor vasculature-targeted therapeutic.


Assuntos
Anexina A1/antagonistas & inibidores , Neoplasias Encefálicas/irrigação sanguínea , Neoplasias Encefálicas/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Proteínas de Neoplasias/antagonistas & inibidores , Neovascularização Patológica/tratamento farmacológico , Peptídeos , Administração Oral , Animais , Anexina A1/metabolismo , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas de Neoplasias/metabolismo , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Peptídeos/síntese química , Peptídeos/química , Peptídeos/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
4.
BMC Cancer ; 21(1): 72, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33446132

RESUMO

BACKGROUND: p-Boronophenylalanine (10BPA) is a powerful 10B drug used in current clinical trials of BNCT. For BNCT to be successful, a high (500 mg/kg) dose of 10BPA must be administered over a few hours. Here, we report BNCT efficacy after rapid, ultralow-dose administration of either tumor vasculature-specific annexin A1-targeting IFLLWQR (IF7)-conjugated 10BPA or borocaptate sodium (10BSH). METHODS: (1) IF7 conjugates of either 10B drugs intravenously injected into MBT2 bladder tumor-bearing mice and biodistribution of 10B in tumors and normal organs analyzed by prompt gamma-ray analysis. (2) Therapeutic effect of IF7-10B drug-mediated BNCT was assessed by either MBT2 bladder tumor bearing C3H/He mice and YTS-1 tumor bearing nude mice. RESULTS: Intravenous injection of IF7C conjugates of either 10B drugs into MBT2 bladder tumor-bearing mice promoted rapid 10B accumulation in tumor and suppressed tumor growth. Moreover, multiple treatments at ultralow (10-20 mg/kg) doses of IF7-10B drug-mediated BNCT significantly suppressed tumor growth in a mouse model of human YTS-1 bladder cancer, with increased Anxa1 expression in tumors and infiltration by CD8-positive lymphocytes. CONCLUSIONS: We conclude that IF7 serves as an efficient 10B delivery vehicle by targeting tumor tissues via the tumor vasculature and could serve as a relevant vehicle for BNCT drugs.


Assuntos
Anexina A1/metabolismo , Compostos de Boro/administração & dosagem , Terapia por Captura de Nêutron de Boro/métodos , Neovascularização Patológica/radioterapia , Fragmentos de Peptídeos/metabolismo , Fenilalanina/análogos & derivados , Neoplasias da Bexiga Urinária/radioterapia , Animais , Apoptose , Compostos de Boro/química , Compostos de Boro/metabolismo , Proliferação de Células , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Camundongos Nus , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Fenilalanina/administração & dosagem , Fenilalanina/química , Fenilalanina/metabolismo , Células Tumorais Cultivadas , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Gene ; 771: 145343, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33333231

RESUMO

Annexin A1 (ANXA1), a calcium-dependent phospholipid binding protein expressed in animals, plants and microorganisms, participates in various cellular physiological activities. Previous proteomics analysis indicates that the level of ANXA1 in mice dorsal skin changes during hair growth cycle, we speculate that ANXA1 may play an important role in hair follicle (HF) development. Thus, Anxa1 knock-out (KO) and over-expression (OE) mice were constructed to test its function. Our results showed that in addition to the diameter of HF and hair shaft, ANXA1 could participate in hair growth by affecting the density of HF, and the proliferation of hair follicle stem cells (HFSCs). Meanwhile, molecular analysis showed that EGF signaling pathway is involved in the function of ANXA1. The expression of Anxa1 is negatively correlated with the levels of Egf, Notch1, Mkk7, and phosphorylated AKT1 and ERK/2 proteins. The levels of Egf, Notch1, Mkk7 and phosphorylation of AKT1 and ERK/2 increased in Anxa1 KO mice but decreased in Anxa1 OE mice. Taken together, our results suggested that ANXA1 could affect the hair growth by regulating the HFSCs proliferation through EGF signaling pathway.


Assuntos
Anexina A1/genética , Anexina A1/metabolismo , Folículo Piloso/crescimento & desenvolvimento , Animais , Proliferação de Células , Fator de Crescimento Epidérmico/metabolismo , Regulação da Expressão Gênica , Técnicas de Inativação de Genes , Folículo Piloso/metabolismo , Camundongos , Fosforilação , Transdução de Sinais
6.
Biomed Pharmacother ; 133: 111033, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33378946

RESUMO

For decades, glucocorticoids (GC) have been used to treat several inflammatory conditions, including chronic and autoimmune diseases, due to their potent anti-inflammatory properties. In the context of infectious diseases, the use of GCs may be effective as adjuvant to antibiotic therapy by controlling excessive inflammatory responses resulting in better outcome in some cases. However, the use of GCs has been associated with a vast number of side effects, including increased probability of immunosuppression and consequent risk of opportunistic infection. Glucocorticoid-induced leucine zipper (GILZ) and Annexin A1 (AnxA1) are GC-induced proteins intrinsically involved with the anti-inflammatory functions of GCs without the associated adverse metabolic effects. Recent studies have shown that these GC-proteins exhibit pro-resolving effects. An essential characteristic of pro-resolving molecules is their ability to coordinate the resolution of inflammation and promote host defense in most experimental models of infection. Although the role of GILZ and AnxA1 in the context of infectious diseases remain to be better explored, herein we provide an overview of the emerging functions of these GC-proteins obtained from pre-clinical models of infectious diseases.


Assuntos
Anexina A1/metabolismo , Anti-Inflamatórios/uso terapêutico , Infecções Bacterianas/tratamento farmacológico , Glucocorticoides/uso terapêutico , Inflamação/tratamento farmacológico , Doenças Parasitárias/tratamento farmacológico , Fatores de Transcrição/metabolismo , Viroses/tratamento farmacológico , Animais , Infecções Bacterianas/imunologia , Infecções Bacterianas/metabolismo , Infecções Bacterianas/microbiologia , Interações Hospedeiro-Patógeno , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Doenças Parasitárias/imunologia , Doenças Parasitárias/metabolismo , Doenças Parasitárias/parasitologia , Indução de Remissão , Transdução de Sinais , Resultado do Tratamento , Viroses/imunologia , Viroses/metabolismo , Viroses/virologia
7.
Sci Rep ; 10(1): 22283, 2020 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-33335138

RESUMO

Chronic inflammation provides a favorable microenvironment for tumorigenesis, which opens opportunities for targeting cancer development and progression. Piplartine (PL) is a biologically active alkaloid from long peppers that exhibits anti-inflammatory and antitumor activity. In the present study, we investigated the physical and chemical interactions of PL with anti-inflammatory compounds and their effects on cell proliferation and migration and on the gene expression of inflammatory mediators. Molecular docking data and physicochemical analysis suggested that PL shows potential interactions with a peptide of annexin A1 (ANXA1), an endogenous anti-inflammatory mediator with therapeutic potential in cancer. Treatment of neoplastic cells with PL alone or with annexin A1 mimic peptide reduced cell proliferation and viability and modulated the expression of MCP-1 chemokine, IL-8 cytokine and genes involved in inflammatory processes. The results also suggested an inhibitory effect of PL on tubulin expression. In addition, PL apparently had no influence on cell migration and invasion at the concentration tested. Considering the role of inflammation in the context of promoting tumor initiation, the present study shows the potential of piplartine as a therapeutic immunomodulator for cancer prevention and progression.


Assuntos
Anexina A1/genética , Inflamação/tratamento farmacológico , Neoplasias/tratamento farmacológico , Piper/química , Piperidonas/farmacologia , Alcaloides/química , Alcaloides/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Carcinogênese/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Quimiocina CCL2/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Inflamação/patologia , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Neoplasias/patologia , Piperidonas/química , Microambiente Tumoral/efeitos dos fármacos
8.
Cells ; 9(9)2020 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-32887260

RESUMO

We have previously shown that the combination of radiotherapy with human umbilical-cord-derived mesenchymal stromal/stem cells (MSCs) cell therapy significantly reduces the size of the xenotumors in mice, both in the directly irradiated tumor and in the distant nonirradiated tumor or its metastasis. We have also shown that exosomes secreted from MSCs preirradiated with 2 Gy are quantitatively, functionally and qualitatively different from the exosomes secreted from nonirradiated mesenchymal cells, and also that proteins, exosomes and microvesicles secreted by MSCs suffer a significant change when the cells are activated or nonactivated, with the amount of protein present in the exosomes of the preirradiated cells being 1.5 times greater compared to those from nonirradiated cells. This finding correlates with a dramatic increase in the antitumor activity of the radiotherapy when is combined with MSCs or with preirradiated mesenchymal stromal/stem cells (MSCs*). After the proteomic analysis of the load of the exosomes released from both irradiated and nonirradiated cells, we conclude that annexin A1 is the most important and significant difference between the exosomes released by the cells in either status. Knowing the role of annexin A1 in the control of hypoxia and inflammation that is characteristic of acute respiratory-distress syndrome (ARDS), we designed a hypothetical therapeutic strategy, based on the transplantation of mesenchymal stromal/stem cells stimulated with radiation, to alleviate the symptoms of patients who, due to pneumonia caused by SARS-CoV-2, require to be admitted to an intensive care unit for patients with life-threatening conditions. With this hypothesis, we seek to improve the patients' respiratory capacity and increase the expectations of their cure.


Assuntos
Raios gama , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/efeitos da radiação , /terapia , Anexina A1/metabolismo , Betacoronavirus/isolamento & purificação , Ensaios Clínicos como Assunto , Infecções por Coronavirus/terapia , Infecções por Coronavirus/virologia , Exossomos/metabolismo , Humanos , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Pandemias , Pneumonia Viral/terapia , Pneumonia Viral/virologia , /virologia
9.
PLoS One ; 15(6): e0234268, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32497150

RESUMO

Annexin A1 (anxA1) is an immunomodulatory protein that has been proposed as a tumor vascular target for antitumor biologic agents, yet to date the vascular expression of anxA1 in specific tumor indications has not been systematically assessed. Attempts to evaluate vascular anxA1 expression by immunohistochemistry are complicated by a lack of available antibodies that are both specific for anxA1 and bind the N-terminal-truncated form of anxA1 that has previously been identified in tumor vasculature. To study the vascular expression pattern of anxA1 in non-small-cell lung carcinoma (NSCLC), we isolated an antibody capable of binding N-terminal-truncated anxA127-346 and employed it in immunohistochemical studies of human lung specimens. Lung tumor specimens evaluated with this antibody revealed vascular (endothelial) anxA1 expression in five of eight tumor samples studied, but no vascular anxA1 expression was observed in normal lung tissue. Tumor microarray analysis further demonstrated positive vascular staining for anxA1 in 30 of 80 NSCLC samples, and positive staining of neoplastic cells was observed in 54 of 80 samples. No correlation was observed between vascular and parenchymal anxA1 expression. Two rodent tumor models, B16-F10 and Py230, were determined to have upregulated anxA1 expression in the intratumoral vasculature. These data validate anxA1 as a potential vascular anti-tumor target in a subset of human lung tumors and identify rodent models which demonstrate anxA1 expression in tumor vasculature.


Assuntos
Anexina A1/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Neoplasias Pulmonares/metabolismo , Regulação para Cima , Animais , Carcinoma Pulmonar de Células não Pequenas/irrigação sanguínea , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Humanos , Neoplasias Pulmonares/irrigação sanguínea , Camundongos
10.
DNA Cell Biol ; 39(9): 1649-1656, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32552056

RESUMO

Annexin A4 (encoded by the ANXA4 gene) is a calcium ion (Ca2+)- and phospholipid-binding protein of the Annexin family. In this study, we checked the expression profile of ANXA4 in basal-like breast cancer (BLBC) and its association with survival outcomes using pan-cancer data from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) project. Then, using MDA-MB-231 and MDA-MB-468 cells, we explored the functional role of ANXA4 in regulating a cancer-related signaling pathway and identified potential partners of ANXA4. The results showed that expression of total ANXA4 and the two dominant ANXA4 protein-coding transcripts (ENST00000409920.5 and ENST00000394295.4) was consistently upregulated in tumor tissues compared with normal breast tissues. BLBC patients with high ANXA4 expression had significantly worse overall survival, progression-free survival, and disease-free survival than those with low ANXA4 expression. ANXA4 could positively modulate cyclin D1 expression and G1/S progression in the two cell lines. An in vivo tumor model showed that ANXA4 inhibition significantly slowed the growth of tumors derived from the two BLBC cell lines. ANXA4 could increase JAK1 expression and STAT3 phosphorylation (Y705). ANXA4 colocalized with ANXA1 in some MDA-MB-231 cells. A co-immunoprecipitation assay confirmed direct binding between ANXA4 and ANXA1. Knockdown of ANXA1 reduced JAK1 expression and STAT3 phosphorylation and impaired ANXA4-induced upregulation of JAK1 and p-STAT3. In conclusion, this study revealed that aberrant ANXA4 upregulation is associated with poor survival in BLBC. ANXA4 could activate JAK-STAT3 signaling by elevating the expression of JAK1 and p-STAT3, which was mediated by direct interaction with ANXA1.


Assuntos
Anexina A1/metabolismo , Anexina A4/metabolismo , Neoplasias Mamárias Experimentais/metabolismo , Transdução de Sinais , Animais , Anexina A1/genética , Anexina A4/genética , Ciclo Celular , Linhagem Celular , Linhagem Celular Tumoral , Ciclina D1/genética , Ciclina D1/metabolismo , Feminino , Humanos , Janus Quinase 1/genética , Janus Quinase 1/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo
11.
Scand J Immunol ; 92(3): e12915, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32533866

RESUMO

Systemic lupus erythematosus is an autoimmune syndrome characterized by the development of autoantibodies to a wide range of antigens. Together with B cells, respective self-reactive T cells have an important contribution in disease progression as being responsible for inflammatory cytokines secretion, B cell activation and promoting amplification of the autoimmune response. Annexin A1 is expressed by many cell types and binds to phospholipids in a Ca2+ -dependent manner. Abnormal expression of annexin A1 was found on activated B and T cells in both murine and human autoimmunity suggesting its potential role as a therapeutic target. In the present study, we have investigated the possibility to suppress autoimmune manifestation in spontaneous mouse model of lupus using anti-annexin A1 antibody. Groups of lupus-prone MRL/lpr mice were treated with the anti-annexin A1 monoclonal antibody, and the disease activity and survival of the animals were following up. Flow cytometry, ELISA assays, and histological and immunofluorescence kidney analyses were used to determine the levels of Annexin A1 expression, cytokines, anti-dsDNA antibodies and kidney injuries. The administration of this monoclonal antibody to MRL/lpr mice resulted in suppression of IgG anti-dsDNA antibody production, modulated IL-10 secretion, decreased disease activity and prolonged survival compared with the control group.


Assuntos
Anexina A1/antagonistas & inibidores , Anexina A1/imunologia , Anticorpos Monoclonais/farmacologia , Fatores Imunológicos/farmacologia , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/metabolismo , Animais , Autoanticorpos/imunologia , Biomarcadores , Citocinas/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Humanos , Imunoglobulina G/imunologia , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/patologia , Camundongos , Camundongos Endogâmicos MRL lpr , Proteinúria/etiologia , Proteinúria/urina , Baço/imunologia , Baço/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Resultado do Tratamento
12.
Dig Dis ; 38(5): 398-407, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32200378

RESUMO

INTRODUCTION: Crohn's disease (CD) is characterized by relapsing intestinal inflammation. The anti-inflammatory protein annexin A1 (ANXA1) has been linked to inflammatory processes in the gut. OBJECTIVE: To examine ANXA1 expression patterns in the inflamed intestine of patients with CD and associate ANXA1 expression capacity with disease characteristics. METHODS: Surgical specimens of patients with CD operated between 2003 and 2015 were examined. Immunohistochemistry and immunofluorescence were performed to delineate ANXA1 expression. Those with pronounced ANXA1 expression were included in further analysis by qPCR. ANXA1 mRNA expression ratio of the inflamed to non-inflamed tissue was determined and defined as expression capacity of the tissue. Depending on their expression capacity, patients were divided into 2 groups (ANXA1-low vs. ANXA1-high), which were associated with clinical characteristics. RESULTS: Immunohistochemical ANXA1 expression was localized in inflamed regions of the intestine. In immunofluorescence, ANXA1 costained with myeloperoxidase as neutrophil marker, CD4 and CD8 as T cell marker but not CD20 as B cell marker or CD68 as macrophage marker. In qPCR, ANXA1 mRNA expression was upregulated by 20-fold in inflamed to noninflamed tissues. Patients with higher intrinsic ANXA1 expression capacity had significantly less severity of inflammation. Furthermore, the ANXA1-high group had significantly more locally restricted disease (p = 0.0070), more stricturating disease (p = 0.0037), and was less frequently treated by preoperative steroid therapy (p = 0.030). CONCLUSIONS: ANXA1 expression was strongly associated with intestinal inflammation and expressed in T cells and neutrophils of the CD tissues. Patients with higher intrinsic ANXA1 expression capacity of the inflamed tissue presented milder inflammatory changes and indolent clinical course.


Assuntos
Anexina A1/genética , Doença de Crohn/genética , Doença de Crohn/patologia , Índice de Gravidade de Doença , Adulto , Anexina A1/metabolismo , Estudos de Coortes , Feminino , Humanos , Imuno-Histoquímica , Inflamação/genética , Inflamação/patologia , Intestinos/patologia , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Esteroides/uso terapêutico , Fator de Necrose Tumoral alfa/antagonistas & inibidores
13.
Oxid Med Cell Longev ; 2020: 6724810, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32215176

RESUMO

Transient receptor potential melastatin subfamily member 7 (TRPM7) was essential in the growth and metastatic ability of prostate cancer cells. However, the effects and the relevant molecular mechanisms of TRPM7 on metastasis of prostate cancer under hypoxic atmosphere remain unclear. This study investigated the role of TRPM7 in the metastatic ability of androgen-independent prostate cancer cells under hypoxia. First, data mining was carried out to disclose the relationship between the TRPM7 gene level and the survival of prostate cancer patients. Specific siRNAs were used to knockdown target genes. Western blotting and qPCR were employed to determine protein and gene expression, respectively. The gene transcription activity was evaluated by luciferase activity assay of promoter gene. The protein interaction was determined by coimmunoprecipitation. Wound healing and transwell assays were employed to evaluated cell migration and invasion, respectively. Open access database results showed that high expression of TRPM7 was closely related to the poor survival of prostate cancer patients. Hypoxia simultaneously increased TRPM7 expression and induced HIF-1α accumulation in androgen-independent prostate cancer cells. Knockdown of TRPM7 significantly promoted HIF-1α degradation through the proteasome and inhibited EMT changes in androgen-independent prostate cancer cells under hypoxic condition. Moreover, TRPM7 knockdown increased the phosphorylation of RACK1 and strengthened the interaction between RACK1 and HIF-1α but attenuated the binding of HSP90 to HIF-1α. Whereas knockdown of RACK1 increased the binding of HSP90 to HIF-1α. Furthermore, both TRPM7 and HIF-1α knockdown significantly suppressed hypoxia-induced Annexin A1 protein expression, and suppression of HIF-1α/Annexin A1 signaling significantly inhibited hypoxia-induced cell migration and invasion of androgen-independent prostate cancer cells. Our findings demonstrate that TRPM7 knockdown promotes HIF-1α degradation via an oxygen-independent mechanism involving increased binding of RAKC1 to HIF-1α, and TRPM7-HIF-1α-Annexin A1 signaling axis plays a crucial role in the EMT, cell migration, and invasion of androgen-independent prostate cancer cells under hypoxic conditions.


Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologia , Proteínas Serina-Treonina Quinases/genética , Receptores de Quinase C Ativada/metabolismo , Canais de Cátion TRPM/genética , Anexina A1/genética , Anexina A1/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Masculino , Fosforilação , Prognóstico , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Ligação Proteica , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais , Canais de Cátion TRPM/metabolismo , Hipóxia Tumoral
14.
Chin J Traumatol ; 23(2): 96-101, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32201231

RESUMO

With the deepening of research, proteomics has developed into a science covering the study of all the structural and functional characteristics of proteins and the dynamic change rules. The essence of various biological activities is revealed from the perspectives of the biological structure, functional activity and corresponding regulatory mechanism of proteins by proteomics. Among them, phospholipid-binding protein is one of the hotspots of proteomics, especially annexin A1, which is widely present in various tissues and cells of the body. It has the capability of binding to phospholipid membranes reversibly in a calcium ion dependent manner. In order to provide possible research ideas for researchers, who are interested in this protein, the biological effects of annexin A1, such as inflammatory regulation, cell signal transduction, cell proliferation, differentiation and apoptosis are described in this paper.


Assuntos
Anexina A1/fisiologia , Apoptose/genética , Proliferação de Células/genética , Inflamação/genética , Transdução de Sinais/genética , Cálcio/metabolismo , Humanos , Fosfolipídeos/metabolismo , Ligação Proteica , Proteômica
15.
Int J Mol Sci ; 21(4)2020 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-32085666

RESUMO

The formyl peptide receptor (FPR) family are a group of G-protein coupled receptors that play an important role in the regulation of inflammatory processes. It is well-established that activation of FPRs can have cardioprotective properties. Recently, more stable small-molecule FPR1/2 agonists have been described, including both Compound 17b (Cmpd17b) and Compound 43 (Cmpd43). Both agonists activate a range of signals downstream of FPR1/2 activation in human-engineered FPR-expressing cells, including ERK1/2 and Akt. Importantly, Cmpd17b (but not Cmpd43) favours bias away from intracellular Ca2+ mobilisation in this context, which has been associated with greater cardioprotection in response to Cmpd17b over Cmpd43. However, it is unknown whether these FPR agonists impact vascular physiology and/or elicit vasoprotective effects in the context of diabetes. First, we localized FPR1 and FPR2 receptors predominantly in vascular smooth muscle cells in the aortae of male C57BL/6 mice. We then analysed the vascular effects of Cmpd17b and Cmpd43 on the aorta using wire-myography. Cmpd17b but not Cmpd43 evoked a concentration-dependent relaxation of the mouse aorta. Removal of the endothelium or blockade of endothelium-derived relaxing factors using pharmacological inhibitors had no effect on Cmpd17b-evoked relaxation, demonstrating that its direct vasodilator actions were endothelium-independent. In aortae primed with elevated K+ concentration, increasing concentrations of CaCl2 evoked concentration-dependent contraction that is abolished by Cmpd17b, suggesting the involvement of the inhibition of Ca2+ mobilisation via voltage-gated calcium channels. Treatment with Cmpd17b for eight weeks reversed endothelial dysfunction in STZ-induced diabetic aorta through the upregulation of vasodilator prostanoids. Our data indicate that Cmpd17b is a direct endothelium-independent vasodilator, and a vasoprotective molecule in the context of diabetes.


Assuntos
Anexina A1/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Substâncias Protetoras/uso terapêutico , Bibliotecas de Moléculas Pequenas/uso terapêutico , Animais , Aorta/metabolismo , Glicemia/metabolismo , Diabetes Mellitus Experimental/sangue , Masculino , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Substâncias Protetoras/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de Formil Peptídeo/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Estreptozocina , Vasodilatadores/farmacologia
16.
J Clin Invest ; 130(3): 1156-1167, 2020 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-32015229

RESUMO

Understanding the circuits that promote an efficient resolution of inflammation is crucial to deciphering the molecular and cellular processes required to promote tissue repair. Macrophages play a central role in the regulation of inflammation, resolution, and repair/regeneration. Using a model of skeletal muscle injury and repair, herein we identified annexin A1 (AnxA1) as the extracellular trigger of macrophage skewing toward a pro-reparative phenotype. Brought into the injured tissue initially by migrated neutrophils, and then overexpressed in infiltrating macrophages, AnxA1 activated FPR2/ALX receptors and the downstream AMPK signaling cascade, leading to macrophage skewing, dampening of inflammation, and regeneration of muscle fibers. Mice lacking AnxA1 in all cells or only in myeloid cells displayed a defect in this reparative process. In vitro experiments recapitulated these properties, with AMPK-null macrophages lacking AnxA1-mediated polarization. Collectively, these data identified the AnxA1/FPR2/AMPK axis as an important pathway in skeletal muscle injury regeneration.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Anexina A1/metabolismo , Músculo Esquelético , Regeneração , Transdução de Sinais , Proteínas Quinases Ativadas por AMP/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Anexina A1/genética , Camundongos , Camundongos Knockout , Músculo Esquelético/lesões , Músculo Esquelético/fisiologia , Receptores de Formil Peptídeo/genética , Receptores de Formil Peptídeo/metabolismo
17.
Immunology ; 160(1): 78-89, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32107769

RESUMO

Annexins are well-known Ca2+ phospholipid-binding proteins, which have a wide variety of cellular functions. The role of annexin A1 (AnxA1) in the innate immune system has focused mainly on the anti-inflammatory and proresolving properties through its binding to the formyl-peptide receptor 2 (FPR2)/ALX receptor. However, studies suggesting an intracellular role of AnxA1 are emerging. In this study, we aimed to understand the role of AnxA1 for interleukin (IL)-1ß release in response to activators of the nucleotide-binding domain leucine-rich repeat (NLR) and pyrin domain containing receptor 3 (NLRP3) inflammasome. Using AnxA1 knockout mice, we observed that AnxA1 is required for IL-1ß release in vivo and in vitro. These effects were due to reduction of transcriptional levels of IL-1ß, NLRP3 and caspase-1, a step called NLRP3 priming. Moreover, we demonstrate that AnxA1 co-localize and directly bind to NLRP3, suggesting the role of AnxA1 in inflammasome activation is independent of its anti-inflammatory role via FPR2. Therefore, AnxA1 regulates NLRP3 inflammasome priming and activation in a FPR2-independent manner.


Assuntos
Anexina A1/metabolismo , Inflamassomos/imunologia , Interleucina-1beta/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Administração Intranasal , Animais , Cartilagem Articular , Caspase 1/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Gota/induzido quimicamente , Gota/imunologia , Gota/patologia , Humanos , Inflamassomos/metabolismo , Injeções Intra-Articulares , Pulmão/imunologia , Pulmão/patologia , Macrófagos , Masculino , Camundongos , Camundongos Knockout , Cultura Primária de Células , Ligação Proteica/imunologia , Dióxido de Silício/administração & dosagem , Dióxido de Silício/toxicidade , Silicose/imunologia , Silicose/patologia , Transcrição Genética/imunologia , Ácido Úrico/administração & dosagem , Ácido Úrico/toxicidade
18.
FASEB J ; 34(2): 2749-2764, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31908042

RESUMO

Streptococcus pneumoniae is a major cause of community-acquired pneumonia leading to high mortality rates. Inflammation triggered by pneumococcal infection is necessary for bacterial clearance but must be spatially and temporally regulated to prevent further tissue damage and bacterial dissemination. Annexin A1 (AnxA1) mainly acts through Formyl Peptide Receptor 2 (FPR2) inducing the resolution of inflammation. Here, we have evaluated the role of AnxA1 and FPR2 during pneumococcal pneumonia in mice. For that, AnxA1, Fpr2/3 knockout (KO) mice and wild-type (WT) controls were infected intranasally with S pneumoniae. AnxA1 and Fpr2/3 KO mice were highly susceptible to infection, displaying uncontrolled inflammation, increased bacterial dissemination, and pulmonary dysfunction compared to WT animals. Mechanistically, the absence of AnxA1 resulted in the loss of lung barrier integrity and increased neutrophil activation upon S pneumoniae stimulation. Importantly, treatment of WT or AnxA1 KO-infected mice with Ac2-26 decreased inflammation, lung damage, and bacterial burden in the airways by increasing macrophage phagocytosis. Conversely, Ac2-26 peptide was ineffective to afford protection in Fpr2/3 KO mice during infection. Altogether, these findings show that AnxA1, via FPR2, controls inflammation and bacterial dissemination during pneumococcal pneumonia by promoting host defenses, suggesting AnxA1-based peptides as a novel therapeutic strategy to control pneumococcal pneumonia.


Assuntos
Anexina A1/metabolismo , Inflamação/metabolismo , Macrófagos/metabolismo , Neutrófilos/metabolismo , Pneumonia Pneumocócica/metabolismo , Receptores de Formil Peptídeo/metabolismo , Animais , Modelos Animais de Doenças , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Fagocitose/efeitos dos fármacos , Receptores de Lipoxinas/metabolismo , Streptococcus pneumoniae/metabolismo
19.
Clin Exp Immunol ; 199(3): 278-293, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31724735

RESUMO

Systemic lupus erythematosus is a chronic inflammatory disease which involves multiple organs. Self-specific B and T cells play a main role in the pathogenesis of lupus and have been defined as a logical target for selective therapy. The protein annexin A1 (ANX A1) is a modulator of the immune system involving many cell types. An abnormal expression of ANX A1 was found on activated B and T cells during autoimmunity, suggesting its importance as a potential therapeutic target. We hypothesize that it may be possible to down-regulate the activity of autoreactive T and B cells from lupus patients in a humanized immunodeficient mouse model by treating them with an antibody against ANX A1. When cultured in the presence of anti-ANX A1, peripheral blood mononuclear cells (PBMC) from lupus patients showed a decreased number of immunoglobulin (Ig)G anti-dsDNA antibody-secreting plasma cells, decreased T cell proliferation and expression of activation markers and increased B and T cell apoptosis. We employed a humanized model of SLE by transferring PBMCs from lupus patients to immunodeficient non-obese diabetic-severe combined immunodeficient (NOD-SCID) mice. The humanized animals presented autoantibodies, proteinuria and immunoglobulin deposition in the renal glomeruli. Treatment of these NOD-SCID mice with an anti-ANX A1 antibody prevented appearance of anti-DNA antibodies and proteinuria, while the phosphate-buffered saline (PBS)-injected animals had high levels after the transfer. The treatment reduced the levels of autoantibodies to several autoantigens, lupus-associated cytokines and disease symptoms.


Assuntos
Anexina A1/imunologia , Anticorpos/imunologia , Linfócitos B/imunologia , Modelos Animais de Doenças , Lúpus Eritematoso Sistêmico/imunologia , Linfócitos T/imunologia , Animais , Anexina A1/metabolismo , Anticorpos/farmacologia , Anticorpos Antinucleares/imunologia , Anticorpos Antinucleares/metabolismo , Apoptose/efeitos dos fármacos , Apoptose/imunologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/metabolismo , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Lúpus Eritematoso Sistêmico/metabolismo , Ativação Linfocitária/imunologia , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo
20.
In Vivo ; 34(1): 177-184, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31882477

RESUMO

BACKGROUND: Epithelial ovarian cancer (EOC) is the major gynecological cause of cancer deaths. Annexin A1 (ANXA1) protein has been implicated in the aggressiveness of several cancer types. MATERIALS AND METHODS: This study retrospectively assessed ANXA1 expression in epithelial cells of 156 pre-chemotherapy EOC samples and 34 normal ovarian samples from patients treated at Salah Azaiez Institute. Using immunohistochemistry, ANXA1 expression was compared in normal versus cancer samples; correlations with clinicopathological features, including overall survival, were sought. RESULTS: Fifty-two percent of tumor samples showed epithelial ANXA1 staining versus only 26% of normal samples (Fisher's exact test, p=0.00794). Epithelial ANXA1 expression was correlated with better overall survival in both univariate and multivariate analyses. CONCLUSION: The possible contribution of ANXA1 overexpression to EOC outcome may be relevant to therapeutic strategies.


Assuntos
Adenocarcinoma de Células Claras/mortalidade , Adenocarcinoma Mucinoso/mortalidade , Anexina A1/metabolismo , Biomarcadores Tumorais/metabolismo , Cistadenocarcinoma Seroso/mortalidade , Neoplasias do Endométrio/mortalidade , Neoplasias Ovarianas/mortalidade , Adenocarcinoma de Células Claras/metabolismo , Adenocarcinoma de Células Claras/patologia , Adenocarcinoma de Células Claras/terapia , Adenocarcinoma Mucinoso/metabolismo , Adenocarcinoma Mucinoso/patologia , Adenocarcinoma Mucinoso/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Terapia Combinada , Cistadenocarcinoma Seroso/metabolismo , Cistadenocarcinoma Seroso/patologia , Cistadenocarcinoma Seroso/terapia , Neoplasias do Endométrio/metabolismo , Neoplasias do Endométrio/patologia , Neoplasias do Endométrio/terapia , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/terapia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...