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1.
Anticancer Res ; 40(6): 3097-3108, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32487604

RESUMO

BACKGROUND/AIM: C-C motif chemokine ligand 18 (CCL18) is overexpressed in the microenvironment of tumors, promotes invasion and metastasis and is thus important for the therapeutic outcome of many tumor entities. The Gs-coupled seven-transmembrane receptor GPR30 is known as both a CCL18 and an estrogen receptor; its activation by estradiol leads to a transactivation of membrane-tethered pro-heparin-binding EGF-like growth factor and the MAPK/ERK pathway. We examined whether this signaling pathway remains the same under CCL18 stimulation, as opposed to estradiol stimulation. MATERIALS AND METHODS: We investigated the effects of CCL18 on the lung cancer cell line A549, that show low GPR30 expression and the breast cancer cell lines MCF-7, that has high GPR30 expression and MDA-MB-231. These cells were stimulated in different media with CCL18 and then analyzed by qPCR, In-Cell Western®, western blot and ELISA. RESULTS: Many similarities on the effect of CCL18 on the already known estradiol-activated signaling pathway via the G protein-coupled estrogen receptor GPR30 were identified. GPR30 is involved in the expression of matrix metalloproteinases (MMPs), which may play a role in the transactivation of ERK-1/-2 via the cleavage of membrane-bound HB-EGF, via Src-related tyrosine kinases and Gßγ-subunits. With increasing CCL18 concentration, the expression of MMP7 decreased in A549 cells. With decreasing estrogen content of the medium, there was an increasing effect of CCL18 on the inhibition of the relative expression of MMP7. Inhibition of GPR30 with G15 also resulted in a decrease in the relative expression of MMP7, irrespective of the subsequent stimulation with CCL18. This is a rather unexpected result, because the estrogen estradiol and CCL18 both activate GPR30. MCF-7 cells which express more GPR30 did not show any dependence of the relative MMP7 expression on CCL18 except in estrogen-free FCS medium. CCL18 induced an increased relative ERK activation in In-Cell western (ICW) at A549 cells. Stimulation with CCL18 caused decreased ERK activation with simultaneous inhibition of adenylate cyclase in MCF-7. However, stimulation with CCL18 and simultaneous inhibition of cyclooxygenase in MCF-7 resulted in increased ERK activation. In A549, stimulation with CCL18 and co-incubation with dbcAMP resulted in decreased ERK activation in both ICW and Western blot. CONCLUSION: In summary, the Gs-coupled receptor GPR30 plays an important role in the signaling pathway of CCL18. CCL18 and estradiol may not lead to the same signaling pathway after activating GPR30.


Assuntos
Quimiocinas CC/metabolismo , Estradiol/metabolismo , Metaloproteinase 7 da Matriz/metabolismo , Receptores Estrogênicos/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Células A549 , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Quimiocinas CC/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Gliceraldeído-3-Fosfato Desidrogenase (Fosforiladora)/metabolismo , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Células MCF-7 , Metaloproteinase 7 da Matriz/biossíntese , Metaloproteinase 7 da Matriz/genética , Fosforilação , RNA Longo não Codificante/biossíntese , RNA Longo não Codificante/genética , Receptores Estrogênicos/antagonistas & inibidores , Receptores Acoplados a Proteínas-G/antagonistas & inibidores , Transdução de Sinais
2.
Parasitol Res ; 119(2): 491-499, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31907667

RESUMO

Following the emergence of human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS), the number of visceral leishmaniasis-HIV (VL-HIV) coinfections has increased worldwide, mainly in Brazil. The development of clinical forms of VL can be influenced by nutritional status, age, and host genetic factors, which are important variables determining susceptibility to disease. There are no studies with a candidate gene approach assayed directly in the VL-HIV-coinfected population. Herein, we determined and analyzed the associations of SLC11A1, LECT2, CCL1, CCL16, and IL4 genetic polymorphisms with susceptibility to VL-HIV coinfection in Northeastern Brazil. We analyzed 309 DNA samples extracted from the peripheral blood of HIV patients, and clinical and hematological data were collected from medical records. The diagnosis of VL was confirmed in 110 out of 309 patients; genotyping was carried out by TaqMan assays afterwards. Our results confirmed the association between the SLC11A1 polymorphism (rs3731865) and VL-HIV coinfection (p = 0.0206, OR 1.8126, 95% CI 1.1050-2.9727). In addition, the SLC11A1 genotype GG (p = 0.0050, OR 3.0395, 95% CI 1.4065-6.5789) and CD4+ T lymphocyte count (p = 0.0030, OR 0.9980, 95% CI 0.9970-0.9990) were associated with VL-HIV coinfection in a multivariate model. The polymorphism of the SLC11A1 gene (rs3731865) was associated with VL-HIV coinfection, suggesting a possible genetic mechanism involved in the susceptibility to VL in HIV patients. This finding can suggest new therapeutic targets and genetic markers for the VL-HIV-coinfected population.


Assuntos
Síndrome de Imunodeficiência Adquirida/epidemiologia , Proteínas de Transporte de Cátions/genética , Predisposição Genética para Doença/genética , Leishmaniose Visceral/epidemiologia , Adulto , Brasil/epidemiologia , Linfócitos T CD4-Positivos/imunologia , Quimiocina CCL1/genética , Quimiocinas CC/genética , Coinfecção/epidemiologia , Coinfecção/genética , Feminino , Genótipo , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Interleucina-4/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético/genética
3.
Blood Adv ; 4(2): 367-379, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31985806

RESUMO

Acute myeloid leukemia (AML) is a genetically heterogeneous disease that is characterized by abnormal clonal proliferation of myeloid progenitor cells found predominantly within the bone marrow (BM) and blood. Recent studies suggest that genetic and phenotypic alterations in the BM microenvironment support leukemogenesis and allow leukemic cells to survive and evade chemotherapy-induced death. However, despite substantial evidence indicating the role of tumor-host interactions in AML pathogenesis, little is known about the complex microenvironment of the BM. To address this, we performed novel proteomic profiling of the noncellular compartment of the BM microenvironment in patients with AML (n = 10) and age- and sex-matched healthy control subjects (n = 10) using an aptamer-based, highly multiplexed, affinity proteomics platform (SOMAscan). We show that proteomic assessment of blood or RNA-sequencing of BM are suboptimal alternate screening strategies to determine the true proteomic composition of the extracellular soluble compartment of AML patient BM. Proteomic analysis revealed that 168 proteins significantly differed in abundance, with 91 upregulated and 77 downregulated in leukemic BM. A highly connected signaling network of cytokines and chemokines, including IL-8, was found to be the most prominent proteomic signature associated with AML in the BM microenvironment. We report the first description of significantly elevated levels of the myelosuppressive chemokine CCL23 (myeloid progenitor inhibitory factor-1) in both AML and myelodysplastic syndrome patients and perform functional experiments supportive of a role in the suppression of normal hematopoiesis. This unique paired RNA-sequencing and proteomics data set provides innovative mechanistic insights into AML and healthy aging and should serve as a useful public resource.


Assuntos
Medula Óssea/patologia , Leucemia Mieloide Aguda/patologia , Proteômica/métodos , Estudos de Casos e Controles , Microambiente Celular , Quimiocinas/análise , Quimiocinas CC/metabolismo , Citocinas/análise , Regulação Leucêmica da Expressão Gênica , Humanos , Interleucina-8/metabolismo , Proteínas de Neoplasias/análise
4.
Scand J Immunol ; 91(3): e12852, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31733111

RESUMO

CCR9 + T helper (Th) cells can induce Sjögren-like symptoms in mice and both CCR9 + Th cells and their ligand CCL25 are increased in the salivary glands of primary Sjögren's syndrome (pSS) patients. Increased circulating CCR9 + Th cells are present in pSS patients. CCR9 + Th cells are hyperresponsive to IL-7, secrete high levels of IFN-γ, IL-21, IL-17 and IL-4 and potently stimulate B cells in both patients and healthy individuals. Our aim was to study co-expression of chemokine receptors on CCR9 + Th cells and whether in pSS this might differentially affect CCR9 + Th cell frequencies. Frequencies of circulating CCR9 + and CCR9- Th cells co-expressing CXCR3, CCR4, CCR6 and CCR10 were studied in pSS patients and healthy controls. CCL25, CXCL10, CCL17, CCL20 and CCL27 mRNA and protein expression of salivary gland tissue of pSS and non-Sjögren's sicca (non-SS) patients was assessed. Chemotaxis assays were performed to study migration induced by CXCL10 and CCL25. Higher expression of CXCR3, CCR4 and CCR6 but not CCR10 was observed on CCR9 + Th cells as compared to cells lacking CCR9. Decreased frequencies of circulating memory CCR9 + CXCR3+ Th cells were found in pSS patients, which was most pronounced in the effector memory subset. Increased salivary gland CCL25 and CXCL10 expression significantly correlated and both ligands functioned synergistically based on in vitro induced chemotaxis. Decreased memory CXCR3 + CCR9+ Th cells in blood of pSS patients may be due to a concerted action of overexpressed ligands at the site of inflammation in the salivary glands facilitating their preferential migration and positioning in the lymphocytic infiltrates.


Assuntos
Quimiotaxia/imunologia , Contagem de Linfócitos , Glândulas Salivares/imunologia , Glândulas Salivares/metabolismo , Síndrome de Sjogren/etiologia , Síndrome de Sjogren/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo , Adulto , Idoso , Biomarcadores , Quimiocina CXCL10/metabolismo , Quimiocinas CC/metabolismo , Feminino , Humanos , Imunofenotipagem , Masculino , Pessoa de Meia-Idade , Receptores CCR/metabolismo , Receptores CXCR3/metabolismo , Glândulas Salivares/patologia , Síndrome de Sjogren/diagnóstico , Síndrome de Sjogren/terapia
5.
Int Arch Allergy Immunol ; 181(3): 159-169, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31825941

RESUMO

INTRODUCTION: Chronic rhinosinusitis (CRS) is a local inflammation of the nasal mucosa and sinus that persists for >12 weeks. As CC chemokine ligand (CCL) 19 expression is known to be elevated in CRS, and CCL 19, CCL21, and CCL25 share the same atypical chemokine receptor 4, so we focused on CCL21 and CCL25. OBJECTIVES: To investigate the expression of CCL21 and CCL25 in different types of CRS and their significance in CRS development. METHODS: A total of 116 patients participated in the study, and uncinate process mucosa or nasal polyp (NP) specimens were collected during surgery. Western blotting and immunohistochemistry were performed to detect the expression of CCL21 and CCL25, respectively, in the nasal mucosa. Immunofluorescence was used to determine their cellular localization in NPs, whereas macrophage culture was used to determine their relationships with macrophages. RESULTS: Immunohistochemistry revealed that the expressions of CCL21 and CCL25 were increased in NPs only. Western blotting revealed that these expressions were gradually increased in control, CRS without NP and CRS with NP groups and were positively correlated with disease severity. Furthermore, increased expressions of CCL21 and CCL25 in NPs were not related to eosinophil infiltration. Immunofluorescence results demonstrated colocalization of CCL25+ cells and CD68+ macrophages. CCL25 expression was increased in macrophage culture, especially in M1 macrophages, while CCL21 expression was not significantly associated with macrophages. CONCLUSIONS: CCL21 and CCL25 were significantly upregulated in NPs and positively correlated with disease severity. CCL25 upregulation was related to M1 macrophages.


Assuntos
Quimiocina CCL21/metabolismo , Quimiocinas CC/metabolismo , Macrófagos/imunologia , Mucosa Nasal/imunologia , Pólipos Nasais/imunologia , Rinite/imunologia , Sinusite/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença Crônica , Progressão da Doença , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Regulação para Cima , Adulto Jovem
6.
J Immunol Res ; 2019: 1278301, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31815149

RESUMO

Aims: To date, the ROS-generating capacities of macrophages in different activation states have not been thoroughly compared. This study is aimed at determining the nature and levels of ROS generated following stimulation with common activators of M1 and M2 macrophages and investigating the potential for this to impact fibrosis. Results: Human primary and THP-1 macrophages were treated with IFN-γ+LPS or IL-4-activating stimuli, and mRNA expression of established M1 (CXCL11, CCR7, IL-1ß) and M2 (MRC-1, CCL18, CCL22) markers was used to confirm activation. Superoxide generation was assessed by L-012-enhanced chemiluminescence and was increased in both M(IFN-γ+LPS) and M(IL-4) macrophages, as compared to unpolarised macrophages (MΦ). This signal was attenuated with NOX2 siRNA. Increased expression of the p47phox and p67phox subunits of the NOX2 oxidase complex was evident in M(IFN-γ+LPS) and M(IL-4) macrophages, respectively. Amplex Red and DCF fluorescence assays detected increased hydrogen peroxide generation following stimulation with IL-4, but not IFN-γ+LPS. Coculture with human aortic adventitial fibroblasts revealed that M(IL-4), but not M(IFN-γ+LPS), enhanced fibroblast collagen 1 protein expression. Macrophage pretreatment with the hydrogen peroxide scavenger, PEG-catalase, attenuated this effect. Conclusion: We show that superoxide generation is not only enhanced with stimuli associated with M1 macrophage activation but also with the M2 stimulus IL-4. Macrophages activated with IL-4 also exhibited enhanced hydrogen peroxide generation which in turn increased aortic fibroblast collagen production. Thus, M2 macrophage-derived ROS is identified as a potentially important contributor to aortic fibrosis.


Assuntos
Fibroblastos/efeitos dos fármacos , Interferon gama/farmacologia , Interleucina-4/farmacologia , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Transdução de Sinais/genética , Catalase/farmacologia , Quimiocina CCL22/genética , Quimiocina CCL22/imunologia , Quimiocina CXCL11/genética , Quimiocina CXCL11/imunologia , Quimiocinas CC/genética , Quimiocinas CC/imunologia , Técnicas de Cocultura , Colágeno Tipo I/genética , Colágeno Tipo I/imunologia , Fibroblastos/citologia , Fibroblastos/imunologia , Regulação da Expressão Gênica , Humanos , Peróxido de Hidrogênio/metabolismo , Interferon gama/antagonistas & inibidores , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Interleucina-4/antagonistas & inibidores , Lipopolissacarídeos/antagonistas & inibidores , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/citologia , Macrófagos/imunologia , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/imunologia , NADPH Oxidase 2/genética , NADPH Oxidase 2/imunologia , Oxirredução/efeitos dos fármacos , Polietilenoglicóis/farmacologia , Cultura Primária de Células , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Receptores CCR7/genética , Receptores CCR7/imunologia , Receptores Imunológicos/genética , Receptores Imunológicos/imunologia , Superóxidos/metabolismo , Células THP-1
7.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 35(10): 903-909, 2019 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-31814567

RESUMO

Objective To investigate the expression of C-C motif chemokine ligand 23 (CCL23) in hepatocellular carcinoma (HCC) and its clinical significance for survival and prognosis. Methods GEPIA, HCCDB, MetaScape, TIMER, TISIDB, Kaplan-Meier Plotter and other online databases were used to analyze the expression level of CCL23 in HCC, the functional notes of co-expression gene and its gene ontology (GO), the enrichment of Kyoto gene and genome encyclopedia (KEGG), the correlation between tumor cell purity, the expression of CCL23 in immune cells and its significance for survival and prognosis of patients. Results The expression of CCL23 in all stages of HCC was negatively correlated with the purity of HCC tumor cells. The short prognosis of HCC patients with low expression of CCL23 was poor. The GO function and KEGG pathway of CCL23 co-expressed gene in HCC were mainly enriched in immune cell activation and complement system activation. CCL23 was the strongest chemokine factor in HCC, and it could bind to multiple receptors including CC chemokine receptor 1 (CCR1), CCR2, CCR7 and CXC chemokine receptor 6 (CXCR6) to exert chemokine effect on immune cells, among which CD8+ T cells and macrophages have the most obvious chemokine effect. Conclusion The low expression of CCL23 in HCC tissue is not conducive to the development of anti-tumor immune defense in HCC patients and significantly shortens the survival of HCC patients.


Assuntos
Carcinoma Hepatocelular/genética , Quimiocinas CC/genética , Neoplasias Hepáticas/genética , Linfócitos T CD8-Positivos , Carcinoma Hepatocelular/imunologia , Biologia Computacional , Humanos , Neoplasias Hepáticas/imunologia , Macrófagos , Receptores CCR1/metabolismo , Receptores CCR2/metabolismo , Receptores CCR7/metabolismo , Receptores CXCR6/metabolismo
8.
Georgian Med News ; (294): 98-103, 2019 Sep.
Artigo em Russo | MEDLINE | ID: mdl-31687958

RESUMO

The article reveals the modern aspects of IPF pathogenesis in with an emphasis on the main proposed prognostic biomarkers. IPF remains the leader among diseases with unknown etiology, the diagnosis and management of which are not very successful, despite the obvious progress in molecular medicine. There is presented analysis of the significance of IPF potential biomarkers and their concentrations in the blood and bronchoalveolar lavage fluids (BAL): endothelin-1, CC-chemokine ligand 18, interleukin-1, surfactant protein SP-D in the review. The role of their changing levels in the blood and BAL for assessing the course of the IPF and its prognosis, as well as the prevailing importance of the polymorphism of the genes encoding them, is shown. Obviously, the progressive accumulation of fibroblast-myofibroblast cells in the lungs IPF patients worsens the prognosis of disease, forms its own environment with a set of cytokines, growth factors, collagen, fibronectin in the extracellular matrix of fibrous lungs. The insufficient amount of studies in the face of the rarity of the disease leaves a lot of controversial issues for solution in the future. Obviously, to assess the prognosis of IPF mortality, it is necessary to include a very large number of patients, to extend the observation period, which increases their cost and reduces the opportunities and desire of pharmaceutical companies to participate in these studies.


Assuntos
Biomarcadores/sangue , Líquido da Lavagem Broncoalveolar/química , Fibrose Pulmonar Idiopática/diagnóstico , Pulmão/metabolismo , Biomarcadores/análise , Quimiocinas CC , Endotelina-1 , Humanos , Fibrose Pulmonar Idiopática/sangue , Fibrose Pulmonar Idiopática/mortalidade , Interleucina-1 , Pulmão/fisiopatologia , Prognóstico , Proteína D Associada a Surfactante Pulmonar/análise , Proteína D Associada a Surfactante Pulmonar/sangue , Surfactantes Pulmonares/análise , Surfactantes Pulmonares/sangue
9.
Zhonghua Yi Xue Za Zhi ; 99(38): 2976-2981, 2019 Oct 15.
Artigo em Chinês | MEDLINE | ID: mdl-31607028

RESUMO

Objective: To explore the expression and clinical significance of chemokine ligand 18 (CCL18) in Bronchoalveolar Lavage Fluid (BALF) of patients with connective tissue disease-associated interstitial lung disease (CTD-ILD). Methods: From January 2016 to June 2017, BALF of patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD group), patients with dermatomyositis-associated interstitial lung disease (DM-ILD group), and patients with primary Sjögren syndrome-associated interstitial lung disease (pSS-ILD group) of Peking University People's Hospital were collected. According to the prognosis of each group of patients during hospitalization, they were divided into the discharged and the died. Besides, 30 patients without ILD served as a control group. Levels of CCL18 in BALF of all patients were tested by enzyme linked immunosorbent assay (ELISA). Cells in BALF of RA-ILD group, DM-ILD group and pSS-ILD group were collected and analyzed by absolute different cell counts. Results of high-resolution CT (HRCT) of these three groups were scored. In addition, the area under the curve (AUC) of CCL18 in predicting mortality during hospitalization was calculated. Results: A total of 38 patients with RA-ILD, 54 patients with DM-ILD, and 35 patients with pSS-ILD were enrolled. Levels of CCL18 of those discharged patients of RA-ILD, DM-ILD, and pSS-ILD groups were 8.27(3.62, 14.36), 11.04 (5.86, 17.38), 5.25(2.68, 8.21) µg/L, respectively, which were all significantly higher than that of the control group [2.54(1.26, 3.66) µg/L, all P<0.05]. Furthermore, levels of CCL18 of those deceased patients of RA-ILD and DM-ILD groups were 18.28 (13.82, 22.39), 18.81 (16.29, 22.90) µg/L, which were significantly higher than that of the discharged patients of same group (all P<0.05). Levels of CCL18 were positively correlated with lymphocyte percentage in BALF of RA-ILD, DM-ILD and pSS-ILD groups (r=0.4356, 0.4029, 0.3939, respectively, all P<0.05). Besides, levels of CCL18 were significantly correlated with HRCT scores of RA-ILD and DM-ILD groups (r=0.4242, 0.3319, respectively, both P<0.05). Areas under the curve (AUCs) of CCL18 to predict mortality during hospitalization of RA-ILD and DM-ILD groups were 0.860, 0.851, respectively. Conclusions: Levels of CCL18 are elevated in BALF of CTD-ILD patients, and may be correlated with the severity and prognosis during hospitalization. CCL18 might be served as an indicator of the severity and prognosis of CTD-ILD.


Assuntos
Doenças do Tecido Conjuntivo , Dermatomiosite , Doenças Pulmonares Intersticiais , Líquido da Lavagem Broncoalveolar , Quimiocinas , Quimiocinas CC , Doenças do Tecido Conjuntivo/metabolismo , Humanos , Doenças Pulmonares Intersticiais/etiologia
10.
Braz Oral Res ; 33: e093, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31664358

RESUMO

Cytokines and chemokines have a fundamental role in the maintenance of inflammation and bone response, which culminate in the development of chronic periapical lesions. Regulatory (Treg) and Th17 cytokines play a key role in regulating the immune response involved in this process. The aim of this study was to investigate the role of Treg and Th17 cells in chronic inflammatory periapical disease, by comparing the expression of the immunoregulatory mediators TGF-ß, IL-10, CCL4, and the proinflammatory IL-17 and CCL20 in the periapical tissue of teeth with pulp necrosis, with and without associated chronic lesions. Eighty-six periapical tissue samples were obtained from human teeth. The samples were divided into three groups: pulp necrosis with a periapical lesion (n=26); pulp necrosis without a periapical lesion (n=30), and control (n=30). All samples were submitted to histopathological analysis and cytokine and chemokine measurement through ELISA. Statistical analyses were done with Kruskal-Wallis and Mann-Whitney tests and Spearman correlation. The group with pulp necrosis and a periapical lesion showed a higher expression of CCL4 and TGF-ß in comparison with pulp necrosis without a lesion. CCL20 was higher in the group with a periapical lesion when compared to the control. In all groups there was a weak positive correlation between IL-17/CCL20, IL-10/CCL4, and IL-17/TGF-ß. Both types of cytokines, pro-inflammatory and immunoregulatory, occur simultaneously in periapical tissue. However, a rise in immunosuppressive cytokines and chemokines (CCL4 and TGF-ß) in periapical lesions suggests a role of these cytokines in stable periapical disease.


Assuntos
Quimiocinas CC/análise , Interleucinas/análise , Periodontite Periapical/patologia , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Fator de Crescimento Transformador beta/análise , Adulto , Estudos de Casos e Controles , Quimiocinas CC/imunologia , Doença Crônica , Necrose da Polpa Dentária/imunologia , Necrose da Polpa Dentária/patologia , Humanos , Interleucinas/imunologia , Pessoa de Meia-Idade , Periodontite Periapical/imunologia , Valores de Referência , Estatísticas não Paramétricas , Fator de Crescimento Transformador beta/imunologia , Adulto Jovem
11.
Eur Arch Otorhinolaryngol ; 276(12): 3367-3372, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31473779

RESUMO

OBJECTIVE: The aim of this study was to investigate the effect of the medical and the surgical treatment on the olfactory functions, clinical scoring systems and inflammation markers in patients with nasal polyposis. In addition, the secondary aim was to investigate the correlation between those investigated parameters. SUBJECTS AND METHODS: A total of 30 patients, who completed the standardized medical and surgical treatment and also came to 3 months of follow-ups regularly after the surgery, were included in the study. The Sniffin' Sticks olfactory tests, radiological and the endoscopic stagings, liver-expressed chemokine (CCL16) and endothelin (ET) levels and sino-nasal outcome test-22 (SNOT-22) were performed at the initial and at the end of the study. RESULTS: The current study had four major findings: (1) significant improvement in odor functions after treatment was determined; however, the majority of the patients had been already hyposmic. (2) In addition, significant improvement was found in ET and CCL16 levels, SNOT-22 results, and radiologic and endoscopic stagings at the end of the study. (3) However, there was no correlation between the olfactory functions and the investigated parameters. (4) There was a positive correlation between polyp recurrence and ET levels. CONCLUSION: The standardized medical and surgical treatment provided a significant improvement in the olfactory functions. However, only one patient (3.3%) had become normosmic at the end of the study.


Assuntos
Quimiocinas CC/sangue , Endoscopia/métodos , Endotelinas/sangue , Pólipos Nasais/tratamento farmacológico , Pólipos Nasais/cirurgia , Transtornos do Olfato/etiologia , Percepção Olfatória/fisiologia , Olfato/fisiologia , Adulto , Biomarcadores , Feminino , Seguimentos , Humanos , Inflamação/complicações , Masculino , Pessoa de Meia-Idade , Pólipos Nasais/complicações , Transtornos do Olfato/fisiopatologia , Prednisolona/uso terapêutico , Estudos Prospectivos , Recuperação de Função Fisiológica , Limiar Sensorial/fisiologia , Resultado do Tratamento
12.
Int J Immunogenet ; 46(6): 437-443, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31433132

RESUMO

Numerous single nucleotide polymorphisms (SNPs) were explored in the Algerian population to evaluate associated ankylosing spondylitis (AS) genetic risk factors, but no study has identified the impact of copy number variations (CNVs). The aim of the study was to determine whether CNVs of CCL3L1, FCGR3A and FCGR3B genes were also associated with the susceptibility of AS disease in Algerian population. The data set of the current study is composed of 81 patients with AS and 119 healthy controls. All samples were genotyped by digital droplet PCR (ddPCR). Chi-square test and OR calculation were used to evaluate association between CNVs and AS and the risk associated with copy numbers (CN). In results, FCGR3A CN less than two copies (<2) was significantly increased in spondylitis patients (p = .0001, OR = 7.74 [2.32-25.74]). Additionally, FCGR3A CN < 2 copies association was present only in HLA-B27 (-) patients. We have concluded that FCGR3A deletions have an independent effect on AS regarding HLA-B27 status. This is the first study that investigated the CCL3L1 CNVs in relation to AS risk disease. It reveals that CCL3L1 and FCGR3B CNVs may not be involved in susceptibility to AS risk in the Algerian population.


Assuntos
Quimiocinas CC/genética , Receptores de IgG/genética , Espondilite Anquilosante/genética , Adulto , Fatores Etários , Argélia , Estudos de Coortes , Variações do Número de Cópias de DNA , Feminino , Proteínas Ligadas por GPI/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Antígeno HLA-B27/genética , Humanos , Masculino , Razão de Chances , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Fatores Sexuais
13.
Clin Lab ; 65(6)2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31232025

RESUMO

BACKGROUND: The diagnostic and prognostic role of Th-1 chemokine receptor and Th-2 chemokine receptor in patients with primary immune thrombocytopenia has not been investigated extensively so far. In this study, our goal is to explore the diagnostic and prognostic role of C-C chemokine receptor 3 (CCR3) and C-C chemokine receptor 5 (CCR5) in patients with primary immune thrombocytopenia. METHODS: The expression levels of CCR3 and CCR5 were measured in peripheral blood mononuclear cells of pa-tients with primary immune thrombocytopenia and healthy subjects. The relationship between the expression levels of CCR3 and CCR5 and clinicopathological characteristics was analyzed. The diagnostic accuracy of CCR3 and CCR5 as biomarkers to discriminate primary immune thrombocytopenia patients from healthy subjects was determined. Univariate and multivariate Cox regression analysis were performed to determine the prognosis value of CCR3 and CCR5 in primary immune thrombocytopenia. The outcome of primary immune thrombocytopenia patients was also evaluated. RESULTS: Compared to healthy subjects, the expression level of CCR3 was significantly downregulated and CCR5 was significantly upregulated (p < 0.05). The expression levels of CCR3 and CCR5 were significantly correlated with bleeding times and platelet counts at diagnosis (p < 0.05). CCR3 and CCR5 could act as a suitable biomarker for differentiating the primary immune thrombocytopenia patients from healthy subjects. CCR3 and CCR5 were independent prognostic factors. Overexpression of CCR5 and low expression of CCR3 lead to poor clinical benefits and indicated poor prognosis of primary immune thrombocytopenia. CONCLUSIONS: To summarize, our results suggested that CCR3 and CCR5 could act as suitable biomarkers and indicated poor prognosis of primary immune thrombocytopenia.


Assuntos
Púrpura Trombocitopênica Idiopática/imunologia , Receptores CCR/imunologia , Células Th1/imunologia , Células Th2/imunologia , Biomarcadores/metabolismo , Quimiocinas CC/imunologia , Quimiocinas CC/metabolismo , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico , Púrpura Trombocitopênica Idiopática/diagnóstico , Púrpura Trombocitopênica Idiopática/metabolismo , Receptores CCR/metabolismo , Receptores CCR3/imunologia , Receptores CCR3/metabolismo , Receptores CCR5/imunologia , Receptores CCR5/metabolismo , Células Th1/metabolismo , Células Th2/metabolismo
14.
Arthritis Rheumatol ; 71(12): 2059-2067, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31233287

RESUMO

OBJECTIVE: To investigate the relationship between Krebs von den Lungen 6 (KL-6) and CCL18 levels and the severity and progression of systemic sclerosis (SSc)-related interstitial lung disease (ILD). METHODS: Patients enrolled in the Scleroderma Lung Study II (cyclophosphamide [CYC] versus mycophenolate mofetil [MMF]) were included. Baseline and 12-month plasma samples were analyzed by enzyme-linked immunosorbent assay to assess CCL18 and KL-6 levels. The forced vital capacity (FVC) and the diffusing capacity for carbon monoxide (DLco) were measured every 3 months. Joint models were created to investigate the relationship between baseline CCL18 and KL-6 levels and the course of the FVC and DLco over 1 year according to treatment arm. RESULTS: Baseline KL-6 and CCL18 levels each correlated with the extent of radiographic fibrosis. Levels of both CCL18 and KL-6 declined significantly at 1 year. In both treatment arms (n = 71 for CYC, n = 62 for MMF), a higher baseline KL-6 level predicted progression of ILD based on the course of FVC (P = 0.024 for CYC; P = 0.005 for MMF) and DLco (P < 0.001 for CYC; P = 0.004 for MMF) over 1 year. A higher baseline CCL18 level predicted progression of ILD based on the course of the FVC (P < 0.001 for CYC; P = 0.007 for MMF) and DLco (P = 0.001 for CYC; P < 0.001 for MMF) over 1 year, as well as mortality (P = 0.0008 for CYC arm only). CONCLUSION: In a rigorously conducted clinical trial for SSc-related ILD, KL-6 and CCL18 levels correlated with ILD severity and declined with immunosuppression. Patients with higher baseline KL-6 and CCL18 levels were more likely to experience disease progression despite treatment. KL-6 and CCL18 levels could be used to identify patients with a progressive ILD phenotype who may benefit from a more aggressive initial treatment approach.


Assuntos
Quimiocinas CC/metabolismo , Doenças Pulmonares Intersticiais/fisiopatologia , Mucina-1/metabolismo , Escleroderma Sistêmico/genética , Adolescente , Adulto , Idoso , Ciclofosfamida/uso terapêutico , Progressão da Doença , Feminino , Humanos , Imunossupressores/uso terapêutico , Pulmão/metabolismo , Doenças Pulmonares Intersticiais/etiologia , Doenças Pulmonares Intersticiais/genética , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Testes de Função Respiratória , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/tratamento farmacológico , Capacidade Vital , Adulto Jovem
15.
Biochim Biophys Acta Mol Basis Dis ; 1865(7): 1845-1852, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31109452

RESUMO

Establishing molecular and cellular indicators that reflect the extent of dilation of the left ventricle (LV) after myocardial infarction (MI) may improve diagnostic and prognostic capabilities. We queried the Mouse Heart Attack Research Tool (mHART) 1.0 for day 7 post-MI mice (age 3-9 months, untreated males and females) with serial echocardiographic data at days 0, 1, and 7 (n = 51). Mice were classified into two subgroups determined by a median fold change of 1.6 in end-diastolic dimensions (EDD) normalized to pre-MI values; n = 26 fell below (moderate; mean of 1.42 ±â€¯0.01) and n = 25 fell above this cut-off (extreme; mean of 1.79 ±â€¯0.01; p < 0.001 vs. moderate). Plasma proteomic profiling of 34 analytes measured at day 7 post-MI from male mice (n = 12 moderate and 12 extreme) were evaluated as the test dataset, and receiver operating curve (ROC) analysis was used to assess strength of biomarkers. Females (n = 6 moderate and 9 extreme) were used as the validation dataset. Both by t-test and characteristic (ROC) curve analysis, lower macrophage inflammatory protein-1 gamma (MIP-1γ), lymphotactin, and granulocyte chemotactic protein-2 (GCP-2) were identified as plasma indicators for dilation status (p < 0.05 for all). Macrophage numbers were decreased and complement C5, laminin 1, and Ccr8 gene levels were significantly higher in the LV infarcts of the extreme dilation group (p < 0.05 for all). A composite panel including plasma MIP-1γ, lymphotactin, and GCP-2, and LV infarct Ccr8 and macrophage numbers strongly mirrored LV dilation status (AUC = 0.92; p < 0.0001). Using the mHART 1.0 database, we determined that a failure to mount sufficient macrophage-mediated inflammation was indicative of exacerbated LV dilation.


Assuntos
Cardiomiopatia Dilatada/etiologia , Cardiomiopatia Dilatada/patologia , Ventrículos do Coração/patologia , Infarto do Miocárdio/complicações , Animais , Cardiomiopatia Dilatada/sangue , Quimiocina CXCL6/sangue , Quimiocinas CC/sangue , Bases de Dados Factuais , Feminino , Linfocinas/sangue , Proteínas Inflamatórias de Macrófagos/sangue , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteômica , Sialoglicoproteínas/sangue
16.
Immunogenetics ; 71(5-6): 363-372, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31049641

RESUMO

The appearance of mammalian-specific skin features was a key evolutionary event contributing for the elaboration of physiological processes such as thermoregulation, adequate hydration, locomotion, and inflammation. Skin inflammatory and autoimmune processes engage a population of skin-infiltrating T cells expressing a specific C-C chemokine receptor (CCR10) which interacts with an epidermal CC chemokine, the skin-specific C-C motif chemokine ligand 27 (CCL27). CCL27 is selectively produced in the skin by keratinocytes, particularly upon inflammation, mediating the adhesion and homing of skin-infiltrating T cells. Here, we examined the evolution and coding condition of Ccl27 in 112 placental mammalian species. Our findings reveal that a number of open reading frame inactivation events such as insertions, deletions, and start and stop codon mutations independently occurred in Cetacea, Pholidota, Sirenia, Chiroptera, and Rodentia, totalizing 18 species. The diverse habitat settings and lifestyles of Ccl27-eroded lineages probably implied distinct evolutionary triggers rendering this gene unessential. For example, in Cetacea, the rapid renewal of skin layers minimizes the need for an elaborate inflammatory mechanism, mirrored by the absence of epidermal scabs. Our findings suggest that the convergent and independent loss of Ccl27 in mammalian evolution concurred with unique adaptive roads for skin physiology.


Assuntos
Quimiocina CCL27/genética , Evolução Molecular , Inativação Gênica , Pele/metabolismo , Sequência de Aminoácidos , Animais , Cetáceos/genética , Quimiocina CCL27/química , Quimiocina CCL27/metabolismo , Quimiocinas CC/química , Quimiocinas CC/genética , Quimiocinas CC/metabolismo , Éxons , Feminino , Loci Gênicos , Predisposição Genética para Doença , Humanos , Mamíferos , Modelos Moleculares , Mutação , Processamento de RNA , Análise de Sequência de DNA , Relação Estrutura-Atividade , Transcrição Genética , Transcriptoma
17.
Int J Mol Sci ; 20(10)2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-31096719

RESUMO

Leukocyte migration, a hallmark of the inflammatory response, is stimulated by the interactions between chemokines, which are expressed in injured or infected tissues, and chemokine receptors, which are G protein-coupled receptors (GPCRs) expressed in the leukocyte plasma membrane. One mechanism for the regulation of chemokine receptor signaling is biased agonism, the ability of different chemokine ligands to preferentially activate different intracellular signaling pathways via the same receptor. To identify features of chemokines that give rise to biased agonism, we studied the activation of the receptor CCR1 by the chemokines CCL7, CCL8, and CCL15(Δ26). We found that, compared to CCL15(Δ26), CCL7 and CCL8 exhibited biased agonism towards cAMP inhibition and away from ß-Arrestin 2 recruitment. Moreover, N-terminal substitution of the CCL15(Δ26) N-terminus with that of CCL7 resulted in a chimera with similar biased agonism to CCL7. Similarly, N-terminal truncation of CCL15(Δ26) also resulted in signaling bias between cAMP inhibition and ß-Arrestin 2 recruitment signals. These results show that the interactions of the chemokine N-terminal region with the receptor transmembrane region play a key role in selecting receptor conformations coupled to specific signaling pathways.


Assuntos
Quimiocinas/metabolismo , Quimiocinas/farmacologia , Receptores CCR1/agonistas , Receptores CCR1/metabolismo , Transdução de Sinais , Quimiocina CCL7/metabolismo , Quimiocina CCL8/metabolismo , Quimiocinas CC/metabolismo , Células HEK293 , Humanos , Ligantes , Proteínas Inflamatórias de Macrófagos/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , beta-Arrestina 2/metabolismo
18.
J Immunol Res ; 2019: 1845128, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31098385

RESUMO

Rationale: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic interstitial lung disease, with high mortality. Currently, the aetiology and the pathology of IPF are poorly understood, with both innate and adaptive responses previously being implicated in the disease pathogenesis. Heat shock proteins (Hsp) and antibodies to Hsp in patients with IPF have been suggested as therapeutic targets and prognostic biomarkers, respectively. We aimed to study the relationship between the expression of Hsp72 and anti-Hsp72 antibodies in the BAL fluid and serum Aw disease progression in patients with IPF. Methods: A novel indirect ELISA to measure anti-Hsp72 IgG was developed and together with commercially available ELISAs used to detect Hsp72 IgG, Hsp72 IgGAM, and Hsp72 antigen, in the serum and BALf of a cohort of IPF (n = 107) and other interstitial lung disease (ILD) patients (n = 66). Immunohistochemistry was used to detect Hsp72 in lung tissue. The cytokine expression from monocyte-derived macrophages was measured by ELISA. Results: Anti-Hsp72 IgG was detectable in the serum and BALf of IPF (n = 107) and other ILDs (n = 66). Total immunoglobulin concentrations in the BALf showed an excessive adaptive response in IPF compared to other ILDs and healthy controls (p = 0.026). Immunohistochemistry detection of C4d and Hsp72 showed that these antibodies may be targeting high expressing Hsp72 type II alveolar epithelial cells. However, detection of anti-Hsp72 antibodies in the BALf revealed that increasing concentrations were associated with improved patient survival (adjusted HR 0.62, 95% CI 0.45-0.85; p = 0.003). In vitro experiments demonstrate that anti-Hsp72 complexes stimulate macrophages to secrete CXCL8 and CCL18. Conclusion: Our results indicate that intrapulmonary anti-Hsp72 antibodies are associated with improved outcomes in IPF. These may represent natural autoantibodies, and anti-Hsp72 IgM and IgA may provide a beneficial role in disease pathogenesis, though the mechanism of action for this has yet to be determined.


Assuntos
Células Epiteliais Alveolares/metabolismo , Autoanticorpos/metabolismo , Proteínas de Choque Térmico HSP72/metabolismo , Fibrose Pulmonar Idiopática/imunologia , Pulmão/imunologia , Macrófagos/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Células Cultivadas , Quimiocinas CC/metabolismo , Progressão da Doença , Feminino , Proteínas de Choque Térmico HSP72/genética , Proteínas de Choque Térmico HSP72/imunologia , Humanos , Fibrose Pulmonar Idiopática/mortalidade , Interleucina-8/metabolismo , Masculino , Pessoa de Meia-Idade , Análise de Sobrevida
19.
Clin Exp Metastasis ; 36(3): 243-255, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31062206

RESUMO

Our previous studies have proved that CCL18 is the most secreted chemokine in breast cancer microenvironment by tumor associated macrophages (TAMs). CCL18 promotes breast cancer invasiveness by binding to its cognate receptor PITPNM3 and activating the downstream signaling pathways. The high level of CCL18 in serum or tumor stroma is associated with tumor metastasis and poor patients overall survival. In this study, we identify an effective small molecular compound (SMC) to antagonize the effect of CCL18. We screen more than 1000 SMCs from Sun Yat-sen University SMC library and select 15 top scored SMCs by using computer-aided virtual screening based on the structure of CCL18. Then in vitro cell migration assay narrows down the selected 15 SMCs to the most effective SMC-21598. We find 10 µM SMC-21598 significantly inhibits CCL18-induced breast cancer cells adherence, invasiveness, and migration. Our further surface plasmon resonance (SPR), fluorescence spectroscopy and isothermal titration calorimetry (ITC) assays reveal that SMC-21598 binds tightly to CCL18, which blocks the binding of CCL18 with its receptor PITPNM3. The in vivo animal experiments show that SMC-21598 doesn't significantly affect xenografts growth, but inhibits lung metastasis. Our study provides a potential lead compound to antagonize CCL18 function. It would be of great significance to develop SMC drugs to ameliorate breast cancer metastasis and prolong patients' survival.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/patologia , Quimiocinas CC/antagonistas & inibidores , Neoplasias Pulmonares/prevenção & controle , Animais , Proteínas de Ligação ao Cálcio/metabolismo , Adesão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Feminino , Humanos , Neoplasias Pulmonares/secundário , Células MCF-7 , Macrófagos/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Simulação de Acoplamento Molecular , Invasividade Neoplásica/patologia , Ressonância de Plasmônio de Superfície , Microambiente Tumoral/fisiologia , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Int J Biol Markers ; 34(2): 156-162, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31046524

RESUMO

BACKGROUND: CC chemokine ligand 18 (CCL18) is a chemotactic cytokine involved in the pathogenesis and progression of various cancers. Our previous research showed that the expression of CCL18 is obviously higher in non-small cell lung cancer (NSCLC) than in the adjacent normal tissues, suggesting its role in NSCLC. METHODS: We further examined the serum level of CCL18 in 80 NSCLC patients with enzyme-linked immunosorbent assay and simultaneously analyzed the survival curve of these patients by the Kaplan-Meier method, and then utilized a log-rank test to evaluate the correlation of CCL18 expression with the malignant progression of NSCLC. RESULTS: Our results showed that the median serum concentration of CCL18 was significantly elevated to 436.11 ng/mL in NSCLC patients compared to 41.97 ng/ml in healthy people (P<0.01), which was also positively related to the expression of lung cancer biomarkers carcinoma-embryonic antigen and cytokeratin fragment antigen 21-1. Moreover, correlation analysis showed that an increased level of serum CCL18 was associated with a worse survival time in NSCLC patients. CONCLUSION: Our findings suggest that the serum CCL18 level of NSCLC patients was negatively correlated with the prognosis, thus suggesting that CCL18 may serve as a potential circulating biomarker for NSCLC diagnosis.


Assuntos
Adenocarcinoma/secundário , Biomarcadores Tumorais/sangue , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/secundário , Quimiocinas CC/sangue , Neoplasias Pulmonares/patologia , Adenocarcinoma/sangue , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma de Células Escamosas/sangue , Estudos de Casos e Controles , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/sangue , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida
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