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1.
J Thorac Oncol ; 15(7): e101-e103, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32353597
3.
Nat Cell Biol ; 22(4): 465-475, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32203421

RESUMO

Advanced clear cell renal cell carcinoma (ccRCC) frequently causes systemic inflammation. Recent studies have shown that cancer cells reshape the immune landscape by secreting cytokines or chemokines. This phenotype, called cancer-cell-intrinsic inflammation, triggers a metastatic cascade. Here, we identified the functional role and regulatory mechanism of inflammation driven by advanced ccRCC cells. The inflammatory nature of advanced ccRCC was recapitulated in a preclinical model of ccRCC. Amplification of cancer-cell-intrinsic inflammation during ccRCC progression triggered neutrophil-dependent lung metastasis. Massive expression of inflammation-related genes was transcriptionally activated by epigenetic remodelling through mechanisms such as DNA demethylation and super-enhancer formation. A bromodomain and extra-terminal motif inhibitor synchronously suppressed C-X-C-type chemokines in ccRCC cells and decreased neutrophil-dependent lung metastasis. Overall, our findings provide insight into the nature of inflammatory ccRCC, which triggers metastatic cascades, and suggest a potential therapeutic strategy.


Assuntos
Carcinoma de Células Renais/genética , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Renais/genética , Neoplasias Pulmonares/genética , Proteínas de Neoplasias/genética , Animais , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/secundário , Linhagem Celular Tumoral , Quimiocinas CXC/genética , Quimiocinas CXC/metabolismo , Progressão da Doença , Perfilação da Expressão Gênica , Humanos , Inflamação , Neoplasias Renais/metabolismo , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/secundário , Metástase Linfática , Masculino , Camundongos , Camundongos Nus , Proteínas de Neoplasias/metabolismo , Neutrófilos/metabolismo , Neutrófilos/patologia , Prognóstico , Análise de Sobrevida , Microambiente Tumoral/genética , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Proc Natl Acad Sci U S A ; 117(10): 5532-5541, 2020 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-32079724

RESUMO

The role of stromal fibroblasts in chronic inflammation is unfolding. In rheumatoid arthritis, leukocyte-derived cytokines TNF and IL-17A work together, activating fibroblasts to become a dominant source of the hallmark cytokine IL-6. However, IL-17A alone has minimal effect on fibroblasts. To identify key mediators of the synergistic response to TNF and IL-17A in human synovial fibroblasts, we performed time series, dose-response, and gene-silencing transcriptomics experiments. Here we show that in combination with TNF, IL-17A selectively induces a specific set of genes mediated by factors including cut-like homeobox 1 (CUX1) and IκBζ (NFKBIZ). In the promoters of CXCL1, CXCL2, and CXCL3, we found a putative CUX1-NF-κB binding motif not found elsewhere in the genome. CUX1 and NF-κB p65 mediate transcription of these genes independent of LIFR, STAT3, STAT4, and ELF3. Transcription of NFKBIZ, encoding the atypical IκB factor IκBζ, is IL-17A dose-dependent, and IκBζ only mediates the transcriptional response to TNF and IL-17A, but not to TNF alone. In fibroblasts, IL-17A response depends on CUX1 and IκBζ to engage the NF-κB complex to produce chemoattractants for neutrophil and monocyte recruitment.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Artrite Reumatoide/metabolismo , Fibroblastos/metabolismo , Proteínas de Homeodomínio/metabolismo , Inflamação/metabolismo , Interleucina-17/fisiologia , Proteínas Repressoras/metabolismo , Fatores de Transcrição/metabolismo , Transcriptoma/fisiologia , Fator de Necrose Tumoral alfa/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Artrite Reumatoide/genética , Células Cultivadas , Quimiocina CXCL1/genética , Quimiocina CXCL2/genética , Quimiocinas CXC/genética , Fatores Quimiotáticos/genética , Fibroblastos/efeitos dos fármacos , Proteínas de Homeodomínio/genética , Humanos , Inflamação/genética , Interleucina-17/farmacologia , Interleucina-6/genética , Metaloproteinase 3 da Matriz/metabolismo , Monócitos/efeitos dos fármacos , Monócitos/fisiologia , RNA Interferente Pequeno/genética , Proteínas Repressoras/genética , Células Estromais/efeitos dos fármacos , Células Estromais/metabolismo , Líquido Sinovial , Fator de Transcrição RelA/metabolismo , Fatores de Transcrição/genética , Transcriptoma/efeitos da radiação , Fator de Necrose Tumoral alfa/farmacologia
5.
Anticancer Res ; 39(12): 6645-6652, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31810929

RESUMO

BACKGROUND/AIM: We have previously reported that chemokine (C-X-C motif) receptor 2 (CXCR2) signaling was associated with the malignant progression of gastric cancer (GC). We thus examined the clinicopathological significance of CXCR2 ligands, CXCL1, CXCL2, CXCL3, CXCL5, CXCL6, CXCL7, and CXCL8, in GC. PATIENTS AND METHODS: The expression of CXCR2 ligands in 590 GC cases was investigated by immunohistochemistry. RESULTS: The expression was as follows: CXCL1, 46.2% (257/557); CXCL2, 20.7% (122/590); CXCL3, 17.1% (101/589); CXCL5/CXCL6, 2.9% (17/589); CXCL7, 36.4% (215/590); and CXCL8 1.7% (10/585) of the cases. High invasion depth was correlated with CXCL1 expression. Lymph node metastasis and peritoneal cytology positivity were correlated with high expression of CXCL1 and CXCL7. The prognoses of the CXCL1-positive patients were significantly poorer than those of the CXCL1-negative patients (p<0.001). CONCLUSION: Among the CXCR2 ligands, CXCL7 and especially CXCL1, might play an important role in the malignant progression of GC via CXCR2 signaling.


Assuntos
Proteínas de Neoplasias/metabolismo , Receptores de Interleucina-8B/metabolismo , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Idoso , Análise de Variância , Quimiocina CXCL1/metabolismo , Quimiocina CXCL2/metabolismo , Quimiocina CXCL5/metabolismo , Quimiocina CXCL6/metabolismo , Quimiocinas CXC/metabolismo , Progressão da Doença , Feminino , Humanos , Interleucina-8/metabolismo , Ligantes , Metástase Linfática , Masculino , Invasividade Neoplásica , Prognóstico , Estudos Retrospectivos , Neoplasias Gástricas/mortalidade , beta-Tromboglobulina/metabolismo
6.
Proc Natl Acad Sci U S A ; 116(48): 24122-24132, 2019 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-31712428

RESUMO

Microglia, the resident immune cells of the central nervous system, play an important role in the brain. Microglia have a special spatiotemporal distribution during the development of the cerebral cortex. Neural progenitor cells (NPCs) are the main source of neural-specific cells in the early brain. It is unclear whether NPCs affect microglial development and what molecular mechanisms control early microglial localization. H2A.Z.2, a histone variant of H2A, has a key role in gene expression regulation, genomic stability, and chromatin remodeling, but its function in brain development is not fully understood. Here, we found that the specific deletion of H2A.Z.2 in neural progenitor cells led to an abnormal increase in microglia in the ventricular zone/subventricular zone (VZ/SVZ) of the embryonic cortex. Mechanistically, H2A.Z.2 regulated microglial development by incorporating G9a into the promoter region of Cxcl14 and promoted H3k9me2 modification to inhibit the transcription of Cxcl14 in neural progenitor cells. Meanwhile, we found that the deletion of H2A.Z.2 in microglia itself had no significant effect on microglial development in the early cerebral cortex. Our findings demonstrate a key role of H2A.Z.2 in neural progenitor cells in controlling microglial development and broaden our knowledge of 2 different types of cells that may affect each other through crosstalk in the central nervous system.


Assuntos
Encéfalo/embriologia , Quimiocinas CXC/metabolismo , Histonas/genética , Microglia/fisiologia , Células-Tronco Neurais/fisiologia , Animais , Encéfalo/citologia , Córtex Cerebral/embriologia , Córtex Cerebral/patologia , Quimiocinas CXC/genética , Epigênese Genética , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Histona-Lisina N-Metiltransferase/metabolismo , Histonas/metabolismo , Lisina/metabolismo , Camundongos Transgênicos , Microglia/citologia , Gravidez , Regiões Promotoras Genéticas , Processamento de Proteína Pós-Traducional
7.
Int J Mol Sci ; 20(22)2019 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-31752131

RESUMO

Chemokines are important in the development and progression of tumors. We investigated the expression of CXCL14 and CXCL16 in colon cancer. Expression of mRNA was assessed in primary tumors and lymph nodes and CXCL16 mRNA levels were correlated to patient's survival. Protein expression was investigated by two-color immunofluorescence and immunomorphometry. CXCL14 and CXCL16 mRNA levels and protein expression were significantly higher in colon cancer primary tumors compared to apparently normal colon tissue. Positive cells were tumor cells, as revealed by anti-CEA and anti-EpCAM staining. CXCL16, but not CXCL14, mRNA levels were significantly higher in hematoxylin and eosin positive (H&E(+)) compared to H&E(-) colon cancer lymph nodes or control nodes (P < 0.0001). CXCL16 mRNA was expressed in 5/5 colon cancer cell lines while CXCL14 was expressed significantly in only one. Kaplan-Meier analysis revealed that colon cancer patients with lymph nodes expressing high or very high levels (7.2 and 11.4 copies/18S rRNA unit, respectively) of CXCL16 mRNA had a decreased mean survival time of 30 and 46 months at the 12-year follow-up (P = 0.04, P = 0.005, respectively). In conclusion, high expression of CXCL16 mRNA in regional lymph nodes of colon cancer patients is a sign of a poor prognosis.


Assuntos
Biomarcadores Tumorais/genética , Quimiocina CXCL16/genética , Neoplasias do Colo/genética , Linfonodos/metabolismo , Regulação para Cima , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Células CACO-2 , Linhagem Celular Tumoral , Quimiocina CXCL16/metabolismo , Quimiocinas CXC/genética , Quimiocinas CXC/metabolismo , Neoplasias do Colo/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Células HT29 , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Análise de Sobrevida
8.
Int J Mol Med ; 44(6): 2181-2188, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31638188

RESUMO

Tacrolimus is one of the most used and effective immunosuppressive agents currently available in the clinic; however, its use is limited by nephrotoxicity, which is the main secondary effect of this drug. The mechanisms underlying tacrolimus­induced nephrotoxicity remain unknown. The present study aimed to investigate the mechanism underlying tacrolimus­induced nephrotoxicity and to identify novel potential targets. Masson staining, Sirius red staining and periodic acid­silver methenamine staining were used to observe kidney pathological changes. Immunohistochemical and immunofluorescent analyses were performed to examine the expression levels of vimentin, E­cadherin and α­smooth muscle actin (α­SMA). Transcriptomics and bioinformatics analyses were performed to investigate the nephrotoxicity mechanism induced by tacrolimus using RNA­sequencing, differentially expressed genes identification and annotation, and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis. The present results demonstrated that compared with the normal control group, the tacrolimus nephrotoxicity group exhibited severe renal fibrosis (P<0.05), upregulated vimentin (P<0.01), downregulated E­cadherin (P<0.05) and upregulated α­SMA (P<0.01). Transcriptomics and bioinformatics analyses identified the pathway 'cytokine­cytokine receptor interaction' as the most significantly enriched (P<0.05). Moreover, KEGG pathway enrichment analysis identified that tacrolimus increased the expression levels of chemokine (C­X­C) motif ligand (CXCL)1, CXCL2 and CXCL3 and the chemokine receptor C­X­C chemokine receptor type 2 (CXCR2). Collectively, the present study suggested that tacrolimus increases the level of chemokine receptor CXCR2 to promote renal fibrosis progression, which is one of the potential mechanisms underlying tacrolimus­induced nephrotoxicity.


Assuntos
Fibrose/tratamento farmacológico , Rim/efeitos dos fármacos , Receptores de Interleucina-8B/genética , Tacrolimo/farmacologia , Transcriptoma/genética , Actinas/genética , Animais , Caderinas/genética , Quimiocina CXCL1/genética , Quimiocinas CXC/genética , Modelos Animais de Doenças , Progressão da Doença , Fibrose/induzido quimicamente , Fibrose/genética , Fibrose/patologia , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Rim/patologia , Mapas de Interação de Proteínas/genética , Ratos , Análise de Sequência de RNA , Transdução de Sinais/genética , Tacrolimo/efeitos adversos , Vimentina/genética
9.
Pregnancy Hypertens ; 17: 36-42, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31487653

RESUMO

BACKGROUND: The disorder of pre-eclampsia is described as a complicated gestational state in which some of bio-molecules, including cytokines and chemokines are involved. The main purpose of the current study was examining of the circulating levels of CXCL9, CXCL10 as inducible, angiostasis chemokines as well as CXCL12 as an angiogenesis, homeostatic chemokine, in pregnant women with and without pre-eclampsia and their neonates. METHODS: Peripheral blood and cord samples were collected from 53 preeclampsia patients and 53 normal pregnant women without preeclampsia and their related neonates. The differences in serum levels of CXCL9, CXCL10 and CXCL12 and the placental tissue expression of these chemokines were investigated by ELISA and western blot analysis, respectively. RESULTS: Findings of the present study demonstrated that the levels of CXCL9 chemokine in parallel with CXCL12 as homeostatic chemokine were induced in pre-eclamptic women compared with normal pregnant women while CXCL10 remained unchanged. The CXCL9 and CXCL10 were both decreased in neonates who were delivered by pre-eclamptic women in compare to normal pregnant women. A CXCL12 level was elevated in neonates and has followed a similar fashion as mothers. CONCLUSION: According to the results, the CXC chemokines are involved in pathogenesis of pre-eclampsia and play important roles in several processes such as neovascularization, embryonic development and inflammatory responses that are mediated by pre-eclampsia.


Assuntos
Biomarcadores/metabolismo , Quimiocinas CXC/metabolismo , Pré-Eclâmpsia/metabolismo , Diagnóstico Pré-Natal , Adulto , Biomarcadores/sangue , Estudos de Casos e Controles , Quimiocina CXCL10/sangue , Quimiocina CXCL10/metabolismo , Quimiocina CXCL12/sangue , Quimiocina CXCL12/metabolismo , Quimiocina CXCL9/sangue , Quimiocina CXCL9/metabolismo , Quimiocinas CXC/sangue , Cordocentese , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Recém-Nascido , Pré-Eclâmpsia/sangue , Valor Preditivo dos Testes , Gravidez , Sensibilidade e Especificidade
10.
Oncol Rep ; 42(5): 1996-2008, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31545503

RESUMO

The diagnostic and prognostic mechanisms of C­X­C motif chemokine ligand 3 (CXCL3) in colon cancer (CC) have not yet been reported. Therefore, the objective of the present study was to use cohorts of patients from Guangxi Medical University and the Gene Expression Omnibus (GEO) database to investigate and validate CXCL3 for the diagnosis and prognosis of CC, and to explore its prospective molecular mechanism. Reverse transcription­quantitative PCR (RT­qPCR) analysis of 38 paired tumor and non­tumor tissues, and immunohistochemistry (IHC) of 212 tumor and 46 non­tumor tissues was conducted to explore the expression of CXCL3 and its diagnostic and prognostic significance in the Guangxi Medical University CC cohort. A GEO dataset, GSE40967, was used to validate the prognostic significance of CXCL3. Gene set enrichment analysis (GSEA) was also conducted to explore the potential molecular mechanisms underlying the effects of CXCL3 in CC. The RT­qPCR results indicated that CXCL3 expression was significantly higher in cancer tissues compared with adjacent normal tissues, suggesting that it may have high diagnostic value for CC. Multivariate Cox analysis based on the IHC results suggested that there was no appreciable association between CXCL3 positivity and the overall survival (OS) time of CC. However, a stratified analysis revealed that high expression of CXCL3 was associated with considerably increased mortality in the subgroup of CC patients with tumor size <5 cm (adjusted P=0.042, adjusted HR=2.298, 95% CI=1.030­5.126) and with tumor thrombus (adjusted P=0.019, adjusted HR=5.096, 95% CI=1.306­19.886). In the GSE40967 dataset, high expression of CXCL3 was closely associated with poor OS in CC (adjusted P=0.049, adjusted HR=1.416, 95% CI=1.002­2.003). Furthermore, GSEA indicated that the high expression of CXCL3 was closely associated with DNA repair, cell cycle process, cell apoptosis process and the P53 regulation pathway. In summary, these result suggest that CXCL3 might serve as a novel biomarker in the diagnosis and prognosis of CC.


Assuntos
Quimiocinas CXC/genética , Quimiocinas CXC/metabolismo , Neoplasias do Colo/diagnóstico , Regulação para Cima , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias do Colo/genética , Neoplasias do Colo/mortalidade , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Análise de Sobrevida , Carga Tumoral
11.
PLoS One ; 14(9): e0222053, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31513621

RESUMO

Congenital cytomegalovirus (CMV) infection is a major cause of birth defects ranging from developmental disorders to stillbirth. Most newborns affected by CMV do not present with symptoms at birth but are at risk of sequelae at later stages of their childhood. Stored dried blood spots (DBS) taken at birth can be used for retrospective diagnosis of hereditary diseases, but detection of pathogens is challenged by potentially low pathogen concentrations in the small blood volume available in a DBS. Here we test four different extraction methods for optimal recovery of CMV DNA from DBS at low to high CMV titers. The recovery efficiencies varied widely between the different extractions (from 3% to 100%) with the most efficient method extracting up to 113-fold more CMV DNA than the least efficient and 8-fold more than the reference protocol. Furthermore, we amplified four immunomodulatory CMV genes from the extracted DNA: the UL40 and UL111A genes which occur as functional knockouts in some circulating CMV strains, and the highly variable UL146 and US28 genes. The PCRs specifically amplified the CMV genes at all tested titers with sufficient quality for sequencing and genotyping. In summary, we here report an extraction method for optimal recovery of CMV DNA from DBSs that can be used for both detection of CMV and for genotyping of polymorphic CMV genes in congenital CMV infection.


Assuntos
Infecções por Citomegalovirus/congênito , Citomegalovirus/fisiologia , Técnicas de Genotipagem/métodos , Proteínas Virais/genética , Quimiocinas CXC/genética , Citomegalovirus/genética , Infecções por Citomegalovirus/diagnóstico , Teste em Amostras de Sangue Seco , Feminino , Humanos , Recém-Nascido , Masculino , Polimorfismo Genético , Receptores de Quimiocinas/genética , Estudos Retrospectivos , Carga Viral
13.
Oncogene ; 38(46): 7166-7180, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31417179

RESUMO

Evasion of the host immune responses is critical for both persistent human papillomavirus (HPV) infection and associated cancer progression. We have previously shown that expression of the homeostatic chemokine CXCL14 is significantly downregulated by the HPV oncoprotein E7 during cancer progression. Restoration of CXCL14 expression in HPV-positive head and neck cancer (HNC) cells dramatically suppresses tumor growth and increases survival through an immune-dependent mechanism in mice. Although CXCL14 recruits natural killer (NK) and T cells to the tumor microenvironment, the mechanism by which CXCL14 mediates tumor suppression through NK and/or T cells remained undefined. Here we report that CD8+ T cells are required for CXCL14-mediated tumor suppression. Using a CD8+ T-cell receptor transgenic model, we show that the CXCL14-mediated antitumor CD8+ T-cell responses require antigen specificity. Interestingly, CXCL14 expression restores major histocompatibility complex class I (MHC-I) expression on HPV-positive HNC cells downregulated by HPV, and knockdown of MHC-I expression in HNC cells results in loss of tumor suppression even with CXCL14 expression. These results suggest that CXCL14 enacts antitumor immunity through restoration of MHC-I expression on tumor cells and promoting antigen-specific CD8+ T-cell responses to suppress HPV-positive HNC.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Quimiocinas CXC/imunologia , Neoplasias de Cabeça e Pescoço/imunologia , Antígenos de Histocompatibilidade Classe I/biossíntese , Infecções por Papillomavirus/imunologia , Evasão Tumoral/imunologia , Animais , Neoplasias de Cabeça e Pescoço/virologia , Camundongos , Camundongos Transgênicos , Infecções por Papillomavirus/complicações , Regulação para Cima
15.
Int J Mol Sci ; 20(14)2019 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-31373289

RESUMO

The pathogenic mechanisms of acute lung injury due to direct and indirect pulmonary insults are incompletely understood. Using an unbiased, discovery and quantitative proteomic approach, we examined bronchoalveolar lavage fluid (BALF) proteome following lipopolysaccharide (LPS)-induced direct and indirect lung injury in mice. A total of 1017 proteins were both identified and quantitated in BALF from control, intratracheal (I.T., direct) and intraperitoneal (I.P., indirect) LPS-treated mice. The two LPS groups shared 13 up-regulated and 22 down-regulated proteins compared to the control group. Ingenuity pathway analysis revealed that acute-phase response signaling was activated by both I.T. and I.P. LPS; however, the magnitude of activation was much greater in the I.T. LPS group. Intriguingly, two canonical signaling pathways, liver X receptor/retinoid X receptor activation, and the production of nitric oxide and reactive oxygen species in macrophages, were activated by I.T. but suppressed by I.P. LPS. Cxcl15 (also known as lungkine) was also up-regulated by I.T. but down-regulated by I.P. LPS. In conclusion, our quantitative discovery-based proteomic approach identified commonalities, as well as significant differences in BALF protein expression profiles between LPS-induced direct and indirect lung injury, and importantly, LPS-induced indirect lung injury resulted in suppression of select components of lung innate immunity.


Assuntos
Lesão Pulmonar Aguda/patologia , Líquido da Lavagem Broncoalveolar/química , Lipopolissacarídeos/efeitos adversos , Pulmão/patologia , Proteoma/análise , Lesão Pulmonar Aguda/induzido quimicamente , Animais , Quimiocinas CXC/biossíntese , Escherichia coli/patogenicidade , Perfilação da Expressão Gênica , Imunidade Inata/efeitos dos fármacos , Imunidade Inata/imunologia , Receptores X do Fígado/metabolismo , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico/metabolismo
16.
Med Sci Monit ; 25: 5299-5305, 2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31311916

RESUMO

BACKGROUND Acute respiratory distress syndrome (ARDS) is a common acute and severe disease in clinic. Recent studies indicated that Cxc chemokine ligand 5 (CXCL5), an inflammatory chemokine, was associated with tumorigenesis. The present study investigated the role of the CXCL5/Cxc chemokine receptor 2 (CXCR2) bio-axis in ARDS, and explored the underlying molecular mechanism. MATERIAL AND METHODS The pathological morphology of lung tissue and degree of pulmonary edema were assessed by hematoxylin-eosin staining and pulmonary edema score, respectively. Real-time PCR and Western blot analysis were performed to detect the expression levels of CXCL5, CXCR2, Matrix metalloproteinases 2 (MMP2), and Matrix metalloproteinases 9 (MMP9) in lung tissues. Enzyme-linked immunosorbent assay (ELISA) was performed to determine the expression levels of CXCL5 and inflammatory factors (IL-1ß, IL-6, TNF-alpha, and IL-10) in serum. RESULTS The results demonstrated that diffuse alveolar damage and pulmonary edema appeared in lipopolysaccharide (LPS)-induced ARDS and were positively correlated with the severity of ARDS. In addition, CXCL5 and its receptor CXCR2 were overexpressed by upregulation of MMP2 and MMP9 in lung tissues of ARDS. In addition, CXCL5 neutralizing antibody effectively alleviated inflammatory response, diffuse alveolar damage, and pulmonary edema, and decreased the expression levels of MMP2 and MMP9 compared to LPS-induced ARDS. CONCLUSIONS We found that CXCL5/CXCR2 accelerated the progression of ARDS, partly by upregulation of MMP2 and MMP9 in lung tissues with the release of inflammatory factors.


Assuntos
Quimiocina CXCL5/metabolismo , Receptores de Interleucina-8B/metabolismo , Síndrome do Desconforto Respiratório do Adulto/metabolismo , Animais , Quimiocinas CXC/metabolismo , Modelos Animais de Doenças , Pulmão/metabolismo , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Síndrome do Desconforto Respiratório do Adulto/induzido quimicamente , Fator de Necrose Tumoral alfa/metabolismo
17.
BMC Cancer ; 19(1): 741, 2019 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-31357969

RESUMO

BACKGROUND: The overall prognosis of non-small cell lung cancer (NSCLC) is poor, and currently only patients with localized disease are potentially curable. Therefore, preferably non-invasively determined biomarkers that detect NSCLC patients at early stages of the disease are of high clinical relevance. The aim of this study was to identify and validate novel protein markers in plasma using the highly sensitive DNA-assisted multiplex proximity extension assay (PEA) to discriminate NSCLC from other lung diseases. METHODS: Plasma samples were collected from a total of 343 patients who underwent surgical resection for different lung diseases, including 144 patients with lung adenocarcinoma (LAC), 68 patients with non-malignant lung disease, 83 patients with lung metastasis of colorectal cancers and 48 patients with typical carcinoid. One microliter of plasma was analyzed using PEA, allowing detection and quantification of 92 established cancer related proteins. The concentrations of the plasma proteins were compared between disease groups. RESULTS: The comparison between LAC and benign samples revealed significantly different plasma levels for four proteins; CXCL17, CEACAM5, VEGFR2 and ERBB3 (adjusted p-value < 0.05). A multi-parameter classifier was developed to discriminate between samples from LAC patients and from patients with non-malignant lung conditions. With a bootstrap aggregated decision tree algorithm (TreeBagger), a sensitivity of 93% and specificity of 64% was achieved to detect LAC in this risk population. CONCLUSIONS: By applying the highly sensitive PEA, reliable protein profiles could be determined in microliter amounts of plasma. We further identified proteins that demonstrated different plasma concentration in defined disease groups and developed a signature that holds potential to be included in a screening assay for early lung cancer detection.


Assuntos
Adenocarcinoma de Pulmão/sangue , Proteínas Sanguíneas/análise , Carcinoma Pulmonar de Células não Pequenas/sangue , Detecção Precoce de Câncer/métodos , Neoplasias Pulmonares/sangue , Programas de Rastreamento/métodos , Idoso , Antígeno Carcinoembrionário/sangue , Quimiocinas CXC/sangue , Estudos de Coortes , Confiabilidade dos Dados , Feminino , Proteínas Ligadas por GPI/sangue , Humanos , Imunoensaio/métodos , Masculino , Modelos Biológicos , Curva ROC , Receptor ErbB-3/sangue , Sensibilidade e Especificidade , Estatísticas não Paramétricas , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/sangue
18.
Glycobiology ; 29(10): 715-725, 2019 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-31264681

RESUMO

CXCL14, chemokine (C-X-C motif) ligand 14, is a novel highly conserved chemokine with unique features. Despite exhibiting the typical chemokine fold, it has a very short N-terminus of just two amino acid residues responsible for chemokine receptor activation. CXCL14 actively participates in homeostatic immune surveillance of skin and mucosae, is linked to metabolic disorders and fibrotic lung diseases and possesses strong anti-angiogenic properties in early tumor development. In this work, we investigated the interaction of CXCL14 with various glycosaminoglycans (GAGs) by nuclear magnetic resonance spectroscopy, microscale thermophoresis, analytical heparin (HE) affinity chromatography and in silico approaches to understand the molecular basis of GAG-binding. We observed different GAG-binding modes specific for the GAG type used in the study. In particular, the CXCL14 epitope for HE suggests a binding pose distinguishable from the ones of the other GAGs investigated (hyaluronic acid, chondroitin sulfate-A/C, -D, dermatan sulfate). This observation is also supported by computational methods that included molecular docking, molecular dynamics and free energy calculations. Based on our results, we suggest that distinct GAG sulfation patterns confer specificity beyond simple electrostatic interactions usually considered to represent the driving forces in protein-GAG interactions. The CXCL14-GAG system represents a promising approach to investigate the specificity of GAG-protein interactions, which represents an important topic for developing the rational approaches to novel strategies in regenerative medicine.


Assuntos
Quimiocinas CXC/metabolismo , Epitopos/genética , Glicosaminoglicanos/metabolismo , Heparina/metabolismo , Sítios de Ligação/genética , Quimiocinas CXC/química , Quimiocinas CXC/genética , Sulfatos de Condroitina/química , Sulfatos de Condroitina/genética , Dermatan Sulfato/química , Dermatan Sulfato/genética , Epitopos/química , Glicosaminoglicanos/química , Glicosaminoglicanos/genética , Heparina/genética , Humanos , Ácido Hialurônico/química , Ácido Hialurônico/genética , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ligação Proteica/genética , Dobramento de Proteína
19.
Life Sci ; 231: 116688, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31348950

RESUMO

The extended infection with Helicobacter pylori (H. pylori), one of the most frequent infectious agents in humans, may cause gastritis, peptic ulcers, gastric mucosa-associated lymphoid tissue (MALT) lymphoma, and gastric cancer. During H. pylori infection, different kinds of inflammatory cells such as dendritic cells, macrophages, neutrophils, mast cells, eosinophils, T cells and B cells are accumulated into the stomach. The interactions between chemokines and their respective receptors recruit particular types of the leukocytes that ultimately determine the nature of immune response and therefore, have a main influence on the consequence of infection. The suitable production of chemokines especially in the early stages of H. pylori infection shapes appropriate immune responses that contribute to the H. pylori elimination. The unbalanced expression of the chemokines can contribute in the induction of inappropriate responses that result in the tissue damage or malignancy. Thus, chemokines and their receptors may be promising potential targets for designing the therapeutic strategies against various types H. pylori-related gastrointestinal disorders. In this review, a comprehensive explanation regarding the roles played by chemokines in H. pylori-mediated peptic ulcer, gastritis and gastric malignancies was provided while presenting the potential utilization of these chemoattractants as therapeutic elements.


Assuntos
Quimiocinas/metabolismo , Quimiocinas/farmacologia , Infecções por Helicobacter/terapia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Quimiocinas CXC/imunologia , Quimiocinas CXC/metabolismo , Mucosa Gástrica/metabolismo , Gastrite , Infecções por Helicobacter/complicações , Infecções por Helicobacter/imunologia , Helicobacter pylori/imunologia , Helicobacter pylori/metabolismo , Helicobacter pylori/patogenicidade , Humanos , Receptores CXCR/imunologia , Receptores CXCR/metabolismo , Receptores de Quimiocinas/imunologia , Receptores de Quimiocinas/metabolismo , Estômago/patologia , Neoplasias Gástricas/patologia , Linfócitos T/imunologia , Linfócitos T/metabolismo
20.
Int Immunopharmacol ; 74: 105664, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31233937

RESUMO

Lysophosphatidic acid (LPA) is a multifunctional phospholipid. Osteocytes are the most abundant cells in bone and can orchestrate bone formation and resorption, in part by producing cytokines that regulate osteoblast and osteoclast differentiation and activity. Interleukin (IL)-6 and IL-8 are two important cytokines that have potent effects on bone fracture healing. Previous studies suggest that platelet-derived LPA may influence fracture healing by inducing osteocyte dendrite outgrowth. However, the biological mechanism through which LPA induces cytokine production in osteocytes is poorly understood. In this study, we report that LPA markedly enhanced IL-6 and CXCL15 (mouse homologue of human IL-8) production in MLO-Y4 cells and that this enhancement was suppressed by the LPA1/3-selective antagonist Ki16425, the Gi/o protein inhibitor PTX or the protein kinase C (PKC) inhibitor sotrastaurin. We also observed that of all the PKC isoform targets of sotrastaurin, only PKCθ was activated by LPA in MLO-Y4 cells and that this activation was blocked by sotrastaurin, Ki16425 or PTX. Taken together, the results of the present study demonstrate that LPA may be a potent inducer of IL-6 and CXCL15 production in MLO-Y4 cells and that this induction is associated with the activation of LPA1, Gi/o protein and the PKCθ pathway. These findings may help us better understand the mechanism of fracture healing and contribute to the treatment of bone damage.


Assuntos
Quimiocinas CXC/metabolismo , Interleucina-6/metabolismo , Lisofosfolipídeos/farmacologia , Animais , Linhagem Celular , Quimiocinas CXC/genética , Interleucina-6/genética , Camundongos , Proteína Quinase C-theta/metabolismo , Receptores de Ácidos Lisofosfatídicos/metabolismo , Transdução de Sinais/efeitos dos fármacos
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