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1.
Med Sci Monit ; 25: 2228-2237, 2019 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-30913205

RESUMO

BACKGROUND The inhibitory effect of arsenic trioxide (As2O3) on lung cancer has been reported in some preclinical studies. However, its effect on small cell lung cancer (SCLC) has been poorly explored. Calcineurin and its substrate, nuclear factor of activated T cells (NFAT), mediate the downstream signaling of VEGF, and is critical in the process endothelium activation and tumor metastasis. In this study, we aimed to evaluate whether As2O3 had inhibitory effects on endothelial cells activation and the metastasis of SCLC, and to explore the possible mechanisms. MATERIAL AND METHODS In vitro, human umbilical vein endothelial cells (HUVECs) were used. Cell Counting Kit-8 assay and cell migration assay were performed to determine the effect of As2O3 on HUVECs proliferation and migration. The level of calcineurin, NFAT, downstream factors for Down syndrome candidate region 1 (DSCR1), and the endogenous inhibitor of calcineurin, were evaluated by quantitative PCR and western blotting. In vivo, SCLC metastasis models were established by injecting NCI-H446 cells into tail veins of nude mice. Tumor-bearing mice were treated with As2O3 or calcineurin inhibitor for 10 days, after which tumor metastasis in target organs was evaluated. RESULTS As2O3 significantly inhibited the proliferation and migration of endothelial cells. Also, As2O3 inhibited the expression levels of calcineurin, NFAT, and the downstream target genes CXCR7 and RND1, while it upregulated the level of DSCR1. Both As2O3 and calcineurin inhibitor exhibited notable inhibitory effect on the metastasis of SCLC, without obvious side effects. CONCLUSIONS These findings suggested that As2O3 had remarkable inhibitory effects on the endothelial cell activation and SCLC metastasis, and the mechanism might be related to the blocking of calcineurin-NFAT signaling by upregulating DSCR1.


Assuntos
Trióxido de Arsênio/farmacologia , Fatores de Transcrição NFATC/efeitos dos fármacos , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Animais , Trióxido de Arsênio/metabolismo , Calcineurina/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , China , Proteínas de Ligação a DNA , Endotélio Vascular/metabolismo , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/efeitos dos fármacos , Masculino , Camundongos , Camundongos Nus , Proteínas Musculares/efeitos dos fármacos , Fatores de Transcrição NFATC/metabolismo , Metástase Neoplásica/tratamento farmacológico , Neovascularização Patológica/metabolismo , Receptores CXCR/efeitos dos fármacos , Transdução de Sinais , Regulação para Cima/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/efeitos dos fármacos , Proteínas rho de Ligação ao GTP/efeitos dos fármacos
2.
Br J Pharmacol ; 171(7): 1706-21, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24372081

RESUMO

BACKGROUND AND PURPOSE: In contrast to T-cell priming in the periphery, therapeutic strategies targeting the initiation step of T-cell trafficking into the CNS have not been extensively investigated. In this study, we examined the effect of NSC-87877, a potent Src homology 2-containing protein tyrosine phosphatase 2 (SHP-2) inhibitor, on experimental autoimmune encephalomyelitis (EAE) and elucidated its unique mechanism of action. EXPERIMENTAL APPROACH: C57BL/6 mice were immunized with myelin oligodendrocyte glycoprotein35-55 and monitored for clinical severity of disease and histopathological features in the CNS. Levels of cytokines in serum were measured by elisa. Effects of NSC-87877 on expressions of chemokines and cytokines in the CNS were determined by quantitative PCR. KEY RESULTS: NSC-87877-treated mice developed conventional TH 1 and TH 17 responses, but were highly resistant to the induction of EAE. NSC-87877 decreased the accumulation of lymphocytes in the CNS and increased the functional expression of chemokine receptor CXCR7 on CD8(+) T-cells. Adoptive transfer of T-cells from 2D2-transgenic mice restored EAE susceptibility in NSC-87877-treated mice, indicating that NSC-87877 only targets the initial migration of pioneer T-cells. Furthermore, T-cell-conditioned SHP-2-deficient mice treated with NSC-87877 were no longer resistant to EAE, suggesting that inhibition of SHP-2 contributes to the amelioration of EAE by NSC-87877. CONCLUSIONS AND IMPLICATIONS: NSC-87877 almost completely abolished the development of EAE by blocking the initial infiltration of pioneer CD8(+) T-cells into the uninflamed CNS. These results reveal a critical role for SHP-2 in regulating EAE pathogenesis and indicate that NSC-87877 is a potential candidate for the treatment of relapsing-remitting multiple sclerosis.


Assuntos
Anti-Inflamatórios/farmacologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Quimiotaxia de Leucócito/efeitos dos fármacos , Encefalomielite Autoimune Experimental/prevenção & controle , Inibidores Enzimáticos/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 11/antagonistas & inibidores , Quinolinas/farmacologia , Medula Espinal/efeitos dos fármacos , Transferência Adotiva , Animais , Biomarcadores/sangue , Linfócitos T CD8-Positivos/enzimologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/transplante , Células Cultivadas , Citocinas/sangue , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/enzimologia , Encefalomielite Autoimune Experimental/imunologia , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Glicoproteína Mielina-Oligodendrócito , Fragmentos de Peptídeos , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Receptores CXCR/efeitos dos fármacos , Receptores CXCR/metabolismo , Medula Espinal/enzimologia , Medula Espinal/imunologia , Fatores de Tempo
3.
Arthritis Rheum ; 65(7): 1736-46, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23633118

RESUMO

OBJECTIVE: To examine the possibility that CXCL16 recruits endothelial cells (ECs) to developing neovasculature in rheumatoid arthritis (RA) synovium. METHODS: We utilized the RA synovial tissue SCID mouse chimera system to examine human microvascular EC (HMVEC) and human endothelial progenitor cell (EPC) recruitment into engrafted human synovium that was injected intragraft with CXCL16-immunodepleted RA synovial fluid (SF). CXCR6-deficient and wild-type (WT) C57BL/6 mice were primed to develop K/BxN serum-induced arthritis and evaluated for angiogenesis. HMVECs and EPCs from human cord blood were also examined for CXCR6 expression, by immunofluorescence and assessment of CXCL16 signaling activity. RESULTS: CXCR6 was prominently expressed on human EPCs and HMVECs, and its expression on HMVECs could be up-regulated by interleukin-1ß. SCID mice injected with CXCL16-depleted RA SF exhibited a significant reduction in EPC recruitment. In experiments using the K/BxN serum-induced inflammatory arthritis model, CXCR6(-/-) mice showed profound reductions in hemoglobin levels, which correlated with reductions in monocyte and T cell recruitment to arthritic joint tissue compared to that observed in WT mice. Additionally, HMVECs and EPCs responded to CXCL16 stimulation, but exhibited unique signal transduction pathways and homing properties. CONCLUSION: These results indicate that CXCL16 and its receptor CXCR6 may be a central ligand/receptor pair that is closely associated with EPC recruitment and blood vessel formation in the RA joint.


Assuntos
Artrite Experimental/metabolismo , Artrite Reumatoide/metabolismo , Quimiocina CXCL6/fisiologia , Quimiocinas CXC/fisiologia , Células Endoteliais/fisiologia , Neovascularização Patológica/metabolismo , Receptores CXCR/fisiologia , Receptores de Quimiocinas/fisiologia , Receptores Depuradores/fisiologia , Receptores Virais/fisiologia , Animais , Artrite Experimental/fisiopatologia , Artrite Reumatoide/fisiopatologia , Quimiocina CXCL16 , Quimiotaxia/fisiologia , Células Endoteliais/metabolismo , Humanos , Interleucina-1beta/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos SCID , Camundongos Transgênicos , Neovascularização Patológica/fisiopatologia , Receptores CXCR/efeitos dos fármacos , Receptores CXCR/genética , Receptores CXCR6 , Receptores de Quimiocinas/metabolismo , Receptores Virais/metabolismo , Transdução de Sinais/fisiologia , Células-Tronco/fisiologia , Membrana Sinovial/metabolismo
4.
Neuropathol Appl Neurobiol ; 39(6): 667-80, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23289420

RESUMO

AIMS: Microglial cells have been originally identified as a target for the CXC chemokine, SDF-1, by their expression of CXCR4. More recently, it has been recognized that SDF-1 additionally binds to CXCR7, which depending on the cell type acts as either a nonclassical, a classical or a scavenger chemokine receptor. Here, we asked whether primary microglial cells additionally express CXCR7 and if so how this chemokine receptor functions in this cell type. METHODS: CXCR4 and CXCR7 expression was analysed in cultured rat microglia and in the brain of animals with permanent occlusion of the middle cerebral artery (MCAO) by either Western blotting, RT-PCR, flow cytometry and/or immunocytochemistry. The function of CXCR4 and CXCR7 was assessed in the presence of selective antagonists. RESULTS: Cultured primary rat microglia expressed CXCR4 and CXCR7 to similar levels. Treatment with SDF-1 resulted in the activation of Erk1/2 and Akt signalling. Erk1/2 and Akt signalling were required for subsequent SDF-1-dependent promotion of microglial proliferation. In contrast, Erk1/2 signalling was sufficient for SDF-1-induced migration of microglial cells. Both SDF-1-dependent signalling and the resulting effects on microglial proliferation and migration were abrogated following pharmacological inactivation of either CXCR4 or CXCR7. Moreover, treatment of cultured microglia with lipopolysaccharide resulted in the co-ordinated up-regulation of CXCR4 and CXCR7 expression. Likewise, reactive microglia accumulating in the area adjacent to the lesion core in MCAO rats expressed both CXCR4 and CXCR7. CONCLUSIONS: CXCR4 and CXCR7 form a functional receptor unit in microglial cells, which is up-regulated during activation of microglia both in vitro and in vivo.


Assuntos
Encéfalo/imunologia , Quimiocina CXCL12/metabolismo , Microglia/imunologia , Receptores CXCR4/metabolismo , Receptores CXCR/metabolismo , Animais , Encéfalo/metabolismo , Células Cultivadas , Quimiocina CXCL12/farmacologia , Infarto da Artéria Cerebral Média/imunologia , Microglia/citologia , Microglia/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores CXCR/efeitos dos fármacos , Receptores CXCR4/efeitos dos fármacos , Transdução de Sinais
5.
Pediatr Res ; 71(6): 682-8, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22337226

RESUMO

INTRODUCTION: Chemokines may directly participate in the pathogenesis of neonatal chronic hypoxia-induced pulmonary hypertension (PH). Although stromal-derived factor-1 (SDF-1) has been shown to be involved in PH, the role of its most recently discovered receptor, chemokine receptor type 7 (CXCR7), remains unclear. We sought to determine whether antagonism of the CXCR7 receptor would decrease pulmonary vascular remodeling in newborn mice exposed to chronic hypoxia by decreasing pulmonary vascular cell proliferation. METHODS: Neonatal mice were exposed to hypoxia (fractional inspired oxygen concentration = 0.12) or room air (RA) for 2 wk. After 1 wk of exposure, mice received daily injections of placebo or a CXCR7 antagonist (CCX771) from postnatal day 7 (P7) to P14. Right ventricular systolic pressure (RVSP), the ratio of the weight of the right ventricle to left ventricle + septum (RV/LV + S), and pulmonary vascular cell proliferation and remodeling were determined at P14. RESULTS: As compared with mice exposed to RA, hypoxia placebo mice had a significant increase in the lung protein expression of CXCR7. Although hypoxic placebo-treated mice had a significant increase in RVSP, RV/LV+S, and pulmonary vascular cell proliferation and remodeling, the administration of CCX771 markedly decreased these changes. DISCUSSION: These results indicate that antagonism of CXCR7 may be a potent strategy to decrease PH and vascular remodeling.


Assuntos
Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/prevenção & controle , Hipóxia/complicações , Receptores CXCR/antagonistas & inibidores , Animais , Animais Recém-Nascidos , Artérias/efeitos dos fármacos , Artérias/patologia , Adesão Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Hipertensão Pulmonar/patologia , Pulmão/irrigação sanguínea , Pulmão/metabolismo , Camundongos , Camundongos Endogâmicos , Modelos Animais , Gravidez , Receptores CXCR/efeitos dos fármacos , Receptores CXCR/metabolismo
6.
J Soc Biol ; 203(2): 197-207, 2009.
Artigo em Francês | MEDLINE | ID: mdl-19527634

RESUMO

Injection of endothelial progenitor cells (EPC) expanded ex vivo has been shown to increase neovascularization in preclinical models of ischemia and in adult patients, but the precise origin and identity of the cell population responsible for these clinical benefits are controversial. Given the potential usefulness of EPC as a cell therapy product, their thorough characterization is of major importance. This review describes the two cell populations currently called EPC and the means to find differential phenotypic markers. We have shown that BMP2/4 are specific markers of late EPC and play a key role in EPC commitment and outgrowth during neovascularization. Several authors have attempted to expand EPC ex vivo in order to obtain a homogeneous cell therapy product. One possible mean of expanding EPC ex vivo is to activate the thrombin receptor PAR-1 with the specific peptide SFLLRN. Indeed, PAR-1 activation increases angiogenic properties of EPC through activation of SDF-1, angiopoietin and IL-8 pathways. This review summarizes the characterization of EPC and different methods of ex vivo expansion.


Assuntos
Células Endoteliais/citologia , Células-Tronco Multipotentes/citologia , Técnicas de Cultura de Tecidos , Adulto , Angiopoietina-2/fisiologia , Animais , Biomarcadores , Proteína Morfogenética Óssea 2/análise , Proteína Morfogenética Óssea 4/análise , Diferenciação Celular , Linhagem da Célula , Células Cultivadas/citologia , Células Cultivadas/efeitos dos fármacos , Quimiocina CXCL12/farmacologia , Quimiocina CXCL12/fisiologia , Humanos , Interleucina-8/fisiologia , Isquemia/cirurgia , Camundongos , Células-Tronco Multipotentes/química , Células-Tronco Multipotentes/metabolismo , Células-Tronco Multipotentes/transplante , Neovascularização Fisiológica , Fragmentos de Peptídeos/farmacologia , Receptor PAR-1/efeitos dos fármacos , Receptores CXCR/efeitos dos fármacos , Receptores CXCR/fisiologia , Trombina/fisiologia
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