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1.
Curr Pharm Biotechnol ; 22(2): 305-316, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-32116188

RESUMEN

BACKGROUND: Clinical studies indicate that recombinant tumor necrosis factor receptor:Fc fusion protein (rhTNFR:Fc) quickly alleviates symptoms and physical signs of active Ankylosing Spondylitis (AS), improving the manifestation of spinal inflammation on radiological imaging. However, the regulatory mechanism of rhTNFR:Fc in the chemokine pathway is unclear. Thus we study the mechanism of phlogogenic activity of CXCL16/CXCR6 in AS and the related mechanism of rhTNFR: Fc treatment. METHODS: Thirty-two cases of active AS were treated with rhTNFR:Fc for 3 consecutive months. Clinical response was evaluated at baseline and after treatment. CXCL16/CXCR6 expression as well as Receptor Activator Of Nuclear Factor-Κb Ligand (RANKL)/Osteoprotegerin (OPG), essential molecules for osteoclast differentiation, were studied in AS before and after treatment. Further, the proliferation of lymphocytes and the RANKL level stimulated by recombinant human CXCL16 (rhCXCL16) were measured in vitro. RESULTS: Thirty cases responded to rhTNFR:Fc treatment. The RANKL level, RANKL/OPG ratio, CXCLl6 level in serum, and CXCLl6 and CXCR6 mRNA levels in active AS were higher than those in controls and treated patients (P<0.001). rhCXCL16 treatment increased lymphocyte proliferation and RANKL level in active AS (P<0.001), but not in controls or treated patients (P>0.05). A positive linear correlation was noted between CXCL16 serum levels and RANKL/OPG ratio and between CXCL16 levels and C-reactive protein results (P<0.001). CONCLUSIONS: Our findings suggest that rhTNFR:Fc suppresses inflammation and bone destruction of AS by reducing the RANKL/OPG ratio through inhibition of the CXCL16/CXCR6 pathway.


Asunto(s)
Quimiocina CXCL16/antagonistas & inhibidores , Etanercept/administración & dosificación , Osteoprotegerina/antagonistas & inhibidores , Ligando RANK/antagonistas & inhibidores , Receptores CXCR6/antagonistas & inhibidores , Espondilitis Anquilosante/tratamiento farmacológico , Adolescente , Adulto , Quimiocina CXCL16/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/fisiología , Femenino , Humanos , Inyecciones Subcutáneas , Masculino , Persona de Mediana Edad , Osteoprotegerina/metabolismo , Ligando RANK/metabolismo , Receptores CXCR6/metabolismo , Espondilitis Anquilosante/metabolismo , Adulto Joven
2.
Mol Med Rep ; 23(1)2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33215222

RESUMEN

Long non­coding RNAs (lncRNAs) serve a crucial role in gastric cancer (GC) progression. However, the molecular mechanism underlying lncRNA JPX transcript, XIST activator (JPX) in the tumorigenesis of GC is not completely understood. Reverse transcription­quantitative PCR (RT­qPCR) and western blotting were performed to detect gene expression. A luciferase reporter gene assay was conducted to determine the relationship between microRNA (miR)­197 and JPX or C­X­C motif chemokine receptor 6 (CXCR6). Cell viability, migration and invasion were determined by performing MTT, wound healing and Transwell assays, respectively. The Cancer Genome Atlas database and the RT­qPCR results indicated that JPX expression was upregulated and miR­197 expression was downregulated in patients with GC and in GC cells. Moreover, high JPX expression and low miR­197 expression in patients with GC indicated poor prognosis. miR­197 expression was directly inhibited by JPX. Compared with the short hairpin RNA (sh) negative control (NC) group, NCI­N87 and MKN­45 cells in the shJPX group displayed decreased cell viability and invasion, as well as a wider scratch width. NCI­N87 and MKN­45 cells in the shJPX + miR­197 inhibitor group had increased viability and invasion, but a narrower scratch width compared with the shJPX group. It was also identified that miR­197 directly inhibited CXCR6 expression. miR­197 inhibited Beclin1 protein expression and promoted p62 protein expression. Compared with the NC group, NCI­N87 and MKN­45 cells in the miR­197 mimic group had decreased cell viability and invasion, and a wider scratch width. Enhanced cell viability and invasion, and a narrower scratch width was also observed in the miR­197 mimic + CXCR6 and miR­197 mimic + Beclin1 groups, compared with the miR­197 mimic group. Collectively, the results indicated that lncRNA JPX promoted GC progression by regulating CXCR6 and autophagy via inhibiting miR­197. Furthermore, JPX knockdown regulated GC cell phenotype by promoting miR­197.


Asunto(s)
Autofagia/genética , MicroARNs/antagonistas & inhibidores , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Receptores CXCR6/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Adulto , Anciano , Beclina-1/metabolismo , Línea Celular Tumoral , Movimiento Celular/genética , Progresión de la Enfermedad , Regulación hacia Abajo , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Masculino , MicroARNs/genética , MicroARNs/metabolismo , Persona de Mediana Edad , Pronóstico , Receptores CXCR6/antagonistas & inhibidores , Regulación hacia Arriba
3.
Bioorg Med Chem Lett ; 30(4): 126899, 2020 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-31882297

RESUMEN

The chemokine system plays an important role in mediating a proinflammatory microenvironment for tumor growth in hepatocellular carcinoma (HCC). The CXCR6 receptor and its natural ligand CXCL16 are expressed at high levels in HCC cell lines and tumor tissues and receptor expression correlates with increased neutrophils in these tissues contributing to poor prognosis in patients. Availability of pharmacologcal tools targeting the CXCR6/CXCL16 axis are needed to elucidate the mechanism whereby neutrophils are affected in the tumor environment. We report the discovery of a series of small molecules with an exo-[3.3.1]azabicyclononane core. Our lead compound 81 is a potent (EC50 = 40 nM) and selective orally bioavailable small molecule antagonist of human CXCR6 receptor signaling that significantly decreases tumor growth in a 30-day mouse xenograft model of HCC.


Asunto(s)
Receptores CXCR6/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas/química , Animales , Compuestos de Azabiciclo/química , Compuestos de Azabiciclo/metabolismo , Compuestos de Azabiciclo/farmacología , Compuestos de Azabiciclo/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Evaluación Preclínica de Medicamentos , Femenino , Humanos , Concentración 50 Inhibidora , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Ratones , Ratones Endogámicos NOD , Ratones SCID , Receptores CXCR6/metabolismo , Transducción de Señal/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas/metabolismo , Bibliotecas de Moléculas Pequeñas/farmacología , Bibliotecas de Moléculas Pequeñas/uso terapéutico , Relación Estructura-Actividad , Trasplante Heterólogo
4.
Cancer Lett ; 454: 1-13, 2019 07 10.
Artículo en Inglés | MEDLINE | ID: mdl-30974114

RESUMEN

Molecular reprogramming in response to chemotherapeutics leads to poor therapeutic outcomes for prostate cancer (PCa). In this study, we demonstrated that CXCR6-CXCL16 axis promotes DTX resistance and acts as a counter-defense mechanism. After CXCR6 activation, cell death in response to DTX was inhibited, and blocking of CXCR6 potentiated DTX cytotoxicity. Moreover, in response to DTX, PCa cells expressed higher CXCR6, CXCL16, and ADAM-10. Furthermore, ADAM-10-mediated release of CXCL16 hyper-activated CXCR6 signaling in response to DTX. Activation of CXCR6 resulted in increased GSK-3ß, NF-κB, ERK1/2 phosphorylation, and survivin expression, which reduce DTX response. Finally, treatment of PCa cells with anti-CXCR6 monoclonal antibody synergistically or additively induced cell death with ∼1.5-4.5 fold reduction in the effective concentration of DTX. In sum, our data imply that co-targeting of CXCR6 would lead to therapeutic enhancement of DTX, leading to better clinical outcomes for PCa patients.


Asunto(s)
Quimiocina CXCL16/metabolismo , Docetaxel/farmacología , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/metabolismo , Receptores CXCR6/metabolismo , Proteína ADAM10/metabolismo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/farmacología , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Resistencia a Antineoplásicos , Sinergismo Farmacológico , Humanos , Masculino , Proteínas de la Membrana/metabolismo , FN-kappa B/metabolismo , Células PC-3 , Neoplasias de la Próstata/patología , Receptores CXCR6/antagonistas & inhibidores , Receptores CXCR6/inmunología , Transducción de Señal
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