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1.
Proc Natl Acad Sci U S A ; 118(3)2021 01 19.
Artículo en Inglés | MEDLINE | ID: mdl-33446504

RESUMEN

Triggering receptor expressed on myeloid cells 2 (TREM2) sustains microglia response to brain injury stimuli including apoptotic cells, myelin damage, and amyloid ß (Aß). Alzheimer's disease (AD) risk is associated with the TREM2R47H variant, which impairs ligand binding and consequently microglia responses to Aß pathology. Here, we show that TREM2 engagement by the mAb hT2AB as surrogate ligand activates microglia in 5XFAD transgenic mice that accumulate Aß and express either the common TREM2 variant (TREM2CV) or TREM2R47H scRNA-seq of microglia from TREM2CV-5XFAD mice treated once with control hIgG1 exposed four distinct trajectories of microglia activation leading to disease-associated (DAM), interferon-responsive (IFN-R), cycling (Cyc-M), and MHC-II expressing (MHC-II) microglia types. All of these were underrepresented in TREM2R47H-5XFAD mice, suggesting that TREM2 ligand engagement is required for microglia activation trajectories. Moreover, Cyc-M and IFN-R microglia were more abundant in female than male TREM2CV-5XFAD mice, likely due to greater Aß load in female 5XFAD mice. A single systemic injection of hT2AB replenished Cyc-M, IFN-R, and MHC-II pools in TREM2R47H-5XFAD mice. In TREM2CV-5XFAD mice, however, hT2AB brought the representation of male Cyc-M and IFN-R microglia closer to that of females, in which these trajectories had already reached maximum capacity. Moreover, hT2AB induced shifts in gene expression patterns in all microglial pools without affecting representation. Repeated treatment with a murinized hT2AB version over 10 d increased chemokines brain content in TREM2R47H-5XFAD mice, consistent with microglia expansion. Thus, the impact of hT2AB on microglia is shaped by the extent of TREM2 endogenous ligand engagement and basal microglia activation.


Asunto(s)
Enfermedad de Alzheimer/genética , Encéfalo/metabolismo , Glicoproteínas de Membrana/genética , Microglía/metabolismo , Receptores Inmunológicos/genética , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/genética , Péptidos beta-Amiloides/metabolismo , Animales , Anticuerpos Monoclonales/farmacología , Anticuerpos Neutralizantes/farmacología , Encéfalo/efectos de los fármacos , Encéfalo/patología , Proliferación Celular , Quimiocinas/genética , Quimiocinas/metabolismo , Modelos Animales de Enfermedad , Femenino , Regulación de la Expresión Génica , Células HEK293 , Humanos , Cinética , Masculino , Glicoproteínas de Membrana/antagonistas & inhibidores , Glicoproteínas de Membrana/metabolismo , Ratones , Ratones Transgénicos , Microglía/clasificación , Microglía/efectos de los fármacos , Microglía/patología , Mutación , Unión Proteica , Receptores Inmunológicos/antagonistas & inhibidores , Receptores Inmunológicos/metabolismo , Factores Sexuales
2.
Mol Cancer ; 11: 70, 2012 Sep 19.
Artículo en Inglés | MEDLINE | ID: mdl-22992329

RESUMEN

BACKGROUND: Non-small-cell lung cancer (NSCLC) is categorized into various histologic subtypes that play an important role in prognosis and treatment outcome. We investigated the antitumor activity of motesanib, a selective antagonist of vascular endothelial growth factor receptors (VEGFR) 1, 2, and 3, platelet-derived growth factor receptor, and Kit, alone and combined with chemotherapy in five human NSCLC xenograft models (A549, Calu-6, NCI-H358, NCI-H1299, and NCI-H1650) containing diverse genetic mutations. RESULTS: Motesanib as a single agent dose-dependently inhibited tumor xenograft growth compared with vehicle in all five of the models (P < 0.05). When combined with cisplatin, motesanib significantly inhibited the growth of Calu-6, NCI-H358, and NCI-H1650 tumor xenografts compared with either single agent alone (P < 0.05). Similarly, the combination of motesanib plus docetaxel significantly inhibited the growth of A549 and Calu-6 tumor xenografts compared with either single agent alone (P < 0.05). In NCI-H358 and NCI-H1650 xenografts, motesanib with and without cisplatin significantly decreased tumor blood vessel area (P < 0.05 vs vehicle) as assessed by anti-CD31 staining. Motesanib alone or in combination with chemotherapy had no effect on tumor cell proliferation in vitro. CONCLUSIONS: These data demonstrate that motesanib had antitumor activity against five different human NSCLC xenograft models containing diverse genetic mutations, and that it had enhanced activity when combined with cisplatin or docetaxel. These effects appeared to be mediated primarily by antiangiogenic mechanisms.


Asunto(s)
Antineoplásicos/farmacología , Carcinoma de Pulmón de Células no Pequeñas , Indoles/farmacología , Neoplasias Pulmonares , Niacinamida/análogos & derivados , Taxoides/farmacología , Animales , Antineoplásicos/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cisplatino/administración & dosificación , Cisplatino/farmacología , Docetaxel , Femenino , Expresión Génica , Humanos , Indoles/administración & dosificación , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Ratones , Ratones Desnudos , Mutación , Niacinamida/administración & dosificación , Niacinamida/farmacología , Oligonucleótidos , Taxoides/administración & dosificación , Carga Tumoral/efectos de los fármacos , Receptor 2 de Factores de Crecimiento Endotelial Vascular/genética , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
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