RESUMEN
OBJECTIVE: To explore the clinical, imaging, and genetic characteristics of an adult patient with sporadic Neuronal intranuclear inclusion disease (NIID). METHODS: A patient who had visited the First People's Hospital of Chenzhou on August 6, 2023 was selected as the study subject. Results of clinical examination, neuroimaging, and genetic testing were retrospectively analyzed along with a literature review. The number of GGC trinucleotide repeats in the 5'-untranslated region of the NOTCH2NLC gene was determined by GC-PCR. RESULTS: The patient had presented with episodic encephalopathy, with enhanced magnetic resonance imaging showing enhancement features of the posterior cerebral cortex during the period of acute episode. Genetic testing revealed an increased number of GGC repeats (n = 97) in the 5'- untranslated region of the NOTCH2NLC gene, which confirmed the diagnosis of NIID. CONCLUSION: Clinical attention should be paid to the enhanced MRI findings of patients with adult-onset NIID, for whom posterior cortical enhancement may be characteristic manifestation during the acute phase of encephalopathy-like episode.
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Cuerpos de Inclusión Intranucleares , Enfermedades Neurodegenerativas , Humanos , Cuerpos de Inclusión Intranucleares/genética , Enfermedades Neurodegenerativas/genética , Imagen por Resonancia Magnética , Masculino , Pruebas Genéticas , Femenino , Persona de Mediana Edad , Receptor Notch2/genética , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/patología , Encéfalo/diagnóstico por imagen , Encéfalo/patología , AdultoRESUMEN
Memory B cells (MBCs) are essential for humoral immunological memory and can emerge during both the pre-germinal center (GC) and GC phases. However, the transcription regulators governing MBC development remain poorly understood. Here, we report that the transcription regulator Notch2 is highly expressed in MBCs and their precursors at the pre-GC stage and required for MBC development without influencing the fate of GC and plasma cells. Mechanistically, Notch2 signaling promotes the expression of complement receptor CD21 and augments B cell receptor (BCR) signaling. Reciprocally, BCR activation up-regulates Notch2 surface expression in activated B cells via a translation-dependent mechanism. Intriguingly, Notch2 is dispensable for GC-derived MBC formation. In summary, our findings establish Notch2 as a pivotal transcription regulator orchestrating MBC development through the reciprocal enforcement of BCR signaling during the pre-GC phase and suggest that the generation of GC-independent and -dependent MBCs is governed by distinct transcriptional mechanisms.
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Activación de Linfocitos , Células B de Memoria , Receptor Notch2 , Receptores de Antígenos de Linfocitos B , Transducción de Señal , Animales , Receptor Notch2/metabolismo , Receptor Notch2/genética , Receptores de Antígenos de Linfocitos B/metabolismo , Ratones , Células B de Memoria/metabolismo , Células B de Memoria/inmunología , Activación de Linfocitos/inmunología , Ratones Endogámicos C57BL , Centro Germinal/inmunología , Centro Germinal/metabolismo , Linfocitos B/metabolismo , Linfocitos B/inmunología , Memoria Inmunológica , Receptores de Complemento 3d/metabolismoRESUMEN
Immune escape is the main reason that immunotherapy is ineffective in hepatocellular carcinoma (HCC). Here, this study illustrates a pathway mediated by neutrophil extracellular traps (NETs) that can promote immune escape of HCC. Mechanistically, we demonstrated that NETs up-regulated CD73 expression through activating Notch2 mediated nuclear factor kappa B (NF-κB) pathway, promoting regulatory T cells (Tregs) infiltration to mediate immune escape of HCC. In addition, we found the similar results in mouse HCC models by hydrodynamic plasmid transfection. The treatment of deoxyribonuclease I (DNase I) could inhibit the action of NETs and improve the therapeutic effect of anti-programmed cell death protein 1 (PD-1). In summary, our results revealed that targeting of NETs was a promising treatment to improve the therapeutic effect of anti-PD-1.
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5'-Nucleotidasa , Carcinoma Hepatocelular , Trampas Extracelulares , Neoplasias Hepáticas , Receptor Notch2 , Escape del Tumor , Regulación hacia Arriba , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/patología , Animales , Humanos , Trampas Extracelulares/inmunología , Trampas Extracelulares/metabolismo , Ratones , 5'-Nucleotidasa/genética , 5'-Nucleotidasa/metabolismo , 5'-Nucleotidasa/inmunología , Receptor Notch2/metabolismo , Receptor Notch2/genética , Proteínas Ligadas a GPI/metabolismo , Proteínas Ligadas a GPI/genética , Proteínas Ligadas a GPI/inmunología , Línea Celular Tumoral , FN-kappa B/metabolismo , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Neutrófilos/inmunología , Neutrófilos/metabolismo , Transducción de Señal , Masculino , Receptor de Muerte Celular Programada 1/metabolismoRESUMEN
Current data on the molecular mechanisms of liver fibrosis and cirrhosis fail to fully explain all stages of their development. Interactions between individual genes and signaling pathways are known to play an important role in their functions. However, data on their relationships are insufficient and often contradictory. For the first time, mRNA expression of Notch1, Notch2, Yap1, Tweak (Tnfsf12), Fn14 (Tnfrsf12a), Ang, Vegfa, Cxcl12 (Sdf), Nos2, and Mmp-9 was studied in detail at several stages of thioacetamide-induced liver fibrosis in Wistar rats. A factor analysis isolated three factors, which combined highly correlated target genes. The first factor included four genes: Cxcl12 (r = 0.829, p < 0.05), Tweak (r = 0.841, p < 0.05), Notch1 (r = 0.848, p < 0.05), and Yap1 (r = 0.921, p < 0.05). The second factor described the correlation between Mmp-9 (r = 0.791, p < 0.05) and Notch2 (r = 0.836, p < 0.05). The third factor included Ang (r = 0.748, p < 0.05) and Vegfa (r = 0.679, p < 0.05). The Nos2 and Fn14 genes were not included in any of the factors. The gene grouping by mRNA expression levels made it possible to assume a pathogenetic relationship between their products in the development of fibrotic changes due to liver toxicity.
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Quimiocina CXCL12 , Citocina TWEAK , ARN Mensajero , Ratas Wistar , Receptor Notch1 , Proteínas Señalizadoras YAP , Animales , Ratas , Proteínas Señalizadoras YAP/genética , Proteínas Señalizadoras YAP/metabolismo , Masculino , Receptor Notch1/genética , Receptor Notch1/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Quimiocina CXCL12/genética , Quimiocina CXCL12/metabolismo , Citocina TWEAK/genética , Citocina TWEAK/metabolismo , Metaloproteinasa 9 de la Matriz/genética , Metaloproteinasa 9 de la Matriz/metabolismo , Regulación de la Expresión Génica , Cirrosis Hepática/genética , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , Cirrosis Hepática/inducido químicamente , Tioacetamida/toxicidad , Receptor Notch2/genética , Receptor Notch2/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/metabolismoRESUMEN
Eosinophils not only function as inflammatory effectors in allergic diseases, but also contribute to tissue homeostasis in steady state. Emerging data are revealing tissue eosinophils to be adaptive cells, imprinted by their local tissue microenvironment and exhibiting distinct functional phenotypes that may contribute to their homeostatic vs. inflammatory capacities. However, signaling pathways that regulate eosinophil tissue adaptations remain elusive. Notch signaling is an evolutionarily conserved pathway that mediates differential cell fate programming of both pre- and postmitotic immune cells. This study investigated a role for notch receptor 2 signaling in regulating eosinophil functions and tissue phenotype in both humans and mice. Notch 2 receptors were constitutively expressed and active in human blood eosinophils. Pharmacologic neutralization of notch 2 in ex vivo stimulated human eosinophils altered their activated transcriptome and prevented their cytokine-mediated survival. Genetic ablation of eosinophil-expressed notch 2 in mice diminished steady-state intestine-specific eosinophil adaptations and impaired their tissue retention in a food allergic response. In contrast, notch 2 had no effect on eosinophil phenotype or tissue inflammation within the context of allergic airways inflammation, suggesting that notch 2-dependent regulation of eosinophil phenotype and function is specific to the gut. These data reveal notch 2 signaling as a cell-intrinsic mechanism that contributes to eosinophil survival, function, and intestine-specific adaptations. The notch 2 pathway may represent a viable strategy to reprogram eosinophil functional phenotypes in gastrointestinal eosinophil-associated diseases.
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Alérgenos , Eosinófilos , Receptor Notch2 , Transducción de Señal , Animales , Eosinófilos/inmunología , Eosinófilos/metabolismo , Receptor Notch2/metabolismo , Humanos , Alérgenos/inmunología , Ratones , Intestinos/inmunología , Intestinos/patología , Ratones Endogámicos C57BL , Adaptación Fisiológica/inmunología , Ratones Noqueados , Hipersensibilidad a los Alimentos/inmunología , Hipersensibilidad a los Alimentos/patologíaRESUMEN
Development of the mammalian oocyte requires physical contact with the surrounding granulosa cells of the follicle, which provide it with essential nutrients and regulatory signals. This contact is achieved through specialized filopodia, termed transzonal projections (TZPs), that extend from the granulosa cells to the oocyte surface. Transforming growth factor (TGFß) family ligands produced by the oocyte increase the number of TZPs, but how they do so is unknown. Using an inducible Cre recombinase strategy together with expression of green fluorescent protein to verify Cre activity in individual cells, we examined the effect of depleting the canonical TGFß mediator, SMAD4, in mouse granulosa cells. We observed a 20-50% decrease in the total number of TZPs in SMAD4-depleted granulosa cell-oocyte complexes, and a 50% decrease in the number of newly generated TZPs when the granulosa cells were reaggregated with wild-type oocytes. Three-dimensional image analysis revealed that TZPs of SMAD4-depleted cells were longer than controls and more frequently oriented towards the oocyte. Strikingly, the transmembrane proteins, N-cadherin and Notch2, were reduced by 50% in SMAD4-depleted cells. SMAD4 may thus modulate a network of cell adhesion proteins that stabilize the attachment of TZPs to the oocyte, thereby amplifying signalling between the two cell types.
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Células de la Granulosa , Oocitos , Proteína Smad4 , Animales , Proteína Smad4/metabolismo , Proteína Smad4/genética , Oocitos/metabolismo , Oocitos/crecimiento & desarrollo , Ratones , Femenino , Células de la Granulosa/metabolismo , Células de la Granulosa/fisiología , Receptor Notch2/metabolismo , Receptor Notch2/genética , Cadherinas/metabolismo , Cadherinas/genética , Seudópodos/metabolismo , Seudópodos/fisiologíaRESUMEN
Neuronal intranuclear inclusion disease, caused by a GGC repeat expansion in the 5'-untranslated region of NOTCH2NLC, is a rare neurodegenerative condition with highly variable clinical manifestations. In recent years, the number of reported cases have increased dramatically in East Asia. We report the first four genetically confirmed cases of neuronal intranuclear inclusion disease in New Zealand, all having Polynesian ancestry (three New Zealand Maori and one Cook Island Maori). Phenotypically, they resemble cases reported from recent large East Asian cohorts.
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Cuerpos de Inclusión Intranucleares , Enfermedades Neurodegenerativas , Humanos , Nueva Zelanda , Cuerpos de Inclusión Intranucleares/patología , Cuerpos de Inclusión Intranucleares/genética , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/patología , Masculino , Femenino , Persona de Mediana Edad , Anciano , Receptor Notch2/genéticaRESUMEN
During periodontitis, the extracellular capsule of Porphyromonas gingivalis favors alveolar bone loss by inducing Th1 and Th17 patterns of lymphocyte response in the infected periodontium. Dendritic cells recognize bacterial antigens and present them to T lymphocytes, defining their activation and polarization. Thus, dendritic cells could be involved in the Th1 and Th17 response induced against the P. gingivalis capsule. Herein, monocyte-derived dendritic cells were obtained from healthy individuals and then stimulated with different encapsulated strains of P. gingivalis or two non-encapsulated isogenic mutants. Dendritic cell differentiation and maturation were analyzed by flow cytometry. The mRNA expression levels for distinct Th1-, Th17-, or T-regulatory-related cytokines and transcription factors, as well as TLR2 and TLR4, were assessed by qPCR. In addition, the production of IL-1ß, IL-6, IL-23, and TNF-α was analyzed by ELISA. The encapsulated strains and non-encapsulated mutants of P. gingivalis induced dendritic cell maturation to a similar extent; however, the pattern of dendritic cell response was different. In particular, the encapsulated strains of P. gingivalis induced higher expression of IRF4 and NOTCH2 and production of IL-1ß, IL-6, IL-23, and TNF-α compared with the non-encapsulated mutants, and thus, they showed an increased capacity to trigger Th1 and Th17-type responses in human dendritic cells.
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Citocinas , Células Dendríticas , Porphyromonas gingivalis , Células Th17 , Receptor Toll-Like 2 , Receptor Toll-Like 4 , Porphyromonas gingivalis/inmunología , Humanos , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Células Dendríticas/microbiología , Células Th17/inmunología , Células Th17/metabolismo , Receptor Toll-Like 2/metabolismo , Receptor Toll-Like 2/genética , Receptor Toll-Like 4/metabolismo , Receptor Toll-Like 4/genética , Citocinas/metabolismo , Diferenciación Celular , Células TH1/inmunología , Factores Reguladores del Interferón/metabolismo , Factores Reguladores del Interferón/genética , Receptor Notch2/genética , Receptor Notch2/metabolismo , Células Cultivadas , Cápsulas Bacterianas/inmunología , Cápsulas Bacterianas/metabolismo , Infecciones por Bacteroidaceae/inmunología , Infecciones por Bacteroidaceae/microbiología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Hajdu-Cheney syndrome (HCS) is an extremely rare autosomal dominant skeletal disorder. The prevalence rate of less than 1 case per 1,000,000 newborns and only 50 cases were reported in the medical literature. HCS is characterized by progressive bone resorption in the distal phalanges (acro-osteolysis), progressive osteoporosis, distinct craniofacial changes, dental anomalies, and occasional association with renal abnormalities. HCS is caused by pathogenic variants in the NOTCH2 gene, 34th exon. We report first familial case of HCS caused by likely pathogenic variant of NOTCH2 gene c.6449delC, p.(Pro2150LeufsTer5).
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Síndrome de Hajdu-Cheney , Receptor Notch2 , Humanos , Síndrome de Hajdu-Cheney/genética , Síndrome de Hajdu-Cheney/patología , Receptor Notch2/genética , Masculino , Femenino , Lituania , LinajeRESUMEN
BACKGROUND AND AIM: NOTCH2 is overexpressed in gastric cancer (GC), and its enhanced activity is significantly correlated with worse tumor characteristics. We aim to analyze the clinicopathologic correlation between NOTCH2 and the molecular typing of GC by immunohistochemistry and by transcriptional sequencing. METHODS: In this immunohistochemical study, we detected NOTCH2, EBER, P53, HER2, MLH1, MSH2, PMS2, and MSH6 and evaluated the association of NOTCH2 with clinical and histopathological features in a large single-institutional series of gastric adenocarcinomas (n = 488). The correlation was also investigated between immunohistochemical results and survival outcomes. RESULTS: High NOTCH2 expression (2+/3+) was found in 139/488 (27.5%) samples analyzed. NOTCH2 expression was correlated with early stage T1 (P < 0.0001), GC in the fundus (P = 0.0364), and positive P53 status (P = 0.0019). We did not find an association between NOTCH2 and HER2, microsatellite instability, EBER, and overall survival. Through RNA sequencing, it was revealed that NOTCH2 plays an important biological function in the pathogenesis and development of GC. CONCLUSIONS: Our findings suggested that NOTCH2 may be a potential diagnostic target for GC due to the fact that its high expression is closely associated with the early stages of cancer.
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Adenocarcinoma , Biomarcadores de Tumor , Receptor Notch2 , Neoplasias Gástricas , Neoplasias Gástricas/patología , Neoplasias Gástricas/genética , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/metabolismo , Humanos , Receptor Notch2/genética , Receptor Notch2/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/patología , Adenocarcinoma/metabolismo , Adenocarcinoma/diagnóstico , Adenocarcinoma/mortalidad , Femenino , Masculino , Persona de Mediana Edad , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/genética , Inmunohistoquímica , Anciano , Estadificación de Neoplasias , Detección Precoz del Cáncer , Expresión Génica/genética , Adulto , Inestabilidad de Microsatélites , Anciano de 80 o más AñosRESUMEN
BACKGROUND/AIM: The prognosis of ovarian cancer (OC) patients is especially poor for patients with chemotherapy resistance. Anlotinib, a novel multi-targeted tyrosine kinase inhibitor, has shown encouraging clinical efficacy in several tumor types. The aim of the present study was to examine the inhibitory efficacy and mechanism of anlotinib on the proliferation and chemosensitivity of OC cells. MATERIALS AND METHODS: The inhibitory effects of Anlotinib on SKOV3 and OVCAR3 OC cells were examined using CCK-8 cell-viability, colony-formation, flow-cytometry, transwell-migration and sphere-formation assays. A xenograft mouse model was used for in vivo studies. RT-qPCR and western blotting were used to detect gene expression. RESULTS: Molecular targets of anlotinib were elevated in OC patient tumors. Anlotinib significantly inhibited ovarian cancer cell proliferation and migration in vitro. Anlotinib enhanced the sensitivity of ovarian cancer cells to cisplatinum both in vitro and in vivo. Anlotinib suppressed sphere formation and the stemness phenotype of OC cells by inhibiting NOTCH2 expression. CONCLUSION: Anlotinib inhibits ovarian cancer and enhances cisplatinum sensitivity, suggesting its future clinical promise.
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Indoles , Neoplasias Ováricas , Quinolinas , Animales , Femenino , Humanos , Ratones , Apoptosis , Línea Celular Tumoral , Proliferación Celular , Cisplatino/farmacología , Cisplatino/uso terapéutico , Indoles/farmacología , Indoles/uso terapéutico , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Quinolinas/farmacología , Quinolinas/uso terapéutico , Receptor Notch2/genética , Transducción de SeñalRESUMEN
The tumour microenvironment (TME) drives bladder cancer (BLCA) progression. Targeting the TME has emerged as a promising strategy for BLCA treatment in recent years. Furthermore, checkpoint blockade therapies are only beneficial for a minority of patients with BLCA, and drug resistance is a barrier to achieving significant clinical effects of anti-programmed cell death protein-1 (PD-1)/programmed death protein ligand-1 (PD-L1) therapy. In this study, higher low-density lipoprotein receptor-related protein 1 (LRP1) levels were related to a poorer prognosis for patients with various cancers, including those with higher grades and later stages of BLCA. Enrichment analysis demonstrated that LRP1 plays a role in the epithelial-mesenchymal transition (EMT), NOTCH signalling pathway, and ubiquitination. LRP1 knockdown in BLCA cells delayed BLCA progression both in vivo and in vitro. Furthermore, LRP1 knockdown suppressed EMT, reduced DLL4-NOTCH2 signalling activity, and downregulated M2-like macrophage polarisation. Patients with BLCA and higher LRP1 levels responded weakly to anti-PD-1 therapy in the IMvigor210 cohort. Moreover, LRP1 knockdown enhanced the therapeutic effects of anti-PD-1 in mice. Taken together, our findings suggest that LRP1 is a potential target for improving the efficacy of anti-PD-1/PD-L1 therapy by preventing EMT and M2-like macrophage polarisation by blocking the DLL4-NOTCH2 axis.
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Resistencia a Antineoplásicos , Transición Epitelial-Mesenquimal , Proteína 1 Relacionada con Receptor de Lipoproteína de Baja Densidad , Receptor Notch2 , Transducción de Señal , Microambiente Tumoral , Neoplasias de la Vejiga Urinaria , Humanos , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/metabolismo , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/inmunología , Proteína 1 Relacionada con Receptor de Lipoproteína de Baja Densidad/metabolismo , Proteína 1 Relacionada con Receptor de Lipoproteína de Baja Densidad/genética , Animales , Ratones , Transición Epitelial-Mesenquimal/efectos de los fármacos , Línea Celular Tumoral , Receptor Notch2/metabolismo , Receptor Notch2/genética , Macrófagos/metabolismo , Macrófagos/inmunología , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Receptor de Muerte Celular Programada 1/metabolismo , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/genética , Proteínas de Unión al Calcio/metabolismo , Proteínas de Unión al Calcio/genética , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Femenino , Masculino , Ensayos Antitumor por Modelo de Xenoinjerto , Quimiocina CCL2RESUMEN
The importance of macrophages in adipose tissue (AT) homeostasis and inflammation is well established. However, the potential cues that regulate their function remain incompletely understood. To bridge this important gap, we sought to characterize novel pathways involved using a mouse model of diet-induced obesity. By performing transcriptomics analysis of AT macrophages (ATMs), we found that late-stage ATMs from high-fat diet mice presented with perturbed Notch signaling accompanied by robust proinflammatory and metabolic changes. To explore the hypothesis that the deregulated Notch pathway contributes to the development of AT inflammation and diet-induced obesity, we employed a genetic approach to abrogate myeloid Notch1 and Notch2 receptors. Our results revealed that the combined loss of Notch1 and Notch2 worsened obesity-related metabolic dysregulation. Body and AT weight gain was higher, blood glucose levels increased and metabolic parameters were substantially worsened in deficient mice fed high-fat diet. Moreover, serum insulin and leptin were elevated as were triglycerides. Molecular analysis of ATMs showed that deletion of Notch receptors escalated inflammation through the induction of an M1-like pro-inflammatory phenotype. Our findings thus support a protective role of myeloid Notch signaling in adipose tissue inflammation and metabolic dysregulation.
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Tejido Adiposo , Dieta Alta en Grasa , Inflamación , Macrófagos , Obesidad , Receptor Notch1 , Receptor Notch2 , Transducción de Señal , Animales , Macrófagos/inmunología , Macrófagos/metabolismo , Tejido Adiposo/metabolismo , Tejido Adiposo/inmunología , Ratones , Dieta Alta en Grasa/efectos adversos , Inflamación/inmunología , Inflamación/metabolismo , Transducción de Señal/inmunología , Obesidad/metabolismo , Obesidad/inmunología , Receptor Notch1/metabolismo , Receptor Notch1/genética , Receptor Notch2/metabolismo , Receptor Notch2/genética , Ratones Noqueados , Ratones Endogámicos C57BL , MasculinoRESUMEN
The Notch signaling pathway plays pivotal roles in cell proliferation, stemness and invasion of non-small cell lung cancer (NSCLC). The human Notch family consists of four receptors, namely Notch1, Notch2, Notch3, and Notch4. These receptors are transmembrane proteins that play crucial roles in various cellular processes. Notch1 mostly acts as a pro-carcinogenic factor in NSCLC but sometimes acts as a suppressor. Notch2 has been demonstrated to inhibit the growth and progression of NSCLC, whereas Notch3 facilitates these biological behaviors of NSCLC. The role of Notch4 in NSCLC has not been fully elucidated, but it is evident that Notch4 promotes tumor progression. At present, drugs targeting the Notch pathway are being explored for NSCLC therapy, a majority of which are already in the stage of preclinical research and clinical trials, with bright prospects in the clinical treatment of NSCLC.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , 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 , Receptor Notch1/metabolismo , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Receptores Notch/metabolismo , Receptor Notch2/metabolismo , Receptor Notch3 , Transducción de SeñalRESUMEN
NOTCH2 is expressed in pituitary stem cells and is necessary for stem cell maintenance, proliferation, and differentiation. However, the pathways NOTCH2 engages to affect pituitary development remain unclear. In this study, we hypothesized that glycoprotein hormone subunit A2 (GPHA2), a corneal stem cell factor and ligand for the thyroid stimulating hormone receptor (TSHR), is downstream of NOTCH2 signaling. We found Gpha2 is expressed in quiescent pituitary stem cells by RNAscope in situ hybridization and scRNA seq. In Notch2 conditional knockout pituitaries, Gpha2 mRNA is reduced compared with control littermates. We then investigated the possible functions of GPHA2. Pituitaries treated with a GPHA2 peptide do not have a change in proliferation. However, in dissociated adult pituitary cells, GPHA2 increased pCREB expression and this induction was reversed by co-treatment with a TSHR inhibitor. These data suggest GPHA2 is a NOTCH2 related stem cell factor that activates TSHR signaling, potentially impacting pituitary development.
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Hipófisis , Factor de Células Madre , Adulto , Humanos , Hipófisis/metabolismo , Receptor Notch2/genética , Receptor Notch2/metabolismo , Receptores de Tirotropina , Factor de Células Madre/metabolismo , Células Madre/metabolismoRESUMEN
Atherosclerosis (AS) is a major chronic non-communicable disease and a primary cause of cardiovascular disease. Recent studies have shown that circRNAs are potential epigenetic factors that regulate vascular endothelial inflammatory responses and AS progression. Therefore, identification of the circRNAs that regulate ox-LDL levels is a critical step to understanding the pathology of AS. Our study is aim to investigate how circLZIC regulates atherosclerosis (AS) via the Micro-330-5p/NOTCH2 regulatory axis. The results showed that CircLZIC and NOTCH2 are highly expressed in human AS clinical samples, while Micro-330-5p is expressed locally. The CCK-8 experiment results showed that circLZIC promotes the proliferation of HUVECS cells. Flow cytometry analysis showed that circLZIC act as an inhibitor of HUVEC cell apoptosis. The expression level of Micro-330-5p can be up-regulated by transfection of small interfering RNA against circLZIC. Further, Starbase predicted that Micro-330-5p could target and regulate NOTCH2. Next, we confirmed that overexpression of Micro-330-5p could significantly reduce the expression of fluorescein using the double Luciferase reporter assay. RIP-qRT-PCR experiment showed that Micro-330-5p and NOTCH2 mRNAs are effectively enriched by ago2 protein. Further, we found that knocking down circLZIC increases the expression of Micro-330-5p and promotes cell apoptosis, while inhibiting the expression of NOTCH2 and cell activity. On the other hand, co-transfection of Micro-330-5p inhibitor decreases Micro-330-5p expression and inhibit cell apoptosis, while increasing NOTCH2 expression and cell activity. In conclusion, CircLZIC regulates HUVEC cell activity by the Micro-330-5p/NOTCH2 signaling pathway, suggesting that circLZIC plays a key role in atherosclerosis development.
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Apoptosis , Aterosclerosis , Proliferación Celular , Células Endoteliales de la Vena Umbilical Humana , Lipoproteínas LDL , ARN Circular , Receptor Notch2 , Humanos , Apoptosis/efectos de los fármacos , Aterosclerosis/metabolismo , Aterosclerosis/patología , Proliferación Celular/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Lipoproteínas LDL/farmacología , MicroARNs/metabolismo , MicroARNs/genética , Receptor Notch2/metabolismo , Receptor Notch2/genética , ARN Circular/genética , Transducción de Señal/efectos de los fármacosRESUMEN
BACKGROUND/AIM: Chronic pelvic pain (CPP) is a common gynecological condition in women with multifactorial etiology. Some studies have revealed that patients with CPP have the same structural and functional changes in the pain matrix in the brain to patients with other types of chronic pain. However, the relationship between localized pelvic pain and changes in the structure and function of the central nervous system is still unclear. MATERIALS AND METHODS: In this study, a rat model of CPP was established by pelvic nerve ligation and behavioral tests were used to validate the model. Afterwards, we compared the expression of CCL2 in CPP and control rats and observed the changes in their behavioral patterns by blocking the expression of CCL2 in the former group. In addition, we upregulated the expression of CCL2 in human microglia cells (HMC3) to further observe the effect of CCL2 on the Notch2 pathway. RESULTS: Our results showed that the expression of chemokine ligand 2 (CCL2) in the serum exosomes, pelvic vascular endothelial cells, and cerebrospinal fluid was higher in the CPP group than the control group (p<0.05). In HMC3 treated with recombinant CCL2 protein, a significant increase in the mRNA and protein expression of Notch2 was observed. CONCLUSION: CCL2 can activate the Notch2 signaling pathway and plays an important role in the central sensitization of chronic pelvic pain.
Asunto(s)
Sensibilización del Sistema Nervioso Central , Dolor Crónico , Animales , Femenino , Humanos , Ratas , Sensibilización del Sistema Nervioso Central/fisiología , Quimiocina CCL2/genética , Quimiocinas , Dolor Crónico/genética , Células Endoteliales/metabolismo , Ligandos , Dolor Pélvico/etiología , Dolor Pélvico/terapia , Receptor Notch2RESUMEN
Notch signaling plays a key regulatory role in bone remodeling and NOTCH2 enhances osteoclastogenesis, an effect that is mostly mediated by its target gene Hes1. In the present study, we explored mechanisms responsible for the enhanced osteoclastogenesis in bone marrow-derived macrophages (BMM) from Notch2tm1.1Ecan, harboring a NOTCH2 gain-of-function mutation, and control mice. Notch2tm1.1Ecan mice are osteopenic and have enhanced osteoclastogenesis. Bulk RNA-Seq and gene set enrichment analysis of Notch2tm1.1Ecan BMMs cultured in the presence of macrophage colony stimulating factor (M-CSF) and receptor activator of NF-κB ligand revealed enrichment of genes associated with enhanced cell metabolism, aerobic respiration, and mitochondrial function, all associated with osteoclastogenesis. These pathways were not enhanced in the context of a Hes1 inactivation. Analysis of single cell RNA-Seq data of pooled control and Notch2tm1.1Ecan BMMs treated with M-CSF or M-CSF and receptor activator of NF-κB ligand for 3 days identified 11 well-defined cellular clusters. Pseudotime trajectory analysis indicated a trajectory of clusters expressing genes associated with osteoclast progenitors, osteoclast precursors, and mature cells. There were an increased number of cells expressing gene markers associated with the osteoclast and with an unknown, albeit related, cluster in Notch2tm1.1Ecan than in control BMMs as well as enhanced expression of genes associated with osteoclast progenitors and precursors in Notch2tm1.1Ecan cells. In conclusion, BMM cultures display cellular heterogeneity, and NOTCH2 enhances osteoclastogenesis, increases mitochondrial and metabolic activity of osteoclasts, and affects cell cluster allocation in BMMs.
Asunto(s)
Osteoclastos , Osteogénesis , Receptor Notch2 , Transcriptoma , Animales , Ratones , Células de la Médula Ósea/metabolismo , Diferenciación Celular/genética , Regulación del Desarrollo de la Expresión Génica/genética , Factor Estimulante de Colonias de Macrófagos/metabolismo , Ratones Endogámicos C57BL , Mutación , Osteoclastos/citología , Osteoclastos/metabolismo , Osteogénesis/genética , Receptor Activador del Factor Nuclear kappa-B/metabolismo , Receptor Notch2/genética , Receptor Notch2/metabolismo , Factor de Transcripción HES-1/metabolismo , Transcriptoma/genéticaRESUMEN
Glioma cell cultures are used in basic researches of tumor processes, personalized medicine for selecting treatment regimens depending on individual characteristics of patients and pharmacology for assessing the effectiveness of chemotherapy. Suppression of glioma culture growth without reduction of malignancy grade is common. Drug cancellation may be followed by substitution of precursor cells by more malignant clones. Therefore, analysis of culture cell malignancy grade is important. In the future, intraoperative analysis of glioma cell malignancy grade can be used to select individual therapy. OBJECTIVE: We analyzed the relationship between expression of marker genes TUBB3, CD133, CDK4, CDK6, CIRBP, DR4, DR5, EGFR, FGFR, FSHR, GDNF, GFAP, L1CAM, LEF1, MAP2, MDM2, MELK, NANOG, NOTCH2, OCT4, OLIG2, PDGFRA, PDGFA, PDGFB and SOX2 and glioma cell malignancy grade, as well as created appropriate prognostic model. MATERIAL AND METHODS: We analyzed expression of 25 marker genes in 22 samples of human glioma cultures using quantitative real-time PCR. Statistical analysis was performed using the IBM SPSS Statistics 26.0 software. We used the Kolmogorov-Smirnov and Shapiro-Wilk tests to assess distribution normality. Nonparametric Jonckheere-Terpstra and Spearman tests were applied. RESULTS: We obtained a prognostic model for assessing the grade III and IV glioma cell malignancy based on expression of marker genes MDM2, MELK, SOX2, CDK4, DR5 and OCT4. Predictive accuracy was 83% (Akaike information criterion -55.125).
Asunto(s)
Glioma , Humanos , Pronóstico , Glioma/genética , Receptor Notch2/genética , Receptor Notch2/metabolismo , Expresión Génica , Proteínas Proto-Oncogénicas c-mdm2/genética , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Proteínas Proto-Oncogénicas c-mdm2/uso terapéutico , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/uso terapéutico , Quinasa 4 Dependiente de la Ciclina/genética , Quinasa 4 Dependiente de la Ciclina/metabolismo , Quinasa 4 Dependiente de la Ciclina/uso terapéutico , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/uso terapéutico , Factores de Transcripción SOXB1/genética , Factores de Transcripción SOXB1/metabolismoRESUMEN
Transfer RNA-derived fragments (tRFs) are a class of small non-coding regulatory RNAs that are involved in the pathophysiology of many diseases. However, the role of tRFs in cancer progression remains largely elusive. Here, we demonstrate that a pan-cancer 3'-tRF, CAT1 (cancer associated tRF 1), is ubiquitously upregulated in tumors and associated with poor prognosis of a variety of cancers, including lung cancer. The upregulated CAT1 in cancer cells binds to RNA-binding protein with multiple splicing (RBPMS) and displaces NOTCH2 association from RBPMS, thereby inhibiting the subsequent CCR4-NOT deadenylation-complex-mediated NOTCH2 mRNA decay. The CAT1-enhanced NOTCH2 expression promotes lung cancer cell proliferation and metastasis in vitro and in vivo. In addition, plasma CAT1 levels are substantially increased in patients with lung cancer compared to non-cancer control subjects. Our findings reveal an intrinsic connection between cancer-specific upregulation of CAT1 and cancer progression, show the regulation of NOTCH signaling in cancer by a 3'-tRF, and highlight its great clinical potential.