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1.
Gene ; 744: 144616, 2020 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-32222531

RESUMO

AIM: The purpose of this study was to investigate the possible effects of Myrtus communis subsp. communis (MC) on cognitive impairment in ovariectomized diabetic rats. MATERIAL AND METHOD: Female Sprague-Dawley rats were divided into 5 groups consisting of 15 rats each; Control (C), Diabetes (D), Ovariectomy and diabetes (OVX + D), Ovariectomy, diabetes and donepezil (OVX + D + Don), Ovariectomy, diabetes and Myrtus communis subsp. communis (OVX + D + MC). Blood glucose measurements were made at the beginning and end of the experiments. The animals underwent the novel object recognition test (NORT) and their performance was evaluated. In hippocampal tissues; amyloid beta (Aß) and neprilysin levels, acetylcholinesterase (AChE), and choline acetyltransferase (ChAT) activities, polysialylated neural cell adhesion molecule (PSA-NCAM), α7 subunit of neuronal nicotinic acetylcholine receptor (α7-nAChR) and brain derived neurotrophic factor (BDNF) gene expressions were examined. RESULTS: Animals with ovariectomy and diabetes showed increased levels of blood glucose, AChE activity and Aß levels, and decreased neprilysin levels, ChAT activity, α7-nAChR, PSA-NCAM and BDNF gene expressions in parallel with a decrease in NORT performance score. On the other hand, in the MC-treated OVX + D group, there was a significant decrease observed in blood glucose levels and AChE activities while there was improvement in NORT performances and an increase in hippocampal ChAT activity, neprilysin levels, α7-nAChR, PSA-NCAM and BDNF expressions. CONCLUSION: These results suggest that MC extract could improve cognitive and neuronal functions with its anticholinesterase and antihyperglycemic properties.


Assuntos
Cognição/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Myrtus , Fitoterapia , Acetilcolinesterase/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Glicemia/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Colina O-Acetiltransferase/metabolismo , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/psicologia , Feminino , Hipocampo/metabolismo , Neprilisina/metabolismo , Molécula L1 de Adesão de Célula Nervosa/genética , Molécula L1 de Adesão de Célula Nervosa/metabolismo , Ovariectomia , Extratos Vegetais/uso terapêutico , Ratos Sprague-Dawley , Ácidos Siálicos/genética , Ácidos Siálicos/metabolismo , Receptor Nicotínico de Acetilcolina alfa7/genética , Receptor Nicotínico de Acetilcolina alfa7/metabolismo
2.
BMC Cancer ; 19(1): 911, 2019 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-31510944

RESUMO

BACKGROUND: Gliomas account for the majority of primary human brain tumors and remain a challenging neoplasm for cure due to limited therapeutic options. Cell adhesion molecules play pivotal roles in the growth and progression of glial tumors. Roles of the adhesion molecules on glia (AMOG) and L1CAM (L1) in glioma cells have been shown to correlate with tumorigenesis: Increased expression of L1 and decreased expression of AMOG correlate with degree of malignancy. METHODS: We evaluated the interdependence in expression of these molecules by investigating the role of AMOG in vitro via modulation of L1 expression and analyzing apoptosis and cell senescence of glioma cells. RESULTS: Immunohistochemical staining of normal human cortical and glioma tissue microarrays demonstrated that AMOG expression was lower in human gliomas compared to normal tissue and is inversely correlated with the degree of malignancy. Moreover, reduction of AMOG expression in human glioblastoma cells elevated L1 expression, which is accompanied by decreased cell apoptosis as well as senescence. CONCLUSION: AMOG and L1 interdependently regulate their expression levels not only in U-87 MG cells but also in U251 and SHG44 human glioma cell lines. The capacity of AMOG to reduce L1 expression suggests that methods for increasing AMOG expression may provide a therapeutic choice for the management of glial tumors with high expression of L1.


Assuntos
Adenosina Trifosfatases/genética , Neoplasias Encefálicas/genética , Proteínas de Transporte de Cátions/genética , Moléculas de Adesão Celular Neuronais/genética , Regulação Neoplásica da Expressão Gênica , Glioblastoma/genética , Molécula L1 de Adesão de Célula Nervosa/genética , Adenosina Trifosfatases/metabolismo , Apoptose/genética , Biomarcadores , Neoplasias Encefálicas/metabolismo , Proteínas de Transporte de Cátions/metabolismo , Adesão Celular/genética , Moléculas de Adesão Celular Neuronais/metabolismo , Linhagem Celular Tumoral , Senescência Celular/genética , Perfilação da Expressão Gênica , Glioblastoma/metabolismo , Humanos , Imuno-Histoquímica , Molécula L1 de Adesão de Célula Nervosa/metabolismo , RNA Interferente Pequeno/genética , Transdução de Sinais
3.
Int J Dev Neurosci ; 78: 49-64, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31421150

RESUMO

Adult human neural progenitor and stem cells have been implicated as a potential source of brain cancer causing cells, but specific events that might cause cells to progress towards a transformed phenotype remain unclear. The L1CAM (L1) cell adhesion/recognition molecule is expressed abnormally by human glioma cancer cells and is released as a large extracellular ectodomain fragment, which stimulates cell motility and proliferation. This study investigates the effects of ectopic overexpression of the L1 long ectodomain (L1LE; ˜180 kDa) on the motility, proliferation, and differentiation of human neural progenitor cells (HNPs). L1LE was ectopically expressed in HNPs using a lentiviral vector. Surprisingly, overexpression of L1LE resulted in reduced HNP motility in vitro, in stark contrast to the effects on glioma and other cancer cell types. L1LE overexpression resulted in a variable degree of maintenance of HNP proliferation in media without added growth factors but did not increase proliferation. In monolayer culture, HNPs expressed a variety of differentiation markers. L1LE overexpression resulted in loss of glutamine synthetase (GS) and ß3-tubulin expression in normal HNP media, and reduced vimentin and increased GS expression in the absence of added growth factors. When co-cultured with chick embryonic brain cell aggregates, HNPs show increased differentiation potential. Some HNPs expressed p-neurofilaments and oligodendrocytic O4, indicating differentiation beyond that in monolayer culture. Most HNP-L1LE cells lost their vimentin and GFAP (glial fibrillary acidic protein) staining, and many cells were positive for astrocytic GS. However, these cells rarely were positive for neuronal markers ß3-tubulin or p-neurofilaments, and few HNP oligodendrocyte progenitors were found. These results suggest that unlike for glioma cells, L1LE does not increase HNP cell motility, but rather decreases motility and influences the differentiation of normal brain progenitor cells. Therefore, the effect of L1LE on increasing motility and proliferation appears to be limited to already transformed cells.


Assuntos
Diferenciação Celular/fisiologia , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Molécula L1 de Adesão de Célula Nervosa/metabolismo , Células-Tronco Neurais/metabolismo , Linhagem Celular , Pré-Escolar , Expressão Ectópica do Gene , Humanos , Masculino , Molécula L1 de Adesão de Célula Nervosa/genética , Células-Tronco Neurais/citologia
4.
Int J Mol Sci ; 20(16)2019 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-31426278

RESUMO

Immunoglobulin superfamily protein L1CAM (L1, CD171) normally facilitates neuronal migration, differentiation, and axon guidance during development. Many types of cancers, including glioblastoma (GBM), also abnormally express L1, and this has been associated with poor prognosis due to increased cell proliferation, invasiveness, or metastasis. We showed previously that the soluble L1 ectodomain, which is proteolyzed from the transmembrane form, can stimulate proliferation and motility of GBM cells in vitro by acting through integrins and fibroblast growth factor receptors (FGFRs). Minute L1-decorated exosomal vesicles also are released by GBM cells and potentially could stimulate cell motility, proliferation, and invasiveness, but this needed to be demonstrated. In the present study, we aimed to determine if minute L1-decorated extracellular vesicles (exosomes) were capable of stimulating GBM cell motility, proliferation, and invasiveness. L1-decorated exosomes were isolated from the conditioned media of the human T98G GBM cell line and were evaluated for their effects on the behavior of glioma cell lines and primary tumor cells. L1-decorated exosomes significantly increased cell velocity in the three human glioma cells tested (T98G/shL1, U-118 MG, and primary GBM cells) in a highly quantitative SuperScratch assay compared to L1-reduced exosomes from L1-attenuated T98G/shL1 cells. They also caused a marked increase in cell proliferation as determined by DNA cell cycle analysis and cell counting. In addition, L1-decorated exosomes facilitated initial GBM cell invasion when mixed with non-invasive T98G/shL1 cells in our chick embryo brain tumor model, whereas mixing with L1-reduced exosomes did not. Chemical inhibitors against focal adhesion kinase (FAK) and fibroblast growth factor receptor (FGFR) decreased L1-mediated motility and proliferation to varying degrees. These novel data show that L1-decoratred exosomes stimulate motility, proliferation and invasion to influence GBM cell behavior, which adds to the complexity of how L1 stimulates cancer cells through not only soluble ectodomain but also through exosomes.


Assuntos
Neoplasias Encefálicas/patologia , Exossomos/patologia , Glioblastoma/patologia , Molécula L1 de Adesão de Célula Nervosa/metabolismo , Animais , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Embrião de Galinha , Exossomos/metabolismo , Glioblastoma/metabolismo , Humanos , Invasividade Neoplásica/patologia , Molécula L1 de Adesão de Célula Nervosa/análise
5.
Int J Mol Sci ; 20(17)2019 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-31455004

RESUMO

L1 cell adhesion molecule (L1CAM) is a glycoprotein involved in cancer development and is associated with metastases and poor prognosis. Cellular processing of L1CAM results in expression of either full-length or cleaved forms of the protein. The different forms of L1CAM may localize at the plasma membrane as a transmembrane protein, or in the intra- or extracellular environment as cleaved or exosomal forms. Here, we systematically analyze available literature that directly relates to L1CAM domains and associated signaling pathways in cancer. Specifically, we chart its domain-specific functions in relation to cancer progression, and outline pre-clinical assays used to assess L1CAM. It is found that full-length L1CAM has both intracellular and extracellular targets, including interactions with integrins, and linkage with ezrin. Cellular processing leading to proteolytic cleavage and/or exosome formation results in extracellular soluble forms of L1CAM that may act through similar mechanisms as compared to full-length L1CAM, such as integrin-dependent signals, but also through distinct mechanisms. We provide an algorithm to guide a step-wise analysis on L1CAM in clinical samples, to promote interpretation of domain-specific expression. This systematic review infers that L1CAM has an important role in cancer progression that can be attributed to domain-specific forms. Most studies focus on the full-length plasma membrane L1CAM, yet knowledge on the domain-specific forms is a prerequisite for selective targeting treatment.


Assuntos
Neoplasias/etiologia , Neoplasias/metabolismo , Molécula L1 de Adesão de Célula Nervosa/metabolismo , Domínios e Motivos de Interação entre Proteínas , Animais , Biomarcadores , Proteínas de Transporte , Adesão Celular , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Humanos , Neoplasias/patologia , Molécula L1 de Adesão de Célula Nervosa/química , Ligação Proteica , Transdução de Sinais
6.
Brain Tumor Pathol ; 36(4): 152-161, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31388782

RESUMO

Immune check-point blockade (ICB) targeting programmed cell death ligand-1 (PD-L1)/programmed death-1 (PD-1) axis has created paradigm shift in cancer treatment. 'ST-RELA' and 'PF-A' molecular subgroups of ependymomas (EPN) show poor outcomes. We aimed to understand the potential candidature of EPNs for ICB. Supratentorial (ST) Grade II/III EPNs were classified into ST-RELA, ST-YAP, and ST-not otherwise specified (NOS), based on RELA/YAP1 fusion transcripts and/or L1CAM and p65 protein expression. Posterior fossa (PF) EPNs were classified into PF-A and PF-B based on H3K27me3 expression. Immunohistochemistry for PD-L1 and CD8 was performed. RelA protein enrichment at PDL1 promoter site was analysed by chromatin immunoprecipitation-qPCR (ChIP-qPCR). Eighty-three intracranial EPNs were studied. Median tumor infiltrating CD8 + cytotoxic T-lymphocyte (CTL) density was 6/mm2, and was higher in ST-EPNs (median 10/mm2) as compared to PF-EPNs (median 3/mm2). PD-L1 expression was noted in 17/83 (20%) EPNs, including 12/31 ST-RELA and rare ST-NOS (2/12), PF-A (2/25) and PF-B (1/13) EPNs. Twelve EPNs (14%) showed high CTL density and concurrent PD-L1 positivity, of which majority (10/12) were ST-RELA EPNs. Enrichment of RelA protein was seen at PDL1 promoter. Increased CTL densities and upregulation of PD-L1 in ST-RELA ependymomas suggests potential candidature for immunotherapy.


Assuntos
Antígeno B7-H1/genética , Ependimoma/imunologia , Ependimoma/patologia , Linfócitos T Citotóxicos/patologia , Antígeno B7-H1/metabolismo , Ependimoma/genética , Feminino , Humanos , Imuno-Histoquímica , Imunoterapia/métodos , Masculino , Molécula L1 de Adesão de Célula Nervosa/metabolismo , Neoplasias Supratentoriais/patologia , Fator de Transcrição RelA/metabolismo
7.
Proc Natl Acad Sci U S A ; 116(30): 15262-15271, 2019 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-31285321

RESUMO

Giant ankyrin-B (ankB) is a neurospecific alternatively spliced variant of ANK2, a high-confidence autism spectrum disorder (ASD) gene. We report that a mouse model for human ASD mutation of giant ankB exhibits increased axonal branching in cultured neurons with ectopic CNS axon connectivity, as well as with a transient increase in excitatory synapses during postnatal development. We elucidate a mechanism normally limiting axon branching, whereby giant ankB localizes to periodic axonal plasma membrane domains through L1 cell-adhesion molecule protein, where it couples microtubules to the plasma membrane and prevents microtubule entry into nascent axon branches. Giant ankB mutation or deficiency results in a dominantly inherited impairment in selected communicative and social behaviors combined with superior executive function. Thus, gain of axon branching due to giant ankB-deficiency/mutation is a candidate cellular mechanism to explain aberrant structural connectivity and penetrant behavioral consequences in mice as well as humans bearing ASD-related ANK2 mutations.


Assuntos
Anquirinas/genética , Transtorno do Espectro Autista/genética , Molécula L1 de Adesão de Célula Nervosa/genética , Crescimento Neuronal , Neurônios/metabolismo , Sinapses/metabolismo , Processamento Alternativo , Animais , Anquirinas/metabolismo , Transtorno do Espectro Autista/metabolismo , Transtorno do Espectro Autista/fisiopatologia , Comportamento Animal , Membrana Celular/metabolismo , Membrana Celular/ultraestrutura , Conectoma , Modelos Animais de Doenças , Função Executiva/fisiologia , Expressão Gênica , Técnicas de Introdução de Genes , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Microtúbulos/metabolismo , Microtúbulos/ultraestrutura , Mutação , Molécula L1 de Adesão de Célula Nervosa/metabolismo , Neurônios/patologia , Cultura Primária de Células , Comportamento Social , Sinapses/patologia
8.
World Neurosurg ; 129: e417-e428, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31150846

RESUMO

OBJECTIVE: Supratentorial cortical ependymomas (CEs) are rare. These lesions, selectively occurring in the superficial cortex, have not been fully characterized. We analyzed the clinicopathological and genetic features of CEs. METHODS: Eight patients with CEs from our institution and 84 other reported CE cases were included in the present study. We retrospectively reviewed their clinical characteristics, imaging findings, treatment methods, pathological features, molecular status, and clinical outcomes. RESULTS: The median age at diagnosis of our 8 patients was 7.5 years. The mean tumor diameter was 70 mm. All the tumors had a cystic appearance, and calcification was observed in 6. Gross total resection was achieved in 6 patients and subtotal resection in 2 patients. Of the 8 tumors, 7 were World Health Organization grade III and 1 was World Health Organization grade II. Six tumors were immunopositive for L1 cell adhesion molecule (L1CAM). We investigated the presence of C11orf95-RELA fusion in 5 patients, all of whom exhibited it. Postoperative radiotherapy was performed for all patients with grade III tumors, except for children aged <3 years. Although 4 patients developed recurrence, all were alive throughout the follow-up period. Compared with previously reported CEs, our patients were younger and had larger tumors; however, the clinical outcomes did not differ significantly. CONCLUSIONS: Although most CEs in our group were immunopositive for L1CAM and showed C11orf95-RELA fusion, which have been associated with a poor prognosis in supratentorial ependymomas, all our patients had good outcomes. Gross total resection and adjuvant radiotherapy contributed to the relatively favorable prognosis of CEs compared with other supratentorial ependymomas.


Assuntos
Ependimoma/patologia , Neoplasias Supratentoriais/patologia , Adolescente , Criança , Pré-Escolar , Ependimoma/genética , Ependimoma/cirurgia , Humanos , Lactente , Molécula L1 de Adesão de Célula Nervosa/metabolismo , Fusão Oncogênica , Radioterapia Adjuvante , Estudos Retrospectivos , Neoplasias Supratentoriais/genética , Neoplasias Supratentoriais/cirurgia , Resultado do Tratamento , Carga Tumoral , Adulto Jovem
9.
Nutrients ; 11(5)2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-31052460

RESUMO

The polyphenol resveratrol (RVT) may drive protective mechanisms of cerebral homeostasis during the hypoperfusion/reperfusion triggered by the transient bilateral common carotid artery occlusion followed by reperfusion (BCCAO/R). This immunochemical study investigates if a single dose of RVT modulates the plasticity-related markers brain-derived neurotrophic factor (BDNF), the tyrosine kinase trkB receptor, Polysialylated-Neural Cell Adhesion Molecule (PSA-NCAM), and Activity-regulated cytoskeleton-associated (Arc) protein in the brain cortex after BCCAO/R. Frontal and temporal-occipital cortical regions were examined in male Wistar rats randomly subdivided in two groups, sham-operated and submitted to BCCAO/R. Six hours prior to surgery, half the rats were gavage fed a dose of RVT (180 mg·kg-1 in 300 µL of sunflower oil as the vehicle), while the second half was given the vehicle alone. In the frontal cortex of BCCAO/R vehicle-treated rats, BDNF and PSA-NCAM decreased, while trkB increased. RVT pre-treatment elicited an increment of all examined markers in both sham- and BCCAO/R rats. No variations occurred in the temporal-occipital cortex. The results highlight a role for RVT in modulating neuronal plasticity through the BDNF-trkB system and upregulation of PSA-NCAM and Arc, which may provide both trophic and structural local support in the dynamic changes occurring during the BCCAO/R, and further suggest that dietary supplements such as RVT are effective in preserving the tissue potential to engage plasticity-related events and control the functional response to the hypoperfusion/reperfusion challenge.


Assuntos
Doenças das Artérias Carótidas/tratamento farmacológico , Córtex Cerebral/efeitos dos fármacos , Traumatismo por Reperfusão/tratamento farmacológico , Resveratrol/farmacologia , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Doenças das Artérias Carótidas/patologia , Artéria Carótida Primitiva/patologia , Proteínas do Citoesqueleto/metabolismo , Suplementos Nutricionais , Masculino , Proteínas do Tecido Nervoso/metabolismo , Molécula L1 de Adesão de Célula Nervosa/metabolismo , Plasticidade Neuronal , Ratos , Ratos Wistar , Receptor trkB/metabolismo , Ácidos Siálicos/metabolismo
10.
Bull Exp Biol Med ; 166(6): 793-796, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31028587

RESUMO

One of the most common models of sporadic form of Alzheimer's disease is injection of streptozotocin into the lateral ventricles of rat brain. In 3 months after this injection, an increase in the expression of astroglia in the corpus callosum and a decrease in the thickness of the corpus callosum and intensity of its staining with luxol fast blue were observed. This can reflect a decrease in the content of myelinated fibers. In layer V of the sensorimotor cortex, intensive degeneration of neurons was revealed. The lateral ventricles were significantly enlarged and the expression of PSA-NCAM protein, a marker of immature neurons, was reduced in subventricular zone, which can be associated with disturbed neurogenesi.


Assuntos
Doença de Alzheimer/patologia , Astrócitos/patologia , Corpo Caloso/patologia , Ventrículos Laterais/patologia , Fibras Nervosas Mielinizadas/patologia , Córtex Sensório-Motor/patologia , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/metabolismo , Animais , Astrócitos/metabolismo , Biomarcadores/metabolismo , Corpo Caloso/metabolismo , Modelos Animais de Doenças , Expressão Gênica , Indóis , Injeções Intraventriculares , Ventrículos Laterais/metabolismo , Masculino , Fibras Nervosas Mielinizadas/metabolismo , Molécula L1 de Adesão de Célula Nervosa/genética , Molécula L1 de Adesão de Célula Nervosa/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Ratos , Ratos Wistar , Córtex Sensório-Motor/metabolismo , Ácidos Siálicos/genética , Ácidos Siálicos/metabolismo , Técnicas Estereotáxicas , Estreptozocina/administração & dosagem
11.
Int J Cancer ; 145(6): 1596-1608, 2019 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-31032901

RESUMO

Heparanase is an endo-ß-d-glucuronidase that cleaves heparan sulfate (HS) side chains of heparan sulfate proteoglycans. Compelling evidence tie heparanase levels with all steps of tumor formation including tumor initiation, growth, metastasis and chemo-resistance, likely involving augmentation of signaling pathways and gene transcription. In order to reveal the molecular mechanism(s) underlying the protumorigenic properties of heparanase, we established an inducible (Tet-on) system in U87 human glioma cells and applied gene array methodology in order to identify genes associated with heparanase induction. We found that CD24, a mucin-like cell adhesion protein, is consistently upregulated by heparanase and by heparanase splice variant devoid of enzymatic activity, whereas heparanase gene silencing was associated with decreased CD24 expression. This finding was further substantiated by a similar pattern of heparanase and CD24 immunostaining in glioma patients (Pearson's correlation; R = 0.66, p = 0.00001). Noteworthy, overexpression of CD24 stimulated glioma cell migration, invasion, colony formation in soft agar and tumor growth in mice suggesting that CD24 functions promote tumor growth. Likewise, anti-CD24 neutralizing monoclonal antibody attenuated glioma tumor growth, and a similar inhibition was observed in mice treated with a neutralizing mAb directed against L1 cell adhesion molecule (L1CAM), a ligand for CD24. Importantly, significant shorter patient survival was found in heparanase-high/CD24-high tumors vs. heparanase-high/CD24-low tumors for both high-grade and low-grade glioma (p = 0.02). Our results thus uncover a novel heparanase-CD24-L1CAM axis that plays a significant role in glioma tumorigenesis.


Assuntos
Neoplasias Encefálicas/patologia , Antígeno CD24/metabolismo , Glioma/patologia , Glucuronidase/metabolismo , Animais , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Progressão da Doença , Feminino , Glioma/metabolismo , Xenoenxertos , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Molécula L1 de Adesão de Célula Nervosa/metabolismo , Transdução de Sinais
12.
Bull Exp Biol Med ; 166(6): 811-815, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31020581

RESUMO

We assessed changes of olfactory bulbs in rata with 6-hydroxydopamine destruction of the substantia nigra. The expression of marker proteins of immature and differentiated neurons and glia (vimentin, PSA-NCAM, tyrosine hydroxylase, and S100) was analyzed by immunohistochemical and morphometric methods. The number of periglomerular dopamine neurons and astroglia in the olfactory bulbs increased on the side of toxin injection and expression of PSA-NCAM and vimentin increased in the rostral migratory stream. Destruction of the substantia nigra shifted differentiation of neuronal progenitors towards the dopaminergic phenotype and increased their survival in the olfactory bulbs, which can be explained by increased expression of PSA-NCAM.


Assuntos
Neuroglia/patologia , Neurônios/patologia , Bulbo Olfatório/patologia , Doença de Parkinson Secundária/patologia , Substância Negra/patologia , Adaptação Fisiológica , Animais , Biomarcadores/metabolismo , Modelos Animais de Doenças , Expressão Gênica , Humanos , Imuno-Histoquímica , Injeções Intraventriculares , Masculino , Atividade Motora/fisiologia , Molécula L1 de Adesão de Célula Nervosa/genética , Molécula L1 de Adesão de Célula Nervosa/metabolismo , Neuroglia/metabolismo , Neurônios/metabolismo , Bulbo Olfatório/metabolismo , Oxidopamina/administração & dosagem , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/genética , Doença de Parkinson Secundária/metabolismo , Ratos , Ratos Wistar , Proteínas S100/genética , Proteínas S100/metabolismo , Ácidos Siálicos/genética , Ácidos Siálicos/metabolismo , Técnicas Estereotáxicas , Substância Negra/metabolismo , Tirosina 3-Mono-Oxigenase/genética , Tirosina 3-Mono-Oxigenase/metabolismo , Vimentina/genética , Vimentina/metabolismo
13.
Elife ; 82019 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-30829570

RESUMO

The biological players involved in angiogenesis are only partially defined. Here, we report that endothelial cells (ECs) express a novel isoform of the cell-surface adhesion molecule L1CAM, termed L1-ΔTM. The splicing factor NOVA2, which binds directly to L1CAM pre-mRNA, is necessary and sufficient for the skipping of L1CAM transmembrane domain in ECs, leading to the release of soluble L1-ΔTM. The latter exerts high angiogenic function through both autocrine and paracrine activities. Mechanistically, L1-ΔTM-induced angiogenesis requires fibroblast growth factor receptor-1 signaling, implying a crosstalk between the two molecules. NOVA2 and L1-ΔTM are overexpressed in the vasculature of ovarian cancer, where L1-ΔTM levels correlate with tumor vascularization, supporting the involvement of NOVA2-mediated L1-ΔTM production in tumor angiogenesis. Finally, high NOVA2 expression is associated with poor outcome in ovarian cancer patients. Our results point to L1-ΔTM as a novel, EC-derived angiogenic factor which may represent a target for innovative antiangiogenic therapies.


Assuntos
Processamento Alternativo , Proteínas Angiogênicas/metabolismo , Células Endoteliais/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Molécula L1 de Adesão de Célula Nervosa/metabolismo , Isoformas de Proteínas/metabolismo , Proteínas de Ligação a RNA/metabolismo , Células Cultivadas , Humanos
14.
Neuron ; 102(2): 358-372.e9, 2019 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-30846310

RESUMO

Among the diverse interneuron subtypes in the neocortex, chandelier cells (ChCs) are the only population that selectively innervate pyramidal neurons (PyNs) at their axon initial segment (AIS), the site of action potential initiation, allowing them to exert powerful control over PyN output. Yet, mechanisms underlying their subcellular innervation of PyN AISs are unknown. To identify molecular determinants of ChC/PyN AIS innervation, we performed an in vivo RNAi screen of PyN-expressed axonal cell adhesion molecules (CAMs) and select Ephs/ephrins. Strikingly, we found the L1 family member L1CAM to be the only molecule required for ChC/PyN AIS innervation. Further, we show that L1CAM is required during both the establishment and maintenance of innervation, and that selective innervation of PyN AISs by ChCs requires AIS anchoring of L1CAM by the cytoskeletal ankyrin-G/ßIV-spectrin complex. Thus, our findings identify PyN-expressed L1CAM as a critical CAM required for innervation of neocortical PyN AISs by ChCs. VIDEO ABSTRACT.


Assuntos
Axônios/metabolismo , Neurônios GABAérgicos/metabolismo , Interneurônios/metabolismo , Molécula L1 de Adesão de Célula Nervosa/metabolismo , Células Piramidais/metabolismo , Animais , Anquirinas/metabolismo , Adesão Celular , Moléculas de Adesão Celular/metabolismo , Efrinas/metabolismo , Camundongos , Neocórtex/citologia , Neocórtex/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Receptor EphA1/metabolismo , Espectrina/metabolismo , Sinapses
15.
Surg Oncol ; 28: 151-157, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30851892

RESUMO

BACKGROUND: The aim of this study was to evaluate the prognostic role of positive peritoneal cytology (PPC) in a cohort of patients with endometrial cancer (EC). The secondary objective was to correlate the PPC and the expression of L1CAM in a group of patients with recurrence endometrial disease. METHODS: All women diagnosed with EC and who performed a peritoneal cytology at "Regina Elena" National Cancer Institute of Rome from 2001 to 2013 were included in the study. Patients were divided into two groups according to positivity at peritoneal cytology. Moreover, patients with a recurrence disease and whose a tissue microarray (TMA) tumor sample was available underwent a L1CAM analysis. RESULTS: Seven hundred sixty six patients underwent to EC staging in our Institute: 696 (90.8%) with negative and 70 (9.2%) with positive cytology. Five-year recurrence rate was higher in women with PPC (46.9% vs 18.4%, p = 0 < 0.0001) and, in particular, distant recurrence (86.7% vs 53.4%, p = 0.03). Moreover, we found an interesting pattern of recurrence disease in the group of early stage of EC with NPC and positive L1CAM. CONCLUSIONS: Our results support the data that PPC may be a potential prognostic factor in early EC, due to its significant association with other risk factors and its significant influence on survival. Our findings confirm the need for large studies that point out the role of PPC and new prognostic factors, including biomarkers as L1CAM.


Assuntos
Adenocarcinoma de Células Claras/patologia , Carcinoma de Células Escamosas/patologia , Cistadenocarcinoma Seroso/patologia , Neoplasias do Endométrio/patologia , Recidiva Local de Neoplasia/patologia , Molécula L1 de Adesão de Célula Nervosa/metabolismo , Neoplasias Peritoneais/patologia , Adenocarcinoma de Células Claras/metabolismo , Adenocarcinoma de Células Claras/cirurgia , Idoso , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/cirurgia , Estudos de Casos e Controles , Cistadenocarcinoma Seroso/metabolismo , Cistadenocarcinoma Seroso/cirurgia , Citodiagnóstico , Neoplasias do Endométrio/metabolismo , Neoplasias do Endométrio/cirurgia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/cirurgia , Estadiamento de Neoplasias , Neoplasias Peritoneais/metabolismo , Neoplasias Peritoneais/cirurgia , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida
16.
Neurotoxicology ; 72: 101-106, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30772382

RESUMO

BACKGROUND: Neural cell adhesion molecule (NCAM) belongs to the immunoglobulin superfamily of adhesion molecules. Polysialic acid (PSA) is attached to NCAM post-translationally. PSA residues are considered to reduce the adhesive properties of NCAM and play an important role in the regulation of cell interactions. PSA-NCAM is largely expressed in the mature retina by glial cells adjacent to retinal ganglion cells (RGCs) but its functions remain unclear. The objective of this study was to explore the role of PSA-NCAM with respect to RGC survival following kainic acid (KA)-induced excitotoxicity. METHODS: Experiments were performed on C57BL/6NTac male mice. KA was injected intravitreally to induce RGC damage. RGCs were visualized using an anti-Brn3a antibody. Endoneuraminidase N (NA) was administrated intravitreally to cleave PSA chains from NCAM. RESULTS: KA induced an 80% reduction in the density of RGCs that was accompanied by a decrease in PSA-NCAM in the RGC layer. KA treatment induced a pronounced increase in the level of matrix metalloproteinase-9 (MMP-9) in the inner layers of the retina. Inhibition of MMP-9 reduced both RGC death and PSA-NCAM shedding in the retina. PSA-NCAM cleavage induced by NA abolished the protective action of the MMP-9 inhibitor and decreased RGC survival following KA-treatment. CONCLUSIONS: A decrease in retinal PSA-NCAM levels following KA administration is due to the induction of active MMP-9, which removes extracellular PSA-NCAM from the surface of astroglial and Müller cells. The MMP-9 induced shedding of PSA-NCAM enhances KA-induced toxicity and at least in part contributes to the observed loss of RGCs following excitotoxic damage.


Assuntos
Agonistas de Aminoácidos Excitatórios/toxicidade , Ácido Caínico/toxicidade , Molécula L1 de Adesão de Célula Nervosa/metabolismo , Células Ganglionares da Retina/efeitos dos fármacos , Células Ganglionares da Retina/metabolismo , Ácidos Siálicos/metabolismo , Animais , Contagem de Células , Sobrevivência Celular/efeitos dos fármacos , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Camundongos Endogâmicos C57BL
17.
Mol Neurobiol ; 56(8): 5856-5865, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30685843

RESUMO

Neurogenesis in the adult dentate gyrus (DG) of the hippocampus allows the continuous generation of new neurons. This cellular process can be disturbed under specific environmental conditions, such as epileptic seizures; however, the underlying mechanisms responsible for their control remain largely unknown. Although different studies have linked the JNK (c-Jun-N-terminal-kinase) activity with the regulation of cell proliferation and differentiation, the specific function of JNK in controlling adult hippocampal neurogenesis is not well known. The purpose of this study was to analyze the role of JNK isoforms (JNK1/JNK2/JNK3) in adult-hippocampal neurogenesis. To achieve this goal, we used JNK-knockout mice (Jnk1-/-, Jnk2-/-, and Jnk3-/-), untreated and treated with intraperitoneal injections of kainic acid (KA), as an experimental model of epilepsy. In each condition, we identified cell subpopulations at different stages of neuronal maturation by immunohistochemical specific markers. In physiological conditions, we evidenced that JNK1 and JNK3 control the levels of one subtype of early progenitor cells (GFAP+/Sox2+) but not the GFAP+/Nestin+ cell subtype. Moreover, the absence of JNK1 induces an increase of immature neurons (Doublecortin+; PSA-NCAM+ cells) compared with wild-type (WT). On the other hand, Jnk1-/- and Jnk3-/- mice showed an increased capacity to maintain hippocampal homeostasis, since calbindin immunoreactivity is higher than in WT. An important fact is that, after KA injection, Jnk1-/- and Jnk3-/- mice show no increase in the different neurogenic cell subpopulation analyzed, in contrast to what occurs in WT and Jnk2-/- mice. All these data support that JNK isoforms are involved in the adult neurogenesis control.


Assuntos
Envelhecimento/metabolismo , Epilepsia do Lobo Temporal/enzimologia , Hipocampo/enzimologia , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Neurogênese , Animais , Calbindinas/metabolismo , Contagem de Células , Giro Denteado/enzimologia , Giro Denteado/patologia , Modelos Animais de Doenças , Proteína Glial Fibrilar Ácida/metabolismo , Hipocampo/patologia , Isoenzimas/metabolismo , Ácido Caínico , Camundongos Endogâmicos C57BL , Nestina/metabolismo , Molécula L1 de Adesão de Célula Nervosa/metabolismo , Células-Tronco Neurais/metabolismo , Neurônios/enzimologia , Neurônios/patologia , Fatores de Transcrição SOXB1/metabolismo , Ácidos Siálicos/metabolismo
18.
J Voice ; 33(1): 52-57, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29169663

RESUMO

OBJECTIVES: A correlation appears to exist between the expression of the polysialic acid neural cell adhesion molecule (PSA-NCAM) and repair in central nervous system (CNS) diseases. However, the expression of PSA-NCAM in the CNS after peripheral nerve injury remains unclear. This study aimed to evaluate the expression of PSA-NCAM in the ipsilateral nucleus ambiguus (NA) after unilateral recurrent laryngeal nerve (RLN) avulsion. MATERIALS AND METHODS: The left RLN of adult Sprague Dawley rats were avulsed. The expression of PSA-NCAM, PSA-NCAM/NeuN, and PSA-NCAM/Tuj1 in the brain stem was investigated using immunohistochemistry. The results were subjected to one-way analysis of variance followed by the Tukey post hoc test for statistical analyses. RESULTS: PSA-NCAM-positive and PSA-NCAM/NeuN and PSA-NCAM/Tuj1 double-labeled positive cells were observed 7 days post injury in the ipsilateral NA. PSA-NCAM/NeuN and PSA-NCAM/Tuj1 double-labeled cells were observed at 21 and 7 days post injury, respectively. PSA-NCAM/NeuN double-labeled cells were also found in the contralateral NA. CONCLUSIONS: After unilateral avulsion of the RLN, the expression of PSA-NCAM in the ipsilateral NA was correlated with the proliferation and the differentiation of neural cells. PSA-NCAM expression may be used as a predictor of the initiation of repair in neural cells.


Assuntos
Bulbo/metabolismo , Regeneração Nervosa , Molécula L1 de Adesão de Célula Nervosa/metabolismo , Traumatismos do Nervo Laríngeo Recorrente/metabolismo , Ácidos Siálicos/metabolismo , Animais , Antígenos Nucleares/metabolismo , Masculino , Proteínas do Tecido Nervoso/metabolismo , Distribuição Aleatória , Ratos Sprague-Dawley
19.
Dev Cell ; 48(2): 215-228.e5, 2019 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-30555000

RESUMO

Neurite fasciculation through contact-dependent signaling is important for the wiring and function of the neuronal circuits. Here, we describe a type of axon-dendrite fasciculation in C. elegans, where proximal dendrites of the nociceptor PVD adhere to the axon of the ALA interneuron. This axon-dendrite fasciculation is mediated by a previously uncharacterized adhesive signaling by the ALA membrane signal SAX-7/L1CAM and the PVD receptor SAX-3/Robo but independent of Slit. L1CAM physically interacts with Robo and instructs dendrite adhesion in a Robo-dependent manner. Fasciculation mediated by L1CAM-Robo signaling aligns F-actin dynamics in the dendrite growth cone and facilitates dynamic growth cone behaviors for efficient dendrite guidance. Disruption of PVD dendrite fasciculation impairs nociceptive mechanosensation and rhythmicity in body curvature, suggesting that dendrite fasciculation governs the functions of mechanosensory circuits. Our work elucidates the molecular mechanisms by which adhesive axon-dendrite signaling shapes the construction and function of sensory neuronal circuits.


Assuntos
Citoesqueleto de Actina/metabolismo , Fasciculação Axônica/fisiologia , Cones de Crescimento/metabolismo , Molécula L1 de Adesão de Célula Nervosa/metabolismo , Actinas/metabolismo , Animais , Axônios/metabolismo , Caenorhabditis elegans/crescimento & desenvolvimento , Proteínas de Caenorhabditis elegans , Citoesqueleto/metabolismo , Dendritos/fisiologia , Proteínas do Tecido Nervoso/metabolismo , Receptores Imunológicos/metabolismo
20.
PLoS One ; 13(12): e0209294, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30557309

RESUMO

BACKGROUND: Risk stratification of endometrial carcinomas is primarily based on surgical staging that requires extensive retroperitoneal lymph node dissection. One of the most powerful predictor of lymph node involvement is the lymph vascular space invasion (LVSI). The objective of this study was to determine the potential of L1 Cell Adhesion Molecule (L1CAM) to predict LVSI and its association with other risk factors in endometrioid endometrial carcinomas. MATERIALS AND METHODS: We studied 47 consecutive patients aged 37-88 (61.34±10.52). Twenty-three patients (48.9%) were submitted to complete surgical staging. Nine patients (19.1%) underwent surgical staging without para-aortic dissection. Seven (14.9%) were submitted to hysterectomy with no lymph node dissection. Eight patients (17.0%) only had the biopsy material for analysis. The 32 patients submitted to lymphadenectomy were staged according to the FIGO system and classified among the risk categories of the ESMO-ESGO-ESTRO guidelines. The following histological characteristics were analyzed: tumor size (mm), depth of myometrial infiltration, presence of microcystic, elongated, and fragmented (MELF) pattern of myoinvasion, and lymph vascular space invasion (LVSI). Immunohistochemical analyses of mismatch repair (MMR) proteins MLH1, MSH2, MSH6, and PMS2, p53, and L1CAM were performed in formalin-fixed paraffin embedded whole tumor tissue sections. RESULTS: LVSI was identified in 26/41 (63,4%) of the cases. L1CAM was positive in 8/47 (17%) cases, all of them positive for LVSI and within the high-risk category of ESMO-ESGO-ESTRO. L1CAM-positive cases were associated with high histological grade and p53 aberrant immunohistochemical profile. Besides, it showed a trend to larger tumors, greater depth of myometrial infiltration, and with a higher frequency of the MELF pattern of myoinvasion. LVSI was also associated with FIGO stage, tumor size, depth of myometrial infiltration, and tumor grade. CONCLUSIONS: L1CAM is highly associated with LVSI and could be used as a pre-operative predictor of lymph node involvement in endometrioid endometrial carcinomas.


Assuntos
Carcinoma Endometrioide/metabolismo , Neoplasias do Endométrio/metabolismo , Metástase Linfática/diagnóstico , Invasividade Neoplásica/diagnóstico , Molécula L1 de Adesão de Célula Nervosa/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Carcinoma Endometrioide/patologia , Carcinoma Endometrioide/cirurgia , Estudos de Coortes , Neoplasias do Endométrio/patologia , Neoplasias do Endométrio/cirurgia , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Dados Preliminares , Período Pré-Operatório
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