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1.
Glia ; 71(4): 926-944, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36479906

RESUMO

Non-myelinating Schwann cells (NMSC) play important roles in peripheral nervous system formation and function. However, the molecular identity of these cells remains poorly defined. We provide evidence that Kir4.1, an inward-rectifying K+ channel encoded by the KCNJ10 gene, is specifically expressed and active in NMSC. Immunostaining revealed that Kir4.1 is present in terminal/perisynaptic SCs (TPSC), synaptic glia at neuromuscular junctions (NMJ), but not in myelinating SCs (MSC) of adult mice. To further examine the expression pattern of Kir4.1, we generated BAC transgenic Kir4.1-CreERT2 mice and crossed them to the tdTomato reporter line. Activation of CreERT2 with tamoxifen after the completion of myelination onset led to robust expression of tdTomato in NMSC, including Remak Schwann cells (RSC) along peripheral nerves and TPSC, but not in MSC. In contrast, activating CreERT2 before and during the onset of myelination led to tdTomato expression in NMSC and MSC. These observations suggest that immature SC express Kir4.1, and its expression is then downregulated selectively in myelin-forming SC. In support, we found that while activating CreERT2 induces tdTomato expression in immature SC, it fails to induce tdTomato in MSC associated with sensory axons in culture. NMSC derived from neonatal sciatic nerve were shown to express Kir4.1 and exhibit barium-sensitive inwardly rectifying macroscopic K+ currents. Thus, this study identified Kir4.1 as a potential modulator of immature SC and NMSC function. Additionally, it established a novel transgenic mouse line to introduce or delete genes in NMSC.


Assuntos
Bainha de Mielina , Células de Schwann , Camundongos , Animais , Células de Schwann/metabolismo , Bainha de Mielina/metabolismo , Camundongos Transgênicos , Nervo Isquiático/metabolismo , Tamoxifeno/farmacologia
2.
Int J Cancer ; 138(8): 2030-42, 2016 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-26595750

RESUMO

Heme oxygenase (HO)-1 catalyzes the degradation of cytotoxic heme into biliverdin and blocks antitumor immune responses, thus protecting cancer against host defense. Whether this scenario also applies to neuroblastoma (NB), the most common extracranial solid childhood tumor, is not known. Here, we demonstrate for the first time a prognostic relevance of HO-1 expression in samples from NB patients and show that targeting of HO-1 prevents both cancer resistance against cellular stress and immune escape in the syngeneic NXS2 A/J mouse model of NB. High HO-1 RNA expression in NB tissues emerged as unfavorable prognostic marker, in particular for patients older than 18 months as indicated by univariate as well as multivariate survival probability analyses including disease stage and MYCN status. On the basis of this observation we aimed to target HO-1 by systemic as well as tumor-specific zinc protoporphyrin-mediated HO-1 suppression in a syngeneic immunocompetent NB mouse model. This resulted in 50% reduction of primary tumor growth and a suppression of spontaneous liver metastases. Importantly, HO-1 inhibition abrogated immune cell paralysis affecting CD4 and CD8 T-effector cells. This in turn reverted HO-1-dependent immune escape mechanisms in NB by increasing NB apoptosis and improved DC maturation. In summary, HO-1 emerges as a novel immune regulator in NB and emerges as a promising target for the development of therapeutic approaches.


Assuntos
Biomarcadores Tumorais/análise , Heme Oxigenase-1/imunologia , Neuroblastoma/imunologia , Evasão Tumoral/imunologia , Animais , Western Blotting , Linhagem Celular Tumoral , Sobrevivência Celular/fisiologia , Modelos Animais de Doenças , Feminino , Heme Oxigenase-1/metabolismo , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Camundongos , Neuroblastoma/enzimologia , Neuroblastoma/patologia , Prognóstico , Modelos de Riscos Proporcionais , Reação em Cadeia da Polimerase Via Transcriptase Reversa
3.
Arch Oral Biol ; 72: 75-86, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27552374

RESUMO

OBJECTIVE: Type I plasminogen deficiency (Plgdef) is an uncommon chronic inflammation of mucous membranes. Gingival enlargements usually proceed with progressive periodontal destruction and tooth-loss. Plasmin(ogen)-independent enzymatic mechanisms for fibrin clearance have already been discussed in the literature. Our primary objective was to verify, immunohistochemically, the occurrence of different enzymatic factors involved in tissue breakdown of inflamed compared to healthy gingiva. Secondly, we tried to find out, if these patients have a similar microbiological profile to the patients with known gingivitis and periodontitis. MATERIALS AND METHODS: Immunohistochemical analysis of enzymes elastase, plasminogen (plg), cathepsin G, matrix-metalloproteinase (MMP)-3 and MMP-7 and of glycoprotein fibrinogen were performed with gingival tissues from 3 healthy controls, 8 patients with Plgdef and 3 patients with gingivitis and periodontitis. Furthermore, plaque from 5 patients with plasminogen deficiency were also obtained to determine the microbiological profile. RESULTS: Significantly high numbers of elastase positive leukocytes were detected in all samples. Staining for MMP-3 and MMP-7 was seen in samples with gingivitis and periodontitis with a stronger staining in samples with periodontitis by Plgdef. Fibrinogen was detectable in all samples. Staining for plg was stronger in samples with periodontitis than in other samples. Staining for cathepsin G was weak in gingivitis and periodontitis. Subgingival microbial flora showed elevated colony forming units of Prevotella intermedia/nigrescens, Fusobacterium spp., Eikenella corrodens, Porphyromonas gingivalis and viridans streptococci. CONCLUSION: Strong staining of elastase, MMP-3 and MMP-7 and weak staining of plg in Plgdef samples supports the plasmin(ogen) - independent fibrin clearance. Similar subgingival microbiological flora was observed in periodontitis with Plgdef as in other periodontal diseases. Further investigations should determine the exact pathomechanism and focus on effective treatment methods of this entity.


Assuntos
Conjuntivite/patologia , Gengiva/patologia , Gengivite/patologia , Periodontite/patologia , Plasminogênio/deficiência , Dermatopatias Genéticas/patologia , Adolescente , Estudos de Casos e Controles , Criança , Ensaio de Imunoadsorção Enzimática , Feminino , Gengiva/enzimologia , Gengiva/microbiologia , Gengivite/enzimologia , Gengivite/microbiologia , Humanos , Imuno-Histoquímica , Masculino , Periodontite/enzimologia , Periodontite/microbiologia , Reação em Cadeia da Polimerase , Adulto Jovem
4.
Clin Cancer Res ; 9(15): 5683-92, 2003 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-14654552

RESUMO

PURPOSE: We compared the expression of the insulin receptor-related receptor (IRR) in primary human neuroblastomas with other biological and clinical parameters and the impact of its expression on prognostic outcome. EXPERIMENTAL DESIGN: We studied 49 neuroblastomas of different clinical stages and histological subtypes for (a) IRR, insulin-like growth factor 1 receptor (IGF-1R), TrkA, p75 neurotrophin receptor, and MYCN mRNA expression by reverse transcription-PCR; (b) MYCN gene amplification by Southern blot analyses; (c) cyclin A protein expression by Western blot analyses indicating proliferation rate; and (d) apoptotic index (AI) by terminal deoxynucleotidyl transferase (Tdt)-mediated dUTP nick end-labeling assay. RESULTS: IRR mRNA expression was found in 25 (51%) neuroblastomas and correlated with stages 1, 2, 3, and 4S disease and with age

Assuntos
Apoptose/fisiologia , Regulação Neoplásica da Expressão Gênica/genética , Neuroblastoma/genética , Neuroblastoma/patologia , Receptor IGF Tipo 1/genética , Receptor de Insulina/genética , Sequência de Bases , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Diferenciação Celular , Criança , Pré-Escolar , Primers do DNA , Humanos , Lactente , Estadiamento de Neoplasias , Neuroblastoma/mortalidade , Estudos Retrospectivos , Análise de Sobrevida
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