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1.
bioRxiv ; 2023 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-37333144

RESUMO

The most prevalent genetic cause of both amyotrophic lateral sclerosis and frontotemporal dementia is a (GGGGCC)n nucleotide repeat expansion (NRE) occurring in the first intron of the C9orf72 gene (C9). Brain glucose hypometabolism is consistently observed in C9-NRE carriers, even at pre-symptomatic stages, although its potential role in disease pathogenesis is unknown. Here, we identified alterations in glucose metabolic pathways and ATP levels in the brain of asymptomatic C9-BAC mice. We found that, through activation of the GCN2 kinase, glucose hypometabolism drives the production of dipeptide repeat proteins (DPRs), impairs the survival of C9 patient-derived neurons, and triggers motor dysfunction in C9-BAC mice. We also found that one of the arginine-rich DPRs (PR) can directly contribute to glucose metabolism and metabolic stress. These findings provide a mechanistic link between energy imbalances and C9-ALS/FTD pathogenesis and support a feedforward loop model that opens several opportunities for therapeutic intervention.

2.
Int J Oral Maxillofac Surg ; 50(7): 906-914, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33144049

RESUMO

The aim of this study was to analyse the effects of gargling with and then swallowing PPAA (polaprezinc in polyacrylic acid solution), in addition to regular oral management, on patients with a haematopoietic neoplasm scheduled for haematopoietic stem cell transplantation (HSCT). A total of 120 patients scheduled for HSCT during the years 2006-2016 were recruited. Patient background, oral adverse events, the incidence and severity of systemic adverse events (sepsis/septic shock, acute graft-versus-host disease (GVHD) after transplantation), and outcomes (survival/death) were compared between groups treated with and without PPAA. The severities of oral adverse events (oral mucositis, oral pain, and dysgeusia) were significantly lower in patients treated with PPAA. There was no significant difference in the incidence of febrile neutropenia (P=0.622) or sepsis/septic shock (P=0.665) as systemic adverse events. The severity of allograft-induced acute graft-versus-host disease (GVHD) was significantly lower in the PPAA group (P=0.011). There was no significant difference in outcome between the two groups (P=0.285). Within the limitations of the study design, it may be concluded that oral management with PPAA reduces adverse events in HSCT. Oral management with concomitant use of PPAA decreased oral adverse events and reduced the systemic complication of GVHD.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Compostos Organometálicos , Carnosina/análogos & derivados , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Transplante Homólogo , Compostos de Zinco
3.
Int J Oral Maxillofac Surg ; 48(11): 1394-1397, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31235391

RESUMO

Werner syndrome (WS) is an autosomal recessive disorder characterized by physical signs and symptoms, including premature aging and scleroderma-like skin changes. The gene responsible for WS is the WRN gene. A significant proportion of WS-related malignant tumours are non-epithelial types, and the incidence of oral squamous cell carcinoma (SCC) is rare. A case of oral SCC of the lower alveolus and gingiva arising in a 63-year-old woman with WS is reported here. Biopsy confirmed moderately differentiated SCC. Surgical resection was performed and there was no recurrence or metastasis at the 3-year follow-up. Mutation analysis using next-generation sequencing, detected no mutations in the genes encoding the molecules strongly involved in the development of oral SCC, such as TP53 or PIK3CA. No obvious mutations were detected. Based on the results of the study, the results of mutation analysis suggest that this case might be genetically different from the common mechanisms of SCC in the oral cavity.


Assuntos
Carcinoma de Células Escamosas , Neoplasias Bucais , Síndrome de Werner , Feminino , Humanos , Pessoa de Meia-Idade , Mutação , Recidiva Local de Neoplasia , Helicase da Síndrome de Werner
4.
Hum Mol Genet ; 27(1): 160-177, 2018 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29112723

RESUMO

Mutations in coiled-coil-helix-coiled-coil-helix-domain containing 10 (CHCHD10), a mitochondrial twin CX9C protein whose function is still unknown, cause myopathy, motor neuron disease, frontotemporal dementia, and Parkinson's disease. Here, we investigate CHCHD10 topology and its protein interactome, as well as the effects of CHCHD10 depletion or expression of disease-associated mutations in wild-type cells. We find that CHCHD10 associates with membranes in the mitochondrial intermembrane space, where it interacts with a closely related protein, CHCHD2. Furthermore, both CHCHD10 and CHCHD2 interact with p32/GC1QR, a protein with various intra and extra-mitochondrial functions. CHCHD10 and CHCHD2 have short half-lives, suggesting regulatory rather than structural functions. Cell lines with CHCHD10 knockdown do not display bioenergetic defects, but, unexpectedly, accumulate excessive intramitochondrial iron. In mice, CHCHD10 is expressed in many tissues, most abundantly in heart, skeletal muscle, liver, and in specific CNS regions, notably the dopaminergic neurons of the substantia nigra and spinal cord neurons, which is consistent with the pathology associated with CHCHD10 mutations. Homozygote CHCHD10 knockout mice are viable, have no gross phenotypes, no bioenergetic defects or ultrastructural mitochondrial abnormalities in brain, heart or skeletal muscle, indicating that functional redundancy or compensatory mechanisms for CHCHD10 loss occur in vivo. Instead, cells expressing S59L or R15L mutant versions of CHCHD10, but not WT, have impaired mitochondrial energy metabolism. Taken together, the evidence obtained from our in vitro and in vivo studies suggest that CHCHD10 mutants cause disease through a gain of toxic function mechanism, rather than a loss of function.


Assuntos
Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/metabolismo , Animais , Proteínas de Transporte , Proteínas de Ligação a DNA , Demência Frontotemporal/genética , Estudos de Associação Genética , Células HEK293 , Células HeLa , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/genética , Mitocôndrias/metabolismo , Proteínas Mitocondriais/química , Modelos Moleculares , Mutação , Domínios e Motivos de Interação entre Proteínas , Mapeamento de Interação de Proteínas , Elementos Estruturais de Proteínas , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
5.
Sci Rep ; 7: 45398, 2017 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-28345664

RESUMO

Aqueous solutions of biomolecules such as proteins are very important model systems for understanding the functions of biomolecules in actual life processes because interactions between biomolecules and the surrounding water molecules are considered to be important determinants of biomolecules' functions. Globule proteins have been extensively studied via dielectric spectroscopy; the results indicate three relaxation processes originating from fluctuations in the protein molecule, the bound water and the bulk water. However, the characteristics of aqueous solutions of collagens have rarely been investigated. In this work, based on broadband dielectric measurements between 500 MHz and 2.5 THz, we demonstrate that the high viscosity of a collagen aqueous solution is due to the network structure being constructed of rod-like collagen molecules surrounding free water molecules and that the water molecules are not responsible for the viscosity. We determine that the macroscopic viscosity is related to the mean lifetime of the collagen-collagen interactions supporting the networks and that the local viscosity of the water surrounded by the networks is governed by the viscosity of free water as in the bulk. This hierarchical structure in the dynamics of the aqueous solution of biomolecules has been revealed for the first time.


Assuntos
Colágeno/química , Tilápia/metabolismo , Animais , Espectroscopia Dielétrica/métodos , Soluções/química , Viscosidade , Água/química
6.
Clin Exp Metastasis ; 33(1): 3-13, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26563151

RESUMO

PRL-3 genomic copy number is increased in colorectal cancer (CRC), and PRL-3 expression is closely associated with lymph node and liver metastasis of CRC. However, the clinical significance of PRL-3 genomic gain for CRC remains obscure. Here, PRL-3 genomic status in 109 primary CRC tumors and in 44 CRC tumors that had metastasized to the liver, was quantified using real time PCR. Association of PRL-3 genomic status with clinicopathological factors and prognosis was assessed in detail. PRL-3 genomic gain was identified in 31 primary CRC (27.4 %) and was more frequently seen in stage III than in stage II (p = 0.025). Among the clinicopathological factors assessed, PRL-3 genomic gain was significantly associated with poorly differentiated histology (p = 0.0039). Moreover, CRC patients with PRL-3 genomic gain exhibited poorer prognosis than those with no gain in stage II-IV CRC (p = 0.017). PRL-3 genomic gain was identified in 18 (41 %) of the liver metastasis tumors, and this frequency of gain was significantly increased as compared to that of the corresponding primary CRCs (11 %) (p = 0.001). Our findings suggested that PRL-3 genomic gain may represent an aggressive phenotype of primary CRC, and may associate with liver metastasis.


Assuntos
Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Neoplasias Hepáticas/genética , Proteínas de Neoplasias/genética , Proteínas Tirosina Fosfatases/genética , Neoplasias Colorretais/mortalidade , Feminino , Dosagem de Genes , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/secundário , Masculino , Prognóstico , Modelos de Riscos Proporcionais , Reação em Cadeia da Polimerase em Tempo Real
7.
Clin Exp Immunol ; 155(1): 16-20, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19016805

RESUMO

The regenerating gene (Reg) was originally isolated from regenerating rat pancreatic islets and revealed recently to constitute a multi-gene family in humans. REG Ialpha protein is known to be overexpressed not only in various human inflammatory diseases but also in various experimental models of inflammation in animal tissues. However, its involvement in pathophysiology of the minor salivary gland (MSG) is not clear. We investigated REG Ialpha expression in the MSG of patients with primary Sjögren's syndrome (SS) and assessed its role in ductal epithelial cell proliferation in such tissues. Lip biopsy specimens were obtained from 40 patients with primary SS and examined using immunohistochemistry for REG Ialpha protein, Ki67 and single-strand DNA (ssDNA). The relationships among clinicopathological factors and expression of REG Ialpha protein, Ki67 and ssDNA in the MSG were then analysed. REG Ialpha protein was expressed rarely in ductal epithelial cells of the normal MSG but was apparently overexpressed in those of patients with SS. The labelling indices for both Ki67 and ssDNA in the ductal cells of the MSGs were significantly higher in SS patients than in controls. Moreover, these labelling indices were significantly higher in REG Ialpha-positive than in negative SS patients. REG Ialpha protein may play a role in the regeneration of ductal epithelial cells in the MSGs of patients with SS.


Assuntos
Células Epiteliais/fisiologia , Litostatina/análise , Regeneração/fisiologia , Ductos Salivares/fisiologia , Glândulas Salivares Menores , Síndrome de Sjogren/patologia , Adolescente , Adulto , Idoso , Biomarcadores/análise , Divisão Celular/fisiologia , DNA de Cadeia Simples/análise , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Feminino , Humanos , Imuno-Histoquímica , Antígeno Ki-67/análise , Litostatina/metabolismo , Masculino , Pessoa de Meia-Idade , Ductos Salivares/metabolismo , Ductos Salivares/patologia , Síndrome de Sjogren/metabolismo , Adulto Jovem
9.
Curr Cancer Drug Targets ; 4(6): 521-9, 2004 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-15379637

RESUMO

TSC-22 (Transforming growth factor-beta stimulated clone-22) was originally isolated as a TGF-beta-inducible gene in mouse osteoblastic cells. TSC-22 encodes a putative transcriptional regulator containing a leucine zipper-like structure. Several differentiation-inducing stimuli up-regulate the TSC-22 gene. Furthermore, TSC-22 acts as an effector that integrates multiple extracellular signals during embryogenesis of Drosophila and mouse. Separately, we identified TSC-22 cDNA as an anti-cancer drug (vesnarinone)-inducible gene in a human salivary gland cancer cell line, TYS. Vesnarinone is known to have a differentiation-inducing activity in several cell types. We showed that TSC-22 negatively regulated the growth of TYS cells, and that down-regulation of TSC-22 played a major role in the salivary gland tumorigenesis. Subsequently, we found that artificial overexpression of TSC-22 enhanced chemosensitivity and radiation-sensitivity by inducing apoptosis in TYS cells. Recently, we isolated TSC-22 genomic DNA and analyzed the transcriptional and post-transcriptional regulation of the TSC-22 gene. Then, we confirmed by the luciferase reporter assay that several differentiation-inducing stimuli directly activated the promoter region of TSC-22 gene. Now we are investigating the chemical compounds, which could enhance the transcription of the TSC-22 gene. Thus, because TSC-22 is a key molecule for differentiation of several cells, it can be used as a molecular target for cancer differentiation therapy in salivary gland cancer.


Assuntos
Diferenciação Celular , Sistemas de Liberação de Medicamentos/métodos , Proteínas Repressoras/genética , Neoplasias das Glândulas Salivares/patologia , Sequência de Aminoácidos , Animais , Sequência de Bases , Diferenciação Celular/genética , Humanos , Dados de Sequência Molecular , Proteínas Repressoras/química , Proteínas Repressoras/fisiologia , Neoplasias das Glândulas Salivares/tratamento farmacológico , Neoplasias das Glândulas Salivares/genética
10.
Br J Cancer ; 91(6): 1131-8, 2004 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-15292943

RESUMO

14-3-3 sigma:, a target gene of the p53 tumour suppressor protein, has been shown to regulate the cell cycle at the G2/M checkpoint. Recent studies have demonstrated that 14-3-3 sigma is downregulated by hypermethylation of the CpG island in several types of cancer. In this study, we investigated the expression and methylation status of 14-3-3 sigma in human salivary gland adenoid cystic carcinoma (ACC) and mucoepidermoid carcinoma (MEC). Immunohistochemical analysis revealed that the positive expression rate of 14-3-3 sigma in ACC (one out of 14) was markedly lower than that in MEC (ten out of 10). Since most of the ACCs carried the wild-type p53 protein, downregulation of 14-3-3 sigma in ACC may not be due to the dysfunction of p53 pathway. Microdissection-methylation-specific PCR revealed that frequent hypermethylation of the 14-3-3 sigma gene was observed in ACC when compared to that in MEC. In cultured-ACC cells, we confirmed the downregulation of 14-3-3 sigma via hemimethylation of the gene by sequencing analysis after sodium bisulphite treatment. Furthermore, re-expression of 14-3-3 sigma in the ACC cells was induced by the treatment with DNA demethylating agent, 5-aza-2'-deoxycytidine. Irradiation apparently induced the enhanced expression of 14-3-3 sigma and G2/M arrest in normal salivary gland cells; however, in the ACC cells, neither induction of 14-3-3 sigma nor G2/M arrest was induced by irradiation. These results suggest that downregulation of 14-3-3 sigma might play critical roles in the neoplastic development and radiosensitivity of ACC.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma Adenoide Cístico/genética , Metilação de DNA , Exonucleases/genética , Proteínas de Neoplasias/genética , Neoplasias das Glândulas Salivares/genética , Proteínas 14-3-3 , Sequência de Bases , Carcinoma Adenoide Cístico/patologia , Primers do DNA , Exorribonucleases , Genes p53 , Humanos , Imuno-Histoquímica , Mutação/genética , Reação em Cadeia da Polimerase/métodos , Neoplasias das Glândulas Salivares/patologia
11.
Gut ; 53(5): 710-6, 2004 May.
Artigo em Inglês | MEDLINE | ID: mdl-15082590

RESUMO

BACKGROUND: Several animal models for human ulcerative colitis (UC) associated neoplasia have been reported. However, most neoplasias developed in these models have morphological and genetic characteristics different from UC associated neoplasia. AIMS: To establish a new colitis associated neoplasia model in p53 deficient mice by treatment with dextran sulphate sodium (DSS). METHODS: DSS colitis was induced in homozygous p53 deficient mice (p53(-/-)-DSS), heterozygous p53 deficient mice (p53(+/-)-DSS) and wild-type mice (p53+/+-DSS) by treatment with 4% DSS. Numbers of developed neoplasias were compared among the experimental groups, and macroscopic and microscopic features of the neoplasias were analysed. Furthermore, K-ras mutation and beta-catenin expression were assessed. RESULTS: p53(-/-)-DSS mice showed 100% incidence of neoplasias whereas the incidences in p53(+/-)-DSS and p53+/+-DSS mice were 46.2% and 13.3%, respectively. No neoplasias were observed in the control groups. The mean numbers of total neoplasias per mouse were 5.0 (p53(-/-)-DSS), 0.62 (p53(+/-)-DSS), and 0.2 (p53+/+-DSS). The number of neoplasias per mouse in the p53(-/-)-DSS group was significantly higher than that in the other DSS groups. The incidences of superficial type neoplasias were 91.7% in p53(-/-)-DSS mice, 75.0% in p53(+/-)-DSS mice, and 33.3% in p53+/+-DSS mice. The K-ras mutation was not detected in any of the neoplasias tested. Translocation of beta-catenin from the cell membrane to the cytoplasm or nucleus was observed in 19 of 23 (82.6%) neoplasias. CONCLUSIONS: The p53(-/-)-DSS mice is an excellent animal model of UC associated neoplasia because the morphological features and molecular genetics are similar to those of UC associated neoplasia. Therefore, this model will contribute to the analysis of tumorigenesis related to human UC associated neoplasia and the development of chemopreventive agents.


Assuntos
Colite Ulcerativa/complicações , Neoplasias do Colo/etiologia , Genes p53 , Animais , Transformação Celular Neoplásica/genética , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/patologia , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Proteínas do Citoesqueleto/metabolismo , Sulfato de Dextrana , Modelos Animais de Doenças , Genes ras , Predisposição Genética para Doença , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Camundongos Knockout , Mutação , Transativadores/metabolismo , beta Catenina
12.
J Exp Clin Cancer Res ; 23(4): 599-606, 2004 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-15743030

RESUMO

Primary cancer of the gallbladder is not unusual. Most cases of gallbladder cancer are found at an advanced stage, accompanied by the invasion to the liver, metastases to the lymph nodes and distant organs, and peritoneal dissemination. In this study, we first examined the effect of mitogen-activated protein kinase kinase (MEK) inhibitors on the production of matrix metalloproteinases (MMPs), urokinase-type plasminogen activator (uPA), and tissue inhibitors of metalloproteinases (TIMPs) in a human gallbladder cancer cell line, NOZ cells in vitro. MEK inhibitors (PD98059 and U0126) inhibited the production of MMP-2, MMP-9 and high MW uPA, and upregulated TIMPs (TIMP-1, TIMP-2 and TIMP-3). Subsequently, we examined the effect of U0126 on invasion and metastasis of orthotopically inoculated NOZ cells in nude mice. Direct liver invasion by cancer cells was detected in all of the mice in the control group, but in only one mouse in the U0126-treated group. Most of the primary tumors in the U0126-treated group expanded to the liver, but did not invade into the liver. Vessel invasion in the liver was evident in 4 out of 5 mice in the control group, but in only one mouse in the U0126-treated group. Lymph node metastases and peritoneal dissemination were recognized in all of the mice in both groups. All 5 mice in the U0126-treated group, and 4 out of 5 mice in the vehicle control group, had metastases in the lungs. The present results suggest that a MEK inhibitor, U0126, prolonged the survival of the mice with NOZ tumor by inhibiting direct liver invasion and vessel invasion of the cancer cells via down-regulation of the matrix degrading ability of the cancer cells.


Assuntos
Butadienos/farmacologia , Inibidores Enzimáticos/farmacologia , Neoplasias da Vesícula Biliar/patologia , Neoplasias Hepáticas/secundário , Transplante de Neoplasias/métodos , Nitrilas/farmacologia , Animais , Linhagem Celular Tumoral , Sobrevivência Celular , Flavonoides/farmacologia , Neoplasias da Vesícula Biliar/metabolismo , Humanos , Fígado/patologia , Metástase Linfática , MAP Quinase Quinase 1/metabolismo , Camundongos , Camundongos Nus , Modelos Anatômicos , Invasividade Neoplásica , Metástase Neoplásica , Ativador de Plasminogênio Tipo Uroquinase/metabolismo
13.
J Exp Clin Cancer Res ; 22(1): 57-60, 2003 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-12725323

RESUMO

Recently, a new concept for cancer therapy termed "tumor dormancy therapy" has been proposed. The concept of this therapy is to prolong the survival time of cancer patients while maintaining their quality of life. We have been developing a differentiation-inducing therapy, which is included in the tumor dormancy therapy, for salivary gland cancer. In this study, we examined the effect of a differentiation-inducing drug, Vesnarinone on the growth of several cancer cells, and examined the molecular mechanism by which Vesnarinone induces the cyclin dependent kinase inhibitor, p21waf1 in the cancer cells. Vesnarinone significantly suppressed the growth of TYS (salivary gland cancer cells), PC3 (prostate cancer cells), and A431 (squamous cell cancer cells). Furthermore, Vesnarinone dose-dependently enhanced the expression of p21waf1 mRNA in TYS cells. Using the luciferase reporter assay it was found that the enhancement of p21waf1 mRNA expression by Vesnarinone was through direct transcriptional activation of the p21waf1 promoter. Thus, analyzing the molecular mechanisms of differentiation inducing drugs may lead to the development of a new therapeutic strategy for several human malignancies, including salivary gland cancer.


Assuntos
Antineoplásicos/uso terapêutico , Ciclinas/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Quinolinas/uso terapêutico , Neoplasias das Glândulas Salivares/patologia , Ativação Transcricional , Diferenciação Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p21 , Quinases Ciclina-Dependentes/genética , Inibidores Enzimáticos , Humanos , Plasmídeos , Pirazinas , RNA Mensageiro/genética , Neoplasias das Glândulas Salivares/tratamento farmacológico , Células Tumorais Cultivadas
14.
J Exp Clin Cancer Res ; 22(1): 117-23, 2003 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-12725331

RESUMO

Carcinoma cells with high metastatic potential often show a dedifferentiated phenotype at the primary site. In this study, a total of 48 cases (24 primary tumors of colorectal cancer (Pr-CRC) with liver metastasis, 24 without) were examined for E-cadherin and ZO-1 expression by immunohistochemical staining, and for their dedifferentiated phenotype. The expression levels of E-cadherin and ZO-1 were markedly decreased in the cancer cells of tumors with liver metastasis. Moreover, dedifferentiation of cancer cells, which was evaluated by the modified Gleason score, was also related to liver metastasis. However, none of the conventional clinicopathologic parameters of invasion, except lymph node metastasis, showed any relationship with liver metastasis. These results indicate that dedifferentiation and a decreased expression of E-cadherin and ZO-1 are closely related to liver metastasis.


Assuntos
Caderinas/metabolismo , Moléculas de Adesão Celular/metabolismo , Neoplasias do Colo/patologia , Neoplasias Colorretais/patologia , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas/secundário , Proteínas de Membrana/metabolismo , Fosfoproteínas/metabolismo , Neoplasias Retais/patologia , Diferenciação Celular , Distribuição de Qui-Quadrado , Feminino , Humanos , Imuno-Histoquímica , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Metástase Neoplásica , Proteína da Zônula de Oclusão-1
15.
Br J Cancer ; 87(9): 1042-6, 2002 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-12434298

RESUMO

We previously demonstrated that a differentiation inducing drug, vesnarinone induced the growth arrest and p21(waf1) gene expression in a human salivary gland cancer cell line, TYS. In the present study, we investigated the mechanism of the induction of p21(waf1) gene by vesnarinone in TYS cells. We constructed several reporter plasmids containing the p21(waf1) promoter, and attempted to identify vesnarinone-responsive elements in the p21(waf1) promoter. By the luciferase reporter assay, we identified the minimal vesnarinone-responsive element in the p21(waf1) promoter at -124 to -61 relative to the transcription start site. Moreover, we demonstrated by electrophoretic mobility shift assay that Sp1 and Sp3 transcription factors bound to the vesnarinone-responsive element. Furthermore, we found that vesnarinone induced the histone hyperacetylation in TYS cells. These results suggest that vesnarinone directly activates p21(waf1) promoter via the activation of Sp1 and Sp3 transcription factors and the histone hyperacetylation in TYS cells.


Assuntos
Antineoplásicos/farmacologia , Ciclinas/genética , Histona Desacetilases/metabolismo , Regiões Promotoras Genéticas , Quinolinas/farmacologia , Fator de Transcrição Sp1/metabolismo , Células Tumorais Cultivadas/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p21 , Ciclinas/metabolismo , Ensaio de Desvio de Mobilidade Eletroforética , Deleção de Genes , Regulação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Luciferases/metabolismo , Plasmídeos , Pirazinas , Neoplasias das Glândulas Salivares/tratamento farmacológico , Neoplasias das Glândulas Salivares/genética , Neoplasias das Glândulas Salivares/metabolismo , Transcrição Gênica , Ativação Transcricional , Células Tumorais Cultivadas/metabolismo , Regulação para Cima
16.
Int J Oncol ; 20(3): 453-61, 2002 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-11836554

RESUMO

The prognosis of extrahepatic biliary tract cancer (EBT) patients is generally accepted to be poor. We immunohistochemically evaluated expression of p16, a cyclin-depend kinase inhibitor, in tumor specimens surgically removed from 99 EBT patients. We also examined whether there was any relationship between expression of p16 and biological malignancy of the tumor by comparing its clinicopathological factors. Consequently, we found that there were three types of p16 expression in the tumor cells; diffuse, heterogeneous and negative types, the percentages of which were 19, 41 and 39%, respectively. Heterogeneous and negative types, whose expression of p16 was considered to be down-regulated, showed scirrhous (p=0.022) and infiltrating growth (p=0.002). In addition, we found that the proportion of down-regulated expression of p16 was different, depending on the location of the tumor. We also observed that the down-regulated p16 expression was the highest in a proportion of patients with the extrahepatic bile duct carcinoma. In contrast, the proportion of down-regulated p16 expression was the least among the patients in the region of the ampulla of Vater with better prognosis, and we showed that the prognosis of patients with down-regulated expression of p16 was the poorest in terms of the cancer location where it is limited to the region of ampulla of Vater. These findings suggest that down-regulated p16 expression is evaluated as a factor of poorer prognosis and also that immunohistochemical pattern of p16 expression becomes a marker reflecting the biological malignancy of EBT patients.


Assuntos
Neoplasias do Sistema Biliar/metabolismo , Carcinoma/metabolismo , Inibidor p16 de Quinase Dependente de Ciclina/biossíntese , Regulação para Baixo , Prognóstico , Ampola Hepatopancreática/metabolismo , Neoplasias do Sistema Biliar/diagnóstico , Western Blotting , Carcinoma/diagnóstico , Humanos , Imuno-Histoquímica , Fatores de Tempo , Resultado do Tratamento , Células Tumorais Cultivadas , Regulação para Cima
18.
J Pharmacol Exp Ther ; 299(2): 645-51, 2001 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-11602677

RESUMO

We have previously shown that immunoglobulin therapy suppressed murine coxsackievirus B3 myocarditis. In the present study, we examined the effects of immunoglobulin upon murine myocarditis induced by encephalomyocarditis virus, which is not pathogenic to humans. Antiviral activity of immunoglobulin (Venilon) against encephalomyocarditis virus could not be detected in vitro. The production of cytokines was decreased in virus-infected macrophages by the treatment of immunoglobulin in vitro. Immunoglobulin (1 g/kg/day) was administered intraperitoneally to the virus-infected C3H/He mice daily for 2 weeks, beginning simultaneously with virus inoculation in experiment I and on day 14 after virus inoculation in experiment II. In experiment I, survival rate did not differ significantly between immunoglobulin-treated and untreated groups. In experiment II, survival rate was higher in immunoglobulin compared with control groups. Immunoglobulin administration suppressed the development of myocardial necrosis with T-lymphocyte infiltrates in mice not only in the acute viremic but in the chronic aviremic stages concomitantly associated with the reduction of inflammatory cytokines, i.e., tumor necrosis factor-alpha, interferon-gamma, macrophage inflammatory protein-2, and interleukin-6. Taken together, immunoglobulin therapy could have the potential to prevent congestive heart failure.


Assuntos
Infecções por Cardiovirus/terapia , Citocinas/biossíntese , Vírus da Encefalomiocardite , Insuficiência Cardíaca/prevenção & controle , Imunização Passiva , Animais , Infecções por Cardiovirus/complicações , Infecções por Cardiovirus/metabolismo , Linhagem Celular , Citocinas/sangue , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/patologia , Camundongos , Miocárdio/patologia , Tamanho do Órgão/efeitos dos fármacos
19.
Acta Neuropathol ; 102(4): 329-34, 2001 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-11603807

RESUMO

Alpha-synuclein, a protein in which two mutations have been identified that cause autosomal dominant Parkinson's disease, is thought to serve as a nidus for the development of a Lewy body. We hypothesized that alpha-synuclein would display different intra- and intermolecular associations in Lewy bodies than it does in its normal intracellular compartments. Using sensitive fluorescence resonance energy transfer (FRET) techniques, we found evidence that alpha-synuclein is more compact and in closer association with other alpha-synuclein molecules in Lewy bodies than it is in the neuropil. In addition, we found evidence of a close, direct intermolecular interaction between the N terminus of alpha-synuclein and ubiquitin. These observations provide support for the hypothesis that in Lewy bodies alpha-synuclein adopts an altered three-dimensional structure and undergoes N-terminal ubiquitination.


Assuntos
Corpos de Lewy/patologia , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/metabolismo , Doença de Parkinson/patologia , Ubiquitina/metabolismo , Hipocampo/patologia , Humanos , Corpos de Lewy/química , Neurópilo/patologia , Conformação Proteica , Espectrometria de Fluorescência , Substância Negra/patologia , Sinucleínas , alfa-Sinucleína
20.
Int J Oncol ; 19(5): 903-7, 2001 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-11604986

RESUMO

The aim of our current study was to establish an orthotopic inoculation model for studying invasion and metastasis of esophageal squamous cell carcinoma (SCC). Male BALB/c nude mice were used for the experiment. A midline incision was made from the upper to middle abdomen. The abdominal esophagus was carefully exposed. Human esophageal T.Tn SCC cells or human cervical HeLa SCC cells, were injected into the submucosa of the lower esophagus. One of the mice injected with T.Tn cells was sacrificed at 5 weeks, and the remaining five sacrificed at 13 weeks after inoculation. The mice injected with HeLa cells were sacrificed at 3-4 weeks after inoculation. T.Tn cells and HeLa cells formed tumors at the esophagus, but did not metastasize to lymph nodes or lungs. HeLa cells produced peritoneal implants, and directly invaded the stomach and the liver. In the present study, we established a novel orthotopic inoculation model of esophageal SCC. This system is an appropriate and a useful model for studying invasion and metastasis of esophageal SCC, and can also be used as a model for developing therapeutic strategies for esophageal cancer in vivo.


Assuntos
Carcinoma de Células Escamosas/patologia , Neoplasias Esofágicas/patologia , Metástase Linfática , Invasividade Neoplásica , Animais , Modelos Animais de Doenças , Células HeLa , Humanos , Injeções Intraperitoneais , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Transplante de Neoplasias , Células Tumorais Cultivadas
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