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1.
Calcif Tissue Int ; 114(5): 502-512, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38555554

RESUMO

Non-alcoholic fatty liver disease (NAFLD) has been found to be associated with osteoporosis (OP) in observational studies. However, the precise causal relationship between NAFLD and OP remains unclear. Here, we used Mendelian randomization (MR) to explore the causal relationship. We selected NAFLD-related single-nucleotide polymorphisms from a genome-wide meta-analysis (8434 cases and 434,770 controls) as instrumental variants. We used inverse variance weighted analysis for the primary MR analysis. Furthermore, we used similar methodologies in parallel investigations of other chronic liver diseases (CLDs). We performed sensitivity analyses to ensure the reliability of the results. We observed a causality between NAFLD and forearm bone mineral density (FABMD) (beta-estimate [ß]: - 0.212; p-value: 0.034). We also found that sclerostin can act as a mediator to influence the NAFLD and FABMD pathways to form a mediated MR network (mediated proportion = 8.8%). We also identified indications of causal relationships between other CLDs and OP. However, we were unable to establish any associated mediators. Notably, our analyses did not yield any evidence of pleiotropy. Our findings have implications in the development of preventive and interventional measures aimed at managing low bone mineral density in patients with NAFLD.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Densidade Óssea , Análise da Randomização Mendeliana , Hepatopatia Gordurosa não Alcoólica , Osteoporose , Polimorfismo de Nucleotídeo Único , Humanos , Densidade Óssea/genética , Densidade Óssea/fisiologia , Hepatopatia Gordurosa não Alcoólica/genética , Osteoporose/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Estudo de Associação Genômica Ampla , Marcadores Genéticos
2.
Nutr Cancer ; 75(7): 1560-1570, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37289106

RESUMO

Currently, it is unknown whether fatty acids (FAs) and primary liver cancer (PLC) are associated. The cause-effect association was established using a two-sample Mendelian randomization (MR) study. Eligible single nucleotide polymorphisms were selected as instrumental variables from six FAs genome-wide association studies. The outcome involved a total of 260,428 subjects and was a summary of genetic data on PLC from FinnGen biobanks. The principal method inverse variance weighted (IVW) and several other analytical approaches (MR-Egger, Weighted Median, and Maximum likelihood) were tested to determine the causal relationship between different FAs and PLC. Furthermore, sensitivity analyses were performed to determine the stability of the results. The two-sample MR analysis revealed a negative causal relationship between omega-3 FAs and PLC. It was discovered that an increase in each standard deviation (0.53 mmol/L; SD: 0.22) in the genetic levels of omega-3 FAs reduced the risk of PLC by 62.1% through the IVW method [odd ratio: 0.379; 95% confidence interval (0.176, 0.816)]. Nevertheless, other FAs were not statistically correlated with PLC. Additionally, no pleiotropy was found between the two. According to the MR study, consuming omega-3 FAs may help prevent PLC.


Assuntos
Ácidos Graxos Ômega-3 , Neoplasias Hepáticas , Humanos , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Ácidos Graxos , Polimorfismo de Nucleotídeo Único , Neoplasias Hepáticas/genética
3.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 45(6): 902-911, 2023 Dec 30.
Artigo em Chinês | MEDLINE | ID: mdl-38173100

RESUMO

Objective To analyze the clinical characteristics of collagenous gastritis (CG) and provide evidence for the precise diagnosis and treatment of CG.Methods Published case reports and case series were collected from PubMed,CNKI,and Wanfang Med Online with the key words of collagenous gastritis,collagenous gastroduodenitis,collagenous gastrointestinal diseases,and gastric mucosal nodules.The demographic and clinical information of each case was collected.Results According to the extent of collagen deposition in the digestive tract,94 CG cases included in this study were assigned into upper digestive tract (UDT)-CG,total digestive tract (TDT)-CG and other groups.The UDT-CG group included 52 cases (57.69% females and 42.31% males) with a median age of 14.50 (11.00,25.75) years old.There were 17 cases in the TDT-CG group,including 70.59% females and 29.41% males,with a median age of 15.00 (9.50,48.50) years old.The other group contained 25 cases,(64.00% females and 36.00% males) with a median age of 25.00 (15.50,59.50) years old.The main clinical manifestations in the UDT-CG group were anemia (59.62%) and diarrhea (17.31%),and those in the TDT-CG group were anemia (29.41%) and diarrhea (94.12%).The nodular appearance of gastric mucosa was observed in 75.00% cases in the UDT-CG group and 35.29% cases in the TDT-CG group.In the initial treatment,symptomatic therapy and hormonal therapy respectively relieved the symptoms in 75.00% (30/40) and 100% (3/3) cases in the UDT-CG group and 57.14% (4/7) and 83.33% (5/6) cases in the TDT-CG group.In the retreatment,symptomatic therapy and hormone therapy respectively achieved the remission rates of 100.00% (3/3) and 88.89% (8/9) in the UDT-CG group and 80.00% (4/5) and 66.67% (2/3) in the TDT-CG group.Conclusions CG,a rare disease of gastric collagen deposition,mainly occurs in young patients,and females are more susceptible than males.The clinical manifestations of CG are nonspecific,and anemia,abdominal pain,diarrhea,weight loss,and gastrointestinal bleeding are the common symptoms of CG.Nodular appearance of gastric mucosa is a relatively specific endoscopic feature of CG.There is no standardized treatment for CG.Symptomatic treatment is commonly adopted to improve the quality of life of the patients,and hormones can be added when necessary.


Assuntos
Anemia , Gastrite , Masculino , Feminino , Humanos , Qualidade de Vida , Gastrite/diagnóstico , Mucosa Gástrica , Colágeno , Anemia/etiologia , Diarreia/complicações
4.
Front Biosci (Landmark Ed) ; 24(5): 935-946, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30844721

RESUMO

The ubiquitously expressed multifunctional protein, CUEDC2 (CUE domain-containing 2), is involved in many physiological and pathological processes, including the cell cycle regulation and inflammation. Although it is known that CUEDC2 is expressed disparately in breast cancer, ovarian carcinoma, hepatocellular carcinoma, cholangiocarcinoma, glioma, lung adenocarcinoma, colon cancers, and is involved in the Warburg's effect, its role in oncogenesis remains to be further explored. In this review, we examine the expression of CUEDC2 in various tumors, and discuss several fundamental signaling pathways that are impacted by CUEDC2.


Assuntos
Carcinogênese/metabolismo , Proteínas de Transporte/metabolismo , Proteínas de Membrana/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Adenocarcinoma/metabolismo , Animais , Neoplasias Encefálicas/metabolismo , Neoplasias da Mama/metabolismo , Carcinoma Hepatocelular/metabolismo , Ciclo Celular , Colangiocarcinoma/metabolismo , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Glioma/metabolismo , Humanos , Inflamação , Neoplasias Hepáticas/metabolismo , Neoplasias Pulmonares/metabolismo , Macrófagos/patologia , Masculino , Camundongos , Mitose , NF-kappa B/metabolismo , Neoplasias Ovarianas/metabolismo
6.
Front Psychiatry ; 9: 115, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29867593

RESUMO

OBJECTIVE: To assess the correlation between the incidence of non-erosive reflux disease (NERD) and mental and psychological factors, deepen the understanding of the pathogenesis of NERD and explore effective treatments. METHODS: NERD patients with mood disorders who met the inclusion criteria were randomly divided into a drug treatment group, a psychotherapy group, and a psychotherapy combined with drug treatment group. Before and after treatment, the patients were retrospectively analyzed using the gastroesophageal reflux disease Questionnaire, Hamilton Depression Scale, Hamilton Anxiety Scale, and SF-36 Quality of Life Scale. RESULTS: All three treatments were found to relieve patients' symptoms and improve their quality of life to some extent. The psychotherapy combined with drug treatment group showed the best overall curative effect. The Hamilton Depression and Anxiety Scale scores were significantly lower in the psychotherapy-alone group and psychotherapy combined with drug treatment group than in the drug treatment alone group at 4, 8, and 12 weeks (P < 0.05). CONCLUSION: Medication, psychotherapy, and psychotherapy combined with medication can relieve clinical symptoms and improve quality of life to varying degrees in patients with NERD.

7.
Cell Physiol Biochem ; 44(2): 817-827, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29176321

RESUMO

BACKGROUND/AIMS: Primary angiosarcoma of the small intestine is a rare neoplasia, and there are limited data from systematic analyses. The aim of this study is to describe the clinical and pathological characteristics in addition to the prognostic factors for this rare neoplasia. METHODS: We retrospectively collected the clinical records and prognostic information of 66 patients with small intestine angiosarcoma reported between 1970 and 2017. We used the Chi-square test, the log-rank test, and Cox regression analyses to evaluate the data. RESULTS: There were 66 patients diagnosed with small intestine angiosarcoma. The onset age ranged from 24-92 years old. There were 24 patients diagnosed before the year 2000, and 42 patients were diagnosed after 2000. The data indicated that 49 cases were diagnosed as primary disease, and the remaining 15 cases were secondary disease. The main clinical symptoms were nonspecific and included gastrointestinal (GI) bleeding and abdominal pain. Additionally, we found multi-center foci were one of the characteristics of this disease. Radiation-induced small intestine angiosarcoma (RSIA) is a special type of disease with a similar prognosis. This type was more frequent in females and decreased after the year 2000. We also found that GI bleeding was less common in RSIA cases. The log-rank test results revealed that old-age, poor differentiation, and GI bleeding were associated with worse prognosis. Surgical treatment showed a trend toward a prolonged survival time. However, the result was not statistically significant. Our results show treatment with adjuvant therapy improved prognosis. The multivariate Cox analysis demonstrated adjuvant therapy was an independent indicator of a favorable outcome in small intestine angiosarcoma patients. CONCLUSION: Pay attention to the unexplained gastrointestinal bleeding could lead to a faster diagnosis and control of small intestine angiosarcoma. Furthermore, treatments including adjuvant therapy can effectively improve the prognosis.


Assuntos
Hemangiossarcoma/diagnóstico , Neoplasias Intestinais/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimioterapia Adjuvante , Bases de Dados Factuais , Feminino , Hemorragia Gastrointestinal , Hemangiossarcoma/mortalidade , Hemangiossarcoma/terapia , Humanos , Neoplasias Intestinais/mortalidade , Neoplasias Intestinais/terapia , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores Sexuais , Adulto Jovem
8.
Tumour Biol ; 39(6): 1010428317705013, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28651486

RESUMO

PTOV1 has been demonstrated to play an extensive role in many types of cancers. This study takes the first step to clarify the potential relationship between esophageal squamous cell carcinoma and PTOV1 expression and highlight the link between PTOV1 and the tumorigenesis, progression, and prognosis of esophageal squamous cell carcinoma. PTOV1 expression was detected by quantitative reverse transcription polymerase chain reaction and western blotting or immunohistochemical staining in esophageal squamous cell carcinoma cell lines, esophageal squamous cell carcinoma tissues, and its paired adjacent non-cancerous tissues. Moreover, we have analyzed the relationship between PTOV1 expression and clinicopathological features of esophageal squamous cell carcinoma. Survival analysis and Cox regression analysis were used to assess its prognostic significance. We found that PTOV1 expression was significantly higher in the esophageal squamous cell carcinoma cell lines and tissues at messenger RNA level (p < 0.001) and protein level (p < 0.001). Gender, tumor size, or differentiation was tightly associated with the PTOV1 expression. Lymph node involvement (p < 0.001) and TNM stage (p < 0.001) promoted a high PTOV1 expression. A prognostic significance of PTOV1 was also found by Log-rank method, and the overexpression of PTOV1 was related to a shorter OS and DFS. Multiple Cox regression analysis indicated overexpressed PTOV1 as an independent indicator for adverse prognosis. In conclusion, this study takes the lead to demonstrate that the overexpressed PTOV1 plays a vital role in the tumorigenesis and progression of esophageal squamous cell carcinoma, and it is potentially a valuable prognostic predicator and new chemotherapeutic target for esophageal squamous cell carcinoma.


Assuntos
Biomarcadores Tumorais/genética , Carcinogênese/genética , Carcinoma de Células Escamosas/genética , Neoplasias Esofágicas/genética , Proteínas de Neoplasias/genética , Prognóstico , Adulto , Idoso , Biomarcadores Tumorais/biossíntese , Carcinoma de Células Escamosas/patologia , Progressão da Doença , Intervalo Livre de Doença , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Metástase Linfática , Pessoa de Meia-Idade , Proteínas de Neoplasias/biossíntese , Estadiamento de Neoplasias
9.
Biomed Res Int ; 2017: 5090534, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28484712

RESUMO

Many factors have been reported to affect the long-term survival of gastric carcinoma patients after gastrectomy; the present study took the first attempt to find out the potential role of weekday carried out surgery in the postoperative prognosis of gastric cancer patients. 463 gastric cancer patients have been followed up successfully. Pearson χ2 test was used for univariate analyses. Survival curves were constructed by using Kaplan-Meier method and evaluated by using the log-rank test. The Cox proportional hazard regression model was used to find out the risk factors, and subgroup analysis was conducted to rule out confounding factors. We found that the patients who underwent gastrectomy on the later weekday (Wednesday-Friday) more easily suffered from a higher postoperative morbidity. Weekday of surgery was one of the independent indicators for the prognosis of patients after gastric cancer surgery. However, the role of weekday of surgery was significantly weakened in the complications group. In conclusion, surgery performed in the later weekday was more likely to lead to increased postoperative complications and an unfavorable role in prognosis of Chinese gastric cancer patients after curative gastrectomy.


Assuntos
Complicações Pós-Operatórias/mortalidade , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/cirurgia , Adulto , Idoso , Povo Asiático , China/epidemiologia , Intervalo Livre de Doença , Humanos , Pessoa de Meia-Idade , Taxa de Sobrevida
10.
Oncotarget ; 7(41): 66851-66864, 2016 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-27588477

RESUMO

Patients with esophageal squamous cell cancer are often diagnosed with advanced diseases that respond poorly to chemotherapy. Overexpression of eIF4E leads to enhance the translation of key malignancy-related proteins and enabling tumor growth and chemoresistance in a variety of human malignancies, but whether it has a role in ESCC remains obscure. We hypothesized that eIF4E promoted ESCC tumorigenesis and facilitated the development of acquired resistance to the cisplatin-based chemotherapy. In this study, we showed that eIF4E expression was increased significantly in clinical ESCC tissues and and ESCC cell lines and its expression level was correlated with lymph node metastasis, TNM stage, as well as overall and disease-free survival of ESCC. We also showed here that knockdown of eIF4E in EC9706 would dramatically reduced cell proliferation, colony formation, migration and invasion, apoptosis in vitro as well as in vivo, and vice versa. Moreover, "weak mRNAs" were demonstrated to be regulated by eIF4E in ESCC, which might interpret the above function. Overexpression of eIF4E decreased the efficacy of cisplatin-induced cell growth inhibition in ESCC cell line and xenograft model (P < 0.05). eIF4E knockdown by shRNA increased cisplatin-induced cytotoxicity in ESCC cell lines, and enhanced chemosensitivity to cisplatin in xenograft tumor models. Furthermore, we found that the PI3K/AKT pathway and Bcl-2/Bax ratio might be responsible for the eIF4E-induced cisplatin resistance in ESCC. Our data collectively show association of eIF4E expression with chemotherapeutic response in ESCC, and suggest that therapeutically targeting eIF4E may be a viable means of improving chemotherapy response in ESCC.


Assuntos
Carcinoma de Células Escamosas/tratamento farmacológico , Cisplatino/farmacologia , Neoplasias Esofágicas/tratamento farmacológico , Fator de Iniciação 4E em Eucariotos/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Antineoplásicos/farmacologia , Carcinogênese/genética , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , Fator de Iniciação 4E em Eucariotos/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Estimativa de Kaplan-Meier , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Interferência de RNA , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética
11.
Mol Med Rep ; 14(3): 1933-40, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27432467

RESUMO

Apollon, an unusually large member of the inhibitors of apoptosis protein family, may be important for oncogenesis development. The aim of the present study was to assess the association between esophageal squamous cell carcinoma (ESCC) and Apollon expression levels, and to highlight the association between Apollon and the occurrence, development and prognosis of ESCC. Apollon expression was detected by immunohistochemical staining and reverse transcription-quantitative polymerase chain reaction in ESCC tissues, adjacent non­cancerous tissues and paired normal tissues respectively, in order to analyze the association between Apollon expression and the clinicopathological features of ESCC. Survival analysis was used to assess the prognostic significance of Apollon expression. It was determined that the mRNA and protein expression levels of Apollon were significantly higher in the carcinoma tissues compared with the adjacent non­cancerous tissues and normal control tissues (P<0.001). There was a significant difference in lymph node involvement and the tumor, nodes, and metastases stage in patients categorized according to different Apollon expression levels. The prognostic significance of Apollon was also determined using the log­rank method. The overexpression of Apollon was associated with shorter overall survival and disease-free survival rates. The present study indicates that Apollon expression is associated with the biological characteristics of ESCC, and may be a valuable prognostic factor and a novel chemotherapeutic target for ESCC treatment.


Assuntos
Carcinoma de Células Escamosas/metabolismo , Neoplasias Esofágicas/metabolismo , Regulação Neoplásica da Expressão Gênica , Proteínas Inibidoras de Apoptose/genética , Adulto , Idoso , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/patologia , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Análise de Sobrevida
12.
World J Gastroenterol ; 22(23): 5342-52, 2016 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-27340350

RESUMO

AIM: To develop a potent and safe gene therapy for esophageal cancer. METHODS: An expression vector carrying fusion suicide gene (yCDglyTK) and shRNA against vascular endothelial growth factor (VEGF) was constructed and delivered into EC9706 esophageal cancer cells by calcium phosphate nanoparticles (CPNP). To achieve tumor selectivity, expression of the fusion suicide gene was driven by a tumor-specific human telomerase reverse transcriptase (hTERT) promoter. The biologic properties and therapeutic efficiency of the vector, in the presence of prodrug 5-fluorocytosine (5-FC), were evaluated in vitro and in vivo. RESULTS: Both in vitro and in vivo testing showed that the expression vector was efficiently introduced by CPNP into tumor cells, leading to cellular expression of yCDglyTK and decreased VEGF level. With exposure to 5-FC, it exhibited strong anti-tumor effects against esophageal cancer. Combination of VEGF shRNA with the fusion suicide gene demonstrated strong anti-tumor activity. CONCLUSION: The shVEGF-hTERT-yCDglyTK/5-FC system provided a novel approach for esophageal cancer-targeted gene therapy.


Assuntos
Neoplasias Esofágicas/terapia , Genes Transgênicos Suicidas , Vetores Genéticos/administração & dosagem , RNA Interferente Pequeno/uso terapêutico , Terapêutica com RNAi/métodos , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Fosfatos de Cálcio/química , Linhagem Celular Tumoral , Portadores de Fármacos/química , Feminino , Flucitosina/administração & dosagem , Flucitosina/uso terapêutico , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas/química , Regiões Promotoras Genéticas , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/metabolismo , Telomerase/genética , Transfecção , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Diagn Pathol ; 10: 202, 2015 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-26576674

RESUMO

BACKGROUND: Flot2, a highly conserved protein of the SPFH domain containing proteins family, has recently been identified as oncogene to be involved in the tumorigenesis and metastasis of several cancers including gastric cancer. However, the underlying molecular mechanism of Flot2 in gastric cancer (GC) is largely unknown. METHODS: qRT-PCR and western blot was performed to detect miR-449a and Flot2 expression in GC cell lines and Normal human gastric epithelial cells. Then, luciferase reporter assay was used to elucidate whether Flot2 is a target gene of miR-449a. Finally, the roles and mechanism of miR-449a in regulation of tumor invasion were further investigated. RESULTS: In this study, miR-449a expression was downregulated and Flot2 was upregulated in all GC cell lines as compared with that in GES-1. luciferase reporter assay identified Flot2 as a novel direct target of miR-449a. miR-449a regulated GC cell invasion by suppressing Flot2 expression. Expression analysis of a set of epithelial-mesenchymal transition (EMT) markers showed that miR-449a reduced the expression of mesenchymal markers (vimentin and N-cadherin) and induced the expression of epithelial marker (E-cadherin), which was consistent with silenced Flot2. Moreover, Flot2 is necessary for TGF-ß-induced EMT in GC cells. CONCLUSIONS: Our results demonstrated that miR-449a suppressed Flot2 expression results in decreased cell invasion through repressing TGF-ß-mediated-EMT, and provides a new theoretical basis to further investigate miR-449a-regulated Flot2 as a potential biomarker and a promising approach for GC treatment.


Assuntos
Transição Epitelial-Mesenquimal , Proteínas de Membrana/metabolismo , MicroRNAs/metabolismo , Neoplasias Gástricas/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Caderinas/metabolismo , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Invasividade Neoplásica , Neoplasias Gástricas/patologia
14.
Cell Biol Int ; 36(10): 893-9, 2012 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-22694478

RESUMO

Primary liver cancer is one of the highly malignant tumours. The traditional surgery, chemotherapy and radiation therapy only established 6% of 5-year survival rate in HCC (hepatocellular carcinoma). Therefore there is an urgent need to develop new therapeutic strategies. HSP90 (heat shock protein 90) is one of the important molecular chaperones and was identified with high expression in the primary liver cancer. In this study, we evaluated the therapeutic effect of specific HSP90 inhibitor 17-DMAG (17-dimethylaminoethylamino-17-demethoxy geldanamycin) in HCC cells. The time and concentration effects of 17-DMAG were investigated in HCC cells. Cell proliferation was measured by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide] assay and cell counting. Apoptosis was detected by flow cytometry with staining of Annexin V-FITC/PI (propidium iodide). The protein levels of survivin, cyclin D1, p53 and NF-κB (nuclear factor κB) were measured by Western blotting. 17-DMAG inhibited the proliferation of HCC cells in a time- and concentration-dependent manner. Treatment with 400 nmol/l 17-DMAG for 48 h significantly induced early-stage apoptosis (22.4%). Conversely, it induced less late-stage apoptosis (3.03%). The 5 mg/l of cisplatin induced significantly less early-stage apoptosis (6.5%), but similar proportion of late-stage apoptosis (4.89%) compared with 17-DMAG. Inhibition of HSP90 activity by 400 nmol/l 17-DMAG decreased protein levels of survivin, cyclin D1 and NF-κB protein levels, whereas increased p53 protein level. HSP90 plays a key role in HCC cell growth and survival through regulation of survivin, cyclin D1, p53 and nucleus NF-κB protein levels and the specific HSP90 inhibitor 17-DMAG can play a therapeutic role in HCC treatment.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Benzoquinonas/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Lactamas Macrocíclicas/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cisplatino/farmacologia , Ciclina D1/antagonistas & inibidores , Ciclina D1/metabolismo , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Proteínas Inibidoras de Apoptose/antagonistas & inibidores , Proteínas Inibidoras de Apoptose/metabolismo , Neoplasias Hepáticas/metabolismo , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Survivina , Proteína Supressora de Tumor p53/agonistas , Proteína Supressora de Tumor p53/metabolismo
15.
Dig Dis Sci ; 57(7): 1822-31, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22466098

RESUMO

BACKGROUND: Pim-1 kinase is involved in the control of cell growth, differentiation and apoptosis. Recent evidence suggests that Pim kinases play a role in immune regulation and inflammation. However, the role of Pim-1 kinase in inflammatory bowel diseases (IBD) remains unclear. AIMS: The aims of this study were to explore the role of Pim-1 kinase in the pathology of IBD and to assess whether inhibiting Pim-1 kinase may be of therapeutic benefit as a treatment regimen for IBD. METHODS: Colitic mouse model was established by the induction of dextran sodium sulfate. The expression of Pim-1 in the colonic samples of control and colitic mice was examined. Furthermore, the mice were treated with Pim-1inhibitor (PIM-Inh), then the body weight and colon inflammation were evaluated, and the production of cytokines including IFN-γ, IL-4, TGF-ß and IL-17 in colon tissues was determined by ELISA. The expression of T cell master transcription factors T-bet, ROR-γt, GATA-3 and Foxp3 and Nuclear factor κB (NF-κB) and inducible nitric oxide synthase in colon tissues was detected by real-time PCR and western blot. Finally, the effect of LPS on Pim-1 expression and the effects of PIM-Inh on LPS-induced upregualtion of p65 and TNF-α in RAW264.7 cells were examined by real-time PCR and western blot. RESULTS: Pim-1 expression was correlated with the degree of mucosal inflammation in vivo, and it was significantly induced by LPS in vitro. PIM-Inh had protective effects on acute colitis in vivo. Mechanistically, PIM-Inh reduced the proinflammatory immune response through the inhibition of the overactivation of macrophages and the down-regulation of excessive Th1- and Th17-type immune responses. Furthermore, PIM-Inh could skew T cell differentiation towards a Treg phenotype. CONCLUSIONS: Pim-1 kinase is involved in mucosal injury/inflammation and Pim-1 kinase inhibitor may provide a novel therapeutic approach for IBD.


Assuntos
Colite/metabolismo , Colite/prevenção & controle , Inibidores Enzimáticos/uso terapêutico , Proteínas Proto-Oncogênicas c-pim-1/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-pim-1/metabolismo , Animais , Células Cultivadas , Colite/induzido quimicamente , Colo/efeitos dos fármacos , Colo/metabolismo , Colo/patologia , Citocinas/metabolismo , Sulfato de Dextrana/efeitos adversos , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Técnicas In Vitro , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Proto-Oncogênicas c-pim-1/efeitos dos fármacos , Fatores de Transcrição/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima/efeitos dos fármacos , eIF-2 Quinase/metabolismo
16.
Med Oncol ; 29(2): 1010-6, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21424326

RESUMO

Hedgehog signaling pathway plays an important role in normal mammalian gastrointestinal development and is implicated in the oncogenesis of various tumors. However, its correlation with progression and prognosis of colon cancer has not been well documented. This study was designed to investigate expression patterns of related proteins in hedgehog signaling pathway in colon cancer to elucidate its prognostic value in this tumor. Using human colon cancer and their corresponding non-diseased colon from 228 patients' biopsies, the expression of sonic hedgehog, its receptor Patched, and downstream transcription factor Gli1 was investigated by immunohistochemical staining to assess their association with the clinicopathological characteristics of colon cancer. Disease-free survival and overall survival were examined by Kaplan-Meier estimates and the log-rank test. Prognostic factors were determined by multivariate Cox analysis. One hundred and thirty-eight patients (59.6%) had sonic hedgehog-positive tumors and that the disease-free survival (43.5 vs. 73.3%, P < 0.001), and overall survival rates (50.7 vs. 88.9%, P < 0.001) of patients with sonic hedgehog-positive tumors were much lower than those of patients with sonic hedgehog-negative tumors. In addition, 163 patients (71.5%) had Patched-positive tumors, and the disease-free survival (41.7 vs. 76.9%, P < 0.001) and overall survival rates (55.2 vs. 80.0%, P = 0.002) of patients with Patched-positive tumors were also lower than those of patients with Patched-negative tumors. Moreover, positive Gli1 expression had a bad effect on the disease-free survival (41.9 vs. 73.2%, P < 0.001) and overall survival rate of patients with colon cancer (50.0 vs. 89.3%, P < 0.001). In a multivariate analysis, sonic hedgehog, Patched, and Gli1 status were indicators for poor disease-free survival and overall survival. These results have shown that the increasing expression of sonic hedgehog, Patched, and Gli1 are indicators for a poor prognosis in patients with colon cancer. This is the first report describing about the relationship between hedgehog signaling pathway and the prognosis of colon cancer.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias do Colo/metabolismo , Proteínas Hedgehog/metabolismo , Receptores de Superfície Celular/metabolismo , Fatores de Transcrição/metabolismo , Colo/metabolismo , Colo/patologia , Neoplasias do Colo/mortalidade , Neoplasias do Colo/patologia , Feminino , Seguimentos , Humanos , Técnicas Imunoenzimáticas , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Receptores Patched , Prognóstico , Taxa de Sobrevida , Proteína GLI1 em Dedos de Zinco
17.
Exp Mol Pathol ; 91(3): 745-52, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21840308

RESUMO

Clinical trials of suicide gene therapy have achieved limited success, which suggests a need for improvement. Angiogenesis plays a crucial role in the progression of cancers, which is greatly regulated by vascular endothelial growth factor (VEGF).The current study was designed to evaluate the anti-tumor effects of VEGF siRNA in combination with fusion suicide gene yCDglyTK. Introduction of a VEGF-targeted small hairpin RNA (shVEGF) to CDTK/5-FC system could induce cell apoptosis more effectively and decrease micro vessel density in xenograft tissue, thus resulted in a significant tumor growth delay in SGC7901 xenografts. These findings for the first time suggest the potential of combination gene therapy using suicide gene therapy and anti-angiogenesis gene therapy.


Assuntos
Genes Transgênicos Suicidas , Terapia Genética/métodos , Neovascularização Patológica/genética , Neovascularização Patológica/terapia , RNA Interferente Pequeno , Neoplasias Gástricas/genética , Neoplasias Gástricas/terapia , Fator A de Crescimento do Endotélio Vascular/genética , Animais , Apoptose/genética , Linhagem Celular Tumoral , Feminino , Fusão Gênica , Humanos , Camundongos , Camundongos Nus , Transplante de Neoplasias , Interferência de RNA , Neoplasias Gástricas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Tumour Biol ; 32(6): 1103-11, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21761115

RESUMO

The strategies for tumor-specific expression of suicide genes and target tumor angiogenesis have been tested in tumors. However, the anti-tumor efficacy of the combination of these two strategies, particularly, delivering suicide gene and anti-angiogenesis agent by nanoparticles, has not yet been evaluated in colon carcinoma. We constructed a cassette to silence VEGF-A expression and express a fused yCDglyTK gene driven by tumor-specific promoter (shVEGF-CDTK). The DNA carrying shVEGF-CDTK was delivered into colon carcinoma cells by calcium phosphate nanoparticles (CPNPs). Cell proliferation was measured by MTT assay, and apoptosis was detected by flow cytometry. The anti-tumor effect of the combined cassette was tested in xenograft animal model. With 5-fluorocytosine (5-FC), CPNP-delivered shVEGF-CDTK DNA (CPNP-shVEGF-CDTK) showed high expression of fused yCDglyTK gene and effectively silenced VEGF-A expression in vitro and in vivo, which significantly inhibited colon carcinoma cell proliferation and induced apoptosis in vitro. With 5-FC, the systemic delivery of CPNP-shVEGF-CDTK significantly inhibited tumor growth in the colon carcinoma xenograft animal model. The combined cassette is obviously effective in inhibiting tumor cell proliferation and inducing apoptosis in vitro and tumor growth in vivo than the CPNP-shVEGF or CPNP-CDTK alone. The combination of VEGF-A-silencing and tumor-specific expression of suicide gene is an effective strategy for colon carcinoma treatment.


Assuntos
Neoplasias do Colo/terapia , Genes Transgênicos Suicidas/genética , Nanopartículas/química , RNA Interferente Pequeno/genética , Fator A de Crescimento do Endotélio Vascular/genética , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Antimetabólitos/farmacologia , Fosfatos de Cálcio/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Citosina Desaminase/genética , Citosina Desaminase/metabolismo , Flucitosina/farmacologia , Imunofluorescência , Técnicas de Transferência de Genes , Terapia Genética/métodos , Vetores Genéticos/química , Vetores Genéticos/genética , Herpesvirus Humano 1/enzimologia , Herpesvirus Humano 1/genética , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , RNA Interferente Pequeno/química , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Timidina Quinase/genética , Timidina Quinase/metabolismo , Leveduras/enzimologia , Leveduras/genética
19.
Med Oncol ; 27(4): 1102-8, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19885748

RESUMO

The aim of this paper was to identify novel proteins involved in the development of gastric cancer (GC). Isobaric tags for relative and absolute quantification (iTRAQ) analysis was adopted to separate the differentially expressed proteins between normal gastric epithelial cell line GES-1 and GC cell line SGC7901. Western blotting was utilized to validate the increased expression of sorcin in SGC7901; immunohistochemistry was performed to investigate its relationship with clinicopathological features of GC. Twelve differential proteins were identified. Seven proteins were found to be significantly upregulated (≥two-fold), while five proteins were markedly downregulated (≤0.5-fold), in SGC7901 cells. Sorcin was detected by this proteomic approach with a 5.4-fold upregulation in SGC7901. Western blotting and immunohistochemistry confirmed the overexpression of sorcin in GC. Immunohistochemistry showed us that sorcin was overexpressed in 55 samples of GC tissue (55/85, 64.71%) and was related closely to the depth of invasion, TNM stage, and lymph node metastasis of GC (P<0.05). The development of GC is regulated by multiple genes. Sorcin will be a novel molecular biomarker for the diagnosis, treatment, and prognosis of GC.


Assuntos
Adenocarcinoma/metabolismo , Biomarcadores/metabolismo , Proteômica , Neoplasias Gástricas/metabolismo , Western Blotting , Proteínas de Ligação ao Cálcio/metabolismo , Eletroforese em Gel Bidimensional , Humanos , Técnicas Imunoenzimáticas , Metástase Linfática , Espectrometria de Massas por Ionização por Electrospray , Células Tumorais Cultivadas , Regulação para Cima
20.
Zhonghua Nei Ke Za Zhi ; 48(2): 111-3, 2009 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-19549463

RESUMO

OBJECTIVE: To evaluate the diagnostic valve of double balloon enteroscopy in patients with obscure abdominal pain and analyze the etiology of chronic abdominal pain resulted from enteral diseases. METHODS: Sixty-seven cases with chronic abdominal pain underwent a previous negative gastroscopy, colonoscopy, gastrointestinal barium, B ultrasound and electrocardiogram were received double balloon enteroscopy during June 2005 to June 2008. RESULTS: Thirty-six of 67 patients was done by enteroscopy via anus, and 19 cases via oral, and 12 cases via both anus and oral. The lesions were found in 41 of the 67 patients, with overall diagnostic yield of 61.19%. Among 41 cases of abdominal pain resulted from small bowel diseases, Crohn's disease were found in 15 cases (36.59%), non-specific small enteritis in 10 cases (24.39%), tumors in 8 cases (19.51%), other enteral diseases in 8 cases (19.51%). CONCLUSIONS: Double balloon enteroscopy was a diagnostic modality with a high diagnostic value for obscure abdominal pain resulted from small bowel diseases. The most common causes of obscure abdominal pain were Crohn's disease, non-specific small enteritis and tumors.


Assuntos
Dor Abdominal/diagnóstico , Dor Abdominal/etiologia , Endoscopia Gastrointestinal/métodos , Adolescente , Adulto , Idoso , Feminino , Humanos , Intestino Delgado , Masculino , Pessoa de Meia-Idade , Adulto Jovem
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