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1.
Oxid Med Cell Longev ; 2019: 4010764, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31737170

RESUMO

Type 2 diabetes mellitus is a chronic metabolic disorder characterized by elevated blood glucose and/or high serum free fatty acids. Chronic hyperlipidemia causes the dysfunction of pancreatic beta cells, which is aggravated in the presence of hyperglycemia (glucolipotoxicity). Long noncoding RNAs (lncRNAs) have been suggested to play key roles in type 1 diabetes mellitus development. However, their roles in glucolipotoxicity-induced beta cell dysfunction are not fully understood. In the present study, we identified the differentially expressed lncRNAs in INS-1 cells exposed to high glucose and palmitate (HG/PA). Among the dysregulated lncRNAs, NONRATT003679.2 (low expression in glucolipotoxicity-treated beta cells (LEGLTBC)) was involved in glucolipotoxicity-evoked rat islet beta cell damage. LEGLTBC functioned as a molecular sponge of miR-34a in INS-1 cells. Additionally, SIRT1 was identified as a target of miR-34a and LEGLTBC promoted SIRT1 expression by sponging miR-34a. The upregulation of LEGLTBC attenuated HG/PA-induced INS-1 cell injury through the promotion of SIRT1-mediated suppression of ROS accumulation and apoptosis. This is the first study to comprehensively identify the lncRNA expression profiling of HG/PA-treated INS-1 beta cells and to demonstrate that LEGLTBC functions as a competing endogenous RNA and regulates miR-34a/SIRT1-mediated oxidative stress and apoptosis in INS-1 cells undergoing glucolipotoxicity.

2.
Onco Targets Ther ; 11: 2169-2176, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29713185

RESUMO

Background: The correlations between lipid profile (lipid molecules and their derivative indexes) and clinical outcome have been widely testified in many carcinomas, but its prognostic value remains unknown in gastric cancer (GC). Our purpose in the study was to comprehensively evaluate the clinical significance of lipid profile in GC. Methods: We retrospectively collected clinical information of 1,201 GC patients who received surgery at Sun Yat-sen University Cancer Center from 2005 to 2010. Kaplan-Meier analysis and Cox proportional hazards regression model were performed to determine its prognostic significance. Results: Lipid profile including cholesterol, triglyceride, high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C), apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB), LDL-C/HDL-C ratio, and ApoB/ApoA1 ratio were analyzed. For the first time, we found ApoB/ApoA1 ratio showed the biggest prognostic potency among all lipid-related variables and could act as an independent prognostic factor in GC. Patients with a high ApoB/ApoA1 ratio (≥1) had a shorter overall survival (hazard ratio: 1.373, 95% confidence interval: 1.123-1.68; P=0.002). Conclusion: Preoperative serum ApoB/ApoA1 ratio might be used as a novel prognostic indicator of GC.

3.
Medicine (Baltimore) ; 97(2): e9097, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29480823

RESUMO

The role of palliative surgery is controversial in advanced gastrointestinal stromal tumors (GIST) after tyrosine kinase inhibitors (TKIs) therapy.We evaluated safety and clinical outcomes in a single institution series of advanced GIST patients from January 2002 to December 2008.One hundred and fifty-six patients had been recruited, including 87 patients underwent surgical resection and 69 patients kept on TKIs treatment. Four patients had major surgical complications. Median follow-up was 38.3 months, the overall survival (OS) and progression-free survival (PFS) of the patients in surgical group were longer than the nonsurgical group, PFS: 46.1 versus 33.8 months (P < .01), OS: 54.8 versus 40.4 months. In the subgroup analysis for the patients received surgery, the median PFS for patients with progression disease, stable disease, and partial response was 33.3, 51.5, and 83.0 months, respectively (P < .01). Median OS was 68.0 months in those with only liver or peritoneal metastases, and 45.3 months in those with both metastases. Median PFS of patients underwent R0/R1 resection was 73.6 months compared with 35.8 months in R2 resection patients (P < .01).Patients with advanced GISTs have prolonged OS after debulking procedures. Surgery for patients who have responsive disease after TKIs treatment should be considered.


Assuntos
Antineoplásicos/uso terapêutico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/cirurgia , Cuidados Paliativos , Inibidores de Proteínas Quinases/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Seguimentos , Tumores do Estroma Gastrointestinal/mortalidade , Tumores do Estroma Gastrointestinal/patologia , Humanos , Mesilato de Imatinib/uso terapêutico , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Neoplasias Peritoneais/mortalidade , Neoplasias Peritoneais/secundário , Proteínas Tirosina Quinases/antagonistas & inibidores , Estudos Retrospectivos , Resultado do Tratamento
4.
Cancer Res ; 76(18): 5361-71, 2016 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-27450454

RESUMO

Long noncoding RNAs (lncRNA) are being implicated in the development of many cancers. Here, we report the discovery of a critical role for the lncRNA GCASPC in determining the progression of gallbladder cancer. Differentially expressed lncRNAs and mRNAs between gallbladder cancer specimens and paired adjacent nontumor tissues from five patients were identified and validated by an expression microarray analysis. Quantitative real-time PCR was used to measure GCASPC levels in tissues from 42 gallbladder cancer patients, and levels of GCASPC were confirmed further in a separate cohort of 89 gallbladder cancer patients. GCASPC was overexpressed or silenced in several gallbladder cancer cell lines where molecular and biological analyses were performed. GCASPC levels were significantly lower in gallbladder cancer than adjacent nontumor tissues and were associated with tumor size, American Joint Committee on Cancer tumor stage, and patient outcomes. GCASPC overexpression suppressed cell proliferation in vitro and in vivo, whereas GCASPC silencing had opposite effects. By RNA pull-down and mass spectrometry, we identified pyruvate carboxylase as an RNA-binding protein that associated with GCASPC. Because GCASPC is a target of miR-17-3p, we confirmed that both miR-17-3p and GCASPC downregulated pyruvate carboxylase level and activity by limiting protein stability. Taken together, our results defined a novel mechanism of lncRNA-regulated cell proliferation in gallbladder cancer, illuminating a new basis for understanding its pathogenicity. Cancer Res; 76(18); 5361-71. ©2016 AACR.


Assuntos
Neoplasias da Vesícula Biliar/genética , Neoplasias da Vesícula Biliar/patologia , MicroRNAs/genética , RNA Longo não Codificante/genética , Western Blotting , Proliferação de Células/fisiologia , Neoplasias da Vesícula Biliar/mortalidade , Técnicas de Silenciamento de Genes , Humanos , Imuno-Histoquímica , Imunoprecipitação , Estimativa de Kaplan-Meier , Espectrometria de Massas , Análise de Sequência com Séries de Oligonucleotídeos , Piruvato Carboxilase/metabolismo , Reação em Cadeia da Polimerase em Tempo Real
5.
Cancer Lett ; 368(1): 88-96, 2015 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-26254540

RESUMO

Sulfasalazine (SSZ) is an anti-inflammatory drug that has been demonstrated to induce apoptosis and tumor regression through inhibition of plasma membrane cystine transporter xc(-). Cysteine is a rate-limiting precursor for intracellular glutathione (GSH) synthesis, which is vital for compound detoxification and maintaining redox balance. Platinum-based chemotherapy is an important regimen used in clinics for various cancers including colorectal cancer (CRC). We hypothesized that targeting xc(-) transporter by SSZ may annihilate cellular detoxification through interruption of GSH synthesis and may enhance the anti-cancer activity of cisplatin (CDDP) by increasing drug transport. In the present study, we revealed that xCT, the active subunit of xc(-), is highly expressed in CRC cell lines and human colorectal carcinoma tissues compared with their normal counterparts. SSZ effectively depleted cellular GSH, leading to significant accumulation of reactive oxygen species and growth inhibition in CRC cells. In contrast, the normal epithelial cells of colon origin were less sensitive to SSZ, showing a moderate ROS elevation. Importantly, SSZ effectively enhanced the intracellular platinum level and cytotoxicity of CDDP in CRC cells. The synergistic effect of SSZ and CDDP was reversed by antioxidant N-acetyl-L-cysteine (NAC). Together, these results suggest that SSZ, a relatively non-toxic drug that targets cystine transporter, may, in combination with CDDP, have effective therapy for colorectal cancer.


Assuntos
Sistema y+ de Transporte de Aminoácidos/antagonistas & inibidores , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Cisplatino/farmacologia , Neoplasias Colorretais/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Glutationa/metabolismo , Sulfassalazina/farmacologia , Sistema y+ de Transporte de Aminoácidos/metabolismo , Antioxidantes/farmacologia , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/patologia , Relação Dose-Resposta a Droga , Células HCT116 , Células HT29 , Histonas/metabolismo , Humanos , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo
6.
Nutrients ; 7(6): 4689-704, 2015 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-26066015

RESUMO

Advanced glycation end products (AGEs), the direct modulators of ß-cells, have been shown to cause insulin-producing ß-cell dysfunction and apoptosis through increase of intracellular reactive oxygen species (ROS) production. Sesamin has been demonstrated to possess antioxidative activity. This study was designed to investigate whether sesamin protects against AGEs-evoked ß-cell damage via its antioxidant property. The effects of sesamin were examined in C57BL/6J mice and MIN6 cell line. In in vivo studies, mice were intraperitoneally injected with AGEs (120 mg/kg) and orally treated with sesamin (160 mg/kg) for four weeks. Intraperitoneal glucose tolerance and insulin releasing tests were performed. Insulin content, ROS generation and ß-cell apoptosis in pancreatic islets were also measured. In in vitro studies, MIN6 cells were pretreated with sesamin (50 or 100 µM) and then exposed to AGEs (200 mg/L) for 24 h. Insulin secretion, ß-cell death, ROS production as well as expression and activity of NADPH oxidase were determined. Sesamin treatment obviously ameliorated AGE-induced ß-cell dysfunction and apoptosis both in vivo and in vitro. These effects were associated with decreased ROS production, down-regulated expression of p67(phox) and p22(phox), and reduced NADPH oxidase activity. These results suggest that sesamin protects ß-cells from damage caused by AGEs through suppressing NADPH oxidase-mediated oxidative stress.


Assuntos
Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Dioxóis/farmacologia , Produtos Finais de Glicação Avançada/metabolismo , Células Secretoras de Insulina/efeitos dos fármacos , Lignanas/farmacologia , Animais , Células Cultivadas , Insulina/metabolismo , Secreção de Insulina , Células Secretoras de Insulina/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , NADPH Oxidases/antagonistas & inibidores , NADPH Oxidases/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo
7.
Oncotarget ; 6(25): 21148-58, 2015 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-26020803

RESUMO

The oncogenic K-Ras can transform various mammalian cells and plays a critical role in development of pancreatic cancer. MicroRNAs (miRNA) have been shown to contribute to tumorigenic progression. However, the nature of miRNAs involved in K-Ras transformation remains to be investigated. Here, by using microarray we identified miR-155 as the most upregulated miRNA after both acute and prolonged activation of K-Ras in a doxycyline-inducible system. Pharmacological inhibition of MAPK and NF-κB pathway blocked the induction of miR-155 in response to K-Ras activation. Overexpression of miR-155 caused inhibition of Foxo3a, leading to decrease of major antioxidants including SOD2 and catalase, and enhanced pancreatic cell proliferation induced by ROS generation. Importantly, correlations of K-Ras, miR-155 and Foxo3a were also validated in human pancreatic cancer tissues. Therefore, we propose that miR-155 plays an important role in oncogenic K-Ras transformation mediated by cellular redox regulation.


Assuntos
Regulação Neoplásica da Expressão Gênica , Genes ras , MicroRNAs/metabolismo , Neoplasias Pancreáticas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteínas ras/metabolismo , Animais , Antioxidantes/metabolismo , Linhagem Celular Tumoral , Transformação Celular Neoplásica , Doxiciclina/química , Feminino , Proteína Forkhead Box O3 , Fatores de Transcrição Forkhead/metabolismo , Humanos , Lentivirus , Camundongos , Camundongos Nus , Transplante de Neoplasias , Oxirredução , Transdução de Sinais , Transfecção , Regulação para Cima
8.
Oncotarget ; 6(6): 3947-62, 2015 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-25714130

RESUMO

Increase in aerobic glycolysis and mitochondrial dysfunction are important biochemical features observed in human cancers. Recent studies suggest oncogenic K-Ras can cause suppression of mitochondrial respiration and up-regulation of glycolytic activity through a yet unknown mechanism. Here we employed proteomic approach and used a K-RasG12V inducible cell system to investigate the impact of oncogenic K-Ras on mitochondria and cell metabolism. Mitochondria isolated from cells before and after K-Ras induction were subjected to protein analysis using stable isotope labeling with amino acids (SILAC) and liquid chromatography coupled with mass spectrometry (LC-MS). 70 mitochondrial proteins with significant expression alteration after K-Ras induction were identified. A majority of these proteins were involved in energy metabolism. Five proteins with significant decrease belong to mitochondrial respiratory chain complex I. NADH dehydrogenase 1 alpha subcomplex assembly factor 1 (NDUFAF1) showed most significant decrease by 50%. Such decrease was validated in primary human pancreatic cancer tissues. Knockdown of NDUFAF1 by siRNA caused mitochondrial respiration deficiency, accumulation of NADH and subsequent increase of glycolytic activity. Our study revealed that oncogenic K-Ras is able to induce significant alterations in mitochondrial protein expression, and identified NDUFAF1 as an important molecule whose low expression contributes to mitochondrial dysfunction induced by K-Ras.


Assuntos
Genes ras , Mitocôndrias/metabolismo , NADH Desidrogenase/genética , NADH Desidrogenase/metabolismo , Proteínas ras/biossíntese , Regulação para Baixo , Técnicas de Silenciamento de Genes , Humanos , Proteínas Mitocondriais/biossíntese , Proteínas Mitocondriais/genética , Proteômica , Ativação Transcricional , Transcriptoma , Proteínas ras/genética
9.
Mol Carcinog ; 54(11): 1397-406, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25213660

RESUMO

The identification of cancer-associated long non-coding RNAs (lncRNAs) and the investigation of their molecular and biological functions are vital for understanding the molecular biology and progression of cancer. The lncRNA-LET, a newly identified lncRNA, was demonstrated to be down-regulated in hepatocellular cancer. However, little is known about its role in gallbladder cancer. In the present study, an obvious down-regulation of lncRNA-LET was observed in gallbladder cancer compared to their adjacent normal tissues. Meanwhile, patients with low expression of lncRNA-LET have significantly poorer prognosis than those with high expression. We confirmed that hypoxia decreased lncRNA-LET levels in gallbladder cancer cells. Moreover, lncRNA-LET overexpression was further validated to inhibit the invasion of gallbladder cancer cells under hypoxic or normoxic conditions in vitro. We demonstrated that lncRNA-LET overexpression conferred a proliferative advantage to tumor cells under hypoxic conditions. The ectopic expression of lncRNA-LET led to the promotion of cell cycle arrest at G0/G1 phase and to the induction of apoptosis under hypoxic conditions. Ectopic expression of LncRNA-LET also suppressed gallbladder tumor growth in vivo. Our findings indicate that lncRNA-LET may represent a prognostic marker and a potential therapeutic target for gallbladder cancer.


Assuntos
Neoplasias da Vesícula Biliar/genética , RNA Longo não Codificante/genética , Animais , Apoptose/genética , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Regulação para Baixo/genética , Feminino , Pontos de Checagem da Fase G1 do Ciclo Celular/genética , Neoplasias da Vesícula Biliar/patologia , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Prognóstico , Fase de Repouso do Ciclo Celular/genética
10.
BMC Complement Altern Med ; 14: 254, 2014 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-25038821

RESUMO

BACKGROUND: Recent studies have demonstrated that side population (SP) cells isolated from various cancer cell lines and primary tumors possess stem cell-like properties. Sesamin, a food-derived agent, possesses anti-cancer activities both in vitro and in vivo. The present study was designed to determine whether sesamin also have effects on cancer stem-like SP cells from gallbladder cancer (GBC). METHODS: In this study, we sorted SP cells by flow cytometry. SP cells were cultured and treated with sesamin. Tumor-sphere formation, colony formation, Matrigel invasion and tumorigenic potential were determined. Expression of nuclear NF-κB, IL-6, p-Stat3, Twist, E-cadherin and Vimentin was measured by Western blot, immunofluorescence staining or RT-PCR analysis. Nuclear NF-κB activity and IL-6 protein level were assessed with ELISA. Xenograft tumors were generated in nude mice. RESULTS: After treated with sesamin, SP cells differentiated into cells expressing the epithelial marker (E-cadherin). Sesamin effectively affected SP cells stem cell-like characteristics (i.e., tumor-sphere formation, colony-formation, Matrigel invasion), weakened the drug-resistance of SP cells and inhibited tumor growth both in vitro and in vivo. Treatment with sesamin significantly reduced the expression of nuclear NF-κB, IL-6, p-Stat3, Twist and Vimentin (a mesenchymal marker) in SP cells. Nuclear NF-κB activity and IL-6 level were also decreased after treatment with sesamin. CONCLUSION: Food-derived sesamin directs the epithelial differentiation of cancer stem-like SP cells from GBC, which is associated with attenuation of NF-κB-IL-6-Stat3-Twist signal pathway.


Assuntos
Dioxóis/farmacologia , Neoplasias da Vesícula Biliar/tratamento farmacológico , Neoplasias da Vesícula Biliar/patologia , Lignanas/farmacologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Células da Side Population/efeitos dos fármacos , Análise de Variância , Animais , Caderinas/metabolismo , Carcinoma/tratamento farmacológico , Carcinoma/metabolismo , Carcinoma/patologia , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Neoplasias da Vesícula Biliar/metabolismo , Humanos , Interleucina-6/metabolismo , Camundongos , Camundongos Nus , NF-kappa B/metabolismo , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Células da Side Population/metabolismo , Células da Side Population/patologia , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Mol Cancer ; 13: 156, 2014 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-24953832

RESUMO

BACKGROUND: Protein coding genes account for only about 2% of the human genome, whereas the vast majority of transcripts are non-coding RNAs including long non-coding RNAs. A growing volume of literature has proposed that lncRNAs are important players in cancer. HOTAIR was previously shown to be an oncogene and negative prognostic factor in a variety of cancers. However, the factors that contribute to its upregulation and the interaction between HOTAIR and miRNAs are largely unknown. METHODS: A computational screen of HOTAIR promoter was conducted to search for transcription-factor-binding sites. HOTAIR promoter activities were examined by luciferase reporter assay. The function of the c-Myc binding site in the HOTAIR promoter region was tested by a promoter assay with nucleotide substitutions in the putative E-box. The association of c-Myc with the HOTAIR promoter in vivo was confirmed by chromatin immunoprecipitation assay and Electrophoretic mobility shift assay. A search for miRNAs with complementary base paring with HOTAIR was performed utilizing online software program. Gain and loss of function approaches were employed to investigate the expression changes of HOTAIR or miRNA-130a. The expression levels of HOTAIR, c-Myc and miRNA-130a were examined in 65 matched pairs of gallbladder cancer tissues. The effects of HOTAIR and miRNA-130a on gallbladder cancer cell invasion and proliferation was tested using in vitro cell invasion and flow cytometric assays. RESULTS: We demonstrate that HOTAIR is a direct target of c-Myc through interaction with putative c-Myc target response element (RE) in the upstream region of HOTAIR in gallbladder cancer cells. A positive correlation between c-Myc and HOTAIR mRNA levels was observed in gallbladder cancer tissues. We predicted that HOTAIR harbors a miRNA-130a binding site. Our data showed that this binding site is vital for the regulation of miRNA-130a by HOTAIR. Moreover, a negative correlation between HOTAIR and miRNA-130a was observed in gallbladder cancer tissues. Finally, we demonstrate that the oncogenic activity of HOTAIR is in part through its negative regulation of miRNA-130a. CONCLUSION: Together, these results suggest that HOTAIR is a c-Myc-activated driver of malignancy, which acts in part through repression of miRNA-130a.


Assuntos
Neoplasias da Vesícula Biliar/genética , MicroRNAs/genética , Proteínas Proto-Oncogênicas c-myc/genética , RNA Longo não Codificante/genética , Adulto , Idoso , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias da Vesícula Biliar/patologia , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Regiões Promotoras Genéticas , Ativação Transcricional
12.
J Diabetes ; 6(6): 535-40, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24720446

RESUMO

BACKGROUND: Methylglyoxal (MG) is a reactive-dicarbonyl that is thought to contribute to the development of diabetes either as a precursor for advanced glycation end products or as a direct toxin. The present study was designed to determine plasma MG level in patients with newly diagnosed type 2 diabetes mellitus (T2DM) and to evaluate the relationship between MG and other parameters, such as oxidative stress and metabolic indices. METHODS: Methylglyoxal was measured by high-performance liquid chromatographic/tandem mass spectrometry in plasma from 48 subjects with newly diagnosed T2DM. The relationship between two variables was analyzed using Spearman's correlation analysis. Multiple stepwise linear regression analysis was used to assess the association of plasma MG and other parameters. RESULTS: Plasma MG level in patients with newly diagnosed T2DM (65.2 ± 19.2 ng/mL) were significantly higher than that in control individuals (40.1 ± 11.1 ng/mL, P < 0.05). The plasma level of MG was positively correlated with the glycosylated hemoglobin A1c (HbA1c, r = 0.670, P < 0.01) and malondialdehyde (MDA, r = 0.694, P < 0.01). Multiple linear regression analysis revealed that both HbA1c and MDA are significant independent determinants of plasma MG level. CONCLUSIONS: These findings suggest that increased plasma MG level is associated with the elevation of HbA1c and MDA in newly diagnosed T2DM patients.


Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Estresse Oxidativo/fisiologia , Aldeído Pirúvico/sangue , Adulto , Diabetes Mellitus Tipo 2/diagnóstico , Feminino , Produtos Finais de Glicação Avançada/sangue , Humanos , Masculino , Pessoa de Meia-Idade
13.
J Renin Angiotensin Aldosterone Syst ; 15(3): 259-70, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23676251

RESUMO

INTRODUCTION: This study was designed to investigate the underlying mechanisms of synergistic antihypertensive effect produced by combination therapy of losartan and pioglitazone in metabolic syndrome (MS) rats. MATERIALS AND METHODS: An MS model was induced by feeding rats a high-fat, high-sodium diet and 20% sucrose solution. Losartan (20 mg/kg/day), pioglitazone (10 mg/kg/day), and their combination were orally administered for eight consecutive weeks. Systolic blood pressure (SBP) and mean arterial pressure (MAP) were measured using the tail-cuff method and carotid arterial catheterization, respectively. The aortas were isolated and in vitro vascular reactivity studies were performed. The protein expression of angiotensin type 1 receptor (AT1), endothelial nitric oxide synthase (eNOS), phosphorylated eNOS and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit p47(phox), level of nitrotyrosine as well as activity of eNOS and NADPH oxidase in aortas of MS rats were detected. RESULTS: After eight weeks of treatment, the SBP and MAP in the losartan (115 ± 5 and 106 ± 6 mmHg), pioglitazone (130 ± 6 and 118 ± 6 mmHg), and combination therapy (105 ± 6 and 98 ± 5 mmHg) groups were lower than those in the model group (150 ± 8 and 136 ± 9 mmHg). Combination therapy of losartan and pioglitazone reduced BP more than either monotherapy, and showed additive effects on improving endothelial dysfunction and abolishing the increased vascular responsiveness to angiotensin II. These synergistic effects were associated with further reductions in protein expression of p47(phox) and AT1, NADPH oxidase activity, and nitrotyrosine level. CONCLUSIONS: Our data indicate that combined treatment exerts more beneficial effects on lowering BP and improving vascular lesions.


Assuntos
Angiotensina II/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Losartan/farmacologia , Tiazolidinedionas/farmacologia , Vasoconstrição/efeitos dos fármacos , Acetilcolina/farmacologia , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Sinergismo Farmacológico , Endotélio Vascular/efeitos dos fármacos , Masculino , NADPH Oxidases/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Nitroprussiato/farmacologia , Fenilefrina/farmacologia , Pioglitazona , Ratos Sprague-Dawley , Receptor Tipo 1 de Angiotensina/metabolismo , Sístole/efeitos dos fármacos , Tirosina/análogos & derivados , Tirosina/metabolismo , Vasodilatação/efeitos dos fármacos
14.
J Exp Clin Cancer Res ; 32: 71, 2013 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-24289824

RESUMO

BACKGROUND: The diagnostic and prognostic value of microRNA (miRNA) expression aberrations in pancreatic ductal adenocarcinoma (PDAC) has been studied extensively in recent years. However, differences in measurement platforms and lab protocols as well as small sample sizes can render gene expression levels incomparable. METHODS: A comprehensive meta-review of published studies in PDAC that compared the miRNA expression profiles of PDAC tissues and paired neighbouring noncancerous pancreatic tissues was performed to determine candidate miRNA biomarkers for PDAC. Both a miRNA vote-counting strategy and a recently published Robust Rank Aggregation method were employed. In this review, a total of 538 tumour and 206 noncancerous control samples were included. RESULTS: We identified a statistically significant miRNA meta-signature of seven up- and three down-regulated miRNAs. The experimental validation results showed that the miRNA expression levels were in accordance with the meta-signature. The results from the vote-counting strategy were consistent with those from the Robust Rank Aggregation method. The experimental validation confirmed that the statistically unique profiles identified by the meta-review approach could discriminate PDAC tissues from paired nonmalignant pancreatic tissues. In a cohort of 70 patients, the high expression of miR-21 (p=0.018, HR=2.610; 95% CI=1.179-5.777) and miR-31 (p=0.039, HR=2.735; 95% CI=1.317-6.426), the low expression of miR-375 (p=0.022, HR=2.337; 95% CI=1.431-5.066) were associated with poor overall survival following resection, independent of clinical covariates. CONCLUSIONS: The identified miRNAs may be used to develop a panel of diagnostic and prognostic biomarkers for PDAC with sufficient sensitivity and specificity for use in a clinical setting.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Ductal Pancreático/genética , MicroRNAs/metabolismo , Neoplasias Pancreáticas/genética , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Estudos de Coortes , Regulação para Baixo , Humanos , MicroRNAs/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Prognóstico
15.
World J Gastroenterol ; 18(3): 257-67, 2012 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-22294829

RESUMO

AIM: To establish a more stable and accurate nude mouse model of pancreatic cancer using cancer cell microencapsulation. METHODS: The assay is based on microencapsulation technology, wherein human tumor cells are encapsulated in small microcapsules (approximately 420 µm in diameter) constructed of semipermeable membranes. We implemented two kinds of subcutaneous implantation models in nude mice using the injection of single tumor cells and encapsulated pancreatic tumor cells. The size of subcutaneously implanted tumors was observed on a weekly basis using two methods, and growth curves were generated from these data. The growth and metastasis of orthotopically injected single tumor cells and encapsulated pancreatic tumor cells were evaluated at four and eight weeks postimplantation by positron emission tomography-computed tomography scan and necropsy. The pancreatic tumor samples obtained from each method were then sent for pathological examination. We evaluated differences in the rates of tumor incidence and the presence of metastasis and variations in tumor volume and tumor weight in the cancer microcapsules vs single-cell suspensions. RESULTS: Sequential in vitro observations of the microcapsules showed that the cancer cells in microcapsules proliferated well and formed spheroids at days 4 to 6. Further in vitro culture resulted in bursting of the membrane of the microcapsules and cells deviated outward and continued to grow in flasks. The optimum injection time was found to be 5 d after tumor encapsulation. In the subcutaneous implantation model, there were no significant differences in terms of tumor volume between the encapsulated pancreatic tumor cells and cells alone and rate of tumor incidence. There was a significant difference in the rate of successful implantation between the cancer cell microencapsulation group and the single tumor-cell suspension group (100% vs 71.43%, respectively, P = 0.0489) in the orthotropic implantation model. The former method displayed an obvious advantage in tumor mass (4th wk: 0.0461 ± 0.0399 vs 0.0313 ± 0.021, t = -0.81, P = 0.4379; 8th wk: 0.1284 ± 0.0284 vs 0.0943 ± 0.0571, t = -2.28, respectively, P = 0.0457) compared with the latter in the orthotopic implantation model. CONCLUSION: Encapsulation of pancreatic tumor cells is a reliable method for establishing a pancreatic tumor animal model.


Assuntos
Modelos Animais de Doenças , Composição de Medicamentos , Camundongos Nus , Transplante de Neoplasias/métodos , Neoplasias Pancreáticas/patologia , Células Tumorais Cultivadas , Animais , Progressão da Doença , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Carga Tumoral
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