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1.
Oncogene ; 2019 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-31597953

RESUMO

The development of chemoresistance remains a major challenge that accounts for colorectal cancer (CRC) lethality. Dichloroacetate (DCA) was originally used as a metabolic regulator in the treatment of metabolic diseases; here, DCA was assayed to identify the mechanisms underlying the chemoresistance of CRC. We found that DCA markedly enhanced chemosensitivity of CRC cells to fluorouracil (5-FU), and reduced the colony formation due to high levels of apoptosis. Using the microarray assay, we noted that miR-149-3p was involved in the chemoresistance of CRC, which was modulated by wild-type p53 after DCA treatment. In addition, PDK2 was identified as a direct target of miR-149-3p. Mechanistic analyses showed that overexpression of miR-149-3p enhanced 5-FU-induced apoptosis and reduced glucose metabolism, similar to the effects of PDK2 knockdown. In addition, overexpression of PDK2 partially reversed the inhibitory effect of miR-149-3p on glucose metabolism. Finally, both DCA treatment and miR-149-3p overexpression in 5-FU-resistant CRC cells were found to markedly sensitize the chemotherapeutic effect of 5-FU in vivo, and this effect was also validated in a small retrospective cohort of CRC patients. Taken together, we determined that the p53/miR-149-3p/PDK2 signaling pathway can potentially be targeted with DCA treatment to overcome chemoresistant CRC.

2.
J Dairy Sci ; 102(9): 7684-7696, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31255276

RESUMO

Oxidative stress is the basic reason for aging and age-related diseases. In this study, we investigated the protective effect of 2 strains of lactic acid bacteria (LAB), Lactobacillus rhamnosus GG and L. plantarum J26, against oxidative stress in Caco-2 cells, and gave an overview of the mechanisms of lactic acid bacteria antioxidant activity using digital gene expression profiling. The 2 LAB strains provided significant protection against hydrogen peroxide (H2O2)-induced reduction in superoxide dismutase activity and increase in glutathione peroxidase activity in Caco-2 cells. However, inactive bacteria had little effect on alleviating oxidation stress in Caco-2 cells. Eight genes related to oxidative stress-FOSB, TNF, PPP1R15A, NUAK2, ATF3, TNFAIP3, EGR2, and FBN2-were significantly upregulated in H2O2-induced Caco-2 cells compared with untreated Caco-2 cells. After incubation of the H2O2-induced Caco-2 cells with L. rhamnosus GG and L. plantarum J26, 5 genes (TNF, EGR2, NUAK2, FBN2, and TNFAIP3) and 2 genes (NUAK2 and FBN2) were downregulated, respectively. In addition, the Kyoto Encyclopedia of Genes and Genomes indicated that some signaling pathways associated with inflammation, immune response, and apoptosis, such as Janus kinase/signal transducers and activators of transcription (Jak-STAT), mitogen-activated protein kinase (MAPK), nuclear factor-κB, and tumor necrosis factor, were all negatively modulated by the 2 strains, especially L. rhamnosus GG. In this paper, we reveal the mechanism of LAB in relieving oxidative stress and provide a theoretical basis for the rapid screening and evaluation of new LAB resources.


Assuntos
Enterócitos/metabolismo , Lactobacillus plantarum/fisiologia , Lactobacillus rhamnosus/fisiologia , Estresse Oxidativo/genética , Transcriptoma/genética , Animais , Apoptose/genética , Células CACO-2 , Enterócitos/efeitos dos fármacos , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/fisiologia , Humanos , Peróxido de Hidrogênio/farmacologia , Imunidade/genética , Inflamação/genética , Probióticos/farmacologia
3.
J Cancer ; 8(8): 1498-1506, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28638466

RESUMO

Background: Colon Cancer-Associated Transcript 2 (CCAT2) has been demonstrated associated with clinical outcomes in various tumors. However, the results from each study were unfortunately insufficient and not completely consistent. Therefore, we conduct a systematic meta-analysis to evaluate the value for a feasible biomarker for metastasis and prognosis. Methods: A meta-analysis was performed using data obtained through a systematic search of PubMed, EMBASE, Cochrane Library, China National Knowledge Infrastructure, Wanfang database and VIP database. The pooled odds ratio (OR) and hazard ratio (HR) with 95% Confidence interval (CI ) using random-effect were used to identify the relationship of CCAT2 with clinical outcome of cancer patients. Subgroup analysis and sensitivity analysis were performed. Results: A total of 867 patients from eight studies were finally included. Patients with high CCAT2 expression underwent an increased risk of lymph node metastasis (LNM) (OR=3.09, 95% CI: 1.53-6.26) and distant metastasis (DM) (OR=7.70, 95% CI: 3.26-18.17). CCAT2 was also significantly correlated with overall survival (OS) (HR=2.19, 95%CI: 1.70-2.82) and progression-free survival (PFS) (HR=2.59, 95% CI: 1.78-3.76). Moderate heterogeneity was observed in meta-analysis for LNM. However, the results remained robust in multiple sensitivity analyses. Conclusions: High expression of CCAT2 was linked with poor clinical outcome. CCAT2 can serve as a potential molecular marker for prognosis in different types of cancers.

4.
Endoscopy ; 49(6): 564-580, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28472835

RESUMO

Background and aims Magnifying endoscopy with narrow-band imaging (M-NBI) has been widely used in the differential diagnosis of deep submucosal colorectal cancers (dSMCs) from superficial submucosal cancers (sSMCs) and intramucosal neoplasms. We aimed to pool the diagnostic efficacy of M-NBI and compare it with that of magnifying chromoendoscopy (M-CE) in diagnosing colorectal dSMC. Methods PubMed, EMBASE, and the Cochrane Library were searched to identify eligible studies. Meeting abstracts were also searched. A bivariate mixed-effects binary regression model was used in the meta-analysis to calculate the pooled diagnostic efficacy of M-NBI and compare it with that of M-CE in the diagnosis of dSMC. Subgroup analyses and meta-regression were conducted to explore sources of heterogeneity. Results We included 17 studies: 14 full texts and 3 meeting abstracts. The pooled sensitivity, specificity, and area under the summary receiver operating characteristic curve (AUC) with 95 % confidence intervals (CIs) in diagnosing dSMC were 74 % (66 % - 81 %; I2 = 84.6 %), 98 % (94 % - 99 %; I2 = 94.4 %), and 0.91 (0.88 - 0.93), respectively, for M-NBI. The pooled sensitivity, specificity and AUC (95 %CI) were 84 % (76 % - 89 %; I2 = 76.9 %), 97 % (94 % - 99 %; I2 = 90.2 %), and 0.97 (0.95 - 0.98), respectively, for M-CE. M-NBI had lower sensitivity (P < 0.01) than M-CE with similar specificity (P = 0.32). Subgroup analyses and meta-regression indicated that endoscopic diagnostic criteria, study type, endoscope type, risk of index test bias, and histopathological diagnostic criteria might be the sources of heterogeneity. Conclusions M-NBI and M-CE had comparable specificities in diagnosing dSMC, but the sensitivity of M-NBI was slightly lower than that of M-CE.


Assuntos
Colonoscopia/métodos , Neoplasias Colorretais/diagnóstico por imagem , Mucosa Intestinal/diagnóstico por imagem , Imagem de Banda Estreita , Área Sob a Curva , Cor , Neoplasias Colorretais/patologia , Diagnóstico Diferencial , Humanos , Mucosa Intestinal/patologia , Curva ROC
5.
J Exp Clin Cancer Res ; 36(1): 50, 2017 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-28399898

RESUMO

BACKGROUND: Itraconazole has been proved therapeutically effective against a variety of human cancers. This study assessed the effect of itraconazole on the Hedgehog (Hh) pathway and proliferation of human gastric cancer cells. METHODS: CCK-8 assay and colony formation assay were used to assess the effects of itraconazole on proliferation of gastric cancer cells. The expression of Hh signaling components in gastric cancer cells treated with itraconazole was evaluated by reverse-transcription polymerase chain reaction, immunoblotting and dual luciferase assay. Tumor xenograft models were used to assess the inhibitory effect of itraconazole on the proliferation of gastric cancer cells in vivo. RESULTS: Itraconazole could remarkably inhibit the proliferation of gastric cancer cells. When in combination with 5-FU, itraconazole significantly reduced the proliferation rate of cancer cells. Furthermore, itraconazole could regulate the G1-S transition and induce apoptosis of gastric cancer cells. Hh signaling was abnormally activated in human gastric cancer samples. In vitro, studies showed that the expression of glioma-associated zinc finger transcription factor 1 (Gli1) was decreased at both transcriptional and translational levels after treatment with itraconazole. Dual luciferase assay also indicated that itraconazole could inhibit the transcription of Gli1. In vivo studies demonstrated that monotherapy with itraconazole by oral administration could inhibit the growth of xenografts, and that itraconazole could significantly enhance the antitumor efficacy of the chemotherapeutic agent 5-FU. CONCLUSIONS: Hh signaling is activated in gastric tumor and itraconazole can inhibit the growth of gastric cancer cells by inhibiting Gli1 expression.


Assuntos
Antineoplásicos/administração & dosagem , Fluoruracila/administração & dosagem , Proteínas Hedgehog/metabolismo , Itraconazol/administração & dosagem , Neoplasias Gástricas/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Itraconazol/farmacologia , Camundongos , Transdução de Sinais/efeitos dos fármacos , Neoplasias Gástricas/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Proteína GLI1 em Dedos de Zinco/genética , Proteína GLI1 em Dedos de Zinco/metabolismo
6.
Sci Rep ; 7: 46650, 2017 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-28440297

RESUMO

Rectal nonsteroidal anti-inflammatory drugs (NSAIDs) are not commonly used clinically for preventing post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis. To evaluate the efficacy and safety of NSAIDs for post-ERCP prophylaxis, we systematically reviewed sixteen randomized controlled trials (involving 6458 patients) that compared rectal NSAIDs with placebo or no treatment for post-ERCP pancreatitis prophylaxis updated to August 2016. GRADE framework was used to assess the quality of evidence. There was "high quality" evidence that rectal NSAIDs were associated with significant reduction in the risk of overall post-ERCP pancreatitis (RR, 0.55; 95% CI, 0.42-0.71). Subgroup analyses demonstrated that diclofenac (RR, 0.41; 95% CI, 0.19-0.90) was probably superior to indomethacin (RR, 0.58; 95% CI, 0.45-0.75), post-ERCP administration (RR, 0.46; 95% CI, 0.24-0.89) was probably superior to pre-ERCP (RR, 0.53; 95% CI, 0.42-0.67), and that mixed-risk population received more benefits (RR, 0.54; 95% CI, 0.33-0.88) than average-risk population (RR, 0.60; 95% CI, 0.41-0.88), but less than high-risk population (RR, 0.41; 95% CI, 0.19-0.91). Moreover, "high quality" evidence showed that rectal NSAIDs were safe when given as a standard dose (RR = 0.80; 95% CI, 0.47-1.36). In conclusion, this meta-analysis revealed that rectal NSAIDs are effective and safe in the prevention of post-ERCP pancreatitis in populations with all levels of risk.

7.
Front Pharmacol ; 8: 968, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29375376

RESUMO

Existing data suggest that proton pump inhibitors (PPIs), particularly omeprazole, have significant anti-tumor action in monotherapy and or combination chemotherapy. Hedgehog (Hh) signaling pathway represents a leading candidate as a molecular mediator of Barrett's esophagus (BE). Studies have indicated reduced miRNAs in BE progression, however, little is known about the latent anti-neoplasm effects of miRNAs in BE cells. Here, we investigated whether omeprazole could inhibit BE progression by regulating Hh pathway and explored the promising Hh-targeted miRNAs in BE cells. We conducted qRT-PCR and immunoblotting assay to evaluate the effects of omeprazole on the expression of Hh signaling components and miR-203a-3p in CP-A and CP-B cells. The promising target genes of miR-203a-3p were predicted by bioinformatics methods, and verified by luciferase assays and qRT-PCR. The effects of omeprazole on BE cell proliferation and cell cycle distribution were determined. The overexpression or silencing of miR-203a-3p was performed to test its anti-proliferative effects. Finally, rescue experiments that miR-203a-3p inhibitor alleviated the effects of omeprazole on decreasing the levels of Gli1 mRNA, protein and luciferase were performed. Mechanistic studies showed that omeprazole could inhibit the expression of Gli1 and the nuclear localization of Gli1. Moreover, we determined that omeprazole could selectively up-regulated the expression of miR-203a-3p, and Gli1 was a bona fide target of miR-203a-3p. miR-203a-3p inhibitor alleviated the suppressing effects of omeprazole on Gli1 luciferase activity, mRNA and protein level. The functional assay suggested that omeprazole could dose-dependently inhibit BE cell growth and induce cell cycle arrest in G0/G1 phase. Additionally, overexpression and silencing of miR-203a-3p in BE cells disrupted cell cycle progress, resulting in suppressing and accelerating cell proliferation, respectively. Taken together, these data provide a novel mechanism of potentially anti-neoplastic effects for omeprazole through modulation of miR-203a-3p expression and thus suppressing Hh/Gli1 signaling in BE cells.

8.
Oncotarget ; 8(5): 8843-8853, 2017 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-27903961

RESUMO

BACKGROUND: Existing data evaluating the impact of metformin on the colorectal adenoma (CRA) risk in patients suffering from type 2 diabetes (T2D) are limited and controversial. We therefore summarized the studies currently available and assessed the relationship between metformin treatment and risk of CRA in T2D patients. METHODS: We systematically searched databases for eligible studies that explored the impact of metformin treatment on the occurrence of CRA in T2D patients from inception to June 2016. The summary odds ratio (OR) estimates with their 95% confidence interval (CI) were derived using random-effect, generic inverse variance methods. Sensitivity analysis and subgroup analysis were performed. RESULTS: Seven studies involving 7178 participants met the inclusion criteria. The pooling showed that metformin therapy has a 27% decrease in the CRA risk (OR, 0.73; 95% CI, 0.58 - 0.90). In subgroup analysis, we detected that metformin exhibits significant chemoprevention effects in Asia region (OR, 0.68; 95% CI, 0.48 - 0.96). Similar results were identified in both studies with adjusted ORs and high-quality studies (OR, 0.66; 95% CI, 0.50 - 0.86 and OR, 0.70; 95% CI, 0.58 - 0.84, respectively). Of note, an inverse relationship was noted that metformin therapy may result in a significant decrease in the advanced adenoma risk (OR, 0.52; 95% CI, 0.38 - 0.72). Low heterogeneity was observed, however, the results remained robust in multiple sensitivity analyses. CONCLUSIONS: This meta-analysis indicates that metformin therapy is correlated with a significant decrease in the risk of CRA and advanced adenoma in T2D patients. Further confirmatory studies are warranted.


Assuntos
Adenoma/prevenção & controle , Neoplasias Colorretais/prevenção & controle , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Adenoma/diagnóstico , Adenoma/epidemiologia , Idoso , Distribuição de Qui-Quadrado , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/epidemiologia , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Prognóstico , Fatores de Proteção , Medição de Risco , Fatores de Risco , Fatores de Tempo
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