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1.
Cell Physiol Biochem ; 46(2): 654-663, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29617683

RESUMO

BACKGROUND/AIMS: Programmed death ligand1(PD-L1) plays a role in the development and progression of non-small cell lung cancer (NSCLC). This study aimed to identify miRNA(s) that are responsible for regulation of expression of PD-L1 in NSCLC, and to investigate the role of PD-L1 in regulation of the cell cycle in NSCLC. METHODS: We predicted the target miRNA of PD-L1, which was miR-140, using the online tools TargetScan and miBase. In NSCLC cells obtained from clinical specimens, in addition to A549 and NCI-H1650 cell cultures, western blots were used to detect the level of expression of proteins, while real-time PCR was used to determine the level of expression of PD-L1, miR-140, cyclin E, and ß-actin. Transfection with miR-140 mimics, miR-140 inhibitors, and PD-L1 siRNA were conducted using commercial kits. To determine whether miR-140 directly binds PD-L1, a luciferase reporter gene with wild type or mutated PD-L1 was used. Cell viability was measured with the MTT assay, and PI staining was used for cell cycle analysis. RESULTS: We found low expression of miR-140 and high expression of PD-L1 and cyclin E in NSCLC cells. Over-expression of miR-140 suppressed the expression of PD-L1 by directly binding its 3' UTR, and was also associated with decreased expression of cyclin E and inhibition of cellular proliferation in A549 and NCI-H1650 cells. Inhibition of PD-L1, in the absence of manipulations to miR-140, also decreased the expression of cyclin E. CONCLUSION: We conclude that miR-140 directly suppresses PD-L1 and inhibits the miR-140/PD-L1/cyclin E pathway in NSCLC.


Assuntos
Antígeno B7-H1/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , MicroRNAs/metabolismo , Regiões 3' não Traduzidas , Células A549 , Antagomirs/metabolismo , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Ciclina E/genética , Ciclina E/metabolismo , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Pontos de Checagem da Fase S do Ciclo Celular
2.
Tumour Biol ; 35(11): 11243-59, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25113251

RESUMO

Genetic variations in the xeroderma pigmentosum group D (XPD) gene may increase cancer susceptibility by affecting the capacity for DNA repair. A lot of studies have reported the association of XPD Lys751Gln polymorphism with risk of cancer, but the results remained controversial. Hence, we performed a systematic review and conducted a meta-analysis to explore association of the XPD Lys751Gln polymorphism with risk of cancer (78,398 cases and 103,178 controls from 224 studies). Overall, a significantly increased cancer risk was found in all genetic models (dominant model: odds ratio (OR) = 1.10, 95% confidence interval (CI) = 1.06-1.14; recessive model: OR = 1.10, 95% CI = 1.05-1.15; homozygous model: OR = 1.14, 95% CI = 1.08-1.21; heterozygous model: OR = 1.09, 95% CI = 1.05-1.12; additive model: OR = 1.08, 95% CI= 1.05-1.11) when all eligible studies were pooled into the meta-analysis. In further stratified and sensitivity analyses, the elevated risk of cancer remained for subgroups of breast cancer, esophageal cancer, hepatocellular cancer, leukemia, lung cancer, and melanoma. In summary, this meta-analysis suggests the XPD Lys751Gln polymorphism is a genetic susceptibility for some cancer types. Moreover, ethnicity, histological type of cancer, and smokers seem to contribute to varying expressions of the Lys751Gln on some cancer risk. In addition, our work also points out the importance of new studies for Lys751Gln association in endometrial cancer and ovarian cancer, where at least some of the covariates responsible for heterogeneity could be controlled, to obtain a more conclusive understanding about the function of the Lys751Gln polymorphism in cancer development.


Assuntos
Predisposição Genética para Doença , Neoplasias/genética , Polimorfismo Genético/genética , Proteína Grupo D do Xeroderma Pigmentoso/genética , Estudos de Casos e Controles , Humanos , Metanálise como Assunto , Prognóstico , Fatores de Risco
3.
Amino Acids ; 44(2): 413-22, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22782214

RESUMO

It was recently discovered that ketamine can relieve depression in a matter of hours through an action on α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. This is much more rapid than the several weeks required for the available antidepressants to show therapeutic efficacy. However, ketamine has negative side effects. The aim of this study was to determine whether the natural prokinetic drug meranzin hydrate (MH) has a fast-acting antidepressant effect mediated by AMPA receptors. By means of in vivo and in vitro experiments, we found that (1) treatment of rats with MH at 9 mg/kg decreased immobility time in a forced swimming test (FST), as did the popular antidepressant fluoxetine and the AMPA receptor positive modulator aniracetam. Pretreatment of rats with NBQX (10 mg/kg), an antagonist of AMPA receptors, blocked this effect of MH. (2) MH increased number of crossings of forced swimming rats in the open field test. (3) FST enhanced hippocampal ERK1/2, p-ERK1/2 and BDNF expression levels. MH (9 mg/kg) treatment further up-regulated hippocampal p-ERK1/2 and BDNF expression levels, and this effect was prevented by NBQX. (4) MH-increased BDNF expression corresponded with MH-decreased immobility time in the FST. (5) In vitro experiments, we found that incubation of rats hippocampus slices with MH (10, 20 µM respectively) increased concentrations of BDNF and p-ERK1/2. This effect of MH (20 µM) were prevented by NBQX. In conclusion, in animals subjected to acute stress, the natural prokinetic drug MH produced a rapid effect mediated by AMPA receptors and involving BDNF modulation through the ERK1/2 pathway.


Assuntos
Antidepressivos/administração & dosagem , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Cumarínicos/administração & dosagem , Depressão/tratamento farmacológico , Depressão/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Receptores de AMPA/metabolismo , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/metabolismo , Animais , Depressão/enzimologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Humanos , Masculino , Ratos , Ratos Sprague-Dawley
4.
Oncotarget ; 6(18): 16043-58, 2015 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-25965824

RESUMO

MicroRNA-155 (miR-155) is dysregulated in human cancers. In this study, we reported that miR-155 was over-expressed in bladder cancer tissues. We found that miR-155 promoted cell proliferation in vitro and tumorigenesis in vivo. MiR-155 directly reduced the expression of the tumor suppressor DMTF1. The expression of DMTF1 was decreased in bladder cancer tissues. Similar to the restoring miR-155 expression, knockdown of DMTF1 promoted cell growth and cell cycle progression, whereas DMTF1 over-expression rescued the effect of miR-155. Moreover, we investigated DMTF1-Arf-p53 pathway and found that DMTF1 worked in both p53-dependent and p53-independent manners. Taken together, our findings suggested that miR-155 functions as a tumor promoter in bladder cancer, which is partially through repressing DMTF1 expression. The identification of miR-155 and its novel target DMTF1 will be valuable in developing diagnostic markers and therapeutic applications for bladder cancer.


Assuntos
Proliferação de Células , MicroRNAs/genética , Recidiva Local de Neoplasia/patologia , Fatores de Transcrição/metabolismo , Neoplasias da Bexiga Urinária/patologia , Bexiga Urinária/patologia , Animais , Apoptose , Western Blotting , Ciclo Celular , Feminino , Humanos , Técnicas Imunoenzimáticas , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Gradação de Tumores , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/metabolismo , Estadiamento de Neoplasias , Prognóstico , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Transcrição/genética , Células Tumorais Cultivadas , Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Neuropharmacology ; 67: 318-25, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23063894

RESUMO

BACKGROUND: In recent years, the brain-gut axis theory has received increasing attention in studies of depression. However, most studies separately address potential antidepressant and prokinetic treatments. Investigations of drugs that could potentially treat comorbid depression and gastrointestinal (GI) dysfunction via a common mechanism of action have not yet been performed in detail. AIM: To find a common mechanism of action of our patented drug, meranzin hydrate (MH), in the antidepressant and prokinetic treatment. METHODS: The forced swimming test (FST) model of depression, plasma ghrelin measurement, and in vivo and in vitro measurements of GI motility were used. RESULTS: 1. Administration of MH (9 mg/kg) decreased the immobility time during the FST after acute treatment; this effect was inhibited by the alpha 2-adrenoceptor antagonist, yohimbine, but not by the alpha 1-adrenoceptor antagonist, prazosin. 2. After chronic treatment, the immobility time of rats during the FST was decreased significantly by MH (2.25 mg/kg). 3. MH (9 mg/kg) increased plasma ghrelin levels in rats subjected to the FST; this increase was enhanced by the ghrelin receptor agonist, GHRP-6. 4. MH (9 mg/kg) also promoted gastric emptying and intestinal transit in rats with or without FST. 5. In vitro, MH (10 µM) increased jejunal contractions in rats subjected to the FST; this effect was inhibited by yohimbine. Furthermore, the inhibitory effect of yohimbine was partly reversed by the ghrelin receptor agonist, GHRP-6. CONCLUSION: Our study revealed that MH from natural resources exhibits antidepressive and prokinetic-like effects through the regulation of the common mediator, the alpha 2-adrenoceptor.


Assuntos
Antidepressivos/uso terapêutico , Encéfalo/fisiologia , Cumarínicos/uso terapêutico , Depressão/tratamento farmacológico , Motilidade Gastrointestinal/fisiologia , Receptores Adrenérgicos alfa 2/fisiologia , Animais , Antidepressivos/farmacologia , Encéfalo/efeitos dos fármacos , Cumarínicos/farmacologia , Depressão/metabolismo , Depressão/psicologia , Motilidade Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/fisiologia , Masculino , Vias Neurais/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Natação/psicologia
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