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1.
Langmuir ; 36(3): 742-753, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31895574

RESUMO

The linear shrinkage behavior in thermoresponsive diblock copolymer films and its potential application in temperature sensors are investigated. The copolymer is composed of two thermoresponsive blocks with different transition temperatures (TTs): di(ethylene glycol) methyl ether methacrylate (MEO2MA; TT1 = 25 °C) and poly(ethylene glycol) methyl ether methacrylate (OEGMA300; TT2 = 60 °C) with a molar ratio of 1:1. Aqueous solutions of PMEO2MA-b-POEGMA300 show a three-stage transition upon heating as seen with optical transmittance and small-angle X-ray scattering: dissolution (T < TT1), self-assembled micelles with core-shell structure (TT1 < T < TT2), and aggregation of collapsed micelles (T > TT2). Due to the restrictions in the polymer chain arrangement introduced by the solid Si substrate, spin-coated PMEO2MA-b-POEGMA300 films exhibit an entirely different internal structure and transition behavior. Neutron reflectivity shows the absence of an ordered structure normal to the Si substrate in as-prepared PMEO2MA-b-POEGMA300 films. After exposure to D2O vapor for 3 h and then increasing the temperature above its TT1 and TT2, the ordered structure is still not observed. Only a D2O enrichment layer is formed close to the hydrophilic Si substrate. Such PMEO2MA-b-POEGMA300 films show a linear shrinkage between TT1 and TT2 in a D2O vapor atmosphere. This special behavior can be attributed to the synergistic effect between the restrained collapse of the PMEO2MA blocks by the still swollen POEGMA300 blocks and the impedance of chain arrangement by the Si substrate. Based on this unique behavior, spin-coated PMEO2MA-b-POEGMA300 films are further prepared into a temperature sensor by implementing Ag electrodes. Its resistance decreases linearly with temperature between TT1 and TT2.

2.
PLoS Pathog ; 16(1): e1008211, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31971995

RESUMO

The decades-long global trend of urbanization has led to a population that spends increasing amounts of time indoors. Exposure to microbes in buildings, and specifically in dust, is thus also increasing, and has been linked to various health outcomes and to antibiotic resistance genes (ARGs). These are most efficiently screened using DNA sequencing, but this method does not determine which microbes are viable, nor does it reveal whether their ARGs can actually disseminate to other microbes. We have thus performed the first study to: 1) examine the potential for ARG dissemination in indoor dust microbial communities, and 2) validate the presence of detected mobile ARGs in viable dust bacteria. Specifically, we integrated 166 dust metagenomes from 43 different buildings. Sequences were assembled, annotated, and screened for potential integrons, transposons, plasmids, and associated ARGs. The same dust samples were further investigated using cultivation and isolate genome and plasmid sequencing. Potential ARGs were detected in dust isolate genomes, and we confirmed their placement on mobile genetic elements using long-read sequencing. We found 183 ARGs, of which 52 were potentially mobile (associated with a putative plasmid, transposon or integron). One dust isolate related to Staphylococcus equorum proved to contain a plasmid carrying an ARG that was detected metagenomically and confirmed through whole genome and plasmid sequencing. This study thus highlights the power of combining cultivation with metagenomics to assess the risk of potentially mobile ARGs for public health.

4.
Kaohsiung J Med Sci ; 35(11): 659-671, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31332950

RESUMO

Prostate cancer (PCa) remains the secondary highest cause of cancer-related death in the United States in men. It has been reported that microRNAs can serve as key regulators in tumor development and progression in various cancers including PCa. In this study, we examined the effect of miR-498 on proliferation, radiosensitivity, invasion, and migration of PCa cells. The proliferation of LNCaP and DU-145 PCa cells with altered expression of miR-498 was evaluated by MTT assay. The invasion and migration of LNCaP and DU-145 PCa cells were assess by matrigel invasion assay and transwell migration assay. The protein expression level in PCa cells was examined by western blot. The function of miR-498 on radiation-induced apoptosis in LNCaP and DU-145 PCa cells was detected by Caspase-Glo3/7 assay. Forced expression of miR-498 improved the proliferation, invasion and migration in PCa cells. Furthermore, miR-498 decreased the sensitivity of PCa cells after ionizing radiation treatment. MiR-498 reduced the radiation-induced apoptosis in PCa cells by regulation of BAX and Bcl-2 expression. Meanwhile, miR-498 altered the expression of E-cadherin, N-cadherin, snail, and Vimentin in both LNCaP and DU-145 PCa cells and regulated epithelial to mesenchymal transition (EMT). Further study showed that aberrant expression of miR-498 changed the expression levels of phosphatase and tensin homolog and p-AKT in LNCaP and DU-145 PCa cells. In a summary, miR-498 displayed important roles in tumor development and progression in PCa cells, and might act as a potential prognostic biomarker and predict radiotherapy response in PCa.

5.
Breast Cancer (Auckl) ; 13: 1178223419844198, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31205415

RESUMO

Purpose: Postmenopausal women with estrogen receptor-positive breast cancers often respond initially to tamoxifen or aromatase inhibitor therapy. Resistance to these treatments usually develops within 12 to 18 months. Clinical studies have demonstrated that high-dose estrogen can induce regression of these endocrine-resistant tumors. However, side-effects of high-dose estradiol (E2) or diethylstilbestrol (DES) limit their usage. Estetrol (E4) is the most abundant estrogen during pregnancy and has a long half-life and a low potential for side-effects. Estetrol might then provide benefits similar to DES on tumor regression but with lesser toxicity. Methods: In this study, we systematically evaluated the effects of E4 on cell proliferation and apoptosis in wild-type MCF-7 and long-term estrogen-deprived (LTED) MCF-7 cells and compared its effects with E2 and estriol (E3). Results: Estetrol induced apoptosis in LTED cells but stimulated growth of MCF-7 cells at concentrations from 10-11 to 10-8 M. These effects of E4 are similar to those of E2 but require much higher doses. Differing from E2, E4 at 10-12 M induced apoptosis in MCF-7 cells and another pregnancy estrogen, E3, acted similarly. No antagonistic effect of E4 or E3 against E2 occurred when they were combined. Conclusions: The pro-apoptotic effects of E4 and E3 on LTED cells and at low doses on MCF-7 cells indicate that these steroids could be used as therapeutic agents for endocrine-resistant or sensitive breast cancer.

6.
J Org Chem ; 84(13): 8423-8439, 2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-31136177

RESUMO

Various functional secondary and tertiary phosphines, or their derivatives, containing stationary chiral phosphorus and flexible chiral axis were prepared, which could be further modified to afford diversely chelating ligands. The flexible axial chirality was fixed by stereogenic phosphorus via a cyclic linkage of chemical bonds or coordination with a metallic ion.

7.
Genome Biol ; 20(1): 75, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30992037

RESUMO

RNA degradation affects RNA-seq quality when profiling transcriptional activities in cells. Here, we show that transcript degradation is both gene- and sample-specific and is a common and significant factor that may bias the results in RNA-seq analysis. Most existing global normalization approaches are ineffective to correct for degradation bias. We propose a novel pipeline named DegNorm to adjust the read counts for transcript degradation heterogeneity on a gene-by-gene basis while simultaneously controlling for the sequencing depth. The robust and effective performance of this method is demonstrated in an extensive set of simulated and real RNA-seq data.


Assuntos
Algoritmos , Estabilidade de RNA , Análise de Sequência de RNA , Linhagem Celular , Humanos , Software
8.
ACS Appl Mater Interfaces ; 11(5): 5414-5426, 2019 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-30640436

RESUMO

Enhanced capabilities of stain removal and comfort control are simultaneously achieved by the light and thermo dual-responsive copolymer poly(triethylene glycol methyl ether methacrylate- co-ethylene glycol methacrylate- co-acrylamide azobenzene) (P(MEO3MA- co-EGMA- co-AAAB)) cross-linked on cotton fabrics. P(MEO3MA- co-EGMA- co-AAAB) is synthesized by sequential atom transfer radical polymerization with a molar ratio of 8 (MEO3MA):1 (EGMA):1 (AAAB). The MEO3MA units induce a thermoresponsive behavior to the copolymer. The hydrophilicity of the copolymer films can be further improved by the light-induced trans- cis isomerization of the AAAB units with UV radiation. The copolymer is facilely immobilized onto cotton fabrics with 1,2,3,4-butane tetracarboxylic acid as cross-linker. Due to the immobilization of P(MEO3MA- co-EGMA- co-AAAB), the hydrophilicity of the fabric surface is increased under UV radiation. Therefore, by simply installing a UV light source in the washing machine, better capability of stain removal is realized for the cross-linked cotton fabrics. It can prominently reduce the consumption of energy, water, and surfactants in laundry. In addition, the trans-AAAB units of the copolymer cause the cross-linked P(MEO3MA- co-EGMA- co-AAAB) layer to be more hydrophobic under ambient conditions. Hence, the copolymer can more easily collapse and form a porous structure on the fabrics. Thus, the air permeability of cotton fabrics cross-linked with P(MEO3MA- co-EGMA- co-AAAB) is enhanced by 13% at human body temperature as compared to P(MEO3MA- co-EGMA), giving improved comfort control during daily wear.

9.
Oncol Lett ; 15(6): 8417-8423, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29805577

RESUMO

The present study aimed to analyze the modification of gene expression in bladder cancer (BC) by identifying significant differentially expressed genes (DEGs) and functionally assess them using bioinformatics analysis. To achieve this, two microarray datasets, GSE24152 (which included 10 fresh tumor tissue samples from urothelial bladder carcinoma patients and 7 benign mucosa samples from the bladder), and GSE42089 (which included 10 tissues samples from urothelial cell carcinoma patients and 8 tissues samples from the normal bladder), were downloaded from the Gene Expression Omnibus database for further analysis. Differentially expressed genes (DEGs) were screened between benign the mucosa and control groups in GSE24152 and GSE42089 datasets. Gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) analysis were performed on overlapping DEGs identified in GSE24152 and GSE42089. Protein-protein interaction (PPI) networks and sub-networks were then constructed to identify key genes and main pathways. GO terms analysis was also performed for the selected clusters. In total, 1,325 DEGs in GSE24152 and 647 DEGs in GSE42089 were screened, in which 619 common DEGs were identified. The DEGs were mainly enriched in pathways and GO terms associated with mitotic and chromosome assembly, including nucleosome assembly, spindle checkpoint and DNA replication. In the interaction network, progesterone receptor (PGR), MAF bZIP transcription factor G (MAFG), cell division cycle 6 (CDC6) and members of the minichromosome maintenance family (MCMs) were identified as key genes. Histones were also considered to be significant factors in BC. Nucleosome assembly and sequence-specific DNA binding were the most significant clustered GO terms. In conclusion, the DEGs, including PGR, MAFG, CDC6 and MCMs, and those encoding the core histone family were closely associated with the development of BC via pathways associated with mitotic and chromosome assembly.

10.
Trials ; 19(1): 200, 2018 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-29587863

RESUMO

BACKGROUND: Diabetic kidney disease (DKD) is a serious complication associated with diabetes mellitus and can cause end-stage renal disease (ESRD). Traditional Chinese medicine (TCM) is widely used in China to treat DKD, and in particular microalbuminuria and macroalbuminuria. This study will address the efficacy and safety of Shenzhuo Formula (SZF), a frequently prescribed TCM, in DKD patients with macroalbuminuria. METHODS/DESIGN: This study is a 24-week, randomized, multi-center, double-blinded, double-dummy, controlled, clinical trial that will include 120 DKD patients aged 18 to 80 years old with a 24-h urinary protein (24-h UP) level of between 0.5 g and 3 g and serum creatinine (SCr) ≤ 133 µmol/L (1.5 mg/dL) and compare SZF to irbesartan. The 24-h UP change from baseline to week 24 will represent the primary endpoint with secondary endpoints including SCr, estimated glomerular filtration rate (eGFR), TCM symptoms, urinary albumin excretion rate (UAER), etc. Safety assessments will also be evaluated. DISCUSSION: This study will provide initial evidence regarding the efficacy and safety of SZF relative to irbesartan in the treatment of DKD patients with macroalbuminuria. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ID: ChiCTR-ICR-15006311 . Registered on 15 April 2015.


Assuntos
Albuminúria/tratamento farmacológico , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Nefropatias Diabéticas/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Irbesartana/uso terapêutico , Rim/efeitos dos fármacos , Albuminúria/diagnóstico , Albuminúria/fisiopatologia , Albuminúria/urina , Bloqueadores do Receptor Tipo 1 de Angiotensina II/efeitos adversos , Biomarcadores/sangue , China , Creatinina/sangue , Nefropatias Diabéticas/diagnóstico , Nefropatias Diabéticas/fisiopatologia , Nefropatias Diabéticas/urina , Método Duplo-Cego , Medicamentos de Ervas Chinesas/efeitos adversos , Taxa de Filtração Glomerular/efeitos dos fármacos , Humanos , Irbesartana/efeitos adversos , Rim/fisiopatologia , Estudos Multicêntricos como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Tempo , Resultado do Tratamento
11.
Org Lett ; 19(19): 5384-5387, 2017 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-28949150

RESUMO

A diastereomeric mixture of secondary phosphine oxide is stereospecifically converted to chlorophosphine salt by treatment with oxalyl chloride, which stereoselectively affords P-inverted or retained tertiary phosphines, depending on the substitution with aliphatic or aromatic Grignard reagents, respectively, in high to 99% yield and 99:1 dr. The repulsion of π-electron on aryl to lone electron pair on phosphorus is proposed for the P-retained substitution.

12.
J Org Chem ; 82(18): 9425-9434, 2017 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-28813606

RESUMO

The secondary RP-(-)-menthyl alkylphosphine oxide was confirmed as configurationally stable toward base and was used in base-promoted alkylation, stereospecifically affording P-retained bis or functional tertiary phosphine oxides in excellent yields. The alkylated products were deoxygenated using oxalyl chloride followed by ZnCl2-NaBH4 to form P-inversed bidentate phosphine boranes in high stereoselectivities.

13.
Trends Genet ; 33(8): 495-507, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28693826

RESUMO

Nucleosomes regulate the transcription output of the genome by occluding the underlying DNA sequences from DNA-binding proteins that must act on it. Knowledge of the precise locations of nucleosomes in the genome is thus essential towards understanding how transcription is regulated. Current nucleosome-mapping strategies involve digesting chromatin with nucleases or chemical cleavage followed by high-throughput sequencing. In this review, we compare the traditional micrococcal nuclease (MNase)-based approach with a chemical cleavage strategy, with discussion on the important insights each has uncovered about the role of nucleosomes in shaping transcriptional processes.


Assuntos
Mapeamento Cromossômico/métodos , Nuclease do Micrococo/genética , Animais , Células Cultivadas , Sequenciamento de Nucleotídeos em Larga Escala , Camundongos , Nucleossomos/metabolismo , Transcrição Genética
14.
Mol Pharm ; 14(1): 1-13, 2017 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-26992462

RESUMO

The RAS and mTOR inhibitor S-trans-trans-farnesylthiosalicylic acid (FTS) is a promising anticancer agent with moderate potency, currently undergoing clinical trials as a chemotherapeutic agent. FTS has displayed its potential against a variety of cancers including endocrine resistant breast cancer. However, the poor pharmacokinetics profile attributed to its high hydrophobicity is a major hindrance for its continued advancement in clinic. One of the ways to improve its therapeutic potential would be to enhance its bioavailability to cancer tissue by developing a method for targeted delivery. In the current study, FTS was conjugated with the cancer-targeting heptamethine cyanine dye 5 to form the FTS-dye conjugate 11. The efficiency of tumor targeting properties of conjugate 11 against cancer cell growth and mTOR inhibition was evaluated in vitro in comparison with parent FTS. Cancer targeting of 11 in a live mouse model of MCF7 xenografts was demonstrated with noninvasive, near-infrared fluorescence (NIRF) imaging. The results from our studies clearly suggest that the bioavailability of FTS is indeed improved as indicated by log P values and cancer cell uptake. The FTS-dye conjugate 11 displayed higher potency (IC50 = 16.8 ± 0.5 µM) than parent FTS (IC50 = ∼51.3 ± 1.8 µM) and inhibited mTOR activity in the cancer cells at a lower concentration (12.5 µM). The conjugate 11 was shown to be specifically accumulated in tumors as observed by in vivo NIRF imaging, organ distribution, and ex vivo tumor histology along with cellular level confocal microscopy. In conclusion, the conjugation of FTS with cancer-targeting heptamethine cyanine dye improved its pharmacological profile.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Carbocianinas/administração & dosagem , Farneseno Álcool/análogos & derivados , Salicilatos/farmacologia , Animais , Disponibilidade Biológica , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sistemas de Liberação de Medicamentos/métodos , Farneseno Álcool/farmacologia , Feminino , Humanos , Células MCF-7 , Camundongos , Camundongos Nus , Serina-Treonina Quinases TOR/antagonistas & inibidores , Distribuição Tecidual , Proteínas ras/metabolismo
15.
J Steroid Biochem Mol Biol ; 170: 61-64, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-27174719

RESUMO

The first tissue-selective estrogen complex (TSEC), consisting of a combination of a conjugated equine estrogen (CEE) and bazedoxifene (BZA), has been approved for treatment of the menopause in the USA and European Union. We have postulated that this TSEC might block the estrogenic effects of CEE on breast tissue and thereby prevent breast cancer growth. This manuscript, representing a presentation at a Festschrift honoring Evan Simpson, reviews our published data BZA blocked the in vitro effects of both estradiol and CEE on cell growth and gene expression in MCF-7 cells. BZA completely blocked CEE- or E2-stimulated ductal and terminal end bud growth of immature murine mammary glands and the growth of experimental breast cancers. These findings provide a rationale for future clinical studies to determine whether this TSEC prevents the growth of occult breast cancer in women.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Estrogênios Conjugados (USP)/farmacologia , Indóis/farmacologia , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Animais , Apoptose/efeitos dos fármacos , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Estrogênios/metabolismo , Feminino , Humanos
16.
Cell ; 167(6): 1555-1570.e15, 2016 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-27889238

RESUMO

Nucleosome organization influences gene activity by controlling DNA accessibility to transcription machinery. Here, we develop a chemical biology approach to determine mammalian nucleosome positions genome-wide. We uncovered surprising features of nucleosome organization in mouse embryonic stem cells. In contrast to the prevailing model, we observe that for nearly all mouse genes, a class of fragile nucleosomes occupies previously designated nucleosome-depleted regions around transcription start sites and transcription termination sites. We show that nucleosomes occupy DNA targets for a subset of DNA-binding proteins, including CCCTC-binding factor (CTCF) and pluripotency factors. Furthermore, we provide evidence that promoter-proximal nucleosomes, with the +1 nucleosome in particular, contribute to the pausing of RNA polymerase II. Lastly, we find a characteristic preference for nucleosomes at exon-intron junctions. Taken together, we establish an accurate method for defining the nucleosome landscape and provide a valuable resource for studying nucleosome-mediated gene regulation in mammalian cells.


Assuntos
Células-Tronco Embrionárias Murinas/metabolismo , Nucleossomos/genética , Animais , Fator de Ligação a CCCTC , Estudo de Associação Genômica Ampla , Camundongos , RNA Polimerase II/metabolismo , Sítios de Splice de RNA , Processamento de RNA , Proteínas Repressoras/metabolismo , Saccharomyces cerevisiae/genética , Sítio de Iniciação de Transcrição , Transcrição Genética
17.
J Org Chem ; 81(17): 7644-53, 2016 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-27463529

RESUMO

Functionalized P,C-stereogenic tertiary phosphine oxides were prepared by the addition of (RP)-menthyl phenylphosphine oxide to activated olefins, in high drP and drC, and were isolated in excellent yields. The reaction was readily catalyzed by Ca(OH)2 or occurred with gentle heating. A wide range of substrates, including vinyl ketones, esters, nitriles, and nitro alkenes, can be used in the reaction.

18.
Elife ; 52016 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-27336723

RESUMO

In yeast and humans, previous experiences can lead to epigenetic transcriptional memory: repressed genes that exhibit mitotically heritable changes in chromatin structure and promoter recruitment of poised RNA polymerase II preinitiation complex (RNAPII PIC), which enhances future reactivation. Here, we show that INO1 memory in yeast is initiated by binding of the Sfl1 transcription factor to the cis-acting Memory Recruitment Sequence, targeting INO1 to the nuclear periphery. Memory requires a remodeled form of the Set1/COMPASS methyltransferase lacking Spp1, which dimethylates histone H3 lysine 4 (H3K4me2). H3K4me2 recruits the SET3C complex, which plays an essential role in maintaining this mark. Finally, while active INO1 is associated with Cdk8(-) Mediator, during memory, Cdk8(+) Mediator recruits poised RNAPII PIC lacking the Kin28 CTD kinase. Aspects of this mechanism are generalizable to yeast and conserved in human cells. Thus, COMPASS and Mediator are repurposed to promote epigenetic transcriptional poising by a highly conserved mechanism.


Assuntos
Quinase 8 Dependente de Ciclina/metabolismo , Epigênese Genética , Regulação Fúngica da Expressão Gênica , Histona-Lisina N-Metiltransferase/metabolismo , Mio-Inositol-1-Fosfato Sintase/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/genética , Humanos , Complexo Mediador/metabolismo , Transcrição Genética
19.
Stat Med ; 35(24): 4380-4397, 2016 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-27222305

RESUMO

Recent advances in human neuroimaging have shown that it is possible to accurately decode how the brain perceives information based only on non-invasive functional magnetic resonance imaging measurements of brain activity. Two commonly used statistical approaches, namely, univariate analysis and multivariate pattern analysis often lead to distinct patterns of selected voxels. One current debate in brain decoding concerns whether the brain's representation of sound categories is localized or distributed. We hypothesize that the distributed pattern of voxels selected by most multivariate pattern analysis models can be an artifact due to the spatial correlation among voxels. Here, we propose a Bayesian spatially varying coefficient model, where the spatial correlation is modeled through the variance-covariance matrix of the model coefficients. Combined with a proposed region selection strategy, we demonstrate that our approach is effective in identifying the truly localized patterns of the voxels while maintaining robustness to discover truly distributed pattern. In addition, we show that localized or clustered patterns can be artificially identified as distributed if without proper usage of the spatial correlation information in fMRI data. Copyright © 2016 John Wiley & Sons, Ltd.


Assuntos
Teorema de Bayes , Mapeamento Encefálico , Imagem por Ressonância Magnética , Encéfalo , Humanos , Análise Multivariada
20.
Int J Clin Exp Pathol ; 8(6): 6397-406, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26261515

RESUMO

Multidrug resistance (MDR) is the main obstacle to successful chemotherapy for patients with gastric cancer. The microRNA miR-218 influences various pathobiological processes in gastric cancer, and its down-regulation in this disease raises the question of whether it normally inhibits MDR. In this study we observed that two MDR gastric cancer cell lines showed lower expression of miR-218 compared with their chemosensitive parental cell line. Overexpressing miR-218 chemosensitizes gastric cancer cells, slowed efflux of adriamycin, and accelerated drug-induced apoptosis. We identified the smoothened (SMO) gene as a functional target of miR-218, and found that SMO overexpression counteracts the chemosensitizing effects of miR-218. These findings suggest that miR-218 inhibits MDR of gastric cancer cells by down-regulating SMO expression.


Assuntos
Resistência a Múltiplos Medicamentos/genética , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica/genética , MicroRNAs/genética , Receptores Acoplados a Proteínas-G/biossíntese , Neoplasias Gástricas/genética , Western Blotting , Linhagem Celular Tumoral , Citometria de Fluxo , Proteínas Hedgehog/biossíntese , Proteínas Hedgehog/genética , Humanos , Reação em Cadeia da Polimerase em Tempo Real , Receptores Acoplados a Proteínas-G/genética , Receptor Smoothened , Transfecção
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