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1.
FEMS Microbiol Lett ; 2019 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-31855230

RESUMO

While there is strong evidence showing that many food-borne probiotics regulate cholesterol metabolism, few studies have examined how probiotics of human origin affect cholesterol metabolism. Because people living in so-called 'longevity villages' are unlikely to have hypercholesterolemia, we hypothesized that probiotics isolated from the residents would have cholesterol-reducing effects on rats with hypercholesterolemia. We isolated 16 strains of Lactobacillus from four longevity populations in China. The strains were tested in vitro for bile salt hydrolase (BSH) activity and two isolates, Lactobacillus reuteri A9 and Lactobacillus mucosae A13, were screened out. These two strains were then administered daily for 28 d to rats fed a cholesterol-rich diet. The serum total cholesterol levels in the L. reuteri A9 and L. mucosae A13 groups decreased by 24.3% and 21.6%, respectively. The serum low density lipoprotein cholesterol levels decreased by 23.8% and 25.2%, respectively. The L. reuteri A9 and L. mucosae A13 groups also exhibited upregulated hepatic mRNA expression of Sterol regulatory element-binding protein 2 (Srebp2) by 2.71-fold and 2.54-fold, respectively. The mRNA expression levels of hepatic low-density lipoprotein receptor (Ldlr) in the two groups were significantly up-regulated by 1.28-fold and 2.17-fold, respectively. The composition of gut microbiota was recovered by oral gavage in both experimental groups, and the destroyed diversity of gut microbiota was relieved.

3.
Analyst ; 144(6): 2179-2185, 2019 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-30768083

RESUMO

An ultrasensitive electrochemical detection of the androgen receptor (AR) was developed based on the protection of a DNA duplex by the AR from restriction endonuclease-mediated digestion and a subsequent hybridization chain reaction (HCR). Two partially complementary DNA probes P1 and P2 were designed to form an androgen receptor binding probe (ARBP) through hybridization. The ARBP contains a duplex at one end and two single-stranded tails at the other end. The duplex part containing the recognition sites of the AR and NspI restriction endonuclease was immobilized on an Au electrode, whereas the single-stranded parts served as capture probes to activate the HCR. In the absence of the AR, NspI can cleave the duplex and release the capture probes, and thus, no HCR occurs. However, the AR can bind to the ARBP and protect the duplex from cleavage; therefore, the capture probes can trigger the HCR between four carefully designed G-quadruplex forming hairpin probes and the capture probes, resulting in the formation of numerous G-quadruplexes. Finally, differential pulse voltammetry (DPV) was carried out to quantify the AR. The assay revealed a detection limit of 7.64 fM. The verification of its high specificity and practicability in serum samples indicated its potential applications in the fields of clinical examination and disease diagnosis.


Assuntos
Técnicas Biossensoriais/métodos , Quadruplex G , Técnicas de Amplificação de Ácido Nucleico/métodos , Hibridização de Ácido Nucleico/métodos , Receptores Androgênicos/sangue , Receptores Androgênicos/genética , Elementos de Resposta , Enzimas de Restrição do DNA/metabolismo , Técnicas Eletroquímicas , Eletrodos , Ouro , Humanos , Limite de Detecção , Receptores Androgênicos/química
4.
Am J Physiol Endocrinol Metab ; 316(4): E590-E604, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30668150

RESUMO

Parathyroid hormone (PTH) and its related peptide (PTH-related peptide 1-34) are two of the Food and Drug Administration-approved bone-promoting drugs for age-related osteoporosis. Treatment with PTH stimulates bone formation. However, the molecular mechanisms of PTH-mediated osteoblast differentiation and cell proliferation are still not completely understood. In this study, we showed that PTH induced endoplasmic reticulum (ER) stress in osteoblasts through the PKR-like endoplasmic reticulum kinase (PERK)-eukaryotic initiation factor 2α (EIF2α)-activating transcription factor 4 (ATF4)-signaling pathway. After separately blocking PERK-EIF2α-ATF4 signaling with two different inhibitors [AMG'44 and integrated stress response inhibitor (ISRIB)] or specific small interfering RNA for PERK and ATF4, the following targets were all downregulated: expression of osteoblast differentiation markers [runt-related transcription factor 2 (Runx2), alkaline phosphatase (Alp), type I collagen (Col1a1), and osteocalcin (Ocn)], cell proliferation markers (CyclinE, CyclinD, and CDC2), amino acid import (Glyt1), and metabolism-related genes (Asns). Additionally, Alp-positive staining cells, Alp activity, matrix mineralization, Ocn secretion, and cell proliferation indexes were inhibited. Interestingly, we found that salubrinal enhanced PTH-induced osteoblast differentiation and proliferation by maintenance of phosphorylation of EIF2α. Furthermore, we observed that PTH increased the association between heat shock protein 90 (HSP90) and PERK and maintained PERK protein stabilization in the early stages of PTH-induced ER stress. Treatment of MC3T3-E1 cells with geldanamycin, an HSP90 inhibitor, decreased PERK protein expression and inhibited osteoblast differentiation and cell proliferation upon PTH treatment. Taken together, our data demonstrate that PTH regulates osteoblast differentiation and cell proliferation, partly by activating the HSP90-dependent PERK-EIF2α-ATF4 signaling pathway.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Osteoblastos/efeitos dos fármacos , Hormônio Paratireóideo/farmacologia , Fator 4 Ativador da Transcrição/metabolismo , Fosfatase Alcalina/efeitos dos fármacos , Fosfatase Alcalina/metabolismo , Animais , Benzoquinonas/farmacologia , Proteína Quinase CDC2/efeitos dos fármacos , Proteína Quinase CDC2/metabolismo , Linhagem Celular , Colágeno Tipo I/efeitos dos fármacos , Colágeno Tipo I/metabolismo , Subunidade alfa 1 de Fator de Ligação ao Core/efeitos dos fármacos , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Ciclina D/efeitos dos fármacos , Ciclina D/metabolismo , Ciclina E/efeitos dos fármacos , Ciclina E/metabolismo , Inibidores Enzimáticos/farmacologia , Fator de Iniciação 2 em Eucariotos/metabolismo , Proteínas da Membrana Plasmática de Transporte de Glicina/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Glicina/metabolismo , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Proteínas de Choque Térmico HSP90/efeitos dos fármacos , Proteínas de Choque Térmico HSP90/metabolismo , Lactamas Macrocíclicas/farmacologia , Camundongos , Osteoblastos/metabolismo , Osteocalcina/efeitos dos fármacos , Osteocalcina/metabolismo , Transdução de Sinais , eIF-2 Quinase/metabolismo
5.
Cell Physiol Biochem ; 48(6): 2318-2336, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30114709

RESUMO

BACKGROUND/AIMS: Rapamycin (Rp), the main mammalian target of rapamycin complex inhibitor, is a promising therapeutic agent for breast cancer. However, metabolic disorders and drug resistance reduce its efficacy. Epidemiological, clinical, and experimental studies have demonstrated that omega-3 polyunsaturated fatty acids (ω-3 PUFAs) significantly reduce the incidence and mortality of breast cancer and improve metabolic disorders. METHODS: Three breast cancer cell lines and immunocompetent and immunodeficient mice were used to evaluate the therapeutic effects of Rp plus ω-3 PUFA treatment. The production of reactive oxygen species (ROS) and glucose uptake were examined by flow cytometry. Metabolic shift was examined by metabonomics, seahorse experiments, and western blot analysis. RESULTS: We found that ω-3 PUFAs and Rp synergistically induced cell cycle arrest and apoptosis in vitro and in vivo, accompanied by autophagy blockage. In addition, Rp-induced hypertriglyceridemia and hypercholesterolemia were completely abolished by ω-3 PUFA supplementation. Moreover, the combined treatment of ω-3 PUFA and Rp significantly inhibited glycolysis and glutamine metabolism. The anti-tumor effects of this combination treatment were dependent on ROS production, which was increased by ß-oxidation and oxidative phosphorylation. CONCLUSION: Our study revealed that ω-3 PUFA enhanced the anti-tumor activity of Rp while minimizing its side effects in vitro and in vivo. These results provide novel insights into the mechanisms underlying the potential beneficial effects of Rp combined with ω-3 PUFAs on the prevention of breast cancer.


Assuntos
Apoptose/efeitos dos fármacos , Ácidos Graxos Ômega-3/farmacologia , Sirolimo/farmacologia , Trifosfato de Adenosina/metabolismo , Animais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Modelos Animais de Doenças , Ácidos Graxos Ômega-3/uso terapêutico , Feminino , Humanos , Ácido Láctico/metabolismo , Células MCF-7 , Malondialdeído/metabolismo , Metabolômica , Camundongos , Proteínas Associadas aos Microtúbulos/metabolismo , Fosforilação Oxidativa/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Sirolimo/uso terapêutico
6.
Biochimie ; 152: 188-197, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30017898

RESUMO

A variety of missense mutations in proto-oncogene protein tyrosine kinase c-Met have been clinically observed in the patients and families of papillary renal cell carcinoma (pRCC), imparting that the kinase mutations can be exploited as a new and potential therapeutic target for pRCC. Here, a systematic inhibitor response-to-kinase mutation profile for ATP-competitive tyrosine kinase inhibitors (TKIs) against pRCC-related c-Met mutations is created using a rigorous thermodynamic cycle scheme, from which we are able to identify a number of representative inhibitor/mutation pairs with passivation and sensitization. It is revealed that passivation is commonly caused by steric hindrance between the mutated residue and inhibitor ligand, while sensitization usually results from the formation of favorable nonbonded interactions upon the mutation. The type II inhibitor Nintedanib possesses a high selectivity (7.2-fold) for c-MetY1248H variant over wild type. Structural and energetic analysis revealed that the Y1248H mutation is located in kinase's activation loop which can directly contact the extended moiety of type II inhibitor. The titratable variant residue His1248 is protonated with stabilization by its vicinal negatively charged residue Asp1246, which can form a geometrically satisfactory hydrogen bond and a weak cation-π interaction with the inhibitor ligand, thus conferring variant selectivity to the Nintedanib/Y1248H sensitization.


Assuntos
Carcinoma de Células Renais/metabolismo , Neoplasias Renais/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Humanos , Mutação de Sentido Incorreto , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Proto-Oncogênicas c-met/metabolismo , Termodinâmica
7.
Mol Med Rep ; 18(1): 308-314, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29749526

RESUMO

Epithelial to mesenchymal transition (EMT) serves important roles in tumor invasion, metastasis, formation of cancer initiating cells (CICs) and drug resistance. HLA­F adjacent transcript 10 (FAT10) has been proposed as an oncogene in bladder cancer. However, the functional contribution of FAT10 to EMT and the formation of CICs remains unclear in bladder cancer. The present study reports that FAT10 protein expression is upregulated in bladder cancer cell lines, and the overexpression of FAT10 promotes EMT and the formation of CICs in bladder cancer UMUC­3 cells. In addition, increased expression of FAT10 in tumor tissue was associated with shorter overall survival and progression free survival in Chinese patients with bladder cancer. Overexpression of FAT10 promotes cisplatin­resistant bladder cancer formation. These results indicated FAT10 may be a novel target for the treatment of bladder cancer.


Assuntos
Cisplatino/administração & dosagem , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica , Proteínas Oncogênicas/biossíntese , Ubiquitinas/biossíntese , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular Tumoral , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida , Neoplasias da Bexiga Urinária/tratamento farmacológico
8.
Front Immunol ; 8: 1345, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29097999

RESUMO

Recent evidence indicates that indigenous Clostridium species induce colonic regulatory T cells (Tregs), and gut lymphocytes are able to migrate to pancreatic islets in an inflammatory environment. Thus, we speculate that supplementation with the well-characterized probiotics Clostridium butyricum CGMCC0313.1 (CB0313.1) may induce pancreatic Tregs and consequently inhibit the diabetes incidence in non-obese diabetic (NOD) mice. CB0313.1 was administered daily to female NOD mice from 3 to 45 weeks of age. The control group received an equal volume of sterile water. Fasting glucose was measured twice a week. Pyrosequencing of the gut microbiota and flow cytometry of mesenteric lymph node (MLN), pancreatic lymph node (PLN), pancreatic and splenic immune cells were performed to investigate the effect of CB0313.1 treatment. Early oral administration of CB0313.1 mitigated insulitis, delayed the onset of diabetes, and improved energy metabolic dysfunction. Protection may involve increased Tregs, rebalanced Th1/Th2/Th17 cells and changes to a less proinflammatory immunological milieu in the gut, PLN, and pancreas. An increase of α4ß7+ (the gut homing receptor) Tregs in the PLN suggests that the mechanism may involve increased migration of gut-primed Tregs to the pancreas. Furthermore, 16S rRNA gene sequencing revealed that CB0313.1 enhanced the Firmicutes/Bacteroidetes ratio, enriched Clostridium-subgroups and butyrate-producing bacteria subgroups. Our results provide the basis for future clinical investigations in preventing type 1 diabetes by oral CB0313.1 administration.

9.
Sci Rep ; 7(1): 7046, 2017 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-28765642

RESUMO

Patients with type 2 diabetes (T2D) have decreased butyrate-producing bacteria. We hypothesized that supplementation with butyrate-producing bacteria may exert beneficial effects on T2D. The current study investigated the effects of well-characterized butyrate-producing bacteria Clostridium butyricum CGMCC0313.1 (CB0313.1) on hyperglycemia and associated metabolic dysfunction in two diabetic mouse models. CB0313.1 was administered daily by oral gavage to leptin db/db mice for 5 weeks starting from 3 weeks of age, and to HF diabetic mice induced by high fat diet (HFD) plus streptozotocin (STZ) in C57BL/6J mice for 13 weeks starting from 4 weeks of age. CB0313.1 improved diabetic markers (fasting glucose, glucose tolerance, insulin tolerance, GLP-1 and insulin secretion), and decreased blood lipids and inflammatory tone. Furthermore, CB0313.1 reversed hypohepatias and reduced glucose output. We also found that CB0313.1 modulated gut microbiota composition, characterized by a decreased ratio of Firmicutes to Bacteroidetes, reduced Allobaculum bacteria that were abundant in HF diabetic mice and increased butyrate-producing bacteria. Changes in gut microbiota following CB0313.1 treatment were associated with enhanced peroxisome proliferator-activated receptor-γ (PPARγ), insulin signaling molecules and mitochondrial function markers. Together, our study suggests that CB0313.1 may act as a beneficial probiotic for the prevention and treatment of hyperglycemia and associated metabolic dysfunction.


Assuntos
Terapia Biológica/métodos , Butiratos/metabolismo , Clostridium butyricum/crescimento & desenvolvimento , Clostridium butyricum/metabolismo , Diabetes Mellitus Tipo 2/terapia , Trato Gastrointestinal/microbiologia , Probióticos/administração & dosagem , Administração Oral , Animais , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Resultado do Tratamento
11.
Oncotarget ; 8(65): 109135-109150, 2017 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-29312596

RESUMO

Retinoic acid (RA), is a promising therapeutic agent for the treatment of breast cancer. However, metabolic disorders and drug resistance reduce the efficacy of RA. In this study, we found that RA and ω-3 polyunsaturated fatty acids (ω-3 PUFAs) synergistically induced cell death in vitro and in vivo and autophagy activation. Moreover, RA-induced hypercholesterolemia was completely corrected by ω-3 PUFA supplementation. In addition, we demonstrated that the effects of this combination on the autophagic flux were independent of the two major canonic regulatory complexes controlling autophagic vesicle formation. The treatment activated Gαq-p38 MAPK signaling pathways, which resulted in autophagy of breast cancer cells. Knockdown of Gαq or P38 expression prevented RA and ω-3 PUFAs from inducing autophagy. Data indicated that Gαq-p38activation was mediated by the co-activation of GPR40 and RARα in lipid rafts, rather than by the activation of GPR120, RARß, or RARγ. The results of this study suggest that hyperlipidemic drug side effects may be ameliorated by the administration of ω-3 PUFAs. Thus, the therapeutic indexes of the corresponding drugs may be increased.

12.
Oncotarget ; 7(39): 63793-63803, 2016 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-27588475

RESUMO

Recurrent chromosome breakpoints at 6q22.31, leading to truncation and potential loss-of-function of the NKAIN2 gene, in Chinese prostate cancer patients were previously identified. In this study we investigated genomic, methylation and expression changes of NKAIN2 in a large number of prostate cancer samples and determined its functional role in prostate cancer cells. Fluorescence in situ hybridization analysis confirmed that NKAIN2 truncation is specific to Chinese while deletion of the gene is frequent in both Chinese and UK prostate cancers. Significantly reduced expression of NKAIN2 was also detected at both RNA and protein levels. Somatic mutations of NKAIN2 in prostate cancer samples exist but at very low frequency, suggesting that it is a putative tumor suppressor gene (TSG) with haploid insufficiency. Our functional studies showed that overexpression of NKAIN2 in prostate cancer cells inhibits cellular growth by promoting cell apoptosis, and decreasing cell migration and invasion. Conversely, knockdown of NKAIN2 promotes prostate cancer cell growth by inhibiting cell apoptosis, and increasing cell migration and invasion. These data imply that NKAIN2 is a novel TSG whose activity is commonly reduced in prostate cancer. It may restrain the disease development and progression by inducing apoptosis and suppressing cancer cell growth, migration and invasion. This study provides new insights into prostate carcinogenesis and opportunities for development of novel therapies for prostate cancer.


Assuntos
Genes Supressores de Tumor , Proteínas de Membrana/genética , Neoplasias da Próstata/metabolismo , Apoptose , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Metilação de DNA , Análise Mutacional de DNA , Deleção de Genes , Genômica , Haploidia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Hibridização in Situ Fluorescente , Masculino , Proteínas de Membrana/metabolismo , Mutação , Invasividade Neoplásica , Regiões Promotoras Genéticas , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , RNA Interferente Pequeno/metabolismo
13.
Oncotarget ; 7(30): 47444-47464, 2016 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-27329728

RESUMO

MicroRNAs (miRNAs) are short, conserved segments of non-coding RNA which play a significant role in prostate cancer development and progression. To identify miRNAs associated with castration resistance, we performed miRNA microarray analysis comparing castration resistant prostate cancer (CRPC) with androgen dependent prostate cancer (ADPC). We identified common underexpression of miR-4638-5p in CRPC compared to ADPC samples, which were further confirmed by quantitative PCR analysis. The role of miR-4638-5p in prostate cancer androgen-independent growth has been demonstrated both in vitro and in vivo. We also identified Kidins220 as a target gene directly regulated by miR-4638-5p and shRNA-mediated knockdown of Kidins220 phenocopied miR-4638-5p restoration. Subsequently, we revealed that Kidins220 activates PI3K/AKT pathway, which plays a key role in CRPC. Loss of miR- 4638-5p may lead to CRPC through the activity of Kidins220 and PI3K/AKT pathway. Furthermore, we found that miR-4638-5p, through regulating Kidins220 and the downstream activity of VEGF and PI3K/AKT pathway, influences prostate cancer progression via angiogenesis. The identification of miR-4638-5p down-regulation in CRPC and the understanding of the functional role of miR-4638-5p and its downstream genes/pathways have the potential to develop biomarkers for CRPC onset and to identify novel targets for novel forms of treatments of this lethal form of PCa.


Assuntos
Proteínas de Membrana/genética , MicroRNAs/fisiologia , Proteínas do Tecido Nervoso/genética , Fosfatidilinositol 3-Quinases/fisiologia , Neoplasias de Próstata Resistentes à Castração/genética , Proteínas Proto-Oncogênicas c-akt/fisiologia , Transdução de Sinais/fisiologia , Animais , Proliferação de Células , Regulação para Baixo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Neovascularização Patológica/etiologia , Neoplasias de Próstata Resistentes à Castração/irrigação sanguínea , Neoplasias de Próstata Resistentes à Castração/patologia
14.
Oncotarget ; 7(16): 21393-403, 2016 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-26881390

RESUMO

Prostate cancer predisposition has been extensively investigated in European populations, but there have been few studies of other ethnic groups. To investigate prostate cancer susceptibility in the under-investigated Chinese population, we performed single-nucleotide polymorphism (SNP) array analysis on a cohort of Chinese cases and controls and then meta-analysis with data from the existing Chinese prostate cancer genome-wide association study (GWAS). Genotyping 211,155 SNPs in 495 cases and 640 controls of Chinese ancestry identified several new suggestive Chinese prostate cancer predisposition loci. However, none of them reached genome-wide significance level either by meta-analysis or replication study. The meta-analysis with the Chinese GWAS data revealed that four 8q24 loci are the main contributors to Chinese prostate cancer risk and the risk alleles from three of them exist at much higher frequencies in Chinese than European populations. We also found that several predisposition loci reported in Western populations have different effect on Chinese men. Therefore, this first extensive single-nucleotide polymorphism study of Chinese prostate cancer in comparison with European population indicates that four loci on 8q24 contribute to a great risk of prostate cancer in a considerable large proportion of Chinese men. Based on those four loci, the top 10% of the population have six- or two-fold prostate cancer risk compared with men of the bottom 10% or median risk respectively, which may facilitate the design of prostate cancer genetic risk screening and prevention in Chinese men. These findings also provide additional insights into the etiology and pathogenesis of prostate cancer.


Assuntos
Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/genética , Grupo com Ancestrais do Continente Asiático/genética , China , Cromossomos Humanos Par 8/genética , Grupo com Ancestrais do Continente Europeu/genética , Frequência do Gene , Loci Gênicos/genética , Predisposição Genética para Doença/etnologia , Genótipo , Humanos , Masculino , Neoplasias da Próstata/etnologia , Fatores de Risco
15.
Sci Rep ; 5: 14164, 2015 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-26369832

RESUMO

Previous studies have investigated the association between osteopontin (OPN) gene polymorphisms, rs17524488 (-156 GG/G), rs11730582 (-443 T/C), and rs9138 (C/A) and cancer risk in the Chinese population. However, the results are controversial and indefinite. We therefore carried out a meta-analysis to derive a more precise estimation of these associations. The PubMed database was systematically searched to identify potentially eligible reports. Crude odds ratios (OR) and 95% confidence intervals (CI) were used to assess the strength of associations between 3 OPN gene polymorphisms and cancer risk in a Chinese population. A total of 10 articles involving 2,391 cases and 3,007 controls were evaluated. The pooled OR indicated that OPN rs17524488 (-156 GG/G) polymorphism was significantly associated with cancer risk in Chinese population. In a stratified analysis by source of control, significant associations were also observed among rs17524488 (-156 GG/G) and rs11730582 (-443 T/C) polymorphisms and cancer. In addition, a stronger association was observed between rs9138 (C/A) polymorphism and cancer risk. In conclusion, this meta-analysis suggests that OPN rs17524488 (-156 GG/G), rs11730582 (-443 T/C), and rs9138 (C/A) polymorphisms may be associated with cancer susceptibility in the Chinese population. Nevertheless, further investigation on a larger population covering different ethnicities are warranted.


Assuntos
Alelos , Grupo com Ancestrais do Continente Asiático/genética , Predisposição Genética para Doença , Neoplasias/epidemiologia , Neoplasias/genética , Osteopontina/genética , Polimorfismo de Nucleotídeo Único , Estudos de Casos e Controles , China/epidemiologia , Haplótipos , Humanos , Razão de Chances , Regiões Promotoras Genéticas , Viés de Publicação , Risco
16.
Cell Biochem Biophys ; 72(3): 821-8, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25726156

RESUMO

Erectile dysfunction (ED) is a common disorder leading to a serious and negative impact on the patient's quality of life. The gene encoding endothelial nitric oxide synthase (eNOS) is an interesting candidate gene for understanding the physiopathology of ED. However, an association between eNOS G894T polymorphism and ED risk is uncertain and should be updated. Therefore, a meta-analysis of the current literature was necessary to clarify this relationship. We searched Pubmed and China National Knowledge Infrastructure (CNKI) (last search updated on Dec 12, 2013) using 'nitric oxide synthase,' 'polymorphism or variant,' 'genotype,' and 'ED' as keywords. We also searched reference lists of studies corresponding to the inclusion criteria for the meta-analysis. These studies involved the total number of 1,445 ED men and 1,459 healthy control men subjects. Odds ratio (OR) and 95 % confidence intervals (CIs) were used to evaluate this relationship. Statistical analysis was performed with STATA10.0. In the overall analysis, significantly decreased associations between ED risk and eNOS G894T polymorphism were found. Moreover, in the subgroup analysis based on ethnicity, similar significant associations were detected in both Caucasians (such as GG+GT vs. TT: OR 0.92, 95 %CI 0.86-0.97) and Asians (such as GG+GT vs. TT: OR 0.24, 95 % CI 0.07-0.85). The Egger's test did not reveal the presence of a publication bias. Our investigations demonstrate that eNOS G894T polymorphism might protect men against ED risk. Further studies based on larger sample size and gene-environment interactions should be conducted.


Assuntos
Disfunção Erétil/genética , Óxido Nítrico Sintase Tipo III/genética , Polimorfismo de Nucleotídeo Único , Estudos de Casos e Controles , Grupos de Populações Continentais , Disfunção Erétil/etnologia , Humanos , Masculino
17.
Cell Rep ; 9(2): 569-80, 2014 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-25310988

RESUMO

Molecular mechanisms underlying tumor VEGF-induced host anemia and bone marrow cell (BMC) mobilization remain unknown. Here, we report that tumor VEGF markedly induced sinusoidal vasculature dilation in bone marrow (BM) and BMC mobilization to tumors and peripheral tissues in mouse and human tumor models. Unexpectedly, anti-VEGFR2, but not anti-VEGFR1, treatment completely blocked VEGF-induced anemia and BMC mobilization. Genetic deletion of Vegfr2 in endothelial cells markedly ablated VEGF-stimulated BMC mobilization. Conversely, deletion of the tyrosine kinase domain from Vegfr1 gene (Vegfr1(TK-/-)) did not affect VEGF-induced BMC mobilization. Analysis of VEGFR1(+)/VEGFR2(+) populations in peripheral blood and BM showed no significant ratio difference between VEGF- and control tumor-bearing animals. These findings demonstrate that vascular dilation through the VEGFR2 signaling is the mechanism underlying VEGF-induced BM mobilization and anemia. Thus, our data provide mechanistic insights on VEGF-induced BMC mobilization in tumors and have therapeutic implications by targeting VEGFR2 for cancer therapy.


Assuntos
Anemia/metabolismo , Células da Medula Óssea/metabolismo , Movimento Celular , Mobilização de Células-Tronco Hematopoéticas , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Vasodilatação , Anemia/etiologia , Anemia/fisiopatologia , Animais , Células da Medula Óssea/fisiologia , Transplante de Medula Óssea , Domínio Catalítico , Linhagem Celular Tumoral , Células Endoteliais/metabolismo , Células Endoteliais/fisiologia , Deleção de Genes , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias Experimentais/complicações , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/terapia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/química , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética
18.
Mol Biol Rep ; 41(11): 7463-70, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25096509

RESUMO

Several genes encoding DNA repair molecules have been proposed as cancer-susceptibility genes. Many studies have suggested that SNPs in XRCC4 could be implicated in altering the risk of prostate cancer (PCa). We examined the role of the functional variant (-652T>G) in the XRCC4 promoter in PCa. The transcriptional activity of XRCC4 gene was measured by luciferase assay. We performed real-time PCR/immunohistochemical assay to verify the association between expression level of XRCC4 mRNA/protein and XRCC4 -652T>G polymorphism. In addition, electrophoretic mobility shift assay (EMSA) was used to confirm whether this polymorphism has an effect on binding ability of the transcription factor. We found that the G variant significantly increased the transcription activity of the XRCC4 gene and the binding ability of transcriptional factor GATA-1 to the XRCC4 promoter. Furthermore, the results suggested that the XRCC4 protein and mRNA were overexpressed in individuals who carried the -652G allele compared to carriers of the -652T allele. In addition, the expression of XRCC4 in PCa tissues was lower than in adjacent normal tissues. Our data suggest that the XRCC4 promoter -652G>T polymorphism is functional and may influence genetic susceptibility to prostate cancer. Case-control studies are required to validate our findings in the future.


Assuntos
Proteínas de Ligação a DNA/genética , Regulação Neoplásica da Expressão Gênica/genética , Polimorfismo de Nucleotídeo Único/genética , Regiões Promotoras Genéticas/genética , Neoplasias da Próstata/genética , Linhagem Celular Tumoral , China , Primers do DNA/genética , Ensaio de Desvio de Mobilidade Eletroforética , Humanos , Imuno-Histoquímica , Luciferases , Masculino , Plasmídeos/genética , Reação em Cadeia da Polimerase em Tempo Real
19.
J Virol ; 88(9): 4987-5000, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24554664

RESUMO

UNLABELLED: Kaposi's sarcoma-associated herpesvirus (KSHV) is causally linked to several AIDS-related malignancies, including Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman's disease. The interaction of human immunodeficiency virus type 1 (HIV-1) and KSHV has a central role in promoting the aggressive manifestations of AIDS-KS. We have previously shown that negative factor (Nef), a secreted HIV-1 protein, synergizes with KSHV viral interleukin-6 (vIL-6) to promote angiogenesis and tumorigenesis by activating the AKT pathway (X. Zhu, et al., Oncogene, 22 April 2013, http://dx.doi.org/10.1038/onc.2013.136). Here, we further demonstrated the role of soluble and ectopic Nef in the regulation of KSHV latency. We found that both soluble Nef protein and ectopic expression of Nef by transfection suppressed the expression of KSHV viral lytic mRNA transcripts and proteins and the production of infectious viral particles. MicroRNA (miRNA) microarray analysis identified a number of Nef-regulated miRNAs. Bioinformatics and luciferase reporter analyses showed that one of the Nef-upregulated miRNAs, cellular miRNA 1258 (hsa-miR-1258), directly targeted a seed sequence in the 3' untranslated region (UTR) of the mRNA encoding the major lytic switch protein (RTA), which controls KSHV reactivation from latency. Ectopic expression of hsa-miR-1258 impaired RTA synthesis and enhanced Nef-mediated inhibition of KSHV replication, whereas repression of hsa-miR-1258 has the opposite effect. Mutation of the seed sequence in the RTA 3'UTR abolished downregulation of RTA by hsa-miR-1258. Collectively, these novel findings demonstrate that, by regulating cellular miRNA, Nef may inhibit KSHV replication to promote viral latency and contribute to the pathogenesis of AIDS-related malignancies. IMPORTANCE: This study found that Nef, a secreted HIV-1 protein, suppressed KSHV lytic replication to promote KSHV latency. Mechanistic studies indicated that a Nef-upregulated cellular miRNA, hsa-miR-1258, inhibits KSHV replication by directly targeting a seed sequence in the KSHV RTA 3'UTR. These results illustrate that, in addition to viral miRNAs, cellular miRNAs also play an important role in regulating the life cycle of KSHV. Overall, this is the first study to report the involvement of Nef in KSHV latency, implying its likely important role in the pathogenesis of AIDS-related malignancies.


Assuntos
HIV-1/fisiologia , Herpesvirus Humano 8/fisiologia , MicroRNAs/metabolismo , Interferência Viral , Latência Viral , Replicação Viral , Produtos do Gene nef do Vírus da Imunodeficiência Humana/metabolismo , Perfilação da Expressão Gênica , Humanos , Análise em Microsséries
20.
Asian J Androl ; 15(6): 735-41, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23974361

RESUMO

The purpose of this study was to elucidate the molecular mechanisms of microRNA-205 (miR-205) as a tumor suppressor in prostate cancer (PCa). In the present study, microRNA microarray analysis suggested that the expression of miR-205 was significantly decreased in advanced PCa compared with early PCa. Real-time PCR analysis also indicated that miR-205 expression was significantly decreased in PCa tissues compared with non-cancerous tissues. Moreover, the expression of miR-205 has been demonstrated to be associated with the clinicopathological stage and total/free prostate-specific antigen (PSA) level of PCa. Functional analyses showed that both the overexpression of miR-205 and the knockdown of c-SRC in PCa cell lines could inhibit cell growth, colony formation, migration, invasion and the cell cycle as well as induce cell apoptosis in vitro. Furthermore, over-expressing miR-205 reduced tumorigenicity in vivo. Through a luciferase activity assay and Western blotting, c-SRC was identified as a target of miR-205 in cells. The overexpression of miR-205 suppressed c-SRC and its downstream signaling molecules, including FAK, p-FAK, ERK1/2 and p-ERK1/2, and attenuated cell proliferation, invasion and tumor growth.


Assuntos
Divisão Celular/genética , Regulação para Baixo , Genes Supressores de Tumor , MicroRNAs/genética , Neoplasias da Próstata/genética , Animais , Linhagem Celular Tumoral , Citometria de Fluxo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias da Próstata/patologia
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