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1.
Gene ; 731: 144364, 2020 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-31935511

RESUMO

Apolipoprotein C2 (ApoC2) is an important member of the apolipoprotein C family and functions as a major activator of lipoprotein lipase (LPL). In cardiovascular and cerebrovascular systems, the lipolytic activity of the LPL-ApoC2 complex is critical for the metabolism of triglyceride-rich lipoproteins and contributes to the pathogenesis of ischemic stroke (IS). However, the regulation of ApoC2 in IS development remains unclear. In this study, we first explored potential ApoC2-targeting microRNAs (miRNAs) by bioinformatics tool and compared the miRNA expression profiles in the blood cells of 25 IS patients and 25 control subjects by miRNA microarray. miR-1275 was predicted to bind with the 3' untranslated region of ApoC2, and a significant reduction of blood miR-1275 levels was observed in IS patients. Dual-luciferase reporter assay and quantitative RT-PCR confirmed the regulation of ApoC2 by miR-1275 in THP-1 derived macrophages. miR-1275 also inhibited cellular uptake of ox-LDL and suppressed formation of macrophage foam cell. Furthermore, the whole blood miR-1275 levels were validated in 279 IS patients and 279 control subjects by TaqMan assay. miR-1275 levels were significantly lower in IS cases and logistic regression analysis showed that miR-1275 level was negatively associated with the occurrence of IS (adjusted OR, 0.76; 95% CI, 0.69-0.85; p < 0.001). Addition of miR-1275 to traditional risk factors showed an additive prediction value for IS. Our study shows that blood miR-1275 levels were negatively associated with the occurrence of IS, and miR-1275 might exert an athero-protective role against the development of IS by targeting ApoC2 and blocking the formation of macrophage foam cells.

2.
Int J Antimicrob Agents ; 55(1): 105856, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31770630

RESUMO

Two novel phosphoethanolamine transferase genes, eptAv7 and eptAv3, were identified in the chromosome of an Aeromonas jandaei isolate from retail fish. The variants showed 79.9% and 80.0% amino acid identity to MCR-7.1 and MCR-3.1, respectively, and increased colistin resistance 128- to 256-fold in Aeromonas salmonicida. The two variants with no mobile genetic element in the flanking regions were also observed in other Aeromonas species. This finding supports the view that Aeromonas is a reservoir for MCR-3 and MCR-7 mobile colistin resistance.

3.
Chemosphere ; 244: 125498, 2019 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-31812049

RESUMO

BACKGROUND: Heavy metal exposure induces oxidative stress, which is critical for adverse male reproductive health. OBJECTIVE: To explore the mediating effect of oxidative stress on the relationship of heavy metal exposure with semen quality. METHODS: Urinary levels of three oxidative stress markers, semen quality, and urinary arsenic, cadmium and lead were examined among 1020 men. Multivariate linear regression was applied to explore cross-sectional associations, and the role of oxidative stress as mediators was investigated. RESULTS: Quartiles of metals showed significant dose-dependent relationships with increasing levels of 8-hydroxy-2deoxyguanosine (8-OHdG), 8-iso-prostaglandin F2α (8-isoPGF2α) and 4-hydroxy-2-nonenal-mercapturic acid (HNE-MA). Significant or suggestive associations were also found between urinary 8-OHdG levels and the percentage of normal sperm morphology (ptrend < 0.001), between urinary 8-isoPGF2α levels and total motility (ptrend = 0.052), progressive motility (ptrend = 0.050) respectively. The mediation analysis showed that about 14.59%, 18.06%, 15.35% or 16.49% of the association between arsenic/cadmium exposure and the decreased total motility/progressive motility was mediated by 8-isoPGF2α, respectively. In addition, about 16.47% of the relationship between lead exposure and the decreased percentage of normal sperm morphology was mediated by 8-OHdG. CONCLUSIONS: Our findings suggest that higher urinary arsenic, cadmium and lead levels were associated with increased oxidative stress markers, which also related with altered semen quality. 8-isoPGF2α and 8-OHdG might be the possible mediators of the associations between urinary heavy metals and total motility, progressive motility or the proportion of normal sperm morphology.

4.
Environ Int ; 130: 104708, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31202027

RESUMO

BACKGROUND: Since its discovery in 2015, the mobile colistin resistance gene mcr-1 has been reported in bacteria from >50 countries. Although aquaculture-associated bacteria may act as a significant reservoir for colistin resistance, systematic investigations of mcr-1 in the aquaculture supply chain are scarce. OBJECTIVES: We investigated the presence of colistin resistance determinants in the aquaculture supply chain in south China and determined their characteristics and relationships. METHODS: A total of 250 samples were collected from a duck-fish integrated fishery, slaughter house, and market in Guangdong Province, China, in July 2017. Colistin-resistant bacteria were isolated on colistin-supplemented CHROMagar Orientation plates, and the species were identified by matrix-assisted laser desorption/ionization time-of-flight assay. The presence of mcr genes was confirmed by polymerase chain reaction analysis. We examined the minimum inhibitory concentrations (MICs) of 16 antimicrobial agents against the isolates using agar diffusion and broth microdilution methods. Whole-genome sequencing (WGS) was used to explore the molecular characteristics and relationships of mcr-1-positive Escherichia coli (MCRPEC). RESULTS: Overall, 143 (57.2%) colistin-resistant bacteria were isolated, of which, 56 (22.4%, including 54 Escherichia coli and two Klebsiella pneumoniae) and four Aeromonas species were positive for mcr-1 and mcr-3, respectively. The animal-derived MCRPEC were significantly more prevalent in integrated fishery samples (40.0%) than those in market (4.8%, P<0.01) samples but not in slaughter house (28.0%, P=0.164). All MCRPEC were highly resistant to ampicillin, tetracycline, and compound sulfamethoxazole (>90%) but were susceptible to carbapenems and tigecycline. WGS analysis suggested that mcr-1 was mainly contained on plasmids, including IncHI2 (29.6%), IncI2 (27.8%), IncX4 (14.8%), and IncP (11.1%). Genomic analysis suggested mcr-1 transmission via the aquatic food chain. CONCLUSIONS: MCRPEC were highly prevalent in the aquaculture supply chain, with the isolates showing resistance to most antibiotics. The data suggested mcr-1 could be transferred to humans via the aquatic food chain. Taking the "One Health" perspective, aquaculture should be incorporated into systematic surveillance programs with animal, human, and environmental monitoring.

5.
Artigo em Inglês | MEDLINE | ID: mdl-31085517

RESUMO

The rapid dissemination of the macrolide resistance gene erm(B) will likely compromise the efficacy of macrolides as the treatment of choice for campylobacteriosis. More importantly, erm(B) is always associated with several multidrug resistance genomic islands (MDRGIs), which confer resistance to multiple other antimicrobials. Continuous monitoring of the emergence of erm(B) and analysis of its associated genetic environments are crucial for our understanding of macrolide resistance in Campylobacter In this study, 290 Campylobacter isolates (216 Campylobacter coli isolates and 74 Campylobacter jejuni isolates) were obtained from 1,039 fecal samples collected in 2016 from pigs and chickens from three regions of China (344 samples from Guangdong, 335 samples from Shanghai, and 360 samples from Shandong). Overall, 74 isolates (72 C. coli isolates and 2 C. jejuni isolates) were PCR positive for erm(B). Combined with data from previous years, we observed a trend of increasing prevalence of erm(B) in C. coli Pulsed-field gel electrophoresis analyses suggested that both clonal expansion and horizontal transmission were involved in the dissemination of erm(B) in C. coli, and three novel types of erm(B)-associated MDRGIs were identified among the isolates. Furthermore, 2 erm(B)-harboring C. jejuni isolates also contained an aminoglycoside resistance genomic island and a multidrug-resistance-enhancing efflux pump, encoded by RE-cmeABC Antimicrobial susceptibility testing showed that most of the isolates were resistant to all clinically important antimicrobial agents used for the treatment of campylobacteriosis. These findings suggest that the increasing prevalence of erm(B)-associated MDRGIs might further limit treatment options for campylobacteriosis.

6.
Nat Microbiol ; 4(9): 1450-1456, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31133751

RESUMO

Tigecycline is a last-resort antibiotic that is used to treat severe infections caused by extensively drug-resistant bacteria. tet(X) has been shown to encode a flavin-dependent monooxygenase that modifies tigecycline1,2. Here, we report two unique mobile tigecycline-resistance genes, tet(X3) and tet(X4), in numerous Enterobacteriaceae and Acinetobacter that were isolated from animals, meat for consumption and humans. Tet(X3) and Tet(X4) inactivate all tetracyclines, including tigecycline and the newly FDA-approved eravacycline and omadacycline. Both tet(X3) and tet(X4) increase (by 64-128-fold) the tigecycline minimal inhibitory concentration values for Escherichia coli, Klebsiella pneumoniae and Acinetobacter baumannii. In addition, both Tet(X3) (A. baumannii) and Tet(X4) (E. coli) significantly compromise tigecycline in in vivo infection models. Both tet(X3) and tet(X4) are adjacent to insertion sequence ISVsa3 on their respective conjugative plasmids and confer a mild fitness cost (relative fitness of >0.704). Database mining and retrospective screening analyses confirm that tet(X3) and tet(X4) are globally present in clinical bacteria-even in the same bacteria as blaNDM-1, resulting in resistance to both tigecycline and carbapenems. Our findings suggest that both the surveillance of tet(X) variants in clinical and animal sectors and the use of tetracyclines in food production require urgent global attention.


Assuntos
Bactérias , Proteínas de Bactérias/genética , Oxigenases de Função Mista/genética , Plasmídeos/genética , Resistência a Tetraciclina/genética , Tigeciclina/farmacologia , Animais , Antibacterianos/metabolismo , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Bactérias/genética , Proteínas de Bactérias/metabolismo , Elementos de DNA Transponíveis , Humanos , Carne/microbiologia , Testes de Sensibilidade Microbiana , Oxigenases de Função Mista/metabolismo , Resistência a Tetraciclina/efeitos dos fármacos , Tigeciclina/metabolismo
7.
Ecotoxicol Environ Saf ; 176: 1-10, 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-30903973

RESUMO

Wide use of titanium dioxide nanoparticles (TiO2 NPs) as white pigments induces unintentionally release in environment which increases concerns about their adverse health effects on respiratory system. So it is crucial to get a deep understanding of the disease process and molecular mechanism. Epigenetic mechanisms, such as DNA methylation, have been found to play a role in the development of lung diseases by affecting expression of key genes. In addition, there could be potential different toxic effects of TiO2 NPs between young and adult. Thus, the comparative toxicity of TiO2 NPs in 5-week (young) and 10-week (adult) old NIH mice is investigated in this study following nasal inhalation of TiO2 NPs at dose of 20 mg/kg (body weight)/day for 30 days. Global DNA methylation and hydroxymethylation in lung were measured. Promoter methylation of inflammatory genes (IFN-γ and TNF-α) and tissue fibrosis gene (Thy-1) were determined. Additional, RNA-sequencing runs were performed on the pulmonic libraries. We found the induced pulmonary inflammation and fibrosis were more severe in young mice. Decreased global methylation and hydroxymethylation were only found in the young group. The altered methylation in promoter of TNF-α and Thy-1 were found to play a role in the inflammatory response and fibration. RNA-sequencing showed that in pathways in cancer expression of 197 genes was up-regulated in the young mice more that in the adult mice. All these results suggested that the young ages are more sensitive to TiO2 NP exposure and the potential of abnormal DNA methylation might be used as biomarkers of both exposure and disease development.


Assuntos
Metilação de DNA , Exposição por Inalação , Pulmão/efeitos dos fármacos , Nanopartículas/toxicidade , Pneumonia/patologia , Titânio/toxicidade , Animais , Biomarcadores/metabolismo , Fibrose/genética , Pulmão/patologia , Nanopartículas Metálicas/toxicidade , Camundongos , Pneumonia/genética , Regiões Promotoras Genéticas , Análise de Sequência de RNA , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima
8.
Environ Int ; 125: 125-134, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30716572

RESUMO

BACKGROUND: Ischemic stroke (IS) is a major cause of morbidity and mortality globally. Environmental exposure to metals may be linked to the risk of IS, but the association remains uncertain in Chinese populations. OBJECTIVES: The present study aimed to examine the associations between the concentrations of 11 metals (aluminum, arsenic, cadmium, cobalt, copper, iron, manganese, molybdenum, selenium, thallium, and zinc) in plasma and the risk of IS in a Chinese population. METHODS: A total of 1277 pairs of newly diagnosed IS patients and controls matched on age (±3 years) and sex were recruited in our study. Plasma metal concentrations were measured using inductively coupled plasma mass spectrometry. Multivariable conditional logistic regression models were conducted to investigate the impacts of single and multiple metals, respectively. RESULTS: In the single-metal model, exposure to seven metals (aluminum, arsenic, cadmium, cobalt, iron, manganese and selenium) was individually associated with the risk of IS based on the trend test. Further stepwise regression analyses with the multiple-metal model revealed increasing trends in the risk of IS associated with aluminum, arsenic, and cadmium quartiles and decreasing trends with iron and selenium quartiles (p-trend < 0.01). Compared to the lowest quartiles, the odds ratios (95% confidence intervals) for the highest quartiles of these five metals were 4.23 (2.63, 6.79), 1.88 (1.25, 2.81), 5.02 (3.30, 7.63), 0.59 (0.40, 0.89), and 0.10 (0.06, 0.17), respectively. CONCLUSIONS: Our study suggested that higher plasma concentrations of aluminum, arsenic, and cadmium, and lower concentrations of iron and selenium may increase the risk of IS. Further prospective studies in larger populations are warranted to confirm our findings.


Assuntos
Isquemia Encefálica/induzido quimicamente , Metais/sangue , Metais/toxicidade , Acidente Vascular Cerebral/induzido quimicamente , Idoso , Grupo com Ancestrais do Continente Asiático , Isquemia Encefálica/sangue , Estudos de Casos e Controles , Exposição Ambiental , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Medição de Risco , Acidente Vascular Cerebral/sangue
9.
J Cell Mol Med ; 23(1): 167-176, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30499219

RESUMO

Spleen tyrosine kinase (SYK) gene has been identified as novel susceptibility locus for ischaemic stroke (IS) previously. However, regulation of SYK gene remains unknown in IS. In this study, we aimed to identify miRNAs that might be involved in the development of IS by targeting SYK gene. miRNAs were firstly screened by bioinformatics predicting tool. The expression levels of SYK gene were detected by qRT-PCR and western blotting, respectively, after miRNA transfection. Luciferase reporter assay was applied to investigate the direct binding between miRNAs and target gene. miRNA levels were detected by miRNA TaqMan assays in the blood cells of 270 IS patients and 270 control volunteers. Results suggest that SYK gene might be a direct target of miR-129-2-3p. The blood level of miR-129-2-3p was significantly lower in IS patients (P < 0.05), and negatively associated with the risk of IS (adjusted OR: 0.88; 95% CI: 0.80-0.98; P = 0.021) by multivariable logistic regression analysis. The blood levels of SYK gene were significantly higher in IS patients, and miR-129-2-3p expression was negatively correlated with mean platelet volume. In summary, our study suggests that miR-129-2-3p might be involved in the pathogenesis of IS through interrupting SYK expression and the platelet function, and further investigation is needed to explore the underlying mechanism.

10.
Oxid Med Cell Longev ; 2018: 3295807, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30327711

RESUMO

Curcumin has several therapeutic properties such as anti-inflammatory effect. Heme oxygenase-1 (HO-1) has been showed to have cytoprotective effects in some pathological conditions. However, the role of HO-1 in anti-inflammatory effect of curcumin is unknown. In this study, we investigate whether the anti-inflammatory effect of curcumin in vascular may be involved in the activation of HO-1. New Zealand white rabbits were fed regular control diet or control diet added with 0.3% curcumin (wt/wt) for four weeks. Acute vascular inflammation of rabbits was induced by putting a collar on the left common carotid artery for 24 hours. HO-1 inhibitor and siRNA were used to investigate the role of HO-1 in the anti-inflammatory effect of curcumin in collared vascular. We also explored the mechanism of curcumin-induced activation of HO-1 in vitro. The serum bilirubin and vascular, liver, and spleen HO-1 mRNA levels were significantly increased in curcumin-treated rabbits. The vascular inflammation was significantly decreased in the curcumin-treated animals compared with the control. Treatment of the rabbits with an inhibitor of HO or HO-1 siRNA to knock down the carotid artery HO-1 abolished the ability of curcumin to inhibit vascular inflammation. Treatment of cultured human artery endothelial cells with curcumin induced the HO-1 expression through the activation of nuclear factor-E2-related factor 2 (Nrf2) and an antioxidant responsive element via the p38 MAPK signalling pathway. In conclusion, curcumin inhibits vascular inflammation in vivo and in vitro through the activation of HO-1.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Curcumina/farmacologia , Endotélio Vascular/efeitos dos fármacos , Heme Oxigenase-1/metabolismo , Animais , Artéria Carótida Primitiva/efeitos dos fármacos , Artéria Carótida Primitiva/metabolismo , Endotélio Vascular/metabolismo , Ativação Enzimática/efeitos dos fármacos , Humanos , Inflamação/metabolismo , Coelhos
11.
Nutr J ; 17(1): 87, 2018 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-30241536

RESUMO

BACKGROUND: Epidemiological studies have found that high whole grain intake may be associated with a reduced risk of breast cancer. However, the evidence has not been consistent. We conducted a meta-analysis to quantitatively assess the association between whole grain intake and breast cancer risk. METHODS: Relevant observational studies were identified by searching PubMed, Embase, Cochrane library databases, and Google Scholar through April 2017. Summary relative risk (RR) estimates were calculated using random-effects meta-analysis. RESULTS: A total of 11 studies, including 4 cohort and 7 case-control studies and involving 131,151 participants and 11,589 breast cancer cases, were included in the current meta-analysis. The pooled RR of breast cancer for those with high versus low whole grain intake was 0.84 (95% confidence interval [CI]: 0.74 to 0.96, p = 0.009; I2 = 63.8%, p for heterogeneity = 0.002). Subgroup analysis by study design found a significant inverse association in the case-control studies (RR: 0.69; 95% CI: 0.56 to 0.87, p = 0.001; I2 = 58.2%, p for heterogeneity = 0.026), but not in the cohort studies (RR, 0.96; 95% CI: 0.82 to 1.14, p = 0.69; I2 = 66.7%, p for heterogeneity = 0.029). In addition, stratified analysis suggested that sample size could be a potential source of heterogeneity. CONCLUSIONS: Results of the current meta-analysis suggest that high intake of whole grains might be inversely associated with a reduced risk of breast cancer, and the inverse association was only observed in case-control but not cohort studies. More large-scale cohort studies are needed to confirm the inverse association observed.


Assuntos
Neoplasias da Mama/prevenção & controle , Dieta/métodos , Dieta/estatística & dados numéricos , Grãos Integrais , Adulto , Idoso , Feminino , Humanos , Pessoa de Meia-Idade , Estudos Observacionais como Assunto , Fatores de Risco
12.
Nutrition ; 54: 129-143, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29852452

RESUMO

OBJECTIVE: Several randomized controlled trials (RCTs) have assessed the effects of nut consumption on inflammatory markers. However, the results have been inconsistent. The aim of this meta-analysis of RCTs was to quantitatively evaluate the effects of nut consumption on selected inflammatory markers. METHODS: PubMed, Embase, Cochrane Library database, and Google Scholar were searched for published RCTs that reported the effects of nuts on inflammatory markers as primary or secondary outcomes in an adult population (aged ≥18 y). Summary estimates of weighted mean differences (WMDs) and 95% confidence intervals (CIs) were calculated using random-effects meta-analysis. RESULTS: Twenty-three RCTs met the inclusion criteria. Overall, nut consumption significantly reduced the levels of intercellular adhesion molecule (ICAM)-1 (WMD, -0.17; 95% CI, -0.32 to -0.03; P = 0.01), but had no significant effect on other inflammatory markers. In the subgroup analyses by nut types, mixed nuts had a significant effect on ICAM-1 reduction. The significant effect of nuts on ICAM-1 reduction was only observed in parallel, but not crossover RCTs. Additionally, nut consumption significantly reduced ICAM-1 and vascular cell adhesion molecule-1 levels in long-term (≥12 wk), but not short-term (<12 wk) RCTs. No significant heterogeneity or publication bias was observed in the studies included. CONCLUSIONS: Nut consumption significantly reduced ICAM-1 levels, but had no effect on other inflammatory markers. More studies are needed to assess the effects of nuts on inflammation.


Assuntos
Dieta/métodos , Ingestão de Alimentos/fisiologia , Mediadores da Inflamação/sangue , Inflamação/dietoterapia , Nozes , Adulto , Biomarcadores/sangue , Feminino , Humanos , Inflamação/sangue , Molécula 1 de Adesão Intercelular/sangue , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , Molécula 1 de Adesão de Célula Vascular/sangue
13.
Anal Chim Acta ; 1001: 125-133, 2018 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-29291795

RESUMO

The enzyme-linked immunosorbent assay (ELISA) has become the most important and widely used rapid detection technology for food safety because of its simple operation, fast speed and high sensitivity. Multiplex synchronous detection is the goal of ELISA that is always pursuing for. However, the reported multiplex ELISAs have not truly realized synchronous detection because of the complex signal generation and collection procedures. Here, we developed a dual-luciferases competitive direct bioluminescent immunoassay (DBL-cdELISA) with only one substrate addition step followed immediately by simultaneous signal acquisition. It is the first report of simultaneous multiplex analysis of small molecules based on microtiter plates and enzymes without any additional steps. The IC50 values for norfloxacin (NOR) and sulfamethazine (SMZ) were 0.051 ng mL-1 and 0.211 ng mL-1, respectively. The results demonstrated that the application of different luciferases and substrates simplified the signal generation and collection procedures and enabled simultaneous detection of small molecules with a simple procedure, high throughput and fast speed, that will be of great significance for the development of multiple assays.


Assuntos
Anti-Infecciosos/análise , Ensaio de Imunoadsorção Enzimática/métodos , Leite/química , Norfloxacino/análise , Sulfametazina/análise , Animais , Limite de Detecção , Luciferases/química
14.
Cytotechnology ; 70(1): 119-128, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28689280

RESUMO

Recent studies have indicated that Di-(2-ethylhexyl) phthalate (DEHP), the most commonly used plasticizer in daily-life products, could be dispersed in indoor air and induce human exposure via inhalation. DEHP has been reported to have effects on the respiratory system in both animal and human researches. The toxicity effects of DEHP exposure on cell proliferation, cell cycle progression, apoptosis, global DNA methylation and the expression levels of DNA methyltransferases (DNMTs) were investigated in this study, using human epithelial cell line 16HBE as an in vitro model. Cells were treated with DEHP at doses of 0, 0.125, 0.5 and 2 mmol/L for 48 h. Cell proliferation, cell cycle and apoptosis were tested by MTT assay and flow cytometer, respectively. The obtained results showed decreased living cell number and cell viability following DEHP exposure at the dose of 2 mmol/L. DEHP also inhibited the cell cycle progression of G1 phase and induced a significant increase in cell apoptosis in 16HBE cells. DEHP exposure could induce cell proliferation inhibition in 16HBE cells via the blocking of cell cycle progression and accelerated cell apoptosis. In addition, decreased global DNA methylation levels and expression levels of DNMTs were observed in DEHP-treated groups which revealed possible epigenetic effects of DEHP.

15.
PLoS One ; 11(10): e0163951, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27776139

RESUMO

Circulating microRNAs (miRNAs) are emerging as novel disease biomarkers. Using a miRNA microarray, we previously showed that the whole blood level of let-7e-5p was significantly higher in ischemic stroke patients than in control subjects. However, the association between let-7e-5p expression and the occurrence of ischemic stroke remains unknown. In this study, we validated the expression levels of let-7e-5p in two case-control populations using miRNA TaqMan assays and further investigated the potential targets of let-7e-5p. The results suggest that the blood level of let-7e-5p was significantly higher in patients with ischemic stroke than in controls (p<0.05). Higher levels of let-7e-5p were associated with increased occurrence of ischemic stroke (adjusted OR, 1.89; 95% CI, 1.61~2.21, p<0.001) in the combined population. The addition of let-7e-5p to traditional risk factors led to an improvement in the area under the curve, which increased from 0.74 (95% CI, 0.70~0.78) to 0.82 (95% CI, 0.78~0.85), with a net reclassification improvement of 16.76% (p<0.0001) and an integrated discrimination improvement of 0.10 (p<0.0001) for patients with ischemic stroke. Bioinformatics prediction and cell experiments suggested that the expression levels of four genes enriched in the MAPK signaling pathway were down-regulated by let-7e-5p transfection. Specifically, the expression levels of the genes CASP3 and NLK were significantly lower in ischemic stroke patients than in controls and were negatively correlated with let-7e-5p expression. In summary, our study suggests the potential use of blood let-7e-5p as a biomarker for ischemic stroke and indicates its involvement in the related pathomechanism.


Assuntos
Biomarcadores/sangue , Isquemia Encefálica/genética , MicroRNAs/sangue , Acidente Vascular Cerebral/genética , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Curva ROC , Células U937
16.
J Mol Endocrinol ; 57(4): 223-231, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27613820

RESUMO

Eight amino acids are considered essential for human nutrition, and three of them, including leucine, isoleucine and valine, are called as branched-chain amino acids (BCAAs). We recently discovered that dietary deficiency of any BCAA for 7 days rapidly reduces the abdominal fat mass in mice. The goal of this study was to investigate (1) whether dietary deficiency of the other five essential amino acids (EAAs), including phenylalanine, threonine, tryptophan, methionine and lysine, would produce similar effects and (2) whether an association between serum AAs and obesity was observed in humans in Chinese Han population. Similar to BCAAs deprivation, dietary deficiency of any of these five EAAs for 7 days significantly reduced abdominal fat mass, which is likely caused by increased energy expenditure. Expression of genes and proteins related to lipolysis, however, were differentially regulated by different EAAs. These results suggest a crucial role of EAAs deprivation on lipid metabolism in mice. Our human studies revealed that levels of four EAAs (leucine, isoleucine, valine and phenylalanine) were elevated in obese humans compared with those in lean controls in Chinese Han population. Based on the results obtained from mice, we speculate that these four EAAs might play important roles in human obesity.


Assuntos
Aminoácidos Essenciais/metabolismo , Metabolismo dos Lipídeos , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Adulto , Aminoácidos Essenciais/sangue , Aminoácidos Essenciais/deficiência , Aminoácidos Essenciais/farmacologia , Animais , Biomarcadores , Peso Corporal , Feminino , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipólise , Masculino , Camundongos , Fatores de Tempo
17.
Obesity (Silver Spring) ; 24(2): 368-78, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26663559

RESUMO

OBJECTIVE: Di(2-ethylhexyl) phthalate (DEHP) is reported to cause obesity and hypothyroidism in both humans and rodents, but the underlying mechanisms were largely unknown. This study was designed to clarify the effects and the mechanisms of DEHP on the pathogenesis of obesity and hypothyroidism and to discover the relationship between them. METHODS: Male C3H/He mice were treated with DEHP for 5 weeks, and the body weight, food intake, and body temperature were recorded during the exposure. After exposure, key organs and serum were analyzed by Q-PCR, Western blot, and ELISA. RESULTS: DEHP induced significant body weight gain and adipogenesis in all exposure groups except for 0.05 mg/kg. Marked hyperphagia and daytime hypothermia were also observed, which were accompanied by disturbed hypothalamic neuropeptide expression and reduced BAT UCP1 expression. In addition, WAT lipid metabolism was significantly deceased at low dose (0.5 mg/kg) and increased at high dose (50 and 200 mg/kg). DEHP also induced hypothyroidism, which was probably attributed to the combined effects of hepatic CAR activation and hypothalamic TRH inhibition induced by hypothalamic leptin resistance. CONCLUSIONS: Chronic DEHP exposure could induce obesity by interrupting energy homeostasis, which is probably due to the synergistic effects of hypothyroidism and hypothalamic leptin resistance.


Assuntos
Dietilexilftalato/efeitos adversos , Hipotálamo/metabolismo , Hipotireoidismo/induzido quimicamente , Obesidade/induzido quimicamente , Plastificantes/efeitos adversos , Adipogenia/efeitos dos fármacos , Animais , Peso Corporal , Dietilexilftalato/administração & dosagem , Hipotireoidismo/metabolismo , Leptina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C3H , Obesidade/metabolismo , Plastificantes/administração & dosagem , Reação em Cadeia da Polimerase em Tempo Real , Ganho de Peso/efeitos dos fármacos
18.
Tohoku J Exp Med ; 237(3): 227-33, 2015 11.
Artigo em Inglês | MEDLINE | ID: mdl-26537765

RESUMO

MicroRNAs (miRNAs) can contribute to the development of cardiovascular diseases, and single nucleotide polymorphisms (SNPs) in miRNA genes may influence disease susceptibility by altering mature miRNA expression levels. However, the effect of SNPs located in miR-146a and miR-196a2 genes on risk of acute coronary syndrome (ACS) has not been reported in the Chinese population. Two miRNA polymorphisms located in miRNA genes (miR-146a rs2910164 C>G and miR-196a2 rs11614913 T>C) were genotyped in 722 ACS patients and 721 control subjects. The CG genotype of rs2910164 was significantly associated with decreased risk of ACS [CG vs. CC, odds ratio (OR) = 0.72, 95% confidence interval (CI): 0.55-0.95, P = 0.020; dominant model, OR = 0.77, 95% CI: 0.60-0.99, P = 0.044]. We did not find any association of rs11614913 with the risk of ACS. Stratification analysis showed that the rs2910164 CG genotype was associated with decreased risk of ACS (dominant model) in males, subjects with body mass index more than 24 kg/m(2), and in hypertensive subjects. Significant combined effects were also observed between rs2910164 and blood lipids or C-reactive protein levels. In summary, this study provides the first evidence that the CG genotype of miR-146a rs2910164 is associated with a significantly decreased risk of ACS in a Chinese population. Moreover, rs2910164 and blood lipids or an inflammatory marker may have a combined effect on the onset of ACS. These findings indicate that miR-146a rs2910164 may act as a novel molecular marker for ACS susceptibility.


Assuntos
Síndrome Coronariana Aguda/genética , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Associação Genética , Predisposição Genética para Doença , MicroRNAs/genética , Polimorfismo de Nucleotídeo Único/genética , Síndrome Coronariana Aguda/sangue , Idoso , Proteína C-Reativa/metabolismo , China , Colesterol/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Triglicerídeos/sangue
19.
PLoS One ; 10(2): e0117007, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25658319

RESUMO

microRNA (miRNA) plays a role in the pathogenesis of ischemic stroke, and single nucleotide polymorphisms in miRNA genes may contribute to disease susceptibility. However, the effect of miR-146a, miR-196a2, and miR-499 polymorphisms on ischemic stroke susceptibility has been rarely reported. Using the TaqMan assay, we evaluated the association of hsa-miR-146a/rs2910164, hsa-miR-196a2/rs11614913, and hsa-miR-499/rs3746444 polymorphisms with the risk of ischemic stroke in a Chinese population with 531 ischemic stroke patients and 531 control subjects. Rs2910164 C/G genotypes were significantly associated with increased risk of ischemic stroke in different genetic model (homozygote comparison: OR = 2.00, 95% CI, 1.29-3.12, P = 0.002; additive model: OR = 1.35, 95% CI, 1.10-1.65, P = 0.004;dominant model: OR = 1.33, 95% CI, 1.00-1.75, P = 0.049; recessive model: OR = 1.82, 95% CI, 1.20-2.74, P = 0.004). Subjects with allele G of hsa-miR-146a/ rs2910164 also showed increased risk of ischemic stroke (OR = 1.33, 95% CI, 1.09-1.62, P = 0.005). Stratification analysis showed that the association between rs2910164 and the risk of ischemic stroke was more pronounced in subjects over 60 years old, females, non-drinkers, subjects without hypertension or diabetes mellitus. There were significant combined effects between miR-146a/rs2910164 and fasting glucose/low-density lipoprotein cholesterol levels on ischemic stroke susceptibility. However, we failed to find any association between the alleles/genotypes of rs11614913 T/C and ischemic stroke, respectively (P> 0.05). In summary, this study provides evidence that miR-146a/rs2910164 might be associated with a significantly increased risk of ischemic stroke in a Chinese population, and the combined effects between miRNA polymorphism and fasting glucose /blood lipid levels may contribute to stroke pathogenesis.


Assuntos
MicroRNAs/genética , Polimorfismo de Nucleotídeo Único , Acidente Vascular Cerebral/genética , Idoso , Alelos , Grupo com Ancestrais do Continente Asiático/genética , Glicemia/análise , Estudos de Casos e Controles , China/epidemiologia , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/epidemiologia
20.
Toxicol Lett ; 230(1): 62-8, 2014 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-25127756

RESUMO

OBJECTIVE: To investigate the potential compensatory effects of hOGG1 and hMTH1 in the repair of oxidative DNA damage. METHODS: The hOGG1 and hMTH1 gene knockdown human embryonic pulmonary fibroblast cell lines were established by lentivirus-mediated RNA interference. The messenger RNA (mRNA) levels of hOGG1 and hM1TH1 were analyzed by the real-time polymerase chain reaction, and 8-hydroxy-2'-deoxyguanosine (8-oxo-dG) formation was analyzed in a high-performance liquid chromatography-electrochemical detection system. RESULTS: The hOGG1 and hMTH1 knockdown cells were obtained through blasticidin selection. After transfection of hOGG1 and hMTH1 small interfering RNA, the expression levels of the mRNA of hOGG1 and hMTH1 genes were decreased by 97.2% and 96.2%, respectively. The cells then were exposed to 100 µmol/L of hydrogen peroxide (H2O2) for 12 h to induce oxidative DNA damage. After H2O2 exposure, hMTH1 mRNA levels were increased by 25% in hOGG1 gene knockdown cells, whereas hOGG1 mRNA levels were increased by 52% in hMTH1 gene knockdown cells. Following the treatment with H2O2, the 8-oxo-dG levels in the DNA of hOGG1 gene knockdown cells were 3.1-fold higher than those in untreated HFL cells, and 1.67-fold higher than those in H2O2-treated wild-type cells. The 8-oxo-dG levels in hMTH1 gene knockdown cells were 2.3-fold higher than those in untreated human embryonic pulmonary fibroblast cells, but did not differ significantly from those in H2O2-treated wild-type cells. CONCLUSION: Our data suggested that hOGG1 could compensate for hMTH1 during oxidative DNA damage caused by H2O2, whereas hMTH1 could not compensate sufficiently for hOGG1 during the process.


Assuntos
Dano ao DNA , DNA Glicosilases/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Fibroblastos/efeitos dos fármacos , Peróxido de Hidrogênio/toxicidade , Oxidantes/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Monoéster Fosfórico Hidrolases/metabolismo , Linhagem Celular , DNA Glicosilases/genética , Enzimas Reparadoras do DNA/genética , Desoxiguanosina/análogos & derivados , Desoxiguanosina/metabolismo , Fibroblastos/enzimologia , Fibroblastos/patologia , Regulação Enzimológica da Expressão Gênica , Técnicas de Silenciamento de Genes , Vetores Genéticos , Humanos , Lentivirus/genética , Monoéster Fosfórico Hidrolases/genética , Interferência de RNA , RNA Mensageiro/metabolismo , Transfecção
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