Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 344
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 42(2): 172-177, 2020 Apr 28.
Artigo em Chinês | MEDLINE | ID: mdl-32385022

RESUMO

Objective To investigate the association of pancreatic steatosis with coronary atherosclerosis in patients with type 2 diabetes mellitus (T2DM). Methods Patients with T2DM who underwent coronary computed tomography angiography(CCTA)in our center due to chest pain were enrolled from January 2016 to February 2019. According to the CCTA findings,patients were divided into normal group,mild-to-moderate coronary atherosclerosis group and severe coronary atherosclerosis group. CT attenuation of pancreas and spleen was measured on abdominal non-enhanced CT,and the CT attenuation indexes including the difference between pancreatic and splenic attenuation (P-S) and the ratio of pancreas-to-spleen attenuation (P/S) were calculated. Analysis of variance or Kruskal-Wallis rank test were used to assess differences among each group. Logistic regression analysis was used to analyze the risk factors of severe coronary stenosis. The accuracy of P/S in predicting severe coronary artery stenosis was assessed by receiver operator characteristic (ROC) curve analysis. Results A total of 173 consecutive T2DM patients were enrolled. These patients included 27 patients with normal coronary artery (15.6%),124 patients with mild to moderate stenosis (71.7%),and 22 patients with severe stenosis (12.7%). There were significant differences in CT attenuation of pancreas (Z=11.543,P=0.003),P-S (Z=11.152,P=0.004) and P/S (Z=11.327,P=0.004) among normal coronary artery group,mild and moderate stenosis group,and severe stenosis group. The CT attenuation of pancreatic head,body,and tail significantly differed in patients with coronary artery stenosis (Z=14.737,P=0.001). After adjusting for confounding factors,multiple Logistic regression showed that P/S (OR=0.062,95%CI=0.008-0.487,P=0.008) was still significantly associated with the severe coronary artery stenosis. The area under the ROC curve of P/S for the diagnosis of severe coronary artery stenosis was 0.701,and the optimal cutoff point was 0.660. Conclusion CT attenuation of pancreas and CT attenuation indexes are associated with the severity of coronary stenosis in T2DM patients,suggesting that pancreatic steatosis may be used as one of the indicators for predicting severe coronary artery stenosis.

2.
Immunity ; 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32362324

RESUMO

Tissue-resident and recruited macrophages contribute to both host defense and pathology. Multiple macrophage phenotypes are represented in diseased tissues, but we lack deep understanding of mechanisms controlling diversification. Here, we investigate origins and epigenetic trajectories of hepatic macrophages during diet-induced non-alcoholic steatohepatitis (NASH). The NASH diet induced significant changes in Kupffer cell enhancers and gene expression, resulting in partial loss of Kupffer cell identity, induction of Trem2 and Cd9 expression, and cell death. Kupffer cell loss was compensated by gain of adjacent monocyte-derived macrophages that exhibited convergent epigenomes, transcriptomes, and functions. NASH-induced changes in Kupffer cell enhancers were driven by AP-1 and EGR that reprogrammed LXR functions required for Kupffer cell identity and survival to instead drive a scar-associated macrophage phenotype. These findings reveal mechanisms by which disease-associated environmental signals instruct resident and recruited macrophages to acquire distinct gene expression programs and corresponding functions.

3.
FASEB J ; 2020 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-32374060

RESUMO

While emerging evidence suggests the link between endothelial activation of TGF-ß signaling, induction of endothelial-to-mesenchymal transition (EndMT), and cardiovascular disease (CVD), the molecular underpinning of this connection remains enigmatic. Here, we report aberrant expression of H19 lncRNA and TET1 in endothelial cells (ECs) of human atherosclerotic coronary arteries. Using primary human umbilical vein endothelial cells (HUVECs) and aortic endothelial cells (HAoECs) we show that TNF-α, a known risk factor for endothelial dysfunction and CVD, induces H19 expression which in turn activates TGF-ß signaling and EndMT via a TET1-dependent epigenetic mechanism. We also show that H19 regulates TET1 expression at the posttranscriptional level. Further, we provide evidence that this H19/TET1-mediated regulation of TGF-ß signaling and EndMT occurs in mouse pulmonary microvascular ECs in vivo under hyperglycemic conditions. We propose that endothelial activation of the H19/TET1 axis may play an important role in EndMT and perhaps CVD.

4.
Environ Technol ; : 1-11, 2020 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-32419659

RESUMO

During the cold winter in northern China, the temperature is generally below 8°C, and low water temperature significantly inhibits biological treatment processes, especially the biological denitrification process. To solve this problem, this study proposed an improved two-stage A/O process with built-in submerged biofilm modules. Experimental water was acquired from the Sanbaotun Wastewater Treatment Plant, which is situated in the city of Fushun, Liaoning Province. After one year of experimental research, the improved two-stage A/O process proved to be significantly better than the traditional two-stage A/O process, especially in winter. In the one-year experiment, the average removal rates of COD, TN, and NH4+-N in the improved two-stage A/O process were 85.2%, 77.6%, and 96.9%, respectively. Microbial properties of the process were studied by means of high-throughput sequencing. High-throughput sequencing was conducted on the biofilm of the improved two-stage A/O terminal aerobic tank and the activated sludge of the conventional two-stage A/O aerobic tank. The result showed that the microbial diversity and abundance of the biofilms were considerably higher than those of the activated sludge during stable operation in winter. Under low-temperature conditions, the main denitrifying bacteria of the improved two-stage A/O process was Terrimonas, belonging to the sphingolipid class of Bacteroides, and the main genus of nitrifying bacteria was Nitrospira, belonging to the nitrite oxidizing bacteria.

5.
Ultrasound Med Biol ; 2020 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-32359807

RESUMO

The aim of the study described here was to compare the effectiveness of focused ultrasound surgery (FUS), which uses high-intensity focused ultrasound to perform tissue ablation, with that of hysteroscopic transcervical resection of myoma (TCRM) for the treatment of type 2 submucosal fibroids. A prospective cohort study was performed in patients who underwent FUS or TCRM from January 2012 to December 2014. Uterine Fibroid Symptom (UFS) and Quality of Life (QoL) questionnaires were used to measure fibroid-related symptoms and quality of life before and at 3, 6 and 12 mo after treatment. Technical results, adverse events and post-operative recovery times of both groups were also compared. A total of 81 patients with at least one type 2 submucosal fibroid were enrolled. The mean diameter of type 2 submucosal fibroids was 3.8 ± 0.9 cm (range: 2.0-5.0 cm) for 39 patients in the FUS group and 3.5 ± 0.8 cm (range: 2.0-4.8 cm) for the 42 patients enrolled in the TCRM group. No major complication occurred in any patients for either treatment. In both groups, the UFS score decreased significantly and the QoL score increased significantly from baseline successively at 3, 6 and 12 mo post-treatment (p < 0.05). Time spent in hospital post-treatment was significantly shorter (2.56 ± 0.98 d) for the FUS group compared with the TCRM group (3.31 ± 0.60 d) (p < 0.05). Time to return to work after treatment was also significantly shorter for the FUS group (3.14 ± 0.83 d) than for the TCRM group (6.09 ± 0.9 d) (p < 0.05). FUS and TCRM are both tolerable and effective treatments with significant improvement of symptom and quality of life for patients with type 2 submucosal fibroids ≤5 cm in diameter.

6.
Sci Total Environ ; 718: 137390, 2020 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-32325612

RESUMO

Biochar stability determines the effectiveness of biochar's functions such as carbon sequestration, soil structure improvement, soil fertility enhancement and soil pollution remediation. However, a fast method for accurately predicting biochar long-term stability in soil remains elusive. Here, firstly, an incubation experiment was conducted on mineralization dynamics of different 13C-labelled biochars over 368 days to explore their actual mineralization in soils and establish their mineralization model. Thereafter, ten treatments of fast chemical oxidation methods using K2Cr2O7 (0.1 M) with different H+ concentrations and oxidation times were applied to the biochars to reveal which method best matches the mineralization of biochar in soils. Results showed that the percentage of biochar­carbon oxidized by the solution containing 0.1 M K2Cr2O7 and 0.2 M H+ at 100 °C for 2 h was in accordance with the one that potentially would be mineralized in soils at a 100-year scale (R2 > 0.99; REMS = 2.53; RD = 15.3). The results provided a chemical oxidation method that was robust, effective, low cost and highly available for measuring the long-term stability of biochar in soils.

7.
Environ Int ; 139: 105682, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32248024

RESUMO

BACKGROUND: The placenta performs crucial functions to ensure normal fetal development. Experimental studies have indicated associations between exposure to elevated temperatures during pregnancy and reduction in placental weight and volume. However, epidemiological studies in humans are lacking. OBJECTIVE: To estimate the associations between prenatal exposure to ambient temperature with placental weight, volume, and the placental weight to birth weight ratio (PFR). METHODS: We conducted a prospective birth cohort study using the Prenatal Environment and Offspring Health Cohort (PEOH Cohort) beginning in 2016 in Guangzhou, China. Women in early pregnancy were recruited and followed up during their hospitalization for childbirth. An inverse distance-weighted method was employed to estimate the average temperature exposure of every 4 weeks as well as the trimester-specific average temperature exposure at the individual's residential address. A generalized linear model was applied to estimate the effects of temperature exposure during pregnancy on the placental weight, volume, and PFR. RESULTS: A total of 4051 pregnant women were enrolled. Compared with the reference temperature of 20 °C, maternal exposure to 29 °C (95th centile) during late pregnancy was associated with an average of -6.03 g (95% confidence interval [CI]: -11.28 g, -0.78 g) in placental weight, -16.15 cm3 (95% CI: -26.24 cm3, -6.07 cm3) in placental volume, and 0.26 (95% CI: 0.07, 0.45) in PFR. The peak effects of high temperatures on placental weight, volume, and PFR were found from 29 to 32 weeks (ß = -3.79 g, 95% CI: -8.39 g, 0.82 g), 37 to 40 weeks (ß = -19.34 cm3, 95% CI: -30.99 cm3, -7.69 cm3), and 25 to 28 weeks (ß = 0.35, 95% CI: 0.04, 0.66), respectively. CONCLUSIONS: Maternal exposure to elevated temperatures was associated with a decrease in placental weight and volume and an increase in PFR. The associations were stronger when exposures occurred during late pregnancy.

8.
Nanoscale ; 2020 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-32239051

RESUMO

The necessity of Earth-abundant low-cost catalysts with activity similar to noble metals such as platinum is indispensable in order to realize the production of hydrogen through electrolysis of water. Herein, we report a relatively low-cost NiAg0.4 3D porous nanocluster catalyst whose activity matches with that of the state-of-the-art Pt/C in 1 M KOH solution. The catalyst is designed on the principle of creating an interface between a metal having a positive Gibbs energy of hydrogen adsorption and a metal of negative Gibbs energy based on the volcano plot, to tune the Gibbs energy of hydrogen adsorption near zero for enhanced hydrogen evolution. The synthesized NiAg0.4 3D porous nanoclusters are comprised of nanoparticles of lateral dimension ∼50 nm forming a 3D porous network with pores of 10 nm-80 nm. A high-resolution transmission electron microscopy image reveals the epitaxial growth of Ag (200) on the Ni (111) plane leading to the creation of abundant interfaces between the Ni and Ag lattices. The catalyst needs a low overpotential of 40 mV@10 mA cm-2 with a Tafel slope of 39.1 mV dec-1 in 1 M KOH solution. Furthermore, the catalyst exhibits a high specific activity of 0.1 mA cm-2(ECSA) at an overpotential (η) of 45 mV which matches with the specific activity of Pt/C 20% wt. catalyst (0.1 mA cm-2@η = 26 mV). Density functional theory calculations reveal that the Ni-Ag interface furnishes a pathway with a reduced Gibbs energy of adsorption of -0.04 eV, thus promoting enhanced hydrogen evolution. In summary, this study reveals excellent HER activity at the Ni-Ag interface.

9.
J Chromatogr A ; 1620: 461013, 2020 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-32201037

RESUMO

Dummy molecularly imprinted microspheres (DMIMs) were synthesized by Pickering emulsion polymerization and used as the matrix solid-phase dispersion extraction (MSPD) sorbent for sample pre-treatment of azole fungicides in fish samples. Alpha-(2,4-Dichlorophenyl)-1H-imidazole-1-ethanol (DCE) was used as the fragment dummy template for the imprinting of climbazole (CBZ), clotrimazole (CMZ) and miconazole (MNZ). The morphology of the microspheres were characterized by scanning electron microscopy (SEM) and nitrogen adsorption measurements, narrow diameter distribution (20-50 µm) with regular spherical shape and high surface area (SBET = 408.91 ± 6.72 m2 g-1) were achieved. Good class-selectivity of the DMIMs was found for CBZ, CMZ and MNZ by static adsorption experiments. The imprinted microspheres as MSPD sorbent was then evaluated for the extraction and purification of CBZ, CMZ and MNZ in fish samples. The extracted azole fungicides were detected by HPLC-DAD analysis at 225 nm. MSPD conditions including elution, mass ratio of sample/sorbent and washing were carefully evaluated. The optimized MSPD method have good recoveries (89.2-101.5%) and reproducibility (RSDs 1.6-4.8%, n = 5) for fish samples spiked at 0.5, 2.5 and 12.5 µg g-1. The limits of detection (LODs) were 0.045, 0.036 and 0.033 µg g-1 for CBZ, CMZ and MNZ, respectively. The results show that this method has a good application prospect for the pretreatment of azole fungicides in fish samples.

10.
Pharmacol Res ; 155: 104739, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32135248

RESUMO

Cardiac hypertrophy (CH) is an enormous risk factor in the process of heart failure development, however, there is still lack of effective treatment for CH. Mitochondrial protection is an effective way against CH. Rheum palmatum L. (rhubarb) has been used to treat chronic heart diseases such as heart failure, especially to inhibit cardiac compensatory enlargement. The aim of this study was to explore the pharmacodynamic component of rhubarb and reveal its pharmacological effects and targets in the treatment of CH. Based on network pharmacology and machine learning approach, ingredients of rhubarb and targets for CH were extracted and surflex docking was conducted for obtaining the optimal ingredient-target combination(s) and emodin-SIRT3 was identified for further functional analysis. Transverse aortic constriction or isoproterenol induced CH mice and phenylephrine injured cardiomyocytes were used to verify the mitochondria protection effect and CH improvement of emodin in vivo and in vitro by modulation of mitochondrial SIRT3 signaling. The results showed that emodin could block agonist-induced and pressure overload-mediated CH. Emodin prevented mitochondrial dysfunction and its underlying mechanism was attributed to the activation of SIRT3, but the effect was not obvious with the presence of SIRT3 inhibitors (3-TYP)/SIRT3 siRNA. Furthermore, PGC-1ɑ was involved in the process of emodin regulating SIRT3 signaling pathway as an upstream target. Our findings clarified the main material basis and mechanism of rhubarb in the treatment of CH. Emodin, as the major ingredient of rhubarb, has therapeutic potential for CH through mitochondrial protection due to the modulation of SIRT3 signaling.

11.
Biomaterials ; 243: 119934, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32163757

RESUMO

Application of 1064 nm activatable NIR-IIa fluorescence imaging (FI) and NIR-II photothermal therapy (PTT) results in high-resolution imaging and good deep-tissue therapy, respectively. Combining NIR-IIa FI with NIR-II PTT may allow precise diagnosis guided efficient treatment of deep-tissue tumors. However, designing a 1064 activatable theranostic nanoplatform using a single dye for both NIR-IIa FI and NIR-II PTT is a challenge. Herein, we synthesized squaraine-based semiconducting polymer nanoparticles (PSQPNs-DBCO) that were excited by a 1064 nm laser for precise NIR-IIa fluorescence imaging guided NIR-II PTT treatment. Combined with bioorthogonal labeling technology, the PSQPNs-DBCO largely accumulated in the tumor section, extremely enhancing signal-to-background ratio (SBR) of imaging and NIR-II PTT efficiency of tumor in live colorectal-bearing animals.

12.
Int J Hyg Environ Health ; 225: 113481, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32058935

RESUMO

Maternal exposures to ambient temperatures during pregnancy may increase the preterm birth (PTB) risk; however, which periods have stronger effects remain controversial. The effects of temperature exposure on PTB in first- and second-born neonate groups may be different during the new baby boom that has followed the Two-child Policy in China. We examined a birth cohort of 4928 pregnant women beginning in 2016 in Guangzhou, China. An inverse distance weighted method was used to estimate the temperature exposure at each individual residential address. A distribution lag non-linear model incorporating a Cox proportional hazard model was employed to estimate the effects of temperature exposure on PTB and test the effects modification of birth order related to the new baby boom. A total of 4101 pregnant women were included, of which 234 (5.7%) experienced PTB. Compared with the mean temperature (23.0 °C), we found a significantly higher risks of PTB associated with high temperatures (i.e, 30 °C [95th centile]) from the 4th to 8th, and 22nd to 27th gestational weeks. A peak effect was found during the 6th week (HR = 1.79, 95% CI: 1.26, 2.54) and 24th week (HR = 1.83, 95% CI: 1.27, 2.62). The risks of PTB were reduced for low temperatures (i.e. 14 °C [5th centile] versus 23.0 °C) from the 2nd to 10th and 20th to 26th gestational weeks, and the negative peak effect was found during the 4th week (HR = 0.43, 95% CI: 0.26, 0.72) and 23rd week (HR = 0.59, 95% CI: 0.43, 0.83). Stratification analyses showed that significant effects of 30 °C versus 23 °C on PTB were observed during the 4th to 8th weeks in the second-born neonate, and the peak effect was found in the 6th week (HR = 2.13, 95% CI: 1.31, 3.47). However, we did not find significant effects of 30 °C during the same weeks in the first-born neonate group. Maternal exposures to higher temperatures during pregnancy may increase the risk of PTB, and lower temperatures may decrease the risk of PTB. Stronger effects of temperature exposures during the first trimester on PTB risk were found among the second-born neonates than among the first-born neonates.

13.
Environ Res ; 183: 109207, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32050130

RESUMO

Although studies have assessed the associations of maternal exposure to ozone (O3) during pregnancy with blood pressure and the risk of hypertensive disorders of pregnancy (HDP), the results were inconsistent. Furthermore, no studies have been conducted in China where the ambient O3 concentration continuedly increased. The present study aimed to estimate the effects of maternal exposure to O3 during pregnancy on the HDP risk, systolic blood pressure (SBP), diastolic blood pressure (DBP) and pulse pressure (PP). All participants of pregnant women were selected from the prospective birth cohort study on Prenatal Environments and Offspring Health conducted in Guangzhou, China. A spatiotemporal land-use-regression model was used to estimate individual monthly air pollution exposure from three months before pregnancy to childbirth date. Information on HDP, SBP, DBP and PP was obtained from maternal medical records. A Logistic regression model and a mixed linear model were used to estimate the associations of maternal exposure to O3 with the risk of HDP and blood pressure (SBP, DBP and PP), respectively. We found significant associations of maternal exposure to O3 during the third (OR = 1.31, 95%CI: 1.07, 1.60) and the second month (OR = 1.25, 95%CI: 1.02, 1.51) before pregnancy with the risk of HDP. Observed significantly positive associations of O3 exposures with SBP, DBP and PP during the two months before pregnancy and during the early pregnancy. The peak effects of O3 exposure on SBP, DBP and PP were respectively observed during the second month of pregnancy (ß = 1.07  mmHg, 95%CI: 0.84, 1.31  mmHg), the first month before pregnancy (ß = 0.40  mmHg, 95%CI: 0.21, 0.50  mmHg) and the second month of pregnancy (ß = 0.78  mmHg, 95%CI: 0.59, 0.97  mmHg). Our results suggest that maternal exposure to O3 were positively associated with blood pressure and the risk of HDP, and the period from three months before pregnancy to the first trimester might be the critical exposure window.

14.
Cell Rep ; 30(5): 1310-1318.e5, 2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-32023451

RESUMO

Pathological activation of TGF-ß signaling is universal in fibrosis. Aberrant TGF-ß signaling in conjunction with transdifferentiation of hepatic stellate cells (HSCs) into fibrogenic myofibroblasts plays a central role in liver fibrosis. Here we report that the DNA demethylase TET3 is anomalously upregulated in fibrotic livers in both humans and mice. We demonstrate that in human HSCs, TET3 promotes profibrotic gene expression by upregulation of multiple key TGF-ß pathway genes, including TGFB1. TET3 binds to target gene promoters, inducing demethylation, which in turn facilitates chromatin remodeling and transcription. We also reveal a positive feedback loop between TGF-ß1 and TET3 in both HSCs and hepatocytes. Furthermore, TET3 knockdown ameliorates liver fibrosis in mice. Our results uncover a TET3/TGF-ß1 positive feedback loop as a crucial determinant of liver fibrosis and suggest that inhibiting TET3 may represent a therapeutic strategy for liver fibrosis and perhaps other fibrotic diseases.

15.
Biomed Pharmacother ; 125: 109118, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32106366

RESUMO

The antitumor effect of magnoflorine (Mag), an alkaloid isolated from Coptidis Rhizoma, in gastric cancer (GC) cells has not been reported. In the study, Mag suppressed the proliferation of GC cells, but showed no influence on normal gastric cells. Mechanistically, Mag induced autophagy in GC cells, as evidenced by the up-regulated expression of LC3B-II and increased autophagosome formation. Furthermore, we found that Mag-triggered autophagic cell death was regulated by reactive oxygen species (ROS)-induced suppression of serine/threonine-protein kinases (AKT) signaling. What's more, Mag treatment led to apoptosis in GC cells through enhancing cleaved Caspase-3 and PARP expressions. In addition, up-regulated expression of p27 and p21, as well as down-regulated expression of Cyclin-A and Cyclin-B1 was detected in Mag-treated GC cells, contributing to the S/G2 cell cycle arrest. Importantly, Mag incubation resulted in a significant increase in jun N-terminal kinase (JNK) phosphorylation but not p38 and ERK1/2, which was involved in the modulation of apoptosis and S/G2 phase arrest. Moreover, ROS production was highly induced by Mag treatment, and Mag-exhibited these functions was largely dependent on the generation of ROS in GC cells. Consistently, the GC cell xenograft mouse model confirmed the anti-tumor role of Mag in vivo. Collectively, these results indicated that Mag showed anti-GC effects, which could be a potential therapeutic target for GC treatment.

16.
Science ; 367(6478): 652-660, 2020 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-32029622

RESUMO

Liver cell death has an essential role in nonalcoholic steatohepatitis (NASH). The activity of the energy sensor adenosine monophosphate (AMP)-activated protein kinase (AMPK) is repressed in NASH. Liver-specific AMPK knockout aggravated liver damage in mouse NASH models. AMPK phosphorylated proapoptotic caspase-6 protein to inhibit its activation, keeping hepatocyte apoptosis in check. Suppression of AMPK activity relieved this inhibition, rendering caspase-6 activated in human and mouse NASH. AMPK activation or caspase-6 inhibition, even after the onset of NASH, improved liver damage and fibrosis. Once phosphorylation was decreased, caspase-6 was activated by caspase-3 or -7. Active caspase-6 cleaved Bid to induce cytochrome c release, generating a feedforward loop that leads to hepatocyte death. Thus, the AMPK-caspase-6 axis regulates liver damage in NASH, implicating AMPK and caspase-6 as therapeutic targets.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Caspase 6/metabolismo , Fígado/enzimologia , Fígado/patologia , Hepatopatia Gordurosa não Alcoólica/enzimologia , Hepatopatia Gordurosa não Alcoólica/patologia , Proteínas Quinases Ativadas por AMP/genética , Animais , Apoptose/genética , Caspase 3/metabolismo , Caspase 7/metabolismo , Inibidores de Caspase/farmacologia , Inibidores de Caspase/uso terapêutico , Ativação Enzimática , Hepatócitos/enzimologia , Hepatócitos/patologia , Humanos , Camundongos , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Fosforilação
17.
DNA Cell Biol ; 39(3): 398-403, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31976761

RESUMO

Diabetic retinopathy (DR) is considered a main cause for vision loss in diabetes. To our knowledge, there were no studies on the association of genetic variants with DR in Chinese Hui nationality. In our research, 34 single nucleotide polymorphisms (SNPs) that were reported to be associated with DR in other ethnics were genotyped in 123 subjects with DR and 12 subjects without DR among Chinese Hui population using MassARRAY system. Association analysis performed by PLINK showed three SNP loci rs2300782, rs2292239, and rs10491034 were correlated with DR incidence. Furthermore, the genotype frequency analysis and association analysis of SNP with DR stage revealed the GT and TT genotypes of rs2292239, CC genotype of rs2300782, and GG genotype of rs10491034 were risk genotypes and associated with the severity of DR, which may be helpful for the study of DR susceptibility in Chinese Hui population. Our study indicates the rs2300782 of gene CAMK4, rs2292239 of gene ERBB3, and rs10491034 of gene ARHGAP22 are associated with DR incidence and severity among Chinese Hui population.


Assuntos
Proteína Quinase Tipo 4 Dependente de Cálcio-Calmodulina/genética , Retinopatia Diabética/genética , Proteínas Ativadoras de GTPase/genética , Polimorfismo de Nucleotídeo Único , Receptor ErbB-3/genética , Idoso , China , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
18.
RNA Biol ; 17(4): 500-516, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31928144

RESUMO

Huntington's Disease (HD) is a monogenetic neurodegenerative disorder mainly caused by the cytotoxicity of the mutant HTT protein (mHTT) encoded by the mutant HTT gene. Lowering HTT mRNA has been extensively studied as a potential therapeutic strategy, but how its level is regulated endogenously has been unclear. Here we report that the RNA-binding protein (RBP) HuR interacts with and stabilizes HTT mRNA in an mHTT-dependent manner. In HD cells but not wild-type cells, siRNA knockdown or CRISPR-induced heterozygous knockout of HuR decreased HTT mRNA stability. HuR interacted with HTT mRNA at a conserved site in exon 11 rather than the 3'-UTR region of the mRNA. Interestingly, this interaction was dependent on the presence of mHTT, likely via the activation of MAPK11, which enhanced cytosolic localization of the HuR protein. Thus, mHTT, MAPK11 and HuR may form a positive feedback loop that stabilizes HTT mRNA and enhances mHTT accumulation, which may contribute to HD progression. Our data reveal a novel regulatory mechanism of HTT mRNA via non-canonical binding of HuR.

19.
Nat Commun ; 11(1): 342, 2020 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-31953394

RESUMO

Precise control of hepatic glucose production (HGP) is pivotal to maintain systemic glucose homeostasis. HNF4α functions to stimulate transcription of key gluconeogenic genes. HNF4α harbors two promoters (P2 and P1) thought to be primarily active in fetal and adult livers, respectively. Here we report that the fetal version of HNF4α is required for HGP in the adult liver. This isoform is acutely induced upon fasting and chronically increased in type-2 diabetes (T2D). P2 isoform induction occurs in response to glucagon-stimulated upregulation of TET3, not previously shown to be involved in HGP. TET3 is recruited to the P2 promoter by FOXA2, leading to promoter demethylation and increased transcription. While TET3 overexpression augments HGP, knockdown of either TET3 or the P2 isoform alone in the liver improves glucose homeostasis in dietary and genetic mouse models of T2D. These studies unmask an unanticipated, conserved regulatory mechanism in HGP and offer potential therapeutic targets for T2D.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Dioxigenases/metabolismo , Fator 4 Nuclear de Hepatócito/metabolismo , Fígado/metabolismo , Isoformas de Proteínas/metabolismo , Animais , Desmetilação do DNA , Metilação de DNA , Proteínas de Ligação a DNA/metabolismo , Dioxigenases/genética , Modelos Animais de Doenças , Jejum , Regulação da Expressão Gênica , Glucagon/metabolismo , Glucose/metabolismo , Fator 3-beta Nuclear de Hepatócito/genética , Fator 4 Nuclear de Hepatócito/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Regiões Promotoras Genéticas , Isoformas de Proteínas/genética , Ativação Transcricional , Transcriptoma , Regulação para Cima
20.
Hum Reprod ; 35(1): 187-194, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31943006

RESUMO

STUDY QUESTION: Are fructose levels altered in women with polycystic ovary syndrome (PCOS)? SUMMARY ANSWER: Elevated serum fructose levels are associated with PCOS in Chinese Han women with overweight/obesity and hyperinsulinemia, and fructose levels are higher in follicular fluids from PCOS patients than from control subjects. WHAT IS KNOWN ALREADY: Both fructose levels and PCOS are closely linked to obesity and insulin resistance. However, the relationship between fructose and PCOS remains largely unknown. STUDY DESIGN, SIZE, DURATION: A total of 157 Chinese Han women (67 controls and 90 PCOS patients) were recruited at Shengjing Hospital of China Medical University. To systematically study the relationship between serum fructose levels and PCOS, the study population of control subjects and PCOS patients was divided into overweight/obese and lean subgroups, and hyper-fasting serum insulin (FSI) and normal-FSI subgroups, respectively. PARTICIPANTS/MATERIALS, SETTING, METHODS: Fructose levels were measured in serum samples collected from 80 patients with PCOS (32 lean, 48 overweight/obese) and 59 control subjects (27 lean, 32 overweight/obese) and in follicular fluid samples collected from mature follicles (17-22 mm) and matched immature follicles (8-13 mm) from 10 patients with PCOS and 8 control subjects. MAIN RESULTS AND THE ROLE OF CHANCE: Serum fructose levels were increased in overweight/obese and hyper-FSI PCOS patients compared with the control subjects. Fructose had an area under the curve (AUC) of 79.7% at a cutoff value of 10.13 pmol/µl, with a sensitivity of 91.7% and a specificity of 59.3% for the prediction of PCOS in overweight/obese patients. In the hyper-FSI group, fructose had an AUC of 72% at a cutoff value of 10.49 pmol/µl, with a sensitivity of 71.1% and a specificity of 64.4% for the prediction of PCOS. There were no differences between fructose, total testosterone, free testosterone or dehydroepiandrosterone sulfate levels with respect to the reliability of predicting PCOS in the overweight/obese or hyper-FSI groups using the method outlined by Hanley and McNeil. Notably, the combination of fructose and total testosterone levels resulted in the highest AUC of 86.0% and high sensitivity (85.4%) and specificity (83.1%) for the prediction of PCOS in overweight/obese patients. The positive predictive value (PPV) and negative predictive value (NPV) were 80.4 and 87.5%, respectively. Similarly, the combination of fructose and total testosterone levels also resulted in a high AUC of 80.2% and moderate sensitivity (73.3%) and high specificity (84.7%) for the prediction of PCOS in hyper-FSI patients. The PPV and NPV were 78.6 and 80.6%, respectively. Furthermore, fructose levels were significantly higher in follicular fluids from PCOS patients than from control subjects, regardless of whether the follicles were mature or immature. LIMITATIONS, REASONS FOR CAUTION: It remains unclear whether fructose levels contribute directly to follicular development and the pathogenesis of PCOS or are merely a biomarker of these processes. WIDER IMPLICATIONS OF THE FINDINGS: The results of the present study, together with our previous study, show that monosaccharide status may be a novel marker for PCOS, highlighting the importance of further investigation into the role of monosaccharides, especially fructose, in the pathogenesis of PCOS. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the National Natural Science Foundation of China (No. 81671423 and No. 81402130), the National Key Research and Development Program of China (No. 2018YFC1003100), Liaoning Provincial Key Research and Development Program (No. 2018225090), the Fok Ying Tung Education Foundation (No. 151039), Distinguished Talent Program of Shengjing Hospital (No. ME76) and Distinguished Teacher Program of China Medical University (No. QGZ2018079). No competing interests were declared.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA