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1.
J Neuroinflammation ; 16(1): 249, 2019 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-31796106

RESUMO

BACKGROUND: Inflammation can induce cognitive dysfunction in patients who undergo surgery. Previous studies have demonstrated that both acute peripheral inflammation and anaesthetic insults, especially isoflurane (ISO), are risk factors for memory impairment. Few studies are currently investigating the role of ISO under acute peri-inflammatory conditions, and it is difficult to predict whether ISO can aggravate inflammation-induced cognitive deficits. HDACs, which are essential for learning, participate in the deacetylation of lysine residues and the regulation of gene transcription. However, the cell-specific mechanism of HDACs in inflammation-induced cognitive impairment remains unknown. METHODS: Three-month-old C57BL/6 mice were treated with single versus combined exposure to LPS injected intraperitoneally (i.p.) to simulate acute abdominal inflammation and isoflurane to investigate the role of anaesthesia and acute peripheral inflammation in cognitive impairment. Behavioural tests, Western blotting, ELISA, immunofluorescence, qRT-PCR, and ChIP assays were performed to detect memory, the expressions of inflammatory cytokines, HDAC2, BDNF, c-Fos, acetyl-H3, microglial activity, Bdnf mRNA, c-fos mRNA, and Bdnf and c-fos transcription in the hippocampus. RESULTS: LPS, but not isoflurane, induced neuroinflammation-induced memory impairment and reduced histone acetylation by upregulating histone deacetylase 2 (HDAC2) in dorsal hippocampal CaMKII+ neurons. The hyperexpression of HDAC2 in neurons was mediated by the activation of microglia. The decreased level of histone acetylation suppressed the transcription of Bdnf and c-fos and the expressions of BDNF and c-Fos, which subsequently impaired memory. The adeno-associated virus ShHdac2, which suppresses Hdac2 after injection into the dorsal hippocampus, reversed microglial activation, hippocampal glutamatergic BDNF and c-Fos expressions, and memory deficits. CONCLUSIONS: Reversing HDAC2 in hippocampal CaMKII+ neurons exert a neuroprotective effect against neuroinflammation-induced memory deficits.

2.
Front Mol Neurosci ; 12: 246, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31708739

RESUMO

Brain-derived neurotrophic factor (BDNF) is essential for cognitive and memory functions. Abnormal BDNF expression in the central nervous system may impair these functions. Anaesthesia and surgery can induce perioperative neurocognitive disorders (PND). Clinical studies show that BDNF expression is decreased in patients presenting with cognitive impairment after anaesthesia and surgery. However, the molecular mechanism is still unclear. Epigenetic regulation plays an important role in cognition. The hypermethylation of H3K9 is crucial for transcriptional silencing and the onset of cognitive disorders. Here, we hypothesised that H3K9 trimethylation repressed BDNF expression and impaired memory formation or recall during anaesthesia and surgery. Laparotomy under isoflurane inhalation anaesthesia, behavioural tests, Western blotting, quantitative real-time reverse-transcription polymerase chain reaction (qRT-PCR), chromatin immunoprecipitation (ChIP), and immunohistochemistry were used in this study. BDNF expression was decreased in the hippocampus after anaesthesia and surgery. Cognitive impairment affected memory formation but not recall. The trimethylation of H3K9 downregulated BDNF expression. The overexpression of BDNF or use of exogenous BDNF improved the impairment of memory formation caused by anaesthesia and surgery. Therefore, inhibiting H3K9 trimethylation and increasing the expression of BDNF may help prevent PND in the clinical setting.

3.
Beilstein J Nanotechnol ; 10: 2116-2127, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31728259

RESUMO

In this work, sulfur-doped (S-doped) TiO2 with the (001) face exposed was synthesized by thermal chemical vapor deposition at 180 or 250 °C using S/Ti molar ratios R S/Ti of 0, 0.5, 1, 2, 3, 4 and 5. The S-doped samples synthesized at 250 °C exhibit a significantly improved photocatalytic performance. More precisely, S-doping has the following effects on the material: (1) S can adopt different chemical states in the samples. Specifically, it exists in the form of S2- replacing O2- at a ratio of R S/Ti = 1 and also in the form of S6+ replacing Ti4+ at R S/Ti ≥ 2. As a result, S-doping causes a lattice distortion, because the ionic radii of S2- and S6+ differ from that of the O2- and Ti4+ ions. (2) S-doping increases the adsorption coefficient A e for methylene blue (MB) from 0.9% to 68.5% due to the synergistic effects of the oxygen vacancies, increased number of surface chemical adsorption centers as a result of SO4 2- adsorption on the TiO2 surface and the larger pore size. (3) S-doping increases the MB degradation rate from 6.9 × 10-2 min-1 to 18.2 × 10-2 min-1 due to an increase in the amount of •OH and •O2- radicals.

4.
J Mater Chem B ; 7(40): 6187-6194, 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31565721

RESUMO

MIT is a promising strategy in antibody free analysis for tumour markers. Conventional nanosized MIPs with off-line analysis are beset by tedious operation and unsatisfactory analysis performance. In this work, an on-line analytical device to directly detect AFP, which is a typical tumour marker in cancer screening, was prepared for the first time. A microscope slide was chosen to be the basis of the device. APBA-PA, a polymerizable fluorescent boronic acid monomer, was synthesised and grafted on the surface of the microscope slide to act as the signal transduction pathway between the templates and the device. Along with the hydrolysis of TEOS and the elution of the templates, a portable, stable, easy to operate and low-cost analysis device for AFP with excellent repeatability was successfully prepared. Owing to the excellent selectivity and highly sensitive fluorescence response ability of the device towards the templates, the on-line detection of AFP in human serum was realized. A series of characterizations were applied to the device, and its analysis performance and possible detection mechanism were carefully studied. Furthermore, the device exhibited appropriate application prospects by comparing its analysis results with those of the commercially available ELISA. In our perception, this work is an important step towards MIPs for clinical applications.

5.
Artigo em Inglês | MEDLINE | ID: mdl-30833930

RESUMO

Objective: This study aimed to test associations between type 2 diabetes mellitus (T2DM) and metabolites in urea cycle including arginine, citrulline and ornithine. Methods:This study used a hospital-based cross-sectional study design. We retrieved medical notes of 401 in-patients with onset of T2DM within 2 years and 1,522 healthy subjects who attended annual physical examination. All cases were admitted to a tertiary care center in Jinzhou, China from May 2015 to August 2016. Binary logistic regression analyses were performed to obtain odds ratios (ORs) and 95% confidence intervals (CIs). Results:Patients with T2DM had higher arginine, and lower ornithine than control subjects. Levels of citrulline were similar in two groups. Arginine was positively associated with T2DM (ORs: 1.20, 1.17-1.23) while ornithine was negatively associated with T2DM (OR: 0.89, 0.88-0.91). After adjustment for other amino acids and traditional risk factors, these associations were still significant and persistent for arginine and ornithine. The association between citrulline and T2DM was not significant. Their ratios of pairs of two amino acids were associated with increased risk of T2DM. After adjustment for other ratios of amino acids, effect size for T2DM remained significant. Further adjustment for traditional risk factors did not lead to large changes (ORs: 1.78, 1.20-2.65 for the ratio of arginine to ornithine; ORs: 1.59, 1.37-1.86 for the ratio of citrulline to ornithine, respectively) except the ratio of arginine to citrulline. Conclusions: Plasma levels of amino acids related to urea cycle and their ratios of these amino-acids were associated with T2DM in Chinese adults.

6.
J Diabetes Investig ; 10(2): 491-498, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29999591

RESUMO

AIMS/INTRODUCTION: Metabolomic markers have the potential to improve the predicting accuracy of existing risk scores for type 2 diabetes mellitus. The present study aimed to test the associations between plasma tyrosine and type 2 diabetes mellitus with special attention to identifying possible cut-off points for type 2 diabetes mellitus, and its interactive effects with low high-density lipoprotein cholesterol (HDL-C) and/or high triglyceride for type 2 diabetes mellitus. METHODS: From 27 May 2015 to 3 August 2016, we retrieved the medical notes of 1,898 inpatients with type 2 diabetes mellitus as the cases, and 1,522 individuals without diabetes as the controls who attended annual medical checkups from the same tertiary care center in Jinzhou, China. Logistic regression analyses were carried out to obtain odds ratios (ORs) and 95% confidence intervals (CIs). Restricted cubic spline analysis nested in the logistic regression analysis was used to identify possible cut-off points of tyrosine for type 2 diabetes mellitus. The additive interaction was used to estimate interactions between high tyrosine and low HDL-C in type 2 diabetes mellitus patients. RESULTS: The OR of tyrosine for type 2 diabetes mellitus did not increase until 46 µmol/L and after that point, the OR rapidly rose with increasing tyrosine in a nearly linear manner. If 46 µmol/L was used to define high tyrosine, high tyrosine was associated with an increased OR of type 2 diabetes mellitus (adjusted OR 1.88, 95% CI 1.44-2.45). The presence of low HDL-C greatly enhanced the ORs of tyrosine for type 2 diabetes mellitus from 1.11 (95% CI 0.82-1.51) to 54.11 (95% CI 33.96-86.22) with significant additive interaction. CONCLUSIONS: In Chinese adults, tyrosine >46 µmol/L was associated with increased odds of type 2 diabetes mellitus, which was contingent on low HDL-C.


Assuntos
Grupo com Ancestrais do Continente Asiático/estatística & dados numéricos , Biomarcadores/sangue , HDL-Colesterol/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Tirosina/sangue , Estudos de Casos e Controles , Estudos Transversais , Diabetes Mellitus Tipo 2/sangue , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Curva ROC , Fatores de Risco
7.
Mikrochim Acta ; 185(12): 565, 2018 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-30498865

RESUMO

Boronate-affinity based molecularly imprinted polymers (MIPs) are beset by the unsatisfied adsorption capacity and narrow working pH ranges. A magnetic molecularly imprinted polymer containing phenylboronic acid groups was placed on the surface of Fe3O4 (magnetite) microspheres coated with porous TiO2 (Fe3O4@pTiO2@MIP). In contrast to its silica analog (Fe3O4@SiO2@MIP), the flowerlike Fe3O4@pTiO2 offers more binding sites for templates. Thus, the adsorption capacity of the Fe3O4@pTiO2@MIP is strongly enhanced. The strong electron-withdrawing effects of Ti(IV) enable the boronic acid of the MIP to have better affinity for glycoproteins at a wide pH range from 6.0 to 9.0. Consequently, the Fe3O4@pTiO2@MIP exhibits higher adsorption for glycoproteins than Fe3O4@SiO2@MIP in both basic and acidic medium. The Fe3O4@pTiO2@MIPs were eluted with 5% acetic acid aqueous solution containing 30% acetonitrile, and the eluate was analyzed by MALDI-TOF MS. The method was applied to the selective extraction and quantitation of horseradish peroxidase (HRP) in spiked fetal bovine serum (FBS). The linear range is 0.40-10 µg·mL-1 with the limit of detection of 0.31 µg·mL-1. In our perception, this work has a wide scope in that is paves the way to a more widespread application of boronate affinity based MIPs for analysis of glycoproteins and related glyco compounds even at moderately acidic pH values. Graphical abstract Schematic presentation of the magnetic boronate modified molecularly imprinted polymer on magnetic spheres modified with porous TiO2 (Fe3O4@pTiO2@MIP). It was applied to extract glycoprotein in spiked both basic fetal bovine serum (FBS) and acidic urine samples prior to quantitation by MALDI-TOF mass spectrometry.


Assuntos
Óxido Ferroso-Férrico/química , Glicoproteínas/química , Microesferas , Impressão Molecular , Polímeros/síntese química , Titânio/química , Adsorção , Animais , Ácidos Borônicos/química , Humanos , Concentração de Íons de Hidrogênio , Cinética , Polímeros/química , Porosidade , Propriedades de Superfície
8.
Psychiatry Res ; 270: 306-309, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30286368

RESUMO

Schizophrenia is a major psychiatric disorder with complex genetic, environmental, and psychological etiologies. Although DISC1 gene has been shown as a risk factor for schizophrenia in some reports, there is a lack of a consensus. We therefore performed separate meta-analyses aiming to assess the associations between DISC1 SNPs and schizophrenia risk. We found that SNP rs821597 is significantly associated with schizophrenia risk in terms of both allelic and genotypic distribution, while SNP rs821616 is associated with schizophrenia in terms of genotypic distribution, especially in cases above 40 years old.


Assuntos
Proteínas do Tecido Nervoso/genética , Esquizofrenia/genética , Alelos , Predisposição Genética para Doença , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único
9.
EBioMedicine ; 35: 317-324, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30120081

RESUMO

BACKGROUND: Bile acid metabolism plays an important role in metabolism but it is uncertain whether bile acid metabolites in early pregnancy are associated with risk of gestational diabetes mellitus (GDM). METHODS: We organized a 1:1 case-control study nested in a prospective cohort of 22,302 pregnant women recruited from 2010 to 2012 in China: 243 women with GDM were matched with 243 non-GDM controls on age (±1 year). Conditional logistic regression and restricted cubic spline were used to examine full-range associations of bile acid metabolites with GDM. FINDINGS: All the 9 detectable bile acids were inversely associated with the risk of GDM, among them, 8 in nonlinear and one in largely linear manners in multivariable analysis. Glycoursodeoxycholic acid (GUDCA) at ≤0.07 nmol/mL and deoxycholic acid (DCA) at ≤0.28 nmol/mL had threshold effects and their decreasing levels below the cutoff points were associated with rapid rises in the risk of GDM. In traditional risk factor model, the stepwise procedure identified that GUDCA ≤ 0.07 nmol/mL and DCA ≤ 0.280 nmol/mL were still significant (OR: 6.84, 95%CI: 1.10-42.48 & 2.06, 1.26-3.37), while other bile acids were not. Inclusion of the two bile acids in the model increased the area under operating characteristic's curve from 0.69 to 0.76 (95% CI: 0.71-0.80) (P < .05). INTERPRETATION: Serum GUDCA ≤ 0.07 nmol/mL and DCA ≤ 0.28 nmol/mL in early pregnancy were independently associated with increased risk of GDM in Chinese pregnant women. FUNDING: Talent Recruitment Scheme grant of Tianjin Medical University and National Key Research and Development Program, etc.


Assuntos
Grupo com Ancestrais do Continente Asiático , Ácidos e Sais Biliares/metabolismo , Diabetes Gestacional/metabolismo , Metaboloma , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Razão de Chances , Gravidez , Curva ROC , Fatores de Risco
10.
Chemosphere ; 212: 513-522, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30165278

RESUMO

Hydroxy metabolites of polychlorinated biphenyls (OH-PCBs) are important substance basis for the toxicity of PCBs. This study aims to investigate the inhibition of OH-PCBs on the activity of UDP-glucuronosyltransferases (UGTs), trying to elucidate the toxicity mechanism of PCBs from a new perspective. In vitrohuman recombinant UGTs-catalyzed glucuronidation of 4-methylumbelliferone (4-MU) was used as the probe reaction. The number of chlorine atom can affect the inhibition potential of OH-PCBs towards different isoforms of UGTs, and complex structure-activity relationship was found for the inhibition of OH-PCBs on the activities of UGT isoforms. For the inhibition kinetic determination, 2'OHPCB106 and 4'OHPCB106 were selected as the representative OH-PCBs, and UGT1A1, 1A7, and 2B7 were chosen as the representative UGT isoforms. Competitive inhibition of 2'OHPCB106 and 4'OHPCB106 on the activities of UGT1A1, UGT1A7, and UGT2B7 was found. For 2'OHPCB106, the inhibition kinetic parameters (Ki) were calculated to be 0.4 µM for UGT1A1, 1.3 µM for UGT1A7, and 2.7 µM for UGT2B7, respectively. For 4'OHPCB106, Ki values were calculated to be 0.7 µM for UGT1A1, 6.8 µM for UGT1A7, and 4.8 µM for UGT2B7, respectively. In silico docking method was utilized to elucidate the inhibition difference of UGT1A1 by four OH-PCBs with similar structures (4'OHPCB9, 4'OHPCB26, 4'OHPCB112 and 4'OHPCB165). In conclusion, these data will be helpful for understanding the toxicity mechanisms of PCBs from a view of metabolic interference.


Assuntos
Glucuronosiltransferase/metabolismo , Bifenilos Policlorados/química , Catálise , Humanos
11.
Cancer Res ; 78(17): 4853-4864, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-29898994

RESUMO

p62 is a receptor that facilitates selective autophagy by interacting simultaneously with cargoes and LC3 protein on the autophagosome to maintain cellular homeostasis. However, the regulatory mechanism(s) behind this process and its association with breast cancer remain to be elucidated. Here, we report that Flightless-I (FliI), a novel p62-interacting protein, promotes breast cancer progression by impeding selective autophagy. FliI was highly expressed in clinical breast cancer samples, and heterozygous deletion of FliI retarded the development of mammary tumors in PyVT mice. FliI induced p62-recruited cargoes into Triton X-100 insoluble fractions (TI) to form aggregates, thereby blocking p62 recognition of LC3 and hindering p62-dependent selective autophagy. This function of Flil was reinforced by Akt-mediated phosphorylation at Ser436 and inhibited by phosphorylation of Ulk1 at Ser64. Obstruction of autophagic clearance of p62-recruited cargoes by FliI was associated with the accumulation of oxidative damage on proteins and DNA, which could contribute to the development of cancer. Heterozygous knockout of FliI facilitated selectively autophagic clearance of aggregates, abatement of ROS levels, and protein oxidative damage, ultimately retarding mammary cancer progression. In clinical breast cancer samples, Akt-mediated phosphorylation of FliI at Ser436 negatively correlated with long-term prognosis, while Ulk1-induced FliI phosphorylation at Ser64 positively correlated with clinical outcome. Together, this work demonstrates that FliI functions as a checkpoint protein for selective autophagy in the crosstalk between FliI and p62-recruited cargoes, and its phosphorylation may serve as a prognostic marker for breast cancer.Significance: Flightless-I functions as a checkpoint protein for selective autophagy by interacting with p62 to block its recognition of LC3, leading to tumorigenesis in breast cancer.Cancer Res; 78(17); 4853-64. ©2018 AACR.


Assuntos
Neoplasias da Mama/genética , Carcinogênese/genética , Proteínas dos Microfilamentos/genética , Proteínas Associadas aos Microtúbulos/genética , Proteínas de Ligação a RNA/genética , Receptores Citoplasmáticos e Nucleares/genética , Adulto , Idoso , Animais , Autofagossomos/metabolismo , Autofagossomos/patologia , Autofagia/genética , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/genética , Mama/metabolismo , Mama/patologia , Neoplasias da Mama/patologia , Progressão da Doença , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Camundongos , Pessoa de Meia-Idade , Fosforilação , Ligação Proteica/genética
12.
Chemosphere ; 206: 9-16, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29723751

RESUMO

Chlorophenols (CPs) are important pollutants extensively utilized in industry, agriculture and forestry. The present study aims to determine the inhibition of CPs on the activity of the important phase II drug-metabolizing enzymes (DMEs) UDP-glucuronosyltransferases (UGTs). 100 µM of fourteen CPs were used for preliminary screening using in vitro incubation. Furthermore, half inhibition concentration (IC50) and inhibition kinetics were determined for CPs with significant inhibition towards UGT isoforms. In silico docking was used to explain the inhibition difference among CPs. Multiple UGT isoforms were inhibited by CPs. In silico docking showed that higher free binding energy due to hydrophobic interactions of 2.4-Dichlorophenol (2.4-DCP) or 4-Chloro-3-methylphenol (4C3MP) with UGT1A9 contributed to stronger inhibition potential of 2.4-Dichlorophenol (2.4-DCP) or 4-Chloro-3-methylphenol (4C3MP) towards UGT1A9 than 4-CP. Pentachlorophenol (PCP) was chosen as the representative CPs to determine the IC50 value towards UGT1A6, UGT1A9 and UGT2B7. IC50 was calculated to be 0.33 µM, 0.24 µM and 31.35 µM for the inhibition of PCP towards UGT1A6, UGT1A9 and UGT2B7. PCP was demonstrated to show competitive inhibition towards UGT1A6, UGT1A9 and UGT2B7, and the inhibition kinetic parameters (Ki) was calculated to be 0.18 µM, 0.01 µM and 5.37 µM for the inhibition of PCP towards UGT1A6, UGT1A9 and UGT2B7. All these information will be beneficial for elucidating the risk of CPs exposure from a new perspective.


Assuntos
Clorofenóis/química , Glucuronosiltransferase/química , Glucuronosiltransferase/antagonistas & inibidores , Humanos , Fatores de Risco
13.
Chemosphere ; 197: 7-13, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29328989

RESUMO

Phthalate monoesters are important metabolites of phthalate esters (PAEs) which have been extensively utilized in industry. This study aims to investigate the inhibition of phthalate monoesters on the activity of various isoforms of UDP-glucuronosyltransferases (UGTs), trying to elucidate the toxicity mechanism of environmental endocrine disruptors from the new perspectives. In vitro recombinant UGTs-catalyzed glucuronidation of 4-methylumbelliferone (4-MU) was employed to evaluate 8 kinds of phthalate monoesters on 11 sorts of main human UGT isoforms. 100 µM phthalate monoesters exhibited negligible inhibition towards the activity of UGT1A1, UGT1A3, UGT1A6, UGT1A8, UGT1A10, UGT2B4, UGT2B7, UGT2B15 and UGT2B17. The activity of UGT1A7 was strongly inhibited by monoethylhexyl phthalate (MEHP), but slightly inhibited by all the other phthalate monoesters. UGT1A9 was broadly inhibited by monobenzyl phthalate (MBZP), monocyclohexyl phthalate (MCHP), MEHP, monohexyl phthalate (MHP) and monooctyl phthalate (MOP), respectively. MEHP exhibited competitive inhibition towards UGT1A7, and MBZP, MCHP, MEHP, MHP and MOP showed competitive inhibition towards UGT1A9. The inhibition kinetic parameters (Ki) were calculated to be 11.25 µM for MEHP-UGT1A7, and 2.13, 0.09, 1.17, 7.47, 0.16 µM for MBZP-UGT1A9, MCHP-UGT1A9, MEHP-UGT1A9, MHP-UGT1A9, MOP-UGT1A9, respectively. Molecular docking indicated that both hydrogen bonds formation and hydrophobic interactions significantly contributed to the interaction between phthalate monoesters and UGT isoforms. All these information will be beneficial for understanding the adverse effects of PAEs.


Assuntos
Glucuronosiltransferase/metabolismo , Ácidos Ftálicos/química , Catálise , Disruptores Endócrinos/metabolismo , Ésteres/metabolismo , Glucuronídeos/metabolismo , Glucuronosiltransferase/química , Humanos , Cinética , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Isoformas de Proteínas/metabolismo
14.
Psychiatry Res ; 259: 501-505, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29154172

RESUMO

To explore the association between schizophrenia and six types of B vitamins, including choline, biotin, riboflavin, pyridoxamine, pyridoxine and nicotinamide, based on the hydrophilic interaction liquid chromatography column (HILIC) Liquid Chromatography-Mass Spectrometry (LC-MS) platform. We conducted the case-control study between November 2015 and September 2016 in Weifang, Shandong Province, China. Blood samples from 128 cases of schizophrenia and 101 controls were collected, and B vitamin were measured by LC-MS coupled with HILIC. The HILIC UPLC-MS based analysis of serum B vitamins levels from 128 cases (30 cases with first-episode, 98 cases with relapse) and 101 controls were performed. The results indicated that lower pyridoxine level and schizophrenia was related. (total cases versus controls: ß= -0.215, 95% CI: -0.271, -0.125, p < 0.001; first-episode cases versus controls: ß = -0.190, 95% CI: -0.277, -0.103, p < 0.001). Higher nicotinamide level was also associated with schizophrenia after adjusting confounders (ß = 0.343, 95% CI: 0.022, 0.664, p = 0.036). Other four B vitamins, including biotin, riboflavin, pridoxamine and choline, were showed no statistically difference in cases versus controls, first episode cases versus relapse cases. Two types of B Vitamins, pyridoxine and nicotinamide, show significant association with the schizophrenia.


Assuntos
Vigilância da População , Esquizofrenia/sangue , Esquizofrenia/diagnóstico , Complexo Vitamínico B/sangue , Adulto , Estudos de Casos e Controles , China/epidemiologia , Cromatografia Líquida/métodos , Estudos Transversais , Feminino , Humanos , Masculino , Espectrometria de Massas/métodos , Vigilância da População/métodos , Esquizofrenia/epidemiologia , Complexo Vitamínico B/análise , Adulto Jovem
15.
Xenobiotica ; 48(5): 452-458, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-28548030

RESUMO

1. Everolimus is an inhibitor of mammalian target of rapamycin (mTOR) and has been clinically utilized to prevent the rejection of organ transplants. This study aims to determine the inhibition of everolimus on the activity of phase-II drug-metabolizing enzymes UDP-glucuronosyltransferases (UGTs). 2. The results showed that 100 µM of everolimus exerted more than 80% inhibition toward UGT1A1, UGT-1A3 and UGT-2B7. UGT1A3 and UGT2B7 were selected to elucidate the inhibition mechanism, and in silico docking showed that hydrogen bonds and hydrophobic interactions mainly contributed to the strong binding of everolimus toward the activity cavity of UGT1A3 and UGT2B7. Inhibition kinetic-type analysis using Lineweaver-Burk plot showed competitive inhibition toward all these UGT isoforms. The inhibition kinetic parameters (Ki) were calculated to be 2.3, 0.07 and 4.4 µM for the inhibition of everolimus toward UGT1A1, UGT-1A3 and UGT-2B7, respectively. 3. In vitro-in vivo extrapolation (IVIVE) showed that [I]/Ki value was calculated to be 0.004, 0.14 and 0.002 for UGT1A1, UGT-1A3 and UGT-2B7, respectively. Therefore, high DDI potential existed between everolimus and clinical drugs mainly undergoing UGT1A3-catalyzed glucuronidation.


Assuntos
Inibidores Enzimáticos/farmacologia , Everolimo/farmacologia , Glucuronosiltransferase/antagonistas & inibidores , Avaliação Pré-Clínica de Medicamentos , Glucuronosiltransferase/metabolismo , Humanos , Interações Hidrofóbicas e Hidrofílicas , Cinética , Simulação de Acoplamento Molecular , Isoformas de Proteínas/metabolismo
16.
Nat Commun ; 8: 14420, 2017 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-28240261

RESUMO

Gluconeogenesis, an essential metabolic process for hepatocytes, is downregulated in hepatocellular carcinoma (HCC). Here we show that the nuclear receptor Nur77 is a tumour suppressor for HCC that regulates gluconeogenesis. Low Nur77 expression in clinical HCC samples correlates with poor prognosis, and a Nur77 deficiency in mice promotes HCC development. Nur77 interacts with phosphoenolpyruvate carboxykinase (PEPCK1), the rate-limiting enzyme in gluconeogenesis, to increase gluconeogenesis and suppress glycolysis, resulting in ATP depletion and cell growth arrest. However, PEPCK1 becomes labile after sumoylation and is degraded via ubiquitination, which is augmented by the p300 acetylation of ubiquitin-conjugating enzyme 9 (Ubc9). Although Nur77 attenuates sumoylation and stabilizes PEPCK1 via impairing p300 activity and preventing the Ubc9-PEPCK1 interaction, Nur77 is silenced in HCC samples due to Snail-mediated DNA methylation of the Nur77 promoter. Our study reveals a unique mechanism to suppress HCC by switching from glycolysis to gluconeogenesis through Nur77 antagonism of PEPCK1 degradation.


Assuntos
Carcinoma Hepatocelular/metabolismo , Gluconeogênese , Neoplasias Hepáticas/metabolismo , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Fosfoenolpiruvato Carboxiquinase (ATP)/metabolismo , Sumoilação , Acetilação , Animais , Carcinogênese/patologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Regulação para Baixo/genética , Proteína p300 Associada a E1A/metabolismo , Estabilidade Enzimática , Regulação Neoplásica da Expressão Gênica , Glucose/metabolismo , Células Hep G2 , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Masculino , Metilação , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Biológicos , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Proteólise , Fatores de Transcrição da Família Snail/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Enzimas de Conjugação de Ubiquitina/metabolismo
17.
J Neurosci ; 36(47): 11959-11973, 2016 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-27881781

RESUMO

Soluble amyloid-ß (Aß) oligomers, also known as Aß-derived diffusible ligands (ADDLs), are thought to be the key pathogenic factor in Alzheimer's disease (AD), but there is still no effective treatment for preventing or reversing the progression of the disease. Targeting NMDA receptor trafficking and regulation is a new strategy for early treatment of AD. Aß oligomers have been found to bind to the fibronectin (FN) type III repeat domain of EphB2 to trigger EphB2 degradation, thereby impairing the normal functioning of NMDA receptors and resulting in cognitive deficits. Here, we identified for the first time the interaction sites of the EphB2 FN domain with ADDLs by applying the peptide array method to design and synthesize four candidate peptides (Pep21, Pep25, Pep32, and Pep63) that might be able to block the EphB2-ADDL interaction. Among them, Pep63 was found to be the most effective at inhibiting the binding between EphB2 and ADDLs. We found that Pep63 not only rescued the ADDL-induced depletion of EphB2- and GluN2B-containing NMDA receptors from the neuronal surface in cultured hippocampal neurons, but also improved impaired memory deficits in APPswe/PS1dE9 (APP/PS1) transgenic mice and the phosphorylation and surface expression of GluN2B-containing NMDA receptors in cultures. Together, these results suggest that blocking the EphB2-ADDL interaction by small interfering peptides may be a promising strategy for AD treatment. SIGNIFICANCE STATEMENT: Alzheimer's disease (AD) is an age-dependent neurodegenerative disorder and amyloid ß-derived diffusible ligands (ADDLs) play a key role in triggering the early cognitive deficits that constitute AD. ADDLs may bind EphB2 and alter NMDA receptor trafficking and synaptic plasticity. Here, we identified the interaction sites of the EphB2 FN domain with ADDLs for the first time to develop a small (10 aa) peptide (Pep63) capable of blocking the EphB2-ADDL interaction. We found that Pep63 not only rescued the ADDL-induced depletion of EphB2 and GluN2B-containing NMDA receptors from the neuronal surface in cultured hippocampal neurons, but also improved impaired memory deficits in APPswe/PS1dE9 (APP/PS1) transgenic mice. Our results suggest that blocking the EphB2-ADDL interaction with Pep63 may be a promising strategy for AD treatment.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Transtornos da Memória/fisiopatologia , Memória/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Peptídeos/farmacologia , Receptor EphB2/metabolismo , Transmissão Sináptica/efeitos dos fármacos , Doença de Alzheimer/fisiopatologia , Doença de Alzheimer/prevenção & controle , Animais , Progressão da Doença , Ligantes , Masculino , Transtornos da Memória/prevenção & controle , Camundongos , Camundongos Transgênicos , Ligação Proteica/efeitos dos fármacos
18.
Exp Ther Med ; 12(6): 3716-3722, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28105103

RESUMO

The aim of the present study was to increase the intestinal transport of octreotide (OCT) by targeting the first-pass impact to identify a potential method for decreasing portal vein pressure (PVP) using oral OCT. Thus, the bioavailability of intestinally absorbed OCT was evaluated in normal rats and rats with portal hypertension (PH) that had been administered P-glycoprotein/multidrug resistance-associated protein 2/cytochrome P450 3A4 (P-gp/MRP2/CYP3A4) inhibitors. The mRNA and protein expression levels of P-gp, MRP2 and CYP3A4 were evaluated in normal and PH rats with or without OCT and the inhibitors using RT-PCR, western blot and immunohistochemical analyses. The potential effects of the inhibitor administration on PVP were also examined. The results suggest that P-gp, MRP2 and CYP3A4 play important roles in prohibiting the enteral absorption of OCT, particularly under a PH environment. Moreover, inhibitors of P-gp, MRP2 and CYP3A4 decrease the first-pass effects of OCT and effectively reduce PVP under PH conditions. Therefore, the present results suggest P-gp, MRP2 and CYP3A4 are key factors in the intestinal absorption of OCT. The inhibition of P-gp, MRP2 and CYP3A4 can markedly decrease the first-pass effects of OCT, and their use may facilitate the use of orally administered OCT.

19.
Exp Ther Med ; 10(6): 2039-2046, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26668593

RESUMO

The aim of the present study was to investigate the effect of endogenous carbon monoxide (CO) on the hydrogen sulfide/cystathionine-γ-lyase (H2S/CSE) pathway in cirrhotic rat livers. The rats were allocated at random into four groups: Sham, cirrhosis, cobalt protoporphyrin (CoPP) and zinc protoporphyrin IX (ZnPP). The expression of hepatic CSE mRNA was evaluated using a quantitative polymerase chain reaction, while CSE protein expression was determined using immunohistochemical analysis. Hematoxylin and eosin staining was performed for the histological evaluation of liver fibrosis. The levels of H2S, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL) and carboxyhemoglobin (COHb) in the arterial blood were determined, in addition to the portal vein pressure. The mRNA and protein expression levels of hepatic CSE and the serum levels of H2S were significantly decreased in the cirrhosis group compared with those in the sham group (P<0.05). Compared with the cirrhosis group, rats in the ZnPP group had significantly lower levels of serum ALT, AST and TBIL, arterial COHb and hepatic fibrosis, while hepatic CSE expression and the production of H2S were significantly increased (P<0.05). The CoPP group exhibited decreased hepatic CSE expression and H2S production, but aggravated hepatic function and fibrosis (P<0.05). In conclusion, the H2S/CSE pathway is involved in the formation of liver cirrhosis and serves a crucial function in protecting liver cells against the progression of liver fibrosis. Endogenous CO downregulates hepatic CSE mRNA and protein expression and the production of H2S in rats with liver cirrhosis.

20.
J Clin Virol ; 70: 29-38, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26305816

RESUMO

BACKGROUND: Although hand, foot, and mouth disease (HFMD) is a major public concern in China, the prevalence and clinical symptoms associated with the different agents of HFMD in this country remain poorly understood. OBJECTIVES: We investigated the clinical and molecular characteristics of enteroviruses in patients with HFMD from Wenzhou, China. STUDY DESIGN: Patients with laboratory-confirmed HFMD admitted to the Yuying Children's Hospital in Wenzhou, China during 2013 were included in this study. Viral RNA sequences were amplified using RT-PCR, determined by sequencing, and compared by phylogenetic analysis. RESULTS: A total of 955 clinically diagnosed HFMD cases were determined using PCR, with whole viral genomes obtained for each enterovirus type. 14 types of enterovirus belonging to two viral species were identified. Notably, Coxsackievirus A6 (CV-A6) was the most common species detected (77.8%), followed by EV-A71 (8.2%) and CV-A10 (8.1%). Phylogenetic analysis revealed multiple independent introductions of these viruses into Wenzhou. In addition, the enterovirus observed in Wenzhou had a recombinant history, with two or three recombination breakpoints. Although the illness associated with CV-A6 was milder than that of EV-A71, CV-A6 infection caused more widespread rash, larger blisters, and subsequent skin peeling and/or nail shedding. CONCLUSION: Our study revealed the co-circulation of 14 types of enteroviruses in a single location - Wenzhou, China - with CV-A6 virus the predominant agent of HFMD. This work highlights the need to perform larger-scale surveillance to fully understand the epidemiology of enteroviruses in China and the wider Asia-Pacific region.


Assuntos
Enterovirus/genética , Doença de Mão, Pé e Boca/epidemiologia , Doença de Mão, Pé e Boca/virologia , Vírus Reordenados , Criança , Pré-Escolar , China/epidemiologia , Comorbidade , Enterovirus/classificação , Feminino , Genótipo , Doença de Mão, Pé e Boca/diagnóstico , Humanos , Lactente , Masculino , Filogenia , Vigilância da População , RNA Viral/genética , Recombinação Genética
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