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1.
Diabetes ; 69(4): 760-770, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31974145

RESUMO

Long-term hyperglycemia in patients with diabetes leads to human serum albumin (HSA) glycation, which may impair HSA function as a transport protein and affect the therapeutic efficacy of anticoagulants in patients with diabetes. In this study, a novel mass spectrometry approach was developed to reveal the differences in the profiles of HSA glycation sites between patients with diabetes and healthy subjects. K199 was the glycation site most significantly changed in patients with diabetes, contributing to different interactions of glycated HSA and normal HSA with two types of anticoagulant drugs, heparin and warfarin. An in vitro experiment showed that the binding affinity to warfarin became stronger when HSA was glycated, while HSA binding to heparin was not significantly influenced by glycation. A pharmacokinetic study showed a decreased level of free warfarin in the plasma of diabetic rats. A preliminary retrospective clinical study also revealed that there was a statistically significant difference in the anticoagulant efficacy between patients with diabetes and patients without diabetes who had been treated with warfarin. Our work suggests that larger studies are needed to provide additional specific guidance for patients with diabetes when they are administered anticoagulant drugs or drugs for treating other chronic diseases.

2.
Postgrad Med J ; 95(1122): 181-186, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30975729

RESUMO

OBJECTIVES: The National Institute of Health Stroke Scale (NIHSS) is a predictor for the prognosis of acute ischaemic stroke (AIS) and its prediction is time-dependent. We examined the performance of NIHSS at different timepoints in predicting functional outcome of patients with thrombolysed AIS. METHODS: This prospective study included 269 patients with AIS treated with recombinant tissue plasminogen activator (rt-PA). Unfavourable functional outcome was defined as modified Rankin Scale score 4-6 at 3 months after rt-PA treatment. Receiver operating characteristic curves were used to examine the predictive power of NIHSS score at admission and 2 hours/24 hours/7 days/10 days after rt-PA treatment. Youden's index was used to select the threshold of NIHSS score. Logistic regression was used to estimate the ORs of unfavourable functional outcome for patients with NIHSS score higher than the selected thresholds. RESULTS: The threshold of NIHSS score at admission was 12 (sensitivity: 0.51, specificity: 0.84) with an acceptable predictive power (area under curve [AUC] 0.74) for unfavourable functional outcome. The threshold changed to 5 at 24 hours after rt-PA treatment (sensitivity: 0.83, specificity: 0.65) and remained unchanged afterwards. The predictive power and sensitivity sequentially increased over time and peaked at 10 days after rt-PA treatment (AUC 0.92, sensitivity: 0.85, specificity: 0.80). NIHSS scores higher than the thresholds were associated with elevated risk of unfavourable functional outcome at all timepoints (all p<0.001). CONCLUSIONS: NIHSS is time-dependent in predicting AIS prognosis with increasing predictive power over time. Since patients whose NIHSS score ≥ 12 are likely to have unfavourable functional outcome with rt-PA treatment only, mechanical thrombectomy should be largely taken into consideration for these patients.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/fisiopatologia , Fibrinolíticos/uso terapêutico , Recuperação de Função Fisiológica , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/fisiopatologia , Terapia Trombolítica/métodos , Ativador de Plasminogênio Tecidual/uso terapêutico , Administração Intravenosa , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Fatores de Tempo , Resultado do Tratamento
3.
J Proteomics ; 195: 11-22, 2019 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-30630120

RESUMO

Oxidized low-density lipoprotein (ox-LDL) can impair endothelial function and lead to the atherosclerosis development. Protein S-nitrosylation is sensitive to cellular redox state and acts as a crucial regulator and executor of nitric oxide (NO) signaling pathways. Aberrant S-nitrosylation contributes to the pathogenesis of cardiovascular and cerebrovascular diseases. However, the effect of ox-LDL on S-nitrosylation and its significance for endothelial dysfunction have not been studied at proteome level. Herein, the combined quantitative analysis of proteome and S-nitrosoproteome was performed using an integrated biotin switch and iTRAQ labeling approach in EA.hy926 cell line derived from human umbilical vein endothelial cell (HUVEC) treated with ox-LDL. A total of 2204 S-nitrosylated (SNO) peptides of 1318 SNO-proteins were quantified. Notably, 352 SNO-peptides of 262 SNO-proteins were significantly regulated after excluding S-nitrosylation changes caused by protein expression alterations. Many of them belonged to mRNA splicing, ribosomal structure and translational regulatory proteins, covering the entire translation process. The results indicated that S-nitrosylation of the splicing and translational machinery in vascular endothelial cells was susceptible to ox-LDL. Abnormal protein S-nitrosylation may be one pivotal mechanism underlying endothelial dysfunction induced by ox-LDL. This study potentially enriches the present understanding of pro-atherogenic effect of ox-LDL from the perspective of S-nitrosylation. SIGNIFICANCE: The role of ox-LDL in endothelial dysfunction and atherosclerosis development has been recognized from the aspect of impaired NO production. However, its effect on S-nitrosylation, which is directly related to NO signaling pathway, still remains largely unexplored. Our work initially provided a systematic characterization of S-nitrosoproteome in ox-LDL-treated endothelial cells after ruling out the changes of S-nitrosylation modification caused by protein expression alone. MS-based approach coupled with iTRAQ technique indicated 262 SNO-proteins were significantly regulated. Functional enrichment and interaction network analysis revealed that proteins involved in mRNA splicing and translational machinery were susceptible to abnormal S-nitrosylation under ox-LDL treatment. This achievement suggested one potential mechanism underlying endothelial dysfunction induced by ox-LDL from the perspective of S-nitrosoproteome.

4.
Front Neurol ; 9: 162, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29615961

RESUMO

Background: Hypertension has been associated with cognitive dysfunction in the general population and patients with Alzheimer's disease (AD). However, there are contradictory data regarding the potential association between hypertension and diagnosis of Parkinson's disease (PD), the second most common neurodegenerative disorder after AD. The purpose of this meta-analysis is to synthesize data from cohort studies to explore the potential association between preexisting hypertension and subsequent PD diagnosis. Methods: The PubMed and Embase databases were searched to identify all relevant studies. Two independent investigators performed the data extraction. Eligible cohort studies providing risk and precision estimates related to hypertension and PD were selected. Pooled risk ratios (RRs) with 95% confidence interval (CI) were calculated by using a random-effects model or a fixed-effects model. Sensitivity analyses after excluding one study at a time were performed to assess the stability of the results. Publication bias was assessed with Begg's test and Egger's test. Results: Seven cohort studies were identified, including 3,170 persons who were confirmed to have developed PD and 339,517 participants who did not have PD during follow-up. The onset of hypertension before PD diagnosis was significantly associated with an increased risk of motor stage PD (RR = 1.799, 95% CI [1.066-3.037]). This relationship was further confirmed by secondary analyses based on estimates adjusted for potential vascular confounders (RR = 1.319, 95% CI [1.073-1.622]). After excluding one study at a time, the sensitivity analyses still showed that hypertension history was significantly associated with an increased risk of motor stage PD (RR with 95% CI ranging from 1.11 [1.075-1.35] to 1.42 [1.65-1.83]). No publication bias was observed in this meta-analysis. Conclusion: The findings of this meta-analysis suggest that hypertension may be a risk factor for motor stage PD, which may provide novel insights into the etiology and pathogenesis of this neurodegenerative disorder. However, large-scale well-designed studies that consider various confounders are still needed to further verify and clarify the association between hypertension and PD diagnosis.

5.
Biomed Res Int ; 2018: 8181374, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30671473

RESUMO

Long intergenic noncoding RNA-p21 (lincRNA-p21) has been reported to be increased in Parkinson's disease (PD). However, the function and underlying mechanisms of lincRNA-p21 remain not clear. In order to explore the role of lincRNA-p21 in PD, we used 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to induce in vivo PD model (C57BL/6 mice) and utilized N-methyl-4-phenylpyridinium (MPP+) to create in vitro PD model (SH-SY5Y cells). Results showed that the expression level of lincRNA-p21 was increased significantly in PD models. High abundance of lincRNA-p21 inhibited viability and promoted apoptosis markedly in SH-SY5Y cells treated with MPP+. Mechanistically, further experiments demonstrated that upregulation of lincRNA-p21 could sponge miR-1277-5p and indirectly increase the expression of α-synuclein to suppress viability and activate apoptosis in SH-SY5Y cells. In short, our study illustrated that lincRNA-p21/miR-1277-5p axis regulated viability and apoptosis in SH-SY5Y cells treated with MPP+ via targeting α-synuclein. LincRNA-p21 might be a novel target for PD.


Assuntos
Apoptose/genética , Sobrevivência Celular/genética , Doença de Parkinson/genética , RNA Longo não Codificante/genética , alfa-Sinucleína/genética , 1-Metil-4-fenilpiridínio/farmacologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Neuroblastoma/genética , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética
6.
Biosci Rep ; 38(1)2018 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-29263145

RESUMO

Objective: The present study aimed to investigate the efficacy and safety of Reteplase (rPA) and Alteplase (rt-PA) in the treatment of hyper-acute cerebral infarction (CI).Methods: Six hundred and eleven patients with hyper-acute CI selected from September 2014 to September 2016 were assigned into the aspirin, rt-PA, rPA, rt-PA + aspirin, and rPA + aspirin groups based on their willingness. The difference of efficacy in five groups were evaluated with National Institute of Health Stroke Scale (NIHSS), modified rankin scale (mRS), and Barthel Index (BI). Coagulation function, blood lipid, and hemodynamics were analyzed. The safety differences were compared by observing the adverse reactions.Results: Compared with the rt-PA, rPA, and aspirin groups, NIHSS score, mRS score, the incidence of non- and symptomatic cerebral hemorrhage as well as the rate of adverse reactions were decreased, while BI were increased in the rt-PA + aspirin and rPA + aspirin groups after treatment. Compared with the rt-PA and rPA groups, total cholesterol (TC), triacylglycerol (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) levels were lower, whereas the hematocrit, whole blood high shear viscosity, whole blood low shear viscosity, plasma viscosity, erythrocyte electrophoresis time, fibrinogen, erythrocyte sedimentation rate (ESR), K value in blood sedimentation equation, and the comprehensive abnormality degree of blood rheology were higher in the rt-PA + aspirin and rPA + aspirin groups.Conclusion: The efficacy and safety of rt-PA or rPA combined with aspirin in the treatment of hyper-acute CI were better than those of rPA or rt-PA monotherapy.


Assuntos
Aspirina/administração & dosagem , Infarto Cerebral/tratamento farmacológico , Ativador de Plasminogênio Tecidual/administração & dosagem , Idoso , Aspirina/efeitos adversos , Infarto Cerebral/sangue , Infarto Cerebral/patologia , Colesterol/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Combinação de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Ativador de Plasminogênio Tecidual/efeitos adversos , Triglicerídeos/sangue
7.
Front Plant Sci ; 8: 931, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28638391

RESUMO

The poor quality and low productivity of cultivated liquorice (Glycyrrhiza uralensis) continues to put pressure on wild plant populations. As arbuscular mycorrhizal fungi are known to support plant growth and in some cases even to enhance the accumulation of valuable molecules in the plant, the effect of Glomus mosseae on the growth and active ingredient contents was evaluated in liquorice plants grown under nutrient deficiency. We created a nutrient-deficient environment by mixing paddy soil, washed river sand, and pumice at a ratio of 1:5:1. Our results showed that the inoculation of pot-grown liquorice plants with G. mosseae significantly increased the shoot and root biomass (by 25- and 17-folds, respectively) and the contents of glycyrrhizic acid, liquiritin, isoliquiritin, and isoliquiritigenin in the main root (by 1.6-, 4.8-, 6.5-, and 4.4-folds, respectively). Both isoliquiritin and isoliquiritigenin were detectable in the lateral roots of the plants inoculated with G. mosseae, but not in plants without G. mosseae inoculation. G. mosseae inoculation improved the features of the root system and increased photosynthetic efficiency of liquorice. The uptake of P and K by liquorice increased when G. mosseae was inoculated, leading to the depletion of these macronutrients in the soil; G. mosseae also improved the availability of Mg, Cu, Zn, and Mn. Based on these results, we concluded that the inoculation of liquorice plants with G. mosseae is beneficial, particularly for those grown in nutrient-deficient soil, and such positive effect is related to the improvement of the root system and an increased photosynthetic efficiency.

8.
Molecules ; 22(2)2017 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-28241438

RESUMO

Lycium barbarum L. polysaccharide (LBP) is prepared from Lycium barbarum L. (L. barbarum), which is a traditional Chinese medicine. LPB has been shown to have hypoglycemic effects. In order to gain some mechanistic insights on the hypoglycemic effects of LBP, we investigated the uptake of LBP and its effect on glucose absorption in the human intestinal epithelial cell line Caco2 cell. The uptake of LBP through Caco2 cell monolayer was time-dependent and was inhibited by phloridzin, a competitive inhibitor of SGLT-1. LPB decreased the absorption of glucose in Caco2 cell, and down-regulated the expression of SGLT-1. These results suggest that LBP might be transported across the human intestinal epithelium through SGLT-1 and it inhibits glucose uptake via down-regulating SGLT-1.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Glucose/metabolismo , Hipoglicemiantes/farmacologia , Lycium/química , Células CACO-2 , Metabolismo dos Carboidratos , Regulação para Baixo , Transportador de Glucose Tipo 2/metabolismo , Humanos , Absorção Intestinal , RNA Mensageiro/genética , Transportador 1 de Glucose-Sódio/metabolismo
9.
Oncotarget ; 8(14): 22524-22533, 2017 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-28186978

RESUMO

JAK-STAT signaling pathway has a crucial role in host innate immunity against viral infections, including HIV-1. We therefore examined the impact of HIV-1 infection and combination antiretroviral therapy (cART) on JAK-STAT signaling pathway. Compared to age-matched healthy donors (n = 18), HIV-1-infected subjects (n = 18) prior to cART had significantly lower expression of toll-like receptors (TLR-1/4/6/7/8/9), the IFN regulatory factors (IRF-3/7/9), and the antiviral factors (OAS-1, MxA, A3G, PKR, and Tetherin). Three months' cART partially restores the impaired functions of JAK-STAT-mediated antiviral immunity. We also found most factors had significantly positive correlations (p < 0.05) between each two factors in JAK-STAT pathway in healthy donors (98.25%, 168/171), but such significant positive associations were only found in small part of HIV-1-infected subjects (43.86%, 75/171), and stably increased during the cART (57.31%, 98/171 after 6 months' cART). With regard to the restoration of some HIV-1 restriction factors, HIV-1-infected subjects who had CD4+ T cell counts > 350//µl responded better to cART than those with the counts < 350/µl. These findings indicate that the impairment of JAK-STAT pathway may play a role in the immunopathogenesis of HIV-1 disease.


Assuntos
Antirretrovirais/uso terapêutico , Linfócitos T CD4-Positivos/efeitos dos fármacos , Quimioterapia Combinada , Infecções por HIV/tratamento farmacológico , HIV-1/fisiologia , Adulto , Contagem de Linfócito CD4 , Linfócitos T CD4-Positivos/imunologia , Feminino , Infecções por HIV/imunologia , Humanos , Janus Quinases/metabolismo , Masculino , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais , Carga Viral , Adulto Jovem
10.
J Diabetes Investig ; 8(5): 687-696, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28122165

RESUMO

AIMS/INTRODUCTION: The present meta-analysis was carried out to assess the association between exposure to the level of atmospheric particulate matter 2.5 (PM2.5; fine particulate matter with aerodynamic diameter less than 2.5 µm) and type 2 diabetes mellitus or gestational diabetes mellitus (GDM). MATERIALS AND METHODS: We searched the Medline, EMBASE, Cochrane and Web of Science databases to obtain articles according to the responding literature search strategies. Among a total of 279 identified articles, 55 were reviewed in depth, of which 10 articles (11 cohort studies) satisfied the inclusion criteria. Only cohort studies that disclosed the association between PM2.5 and type 2 diabetes mellitus or GDM were included in this article. A fixed-effects model was selected if P > 0.1 and I2 < 50%; otherwise, a random-effects model would be used to calculate the total effect value. Subgroup analysis was further carried out according to the types of diabetes mellitus (type 2 diabetes mellitus and GDM). The relative risk was used to estimate the association between PM2.5 and diabetes mellitus. RESULTS: The positive associations between PM2.5 and the incidence of type 2 diabetes mellitus were found in the long-term exposure period (relative risk 1.25, 95% confidence interval 1.10-1.43), which showed that with every 10-µg/m3 increase in PM2.5, the risk of type 2 diabetes mellitus would increase by 25% in the long-term exposure. Although the significant associations were not identified between maternal exposure to PM2.5 and GDM in the first trimester, the second trimester and the entire pregnancy periods, we could conclude that maternal exposure to PM2.5 in the entire pregnancy period would be more likely to lead to developing GDM (relative risk 1.162, 95% confidence interval 0.806-1.675) than the other two periods. CONCLUSIONS: Long-term exposure to PM2.5 would be more likely to lead to developing type 2 diabetes mellitus, but more studies would be required to confirm the association between PM2.5 and GDM. It might be a wise to take effective measures to reduce PM2.5 exposure in vulnerable populations, especially for pregnant women.


Assuntos
Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Gestacional/epidemiologia , Exposição Ambiental/estatística & dados numéricos , Estudos de Coortes , Diabetes Mellitus Tipo 2/etiologia , Diabetes Gestacional/etiologia , Feminino , Humanos , Masculino , Material Particulado/efeitos adversos , Material Particulado/análise , Gravidez
11.
Eur Spine J ; 26(7): 1852-1861, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28028649

RESUMO

PURPOSE: In the present prospective randomized controlled study, we compared the feasibility and effectiveness of our modified thoracoabdominal approach to anterior thoracolumbar spine surgery without cutting open the costal portion of diaphragm (extradiaphragmatic approach) with the traditional transdiaphragmatic thoracoabdominal approach. The traditional combined thoracoabdominal approach in anterior thoracolumbar surgery for spine tuberculosis is effective but seriously damages the diaphragm and causes various lung complications. We used an extradiaphragmatic approach for complete anterior debridement, bone grafting, and nerve decompression and compared its efficacy and complications with those of the traditional transdiaphragmatic thoracolumbar approach. METHODS: The study included 106 patients with spinal tuberculosis. After a standard preoperative chemotherapy regimen, all patients underwent posterior deformity correction and internal fixation, anterior debridement, decompression, and bone grafting. Patients were divided into the modified extradiaphragmatic thoracolumbar approach group (the modified group) and the traditional transdiaphragmatic thoracolumbar approach group (the traditional group). During the treatment, we strictly followed the standard chemotherapy regimen. RESULTS: The mean follow-up duration was 36.2 months (range 25-38 months). There were significant differences between the two groups in intraoperative blood loss, length of incision, recovery time, and postoperative complications but no significant differences in preoperative and postoperative erythrocyte sedimentation rates and C-reactive protein values, kyphosis, and neurologic function, recovery of ability to live and work, and postoperative healing of bone grafts. CONCLUSION: The modified extradiaphragmatic thoracolumbar approach for anterior thoracolumbar spine surgery is as effective as the traditional approach. However, associated surgical trauma is minimal, and the incidence of pulmonary complications is low.


Assuntos
Transplante Ósseo/métodos , Descompressão Cirúrgica/métodos , Diafragma/cirurgia , Vértebras Lombares/cirurgia , Fusão Vertebral/métodos , Vértebras Torácicas/cirurgia , Tuberculose da Coluna Vertebral/cirurgia , Adulto , Desbridamento/métodos , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Costelas , Resultado do Tratamento
12.
Soc Psychiatry Psychiatr Epidemiol ; 51(11): 1547-1557, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27803977

RESUMO

China Mental Health Survey (CMHS), which was carried out from July 2013 to March 2015, was the first national representative community survey of mental disorders and mental health services in China using computer-assisted personal interview (CAPI). Face-to-face interviews were finished in the homes of respondents who were selected from a nationally representative multi-stage disproportionate stratified sampling procedure. Sample selection was integrated with the National Chronic Disease and Risk Factor Surveillance Survey administered by the National Centre for Chronic and Non-communicable Disease Control and Prevention in 2013, which made it possible to obtain both physical and mental health information of Chinese community population. One-stage design of data collection was used in the CMHS to obtain the information of mental disorders, including mood disorders, anxiety disorders, and substance use disorders, while two-stage design was applied for schizophrenia and other psychotic disorders, and dementia. A total of 28,140 respondents finished the survey with 72.9% of the overall response rate. This paper describes the survey mode, fieldwork organization, procedures, and the sample design and weighting of the CMHS. Detailed information is presented on the establishment of a new payment scheme for interviewers, results of the quality control in both stages, and evaluations to the weighting.


Assuntos
Inquéritos Epidemiológicos , Transtornos Mentais/epidemiologia , Serviços de Saúde Mental , Saúde Mental , Adulto , China , Feminino , Humanos , Pessoa de Meia-Idade , Projetos de Pesquisa
13.
J Alzheimers Dis ; 50(3): 669-85, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26757041

RESUMO

Recently, there is an increasing concern over the association between sleep disorders and Alzheimer's disease (AD). Clinical observations have reported that chronic sleep deprivation (SD) may serve as a risk factor for AD. However, the pathological evidence for this assumption is still lacking. In the present study, we examined the potential impacts of chronic SD on learning-memory and AD-related pathologies in AßPP(swe)/PS1(ΔE9) transgenic (TG) mice and their wild-type (WT) littermates. Results indicated that mice (both TG and WT) exposed to 2-month SD showed an altered amyloid-ß protein precursor processing, an elevated level of phosphorylated tau protein, and impaired cognitive performance as compared to non-sleep deprivation (NSD) controls. Moreover, the SD-treated TG mice exhibited more amyloid-ß(1-42) production and developed more senile plaques in the cortex and hippocampus than NSD-treated TG mice. In addition, SD caused a striking neuronal mitochondrial damage, caspase cascade activation, and neuronal apoptosis in the hippocampus of both TG and WT mice. More importantly, all these behavioral, neuropathological, and biochemical changes induced by chronic SD were long lasting and were irreversible during a 3-month normal housing condition. Collectively, these results indicate that chronic SD impairs learning and memory, exacerbates AD pathologies, and aggravates the mitochondria-mediated neuronal apoptosis in a long-lasting manner. Our findings provide important experimental evidence to prove that chronic SD is a risk factor for AD.


Assuntos
Doença de Alzheimer/complicações , Doença de Alzheimer/patologia , Encéfalo/patologia , Deficiências da Aprendizagem/etiologia , Privação do Sono/complicações , Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Animais , Apoptose/genética , Encéfalo/metabolismo , Encéfalo/ultraestrutura , Transtornos Cognitivos/etiologia , Modelos Animais de Doenças , Humanos , Marcação In Situ das Extremidades Cortadas , Deficiências da Aprendizagem/genética , Camundongos , Camundongos Transgênicos , Doenças Mitocondriais/etiologia , Doenças Mitocondriais/genética , Mutação/genética , Fosforilação/genética , Placa Amiloide/genética , Placa Amiloide/patologia , Presenilina-1/genética , Reversão de Aprendizagem/fisiologia , Proteínas tau/metabolismo
14.
Alzheimers Dement ; 12(2): 130-143, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26121910

RESUMO

INTRODUCTION: Environmental factors and epigenetic mechanisms are believed to contribute to Alzheimer's disease (AD). We previously documented that prenatal hypoxia aggravated the cognitive impairment and neuropathology in offspring mice. Here, we investigate the chronic hypoxia-induced epigenetic modifications in AD. METHODS: The 3-month-old APP(swe)/PS1(dE9) mice were exposed to hypoxic environment 6 hour/day for 30 days, followed by learning and memory tests and biochemical and neuropathology measurement at the age of 4, 6, and 9 months. RESULTS: We found hypoxia exaggerated the neuropathology and cognitive impairment in AD mice. Chronic hypoxia induced demethylation on genomic DNA and decreased the expression of DNA methyltransferase 3b (DNMT3b) in vivo. We further found that DNMTs inhibition elevated the protein levels of amyloid precursor protein, ß- and γ-secretases, whereas overexpression of DNMT3b suppressed the levels of them in vitro. DISCUSSION: Our study suggests chronic hypoxia can aggravate AD progression through demethylation of genes encoding γ-secretase components by downregulation of DNMT3b.


Assuntos
Doença de Alzheimer/etiologia , Secretases da Proteína Precursora do Amiloide/metabolismo , DNA (Citosina-5-)-Metiltransferases/metabolismo , Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Transtornos Cognitivos/patologia , Modelos Animais de Doenças , Regulação para Baixo , Hipóxia/complicações , Memória/fisiologia , Camundongos , Camundongos Transgênicos
15.
Biol Trace Elem Res ; 169(2): 254-60, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26150404

RESUMO

Selenium is an important trace element for human health. Previous studies have raised concern that dietary selenium intake may change energy metabolism. AMP-activated protein kinase (AMPK) is a sensor of energy status that controls cellular energy homeostasis. We aimed to determine the effect of selenium on the phosphorylation of AMPK pathway between Se-deficient and normal Sprague-Dawley rats. Twenty-four weaning rats were fed either a Se-deficient diet (0.02 mg Se/kg) or a standard diet (0.18 mg Se/kg). After 109 days, total serum levels of non-esterified fatty acid and total amino acids were significantly higher and the serum insulin concentration was significantly lower in Se-deficient rats than in healthy controls. Selenium concentration and the activity of glutathione peroxidase (GPx) in myocardial tissue were significantly lower in Se-deficient rats. Importantly, mRNA levels of acetyl-CoA carboxylase beta (ACACB), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), and protein levels of p-AMPKα were increased in the Se-deficient group compared to normal controls (p < 0.05). In conclusion, our results suggest that selenium deficiency induces changes in metabolic and molecular parameters involved in energy metabolism in the AMPK pathway.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Metabolismo Energético , Selênio/deficiência , Proteínas Quinases Ativadas por AMP/genética , Aminoácidos/sangue , Animais , Ácidos Graxos não Esterificados/sangue , Feminino , Expressão Gênica/efeitos dos fármacos , Insulina/sangue , Masculino , Miocárdio/metabolismo , Fosforilação , Ratos Sprague-Dawley , Transdução de Sinais
16.
Blood Press ; 25(3): 169-76, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26634767

RESUMO

This systematic review and meta-analysis was conducted to assess the association between the level of atmospheric particulate matter (PM) and the increase in blood pressure (BP) for different exposure terms (≤ 7 vs > 7 days) and age groups (< 65 vs ≥ 65 years). Some databases were searched to investigate the association between increased atmospheric PM (diameter < 2.5 mm [PM2.5] or < 10 mm [PM10]) and BP (systolic blood pressure [SBP] and diastolic blood pressure [DBP]). Among a total of 719 identified articles, 68 were reviewed in depth, of which only 20 satisfied the inclusion criteria. A significant association was found between PM10 levels and higher BP. The ß values were 0.270mmHg (95% confidence interval [CI] 0.068-0.482) for SBP and 0.215mmHg (95% CI 0.058-0.372) for DBP. These ß values mean that, for every 10 mg/m(3) increase in PM10, SBP increased by 0.270mmHg and DBP by 0.215 mmHg. Subgroup analyses were conducted for different exposure terms and age groups. A positive association was seen between PM2.5 and SBP. The ß value of SBP was 0.495mmHg (95% CI 0.03-0.96) with every 10 mg/m(3) increase in PM2.5. There were no significant associations in both age groups and non-older groups. There was no significant association between PM2.5 and DBP, either in the overall effect or in the subgroup effects. In conclusion, significant associations were found between higher BP and higher PM10 levels, but the association between BP and levels of PM2.5 levels was unclear.


Assuntos
Poluentes Atmosféricos/efeitos adversos , Hipertensão/etiologia , Material Particulado/efeitos adversos , Poluentes Atmosféricos/análise , Pressão Sanguínea , Determinação da Pressão Arterial , Feminino , Humanos , Hipertensão/diagnóstico , Masculino , Material Particulado/análise
17.
Medicine (Baltimore) ; 94(46): e2116, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26579828

RESUMO

A number of cellular microRNAs (miRNAs) have been identified to have the ability to inhibit HIV-1 replication. In this study, we examined the impact of combination antiretroviral therapy (cART) on the expression of HIV-1 restriction miRNAs in peripheral blood mononuclear cells of HIV-1-infected men who have sex with men (MSM). Compared with male healthy donors, HIV-infected MSM had significantly lower levels of 9 HIV-1 restriction miRNAs. The treatment of HIV-1-infected MSM with cART, however, failed to restore the levels of these miRNAs in peripheral blood mononuclear cells. These observations suggest that the suppression of the cellular restriction miRNAs by HIV-1 may attribute to the virus latency during cART.


Assuntos
Fármacos Anti-HIV/farmacologia , Terapia Antirretroviral de Alta Atividade , Infecções por HIV/tratamento farmacológico , HIV-1 , Homossexualidade Masculina , Leucócitos Mononucleares/efeitos dos fármacos , MicroRNAs/sangue , Adulto , Fármacos Anti-HIV/uso terapêutico , Biomarcadores/sangue , Estudos de Casos e Controles , Infecções por HIV/sangue , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/fisiologia , Humanos , Imunidade Inata/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Masculino , MicroRNAs/imunologia , Pessoa de Meia-Idade , Resultado do Tratamento , Replicação Viral/genética
18.
J Alzheimers Dis ; 48(4): 1019-32, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26444766

RESUMO

Alzheimer's disease (AD) is the most common form of dementia with the accumulation of senile plaques and neurofibrillary tangles in the brain. Autophagy is the key machinery for mammalian cells to degrade damaged organelles and abnormal proteins. Enormous evidence suggests that the autophagy pathway is impaired in AD. Our previous study revealed that hypoxia induced autophagic activation leading to more amyloid-ß production in vitro. In this study, we investigated whether autophagic dysfunction is involved in the hypoxia mediated-pathogenesis of AD. We used APPSwe/PS1dE9 transgenic (Tg) mice and wildtype (Wt) littermates. We documented that chronic hypoxia caused more and larger senile plaques in the brains of Tg mice. In addition, chronic hypoxia induced activation of autophagy in the brains of both Wt and Tg mice, and compared to the normal autophagic flux in Wt mice, the autophagic flux was impaired in the brains of H-Tg mice with a large amount of autophagic vacuole accumulation and significant high level of P62. In an in vitro study, we showed that hypoxia-induced autophagy significantly elevated the level of hAß42. Furthermore, we found that chronic hypoxia activated AMPK and further inhibited the mTOR signaling pathway, while inhibition of AMPK attenuated autophagy induction through the enhancement of mTOR phosphorylation. In short, our study provides new insight into the mechanism underlying chronic hypoxia-mediated AD pathogenesis.


Assuntos
Adenilato Quinase/metabolismo , Doença de Alzheimer/enzimologia , Autofagia/fisiologia , Encéfalo/enzimologia , Hipóxia/enzimologia , Serina-Treonina Quinases TOR/metabolismo , Adenilato Quinase/antagonistas & inibidores , Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Linhagem Celular Tumoral , Doença Crônica , Modelos Animais de Doenças , Humanos , Hipóxia/patologia , Camundongos Transgênicos , Presenilina-1/genética , Presenilina-1/metabolismo , Distribuição Aleatória , Transdução de Sinais/efeitos dos fármacos
19.
CNS Neurosci Ther ; 21(8): 662-71, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26122704

RESUMO

AIMS: To evaluate the effectiveness of a new VMAT-2 inhibitor NBI-641449 in controlling hyperkinetic movements of Huntington disease (HD) and to investigate its possible therapeutic effects. METHODS: We applied three different doses of NBI-641449 (1, 10, 100 mg/kg/day) for 2 weeks in 4-month-old YAC128 mice and wild-type (WT) mice. Rotarod performance and locomotive activities were tested during the administration of the drug. The concentration of dopamine (DA) and its metabolites was quantified in the striatal tissues by high-performance liquid chromatography (HPLC). Neuron survival in striatum and huntingtin protein aggregates were assessed with immunostaining. Expression levels of endoplasmic reticulum (ER) stress proteins were detected by immunoblotting. RESULTS: Rotarod performance was significantly improved after treatment with low or middle dose of NBI-641449 in YAC128 mice. Open field test showed that NBI-641449 treatment could attenuate the increased horizontal activity (HACTV), total vertical movement, moving time, and moving distance in YAC128 mice. High dose of NBI-641449 might cause sedative effects in WT and YAC128 mice. HPLC showed that NBI-641449 caused a dose-dependent decrease of DA, 3,4-dihydroxyphenylacetic acid, and homovanillic acid levels in the striatum. NeuN and DARPP-32 immunostaining revealed that NBI-641449 had no significant effect on the neuron survival in the striatum. However, NBI-641449 treatment reduced the huntingtin protein aggregates in the cortex of YAC128 mice. In addition, the levels of ER stress proteins were increased in YAC128 mice, which can be suppressed by NBI-641449. CONCLUSIONS: These findings suggest that this new VMAT-2 inhibitor NBI-641449 may have therapeutic potential for the treatment of HD.


Assuntos
Doença de Huntington/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Proteínas Vesiculares de Transporte de Monoamina/antagonistas & inibidores , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Animais , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Corpo Estriado/patologia , Proteínas de Ligação a DNA , Modelos Animais de Doenças , Dopamina/metabolismo , Fosfoproteína 32 Regulada por cAMP e Dopamina/metabolismo , Relação Dose-Resposta a Droga , Feminino , Ácido Homovanílico/metabolismo , Doença de Huntington/patologia , Doença de Huntington/fisiopatologia , Camundongos Transgênicos , Atividade Motora/efeitos dos fármacos , Proteínas do Tecido Nervoso/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Proteínas Nucleares/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo , Proteínas Vesiculares de Transporte de Monoamina/metabolismo
20.
Oncol Lett ; 9(2): 777-779, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25624902

RESUMO

Granular cell tumors (GCTs) are soft tissue neoplasms that originate in the nervous system, which may arise anywhere in the body. However, GCTs are extremely uncommon in thyroid tumors, with a favorable prognosis. The diagnosis of GCTs is dependent on pathological and immunohistochemical analysis and at present, surgical resection is considered the only suitable treatment. Regular follow-up after surgery is an important way to monitor treatment outcome and recurrence. The present study describes a new pathological type of thyroid GCTs diagnosed by pathology and immunohistochemistry. A 14-year-old female was referred to the West China Hospital of Sichuan University (Chengdu, China), for thyroid incidentaloma. Laboratory examinations were within the normal range. Thyroid sonography demonstrated a solid hypoechoic mass in the right lobe of the thyroid. Fine needle aspiration cytology showed a suspicious malignant tumor and subsequently a total thyroidectomy was performed. Analysis of frozen sections, from obtained samples, did not facilitate a definite diagnosis. Finally, a thyroid benign granular tumor with atypical changes was diagnosed by postoperative pathology and immunohistochemistry. A 14-month post-operative follow-up showed that the patient experienced a stable recovery and had no signs of recurrence or metastasis. The case emphasizes that the diagnosis of thyroid granular cell tumors is predominantly based on postoperative morphology and immunophenotype. The clinical routine for the differential diagnosis may be due to: (i) neoplasms displaying a granular appearance mimicking granular cell tumors, or (ii) differential diagnosis in the pathological category of granular cell tumors. Further accumulation of such rare cases may be of clinical significance in aiding the diagnosis and treatment of GCTs.

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