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1.
Artigo em Inglês | MEDLINE | ID: mdl-32681471

RESUMO

Lung toxicity is the main cause of the death from methamphetamine (MA) abuse, but its mechanism has remained unclear. The purpose of our study was to investigate if MA can induce epithelial-to-mesenchymal transition (EMT) and if RUNX3 is involved in oxidative EMT in MA-induced chronic lung injury. The rats were divided into the control group and MA group. Extracted lungs were used for morphological measurements and Western blot. The alveolar epithelial cells were cultured or transfected and then treated with MA or/and N-acetyl cysteine (NAC) followed by flow cytometry, Western blot, and immunohistochemistry. Chronic exposure to MA resulted in the lower growth ratio of weight, increased right ventricular index, thickened alveolar walls, and reduced number of alveolar sacs. Long-term administration with MA caused oxidative stress and pulmonary EMT. NAC increased RUNX3 and alleviated EMT. However, after knockdown of RUNX3, reactive oxygen species (ROS) levels were significantly upregulated, indicating that RUNX3 was closely related to oxidative stress. Knockdown of RUNX3 aggravated MA-induced EMT by activating RUNX3-dependent TGF-ß signaling. Therefore, RUNX3 may be the key to oxidative EMT in methamphetamine-induced chronic lung injury.

2.
Biomed Pharmacother ; 129: 110355, 2020 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-32559622

RESUMO

Pulmonary arterial hypertension (PAH) is a progressive disease with limited effective therapies that can be lethal in the terminal stage. Since the universal use of traditional PAH-specific drugs affecting the nitric oxide pathway, endothelin pathway and prostacyclin pathway, major advances to treat this devastating condition have been made. For example, it has been recently demonstrated that PAH is associated with various dysfunctional genes and molecular signaling pathways, abnormal metabolism and endocrine systems, inflammation and immune dysfunction. Numerous descriptions of novel mechanisms in PAH have been presented, and some new drugs targeted to ease, reverse or cure PAH have been developed at the laboratory-level and/or tested in clinical trials. There are also some investigated drugs that have shown promising efficacy and safety in animal models but have failed in human beings. Inspiringly, immunotherapies also seem to be valuable therapies for PAH patients. In this review, we update the advances in investigational pharmacotherapy and immunotherapy of PAH. Hopefully this work can help promote more non-invasive treatment for PAH patients.

4.
Am J Surg ; 2020 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-32423601

RESUMO

BACKGROUND: Intraoperative imaging is used to address the challenges of parathyroidectomy, but no standard modality has been established. This study aimed to assess whether carbon nanoparticle injection is useful in localizing parathyroid glands (PGs) during parathyroidectomy. METHODS: Patients who underwent total parathyroidectomy (TPTX) between September 2015 and November 2018 were included. The operative duration and intact parathyroid hormones (iPTH) were analyzed. RESULTS: A total of 61 patients were included; of these, 32 with carbon nanoparticle injection (TPTX + CN group) and 29 without (TPTX group). The operative duration in the TPTX + CN group was significantly shorter (90.6 ± 21.2 vs 101.4 ± 19.4 min, P = 0.042), which is more apparent in those with normal sized PGs. For those with four enlarged PGs, iPTH levels on 1 day and 1 year postoperatively were significantly lower in the TPTX + CN group (P = 0.032 and P = 0.036, respectively). CONCLUSION: Carbon nanoparticles are useful in the identification normal sized PGs and complete resection of enlarged PGs.

5.
BMC Pulm Med ; 20(1): 150, 2020 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-32471403

RESUMO

BACKGROUND: Variants in the gene encoding bone morphogenetic protein receptor type II (BMPR2) are the most common genetic cause of pulmonary arterial hypertension (PAH), whereas biallelic variants in the eukaryotic translation initiation factor 2 alpha kinase 4 gene (EIF2AK4) are described in pulmonary veno-occlusive disease/pulmonary capillary haemangiomatosis (PVOD/PCH). Racial background may influence the clinical characteristics of patients diagnosed with PAH or PVOD/PCH. Here, we compared the clinical characteristics and survival between patients with BMPR2 variants or EIF2AK4 variants in a Chinese population. METHODS: Heterozygous variants in BMPR2 and homozygous or compound heterozygous biallelic EIF2AK4 variants predicted to be deleterious were identified as potentially causal. Clinical and radiological data were collected and analysed. The primary outcomes were death or lung transplantation. Hazard ratios (HRs) for death or transplantation associated with the presence of BMPR2 or biallelic EIF2AK4 variants were calculated using Cox proportional hazards models to analyse patient survival. RESULTS: Two hundred thirty-two patients with PAH were enrolled for genetic testing, and PAH patients with associated conditions were excluded from the study. Forty-five patients with BMPR2 variants and 11 patients with biallelic EIF2AK4 variants were recruited. PAH patients with BMPR2 or biallelic EIF2AK4 variants presented symptoms at the ages of 25.57 ± 10.17 years and 31.6 ± 9.38 years, respectively. The whole group of patients showed female dominance either with BMPR2 variants or biallelic EIF2AK4 variants. Specific radiological abnormalities are more prominent in EIF2AK4 variant carriers but can also be found in some patients with BMPR2 variants. Biallelic EIF2AK4 variant carriers had worse survival than BMPR2 variant carriers (p < 0.0001). CONCLUSIONS: Clinical pictures of PAH patients with BMPR2 and biallelic EIF2AK4 variants in the Chinese population differ from other populations by a younger age at diagnosis and demonstrate female dominance in the whole patient group. High-resolution chest CT can help assist in differentiating PAH with PVOD/PCH. BMPR2 variants and biallelic EIF2AK4 variants are associated with adverse outcomes, but the survival of patients with biallelic EIF2AK4 variants is dismal.

6.
Int J Biol Macromol ; 156: 669-680, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32320802

RESUMO

We reported a new approach for development of lignin-based carbon nanofibers (LCNFs) from two lignin-derived bio-oil (LB) obtained from catalytic depolymerization reaction combined with the organic solvent gradient separation process (including ethanol-soluble LB (EL) and tetrahydrofuran-soluble LB (TL)). This approach was particularly unique and translatable as it uses small molecule TL with high reactivity and low heterogeneity obtained via stalk lignin depolymerization to produce good morphologies and mechanical performances of LCNFs mixed with polyacrylonitrile under 85% high replacement rates. We first detailed characterization studies such as 2D-HSQC NMR, 31P NMR, FT-IR, GPC, TGA and DSC were conducted to understand the properties of EL and TL. Then, the goal of the influence of EL and TL on the LCNFs morphologies and mechanical properties were accomplished by using SEM, XRD, Raman and material testing machine. As compared with EL, the TL had excellent linear structure with relatively less total phenolic-OH groups and heterogeneity, which could improve lignin structure with better alignment along PAN, and thus increased the lignin replacement rates and mechanical performances of LCNFs.

7.
Hypertens Res ; 43(6): 511-517, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32042143

RESUMO

MicroRNAs are key molecules involved in the regulation of endothelial function. They are important risk factors and biomarkers for the development of hypertension related to endothelial dysfunction. However, the gene expression patterns associated with hypertension development related to endothelial dysfunction have not been fully elucidated. We conducted a case-control study of 65 patients with essential hypertension (EH) and 61 controls without EH. Plasma levels of miR-122 and its target protein high-affinity cationic amino acid transporter 1 (CAT-1) were measured by qRT-PCR and ELISA, respectively. miR-122 expression in plasma of patients with EH was significantly higher than that of the control group (p = 0.001), while CAT-1 expression in patients with EH was significantly lower than that in the control group (p = 0.018). miR-122 expression in plasma of young patients with EH was significantly higher than that in young people without EH (p = 0.0004), and CAT-1 expression in plasma of young patients with EH was also significantly lower than that of the control group (p = 0.002). CAT-1 expression in the plasma of young participants was significantly higher than that of individuals aged ≥40 years (p = 0.003), whereas miR-122 expression was significantly lower (p = 0.001). We showed that among patients with EH, the high expression of miR-122 contributed to endothelial dysfunction by suppressing the expression of the CAT-1 protein, which led to a decrease in CAT-1 expression in plasma. Therefore, high expression of miR-122 appears to be a risk factor for endothelial dysfunction in EH, especially in younger patients.

8.
Int J Cardiovasc Imaging ; 36(4): 577-584, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31853819

RESUMO

To explore the value of right ventricular (RV) parameters detected by three-dimensional echocardiography (3DE) in risk stratification in pulmonary arterial hypertension (PAH) patients. We prospectively recruited 130 pulmonary hypertension patients from National Center for Cardiovascular Diseases, Fuwai Hospital. Each participant was performed a transthoracic echocardiography and 3DE parameters were measured using an off-line software (4D RV Function 2.0, TomTec). Patients were classified into low, intermediate-high risk group based on 2015 ESC Guidelines. A total of 91 PAH patients (34 ± 12 years old, 25 males) were enrolled, among which, 42 were classified into low risk group, while 49 were intermediate-high risk group. Compared with low-risk patients, those with intermediate-high risk had significantly larger 3DE-RV volumes, worse ejection fraction (EF) and tricuspid annular plane systolic excursion, and decreased longitudinal strain (LS). Receive operating characteristic curves illustrated all the 3DE parameters were able to predict intermediate-high risk stratification, especially 3D-RVEF (area under curve, 0.82, 95% CI 0.73-0.91, P < 0.001). And 3D-RVEF < 26.39% had a 81.6% sensibility and 73.8% specificity to predict intermediate-high risk stratification. Univariate and multivariate Logistic regression analyses identified 3D-RV end-diastolic (OR 1.02, 95% CI 1.01-1.03, P = 0.002) and end-systolic (OR 1.03, 95% CI 1.01-1.04, P < 0.001) volumes, 3D-RVEF (OR 0.82, 95% CI 0.75-0.90, P < 0.001) and LS of free wall (OR 1.17, 95% CI 1.05-1.31, P = 0.005) as independent predictors of intermediate-high risk stratification. In conclusion, RV volumes, EF and free wall strain detected by 3DE were independent predictors of intermediate-high risk stratification in PAH patients, among which, RVEF showed the best predictive capacity.


Assuntos
Ecocardiografia Tridimensional , Hipertensão Arterial Pulmonar/diagnóstico por imagem , Volume Sistólico , Disfunção Ventricular Direita/diagnóstico por imagem , Função Ventricular Direita , Adulto , Pressão Arterial , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Hipertensão Arterial Pulmonar/complicações , Hipertensão Arterial Pulmonar/fisiopatologia , Artéria Pulmonar/diagnóstico por imagem , Artéria Pulmonar/fisiopatologia , Reprodutibilidade dos Testes , Medição de Risco , Fatores de Risco , Disfunção Ventricular Direita/etiologia , Disfunção Ventricular Direita/fisiopatologia , Adulto Jovem
9.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 50(6): 792-797, 2019 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-31880107

RESUMO

OBJECTIVE: The aim of this study is to explore the diagnostic and therapeutic accuracy of pathophysiology and clinic oriented critical care ultrasound exam (POCCUE) protocol in acute respiratory and circulatory compromise of critically ill patients. METHODS: Prospectively included patients with acute respiratory and circulatory compromise from ICU of West China Hospital of Sichuan University from March to April 2018. The POCCUE protocol designed according to the pathophysiological changes of acute respiratory and circulatory disorders includes: the first part is the acquiring an ultrasound section and measuring corresponding indicators including pulmonary and echocardiographic indicators; the second part is a comprehensive analysis according to the former examination which evaluates the pathophysiological changes of acute respiratory and circulatory disorders, and then establish the initial etiology diagnosis and start treatment. The clinical value of the POCCUE protocol, including the accuracy of diagnosis, and the differences in treatment was verified by comparing the clinical outcome with the traditional treatment group. RESULTS: A total of 82 subjects were used for statistics. Compare with the traditional group, POCCUE can notably increase the diagnostic and therapeutic accuracy of clinic and pathophysiology (diagnostic accuracy: 93.90% vs. 68.29%, P < 0.01; therapeutic accuracy: 93.90% vs. 62.20%, P < 0.01). CONCLUSION: The POCCUE has a higher accuracy of diagnosis and treatment for patients with acute respiratory and circulatory compromise.


Assuntos
Cuidados Críticos , Estado Terminal , China , Humanos , Unidades de Terapia Intensiva , Pulmão , Ultrassonografia
10.
Pulm Circ ; 9(4): 2045894019883609, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31692686

RESUMO

Idiopathic pulmonary arterial hypertension is a progressive disease with high mortality with an increasing burden of right ventricular. Right ventricular dyssynchrony was observed in idiopathic pulmonary arterial hypertension, but the association with mortality is unclear. This study aimed to investigate the impact of right ventricular dyssynchrony on the survival of idiopathic pulmonary arterial hypertension. A total of 116 patients with idiopathic pulmonary arterial hypertension were enrolled in this study. All these patients underwent comprehensive clinical evaluation. Right ventricular dyssynchrony was assessed by two-dimensional speckle-tracking echocardiography. The time to peak strain (Tpeak) of right ventricular segments were obtained. Right ventricular dyssynchrony was quantified by the standard deviation of the heart rate-corrected Tpeak of right ventricular four segments. All patients were followed up and the primary endpoint was all cause of death. Results found patients with significant right ventricular dyssynchrony present with advanced World Health Organization functional class, worse hemodynamic status and right ventricular function. Right ventricular dyssynchrony was an independent predictive factor for the survival of idiopathic pulmonary arterial hypertension. Kaplan-Meier survival curves showed patients with right ventricular dyssynchrony had worse prognosis. In conclusion, right ventricular dyssynchrony analyzed by speckle-tracking echocardiography provided added value to hemodynamic and echocardiographic parameters in evaluating the survival of patients with idiopathic pulmonary arterial hypertension.

12.
Chin Med J (Engl) ; 132(13): 1591-1598, 2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-31205077

RESUMO

BACKGROUND: Natural anti-sense transcripts (NATs), which are transcribed from the complementary DNA strand of annotated genes, exert regulatory function of gene expression. Increasing studies recognized anti-sense transcription widespread throughout human cytomegalovirus (HCMV) genome, whereas the anti-sense transcription of RNA1.2 gene locus has never been investigated. In this study, the transcription of the RNA1.2 anti-sense strand was investigated in clinically isolated HCMV strain. METHODS: Strand-specific high-through RNA-sequencing (RNA-seq) was performed to find possible anti-sense transcripts (ASTs). For analyzing and visualization of RNA-seq data sets, Integrative Genomics Viewer software was applied. To confirm these possibilities, Northern blotting and rapid amplification of cDNA ends (RACE) were used. RESULTS: Transcription of the opposite strand of RNA1.2 gene locus was detected by RNA-sequencing using RNAs extracted from human embryonic lung fibroblasts infected with HCMV clinical isolate HAN. At least three HCMV NATs, named RNA1.2 AST 1, RNA1.2 AST2, and RNA1.2 AST3, were characterized by Northern blotting and RACE analyses. These RNA1.2 ASTs orientated from the complementary strand of RNA1.2 locus during the late phase of HCMV infection. The 5'- and 3'-termini of these transcripts were located within the opposite sequence of the predicted RNA1.2 gene. CONCLUSION: A cluster of novel NATs was transcribed from the opposite sequence of the HCMV RNA1.2 gene region.


Assuntos
Citomegalovirus/genética , RNA Antissenso/genética , Northern Blotting , Células Cultivadas , Genoma Viral/genética , Humanos , Software
13.
ChemistryOpen ; 8(5): 643-649, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31143561

RESUMO

Herein we studied the chemical structure of different types of lignin samples and the potential to prepare phenolic monomers was illustrated by phosphotungstic acid catalysts. Different types of H/G/S lignin components had different structures. The lignin extracted from poplar had the highest molecular weight and ß-O-4 aryl ether contents, followed by pine and straw lignin samples. After depolymerization by PTA catalyst, the yields of phenolic monomers detected was 8.06 wt % (poplar), 5.44 wt % (pine) and 4.52 wt % (straw), respectively. Further, the ratios of H/G/S in the phenol monomers were also different, indicating that the S, G and H types structural units were continuously transformed with each other during the reaction. In our study, the change in the types of lignin samples resulted into an improvement of the distribution of phenolic products, and also the selectivity of phenolic monomers significantly.

14.
Eur J Drug Metab Pharmacokinet ; 44(6): 771-776, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31087280

RESUMO

BACKGROUND AND OBJECTIVES: Effective management of immunosuppressants is extemely important to improve prognosis of heart transplant recipients. We aim to investigate the effects of cytochrome P450 (CYP) 3A5 (rs776746) single nucleotide polymorphisms (SNPs) on serum tacrolimus concentrations/doses (C/Ds, ng/mL per mg/kg) and long-term prognosis in Chinese heart transplant recipients. METHODS: We detected the CYP3A5 SNPs of 203 consecutive Chinese heart transplant recipients between August 2005 and July 2012, and 55 of them who received tacrolimus-based immunosuppressive therapy were enrolled in this study. The tacrolimus C/Ds at 1, 3, 6, 12, 24 and 36 months after transplantation were routinely calculated. X-ray-guided endomyocardial biopsies (EMBs) were performed at 1, 3 and 6 months after heart transplantion to evaluate acute rejection degrees. All participants were then followed up annually until May 2018. The designed primary endpoint was all-cause mortality. RESULTS: In 55 heart transplant recipients (43 males and 12 females), CYP3A5 non-expressors (CYP3A5*3/*3, n = 40) had significantly higher tacrolimus C/Ds than expressors (CYP3A5*1/*3, n = 15) at all time points (P < 0.001). Chi-squared test showed no significant differences in EMB-proven acute rejections between the two groups within 6 months after heart transplantion. The median follow-up period was 94.7 months, and eight patients died. Kaplan-Meier analysis showed CYP3A5 expressors tend to have higher mortality than non-expressors (20% vs 12.5%, log-rank: P = 0.314). CONCLUSIONS: CYP3A5 SNPs affect tacrolimus pharmacokinetics in Chinese heart transplant recipients, and non-expressors have higher tacrolimus C/Ds. In addition, expressors tend to have a worse long-term prognosis than non-expressors.


Assuntos
Citocromo P-450 CYP3A/genética , Imunossupressores/administração & dosagem , Imunossupressores/sangue , Tacrolimo/administração & dosagem , Tacrolimo/sangue , Adulto , Grupo com Ancestrais do Continente Asiático , Feminino , Genótipo , Transplante de Coração , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Prognóstico
15.
Cancer Chemother Pharmacol ; 84(1): 73-81, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31041509

RESUMO

PURPOSE: This phase II, multicenter, single arm clinical study was first performed to evaluate the therapeutic efficacy and safety of the regimen-a combination of lobaplatin (LBP) and etoposide (VP-16)-and investigate the pharmacokinetics of LBP in Chinese men older than 65 years with extensive-stage small cell lung cancer (SCLC). METHODS: Patients older than 65 were treated with the combination of LBP and VP-16 for 4-6 cycles through intravenous drip. The initial dose of VP-16 was 100 mg/m2/day for d1-d3 in each 21-day cycle, while LBP was administrated for d1 in each cycle based on creatinine clearance (Ccr), 20 mg/m2 for Ccr < 60 mL/min; 25 mg/m2 for 60 ≤ Ccr < 80 mL/min and 30 mg/m2 for Ccr ≥ 80 mL/min. Efficacy, safety and pharmacokinetics were evaluated to confirm the therapeutic effect. RESULTS: Thirteen elderly patients were enrolled and three patients were discontinued. The median progress-free survival was 129 days and the median overall survival was 238 days, which caused a significantly prolonged survival rate of 38.5% and a higher disease control rate of 80%. Most frequent adverse events were mild to moderate containing leukopenia, neutropenia, anemia, nausea and anorexia. Pharmacokinetic analysis revealed that there is no significant difference between LP-D1 and LP-D2 at the same dosage level. With the dosage increasing, the elimination clearance showed a slowing tendency, especially for 30 mg/m2 group. CONCLUSIONS: LBP (20, 25, 30 mg/m2) in combination with VP-16 (100 mg/m2) could inhibit the elderly SCLC disease process, prolong their survival time and reduce adverse reactions via preliminary assessment and provide guidance for further investigation.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Grupo com Ancestrais do Continente Asiático , Ciclobutanos/administração & dosagem , Relação Dose-Resposta a Droga , Etoposídeo/administração & dosagem , Humanos , Masculino , Compostos Organoplatínicos/administração & dosagem , Intervalo Livre de Progressão , Taxa de Sobrevida
16.
Int J Cardiovasc Imaging ; 35(8): 1499-1508, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31037475

RESUMO

Resting two-dimensional speckle tracking echocardiography (2D-STE) identified right ventricular (RV) systolic function were reported to predict exercise capacity in pulmonary hypertension (PH) patients, but little attention had been payed to 2D-STE detected RV diastolic function. Therefore, we aim to elucidate and compare the relations between 2D-STE identified RV diastolic/systolic functions and peak oxygen consumption (PVO2) determined by cardiopulmonary exercise testing (CPET) in pre-capillary PH. 2D-STE was performed in 66 pre-capillary PH patients and 28 healthy controls. Linear correlation and multivariate regression analyses were performed to evaluate and compare the relations between RV 2D-STE parameters and PVO2. Receiver operating characteristic curves were used to compare the predictive value of 2D-STE parameters in predicting the cut-off-PVO2 < 11 ml/min/kg. There were significant differences of all the 2D-STE parameters between PH patients and healthy controls. In patients, RV-peak global longitudinal strain (GLS, rs = - 0.498, P < 0.001), RV- peak systolic strain rate (GSRs, rs = - 0.537, P < 0.001) and RV- peak early diastolic strain rate (GSRe, rs = 0.527, P < 0.001) significantly correlated with PVO2, but no significant correlation was observed between RV- peak late diastolic strain rate (GSRa, rs = 0.208, P = 0.093) and PVO2. The first multivariate regression analysis of clinical data without echocardiographic parameters identified WHO functional class, NT-proBNP and BMI as independent predictors of PVO2 (Model-1, adjusted r2 = 0.421, P < 0.001); Then we added conventional echocardiographic parameters and 2D-STE parameters to the clinical data, identified S,(Model-2,adjusted r2 = 0.502, P < 0.001), RV-GLS (Model-3, adjusted r2 = 0.491, P < 0.001), RV-GSRe (Model-4, adjusted r2 = 0.500, P < 0.001) and RV-GSRs (Model-5, adjusted r2 = 0.519, P < 0.001) as independent predictors of PVO2, respectively. The predictive power was increased, and Model-5 including RV-GSRs showed the highest predictive capability. ROC curves found RV-GSRs expressed the strongest predictive value (AUC = 0.88, P < 0.001), and RV-GSRs > - 0.65/s had a 88.2% sensibility and 82.2% specificity to predict PVO2 < 11 ml/min/kg. 2D-STE assessed RV function improves the prediction of exercise capacity represented by PVO2 in pre-capillary PH.


Assuntos
Ecocardiografia Doppler/métodos , Tolerância ao Exercício , Hipertensão Pulmonar/diagnóstico por imagem , Função Ventricular Direita , Adulto , Estudos de Casos e Controles , Estudos Transversais , Teste de Esforço , Feminino , Humanos , Hipertensão Pulmonar/fisiopatologia , Masculino , Pessoa de Meia-Idade , Consumo de Oxigênio , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Adulto Jovem
17.
Respir Res ; 19(1): 87, 2018 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-29743074

RESUMO

BACKGROUND: Pulmonary arterial hypertension (PAH) is a progressive and fatal disorder associated with high pulmonary artery pressure. Genetic testing enables early diagnosis and offers an opportunity for family screening. To identify genetic mutations and help make a precise diagnosis, we performed genetic testing in 191 probands with PAH and tried to analyze the genotype-phenotype correlation. METHODS: Initially, PAH samples (n = 119) were submitted to BMPR2 screening using Sanger sequencing. Later, we developed a PAH panel test to identify causal mutations in 13 genes related to PAH and tried to call BMPR2 copy number variations (CNVs) with the panel data. Multiplex ligation-dependent probe amplification (MLPA) was used to search for CNVs in BMPR2, ACVRL1 and ENG. Notably, EIF2AK4 gene was also involved in the panel, which allowed to distinguish pulmonary veno-occlusive disease (PVOD)/pulmonary capillary hemangiomatosis (PCH) patients from idiopathic PAH (IPAH). Characteristics of patients were compared using t test for continuous variables. RESULTS: Pathogenic BMPR2 mutations were detected most frequently in 32 (17.9%) IPAH and 5 (41.7%) heritable PAH (HPAH) patients by sequencing, and 12 BMPR2 CNVs called from the panel data were all successfully confirmed by MLPA analysis. In addition, homozygous or compound heterozygous EIF2AK4 mutations were identified in 6 patients, who should be corrected to a diagnosis of PVOD/PCH. Genotype-phenotype correlation analysis revealed that PAH patients with BMPR2 mutations were younger at diagnosis (27.2y vs. 31.6y, p = 0.0003) and exhibited more severe pulmonary hemodynamic impairment and a worse cardiac index compared with those without BMPR2 mutations. CONCLUSIONS: The panel assay represented a highly valuable tool in PAH genetic testing, not only for the detection of small sequence alterations, but also for an indication of BMPR2 CNVs, which had implications for the specific samples to perform further MLPA assay. Analyses of PAH causal genes have a great help to clinical diagnosis and deep implications in disease treatment.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/genética , Testes Genéticos/métodos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/genética , Mutação/genética , Adolescente , Adulto , Estudos de Coortes , Feminino , Humanos , Hipertensão Pulmonar/epidemiologia , Masculino , Adulto Jovem
18.
Mol Metab ; 12: 25-38, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29661693

RESUMO

OBJECTIVE: The inappropriate release of free fatty acids from obese adipose tissue stores has detrimental effects on metabolism, but key molecular mechanisms controlling FFA release from adipocytes remain undefined. Although obesity promotes systemic inflammation, we find activation of the inflammation-associated Mitogen Activated Protein kinase ERK occurs specifically in adipose tissues of obese mice, and provide evidence that adipocyte ERK activation may explain exaggerated adipose tissue lipolysis observed in obesity. METHODS AND RESULTS: We provide genetic and pharmacological evidence that inhibition of the MEK/ERK pathway in human adipose tissue, mice, and flies all effectively limit adipocyte lipolysis. In complementary findings, we show that genetic and obesity-mediated activation of ERK enhances lipolysis, whereas adipose tissue specific knock-out of ERK2, the exclusive ERK1/2 protein in adipocytes, dramatically impairs lipolysis in explanted mouse adipose tissue. In addition, acute inhibition of MEK/ERK signaling also decreases lipolysis in adipose tissue and improves insulin sensitivity in obese mice. Mice with decreased rates of adipose tissue lipolysis in vivo caused by either MEK or ATGL pharmacological inhibition were unable to liberate sufficient White Adipose Tissue (WAT) energy stores to fuel thermogenesis from brown fat during a cold temperature challenge. To identify a molecular mechanism controlling these actions, we performed unbiased phosphoproteomic analysis of obese adipose tissue at different time points following acute pharmacological MEK/ERK inhibition. MEK/ERK inhibition decreased levels of adrenergic signaling and caused de-phosphorylation of the ß3-adrenergic receptor (ß3AR) on serine 247. To define the functional implications of this phosphorylation, we showed that CRISPR/Cas9 engineered cells expressing wild type ß3AR exhibited ß3AR phosphorylation by ERK2 and enhanced lipolysis, but this was not seen when serine 247 of ß3AR was mutated to alanine. CONCLUSION: Taken together, these data suggest that ERK activation in adipocytes and subsequent phosphorylation of the ß3AR on S247 are critical regulatory steps in the enhanced adipocyte lipolysis of obesity.


Assuntos
Adipócitos Brancos/metabolismo , Lipólise , Sistema de Sinalização das MAP Quinases , Obesidade/metabolismo , Receptores Adrenérgicos beta 3/metabolismo , Células 3T3 , Animais , Drosophila melanogaster , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Fosforilação , Receptores Adrenérgicos beta 3/química , Serina/metabolismo
19.
Iran J Basic Med Sci ; 20(6): 715-721, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28868127

RESUMO

OBJECTIVES: It has been widely reported that Mori cortex extract (MCE) is used for the treatment of diabetes mellitus in traditional medicine. The present study was designed to investigate its mechanism of action in the treatment of diabetic nephropathy (DN). We assessed whether MCE preventive treatment ameliorates kidney damage in high-fat diet and streptozotocin (STZ)-induced type 2 diabetic rats. MATERIALS AND METHODS: Rats were fed a high-fat diet and injected with STZ. MCE was given to rats daily at 10 g/kg. Fasting blood glucose (FBG) and postprandial plasma glucose were measured. Blood and urine biochemical parameters, renal tissue morphology, and inflammation were investigated. RESULTS: Prevention with MCE significantly decreased FBG and homoeostasis model assessment (HOMA) of IR (HOMA-IR) levels and increased insulin levels in diabetic rats. MCE prevention significantly decreased levels of KW/BW, BUN, Cr, and 24 hr urinary protein. MCE inhibited glomerular basement membrane thickening, tubular epithelial cell hypertrophy, and glomerular capillary dilation. MCE also prevented the disappearance of bowman's space and renal tubular lumen and decreased collagen deposition in rat kidney. Moreover, MCE reduced the levels of inflammatory factors (MCP-1 and TNF-α) and fibrosis factors (collagen IV and fibronectin). CONCLUSION: MCE prevents DN through inhibition of inflammation and fibrosis in a rat model. It might provide a safe and effective way to prevent DN.

20.
Biochem Biophys Res Commun ; 482(4): 1114-1121, 2017 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-27914810

RESUMO

The root-knot nematode (RKN) Meloidogyne incognita reproduces on the roots of tobacco (Nicotiana tabacum), damaging crops, reducing crop yield, and causing economic losses annually. The development of resistant genotypes is an alternative strategy to effectively control these losses. However, the molecular mechanism responsible for host pathogenesis and defense responses in tobacco specifically against RKNs remain poorly understood. Here, root transcriptome analysis of resistant (Yuyan12) and susceptible (Changbohuang) tobacco varieties infected with RKNs was performed. Moreover, 2623 and 545 differentially expressed genes (DEGs) in RKN-infected roots were observed in Yuyan12 and Changbohuang, respectively, compared to those in non-infected roots, including 289 DEGs commonly expressed in the two genotypes. Among these DEGs, genes encoding cell wall modifying proteins, auxin-related proteins, the ROS scavenging system, and transcription factors involved in various biological and physiochemical processes were significantly expressed in both the resistant and susceptible genotypes. This work is thus the first report on the relationships in the RKN-tobacco interaction using transcriptome analysis, and the results provide important information on the mechanism of RKN resistance in tobacco.


Assuntos
Tabaco/metabolismo , Tabaco/parasitologia , Transcriptoma , Tylenchoidea/patogenicidade , Animais , Biomassa , Mapeamento Cromossômico , Análise por Conglomerados , Biologia Computacional , Produtos Agrícolas/metabolismo , Produtos Agrícolas/parasitologia , Resistência à Doença , Perfilação da Expressão Gênica , Regulação da Expressão Gênica de Plantas , Genótipo , Doenças das Plantas/parasitologia , Raízes de Plantas/metabolismo , Raízes de Plantas/parasitologia , Espécies Reativas de Oxigênio/metabolismo , Análise de Sequência de RNA
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