共查询到20条相似文献,搜索用时 31 毫秒
1.
Kui Zhai Fabien Hubert Valérie Nicolas Guangju Ji Rodolphe Fischmeister Véronique Leblais 《PloS one》2012,7(10)
Background
We investigated the role of cyclic nucleotide phosphodiesterases (PDEs) in the spatiotemporal control of intracellular cAMP concentrations in rat aortic smooth muscle cells (RASMCs).Methodology/Principal Findings
The rank order of PDE families contributing to global cAMP-PDE activity was PDE4> PDE3 = PDE1. PDE7 mRNA expression but not activity was confirmed. The Fluorescence Resonance Energy Transfer (FRET)-based cAMP sensor, Epac1-camps, was used to monitor the time course of cytosolic cAMP changes. A pulse application of the β-adrenoceptor (β-AR) agonist isoproterenol (Iso) induced a transient FRET signal. Both β1- and β2-AR antagonists decreased the signal amplitude without affecting its kinetics. The non-selective PDE inhibitor (IBMX) dramatically increased the amplitude and delayed the recovery phase of Iso response, in agreement with a role of PDEs in degrading cAMP produced by Iso. Whereas PDE1, PDE3 and PDE7 blockades [with MIMX, cilostamide (Cil) and BRL 50481 (BRL), respectively] had no or minor effect on Iso response, PDE4 inhibition [with Ro-20-1724 (Ro)] strongly increased its amplitude and delayed its recovery. When Ro was applied concomitantly with MIMX or Cil (but not with BRL), the Iso response was drastically further prolonged. PDE4 inhibition similarly prolonged both β1- and β2-AR-mediated responses. When a membrane-targeted FRET sensor was used, PDE3 and PDE4 acted in a synergistic manner to hydrolyze the submembrane cAMP produced either at baseline or after β-AR stimulation.Conclusion/Significance
Our study underlines the importance of cAMP-PDEs in the dynamic control of intracellular cAMP signals in RASMCs, and demonstrates the prominent role of PDE4 in limiting β-AR responses. PDE4 inhibition unmasks an effect of PDE1 and PDE3 on cytosolic cAMP hydrolyzis, and acts synergistically with PDE3 inhibition at the submembrane compartment. This suggests that mixed PDE4/PDE1 or PDE4/PDE3 inhibitors would be attractive to potentiate cAMP-related functions in vascular cells. 相似文献2.
Kyriakos Ioannou Vianda S. Stel Evangelia Dounousi Kitty J. Jager Aikaterini Papagianni Konstantinos Pappas Kostas C. Siamopoulos Carmine Zoccali Dimitrios Tsakiris 《PloS one》2015,10(9)
Introduction
Within this longitudinal study we investigated the association of inflammation markers C-reactive protein (CRP), interleukin-6 (IL-6) and tumor necrosis factor-α (TNFα) and endothelial dysfunction markers intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) with left ventricular mass indexed for height2·71 (LVMI) in hypertensive predialysis CKD patients.Material and Methods
From 2004 to 2005, 182 incident consecutive adult patients from the outpatient CKD clinics of two hospitals in Greece with CKD and hypertension or using antihypertensive medication, were included. Of these, 107 patients underwent CRP (mg/l) and LVMI (g/height2·71) measurements annually for three years.Results
In the longitudinal analyses, using linear mixed modeling, a higher IL-6 (ß = 1.9 (95%ci:0.38;3.5), inflammation score based on CRP, IL-6 and TNF-α (ß = 5.0 (95%ci:0.72; 9.4) and VCAM-1 (ß = 0.01 (95%ci:0.005;0.02) were associated with higher LVMI. These models were adjusted for age, gender and primary renal disease, and for confounders that on top changed the beta with ≥10%, i.e. diuretic use (for IL-6 and inflammation score).Conclusion
The results suggest that in predialysis CKD patients, inflammation as well as endothelial dysfunction may play an important role towards the increase in LVMI. 相似文献3.
Melanie Werner Sabrina Driftmann Kathrin Kleinehr Gernot M. Kaiser Zotlan Mathé Juergen-Walter Treckmann Andreas Paul Kathrin Skibbe Joerg Timm Ali Canbay Guido Gerken Joerg F. Schlaak Ruth Broering 《PloS one》2015,10(9)
Background & Aims
Liver cells are key players in innate immunity. Thus, studying primary isolated liver cells is necessary for determining their role in liver physiology and pathophysiology. In particular, the quantity and quality of isolated cells are crucial to their function. Our aim was to isolate a large quantity of high-quality human parenchymal and non-parenchymal cells from a single liver specimen.Methods
Hepatocytes, Kupffer cells, liver sinusoidal endothelial cells, and stellate cells were isolated from liver tissues by collagenase perfusion in combination with low-speed centrifugation, density gradient centrifugation, and magnetic-activated cell sorting. The purity and functionality of cultured cell populations were controlled by determining their morphology, discriminative cell marker expression, and functional activity.Results
Cell preparation yielded the following cell counts per gram of liver tissue: 2.0±0.4×107 hepatocytes, 1.8±0.5×106 Kupffer cells, 4.3±1.9×105 liver sinusoidal endothelial cells, and 3.2±0.5×105 stellate cells. Hepatocytes were identified by albumin (95.5±1.7%) and exhibited time-dependent activity of cytochrome P450 enzymes. Kupffer cells expressed CD68 (94.5±1.2%) and exhibited phagocytic activity, as determined with 1μm latex beads. Endothelial cells were CD146+ (97.8±1.1%) and exhibited efficient uptake of acetylated low-density lipoprotein. Hepatic stellate cells were identified by the expression of α-smooth muscle actin (97.1±1.5%). These cells further exhibited retinol (vitamin A)-mediated autofluorescence.Conclusions
Our isolation procedure for primary parenchymal and non-parenchymal liver cells resulted in cell populations of high purity and quality, with retained physiological functionality in vitro. Thus, this system may provide a valuable tool for determining liver function and disease. 相似文献4.
Purpose
Absolute concentrations of high-energy phosphorus (31P) metabolites in liver provide more important insight into physiologic status of liver disease compared to resonance integral ratios. A simple method for measuring absolute concentrations of 31P metabolites in human liver is described. The approach uses surface spoiling inhomogeneous magnetic field gradient to select signal from liver tissue. The technique avoids issues caused by respiratory motion, chemical shift dispersion associated with linear magnetic field gradients, and increased tissue heat deposition due to radiofrequency absorption, especially at high field strength.Methods
A method to localize signal from liver was demonstrated using superficial and highly non-uniform magnetic field gradients, which eliminate signal(s) from surface tissue(s) located between the liver and RF coil. A double standard method was implemented to determine absolute 31P metabolite concentrations in vivo. 8 healthy individuals were examined in a 3 T MR scanner.Results
Concentrations of metabolites measured in eight healthy individuals are: γ-adenosine triphosphate (ATP) = 2.44 ± 0.21 (mean ± sd) mmol/l of wet tissue volume, α-ATP = 3.2 ± 0.63 mmol/l, β-ATP = 2.98 ± 0.45 mmol/l, inorganic phosphates (Pi) = 1.87 ± 0.25 mmol/l, phosphodiesters (PDE) = 10.62 ± 2.20 mmol/l and phosphomonoesters (PME) = 2.12 ± 0.51 mmol/l. All are in good agreement with literature values.Conclusions
The technique offers robust and fast means to localize signal from liver tissue, allows absolute metabolite concentration determination, and avoids problems associated with constant field gradient (linear field variation) localization methods. 相似文献5.
Christian Agebratt Edvin Str?m Thobias Romu Olof Dahlqvist-Leinhard Magnus Borga Per Leandersson Fredrik H. Nystrom 《PloS one》2016,11(1)
Background
Fruit has since long been advocated as a healthy source of many nutrients, however, the high content of sugars in fruit might be a concern.Objectives
To study effects of an increased fruit intake compared with similar amount of extra calories from nuts in humans.Methods
Thirty healthy non-obese participants were randomized to either supplement the diet with fruits or nuts, each at +7 kcal/kg bodyweight/day for two months. Major endpoints were change of hepatic fat content (HFC, by magnetic resonance imaging, MRI), basal metabolic rate (BMR, with indirect calorimetry) and cardiovascular risk markers.Results
Weight gain was numerically similar in both groups although only statistically significant in the group randomized to nuts (fruit: from 22.15±1.61 kg/m2 to 22.30±1.7 kg/m2, p = 0.24 nuts: from 22.54±2.26 kg/m2 to 22.73±2.28 kg/m2, p = 0.045). On the other hand BMR increased in the nut group only (p = 0.028). Only the nut group reported a net increase of calories (from 2519±721 kcal/day to 2763±595 kcal/day, p = 0.035) according to 3-day food registrations. Despite an almost three-fold reported increased fructose-intake in the fruit group (from 9.1±6.0 gram/day to 25.6±9.6 gram/day, p<0.0001, nuts: from 12.4±5.7 gram/day to 6.5±5.3 gram/day, p = 0.007) there was no change of HFC. The numerical increase in fasting insulin was statistical significant only in the fruit group (from 7.73±3.1 pmol/l to 8.81±2.9 pmol/l, p = 0.018, nuts: from 7.29±2.9 pmol/l to 8.62±3.0 pmol/l, p = 0.14). Levels of vitamin C increased in both groups while α-tocopherol/cholesterol-ratio increased only in the fruit group.Conclusions
Although BMR increased in the nut-group only this was not linked with differences in weight gain between groups which potentially could be explained by the lack of reported net caloric increase in the fruit group. In healthy non-obese individuals an increased fruit intake seems safe from cardiovascular risk perspective, including measurement of HFC by MRI.Trial Registration
ClinicalTrials.gov NCT02227511相似文献6.
Marcello Fonseca Salgado Filho Marselha Barral Louis Barrucand Ismar Lima Cavalcanti Nubia Ver?osa 《PloS one》2015,10(12)
Background
The objective was to evaluate the effect of epinephrine and levosimendan on the left ventricle myocardial performance index in patients undergoing on-pump coronary artery by-pass grafting (CABG).Methods
In a double-blind, randomized clinical trial, 81 patients (age: 45–65 years) of both genders were randomly divided to receive either epinephrine at a dosage of 0.06 mcg.kg1.min-1 (epinephrine group, 39 patients) or levosimendan at 0.2 mcg.kg1.min-1 (levosimendan group, 42 patients) during the rewarming of cardiopulmonary by-pass (CPB). Hemodynamic data were collected 30 minutes after tracheal intubation, before chest open (pre-CPB) and 10 minutes after termination of protamine (post-CPB). As the primary outcome, we evaluated the left ventricle myocardial performance index by the Doppler echocardiography. The myocardial performance index is the sum of the isovolumetric contraction time and the isovolumetric relaxation time, divided by the ejection time. Secondary outcomes were systolic and diastolic evaluations of the left ventricle and postoperative troponin I and MB-CK levels.Results
Of the 81 patients allocated to the research, we excluded 2 patients in the epinephrine group and 6 patients in the levosimendan group because they didn’t wean from CPB in the first attempt. There was no statistical difference between the groups in terms of patient characteristics, risk factors, or CPB time. The epinephrine group had a lower left ventricle myocardial performance index (p = 0.0013), higher cardiac index (p = 0.03), lower systemic vascular resistance index (p = 0.01), and higher heart rate (p = 0.04) than the levosimendan group at the post-CPB period. There were no differences between the groups in diastolic dysfunction. The epinephrine group showed higher incidence of weaning from CPB in the first attempt (95% vs 85%, p = 0.0001) when compared to the levosimendan group and the norepinephrine requirement was higher in the levosimenandan group than epinephrine group (16% vs. 47%; p = 0.005) in post-CPB period. Twenty-four hours after surgery, the plasma levels of troponin I (epinephrine group: 4.5 ± 5.7 vs. levosimendan group: 2.5 ± 3.2 g/dl; p = 0.09) and MB-CK (epinephrine group: 50.7 ± 31 vs. levosimendan group: 37 ± 17.6 g/dl; p = 0.08) were not significantly different between the two groups.Conclusion
When compared to levosimendan, patients treated with epinephrine had a lower left ventricle myocardial performance index in the immediate post-CPB period, encouraging an efficient weaning from CPB in patients undergoing on-pump CABG.Trial Registration
ClinicalTrials.gov NCT01616069相似文献7.
Intraocular Pressure Changes during Accommodation in Progressing Myopes,Stable Myopes and Emmetropes
Purpose
To investigate the changes of intraocular pressure (IOP) induced by 3-diopter (3 D) accommodation in progressing myopes, stable myopes and emmetropes.Design
Cross-sectional study.Participants
318 subjects including 270 myopes and 48 emmetropes.Methods
195 progressing myopes, 75 stable myopes and 48 emmetropes participated in this study. All subjects had their IOP measured using iCare rebound tonometer while accommodative stimuli of 0 D and 3 D were presented.Main Outcome Measures
IOP values without accommodation and with 3 D accommodation were measured in all subjects. Baseline IOPs and IOP changes were compared within and between groups.Results
There was no significant difference in IOPs between progressing myopes, stable myopes and emmetropes when no accommodation was induced (17.47±3.46, 16.62±2.98 and 16.80±3.62 respectively, p>0.05). IOP experienced an insignificantly slight decrease after 3 D accommodation in three groups (mean change -0.19±2.16, -0.03±1.68 and -0.39±2.65 respectively, p>0.05). Subgroup analysis showed in progressing myopic group, IOP of children (<18 years old) declined with accommodation while IOP of adults (≥18 years) increased, and the difference was statistically significant (p = 0.008). However, after excluding the age factor, accommodation induced IOP changes of high progressing myopes (≤-6 D), low, moderate and non-myopes (>-6 D) was not significantly different after Bonferroni correction (p = 0.838).Conclusions
Although no difference was detected between the baseline IOPs and accommodation induced IOP changes in progressing myopes, stable myopes and emmetropes, this study found accommodation could cause transient IOP elevation in adult progressing myopes. 相似文献8.
Jagadish Vangipurapu Alena Stan?áková Teemu Kuulasmaa Johanna Kuusisto Markku Laakso 《PloS one》2015,10(4)
Background
Hyperproinsulinemia is an indicator of β-cell dysfunction, and fasting proinsulin levels are elevated in patients with hyperglycemia. It is not known whether proinsulin levels after a glucose load are better predictors of hyperglycemia and type 2 diabetes than fasting proinsulin.Methods
Participants were 9,396 Finnish men (mean±SD, age 57.3±7.1 years, BMI 27.0±4.0 kg/m2) of the population-based METabolic Syndrome In Men Study who were non-diabetic at the recruitment, and who participated in a 6-year follow-up study. Proinsulin and insulin levels were measured in the fasting state and 30 and 120 min after an oral glucose load. Area under the curve (AUC) and proinsulin to insulin ratios were calculated.Results
Fasting proinsulin, proinsulin at 30 min and proinsulin AUC during the first 30 min of an oral glucose tolerance test significantly predicted both the worsening of hyperglycemia and type 2 diabetes after adjustment for confounding factors. Further adjustment for insulin sensitivity (Matsuda index) or insulin secretion (Disposition index) weakened these associations. Insulin sensitivity had a major impact on these associations.Conclusion
Our results suggest that proinsulin in the fasting state and after an oral glucose load similarly predict the worsening of hyperglycemia and conversion to type 2 diabetes. 相似文献9.
Florian St?ckigt Klara Brixius Lars Lickfett René Andrié Markus Linhart Georg Nickenig Jan Wilko Schrickel 《PloS one》2012,7(11)
Introduction
Beta-adrenoceptors (β-AR) play an important role in the neurohumoral regulation of cardiac function. Three β-AR subtypes (β1, β2, β3) have been described so far. Total deficiency of these adrenoceptors (TKO) results in cardiac hypotrophy and negative inotropy. TKO represents a unique mouse model mimicking total unselective medical β-blocker therapy in men. Electrophysiological characteristics of TKO have not yet been investigated in an animal model.Methods
In vivo electrophysiological studies using right heart catheterisation were performed in 10 TKO mice and 10 129SV wild type control mice (WT) at the age of 15 weeks. Standard surface ECG, intracardiac and electrophysiological parameters, and arrhythmia inducibility were analyzed.Results
The surface ECG of TKO mice revealed a reduced heart rate (359.2±20.9 bpm vs. 461.1±33.3 bpm; p<0.001), prolonged P wave (17.5±3.0 ms vs. 15.1±1.2 ms; p = 0.019) and PQ time (40.8±2.4 ms vs. 37.3±3.0 ms; p = 0.013) compared to WT. Intracardiac ECG showed a significantly prolonged infra-Hisian conductance (HV-interval: 12.9±1.4 ms vs. 6.8±1.0 ms; p<0.001). Functional testing showed prolonged atrial and ventricular refractory periods in TKO (40.5±15.5 ms vs. 21.3±5.8 ms; p = 0.004; and 41.0±9.7 ms vs. 28.3±6.6 ms; p = 0.004, respectively). In TKO both the probability of induction of atrial fibrillation (12% vs. 24%; p<0.001) and of ventricular tachycardias (0% vs. 26%; p<0.001) were significantly reduced.Conclusion
TKO results in significant prolongations of cardiac conduction times and refractory periods. This was accompanied by a highly significant reduction of atrial and ventricular arrhythmias. Our finding confirms the importance of β-AR in arrhythmogenesis and the potential role of unspecific beta-receptor-blockade as therapeutic target. 相似文献10.
Ulugbek Negmadjanov Zarko Godic Farhan Rizvi Larisa Emelyanova Gracious Ross John Richards Ekhson L. Holmuhamedov Arshad Jahangir 《PloS one》2015,10(4)
Objectivs
Cytokine-dependent activation of fibroblasts to myofibroblasts, a key event in fibrosis, is accompanied by phenotypic changes with increased secretory and contractile properties dependent on increased energy utilization, yet changes in the energetic profile of these cells are not fully described. We hypothesize that the TGF-β1-mediated transformation of myofibroblasts is associated with an increase in mitochondrial content and function when compared to naive fibroblasts.Methods
Cultured NIH/3T3 mouse fibroblasts treated with TGF-β1, a profibrotic cytokine, or vehicle were assessed for transformation to myofibroblasts (appearance of α-smooth muscle actin [α-SMA] stress fibers) and associated changes in mitochondrial content and functions using laser confocal microscopy, Seahorse respirometry, multi-well plate reader and biochemical protocols. Expression of mitochondrial-specific proteins was determined using western blotting, and the mitochondrial DNA quantified using Mitochondrial DNA isolation kit.Results
Treatment with TGF-β1 (5 ng/mL) induced transformation of naive fibroblasts into myofibroblasts with a threefold increase in the expression of α-SMA (6.85 ± 0.27 RU) compared to cells not treated with TGF-β1 (2.52 ± 0.11 RU). TGF-β1 exposure increased the number of mitochondria in the cells, as monitored by membrane potential sensitive dye tetramethylrhodamine, and expression of mitochondria-specific proteins; voltage-dependent anion channels (0.54 ± 0.05 vs. 0.23 ± 0.05 RU) and adenine nucleotide transporter (0.61 ± 0.11 vs. 0.22 ± 0.05 RU), as well as mitochondrial DNA content (530 ± 12 μg DNA/106 cells vs. 307 ± 9 μg DNA/106 cells in control). TGF-β1 treatment was associated with an increase in mitochondrial function with a twofold increase in baseline oxygen consumption rate (2.25 ± 0.03 vs. 1.13 ± 0.1 nmol O2/min/106 cells) and FCCP-induced mitochondrial respiration (2.87 ± 0.03 vs. 1.46 ± 0.15 nmol O2/min/106 cells).Conclusions
TGF-β1 induced differentiation of fibroblasts is accompanied by energetic remodeling of myofibroblasts with an increase in mitochondrial respiration and mitochondrial content. 相似文献11.
Dominik Gruszka Robert Herr Hans Hely Peer Hofmann Daniela Klitscher Alexander Hofmann Pol Maria Rommens 《PloS one》2016,11(1)
Purpose
The use of new headless compression screws (HCSs) for scaphoid fixation is growing, but the nonunion rate has remained constant. The aim of this study was to compare the stability of fixation resulting from four modern HCSs using a simulated fracture model to determine the optimal screw design(s).Methods
We tested 40 fresh-frozen cadaver scaphoids treated with the Acumed Acutrak 2 mini (AA), the KLS Martin HBS2 midi (MH), the Stryker TwinFix (ST) and the Synthes HCS 3.0 with a long thread (SH). The bones with simulated fractures and implanted screws were loaded uniaxially into flexion for 2000 cycles with a constant bending moment of 800 Nmm. The angulation of the fracture fragments was measured continuously. Data were assessed statistically using the univariate ANOVA test and linear regression analysis, and the significance level was set at p < 0.05.Results
The median angulation of bone fragments φ allowed by each screw was 0.89° for AA, 1.12° for ST, 1.44° for SH and 2.36° for MH. With regards to linear regression, the most reliable curve was achieved by MH, with a coefficient of determination of R2 = 0.827. This was followed by AA (R2 = 0.354), SH (R2 = 0.247) and ST (R2 = 0.019). Data assessed using an adapted ANOVA model showed no statistically significant difference (p = 0.291) between the screws.Conclusions
The continuous development of HCSs has resulted in very comparable implants, and thus, at this time, other factors, such as surgeons’ experience, ease of handling and price, should be taken into consideration. 相似文献12.
Background
Reliability of the Actigraph GT3X+ accelerometer has not been determined under normal wear time criteria in a large sample of subjects and accelerometer units. The aim of this study was to assess contralateral hip difference and inter-instrument reliability of the Actigraph GT3X+ monitor in adults under long-term free-living conditions.Methods
Eighty-seven adult subjects (28 men; mean (standard deviation) age 31.3 (12.2) years; body mass index 23.7 (3.1) kg/m2) concurrently wore two GT3X+ accelerometers (174 units in total) attached to contralateral hips for 21 days. Reliability was assessed using Bland-Altman plots, mixed model regression analyses and absolute measures of agreement for different lengths of data accumulation (single-day-, 7-day- and 21-day periods).Results
There were no significant differences between contralateral hips (effect size ≤0.042; p ≥.213). Inter-instrument reliability increased with increased length of data-accumulation. For a 7-day measurement period (n = 232 weeks), limits of agreement were ±68 cpm (vertical axis) and ±81.3 cpm (vector magnitude) for overall physical activity (PA) level, ±51 min for sedentary time, ±18.2 min for light PA, ±6.3 min for moderate PA, ±3.5 min for vigorous PA, and ±6.7 min for moderate-to-vigorous PA.Conclusions
The Actigraph GT3X+ accelerometer is a reliable tool for measuring PA in adults under free-living conditions using normal data-reduction criteria. Contralateral hip differences are very small. We suggest accelerometers be attached to the right hip and data to be accumulated over several days of measurement. 相似文献13.
Background
Skiers have to differ between slow to moderate and fast skiing speed to determine their skiing style according to the ISO 11088 standard for setting binding release values. Despite existing evidence that males ski significantly faster than females, no sex-specific factor was inserted into the ISO 11088 standard.Objective
To evaluate factors potentially associated with the perception of individual skiing speed among recreational skiers.Methods
Skiing speeds of 416 adult skiers (62% males,) were measured with a radar speed gun. Skiers were interviewed about their age, sex, skill level, risk taking behaviour and helmet use. Finally, skiers had to rate their perceived speed on one out of three speed categories (fast, moderate, slow).Results
The measured mean speed of this cohort was 48.2±14.3 km/h (30.0±8.9 mph). A total of 32%, 52%, and 16% of skiers perceived their actual speed as fast, moderate and slow, respectively. Mean speed differed significantly between the 3 speed categories with a mean of about 53.5±13.7 km/h (33.2±8.5 mph) for fast, 47.6±14.0 km/h (29.6±8.7 mph) for moderate, and 39.4±12.2 km/h (24.5±7.6 mph) for slow skiing, respectively. Sex (η2 = .074), skill level (η2 = .035) and risk taking behavior (η2 = .033) showed significant differences of skiing speeds with regard to the 3 categories of speed perception (all p < .001) while age groups and ski helmet use did not. Males, more skilled skiers and risky skiers perceived their actual speed as fast, moderate and slow, when skiing up to 10 km/h (6 mph) faster compared to females, less skilled and cautious skiers.Conclusion
The perception of skiing speed as fast, moderate or slow depends on sex, skill level, and risk taking behaviour. These findings should be considered when discussing the introduction of a sex factor into the ISO 11088 standard for setting binding release values. 相似文献14.
Victòria Ceperuelo-Mallafré Miriam Ejarque Xavier Duran Gisela Pachón Ana Vázquez-Carballo Kelly Roche Catalina Nú?ez-Roa Lourdes Garrido-Sánchez Francisco J. Tinahones Joan Vendrell Sonia Fernández-Veledo 《PloS one》2015,10(6)
Objective
Evidence from mouse models suggests that zinc-α2-glycoprotein (ZAG) is a novel anti-obesity adipokine. In humans, however, data are controversial and its physiological role in adipose tissue (AT) remains unknown. Here we explored the molecular mechanisms by which ZAG regulates carbohydrate metabolism in human adipocytes.Methods
ZAG action on glucose uptake and insulin action was analyzed. β1 and β2-adrenoreceptor (AR) antagonists and siRNA targeting PP2A phosphatase were used to examine the mechanisms by which ZAG modulates insulin sensitivity. Plasma levels of ZAG were measured in a lean patient cohort stratified for HOMA-IR.Results
ZAG treatment increased basal glucose uptake, correlating with an increase in GLUT expression, but induced insulin resistance in adipocytes. Pretreatment of adipocytes with propranolol and a specific β1-AR antagonist demonstrated that ZAG effects on basal glucose uptake and GLUT4 expression are mediated via β1-AR, whereas inhibition of insulin action is dependent on β2-AR activation. ZAG treatment correlated with an increase in PP2A activity. Silencing of the PP2A catalytic subunit abrogated the negative effect of ZAG on insulin-stimulated AKT phosphorylation and glucose uptake but not on GLUT4 expression and basal glucose uptake. ZAG circulating levels were unchanged in a lean patient cohort stratified for HOMA-IR. Neither glucose nor insulin was associated with plasma ZAG.Conclusions
ZAG inhibits insulin-induced glucose uptake in human adipocytes by impairing insulin signaling at the level of AKT in a β2-AR- and PP2A-dependent manner. 相似文献15.
Braulio Henrique Magnani Branco David Hideyoshi Fukuda Leonardo Vidal Andreato Jonatas Ferreira da Silva Santos Jo?o Victor Del Conti Esteves Emerson Franchini 《PloS one》2016,11(3)
Objectives
The present study aimed to evaluate the effects of using hyperbaric oxygen therapy during post-training recovery in jiu-jitsu athletes.Methods
Eleven experienced Brazilian jiu-jitsu athletes were investigated during and following two training sessions of 1h30min. Using a cross-over design, the athletes were randomly assigned to passive recovery for 2 hours or to hyperbaric oxygen therapy (OHB) for the same duration. After a 7-day period, the interventions were reversed. Before, immediately after, post 2 hours and post 24 hours, blood samples were collected to examine hormone concentrations (cortisol and total testosterone) and cellular damage markers [creatine kinase (CK), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH)]. Moreover, the rating of perceived exertion (RPE) and recovery (RPR) scales were applied.Results
Final lactate [La] values (control: 11.9 ± 1.4 mmol/L, OHB: 10.2 ± 1.4 mmol/L) and RPE [control: 14 (13–17 a.u.), OHB: 18 (17–20 a.u.)] were not significantly different following the training sessions. Furthermore, there was no difference between any time points for blood lactate and RPE in the two experimental conditions (P>0.05). There was no effect of experimental conditions on cortisol (F1,20 = 0.1, P = 0.793, η2 = 0.00, small), total testosterone (F1,20 = 0.03, P = 0.877, η2 = 0.00, small), CK (F1,20 = 0.1, P = 0.759, η2 = 0.01, small), AST (F1,20 = 0.1, P = 0.761, η2 = 0.01, small), ALT (F1,20 = 0.0, P = 0.845, η2 = 0.00, small) or LDH (F1,20 = 0.7, P = 0.413, η2 = 0.03, small). However, there was a difference between the two experimental conditions in RPR with higher values at post 2 h and 24 h in OHB when compared to the control condition (P<0.05).Conclusions
Thus, it can be concluded that OHB exerts no influence on the recovery of hormonal status or cellular damage markers. Nonetheless, greater perceived recovery, potentially due to the placebo effect, was evident following the OHB condition. 相似文献16.
Background
Obesity is associated with diabetes mellitus and cardiovascular diseases. However, it has been reported that weight loss is associated with incident chronic kidney disease (CKD) in healthy males. The purpose of this prospective cohort study is to investigate the effects of weight loss on kidney function in healthy people in terms of body mass index (BMI) and gender.Methods
A total of 8447 nondiabetic healthy people were enrolled in the Saitama Cardiometabolic Disease and Organ Impairment Study, Japan. Relationships between estimated glomerular filtration rate (eGFR) change, BMI, and BMI change were evaluated using 3D-scatter plots with spline and generalized additive models (GAMs) adjusted for baseline characteristics.Results
The subjects were stratified into four groups according to BMI. The mean±standard deviations for males and females were, respectively, 40.11±9.49, and 40.3±9.71 years for age and 76.39±17.72 and 71.49±18.4 ml/min/1.73m2 for eGFR. GAMs showed that a decreasing BMI change (<-1 kg/m2/year) was associated with a decreasing eGFR change in males with high normal BMIs (22 kg/m2≤BMI<25 kg/m2). A decreasing BMI change (<-2 kg/m2/year) was associated with an increasing eGFR change in overweight males (25 kg/m2≤BMI). Among underweight females (BMI<18.5 kg/m2), decreasing BMI was observed with decreasing eGFR.Conclusions
These findings suggest that the benefit and risk of weight loss in relation to kidney function differs depending on BMI and weight loss speed, especially in males. 相似文献17.
Background
Bispecific T cell engager (BiTE®) are single-chain bispecific antibody constructs with dual specificity for CD3 on T cells and a surface antigen on target cells. They can elicit a polyclonal cytotoxic T cell response that is not restricted by T cell receptor (TCR) specificity, and surface expression of MHC class I/peptide antigen complexes. Using human EpCAM/CD3-bispecific BiTE® antibody construct AMG 110, we here assessed to what extent surface expression of PD-L1, cytoplasmic expression of indoleamine-2,3-deoxygenase type 1, Bcl-2 and serpin PI-9, and the presence of transforming growth factor beta (TGF-β), interleukin-10 (IL-10) and adenosine in culture medium can impact redirected lysis by AMG 110-engaged T cells.Methods
The seven factors, which are all involved in inhibiting T cell functions by cancer cells, were tested with human EpCAM-expressing Chinese hamster ovary (CHO) target cells at levels that in most cases exceeded those observed in a number of human cancer cell lines. Co-culture experiments were used to determine the impact of the evasion mechanisms on EC50 values and amplitude of redirected lysis by AMG 110, and on BiTE®-induced proliferation of previously resting human peripheral T cells.Findings
An inhibitory effect on redirected lysis by AMG 110-engaged T cells was seen upon overexpression of serpin PI-9, Bcl-2, TGF-βand PD-L1. An inhibitory effect on induction of T cell proliferation was only seen with CHO cells overexpressing IDO. In no case, a single evasion mechanism rendered target cells completely resistant to BiTE®-induced lysis, and even various combinations could not.Conclusions
Our data suggest that diverse mechanisms employed by cancer cells to fend off T cells cannot inactivate AMG 110-engaged T cells, and that inhibitory effects observed in vitro may be overcome by increased concentrations of the BiTE® antibody construct. 相似文献18.
Lucyna Mastalerz Magdalena Celińska-L?wenhoff Piotr Krawiec Bogdan Batko Witold T?ustochowicz Anetta Undas 《PloS one》2015,10(11)
Objectives
Given reports on the increased prevalence of thromboembolic incidents in patients with eosinophilic granulomatosis with polyangiitis (EGPA; Churg-Strauss syndrome), we investigated whether fibrin clot properties are unfavorably altered in EGPA.Methods
Ex vivo plasma fibrin clot characteristics, including clot permeability, turbidimetry and efficiency of fibrinolysis using two assays, were investigated in 34 consecutive patients with remission in EGPA according to the Birmingham Vasculitis Activity Score version 3 (23 female, 11 male), aged 48 (range, 21–80) years. The control group comprised 34 age- and sex- matched volunteers.Results
Compared with controls, patients with EGPA were characterized by denser fiber clots (estimated pore size, Ks, 7.30±0.93 vs 10.14±1.07 10−9 cm2), faster fibrin polymerization (lag phase in a turbidimetric curve, 41.8±3.6 vs 47.4±2.9 s), thicker fibrin fibers (maximum absorbance, ΔAbs, 0.87±0.09 vs 0.72±0.07), higher maximum levels of D-dimer released from clots (DDmax 4.10±0.46 vs 3.54±0.35 mg/L), and prolonged clot lysis time (t50%; 9.50±1.45 vs 7.56±0.87 min); all p<0.0001. Scanning electron microscopy images confirmed denser plasma fibrin networks composed of thinner fibers formed in EGPA. Antineutrophil cytoplasmic antibody status and C-reactive protein did not affect clot variables. Multivariate analysis adjusted for fibrinogen showed that Ks was predicted by eosinophil count, peak thrombin generation, factor VIII, and soluble CD40 ligand, whereas eosinophil count, peak thrombin generation and antiplasmin predicted t50%.Conclusion
This study is the first to show that EGPA is associated with prothrombotic plasma fibrin clot phenotype, which may contribute to thromboembolic manifestations reported in this disease. 相似文献19.
Guobin Miao Zhe Chen Xiangyang Fang Miaobing Liu Gang Hao Huiling An Zhiyong Zhang Lingqiao Lu Jian Zhang Lin Zhang 《PloS one》2013,8(7)
Background
Evidences suggest that β3 -adrenoceptor (β3-AR) plays an important role in heart failure (HF), although no data is reported indicating how these effects may change with the increasing age. Pulmonary congestion and edema are the major life-threatening complications associated with HF. The purpose of this study is to explore the relationship between the anti-β3-AR autoantibody and the expression of β3-AR in the lungs and heart for both aged patients and rats with HF.Methods
Synthetic β3-AR peptides served as the target antigens in ELISA were used to screen the anti-β3-AR autoantibody in aged patients and rats. Two aged rat models were constructed based on aortic banding and sham-operation. The expression of β3-AR mRNA and protein in the lung and heart was measured in intervention and non-intervention groups by Western blot analysis at the baseline, 5th, 7th, 9th and 11th week, respectively.Results
The frequency and titer of anti-β3-AR autoantibody in aged patients and rats with HF were higher than those in the control group (p<0.05). The expression of β3-AR mRNA and protein in pulmonary tissues decreased continually from the 7th week (p<0.05), followed by HF observed during the 9th week. The expression of β3-AR in myocardial tissues continued to increase after the 9th week (p<0.05), and the expression of both β3-AR mRNA and protein in the BRL group [HF group with BRL37344 (4-[-[2-hydroxy-(3-chlorophenyl)ethyl-amino] phenoxyacetic acid) (a β3-AR agonist) injection] was positively correlated with BRL37344 when compared with non-BRL group (HF group without BRL37344 injection) (p<0.05).Conclusion
Anti-β3-AR autoantibody was detected in aged patients and rats with HF. The expression of β3-AR mRNA and protein in pulmonary tissues decreased continually, and began earlier than in the heart, but its expression in myocardial tissues increased continually and could be further promoted by β3-AR agonist. 相似文献20.
Po-Cheng Chang Hung-Ta Wo Hui-Ling Lee Shien-Fong Lin Ming-Shien Wen Yen Chu San-Jou Yeh Chung-Chuan Chou 《PloS one》2015,10(4)