PS10
目录号 : GC60309
PS10 是一种新型，有效且具有 ATP 竞争性的广谱 PDK 抑制剂，可抑制所有 PDK 同工型，对 PDK2，PDK4，PDK1 和 PDK3 的 IC50 分别为 0.8 μM，0.76 μM，2.1 μM 和 21.3 μM。 PS10 对 PDK2 (Kd= 239 nM) 的亲和力高于对 Hsp90 (Kd= 47 μM)。 PS10 改善葡萄糖耐量，刺激饮食引起的肥胖症中的心肌碳水化合物氧化。 PS10 具有研究糖尿病性心肌病的潜力。
Cas No.:1564265-82-2
Sample solution is provided at 25 µL, 10mM.
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PS10 is a novel, potent and ATP-competitive pan-PDK inhibitor, inhibits all PDK isoforms with IC50 of 0.8 μM, 0.76 μM, 2.1 μM and 21.3 μM for PDK2, PDK4, PDK1, and PDK3, respectively. PS10 shows high affinity for PDK2 (Kd= 239 nM) than for Hsp90 (Kd= 47 μM)[1]. PS10 improves glucose tolerance, stimulates myocardial carbohydrate oxidation in diet-induced obesity. PS10 has the potential for the investigation of diabetic cardiomyopathy[2].PDK: pyruvate dehydrogenase kinase
PS10 shows a higher affinity of PS10 for PDK2 (Kd= 239 nM) than for Hsp90 (Kd= 47,000 nM)[1].PS10 is less potent than cycloheximide in HeLa cells, it shows an IC50 value of 284 μM for the growth inhibition and PS10 has low toxicity in cells[1].
PS10 (Intraperitoneal injection; 70 mg/kg; single dose) treatment lead to 11- and 23-fold higher PDC activity in heart and liver, respectively. Meanwhile, there results in a 1.4-fold enhancement of PDC activity in kidneys compared with vehicle-group[1].PS10 (Intraperitoneal injection; 70 mg/kg; 3 days) treatment results that thePDC activity profiles and the phospho-E1α subunit level is similar to the single-dose. Notably, the three-day treatment attenuates the enhancement of PDK activity in heart[1].PS10 (intraperitoneal injection; 70 mg/kg; 4 weeks) is treated in mice and subjected to a glucose tolerance test. when challenged with 1.5 g/kg glucose, the plasma glucose level in the vehicle-treated control is at 200 mg/dl at 0 min, peaks at 482 mg/dl at 30 min, and reduces to 210 mg/dl at 120 min. In PS10-treated DIO mice, the glucose level at 168 mg/dl at 0 min is lower than that in vehicle-treated animals, reachs 312 mg/dl at 30 min, and returns to 163 mg/dl at 120 min[1].PS10 (intraperitoneal injection; 70 mg/kg) and DCA both stimulates flux through PDC as measured by the appearance of hyperpolarized [13C]bicarbonate. It shows similar glucose tolerance response to glucose challenge restores PDC activity in the DIO mouse hearts[2]. Animal Model: C57BL/6J male mice at 6 to 8 weeks old[2]
[1]. Structure-guided development of specific pyruvate dehydrogenase kinase inhibitors targeting the ATP-binding pocket.J Biol Chem. 2014 Feb 14;289(7):4432-43. [2]. Wu CY, et al. A novel inhibitor of pyruvate dehydrogenase kinase stimulates myocardial carbohydrate oxidation in diet-induced obesity.J Biol Chem. 2018 Jun 22;293(25):9604-9613.
| Cas No. | 1564265-82-2 | SDF | |
| Canonical SMILES | OC1=CC(O)=CC2=C1CN(S(=O)(C3=CC=C(O)C=C3O)=O)C2 | ||
| 分子式 | C14H13NO6S | 分子量 | 323.32 |
| 溶解度 | DMSO: 62.5 mg/mL (193.31 mM) | 储存条件 | Store at -20°C |
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1 mg | 5 mg | 10 mg |
| 1 mM | 3.0929 mL | 15.4646 mL | 30.9291 mL |
| 5 mM | 0.6186 mL | 3.0929 mL | 6.1858 mL |
| 10 mM | 0.3093 mL | 1.5465 mL | 3.0929 mL |
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Automatic Tube Compensation During Spontaneous Breathing Trials
Respir Care 2022 Oct;67(10):1335-1342.PMID:36137582DOI:10.4187/respcare.09920.
Background: Automatic tube compensation (ATC) is an option available in any ICU ventilator that compensates for the resistive pressure drop due to the endotracheal tube. The goal of the present study was to compare ATC to other patient triggered modes of support in terms of spontaneous breathing trial (SBT) and extubation success. Methods: Two authors (JB and PCF), independently and blinded to each other, searched through PubMed, Web of Science, and Cochrane from inception-May 26, 2021, with the following search terms entered as MeSH terms in all fields: "Automatic Tube Compensation." Inclusion criteria: randomized studies that included subjects > 16 y old undergoing an SBT. Exclusion criteria: crossover studies, pediatric studies, animal studies, or experimental studies on test lungs or on computer simulation; other languages than French, Spanish, or English; studies not published in a full-text format (eg, abstract or letter); and reviews. A frequentist network meta-analysis was conducted with the aim to investigate the effectiveness of ATC on SBT and extubation outcomes. SBT was defined as successful if patients could tolerate the SBT based on predetermined criteria, whether it was followed by extubation. Successful extubation was defined as the absence of re-intubation, noninvasive ventilation, or signs of respiratory distress within the 48 h after extubation. The pooled analyses used random-effect models, and the effect size was expressed as relative risk or mean difference for categorical and continuous variables, respectively. P-scores were used to rank all treatments and to identify the intervention with the highest probability of being the best. Results: Of the 234 retrieved papers, 7 met the inclusion criteria. In terms of SBT success, ATC100+PEEP < 7.5 and PS10+PEEP < 7.5 were superior to T-piece. Likewise, PS10+PEEP < 7.5 was the intervention with the highest probability of being the best (P-score: 0.90). In terms of extubation success, ATC100+PEEP < 7.5 cm H2O was significantly better than PEEP < 7.5 and T-piece. Likewise, it had the highest probability of being the best (P-score= 0.90). Conclusions: ATC is the modality with the highest probability of extubation success but not in terms of SBT success.
A novel inhibitor of pyruvate dehydrogenase kinase stimulates myocardial carbohydrate oxidation in diet-induced obesity
J Biol Chem 2018 Jun 22;293(25):9604-9613.PMID:29739849DOI:10.1074/jbc.RA118.002838.
The pyruvate dehydrogenase complex (PDC) is a key control point of energy metabolism and is subject to regulation by multiple mechanisms, including posttranslational phosphorylation by pyruvate dehydrogenase kinase (PDK). Pharmacological modulation of PDC activity could provide a new treatment for diabetic cardiomyopathy, as dysregulated substrate selection is concomitant with decreased heart function. Dichloroacetate (DCA), a classic PDK inhibitor, has been used to treat diabetic cardiomyopathy, but the lack of specificity and side effects of DCA indicate a more specific inhibitor of PDK is needed. This study was designed to determine the effects of a novel and highly selective PDK inhibitor, 2((2,4-dihydroxyphenyl)sulfonyl) isoindoline-4,6-diol (designated PS10), on pyruvate oxidation in diet-induced obese (DIO) mouse hearts compared with DCA-treated hearts. Four groups of mice were studied: lean control, DIO, DIO + DCA, and DIO + PS10. Both DCA and PS10 improved glucose tolerance in the intact animal. Pyruvate metabolism was studied in perfused hearts supplied with physiological mixtures of long chain fatty acids, lactate, and pyruvate. Analysis was performed using conventional 1H and 13C isotopomer methods in combination with hyperpolarized [1-13C]pyruvate in the same hearts. PS10 and DCA both stimulated flux through PDC as measured by the appearance of hyperpolarized [13C]bicarbonate. DCA but not PS10 increased hyperpolarized [1-13C]lactate production. Total carbohydrate oxidation was reduced in DIO mouse hearts but increased by DCA and PS10, the latter doing so without increasing lactate production. The present results suggest that PS10 is a more suitable PDK inhibitor for treatment of diabetic cardiomyopathy.
Targeting hepatic pyruvate dehydrogenase kinases restores insulin signaling and mitigates ChREBP-mediated lipogenesis in diet-induced obese mice
Mol Metab 2018 Jun;12:12-24.PMID:29656110DOI:10.1016/j.molmet.2018.03.014.
Objective: Mitochondrial pyruvate dehydrogenase kinases 1-4 (PDKs1-4) negatively regulate activity of the pyruvate dehydrogenase complex (PDC) by reversible phosphorylation. PDKs play a pivotal role in maintaining energy homeostasis and contribute to metabolic flexibility by attenuating PDC activity in various mammalian tissues. Cumulative evidence has shown that the up-regulation of PDK4 expression is tightly associated with obesity and diabetes. In this investigation, we test the central hypothesis that PDKs1-4 are a pharmacological target for lowering glucose levels and restoring insulin sensitivity in obesity and type 2 diabetes (T2D). Methods: Diet-induced obese (DIO) mice were treated with a liver-specific pan-PDK inhibitor 2-[(2,4-dihydroxyphenyl) sulfonyl]isoindoline-4,6-diol (PS10) for four weeks, and results compared with PDK2/PDK4 double knockout (DKO) mice on the same high fat diet (HFD). Results: Both PS10-treated DIO mice and HFD-fed DKO mice showed significantly improved glucose, insulin and pyruvate tolerance, compared to DIO controls, with lower plasma insulin levels and increased insulin signaling in liver. In response to lower glucose levels, phosphorylated AMPK in PS10-treated DIO and HFD-fed DKO mice is upregulated, accompanied by decreased nuclear carbohydrate-responsive element binding protein (ChREBP). The reduced ChREBP signaling correlates with down-regulation of hepatic lipogenic enzymes (ACC1, FAS, and SCD1), leading to markedly diminished hepatic steatosis in both study groups, with lower circulating cholesterol and triacylglyceride levels as well as reduced fat mass. PS10-treated DIO as well as DKO mice showed predominant fatty acid over glucose oxidation. However, unlike systemic DKO mice, increased hepatic PDC activity alone in PS10-treated DIO mice does not raise the plasma total ketone body level. Conclusion: Our findings establish that specific targeting of hepatic PDKs with the PDK inhibitor PS10 is an effective therapeutic approach to maintaining glucose and lipid homeostasis in obesity and T2D, without the harmful ketoacidosis associated with systemic inhibition of PDKs.
Bi-level Positive Airway Pressure (BiPAP) with standard exhalation valve does not improve maximum exercise capacity in patients with COPD
COPD 2015 Feb;12(1):46-54.PMID:24946024DOI:10.3109/15412555.2014.908830.
Background: Although BiPAP has been used as an adjunct to exercise, little is know about its effect on exercise in COPD. We aimed to evaluate the acute effect of BiPAP delivered with a standard valve (Vision, Respironics), compared to no assist, on exercise capacity in individuals with COPD. Methods: Peak exercise workload (WLpeak), dyspnea (Borg), end-expiratory lung volume (EELV), tidal volume (VT), minute ventilation (VE), O2 uptake (VO2), and CO2 production (VCO2) were assessed in 10 COPD patients (FEV1 53 ± 22% pred) during three symptom-limited bicycle exercise tests while breathing i) without a ventilator (noPS), ii) with a pressure support (PS) of 0 cm H2O (PS0; IPAP & EPAP 4 cm H2O) and iii) PS of 10 cm H2O (PS10; IPAP 14 & EPAP 4 cm H2O) on separate days using a randomized crossover design. Results: WLpeak was significantly lower with PS10 (33 ± 16) and PS0 (30.5 ± 13) than noPS (43 ± 19) (p < 0.001). Dyspnea at peak exercise was similar with noPS, PS0 and PS10; at isoload it was lower with noPS compared to PS10 and PS0 (p < 0.01). VT and VE were highest with PS10 and lowest with noPS both at peak exercise and isoload (p < 0.001). EELV was similar at peak exercise with all three conditions. VO2 and VCO2 were greater with PS10 and PS0 than noPS (p < 0.001), both at peak exercise and isoload. Conclusion: Use of BiPAP with a standard exhalation valve during exercise increases VT and VE at the expense of augmenting VCO2 and dyspnea, which in turns reduces WLpeak in COPD patients.
Impact of Blood Flow Restriction Exercise on Muscle Fatigue Development and Recovery
Med Sci Sports Exerc 2018 Mar;50(3):436-446.PMID:29112627DOI:10.1249/MSS.0000000000001475.
Purpose: The present study was designed to provide mechanistic insight into the time course and etiology of muscle fatigue development and recovery during and after low-intensity exercise when it is combined with blood flow restriction (BFR). Methods: Seventeen resistance-trained males completed four sets of low-intensity isotonic resistance exercise under two experimental conditions: knee extension exercise (i) with BFR and (ii) without BFR (CON). Neuromuscular tests were performed before, during (immediately after each set of knee extension exercise), and 1, 2, 4, and 8 min after each experimental condition. Maximal voluntary torque, quadriceps twitch torque in response to paired electrical stimuli at 10 Hz (PS10) and 100 Hz (PS100), PS10·PS100 ratio as an index of low-frequency fatigue, and voluntary activation were measured under isometric conditions. Perceptual and EMG data were recorded during each exercise condition. Results: After the first set of exercise, BFR induced significantly greater reductions in maximal voluntary torque, PS100, and PS10·PS100 ratio compared with CON. These parameters progressively declined throughout the BFR protocol but recovered substantially within 2 min postexercise when blood flow was restored. Neither a progressive decline in the course of the exercise protocol nor a substantial recovery of these parameters occurred during and after CON. Only at exercise termination, voluntary activation differed significantly between BFR and CON with greater reductions during BFR. Conclusion: At the early stage of exercise, BFR exacerbated the development of muscle fatigue mainly due to a pronounced impairment in contractile function. Despite the high level of muscle fatigue during BFR exercise, the effect of BFR on muscle fatigue was diminished after 2 min of reperfusion, suggesting that BFR has a strong but short-lasting effect on neuromuscular function.