Abstract The fusion gene bcr-abl develops chronic myeloid leukemia (CML), and stimulates PI3K/Akt/mTOR signaling, leading to impaired autophagy. PI3K/Akt/mTOR signaling also plays an important role ...in cell metabolism. The Warburg effect is a well-recognized hallmark of cancer energy metabolism, and is regulated by the mTOR/c-Myc/hnRNP/PKM signaling cascade. To develop a new strategy for the treatment of CML, we investigated the associations among bcr-abl, the cascade related to cancer energy metabolism, and autophagy induced by a fatty-acid derivative that we had previously reported as being an autophagy inducer. Here we report that a fatty-acid derivative, AIC-47, induced transcriptional repression of the bcr-abl gene and modulated the expression profile of PKM isoforms, resulting in autophagic cell death. We show that c-Myc functioned as a transcriptional activator of bcr-abl, and regulated the hnRNP/PKM cascade. AIC-47, acting through the PPARγ/β-catenin pathway, induced down-regulation of c-Myc, leading to the disruption of the bcr-abl/mTOR/hnRNP signaling pathway, and switching of the expression of PKM2 to PKM1. This switching caused autophagic cell death through an increase in the ROS level. Our findings suggest that AIC-47 induced autophagic cell death through the PPARγ/β-catenin/bcr-abl/mTOR/hnRNP/PKM cascade.
Herein, we reported an attractive method for synthesizing medium-sized rings that are catalyzed by erythrosine B under fluorescent light irradiation. This synthetic approach featured mild conditions, ...a facile procedure, a broad substrate scope, and moderate-to-good yields.
Cyclic-1,N2-propano-2′-deoxyguanosine-d7 (CPr-dG-d7) was prepared as an isotopic internal standard (IS) for electrospray ionization tandem mass spectrometry (ESI-MS/MS) quantification of CPr-dG in ...DNA as a candidate cancer risk marker of acetaldehyde intake, mainly from drinking. The deuterated compound was reasonably synthesized from acetaldehyde-d4 and 2′-deoxyguanosine in deuterium oxide (D2O), preventing the deuterium atoms of acetaldehyde-d4 from being substituted by hydrogen atoms, which occurred seriously in aqueous synthesis media via keto–enol tautomerism. Furthermore, another deuterium atom was added from D2O to form CPr-dG-d7. After four weeks of storage in H2O at 10°C, CPr-dG-d7 was found to be sufficiently stable for practical use. The calibration curve of CPr-dG by using a hydrophilic interaction chromatography–ESI-MS/MS system with CPr-dG-d7 as the IS showed sufficient linearity from 1.0 × 10−10 to 4.0 × 10−9 M with r2 = 0.998.
Background:The role of endogenous adenosine in cardiac patients is still unclear, so we investigated the relationship between the plasma adenosine concentration and left ventricular (LV) function, LV ...dilation and LV wall thinning in cardiac patients.Methods and Results:In 97 cardiac patients, with angina pectoris, old myocardial infarction, dilated or hypertrophic cardiomyopathy, and valvular heart disease, plasma adenosine concentrations were measured using the LC-MS/MS system, and the LV function, LV end-diastolic dimension (LVDd), LV posterior wall thickness (LVPWth), and interventricular septum thickness (IVSth) were assessed by echocardiography. The plasma adenosine concentration was significantly higher in patients with a LV ejection fraction (EF), an indicator of the LV systolic function, <47% compared with those with LVEF ≥47% (P=0.027). There was no difference between the plasma adenosine concentration and E/e’, an indicator of LV diastolic function. The plasma adenosine concentration was significantly higher in patients with LVDd ≥50 mm than in those with LVDd <50 mm (P=0.030). The plasma adenosine concentration was inversely correlated with IVSth (P=0.003) and LVPWth (P=0.0007). The plasma adenosine concentration was significantly higher in patients with IVSth <8 mm than in those with IVSth ≥8 mm (P=0.015), and was significantly higher in patients with LVPWth <8 mm than in those with LVPWth ≥8 mm (P=0.020).Conclusions:Endogenous adenosine may be related to LV dysfunction, dilation, and wall thinning in cardiac patients.
This study demonstrated that the electro-chemical analysis of hydrophobic quinones can be performed in liposome suspension systems. We prepared and analyzed liposome suspensions containing lapachol, ...which is a quinone-based anti-tumor activity compound. In this suspension system, a simple one redox couple of lapachol is observed. These results are quite different from those obtained in organic solvents. In addition, the pH dependence of redox behaviors of lapachol could be observed in multilamellar vesicle (MLV) suspension system. This MLV suspension system method may approximate the electrochemical behavior of hydrophobic compounds in aqueous conditions. A benefit of this liposome suspension system for electrochemical analysis is that it enables to observe water-insoluble compounds without using organic solvents.
A simple pretreatment method and separation mode for the LC-ESI-MS/MS determination of adenosine in human plasma have been developed. Deproteinization by acetonitrile and ultrafiltration followed by ...chromatographic separation with a hydrophilic interaction chromatographic (HILIC) column give a highly sensitive MS/MS response without ionic suppression caused by the matrix compounds in human plasma. In addition, the presence of ammonium acetate in the mobile phase contributes to high sensitivity in MS/MS detection, facilitating the ionization of adenosine. This method seems to be amenable to the treatment of many samples in clinical practice.
•LPFOS and LDS micelles function sequentially in a separation run.•Working periods of the each micelles are changed to optimize separation.•Simulation of separations is simpler than that for mixed ...micellar methods.•Isotachophoretic approach to form steady micellar zones of the same velocity.
An effective stepwise micellar electrokinetic chromatography (MEKC) elution method was developed using lithium perfluorooctadecyl sulfonate (LPFOS) and lithium dodecyl sulfate (LDS). The hydrogen-bonding property of LPFOS micelles differs from that of LDS micelles, which leads to remarkably different selectivity in the transfer of solutes to the micelles. The present stepwise method is performed by replacing the inlet reservoir of a first running solution containing LPFOS with that of a second running solution containing LDS during a single separation run in the absence of electroosmotic flow under acidic conditions, where LPFOS micelles work as carriers in first and then LDS micelles turn over. Effective separation of 15 nonionic aromatic compounds was controlled well by adjusting the time in the inlet reservoir, which could not be accomplished with systems using only LPFOS or only LDS, with significant changes in the elution order where necessary. Furthermore, separations with the present stepwise method were easily simulated, and the replacement time was optimized for 3.1min from a 70.0mM LPFOS solution to a 67.5mM LDS solution with nearly complete separation within 15min using the simulated parameters.
Summary
1. The present study examined whether or not cilostazol reduces the myocardial infarct size, and investigated its mechanism in a rabbit model of myocardial infarction.
2. Japanese white ...rabbits underwent 30 min of coronary occlusion, followed by 48 h of reperfusion. Cilostazol (1 and 5 mg/kg) or vehicle was given intravenously 5 min before ischaemia. 8‐p‐sulfophenyl theophylline (8SPT; an adenosine receptor blocker, 7.5 mg/kg), Nω‐nitro‐l‐arginine methylester (l‐NAME; an NOS inhibitor, 10 mg/kg) or 5‐hydroxydecanoic acid sodium salt (5‐HD; a mitochondrial ATP‐sensitive potassium (KATP) channel blocker, 5 mg/kg) was given intravenously 5 min before cilostazol injection. Infarct size was determined as a percentage of the risk area.
3. The myocardial interstitial levels of adenosine and nitrogen oxide (NOx) during ischaemia and reperfusion, and the intensity of myocardial dihydroethidium staining were determined.
4. Infarct size was significantly reduced in the cilostazol 1 mg/kg (38.4% (2.9%)) and cilostazol 5 mg/kg (30.7% (4.7%)) groups compared with that in the control group (46.5% (4.2%)). The infarct size‐reducing effect of cilostazol was completely abolished by 8SPT (46.6% (3.5%)), l‐NAME (49.0% (5.5%)), or 5HD (48.5% (5.1%)). 8SPT, l‐NAME or 5HD alone did not affect the infarct size. Cilostazol treatment significantly increased myocardial levels of adenosine and NOx during ischaemia, and attenuated the intensity of dihydroethidium staining during reperfusion.
5. These findings show that cilostazol reduces the myocardial infarct size by increasing adenosine and NOx levels, attenuating superoxide production and opening the mitochondrial KATP channels. Cilostazol might provide a new strategy for the treatment of coronary heart disease.
See editorial on page 651
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