Metabolic profile, bioavailability and toxicokinetics of zearalenone-14-glucoside in rats after oral and intravenous administration by liquid chromatography high-resolution mass spectrometry and tandem mass spectrometry

Zearalenone-14-glucoside (ZEN-14G), a key modified mycotoxin, has attracted a great deal of attention due to the possible conversion to its free form of zearalenone (ZEN) exerting toxicity. In this study, the toxicokinetics of ZEN-14G were investigated in rats after oral and intravenous administration. The plasma concentrations of ZEN-14G and its major five metabolites were quantified using a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) method. The data were analyzed via non-compartmental analysis using software WinNonlin 6.3. The results indicated that ZEN-14G was rapidly hydrolyzed into ZEN in vivo. In addition, the major parameters of ZEN-14G following intravenous administration were: area under the plasma concentration-time curve (AUC), 1.80 h.ng/mL; the apparent volume of distribution (V-Z), 7.25 L/kg; and total body clearance (CL), 5.02 mL/h/kg, respectively. After oral administration, the typical parameters were: AUC, 0.16 h.ng/mL; V-Z, 6.24 mL/kg; and CL, 4.50 mL/h/kg, respectively. The absolute oral bioavailability of ZEN-14G in rats was about 9%, since low levels of ZEN-14G were detected in plasma, which might be attributed to its extensive metabolism. Therefore, liquid chromatography high-resolution mass spectrometry (LC-HRMS) was adopted to clarify the metabolic profile of ZEN-14G in rats' plasma. As a result, eight metabolites were identified in which ZEN-14-glucuronic acid (ZEN-14GlcA) had a large yield from the first time-point and continued accumulating after oral administration, indicating that ZEN-14-glucuronic acid could serve a potential biomarker of ZEN-14G. The obtained outcomes would prompt the accurate safety evaluation of ZEN-14G

Regulation of dopamine transporter activity by carboxypeptidase E

<p>Abstract</p> <p>Background</p> <p>The dopamine transporter (DAT) plays a critical role in terminating the action of dopamine by rapid reuptake into the presynaptic neuron. Previous studies have revealed that the DAT carboxyl terminus (DAT-CT) can directly interact with other cellular proteins and regulate DAT function and trafficking.</p> <p>Results</p> <p>Here, we have identified that carboxypeptidase E (CPE), a prohormone processing exopeptidase and sorting receptor for the regulated secretory pathway, interacts with the DAT-CT and affects DAT function. Mammalian cell lines coexpressing CPE and DAT exhibited increased DAT-mediated dopamine uptake activity compared to cells expressing DAT alone. Moreover, coexpression of an interfering DAT-CT minigene inhibited the effects of CPE on DAT. Functional changes caused by CPE could be attributed to enhanced DAT expression and subsequent increase in DAT cell surface localization, due to decreased DAT degradation. In addition, CPE association could reduce the phosphorylation state of DAT on serine residues, potentially leading to reduced internalization, thus stabilizing plasmalemmal DAT localization.</p> <p>Conclusion</p> <p>Taken together, our results reveal a novel role for CPE in the regulation of DAT trafficking and DAT-mediated DA uptake, which may provide a novel target in the treatment of dopamine-governed diseases such as drug addiction and obesity.</p

Study on Mechanism and Improvement of Triple Frequency Noise of Rotary Compressor

With the continuous improvement of social life, people have more stringent noise requirements for home air conditioners. As the kernel of an air conditioner, compressor provides power for the whole system, inevitably generating vibration and noise. Therefore, Reducing the vibration and noise of the compressor is great significance for the noise reduction of the air conditioner. Generally, vibration is mainly transferred through the suction and exhaust pipes to the air conditioning pipe system. However, due to the complicated configuration, there are intensive modals for the pipe system, especially those in low frequency range, which may lead to resonance and large acoustic radiation. This paper studies the generation and transmission mechanism of triple frequency vibration of compressor, the compressor exhaust pressure fluctuation stimulates the exhaust pipe to vibrate, and then results in vibration of the air conditioning pipe systems, and vibration generated by the rotor is transferred to intake pipe via the accumulator, and cause the pipe systems to vibrate. Based on this research, we find some main factors which influence the triple frequency vibration and noise of the compressor, which are the exhaust pressure pulsation, the natural frequency of the rotor-crankshaft system swing, the natural frequency of the accumulator swing. Then, above factors which affect the compressor vibration and noise are analyzed and improved separately, and conducted noise tests on the improved compressor at 90Hz. The results show that the compressor noise are reduced by 29.8% around 250Hz

The influence of online review adoption on the profitability of capacitated supply chains

The paper explores the influence of online review adoption on supply chain profitability under the presence of a capacity constraint. Nowadays, customers increasingly rely on online reviews for decision making, and online retailers regard reviews as a norm. Although online reviews have been extensively examined in marketing disciplines, little research has been conducted to investigate their influence from a supply chain perspective. In addition, previous research has largely focused on how online review information can influence customer purchase behaviours, but ignores the more basic decision: whether and when companies should adopt reviews. This paper examines the online review adoption decision from a capacitated supply chain perspective through mathematical modelling and simulation. The simulation considers the influence of variables including online review adoption decision, capacity constraint level, lost sales penalty level, and product quality estimation on supply chain profitability. Generally, we find that online reviews can bring more profit to the supply chain than without online reviews, although such influence is moderated by the other three variables. The findings reveal the complexity of the contextual variable impacts on online review adoption, and demonstrate that decisions concerning the adoption of online reviews should take all supply-chain-related variables into consideration rather than only aiming for increasing customer orders

Carveol a Naturally-Derived Potent and Emerging Nrf2 Activator Protects Against Acetaminophen-Induced Hepatotoxicity

Acetaminophen (N-acetyl p-aminophenol or APAP) is used worldwide for its antipyretic and anti-inflammatory potential. However, APAP overdose sometimes causes severe liver damage. In this study, we elucidated the protective effects of carveol in liver injury, using molecular and in silico approaches. Male BALB/c mice were divided into two experimental cohorts, to identify the best dose and to further assess the role of carveol in the nuclear factor E2-related factor; nuclear factor erythroid 2; p45-related factor 2 (Nrf2) pathway. The results demonstrated that carveol significantly modulated the detrimental effects of APAP by boosting endogenous antioxidant mechanisms, such as nuclear translocation of Nrf2 gene, a master regulator of the downstream antioxidant machinery. Furthermore, an inhibitor of Nrf2, called all-trans retinoic acid (ATRA), was used, which exaggerated APAP toxicity, in addition to abrogating the protective effects of carveol; this effect was accompanied by overexpression of inflammatory mediators and liver = 2ltoxicity biomarkers. To further support our notion, we performed virtual docking of carveol with Nrf2-keap1 target, and the resultant drug-protein interactions validated the in vivo findings. Together, our findings suggest that carveol could activate the endogenous master antioxidant Nrf2, which further regulates the expression of downstream antioxidants, eventually ameliorating the APAP-induced inflammation and oxidative stress

Thrombocytopenia Is Associated with Acute Respiratory Distress Syndrome Mortality: An International Study

Background: Early detection of the Acute Respiratory Distress Syndrome (ARDS) has the potential to improvethe prognosis of critically ill patients admitted to the intensive care unit (ICU). However, no reliable biomarkers are currently available for accurate early detection of ARDS in patients with predisposing conditions. Objectives: This study examined risk factors and biomarkers for ARDS development and mortality in two prospective cohort studies. Methods: We examined clinical risk factors for ARDS in a cohort of 178 patients in Beijing, China who were admitted to the ICU and were at high risk for ARDS. Identified biomarkers were then replicated in a second cohort of1,878 patients in Boston, USA. Results: Of 178 patients recruited from participating hospitals in Beijing, 75 developed ARDS. After multivariate adjustment, sepsis (odds ratio [OR]:5.58, 95% CI: 1.70–18.3), pulmonary injury (OR: 3.22; 95% CI: 1.60–6.47), and thrombocytopenia, defined as platelet count <80×103/µL, (OR: 2.67; 95% CI: 1.27–5.62)were significantly associated with increased risk of developing ARDS. Thrombocytopenia was also associated with increased mortality in patients who developed ARDS (adjusted hazard ratio [AHR]: 1.38, 95% CI: 1.07–1.57) but not in those who did not develop ARDS(AHR: 1.25, 95% CI: 0.96–1.62). The presence of both thrombocytopenia and ARDS substantially increased 60-daymortality. Sensitivity analyses showed that a platelet count of <100×103/µLin combination with ARDS provide the highest prognostic value for mortality. These associations were replicated in the cohort of US patients. Conclusions: This study of ICU patients in both China and US showed that thrombocytopenia is associated with an increased risk of ARDS and platelet count in combination with ARDS had a high predictive value for patient mortality

Melatonin Protects MCAO-Induced Neuronal Loss via NR2A Mediated Prosurvival Pathways

Stroke is the significant cause of human mortality and sufferings depending upon race and demographic location. Melatonin is a potent antioxidant that exerts protective effects in differential experimental stroke models. Several mechanisms have been previously suggested for the neuroprotective effects of melatonin in ischemic brain injury. The aim of this study is to investigate whether melatonin treatment affects the glutamate N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor signaling in cerebral cortex and striatum 24 h after permanent middle cerebral artery occlusion (MCAO). Melatonin (5 mg/kg) attenuated ischemia-induced down regulation of NMDA receptor 2 (NR2a), postsynaptic density-95 (PSD95) and increases NR2a/PSD95 complex association, which further activates the pro-survival PI3K/Akt/GSK3β pathway with mitigated collapsin response mediator protein 2 (CRMP2) phosphorylation. Furthermore, melatonin increases the expression of γ-enolase, a neurotrophic factor in ischemic cortex and striatum, and preserve the expression of presynaptic (synaptophysin and SNAP25) and postsynaptic (p-GluR1845) protein. Our study demonstrated a novel neuroprotective mechanism for melatonin in ischemic brain injury which could be a promising neuroprotective agent for the treatment of ischemic stroke

Measuring the dislocation density of VT1-0 titanium alloys with different content of hydrogen by x-ray diffraction method

In this study, the distributions of dislocation density with hydrogen concentration in titanium VT1-0 were obtained. The samples with different hydrogen concentrations was carried out by using the Sieverts method. The dislocation densities were obtained by using the full width at height medium calculations from the XRD results of Gaussian approximation fitting. For accurate calculation of the dislocation density in titanium alloys, the double-line separation phenomenon of the XRD results and the variation of the Burgers vector in different lattice directions were considered. The phenomenon of the double-line separation is more evident when the diffraction angle 20 is larger than 40°. The mean value of dislocation density for the different hydrogen concentrations is about 1013 ~ 1014 m-2 . Moreover, as the increases of hydrogen content in the titanium alloy, the dislocation density also increases