Inhibitory mechanism of vortioxetine on CYP450 enzymes in human and rat liver microsomes

Vortioxetine is a novel anti-major depression disorder drug with a high safety profile compared with other similar drugs. However, little research has been done on drug-drug interactions (DDI) about vortioxetine. In this paper, the inhibitory effect of vortioxetine on cytochrome P450 (CYP450) and the type of inhibitory mechanism were investigated in human and rat liver microsomes. We set up an in vitro incubation system of 200 μL to measure the metabolism of probe substrates at the present of vortioxetine at 37°C. The concentrations of the metabolites of probe substrates were all measured by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method. It was found no time-dependent inhibition (TDI) of vortioxetine through determination of half-maximal inhibitory concentration (IC50) shift values. The enzymes and metabolites involved in this experiment in human and rats were as follows: CYP3A4/CYP3A (midazolam); CYP2B6/CYP2B (bupropion); CYP2D6/CYP2D (dextromethorphan); CYP2C8/CYP2C-1 (amodiaquine); CYP2C9/CYP2C-2 (losartan); and CYP2C19/CYP2C-3 (mephenytoin). We found that vortioxetine competitively inhibited CYP2C19 and CYP2D6 in human liver microsomes (HLMs) with inhibition constant (Ki) values of 2.17 μM and 9.37 μM, respectively. It was noncompetitive inhibition for CYP3A4 and CYP2C8, and its Ki values were 7.26 μM and 6.96 μM, respectively. For CYP2B6 and CYP2C9, vortioxetine exhibited the mixed inhibition with Ki values were 8.55 μM and 4.17 μM, respectively. In RLMs, the type of vortioxetine inhibition was uncompetitive for CYP3A and CYP2D (Ki = 4.41 and 100.9 μM). The inhibition type was competitive inhibition, including CYP2B and CYP2C-2 (Ki = 2.87 and 0.12 μM). The inhibition types of CYP2C-1 and CYP2C-3 (Ki = 39.91 and 4.23 μM) were mixed inhibition and noncompetitive inhibition, respectively. The study of the above mechanism will provide guidance for the safe clinical use of vortioxetine so that the occurrence of DDI can be avoided

Systematic and statistical uncertainty evaluation of the HfF+^+ electron electric dipole moment experiment

We have completed a new precision measurement of the electron's electric dipole moment using trapped HfF$^+$ in rotating bias fields. We report on the accuracy evaluation of this measurement, describing the mechanisms behind our systematic shifts. Our systematic uncertainty is reduced by a factor of 30 compared to the first generation of this measurement. Our combined statistical and systematic accuracy is improved by a factor of 2 relative to any previous measurement

A new bound on the electron's electric dipole moment

The Standard Model cannot explain the dominance of matter over anti-matter in our universe. This imbalance indicates undiscovered physics that violates combined CP symmetry. Many extensions to the Standard Model seek to explain the imbalance by predicting the existence of new particles. Vacuum fluctuations of the fields associated with these new particles can interact with known particles and make small modifications to their properties; for example, particles which violate CP symmetry will induce an electric dipole moment of the electron (eEDM). The size of the induced eEDM is dependent on the masses of the new particles and their coupling to the Standard Model. To date, no eEDM has been detected, but increasingly precise measurements probe new physics with higher masses and weaker couplings. Here we present the most precise measurement yet of the eEDM using electrons confined inside molecular ions, subjected to a huge intra-molecular electric field, and evolving coherently for up to 3 s. Our result is consistent with zero and improves on the previous best upper bound by a factor $\sim2.4$. Our sensitivity to $10^{-19}$ eV shifts in molecular ions provides constraints on broad classes of new physics above $10^{13}$ eV, well beyond the direct reach of the LHC or any other near- or medium-term particle collider.Comment: Update to figure 2 which displays better in some pdf viewer

Cardioprotective Effect of Betulinic Acid on Myocardial Ischemia Reperfusion Injury in Rats

Objectives. This study aims to investigate the effect of betulinic acid (BA) on myocardial ischemia reperfusion/injury in an open-chest anesthetized rat model. Methods. The model was induced by 30 minutes left anterior descending occlusion followed by 2 hours reperfusion. There are six groups in our present study: sham operation group, ischemia/reperfusion group, low-dosage BA group, medium-dosage BA group, high-dosage BA group, and fosinopril sodium group. Rats in the latter four groups were administrated with BA (50, 100, and 200 mg/kg, i.g.) or fosinopril sodium (10 mg/kg, i.g.) once a day for 7 days before operation, respectively. Rats in the former two groups were given the same volume of vehicle (0.5% CMC-Na, i.g.). During the operation, cardiac function was continuously monitored. Serum LDH and CK were measured with colorimetric assays. The expression of Bcl-2 and Bax and the apoptosis of cardiomyocytes were investigated with western blot and TUNEL assay, respectively. Results. Pretreatment with BA improved cardiac function and attenuated LDH and CK activities compared with IR group. Further investigation demonstrated that the expression of Bcl-2 and Bax and TUNEL assay was in line with the above results. Conclusion. BA may reduce the release of LDH and CK, prevent cardiomyocytes apoptosis, and eventually alleviate the extent of the myocardial ischemia/reperfusion injury

A method to measure heat flux in convection using Gardon gauge

This work was supported by the National Natural Science Foundation of China (No. 51576110), the Science Fund for Creative Research Groups of the National Natural Science Foundation of China (No. 51321002) and the Program for New Century Excellent Talents in University (NCET-13-0315)

Spatio–Temporal Variation of Extreme Climates and Its Relationship with Teleconnection Patterns in Beijing–Tianjin–Hebei from 1980 to 2019

Extreme climate events have a significant impact both on the ecological environment and human society, and it is crucial to analyze the spatial–temporal evolutionary trends of extreme climate. Based on the RClimDex model, this study used trend analysis, probability density function, and wavelet coherence analysis to analyze the spatiotemporal variation characteristics of extreme climate indices and their response mechanisms to teleconnection patterns. The results of the study show that: (1) All the extreme precipitation indices, except max 1-day precipitation amount, max 5-day precipitation amount, and extremely wet days increased, with no significant abrupt changes. The extreme warm indices increased and extreme cold indices decreased. The years with abrupt changes were mainly distributed between 1988 and 1997. (2) Spatially, the extreme precipitation indices of most meteorological stations decreased, except for the simple daily intensity index and the number of very heavy precipitation days. The extreme warm indices of most meteorological stations increased, and the extreme cold indices decreased. (3) Except for consecutive dry days, the frequency of extreme precipitation indices increased significantly, the severity and frequency of high-temperature events increased, while the frequency of low-temperature events increased, but the severity decreased. The results of rescaled range (R/S) analysis indicated that the climate in the Beijing–Tianjin–Hebei region will further tend to be warm and humid in the future. (4) The Polar/Eurasia Pattern, the East Atlantic Pattern, the Arctic Oscillation, and the East Atlantic/West Russian Pattern were most closely associated with extreme climate events in the Beijing–Tianjin–Hebei region. The multi-factor combination greatly enhanced the explanatory power of the teleconnection pattern for extreme climates

Identification and Functional Analysis of Tomato CIPK Gene Family

The calcineurin B-like interacting protein kinase (CIPK) protein family is a critical protein family in plant signaling pathways mediated by Ca2+, playing a pivotal role in plant stress response and growth. However, to the best of our knowledge, no study of the tomato CIPK gene family in response to abiotic stress has been reported. In this study, 22 members of the tomato CIPK gene family were successfully identified by using a combination of bioinformatics techniques and molecular analyses. The expression level of each member of tomato CIPK gene family under abiotic stress (low temperature, high salt, drought treatment) was determined by qRT-PCR. Results indicated that tomato CIPK demonstrated different degrees of responding to various abiotic stresses, and changes in SlCIPK1 and SlCIPK8 expression level were relatively apparent. The results of qRT-PCR showed that expression levels of SlCIPK1 increased significantly in early stages of cold stress, and the expression level of SlCIPK8 increased significantly during the three treatments at different time points, implicating Solanum lycopersicum CIPK1(SlCIPK1) and Solanum lycopersicum CIPK8 (SlCIPK8) involvement in abiotic stress response. SlCIPK1 and SlCIPK8 were silenced using Virus-induced gene silencing (VIGS), and physiological indexes were detected by low temperature, drought, and high salt treatment. The results showed that plants silenced by SlCIPK1 and SlCIPK8 at the later stage of cold stress were significantly less resistant to cold than wild-type plants. SlCIPK1 and SlCIPK8 silenced plants had poor drought resistance, indicating a relationship between SlCIPK1 and SlCIPK8 with response to low temperature and drought resistance. This is the first study to uncover the nucleotide sequence for tomato CIPK family members and systematically study the changes of tomato CIPK family members under abiotic stress. Here, we investigate the CIPK family’s response under abiotic stress providing understanding into the signal transduction pathway. This study provides a theoretical basis for elucidating the function of tomato CIPK at low temperature and its molecular mechanism of regulating low temperatures

Effects of Nanoparticles on Algae: Adsorption, Distribution, Ecotoxicity and Fate

With the rapid development of nanotechnology and widespread use of nanoproducts, the ecotoxicity of nanoparticles (NPs) and their potential hazards to the environment have aroused great concern. Nanoparticles have increasingly been released into aquatic environments through various means, accumulating in aquatic organisms through food chains and leading to toxic effects on aquatic organisms. Nanoparticles are mainly classified into nano-metal, nano-oxide, carbon nanomaterials and quantum dots according to their components. Different NPs may have different levels of toxicity and effects on various aquatic organisms. In this paper, algae are used as model organisms to review the adsorption and distribution of NPs to algal cells, as well as the ecotoxicity of NPs on algae and fate in a water environment, systematically. Meanwhile, the toxic effects of NPs on algae are discussed with emphasis on three aspect effects on the cell membrane, cell metabolism and the photosynthesis system. Furthermore, suggestions and prospects are provided for future studies in this area