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Cannabidiol (CBD) is a pharmacologically active metabolite of cannabis that is US Food and Drug Administration approved to treat seizures associated with Lennox-Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex in children aged 1 year and older. During clinical trials, CBD caused dose-dependent hepatocellular toxicity at therapeutic doses. The risk for toxicity was increased in patients taking valproate, another hepatotoxic antiepileptic drug, through an unknown mechanism. With the growing popularity of CBD in the consumer market, an improved understanding of the safety risks associated with CBD is needed to ensure public health. This review details current efforts to describe CBD pharmacokinetics and mechanisms of hepatotoxicity using both pharmacokinetic models and in vitro models of the liver. In addition, current evidence and knowledge gaps related to intracellular mechanisms of CBD-induced hepatotoxicity are described. The authors propose future directions that combine systems-based models with markers of CBD-induced hepatotoxicity to understand how CBD pharmacokinetics may influence the adverse effect profile and risk of liver injury for those taking CBD.SIGNIFICANCE STATEMENTThis review describes current pharmacokinetic modeling approaches to capture the metabolic clearance and safety profile of cannabidiol (CBD). CBD is an increasingly popular natural product and US Food and Drug Administration–approved antiepileptic drug known to cause clinically significant enzyme-mediated drug interactions and hepatotoxicity at therapeutic doses. CBD metabolism, pharmacokinetics, and putative mechanisms of CBD-induced liver injury are summarized from available preclinical data to inform future modeling efforts for understanding CBD toxicity.

Here, a strategy to overcome the stiff and brittle nature of cellulose-derived carbon nanofibrils (CCNFs) is proposed through a facile, low-cost, and scalable approach. Flexible and conformal CCNFs with a low bending rigidity below 55.4 mN and tunable conductivities of 0.14–45.5 S m–1are developed by introducing silanol as a multieffect additive in the electrospun hybrid nanofibrous network and subsequent carbonization at a relatively high temperature (900 °C) and chemical vapor deposition of polypyrrole (PPy) on the hybrid carbon nanofibril surface. Silica acts as a lubricant in each rigid carbon fiber to improve flexibility of the CCNF structure as well as a template during cellulose carbonization to prevent the melting of carbon nanofibrils. Meanwhile, the uniform coating of PPy leads to an improvement in electrical conductivity while conserving the porous structure and compressibility of the CCNF nets. These conductive hybrid CCNF films are evaluated as mechanoreceptors and physiological sensors, which are demonstrated to be applied in intelligent electronics including electronic skin, human–machine interfaces, and epidermic electrodes. The design or working principles of the hybrid CCNFs for achieving optimum applicable effects when applied in different scenarios are revealed.

Urban rail transit in high-altitude areas is developing gradually, but the failure of short circuit breaking of on-board large-capacity DC air circuit breaker (LC-DCCB) at 2–4 km altitudes has become severe and common. To interrupt short circuit current at 2–4 km altitudes of on-board LC-DCCB successfully, multi-physical coupling simulation of short circuit breaking of LC-DCCB at 2–4 km altitudes was conducted in this research based on the magneto-hydro-dynamics (MHD) model, and the simulation results were compared with those at 0 km altitude. The two-dimensional (2-D) transient distribution of physical parameters such as temperature, airflow, and electromagnetic fields in the arc chamber were obtained. The results indicate that the fundamental reasons for the failure of LC-DCCB to interrupt short circuit current arc at high altitudes are the arc root stagnation and arc reverse movement between splitter plates. Based on the simulation results, the arc chamber structure was optimized by setting U-shaped splitter plates to improve the interruption performance of LC-DCCB at high altitudes. Compared with the previous structure, the improved structure with three intercalary U-shaped splitter plates on both sides of the center line of the arc chamber has the best arc extinguishing performance at high altitudes, which can interrupt 18 kA short circuit current successfully at 3 km altitude, with an arc duration of 19.5 ms. This research reveals the fundamental cause for the difficulty in interrupting short circuit current arc in LC-DCCB at high altitudes, which can provide theoretical and technical guidance for the research and design of such a product.

A computational search for functional transcription-factor (TF) combinations is described using phylogenetically conserved sequences and microarray-based expression data. The search led to the discovery of several experimentally established TF associations, and also detected many homotypic combinations, supporting the importance of binding-site density in transcriptional regulation of higher eukaryotes.

Background: Ilexsaponin A1, one of the most representative triterpene saponin components in the roots of I. pubescens, showed its effects in anticoagulation and antithrombosis, attenuating ischemia-reperfusion-induced myocardial, angiogenesis and inhibiting phosphodiesterase. Objective: Reveal the key intestinal bacterial strains responsible for ilexsaponin A1 metabolism, and clarify their metabolic behavior. Methods: An accurate and sensitive LC-MS/MS method for the determination of “ilexsaponin A1 in General Anaerobic Medium (GAM) broth” was established and systematically validated. Then it was applied to screen and study the metabolic potential of the intestinal bacterial strains in an anaerobic incubation system. Results: Quantitation of ilexsaponin A1 could be performed within an analytical run time of 14.5 min, in the linear range of 2 - 2000 ng/ml. Enterobacter sakazakii, Bifidobacterium breve, Bifidobacterium adolescentis, Bifidobacterium catenulatum, and Bifidobacterium angulatum were identified to have a potential effect to metabolize ilexsaponin A1 to different extents; and further bacterial metabolic studies were performed to clarify their metabolic capacity and behavior. Conclusion: This paper contributes to a better understanding of the intestinal bacterial metabolism of ilexsaponin A1 and provides scientific evidence for its clinical application. Additionally, the importance of intestinal bacterial strains in the disposition of natural products was also highlighted.

In this report, the originally proposed rupestonic acid (5) and pechueloic acid (3) were efficiently synthesized. The chiral lactone 13, recycled from the degradation of saponin glycosides, was utilized to prepare the key chiral fragment 11. During the exploration of this convergent assembly strategy, the ring-closing metathesis (RCM), SmI2-prompted intermolecular addition, and [2,3]-Wittig rearrangement proved to be effective transformations for the synthesis of subunits.

Inoculation of wheat (Triticum aestivumL.) leaves with wheat powdery mildew fungus (Blumeria graminisf. sp. tritici) induces the cell death in adventitious roots. Reactive oxygen species (ROS) play a key role in respond to biotic stress in plants. To study the involvement of ROS and the degree of cell death in the wheat roots following inoculation, ROS levels and microstructure of root cells were analyzed in two wheat cultivars that are susceptible (Huamai 8) and resistant (Shenmai 8) to powdery mildew fungus. At 18 d after powdery mildew fungus inoculation, only Huamai 8 displayed the leaf lesions, while root cell death occurred in both varieties. Huamai 8 had a high level of ROS accumulation, which is associated with increased root cell degradation, while in Shenmai 8, there was little ROS accumulation correlating with slight root cell degradation. The molecular study about the expression levels of ROS scavenging genes (MnSODand CAT) in wheat roots showed that these genes expression decreased after the leaves of wheat was inoculated. The difference between Huamai 8 and Shenmai 8 on subcellular localization of H2O2and O2–was corresponded with the different down-regulation of the genes encoding for superoxide dismutase and catalase in two wheat cultivars. These results suggested that ROS were involved in the process by which powdery mildew fungus induced cell death in wheat roots.

Hesperetin, an abundant bioactive component of citrus fruits, is poorly water-soluble, resulting in low oral bioavailability. We developed new formulations to improve the water solubility, antioxidant activity, and oral absorption of hesperetin. Two nano-based formulations were developed, namely hesperetin-TPGS (D-α-tocopheryl polyethylene glycol 1000 succinate) micelles and hesperetin-phosphatidylcholine (PC) complexes. These two formulations were prepared by a simple technique called solvent dispersion, using US Food and Drug Administration (FDA)-approved excipients for drugs. Differential scanning calorimetry (DSC) and dynamic light scattering (DLS) were used to characterize the formulations’ physical properties. Cytotoxicity analysis, cellular antioxidant activity assay, and a pharmacokinetic study were performed to evaluate the biological properties of these two formulations. The final weight ratios of both hesperetin to TPGS and hesperetin to PC were 1:12 based on their water solubility, which increased to 21.5- and 20.7-fold, respectively. The hesperetin-TPGS micelles had a small particle size of 26.19 nm, whereas the hesperetin-PC complexes exhibited a larger particle size of 219.15 nm. In addition, the cellular antioxidant activity assay indicated that both hesperetin-TPGS micelles and hesperetin-PC complexes increased the antioxidant activity of hesperetin to 4.2- and 3.9-fold, respectively. Importantly, the in vivo oral absorption study on rats indicated that the micelles and complexes significantly increased the peak plasma concentration (Cmax) from 2.64 μg/mL to 20.67 and 33.09 μg/mL and also increased the area under the concentration–time curve of hesperetin after oral administration to 16.2- and 18.0-fold, respectively. The micelles and complexes increased the solubility and remarkably improved the in vitro antioxidant activity and in vivo oral absorption of hesperetin, indicating these formulations’ potential applications in drugs and healthcare products.

An efficient asymmetric approach to access functionalized pyrido- and pyrrolo[1,2-c][1,3]oxazin-1-ones has been developed through a nucleophilic addition–cyclization process of N,O-acetal with ynamides. A number of substituted ynamides 8a–8oand 3-silyloxypyrrolidine or piperidine N,O-acetals 6a, 7were amenable to this transformation, and the desired products 9a–9o, 10a–10mwere obtained with excellent regioselectivities and outstanding diastereoselectivities. Moreover, chiral ynamides 14a–14fcould also experience this addition–cyclization process to afford products 15a–15fin excellent yields.

A total of 103 drugs (including 14 combination drugs) were approved by the U.S. Food and Drug Administration from 2013 to 2016. Pharmacokinetic-based drug interaction profiles were analyzed using the University of Washington Drug Interaction Database, and the clinical relevance of these observations was characterized based on information from new drug application reviews. CYP3A was involved in approximately two-thirds of all drug-drug interactions (DDIs). Transporters (alone or with enzymes) participated in about half of all interactions, but most of these were weak-to-moderate interactions. When considered as victims, eight new molecular entities (NMEs; cobimetinib, ibrutinib, isavuconazole, ivabradine, naloxegol, paritaprevir, simeprevir, and venetoclax) were identified as sensitive substrates of CYP3A, two NMEs (pirfenidone and tasimelteon) were sensitive substrates of CYP1A2, one NME (dasabuvir) was a sensitive substrate of CYP2C8, one NME (eliglustat) was a sensitive substrate of CYP2D6, and one NME (grazoprevir) was a sensitive substrate of OATP1B1/3 (with changes in exposure greater than 5-fold when coadministered with a strong inhibitor). Approximately 75% of identified CYP3A substrates were also substrates of P-glycoprotein. As perpetrators, most clinical DDIs involved weak-to-moderate inhibition or induction. Only idelalisib showed strong inhibition of CYP3A, and lumacaftor behaved as a strong CYP3A inducer. Among drugs with large changes in exposure (≥5-fold), whether as victim or perpetrator, the most-represented therapeutic classes were antivirals and oncology drugs, suggesting a significant risk of clinical DDIs in these patient populations.

Autophagy induced by titanium dioxide nanoparticles (TiO2NPs) has been realized nowadays, but the underlying mechanisms remain largely unknown. Animal studies have confirmed that autophagy might be an important mechanism to impair placenta development, but the reversal of damage is not clear. Here, we used human HTR-8/SVneo (HTR) cells as a proper model to explore how autophagy is regulated in TiO2NP-exposed human placenta cells. Our studies showed that TiO2NPs could enter HTR cells and locate in cytoplasm. Although they did not affect cell viability even under 100 μg ml−1, autophagy was observed and cell migration ability was severely impaired. Further study showed that TiO2NPs increased the expressions of both miR-96-5p and miR-101-3p and then, they targeted mTORand decreased the expression of mTOR proteins. In addition, miR-96-5p also targeted Bcl-2to down-regulate Bcl-2 protein level, which is also a key regulator of autophagy. We proved that when two microRNA inhibitors were added, cell autophagy was, to a greater extent, reversed compared with the result when one inhibitor was added, and the cell migration ability was also reversed to a greater degree. Our studies revealed that TiO2NPs might impair placenta development viaautophagy. Moreover, miR-96-5p as well as miR-101-3p may act as potential targets to reverse TiO2NP-induced autophagy and placenta dysfunction.

This paper demonstrates the principles of static and dynamic north-finding methods by measuring the projection of the Earth’s rotation rate with a fiber optic gyroscope. For a comprehensive comparison of the two methods, the influence of a closed-loop feedback mechanism of a servo motor in a turntable is taken into consideration. Thus, we proposed the static and dynamic north-finding experimental implementations according to the different impact of the motor jitters and the different seeking times. Experimental results show that the dynamic method can reduce the north-finding bias error and instability by 60.1% and 54.6%, respectively, in the seeking time of 360 s, while the reduced proportions are 81.3% and 82.5%, respectively, in the seeking time of 120 s, compared with the static method under the jittering effect of the turntable. Therefore, it can be concluded that the dynamic method is more accurate and robust to the jittering effect.

Based on improved multi-objective particle swarm optimization (MOPSO) algorithm with principal component analysis (PCA) methodology, an efficient high-dimension multi-objective optimization method is proposed, which, as the purpose of this paper, aims to improve the convergence of Pareto front in multi-objective optimization design. The mathematical efficiency, the physical reasonableness and the reliability in dealing with redundant objectives of PCA are verified by typical DTLZ5 test function and multi-objective correlation analysis of supercritical airfoil, and the proposed method is integrated into aircraft multi-disciplinary design (AMDEsign) platform, which contains aerodynamics, stealth and structure weight analysis and optimization module. Then the proposed method is used for the multi-point integrated aerodynamic optimization of a wide-body passenger aircraft, in which the redundant objectives identified by PCA are transformed to optimization constraints, and several design methods are compared. The design results illustrate that the strategy used in this paper is sufficient and multi-point design requirements of the passenger aircraft are reached. The visualization level of non-dominant Pareto set is improved by effectively reducing the dimension without losing the primary feature of the problem.

As a follow up to previous reviews, the aim of the present analysis was to systematically examine all drug metabolism, transport, pharmacokinetics (PK), and drug-drug interaction (DDI) data available in the 33 new drug applications (NDAs) approved by the Food and Drug Administration (FDA) in 2015, using the University of Washington Drug Interaction Database, and to highlight the significant findings. In vitro, a majority of the new molecular entities (NMEs) were found to be substrates or inhibitors/inducers of at least one drug metabolizing enzyme or transporter. In vivo, 95 clinical DDI studies displayed positive PK interactions, with an area under the curve (AUC) ratio ≥ 1.25 for inhibition or ≤ 0.8 for induction. When NMEs were considered as victim drugs, 21 NMEs had at least one positive clinical DDI, with three NMEs shown to be sensitive substrates of CYP3A (AUC ratio ≥ 5 when coadministered with strong inhibitors): cobimetinib, isavuconazole (the active metabolite of prodrug isavuconazonium sulfate), and ivabradine. As perpetrators, nine NMEs showed positive inhibition and three NMEs showed positive induction, with some of these interactions involving both enzymes and transporters. The most significant changes for inhibition and induction were observed with rolapitant, a moderate inhibitor of CYP2D6 and lumacaftor, a strong inducer of CYP3A. Physiologically based pharmacokinetics simulations and pharmacogenetics studies were used for six and eight NMEs, respectively, to inform dosing recommendations. The effects of hepatic or renal impairment on the drugs’ PK were also evaluated to support drug administration in these specific populations.

Regulatory approval documents contain valuable information, often not published, to assess the drug–drug interaction (DDI) profile of newly marketed drugs. This analysis aimed to systematically review all drug metabolism, transport, pharmacokinetics, and DDI data available in the new drug applications and biologic license applications approved by the U.S. Food and Drug Administration in 2014, using the University of Washington Drug Interaction Database, and to highlight the significant findings. Among the 30 new drug applications and 11 biologic license applications reviewed, 35 new molecular entities (NMEs) were well characterized with regard to drug metabolism, transport, and/or organ impairment and were fully analyzed in this review. In vitro, a majority of the NMEs were found to be substrates or inhibitors/inducers of at least one drug metabolizing enzyme or transporter. In vivo, when NMEs were considered as victim drugs, 16 NMEs had at least one in vivo DDI study with a clinically significant change in exposure (area under the time-plasma concentration curve or Cmaxratio ≥2 or ≤0.5), with 6 NMEs shown to be sensitive substrates of cytochrome P450 enzymes (area under the time-plasma concentration curve ratio ≥5 when coadministered with potent inhibitors): paritaprevir and naloxegol (CYP3A), eliglustat (CYP2D6), dasabuvir (CYP2C8), and tasimelteon and pirfenidone (CYP1A2). As perpetrators, seven NMEs showed clinically significant inhibition involving both enzymes and transporters, although no clinically significant induction was observed. Physiologically based pharmacokinetic modeling and pharmacogenetics studies were used for six and four NMEs, respectively, to optimize dosing recommendations in special populations and/or multiple impairment situations. In addition, the pharmacokinetic evaluations in patients with hepatic or renal impairment provided useful quantitative information to support drug administration in these fragile populations.

Experiment design method is a key to construct a highly reliable surrogate model for numerical optimization in large-scale project. Within the method, the experimental design criterion directly affects the accuracy of the surrogate model and the optimization efficient. According to the shortcomings of the traditional experimental design, an improved adaptive sampling method is proposed in this paper. The surrogate model is firstly constructed by basic sparse samples. Then the supplementary sampling position is detected according to the specified criteria, which introduces the energy function and curvature sampling criteria based on radial basis function (RBF) network. Sampling detection criteria considers both the uniformity of sample distribution and the description of hypersurface curvature so as to significantly improve the prediction accuracy of the surrogate model with much less samples. For the surrogate model constructed with sparse samples, the sample uniformity is an important factor to the interpolation accuracy in the initial stage of adaptive sampling and surrogate model training. Along with the improvement of uniformity, the curvature description of objective function surface gradually becomes more important. In consideration of these issues, crowdness enhance function and root mean square error (RMSE) feedback function are introduced in Ccriterion expression. Thus, a new sampling method called RMSE and crowdness enhance (RCE) adaptive sampling is established. The validity of RCE adaptive sampling method is studied through typical test function firstly and then the airfoil/wing aerodynamic optimization design problem, which has high-dimensional design space. The results show that RCE adaptive sampling method not only reduces the requirement for the number of samples, but also effectively improves the prediction accuracy of the surrogate model, which has a broad prospects for applications.

A model of ion energy distribution of dual frequencies capacitively coupled plasma (CCP) has been investigated, it is important to analyze these phenomenon and mechanism in order to control the microelectronic processes of integrated circuit and develop the base theories of plasma physics. We focused on the function of the ion energy distributions under high and low frequencies (dual frequencies) drive in capacitive discharges, we derived a theory model of the dual frequencies driven IEDs from analyzing theories. The model can analyze and predict the IEDs under different high and low frequencies driven, which results in accurate multi-peaks IEDs and energy width for the given control parameters, particle-in-cell (PIC) simulations are used to verify this model.

Based on the physical models of PROSPECT, SAIL and porosity model, hyperspectral data and canopy coverage data of different combined scenes were simulated. According to the simulated data, we chose four sensitive bands and four sensitive vegetation indexes highly correlated to vegetation canopy coverage, and analyzed the correlation between sensitive bands, sensitive vegetation indexes and canopy coverage. Then we built a regression model of canopy coverage with EVI highly correlated with canopy coverage. At last, we verified this model by experimental data from ground measurement experiment. It shows that there is a high correlation between EVI and canopy coverage and the regression model built by EVI can produce an effective result and the RMSE is less than 0.09.

The objective of this paper is to compare and analyze the forest height retrieval methods from Polarimetric SAR Interferometry(POLINSAR).Both of the methods based on DEM difference and that on interferometry coherence amplitude are generalized, analyzed, and compared.Also in this paper combined methods of DEM difference and interferometry coherence amplitude are proposed and validated.The ESA full[removed info]polarimetric interferometry L-band data are used for forest height analysis.The results show that the height is severely underestimated using DEM difference method,In constast,interferometry coherence amplitude method has a overest imation of height.The combined method of DEM difference and interferometry coherence amplitude has a much better estimate,closer to the true height than these two methods.

The voltages, resonant waves and frequencies how to influence on the ion energy distributions (IEDs) from multiple frequencies driven in capacitive discharges, it is important to analyze these phenomenon and mechanism in order to control the microelectronic processes of integrated circuit and develop the base theories of plasma physics. We focused on the function of the ion energy distributions under high and low frequencies (dual frequency) drive in capacitive discharges, we derived a model of computation of the multiple frequencies driven IEDs from analyzing theories. The model can analyze and predict the IEDs under different high and low frequencies driven, the results from the model are in good agreement with these important data from public publish.

In this paper, two typical chemical agents SAP and PAM were selected to reduce NPS pollution. Soil water content, nutrient transport and soil erosion have been researched. The results showed that the water deep percolation was reduced and the moisture of root zone increased by 3.6%-12.69% after chemical agents application; PAM can immobile soil grains, and significantly reduce soil erosion on sloping land by 25.5%-53.4%. The synergies of PAM and SAP can significantly influence transport of nutrients in the soil vertical profile, moreover, the content of nutrient was enriched in root zone that the content of Nitrate-N increased 14.7% and Ammonium-N increased 9.8%. It can been found that CL2 (SAP150 kg/k㎡+PAM4.5 kg/k㎡) treatment is superior to CL1 (SAP150 kg/k㎡+PAM2.25 kg/k㎡) in soil moisture conservation and reducing NPS pollution in two slopes orchards.

The interference suppression of GPS received signal is realized by utilizing array antenna in this paper, and time delay is introduced for signal processing, thus forming a spatial-time two dimension processing mode. To realize the two dimensional processing on interference suppression, the large amount of operation is a difficulty, so it is necessary to reduce the rank. Multistage Weiner Filter (MWF) is an effective way to reduce the rank of the filter, but a drawback exists, that the subspace rank of noise can't be estimated with the classical MWF method. The MWF is analyzed in this paper, and the analytical part of MWF is adopted to map the received signal into a new signal vector. Through analyzing the covariance matrix of the new signal vector, a robust method is proposed to estimate the subspace rank. Simulations show that the subspace rank can be estimated accurately by the proposed method. Comparing the proposed method with the traditional method of setting the threshold of MSE, the subspace rank estimated is more accurate and credible, and it exhibits superior anti-jam performance. [ABSTRACT FROM AUTHOR]

Mullite was synthesized by firing precursors prepared from kaolinite via a wet chemistry method at various temperatures. The acicular mullite grains were formed in samples with addition of AlF3 by this process. The phase evolution and morphology of the fired samples were investigated. For the samples without AlF3, the mullitization began to occur at 1300 and almost completed at 1550 , the grains formed were normal-shaped. For the samples with AlF3, acicular mullite was formed, and mullitization began to occur at 1100 and completed at 1250 . The growth of the acicular mullite was associated with a liquid phase. The formed acicular mullite was alumina-rich and had a composition of about 73.4 wt% Al2O3 and 26.6 wt% SiO2 (Al2O3/SiO2=1.65, molar ratio).

Spherical α-Fe2O3/Ag core/shell nanoparticles were prepared by reducing Ag(NH3)2+ with formaldehyde using the seeding method. 3- Aminopropyltriethoxysilane (APS) acts as a “bridge” to link between α-Fe2O3 core and Ag shell. The obtained nanoparticles were characterized by XRD, TEM, SEM, EDS, and Roman. The results show thatα-Fe2O3 cores are coated by Ag shell completely. The average size of α-Fe2O3/Ag nanoparticles is 95 nm and the thicknesses of Ag shell are 15nm in 3.7% HCHO and 1.0M AgNO3. The thickness of Ag shell can be tunable by changing reaction conditions, such as the concentration of AgNO3, reduction reaction rate. The surface-enhanced Raman scattering (SERS) effect of the core/shell particles are measured with Pyridine (Py) as molecule probe. SERS indicate that the Raman signals of Py adsorbed on α-Fe2O3/Ag nanoparticles exhibit large enhancement at 1010 and 1038 cm-1 respectively. And the intensity of signals is enhanced with the increase of the thickness of Ag shell. The uniform and rough surface of α-Fe2O3/Ag particles exhibits strong SERS activity in 3.7% HCHO and 1.0M AgNO3. The spherical α-Fe2O3/Ag core/shell nanoparticles exhibit SERS activity.

Rutaecarpine is reported as a potent inducer of CYP1A2 enzyme in rats. There are natural herbal supplements containing rutaecarpine that are designed to enhance the CYP1A2-dependent removal of caffeine from blood so that people can have coffee later in the day without causing sleep interference. This study aimed to determine the minimum amount of time needed from oral rutaecarpine administration until the observed effect of rutaecarpine on caffeine pharmacokinetics (PK) in 15 male Sprague-Dawley rats. PK parameters for caffeine and its metabolites in the control and rutaecarpine groups were calculated using WinNonlin®. Results showed that orally administered rutaecarpine at 100 mg/kg dose as early as 3 h before oral caffeine administration significantly decreased the oral systemic exposure and mean residence time of caffeine and its metabolites due to decreased caffeine bioavailability (by up to 75%) and increased clearance. The systemic exposure of caffeine and its metabolites were also decreased when caffeine was given intravenously, though this effect was less pronounced than when caffeine was given orally. Although plasma level of rutaecarpine was undetectable (less than 10 ng/mL), rutaecarpine still induced hepatic CYP1A2 activity. Results from 7-methoxyresorufin O-demethylation activity, which is specific to CYP1A2, showed that 3 h after one rutaecarpine oral dose, CYP1A2 activity in rat liver tissue was increased by 3- fold. This finding suggested that rutaecarpine effectively induced CYP1A2 activity in the liver.

The interaction of tumor necrosis factor (TNF)-α with the endothelium is a pivotal factor during endotoxemia. Inflammatory conditions are characterized by the activation of the transcription factor NF-κB and the expression of inflammatory mediators. Previous reports indicate that inhibition of NF-κB activation during sepsis may be beneficial to the microvasculature. In addition, the phosphatidylinositol-3-kinase/Akt signaling pathway (PI3-kinase/Akt) has been shown to be cytoprotective. In this study, we examined the effect of inhibition of NF-κB and PI3-kinase/Akt on cell viability, cytokine production, inducible nitric oxide synthase (iNOS) expression, and nitric oxide (NO) generation by TNF-α-treated cultured microvascular endothelial cells. TNF-α induced significant cytotoxicity and was associated with increased inflammatory cytokines and NO and increased expression of iNOS. The NF-κB inhibitor, pyrrolidine dithiocarbamate (PDTC), prevented these increases and significantly attenuated the TNF-α-induced cytotoxicity. TNF-α also caused PI3-kinase/Akt activation, which was further increased by PDTC and prevented by the PI3-kinase inhibitor, LY294002. Inhibition of PI3-kinase/Akt also significantly potentiated TNF-α-mediated cytotoxicity. LY294002 treatment resulted in the appearance of increased apoptosis, compatible with the known anti-apoptotic properties of PI3-kinase/Akt. The present results therefore demonstrate a cytotoxic effect of TNF-α in microvascular endothelial cells which can be attenuated by NF-κB inhibition. In addition, PI3-kinase/Akt activation during TNF-α exposure may represent a compensatory anti-necrotic and anti-apoptotic pathway. The cytoprotective effects of NF-κB inhibition and PI3-kinase/Akt activation may have potential implications in the treatment of endotoxemia and septic shock.

The interaction of tumor necrosis factor (TNF)- with the endothelium is a pivotal factor during endotoxemia. Inflammatory conditions are characterized by the activation of the transcription factor NF-B and the expression of inflammatory mediators. Previous reports indicate that inhibition of NF-B activation during sepsis may be beneficial to the microvasculature. In addition, the phosphatidylinositol-3-kinase/Akt signaling pathway (PI3-kinase/Akt) has been shown to be cytoprotective. In this study, we examined the effect of inhibition of NF-B and PI3-kinase/Akt on cell viability, cytokine production, inducible nitric oxide synthase (iNOS) expression, and nitric oxide (NO) generation by TNF--treated cultured microvascular endothelial cells. TNF- induced significant cytotoxicity and was associated with increased inflammatory cytokines and NO and increased expression of iNOS. The NF-B inhibitor, pyrrolidine dithiocarbamate (PDTC), prevented these increases and significantly attenuated the TNF--induced cytotoxicity. TNF- also caused PI3-kinase/Akt activation, which was further increased by PDTC and prevented by the PI3-kinase inhibitor, LY294002. Inhibition of PI3-kinase/Akt also significantly potentiated TNF--mediated cytotoxicity. LY294002 treatment resulted in the appearance of increased apoptosis, compatible with the known anti-apoptotic properties of PI3-kinase/Akt. The present results therefore demonstrate a cytotoxic effect of TNF- in microvascular endothelial cells which can be attenuated by NF-B inhibition. In addition, PI3-kinase/Akt activation during TNF- exposure may represent a compensatory anti-necrotic and anti-apoptotic pathway. The cytoprotective effects of NF-B inhibition and PI3-kinase/Akt activation may have potential implications in the treatment of endotoxemia and septic shock.

Endotoxin-related acute kidney injury has been shown to profoundly induce nitric oxide (NO), which activates sympathetic and renin-angiotensin system, resulting in renal vasoconstriction. While vascular muscle cells are known to upregulate inducible NO synthase (iNOS), less is known about the endothelium as a source of NO during endotoxemia. Studies were, therefore, undertaken both in vitro in mouse microvascular endothelial cells and in vivo in transgenic mice with overexpression of endothelial GTP cyclohydrolase, the rate-limiting enzyme for tetrahydrobiopterin, a cofactor for NO synthase. LPS significantly induced endothelial cell iNOS expression and NO concentration in the culture media, with no change in endothelial NO synthase expression. GTP cyclohydrolase-1 transgenic (Tg) mice demonstrated a significant increase in baseline urine NO-to-creatinine ratio and a more significant increase in renal iNOS expression and serum NO levels with LPS treatment compared with the wild-type (WT) mice. Glomerular filtration rate and renal blood flow decreased significantly in Tg mice with 1.0 mg/kg LPS, while no changes were observed in WT with the same dose of LPS. Serum IL-6 levels were significantly higher in Tg compared with WT mice during endotoxemia. The antioxidant tempol improved the glomerular filtration rate in the Tg mice. Thus endothelium can be an important source of iNOS and serum NO concentration during endotoxemia, thereby increasing the sensitivity to AKI. Reactive oxygen species appear to be involved in this acute renal injury in Tg mice during endotoxemia.

Three new sesquiterpenes (1−3), together with four known sesquiterpene lactones, were isolated from the flowers of Inula britannica var. chinensis. Structures were established on the basis of high-field 1D and 2D NMR methods supported by HRMS. All sesquiterpene lactones were tested for cytotoxicity as well as apoptotic ratio in human COLO 205, HT 29, HL-60, and AGS cancer cells. Compounds 3 and 4, two α-methylene γ-lactone-bearing sesquiterpenes, were modestly active in these assays.

As a triterpene saponin, ilexsaponin A1 is one of the most abundant, representative and active components in plants of Ilex pubescens, used in the treatment of cardiovascular diseases. This study aimed to identify the metabolites of ilexsaponin A1 and evaluate its in vitroinhibitory drug-drug interaction (DDI) potential by using human liver microsomes (HLM) and cytochrome P450 enzymes (CYPs)-specific probes, with all the qualitative and quantitative analysis performed by LC-MS/MS. As a result, two metabolites generated through the metabolic pathways of glucuronic acid conjugation and glucose conjugation were first time detected in the HLM. An inhibitory DDI evaluating system consisting of 7 major CYP enzymes involving 8 CYP-catalyzed reactions was established, validated and then used for the DDI evaluation. Our data suggested ilexsaponin A1 and its metabolite, ilexgenin A, are not direct or mechanism-based inhibitors of CYP1A2, 2B6, 2C8, 2C9, 2D6, 2E1 or 3A4/5 at 0.05–10 μM. A significant decreased remaining activity of CYP2B6 (from 77.89 % to 23.19 %) was observed in a dose-dependent manner when increased the concentration of ilexsaponin A1 from 50 to 500 μM. Collectively, our data demonstrate ilexsaponin A1 is unlikely to cause DDIs by inhibiting co-administered drugs metabolized by these CYP enzymes.

An experimental apparatus for X-Yelectrostatic scanning implantation of MeV ions and in situ Rutherford backscattering analysis has been set up on a 3 MV tandem accelerator at Fudan University. MeV ion beam mixing in Au/Si and Au/Ge systems has been studied. The uniformity of the scanning beam was checked by the implanted Au+ion distribution in a Si wafer. Au thin films with thickness of about 32 nm were evaporated on Si and Ge single-crystal substrates, and the samples were then bombarded by 1 MeV Ag+ions with various fluences at room temperature and analyzed in situ using the 2 MeV He+ion RBS technique.

The correction to the funding in Appl. Opt.56, 6504 (2017)APOPAI0003-693510.1364/AO.56.006504 is presented in this erratum.

The possibility of using visible/near infrared (Vis/NIR) transmission spectroscopic technique in the 513–850 nm region coupled with partial least squares-linear discriminant analysis (PLS-LDA) and other chemometric methods to classify potatoes with blackheart was investigated. The discrimination performance of different morphological correction methods, including weight correction, height correction, and volume correction, was compared. The results showed that height corrected transmittance has the best performance, with both calibration and validation sets having a success rate of 97.11%. Out of 1800 wavelengths, only six wavelengths (711, 817, 741, 839, 678, and 698 nm) were selected as the optimum wavelengths for the discrimination of blackheart tubers based on principal component analysis (PCA). The data analysis showed that the overall classification rate by PLS-LDA method decreased from 97.11% to 96.82% in calibration set and from 97.11% to 96.53% in validation set, which was acceptable. The importance of these conclusions may be helpful to transfer Vis/NIR transmission technology from laboratory to industrial application in nondestructive, real-time, or portable measurement of potatoes quality.