Search

DHDK is a novel diaryl heptanone analog isolated from mistletoe. (1 E, 4 E) 1,7‐bis (4‐hydroxyphenyl) hept‐1,4‐diene‐3‐one (DHDK) exhibits good antitumor activity and excellent stability, but it doesn't have good solubility or bioavailability. In order to improve this deficiency, the structure was modified and five new DHDK derivatives were successfully synthesized. The in vitro cytotoxic activity of DHDK derivatives against four cancer cell lines was determined by Cell Counting Kit‐8 (CCK‐8) assay. The results show that DHDK derivatives exhibit excellent potential, especially for human multiple myeloma cells (KMS‐11) and triple‐negative breast cancer cell line (MDA‐MB 231). The equilibrium solubility and oil‐water partition coefficient of DHDK derivatives were better improved by structural modification. [ABSTRACT FROM AUTHOR]

A large number of pollutants existing in the environment can last for a long time, and their potential toxic effects can transfer from parents to their offspring. Thus, it is necessary to investigate the toxicity of environmental pollutants across multigenerations and the underlying mechanisms in organisms. Due to its short life cycle and sensitivity to environmental exposures, Caenorhabditis elegans is an important animal model for toxicity assessment of environmental pollutants across multigenerations. In this review, we introduced the transgenerational and multigenerational toxicity caused by various environmental pollutants in C. elegans. Moreover, we discussed the underlying mechanisms for the observed transgenerational and multigenerational toxicity of environmental contaminants in C. elegans. Caenorhabditis elegans is an important animal model for the study of transgenerational and multigenerational toxicology. In this review, the transgenerational and multigenerational toxicity induction of toxicants in nematodes was introduced and summarized. Moreover, the underlying cellular and molecular mechanisms for the transgenerational toxicity of toxicants were further discussed. This review will be helpful for understanding the important value of C. elegans for the assessment of transgenerational and multigenerational toxicity and the study of transgenerational toxicology. [ABSTRACT FROM AUTHOR]

Mental disorders are associated with dysregulated metabolism, but comprehensive investigations of their metabolic similarities and differences and their clinical relevance are few. Here, based on the plasma metabolome and lipidome of subcohort1, comprising 100 healthy participants, 55 cases with anxiety, 52 persons with depression, and 41 individuals with comorbidity, which are from WCHAT, a perspective cohort study of community‐dwelling older adults aged over 50, multiple metabolites as potential risk factors of mental disorders were identified. Furthermore, participants with mental illnesses were classified into three subtypes (S1, S2, and S3) by unsupervised classification with lipidomic data. Among them, S1 showed higher triacylglycerol and lower sphingomyelin, while S2 displayed opposite features. The metabolic profile of S3 was like that of the normal group. Compared with S3, individuals in S1 and S2 had worse quality of life, and suffered more from sleep and cognitive disorders. Notably, an assessment of 6,467 individuals from the WCHAT showed an age‐related increase in the incidence of depression. Seventeen depression‐related metabolites were significantly correlated with age, which were validated in an independent subcohort2. Collectively, this work highlights the clinical relevance of metabolic perturbation in mental disorders, and age‐related metabolic disturbances may be a bridge‐linking aging and depressive. [ABSTRACT FROM AUTHOR]

Aconiti Radix [Chuanwu (CW)] is widely used to treat chronic and intractable diseases due to its remarkable curative effect. CW has been combined with honey for thousands of years to reduce toxicity and enhance efficacy. This study first determined the compatibility mechanism of CW with honey using a comparative pharmacokinetic concept. We developed and validated a simple, sensitive, specific, and accurate UHPLC–MS/MS method to simultaneously determine five Aconitum alkaloids in rat plasma after the oral administration of CW decoction and CW–honey concentrated solution. Pharmacokinetic parameters were significantly different between the two groups (P < 0.01 and P < 0.05). Compared with the CW group, Cmax and AUC0 → t decreased in the CW–honey group for three diester‐diterpenoid alkaloids (hypaconitine, mesaconitine, and aconitine); Tmax and T1/2 were prolonged. However, Cmax and AUC0 → t increased in the CW–honey group for two monoester‐diterpenoid alkaloids (benzoylaconine and benzoylmesaconine); Tmax was shortened, and T1/2 was prolonged. These findings suggest that honey affected the pharmacokinetic behaviors of five Aconitum alkaloids. We speculate that the detoxification and synergism of honey might result from reducing the toxicity of diester‐diterpenoid alkaloids and promoting the biological activity of monoester‐diterpenoid alkaloids in vivo. This study provides a theoretical basis for the clinical use of CW combined with honey. [ABSTRACT FROM AUTHOR]

The quaternary ammonium oxime reactivators are a class of important reactivators for nerve agents poisoning, and their sensitive and specific analysis in biomedical samples meets many challenges due to their highly polar properties. In present paper, a novel determination method based on surface‐enhanced Raman spectrometry (SERS) was developed for series of quaternary ammonium oxime reactivators. The self‐cleaning effect of iodine anion on the surface of porous shell‐insulated nanoparticles and the electrostatic adsorption effect were proved to be effective to remove the strong interference of protein and other coexisting substances and significantly improve the response intensity and fingerprint feature of Raman peaks. The analysis of five important quaternary ammonium oxime reactivators (PAM‐Cl, TMB‐4, MMB‐4, HI‐6, LüH6) was achieved in biomedical samples, which had the merit of simple sample pretreatment, rapid speed, high sensitivity, and fingerprint peak characteristics. The detection limits reached values of as low as 0.5 ng·mL−1 for dipyridyl quaternary ammonium oxime reactivators. The method has been successfully used for blood concentration monitoring in vivo and evaluation of the liposomes drug delivery ability to penetrate the blood–brain barrier in mice. [ABSTRACT FROM AUTHOR]

Polythiophenes (PTs) are promising electron donors in organic solar cells (OSCs) due to their simple structures and excellent synthetic scalability. However, the device performance of PT‐based OSCs is rather poor due mainly to large photon energy losses and an unfavorable active layer morphology. Herein, the authors report a new PT, which is abbreviated as P5TCN‐2F and features cyano‐group substituents for high‐efficiency OSCs. The cyano‐group endows P5TCN‐2F with a deep‐lying highest occupied molecular orbital energy level, which thereby contributed to high open‐circuit voltage in OSCs as a result of reduced non‐radiative recombination energy loss. Moreover, the cyano‐group leads to strong interchain interaction, improved polymer crystallinity, and appropriate miscibility with the prevailing non‐fullerene acceptors. Consequently, P5TCN‐2F offers over 15% power conversion efficiency when blended with various Y‐series non‐fullerene acceptors (Y6, Y6‐BO, eC9, and L8‐BO). Particularly, a champion efficiency of 16.1% is obtained by the P5TCN‐2F:Y6 blend, which is largely higher than that of any previous PT‐based OSCs. Moreover, the average figure of merit of the active layer based on P5TCN‐2F is much superior to that of benzodithiophene‐based polymers. These results suggest the renaissance of PT‐based OSCs and have opened an avenue to access high‐performance materials for the large‐scale production of OSC modules. [ABSTRACT FROM AUTHOR]

Background and purpose: Motoric cognitive risk (MCR) syndrome characterized by subjective cognitive complaints and slow gait has been proposed and validated as a pre‐dementia syndrome. The overall and specific ethnic prevalence of MCR and the associated factors are poorly understood in middle‐aged to older community‐dwelling residents in west China. Methods: The present study included 6091 samples from the prospective cohort study, West China Health and Aging Trend (WCHAT). Multidimensional factors of demography, lifestyle, social support, anthropometrics and body components, and clinical status were investigated and analyzed by univariate and multivariate logistic regression models. Lasso regression and K‐fold cross‐validation were conducted to construct the most predictive model with fitted factors. Results: The overall prevalence of MCR was 9.74%, and ethnically the prevalence was 14.25% in Tibetan, 11.03% in Yi, 10.72% in Han, 5.18% in Uighur and 4.55% in Qiang, respectively. In the adjusted models, the positively associated risk factors included diabetes mellitus (odds ratio [OR] = 1.51, p = 0.007), osteoarthritis (OR = 1.50, p = 0.002), depression (OR = 1.36, p = 0.005), poor sleep (OR = 1.21, p = 0.045), comorbidity (OR = 1.49, p = 0.001) and falls in the last 12 months (OR = 1.34, p = 0.031). Of note, every 1‐unit increase of value in stroke was associated with an approximate 3‐fold higher risk of having MCR, whilst in high‐density lipoprotein with a 30% lower risk of MCR,respectively. Conclusions: Profiles of MCR from the aspects of ethnicity and the presenium stage need further exploration. It is a promising strategy to apply MCR as a primary prevention tool to prevent dementia. [ABSTRACT FROM AUTHOR]

UHPLC combined with Fourier‐transform ion cyclotron resonance MS metabonomic approach was employed to screen the differential components between normal rats and yeast‐induced pyrexia rats after an oral administration of Gegenqinlian decoction (GQLD). Nine compounds, namely puerarin, daidzein, baicalin, wogonoside, wogonin, berberine, palmatine, jateorhizine, and coptisine, were identified as differential components in the plasma. A rapid, sensitive, selective, and accurate UHPLC–MS method was developed and fully validated for the simultaneous determination of the screened components in rat plasma after an oral administration of GQLD. The values for the limit of quantification ranged from 0.025 to 5.0 ng/mL. The inter‐ and intra‐day precision of all analytes was ≤10.7%, with an accuracy of ≤10.5%. Good extraction recovery and matrix effects were also obtained. The method was successfully applied to a comparative pharmacokinetic study of GQLD in normal and pyrexia rats. The results showed that the pharmacokinetic behavior of the analytes was changed in pyrexia rats compared to normal rats. These results could provide beneficial guidance for clinical applications of GQLD. [ABSTRACT FROM AUTHOR]

R‐/S‐2‐(2‐hydroxypropanamido)‐5‐trifluoromethyl benzoic acid (R‐/S‐HFBA) is a novel COX inhibitor with remarkable anti‐inflammatory and antiplatelet aggregation activities, but no gastrointestinal toxicity. In our previous study, the different pharmacokinetic profiles of the two enantiomers in rats were observed after administration of R‐HFBA and S‐HFBA. Stereoselective protein binding of the two enantiomers may be a reason for the different pharmacokinetic behaviors. In this study, we developed and validated an UPLC‐MS/MS method for determining stereoselective binding of HFBA enantiomers to rat, dog, and human plasma in vitro. Chromatographic separation was achieved by gradient elution with a flow rate of 0.4 mL/min. MS/MS detection was operated in positive electrospray using multiple reaction monitoring (MRM) mode. The method was proved to be linear over the concentration range of 0.005 to 10 μg/mL with a lower limit of quantification of 0.005 μg/mL. The developed method was successfully employed to the plasma protein binding study of HFBA enantiomers. Equilibrium dialysis method was applied to assess drug‐plasma protein interactions. The results showed that the enantiomers were both extensively bound to three species plasma and protein binding of R‐/S‐HFBA was concentration dependent. R‐HFBA and S‐HFBA showed significant species difference among rat, dog, and human plasma and stereoselective plasma protein binding. [ABSTRACT FROM AUTHOR]

Abstract: A rapid, simple and sensitive ultra‐fast liquid chromatography tandem mass spectrometric method was developed and validated for simultaneous determination and tissue distribution studies of rosmarinic acid, salvianolic acid D, lithospermic acid and salvianolic acid B in rats after intravenous administration of salvianolic acid for injection. The tissue homogenate samples were pretreated by protein precipitation with pre‐cooled acetonitrile. Chromatographic separation was achieved on a Waters Cortecs UPLC C18 column (1.6 μm, 2.1 × 100 mm) with a mobile phase composed of 0.1% formic acid–water and 0.1% formic acid–acetonitrile. Analytes were detected by electrospray ionization mass spectrometry and quantitated using multiple reaction monitoring. The method was fully validated. The calibration curves for the four phenolic acids were linear in the given concentration ranges. The precisions (relative standard deviation) in the measurement of quality control samples were <10% and the accuracies (relative error) were in the range of 0.28–11.22%. The reliable method was successfully applied to the tissue distribution studies of the four phenolic acids. The results showed that rosmarinic acid, salvianolic acid D, lithospermic acid and salvianolic acid B were rapidly distributed in tissues with the major amount found in kidney, and little crossed the blood–brain barrier. The developed method and the results provide a basis for further studies. [ABSTRACT FROM AUTHOR]

The purpose of this study was to compare intestinal permeability between enantiomers of 2-(2-hydroxypropanamido) benzoic acid (( R) -/( S) -HPABA), a marine-derived antiinflammatory drug, using an in situ single-pass intestinal perfusion (SPIP) model in rats. Concentrations, isolated regions of small intestine, and p-glycoprotein (P-gp) inhibitor were performed to investigate their influences on the intestinal absorption of ( R) -/( S) -HPABA. In addition, a molecular docking method was performed to illustrate our prediction. The absorption rate coefficients ( K a) and permeability values ( P eff) of ( R) -/( S) -HPABA were calculated. The permeability of ( S)-HPABA was significantly ( P < 0.01) higher than that of ( R)-HPABA in jejunum, and ileum permeability of ( R) -/( S) -HPABA appeared best in ileum; the investigated concentrations ranged from 20 to 80 μg/mL, K a and P eff values of ( R) -/( S) -HPABA increased linearly; in the presence of P-gp inhibitor (verapamil), P eff values of two enantiomers were increased significantly; and the effect of P-gp on absorption of ( R)-HPABA is stronger than that of ( S)-HPABA in ileum segment. Based on these results, carrier-mediated transport or passive transport combined with carrier-mediated transport seems to be the mechanism for intestinal absorption of ( R) -/( S) -HPABA, and ( R) -/( S) -HPABA may be recognized as the P-gp substrate. In addition, the intestinal permeability of ( S)-HPABA is higher than that of ( R)-HPABA. [ABSTRACT FROM AUTHOR]

TM-2 is a novel semi-synthetic taxane derivative, selected for preclinical development based on its greater anticancer activity and lower toxicity compared with docetaxel. In this study, a rapid and sensitive analytical method based on ultra performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) has been developed for the determination of TM-2 in rat plasma. The biological samples were extracted with methyl tert-butyl ether and separated on a C18 column (50 mm × 2.1 mm, 1.7 µm) using a mobile phase consisting of acetonitrile and 2 mM ammonium acetate. The standard curves were linear over the range 5-1000 ng/mL in rat plasma. The precision (relative standard deviation, RSD, %) were within 14.5%, and the accuracy (relative error, RE, %) ranged from −1.56 to 2.36%. Recovery and matrix effect were satisfactory in rat plasma. The validated method was successfully applied to pharmacokinetic studies after intravenous administration of TM-2 to rats. The pharmacokinetics of TM-2 in rats were characterized by a large volume of distribution and a long half-life of elimination after single dose (4, 8, and 16 mg/kg), and a good correlation was observed between AUC and dose. The preclinical data will be useful for the design of subsequent trials of TM-2. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

ABSTRACT A simple and sensitive method based on ultra-high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) has been developed for the determination of TM-2, which was a novel semi-synthetic taxane derivative in beagle dog plasma. Cabazitaxel was chosen as internal standard. Following extraction by methyl tert-butyl ether, the chromatographic separation was achieved on a Thermo Syncronis C18 column (50 × 2.1 mm, 1.7 µm) by gradient elution within a runtime of 3.5 min. The mobile phase consisted of (A) acetonitrile and (B) 2 mmol/L ammonium acetate in water. The detection was accomplished using positive ion electrospray ionization in multiple reaction monitoring mode. The MS/MS ion transitions were monitored at m/ z 812.39 → 551.35 for TM-2 and 836.36 → 555.26 for IS, respectively. The method was linear for TM-2 ( r = 0.9924) ranging from 2.5 to 1000 ng/mL. The intra-day and inter-day precisions (relative standard deviation) were within 8.0 and 17.6%, respectively, and the accuracy (relative error) was less than 2.3%. The extraction recovery ranged from 83.1 to 97.1%. The reliable method was successfully applied to a pharmacokinetic study of TM-2 in beagle dogs after intravenous drip with different doses of 0.6, 1.2, and 2.4 mg/kg, respectively. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

RATIONALE TM-2 (13-( N-Boc-3-i-butylisoserinoyl-4,10-β-diacetoxy-2-α-benzoyloxy-5-β,20-epoxy-1,13-α-dihydroxy-9-oxo-19-norcyclopropa[g]tax-11-ene) is a novel semi-synthetic taxane derivative. Our previous study demonstrated that it is a promising taxane derivative. The in vitro comparative metabolic profile of a drug between animals and humans is a key issue that should be investigated at early stages of drug development to better select drug candidates. In this study, the in vitro metabolic pathways of TM-2 in rat, dog and human liver microsomes were established and compared. METHODS TM-2 was incubated with liver microsomes in the presence of NADPH. Two different types of mass spectrometers - a hybrid linear trap quadrupole orbitrap (LC/LTQ-Orbitrap) mass spectrometer and a triple-quadrupole tandem mass spectrometer (LC/QqQ) were employed to acquire structural information of TM-2 metabolites. Accurate mass measurement using LC/LTQ-Orbitrap was used to determine the accurate mass data and elemental compositions of metabolites thereby confirming the proposed structures of the metabolites. For the chemical inhibition study, selective P450 inhibitors were added to incubations to initially characterize the cytochrome P450 (CYP) enzymes involved in the metabolism of TM-2. RESULTS A total of 12 components (M1-M12) were detected and identified as the metabolites of TM-2 in vitro. M1-M5 were formed by hydroxylation of the taxane ring or the lateral chain. Hydroxylated products can be further oxidized to the dihydroxylated metabolites M6-M10. M11 was a trihydroxylated metabolite. M12 was tentatively identified as a carboxylic acid derivative. The metabolism of TM-2 is much the same in all three species with some differences. The chemical inhibition study initially demonstrated that the formation of M2, the major metabolite of TM-2, is mainly mediated by CYP3A4. CONCLUSIONS Hydroxylation is the major biotransformation of the TM-2 pathway in vitro. CYP3A4 may play a dominant role in the formation of M2 in liver microsomes. The knowledge of the metabolic pathways of TM-2 is important to support further research of TM-2. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

ABSTRACT The study was aimed to investigate the effects of single and multiple oral administration of mungbean ( Phaseolus radiatus L.) seed extract (ME) on the pharmacokinetics of aconitine in rats. The Sprague-Dawley rats were randomly divided into three groups (six rats each group). In group 1, rats were orally administered 500 µg/kg aconitine after receiving a single oral dose of 1 g/kg ME. In group 2, rats were orally administered with 500 µg/kg aconitine at day 7 of treatment with 1 g/kg/day ME. In group 3, rats were orally administered with 500 µg/kg aconitine. Blood samples were collected at different time points (0.083, 0.25, 0.5, 1.0, 1.5, 2.0, 4.0, 6.0, 8.0 and 10.0 h). The concentration of aconitine in rats plasma was determined by a fully validated ultra-high-performance liquid chromatography coupled with mass spectrometry method. The results showed that single and multiple oral co-administration of ME significantly altered the pharmacokinetic parameters of aconitine. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

A high-performance liquid chromatographic method was developed for the simultaneous determination and pharmacokinetic studies of safflor yellow A, puerarin, 3′-methoxyl-puerarin, and puerarinapioside in the plasma and tissues of rats that had been administered with the traditional Chinese medicine (TCM) preparation Naodesheng via the caudal vein. Samples taken from rats were subjected to protein precipitation with acetone. Separation of these four compounds was accomplished on a Kromisil C18 stationary phase using a mobile phase of acetonitrile-0.1% phosphoric acid-tetrahydrofuran (8:92:2, v/v/v) at a flow-rate of 1.0 mL/min. The detection wavelength was set at 250 nm. The calibration curves of the four components were linear in the given concentration ranges. The intra- and inter-day precisions in plasma and tissues were less than 15% and the extraction recoveries were higher than 60%. The lower limits of quantitation of four components were low enough to determine the four components. These four components all exhibited kinetics that fitted a two-compartment model in rats. The elimination half-life was 1.19 h for safflor yellow A, 2.69 h for puerarin, 2.94 h for 3′-methoxyl-puerarin, and 0.87 h for puerarinapioside, respectively. Following administration of a single injection of Naodesheng, the concentration ( C) of the four components in the tissues showed Ckidney > Clung, Cliver > Cspleen, Cstomach, Cheart, approximately. The method is a reliable tool for performing studies of safflor yellow A and three puerarin isoflavones in different biological material. Copyright © 2007 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

isolation, structure elucidation and in vitro antioxidant activity of the new flavonoid glycoside (I) and four known compounds [ABSTRACT FROM AUTHOR]