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Mechanistic study on the pharmacokinetic process of salidroside in hypoxic rats

中国药理学与毒理学杂志 2017年第10期31卷 996-997页

作者： Te QI Bei-kang GE Liang ZHAO ping-xiang xu Ming xuE Department of Pharmacology School of Basic Medical SciencesCapital Medical University

OBJECTIVE To investigate the effect of hypoxia on the pharmacokinetic process of salidrosidein rats and to explore its underlying mechanisms.METHODS The Caco-2 cell monolayer was exposed to 1% oxygen(O_2) concentration for 24 h to build the hypoxiccell model.The transportation mode of salidroside was investigated with the aid of this hypoxia model by detecting the apparent permeability coefficient(P app).Healthy Sprague Dawley(SD) rats were exposed to 9% O_2 for 72 h for the construction of hypoxic rat model.Liver sample was subsequently collected from the hypoxic rats with an aim to identify enzymes responsible for salidroside metabolism.The expression levels of salidroside-transporting and salidroside-metabolizing enzymes,including Sodium-dependent glucose cotransporters(SGLT1),β-glucosidase(GBA3)and sulfotransferase(SULT2A1),were thereafter detected by RT-PCR and Western blot.The metabolic activity of GBA3 and SULT2A1 was monitored by rat liver microsome incubation.In addition,the renal function of rats under hypoxia was assessed by detecting concentrations of blood urea nitrogen and creatinine.RESULTS The AUC and t1/2 values of salidroside in hypoxic rats were more than doubled,while the in vivo clearance was significantly reduced.Mechanistic study demonstrated that the Papp A-B/Papp B-A eualsto 10.3,indicating the potential active transport of salidrosile.The expression of SGLT1 and GBA3 was significantly decreased,which indicated a reduced metabolism of salidroside under hypoxia.Moreover,rat under hypoxia was found to suffer from renal dysfunction,with an abnormal value of blood urea nitrogen.CONCLUSION Due to the reduced metabolism and the abnormal renal function under hypoxia,the systemic exposure of salidroside in rats was significantly enhanced.

关键词： hypoxia salidroside pharmacokinetics transport metabolism

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Inhibitory effects of lapachol on rat C6 glioma in vitro and in vivo by targeting DNA topoisomeraseⅠ and topoisomeraseⅡ

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中国药理学与毒理学杂志 2017年第10期31卷 1005-1006页

作者： Huan-li xu Qun-ying CHEN Hong WANG ping-xiang xu Ru YUAN Xiao-rong LI Lu BAI Ming xuE Department of Pharmacology School of Basic Medical SciencesCapital Medical University

OBJECTIVE Lapachol is a natural naphthoquinone compound that possesses extensive biological activities.The aim of this study is to investigate the inhibitory effects of lapachol on rat C6 glioma both in vitro and in vivo,as well as the potential mechanisms.METHODS The antitumor effect of lapachol was firstly evaluated in the C6 glioma model in Wistar rats.The effects of lapachol on C6 cell proliferation,apoptosis and DNA damage were detected by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium(MTS)/phenazinemethosulfate(PMS)assay,hoechst 33358 staining,annexinⅤ-FITC/PI staining,and comet assay.Effects of lapachol on topoisomerase I(TOP I)and topoisomeraseⅡ(TOPⅡ)activities were detected by TOPⅠand TOPⅡmediated supercoiled p BR322DNA relaxation assays and molecular docking.TOPⅠand TOPⅡexpression levels in C6 cells were also determined.RESULTS High dose lapachol showed significant inhibitory effect on the C6 glioma in Wistar rats(P<0.05).It was showed that lapachol could inhibit proliferation,induce apoptosis and DNA damage of C6 cel s in dose dependent manners.Lapachol could inhibit the activities of both TOPⅠ and Ⅱ.Lapachol-TOPⅠshowed relatively stronger interaction than that of lapachol-TOPⅡin molecular docking study.Also,lapachol could inhibit TOPⅡexpression levels,but not TOPⅠexpression levels.CONCLUSION These results showed that lapachol could significantly inhibit C6 glioma both in vivo and in vitro,which might be related with inhibiting TOPⅠ and TOPⅡ activities,as wel as TOPⅡ expression.

关键词： lapachol C6 glioma topoisomeraseⅠ topoisomeraseⅡ

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Analysis of the key networks,metabolic pathways,and regulation substances of hypoxia based on the omics and zebrafish model

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中国药理学与毒理学杂志 2017年第10期31卷 1023-1024页

作者： Yi MA Bin-bin XIA Jing-yi LI Zheng-chao XIA ping-xiang xu LI Xiao-rong Ming xuE Department of Pharmacology School of Basic Medical SciencesCapital Medical University

OBJECTIVE Hypoxia is associated with many complicated pathophysiological and biochemical processes that integrated and regulated via the key gene,protein and endogenous metabolite levels.Up to date,the exact molecular mechanism of hypoxia still remains unclear.In this work,we further explore the molecular mechanism of hypoxia and adaption to attenuate the damage in zebrafish model that have potential to resist hypoxic environment.METHODS The hypoxic zebrafish model was established in different concentration of oxygen with 3%,5%,10%,21%in water.The brain tissue was separated and the RNA-seq was used to identify the differentially expressed genes.The related endogenous metabolites profiles were obtained by LC-HDMS,and the multivariate statistics was applied to discover the important metabolites candidates in hypoxic zebrafish.The candidates were searched in HMDB,KEGG and Lipid Maps databases.RESULTS The zebrafish hypoxic model was successfully constructed via the different concentration of oxygen,temperature and hypoxic time.The activities of the related hypoxic metabolic enzymes and factors including HIF-1a,actate dehydrogenase(LDH)and citrate synthase(CS)were evaluated.Significant differences(P2)in the expression of 422 genes were observed between the normal and 3% hypoxic model.Among them,201 genes increased depended on the lower concentration of oxygen.53 metabolites were identified that had significant difference between the hypoxia and control groups(P1.5 and VIP>1.5).The ten key metabolites were increased gradually while six compounds were decreased.The endogenous hypoxic metabolites of phenylalanine,D-glucosamine-6P and several important lipids with the relevant hub genes had similar change in hypoxic model.In addition,the metabolic pathways of phenylalanine,glutamine and glycolipid were influenced in both the levels of genes and metabolites.CONCLUSION The up-regulation of phenylalanine,D-glucosamine-6P and lipid may have further understanding of protective effect in

关键词： hypoxia adaptation metabolic pathway omics zebrafish model

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The innovative safe herbicide dienediamine saves paraquat

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Molecular Plant 2024年第1期17卷 11-12页

作者： Jin-Qiu Xia ping xu Cheng-Bin xiang Division of Life Sciences and Medicine Division of Molecular&Cell BiophysicsHefei National Science Center for Physical Sciences at the MicroscaleMOE Key Laboratory for Membraneless Organelles and Cellular DynamicsUniversity of Science and Technology of ChinaThe Innovation Academy of Seed DesignChinese Academy of SciencesHefeiAnhui Province 230027China Shanghai Key Laboratory of Plant Functional Genomics and Resources Shanghai Chenshan Botanical GardenShanghai Chenshan Plant Science Research CenterCAS Center for Excellence in Molecular Plant SciencesShanghai 201602China

Throughout the history of agriculture,the challenge of weed management has endured,necessitating significant investments to facilitate ideal crop growth and maximize yields.Strategies for weed control mainly involve manual and chemical methodologies.While manual weeding persists in certain regions,chemical herbicides notably represent the primary approach.

关键词： approach. manual chemical

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Pharmacokinetics and pharmacodynamics of cisatracurium in children undergoing cleft lip or cleft palate repair surgery

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中国药理学与毒理学杂志 2017年第10期31卷 1021-1022页

作者： Wei-jia HAO LI Jing-yi Yi MA Jie XIONG ping-xiang xu Yu-hang LI Xiao-tong ZHANG Xiao-rong LI Capital Medical University Department of PharmacologySchool of Basic Medical Sciences Capital Medical University Beijing Friendship Hospital Capital Medical University Beijing Stomatological Hospital

OBJECTIVE The aim of the study was to characterize the pharmacokinetics(PK) and pharmacodynamics(PD) profile of cisatracurium in 0-2 years and 2-5 years old children patients with cheilopalatognathus,to find if there are some connections between the different muscle relaxation action and different PK procedure.METHODS 14 children patients were divided into two groups,≤2 years and 2-5 years group,venous samples were taken before injection of a 0.15 mg·kg-1 dose of cisatracurium and then at 2,5,10,30,60,90,and 120 min.Cisatracurium plasma concentrations were determined by ultra-performance liquid chromatography/electrospray ionization/triple quadrupole tandem mass spectrometer system(UPLC/MS/MS).The degree of neuromuscular block was measured by train of four(TOF) testing.An indirect PK-PD link model with a sigmoid E max model was established using Win Nonlin software.The model were applied to PK and PD data analysis,respectively.RESULTS The TOF monitor parameters showed that cisatracurium works very quickly,the onset time were(2.64±0.93) min and(2.59 ± 0.90) min for ≤2 years and 2-5 years group respectively.Young children ≤2 years have longer muscle blocking duration time(62.5 ± 6.01 min vs 53.86 ± 12.18 min) and slower recovery index(32.14±7.10 min and 27.43±10.63 min) than those children in group of 2-5 years.More children ≤2 years have postoperative complication than that in 2-5 children.PK parameters showed that there were no statistical differences in blood concentration and pharmacokinetic parameters.While the concentration of cisatracurium in muscle site calculated by using PK/PD model were higher and longer for ≤2 year children than that of 2-5 year children.This means that cisatracurium could stay at high concentration for a longer time in younger children' muscle tissue.CONCLUSION As a result young children tend to have postoperative complications related to slower muscle recovery action and increased concentration in skeletal muscle.So more careful observation and monitor are needed for younger children,

关键词： cisatracurium children PK/PD

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Alkylene-functionality in bridged and fused nitrogen-rich poly-cyclic energetic materials:Synthesis,structural diversity and energetic properties

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Defence Technology（防务技术） 2024年第5期35卷 18-46页

作者： Man xu Nanxi xiang ping Yin Qi Lai Siping Pang School of Materials Science&Engineering Beijing Institute of TechnologyBeijing 100081China Beijing Institute of Technology Chongqing Innovation Center Chongqing 401120China

From the standpoint of chemical structures,the organic backbones of energetic materials can be classified into aromatic rings,nonaromatic rings,and open chains.Although the category of aromatic energetic compounds exhibits several advantages in the regulation of energetic properties,the nonaromatic heterocycles,assembling nitramino explosophores with simple alkyl bridges,still have prevailed in benchmark materials.The methylene bridge plays a pivotal role in the constructions of the classic nonaromatic heterocycle-based energetic compounds,e.g.,hexahydro-1,3,5-trinitro-1,3,5-triazine(RDX)and octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine(HMX),whereas ethylene bridge is the core moiety of state-of-the-art explosive 2,4,6,8,10,12-hexanitro-2,4,6,8,10,12-hexaazaisowurtzitane(CL-20).In this context,it is of great interest to employ simple and practical bridges to assemble aromatic and nonaromatic nitrogen-rich heterocycles,thereby expanding the structural diversity of energetic materials,e.g.,bridged and fused nitrogen-rich poly-heterocycles.Furthermore,alkyl-bridged poly-heterocycles highlight the potential for the open chain type of energetic materials.In this review,the development of alkyl bridges in linking nitrogen-rich heterocycles is presented,and the perspective of the newly constructed energetic backbones is summarized for the future design of advanced energetic materials.

关键词： Energetic materials Alkyl bridge strategy Nitrogen-rich azoles Fused heterocycles Azoles

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MdbHLH162 connects the gibberellin and jasmonic acid signals to regulate anthocyanin biosynthesis in apple

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Journal of Integrative Plant Biology 2024年第2期66卷 265-284页

作者： Jian-ping An Rui-Rui xu Xiao-Na Wang Xiao-Wei Zhang Chun-xiang You Yuepeng Han Apple technology innovation center of Shandong Province College of Horticulture Science and EngineeringShandong Agricultural UniversityTai-An 271018China CAS Key Laboratory of Plant Germplasm Enhancement and Specialty Agriculture Wuhan Botanical GardenHubei Hongshan LaboratoryThe Innovative Academy of Seed Design of Chinese Academy of SciencesWuhan 430074China College of Biology and Oceanography Weifang UniversityWeifang 261061China

Anthocyanins are secondary metabolites induced by environmental stimuli and developmental signals.The positive regulators of anthocyanin biosynthesis have been reported,whereas the anthocyanin repressors have been neglected.Although the signal transduction pathways of gibberellin(GA)and jasmonic acid(JA)and their regulation of anthocyanin biosynthesis have been investigated,the cross-talk between GA and JA and the antagonistic mechanism of regulating anthocyanin biosynthesis remain to be investigated.In this study,we identified the anthocyanin repressor MdbHLH162 in apple and revealed its molecular mechanism of regulating anthocyanin biosynthesis by integrating the GA and JA signals.MdbHLH162 exerted passive repression by interacting with MdbHLH3 and MdbHLH33,which are two recognized positive regulators of anthocyanin biosynthesis.MdbHLH162 negatively regulated anthocyanin biosynthesis by disrupting the formation of the anthocyanin-activated MdMYB1-MdbHLH3/33complexes and weakening transcriptional activation of the anthocyanin biosynthetic genes MdDFR and MdUF3GT by MdbHLH3 and MdbHLH33.The GA repressor MdRGL2a antagonized MdbHLH162-mediated inhibition of anthocyanins by sequestering MdbHLH162 from the MdbHLH162-MdbHLH3/33 complex.The JA repressors MdJAZ1 and MdJAZ2 interfered with the antagonistic regulation of MdbHLH162 by MdRGL2a by titrating the formation of the MdRGL2a-MdbHLH162 complex.Our findings reveal that MdbHLH162 integrates the GA and JA signals to negatively regulate anthocyanin biosynthesis.This study provides new information for discovering more anthocyanin biosynthesis repressors and explores the cross-talk between hormone signals.

关键词： anthocyanin biosynthesis bHLH transcription factor gibberellin jasmonic acid regulatory network transcriptional regulation

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Decomposition mechanisms of nuclear-grade cationic exchange resin by advanced oxidation processes:Statistical molecular fragmentation model and DFT calculations

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Journal of Environmental Sciences 2024年第1期135卷 433-448页

作者： xiang Meng Pierre Désesquelles Lejin xu Department of Nuclear Engineering and Technology School of Energy and Power EngineeringHuazhong University of Science&TechnologyWuhan 430074China CNRS Laboratoire de Physique des Gaz et des PlasmasUniversitéParis-SaclayOrsay 91405France State Key Laboratory of Coal Combustion School of Energy and Power EngineeringHuazhong University of Science and TechnologyWuhan 430074China

The treatment and disposal of radioactive waste are presently facing great challenges.Spent ion exchange resins have become a focus of attention due to their high production and serious environmental risks.In this paper,a simplified model of cationic exchange resin is proposed,and the degradation processes of cationic resin monomer initiated by hydroxyl radicals(·OH)are clarified by combining statistical molecular fragmentation(SMF)model and density functional theory(DFT)calculations.The prediction of active sites indicates that the S-O bonds and the C-S bond of the sulfonic group are more likely to react during the degradation.The meta-position of the sulfonic group on the benzene ring is the most active site,and the benzene ring without the sulfonic group has a certain reactivity.The C11-C14 and C17-C20 bonds,on the carbon skeleton,are the most easily broken.It is also found that dihydroxy addition and elimination reactions play a major role in the process of desulfonation,carbon skeleton cleavage and benzene ring separation.The decomposition mechanisms found through the combination of physical models and chemical calculations,provide theoretical guidance for the treatment of complex polycyclic aromatic hydrocarbons.

关键词： Cationic exchange resin Statistical molecular fragmentation model Density functional theory Hydroxyl radical Decomposition mechanism

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Glucuronidation is the dominating in-vivo metabolism pathway of herbacetin:elucidation of herbacetin pharmacokinetics after intravenous and oral administration in rats

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中国药理学与毒理学杂志 2017年第10期31卷 1019-1019页

作者： Bei-kang GE Liang ZHAO Te QI ping-xiang xu Ming xuE Department of Pharmacology School of Basic Medical SciencesCapital Medical University

OBJECTIVE To map a comprehensive metabolic pathway of herbacetin in rats,specifically,to elucidate the biotransformation of herbacetin in vivo and to simultaneously monitor the pharmacokinetic process of both parent drug and its major metabolites.METHODS liquid chromatography/ion trap mass spectrometry(LC/MS n) and ultra-liquid chromatography coupled with mass spectrometry(UPLC/MS) were combined in the current study for qualitative and quantitative determinations of herbacetin and its metabolites in bile,urine and feces after both oral and intravenous administration of herbacetin to rats.Enzyme kinetic studies on the intestinal and hepatic metabolism of herbacetin were further conducted to elucidate metabolic profiles of herbacetin in rat tissues and organs.Additionally,plasma concentration profiles of herbacetin and its metabolites in rats were obtained to characterize the overall pharmacokinetic behavior of herbacetin.RESULTS It was found that herbacetin was excreted primarily from rat urine in the form of glucuronide-conjugations.Subsequent in vitro enzyme kinetic studies and in vivo pharmacokinetic investigations suggested an extensive hepatic metabolism of herbacetin and the high exposure of herbacetin-glucuronides in systemic circulation.The clearance,half-life and bioavailability of herbacetin in rats were determined as(16.4±1.92)mL·kg^(-1)·min^(-1),(11.9±2.7)min,and 1.32%,respectively.On basis of these findings,a comprehensive metabolic pathway of herbacetin in rats was composed.In addition,a physiology based pharmacokinetic(PBPK) model was successfully developed with the aid of the Gastro Plus to simulate the pharmacokinetic process of herbacetin in rats.Application of the PBPK modeling can provide a useful starting point to understand and extrapolate pharmacokinetic parameters among different species,populations,and disease states.CONCLUSION After oral administration,herbacetin was subjected to colonic degradation and extensive first pass metabolism,with glucuronidation as its dominating in vivo metabol

关键词： herbacetin pharmacokinetics biotransformation glucuronidation hepatic metabolism colonic degradation

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Fracture sealing performance of granular lost circulation materials at elevated temperature:A theoretical and coupled CFD-DEM simulation study

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Petroleum Science 2024年第1期21卷 567-581页

作者： Chong Lin Qi-Cong xu Lie-xiang Han Gao Li Hai He Hong-Ling Zhou Ji-ping She CCDC Drilling&Production Technology Research Institute Guanghan618300SichuanChina State Key Laboratory of Oil and Gas Reservoir Geology and Exploitation Southwest Petroleum UniversityChengdu610500SichuanChina College of Materials Science and Engineering Chongqing UniversityChongqing400044China State Key Lab of Oil and Gas Reservoir Geology and Exploitation(Chengdu University of Technology) Chengdu610059SichuanChina College of Energy Chengdu University of TechnologyChengdu610059SichuanChina

Lost circulation is a common downhole problem of drilling in geothermal and high-temperature,high-pressure(HTHP)formations.Lost circulation material(LCM)is a regular preventive and remedial measure for lost circulation.However,conventional LCMs seem ineffective in high-temperature formations.This may be due to the changes in the mechanical properties of LCMs and their sealing performance under high-temperature conditions.To understand how high temperature affects the fracture sealing performance of LCMs,we developed a coupled computational fluid dynamics-discrete element method(CFD-DEM)model to simulate the behavior of granular LCMs in fractures.We summarized the literature on the effects of high temperature on the mechanical properties of LCMs and the rheological properties of drilling fluid.We conducted sensitivity analyses to investigate how changing LCM slurry properties affected the fracture sealing efficiency at increasing temperatures.The results show that high temperature reduces the size,strength,and friction coefficient of LCMs as well as the drilling fluid viscosity.Smaller,softer,and less frictional LCM particles have lower bridging probability and slower bridging initiation.Smaller particles tend to form dual-particle bridges rather than single-particle bridges.These result in a deeper,tighter,but unstable sealing zone.Reduced drilling fluid viscosity leads to faster and shallower sealing zones.

关键词： Geothermal well drilling HTHP formationLost circulation material CFD-DEM Fracture sealing

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