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Some recent advances in transition-metal-catalyzed ortho SP^2 C–H functionalization using Ru, Rh, and Pd

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Science China Chemistry 2014年第7期57卷 930-944页

作者： RAO Yu SHAN Gang YANG XingLin MOE Key Laboratory of Protein sciences Department of Pharmacology and Pharmaceutical Sciences School of Medicine and School of Life Sciences Tsinghua University

In the past decade,transition-metal-catalyzed C–H functionalization by weak coordination has emerged as a practical and powerful tool to access many valuable *** classes of weakly coordinating directing groups,commonly occurring functional groups,and easily removable auxiliaries,have been found to be efficient and practical for C–H activation *** mini-review contains examples of recent research advances on transition-metal-catalyzed SP2 C–H functionalization via weak coordination,using Ru,Rh,and Pd.A number of weakly coordinating functional groups(e.g.,ketone,ester,carbamate,tertiary amide,ether,thioether,alcohol,and some others)are *** the field of transition-metal-catalyzed C–H functionalization continues to develop and more synthetically useful chemo-,regio-,and enantioselective reactions catalyzed by transition metal via weak coordination are discovered,this promising and attractive strategy will play a more important role in modern organic synthesis.

关键词： transition metal catalysis SP2 C-H functionalization weak coordination ortho-selectivity directing group

Calcium channel blocking activity of calycosin,a major active component of Astragali Radix,on rat aorta

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Acta Pharmacologica Sinica 2006年第8期27卷 1007-1012页

作者： Xiu-li WU~2 Yin-ye WANG~(2,4) Jun CHENG~3 Yu-ying ZHAO~3 ~2department of Molecular and Cellular pharmacology:~3department of Natural Medicinal Chemistry,school of pharmaceutical sciences,Peking university,Beijing 100083,China department of Molecular and Cellular pharmacology School of Pharmaceutical Sciences Peking University Beijing China department of Natural Medicinal Chemistry School of Pharmaceutical Sciences Peking University Beijing China

Aim:To investigate the vasoactivity of calycosin,a major active component ofAstragali ***:Experiments were performed on isolated rat thoracicaortic rings pre-contracted with phenylephrine(PHE)or ***:Calycosinproduced a concentration-dependent relaxation on the tissue pre-contractedusing PHE with 4.46±0.13 of pD2and 95.85%±2.67% of Emax;or using KCl with4.27±0.05 of pD2and 99.06%±2.15% of Emax,and displaced downwards the con-centration-response curves of aortic rings to PHE or *** relaxant effect ofcalycosin on denuded endothelium aortic rings was the same as on intact endot-helium aortic rings,and its vasorelaxant effect was not influenced by L-NAME *** Ca2+-free solution,calycosin(30 μmol/L)did not have an effecton PHE (1×10-6mol/L)-induced aortic ring *** effects of calycosinand nifedipine where somewhat different;calycosin decreased aortic ring con-tractions induced by the two agonists,but nifedipine displayed a more potentinhibitory effect on KCl-induced contractions than on PHE-induced contractions,and the vascular relaxing effects of calycosin and nifidipine were additive on PHE-induced contraction but not ***:Calycosin is a *** action is endothelium-independent and is unrelated to intracellular Ca2+*** is a noncompetitive Ca2+channel *** effect of calycosin on Ca2+chan-nel blockade may be different from that of *** study demon-strated a novel pharmacological activity of calycosin,and supplied a theoreticfoundation for Astragali Radix application.

关键词： catycosin rat aorta vasodilation calcium channel

Impact of obese levels on the hepatic expression of nuclear receptors and drug-metabolizing enzymes in adult and offspring mice

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Acta Pharmaceutica Sinica B 2020年第1期10卷 171-185页

作者： Pei Wang Xueyan Shao Yifan Bao Junjie Zhu Liming Chen Lirong Zhang Xiaochao Ma Xiao-bo Zhong department of pharmacology School of Basic Medical SciencesZhengzhou UniversityZhengzhou 450001China department of pharmaceutical sciences School of PharmacyUniversity of ConnecticutStorrsCT 06269USA department of pharmaceutical sciences School of PharmacyUniversity of PittsburghPittsburghPA 15261USA

The prevalence of obesity-associated conditions raises new challenges in clinical *** altered expression of drug-metabolizing enzymes(DMEs)has been shown in obesity,the impacts of obese levels(overweight,obesity,and severe obesity)on the expression of DMEs have not been ***,limited information is available on whether parental obese levels affect ontogenic expression of DMEs in ***,a high-fat diet(HFD)and three feeding durations were used to mimic different obese levels in C57BL/6 *** hepatic expression of five nuclear receptors(NRs)and nine DMEs was *** general,a trend of induced expression of NRs and DMEs(except for Cyp2c29 and 3a11)was observed in HFD groups compared to low-fat diet(LFD)*** of HFD on the hepatic expression of DMEs were found in adult mice at different obese ***-based dietary style of an HFD altered the ontogenic expression of DMEs in the offspring older than 15 ***,obese levels of parental mice affected the hepatic expression of DMEs in ***,the results indicate that obese levels affected expression of the DMEs in adult individuals and that of their *** dosage might need to be optimized based on the obese levels.

关键词： Diet-induced obesity Overweight High-fat diet Drug-metabolizing enzymes Nuclear receptors Ontogenic expression

Evaluation of micelles incorporated into thermosensitive hydrogels for intratumoral delivery and controlled release of docetaxel:A dual approach for in situ treatment of tumors

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Asian Journal of pharmaceutical sciences 2018年第4期13卷 373-382页

作者： Meng Xu Yanhua Mou Mingming Hu Wenxiang Dong Xitong Su Rongxiaa Wu Peng Zhang school of Pharmacy Shenyang Pharmaceutical University department of pharmacology Shenyang Pharmaceutical University

The in situ gelling hybrid hydrogel system has been reported to effectively concentratechemotherapeutic drugs at the tumor site and sustain their release for a long period. DTX-micelles(docetaxel-loaded mixed micelles) are able to increase the solubility of DTX inwater, and then a high drug loading rate of hydrogels can be achieved by encapsulatingthe docetaxel-loaded mixed micelles into the hydrogels. The thermosensitive nature ofDTX-MM-hydrogels(thermosensitive hydrogels incorporated with docetaxel-loaded mixedmicelles) can accelerate the formation of a depot of this drug-loaded system at the siteof administration. Therefore, the hydrogels provide a much slower release compared withDTX-micelles and DTX-injection. An in vivo retention study has demonstrated that the DTX-MM-hydrogels can prolong the drug retention time and in viv o trials have shown that theDTX-MM-hydrogels have a higher antitumor efficacy and systemic safety. In conclusion, theDTX-MM-hydrogels prepared in this study have considerable potential as a drug deliverysystem, with higher tumor inhibition effects and are less toxic to normal tissues.

关键词： Docetaxel Thermosensitive Micelles Hydrogels Intratumoral

Intracellular distribution and internalization pathways of guanidinylated bioresponsive poly(amido amine)s in gene delivery

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Asian Journal of pharmaceutical sciences 2018年第4期13卷 360-372页

作者： Jinmina Zhang Chunxi Wang Mei Lu Haonan Xing Tianzhi Yang Cuifang Cai Xiaoyun Zhao Minjie Wei Jiankun Yu Pingtian Ding school of Pharmacy Shenyang Pharmaceutical University department of Basic pharmaceutical sciences School of PharmacyHusson University department of Microbiology and Cell Biology School of life Science and BiopharmaceuticsShenyang Pharmaceutical University department of pharmacology School of PharmacyChina Medical University department of Ion Channel pharmacology School of PharmacyChina Medical University

Guanidinylated bioresponsive poly(amido amine)s polymers, CAR-CBA and CHL-CBA, weresynthesized by Michael-type addition reaction between guanidine hydrochloride(CAR) orchlorhexidine(CHL) and N,N-cystaminebisacrylamide(CBA). Previous studies have shownthat both polymers had high transfection efficiencies as gene delivery carriers. In this study,we investigated the nucleolus localization abilities and cellular internalization pathways ofthese two polymers in gene delivery. Each polymer condensed plasmid DNA(p DNA) andformed nanoparticle complexes, and then their transfection studies were performed inMCF-7 cells. Both complexes were found enriched in nucleolus after cellular transfection,and their transfection efficiencies were significantly improved when transfection was per-formed on MCF-7 cells arrested at M phase. The transfection efficiency of CAR-CBA-pDNAwas inhibited by chlorpromazine, and cell endosomes were disrupted after being exposedto CAR-CBA-pDNA. In regards to CHL-CBA-pDNA, its transfection efficiency was not affected by three types of endocytosis inhibitors used in the study, and CHL-CBA-pDNA showed no effect on endosomes. Cellular lactate dehydrogenase release and membrane morphology were changed after cells were transfected by the two complexes. The results indicated that both CAR-CBA and CHL-CBA polymers demonstrated good nucleolus localization abilities. It was beneficial for transfection when cells were arrested at M phase. CAR-CBA-pDNA cellular internalization was involved with clathrin-mediated endocytosis pathway, and escaping from endosomal entrapment, while the cellular uptake of CHL-CBA-pDNA occurs via clathrin-and caveolae-independent mechanism.

关键词： Guanidinylated poly(amido amine)s polymers Nucleolus localization Cell cycle status Internalization pathways

Alteration of ADP-ribosylation in aging rat brain astrocytes

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BIOCELL 2019年第1期43卷 37-40页

作者： Manoochehr MESSRIPOUR Azadeh MESRIPOUR department Clinical Biochemistry School of Pharmacy and Pharmaceutical SciencesIsfahan University of Medical SciencesIsfahanIran department of pharmacology and Toxicology School of Pharmacy and Pharmaceutical SciencesIsfahan University of Medical SciencesIsfahanIran

DNA damage and the enzyme poly(ADP-ribose)polymerase(PARP)associated with the pathogenesis of numerous age-related neurodegenerative *** play crucial roles in both support metabolic functions and cell viability of the *** regulates DNA damage and repair in the brain *** this study PARP activity and DNA strand break were investigated in the astrocytes isolated from young and aged rat *** and 30-month-old rats were killed by decapitation and brains were removed onto an ice cooled glass *** were isolated by sucrose density gradient centrifugation and glutamine synthetase(GS)served as a marker of the astrocytes *** specific activity of PARP was assayed in permeabilized cells by measuring the incorporation of the ADP-ribose moiety of[3H]NAD into the nuclear acceptor *** rate of DNA strand breaks was determined using a fluorescent dye and monitored *** increase(about 75%)in the PARP activity was observed in the whole homogenates of aged rats,whereas this rise was more pronounced(about 360%)when the reaction was measured in the purified astrocyte *** amount of DNA strand breaks was also higher in the astrocytes isolated from the aged brain as compared to that of young *** close relationship between the level of DNA strand breaks and PARP activity in the astrocytes suggest that these cells are susceptible to the metabolic alterations in *** is concluded that the astrocytes PARP might be considered as a therapeutic target for combating age related neurodegenerative disorders.

关键词： ADP-ribosyl polymerase DNA damages Glutamine synthetase

Development of a mechanism-based pharmacokinetic/pharmacodynamic model to characterize the thermoregulatory effects of serotonergic drugs in mice

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Acta Pharmaceutica Sinica B 2016年第5期6卷 492-503页

作者： Xi-Ling Jiang Hong-Wu Shen Donald E.Mager Stephan Schmidt Ai-Ming Yu department of pharmaceutical sciences School of Pharmacy and Pharmaceutical SciencesUniversity at BuffaloThe State University of New York department of Pharmaceutics Center for Pharmacometrics and Systems PharmacologyUniversity of Florida department of Biochemistry & Molecular Medicine UC Davis School of Medicine2700 Stockton Boulevard

We have shown recently that concurrent harmaline,a monoamine oxidase-A inhibitor(MAOI),potentiates serotonin(5-HT) receptor agonist 5-methoxy-N,N-dimethyltryptamine(5-Me O-DMT)-induced *** objective of this study was to develop an integrated pharmacokinetic/pharmacodynamic(PK/PD) model to characterize and predict the thermoregulatory effects of such serotonergic drugs in *** thermoregulation was described by a mechanism-based indirect-response model with adaptive feedback ***-induced hypothermia and 5-Me O-DMT–elicited hyperthermia were attributable to the loss of heat through the activation of 5-HT1 Areceptor and thermogenesis via the stimulation of 5-HT2 Areceptor,*** serotonergic 5-Me O-DMT–induced hyperthermia was readily distinguished from handling/injection stress-provoked hyperthermic *** PK/PD model was able to simultaneously describe all experimental data including the impact of drug-metabolizing enzyme status on5-Me O-DMT and harmaline PK properties,and drug- and stress-induced simple hypo/hyperthermic and complex biphasic ***,the modeling results revealed a 4-fold decrease of apparent SC_(50) value(1.88–0.496 mmol/L) for 5-Me O-DMT when harmaline was co-administered,providing a quantitative assessment for the impact of concurrent MAOI harmaline on 5-Me ODMT–induced *** addition,the hyperpyrexia caused by toxic dose combinations of harmaline and 5-Me O-DMT were linked to the increased systemic exposure to harmaline rather than5-Me O-DMT,although the body temperature profiles were mispredicted by the *** results indicate that current PK/PD model may be used as a new conceptual framework to define the impact of serotonergic agents and stress factors on thermoregulation.

关键词： PK/PD model Thermoregulation Indolealkylamine Serotonin Monoamine oxidase-A inhibitor Stress

Mechanism underlying berberine's effects on HSP70/TNFα under heat stress:Correlation with the TATA boxes

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Chinese Journal of Natural Medicines 2017年第3期15卷 178-191页

作者： JIANG Jing-Fei LEI Fan YUAN Zhi-Yi WANG Yu-Gang WANG Xin-Pei YAN Xiao-Jin YU Xuan XING Dong-Ming DU Li-Jun MOE(Ministry of Education)Key Laboratory of Protein sciences Laboratory of Molecular Pharmacology and Pharmaceutical SciencesSchool of Life SciencesTsinghua UniversityBeijing 100084China department of pharmacology and pharmaceutical sciences School of MedicineTsinghua UniversityBeijing 100084China MD Anderson Cancer Center University of TexasHoustonTX 77030USA

Heat stress can stimulate an increase in body temperature, which is correlated with increased expression of heat shock protein 70 （HSP70） and tumor necrosis factor a （TNFa）. The exact mechanism underlying the HSP70 and TNFa induction is unclear. Berberine （BBR） can significantly inhibit the temperature rise caused by heat stress, but the mechanism responsible for the BBR effect on HSP70 and TNFa signaling has not been investigated. The aim of the present study was to explore the relationship between the expression of HSP70 and TNFa and the effects of BBR under heat conditions, using in vivo and in vitro models. The expression levels of HSP70 and YNFa were determined using RT-PCR and Western blotting analyses. The results showed that the levels of HSP70 and TNFa were ap-regulated under heat conditions （40 ~C）. HSP70 acted as a chaperone to maintain TNFa homeostasis with rising the temperature, but knockdown of HSP70 could not down-regulate the level of TNFa. Furthermore, TNFa could not influence the expression of HSP70 under aormal and heat conditions. BBR targeted both HSP70 and TNFa by suppressing their gene transcription, thereby decreasing body temperature under heat conditions. In conclusion, BBR has a potential to be developed as a therapeutic strategy for suppressing the thermal effects in hot environments.

关键词： Berberine Hyperthermia HSP70 TNFa TATA box

Inhibition of intracellular proton-sensitive Ca^(2+)-permeable TRPV3 channels protects against ischemic brain injury

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Acta Pharmaceutica Sinica B 2022年第5期12卷 2330-2347页

作者： Xiaoling Chen Jingliang Zhang KeWei Wang department of Molecular and Cellular pharmacology State Key Laboratory of Natural and Biomimetic DrugsSchool of Pharmaceutical SciencesPeking UniversityBeijing 100191China department of pharmacology Qingdao University School of PharmacyQingdao 266021China

Ischemic brain stroke is pathologically characterized by tissue acidosis, sustained calcium entry and progressive cell death. Previous studies focusing on antagonizing N-methyl-D-aspartate(NMDA) receptors have failed to translate any clinical benefits, suggesting a non-NMDA mechanism involved in the sustained injury after stroke. Here, we report that inhibition of intracellular proton-sensitive Ca^(2+)-permeable transient receptor potential vanilloid 3(TRPV3) channel protects against cerebral ischemia/reperfusion(I/R) injury. TRPV3 expression is upregulated in mice subjected to cerebral I/R injury. Silencing of TRPV3 reduces intrinsic neuronal excitability, excitatory synaptic transmissions, and also attenuates cerebral I/R injury in mouse model of transient middle cerebral artery occlusion(tMCAO). Conversely, overexpressing or re-expressing TRPV3 increases neuronal excitability, excitatory synaptic transmissions and aggravates cerebral I/R injury. Furthermore, specific inhibition of TRPV3 by natural forsythoside B decreases neural excitability and attenuates cerebral I/R injury. Taken together, our findings for the first time reveal a causative role of neuronal TRPV3 channel in progressive cell death after stroke, and blocking overactive TRPV3 channel may provide therapeutic potential for ischemic brain injury.

关键词： TRPV3 Ca^(2+)influx Acidosis Cerebral ischemia/reperfusion injury Excitotoxicity Neural excitability Forsythoside B tMACO OGD TRP