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Changes of chymase,angiotensin converting enzyme and angiotensin Ⅱ type 1 receptor expressions in the hamster heart during the development of heart failure

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Chinese medical Journal 2005年第22期118卷 1886-1892页

作者： CHEN Peng-min LENG Xi-gang FAN Li-li MA Jun WANG Ya-fang CHEN Lan-ying Department of Biochemistry Institute of Clinical Medicine China-Japan Friendship Hospital Beijing 100029 Department of Biochemistry Fuwai Hospital and CardiovascularInstitute Chinese Academy of Medical Sciences and Peking Union Medical College Beijing 100037 China Department of Biochemistry Institute of Biomedical EngineeringChinese Academy of Medical Sciences and Peking Union Medical College Tianjin 300192 China Department of pharmacology Institute of Materia Medica Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050 China

Background Little is known about the role of dual angiotensin Ⅱ forming pathways during heart failure. In the present study, the changes of chymase and angiotensin converting enzyme （ACE） expressions in the failing hearts of hamsters were analysed. Methods Heart failure was induced by ligation of left anterior descending branch of the coronary artery. Chymase, ACE and angiotensin Ⅱ type 1 receptor （AT1R） mRNA levels were analysed by reverse transcription polymerase chain reaction （RT-PCR）. The activities of chymase and ACE were determined by radioimmunoassay （RIA）. Myocardial collagen fibre analysis was performed under optical microscope. Results Left ventricular systolic pressure （LVSP） and maximum left ventricular developed pressure increase rate （ dp/dtmax, mmHg/s） gradually moved lower at 2, 3,4 and 8 weeks after operation. On the other hand, left ventricular end-diastolic pressure （LVEDP） increased gradually after operation. Compared with the control group （3.55±0. 06, 4.79±0.70）, the heart weight/body weight ratio in operation group had increased significantly at 4 weeks and 8 weeks （4. 28±0. 43, 6. 17±0.73）（P 〈0. 01 ）. Collagen staining showed that the quantity of myocardial collagen fibre increased significantly in the operation group. RT-PCR showed that the chymase mRNA level in the operation group was consistently greater than that in the control group. ATIR mRNA level was also increased significantly at 3 weeks and 4 weeks, both being 1.3 times that of the control group （ P〈0.01 ）, whereas ACE mRNA level was not changed. Higher activity of chymase was detected in operation group, being 4, 8, 13 and 19 times that of the control group at 2, 3, 4 and 8 weeks （P〈0.01 ）, respectively. ACE activity was also significantly higher at the same time, being 7, 10, 10 and 3.5 times that of the control（P〈0.01）. Angiotensin Ⅱ （Ang Ⅱ） level in operation group increased significantly, being 2.5, 2.7, 3.5 and 2 times that of the control group at 2, 3, 4 and 8 weeks, res

关键词： chymase angiotensin converting enzyme angiotensin Ⅱ· heart failure ·angiotensin Ⅱ type 1 receptor

Efficacy of combined inhibition of mTOR and ERK/MAPK pathways in treating a tuberous sclerosis complex cell model

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Journal of Genetics and Genomics 2009年第6期36卷 355-361页

作者： Ruifang Mi Jianhui Ma Dechang Zhang Limin Li Hongbing Zhang Department of Physiology Institute of Basic Medical Sciences and School of Basic Medicine Chinese Academy of Medical Sciences and Peking Union Medical College Beijing 100005 China Department of Pathology Institute of Basic Medical Sciences and School of Basic Medicine Chinese Academy of Medical Sciences and Peking Union Medical College Beijing 100005 China Department of pharmacology Institute of Basic Medical Sciences and School of Basic Medicine Chinese Academy of Medical Sciences and Peking Union Medical College Beijing 100005 China

Tuberous sclerosis complex （TSC） is an autosomal dominant tumor syndrome which afflicts multiple organs and for which there is no cure, such that TSC patients may develop severe mental retardation and succumb to renal or respiratory failure. TSC derives from inacti- vating mutations of either the TSC1 or TSC2 tumor suppressor gene, and the resulting inactivation of the TSC1/TSC2 protein complex causes hyperactivation of the mammalian target of rapamyein （mTOR）, leading to uncontrolled cell growth and proliferation. Recent clinical trials of targeted suppression of mTOR have yielded only modest success in TSC patients. It was proposed that abrogation of a newly identified mTOR-mediated negative feedback regulation on extracellular signal-regulated kinase/mitogen-activated protein kinase （ERK/MAPK） signaling pathway and on the well-documented RTK-PI3K-AKT signaling cascade could limit the efficacy of mTOR inhibitors in the treatment of TSC patients. Therefore, we speculate that dual inhibition of mTOR and ERK/MAPK pathways may overcome the disadvantage of single agent therapies and boost the efficacy of mTOR targeted therapies for TSC patients. Investigation of this hypothesis in a TSC cell model revealed that mTOR suppression with an mTOR inhibitor, rapamycin （sirolimus）, led to up-regulation of ERK/MAPK signaling in mouse Tsc2 knockout cells and that this augmented signaling was attenuated by concurrent administration of a MEK1/2 inhibitor, PD98059. When compared with monotherapy, combinatorial application of rapamycin and PD98059 had greater inhibitory effects on Tsc2 deficient cell proliferation, suggesting that combined suppression of mTOR and ERK/MAPK signaling pathways may have advantages over single mTOR inhibition in the treatment of TSC patients.

关键词： TSC mTOR ERK/MAPK rapamycin PD98059

Cordycepin promotes browning of white adipose tissue through an AMP-activated protein kinase(AMPK)-dependent pathway

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Acta Pharmaceutica Sinica B 2019年第1期9卷 135-143页

作者： Guihong Qi Yue Zhou Xiaopo Zhang Jiaqi Yu Xin Li Xiaoxue Cao Chongming Wu Peng Guo pharmacology and Toxicology Research Center Institute of Medicinal Plant Development Chinese Academy of Medical Sciences &Peking Union Medical College School of Pharmaceutical Science Hainan Medical University

Obesity is a worldwide epidemic. Promoting browning of white adipose tissue(WAT)contributes to increased energy expenditure and hence counteracts obesity. Here we show that cordycepin(Cpn), a natural derivative of adenosine, increases energy expenditure, inhibits weight gain, improves metabolic profile and glucose tolerance, decreases WAT mass and adipocyte size, and enhances cold tolerance in normal and high-fat diet-fed mice. Cpn markedly increases the surface temperature around the inguinal WAT and turns the inguinal fat browner. Further investigations show that Cpn induces the development of brown-like adipocytes in inguinal and, to a less degree, epididymal WAT depots. Cpn also increases the expression of uncoupling protein 1(UCP1) and other thermogenic genes in WAT and3T3-L1 differentiated adipocytes, in which AMP-activated protein kinase(AMPK) plays an important role. Our results provide novel insights into the function of Cpn in regulating energy balance, and suggest a potential utility of Cpn in the treatment of obesity.

关键词： Cordycepin Browning of white adi pose tissue(WAT) Thermogenesis AMP-activated protein kinase(AMPK) Obesity

N-Oxide heterocycles and imidazoles replacing ring D of calanolides against Mycobacterium tuberculosis

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Chinese Chemical Letters 2016年第1期27卷 51-54页

作者： Zi-Jie Liu Xiao-Yong Guo Gang Liu Institute of Materia Medica Chinese Academy of Medical Sciences and Peking Union Medical College Tsinghua-peking Center for Life Sciences and Department of pharmacology and Pharmaceutical Sciences School of Medicine Tsinghua University

We have explored the chemistry of N-oxide heterocycles and imidazoles replacing ring D of the natural product（＋）-calanolide A, and have synthesized 12 new analogues, two of which were active against both R Mtb and ... 详细信息

关键词： Mycobacterium tuberculosis (+)-Calanolide A N-Oxide heterocycle Benzoimidazole Bioreductive drug

Immunoenhancing activity of protopanaxatriol-type ginsenoside-F3 in murine spleen cells

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Acta Pharmacologica Sinica 2004年第12期25卷 105-110页

作者： Jun-li YU, De-qiang DOU2, Xiao-hong CHEN, Hong-zhen YANG, Na GUO2,Gui-fang CHENG3 Department of pharmacology, Institute of Materia Medica, Chinese Academy of medicalSciences, peking union medicalcollege, Beijing 100050 Departmentof Natural ProductsChemistry, Shenyang Pharmaceutical University, Shenyang 110001, China 2 Department of pharmacology Institute of Materia Medica Chinese Academy of Medical Sciences Peking Union Medical College 北京 100050 Department of Natural Products Chemistry Shenyang Pharmaceutical University Shenyang 110001

AIM: To investigate the immunoenhancing activity of ginsenoside-F3 inmurine spleen cells andexplore itsmechanism. METHODS: The enhancing effect of ginsenoside-F3 on murine spleen cell proliferation was studied using [3H] thymidine incorporation assay. Effects of ginsenoside-F3 on the production of type 1 cytokines IL-2, IFN-γ, and type 2 cytokines IL-4 and IL-10 from murine spleen cells were detected by ELISA method. Effects of ginsenoside- F3 on mRNA level of cytokines IL-4, IFN-γ, and transcription factors T-bet and GATA-3 were evaluated by RT- PCR analysis. Effect of ginsenoside-F3 on NF-κB DNA binding activity in murine spleen cells was investigated by electrophoretic mobility shift assays (EMSA). RESULTS: Ginsenoside-F3 at 0.1-100 μmol/L not only promoted the murine spleen cell proliferation, but also increased the production of IL-2 and IFN-γ, while decreased the production of IL-4 and IL-10 from murine spleen cells with the maximal effect at 10 μmol/L. RT-PCR analysis displayed that ginsenoside-F3 enhanced the IFN-γ and T-bet gene expression and decreased IL-4 and GATA-3 gene expression. EMSA experiment showed that ginsenoside-F3 10 μmol/L enhanced the NF-κB DNA binding activity induced by ConA in murine spleen cells. CONCLUSION: Ginsenoside-F3 has immunoenhancing activity by regu- lating production and gene expression of type 1 cytokines and type 2 cytokines in murine spleen cells.

关键词： ginsenoside F3 immunity cytokines transcription factors

Establishment of pseudovirus infection mouse models for in vivo pharmacodynamics evaluation of filovirus entry inhibitors

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Acta Pharmaceutica Sinica B 2018年第2期8卷 200-208页

作者： Qing Chen Ke Tang Xiaoyu Zhang Panpan Chen Ying Guo State Key Laboratory of Bioactive Substances and Function of Natural Medicines Department of Pharmacology Institute of Materia Medica Chinese Academy of Medical Sciences Peking Union Medical College

Filoviruses cause severe and fatal viral hemorrhagic fever in humans. Filovirus research has been extensive since the 2014 Ebola outbreak. Due to their high pathogenicity and mortality, live filoviruses require Biosafety Level-4(BSL-4) facilities, which have restricted the development of anti-filovirus vaccines and *** HIV-based pseudovirus cell infection assay is widely used for viral entry studies in BSL-2 conditions. Here,we successfully constructed nine in vitro pseudo-filovirus models covering all filovirus genera and three in vivo pseudo-filovirus-infection mouse models using Ebola virus, Marburg virus, and Lloviu virus as representative viruses. The pseudo-filovirus-infected mice showed visualizing bioluminescence in a dose-dependent manner. A bioluminescence peak in mice was reached on day 5 post-infection for Ebola virus and Marburg virus and on day4 post-infection for Lloviu virus. Two known filovirus entry inhibitors, clomiphene and toremiphene, were used to validate the model. Collectively, our study shows that all genera of filoviruses can be well-pseudotyped and are infectious in vitro. The pseudo-filovirus-infection mouse models can be used for in vivo activity evaluation of anti-filovirus drugs. This sequential in vitro and in vivo evaluation system of filovirus entry inhibitors provides a secure and efficient platform for screening and assessing anti-filovirus agents in BSL-2 facilities.

关键词： Filovirus Ebola Marburg Pseudovirus Entry inhibitor Mouse model

Synthesis and Crystal Structure of Ethyl 4-(2-Chloro-4-fluorophenyl)-6-hydroxy-3-oxo-1,3-dihydro-5-isobenzofurancarboxylate

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Chinese Journal of Structural Chemistry 2010年第1期29卷 43-46页

作者：徐晓倩王晓奎杨世颖郑志兵赵国明李松 Institute of pharmacology and Toxicology Academy of Military Medical Sciences Shenyang Pharmaceutical University Institute of Materia Medica Chinese Academy of medical Sciences & peking union medical college

The crystal structure of the title compound（C17H12ClFO5,Mr=350.72） was determined by single-crystal X-ray *** crystal belongs to monoclinic,space group P21/c,with a=7.693（1）,b=15.767（1）,c=12.986（1）,β=97.23（1）°,V=1562.6（2）3,Z=4,Dc= 1.491 g/cm3,λ（MoKα）=0.71073,F（000）=720,μ（MoKα）=0.280 mm-1,R=0.0563 and wR=0.1674.A total of 3592 unique reflections were collected,of which 2462 with Ⅰ＆gt;2σ（Ⅰ） were ***-membered lactone rings and hydroxyl-substituted phenyl rings are approximately coplanar with their dihedral angle of 4.1°. The dihedral angle between two different phenyl rings is 71.3°. To our interest, intramolecular O（1）-H（1）…O（4） hydrogen bonds could be found in each molecule. Intramolecular hydrogen bonds and intermolecular van der Waals force contribute to the stability of the structure.

关键词： isobenzofurancarboxylate phthalide crystal structure synthesis

Synthesis and Crystal Structure of (R)-1-acetyl-6-(2-chloro-4-fluorophenyl)-4-methyl-N-((R)-1-phenylethyl)-2-(2,4,6-trifluorophenyl)-1,6-dihydropyrimidine-5-carboxamide

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Chinese Journal of Structural Chemistry 2013年第7期32卷 989-992页

作者：杨秀岩赵国明杨世颖李松 Shenyang Pharmaceutical University Institute of pharmacology and Toxicology Academy of Military Medical Sciences Institute of Materia Medica Chinese Academy of medical Sciences & peking union Medical College

The crystal structure of the title compound （C28H22C1F4N302, Mr = 543.14） was determined by single-crystal X-ray diffraction. The crystal belongs to the monoclinic system, space group P21 with a = 12.2113（11）, b = 9.4956（9）, c = 25.484（2） A, β= 98.486（1）~, V= 2922.6（5） A, Z = 2, Dc = 1.302 Mg/m3, F（000） = 1184, μ = 0.19 mm-1, R = 0.068 and wR = 0.186. The asymmetric unit of the title compound contains two organic molecules and two solvent acetone molecules with 50% occupancy each. In each organic molecule, the dihydropyridine ring adopts a half boat conformation. In the crystal, the molecules are linked by N-H...O hydrogen bonds.

关键词： HAPs crystal structure synthesis

Anti-tumor Activities of Novel Estrogen Compound 17aα-D-Homo-Ethynylestradiol-3-Acetate

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Chinese Journal of Cancer Research 2008年第1期20卷 17-20页

作者：周则卫唐卫生沈秀韩英王晓雪张良安 Institute of Radiation Medicine Chinese Academy of medical Sciences & peking union medical college

Objective： To study the anti-tumor activities of novel estrogen compound 17a α-D-homo-ethynylestradiol-3-acetate in vitro and in vivo. Methods： In vitro anti-tumor activity was assayed in adenoma cells A549 and human liver cancer cells Bel-7402 using MTT method, and half-inhibitory concentration （IC50） were observed. In vivo the pulmonary adenoma LA795 cells was selected and the conventional assay method of anti-tumor activity was employed. 5, 7.5, 10 mg/kg of 17a α-D-homo-ethynylestradiol-3-acetate was administered by i.p., and tumor-inhibitory rate, thymus and spleen indexes, bone marrow cells （BMC） were observed. Results： IC50 of 17a α-D-homo-ethynylestradiol-3-acetate in vitro for A549 and Bel-7402 cells were 12.28 μg/ml and 17.79 μg/ml, respectively. In vivo the highest tumor-inhibitory rates for LA795 was 60.0% （P〈0.01）. The drug had hardly any side-effect in spleen indexes, thymus indexes, and BMC compared with control mice. Nevertheless, compared with the positive control drug cyclophosphamide （CY）, thymus and spleen indexes, BMC showed obvious differences （P〈0.01）. Conclusion： 17a α-D-homo-ethynylestradiol-3-acetate has obvious anti-tumor activities in vitro and in vivo with low side-effect, thus worth further investigation.

关键词： 17a α-D-homo-ethynylestradioi-3-acetate Estrogen Anti-tumor pharmacology