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亨廷顿舞蹈症实验动物模型研究进展

中国实验动物学报 2024年第8期32卷 1065-1076页

作者：付铄张雯宋俊科杜冠华中国医学科学院药物研究所北京协和医学院药物靶点研究与新药筛选北京市重点实验室北京100050

亨廷顿舞蹈症(Huntington’s disease,HD)是一类常染色体显性遗传的神经退行性疾病,患者主要症状为舞蹈状的不自主运动、精神行为异常和认知障碍,严重影响患者的生活,消耗大量社会医疗资源。为了更好地理解其病理机制并探索治疗方法,已... 详细信息

亨廷顿舞蹈症(Huntington’s disease,HD)是一类常染色体显性遗传的神经退行性疾病,患者主要症状为舞蹈状的不自主运动、精神行为异常和认知障碍,严重影响患者的生活,消耗大量社会医疗资源。为了更好地理解其病理机制并探索治疗方法,已有多种HD实验动物模型被成功构建。本文概述了从秀丽隐杆线虫、果蝇、斑马鱼到小鼠、大鼠和小型猪等多种动物模型的建立与应用情况,并对不同动物模型的特点和优势进行了分析。通过综述不同动物模型及其相关评价指标,本文强调了综合运用多种动物模型的重要性,以期深入理解疾病的机制并制定有效的治疗策略。

关键词：亨廷顿舞蹈症动物模型模型特点评价指标

Pharmacokinetic study of gallocatechin-7-gallate from Pithecellobium clypearia Benth. in rats

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Acta Pharmaceutica Sinica B 2016年第1期6卷 64-70页

作者： Chao Li Xiaowei song junke song Xiaocong Pang Zhe Wang Ying Zhao Wenwen Lian Ailin Liu Guanhua Du Institute of Materia Medica Chinese Academy of Medical Sciences and Peking Union Medical College Beijing Key Laboratory of Drug Target and Screening Research State Key Laboratory of Bioactive Substance and Function of Natural Medicines

The pharmacokinetic profile of gallocatechin-7-gallate (J10688) was studied in rats after intravenous administration. Male and female Sprague-Dawley (SD) rats received 1, 3, and 10 mg/kg (i.v.) of J10688 and plasma drug concentrations were determined by a high performance liquid chromatography-mass spectrometry (LC-MS) method. The pharmacokinetic software Data Analysis System (Version 3.0) was used to calculate the pharmacokinetic parameters. For different i.v. doses of J10688, the mean peak plasma concentration (C-0) values ranged from 11.26 to 50.82 mg/L, and mean area under the concentration -time curve (ALC(0-i)) values ranged from 1.75 to 11.80 (mg ' h/L). J10688 lacked dose dependent pharmacokinetic properties within doses between 1 and 10 mg/kg, based on the power model. The method developed in this study was sensitive, precise, and stable. The pharmacokinetic properties of J10688 in SD rats were shown to have rapid distribution and clearance values. These pharmacokinetic results may contribute to an improved understanding of the pharmacological actions of J10688. (C) 2016 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.

关键词： Galloeatechin-7-gallata LC-MS Pharmacokinetics Dose proportionality Non-compartment mode

Inhibition of FOXO3a/BIM signaling pathway contributes to the protective effect of salvianolic acid A against cerebral ischemia/reperfusion injury

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Acta Pharmaceutica Sinica B 2019年第3期9卷 505-515页

作者： junke song Wen Zhang Jinhua Wang Haiguang Yang Qimeng Zhou Haigang Wang Li Li Guanhua Du State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing100050China Beijing Key Laboratory of Drug Target Identification and Drug Screening Institute of Materia MedicaChinese Academy of MedicalSciences and Peking Union Medical CollegeBeijing100050China

Salvianolic acid A(SalA) is an effective compound extracted from traditional Chinese medicine Salvia miltiorrhiza Bunge. The Forkhead box O3a(FOXO3a) signaling pathway plays crucial roles in the modulation of ischemia-induced cell apoptosis. However, no information about the regulatory effect of SalA on FoxO3a is available. To explore the anti-cerebral ischemia effect and clarify the therapeutic mechanism of SalA, SH-SY5Y cells and Sprague–Dawley rats were applied, which were exposed to oxygen glucose deprivation/reoxygenation(OGD/R) and middle cerebral artery occlusion/reperfusion(MCAO/R) injuries, respectively. The involved pathway was identified using the specific inhibitor LY294002. Results showed that SalA concentration-dependently inhibited OGD/R injury triggered cell viability loss. SalA reduced cerebral infarction, lowered brain edema, improved neurological function, and inhibited neuron apoptosis in MCAO/R rats, which were attenuated by the treatment of phosphatidylinositol-4,5-bisphosphate 3-kinase(PI3K) specific inhibitor LY294002. SalA time-and concentration-dependently upregulated the phosphorylation levels of protein kinase B(AKT) and its downstream protein FOXO3a. Moreover, the nuclear translocation of FOXO3a was inhibited by SalA both in vivo and in vitro, which was also reversed by LY294002. The above results indicated that SalA fought against ischemia/reperfusion damage at least partially via the AKT/FOXO3a/BIM pathway.

关键词： Salvianolic acid A Ischemia reperfusion FOXO3a BIM Neuroprotection

Antihyperuricemic effect of mangiferin aglycon derivative J99745 by inhibiting xanthine oxidase activity and urate transporter 1 expression in mice

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Acta Pharmaceutica Sinica B 2018年第2期8卷 306-315页

作者： Zhizhen Qin Shoubao Wang Yihuang Lin Ying Zhao Shengqian Yang junke song Tao Xie Jinlong Tian song Wu Guanhua Du Beijing Key Laboratory of Drug Target and Screening Research Department of New Drug R&D Institute of Materia Medica Chinese Academy of Medical Science and Peking Union Medical College

A mangiferin aglycon derivative J99745 has been identified as a potent xanthine oxidase(XOD) inhibitor by previous in vitro study. This study aimed to evaluate the hypouricemic effects of J99745 in experimental hyperuricemia mice, and explore the underlying mechanisms. Mice were orally administered 600 mg/kg xanthine once daily for 7 days and intraperitoneally injected 250 mg/kg oxonic acid on the 7 th day to induce hyperuricemia. Meanwhile, J99745(3, 10, and 30 mg/kg), allopurinol(20 mg/kg) or benzbromarone(20 mg/kg) were orally administered to mice for 7 days. On the 7 th day,uric acid and creatinine in serum and urine, blood urea nitrogen(BUN), malondialdehyde(MDA) content and XOD activities in serum and liver were determined. Morphological changes in kidney were observed using hematoxylin and eosin(H&E) staining. Hepatic XOD, renal urate transporter 1(URAT1), glucose transporter type 9(GLUT9), organic anion transporter 1(OAT1) and ATP-binding cassette transporter G2(ABCG2) were detected by Western blot and real time polymerase chain reaction(PCR). The results showed that J99745 at doses of 10 and 30 mg/kg significantly reduced serum urate, and enhanced fractional excretion of uric acid(FEUA). H&E staining confirmed that J99745 provided greater nephroprotective effects than allopurinol and benzbromarone. Moreover, serum and hepatic XOD activities and renal URAT1 expression declined in J99745-treated hyperuricemia mice. In consistence with the ability to inhibit XOD, J99745 lowered serum MDA content in hyperuricemia mice. Our resultssuggest that J99745 exerts urate-lowering effect by inhibiting XOD activity and URAT1 expression, thus representing a promising candidate as an anti-hyperuricemia agent.

关键词： Antihyperuricemic effect Mangiferin aglycon Derivative Xanthine oxidase Urate transporter 1

Pharmacokinetic study of salvianolic acid D after oral and intravenous administration in rats

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Acta Pharmaceutica Sinica B 2015年第3期5卷 246-253页

作者： junke song Wen Zhang Jialin Sun Xiaona Xu Xue Zhang Li Zhang Zhangying Feng Guan-hua Du State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Beijing Key Laboratory of Drug Target Identification and Drug ScreeningInstitute of Materia MedicaChinese Academy of Medical Sciences & Peking Union Medical College Pharmacy Department of the Affiliated Hospital of Medical College of Qingdao University The Fourth Hospital of Hebei Medical University

A sensitive, specific and rapid LC-MS method was developed and validated for the determination of salvianolic acid D (SAlD) in rat plasma. This method used a single quadrupole mass spectrometer with an electrospray ionization (ESI) source. A single ion monitoring scanning (SIM) mode was employed. it showed good linearity over the concentration range from 3.3 to 666.7 ngfint. for the determination of Sala The R.S.D.% of intra-day and inter-day precision values were no more than 7.69%, and the accuracy was within 91%-104% at all quality control Levels. This LC MS method was applied to the pharmacokinetic study of SaID in rats. A two-compartmental model analysis was employed. The plasma concentrations at 2 mm (C-2min) were 5756.06 +/- 719.61, 11,073.01 +/- 1783.46 and 21,077.58 +/- 5581.97 nit, for 0.25, 0.5 and I mg/kg intravenous injection, respectively. The peak plastna concentration (C-max) was 333.08 +/- 61.21 pg/L for 4 mg/kg oral administration. The area under curve (AUC(0-t)) was 14,384.379 +/- 8443.t84. 22,813.369 +/- 11,860.823, 46,406.122 +/- 27,592.645 and 8201.740+4711.961 mu g/L.h for intravenous injection (0.25, 0.5 and 1 mg/kg) and oral administration (4 mg/kg), respectively. The bioavailability of SalD) was calculated to be 4.159% +/- 0.517%. (C) 2015 Chinese Pharmaceutical Association and Institute of Materia IMedica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.

关键词： Salvianolic acid D LC-MS Pharmacokinetics Bioavilability Dose proportiionality salvia miltiorrhiza Danshen Analysis method

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犬新孢子虫miRNAs的鉴定与分析

畜牧兽医学报 2024年第7期55卷 3085-3093页

作者：李京宇陈金铭张明一赵姗姗陶德良宋军科杨新樊莹莹赵光辉西北农林科技大学动物医学院杨凌712100

为鉴定犬新孢子虫(Neospora caninum)特异表达的miRNAs,并研究其在宿主细胞中的表达情况,本研究收集***速殖子感染的山羊子宫内膜上皮细胞(caprine endometrial epithelial cells,EECs)24和48 h的样本,用Illumina高通量测序平台和生物... 详细信息

为鉴定犬新孢子虫(Neospora caninum)特异表达的miRNAs,并研究其在宿主细胞中的表达情况,本研究收集***速殖子感染的山羊子宫内膜上皮细胞(caprine endometrial epithelial cells,EECs)24和48 h的样本,用Illumina高通量测序平台和生物信息学分析犬新孢子虫特异表达的miRNAs及其体外表达情况,并研究了一个上调的miRNA novel3_mature对犬新孢子虫在山羊EECs增殖的影响。结果发现,共鉴定出3404个犬新孢子虫特异表达的miRNAs(155个新预测miRNAs),其中77个(47个上调和30个下调)miRNAs显著差异表达;随机选取7个显著差异表达的miRNAs进行实时荧光定量PCR分析,结果与高通量测序结果一致;预测分析发现61个miRNAs的3978个靶基因,功能富集分析发现这些靶基因可能主要参与MAPK信号通路、突触导向、黏着斑、cMAP信号通路、钙信号通路等;转染novel3_mature的模拟物显著促进犬新孢子虫在山羊EECs中的增殖。犬新孢子虫存在多个特异表达的miRNAs,其在虫体增殖中发挥重要作用,研究成果为深入理解犬新孢子虫胞内生存提供了新的思路。

关键词：犬新孢子虫山羊子宫内膜上皮细胞 miRNAs novel3_mature 增殖

An innovative rhein-matrine cocrystal: Synthesis, characterization,formation mechanism and pharmacokinetic study

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Chinese Chemical Letters 2023年第2期34卷 546-549页

作者： Hongjuan Wang Dezhi Yang Wen Zhang junke song Ningbo Gong Mingchao Yu Shiying Yang Baoxi Zhang Qiwen Liu Guanhua Du Yang Lu Beijing Key Laboratory of Polymorphic Drugs Center of Pharmaceutical PolymorphsInstitute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China Beijing Key Laboratory of Drug Targets Identification and Drug Screening National Center for Pharmaceutical ScreeningInstitute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China

Rhein(Rhe), an anthraquinone derivative, exhibits excellent anti-inflammatory effects and other pharmacological activities, but its clinical application remains limited due to poor solubility. The present work aims at the improvement of solubility and oral bioavailability of Rhe through cocrystal formation. For this purpose, Rhe and matrine(Mat) were selected as pharmaceutical ingredient(API) and cocrystal former(CCF), respectively, and the Rhe-Mat cocrystal was synthesized and characterized by single crystal X-ray diffraction(SXRD), powder X-ray diffraction(PXRD), thermogravimetric analysis(TGA), differential scanning calorimetry(DSC). The formation mechanism of Rhe-Mat cocrystal was elucidated by molecular surface electrostatic potential(MSEP). It is worth mentioning that the 50-fold increment of dissolution in vitro was observed in pure water in the form of Rhe-Mat cocrystal. Furthermore, the in vivo studies revealed that Rhe-Mat cocrystal indicated the faster absorption rate and the higher peak blood concentration than the pure Rhe. Hence, it can be concluded that current study successfully improved the solubility and oral bioavailability of Rhe.

关键词： Rhein Matrine Cocrystal Poor solubility Molecular surface electrostatic potential

Research Progress of the Antiviral Bioactivities of Natural Flavonoids

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Natural Products and Bioprospecting 2020年第5期10卷 271-283页

作者： Lin Wang junke song Ailin Liu Bin Xiao Sha Li Zhang Wen Yang Lu Guanhua Du Beijing Key Laboratory of Drug Targets Identification and Drug Screening Institute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical College1 Xian Nong Tan StreetBeijing 100050China Laboratory of Clinical Pharmacy Ordos Central HospitalOrdos School of Clinical MedicineInner Mongolia Medical UniversityOrdos 017000China

Flavonoids are now considered as an indispensable component in a variety of nutraceutical and pharmaceutical *** recent researches have focused on the health aspects of flavonoids for ***,different flavonoids have been investigated for their potential antiviral activities,and several natural flavonoids exhibited significant antiviral properties both in vitro and in *** review provides a survey of the literature regarding the evidence for antiviral bioactivities of natural flavonoids,highlights the cellular and molecular mechanisms of natural flavonoids on viruses,and presents the details of most reported ***,future perspectives on therapeutic applications of flavonoids against viral infections were discussed.

关键词： Antiviral bioactivities Natural flavonoids Cellular and molecular mechanisms Therapeutic applications

Preparation and Certification of a New Salvianolic Acid A Reference Material for Food and Drug Research

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Natural Products and Bioprospecting 2020年第2期10卷 67-75页

作者： Dezhi Yang Bin Su Yancai Bi Li Zhang Baoxi Zhang junke song Yang Lu Guanhua Du Beijing City Key Laboratory of Polymorphic Drugs Center of Pharmaceutical PolymorphsInstitute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050People’s Republic of China Soteria Pharmaceutical Co. Ltd.Laiwu 271100People’s Republic of China Beijing City Key Laboratory of Drug Target and Screening Research National Center for Pharmaceutical ScreeningInstitute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050People’s Republic of China

Salvianolic acid A(Sal A),a water-soluble ingredient in Danshen,has various biological *** A and its impurities have similar physical and chemical properties,as well as strong reducibility;therefore,they are difficult to prepare and *** this study,high-purity Sal A was obtained by purification of sephadex chromatography and preparative ***,HPLC-DAD tandem ECD and HPLC-DAD tandem MS methods were used for non-volatile organic impurity analysis,ICP-MS method was used for non-volatile inorganic impurities and mass balance method and quantitative nuclear magnetic resonance were employed to certify the *** structures of Sal A and its relative impurities were validated by nuclear magnetic resonance spectroscopy and mass spectrometry,and their contents were quantified as *** the principles of ISO Guides 34:2009 and 35:2005,a Sal A reference material was certified,covering homogeneity studies,stability studies,characterization,and uncertainty estimations.

关键词： Certified reference material Salvianolic acid A Mass balance method qNMR High resolution mass spectrum