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Effects of diammonium glycyrrhizinate on hepatic and intestinal UDP-Glucuronosyltransferases in rats: Implication in herb-drug interactions

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Chinese Journal of Natural Medicines 2016年第7期14卷 534-540页

作者： LI Fei-Yan XIE hao WENG Lin WANG Hong CAO Li-Juan hao hai-ping WANG Guang-Ji State Key Laboratory of Natural Medicines Key Laboratory of Drug Metabolism and Pharmacokinetics China Pharmaceutical University Department of Good Clinical Practice Zhejiang Cancer Hospital

Glycyrrhizin is a major bioactive component of liquorice, which exerts multiple biochemical and pharmacological activities and is frequently used in combination with other drugs in the clinic. Mycophenolate mofetil(MMF), an immunosuppressant widely used in transplant patients, is metabolized by UDP-glucuronyltransferases(UGTs). Although significant evidence supports that glycyrrhizin could interact with the cytochrome P450s(CYPs), few studies have addressed its effects on UGTs. The present study aimed at investigating the regulatory effects of diammonium glycyrrhizinate(GLN) on UGTs in vitro and in vivo. We found that long-term administration of GLN in rats induced overall metabolism of MMF, which might be due to the induction of UGT1A protein expression. Hepatic UGT1A activity and UGT1A mRNA and protein expression were significantly increased in GLN-treated rats. UGT1A expression levels were also increased in the intestine, contradicting with the observed decrease in intestinal UGT1A activities. This phenomenon may be attributed to different concentrations of glycyrrhetinic acid(GA) in liver and intestine and the inhibitory effects of GA on UGT1A activity. In conclusion, our study revealed that GLN had multiple effects on the expression and activities of UGT1A isoforms, providing a basis for a better understanding of interactions between GLN and other drugs.

关键词： Diammonium glycyrrhizinate UDP-glucuronosyltransferase Sprague-Dawley rat Drug-drug interaction

NAMPT inhibition synergizes with NQO1-targeting agents in inducing apoptotic cell death in non-small cell lung cancer cells

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Chinese Journal of Natural Medicines 2016年第8期14卷 582-589页

作者： LIU Hui-Ying LI Qing-Ran CHENG Xue-Fang WANG Guang-Ji hao hai-ping State Key Laboratory of Natural Medicines Key Lab of Drug Metabolism and Pharmacokinetics China Pharmaceutical University Department of Physiology and Pathophysiology School of Basic Medical Sciences Peking University

Nicotinamide phosphoribosyltransferase(NAMPT) catalyzes the first rate-limiting step in converting nicotinamide to NAD^+, essential for a number of enzymes and regulatory proteins involved in a variety of cellular processes, including deacetylation enzyme SIRT1 which modulates several tumor suppressors such as p53 and FOXO. Herein we report that NQO1 substrates Tanshione IIA(TSA) and β-lapachone(β-lap) induced a rapid depletion of NAD^+ pool but adaptively a significant upregulation of NAMPT. NAMPT inhibition by FK866 at a nontoxic dose significantly enhanced NQO1-targeting agent-induced apoptotic cell death. Compared with TSA or β-lap treatment alone, co-treatment with FK866 induced a more dramatic depletion of NAD^+, repression of SIRT1 activity, and thereby the increased accumulation of acetylated FOXO1 and the activation of apoptotic pathway. In conclusion, the results from the present study support that NAMPT inhibition can synergize with NQO1 activation to induce apoptotic cell death, thereby providing a new rationale for the development of combinative therapeutic drugs in combating non-small lung cancer.

关键词： FK866 NQOl-targeting agents Synergy NAD+ SIRT1

Silybin alleviates hepatic lipid accumulation in methionine-choline deficient diet-induced nonalcoholic fatty liver disease in mice via peroxisome proliferator-activated receptorα

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Chinese Journal of Natural Medicines 2021年第6期19卷 401-411页

作者： CUI Shuang PAN Xiao-Jie GE Chao-Liang GUO Yi-Tong ZHANG Peng-Fei YAN Ting-Ting ZHOU Ji-Yu HE Qing-Xian CHENG Long-hao WANG Guang-Ji hao hai-ping WANG Hong State Key Laboratory of Natural Medicines Key Laboratory of Drug Metabolism&PharmacokineticsChina Pharmaceutical UniversityNanjing 210009China Department of Pharmacy The First Affiliated Hospital of Anhui Medical UniversityHefei 230022China Laboratory of Metabolism Center for Cancer ResearchNational Cancer InstituteNational Institutes of HealthBethesdaMD 20892USA

Nonalcoholic fatty liver disease(NAFLD)is regarded as the most common liver disease with no approved therapeutic drug ***,an extract from the seeds of Silybum marianum,has been used for centuries for the treatment of various liver *** the hepatoprotective effect of silybin against NAFLD is widely accepted,the underlying mechanism and therapeutic target remain *** this study,NAFLD mice caused by methionine-choline deficient(MCD)diet were orally administrated with silybin to explore the possible mechanism and *** clarify the contribution of peroxisome proliferator-activated receptorα(PPARα),PPARαantagonist GW6471 was co-administrated with silybin to NAFLD *** silybin was proven as a PPARαpartial agonist,the combined effect of silybin with PPARαagonist,fenofibrate,was then evaluated in NAFLD *** and liver samples were collected to analyze the pharmacological efficacy and expression of PPARαand its *** expected,silybin significantly protected mice from MCD-induced ***,silybin reduced lipid accumulation via activating PPARα,inducing the expression of liver cytosolic fatty acid-binding protein,carnitine palmitoyltransferase(Cpt)-1a,Cpt-2,medium chain acyl-CoA dehydrogenase and stearoyl-CoA desaturase-1,and suppressing fatty acid synthase and acetyl-CoA carboxylaseα.GW6471 abolished the effect of silybin on PPARαsignal and hepatoprotective effect against ***,as a partial agonist for PPARα,silybin impaired the powerful lipid-lowering effect of fenofibrate when used *** together,silybin protected mice against NAFLD via activating PPARαto diminish lipid accumulation and it is not suggested to simultaneously take silybin and classical PPARαagonists for NAFLD therapy.

关键词： Silybin NAFLD PPARa Lipid metabolism Fenofibrate

Pharmacodynamics and potential synergistic effects of Mai-Luo-Ning injection on cardiovascular protection, based on molecular docking

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Chinese Journal of Natural Medicines 2015年第11期13卷 815-822页

作者： WU Liang SHEN Han-Yuan WU Yu-Zheng YU Xiao-Yi WANG Hong CHENG Xue-Fang WANG Guang-Ji hao hai-ping State Key Laboratory of Natural Medicines Key Lab of Drug Metabolism and Pharmacokinetics China Pharmaceutical University School of Pharmacy Nanjing University of Chinese Medicine

As a computer-assisted approach, molecular docking has been universally applied in drug research and development and plays an important role in the investigation and evaluation of herbal medicines. Herein, the method was used to estimate the pharmacodynamics of Mai-Luo-Ning injection, a traditional Chinese compound herbal prescription. Through investigating the interactions between several important proteins in cardiovascular system and characteristic components of the formula, its effect on cardiovascular protection was evaluated. Results showed the differences in the interactions between each component and the selected target proteins and revealed the possible mechanisms for synergistic effects of various characteristic components on cardiovascular protection. The study provided scientific evidence supporting the mechanistic study of the interactions among multi-components and targets, offering a general approach to investigating the pharmacodynamics of complicated materials in compound herbal prescriptions.

关键词： Molecular docking Mai-Luo-Ning injection Multiple-components and targets Compound herbal prescription Pharmacodynamics

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临床前药物代谢动力学关键技术与研究体系

中国药科大学学报 2008年第2期39卷 97-102页

作者：郝海平王广基中国药科大学药物代谢动力学重点实验室南京210009

临床前药物代谢动力学研究在创新药物研发中占有十分重要的作用,贯穿于创新药物研发的每一环节。我国临床前药物代谢动力学研究水平在"九五"以前相当落后,本课题组在国家自然科学基金、国家高技术研究发展计划("八六三"计划)、国家重点... 详细信息

临床前药物代谢动力学研究在创新药物研发中占有十分重要的作用,贯穿于创新药物研发的每一环节。我国临床前药物代谢动力学研究水平在"九五"以前相当落后,本课题组在国家自然科学基金、国家高技术研究发展计划("八六三"计划)、国家重点基础研究发展计划("九七三"计划)及江苏省药物代谢动力学重点实验室建设等多项课题的资助下,围绕我国药物代谢动力学研究的薄弱环节和亟待解决的关键问题,通过近十年的创新攻关研究,解决了生物样品中微量/痕量药物高灵敏度、快速定量分析,体内外吸收、分布、代谢与排泄特性快速筛选与评价等11项关键技术,建立了较为完善的先导/候选化合物快速筛选体系、创新药物体内外临床前药物代谢动力学评价体系以及中药整体药物代谢动力学研究体系,项目研究成果对促进我国药物代谢动力学水平的整体提高、推动创新药物研发与中药现代化研究进程具有重要意义。

关键词：临床前药物代谢动力学关键技术研究体系

内源性代谢物靶标发现及其在精准靶向肿瘤治疗中的应用前景

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医学研究生学报 2019年第5期32卷 468-473页

作者：叶慧郝海平中国药科大学天然药物活性组分与药效国家重点实验室江苏省药物代谢动力学重点实验室

随着生物质谱和功能组学等技术的发展,内源性代谢物能作为功能性配体,与体内多种蛋白发生相互作用,进而影响肿瘤细胞的生存和增殖。然而,大多数功能性代谢物在肿瘤内的直接作用靶标和调控机制尚不明确,对其认知的缺失阻碍了进一步基于... 详细信息

随着生物质谱和功能组学等技术的发展,内源性代谢物能作为功能性配体,与体内多种蛋白发生相互作用,进而影响肿瘤细胞的生存和增殖。然而,大多数功能性代谢物在肿瘤内的直接作用靶标和调控机制尚不明确,对其认知的缺失阻碍了进一步基于肿瘤代谢重编程现象研发精准靶向药物的探索。因此,寻找内源性代谢物在体内的直接作用靶标,不仅有助于基于靶向肿瘤代谢的先导化合物的新药研发,也为实现肿瘤患者个性化治疗提供了新思路。文中就肿瘤代谢的特点及内源性代谢物对肿瘤生存的影响,以及目前适用于内源性代谢物的靶标发现方法进行阐述,以期为基于肿瘤代谢的精准治疗提供参考。

关键词：肿瘤代谢内源性代谢物靶标发现精准治疗

抑郁症中的免疫代谢调控异常与药物干预研究进展

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药学学报 2017年第1期52卷 19-25页

作者：郑啸王广基郝海平中国药科大学药物代谢动力学重点实验室江苏南京210009

针对单胺类神经递质失衡的经典抗抑郁治疗方案有着较大的局限性。近年来,临床和动物实验不断揭示炎症免疫机制与抑郁症的发生、发展密切相关。随着神经-免疫-代谢互动研究的深入,免疫代谢异常驱动的神经炎症反应和病变已成为抑郁病理机... 详细信息

针对单胺类神经递质失衡的经典抗抑郁治疗方案有着较大的局限性。近年来,临床和动物实验不断揭示炎症免疫机制与抑郁症的发生、发展密切相关。随着神经-免疫-代谢互动研究的深入,免疫代谢异常驱动的神经炎症反应和病变已成为抑郁病理机制和药物干预研究的重要方向。本文在阐述抑郁症病理网络中免疫代谢失调环节的基础上,总结抗抑郁活性化合物免疫代谢调控的新作用,并探讨以上研究进展对于抗抑郁症药物研发策略和临床治疗的启示。

关键词：抑郁症免疫代谢调控异常中枢外周互动抗抑郁靶点

Dissipation-free approach for realizing non-Hermitian dynamics in a superconducting circuit

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Science China(Physics,Mechanics & Astronomy) 2025年

作者： Yi-hao Kang Yang Xiao Yu Wang Qi-ping Su Chui-ping Yang School of Physics Hangzhou Normal University Fujian Key Laboratory of Quantum Information and Quantum Optics Fuzhou University Department of Physics Fuzhou University

Non-Hermitian dynamics exhibits a wealth of surprising and potentially useful phenomena. However, it is typically realized by coupling a system with thermal reservoirs, which makes the system suffer from thermal fluctuations associated with the dissipation. Here, we propose a dissipation-free approach to realize non-Hermitian dynamics using a superconducting circuit composed of two resonators and a superconducting qutrit. The non-Hermiticity arises in the dynamical matrix for the evolution of the two resonators in the Heisenberg picture, via a photon-number non-conserved dynamics. The energy spectrum of the non-Hermitian dynamical matrix can be retrieved by measuring the state of the two resonators, and a phase transition of the energy spectrum can be observed by varying the control parameters. In the realization of the non-Hermitian dynamics, the dissipation of the system and the post-selection are not required. Thus, the approach is implemented in a deterministic way, and the reservoir-induced noise is suppressed. Numerical simulations indicate that the energy spectrum of the non-Hermitian dynamical matrix obtained via the measurement of the resonators is in accordance with the theoretical prediction. Moreover, we demonstrate the parity discrimination for the state of two four-level qudits as an application, exhibiting the potential of the non-Hermitian dynamics in the field of quantum measurement. This work opens a new avenue for the realization of non-Hermitian dynamics and may have a significant implication in exploring the non-Hermitian phenomena.

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高血压病中医分型的代谢组学研究(英文)

中国临床药理学与治疗学 2007年第10期12卷 1144-1150页

作者： LU Yi-hong hao hai-ping WANG Guang-ji CHEN Hu-xiao ZHU Xuan-xuan XIANG Bing-ren HUANG Qing A Ji-Y Key Laboratory of Drug Metabolism and Pharmacokinetics China Pharmaceutical University Nanjing 210009 Jiangsu China Jinagsu Provincial Traditional Chinese Medicinal Hospital Nanjing 210009 Jiangsu China Jiangsu Institute for Drug Control Nanjing 210008 Jiangsu China

目的:将传统中医辨证方法同现代系统生物学理论相结合,探讨原发性高血压辨证分型与基于GC/MS的血清代谢组学的关系。方法:原发性高血压辨证分为肝火亢盛、痰湿雍盛及阴虚阳亢三型。应用GC/MS测定健康人及原发性高血压病人血清内源性代谢... 详细信息

目的:将传统中医辨证方法同现代系统生物学理论相结合,探讨原发性高血压辨证分型与基于GC/MS的血清代谢组学的关系。方法:原发性高血压辨证分为肝火亢盛、痰湿雍盛及阴虚阳亢三型。应用GC/MS测定健康人及原发性高血压病人血清内源性代谢物,并用主成分分析(PCA)、偏最小乘方分析(PLS-DA)和马氏距离(MD)分析他们的代谢谱。结果:PCA和PLS-DA分析的结果表明:健康人与高血压病人血清代谢谱有明显差异,能够被区分开,但PCA和PLS-DA不能将中医高血压的三型完全分开。利用MD不仅可以清晰地区分上述三种类型的高血压,同时还显示高血压的发展过程。结论:基于GC/MS和模式识别的代谢组学在揭示传统中医理论本质上有着广泛的应用前景。

关键词：代谢组学中医证型高血压 GC/MS