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Chinese Herbal Medicines 2017年第4期9卷 335-343页

作者： Si-qi Feng Jian-liang Geng Run-bin Sun Jing-qiu Huang Zhao-yi Tan Cai-xia Yan Ji-ye AA Guang-ji Wang Lab of Metabolomics Key laboratory of Drug Metabolism and pharmacokinetics China Pharmaceutical University

Objective Salvianolic acid A（SAA） has a significant protective effect on ischemia/reperfusion injury of brain. However, it is not clear for SAA to exert its cerebral protection by targeting at the microvascular endothelial cells of blood brain barrier（BBB）. Our previous study demonstrated that SAA could hardly pass through the BBB. This present study was therefore designed to investigate the protective effect of SAA on brain microvascular endothelial cells（BMECs） induced by deprivation and reperfusion with oxygen-glucose. Methods Rat BMECs were treated with oxygen glucose deprivation（OGD）, followed by reperfusion（OGD/R）. Cell viability was assessed by MTT and the content of reactive oxygen species（ROS） in cells after OGD/R in the absence or presence of SAA. GC-MS based metabolomic platform was applied to evaluate the regulation of SAA on the cellular metabolic perturbation induced by OGD/R. Results OGD/R significantly increased the production of intracellular reactive oxygen species（ROS）, and decreased the activity of cells. SAA significantly reduced ROS and improve the cell viability. Metabolomic study revealed distinct perturbation of metabolic pathways of energy metabolism in the BMEC induced by OGD/R, while SAA significantly regulated the perturbed metabolism involved in energy metabolism pathways, especially for intermediates in TCA cycle. Conclusion SAA shows protective effects on BMECs involved in central nervous system.

关键词： metabolomics oxygen glucose deprivation reperfusion salvianolic acid A

Recent progress in tumor photodynamic immunotherapy

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Chinese Chemical Letters 2020年第7期31卷 1709-1716页

作者： Lijun Shen Tianjiao Zhou Yatong Fan Xin Chang Yi Wang Jianguo Sun Lei Xing Hulin Jiang State Key laboratory of Natural Medicines Department of PharmaceuticsChina Pharmaceutical UniversityNanjing 210009China Jiangsu Key laboratory of Druggability of Biopharmaceuticals China Pharmaceutical UniversityNanjing 210009China Jiangsu Key laboratory of Drug Screening China Pharmaceutical UniversityNanjing 210009China Jiangsu Key laboratory of Drug Discovery for Metabolic Diseases China Pharmaceutical UniversityNanjing 210009China Key Lab of Drug Metabolism and pharmacokinetics State Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjing 210009China

Photodynamic therapy(PDT)is a promising alternative approach for effective cancer treatment,which can directly destroy local tumor cells due to the generation of cytotoxic singlet oxygen and reactive oxygen species(ROS)in the tumor ***,PDT-mediated cell death is also associated with anti-tumor immune *** r,immunosuppre s sion of tumor microe nvironment is able to limit the immune response induced by PDT,it is therefore necessary to combine with immunocheckpoint inhibitor and immunoadjuvant for synergistic treatment of ***,the recent advances of PDT,immunotherapy,and photodynamic immunotherapy are reviewed.

关键词： Cancer therapy Photodynamic therapy Immunotherapy Reactive oxygen species Singlet oxygen

Evaluation of Chito-Oligosaccharide(COS)in Vitro and in Vivo:Permeability Characterization in Caco-2 Cells Monolayer and pharmacokinetics Properties in Rats

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Journal of Ocean University of China 2022年第3期21卷 782-788页

作者： ZHANG Pengpeng ZHANG Miaomiao DONG Kaiyu ZHANG Yicong YANG Shuang WANG Yuanhong JIANG Tingfu YU Mingming LV Zhihua School of Medicine and Pharmacy Ocean University of ChinaQingdao266003China laboratory for Marine Drugs and Bioproducts of Qingdao National laboratory for Marine Science and Technology Qingdao266003China Key laboratory of Glycoscience&Glycotechnology of Shandong Province Qingdao266003China Key laboratory of Marine Drugs Ministry of Education of ChinaQingdao266003China

Chito-oligosaccharide(COS)had shown a variety of biological activities and potential biomedical *** present study investigated the pharmacokinetics,bioavailability,and in vitro absorption of COS with degrees of polymerization(DPs)2-7 and explored the influence of DPs on *** Caco-2 cell permeation studies,COS were low permeability compounds with no directional effects,suggesting a low in vivo absorption mediated by facilitation diffusion and paracellular *** an intragastrical administration to rats,COS2 showed the highest systemic exposure in six *** bioavailability of COS2-7 was 7.33%,6.11%,4.67%,4.13%,4.02%,0.99%,*** in bioavailability for each COS correlated to structural variations,with high DPs contributing to a decrease in *** conclusion,COS could be absorbed by the intestinal tract both in vitro and in *** very low oral bioavailability of COS could be due to low *** can affect absorption and bioavailability of *** study provided evidence for the absorption characteristics of COS2-7 to help us better understanding the pharmacological actions.

关键词： chito-oligosaccharide(COS) Caco-2 transport pharmacokinetics bioavailability

A review of lignans from genus Kadsura and their spectrum characteristics

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Chinese Herbal Medicines 2021年第2期13卷 157-166页

作者： Liu Zhang Yan-zhe Jia Bin Li Cai-yun Peng Yu-pei Yang Wei Wang Chang-xiao Liu TCM and Ethnomedicine Innovation&Development International laboratory School of PharmacyHunan University of Chinese MedicineChangsha 410208China State Key laboratory of Drug Delivery Technology and pharmacokinetics Tianjin Institute of Pharmaceutical ResearchTianjin 300193China

Kadsura belongs to the Schisandroideae subfamily of *** from genus Kadsura are widely distributed in the South and Southwest of *** plants of the genus are widely used as folk medicine for a long time in history,with the functions of relieving pain,promoting 'qi' circulation,activating blood resolve stasis,and applications in the treatment of rheumatoid arthritis and gastroenteric *** are the primary characteristic constituents with various biological activities of plants from genus *** paper summarized 81 lignans isolated from the plants of genus Kadsura over the past eight years(from 2014 to 2021),which belong to five types:dibenzocyclooctadienes,spirobenzofuranoid dibenzocyclooctadienes,aryltetralins,diarylbutanes and *** type of these lignans possess typical characteristics in proton magnetic resonance(^(1)H NMR) and carbon-13 nuclear magnetic resonance(^(13)C NMR) spectra,the NMR regularities of these types of lingans were summarized,which provided a useful reference for the structural analysis of *** relationships between lignans and pharmacodynamics were also systematically analyzed,lignans were predicted to be the quality markers(Q-marker) of Kadsura genus.

关键词： Kadsura ^(1)H NMR and^(13)C NMR spectrum characteristics pharmacodynamics Q-marker lignans structure classifications

Effects of Puerarin on Experimental Model of Retinal Vein Occlusion in Rats

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Chinese Herbal Medicines 2014年第2期6卷 110-114页

作者： Chun-hua Hao Wei-ting Wang Ming-xiang Shao Zhuan-you Zhao Li-da Tang State Key laboratory of pharmacokinetics and Pharmacodynamics Tianjin Institute of Pharmaceutical Research

Objective To establish a model of retinal vein occlusion（RVO）in rats and to study the effect of puerarin on ischemic retinal disease and the corresponding *** RVO was induced in 10 adult male Sprague-Dawley（SD）rats by laser *** blood flow was examined before and after 1 h of the operation,and model rats with the retinal vein blood flow decreasing by 50%compared to the basic value were chosen and then puerarins（20,40,and 80 mg/kg）were *** levels of vascular endothelial growth factor（VEGF）,interleukin-1β（IL-1β）,and nitric oxide（NO）were *** addition,the histopathology of RVO-eyes was *** RVO-eyes displayed the signs of retinal damage and ischemia on Doppler Flowmeter and ***（20,40,and 80 mg/kg）increased blood flow by 9.3%（P〈0.05）,33.1%（P〈0.001）,and 41.5%（P〈0.001）,*** the other hand,the histological changes were less severe at different degrees,relieving the symptoms such as edematous and thick neuroretinal layers,lax,edematous,and disorganized optic fibers layers,swollen and confused inner and outer nuclear ***,dose-dependent decrease of VEGF and IL-1βand increase of NO in vitreous fluid were observed,with respect to the model *** A rat model of laser photochemical-induced RVO is established and a decrease in the retinal blood flow and histological damage is *** puerarin has therapeutic benefit in the rat model of RVO,through the pathway of neovascularization,anti-inflammation,and increase of NO.

关键词： interleukin-1β puerarin retinal vein occlusion vascular endothelial growth factor

The influence of genetic polymorphisms in drug metabolism enzymes and transporters on the pharmacokinetics of different fluvastatin formulations

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Asian Journal of Pharmaceutical Sciences 2020年第2期15卷 264-272页

作者： Qian Xiang Weidang Wu Nan Zhao Chuan Li Junyu Xu Lingyue Ma Xiaodan Zhang Qiufen Xie Zhuo Zhang Jiancheng Wang Weiren Xu Xia Zhao Yimin Cui Department of Pharmacy Peking University First HospitalBeijing 100034China State Key laboratory of Drug Release Technology and pharmacokinetics Tianjin Institute of Pharmaceutical ResearchTianjin 300193China School of Pharmaceutical Science Peking UniversityBeijing 100191China

The purpose of the present study was to investigate the impact of genetic polymorphism on fluvastatin *** addition,we compared the fluvastatin pharmacokinetics differences between extended-release(ER)80 mg tablet and immediate-release(IR)40 mg capsule in terms of drug metabolism enzyme and transporter genetic *** this open-label,randomized,two-period,two-treatment,crossover study(n=24),effects of ABCG2,SLCO1B1,ABCB1,CYP2C9 and CYP3A5 polymorphisms on the pharmacokinetics of fluvastatin were *** administration dosage for IR 40 mg and ER 80 mg were twice and once daily,respectively,for total 7 *** samples for pharmacokinetic evaluation were taken on the 1st and 7th *** lower exposure following ER was *** ER tablets,SLCO1B1 T521C genotype correlated with AUC 0-24 of repeat doses(P=0.010).SLCO1B1 T521C genotype had no statistically significant effect on AUC 0-24 of IR capsule of fluvastatin after single or repeated *** vitro study demonstrated that when the concentration of fluvastatin was low(1μmol/l),transport velocity of fluvastatin by HEK293-OATP1B1 with SLCO1B1521TT(K m=11.4μmol/l)and with SLCO1B1521TCC(K m=15.1μmol/l)tend to be the *** suggests that the increased effect of SLCO1B1 T521C genotype on ER formulation of fluvastatin was mainly caused by lower blood *** recommend that formulation should be incorporated into future pharmacogenomics studies.

关键词： Genetic polymorphisms SLCO1B1 Fluvastatin Immediate-release Extended-release

Cilastatin protects against imipenem-induced nephrotoxicity via inhibition of renal organic anion transporters(OATs)

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Acta Pharmaceutica Sinica B 2019年第5期9卷 986-996页

作者： Xiaokui Huo Qiang Meng Changyuan Wang Yanna Zhu Zhihao Liu Xiaodong Ma Xiaochi Ma Jinyong Peng Huijun Sun Kexin Liu Department of Clinical Pharmacology College of PharmacyDalian Medical UniversityDalian116044China College(Institute)of Integrative Medicine Dalian Medical UniversityDalian116044China Provincial Key laboratory for pharmacokinetics and Transport Dalian Medical UniversityDalian116044China

Imipenem is a carbapenem antibiotic. However, Imipenem could not be marketed owing to its instability and nephrotoxicity until cilastatin, an inhibitor of renal dehydropeptidase-I(DHP-I),was developed. In present study, the potential roles of renal organic anion transporters(OATs) in alleviating the nephrotoxicity of imipenem by cilastatin were investigated in vitro and in rabbits. Our results indicated that imipenem and cilastatin were substrates of h OAT1 and h OAT3. Cilastatin inhibited h OAT1/3-mediated transport of imipenem with IC50 values comparable to the clinical concentration, suggesting the potential to cause a clinical drug–drug interaction(DDI). Moreover,imipenem exhibited h OAT1/3-dependent cytotoxicity, which was alleviated by cilastatin and probenecid. Furthermore, cilastatin and probenecid ameliorated imipenem-induced rabbit acute kidney injury, and reduced the renal secretion of imipenem. Cilastatin and probenecid inhibited intracellular accumulation of imipenem and sequentially decreased the nephrocyte toxicity in rabbit primary proximal tubule cells. Renal OATs, besides DHP-I, was also the target of interaction between imipenem and cilastatin, and contributed to the nephrotoxicity of imipenem. This therefore gives in part the explanation about the mechanism by which cilastatin protected against imipenem-induced nephrotoxicity. Thus, OATs can potentially be used as a therapeutic target to avoid the renal adverse reaction of imipenem in clinic.

关键词： Imipenem Cilastatin Probenecid OATs h OAT1 h OAT3 Nephrotoxicity

A comprehensive review of integrative pharmacology-based investigation:A paradigm shift in traditional Chinese medicine

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Acta Pharmaceutica Sinica B 2021年第6期11卷 1379-1399页

作者： Haiyu Xu Yanqiong Zhang Ping Wang Junhong Zhang Hong Chen Luoqi Zhang Xia Du Chunhui Zhao Dan Wu Feng Liu Hongjun Yang Changxiao Liu Institute of Chinese Materia Medica China Academy of Chinese Medical SciencesBeijing 100700China Shaanxi Institute of International Trade&Commerce Xianyang 7120462China State Key laboratory of Drug Delivery Technology and pharmacokinetics Tianjin Institute of Pharmaceutical ResearchTianjin 300193China

Over the past decade,traditional Chinese medicine(TCM) has widely embraced systems biology and its various data integration approaches to promote its ***,integrative pharmacology-based traditional Chinese medicine(TCMIP) was proposed as a paradigm shift in *** review focuses on the presentation of this novel concept and the main research contents,methodologies and applications of ***,TCMIP is an interdisciplinary science that can establish qualitative and quantitative pharmacokinetics-pharmacodynamics(PK-PD) correlations through the integration of knowledge from multiple disciplines and techniques and from different PK-PD processes in ***,the main research contents of TCMIP are introduced as follows:chemical and ADME/PK profiles of TCM formulas;confirming the three forms of active substances and the three action modes;establishing the qualitative PK-PD correlation;and building the quantitative PK-PD correlations,*** that,we summarize the existing data resources,computational models and experimental methods of TCMIP and highlight the urgent establishment of mathematical modeling and experimental ***,we further discuss the applications of TCMIP for the improvement of TCM quality control,clarification of the molecular mechanisms underlying the actions of TCMs and discovery of potential new drugs,especially TCM-related combination drug disco very.

关键词： Integrative pharmacology-based traditional Chinese medicine PK-PD correlations Big data Mathematical modeling Multidimensional association network

Herbal drug discovery for the treatment of nonalcoholic fatty liver disease

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Acta Pharmaceutica Sinica B 2020年第1期10卷 3-18页

作者： Tingting Yan Nana Yan Ping Wang Yangliu Xia Haiping Hao Guangji Wang Frank JGonzalez laboratory of Metabolism Center for Cancer ResearchNational Cancer InstituteNational Institutes of HealthBethesdaMD 20892USA State Key laboratory of Natural Medicines Key Laboratory of Drug Metabolism and PharmacokineticsChina Pharmaceutical UniversityNanjing 210009China Institute of Interdisciplinary Integrative Medicine Research Shanghai University of Traditional Chinese MedicineShanghai 201203China School of Life Science and Medicine Dalian University of TechnologyPanjin 124221China

Few medications are available for meeting the increasing disease burden of nonalcoholic fatty liver disease(NAFLD)and its progressive stage,nonalcoholic steatohepatitis(NASH).Traditional herbal medicines(THM)have been used for centuries to treat indigenous people with various symptoms but without clarified modern-defined disease types and *** modern times,NAFLD was defined as a common chronic disease leading to more studies to understand NAFLD/NASH pathology and *** have garnered increased attention for providing therapeutic candidates for treating *** this review,a new model called"multiple organs-multiple hits"is proposed to explain mechanisms of NASH *** this proposed model,the effects and mechanisms of the frequentlystudied THM-yielded single anti-NAFLD drug candidates and multiple herb medicines are reviewed,among which silymarin and berberine are already under ***-sanctioned phase 4 clinical ***,experimental designs for anti-NAFLD drug discovery from THM in treating NAFLD are *** opportunities and challenges of reverse pharmacology and reverse pharmacokinetic concepts-guided strategies for THM modernization and its global recognition to treat NAFLD are *** mechanistic evidence is being generated to support the beneficial role of THM in treating NAFLD and anti-NAFLD drug discovery.

关键词： Natural products Fatty liver Metabolic syndrome TCM NAFLD

Spectrum-Toxicity Correlation Study Revealed the Influence of the Nine-Time Steaming and Sun Drying Method on Hepatotoxic Components of Polygoni Multiflori Radix

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World Journal of Traditional Chinese Medicine 2021年第2期7卷 227-233页

作者： Zhuo Shi Xiao-Fei Li Ya-Lei Liu Peng-Yan Li Ming Niu Zhao-Fang Bai Guang-Qin Zhang Yang Lu Jia-Bo Wang Clinical pharmacokinetics laboratory School of Basic Medicine and Clinical PharmacyChina Pharmaceutical UniversityNanjing The Fifth Medical Center China Military Institute of Chinese MedicineGeneral Hospital of PLABeijingChina

Objective:Polygoni Multiflori Radix(PM)is a traditional herbal medicine with repeated reports of liver injury events in recent *** wondered whether the classical processing method,namely,nine-time steaming and sun drying(NSSD),had toxicity-attenuating effects on PM and the relationships between toxicity and times of processing,as well as with the alteration trends of its *** and Methods:The chemical fingerprints of different PM extracts were developed using ultra-high-performance liquid *** spectrum-toxicity correlation between the chemical fingerprints and hepatocellular toxicity was analyzed with multiple correlation ***:The results suggested that the hepatotoxicity of NSSD processing products markedly decreased with the repeated steaming and sun drying,which was obviously superior to the product processed by the modern *** analysis revealed that the contents of cis-stilbene glycoside and emodin-8-O-β-D-glucoside related to liver injury susceptibility were reduced with the times of NSSD processing,which was consistent with the decreased trend of hepatocellular *** the five times of NSSD,the contents of them as well as the hepatotoxicity of PM were ***,we found that the contents of catechin and physcion declined rapidly after the one time of NSSD and then remained stable until the nine times of *** on the fact,they could be utilized to indicate whether PM products were processed by steaming and sun ***:This paper confirmed that the NSSD had a good influence on the toxicity attenuating to PM and found four compounds which could apply for the quality control of PM.

关键词： Hepatotoxicity nine-time steaming and sun drying polygoni multiflori radix spectrum-toxicity correlation toxicity attenuation by processing