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A novel PGAM5 inhibitor LFHP-1c protects bloodebrain barrier integrity in ischemic stroke

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Acta Pharmaceutica Sinica B 2021年第7期11卷 1867-1884页

作者： Chenglong Gao Yazhou Xu Zhuangzhuang Liang Yunjie Wang Qinghong Shang Shengbin Zhang Cunfang Wang Mingmin Ni Dalei Wu Zhangjian Huang Tao Pang state key laboratory of Natural Medicines Jiangsu Key Laboratory of Drug ScreeningJiangsu Key Laboratory of Drug Discovery for Metabolic DiseasesChina Pharmaceutical UniversityNanjing 210009China Helmholtz International lab State Key Laboratory of Microbial TechnologyShandong UniversityQingdao 266237China Guangdong Long Fu pharmaceutical Co. Ltd.Zhongshan 528451China key laboratory of drug Quality Control and Pharmacovigilance(China pharmaceutical University) Ministry of EducationNanjing 210009China

Bloodebrain barrier(BBB)damage after ischemia significantly influences stroke *** LFHP-1 c was previously discovered with neuroprotective role in stroke model,but its mechanism of action on protection of BBB disruption after stroke remains ***,we show that LFHP-1 c,as a direct PGAM5 inhibitor,prevented BBB disruption after transient middle cerebral artery occlusion(tMCAO)in ***,LFHP-1 c binding with endothelial PGAM5 not only inhibited the PGAM5 phosphatase activity,but also reduced the interaction of PGAM5 with NRF2,which facilitated nuclear translocation of NRF2 to prevent BBB disruption from ***,LFHP-1 c administration by targeting PGAM5 shows a trend toward reduced infarct volume,brain edema and neurological deficits in nonhuman primate Macaca fascicularis model with t ***,our study identifies compound LFHP-1 c as a firstly direct PGAM5 inhibitor showing amelioration of ischemia-induced BBB disruption in vitro and in vivo,and provides a potentially therapeutics for brain ischemic stroke.

关键词： Ischemic stroke Bloodebrain barrier Brain microvascular endothelial cells Target identification Surface plasmon resonance PGAM5 NRF2 LFHP-1c

Mitophagy in acute central nervous system injuries:regulatory mechanisms and therapeutic potentials

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Neural Regeneration Research 2025年第9期20卷 2437-2453页

作者： Siyi Xu Junqiu Jia Rui Mao Xiang Cao Yun Xu Department of Neurology Nanjing Drum Tower HospitalClinical College of Jiangsu UniversityNanjingJiangsu ProvinceChina Department of Neurology Nanjing Drum Tower HospitalChinese Academy of Medical Science&Peking Union Medical CollegeNanjingJiangsu ProvinceChina Department of Neurology Nanjing Drum Tower HospitalAffiliated Hospital of Medical SchoolNanjing UniversityNanjingJiangsu ProvinceChina state key laboratory of pharmaceutical Biotechnology and Institute of Translational Medicine for Brain Critical Diseases Nanjing UniversityNanjingJiangsu ProvinceChina Jiangsu key laboratory for Molecular Medicine Medical School of Nanjing UniversityNanjingJiangsu ProvinceChina Nanjing Neurology Medical Center NanjingJiangsu ProvinceChina

Acute central nervous system injuries,including ischemic stro ke,intracerebral hemorrhage,subarachnoid hemorrhage,traumatic brain injury,and spinal co rd injury,are a major global health *** optimal therapies and improving the long-term neurological functions of patients with acute central nervous system injuries are urgent *** are susceptible to damage after acute central nervous system injury,and this leads to the release of toxic levels of reactive oxygen species,which induce cell ***,a selective form of autophagy,is crucial in eliminating redundant or damaged mitochondria during these *** evidence has highlighted the significant role of mitophagy in acute central nervous system *** this review,we provide a comprehensive overview of the process,classification,and related mechanisms of *** also highlight the recent developments in research into the role of mitophagy in various acute central nervous system injuries and drug therapies that regulate *** the final section of this review,we emphasize the potential for treating these disorders by focusing on mitophagy and suggest future research paths in this area.

关键词： autophagy intracerebral hemorrhage ischemic stroke mitochondria mitochondrial biogenesis mitochondrial quality control mitophagy spinal cord injury subarachnoid hemorrhage traumatic brain injury

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

Identifying the molecular basis of Jinhong tablets against chronic superficial gastritis via chemical profile identification and symptom-guided network pharmacology analysis

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Journal of pharmaceutical Analysis 2022年第1期12卷 65-76页

作者： Danfeng Shi Lingxian Liu Haibo Li Dabo Pan Xiaojun Yao Wei Xiao Xinsheng Yao Yang Yu Institute of Traditional Chinese Medicine&Natural Products College of Pharmacy and Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drug ResearchJinan UniversityGuangzhou510632China Kanion pharmaceutical Co. Ltd.State Key Laboratory of New-tech for Chinese Medicine Pharmaceutical ProcessLianyungangJiangsu222001China state key laboratory of Quality Research in Chinese Medicine Macao Institute for Applied Research in Medicine and HealthMacao University of Science and TechnologyTaipaMacaoChina

Chronic superficial gastritis(CSG)is a common disease of the digestive system that possesses a serious *** tablet(JHT),a traditional Chinese medicine(TCM)prescription,exerts therapeutic effects against ***,the molecular basis of its therapeutic effect has not been ***,we employed ultra-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry(UPLC-Q/TOF-MS)based chemical profile identification to determine the chemical components in ***,we applied network pharmacology to illustrate its molecular mechanisms.A total of 96 chemical constituents were identified in JHT,31 of which were confirmed using reference *** on the bioinformatics analysis using the symptom-guided pharmacological networks of“chi,”“blood,”“pain,”and“inflammation,”and target screening through the interaction probabilities between compounds and targets,matrix metalloproteinase 2(MMP2),dopamine d2 receptor(DRD2),and Aldo-keto reductase family 1 member B1(AKR1B1)were identified as key targets in the therapeutic effect exhibited by JHT against ***,according to the inhibitory activities presented in the literature and binding mode analysis,the structural types of alkaloids,flavonoids,organic acids,including chlorogenic acid(10),caffeic acid(13),(-)-corydalmine(33),(-)-isocorypalmine(36),isochlorogenic acid C(38),isochlorogenic acid A(41),quercetin-3-O-a-L-rhamnoside(42),isochlorogenic acid B(47),quercetin(63),and kaempferol(70)tended to show remarkable activities against *** to the above findings,we systematically identified the chemical components of JHT and revealed its molecular mechanisms based on the symptoms associated with CSG.

关键词： Chronic superficial gastritis Jinhong tablets UPLC-Q/TOF-MS Symptom-guided network pharmacology Molecular docking

Data-driven engineering framework with AI algorithm of Ginkgo Folium tablets manufacturing

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Acta Pharmaceutica Sinica B 2023年第5期13卷 2188-2201页

作者： Lijuan Ma Jing Zhang Ling Lin Tuanjie Wang Chaofu Ma Xiaomeng Wang Mingshuang Li Yanjiang Qiao Yongxiang Wang Guimin Zhang Zhisheng Wu Beijing University of Chinese Medicine Engineering Research Center for Pharmaceutics of Chinese Materia Medica and New Drug DevelopmentMinistry of EducationBeijing 100029China Jiangsu Kanion pharmaceutical Co. Ltd.State Key Laboratory of New Technology in Pharmaceutical Process of Traditional Chinese MedicineLianyungang 222001China Yangtze River pharmaceutical(Group)Co. Ltd.State Pharmaceutical Engineering Technology Research Center of Traditional Chinese MedicineTaizhou 225321China Lunan pharmaceutical Group Co. Ltd.State Key Laboratory of Generic Technology of Traditional Chinese MedicineLinyi 276005China

Smart manufacturing still remains critical challenges for pharmaceutical ***,an original data-driven engineering framework was proposed to tackle the ***,from sporadic indicators to five kinds of systematic quality characteristics,nearly 2,000,000 real-world data points were successively characterized from Ginkgo Folium tablet ***,from simplex to the multivariate system,the digital process capability diagnosis strategy was proposed by multivariate C_(pk)integrated *** C_(pk)of Ginkgo Folium extracts,granules,and tablets were discovered,which was 0.59,0.42,and 0.78,respectively,indicating a relatively weak process capability,especially in ***,the quality traceability was discovered from unit to end-to-end analysis,which decreased from 2.17 to *** further proved that attention should be paid to granulating to improve the quality *** conclusion,this paper provided a data-driven engineering strategy empowering industrial innovation to face the challenge of smart pharmaceutical manufacturing.

关键词： Smart manufacturing Data-driven engineering Artificial intelligence Information fusion process capability index End-to-end Quality traceability Real-world Ginkgo Folium products

Pharmacokinetics of the prototype and hydrolyzed carboxylic forms of ginkgolides A, B, and K administered as a ginkgo diterpene lactones meglumine injection in beagle dogs

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Chinese Journal of Natural Medicines 2017年第10期15卷 775-784页

作者： WANG Shu-Yao A Ji-Ye FEI Fei GENG Jian-Liang PENG Ying OUYANG Bing-Chen WANG Pei JIN Xiao-Liang ZHAO Yu-Qing WANG Jian-Kun GENG Ting LI Yan-Jing HUA NG Wen-Zhe WANG Zhen-Zhong XIAO Wei WANG Guang-Ji School of Chinese Pharmacy Beijing University of Chinese Medicine Beijing 100102 China Jiangsu Kanion Modern Chinese Medicine Institute Nanjing 210017 China state key labonatory of pharmaceutical new-Techfor Chinese Medicine Jiangsu Kanion Pharmaceutical Co. Ltd. Lianyungang222001 China key lab of drug Metabolism and Pharmacokinetics state key laboratory of Natural Medicines China Pharmaceutical UniversityNanjing 210009 China

Ginkgo diterpene lactones meglumine injection(GDLI)is a commercially available product used for ***,the pharmacokinetic properties of the prototypes and hydrolyzed carboxylic forms of the primary components in GDLI,i.e.,ginkgolide A(GA),ginkgolide B(GB),and ginkgolide K(GK),have never been fully evaluated in beagle *** this work,a simple,sensitive,and reliable method based on ultra-fast liquid chromatography-tandem mass spectrometry(UFLC-MS/MS)was developed,and the prototypes and total amounts of GA,GB,and GK were determined in beagle dog *** plasma concentrations of the hydrolyzed carboxylic forms were calculated by subtracting the prototype concentrations from the total lactone *** the first time,the pharmacokinetics of GA,GB,and GK were fully assessed in three forms,i.e.,the prototypes,the hydrolyzed carboxylic forms,and the total amounts,after intravenous administration of GDLI in beagle *** was shown that ginkgolides primarily existed in the hydrolyzed form in plasma,and the ratio of hydrolysates to prototype forms of GA and GB decreased gradually to a homeostatic *** of the three forms of the three ginkgolides showed linear exposure of AUC to the ***,GB,and GK showed a constant half-life approximately 2.7,3.4,and 1.2 h,respectively,which were consistent for the forms at three dose levels(0.3,1.0,and 3.0 mg·kg^(-1))and after a consecutive injection of GDLI for 7 days(1.0 mg·kg^(-1)).

关键词： Hydrolysates of ginkgolides LC-MS/MS Pharmacokinetics Ginkgo diterpene lactones Beagle dog

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

Ginkgolide K protects the heart against ER stress injury by activating the IRE1α/XBP1 pathway

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中国药理学与毒理学杂志 2016年第10期30卷 1009-1010页

作者： WANG Shou-bao WANG Zhen-zhong FAN Qi-ru GUO Jing GINA GA-LI DU Guan-hua WANG Xin XIAO Wei Faculty of Life Sciences The University of Manchester Beijing key laboratory of drug Targets Identification and drug Screening Institute of Materia MedicaChinese Academy of Medical Sciences & Peking Union Medical College state key laboratory of new-tech for Chinese Medicine pharmaceutical process Faculty of Life Science and Technology China Pharmaceutical University

OBJECTIVE Here we investigated the effects and the underlying mechanism of Ginkgolide K(1,10-dihydroxy-3,14-didehydroginkgolide,GK)on cardiac ER *** Cell death,apoptosis,and ER stressrelated signalling pathwayswere measuredin cultured neonatal rat cardiomyocytes(NRCMs),treated with the ER stress inducers tunicamycin,hydrogen peroxide,and *** myocardial infarction was established using left coronary artery occlusion in mice,and infarct size was measured by triphenyltetrazolium chloride(TTC)*** was used to assess heart function and transmission electron microscopy for evaluating ER *** GK significantly decreased ER stress-induced cell death in both in vitro and in *** ischemic injured mice,GK treatment reduced infarct size,rescued heart dysfunction and ameliorated ER *** studies revealed that the beneficial effects of GK occur through enhancement of inositol-requiring enzyme 1α(IRE1α)/X box-binding protein-1(XBP1)activity,which in turn leads to increased ER-associated degradation(ERAD)-mediated clearance of misfolded proteins and *** addition,GK is also able to partially repress the pro-apoptotic action of regulated IRE1-dependent decay(RIDD)and JNK *** GK acts through selective activation of the IRE1α/XBP1 pathway to limit ER stress *** is revealed as a promising therapeutic agent to ameliorate ER stress for treating cardiovascular diseases.

关键词： Ginkgolide K ER stress IRE1α XBP1 ER-associated degradation autophagy

Monosaccharide analysis and fingerprinting identification of polysaccharides from Poria cocos and Polyporus umbellatus by HPLC combined with chemometrics methods

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Chinese Herbal Medicines 2019年第4期11卷 406-411页

作者： Jie Liu Jing Zhou Qian-qian Zhang Min-hang Zhu Mo-li Hua Yun-hui Xu state key laboratory of new drug and pharmaceutical process Shanghai Institute of Pharmaceutical IndustryChina State Institute of Pharmaceutical IndustryShanghai 201203China

Objective:Poria cocos and Polyporus umbellatus are similar medicinal fungi in traditional Chinese medicines.A method for fingerprint analysis of monosaccharide composition of polysaccharides by HPLC combined with chemometrics methods has been developed for characterization and discrimination of them in this ***:The polysaccharides were extracted by decocting in water,and then completely hydrolyzed with *** in the hydrolyzates were derivatized with 1-phenyl-3-methyl-5-pyrazolone(PMP)for HPLC *** than 20 batches of *** and *** from different regions were ***:The fingerprints of *** showed five common characteristic peaks,which were identified by comparing with the reference *** five peaks corresponded to the derivatives of mannose,ribose,glucose,galactose,and *** the same time,the fingerprints of *** showed eight common characteristic peaks,of which seven were identified as the derivatives of mannose,ribose,rhamnose,glucose,galactose,xylose,and ***,the similarity of their fingerprints was respectively calculated by the Similarity Evaluation System for Chromatographic Fingerprint of TCM published by China Pharmacopoeia Committee(Version 2004 A).And the data were further processed by hierarchical cluster analysis(HCA)and principal component analysis(PCA).The similarity evaluation and HCA indicated that there were no significant difference in *** or *** samples from different geographical regions,but PCA was performed to characterize the difference in monosaccharide constituents between *** and ***,and linear discriminant analysis(LDA)showed the overall correct classification rate was 100%.Conclusion:The fingerprint analysis method of monosaccharide composition of water-soluble polysaccharides can distinguish *** and ***,and can be applied for the authentication or quality control for *** and ***.

关键词： fingerprint hierarchical cluster analysis(HCA) linear discriminant analysis(LDA) Polyporus umbellatus(Pers.)Fries polysaccharides Poria cocos(Schw.)Wolf principal component analysis(PCA)