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Mechanisms of Compound Kushen Injection for the treatment of bladder cancer based on bioinformatics and network pharmacology with experimental validation

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Chinese Journal of Natural Medicines 2022年第1期20卷 43-53页

作者： ZHANG Li-Hui ZHANG Wan-Ying XIONG Jia-Ming DUAN Xiu-Mei HAI Li-Na ZHANG Yu-Liang ZHANG Miao-Miao QIN Gui-Fang ZHANG Guo-Wei College of Traditional Chinese Medicine Hebei UniversityBaoding 071002China beijing zhendong guangming pharmaceutical research institute Beijing 100085China Academy for Advanced Interdisciplinary Studies Peking UniversityBeijing 100871China

Bladder cancer is the most common malignancy of the urinary *** Kushen Injection(CKI)is a Chinese medicinal preparation that has been widely used in the treatment of various types of cancers in the past two ***,the pharmacological effect of CKI on bladder cancer is not still completely *** the current study,network pharmacology com-bined with bioinformatics was used to elucidate the therapeutic mechanism and potential targets of CKI in bladder *** mech-anism by which CKI was effective against bladder cancer was further verified in vitro using human bladder cancer cell line ***-work pharmacology analysis identified 35 active compounds and 268 target genes of *** data indicated 5500 differen-tially expressed genes associated with bladder *** genes of CKI and bladder cancer suggested that CKI exerted anti-blad-der cancer effects by regulating genes such as MMP-9,JUN,EGFR,and *** enrichment analysis indicated that CKI ex-erted therapeutic effects on bladder cancer by regulating certain biological processes,including cell proliferation,cell migration,and cell *** addition,Kyoto Encyclopedia of Genes and Genomes enrichment analysis implicated pathways related to cancer,bladder cancer,and the PI3K-Akt signaling ***,cell experiments indicated that CKI inhibited the proliferation and migration of T24 cells,and induced their ***,RT-qPCR and Western blot results demonstrated that CKI was likely to treat bladder cancer by down-regulating the gene and protein expression of MMP-9,JUN,EGFR,and *** inhibited the prolif-eration and migration,and induced the apoptosis of T24 bladder cancer cells through multiple biological pathways and *** also exhibited significant effects on the regulation of key genes and proteins associated with bladder ***,our findings provide solid evidence and deepen current understanding of the therapeutic effects

关键词： Compound Kushen Injection Bladder cancer Network pharmacology GEO Molecular mechanism

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Designing cancer nanodrugs that are highly loaded,pH-responsive,photothermal, and possess a favored morphology:A hierarchical assembly of DOX and layer-by-layer modified rGO

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Chinese Chemical Letters 2019年第2期30卷 489-493页

作者： Xiangming Li Yihe Zhang Zequn Ma Chengjun He Yaling Wu Qi An beijing Key Laboratory of Materials Utilization of Nonmetallic Minerals and Solid Wastes National Laboratory of Mineral Materials School of Materials Sciences and Technology China University of Geosciences beijing zhendong guangming pharmaceutical research institute Co. Ltd.

An effective cancer nanodrug not only needs to load a large fraction of pharmaceutical molecules and release them in responsive ways, to function as imaging and photothermal agents, but also needs to possess the favorable morphologies that are favored by the EPR effect of cancer tissues. In this study, we designed a spherical nanodrug by forming clusters using DOX and a polymer-engineered rGO. These spherical nanodrugs had a diameter of around 750 nm and assumed both functionalities of chemical therapy and the photothermal effect. In addition, this nanodrug featured a high-loading capability of DOX, a pH-responsive release profile, a self-fluorescent capability, and an effective accumulation in cancer cells. The layer-by-layer assembly of three cycles of polyethylene glycol (PEG) and polyacrylic acid (PAA) around the rGO core was indispensable in achieving a chemically-modified rGO precursor that assembled with DOX to produce the spherical nanodrug. The spherical nanodrug effectively decreased cell viability upon NIR irradiations.

关键词： Graphene oxide Polyethylene glycol Polyacrylic acid Hydrogen bonds pH-Responsive

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Quality evaluation of Farfarae Flos by ITS/ITS2 and HPLC fingerprint analysis

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Journal of Chinese pharmaceutical Sciences 2021年第1期30卷 58-68页

作者： Zijuan Lu Yan Jia Jie Xing Shuxian Xiao Yulong Wang Wenjie Qin Xuemei Qin Zhenyu Li Modern research Center for Traditional Chinese Medicine Shanxi UniversityTaiyuan 030006China Shanxi zhendong Genuine Medicinal Materials Development Co. Ltd.Changzhi 047100China beijing zhendong guangming pharmaceutical research institute Co. Ltd.Beijing 100085China

The flower bud of Tussilago farfara L.,also known as Farfarae Flos(FF),is commonly used in the traditional Chinese medicine(TCM)for the treatment of cough,bronchitis and asthmatic *** this study,26 samples from five provinces across northern China were collected,and internal transcribed spacer-polymerase chain reaction(ITS-PCR)coupled with high performance liquid chromatography(HPLC)fingerprint profiling was used for the quality evaluation of *** results of the ITS sequence analysis showed the high similarity values among these ***2 sequence exhibited less molecular diversity compared with ITS1,and no obvious correlation was found between the variation of ITS with the production areas or cultivation *** results of HPLC fingerprints in combination with the similarity analysis suggested that relative contents of phenylpropanoids and flavonoids varied among the 26 FF samples,and there was also no obvious difference among the different *** phenylpropanoids and the flavonoids showed similar fluctuating patterns,and positive correlation among them was also *** results presented in this study suggested that FF from different habits showed high similarities,and ITS-PCR coupled with HPLC fingerprint profiling could be used as a valuable approach for the quality evaluation of FF.

关键词： Farfarae Flos ITS ITS2 HPLC fingerprints Multivariate analysis

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Compound Kushen injection induces immediate hypersensitivity reaction through promoting the production of platelet-activating factor via de novo pathway

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中国药理学与毒理学杂志 2021年第10期35卷 730-730页

作者： GAO Yuan HAI Li-na KANG Yuan QIN Wen-jie LIU Fang CAI Run-lan YANG Xiu-wei QI Yun institute of Medicinal Plant Development Chinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100193China Academy for Advanced Interdisciplinary Studies Peking UniversityBeijing 100871China beijing zhendong guangming pharmaceutical research institute Beijing 100085China State Key Laboratory of Natural and Biomimetic Drugs Department of Natural MedicinesSchool of Pharmaceutical SciencesPeking UniversityBeijing 100191China

OBJECTIVE Compound Kushen injection(CKI)is a bis-herbal formulation extracted from Kushen(Radix Sophorae Flavescentis)and Baituling(Rhizoma Heterosmilacis Japonicae).Clinically,it is used as the adjuvant treatment of ***,with the increased application,the cases of immediate hypersensitivity reactions(IHRs)also gradually *** this study,we investigated the underlying mechanism(s)and active constituent(s)for CKI-induced IHRs in experimental *** T helper 2(Th2)immunity-amplified mice were prepared by aluminum *** shock was detected by measuring rectal thermometry in propranolol pretreated *** evaluating microvascular permeability,Evans blue extravasation assay was ***-activating factor(PAF),serum total IgE(tIgE)and mouse mast cell protease 1(MMCP1)were measured by *** The obtained results showed that CKI did not elevate serum tIgE and MMCP1 after consecutive immunization for five weeks,but could induce Evans blue extravasation(local)and cause obvious hypothermia(systemic)after a single *** study showed that alkaloids in Kushen,especially matrine,were responsible for CKI-induced *** study showed that various PAF receptor antagonists could significantly counter CKI-induced IHRs locally or *** cell system,CKI was able to promote PAF production in a non-cell-selective *** cell lysate,the effect of CKI on PAF production became stronger and could be abolished by blocking de novo *** In conclusion,our study identifies,for the first time,that CKI is a PAF *** causes non-immunologic IHRs,rather than IgE-dependent IHRs,by promoting PAF production through de novo *** in Kushen,especially matrine,are the prime culprits for *** findings may provide a potential approach for preventing and treating CKI-induced IHRs.

关键词： Compound Kushen injection matrine platelet-activating factor non-immunologic immediate hypersen⁃sitivity reactions de novo pathway

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Liquid chromatography-mass spectrometry method for the quantification of an anti-sclerostin monoclonal antibody in cynomolgus monkey serum

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Journal of pharmaceutical Analysis 2021年第4期11卷 472-479页

作者： Yuxiong Gao zhendong Chen Changyong Yang Dafang Zhong State Key Laboratory of Drug research Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai201210China University of Chinese Academy of Sciences Beijing100049China Preclinical Department Hengrui Medicine Co.Ltd.LianyungangJiangsu Province222047China

Liquid chromatography tandem mass spectrometry(LC-MS/MS)has gradually become a promising alternative to ligand binding assay for the bioanalysis of biotherapeutic molecules,due to its rapid method development and high *** this study,we established a new LC-MS/MS method for the determination of the anti-sclerostin monoclonal antibody(SHR-1222)in cynomolgus monkey serum,and compared it to a previous electrochemiluminescence *** antibody was quantified by detecting the surrogate peptide obtained by trypsin *** surrogate peptide was carefully selected by investigating its uniqueness,stability and MS *** quantitative range of the proposed method was 2.00-500μg/mL,and this verified method was successfully applied to the toxicokinetic assessment of SHR-1222 in cynomolgus monkey *** was found that the concentrations of SHR-1222 in cynomolgus monkeys displayed an excellent agreement between the LC-MS/MS and electrochemiluminescence methods(ratios of drug exposure,0.8-1.0).Notably,two monkeys in the60 mg/kg dose group had abnormal profiles with a low detection value of SHR-1222 in their individual *** the high-level anti-drug antibodies(ADAs)in these samples and the consistent quantitative results of the two methods,we found that the decreased concentration of SHR-1222 was due to the accelerated clearance mediated by ADAs rather than the interference of ADAs to the detection *** together,we successfully developed an accurate,efficient and cost-effective LC-MS/MS method for the quantification of SHR-1222 in serum samples,which could serve as a powerful tool to improve the preclinical development of antibody drugs.

关键词： Anti-sclerostin monoclonal antibody (SHR-1222) LC-MS/MS Anti-drug antibody Toxicokinetic

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Equivalent efficacy study of QL1101 and bevacizumab on untreated advanced non-squamous non-small cell lung cancer patients: a phase 3 randomized, double-blind clinical trial

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Cancer Biology & Medicine 2021年第3期18卷 816-824页

作者： Tianqing Chu Jun Lu Minghong Bi Helong Zhang Wu Zhuang Yan Yu Jianhua Shi zhendong Chen Xiaochun Zhang Qisen Guo Quan Liu Huijuan Wu Jian Fang Yi Hu Xiuwen Wang Cuicui Han Kai Li Baohui Han Department of Pulmonary Medicine Shanghai Chest HospitalShanghai Jiao Tong UniversitySha nghai 200030China Department of Oncology The First Affiliated Hospital of Bengbu Medical CollegeBengbu 233004China Department of Oncology Tangdu HospitalAir Force Medical University of PLAXi'an 710038China Department of Medical Thoracic Oncology Fujian Cancer HospitalFujian Medical University Cancer HospitalFuzhou 350014China Department of Oncology Harbin Medical University Cancer HospitalHarbin 150081China Department of Oncology Linyi Cancer HospitalLinyi 276000China Department of Oncology The Second Hospital of Anhui Medical UniversityHefei 230601China Department of Oncology The Affiliated Hospital of Qingdao UniversityQingdao 266071China Department of Internal Medicine Shandong Cancer Hospital Affiliated to Shandong UniversityJinan 250117China Department of Oncology Affiliated Hospital of Jiang Nan UniversityWuxi 214122China Department of Internal Medicine Henan Province Tumor HospitalZhengzhou UniversityZhengzhou 450008China Department of Thoracic OncologyⅡ Peking University Cancer Hospital and InstituteBeijing 100142China Department of Oncology Chinese PLA General HospitalBeijing 100039China Department of Oncology Qilu Hospital of Shandong UniversityJinan 250012China Department of Clinical research Centre Qilu Pharmaceutical Co.LtdJinan 250101China Department of Thoracic Oncology Tianjin Medical University Cancer Institute and HospitalNational Clinical Research Center for CancerKey Laboratory of Cancer Prevention and TherapyTianjinTianjin’s Clinical Research Center for CancerTianjin 300060China

Objective:This phase 3 study aimed to test equivalence in efficacy and safety for QL1101,a bevacizumab analogue in Chinese patients with untreated locally advanced non-squamous non-small cell lung cancer(NSCLC).Methods:Eligible patients were randomly assigned 1:1 to receive carboplatin and paclitaxel in combination with either QL1101 or bevacizumab,15 mg/kg every 3-week for 6 *** was followed by maintenance treatment with single agent QL1101 every *** primary end-point was objective response rate(ORR),with secondary end-points being progression-free survival(PFS),overall survival(OS),disease control rate(DCR),and adverse events(AEs).Results:Of 675 patients,535 eligible patients were randomized to the QL1101 group(n=269)and bevacizumab group(n=266).ORRs were 52.8%and 56.8%,respectively,for the QL1101 and bevacizumab groups,with an ORR hazard ratio 0.93(95%confidence interval:0.8-0131.1).The PFS,OS,DCR,and AEs were comparable between the 2 groups,which remained the same after stratification according to epidermal growth factor receptor mutation or smoking ***:QL1101 showed similar efficacy and safety profiles as compared to bevacizumab among Chinese patients with untreated locally advanced non-squamous NSCLC.

关键词： Biosimilar bevacizumab equivalence non-squamous NSCLC clinical efficacy

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