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Coptis,Pinellia,and Scutellaria as a promising new drug combination for treatment of Helicobacter pylori infection

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World Journal of Clinical Cases 2022年第34期10卷 12500-12514页

作者： Zhang Yu Wu-Dong Sheng Xu Yin Yu Bin Department of Internal Medicine The First Hospital of Hunan University of Chinese MedicineChangsha 410007Hunan ProvinceChina Department of Surgery The First Hospital of Hunan University of Chinese MedicineChangsha 410007Hunan ProvinceChina

BACKGROUND Helicobacter pylori(H.pylori)is the most important infectious agent and plays an important role in the progression of chronic gastritis and the development of gastric cancer.AIM To identify efficient therapeutic agents or strategies that can treat H.pylori infection.METHODS We performed literature analysis,experimental validation,and network pharmacology.First,traditional Chinese medicine(TCM)prescriptions for the treatment of H.pylori infection were obtained from the China National Knowledge Infrastructure,China Biology Medicine,China Science and Technology Journal Database,and WanFang databases.In addition,we conducted a relevant search by Reference Citation Analysis(RCA)(https://***).Next,we used TCM Inheritance Support System V2.5 to identify core drug combinations in the TCM prescriptions.Then,an H.pylori-associated chronic mouse model of gastritis was established.The antibacterial properties and antiinflammatory potential of the core drug combination were evaluated by the rapid urease test,modified Warthin-Starry silver staining,histopathological analysis,and enzyme linked immunosorbent assay.Finally,the active compounds,hub targets,and potential signaling pathways associated with the core drug combination were analyzed by network pharmacology.RESULTS The TCM treatment of H.pylori was mainly based on reinforcing the healthy Qi and eliminating pathogenic factors by simultaneously applying pungent dispersing,bitter descending,cold and warm drugs.The combination of Coptis,Pinellia,and Scutellaria(CPS)was identified as the core drug combination from 207 prescriptions and 168 herbs.This drug combination eradicated H.pylori,alleviated the gastric pathology induced by H.pylori infection,and reduced the expression levels of tumor necrosis factor-α(P=0.024)and interleukin-1β(P=0.001).Moreover,a total of 35 compounds and 2807 targets of CPS were identified using online databases.Nine key compounds(tenaxin I,neobaicalein,norwogonin,skullcapflavone II,baicalein,5,8,2'-trihydroxy-7-methoxyflavone,acacetin,pan

关键词： Coptis Pinellia Scutellaria Anti-Helicobacter pylori drug combination Traditional Chinese medicine

A proteomic landscape of pharmacologic perturbations for functional relevance

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Journal of Pharmaceutical Analysis 2024年第1期14卷 128-139页

作者： Zhiwei Liu Shangwen Jiang Bingbing Hao Shuyu Xie Yingluo Liu Yuqi Huang Heng Xu Cheng Luo Min Huang Minjia Tan Jun-Yu Xu State Key Laboratory of drug Research Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai201203China School of Chinese Materia Medica Nanjing University of Chinese MedicineNanjing210023China Zhongshan Institute for drug Discovery Shanghai Institute of Materia MedicaChinese Academy of SciencesZhongshanGuangdong528400China State Key Laboratory of Pharmaceutical Biotechnology Nanjing UniversityNanjing210023China

Pharmacological perturbation studies based on protein-level signatures are fundamental for drug discovery. In the present study, we used a mass spectrometry (MS)-based proteomic platform to profile the whole proteome of the breast cancer MCF7 cell line under stress induced by 78 bioactive compounds. The integrated analysis of perturbed signal abundance revealed the connectivity between phenotypic behaviors and molecular features in cancer cells. Our data showed functional relevance in exploring the novel pharmacological activity of phenolic xanthohumol, as well as the noncanonical targets of clinically approved tamoxifen, lovastatin, and their derivatives. Furthermore, the rational design of synergistic inhibition using a combination of histone methyltransferase and topoisomerase was identified based on their complementary drug fingerprints. This study provides rich resources for the proteomic landscape of drug responses for precision therapeutic medicine.

关键词： Proteomics drug Perturbation drug target drug combination

Cocktail hepatocarcinoma therapy by a super-assembled nano-pill targeting XPO1 and ATR synergistically

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Journal of Pharmaceutical Analysis 2023年第6期13卷 603-615页

作者： Liuyun Gong Yinliang Lu Jing Wang Xinyue Li Jing Zhao Yuetong Chen Rongze Ma Jinlu Ma Tianya Liu Suxia Han Department of Radiation Oncology The First Affiliated Hospital of Xi'an Jiaotong UniversityXi'an710061China National&Local Joint Engineering Research Center of Biodiagnosis and Biotherapy The Second Affiliated Hospital of Xi'an Jiaotong UniversityXi'an710004China Department of Radiotherapy The First Affiliated Hospital Soochow UniversitySuzhouJiangsu215000China

Intensive cancer treatment with drug combination is widely exploited in the clinic but suffers from inconsistent pharmacokinetics among different therapeutic agents.To overcome it,the emerging nanomedicine offers an unparalleled opportunity for encapsulating multiple drugs in a nano-carrier.Herein,a two-step super-assembled strategy was performed to unify the pharmacokinetics of a peptide and a small molecular compound.In this proof-of-concept study,the bioinformatics analysis firstly revealed the potential synergies towards hepatoma therapy for the associative inhibition of exportin 1(XPO1)and ataxia telangiectasia mutated-Rad3-related(ATR),and then a super-assembled nano-pill(gold nano drug carrier loaded AZD6738 and 97110 amino acids of apoptin(AP)(AA@G))was constructed through camouflaging AZD6738(ATR small-molecule inhibitor)-binding human serum albumin onto the AP-Au supramolecular nanoparticle.As expected,both in vitro and in vivo experiment results verified that the AA@G possessed extraordinary biocompatibility and enhanced therapeutic effect through inducing cell cycle arrest,promoting DNA damage and inhibiting DNA repair of hepatoma cell.This work not only provides a co-delivery strategy for intensive liver cancer treatment with the clinical translational potential,but develops a common approach to unify the pharmacokinetics of peptide and small-molecular compounds,thereby extending the scope of drugs for developing the advanced combination therapy.

关键词： Liver cancer drug combination Cancer therapy ATR inhibitor XPO1 inhibitor

Intelligent lesion blood–brain barrier targeting nano-missiles for Alzheimer's disease treatment by anti-neuroinflammation and neuroprotection

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Acta Pharmaceutica Sinica B 2022年第4期12卷 1987-1999页

作者： Xueqin He Xiaorong Wang Lianyi Yang Zhihang Yang Wenqi Yu Yazhen Wang Rui Liu Meiwan Chen Huile Gao Key Laboratory of drug-Targeting and drug Delivery System of the Education Ministry and Sichuan Province Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial TechnologyWest China School of PharmacySichuan UniversityChengdu 610041China State Key Laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical SciencesUniversity of MacaoMacao 999078China

The treatment of Alzheimer's disease(AD)is one of the most difficult challenges in neurodegenerative diseases due to the insufficient blood‒brain barrier(BBB)permeability and unsatisfactory intra-brain distribution of drugs.Therefore,we established an ibuprofen and FK506 encapsulated drug co-delivery system(Ibu&FK@RNPs),which can target the receptor of advanced glycation endproducts(RAGE)and response to the high level of reactive oxygen species(ROS)in AD.RAGE is highly and specifically expressed on the lesion neurovascular unit of AD,this property helps to improve targeting specificity of the system and reduce unselective distribution in normal brain.Meanwhile,these two drugs can be specifically released in astrocytes of AD lesion in response to high levels of ROS.As a result,the cognition of AD mice was significantly improved and the quantity of Aβplaques was decreased.Neurotoxicity was also alleviated with structural regeneration and functional recovery of neurons.Besides,the neuroinflammation dominated by NF-κB pathway was significantly inhibited with decreased NF-κB and IL-1βin the brain.Overall,Ibu&FK@RNPs can efficiently and successively target diseased BBB and astrocytes in AD lesion.Thus it significantly enhances intracephalic accumulation of drugs and efficiently treats AD by anti-neuroinflammation and neuroprotection.

关键词： Receptor for advanced glycation end products ROS-responsive Blood‒brain barrier transcytosis Alzheimer’s disease drug combination Anti-neuroinflammation Neuroprotection Nano drug delivery system

Preclinical studies of the triazolo[1,5-a]pyrimidine derivative WS-716 as a highly potent,specific and orally active P-glycoprotein(P-gp)inhibitor

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Acta Pharmaceutica Sinica B 2022年第8期12卷 3263-3280页

作者： Sai-Qi Wang Qiu-Xu Teng Shuai Wang Zi-Ning Lei Hui-Hui Hu Hui-Fang Lv Bei-Bei Chen Jian-Zheng Wang Xiao-Jing Shi Wei-Feng Xu Hong-Min Liu Xiao-Bing Chen Zhe-Sheng Chen Bin Yu Department of Oncology the Affiliated Cancer Hospital of Zhengzhou UniversityHenan Cancer HospitalHenan Cancer InstituteZhengzhou 450008China School of Pharmaceutical Sciences Zhengzhou UniversityZhengzhou 450001China State Key Laboratory of Esophageal Cancer Prevention&Treatment Zhengzhou UniversityZhengzhou 450052China College of Pharmacy and Health Sciences St.John’s UniversityQueensNY 11439USA Laboratory Animal Center Academy of Medical ScienceZhengzhou UniversityZhengzhou 450052China

Multidrug resistance(MDR) is the main cause of clinical treatment failure and poor prognosis in cancer. Targeting P-glycoprotein(P-gp) has been regarded as an effective strategy to overcome MDR. In this work, we reported our preclinical studies of the triazolo[1,5-a]pyrimidine-based compound WS-716 as a highly potent, specific, and orally active P-gp inhibitor. Through direct binding to P-gp,WS-716 inhibited efflux function of P-gp and specifically reversed P-gp-mediated MDR to paclitaxel(PTX) in multiple resistant cell lines, without changing its expression or subcellular localization. WS-716 and PTX synergistically inhibited formation of colony and 3D spheroid, induced apoptosis and cell cycle arrest at G2/M phase in resistant SW620/Ad300 cells. In addition, WS-716 displayed minimal effect on the drug-metabolizing enzyme cytochrome P4503A4(CYP3A4). Importantly, WS-716 increased sensitivity of both pre-clinically and clinically derived MDR tumors to PTX in vivo with the T/C value of 29.7% in patient-derived xenograft(PDX) models. Relative to PTX treatment alone, combination of WS-716 and PTX caused no obvious adverse reactions. Taken together, our preclinical studies revealed therapeutic promise of WS-716 against MDR cancer, the promising data warrant its further development for cancer therapy.

关键词： Multidrug resistance(MDR) ATP-Binding cassette P-gp inhibitors Triazolo[1,5-a]pyrimidine drug combination Preclinical studies Cancer therapy

Downregulation of hTERT with drug combination of HDE and BIIB021 Efficiently Inhibit Cell Proliferation of and Induce Apoptosis in Myelodysplastic Syndromes

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Downregulation of hTERT with Drug Combination of HDE and BII...

Discovery of the anti-influenza A virus activity of SB216763 and cyclosporine A by mining infected cells and compound cellular signatures

2019年中国中西医结合学会血液病专业委员会学术年会暨...

作者：王博张蕴沈英英武利强周郁鸿林圣云浙江中医药大学附属第一医院

More and more plant extracts have been reported to show anti-tumor effects, providing new therapeutic strategies for cancer treatment. In this study, we reported that a newly extracted coumarins HDE, the active component in Oldenlandia diffusa Willd, could efficiently inhibit proliferation and induce apoptosis of myelodysplastic syndrome(MDS) cell line SKM-1 as measured by CCK-8 assay and flow cytometry analysis, and this effect was related to decreased telomerase activity. Hsp90 inhibitor BIIB021 significantly enhanced the anti-tumor effects of HDE on SKM-1 cells. In addition,knockdown of human telomerase reverse transcriptase(hTERT) by siRNA further induced SKM-1 cell apoptosis as increased levels of cleaved-caspase3, cleaved-caspase8 and cleaved-PARP were observed. All these consistent results demonstrated synergistic anti-tumor effects of HDE with BIIB021, providing new therapeutic combination for MDS treatment.

关键词： Myelodysplastic syndrome Anti-tumor effects human Telomerase Reverse Transcriptase drug combination

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Chinese Chemical Letters 2022年第5期33卷 2541-2544页

作者： Ke Tang You Wu Shubing Chen Yijing Xin Ying Guo State Key Laboratory of Bioactive Substance and Function of Natural Medicines Institute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China Department of Pharmacology Institute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China

In this study,SB216763 and cyclosporine A were identified as anti-influenza A virus(IAV)agents by tran-scriptome signature reversion(TSR)analysis through deep mining of the cellular transcriptome of hu-man airway and lung cell lines infected with 3 strains of IAV and the chemical perturbations library.A synergistic effect of SB216763 and cyclosporine A against influenza A was disclosed by quantification of the network-based relationship,which was validated in vitro.Along with burgeoning omics approaches,transcriptome-based drug development is flourishing,which provides a novel insight into antivirals dis-covery with comprehensive cellular transcriptional information of disease and chemical perturbations in multicomponent intervention.This strategy can be applied as a new approach in discovering multitar-get antiviral agents from approved drugs,clinical compounds,natural products or other known bioactive compounds.

关键词： Chemical perturbagen signature Host factor Transcriptome signature reversion Influenza A virus SB216763 Cyclosporine A drug combination

Advances and challenges in the treatment of esophageal cancer

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Acta Pharmaceutica Sinica B 2021年第11期11卷 3379-3392页

作者： Shiming He Jian Xu Xiujun Liu Yongsu Zhen Institute of Medicinal Biotechnology Chinese Academy of Medical SciencesPeking Union Medical CollegeBeijing 100050China

Esophageal cancer(EC)is one of the most common cancers with high morbidity and mortality rates.EC includes two histological subtypes,namely esophageal squamous cell carcinoma(ESCC)and esophageal adenocarcinoma(EAC).ESCC primarily occurs in East Asia,whereas EAC occurs in Western countries.The currently available treatment strategies for EC include surgery,chemotherapy,radiation therapy,molecular targeted therapy,and combinations thereof.However,the prognosis remains poor,and the overall five-year survival rate is very low.Therefore,achieving the goal of effective treatment remains challenging.In this review,we discuss the latest developments in chemotherapy and molecular targeted therapy for EC,and comprehensively analyze the application prospects and existing problems of immunotherapy.Collectively,this review aims to provide a better understanding of the currently available drugs through in-depth analysis,promote the development of new therapeutic agents,and eventually improve the treatment outcomes of patients with EC.

关键词： drug combination Esophageal adenocarcinoma Esophageal squamous cell carcinoma Immune therapy Molecular targeted therapy

Determination of Polynomial Degree in the Regression of drug combinations

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IEEE/CAA Journal of Automatica Sinica 2017年第1期4卷 41-47页

作者： Boqian Wang Xianting Ding Fei-Yue Wang School of Biomedical Engineering Shanghai Jiao Tong University IEEE State Key Laboratory of Management and Control for Complex Systems Institute of Automation Chinese Academy of Science (SKL-MCCS CASIA) Research Center of Computational Experiments and Parallel Systems National University of Defense Technology

Studies on drug combinations are becoming more and more popular in the past few decades, with the development of computer and algorithms. One of the most common methods in optimizing drug combinations is regression of a polynomial model based on certain number of experimental observations. In this paper, we study how to determine the degree of polynomials in different circumstances of drug combination optimization. Using cross-validation, we have found that in most cases, a high degree results in failures of accurate prediction, named overfitting. An anti-noise test has also revealed that polynomial model with high degree tends to be less resistant to random errors in the observations.

关键词： Cross-validation drug combination polynomial regression polynomial degree overfitting