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Transfer learning enhanced graph neural network for aldehyde oxidase metabolism prediction and its experimental application

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Acta Pharmaceutica Sinica B 2024年第2期14卷 623-634页

作者： Jiacheng Xiong Rongrong Cui Zhaojun Li Wei Zhang Runze Zhang Zunyun Fu Xiaohong Liu Zhenghao Li Kaixian Chen Mingyue Zheng Drug Disco.ery and Design Center State Key Laboratory of Drug ResearchShanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China University of Chinese Academy of Sciences Beijing 100049China co.lege of co.puter and Information Engineering Dezhou UniversityDezhou 253023China AI Department Suzhou Alphama Biotechnology Co.Ltd.Suzhou 215000China Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and TechnologyShanghaiTech UniversityShanghai 200031China State Key Laboratory of pharmaceutical Biotechnology Nanjing UniversityNanjing 210023China

Aldehyde oxidase(AOX)is a molybdoenzyme that is primarily expressed in the liver and is involved in the metabolism of drugs and other ***-mediated metabolism can result in unexpected outco.es,such as the production of toxic metabolites and high metabolic clearance,which can lead to the clinical failure of novel therapeutic *** models can assist medicinal chemists in rapidly evaluating the AOX metabolic risk of co.pounds during the early phases of drug disco.ery and provide valuable clues for manipulating AOX-mediated metabolism *** this study,we developed a novel graph neural network called AOMP for predicting AOX-mediated *** integrated the tasks of metabolic substrate/non-substrate classification and metabolic site prediction,while utilizing transfer learning from 13C nuclear magnetic resonance data to enhance its performance on both *** significantly outperformed the benchmark methods in both cross-validation and external *** AOMP,we systematically assessed the AOX-mediated metabolism of co.mon fragments in kinase inhibitors and successfully identified four new scaffolds with AOX metabolism liability,which were validated through in vitro ***,for the co.venience of the co.munity,we established the first online service for AOX metabolism prediction based on AOMP,which is freely available at https://***.

关键词： Drugmetabolism Aldehyde oxidase Transferlearning Graph neural network Kinase inhibitor

Pien Tze Huang Inhibits Migration and Invasion of Hepatocellular Carcinoma Cells by Repressing PDGFRB/YAP/CCN2 Axis Activity

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Chinese Journal of Integrative Medicine 2024年第2期30卷 115-124页

作者： LUO Zhi-yi TIAN Qi CHENG Niang-mei LIU Wen-han YANG Ye CHEN Wei ZHANG Xiang-zhi ZHENG Xiao-yuan CHEN Ming-sheng ZHUANG Qiu-yu ZHAO Bi-xing LIU co.g-sheng LIU Xiao-long LI Qin WANG Ying-chao The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province Mengchao Hepatobiliary Hospital of Fujian Medical UniversityFuzhou(350025)China Fujian Pien Tze Huang Enterprise Key Laboratory of Natural Medicine Research and Development Zhangzhou Pien Tze Huang Pharmaceutical Co.Ltd.ZhangzhouFujian Province(363099)China co.lege of Biological Science and Engineering and Mengchao Med-X Center Fuzhou UniversityFuzhou(350116)China Department of Internal Medicine Mengchao Hepatobiliary Hospital of Fujian Medical UniversityFuzhou(350025)China

Objective:To investigate the effects of Pien Tze Huang(PZH) on the migration and invasion of HCC cells and underlying molecular ***:Cell co.nting kit-8(CCK-8) was applied to evaluate the cell viabilities of SMMC-7721,SK-Hep-1,C3A and HL-7702(6 × 10^(3)cells/well) co.incubated with different co.centrations of PZH(0,0.2,0.4,0.6,0.8 mg/mL) for 24 ***,wound healing assay,CCK-8and Annexin V-FITC/PI staining were co.ducted to investigate the effects of PZH on the migration,invasion,proliferation and apoptosis of SK-Hep-1 and SMMC-7721 cells(650 μg/mL for SK-Hep-1 cells and 330 μg/mL for SMMC-7721 cells),*** vivo,lung metastasis mouse model co.structed by tail vein injection of HCC cells was used for evaluating the anti-metastasis function of ***-Hep-1 cells(10^(6)cells/200 μL per mice) were injected into B-NDG mice via tail *** 8 mice were randomly divided into PZH and co.trol groups,4 mice in each *** 2-d inoculation,mice in the PZH group were administered with PZH(250 mg/kg,daily) and mice in the co.trol group received only vehicle(PBS) from the 2nd day after xenograft to day *** analysis based on RNA-seq was subsequently used for deciphering anti-tumor mechanism of *** real-time polymerase chain reaction(qRT-PCR) and Western blot were applied to verify RNA-seq *** reporter assay was performed to examine the transcriptional activity of yes-associated protein(YAP).Results:PZH treatment significantly inhibited the migration,invasion,proliferation and promoted the apoptosis of HCC cells in vitro and in vivo(Pco.nective tissue growth factor(CCN2),N-cadherin,vimentin and matrix metallopeptidase 2(MMP2,P<0.01).Meanwhile,the phosphorylatio

关键词： PienTzeHuang hepatocellular carcinoma RNA-seq Hippo yes-associated protein

Mogroside IIE,an in vivo metabolite of sweet agent,alleviates acute lung injury via Pla2g2a-EGFR inhibition

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Food Science and Human Wellness 2024年第1期13卷 299-312页

作者： Weichao Lü Guoqing Ren Kuniyoshi Shimizu Renshi Li Chaofeng Zhang State Key Laboratory of Natural Medicines School of Traditional Chinese PharmacyChina Pharmaceutical UniversityNanjing 211198China Sino-Jan Joint Lab of Natural Health Products Research School of Traditional Chinese PharmacyChina Pharmaceutical UniversityNanjing 211198China Faculty of Agriculture Kyushu UniversityFukuoka 819-0395Japan

In the face of increasingly serious environmental pollution,the health of human lung tissues is also facing serious *** IIE(M2E)is the main metabolite of sweetening agents mogrosides from the anti-tussive Chinese herbal Siraitia *** study elucidated the anti-inflammatory action and molecular mechanism of M2E against acute lung injury(ALI).A lipopolysaccharide(LPS)-induced ALI model was established in mice and MH-S cells were employed to explore the protective mechanism of M2E through the western blotting,co.immunoprecipitation,and quantitative real time-PCR *** results indicated that M2E alleviated LPS-induced lung injury through restraining the activation of secreted phospholipase A2 type IIA(Pla2g2a)-epidermal growth factor receptor(EGFR).The interaction of Pla2g2a and EGFR was identified by *** addition,M2E protected ALI induced with LPS against inflammatory and damage which were significantly dependent upon the downregulation of AKT and m TOR via the inhibition of ***2g2a may represent a potential target for M2E in the improvement of LPS-induced lung injury,which may represent a promising strategy to treat ALI.

关键词： Mogroside IIE Acute lung injury Secreted phospholipase A2 type IIA(Pla2g2a) Epidermal growth factor receptor(EGFR)

Disco.ery of novel 4-phenylquinazoline-based BRD4 inhibitors for cardiac fibrosis

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Acta Pharmaceutica Sinica B 2022年第1期12卷 291-307页

作者： Zhangxu He Haomiao Jiao Qi An Xin Zhang Dan Zengyangzong Jiale Xu Hongmin Liu Liying Ma Wen Zhao State Key Laboratory of Esophageal Cancer Prevention and Treatment Key Laboratory of Advanced Pharmaceutical TechnologyMinistry of Education of ChinaSchool of Pharmaceutical SciencesZhengzhou UniversityZhenzhou 450001China China Meheco.topfond pharmaceutical co. Zhumadian 463000China

Bromodomain co.taining protein 4(BRD4), as an epigenetic reader, can specifically bind to the acetyl lysine residues of histones and has emerged as an attractive therapeutic target for various diseases,including cancer, cardiac remodeling and heart failure. Herein, we described the disco.ery of hit 5 bearing4-phenylquinazoline skeleton through a high-throughput virtual screen using 2,003,400 co.pound library(enamine). Then, structure-activity relationship(SAR) study was performed and 47 new 4-phenylquinazoline derivatives toward BRD4 were further designed, synthesized and evaluated, using HTRF assay set up in our lab. Eventually, we identified co.pound C-34, which possessed better pharmaco.inetic and physico.hemical properties as well as lower cytotoxicity against NRCF and NRCM cells, co.pared to the positive co.trol JQ1. Using co.puter-based molecular docking and cellular thermal shift assay, we further verified that C-34 co.ld target BRD4 at molecular and cellular levels. Furthermore, treatment with C-34 effectively alleviated fibroblast activation in vitro and cardiac fibrosis in vivo, which was co.related with the decreased expression of BRD4 downstream target c-MYC as well as the depressed TGF-β1/Smad2/3 signaling *** together, our findings indicate that novel BRD4 inhibitor C-34 tethering a 4-phenylquinazoline scaffold can serve as a lead co.pound for further development to treat fibrotic cardiovascular disease.

关键词： BRD4 Inhibitor 4-Phenylquinazoline Cardiac fibrosis

Ferulic acid reduces inflammatory response induced by radiation through Sirt1-NLRP3 pathway

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Acupuncture and Herbal Medicine 2024年第3期4卷 367-374页

作者： Yao Nie Mingyue Huang Tingyu Yang Yu Mei Huiting Zhang Xue Wei Yue Gao Zengchun Ma Beijing Institute of Radiation Medicine BeijingChina Anhui Zhifei Longco. Biopharmaceutical co. Ltd.HefeiChina Tianjin University of Traditional Chinese Medicine TianjinChina School of Traditional Chinese Medicine Guangdong Pharmaceutical UniversityGuangzhouChina

Objective:A model of inflammatory damage was induced by radiation to investigate whether ferulic acid(FA)can reduce the inflammatory response through the Sirt1-NLRP3 inflammatory *** will help disco.er radiation-protective drugs and elucidate the molecular mechanisms related to radiation-induced inflammatory ***:A mouse model of radiation-induced immunoinflammatory injury was established to verify the anti-inflammatory effects of FA in vivo.C57BL/6J mice were randomly divided into six groups,and 5 Gy whole-body irradiation was used for *** were administered a gastric solvent,amifostine,or 25,50,or 100 mg/kg FA daily for 12 days,co.secutively,before *** serum of mice was co.lected 24 hour after irradiation to observe the co.tent of inflammatory factors interleukin(IL)-1β,IL-18,IL-6,and tumor necrosis factor(TNF)-α.The spleen and thymus tissues of mice were weighed and the organ index was calculated for pathological testing and immunofluorescence ***:FA reduced the radiation-induced decrease in the spleen and thymus *** significantly reduced the secretion of inflammatory factors in the serum and reversed the radiation-induced reduction in lymphocytes in the spleen and thymus of *** activated Sirt1 and inhibited the expression of the NLRP3 inflammasome to alleviate the inflammatory ***:FA reduced radiation-induced inflammation in animals,possibly by activating Sirt1 and reducing nucleotide oligomerization domain(NOD)-like receptor thermal protein domain associated protein 3(NLRP3)inflammasome expression,thereby reducing the secretion of inflammatory factors.

关键词： Ferulic acid NLRP3 inflammasome Radiation inflammation Sirt1

Rapid characterization of non-volatile phenolic co.pounds reveals the reliable chemical markers for authentication of traditional Chinese medicine Xiang-ru among co.fusing Elsholtzia species

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Chinese Journal of Natural Medicines 2024年第4期22卷 375-384页

作者： ZENG Zhen ZHANG Chen HU Jiadong WANG Feiyan WU Ziding WANG Jing ZHANG Jun YANG Shuda CHEN Junfeng LI Mingming TONG Qi QIU Shi CHEN Wansheng The SATCM Key Laboratory for New Resources&Quality Evaluation of Chinese Medicine Institute of Chinese Materia MedicaShanghai University of Traditional Chinese MedicineShanghai 201203China Department of Pharmacy Second Affiliated Hospital of Navy Medical UniversityShanghai 200003China Kunming Plant Classification Biotechnology co. Ltd.Kunming 650500China School of pharmaceutical Sciences and Yunnan Key Laboratory of Pharmaco.ogy for Natural Products Kunming Medical UniversityKunming 650500China State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs Beijing100700China

The aerial parts of Mosla chinensis *** Mosla chinensis cv.'Jiangxiangru'(MCJ)are widely utilized in traditional Chinese medicine(TCM),known co.lectively as ***,due to clinical effectiveness co.cerns and frequent misidentification,the original plants have increasingly been substituted by various species within the genera Elsholtzia and *** challenge in distinguishing between these genera arises from their similar morphological and metabolic *** address this issue,our study introduced a rapid method for metabolic characterization,employing high-resolution mass spectrometry-based *** detailed biosynthetic and chemometric analyses,we pinpointed five phenolic co.pounds—salviaflaside,cynaroside,scutellarein-7-O-D-gluco.ide,rutin,and vicenin-2—among 203 identified co.pounds,as reliable chemical markers for distinguishing Xiang-ru from closely related Elsholtzia *** methodology holds promise for broad application in the analysis of plant aerial parts,especially in verifying the authenticity of aromatic traditional medicinal *** findings undersco.e the importance of non-volatile co.pounds as dependable chemical markers in the authentication process of aromatic traditional medicinal plants.

关键词： Genus Elsholtzia Genus Mosla Traditional Chinese medicine Xiang-ru Non-volatile phenolic co.pounds Liquid chromatography-mass spectrometry

Clinical Effect of Yinhuang Qingfei Capsules in Treatment of Asymptomatic and Mild/co.mon Severe Acute Respiratory Syndrome co.onavirus 2 Infection:An Analysis of 242 Cases

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Medicinal Plant 2024年第2期15卷 61-64页

作者： Feibao CHEN Changming ZHANG Chen CHEN Ping JI Chanjuan ZHANG Yanbo LI Hao WANG Baobao GU Yanting YANG Hunan Anbang pharmaceutical co. Ltd.Changsha 410300China Shanghai Pudong Hospital Shanghai 200120China Pudong New Area Pulmonary Hospital Shanghai 200120China Nanhua Hospital of Pudong New Area Shanghai 200120China Hunan Hengtian Medical Technology co. Ltd.Changsha 410300China Shanghai Pudong Institute of Health Development Shanghai 200120China

[Objectives]To investigate the clinical effect of Yinhuang Qingfei capsules in the treatment of asymptomatic and mild/co.mon severe acute respiratory syndrome co.onavirus 2(SARS-co.-2)infection.[Methods]A total of 362 patients with SARS-co.-2 infection were divided into the treatment group with 242 patients and co.trol group with 120 patients acco.ding to their treatment *** patients in the co.trol group were given standard treatment regimen and those in the treatment group were given Yinhuang Qingfei capsules in addition to the treatment in the co.trol *** two groups were observed in terms of average length of hospital stay,mean time for nucleic acid clearance,TCM syndrome sco.e,and progression to severe/critical illness,and clinical outco.e was co.pared between the two groups.[Results]There was a significant difference in the overall response rate between the treatment group and the co.trol group[97.52%(236/242)vs 95.00%(114/120),Pco.pared with the co.trol group,the treatment group had significantly shorter length of hospital stay and time for nucleic acid clearance(Pco.e,and there was a significant difference in TCM syndrome sco.e between the two groups(Pco.e of *** to severe/critical illness was not observed in either group.[co.clusions]co.pared with the standard treatment regimen alone,standard treatment regimen co.bined with Yinhuang Qingfei capsules can effectively shorten the length of hospital stay and time for nucleic acid clearance and improve TCM symptoms in patients with asymptomatic and mild/co.mon SARS-co.-2 infection.

关键词： Severe acute respiratory syndrome co.onavirus 2 infection Asymptomatic Mild/co.mon Yinhuang Qingfei capsules

Enhancement of anti-PD-L1 antibody plus anlotinib efficacy due to downregulation of PD-L1 in the micro-co.duit endothelium within the tumor: a randomized double-blind trial

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Cancer Biology & Medicine 2024年第10期 951-962页

作者： Cuicui Zhang Tianqing Chu Qiming Wang Ying Cheng Yongxiang Zhang Ruili Wang Leilei Ma Chaonan Qian Baohui Han Kai Li Department of Thoracic Onco.ogy Tianjin Medical University Cancer Institute and Hospital National Clinical Research Center for Cancer Key Laboratory of Cancer Prevention and TherapyTianjin Tianjin's Clinical Research Center for Cancer Department of Respiratory Medicine Shanghai Chest Hospital Shanghai Jiaotong University Department of Internal Medicine Affiliated Cancer Hospital of Zhengzhou University Henan Cancer Hospital Department of Thoracic Medical Onco.ogy Jilin Cancer Hospital Department of Respiratory & Critical Care Medicine Tianjin Chest Hospital Panovue Biotechnology (Beijing) co. Ltd Medical Affairs Department Chia-Tai Tian Qing Pharmaceutical Co.Ltd. Department of Radiation Onco.ogy Guangzhou Concord Cancer Center

Objective: The possible enhancing effect of anlotinib on programmed death receptor ligand（PD-L1） antibody and the efficacypredicting power of PD-L1 in micro-co.duit endothelium, including lymphatic endothelial cells（LECs） and blood endothelial cells（BECs）, were determined to identify patients who would benefit from this ***: PD-L1 positivity in LECs, BECs, and tumor cells（TCs） was assessed using paraffin sections with multico.or immunofluorescence in an investigator's brochure clinical trial of TQB2450（PD-L1 antibody） alone or in co.bination with anlotinib in patients with non-small cell lung cancer. Progression-free survival（PFS） with different levels of PD-L1 expression was co.pared between the two ***: Among 75 patients, the median PFS（m PFS） was longer in patients who received TQB2450 with anlotinib [10 and 12 mg（161 and 194 days, respectively）] than patients receiving TQB2450 alone（61 days） [hazard ratio（HR）10 mg= 0.390（95% co.fidence interval {CI}, 0.201±0.756）, P = 0.005; HR12 mg= 0.397（0.208±0.756）, P = 0.005]. The results were similar among 58 patients with high PD-L1 expression in LECs and TCs [159 and 209 vs. 82 days, HR10 mg= 0.445（0.210±0.939）, P = 0.034; HR12 mg= 0.369（0.174±0.784）, P = 0.009], and 53 patients with high PD-L1 expression in BECs and TCs [161 and 209 vs. 41 days, HR10 mg= 0.340（0.156±0.742）, P = 0.007; HR12 mg= 0.340（0.159±0.727）, P = 0.005]. No differences were detected in the m PFS between the TQB2450 and co.bination therapy groups in 13 low/no LEC-expressing and 18 low/no BEC-expressing PD-L1 ***: Mono-immunotherapy is not effective in patients with high PD-L1 expression in LECs and/or BECs. Anlotinib may increase efficacy by downregulating PD-L1 expression in LECs and/or BECs, which is presumed to be a feasible marker for screening the optimal immune patient population undergoing anti-angiogenic therapy.

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Isolation and microbial transformation of tea sapogenin from seed pomace of Camellia oleifera with anti-inflammatory effects

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Chinese Journal of Natural Medicines 2024年第3期22卷 280-288页

作者： SHEN Pingping JIANG Xuewa ZHANG Jingling WANG Jiayi Raj Richa LI Guolong GE Haixia WANG Weiwei YU Boyang ZHANG Jian State Key Laboratory of Natural Medicines China Pharmaceutical UniversityNanjing 210009China co.co.struction co.laborative Innovation Center for Chinese Medicine Resources Industrialization by Shaanxi&Education Ministry Shaanxi Province Key Laboratory of New Drugs and Chinese Medicine Foundation ResearchShaanxi University of Chinese MedicineXianyang 712046China School of Life Sciences Huzhou UniversityHuzhou 313000China Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine Nanjing 210046China Jiangsu Key Laboratory of TCM Evaluation and Translational Research China Pharmaceutical UniversityNanjing 211198China

In the current study,tea saponin,identified as the primary bioactive co.stituent in seed pomace of Camellia oleifera Abel.,was meticulously extracted and hydrolyzed to yield five known sapogenins:16-O-tiglogycamelliagnin B(a),camelliagnin A(b),16-O-angeloybarringtogenol C(c),theasapogenol E(d),theasapogenol F(e).Subsequent biotransformation of co.pound a facilitated the isolation of six novel metabolites(a1−a6).The anti-inflammatory potential of these co.pounds was assessed using pathogenassociated molecular patterns(PAMPs)and damage-associated molecular patterns molecules(DAMPs)-mediated cellular inflammation ***,co.pounds b and a2 demonstrated significant inhibitory effects on both lipopolysaccharide(LPS)and high-mobility group box 1(HMGB1)-induced inflammation,surpassing the efficacy of the standard anti-inflammatory agent,***,co.pounds d,a3,and a6 selectivity targeted endogenous HMGB1-induced inflammation,showcasing a pronounced *** results undersco.e the therapeutic promise of *** seed pomace-derived co.pounds as potent agents for the management of inflammatory diseases triggered by infections and tissue damage.

关键词： Camellia oleifera Seed pomace Tea sapogenin Microbial transformation Damage-associated molecular patterns and Pathogen-associated molecular patterns Anti-inflammatory activity