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Two types of coumarins-specific enzymes complete the last missing steps in pyran- and furanocoumarins biosynthesis

Acta Pharmaceutica Sinica B 2024年第2期14卷 869-880页

作者： Yucheng Zhao Yuedong He Liangliang Han Libo Zhang Yuanzheng Xia Fucheng Yin Xiaobing Wang Deqing Zhao Sheng Xu Fei Qiao Yibei Xiao Lingyi Kong department of Resources Science of Traditional Chinese Medicines School of Traditional Chinese Pharmacyand State Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjing 210009China College of Bioscience and biotechnology Hunan Agricultural UniversityChangsha 410128China Jiangsu key laboratory of Bioactive Natural Product Research and state key laboratory of Natural Medicines Department of Natural Medicinal ChemistryChina Pharmaceutical UniversityNanjing 210009China key laboratory of Crop Gene Resources and Germplasm Enhancement in Southern China Ministry of AgricultureTropical Crops Genetic Resources InstituteChinese Academy of Tropical Agricultural SciencesHaikou 517317China Institute of Botany Jiangsu Province and Chinese Academy of SciencesNanjing 210014China department of Pharmacology School of Pharmacyand State Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjing 210009China

Pyran-and furanocoumarins are key representatives of tetrahydropyrans and tetrahydrofurans,respectively,exhibiting diverse physiological and medical bioactivities.However,the biosynthetic mechanisms for their core structures remain poorly understood.Here we combined multiomics analyses of biosynthetic enzymes in Peucedanum praeruptorum and in vitro functional verification and identified two types of key enzymes critical for pyran and furan ring biosynthesis in plants.These included three distinct P.praeruptorum prenyltransferases(PpPT1e3)responsible for the prenylation of the simple coumarin skeleton 7 into linear or angular precursors,and two novel CYP450 cyclases(PpDC and PpOC)crucial for the cyclization of the linear/angular precursors into either tetrahydropyran or tetrahydrofuran scaffolds.Biochemical analyses of cyclases indicated that acid/base-assisted epoxide ring opening contributed to the enzyme-catalyzed tetrahydropyran and tetrahydrofuran ring refactoring.The possible acid/base-assisted catalytic mechanisms of the identified cyclases were theoretically investigated and assessed using site-specific mutagenesis.We identified two possible acidic amino acids Glu303 in PpDC and Asp301 in PpOC as vital in the catalytic process.This study provides new enzymatic tools in the epoxide formation/epoxide-opening mediated cascade reaction and exemplifies how plants become chemically diverse in terms of enzyme function and catalytic process.

关键词： Tetrahydropyrans Tetrahydrofurans Baldwin rules Coumarins CYP450cyclase

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Allosterically activating SHP2 by oleanolic acid inhibits STAT3-Th17 axis for ameliorating colitis

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Acta Pharmaceutica Sinica B 2024年第6期14卷 2598-2612页

作者： Jinbo Hu Wen Liu Yi Zou Chenyang Jiao Jiazhen Zhu Qiang Xu Jianjun Zou Yang Sun Wenjie Guo state key laboratory of pharmaceutical biotechnology Nanjing Drum Tower HospitalSchool of Life SciencesNanjing UniversityNanjing 210093China department of Clinical Pharmacology Nanjing First HospitalNanjing Medical UniversityNanjing 210006China Jiangsu key laboratory of New Drug Research and Clinical Pharmacy Xuzhou Medical UniversityXuzhou 221004China

Src homology 2 domain-containing tyrosine phosphatase 2(SHP2)is an essential tyrosine phosphatase that is pivotal in regulating various cellular signaling pathways such as cell growth,differentiation,and survival.The activation of SHP2 has been shown to have a therapeutic effect in colitis and Parkinson's disease.Thus,the identification of SHP2 activators and a complete understanding of their mechanism is required.We used a two-step screening assay to determine a novel allosteric activator of SHP2 that stabilizes it in an open conformation.Oleanolic acid was identified as a suitable candidate.By binding to R362,K364,and K366 in the active center of the PTP domain,oleanolic acid maintained the active open state of SHP2,which facilitated the binding between SHP2 and its substrate.This oleanolic acid-activated SHP2 hindered Th17 differentiation by disturbing the interaction between STAT3 and IL-6Rαand inhibiting the activation of STAT3.Furthermore,via the activation of SHP2 and subsequent attenuation of the STAT3-Th17 axis,oleanolic acid effectively mitigated colitis in mice.This protective effect was abrogated by SHP2 knockout or administration of the SHP2 inhibitor SHP099.These findings underscore the potential of oleanolic acid as a promising therapeutic agent for treating inflammatory bowel diseases.

关键词： Oleanolic acid SHP2 STAT3 Th17 Colitis Allosteric activator

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Camouflaging attenuated Salmonella by cryo-shocked macrophages for tumor-targeted therapy

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Signal Transduction and Targeted Therapy 2024年第2期9卷 709-723页

作者： Leyang Wu Zengzheng Du Lin Li Liyuan Qiao Shuhui Zhang Xingpeng Yin Xiaoyao Chang Chenyang Li Zichun Hua The state key laboratory of pharmaceutical biotechnology and department of Neurology of Nanjing Drum Tower Hospital School of Life Sciences and The Affiliated Hospital of Nanjing University Medical SchoolNanjing UniversityNanjing 21008 JiangsuChina Nanjing Generecom biotechnology Co. LtdNanjing 210023China Changzhou High-Tech Research Institute of Nanjing University and Jiangsu TargetPharma Laboratories Inc Changzhou 213164 JiangsuChina School of Biopharmacy China Pharmaceutical UniversityNanjing 210023 JiangsuChina

Live bacteria-mediated antitumor therapies mark a pivotal point in cancer immunotherapy.However,the difficulty in reconciling the safety and efficacy of bacterial therapies has limited their application.Improving bacterial tumor-targeted delivery while maintaining biosafety is a critical hurdle for the clinical translation of live microbial therapy for cancer.Here,we developed“dead”yet“functional”Salmonella-loaded macrophages using liquid nitrogen cold shock of an attenuated Salmonella typhimurium VNP20009-contained macrophage cell line.The obtained“dead”macrophages achieve an average loading of approximately 257 live bacteria per 100 cells.The engineered cells maintain an intact cellular structure but lose their original pathogenicity,while intracellular bacteria retain their original biological activity and are delay freed,followed by proliferation.This“Trojan horse”-like bacterial camouflage strategy avoids bacterial immunogenicity-induced neutrophil recruitment and activation in peripheral blood,reduces the clearance of bacteria by neutrophils and enhances bacterial tumor enrichment efficiently after systemic administration.Furthermore,this strategy also strongly activated the tumor microenvironment,including increasing antitumor effector cells(including M1-like macrophages and CD8+Teffs)and decreasing protumor effector cells(including M2-like macrophages and CD4+Tregs),and ultimately improved antitumor efficacy in a subcutaneous H22 tumor-bearing mouse model.The cryo-shocked macrophage-mediated bacterial delivery strategy holds promise for expanding the therapeutic applications of living bacteria for cancer.

关键词： shock holds maintain

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Computer-aided molecular design and optimization of potent inhibitors disrupting APC-Asef interaction

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Acta Pharmaceutica Sinica B 2024年第6期14卷 2631-2645页

作者： Xuefei Wang Zeqian Du Yuegui Guo Jie Zhong Kun Song Junyuan Wang Jianqiang Yu Xiuyan Yang Chen-Ying Liu Ting Shi Jian Zhang department of Pathophysiology Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of EducationShanghai Jiao Tong UniversitySchool of MedicineShanghai 200025China key laboratory of Protection Development and Utilization of Medicinal Resources in Liupanshan AreaMinistry of EducationPeptide&Protein Drug Research CenterSchool of PharmacyNingxia Medical UniversityYinchuan 750004China state key laboratory of Microbial Metabolism Joint International Research Laboratory of Metabolic and Developmental SciencesSchool of Life Sciences and BiotechnologyShanghai Jiao Tong UniversityShanghai 200240China department of Colorectal and Anal Surgery Xinhua HospitalShanghai Jiao Tong University School of MedicineShanghai 200025China Basic Science Research Center Base(pharmaceutical Science) Yantai UniversityYantai 264005China Medicinal Chemistry and Bioinformatics Center Shanghai Jiao Tong UniversitySchool of MedicineShanghai 200025China state key laboratory of pharmaceutical biotechnology Nanjing UniversityNanjing 210023China

Colorectal cancer(CRC)is the second leading cause of cancer mortality worldwide.At initial diagnosis,approximately 20%of patients are diagnosed with metastatic CRC(mCRC).Although the APC-Asef interaction is a well-established target for mCRC therapy,the discovery and development of effective and safe drugs for mCRC patients remains an urgent and challenging endeavor.In this study,we identified a novel structural scaffold based on MAI inhibitors,the first-in-class APC-Asef inhibitors we reported previously.ONIOM model-driven optimizations of the N-terminal cap and experimental evaluations of inhibitory activity were performed,and 24-fold greater potency was obtained with the best inhibitor compared to the parental compound.In addition,the cocrystal structure validated that the two-layerπ-πstacking interactions were essential for inhibitor stabilization in the bound state.Furthermore,in vitro and in vivo studies have demonstrated that novel inhibitors suppressed lung metastasis in CRC by disrupting the APC-Asef interaction.These results provide an intrinsic structural basis to further explore drug-like molecules for APC-Asef-mediated CRC therapy.

关键词： APC-Asef Peptidomimetic Computer-aided molecular design ONIOM model π-πstacking Metastatic colorectal cancer

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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 Discovery 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 College of Computer 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 xenobiotics.AOX-mediated metabolism can result in unexpected outcomes,such as the production of toxic metabolites and high metabolic clearance,which can lead to the clinical failure of novel therapeutic agents.Computational models can assist medicinal chemists in rapidly evaluating the AOX metabolic risk of compounds during the early phases of drug discovery and provide valuable clues for manipulating AOX-mediated metabolism liability.In this study,we developed a novel graph neural network called AOMP for predicting AOX-mediated metabolism.AOMP 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 tasks.AOMP significantly outperformed the benchmark methods in both cross-validation and external testing.Using AOMP,we systematically assessed the AOX-mediated metabolism of common fragments in kinase inhibitors and successfully identified four new scaffolds with AOX metabolism liability,which were validated through in vitro experiments.Furthermore,for the convenience of the community,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

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Ce6 nanoassemblies:Molecular mechanism and strategies for combinational anticancer therapy Special Collection:Aggregation-Induced Processes and Functions

Aggregate

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Aggregate 2024年第1期5卷 130-147页

作者： Yuwei Liu Shuting Xu Qingyang Lyu Yi Huang Weiping Wang state key laboratory of pharmaceutical biotechnology The University of Hong KongHong KongChina department of Pharmacology and Pharmacy Li Ka Shing Faculty of MedicineThe University of Hong KongHong KongChina laboratory of Molecular Engineering and Nanomedicine Dr.Li Dak-Sum Research CentreThe University of Hong KongHong KongChina

Nowadays,cancer has become the leading cause of death worldwide,driving the need for effective therapeutics to improve patient prognosis.Photodynamic therapy(PDT)has been widely applied as an antitumor modality,owing to its minimal invasiveness,localized tumor damage,and high safety profile.However,its efficacy is limited by poor stability of photosensitizers,inadequate tumor accumulation,and a complex tumor microenvironment.To overcome these challenges,extensive endeavors have been made to explore the co-assembly of the widely used photosensitizer chlorin e6(Ce6)with various functional small molecules to enhance pharmacodynamic activity.This review provides a comprehensive overview of current studies on Ce6-based nanoparticles for effective PDT and precise delivery of functional molecules.The self-assembly mechanism will be discussed in detail,with a focus on potential strategies for combinational therapy with PDT.

关键词： cancer treatment carrier-free chlorin e6(Ce6) light nanomedicine photodynamic therapy(PDT) selfassembly

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Network Pharmacology of Xian-Lian-Jie-Du Decoction in Ameliorating Colorectal Cancer

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World Journal of Traditional Chinese Medicine 2024年第1期10卷 83-92页

作者： Ming-Xia Zhao Cheng-Lin Song Qin-Chang Zhang Hao-Jie Du Shu-Qiong Zhang Yu-Xian Shen Yang Sun Hai-Bo Cheng Wen Lv department of Pharmacy School of Basic Medical SciencesAnhui Medical UniversityHefeiAnhuiChina department of Biopharmaceutical Research Institute Anhui Medical UniversityHefeiAnhuiChina department of pharmaceutical Analysis State Key Laboratory of Natural and Biomimetic DrugsSchool of Pharmaceutical SciencesPeking UniversityBeijingChina Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine in Prevention and Treatment of Tumor First Clinical CollegeNanjing University of Chinese MedicineNanjingJiangsuChina Deparment of biotechnology and pharmaceutical Sciences State Key Laboratory of Pharmaceutical BiotechnologySchool of Life SciencesNanjing UniversityNanjingJiangsuChina Deparment of Gynecology Institute of Traditional Chinese Medicine of Zhejiang ProvinceTongde Hospital of Zhejiang ProvinceHangzhouZhejiangChina

Objective:In this study,we screened for therapeutic targets of the Xian-Lian-Jie-Du decoction(XLJDD)for colorectal cancer(CRC)and explored the underlying mechanisms using network pharmacology techniques.Methods:Genes associated with CRC were collected from the Gene Cards database.The names of the active compounds of XLJDD were used as keywords in the“chemical name”in the Traditional Chinese Medicine Systems Pharmacology(TCMSP)database to search the targets.The protein-protein interaction(PPI)network was constructed using Cytoscape 3.8.1.Gene Ontology functional enrichment and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analyses were performed to identify key target proteins.Results:A total of 234 XLJDD-related targets and 250 cross-targets between XLJDD and CRC were collected based on the TCMSP and HIT 2.0 databases.A PPI network constructed based on the STRING database revealed interactions for all 250 proteins.The network results revealed TP53,MYC,CCND1,AKT1,CASP3,and STAT3 as core potential targets.KEGG pathway analysis of the 250 potential XLJDD targets for CRC in the Metascape database was performed using RStudio software.The top 12 gene ratio aggregated analysis results were visualized in bubble charts.The interleukin(IL)-17 signaling pathway had the highest correlation with the tumor necrosis factor(TNF)signaling pathway.Conclusions:XLJDD may be effective in ameliorating CRC by controlling inflammatory factors related to the IL-17 and TNF pathways and targeting proto-oncogenes and tumor suppressor genes,including MYC,CCND1,CTNNB1,and TP53.

关键词： Colorectal cancer network pharmacology Xian-Lian-Jie-Du decoction

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Rapid characterization of non-volatile phenolic compounds reveals the reliable chemical markers for authentication of traditional Chinese medicine Xiang-ru among confusing 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 Pharmacology 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 Maxim.and Mosla chinensis cv.'Jiangxiangru'(MCJ)are widely utilized in traditional Chinese medicine(TCM),known collectively as Xiang-ru.However,due to clinical effectiveness concerns and frequent misidentification,the original plants have increasingly been substituted by various species within the genera Elsholtzia and Mosla.The challenge in distinguishing between these genera arises from their similar morphological and metabolic profiles.To address this issue,our study introduced a rapid method for metabolic characterization,employing high-resolution mass spectrometry-based metabolomics.Through detailed biosynthetic and chemometric analyses,we pinpointed five phenolic compounds—salviaflaside,cynaroside,scutellarein-7-O-D-glucoside,rutin,and vicenin-2—among 203 identified compounds,as reliable chemical markers for distinguishing Xiang-ru from closely related Elsholtzia species.This methodology holds promise for broad application in the analysis of plant aerial parts,especially in verifying the authenticity of aromatic traditional medicinal plants.Our findings underscore the importance of non-volatile compounds 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 compounds Liquid chromatography-mass spectrometry

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Understanding the Novel Approach of Nanoferroptosis for Cancer Therapy

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Nano-Micro Letters 2024年第9期16卷 501-556页

作者： Afsana Sheikh Prashant Kesharwani Waleed H.Almalki Salem Salman Almujri Linxin Dai Zhe‑Sheng Chen Amirhossein Sahebkar Fei Gao department of Pharmaceutics School of Pharmaceutical Education and ResearchJamia HamdardNew Delhi 110062India department of Pharmacology and Toxicology Faculty of PharmacyUmm Al-Qura UniversityMakkahSaudi Arabia department of Pharmacology College of PharmacyKing Khalid University61421 Asir‑AbhaSaudi Arabia state key laboratory of Southwestern Chinese Medicine Resources Pharmacy SchoolChengdu University of Traditional Chinese MedicineChengdu 611130People’s Republic of China department of pharmaceutical Sciences College of Pharmacy and Health SciencesSt.John’s UniversityNew York 11439USA biotechnology Research Center Pharmaceutical Technology InstituteMashhad University of Medical SciencesMashhadIran Applied Biomedical Research Center Mashhad University of Medical SciencesMashhadIran

As a new form of regulated cell death,ferroptosis has unraveled the unsolicited theory of intrinsic apoptosis resistance by cancer cells.The molecular mechanism of ferroptosis depends on the induction of oxidative stress through excessive reactive oxygen species accumulation and glutathione depletion to damage the structural integrity of cells.Due to their high loading and structural tunability,nanocarriers can escort the delivery of ferro-therapeutics to the desired site through enhanced permeation or retention effect or by active targeting.This review shed light on the necessity of iron in cancer cell growth and the fascinating features of ferroptosis in regulating the cell cycle and metastasis.Additionally,we discussed the effect of ferroptosis-mediated therapy using nanoplatforms and their chemical basis in overcoming the barriers to cancer therapy.

关键词： Ferroptosis Nanoparticles Ferrotherapy Cancer Genes Nanotechnology Toxicity Reactive oxygen species

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LonP1 Links Mitochondria–ER Interaction to Regulate Heart Function

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Research 2024年第1期2023卷 595-609页

作者： Yujie Li Dawei Huang Lianqun Jia Fugen Shangguan Shiwei Gong Linhua Lan Zhiyin Song Juan Xu Chaojun Yan Tongke Chen Yin Tan Yongzhang Liu Xingxu Huang Carolyn K.Suzuki Zhongzhou Yang Guanlin Yang Bin Lu The Affiliated Nanhua Hospital and School of Basic Medical Sciences Hengyang Medical SchoolUniversity of South ChinaHengyangHunan 421001China School of laboratory Medicine and Life Sciences Wenzhou Medical UniversityWenzhouZhejiang 325035China National Health Commission key laboratory of Birth Defect Research and Prevention Hunan Provincial Maternal and Child Health Care HospitalChangshaHunan 410008China key laboratory of Ministry of Education for TCM Viscera-state Theory and Applications Ministry of Education of ChinaLiaoning University of Traditional Chinese MedicineShenyangLiaoning 110847China key laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province The First Affiliated Hospital of Wenzhou Medical UniversityWenzhouZhejiangChina Hubei key laboratory of Cell Homeostasis College of Life SciencesWuhan UniversityWuhanHubei 430072China Nanjing Maternity and Child Health Care Hospital Obstetrics and Gynecology Hospital Affiliated to Nanjing Medical UniversityNanjing 210004China Animal Center Wenzhou Medical UniversityWenzhouZhejiang 325035China department of Cardiology The First Affiliated Hospital of University of South ChinaHengyangHunanChina School of Life Science and Technology Shanghai Tech UniversityShanghai 201210China department of Microbiology Biochemistry and Molecular GeneticsNew Jersey Medical School-RutgersThe State University of New JerseyNewarkNJUSA state key laboratory of pharmaceutical biotechnology Department of CardiologyNanjing Drum Tower HospitalThe Affiliated Hospital of Nanjing University Medical School and MOE Key Laboratory of Model Animal for Disease StudyModel Animal Research CenterNanjing UniversityNanjing 210061China

Interorganelle contacts and communications are increasingly recognized to play a vital role in cellular function and homeostasis.In particular,the mitochondria–endoplasmic reticulum(ER)membrane contact site(MAM)is known to regulate ion and lipid transfer,as well as signaling and organelle dynamics.However,the regulatory mechanisms of MAM formation and their function are still elusive.Here,we identify mitochondrial Lon protease(LonP1),a highly conserved mitochondrial matrix protease,as a new MAM tethering protein.The removal of LonP1 substantially reduces MAM formation and causes mitochondrial fragmentation.Furthermore,deletion of LonP1 in the cardiomyocytes of mouse heart impairs MAM integrity and mitochondrial fusion and activates the unfolded protein response within the ER(UPR^(ER)).Consequently,cardiac-specific LonP1 deficiency causes aberrant metabolic reprogramming and pathological heart remodeling.These findings demonstrate that LonP1 is a novel MAM-localized protein orchestrating MAM integrity,mitochondrial dynamics,and UPR^(ER),offering exciting new insights into the potential therapeutic strategy for heart failure.

关键词： offering programming insight

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