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Maslinic acid modulates glycogen metabolism by enhancing the insulin signaling pathway and inhibiting glycogen phosphorylase

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Chinese Journal of Natural Medicines 2014年第4期12卷 259-265页

作者： LIU Jun WANG Xue CHEN Yu-Peng MAO Li-Fei SHANG Jing SUN Hong-Bin ZHANG Lu-Yong State Key Laboratory of Natural Medicines National Drug Screening Center China Pharmaceutical University center for drug discovery College of Pharmacy China Pharmaceutical University

AIM: To investigate the molecular signaling mechanism by which the plant-derived, pentacyclic triterpene maslinic acid(MA) exerts anti-diabetic effects. METHOD: HepG2 cells were stimulated with various concentrations of MA. The effects of MA on glycogen phosphorylase a(GPa) activity and the cellular glycogen content were measured. Western blot analyses were performed with anti-insulin receptor β(IRβ), protein kinase B(also known as Akt), and glycogen synthase kinase-3β(GSK3β) antibodies. Activation status of the insulin pathway was investigated using phospho-IRβ, as well as phospho-Akt, and phospho-GSK3β antibodies. The specific PI3-kinase inhibitor wortmannin was added to the cells to analyze the Akt expression. Enzyme-linked immunosorbent assay(ELISA) was used to measure the effect of MA on IRβ auto-phosphorylation. Furthermore, the effect of MA on glycogen metabolism was investigated in C57BL/6J mice fed with a high-fat diet(HFD). RESULTS: The results showed that MA exerts anti-diabetic effects by increasing glycogen content and inhibiting glycogen phosphorylase activity in HepG2 cells. Furthermore, MA was shown to induce the phosphorylation level of IRβ-subunit, Akt, and GSK3β. The MA-induced activation of Akt appeared to be specific, since it could be blocked by wortmannin. Finally, MA treatment of mice fed with a high-fat diet reduced the model-associated adiposity and insulin resistance, and increased the accumulated hepatic glycogen content. CONCLUSION: The results suggested that maslinic acid modulates glycogen metabolism by enhancing the insulin signaling pathway and inhibiting glycogen phosphorylase.

关键词： Maslinic acid Insulin signal transduction Glycogen phosphorylation a Glycogen metabolism

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Construction of the Hexacyclic Core of Dispirocochlearoids A-C via a Diels-Alder Reaction

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Chinese Journal of Chemistry 2022年第13期40卷 1566-1570页

作者： Qiang Fu Yonghui Wang Fajun Nan Department of Medicinal Chemistry School of PharmacyFudan University826 Zhangheng RoadShanghai 201203China State Key Laboratory of drug research National Center for Drug ScreeningShanghai Institute of Materia MedicaChinese Academy of Sciences555 Zuchongzhi RoadShanghai 201203China drug discovery Shandong Laboratory Bohai Rim Advanced Research Institute for Drug DiscoveryYantaiShandong 264117China

The natural products of dispirocochlearoids are complex Ganoderma meroterpenoids featuring a 6/6/5/6/6/6 ring system and are selective cox-2 ***,we describe our progress regarding the total synthesis of dispirocochlearoids A-C,in which a hexacyclic skeleton was constructed *** key steps of this work involve an intermolecular[4+2]cycloaddition reaction,a ring cleavage approach via Ticla,and the installation of a profoundly sterically hindering lactone.

关键词： Natural products Dispirocochlearoids Hexacyclic skeleton Cycloaddition Total synthesis

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Development of SV2A Ligands for Epilepsy Treatment:A Review of Levetiracetam,Brivaracetam,and Padsevonil

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Neuroscience Bulletin 2024年第5期40卷 594-608页

作者： Peng-Peng Wu Bi-Rong Cao Fu-Yun Tian Zhao-Bing Gao center for Neurological and Psychiatric research and drug discovery Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai201203China University of Chinese Academy of Sciences Beijing100049China Zhongshan Institute for drug discovery Shanghai Institute of Materia MedicaChinese Academy of SciencesZhongshan528400China

Epilepsy is a common neurological disorder that is primarily treated with antiseizure medications(ASMs).Although dozens of ASMs are available in the clinic,approximately 30%of epileptic patients have medically refractory seizures;other limitations in most traditional ASMs include poor tolerability and drug-drug ***,there is an urgent need to develop alternative ***(LEV)is a first-line ASM that is well tolerated,has promising efficacy,and has little drug-drug *** it is widely accepted that LEV acts through a unique therapeutic target synaptic vesicle protein(SV)2A,the molecular basis of its action remains *** so,the next-generation SV2A ligands against epilepsy based on the structure of LEV have achieved clinical *** review highlights the research and development(R&D)process of LEV and its analogs,brivaracetam and padsevonil,to provide ideas and experience for the R&D of novel ASMs.

关键词： Levetiracetam Epilepsy Antiseizure medications Synaptic vesicle protein 2A Brivaracetam Padsevonil

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Subretinal fibrosis secondary to neovascular age-related macular degeneration:mechanisms and potential therapeutic targets

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Neural Regeneration research 2025年第2期20卷 378-393页

作者： Jingxiang Zhang Xia Sheng Quanju Ding Yujun Wang Jiwei Zhao Jingfa Zhang Department of Ophthalmology People’s Hospital of Huangdao DistrictQingdaoShandong ProvinceChina Department of Urology People’s Hospital of Huangdao DistrictQingdaoShandong ProvinceChina Department of Ophthalmology Shanghai General Hospital(Shanghai First People’s Hospital)Shanghai Jiao Tong University School of MedicineShanghaiChina National Clinical research center for Eye Diseases Shanghai Key Laboratory of Ocular Fundus DiseasesShanghai Engineering Center for Visual Science and PhotomedicineShanghai Engineering Center for Precise Diagnosis and Treatment of Eye DiseasesShanghaiChina

Subretinal fibrosis is the end-stage sequelae of neovascular age-related macular *** causes local damage to photoreceptors,retinal pigment epithelium,and choroidal vessels,which leads to permanent central vision loss of patients with neovascular age-related macular *** pathogenesis of subretinal fibrosis is complex,and the underlying mechanisms are largely ***,there are no effective treatment options.A thorough understanding of the pathogenesis of subretinal fibrosis and its related mechanisms is important to elucidate its complications and explore potential *** current article reviews several aspects of subretinal fibrosis,including the current understanding on the relationship between neovascular age-related macular degeneration and subretinal fibrosis;multimodal imaging techniques for subretinal fibrosis;animal models for studying subretinal fibrosis;cellular and non-cellular constituents of subretinal fibrosis;pathophysiological mechanisms involved in subretinal fibrosis,such as aging,infiltration of macrophages,different sources of mesenchymal transition to myofibroblast,and activation of complement system and immune cells;and several key molecules and signaling pathways participating in the pathogenesis of subretinal fibrosis,such as vascular endothelial growth factor,connective tissue growth factor,fibroblast growth factor 2,platelet-derived growth factor and platelet-derived growth factor receptor-β,transforming growth factor-βsignaling pathway,Wnt signaling pathway,and the axis of heat shock protein 70-Toll-like receptors 2/*** review will improve the understanding of the pathogenesis of subretinal fibrosis,allow the discovery of molecular targets,and explore potential treatments for the management of subretinal fibrosis.

关键词： choroidal neovascularization epithelial-mesenchymal transition mesenchymal transition myofibroblast neovascular age-related macular degeneration submacular fibrosis subretinal fibrosis therapeutic targets transforming growth factor-β vascular endothelial growth factor

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Deciphering fungal metabolon coupling tandem inverse-electrondemand Diels-Alder reaction and semipinacol rearrangement for the biosynthesis of spiro polycyclic alkaloids

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Science China Chemistry 2025年第1期68卷 288-296页

作者： Shuai Liu Wen-Qiang Xu Ying-Tong Di Man-Cheng Tang Ding-Kang Chen Ming-Ming Cao Yao-Wen Chang Hong-Yu Tang Chun-Mao Yuan Jun-Bo Yang Zhi-Li Zuo Han Guo Zi-Fei Xu Ying Zeng Yun-Dong Wu Xiao-Jiang Hao Key Laboratory of Phytochemistry and Natural Medicines (Chinese Academy of Sciences) Kunming Institute of Botany Chinese Academy of Sciences University of Chinese Academy of Sciences Lab of Computational Chemistry and drug Design State Key Laboratory of Chemical Oncogenomics Peking University Shenzhen Graduate School Shenzhen Bay Laboratory State Key Laboratory of Microbial Metabolism School of Life Sciences & Biotechnology Shanghai Jiao Tong University State Key Laboratory of Functions and Applications of Medicinal Plants Guizhou Medical University Molecular Biology Experimental center Germplasm Bank of Wild Species in Southwest China Kunming Institute of Botany Chinese Academy of Sciences Yunnan Key Laboratory for Wild Plant Resources Kunming Institute of Botany Chinese Academy of Sciences research Unit of Chemical Biology of Natural Anti-Virus Products Chinese Academy of Medical Sciences

In the intricate process of natural product biosynthesis, a metabolon can enhance metabolic flux by associating sequential enzymes. A fungal metabolon, comprising of flavin-dependent monooxygenase Spe F and P450 monooxygenase Spe G, is identified in the biosynthesis of spiro polycyclic alkaloids(+)-notoamide B and its diastereomer(+)-versicolamide B. Using notoamide E as a substance, Spe F/Spe G metabolon can control the stereoselectivity of its 2,3-epoxidation, followed by hydrogen atom ion at C-17 to generate reactive epoxide tau-m A with dienyl iminium unit. Subsequently,(+)-notoamide B and(+)-versicolamide B are produced via tandem nonenzymatic inverse-electron-demand Diels-Alder reaction and semipinacol rearrangement. This provides the first example of metabolon in the biosynthesis of spiro-prenylated indole alkaloids.

关键词： metabolon Diels-Alder reaction semipinacol rearrangement biosynthesis notoamides spiro polycyclic alkaloids

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New glowing dyes in vivo imaging with wavelengths beyond 1500 nm

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Science China Chemistry 2019年第1期62卷 7-8页

作者： Jing Yang Xuechuan Hong State Key Laboratory of Virology Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (MOE) and Hubei Province Engineering and Technology Research Center for Fluorinated Pharmaceuticals Wuhan University School of Pharmaceutical Sciences

Near-infrared (NIR)fluorescence imaging in the second near-infrared region (NIR-H,1000-1700 nm)is an important and attractive imaging method for biomedical research and clinical applications,and can achieve high spatial resolution, high signal-to-background ratio (SBR)and deeper tissue imaging owing to nearly zero auto-fluorescence background and tissue scattering .Smaller optical sub-window such as NIR-IIb (1500-1700 nm)has provided significant improvements in in vivo fluorescence imaging clarity and penetration depth.

关键词： Near-infrared (NIR)fluorescence Smaller optical fluorescence

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Synthesis and Crystal Structure of 2-[(2-Chloropyridin-4-yl)oxy]-3,3-diphenyl-3-methoxypropionic Acid

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Chinese Journal of Structural Chemistry 2011年第4期30卷 545-549页

作者：于秀玲赵桂龙谭初兵邵华徐为人 Tianjin Key Laboratory of Molecular Design and drug discovery Tianjin Institute of Pharmaceutical Research Tianjin University of TCM

The title compound was synthesized and its crystal structure was determined by single-crystal X-ray *** crystal is of orthorhombic system（C21H18ClNO4,Mr = 383.81）,space group Pca21 with a = 13.913（3）,b = 10.273（2）,c = 26.488（5）,V = 3786.1（13） 3,Z = 8,Dc = 1.347 g/cm3,F（000） = 1600,μ = 0.228 mm-1,the final R = 0.0550 and wR = 0.1278 for 5065 observed reflections（I 2σ（I））.The title compound in a racemic form was found to exist as a mixture of two enantiomers in an equal ratio in the unit *** intermolecular hydrogen bonds link the molecules in a head-to-end manner to generate an infinite chain.

关键词： synthesis crystal structure pyridine propionic acid ETR antagonist

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Harnessing generative AI to decode enzyme catalysis and evolution for enhanced engineering

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National Science Review 2023年第12期10卷 13-25页

作者： Wen Jun Xie Arieh Warshel Department of Medicinal Chemistry Center for Natural Products Drug Discovery and DevelopmentGenetics InstituteUniversity of Florida Department of Chemistry University of Southern California

Enzymes, as paramount protein catalysts, occupy a central role in fostering remarkable progress across numerous fields. However, the intricacy of sequence-function relationships continues to obscure our grasp of enzyme behaviors and curtails our capabilities in rational enzyme engineering. Generative artificial intelligence(AI), known for its proficiency in handling intricate data distributions, holds the potential to offer novel perspectives in enzyme research. Generative models could discern elusive patterns within the vast sequence space and uncover new functional enzyme sequences. This review highlights the recent advancements in employing generative AI for enzyme sequence analysis. We delve into the impact of generative AI in predicting mutation effects on enzyme fitness, catalytic activity and stability, rationalizing the laboratory evolution of de novo enzymes, and decoding protein sequence semantics and their application in enzyme engineering. Notably, the prediction of catalytic activity and stability of enzymes using natural protein sequences serves as a vital link, indicating how enzyme catalysis shapes enzyme evolution. Overall,we foresee that the integration of generative AI into enzyme studies will remarkably enhance our knowledge of enzymes and expedite the creation of superior biocatalysts.

关键词： generative AI mutation effects evolution–catalysis relationship enzyme engineering enzyme evolution

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Future of the current anticoronaviral agents: A viewpoint on thevalidation for the next COVIDs and pandemics

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BIOCELL 2023年第10期47卷 2133-2139页

作者： AMGAD M.RABIE drug discovery&Clinical research Department Dikernis General Hospital(DGH)Dikernis35744Egypt

Despite the global decline in the severity of the coronavirus disease 2019 (COVID-19) cases, the disease stillrepresents a major concern to the relevant scientific and medical communities. The primary concern of drug scientists,virologists, and other concerned specialists in this respect is to find ready-to-use suitable and potent anticoronaviraltherapies that are broadly effective against the different species/strains of the coronaviruses in general, not only againstthe current and previous coronaviruses (e.g., the recently-appeared severe acute respiratory syndrome coronavirus 2“SARS-CoV-2”), i.e., effective antiviral agents for treatment and/or prophylaxis of any coronaviral infections, includingthose of the coming ones from the next species and strains (if any). As an expert in this field, I tried, in this up-to-dateperspective “viewpoint” article, to evaluate the suitability and applicability of using the currently-availableanticoronaviral agents for the next coronavirus diseases (COVIDs) and coronaviral pandemics, highlighting the mostimportant general guidelines that should be considered in the next pandemics from the therapeutic points of view.

关键词： SARS-CoV-2/COVID-19 Spike(S)protein/Main protease(Mpro)/RNA-dependent RNA polymerase(RdRp) General anticoronaviral drug Specific anti-COVID-19 medication Molnupiravir/Nirmatrelvir/Riboprine/Ensitrelvir drug design and development

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Structure-based drug discovery of novel fusedpyrazolone carboxamide derivatives as potent and selective AXL inhibitors

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Acta Pharmaceutica Sinica B 2023年第12期13卷 4918-4933页

作者： Feifei Fang Yang Dai Hao Wang Yinchun Ji Xuewu Liang Xia Peng Jiyuan Li Yangrong Zhao Chunpu Li Danyi Wangh Yazhou Li Dong Zhang Dan Zhang Meiyu Geng Hong Liu Jing Ai Yu Zhou Lingang Laboratory Shanghai 200031China State Key Laboratory of drug research Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China drug discovery&Development center Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China University of Chinese Academy of Sciences Beijing 100049China Shandong Laboratory of Yantai drug discovery Bohai Rim Advanced Research Institute for Drug DiscoveryYantai 264117China School of Pharmaceutical Science and Technology Hangzhou Institute for Advanced StudyUCASHangzhou 310024China

a novel and promising antitumor target,AXL plays an important role in tumor growth,metastasis,immunosuppression and drug resistance of various malignancies,which has attracted extensive research interest in recent *** this study,by employing the structure-based drug design and bioisosterism strategies,we designed and synthesized in total 54 novel AXL inhibitors featuring a fusedpyrazolone carboxamide scaffold,of which up to 20 compounds exhibited excellent AXL kinase and BaF3/TEL-AXL cell viability ***,compound 59 showed a desirable AXL kinase inhibitory activity(IC_(50):3.5 nmol/L)as well as good kinase selectivity,and it effectively blocked the cellular AXL *** turn,compound 59 could potently inhibit BaF3/TEL-AXL cell viability(IC_(50):1.5 nmol/L)and significantly suppress GAS6/AXL-mediated cancer cell invasion,migration and wound healing at the nanomolar *** importantly,compound 59 oral administration showed good pharmacokinetic profile and in vivo antitumor efficiency,in which we observed significant AXL phosphorylation suppression,and its antitumor efficacy at 20 mg/kg(qd)was comparable to that of BGB324 at 50 mg/kg(bid),the most advanced AXL *** together,this work provided a valuable lead compound as a potential AXL inhibitor for the further antitumor drug development.

关键词： Potential AXL inhibitor Antitumor activity Structure-based drug design Fused-pyrazolone carboxamide

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