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Reverse metabolomics as a novel strategy to annotate the human metabolome

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Chinese Journal of Natural Medicines 2024年第4期22卷 289-290页

作者： YAN Tingting NIE Liangliang hao haiping State Key Laboratory of Natural Medicines China Pharmaceutical UniversityNanjing 211198China Laboratory of Metabolic Regulation and Drug Target Discovery School of PharmacyChina Pharmaceutical UniversityNanjing 210009China

Identifying chemical structures inhuman-derived samples presents significant challenges due to limited structural data obtained from untargeted metabolomics *** the chemical structures of molecules are closely related to the phenotypic status of human ecosystems,it becomes invaluable to devise a method for efficiently and systematically determining structures that correlate with the pathophysiological status of humans in a high-throughput approach.

关键词： Reverse metabolomics Human metabolome Combinational synthesis Bile amidates

Prediction of fibril formation by early-stage amyloid peptide aggregation

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Journal of Pharmaceutical Analysis 2020年第2期10卷 194-199页

作者： Jiaojiao Hu Huiyong Sun haiping hao Qiuling Zheng Department of Pharmaceutical Analysis School of PharmacyChina Pharmaceutical UniversityTongjiaxiang#24NanjingJiangsu210009China Department of Medicinal Chemistry School of PharmacyChina Pharmaceutical UniversityTongjiaxiang#24NanjingJiangsu210009China Key Laboratoryof Drug Metabolism and Pharmacokinetics China Pharmaceutical UniversityTongjiaxiang#24NanjingJiangsu210009China State Key Laboratory of Natural Medicines China Pharmaceutical UniversityTongjiaxiang#24NanjingJiangsu210009China

Amyloid fibrils are found in systemic amyloidosis diseases such as Alzheimer's disease,Parkinson's disease,and type II ***,these diseases are diagnosed by observation of fibrils or plaques,which is an ineffective method for early diagnosis and treatment of *** goal of this study was to develop a simple and quick method to predict the possibility and speed of fibril formation before its *** generated from seven representative peptide segments were first isolated and detected by ion-mobility mass spectrometry(IM-MS).Then,their assemblies were disrupted using formic acid(FA).Interestingly,oligomers that showed small ion intensity changes upon FA addition had rapid fibril *** contrast,oligomers that had large ion intensity changes generated fibrils *** control peptides(aggregation/no fibrils and no aggregation/no fibrils)did not show changes in their ion intensities,which confirmed the ability of this method to predict amyloid *** summary,the developed method correlated MS intensity ratio changes of peptide oligomers on FA addition with their amyloid *** method will be useful for monitoring peptide/protein aggregation behavior and essential for their mechanism studies.

关键词： Mass spectrometry Amyloid fibril Early-stage oligomer Peptide aggregation

Bile acid coordinates microbiota homeostasis and systemic immunometabolism in cardiometabolic diseases

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Acta Pharmaceutica Sinica B 2022年第5期12卷 2129-2149页

作者： Baoyi Guan Jinlin Tong haiping hao Zhixu Yang Keji Chen hao Xu Anlu Wang Xiyuan Hospital China Academy of Chinese Medical SciencesBeijing 100091China National Clinical Research Center for Chinese Medicine Cardiology Beijing 100091China State Key Laboratory of Natural Medicines China Pharmaceutical UniversityNanjing 210009China

Cardiometabolic disease(CMD), characterized with metabolic disorder triggered cardiovascular events, is a leading cause of death and disability. Metabolic disorders trigger chronic low-grade inflammation, and actually, a new concept of metaflammation has been proposed to define the state of metabolism connected with immunological adaptations. Amongst the continuously increased list of systemic metabolites in regulation of immune system, bile acids(BAs) represent a distinct class of metabolites implicated in the whole process of CMD development because of its multifaceted roles in shaping systemic immunometabolism. BAs can directly modulate the immune system by either boosting or inhibiting inflammatory responses via diverse mechanisms. Moreover, BAs are key determinants in maintaining the dynamic communication between the host and microbiota. Importantly, BAs via targeting Farnesoid X receptor(FXR) and diverse other nuclear receptors play key roles in regulating metabolic homeostasis of lipids, glucose, and amino acids. Moreover, BAs axis per se is susceptible to inflammatory and metabolic intervention, and thereby BAs axis may constitute a reciprocal regulatory loop in metaflammation. We thus propose that BAs axis represents a core coordinator in integrating systemic immunometabolism implicated in the process of CMD. We provide an updated summary and an intensive discussion about how BAs shape both the innate and adaptive immune system, and how BAs axis function as a core coordinator in integrating metabolic disorder to chronic inflammation in conditions of CMD.

关键词： Bile acid Nuclear receptors Cardiometabolic diseases Systemic immunometabolism Therapeutic opportunities

Selective inhibition of CDK4/6: A safe and effective strategy for developing anticancer drugs

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Acta Pharmaceutica Sinica B 2021年第1期11卷 30-54页

作者： Kai Yuan Xiao Wang haojie Dong Wenjian Min haiping hao Peng Yang State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization China Pharmaceutical UniversityNanjing 210009China Department of Medicinal Chemistry School of PharmacyChina Pharmaceutical UniversityNanjing 210009China

The sustained cell proliferation resulting from dysregulation of the cell cycle and activation of cyclin-dependent kinases(CDKs)is a hallmark of *** inhibition of CDKs is a highly promising and attractive strategy for the development of anticancer *** particular,third-generation CDK inhibitors can selectively inhibit CDK4/6 and regulate the cell cycle by suppressing the G1 to S phase transition,exhibiting a perfect balance between anticancer efficacy and general *** date,three selective CDK4/6 inhibitors have received approval from the *** and Drug Administration(FDA),and 15 CDK4/6 inhibitors are in clinical trials for the treatment of *** this perspective,we discuss the crucial roles of CDK4/6 in regulating the cell cycle and cancer cells,analyze the rationale for selectively inhibiting CDK4/6 for cancer treatment,review the latest advances in highly selective CDK4/6 inhibitors with different chemical scaffolds,explain the mechanisms associated with CDK4/6inhibitor resistance and describe solutions to overcome this issue,and briefly introduce proteolysis targeting chimera(PROTAC),a new and revolutionary technique used to degrade CDK4/6.

关键词： CDK4/6 Cell cycle Cancer Selectivity Drug resistance PROTAC

Protocatechuic aldehyde protects cardiomycoytes against ischemic injury via regulation of nuclear pyruvate kinase M2

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Acta Pharmaceutica Sinica B 2021年第11期11卷 3553-3566页

作者： Xunxun Wu Lian Liu Qiuling Zheng haiping hao Hui Ye Ping Li Hua Yang State Key Laboratory of Natural Medicines China Pharmaceutical UniversityNanjing 210009China College of Pharmacy China Pharmaceutical UniversityNanjing 210009China Jiangsu Provincial Key Laboratory of Drug Metabolism and Pharmacokinetics China Pharmaceutical UniversityNanjing 210009China

Rescuing cells from stress damage emerges a potential therapeutic strategy to combat myocardial *** aldehyde(PCA)is a major phenolic acid in Chinese herb Danshen(Salvia miltiorrhiza root).This study investigated whether PCA regulated nuclear pyruvate kinase isoform M2(PKM2)function to protect *** rats subjected to isoprenaline,PCA attenuated heart injury and protected cardiomyocytes from *** DARTS and CETSA assays,we identified that PCA bound and promoted PKM2 nuclear translocation in cardiomyocytes exposed to oxygen/glucose deprivation(OGD).In the nucleus,PCA increased the binding of PKM2 to β-Catenin via preserving PKM2 acetylation,and the complex,in cooperation with T-cell factor 4(TCF4),was required for transcriptional induction of genes encoding anti-apoptotic proteins,contributing to rescuing cardiomyocyte *** addition,PCA ameliorated mitochondrial dysfunction and prevented mitochondrial apoptosis dependent on ***,PCA increased the binding of PKM2 to β-Catenin,improved heart contractive function,normalized heart structure and attenuated oxidative damage in mice subjected to artery ligation,but the protective effects were lost in Pkm2-deficient ***,we showed that PCA regulated nuclear PKM2 function to rescue cardiomyocyte survival via β-Catenin/TCF4 signaling cascade,suggesting the potential of pharmacological intervention of PKM2 shuttle to protect the heart.

关键词： Protocatechuic aldehyde PKM2 β-Catenin TCF4 Heart ischemia Myocardial infarction Apoptosis Mitochondrial damage Nuclear translocation

Dihydrotanshinone I preconditions myocardium against ischemic injury via PKM2 glutathionylation sensitive to ROS

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Acta Pharmaceutica Sinica B 2023年第1期13卷 113-127页

作者： Xunxun Wu Lian Liu Qiuling Zheng Hui Ye Hua Yang haiping hao Ping Li State Key Laboratory of Natural Medicines Department of PharmacognosySchool of Traditional Chinese PharmacyChina Pharmaceutical UniversityNanjing 210009China College of Pharmacy China Pharmaceutical UniversityNanjing 210009China State Key Laboratory of Natural Medicines Jiangsu Provincial Key Laboratory of Drug Metabolism and PharmacokineticsChina Pharmaceutical UniversityNanjing 210009China

Ischemic preconditioning(IPC)is a potential intervention known to protect the heart against ischemia/reperfusion injury,but its role in the no-reflow phenomenon that follows reperfusion is *** I(DT)is a natural compound and this study illustrates its role in cardiac ischemic injury from the aspect of *** with DT induced modest ROS production and protected cardiomyocytes against oxygen and glucose deprivation(OGD),but the protection was prevented by a ROS *** addition,DT administration protected the heart against isoprenaline ***,PKM2 reacted to transient ROS via oxidization at Cys423/Cys424,leading to glutathionylation and nuclear translocation in dimer *** the nucleus,PKM2 served as a co-factor to promote HIF-1a-dependent gene induction,contributing to adaptive *** mice subjected to permanent coronary ligation,cardiac-specific knockdown of Pkm2 blocked DT-mediated preconditioning protection,which was rescued by overexpression of wild-type Pkm2,rather than Cys423/424-mutated *** conclusion,PKM2 is sensitive to oxidation,and subsequent glutathionylation promotes its nuclear *** IPC has been viewed as a protective means against reperfusion injury,our study reveals its potential role in protection of the heart from no-reflow ischemia.

关键词： Dihydrotanshinone I Ischemic preconditioning PKM2 Glutathionylation Myocardial ischemia ROS Oxidation modification Nuclear translocation

Herbal drug discovery for the treatment of nonalcoholic fatty liver disease

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Acta Pharmaceutica Sinica B 2020年第1期10卷 3-18页

作者： Tingting Yan Nana Yan Ping Wang Yangliu Xia haiping hao Guangji Wang Frank JGonzalez Laboratory of Metabolism Center for Cancer ResearchNational Cancer InstituteNational Institutes of HealthBethesdaMD 20892USA State Key Laboratory of Natural Medicines Key Laboratory of Drug Metabolism and PharmacokineticsChina Pharmaceutical UniversityNanjing 210009China Institute of Interdisciplinary Integrative Medicine Research Shanghai University of Traditional Chinese MedicineShanghai 201203China School of Life Science and Medicine Dalian University of TechnologyPanjin 124221China

Few medications are available for meeting the increasing disease burden of nonalcoholic fatty liver disease(NAFLD)and its progressive stage,nonalcoholic steatohepatitis(NASH).Traditional herbal medicines(THM)have been used for centuries to treat indigenous people with various symptoms but without clarified modern-defined disease types and *** modern times,NAFLD was defined as a common chronic disease leading to more studies to understand NAFLD/NASH pathology and *** have garnered increased attention for providing therapeutic candidates for treating *** this review,a new model called"multiple organs-multiple hits"is proposed to explain mechanisms of NASH *** this proposed model,the effects and mechanisms of the frequentlystudied THM-yielded single anti-NAFLD drug candidates and multiple herb medicines are reviewed,among which silymarin and berberine are already under ***-sanctioned phase 4 clinical ***,experimental designs for anti-NAFLD drug discovery from THM in treating NAFLD are *** opportunities and challenges of reverse pharmacology and reverse pharmacokinetic concepts-guided strategies for THM modernization and its global recognition to treat NAFLD are *** mechanistic evidence is being generated to support the beneficial role of THM in treating NAFLD and anti-NAFLD drug discovery.

关键词： Natural products Fatty liver Metabolic syndrome TCM NAFLD

Metabolic dysregulation and emerging therapeutical targets for hepatocellular carcinoma

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Acta Pharmaceutica Sinica B 2022年第2期12卷 558-580页

作者： Danyu Du Chan Liu Mengyao Qin Xiao Zhang Tao Xi Shengtao Yuan haiping hao Jing Xiong Department of Pharmacology School of PharmacyChina Pharmaceutical UniversityNanjing 210009China Research Center of Biotechnology School of Life Science and TechnologyChina Pharmaceutical UniversityNanjing 210009China Jiangsu Key Laboratory of Drug Screening China Pharmaceutical UniversityNanjing 210009China State Key Laboratory of Natural Medicines China Pharmaceutical UniversityNanjing 210009China Key Laboratory of Drug Metabolism and Pharmacokinetics China Pharmaceutical UniversityNanjing 210009China

Hepatocellular carcinoma(HCC)is an aggressive human cancer with increasing incidence *** efforts have been made to explore pharmaceutical therapies to treat HCC,such as targeted tyrosine kinase inhibitors,immune based therapies and combination of ***,limitations exist in current strategies including chemoresistance for *** initiation and progression is driven by reprogramming of metabolism,in particular during HCC ***,metabolic associated fatty liver disease(MAFLD),a reappraisal of new nomenclature for nonalcoholic fatty liver disease(NAFLD),indicates growing appreciation of metabolism in the pathogenesis of liver disease,including HCC,thereby suggesting new strategies by targeting abnormal metabolism for HCC *** this review,we introduce directions by highlighting the metabolic targets in glucose,fatty acid,amino acid and glutamine metabolism,which are suitable for HCC pharmaceutical *** also summarize and discuss current pharmaceutical agents and studies targeting deregulated metabolism during HCC ***,opportunities and challenges in the discovery and development of HCC therapy targeting metabolism are discussed.

关键词： Metabolic dysregulation Hepatocellular carcinoma Glycolysis Tricarboxylic acid cycle Pentose phosphate pathway Fatty acidβ-oxidation Glutamine metabolism Cancer therapy

Super-sensitive bifunctional nanoprobe: Self-assembly of peptide-driven nanoparticles demonstrating tumor fluorescence imaging and therapy

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Acta Pharmaceutica Sinica B 2022年第3期12卷 1473-1486页

作者： Han Xiao Rui Zhang Xiaobo Fan Xinglu Jiang Mingyuan Zou Xuejiao Yan haiping hao Guoqiu Wu Medical School Southeast UniversityNanjing 210009China Department of Clinical Laboratory the Fifth Affiliated Hospital of Sun Yat-sen UniversityNanjing 210009China Department of Cardiology the Affiliated Changzhou No.2 People’s Hospital of Nanjing Medical UniversityNanjing 210009China State Key Laboratory of Natural Medicines Key Lab of Drug Metabolism and PharmacokineticsChina Pharmaceutical UniversityZhuhai 519000China Center of Clinical Laboratory Medicine Zhongda HospitalSoutheast UniversityNanjing 21009China Jiangsu Provincial Key Laboratory of Critical Care Medicine Southeast UniversityChangzhou 213000China

The development of nanomedicine has recently achieved several breakthroughs in the field of cancer treatment;however,biocompatibility and targeted penetration of these nanomaterials remain as limitations,which lead to serious side effects and significantly narrow the scope of their *** self-assembly of intermediate filaments with arginine-glycine-aspartate(RGD)peptide(RGDIFP)was triggered by the hydrophobic cationic molecule 7-amino actinomycin D(7-AAD)to synthesize a bifunctional nanoparticle that could serve as a fluorescent imaging probe to visualize tumor *** designed RGD-IFP peptide possessed the ability to encapsulate 7-AAD molecules through the formation of hydrogen bonds and hydrophobic interactions by a one-step *** fluorescent nanoprobe with RGD peptide could be targeted for delivery into tumor cells and released in acidic environments such as endosomes/lysosomes,ultimately inducing cytotoxicity by arresting tumor cell cycling with inserted *** is noteworthy that the RGD-IFP/7-AAD nanoprobe tail-vein injection approach demonstrated not only high tumor-targeted imaging potential,but also potent antitumor therapeutic effects in *** proposed strategy may be used in peptide-driven bifunctional nanoparticles for precise imaging and cancer therapy.

关键词： Nanoprobe 7-Amino actinomycin D Intermediate filament protein Tumor image Antitumor therapy Integrin avβ3