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A potential strategy for treating atherosclerosis: improving endothelial function via AMP-activated protein kinase

中国科学（生命科学） 2018年第9期61卷 1024-1029页

作者： Feng Gao Jiemei Chen Haibo Zhu State Key Laboratory for Bioactive Substances and Functions of Natural Medicines Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study Institute of Materia Medica Chinese Academy of Medical Sciences & Peking Union Medical CollegeBeijing 100050 China

Endothelial dysfunction is caused by many factors,such as dyslipidemia,endoplasmic reticulum (ER) stress,and *** has been demonstrated that endothelial dysfunction is the initial process of ***-activated protein kinase (AMPK) is an important metabolic switch that plays a crucial role in lipid metabolism and ***,recent evidence indicates that AMPK could be a target for atherosclerosis by improving endothelial *** instance,activation of AMPK inhibits the production of reactive oxygen species induced by mitochondrial dysfunction,ER stress,and NADPH ***,activation of AMPK inhibits the production of pro-inflammatory factors induced by dyslipidemia and hyperglycemia and restrains production of perivascular adipose tissue-released *** activation prevents endothelial dysfunction by increasing the bioavailability of nitric ***,we focused on the primary risk factors involved in endothelial dysfunction,and summarize the features of AMPK in the protection of endothelial function,by providing signaling pathways thought to be important in the pathological progress of risk factors.

关键词： atherosclerosis AMP-activated protein kinase cardiovascular diseases inflammation autophagy

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The regulation effect of AMPK in immune related diseases

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Science China(Life Sciences) 2018年第5期61卷 523-533页

作者： Jing Wang Zhenyu Li Li Gao Yanshuang Qi Haibo Zhu Xuemei Qin Modern Research Center for Traditional Chinese Medicine Shanxi University Taiyuan 030006 China State Key Laboratory for Bioactive Substances and Functions of Natural Medicines，Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study，Institute of Materia Medica Chinese Academy of Medical Sciences & Peking Union Medical College Beijing 100050 China

AMP-activated protein kinase (AMPK) is a sensor of cellular energy status that plays a key role in energetic metabolism *** changes in immune cells, such as dendritic cell (DC), macrophages, neutrophils and lymphocytes that participate in the signal directed programs that promote or inhibit immune mediated diseases, including cancer, atherosclerosis and inflammatory diseases. Multiple pathogenic mechanisms are involved in the initiation and progression of disease, and many pathways have been uncovered. The mechanistic overlap in the metabolic changes and inflammation could indicate that some of the targets they have are in common, whereas AMPK could be useful in treatment of both disorders. The insight into identification of AMPK responsible for specific immune regulation, anti-inflammatory actions and understanding of the underlying molecular mechanism will promote the generation of novel AMPK activators, and provide novel therapy strategy.

关键词： AMPK metabolic changes immune cells atherosclerosis cancer inflammation

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Correction: CKLF1 Aggravates Focal Cerebral Ischemia Injury at Early Stage Partly by Modulating Microglia/Macrophage Toward M1 Polarization Through CCR4

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Cellular and molecular neurobiology 2024年第1期44卷 45页

作者： Chen Chen Shi-Feng Chu Qi-Di Ai Zhao Zhang Fei-Fei Guan Sha-Sha Wang Yi-Xiao Dong Jie Zhu Wen-Xuan Jian Nai-Hong Chen State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia Medica & Neuroscience Center Chinese Academy of Medical Sciences and Peking Union Medical College Beijing 100050 China. Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces & Hunan University of Chinese Medicine First-Class Disciple Construction Project of Chinese Materia Medica Changsha 410208 China. Key Laboratory of Human Disease Comparative Medicine Institute of Laboratory Animal Science NHFPC Peking Union Medicine College and Chinese Academy of Medical Sciences Beijing 100021 China. School of Basic Medicine Shanxi University of Traditional Chinese Medicine Taiyuan 030619 China. Tianjin University of Traditional Chinese Medicine Tianjin 300193 China. Institute of Process Engineering Chinese Academy of Sciences Beijing 100050 China. DME Center Clinical Pharmacology Institute Guangzhou University of Chinese Medicine Guangzhou 510000 China. State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia Medica & Neuroscience Center Chinese Academy of Medical Sciences and Peking Union Medical College Beijing 100050 China. chennh@***. Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces & Hunan University of Chinese Medicine First-Class Disciple Construction Project of Chinese Materia Medica Changsha 410208 China. chennh@***.

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Prion-like propagation of α-synuclein in gutbrain axis

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中国药理学与毒理学杂志 2018年第9期32卷 685-686页

作者： CHEN Ying SHAO Qian-hang YUAN Yu-he CHEN Nai-hong State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia Medica & Neuroscience CenterChinese Academy of Medical Sciences and Peking Union Medical College College of Pharmacy Hunan University of Chinese Medicine

Parkinson disease(PD) is a progressive degenerative disease of the nervous system,which is characterized by movement disorders,such as static tremor,rigidity,and bradykinesia in advanced ***(GI) dysfunction,such as gastric dysmotility,constipation,and anorectic dysfunction,is common non-motor symptom in the early stage of *** progression of PD includes the degenerative loss of dopaminergic neurons and aggregation ofα-synuclein in the substantia ***,both of them are also present in the enteric nervous system of PD *** this review,we describe the relationship between non-motor symptoms particularly GI dysfunction and the pathogenesis of PD,aiming to show the powerful evidences about the prion-like propagation of α-synuclein and support the hypothesis of gut-brain axis in *** then summarize the mechanism of the gut-brain axis and confirmα-synuclein as a potential target for drug design or new clinical treatment.

关键词： α-synuclein prion-like propagation enteric nervous system gut-brain axis non-motor symptom Parkinson disease

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Chemokines play complex roles in cerebral ischemia

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中国药理学与毒理学杂志 2018年第9期32卷 672-673页

作者： CHEN Chen CHU Shi-feng LIU Dan-dan ZHANG Zhao KONG Ling-lei ZHOU Xin CHEN Nai-hong State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia Medica & Neuroscience Center Chinese Academy of Medical Sciences and Peking Union Medical College Beijing 100050 China Tianjin University of Tra

Ischemic stroke(IS) is a disease caused by deficiency of blood and oxygen in focal or complete brain,followed by inflammation cascade and other pathological reactions,which finally lead to irreversible damage to the *** the inflammation is a key progress at the initiation of ischemia and poststroke,and chemokines work as vital cytokines in inflammation,we focus the roles of chemokines in *** have shown cerebral ischemia is associated with marked induction of both CXC and CC chemokines which resulting in extensive leukocyte infiltration in the ischemic brain,and neutrophil infiltration may increase cerebral edema inducing injury in the ischemic *** addition,chemokines also shows other functions such as promote neuroblast migration,hematogenous cell recruitment and functional brain ***,a similar chemokine ligand/chemokine receptor pair can mediate both beneficial and detrimental effects depending on the window of observation and pathophysiological *** manuscript reviews the studies about chemokine-mediated effects in cerebral ischemia/reperfusion and discusses the potential significance of these interactions in injury and repair of ischemic *** also refer drug development based on the chemokines and clinical applications using chemokines as diagnostic or prognostic biomarkers in ischemic stroke.

关键词： chemokine cerebral ischemia ischemic stroke

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Ginsenoside Rg1 protects against ischemia reperfusion-induced neurotoxicity through miR-144/Nrf2/ARE pathway

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中国药理学与毒理学杂志 2018年第9期32卷 669-670页

作者： CHU Shi-feng ZHANG Zhao ZHOU Xin HE Wen-bin CHEN Nai-hong State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia MedicaNeuroscience CenterChinese Academy of Medical Sciences and Peking Union Medical College Shanxi Key Laboratory of Chinese Medicine Encephalopathy Shanxi University of Chinese Medicine

OBJECTIVE Ginsenoside Rg1(Rg1),a purified compound from Panax ginseng,has been well documented to be effective against ischemia/reperfusion(I/R) ***,the underlying mechanism is stil *** The anti-I/R effect of Rg1 were investigated in vitro and in vivo,and the dynamics of nuclear accumulation and the transcriptional activity of NF-E2-related factor 2(Nrf2) determined by Western blotting and Dual Luciferase Reporter Assay,***2 siRNA was employed to investigate Nrf2′s role in the protective effect of Rg1 against I/***,the role of miR-144,which could regulate post-translational Nrf2 levels,was investigated in the anti-I/R effect of Rg1 by injection of AAV-hypoxia-inducible factor miR-144-shRNA in the predicted ischemic *** It was found that the anti-I/R effect of Rg1 was related to its anti-oxidative capacity,which is mainly regulated by the Nrf2/antioxidant response element(ARE) *** study suggested that Rg1 contributes to the enhancement of the Nrf2/ARE pathway,as manifested by increasing the dynamic peak content of Nrf2,which prolonged the maintenance stage,and promoting the expression of ARE-target genes after oxygen glucose deprivation/reperfusion(OGD/R) in PC12 ***2-siRNA application significantly reduced these ***,the enhancement of the Nrf2/ARE pathway by Rg1 was independent of disassociation from Keap1;rather it was a result of posttranslational *** was found that Rg1 significantly reduced the expression of miR-144,which down-regulates Nrf2 production by targeting its 3′-untranslated region,after OGD/*** of Nrf2 showed no effect on the expression of miR-144,indicating that miR-144 is an upstream regulator of ***,direct binding between Nrf2 and miR-144 in the PC12 cells was *** of anti-miR-144 significantly reduced Rg1′s anti-OGD/R *** y,the role of miR-144 in Rg1′ s anti-I/R effect was tested by inhibiting

关键词： ginsenoside Rg1 ischemia reperfusion NF-E2-related factor 2 antioxidant responseelement miR-144

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IMM-H007 promotes hepatic cholesterol and triglyceride metabolism by activating AMPK α to attenuate hypercholesterolemia

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Acta Pharmaceutica Sinica B 2025年

作者： Jiaqi Li Mingchao Wang Kai Qu Yuyao Sun Zequn Yin Na Dong Xin Sun Yitong Xu Liang Chen Shuang Zhang Xunde Xian Suowen Xu Likun Ma Yajun Duan Haibo Zhu Department of Cardiology the First Affiliated Hospital of USTC Division of Life Sciences and Medicine University of Science and Technology of China Hefei 230001 China State Key Laboratory for Bioactive Substances and Functions of Natural Medicines Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study Institute of Materia Medica Chinese Academy of Medical Sciences and Peking Union Medical College Beijing 100050 China College of Life Sciences State Key Laboratory of Medicinal Chemical Biology Key Laboratory of Bioactive Materials of Ministry of Education Nankai University Tianjin 300071 China State Key Laboratory of Common Mechanism Research for Major Diseases Department of Biochemistry and Molecular Biology Institute of Basic Medical Sciences Chinese Academy of Medical Sciences and Peking Union Medical College Beijing 100005 China Institute of Cardiovascular Sciences State Key Laboratory of Vascular Homeostasis and Remodeling School of Basic Medical Sciences Peking University Beijing 100083 China College of Life Science Anhui Medical University Hefei 230032 China Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes College of Food and Biological Engineering Hefei University of Technology Hefei 230009 China Department of Endocrinology the First Affiliated Hospital of USTC Division of Life Sciences and Medicine University of Science and Technology of China Hefei 230001 China Anhui Provincial Key Laboratory of Metabolic Health and Panvascular Diseases Hefei 23001 China

Hypercholesterolemia is a significant risk factor for the development of atherosclerosis. 2′,3′,5′-Tri- O -acetyl-N6-(3-hydroxyphenyl) adenosine (IMM-H007), a novel AMPK agonist, has shown protective effects in metabolic diseases. However, its impact on cholesterol and triglyceride metabolism in hypercholesterolemia remains unclear. In this study, we aimed to elucidate the effects and specific mechanisms by which IMM-H007 regulates cholesterol and triglyceride metabolism. To achieve this goal, we used Apoe −/− and Ldlr −/− mice to establish a hypercholesterolemia/atherosclerosis model. Additionally, hepatocyte-specific Ampka 1/2 knockout mice were subjected to a 5-week high-cholesterol diet to establish hypercholesterolemia, while atherosclerosis was induced via AAV- PCSK9 injection combined with a 16-week high-cholesterol diet. Our results demonstrated that IMM-H007 improved cholesterol and triglyceride metabolism in mice with hypercholesterolemia. Mechanistically, IMM-H007 modulated the AMPK α 1/2–LDLR signaling pathway, increasing cholesterol uptake in the liver. Furthermore, IMM-H007 activated the AMPK α 1–FXR pathway, promoting the conversion of hepatic cholesterol to bile acids. Additionally, IMM-H007 prevented hepatic steatosis by activating the AMPK α 1/2–ATGL pathway. In conclusion, our study suggests that IMM-H007 is a promising therapeutic agent for improving hypercholesterolemia and atherosclerosis through the activation of AMPK α .

关键词： IMM-H007 AMPK cholesterol LDLR FXR Hypercholesterolemia Triglyceride Atherosclerosis

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CKLF1 aggravates focal cerebral ischemia injury at early stage partly by modulating microglia/macrophage toward M1 polarization

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中国药理学与毒理学杂志 2018年第9期32卷 673-674页

作者： CHEN Chen CHU Shi-feng AI Qi-di ZHANG Zhao GUAN Fei-fei WANG Sha-sha DONG Yi-xiao ZHU Jie JIAN Wen-xuan CHEN Nai-hong State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia Medica & Neuroscience Center Chinese Academy of Medical Sciences and Peking Union Medical College Beijing 100050 China Hunan University of Tradi

OBJECTIVE To investigate the CKLF1 mediated expression of microglia/macrophage phenotypes in vitro and in vivo,discussing the involved *** In vitro,primary microglia isolated from mice cortex were used to study the effects of CKLF1 by qPCR analysis and immunofluorescence *** vivo,WT C57 and CKLF1 deficient mice were used to explore the effects of *** staining,MRI and Nissl staining were applied to examine the infarction or neuron *** longa test was used to evaluate the neurological deficit of *** blotting was used to investigate the changes of specific protein and discuss the involved *** also used qPCR analysis and immunofluorescence staining for polarization markers to determine the effects of *** CKLF1 could drive primary microglia to M1 phenotype for 24 h stimulation in primary *** mice transient ischemic stroke model,CKLF1 attenuated ischemic injury,and accompanied by promoting microglia/macrophage toward M1 *** expression of pro-inflammatory cytokines and decreased expression of neurotropic factors and anti-inflammatory cytokines were observed in mice subjected to cerebral ischemia with ***,NF-κB activation enhancement was detected in C27 modulated M1 polarization *** CKLF1 is an important mediator of driving M1 phenotype of microglia/macrophage at early stage of cerebral ischemic injury,contributing to aggravation of cerebral ischemia injury,which closely related to microglia/macrophage M1 polarization guided inflammatory *** CKLF1 has the potential to treat ischemic stroke.

关键词： chemokine cerebral ischemia ischemic stroke

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Cell-Active, Reversible, and Irreversible Covalent Inhibitors That Selectively Target the Catalytic Lysine of BCR-ABL Kinase

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Angewandte Chemie 2022年第26期134卷

作者： Peng Chen Jie Sun Chengjun Zhu Dr. Guanghui Tang Wei Wang Manyi Xu Menghua Xiang Dr. Chong-Jing Zhang Prof. Dr. Zhi-Min Zhang Prof. Dr. Liqian Gao Prof. Dr. Shao Q. Yao School of Pharmaceutical Sciences (Shenzhen) Sun Yat-sen University Shenzhen 518107 China School of Pharmacy Jinan University 601 Huangpu Avenue West Guangzhou 510632 China Guangdong Youmei Institute of Intelligent Bio-manufacturing Foshan Guangdong 528200 China Department of Chemistry National University of Singapore Singapore 117543 Singapore State Key Laboratory of Bioactive Substances and Functions of Natural Medicines and Beijing Key Laboratory of Active Substances Discovery and Drugability Evaluation Institute of Materia Medica Peking Union Medical College and Chinese Academy of Medical Sciences Beijing 100050 China

Despite recent interests in developing lysine-targeting covalent inhibitors, no general approach is available to create such compounds. We report herein a general approach to develop cell-active covalent inhibitors of protein kinases by targeting the conserved catalytic lysine residue using key SuFEx and salicylaldehyde-based imine chemistries. We validated the strategy by successfully developing (irreversible and reversible) covalent inhibitors against BCR-ABL kinase. Our lead compounds showed high levels of selectivity in biochemical assays, exhibited nanomolar potency against endogenous ABL kinase in cellular assays, and were active against most drug-resistant ABL mutations. Among them, the salicylaldehyde-containing A5 is the first-ever reversible covalent ABL inhibitor that possessed time-dependent ABL inhibition with prolonged residence time and few cellular off-targets in K562 cells. Bioinformatics further suggested the generality of our strategy against the human kinome.

关键词： Cancer Lysine Proteomics Reversible Targeted Covalent Inhibitor

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The effects of glucocorticoids on depressive and anxiety-like behaviors, mineralocorticoid receptor-dependent cell proliferation regulates anxiety-like behaviors

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Behavioural brain research 2019年 362卷 288-298页

作者： Jiao Chen Zhen-Zhen Wang Shuai Zhang Shi-Feng Chu Zheng Mou Nai-Hong Chen State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia Medica & Neuroscience Center Chinese Academy of Medical Sciences and Peking Union Medical College Beijing 100050 China. State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia Medica & Neuroscience Center Chinese Academy of Medical Sciences and Peking Union Medical College Beijing 100050 China Hunan University of Chinese Medicine Changsha Hunan 410208 China. Hunan University of Chinese Medicine Changsha Hunan 410208 China Guangzhou University of Chinese Medicine Guangzhou 510000 China. Electronic address: chennh@***.

Glucocorticoids are vital stress response hormones and facilitate stress coping. However, sustained glucocorticoid exposure is associated with negative effects on brain. The precise role of glucocorticoids in depression and anxiety remains unclear. In the present study, we found that rats exposed to chronic unpredictable stress (CUS) showed anxiety-like behavior but not depressive-like behavior in the absence of glucocorticoid production. It was interesting to find that the level of serotonin (5-HT) and the expression of tryptophan hydroxylase-2 (TPH2) were decreased after CUS in the hippocampus in sham rats, while adrenalectomy (ADX) prevented such decreases. In addition, the neurogenesis in hippocampus decreased in both sham and ADX rats after stress exposure. Furthermore, inhibition of mineralocorticoid receptor (MR) with spironolactone induced anxiety like behavior in sham rats but not ADX rats. The proliferation of cells was blocked by spironolactone. In conclusion, our results indicate that MR-dependent neurogenesis was closely related with anxiety-like behavior.

关键词： Anxiety Cell proliferation Depression Glucocorticoids Mineralocorticoid receptor Serotonin

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