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The raphe nuclei are the early lesion site of gastric α-synuclein propagation to the substantia nigra

Acta Pharmaceutica Sinica B 2024年第5期14卷 2057-2076页

作者： Chenglu Zhang Ruxue Bo Tiantian Zhou Naihong Chen Yuhe Yuan State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Chinese Academy of Medical Sciences&Peking Union Medical College Institute of Materia MedicaBeijing 100050China

Parkinson's disease(PD)is a neurodegeneration disease withα-synuclein accumulated in the substantia nigra pars compacta(SNpc)and most of the dopaminergic neurons are lost in SNpc while patients are diagnosed with *** the pathology at an early stage contributes to the development of the disease-modifying *** the“gut–brain”hypothesis is proposed to explain the underlying mechanism,where the earlier lesioned site in the brain of gastricα-synuclein and howα-synuclein further spreads are not fully *** we report that caudal raphe nuclei(CRN)are the early lesion site of gastricα-synuclein propagating through the spinal cord,while locus coeruleus(LC)and substantia nigra pars compacta(SNpc)were further affected over a time frame of 7 ***α-synuclein propagation via CRN leads to neuron loss and disordered neuron activity,accompanied by abnormal motor and non-motor *** neuron circuits are observed among CRN,LC,and SNpc,which contribute to the venerability of dopaminergic neurons in *** results show that CRN is the key region for the gastricα-synuclein spread to the *** study provides valuable details for the“gut–brain”hypothesis and proposes a valuable PD model for future research on early PD intervention.

关键词： Raphe nuclei α-Synuclein Gastrointestinal tract Electrophysiology Locus coeruleus Substantia nigra pars compacta Parkinson's disease Spinal cord

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The toxic natural product tutin causes epileptic seizures in mice by activating calcineurin

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Signal Transduction and Targeted Therapy 2023年第4期8卷 1916-1925页

作者： Qing-Tong Han Wan-Qi Yang Caixia Zang Linchao Zhou Chong-Jing Zhang Xiuqi Bao Jie Cai Fangfei Li Qinyan Shi Xiao-Liang Wang Jing Qu Dan Zhang Shi-Shan Yu State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia MedicaPeking Union Medical College and Chinese Academy of Medical SciencesBeijing 100050China

Tutin,an established toxic natural product that causes epilepsy in rodents,is often used as a tool to develop animal model of acute epileptic ***,the molecular target and toxic mechanism of tutin were *** this study,for the first time,we conducted experiments to clarify the targets in tutin-induced epilepsy using thermal proteome *** studies showed that calcineurin(CN)was a target of tutin,and that tutin activated CN,leading to *** site studies further established that tutin bound within the active site of CN catalytic *** inhibitor and calcineurin A(CNA)knockdown experiments in vivo proved that tutin induced epilepsy by activating CN,and produced obvious nerve ***,these findings revealed that tutin caused epileptic seizures by activating ***,further mechanism studies found that N-methyl-D-aspartate(NMDA)receptors,gammaaminobutyric acid(GABA)receptors and voltage-and Ca2+-activated K+(BK)channels might be involved in related signaling *** study fully explains the convulsive mechanism of tutin,which provides new ideas for epilepsy treatment and drug development.

关键词： epilepsy seizures epileptic

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Chemoproteomics identifies Ykt6 as the direct target of schisandrin A for neuroprotection

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Chinese Chemical Letters 2023年第6期34卷 401-405页

作者： Tiantian Wang Yu Zhou Hao Zheng Tao Shen Dongmei Wang Jinlan Zhang State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China

Schisandrin A is a natural dibenzocyclooctene lignan with potent neuroprotective ***,the specific mechanisms or direct target proteins have not been clarified up to *** this study,we designed and synthesized the probes of schisandrin A with photoreactive diazirine and clickable alkyne to identify its direct target in SH-SY5Y cells by employing activity-based protein profiling(ABPP)***6 was prominent among the 13 proteins obtained with high confidence and we confirmed Ykt6 as the direct target of schisandrin A by CETSA,IF,SPR and knockdown ***,schisandrin A protected the cells against the injury induced by glutamate by regulating autophagy via *** discovery may provide a novel therapeutic option for various neuronal cell damage-mediated diseases.

关键词： Schisandrin A Activity-based protein profiling(ABPP) Neuroprotection Ykt6 Autophagy

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ACAT1 deficiency in myeloid cells promotes glioblastoma progression by enhancing the accumulation of myeloid-derived suppressor cells

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Acta Pharmaceutica Sinica B 2023年第12期13卷 4733-4747页

作者： Mingjin Wang Weida Wang Shen You Zhenyan Hou Ming Ji Nina Xue Tingting Du Xiaoguang Chen Jing Jin Department of Pharmacology State Key Laboratory of Bioactive Substances and Functions of Natural MedicinesInstitute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China

Glioblastoma(GBM)is a highly aggressive and lethal brain tumor with an immunosuppressive tumor microenvironment(TME).In this environment,myeloid cells,such as myeloid-derived suppressor cells(MDSCs),play a pivotal role in suppressing antitumor *** is closely related to the function of myeloid ***,our study reports that acetyl-CoA acetyltransferase 1(ACAT1),the key enzyme of fatty acid oxidation(FAO)and ketogenesis,is significantly downregulated in the MDSCs infiltrated in GBM *** investigate the effects of ACAT1 on myeloid cells,we generated mice with myeloid-specific(LyzM-cre)depletion of *** results show that these mice exhibited a remarkable accumulation of MDSCs and increased tumor progression both ectopically and *** mechanism behind this effect is elevated secretion of C-X-C motif ligand 1(CXCLI)of macrophages(Mo).Overall,our findings demonstrate that ACAT1 could serve as a promising drug target for GBM by regulating the function of MDSCs in the TME.

关键词： Glioblastoma Myeloid cells Myeloid-derived suppressor cells Acetyl-CoA acetyltransferase 1 CXCL1 Tumor microenvironment Lipid metabolism Macrophages

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TCP-1,a novel peptide to diagnose early colon cancer

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Chinese Chemical Letters 2024年第3期35卷 226-233页

作者： Hang Yu Baoying Wen Min Huang Ru Feng Libin Pan Manyi Xu Hao Lin Lin Cong Sen Zhang Yan Li Chi-Hin Cho Chongjing Zhang Xiaoguang Chen Yan Wang State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia MedicaChinese Academy of Medical SciencesBeijing 100050China School of Biomedical Sciences Faculty of MedicineThe Chinese University of Hong KongHong KongChina

A nine cyclic peptide(TCP-1)showed excellent specificity for colon ***-1 binds with human tumor tissues at early stages and mice tumor with diameters of 1-4 mm,suggesting that TCP-1 may be used for early diagnosis of colon *** mechanism of the targeted binding of TCP-1 to colon cancer was also studied using immunoprecipitation,LC-MS and *** screening and identifying of the possible binding target proteins of TCP-1,keratin,typeⅡcytoskeletal 5 was speculated to be the specific binding target protein of TCP-1 in human tumor *** studies were conducted to investigate the target-mediated drug disposition of the new tumor-specific peptide by LC-MS/*** tissue distribution study showed that TCP-1 was found only in colon tumors(the target site)in tumor mice did not bind to any other *** TCP-1 to tumor markedly increased its removal rate from blood circulation but mildly extended its staying time in *** tumor mice,a lower AUC of TCP-1(reduced by almost 35%)and 2-fold higher clearance were found compared to that of normal *** proposed metabolic pathway of TCP-1 in the kidney was also determined using LC-MS^(n)-*** high specificity and low toxicity of the peptide may be caused by its extremely tight binding to the *** applications for future clinical use,including MRI and PET/CT were also explored,and this research may promote the development of colon cancer diagnostic technology research and provide new ideas and technical routes for tumor diagnostic technology.

关键词： Colon cancer TCP-1 Peptide Cytokeratin 5 Pharmacokinetics/pharmacodynamics(PK/PD)

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A novel small-molecule PCSK9 inhibitor E28362 ameliorates hyperlipidemia and atherosclerosis

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中国药理学报（英文版） 2024年第10期45卷 2119-2133页

作者： Wei-zhi Wang Chao Liu Jin-que Luo Li-juan Lei Ming-hua Chen Yu-yan Zhang Ren Sheng Yi-ning Li Li Wang Xin-hai Jiang Tong-mei Xiao Yu-hao Zhang Shun-wang Li Ye-xiang Wu Yang Xu Yan-ni Xu Shu-yi Si State Key Laboratory of Bioactive Substances and Functions of Natural Medicines NHC Key Laboratory of Biotechnology for Microbial DrugsNational Center for New Microbial Drug ScreeningInstitute of Medicinal BiotechnologyChinese Academy of Medical Sciences and Peking Union Medical College(CAMS & PUMC)Beijing 100050China State Key Laboratory of Bioactive Substances and Functions of Natural Medicines NHC Key Laboratory of Biotechnology for Microbial DrugsNational Center for New Microbial Drug ScreeningInstitute of Medicinal BiotechnologyChinese Academy of Medical Sciences and Peking Union Medical College(CAMS & PUMC)Beijing 100050China Hunan Provincial Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations Changsha Medical UniversityChangsha 410219China State Key Laboratory of Bioactive Substances and Functions of Natural Medicines NHC Key Laboratory of Biotechnology for Microbial DrugsNational Center for New Microbial Drug ScreeningInstitute of Medicinal BiotechnologyChinese Academy of Medical Sciences and Peking Union Medical College(CAMS & PUMC)Beijing 100050China Xinjiang Key Laboratory of Uighur Medicine Xinjiang Institute of Materia MedicaUrumqi 830002China

Proprotein convertase subtilisin/kexin type 9(PCSK9)binds to the epidermal growth factor precursor homologous domain A(EGF-A)of low-density lipoprotein receptor(LDLR)in the liver and triggers the degradation of LDLR via the lysosomal pathway,consequently leading to an elevation in plasma LDL-C *** PCSK9 prolongs the lifespan of LDLR and maintains cholesterol homeostasis in the ***,PCSK9 is an innovative pharmacological target for treating hypercholesterolemia and *** this study,we discovered that E28362 was a novel small-molecule PCSK9 inhibitor by conducting a virtual screening of a library containing 40,000 compounds.E28362(5,10,20 μM)dose-dependently increased the protein levels of LDLR in both total protein and the membrane fraction in both HepG2 and AML12 cells,and enhanced the uptake of Dil-LDL in AML12 *** assay showed that E28362 up to 80 μM had no obvious toxicity in HepG2,AML12,and HEK293a *** effects of E28362 on hyperlipidemia and atherosclerosis were evaluated in three different animal *** high-fat diet-fed golden hamsters,administration of E28362(6.7,20,60 mg·kg-1·d-1,i.g.)for 4 weeks significantly reduced plasma total cholesterol(TC),triglyceride(TG),low-density lipoprotein-cholesterol(LDL-C)and PCSK9 levels,and reduced liver TC and TG *** Western diet-fed ApoE-/-mice(20,60 mg·kg-1·d-1,i.g.)and human PCSK9 D374Y overexpression mice(60 mg·kg-1·d-1,i.g.),administration of E28362 for 12 weeks significantly decreased plasma LDL-C levels and the area of atherosclerotic lesions in en face aortas and aortic ***,E28362 significantly increased the protein expression level of LDLR in the *** revealed that E28362 selectively bound to PCSK9 in HepG2 and AML12 cells,blocked the interaction between LDLR and PCSK9,and induced the degradation of PCSK9 through the ubiquitin-proteasome pathway,which finally resulted in increased LDLR protein *** conclusion,E28362 can block the interactio

关键词： atherosclerosis hyperlipidemia PCSK9 inhibitor E28362 LDLR

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PHPB ameliorates memory deficits and reduces oxidative injury in Alzheimer's disease mouse model by activating Nrf2 signaling pathway

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中国药理学报（英文版） 2024年第6期45卷 1142-1159页

作者： Nian-ying Shang Long-jian Huang Jia-qi Lan Yu-ying Kang Jing-shu Tang Hong-yue Wang Xin-nan Li Zhuo Sun Qiu-yu Chen Meng-yao Liu Zi-peng Wen Xin-hong Feng Lei Wu Ying Peng State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia MedicaChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijing 100050China Department of Neurology Beijing Tsinghua Changgung HospitalSchool of Clinical MedicineTsinghua UniversityBeijing 102218China

Alzheimer's disease(AD),a progressive neurodegenerative disorder,is the most common cause of dementia in elderly people and substantially affects patient quality of *** stress is considered a key factor in the development of ***2 plays a vital role in maintaining redox homeostasis and regulating neuroinflammatory responses in *** studies show that potassium 2-(1-hydroxypentyl)-benzoate(PHPB)exerts neuroprotective effects against cognitive impairment in a variety of dementia animal models such as APP/PS1 transgenic *** this study we investigated whether PHPB ameriorated the progression of AD by reducing oxidative stress(OS)*** 5-and 13-month-old APP/PS1 mice were administered PHPB(100mg·kg-1-d-1,i.g.)for 10 *** the cognition assessment,the mice were euthanized,and the left hemisphere of the brain was harvested for *** showed that 5-month-old APP/PS1 mice already exhibited impaired performance in the step-down test,and knockdown of Nrf2 gene only slightly increased the impairment,while knockdown of Nrf2 gene in 13-month-old APP/PS1 mice resulted in greatly worse *** administration significantly ameliorated the cognition impairments and enhanced antioxidative capacity in APP/PS1 *** addition,PHPB administration significantly increased the p-AKT/AKT and p-GSK3β/GSK3βratios and the expression levels of Nrf2,HO-1 and NQO-1 in APP/PS1 mice,but these changes were abolished by knockdown of Nrf2 *** SK-N-SH APPwt cells and primary mouse neurons,PHPB(10 μM)significantly increased the p-AKT/AKT and p-GSK3β/GSK3βratios and the level of Nrf2,which were blocked by knockdown of Nrf2 *** summary,this study demonstrates that PHPB exerts a protective effect via the Akt/GSK3β/Nrf2 pathway and it might be a promising neuroprotective agent for the treatment of AD.

关键词： Alzheimer disease potassium 2-(1-hydroxypentyl)-benzoate(PHPB) cognition oxidative stress NF-E2-related factor 2

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Author correction to‘Protective effects of VMY-2-95 on corticosterone-induced injuries in mice and cellular models’[Acta Pharmaceutica Sinica B 11(2021)1903-1913]

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Acta Pharmaceutica Sinica B 2023年第8期13卷 899-901页

作者： Ziru Yu Dewen Kong Yu Liang Xiaoyue Zhao Guanhua Du State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Beijing Key Laboratory of Drug Target and Screening ResearchInstitute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China

The authors regret that there was a picture error in Fig.5F owing to the inappropriate data statistics—forgetting gating when data collecting and a picture error in Fig.6F owing to the data copy mistake when drawing ... 详细信息

关键词： correction injuries getting

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Druggability of lipid metabolism modulation against renal fibrosis

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中国药理学报（英文版） 2022年第3期43卷 505-519页

作者： Yuan-yuan Chen Xiao-guang Chen Sen Zhang State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia MedicaChinese Academy of Medical Sciences&Peking Union medical collegeBeijing 100050China

Renal fibrosis contributes to progressive damage to renal structure and *** is a common pathological process as chronic kidney disease develops into kidney failure,irrespective of diverse etiologies,and eventually leads to ***,there are no effective drugs for renal fibrosis treatment at *** aggregation in the kidney and consequent lipotoxicity always accompany chronic kidney disease and *** studies have revealed that restoring the defective fatty acid oxidation in the kidney cells can mitigate renal ***,it is an important strategy to reverse the dysfunctional lipid metabolism in the kidney,by targeting critical regulators of lipid *** this review,we highlight the potential "druggability" of lipid metabolism to ameliorate renal fibrosis and provide current pre-clinical evidence,exemplified by some representative druggable targets and several other metabolic regulators with anti-renal fibrosis ***,we introduce the preliminary progress of noncoding RNAs as promising anti-renal fibrosis drug targets from the perspective of lipid ***,we discuss the prospects and deficiencies of drug targeting lipid reprogramming in the kidney.

关键词： lipid metabolism anti-renal fibrosis drug targets fatty acid oxidation noncoding RNA

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Regulatory T cells in ischemic stroke

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中国药理学报（英文版） 2022年第1期43卷 1-9页

作者： Hong-yun Wang Jun-rui Ye Li-yuan Cui Shi-feng Chu Nai-hong Chen State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia Medica and Neuroscience CenterChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China

Recent evidence shows that when ischemic stroke(IS)occurs,the BBB would be destructed,thereby promoting the immune cells to migrate into the brain,suggesting that the immune responses can play a vital role in the pathology of *** an essential subpopulation of immunosuppressive T cells,regulatory T(Treg)cells are involved in maintaining immune homeostasis and suppressing immune responses in the pathophysiological conditions of *** the past decades,the regulatory role of Treg cells has attracted the interest of numerous ***,whether they are beneficial or detrimental to the outcomes of IS remains ***,Treg cells exert distinctive effects in the different stages of ***,it is urgent to elucidate how Treg cells modulate the immune responses induced by *** this review,we describe how Treg cells fluctuate and play a role in the regulation of immune responses after IS in both experimental animals and humans,and summarize their biological functions and mechanisms in both CNS and *** also discuss how Treg cells participate in poststroke inflammation and immunodepression and the potential of Treg cells as a novel therapeutic approach.

关键词： regulatory T cells ischemic stroke inflammation crosstalk stroke-induced immunodepression ischemic stroke therapy

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