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Exploiting kinase polypharmacology for nerve regeneration

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Neural Regeneration Research 2016年第1期11卷 71-72页

作者： Hassan Al-Ali John L.Bixby Vance P.Lemmon Miami Project to Cure Paralysis University of Miami Center for Computational Science University of Miami Department of Neurological Surgery University of Miami Department of molecular & cellular pharmacology University of Miami

The human central nervous system（CNS）has a markedly poor capacity for regenerating its axons following *** appears to be due to two main causes：1）a developmentally regulated decline in regenerative capacity within mature CNS neurons,and 2）the presence of biological components that constitute barriers to axon regeneration（e.g.,growth-inhibitory molecules）.

关键词： regeneration alterations mature markedly constitute regenerative barriers phenotypic similarity inhibit

Bioorthogonal microglia-inspired mesenchymal stem cell bioengineering system creates livable niches for enhancing ischemic stroke recovery via the hormesis

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Acta Pharmaceutica Sinica B 2024年第3期14卷 1412-1427页

作者： Jianpei Xu Yinzhe Sun Yang You Yuwen Zhang Dan Huang Songlei Zhou Yipu Liu Shiqiang Tong Fenfen Ma Qingxiang Song Chengxiang Dai Suke Li Jigang Lei Zhihua Wang Xiaoling Gao Jun Chen Shanghai Pudong Hospital&Department of Pharmaceutics School of PharmacyFudan UniversityShanghai 201203China Key Laboratory of Smart Drug Delivery Ministry of EducationSchool of PharmacyFudan UniversityShanghai 201203China Department of pharmacology and Chemical Biology State Key Laboratory of Oncogenes and Related GenesShanghai Universities Collaborative Innovation Center for Translational MedicineShanghai Jiao Tong University School of MedicineShanghai 200025China Department of Emergency Shanghai Pudong HospitalFudan University Pudong Medical CenterShanghai 201399China Institute of Science and Technology for Brain-Inspired Intelligence&Department of Neurology Fudan UniversityShanghai 201203China Department of Rehabilitation Medicine Huashan HospitalFudan UniversityShanghai 201203China Daxing Research Institute University of Science and Technology BeijingBiomedical Industry BaseZhongguancun Science and Technology ParkBeijing 102600China cellular Biomedicine Group Inc. Shanghai 201210China

Mesenchymal stem cells(MSCs)experience substantial viability issues in the stroke infarct region,limiting their therapeutic efficacy and clinical *** levels of deadly reactive oxygen radicals(ROS)and proinflammatory cytokines(PC)in the infarct milieu kill transplanted MSCs,whereas low levels of beneficial ROS and PC stimulate and improve engrafted MSCs’*** on the intrinsic hormesis effects in cellular biology,we built a microglia-inspired MSC bioengineering system to transform detrimental high-level ROS and PC into vitality enhancers for strengthening MSC *** system is achieved by bioorthogonally arming metabolic glycoengineered MSCs with microglial membrane-coated nanoparticles and an antioxidative extracellular protective *** this system,extracellular ROSscavenging and PC-absorbing layers effectively buffer the deleterious effects and establish a microlivable niche at the level of a single MSC for ***,the infarct’s inanimate milieu is transformed at the tissue level into a new living niche to facilitate *** engineered MSCs achieved viability five times higher than natural MSCs at seven days after transplantation and exhibited a superior therapeutic effect for stroke recovery up to 28 *** vitality-augmented system demonstrates the potential to accelerate the clinical translation of MSC treatment and boost stroke recovery.

关键词： Ischemic stroke Mesenchymal stem cell Cell engineering Hormesis effect Bioorthogonal chemistry Microglia Reactive oxygen spices Proinflammatory cytokines

Genetic Encoding of a Photocaged Glutamate for Optical Control of Protein Functions

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CCS Chemistry 2023年第6期5卷 1301-1307页

作者： Xinyu Ling Yi Zuo Heqi Chen Dezhong Ji Jingjing Wang Liying Chang Tao Liu State Key Laboratory of Natural and Biomimetic Drugs Chemical Biology CenterDepartment of Molecular and Cellular PharmacologyPharmaceutical SciencesPeking UniversityHaidian DistrictBeijing 100191

Genetic encoding of photocaged noncanonical amino acids provides a powerful tool to study protein functions through optical control but is not yet available for acidic amino ***,we report the first site-specific genetic encoding of a photocaged glutamate,4-methoxy-7-nitroindolinyl caged glutamate(MNI-Glu),into recombinant proteins via an expanded genetic code through evolved EcLeuRS/tRNA *** two enzymes as examples,we demonstrate that substituting the conserved-active-site glutamate of a secreted alkaline phosphatase and a protease HRV3C to MNI-Glu allows photoregulatory control of their enzymatic *** approach is an important addition to the photocaged noncanonical amino-acid toolbox and provides a general method to photocontrol protein activity based on caging a critical glutamate.

关键词： noncanonical amino acid genetic code expansion MNI-Glu photocaged glutamate optical control

AAV8 transduction capacity is reduced by prior exposure to endosome-like pH conditions

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Neural Regeneration Research 2021年第5期16卷 851-855页

作者： Jeffrey ALowell Kar Men Mah John LBixby Vance PLemmon Miami Project to Cure Paralysis University of MiamiMiamiFLUSA Department of Neurological Surgery University of MiamiMiamiFLUSA Department of molecular and cellular pharmacology University of MiamiMiamiFLUSA

Adeno-associated virus(AAV)is an essential instrument in the neuroscientist’s toolkit,which allows delivery of DNA to provide labeling with fluorescent proteins or genetic instructions to regulate gene *** the field of neural regeneration,the transduction of neurons enables the observation and regulation of axon growth and regeneration,and in the future will likely be a mechanism for delivering molecular therapies to promote sprouting and regeneration after central nervous system *** formulations of AAV preparations permit efficient viral transduction under physiologic conditions,but an improved understanding of the mechanistic limitations of AAV transduction may facilitate production of more resilient AAV strains for investigative and therapeutic *** studied AAV transduction in the context of prior exposure of AAV serotype 8(AAV8)to environmental pH within the range encountered during endosomal endocytosis(pH 7.4 to pH 4.4),during which low pH-triggered structural and autoproteolytic changes to the viral capsid are believed to be necessary for endosome escape and virus *** to the fundamental nature of these processes,we hypothesized that premature exposure of AAV8 particles to acidic pH would decrease viral transduction of HT1080 cells in vitro,as measured by fluorescent reporter gene expression using high-content imaging *** found that increasingly acidic incubation conditions were associated with concomitant reductions in transduction efficiency,and that quantitative levels of reporter gene expression in transduced cells were similarly *** biggest decrease in transduction occurred between pH 7.4 and pH 6.4,suggesting the possible co-occurrence of a pH-associated event and viral inactivation within that *** together,these findings indicate that exposure of AAV8 to acidic pH for as little as 1 hour is deleterious to transduction *** studies are necessary to understand the pH-associated

关键词： adeno-associated virus autolytic capsid low pH protease proteolytic temperature trafficking transduction viral inactivation

Buyang Huanwu Decoction ameliorates ischemic stroke by modulating multiple targets with multiple components: In vitro evidences

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Chinese Journal of Natural Medicines 2018年第3期16卷 194-202页

作者： ZHANG Wei-Wei XU Feng WANG Ding YE Jia CAI Shao-Qing Department of molecular and cellular pharmacology School of Pharmaceutical Sciences Peking University Department of Clinical Pharmacy Beijing Tsinghua Changgung Hospital Medical Center Tsinghua University State Key Laboratory of Natural and Biomimetic Drugs Peking University

Buyang Huanwu Decoction （BYHWD） is a well-known traditional Chinese medicine prescription which is used to treat ischaemic stroke and stroke-induced disabilities. However, the exact mechanism underlying BYHWD＇s amelioration of ischaemic stroke and its effective constituents remain unclear. The present study aimed to identify the effective constituents of BYHWD and to further explore its action mechanisms in the amelioration of ischaemic stroke by testing the activities of 15 absorbable chemical constituents of BYHWD with the same methods under the same conditions. The following actions of these 15 compounds were revealed： 1） Ferulic acid, calycosin, formononetin, astrapterocarpan-3-O-β-D-glucoside, paeonol, calycosin-7-O-β-D-glucoside, astraisofla- van-7-O-β-D-glucoside, ligustrazine, and propyl gallate significantly suppressed concanavalin A （Con A）-induced T lymphocyte proliferation; 2） Propyl gallate, calycosin-7-O-β-D-glucoside, paeonol, and ferulic acid markedly inhibited LPS-induced apoptosis in RAW264.7 cells; 3） Propyl gallate and formononetin significantly inhibited LPS-induced NO release; 4） Hydroxysaffior yellow A and inosine protected PC12 cells against the injuries caused by glutamate; and 5） Formononetin, astragaloside IV, astraisofiavan-7-O-β-D- glucoside, inosine, paeoniflorin, ononin, paeonol, propyl gallate, ligustrazine, and ferulic acid significantly suppressed the constriction of the thoracic aorta induced by KCI in rats. In conclusion, the results from the present study suggest that BYHWD exerts its ischaemic stroke ameliorating activities by modulating multiple targets with multiple components.

关键词： Buyang Huanwu Decoction Chemical constituents Ischemic stroke Anti-inflammatory-immunity Neuroprotection Vasodilation

Step further towards targeted senolytic therapy:therapeutic potential of uPAR-CAR T cells for senescence-related diseases

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Signal Transduction and Targeted Therapy 2020年第1期5卷 1137-1138页

作者： Yujia Huang Tao Liu State Key Laboratory of Natural and Biomimetic Drugs Peking University100191 BeijingChina Department of molecular and cellular pharmacology School of Pharmaceutical SciencesPeking University100191 BeijingChina

A very recent study published in Nature by Amor et al.1 identifies the urokinase-type plasminogen activator receptor(uPAR)as a broadly induced specific cell-surface marker during cell senescence,which could be used as a target for chimeric antigen receptor(CAR)T cell to specifically ablate senescent cells in vitro and in *** authors intriguingly show that uPAR-specific CAR T-cell therapy improves the treatment outcome of lung adenocarcinomas and efficiently reduces liver fibrosis in mouse models,thus offering a promising novel therapeutic strategy for senescence-associated diseases(Fig.1).

关键词： uPAR therapeutic diseases

Chromophore-assisted laser inactivation in neural development

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Neuroscience Bulletin 2012年第4期28卷 333-341页

作者： Wei Li Nico Stuurman Guangshuo Ou National Laboratory of Biomacromolecules Institute of Biophysics Chinese Academy of Sciences Beijing 100101 China The Howard Hughes Medical Institute and the Department of cellular and molecular pharmacology University ofCalifornia San Francisco San Francisco CA 94158 USA

Chromophore-assisted laser inactivation（CALI） is a technique that uses photochemically-generated reactive oxygen species to acutely inactivate target proteins in living *** development includes highly dynamic cellular processes such as asymmetric cell division,migration,axon and dendrite outgrowth and *** many key molecules of neural development have been identified since the past decades,their spatiotemporal contributions to these cellular events are not well *** provides an appealing tool for elucidating the precise functions of these molecules during neural *** this review,we summarize the principles of CALI,a recent microscopic setup to perform CALI experiments,and the application of CALI to the study of growth-cone motility and neuroblast asymmetric division.

关键词： chromophore-assisted laser inactivation growth cone neuroblast asymmetric cell division

Deciphering the dual role and prognostic potential of PINK1 across cancer types

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Neural Regeneration Research 2021年第4期16卷 659-665页

作者： Katherine Dai Daniel P.Radin Donna Leonardi Department of molecular Cellularand Developmental BiologyYale UniversityNew HavenCTUSA Department of pharmacology Stony Brook University School of MedicineStony BrookNYUSA Bergen County Academies HackensackNJUSA

Metabolic rewiring and deregulation of the cell cycle are hallmarks shared by many *** mutations in key tumor suppressor genes,such as PTEN,and oncogenes predispose cancer cells for marked utilization of resources to fuel accelerated cell proliferation and chemotherapeutic *** research has demonstrated that PTEN-induced putative kinase 1(PINK1)acts as a pivotal regulator of mitochondrial homeostasis in several cancer types,a function that also extends to the regulation of tumor cell proliferative *** addition,involvement of PINK1 in modulating inflammatory responses has been highlighted by recent studies,further expounding PINK1’s multifunctional *** review discusses the oncogenic roles of PINK1 in multiple tumor cell types,with an emphasis on maintenance of mitochondrial homeostasis,while also evaluating literature suggesting a dual oncolytic mechanism based on PINK1’s modulation of the Warburg *** a clinical standpoint,its expression may also dictate the response to genotoxic stressors commonly used to treat multiple *** detailing the evidence suggesting that PINK1 possesses distinct prognostic value in the clinical setting and reviewing the duality of PINK1 function in a context-dependent manner,we present avenues for future studies of this dynamic protein.

关键词： apoptosis cancer cell cycle inflammation metabolic stress mitochondral quality control mitophagy PINK1 tumor Warburg effect

iBioChina and iBiology: spreading scientific knowledge together

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Science China(Life Sciences) 2015年第11期58卷 1180-1182页

作者： DELL Karen R VALE Ronald D i Biology University of California Howard Hughes Medical Institute Department of Cellular and Molecular PharmacologyUniversity of California

It is becoming increasingly important for the public to un- derstand how new scientific information and technology impact their lives and how scientists obtain new knowledge. Without this understanding, how do people know if global warming is real or if it is safe to eat genetically modified crops？ Dr. Chen ZhangLiang, the Vice President of China Association of Science and Technology （CAST）, conveyed this message in his talk at the Chinese Society for Cell Bi- ology （CSCB） Biennial Conference held in Shenzhen in April, 2015.

关键词：科学知识科学技术协会传播科学信息转基因作物全球变暖联合国科学家