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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 translation.High 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’viability.Based 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 therapy.This system is achieved by bioorthogonally arming metabolic glycoengineered MSCs with microglial membrane-coated nanoparticles and an antioxidative extracellular protective layer.In 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 transplantation.Meanwhile,the infarct’s inanimate milieu is transformed at the tissue level into a new living niche to facilitate healing.The 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 days.This 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

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Reconstituted high-density lipoproteins: novel biomimetic nanocarriers for drug delivery

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Acta Pharmaceutica Sinica B 2018年第1期8卷 51-63页

作者： Xinyi Ma qingxiang song Xiaoling Gao Department of Pharmacology and Chemical Biology Faculty of Basic Medicine Shanghai Jiao Tong University School of Medicine

High-density lipoproteins(HDL) are naturally-occurring nanoparticles that are biocompatible,non-immunogenic and completely biodegradable. These endogenous particles can circulate for an extended period of time and transport lipids, proteins and micro RNA from donor cells to recipient cells.Based on their intrinsic targeting properties, HDL are regarded as promising drug delivery systems. In order to produce on a large scale and to avoid blood borne pollution, reconstituted high-density lipoproteins(rHDL) possessing the biological properties of HDL have been developed. This review summarizes the biological properties and biomedical applications of rHDL as drug delivery platforms. It focuses on the emerging approaches that have been developed for the generation of biomimetic nanoparticles rHDL to overcome the biological barriers to drug delivery, aiming to provide an alternative,promising avenue for efficient targeting transport of nanomedicine.

关键词： Biomimetic nanocarrier Reconstituted high-density lipoprotein Biological barriers Efficient targeting Nanodrug delivery systems

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Nanopolyphenol rejuvenates microglial surveillance of multiple misfolded proteins through metabolic reprogramming

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Acta Pharmaceutica Sinica B 2023年第2期13卷 834-851页

作者： Dayuan Wang Xiao Gu Xinyi Ma Jun Chen Qizhi Zhang Zhihua Yu Juan Li Meng Hu Xiaofang Tan Yuyun Tang Jianrong Xu Minjun Xu qingxiang song Huahua song Gan Jiang Zaiming Tang Xiaoling Gao Hongzhuan Chen 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 Key Laboratory of Smart Drug Delivery Ministry of EducationSchool of PharmacyFudan UniversityShanghai 201203China Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education Shanghai Jiao Tong University School of MedicineShanghai 200025China Shanghai Frontiers Science Center of TCM Chemical Biology Institute of Interdisciplinary Integrative Medicine ResearchShanghai University of Traditional Chinese MedicineShanghai201203China

Microglial surveillance plays an essential role in clearing misfolded proteins such as amyloid-beta,tau,andα-synuclein aggregates in neurodegenerative diseases.However,due to the complex structure and ambiguous pathogenic species of the misfolded proteins,a universal approach to remove the misfolded proteins remains unavailable.Here,we found that a polyphenol,α-mangostin,reprogrammed metabolism in the disease-associated microglia through shifting glycolysis to oxidative phosphorylation,which holistically rejuvenated microglial surveillance capacity to enhance microglial phagocytosis and autophagy-mediated degradation of multiple misfolded proteins.Nanoformulation ofα-mangostin efficiently deliveredα-mangostin to microglia,relieved the reactive status and rejuvenated the misfolded-proteins clearance capacity of microglia,which thus impressively relieved the neuropathological changes in both Alzheimer’s disease and Parkinson’s disease model mice.These findings provide direct evidences for the concept of rejuvenating microglial surveillance of multiple misfolded proteins through metabolic reprogramming,and demonstrate nanoformulatedα-mangostin as a potential and universal therapy against neurodegenerative diseases.

关键词： Microglia Metabolism Misfolded proteins Phagocytosis Degradation Polyphenol Nanoparticles Neurodegenerative diseases

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The shape effect of reconstituted high-density lipoprotein nanocarriers on brain delivery and Aβ clearance

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Nano Research 2018年第10期11卷 5615-5628页

作者： Huahua song Xinyi Ma Jianrong Xu qingxiang song Meng Hu Xiao Gu Qian Zhang Lina Hou Lepei Chen Yukun Huang Ping Yu Dayuan Wang Gan Jiang Meng Huang Jun Chen Hongzhuan Chen Xiaoling Gao Department of Pharmacology and Chemical Biology Faculty of Basic Medicine School of Medicine Shanghai.liao Tong University Shanghai 200025 China Key Laboratory of Smart Drug Delivery Ministry of Education School of Pharmacy Fudan University Lane 826 Zhangheng Road Shanghai 201203 China Department of Pharmacy Ren Ji Hospital School of Medicine Shanghai Jiao Tong University Shanghai 200127 China

Accumulation of extracellular β-amyloid （Aβ） is crucial for the pathogenesis of Alzheimer＇s disease （AD）, and the development of novel therapeutic agents that can both accelerate Aβ clearance and inhibit the subsequent pathological cascades is regarded as a promising strategy for AD management. In our previous study, we have constructed discoidal apolipoprotein E3-reconstituted high-density lipoprotein （ApoE3-rHDL） as an efficient nanoplatform that can penetrate the blood-brain barrier and accelerate Aβ clearance for a combination treatment of AD. To further improve its drug loading capacity, we hypothesized that spherical rHDL might serve as a more powerful nanocarrier if it has the same brain delivery and Aβ clearance abilities as the discoidal rHDL does. To evaluate the potential of spherical rHDL as a promising alternative for the combination therapy for AD, here, we investigated the effect of the shape of rHDL on its brain delivery, Aβ clearance, and anti-AD efficacy. We found that spherical rHDL had stronger Aβ-binding affinity than discoidal rHDL did, more effectively facilitated microglial uptake and degradation of Aβ-42, achieved better brain distribution after intravenous administration, and more powerfully reduced Aβ deposition, decreased microglia activation, attenuated neurological damage, and rescued memory deficits in a mouse model of AD. Among the rHDLs evaluated, monosialotetrahexosyl ganglioside-incorporated spherical rHDL exerted the best effect. The findings of this study for the first time show a shape effect of an rHDL nanocarrier on its biological functions and suggest that a spherical lipoprotein-mimic nanocarrier may serve as a more efficient multifunctional nanoplatforrn for AD therapy.

关键词： reconstituted high density lipoprotein β-amyloid apolipoprotein E spherical discoidal Alzheimer＇s disease

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Clinical safety and efficacy of allogenic human adipose mesenchymal stromal cells-derived exosomes in patients with mild to moderate Alzheimer’s disease:a phaseⅠ/Ⅱclinical trial

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General Psychiatry 2023年第5期36卷 350-360页

作者： Xinyi Xie qingxiang song Chengxiang Dai Shishuang Cui Ran Tang Suke Li Jing Chang Ping Li Jintao Wang Jianping Li Chao Gao Hongzhuan Chen Shengdi Chen Rujing Ren Xiaoling Gao Gang Wang Department of Neurology and Institute of Neurology Shanghai Jiao Tong University Medical School Affiliated Ruijin HospitalShanghaiChina 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 MedicineShanghaiChina Department of Regenerative Medicine Business Cellular Biomedicine GroupShanghaiChina Daxing Research Institute University of Science and TechnologyBeijingChina Shanghai Frontiers Science Center of TCM Chemical Biology Institute of Interdisciplinary Integrative Medicine ResearchShanghai University of Traditional Chinese MedicineShanghaiChina

Background There have been no effective treatments for slowing or reversing Alzheimer’s disease(AD)until now.Growing preclinical evidence,including this study,suggests that mesenchymal stem cells-secreted exosomes(MSCs-Exos)have the potential to cure AD.Aims The first three-arm,drug-intervention,phase I/II clinical trial was conducted to explore the safety and efficacy of allogenic human adipose MSCs-Exos(ahaMSCs-Exos)in patients with mild to moderate AD.Methods The eligible subjects were assigned to one of three dosage groups,intranasally administrated with ahaMSCs-Exos two times per week for 12 weeks,and underwent follow-up visits at weeks 16,24,36 and 48.Results No adverse events were reported.In the medium-dose arm,Alzheimer’s Disease Assessment Scale–Cognitive section(ADAS-cog)scores decreased by 2.33(1.19)and the basic version of Montreal Cognitive Assessment scores increased by 2.38(0.58)at week 12 compared with baseline levels,indicating improved cognitive function.Moreover,the ADAS-cog scores in the medium-dose arm decreased continuously by 3.98 points until week 36.There were no significant differences in altered amyloid or tau deposition among the three arms,but hippocampal volume shrank less in the medium-dose arm to some extent.Conclusions Intranasal administration of ahaMSCs-Exos was safe and well tolerated,and a dose of at least 4×10^(8)particles could be selected for further clinical trials.

关键词： clinical Alzheimer dosage

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RB-DEM Modeling and Simulation of Non-Persisting Rough Open Joints Based on the IFS-Enhanced Method

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Computer Modeling in Engineering & Sciences 2024年第4期139卷 337-359页

作者： Hangtian song Xudong Chen Chun Zhu Qian Yin Wei Wang qingxiang Meng Key Laboratory of Ministry of Education for Geomechanics and Embankment Engineering Hohai UniversityNanjing210098China Research Institute of Geotechnical Engineering Hohai UniversityNanjing210098China School of Earth Sciences and Engineering Hohai UniversityNanjing210098China State Key Laboratory for Geomechanics and Deep Underground Engineering China University of Mining and TechnologyXuzhou221116China

When the geological environment of rock masses is disturbed,numerous non-persisting open joints can appear within it.It is crucial to investigate the effect of open joints on the mechanical properties of rock mass.However,it has been challenging to generate realistic open joints in traditional experimental tests and numerical simulations.This paper presents a novel solution to solve the problem.By utilizing the stochastic distribution of joints and an enhanced-fractal interpolation system(IFS)method,rough curves with any orientation can be generated.The Douglas-Peucker algorithm is then applied to simplify these curves by removing unnecessary points while preserving their fundamental shape.Subsequently,open joints are created by connecting points that move to both sides of rough curves based on the aperture distribution.Mesh modeling is performed to construct the final mesh model.Finally,the RB-DEM method is applied to transform the mesh model into a discrete element model containing geometric information about these open joints.Furthermore,this study explores the impacts of rough open joint orientation,aperture,and number on rock fracture mechanics.This method provides a realistic and effective approach for modeling and simulating these non-persisting open joints.

关键词： Non-persisting rough open joints stochastic distribution of joints enhanced-IFS method RB-DEM

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基于聚丙烯石灰改性技术的土遗址修复材料试验研究

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施工技术（中英文） 2024年第10期53卷 156-166页

作者：王贵军刘义孔德泉顿帅康悦腾达吴小龙宋庆祥陕建安城(甘肃)建设投资有限公司甘肃兰州730070 陕西省建筑科学研究院有限公司陕西西安710082 长安大学建筑工程学院陕西西安710061

土遗址主要建筑材料为土,长期暴露在自然环境下,损坏情况普遍且严重,亟待修复。在粉土中单独及混合掺入石灰和聚丙烯纤维制备改性土试样,开展直剪、压缩、风沙侵蚀、冻融和水稳性试验,以检验聚丙烯与石灰作为粉土遗址修复材料的可行性... 详细信息

土遗址主要建筑材料为土,长期暴露在自然环境下,损坏情况普遍且严重,亟待修复。在粉土中单独及混合掺入石灰和聚丙烯纤维制备改性土试样,开展直剪、压缩、风沙侵蚀、冻融和水稳性试验,以检验聚丙烯与石灰作为粉土遗址修复材料的可行性。试验表明,单独掺入石灰或聚丙烯纤维均能提高土的抗剪强度,当掺入9%石灰或0.25%聚丙烯纤维时,改性土内摩擦角和黏聚力可高达48.9°和107.11kPa,土的压缩性也显著降低。但单独加入聚丙烯纤维反而会导致改性土的水稳性变差,这是由于土中的聚丙烯纤维增加了水的入渗通道。通过以0.25%聚丙烯纤维和9%石灰制成混掺改性土试样,其黏聚力和内摩擦角不仅比单掺改性土最高提升了66.7%和28.9%,且试样水稳定性也显著增强,抵抗风沙侵蚀和冻融的能力也有较大改善,总体性能较优。因此混合使用石灰和聚丙烯纤维能更有效地改善粉土的工程性能。

关键词：土遗址聚丙烯纤维石灰粉土改性土试验

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温度对水工沥青混凝土弯曲性能影响的试验

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水力发电学报 2022年第8期41卷 104-112页

作者：韩群柱宋戈张应波宋洪林宋庆象西北旱区生态水利工程国家重点实验室西安710048 西安理工大学土木建筑工程学院西安710048

本文针对-30℃~25℃温度条件下的水工沥青混凝土开展了小梁弯曲试验,重点分析温度对水工沥青混凝土面板的各项力学性能指标的影响。试验结果表明:(1)温度对水工沥青混凝土的应力-应变特性有着密切关系。在-30℃~0℃温度区间,应力-应变... 详细信息

本文针对-30℃~25℃温度条件下的水工沥青混凝土开展了小梁弯曲试验,重点分析温度对水工沥青混凝土面板的各项力学性能指标的影响。试验结果表明:(1)温度对水工沥青混凝土的应力-应变特性有着密切关系。在-30℃~0℃温度区间,应力-应变曲线近似成线性关系,试件的应力达到峰值后发生断崖式下跌,呈脆性破坏;在0℃~25℃温度区间,试件应力达到峰值后经历一定程度的塑性变形后断裂,呈延性破坏。(2)水工沥青混凝土随着温度升高,其抗弯强度、弯曲模量逐渐降低,变形能力提高;随着温度的降低,峰值应变减小。(3)研究提出的经验公式较好反映了水工沥青混凝土在不同温度条件下弯曲性能的变化特性,与试验结果吻合较好。

关键词：水工沥青混凝土小梁弯曲试验力学性能弯曲性能

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船用发电机起励失败故障分析

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航海技术 2022年第4期 31-33页

作者：宋庆祥广州海运技工学校

发电机是船舶的心脏,船上一旦发生停电事故,整个船舶都会异常紧张。船舶供电系统的长期稳定运行,是保障船舶安全的前提。本文介绍的发电机故障案例比较特殊、极为罕见,整理并与大家共同探讨。1故障现象某船是船舶所有人从国外购买的8万... 详细信息

发电机是船舶的心脏,船上一旦发生停电事故,整个船舶都会异常紧张。船舶供电系统的长期稳定运行,是保障船舶安全的前提。本文介绍的发电机故障案例比较特殊、极为罕见,整理并与大家共同探讨。1故障现象某船是船舶所有人从国外购买的8万吨级二手散货船,22年船龄。有3台同型号有刷自励同步主发电机,其励磁电源由发电机本身的定子交流电经过整流元件整流后,通过电刷、滑环供给励磁绕组。

关键词：船舶所有人发电机故障船舶安全船用发电机整流元件励磁绕组励磁电源国外购买

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Shape effect of Reconstituted High-Density Lipoprotein Nanocarriers on Brain delivery and Aβ Clearance

Shape effect of Reconstituted High-Density Lipoprotein Nanoc...

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首届东方药理论坛暨2018年全国心脑血管药理学术会议、上海市药理学会第十九届学术年会

作者： Huahua song Xinyi Ma Jianrong Xu qingxiang song Meng Hu Xiao Gu Qian Zhang Lina Hou Lepei Chen Yukun Huang Ping Yu Dayuan Wang Gan Jiang Meng Huang Jun Chen Hongzhuan Chen Xiaoling Gao Department of Pharmacology and Chemical Biology Faculty of Basic MedicineShanghai Jiao Tong University School of Medicine Department of Pharmacy Ren Ji HospitalSchool of MedicineShanghai Jiao Tong University Key Laboratory of Smart Drug Delivery Ministry of EducationSchool of PharmacyFudan University

The accumulation of extracellular β-amyloid（Aβ） is crucial in the pathogenesis of Alzheimer’s disease（AD）,and the development of novel therapeutic agents that can both accelerate Aβ clearance and inhibit the subsequent pathological cascades has been taken as a promising strategy for AD management.Our previous work has constructed discoidal apolipoprotein E3-reconstituted high-density lipoprotein（ApoE3-rHDL） as an efficient nanoplatform that could penetrate the blood-brain barrier（BBB） and accelerate Aβ clearance for the combination therapy of AD.To further improve its drug loading capacity,we proposed that spherical rHDL might serve as a more powerful nanocarrier if it owns the same brain delivery and Aβclearance abilities as the discoidal rHDL.To evaluate the potential of spherical rHDL as a promising alternative for the combination therapy of AD,here we investigated the effect of shape of rHDL on its brain delivery,Aβ clearance and anti-AD efficacy.We found that spherical rHDL illustrated higher Aβ binding affinity than discoidal rHDL,more efficiently facilitated microglia uptake and degradation of Aβ1-42,achieved higher brain distribution following intravenous administration,and more powerfully reduced Aβ deposition,decreased microglia-activation,attenuated neurological damage,and rescued memory deficits in AD model mice,among which monosialotetrahexosyl ganglioside-incorporated spherical rHDL exhibited the best effect.The findings of this work firstly demonstrated the shape effect of rHDL nanocarrier on its biological functions and suggested that spherical lipoprotein-mimic nanocarrier might serve as a more efficient multi-functional nanoplatform for AD therapy.

关键词： reconstitutedhighdensitylipoprotein β-amyloid apolipoproteinE,spherical discoidal Alzheimer’sdisease

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