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高分子囊泡领域面临的挑战和未来研究方向

Science China Materials 2024年第1期67卷 18-30页

作者：石隽秋孙青梅王文立李畅尹海洋李浩澜滕润鑫范震朱云卿杜建忠 Department of Gynaecology and Obstetrics Shanghai Key Laboratory of Anesthesiology and Brain Functional ModulationClinical Research Center for Anesthesiology and Perioperative MedicineTranslational Research Institute of Brain and Brain-Like IntelligenceShanghai Fourth People’s HospitalSchool of MedicineTongji UniversityShanghai 200434China Department of Polymeric Materials School of Materials Science and EngineeringTongji UniversityShanghai 201804China

作为细胞中的主要运输系统,天然囊泡在物质的定点输运过程中具有至关重要的作用.高分子囊泡是与之结构相似的一种人工囊泡,具有优异的膜稳定性和胶体稳定性、高药物负载率、低膜穿透性、优异的可修饰性和长循环时间等优势,在生物医用领... 详细信息

作为细胞中的主要运输系统,天然囊泡在物质的定点输运过程中具有至关重要的作用.高分子囊泡是与之结构相似的一种人工囊泡,具有优异的膜稳定性和胶体稳定性、高药物负载率、低膜穿透性、优异的可修饰性和长循环时间等优势,在生物医用领域具有广泛的应用前景.然而,目前该领域尚面临一系列重要挑战,如合成和制备方法较为复杂、生物相容性较难预测、功能和递送途径有限等,限制了其临床转化之路.本文从囊泡的构建模块合成、自组装技术和潜在的生物医学应用等角度,提出了设计和制备下一代高分子囊泡需要解决的五个关键科学问题,指出了未来面临的重要挑战和发展方向,例如简化设计和合成过程,优化和规范自组装过程,拓展潜在的应用前景.

关键词：生物医学应用胶体稳定性自组装技术运输系统膜稳定性输运过程穿透性高分子

Targeted regulation of neuroinflammation via nanobiosignaler for repairing the central nerve system injuries

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Nano Research 2023年第2期16卷 2938-2948页

作者： Xiaoru Sun Huitong Ruan Qidong Liu Silu Cao Qi Jing Yaru Xu Lize Xiong Wenguo Cui Cheng Li Department of anesthesiology and Perioperative Medicine Shanghai Fourth People’s HospitalSchool of MedicineTongji UniversityShanghai 200434China Department of Orthopaedics Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint DiseasesShanghai Institute of Traumatology and OrthopaedicsRuijin HospitalShanghai Jiao Tong University School of MedicineShanghai 200025China Translational Research Institute of brain and brain-Like Intelligence Shanghai Fourth People’s HospitalSchool of MedicineTongji UniversityShanghai 200434China Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation Shanghai 200434China

Neuroinflammation,commonly associated with various central nervous system(CNS)diseases such as postoperative cognitive dysfunction(POCD),is primarily mediated by the disruption of biological signals in microglia.However,the effective treatment of CNS diseases remains an ongoing challenge as biological signals show limited microglia-targeting effect.In this study,taking advantage of the highly expressed lipoprotein receptor-related protein-1(LRP1)on the microglia,a nanobiosignal delivery system modified by LRP1 high-affinity peptide ligand RAP12(RAP:receptor-associated protein)was constructed to specifically regulate neuroinflammation via targeting microglia.The uptake of the RAP12 modified-nanobiosignaler by microglia increased significantly,indicating its microglia-targeting ability.Both in vitro/vivo studies proved that the“nanobiosignaler”significantly reduced the secretion of pro-inflammatory cytokines,induced specific M2(anti-inflammatory type)microglia differentiation,and remarkably alleviated cognitive function impairment in the mice model when compared with unmodified groups.It was indicated that the“nanobiosignaler”could target microglia to deliver the biological signal and inhibit the excessive activation of microglia.Overall,the cell-targeted biological signal transmission system inspired by“nanobiosignaler”has broad application prospects in the future.

关键词： biosignal nanoparticles microglia neuroinflammation targeted delivery

Dependence of Generation of Hippocampal CAI Slow Oscillations on Electrical Synapses

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Neuroscience Bulletin 2020年第1期36卷 39-48页

作者： Yuan Xu Feng-Yan Shen Yu-Zhang Liu Lidan Wang Ying-Wei Wang Zhiru Wang Institute and key laboratory of brain functional Genomics of The Chinese Ministry of Education Shanghai Key Laboratory of Brain Functional GenomicsSchool of Life SciencesEast China Normal UniversityShanghai 200062China Department of anesthesiology Huashan HospitalFudan UniversityShanghai 200040China

Neuronal oscillations in the hippocampus are critical for many brain functions including learning and memory.The underlying mechanism of oscillation generation has been extensively investigated in terms of chemical synapses and ion channels.Recently,electrical synapses have also been indicated to play important roles,as reported in various brain areas in vivo and in brain slices.However,this issue remains to be further clarified,including in hippocampal networks.Here,using the completely isolated hippocampus,we investigated in vitro the effect of electrical synapses on slow CA1 oscillations(0.5 Hz-1.5 Hz)generated intrinsically by the hippocampus.We found that these oscillations were totally abolished by bath application of a general blocker of gap junctions(carbenoxolone)or a specific blocker of electrical synapses(mefloquine),as determined by whole-cell recordings in both CA1 pyramidal cells and fast-spiking cells.Our findings indicate that electrical synapses are required for the hippocampal generation of slow CA1 oscillations.

关键词： Electrical synapse Hippocampus Oscillation CA1 Mefloquine Carbenoxolone Introduction

高分子囊泡领域面临的挑战和未来研究方向（英文）

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Science China Materials 2024年第1期 18-30页

作者：石隽秋孙青梅王文立李畅尹海洋李浩澜滕润鑫范震朱云卿杜建忠 Department of Gynaecology and Obstetrics Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation Clinical Research Center for Anesthesiology and Perioperative Medicine Translational Research Institute of Brain and Brain-Like Intelligence Shanghai Fourth People's Hospital School of Medicine Tongji University Department of Polymeric Materials School of Materials Science and Engineering Tongji University

作为细胞中的主要运输系统,天然囊泡在物质的定点输运过程中具有至关重要的作用.高分子囊泡是与之结构相似的一种人工囊泡,具有优异的膜稳定性和胶体稳定性、高药物负载率、低膜穿透性、优异的可修饰性和长循环时间等优势,在生物医用领...

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Hexafluoropropylene oxide trimer acid,a perfluorooctanoic acid alternative,induces cardiovascular toxicity in zebrafish embryos

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Journal of Environmental Sciences 2024年第5期139卷 460-472页

作者： Sujie Sun Li Zhang Xue Li Lu Zang Ling Huang Junquan Zeng Zigang Cao Xinjun Liao Zilin Zhong Huiqiang Lu Jianjun Chen Jiangxi Engineering laboratory of Zebrafish Modeling and Drug Screening for Human Diseases Jiangxi Key Laboratory of Developmental Biology of OrgansCenter for Clinical Research Center of the Affiliated Hospital of Jinggangshan UniversityJi’an 343009China Translational Research Institute of brain and brain-like Intelligence Shanghai Key Laboratory of Anesthesiology and Brain Functional ModulationDepartment of PediatricsShanghai Fourth People’s HospitalSchool of MedicineTongji UniversityShanghai 200434China State Environmental Protection key laboratory of Environmental Health Impact Assessment of Emerging Contaminants School of Environmental Sciences and EngineeringShanghai Jiao Tong UniversityShanghai 200240China Department of Interventional and Vascular Surgery Affiliated Hospital of Jinggangshan UniversityJi’an 343009China Department of Internal Medicine and Hematology Affiliated Hospital of Jinggangshan UniversityJi’an 343009China

As an increasingly used alternative to perfluorooctanoic acid(PFOA),hexafluoropropylene oxide trimer acid(HFPO-TA)has been widely detected in global water environments.However,little is known regarding its toxic effects on cardiovascular development.Here,zebrafish embryos were treated with egg water containing 0,60,120,or 240 mg/L HFPO-TA.Results showed that HFPO-TA treatment led to a significant reduction in both larval survival percentage and heart rate.Furthermore,HFPO-TA exposure caused severe pericardial edema and elongation of the sinus venous to bulbus arteriosus distance(SV-BA)in Tg(myl7:GFP)transgenic larvae,disrupting the expression of genes involved in heart development and thus causing abnormal heart looping.Obvious sprouting angiogenesis was observed in the 120 and 240 mg/L exposed Tg(fli:GFP)transgenic larvae.HFPO-TA treatment also impacted the mRNA levels of genes involved in the vascular endothelial growth factor(VEGF)pathway and embryonic vascular development.HFPO-TA exposure significantly decreased erythrocyte number in Tg(gata1:DsRed)transgenic embryos and influenced gene expression associated with the heme metabolism pathway.HFPO-TA also induced oxidative stress and altered the transcriptional levels of genes related to cell cycle and apoptosis,inhibiting cell proliferation while promoting apoptosis.Therefore,HFPO-TA exposure may induce abnormal development of the cardiovascular and hematopoietic systems in zebrafish embryos,suggesting it may not be a suitable or safe alternative for PFOA.

关键词： Hexafluoropropylene oxide trimer acid Heart development Vascular development Hemopoiesis Zebrafish embryos

Status of biomarker development for frontotemporal dementia and amyotrophic lateral sclerosis

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Neural Regeneration Research 2024年第10期19卷 2117-2118页

作者： Yue Yang Qi Cheng Jianqun Gao Woojin Scott Kim brain and Mind Centre&School of Medical Sciences The University of SydneySydneyNSWAustralia Department of Neurology and Neurophysiology Liverpool HospitalSydneyNSWAustralia Stroke and Neurology Research Group Ingham Institute for Applied Medical ResearchSydneyNSWAustralia Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation ShanghaiChina Clinical Research Center for anesthesiology and Perioperative Medicine ShanghaiChina Translational Research Institute of brain and brain-Like Intelligence Shanghai Fourth People’s HospitalSchool of MedicineTongji UniversityShanghaiChina

Frontotemporal dementia(FTD) and amyotrophic lateral sclerosis(ALS) are neurodegenerative diseases that belong to the same disease spectrum,with overlapping of genetic and pathological features.Genetic mutations in TA... 详细信息

关键词： amyotrophic sclerosis diseases

3D-bioprinted cholangiocarcinoma-on-a-chip model for evaluating drug responses

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Bio-Design and Manufacturing 2023年第4期6卷 373-389页

作者： Qiong Liu Luis SMille Cesar Villalobos Ingrid Anaya Matthias Vostatek Sili Yi Wanlu Li Junlong Liao Huanghui Wu Yongteng Song Lize Xiong Yu Shrike Zhang Division of Engineering in Medicine Department of MedicineBrigham and Women’s HospitalHarvard Medical SchoolCambridgeMA 02139USA Translational Research Institute of brain and brain-Like Intelligence Shanghai Fourth People’s HospitalSchool of MedicineTongji UniversityShanghai 200434China Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation Shanghai 200434China Department of Bioengineering Stanford UniversityPalo AltoCA 94305USA Biotechnological Engineering Program Monterrey Institute of Technology and Higher Education64849 MonterreyNuevo LeónMexico Molecular Biotechnology University of Applied Sciences Campus Vienna1100 ViennaAustria Rapid Manufacturing Engineering Center School of Mechatronical Engineering and AutomationShanghai UniversityShanghai 200444China

Cholangiocarcinoma(CCA)is characterized by heterogeneous mutations and a refractory nature.Thus,the development of a model for effective drug screening is urgently needed.As the established therapeutic testing models for CCA are often ineffective,we fabricated an enabling three-dimensional(3D)-bioprinted CCA-on-a-chip model that to a good extent resembled the multicellular microenvironment and the anatomical microstructure of the hepato-vascular-biliary system to perform high-content antitumor drug screening.Specifically,cholangiocytes,hepatocytes,and vascular endotheliocytes were employed for 3D bioprinting of the models,allowing for a high degree of spatial and tube-like microstructural control.Interestingly,it was possible to observe CCA cells attached to the surfaces of the gelatin methacryloyl(GelMA)hydrogelembedded microchannels and overgrown in a thickening manner,generating bile duct stenosis,which was expected to be analogous to the in vivo configuration.Over 4000 differentially expressed genes were detected in the CCA cells in our 3D coculture model compared to the traditional two-dimensional(2D)monoculture.Further screening revealed that the CCA cells grown in the 3D traditional model were more sensitive to the antitumoral prodrug than those in the 2D monoculture due to drug biotransformation by the neighboring functional hepatocytes.This study provides proof-of-concept validation of our bioprinted CCA-on-a-chip as a promising drug screening model for CCA treatment and paves the way for potential personalized medicine strategies for CCA patients in the future.

关键词： Tumor-on-a-chip Biliary tumor 3D bioprinting Tumor microenvironment Drug screening

One-step generation of zebrafish carrying a conditional knockoutknockin visible switch via CRISPR/Cas9-mediated intron targeting

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Science China(Life Sciences) 2020年第1期63卷 59-67页

作者： Jia Li Hong-Yu Li Shan-Ye Gu Hua-Xing Zi Lai Jiang Jiu-Lin Du Institute of Neuroscience State Key Laboratory of NeuroscienceCAS Center for Excellence in Brain Science and Intelligence TechnologyShanghai Research Center for Brain Science and Brain-Inspired IntelligenceChinese Academy of SciencesShanghai 200031China University of Chinese Academy of Sciences Beijing 100049China Department of anesthesiology and Surgical Intensive Care Unit Xinhua HospitalShanghai Jiao Tong University School of MedicineShanghai 200092China School of Life Science and Technology Shanghai Tech UniversityShanghai 200031China

The zebrafish has become a popular vertebrate animal model in biomedical research.However,it is still challenging to make conditional gene knockout(CKO)models in zebrafish due to the low efficiency of homologous recombination(HR).Here we report an efficient non-HR-based method for generating zebrafish carrying a CKO and knockin(KI)switch(zCKOIS)coupled with dual-color fluorescent reporters.Using this strategy,we generated hey2^zCKOIS which served as a hey2 KI reporter with EGFP expression.Upon Cre induction in targeted cells,the hey2^zCKOIS was switched to a non-functional CKO allele hey2^zCKOIS-inv associated with Tag RFP expression,enabling visualization of the CKO alleles.Thus,simplification of the design,and the visibility and combination of both CKO and KI alleles make our z CKOIS strategy an applicable CKO approach for zebrafish.

关键词： NHEJ non-HR knockin conditional knockout visible switch zCKOIS zebrafish

KCNQ Channels in the Mesolimbic Reward Circuit Regulate Nociception in Chronic Pain in Mice

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Neuroscience Bulletin 2021年第5期37卷 597-610页

作者： Hao-Ran Wang Su-Wan Hu Song Zhang Yu Song Xiao-Yi Wang Lei Wang Yang-Yang Li Yu-Mei Yu He Liu Di Liu Hai-Lei Ding Jun-Li Cao Jiangsu Province key laboratory of anesthesiology Xuzhou Medical UniversityXuzhou 221004China Jiangsu Province key laboratory of Anesthesia and Analgesia Application Technology Xuzhou Medical UniversityXuzhou 221004China Department of anesthesiology The First Affiliated Hospital of Nanjing Medical University(Jiangsu Province Hospital)Nanjing 210029China Department of anesthesiology Renji HospitalShanghai Jiaotong University School of MedicineShanghai 200000China Department of anesthesiology The Affiliated Hospital of Xuzhou Medical UniversityXuzhou 221002China

Mesocorticolimbic dopaminergic(DA) neurons have been implicated in regulating nociception in chronic pain, yet the mechanisms are barely understood. Here, we found that chronic constructive injury(CCI) in mice increased the firing activity and decreased the KCNQ channel-mediated M-currents in ventral tegmental area(VTA) DA neurons projecting to the nucleus accumbens(NAc). Chemogenetic inhibition of the VTA-to-NAc DA neurons alleviated CCI-induced thermal nociception.Opposite changes in the firing activity and M-currents were recorded in VTA DA neurons projecting to the medial prefrontal cortex(mPFC) but did not affect nociception. In addition, intra-VTA injection of retigabine, a KCNQ opener, while reversing the changes of the VTA-to-NAc DA neurons, alleviated CCI-induced nociception, and this was abolished by injecting exogenous BDNF into the NAc.Taken together, these findings highlight a vital role of KCNQ channel-mediated modulation of mesolimbic DA activity in regulating thermal nociception in the chronic pain state.

关键词： Nociception Mesocorticolimbic system Ventral tegmental area brain-derived neurotrophic factor KCNQ Retigabine Chronic neuropathic pain