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Nanopolyphenol rejuvenates microglial surveillance of multiple misfolded proteins through metabolic reprogramming

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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Neddylation inhibitor MLN4924 suppresses cilia formation by modulating AKT1

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Protein & Cell 2019年第10期10卷 726-744页

作者： Hongmei Mao zaiming tang Hua Li Bo Sun Mingjia Tan Shaohua Fan Yuan Zhu Yi Sun The Cancer Institute of the Second Affiliated Hospital and Institute of Translational MedicineZhejiang University School of MedicineHangzhou 310029China Division of Radiation and Cancer Biology Department of Radiati on OncologyUniversity of MichiganAnn ArborMl 48109USA Gilbert Family Neurofibromatosis In stitute Center for Cancer and Immuno logy ResearchChildren's Research In stituteChildren's National Medical CenterWashingtonDC 20010USA

The primary cilium is a microtubule-based sensory organelle.The molecular mechanism that regulates ciliary dynamics remains elusive.Here,we report an unexpected finding that MLN4924,a small molecule inhibitor of NEDD8-activating enzyme(NAE),blocks primary ciliary formation by inhibiting synthesis/assembly and promoting disassembly.This is mainly mediated by MLN4924-induced phosphorylation of AKT1 at Ser473 under serum-starved,ciliary-promoting conditions.Indeed,pharmaceutical inhibition(by MK2206)or genetic depletion(via siRNA)of AKT1 rescues MLN4924 effect,indicating its causai role.Interestingly,pAKT 1-Ser473 activity regulates both ciliary synthesis/assembly and disassembly in a MLN4924 dependent manner,whereas pAKT-Thr308 determines the ciliary length in MLN4924-independent but VHL-dependent manner.Finally,MLN4924 inhibits mouse hair regrowth,a process requires ciliogenesis?Collectively,our study dem on strates an unexpected role of a neddylation inhibitor in regulation of ciliogenesis via AKT1,and pro?vides a proof-of-concept for potential utility of MLN4924 in the treatment of human diseases associated with abnormal ciliogenesis.

关键词： AKT Cilia MLN4924 neddylation siRNA VHL

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Flexible and Robust Functionalized Boron Nitride/Poly(p‑Phenylene Benzobisoxazole)Nanocomposite Paper with High Thermal Conductivity and Outstanding Electrical Insulation

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Nano-Micro Letters 2024年第2期16卷 423-437页

作者： Lin tang Kunpeng Ruan Xi Liu Yusheng tang Yali Zhang Junwei Gu Chongqing Key Laboratory of Green Synthesis and Applications College of ChemistryChongqing Normal UniversityChongqing 401331People’s Republic of China Shaanxi Key Laboratory of Macromolecular Science and Technology School of Chemistry and Chemical EngineeringNorthwestern Polytechnical UniversityXi’an 710072People’s Republic of China

With the rapid development of 5G information technology,thermal conductivity/dissipation problems of highly integrated electronic devices and electrical equipment are becoming prominent.In this work,“high-temperature solid-phase&diazonium salt decomposition”method is carried out to prepare benzidine-functionalized boron nitride(m-BN).Subsequently,m-BN/poly(pphenylene benzobisoxazole)nanofiber(PNF)nanocomposite paper with nacremimetic layered structures is prepared via sol–gel film transformation approach.The obtained m-BN/PNF nanocomposite paper with 50 wt%m-BN presents excellent thermal conductivity,incredible electrical insulation,outstanding mechanical properties and thermal stability,due to the construction of extensive hydrogen bonds andπ–πinteractions between m-BN and PNF,and stable nacre-mimetic layered structures.Itsλ∥andλ_(⊥)are 9.68 and 0.84 W m^(-1)K^(-1),and the volume resistivity and breakdown strength are as high as 2.3×10^(15)Ωcm and 324.2 kV mm^(-1),respectively.Besides,it also presents extremely high tensile strength of 193.6 MPa and thermal decomposition temperature of 640°C,showing a broad application prospect in high-end thermal management fields such as electronic devices and electrical equipment.

关键词： Poly(p-phenylene-2,6-benzobisoxazole)nanofiber Boron nitride Thermal conductivity Electrical insulation

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Orthogonal Combinatorial Raman Codes Enable Rapid High-Throughput-Out Library Screening of Cell-Targeting Ligands

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Research 2024年第1期2023卷 199-208页

作者： Yuchen tang Xingxing Zheng Tingjuan Gao China Key Laboratory of Pesticide and Chemical Biology of Ministry of Education College of ChemistryCentral China Normal UniversityWuhan 430079China

High-throughput assays play an important role in the fields of drug discovery,genetic analysis,and clinical diagnostics.Although super-capacity coding strategies may facilitate labeling and detecting large numbers of targets in a single assay,practically,the constructed large-capacity codes have to be decoded with complicated procedures or are lack of survivability under the required reaction conditions.This challenge results in either inaccurate or insufficient decoding outputs.Here,we identified chemical-resistant Raman compounds to build a combinatorial coding system for the high-throughput screening of cell-targeting ligands from a focused 8-mer cyclic peptide library.The accurate in situ decoding results proved the signal,synthetic,and functional orthogonality for this Raman coding strategy.The orthogonal Raman codes allowed for a rapid identification of 63 positive hits at one time,evidencing a high-throughput-out capability in the screening process.We anticipate this orthogonal Raman coding strategy being generalized to enable efficient high-throughput-out screening of more useful ligands for cell targeting and drug discovery.

关键词： enable throughput allowed

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Role of N-formyl peptide receptor 2 in germinal matrix hemorrhage:an intrinsic review of a hematoma resolving pathway

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Neural Regeneration Research 2024年第2期19卷 350-354页

作者： Jerry Flores Jiping tang Department of Physiology&Pharmacology Loma Linda University School of MedicineLoma LindaCAUSA

Germinal matrix hemorrhage is one of the leading causes of morbidity,mortality,and acquired infantile hydrocephalus in preterm infants in the United States,with little progress made in its clinical management.Blood clots have been shown to elicit secondary brain injury after germinal matrix hemorrhage,by disrupting normal cerebrospinal fluid circulation and absorption after germinal matrix hemorrhage causing post-hemorrhagic hydrocephalus development.Current evidence suggests that rapid hematoma resolution is necessary to improve neurological outcomes after hemorrhagic stroke.Various articles have demonstrated the beneficial effects of stimulating the polarization of microglia cells into the M2 phenotype,as it has been suggested that they play an essential role in the rapid phagocytosis of the blood clot after hemorrhagic models of stroke.N-formyl peptide receptor 2(FPR2),a G-protein-coupled receptor,has been shown to be neuroprotective after stroke.FPR2 activation has been associated with the upregulation of phagocytic macrophage clearance,yet its mechanism has not been fully explored.Recent literature suggests that FPR2 may play a role in the stimulation of scavenger receptor CD36.Scavenger receptor CD36 plays a vital role in microglia phagocytic blood clot clearance after germinal matrix hemorrhage.FPR2 has been shown to phosphorylate extracellular-signal-regulated kinase 1/2(ERK1/2),which then promotes the transcription of the dual-specificity protein phosphatase 1(DUSP1)gene.In this review,we present an intrinsic outline of the main components involved in FPR2 stimulation and hematoma resolution after germinal matrix hemorrhage.

关键词： AnxA1 FPR2 GMH hematoma resolution hemorrhagic stroke M1 M2 microglia polarization microglia phagocytosis

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A Rab2-centric signaling cascade regulates autophagosome biogenesis,maturation and selective autophagy

A Rab2-centric signaling cascade regulates autophagosome bio...

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华东地区生物化学与分子生物学学会联合会2017年学术交...

作者： Xianming Ding Rui Tian Lin Li Xiawei,Cheng Xiao Jiang Xinyi Wang Xiuling Ma She Chen Wei Liu zaiming tang 孙启明 Department of Biochemistry and Molecular Biology School of MedicineZhejiang University National Institute of Biological Sciences Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease First Affiliated HospitalZhejiang University School of Medicine Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education Shanghai Jiao Tong University School of Medicine

The biogenesis of autophagosomes requires steady incorporation of donor membrane into pre-autophagosomal structures,however,the underlying molecular mechanisms remain elusive.Small GTPases are essential regulators in autophagy,how they seamlessly relay signals from the early to the late stage of autophagy remains largely unexplored.Here,we report a Rab2-centric pathway regulating autophagosome biogenesis,maturation and selective autophagy by sequentially engaging distinct autophagy machineries.In unstressed cells,GM130 reserves a small population of Rab2+Atg9+vesicles on Golgi apparatus through direet interaction with Rab2.Autophagy stimuli liberate Rab2+Atg9+ vesicles from GM130-restriction to recruit ULK1,which dictates the incorporation of the Rab2+Atg9+ULK1 + vesicles into pre-autophagosomal structures.During the process of autophagosome formation,Rab2 further switches to interact with autophagosomal Pacer and Stx17 to stabilize its own residency on autophagosomes by preventing GPI-mediated membrane extraction.The complex containing Pacer,Stx17 and Rab2 then recruits HOPS complex to ensure the specific fusion of autophagosomes with late endosomes or lysosomes.Furthermore,Rab2 directly binds to p62 to contribute p62-mediated selective autophagy for protein aggregate clearance.Together,our study identifies a highly conserved multivalent signaling pathway which regulates autophagosome biogenesis,maturation and selective autophagy.

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Commentary:Mammokine directs beige adipocytes to reserve energy for milk production in breast

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Acta Pharmaceutica Sinica B 2024年第3期14卷 1472-1476页

作者： Lina tang Jianping Ye Metabolic Disease Research Center Zhengzhou University Affiliated Zhengzhou Central HospitalZhengzhou 450007China Research Center for Basic Medicine Academy of Medical SciencesZhengzhou UniversityZhengzhou 450052China

Beige/brown adipocytes play a crucial role in regulating the body’s overall energy balance.The thermogenic function is under the influence of various tissues,including the brain,muscles,and liver.However,the breast t... 详细信息

关键词： Beige Breast Epitheliail cells scRNA-seq Thermogenesis

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Single-cell RNA sequencing in juvenile idiopathic arthritis

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Genes & Diseases 2024年第2期11卷 633-644页

作者： Xiwen Luo Xuemei tang Department of Rheumatology and Immunology Children’s Hospital of Chongqing Medical UniversityChongqing 400014China Chongqing Key Laboratory of Child Infection and Immunity Ministry of Education Key Laboratory of Child Development and DisordersNational Clinical Research Center for Child Health and DisordersChina International Science and Technology Cooperation Base of Child Development and Critical DisordersChildren's Hospital of Chongqing Medical UniversityChongqing 400014China

Juvenile idiopathic arthritis (JIA) is one of the most common chronic inflammatory rheumatic diseases in children,with onset before age 16 and lasting for more than 6 weeks.JIA is a highly heterogeneous condition with various consequences for health and quality of life.For some JIA patients,early detection and intervention remain challenging.As a result,further investigation of the complex and unknown mechanisms underlying JIA is required.Advances in technology now allow us to describe the biological heterogeneity and function of individual cell populations in JIA.Through this review,we hope to provide novel ideas and potential targets for the diagnosis and treatment of JIA by summarizing the current findings of single-cell RNA sequencing studies and understanding how the major cell subsets drive JIA pathogenesis.

关键词： Juvenile idiopathic arthritis Macrophage Macrophage activation syndrome Monocyte Single-cell RNA sequencing Synoviocyte T cell

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Cronkhite-Canada syndrome with esophagus involvement and sixyear follow-up:A case report

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World Journal of Gastroenterology 2024年第8期30卷 984-990页

作者： Yu-Chen tang Department of Endocrinology The First Affiliated Hospital of Ningbo UniversityNingbo 315000Zhejiang ProvinceChina

BACKGROUND Cronkhite-Canada syndrome(CCS)is a rare,noninherited disease characterized by gastrointestinal polyposis with diarrhea and ectodermal abnormalities.CCS polyps are distributed through the whole digestive tract,and they are common in the stomach and colon but very uncommon in the esophagus.CASE SUMMARY Here,we present a case of a 63-year-old man with skin hyperpigmentation accompanied by diarrhea,alopecia,and loss of his fingernails.Laboratory data indicated anemia,hypoalbuminemia,hypocalcemia,hypokalemia,and positive fecal occult blood.Endoscopy showed numerous polyps scattered throughout the digestive tract,including the esophagus.He was treated with nutritional support and glucocorticoids with remission of his symptoms.CONCLUSION Comprehensive treatment led by hormonal therapy can result in partial or full remission of clinical symptoms.Treatment should be individualized for each patient according to their therapy response.Surveillance endoscopy is necessary for assessing mucosal disease activity and detecting malignant transformation.

关键词： Cronkhite-Canada syndrome Gastrointestinal polyposis Hormonal therapy Prognosis Case report

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Microglial Calcium Homeostasis Modulator 2:Novel Anti-neuroinflammation Target for the Treatment of Neurodegenerative Diseases

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Neuroscience Bulletin 2024年第4期40卷 553-556页

作者： Yuan Dong Li tang Neuropsychiatry Research Institute The Affiliated Hospital of Qingdao UniversityQingdao UniversityQingdao266000China Qingdao Institute of Measurement Technology Qingdao266000China

Neurodegenerative diseases,including Alzheimer's disease(AD)and Parkinson's disease(PD),are the most common causes of dementia.Current drugs for such diseases can only provide temporary help with the symptoms,leaving the discovery of new drugs urgently in need.Microglial cells are the local immune cells in the nervous system and have been recognized as the key player in neuroinflammation that contributes to the process of neurodegeneration[1],raising the discussion of aiming microglia as the therapeutic target for clinical treatment of neurodegenerative diseases.

关键词： inflammation degenerative drugs

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