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Enhancement of lysosome biogenesis as a potential therapeutic approach for neurodegenerative diseases

Neural Regeneration Research 2023年第11期18卷 2370-2376页

作者： Wenlong Xue Jie Zhang Yang Li Department of Pharmacology State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain ScienceKey Laboratory of Metabolism and Molecular MedicineMinistry of EducationSchool of Basic Medical ScienceFudan UniversityShanghaiChina

Millions of people are suffering from Alzheimer’s disease globally,but there is still no effective treatment for this neurodegenerative disease.Thus,novel therapeutic approaches for Alzheimer’s disease are needed,which requires further evaluation of the regulato ry mechanisms of protein aggregate degradation.Lysosomes are crucial degradative organelles that maintain cellular homeostasis.Transcription factor EB-mediated lysosome biogenesis enhances autolysosomedependent degradation,which subsequently alleviates neurodege nerative diseases,including Alzheimer’s disease,Parkinson’s disease,and Huntington’s disease.In this review,we start by describing the key features of lysosomes,including their roles in nutrient sensing and degradation,and their functional impairments in different neurodegenerative diseases.We also explain the mechanisms—especially the post-translational modifications—which impact transcription factor EB and regulate lysosome biogenesis.Next,we discuss strategies for promoting the degradation of toxic protein aggregates.We describe Proteolysis-Ta rgeting Chimera and related technologies for the targeted degradation of specific proteins.We also introduce a group of LYsosome-Enhancing Compounds,which promote transcription factor EB-mediated lysosome biogenesis and improve learning,memory,and cognitive function in APP-PSEN1 mice.In summary,this review highlights the key aspects of lysosome biology,the mechanisms of transcription factor EB activation and lysosome biogenesis,and the promising strategies which are emerging to alleviate the pathogenesis of neurodegenerative diseases.

关键词： Alzheimer’s disease degradation lysosome biogenesis LYsosome-Enhancing Compounds neurodegenerative diseases post-translational modifications protein aggregates transcription factor EB

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TRPM7 Kinase Domain is Part of the Rac1-SSH2-cofilin Complex Regulating F-actin in the Mouse Nervous System

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Neuroscience Bulletin 2023年第6期39卷 989-993页

作者： Junzhuang Chang Cui Chen Wei Li Nashat Abumaria State Key laboratory of medical Neurobiology and MOE Frontiers Center for Brain science Department of Laboratory Animal ScienceInstitutes of Brain ScienceFudan UniversityShanghai200032China

Dear Editor,The ion channel transient receptor potential melastatin-like 7(TRPM7)has a serine-threonineα-kinase domain(M7CK)on its intracellular C-terminal[1,2].In cell lines,M7CK is cleaved and translocated to the nucleus to regulate a variety of cellular processes including cell proliferation and survival[3].In neuroblastoma cells.

关键词： Rac1 SSH2 neuroblastoma

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Prevalence and risks of soil transmitted helminths among Ethiopian school children:A cross-sectional study

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Asian Pacific Journal of Tropical Medicine 2022年第3期15卷 121-127页

作者： Abebe Fenta Bewket Mesganaw Feven Belachew Getachew Teshale Gashaw Abebaw Elias Tesfa Getaye Alemayehu Department of medical laboratory science Health Science CollegeDebre Markos UniversityDebre MarkosEthiopia

Objective:To assess the prevalence and associated factors of soil transmitted helminths(STHs)among Endemata primary school in North West Ethiopia,2021.Methods:A cross-sectional study with 195 school children was conducted from May to July 2021 at Endemata primary school.The study participants were selected by using systematic random sampling technique.Stool samples were processed via direct wet mount and formol-ether concentration techniques.Data was entered by Epi-Dara version 3.1 and data analysis was done using SPSS version 20.0.Variables were considered to be statistically significant if P<0.05 at 95%confidence level.Results:The overall prevalence of STHs was 10.8%(95%CI 7.1-16.0).The prevalence of Ascaris lumbricoides,hookworm and Trichuris trichiura were 5.6%(95%CI 3.1-9.9),3.1%(95%CI 1.3-6.7)and 2.1%(95%CI 0.6-5.3),respectively.Grade 1-4 students were more likely to get infected with STHs as compared to grade 5-8 students(adjusted OR 4.7,95%CI 1.3-16.6).Students who did not have latrines at their home were at higher risk to develop STHs infection comparing with those who had latrine at their home(adjusted OR 5.0,95%CI 1.7-15.2).Similarly,the school children who did not wear shoes were more likely to be infected by STH parasite than those who did it(adjusted OR 6.3,95%CI 1.9-20.7).The odds of being infected by STH parasites in children who did not trim their fingernails were 4.9 as compared to those who did it(adjusted OR 4.9,95%CI 1.5-15.7).Conclusions:The prevalence of STHs among Endemata primary school children was low.Student grade level,latrine availability,shoes wear and nail status were significantly associated with STHs infection.Therefore,we recommend policy makers and stakeholders to follow the integration of deworming with water,hygiene and sanitation as well as the consistent health education of school children to control and prevent STH infections.

关键词： Soil transmitted helminths Prevalence Associated factors School children Ethiopia

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Mechanical Force Remodeling the Adult Brain

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Neuroscience Bulletin 2023年第5期39卷 877-879页

作者： Chen Zhang Shuai Liu Yong-Chun Yu Qingjian Han State Key laboratory of medical Neurobiology and MOE Frontiers Center for Brain science Institutes of Brain ScienceFudan UniversityShanghai 200032China

The interactions between neural stem cells(NSCs)and their niche are essential for their maintenance,proliferation,differentiation,and migration,which contribute to brain plasticity,learning and memory,and cognition[1].As one of the key components of the NSC niche,astrocytes are vital in regulating the processes underlying brain development such as neuro-/gliogenesis,angiogenesis,axonal outgrowth,synaptogenesis,and synaptic pruning[2].Chemical and electrical signals mediated by adhesion molecules,the extracellular matrix,paracrine secretion.

关键词： vital maintenance migration

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Sonocatalytic hydrogen/hole-combined therapy for anti-biofilm and infected diabetic wound healing

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National science Review 2023年第5期10卷 262-271页

作者： Qingqing Xu Shengqiang Chen Lingdong Jiang Chao Xia Lingting Zeng Xiaoqing Cai Zhaokui Jin Shucun Qin Wenjiang Ding Qianjun He Taishan Institute for Hydrogen Biomedical Research School of Basic Medical SciencesThe Second Affiliated Hospital of Shandong First Medical University&Shandong Academy of Medical Sciences Guangdong Key laboratory for Biomedical Measurements and Ultrasound Imaging School of Biomedical EngineeringMedical SchoolShenzhen University Shanghai Key laboratory of Hydrogen science&Center of Hydrogen science School of Materials Science and EngineeringShanghai Jiao Tong University

It is a great challenge to effectively eradicate biofilm and cure biofilm-infected diseases because dense extracellular polymeric substance matrix prevents routine antibacterial agents from penetrating into biofilm.H2is an emerging energy-regulating molecule possessing both high biosafety and high tissue permeability.In this work,we propose a concept of sonocatalytic hydrogen/hole-combined ’inside/outside-cooperation’anti-biofilm for promoting bacteria-infected diabetic wound healing based on two-dimensional piezoelectric nanomaterials.Proof-of-concept experiments using C3N4nanosheets as a representative piezoelectric catalyst with wide band gap and high biosafety have verified that sonocatalytically generated H2and holes rapidly penetrate into biofilm to inhibit bacterial energy metabolism and oxidatively deprive polysaccharides/NADH in biofilm to destroy the bacterial membrane/electron transport chain,respectively,inside/outside-cooperatively eradicating biofilm.A bacteria-infected diabetic wound model is used to confirm the excellent in vivo antibacterial performance of sonocatalytic hydrogen/hole-combined therapy,remarkably improving bacteria-infe cted diabetic wound healing.The proposed strategy of sonocatalytic hole/hydrogen-combined ’inside/outside-cooperation’ will make a highway for treatment of deep-seated biofilm infection.

关键词： nanocatalytic medicine hydrogen therapy biofilm diabetic foot piezoelectric catalysis

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The effects of inactivated SARS-CoV-2 vaccination and subsequent infection of pregnant mice on the behaviors of offspring

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Animal Models and Experimental Medicine 2022年第5期5卷 430-435页

作者： Kaili Lin Meixuan Liu Lu Sun Hongwei Qiao Shunyi Wang Sidan Pan Hanjun Fu Jingzhu Wang Qiang Wei Hong Gao Institute of laboratory Animal science Chinese Academy of Medical Sciences and Comparative Medicine CenterPeking Union Medical CollegeBeijingChina

The mass inoculation of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)vaccines to induce herd immunity is one of the most effective measures we can deploy in the fight against coronavirus disease 2019(COVID-19).Pregnant women are prone to a higher risk of COVID-19,and maternal infection is a risk fac-tor for a range of neurological disorders leading to abnormal behavior in adulthood.However,there are limited clinical data to support whether vaccination or infection post-immunization in pregnant women can affect the behavioral cognition of fetuses in adulthood.In this study,human angiotensin-converting enzyme 2 pregnant mice(F0 generation)were immunized with CoronaVac and then infected with SARS-CoV-2.Subsequently,we analyzed the behavioral cognition of their adult offspring(F1 gen-eration)using the open-field test and Morris water maze test.The adult F1 generation did not exhibit any impairments in spontaneous locomotor activity or spatial refer-ence memory.

关键词： offspring spatial reference memory spontaneous locomotor activity

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Richard Ho-Ping Sia:pioneer of infectiology in China

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Protein & Cell 2023年第4期14卷 235-237页

作者： Xudong Liu Yuanmeng Li Naishi Li medical science Rsearch Center State Key Laboratory of Complex Severe and Rare DiseasesPeking Union Medical Cllege HopitalChinese Academy of Medical Science and Peking Union Medical CollegeBeijing 10050 China Department of Endocrinology NHC Key laboratory of Endocrinology.State Key Labontory of Complex Severe and Rare Diseases Peking Union Medical College HospitalChinese Academy of Medical Science and Peking Union Medical CollegeBeijing 100730China School of Humanity and Social sciences.Chinese Academy of medical science and Peking Union medical College Beijing 100730.China

Dr.Richard Ho-Ping Sia(谢和平)was bom in Xiamen(Amoy)on 28 April 1895.After graduating from Boone University in Wuchang in 1914,he went to the medical School of Westerm Reserve University in Cleveland,USA,to study clinical medicine,and received his MD degree in 1918.After completing 1-year clinical rotation training at Cleveland City Hospital,he returmed to China in 1919 and joined Peking Union medical College(PUMC)Hospital as an Assistant Resident.He was promoted to Assistant in 1920,and then worked as a physician treating infectious diseases in the Department of Medicine of PUMC Hospital.

关键词： Xiamen rotation Assistant

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A neuron-specific Isca1 knockout rat developments multiple mitochondrial dysfunction syndromes

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Animal Models and Experimental Medicine 2023年第2期6卷 155-167页

作者： Hanxuan Sheng Dan Lu Xiaolong Qi Yahao Ling Jing Li Xu Zhang Wei Dong Wei Chen Shan Gao Xiang Gao Li Zhang Lianfeng Zhang Key laboratory of Human Disease Comparative Medicine National Health Commission of China(NHC)Institute of Laboratory Animal SciencePeking Union Medical CollegeChinese Academy of Medical SciencesBeijingChina Beijing Engineering Research Center for Experimental Animal Models of Human Diseases Institute of Laboratory Animal SciencePeking Union Medical CollegeChinese Academy of Medical SciencesBeijingChina

Background:Multiple mitochondrial dysfunction syndromes(MMDS)are rare mitochondrial diseases caused by mutation of mitochondrial iron–sulfur cluster synthesis proteins.This study established a rat model simulating MMDS5 disease in the nervous system to investigate its pathological features and neuronal death.Methods:We generated neuron-specific Isca1 knockout rat(Isca1 flox/flox-NeuN-Cre)using CRISPR-Cas9 technology.The brain structure changes of CKO rats were studied with MRI,and the behavior abnormalities were analyzed through gait analysis and open field tests,Y maze tests and food maze tests.The pathological changes of neurons were analyzed through H&E staining,Nissl staining,and Golgi staining.Mitochondrial damage was assessed by TEM,western blot and ATP assay,and the morphology of neurons was assessed by WGA immunofluorescence to detect the death of neurons.Results:This study established the disease model of MMDS5 in the nervous system for the first time,and found that after Isca1 loss,the rats suffered from developmental retardation,epilepsy,memory impairment,massive neuronal death,reduced number of Nissl bodies and dendritic spines,mitochondrial fragmentation,cristae fracture,reduced content of respiratory chain complex protein,and reduced production of ATP.Isca1 knockout caused neuronal oncosis.Conclusions:This rat model can be used to study the pathogenesis of MMDS.In addition,compared with human MMDS5,the rat model can survive up to 8 weeks of age,effectively extending the window of clinical treatment research,and can be used for the treatment of neurological symptoms in other mitochondrial diseases.

关键词： ISCA1 mitochondrial iron-sulfur cluster MMDS5 neuron oncosis

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Characteristics of the traditional Liu-Wei-Di-Huang prescription reassessed in modern pharmacology

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Chinese Journal of Natural Medicines 2019年第2期17卷 103-121页

作者： CHENG Xiao-Rui QI Chun-Hui WANG Tong-Xing ZHOU Wen-Xia ZHANG Yong-Xiang Academy of Military medical science Institute of Pharmacology and Toxicology State Key laboratory of Toxicology and medical Countermeasures

Liu-Wei-Di-Huang(LW) is a Yin nourishing and kidney tonifying prescription in traditional Chinese medicine with promising pharmacological characteristics that can be further exploited and developed in modern medicine. We provide a comprehensive and detailed literature report on the clinical and experimental pharmacology of LW,including its quality control parameters, phytochemistry, pharmacokinetics, and toxicology. Our literature review indicates that the LW prescription possesses a unique combination of pharmacological characteristics that can be safely used for treating very different diseases. Quality control and pharmacokinetic parameters of LW are mostly based on its major bioactive phytochemical constituents. We postulate that modulating or rebalancing the neuroendocrine immunomodulation network in the body is the underlying mechanism of the multiple pharmacological activities displayed by LW.

关键词： Liu-Wei-Di-Huang Traditional Chinese medicine Pharmacology Phytochemistry Pharmacokinetics Toxicology

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Signaling Mechanism for Modulation by GLP-1 and Exendin-4 of GABA Receptors on Rat Retinal Ganglion Cells

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Neuroscience Bulletin 2022年第6期38卷 622-636页

作者： Tao Zhang Hang-Ze Ruan Yong-Chen Wang Yu-Qi Shao Wei Zhou Shi-Jun Weng Yong-Mei Zhong State Key laboratory of medical Neurobiology and MOE Frontiers Center for Brain science Institutes of Brain ScienceFudan UniversityShanghai 200032.China

Glucagon-like peptide-1(GLP-1)is expressed in retinal neurons,but its role in the retina is largely unknown.Here,we demonstrated that GLP-1 or the GLP-1 receptor(GLP-1R;a G protein-coupled receptor)agonist exendin-4 suppressed-aminobutyric acid receptor(GABAR)-mediated currents through GLP-1Rs in isolated rat retinal ganglion cells(GCs).Pre-incubation with the stimulatory G protein(G,)inhibitor NF 449 abolished the exendin-4 effect.The exendin-4-induced suppression was mimicked by perfusion with 8-Br-cAMP(a cAMP analog),but was eliminated by the protein kinase A(PKA)inhibitor RpcAMP/KT-5720.The_exendin-4 effect was accompanied by an increase in[Ca2+];of GCs through the IP3-sensitive pathway and was blocked in Ca2+-free solution.Furthermore,when the activity of calmodulin(CaM)and CaMdependent protein kinase II(CaMKII)was inhibited,the exendin-4 effect was eliminated.Consistent with this,exendin-4 suppressed GABAR-mediated light-evoked inhibitory postsynaptic currents in GCs in rat retinal slices.These results suggest that exendin-4-induced suppression may be mediated by a distinct G,/cAMP-PKA/IPs/Ca+/CaM/CaMKIl signaling pathway,following the activation of GLP-1Rs.

关键词： Glucagon-like peptide-1 Exendin-4 GABA current Retinal ganglion cells Neuromodulation

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