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Enhanced autophagic clearance of amyloid-βvia histone deacetylase 6-mediated V-ATPase assembly and lysosomal acidification protects against Alzheimer's disease in vitro and in vivo

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Neural Regeneration Research 2025年第9期20卷 2633-2644页

作者： Zhimin Long Chuanhua Ge Yueyang Zhao Yuanjie Liu Qinghua Zeng Qing Tang Zhifang Dong Guiqiong He Institute of Neuroscience School of Basic Medical SciencesChongqing Medical UniversityChongqingChina Department of Anatomy Chongqing Medical UniversityChongqingChina Department of Physiology Chongqing Medical UniversityChongqingChina Pediatric Research Institute Children’s Hospital of Chongqing Medical UniversityChongqingChina Ministry of Education Key Laboratory of Child Development and Disorders Children’s Hospital of Chongqing Medical UniversityChongqingChina national Clinical Research Center for Child Health and Disorders Children’s Hospital of Chongqing Medical UniversityChongqingChina chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders Children’s Hospital of Chongqing Medical UniversityChongqingChina

Recent studies have suggested that abnormal acidification of lysosomes induces autophagic accumulation of amyloid-βin neurons,which is a key step in senile plaque ***,resto ring normal lysosomal function and rebalancing lysosomal acidification in neurons in the brain may be a new treatment strategy for Alzheimer's *** acetylation/deacetylation plays a central role in lysosomal ***,we show that inhibiting the classic microtubule deacetylase histone deacetylase 6 with an histone deacetylase 6 shRNA or thehistone deacetylase 6 inhibitor valproic acid promoted lysosomal reacidification by modulating V-ATPase assembly in Alzheimer's *** rthermore,we found that treatment with valproic acid markedly enhanced *** clearance of amyloid-βaggregates,and ameliorated cognitive deficits in a mouse model of Alzheimer's *** findings demonstrate a previously unknown neuroprotective mechanism in Alzheimer's disease,in which histone deacetylase 6 inhibition by valproic acid increases V-ATPase assembly and lysosomal acidification.

关键词： Alzheimer's disease amyloid-β APP/PS1 mice autophagy cognitive impairment histone deacetylase 6 lysosomal acidification microtubule acetylation valproic acid V-ATPase

Investigating Müller glia reprogramming in mice: a retrospective of the last decade, and a look to the future

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Neural Regeneration Research 2025年第4期20卷 946-959页

作者： Zhiyuan Yin Jiahui Kang Xuan Cheng Hui Gao Shujia Huo Haiwei Xu Key Lab of Visual Damage and Regeneration&Restoration of chongqing Southwest Eye HospitalSouthwest HospitalThird Military Medical University(Army Medical University)ChongqingChina

Müller glia,as prominent glial cells within the retina,plays a significant role in maintaining retinal homeostasis in both healthy and diseased *** lower vertebrates like zebrafish,these cells assume responsibility for spontaneous retinal regeneration,wherein endogenous Müller glia undergo proliferation,transform into Müller glia-derived progenitor cells,and subsequently regenerate the entire retina with restored ***,Müller glia in the mouse and human retina exhibit limited neural reprogramming.Müller glia reprogramming is thus a promising strategy for treating neurodegenerative ocular disorders.Müller glia reprogramming in mice has been accomplished with remarkable success,through various *** in molecular,genetic,epigenetic,morphological,and physiological evaluations have made it easier to document and investigate the Müller glia programming process in ***,there remain issues that hinder improving reprogramming efficiency and ***,understanding the reprogramming mechanism is crucial toward exploring factors that will improve Müller glia reprogramming efficiency,and for developing novel Müller glia reprogramming *** review describes recent progress in relatively successful Müller glia reprogramming *** also provides a basis for developing new Müller glia reprogramming strategies in mice,including epigenetic remodeling,metabolic modulation,immune regulation,chemical small-molecules regulation,extracellular matrix remodeling,and cell-cell fusion,to achieve Müller glia reprogramming in mice.

关键词： cell fusion chemical small-molecules epigenetic extracellular matrix immune metabolic mice Müller glia neurodegenerative diseases reprogramming retina regeneration

Nanoparticles for the treatment of spinal cord injury

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Neural Regeneration Research 2025年第6期20卷 1665-1680页

作者： Qiwei Yang Di Lu Jiuping Wu Fuming Liang Huayi Wang Junjie Yang Ganggang Zhang Chen Wang Yanlian Yang Ling Zhu Xinzhi Sun Department of Orthopedic Surgery The First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan ProvinceChina CAS Key Laboratory of Standardization and Measurement for Nanotechnology CAS Key Laboratory for Biomedical Effects of Nanomaterials and NanosafetyCAS Center for Excellence in NanoscienceNational Center for Nanoscience and TechnologyBeijingChina University of Chinese Academy of Sciences BeijingChina Department of Neurosurgery The First Affiliated Hospital of Chongqing Medical UniversityChongqingChina

Spinal cord injuries lead to significant loss of motor, sensory, and autonomic functions, presenting major challenges in neural regeneration. Achieving effective therapeutic concentrations at injury sites has been a slow process, partly due to the difficulty of delivering drugs effectively. Nanoparticles, with their targeted delivery capabilities, biocompatibility, and enhanced bioavailability over conventional drugs, are garnering attention for spinal cord injury treatment. This review explores the current mechanisms and shortcomings of existing treatments, highlighting the benefits and progress of nanoparticle-based approaches. We detail nanoparticle delivery methods for spinal cord injury, including local and intravenous injections, oral delivery, and biomaterial-assisted implantation, alongside strategies such as drug loading and surface modification. The discussion extends to how nanoparticles aid in reducing oxidative stress, dampening inflammation, fostering neural regeneration, and promoting angiogenesis. We summarize the use of various types of nanoparticles for treating spinal cord injuries, including metallic, polymeric, protein-based, inorganic non-metallic, and lipid nanoparticles. We also discuss the challenges faced, such as biosafety, effectiveness in humans, precise dosage control, standardization of production and characterization, immune responses, and targeted delivery in vivo. Additionally, we explore future directions, such as improving biosafety, standardizing manufacturing and characterization processes, and advancing human trials. Nanoparticles have shown considerable progress in targeted delivery and enhancing treatment efficacy for spinal cord injuries, presenting significant potential for clinical use and drug development.

关键词： antioxidants axon regeneration biocompatible materials drug carriers nanoparticles nerve regeneration neuroinflammatory diseases neuroprotection spinal cord injury stem cells

Cerebral fat embolism following autologous fat injection in facial reconstruction:A case report

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World Journal of Clinical Cases 2025年第2期13卷 50-58页

作者： Xiu-Ying Chen Fa Shen Chang Cheng Yu-Han Wang Wen-Chao Cheng De-Zhi Yuan Wen Huang Department of Neurology Chongqing Emergency Medical CenterChongqing University Central HospitalChongqing 400000China Department of Neurology Xinqiao HospitalThe Army Medical University(Third Military Medical University)Chongqing 400000China

BACKGROUND Autologous fat injection in facial reconstruction is a common cosmetic *** cerebral fat embolism(CFE)as a complication is rare,it carries serious health *** SUMMARY We present a case of a 29-year-old female patient who developed acute CFE following facial fat filling *** the surgery,the patient experienced symptoms including headache,nausea,vomiting,and difficulty breathing,which was followed by neurological symptoms such as slurred speech and left-sided *** physical examination and auxiliary investigations,including blood tests,head and neck computed tomography angiography,and cranial magnetic resonance diffusion-weighted imaging,were performed upon *** clinical diagnosis was acute cerebral embolism following facial fat filling *** included measures to improve cerebral circulation,dehydration for intracranial pressure reduction,nutritional support,and rehabilitation therapy for left limb *** patient showed a significant improvement in symptoms after 2 weeks of *** recovered left limb muscle strength to grade 5,had clear speech,and experienced complete relief of *** Our case highlights the potential occurrence of severe complications in patients undergoing fat injection in facial *** prevent these complications,plastic surgeons should enhance their professional knowledge and skills.

关键词： Cerebral fat embolism Mechanical thrombectomy Thrombolysis Steroid therapy Symptomatic treatment Case report

Searching for new drugs to treat Alzheimer’s disease dementia through multiple pathways

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World Journal of Clinical Cases 2025年第1期13卷 22-28页

作者： Hua Bai Xiao-Feng Feng Department of Neurology The Third Affiliated Hospital of Guizhou Medical UniversityDuyun 558099Guizhou ProvinceChina Department of Neurology Wulong Branch of the People's Hospital Affiliated to Chongqing UniversityWulong 408500ChongqingChina Department of Neurology Guizhou Medical UniversityGuiyang 550004Guizhou ProvinceChina

Dementia is a group of diseases,including Alzheimer's disease(AD),vascular dementia,Lewy body dementia,frontotemporal dementia,Parkinson's disease dementia,metabolic dementia and toxic *** treatment of dementia mainly includes symptomatic treatment by controlling the primary disease and accompanying symptoms,nutritional support therapy for repairing nerve cells,psychological auxiliary treatment,and treatment that improves cognitive function through *** them,drug therapy to improve cognitive function is *** review focuses on introducing and commenting on some recent progress in exploring drugs to improve cognitive function,especially the new progress in drug treatment for *** mainly discuss the opportunities and challenges in finding and developing new therapeutic drugs from the aspects of acetylcholinesterase,N-methyl-D-aspartate glutamate receptor,amyloid protein,tau protein and chronic immune inflammation.

关键词： Alzheimer's disease Dementia Cholinesterase inhibitor Beta amyloid Tau protein

Discovery of 4-Thiazol-N-(pyridin-2-yl)pyrimidin-2-amine as Novel Cyclin-dependent Kinases 4 and 6 Dual Inhibitors via 3D-QSAR and Molecular Simulation

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Chinese Journal of Structural Chemistry 2022年第3期41卷 108-124,I0010页

作者： FU Le ZHAO Li-Nan GUO Hong-Mei YU Na QUAN Wen-Xuan CHEN Yi SHU Mao WANG Rui LIN Zhi-Hua School of Pharmacy and Bioengineering Chongqing University of TechnologyChongqing 400054China qianjiang Central hospital of chongqing Chongqing 409099China

Cyclin D dependent kinases 4/6 regulate the entry of cells into S phase and are effective target for the discovery of anticancer *** this article,3D-QSAR modeling including comparative molecular field analy-sis(CoMFA)and comparative molecular similarity indices analysis fields(CoMSIA)was implemented on 52 dual CDK4/6 *** a result,we obtained a pretty good 3D-QSAR model,which is CoMFACDK4 with q2 to be 0.543 and r^(2) to be 0.967;CoMSIACDK4 with q2 being 0.518 and r^(2) being 0.937;CoMFACDK6 with q2 to be 0.624 and r^(2) to be 0.984;CoMSIACDK6 with q2 being 0.584 and r^(2) being *** docking confirmed the important residues for *** dynamics simulation further confirmed binding affinity with key residues of protein,such as Lys22,Lys35,Val96 for CDK4 and Lys43,His100,Val101 for CDK6 at the active *** these results offered new directions to explore new inhibitors of CDK4/***,we designed 10 novel compounds with promising expected activity and ADME/T properties,and provided referable synthetic routes.

关键词： cyclin-dependent kinases 4 and 6 dual inhibitors 3D-QSAR drug design molecular simulation

Autophagic cell death induced by reactive oxygen species is involved in hyperthermic sensitization to ionizing radiation in human hepatocellular carcinoma cells

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World Journal of Gastroenterology 2017年第30期23卷 5530-5537页

作者： Guang-Jin Yuan Jun-Jian Deng De-Dong Cao Lei Shi Xin Chen Jin-Ju Lei Xi-Ming Xu Department of Oncology Nationality Hospital of Qianjiang cancer Center Renmin Hospital of Wuhan University

AIM To investigate whether autophagic cell death is involved in hyperthermic sensitization to ionizing radiation in human hepatocellular carcinoma cells, and to explore the underlying *** Human hepatocellular carcinoma cells were treated with hyperthermia and ionizing radiation. MTT and clonogenic assays were performed to determine cell survival. Cell autophagy was detected using acridine orange staining and flow cytometric analysis, and the expression of autophagy-associated proteins, LC3 and p62, was determined by Western blot analysis. Intracellular reactive oxygen species(ROS) were quantified using the fluorescent probe *** Treatment with hyperthermia and ionizing radiation significantly decreased cell viability and surviving fraction as compared with hyperthermia or ionizing radiation alone. Cell autophagy was significantly increased after ionizing radiation combined with hyperthermia treatment, as evidenced by increased formation of acidic vesicular organelles, increased expression of LC3 II and decreased expression of p62. Intracellular ROS were also increased after combined treatment with hyperthermia and ionizing radiation. Pretreatment with N-acetylcysteine, an ROS scavenger, markedly inhibited the cytotoxicity and cell autophagy induced by hyperthermia and ionizing *** Autophagic cell death is involved in hyperthermic sensitization of cancer cells to ionizing radiation, and its induction may be due to the increased intracellular ROS.

关键词： Autophagic cell death Hyperthermia Ionizing radiation Hepatocellular carcinoma Reactive oxygen species

Inflammation and tumor progression:signaling pathways and targeted intervention

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Signal Transduction and Targeted Therapy 2021年第8期6卷 2426-2471页

作者： Huakan Zhao Lei Wu Guifang Yan Yu Chen Mingyue Zhou Yongzhong Wu Yongsheng Li Department of Medical Oncology Chongqing University Cancer HospitalChongqingChina Department of Radiotherapy Chongqing University Cancer HospitalChongqingChina

cancer development and its response to therapy are regulated by inflammation,which either promotes or suppresses tumor progression,potentially displaying opposing effects on therapeutic *** inflammation facilitates tumor progression and treatment resistance,whereas induction of acute inflammatory reactions often stimulates the maturation of dendritic cells(DCs)and antigen presentation,leading to anti-tumor immune *** addition,multiple signaling pathways,such as nuclear factor kappa B(NF-kB),Janus kinase/signal transducers and activators of transcription(JAK-STAT),toll-like receptor(TLR)pathways,cGAS/STING,and mitogen-activated protein kinase(MAPK);inflammatory factors,including cytokines(e.g.,interleukin(IL),interferon(IFN),and tumor necrosis factor(TNF)-a),chemokines(e.g.,C-C motif chemokine ligands(CCLs)and C-X-C motif chemokine ligands(CXCLs)),growth factors(e.g.,vascular endothelial growth factor(VEGF),transforming growth factor(TGF)-P),and inflammasome;as well as inflammatory metabolites including prostaglandins,leukotrienes,thromboxane,and specialized proresolving mediators(SPM),have been identified as pivotal regulators of the initiation and resolution of ***,local irradiation,recombinant cytokines,neutralizing antibodies,small-molecule inhibitors,DC vaccines,oncolytic viruses,TLR agonists,and SPM have been developed to specifically modulate inflammation in cancer therapy,with some of these factors already undergoing clinical ***,we discuss the initiation and resolution of inflammation,the crosstalk between tumor development and inflammatory *** also highlight potential targets for harnessing inflammation in the treatment of cancer.

关键词： inflammation interferon acute

Autophagic dysfunction of β cell dysfunction in type 2 diabetes,a double-edged sword

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Genes & Diseases 2021年第4期8卷 438-447页

作者： Ding Yao Yang GangYi Wu QiNan Endocrinology and Nephrology Department Chongqing University Cancer Hospital and Chongqing Cancer Institute and Chongqing Cancer HospitalChongqing400030PR China Endocrinology Department The Second Affiliated Hospital of the Chongqing Medical UniversityChongqing400010PR China

Diabetes is an age-related disease,most of which is type 2 diabetes,and islet β cell dysfunction and insulin resistance are the main mechanisms of type 2 *** studies have revealed that autophagy plays an important role in maintaining the structure and func-tion of islet beta cells and inhibiting insulin resistance and apoptosis induced by oxidative *** this review,we discussed the positive and negative effects of autophagy and its dysfunction on type 2 diabetes mellitus,which is the so-called double-edged sword,analysed its possible mechanism,and identifed possible research hot spots.

关键词： Apoptosis Autophagic dysfunction Insulin resistance Islet beta cell dysfunction Type 2 diabetes mellitus