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CCS Chemistry 2024年第1期6卷 177-195页

作者： Lang Zhao Shao-Hua Zhuo Tian-Yang Wang Jun-Jun Wu Jing-Yun Su Wen-Hao Li Bo-Dou Zhang Yan-Mei Li Key Lab of Bioorganic Phosphorus Chemistry&Chemical Biology Department of ChemistryTsinghua UniversityBeijing 100084 Beijing Institute for Brain disorders Beijing 100069 Center for Synthetic and Systems Biology Tsinghua UniversityBeijing 100084

Cyclic dinucleotides(CDNs)are natural agonists of the stimulator of interferon genes(STING),which is an attractive immunotherapy ***,CDNs and their derivatives are being investigated ***,the poor bioavailability of exogenous CDNs has limited their application in *** nanocarriers are widely used for cytosolic delivery of CDNs,their loading capacity is insufficient,and their complicated composition and purification process raises bio-compatibility ***,we report a super-simplified CDN self-assembly strategy for carrier-free delivery of *** the presence of excess K^(+),CDNs form oligomers which further self-assemble with divalent metal ions(such as Mn^(2+))to form nanoparticles(NPs)in aqueous *** demonstrate that the self-assembled CDN NPs promote cellular uptake of CDNs and enhance tumor immunogenicity by remodeling the tumor microenvironment,inducing immunogenic tumor cell death and increasing tumorinfiltrating lymphocytes,which is conducive to the generation of tumor neoantigen-specific T-cell *** also demonstrate that the use of CDN NPs alone or in combination with immune checkpoint blockades inhibits tumor growth,highlighting the fact that CDN NPs are a potent platform for cancer immunotherapy.

关键词： cyclic dinucleotide STING carrierfree delivery tumor immunogenicity cancer immunotherapy

Mitochondrial GRIM19 Loss Induces Liver Fibrosis through NLRP3/IL33 Activation via Reactive Oxygen Species/NF-κB Signaling

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Journal of Clinical and Translational Hepatology 2024年第6期12卷 539-550页

作者： Xiaohui Xu Jinmei Feng Xin Wang Xin Zeng Ying Luo Xinyu He Meihua Yang Tiewei Lv Zijuan Feng Liming Bao Li Zhao Daochao Huang Yi Huang Institute of Pediatrics Children’s Hospital of Chongqing Medical UniversityNational Clinical Research Center for Child Health and DisordersMinistry of Education Key Laboratory of Child Development and DisordersChongqing Key Laboratory of Pediatric Metabolism and Inflammatory DiseasesChongqingChina Department of Cardiology Children’s Hospital of Chongqing Medical UniversityNational Clinical Research Center for Child Health and DisordersMinistry of Education Key Laboratory of Child Development and DisordersNational Clinical Key Cardiovascular SpecialtyLaboratory of Children’s Important Organ Development and Diseases of Chongqing Municipal Health CommissionChongqingChina Department of Laboratory Medicine Chongqing Western HospitalChongqingChina Key Laboratory of Molecular Biology for Infectious Diseases Ministry of EducationInstitute for Viral HepatitisChongqing Medical UniversityChongqingChina Department of Laboratory Medicine The Third People’s Hospital of ChengduChengduSichuanChina Departments of Neurology Epilepsy CenterBarnes-Jewish Hospital and Washington University School of MedicineSt.LouisMOUSA Department of Clinical Pathology and Laboratory Medicine Weill Cornell Medical College of Cornell UniversityNew YorkNYUSA Departments of Medicine(Oncology) Washington University School of MedicineSt.LouisMOUSA

Background and Aims:Hepatic fibrosis(HF)is a critical step in the progression of hepatocellular carcinoma(HCC).Gene associated with retinoid-IFN-induced mortality 19(GRIM19),an essential component of mitochondrial respiratory chain complex I,is frequently attenuated in various human cancers,including ***,we aimed to investigate the potential relationship and underlying mechanism between GRIM19 loss and HF ***:GRIM19 expression was evaluated in normal liver tissues,hepatitis,hepatic cirrhosis,and HCC using human liver disease spectrum tissue *** studied hepatocyte-specific GRIM19 knockout mice and clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPR-associated protein-9(Cas9)lentivirus-mediated GRIM19 gene-editing in murine hepatocyte AML12 cells in vitro and in *** performed flow cytometry,immunofluorescence,immunohistochemistry,western blotting,and pharmacological intervention to uncover the potential mechanisms underlying GRIM19 loss-induced ***:Mitochondrial GRIM19 was progressively downregulated in chronic liver disease tissues,including hepatitis,cirrhosis,and HCC ***-specific GRIM19 heterozygous deletion induced spontaneous hepatitis and subsequent liver fibrogenesis in *** addition,GRIM19 loss caused chronic liver injury through reactive oxygen species(ROS)-mediated oxidative stress,resulting in aberrant NF-κB activation via an IKK/IKB partner in ***-more,GRIM19 loss activated NLRP3-mediated IL33 signaling administration of the NLRP3 inhibitor MCC950 dramatically via the ROS/NF-κB pathway in *** alleviated GRIM19 loss-driven HF in ***:The mitochondrial GRIM19 loss facilitates liver fibrosis through NLRP3/IL33 activation via ROS/NF-κB signaling,providing potential therapeutic approaches for earlier HF prevention.

关键词： Liver fibrosis GRIM19 Reactive Oxygen Species NF-κB NLRP3 inflammasome IL33.

The role of selective serotonin reuptake inhibitors and tricyclic antidepressants in addressing reduction of Meniere's disease burden:A scoping review

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World Journal of Otorhinolaryngology-Head and Neck Surgery 2024年第3期10卷 206-212页

作者： Alexander A.Missner Mana Sheykhsoltan Amir Hakimi Michael Hoa Georgetown University School of Medicine WashingtonDistrict of ColumbiaUSA Department of Otolaryngology-Head and Neck Surgery Georgetown University Medical CenterWashingtonDistrict of ColumbiaUSA Auditory Development and Restoration program National Institute on Deafness and Other Communication DisordersNational Institutes of HealthBethesdaMarylandUSA

Objective:To assess the effect of selective serotonin reuptake inhibitors(SSRIs)and tricyclic antidepressants(TCAs)in reducing vertigo,tinnitus,and hearing loss among patients with Meniere's disease(MD).Data Sources:The following databases were utilized in this scoping review:Ovid Medline,PubMed-NCBI,CINAHL,Cochrane Library,Web of Science,and ***:Studies were identified through the following search phrases:"serotonin specific reuptake inhibitors"OR"tricyclic antidepressants"AND"Meniere's disease."References from included manuscripts were examined for possible inclusion of additional ***:The literature search yielded 23 results,which were screened by three independent *** studies and three duplicates were *** examination of references from the included studies yielded two additional publications.A total of four published studies assessing SSRIs and TCAs among 147 patients with MD were ultimately *** studies described significant reductions in vertigo attack frequency among patients treated with either SSRIs or TCAs compared to their pretreatment *** studies assessed the drugs'effects on hearing,of which none found a significant difference among patients treated with SSRIs or *** study found a significant decrease in patient-reported tinnitus following treatment with TCAs or SSRIs compared to their pretreatment ***:Data exploring SSRIs and TCAs among patients with MD suggests that these medications may reduce the frequency of tinnitus and vertigo,although there was significant heterogeneity in outcome *** remains a need for larger-scale prospective studies that emphasize objective data to evaluate their effective-ness in reducing common MD symptoms.

关键词： aural fullness clinical trials Meniere's disease scoping review sensorineural hearing loss serotonin specific reuptake inhibitors tricyclic antidepressants vertigo

Brain-wide activation involved in 15 mA transcranial alternating current stimulation in patients with first-episode major depressive disorder

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General Psychiatry 2024年第2期37卷 265-273页

作者： Jie Wang Wenfeng Zhao Huang Wang Haixia Leng Qing Xue Mao Peng Baoquan Min Xiukun Jin Liucen Tan Keming Gao Hongxing Wang Songjiang Hospital and Songjiang Research Institute Shanghai Key Laboratory of Emotions and Affective DisordersShanghai Jiao Tong University School of MedicineShanghaiChina Institute of Neuroscience and Brain Diseases Xiangyang Central HospitalAffiliated Hospital of Hubei University of Arts and ScienceXiangyangHubeiChina Division of Neuropsychiatry and Psychosomatics Department of NeurologyXuanwu Hospital of Capital Medical UniversityBeijingChina Electroconvulsive Therapy University Hospitals Cleveland Medical CenterClevelandOhioUSA Department of Psychiatry Case Western Reserve University School of MedicineClevelandOhioUSA Institute of Sleep and Consciousness disorders Center of EpilepsyBeijing Institute for Brain DisordersCapital Medical UniversityBeijingChina Institute of Special Medical Sciences School of Forensic MedicineShanxi Medical UniversityTaiyuanShanxiChina

Background Although 15 mA transcranial alternating current stimulation(tACS)has a therapeutic effect on depression,the activations of brain structures in humans accounting for this tACS configuration remain largely *** To investigate which intracranial brain structures are engaged in the tACS at 77.5 Hz and 15 mA,delivered via the forehead and the mastoid electrodes in the human *** Actual human head models were built using the magnetic resonance imagings of eight outpatient volunteers with drug-naïve,first-episode major depressive disorder and then used to perform the electric field distributions with SimNIBS *** The electric field distributions of the sagittal,coronal and axial planes showed that the bilateral frontal lobes,bilateral temporal lobes,hippocampus,cingulate,hypothalamus,thalamus,amygdala,cerebellum and brainstem were visibly stimulated by the 15 mA tACS *** Brain-wide activation,including the cortex,subcortical structures,cerebellum and brainstem,is involved in the 15 mA tACS intervention for first-episode major depressive *** results indicate that the simultaneous involvement of multiple brain regions is a possible mechanism for its effectiveness in reducing depressive symptoms.

关键词： stimulation involvement activation

Fibroblast-localized lncRNA CFIRL promotes cardiac fibrosis and dysfunction in dilated cardiomyopathy

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Science China(Life Sciences) 2024年第6期67卷 1155-1169页

作者： Shuai Yuan Xudong Zhang Jiabing Zhan Rong Xie Jiahui Fan Beibei Dai Yanru Zhao Zhongwei Yin Qian Liu Dao Wen Wang Huaping Li Chen Chen Division of Cardiology Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological disorders Wuhan 430030China Department of Forensic Medicine Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China

CFIRL is a long noncoding RNA(lnc RNA),we previously identified as the most significantly upregulated lnc RNA in the failing hearts of patients with dilated cardiomyopathy(DCM).In this study,we determined the function of CFIRL and its role in ***-time polymerase chain reaction and in situ hybridization assays revealed that CFIRL was primarily localized in the nucleus of cardiac fibroblasts and robustly increased in failing *** knockdown or fibroblast-specific knockout of CFIRL attenuated transverse aortic constriction(TAC)-induced cardiac dysfunction and fibrosis in *** of CFIRL in vitro promoted fibroblast proliferation and aggravated angiotensin II-induced differentiation to *** knockdown attenuated these ***,RNA pull-down assay and gene expression profiling revealed that CFIRL recruited ENO1,a newly identified noncanonical transcriptional factor,to activate ***-6 exerted a paracrine effect on cardiomyocytes to promote cardiac hypertrophy,which can be prevented by CFIRL *** findings uncover the critical role of CFIRL,a fibroblast-associated lnc RNA,in heart failure by facilitating crosstalk between fibroblasts and *** knockdown might be a potent strategy to prevent cardiac remodeling in heart failure,particularly in DCM.

关键词： lncRNA fibroblast fibrosis dilated cardiomyopathy heart failure

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

Variable frequency deep brain stimulation of subthalamic nucleus to improve freezing of gait in Parkinson's disease

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National Science Review 2024年第6期11卷 102-104页

作者： Fumin Jia Aparna Wagle Shukla Wei Hu Yu Ma Jianguo Zhang Leonardo Almeida Chris Kao Yi Guo Shizhong Zhang Yingqun Tao Zhipei Ling Xin Xu Zhiquan Yang Fan-gang Meng Xinhua Wan Hesheng Liu Peter E.Konard Luming Li National Engineering Laboratory for Neuromodulation Tsinghua University University of Florida Center for Movement disorders and Neurorestoration Tsinghua University Yuquan Hospital Beijing Tiantan Hospital Capital Medical University School of Medicine Vanderbilt University Peking Union Medical College Hospital ZhuJiang Hospital of Southern Medical University The General Hospital of Shenyang Military Chinese PLA General Hospital Xiangya Hospital Central South University Beijing Neurosurgical Institute Capital Medical University Athinoula A. Martinos Center for Biomedical Imaging Harvard Medical School Precision Medicine & Healthcare Research Center Tsinghua-Berkeley Shenzhen Institute Man-Machine-Environment Engineering Institute School of Aerospace EngineeringTsinghua University Center of Epilepsy Beijing Institute for Brain Disorders

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a welle-stablished therapy for patients with Parkinson’s disease (PD) presenting with medication refractory tremors, motor fluctuations and dyskinesias induced by dopaminergic medications [1]. However,traditional high-frequency stimulation(HFS) does not effectively control axial symptoms such as gait dysfunction,postural instability and freezing of gait(FOG)[2,3].

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RANKL inhibition reduces lesional cellularity and Gαs variant expression and enables osteogenic maturation in fibrous dysplasia

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Bone Research 2024年第1期12卷 165-179页

作者： Luis F.de Castro Jarred M.Whitlock Zachary Michel Kristen Pan Jocelyn Taylor Vivian Szymczuk Brendan Boyce Daniel Martin Vardit Kram Rebeca Galisteo Kamran Melikov Leonid V.Chernomordik Michael T.Collins Alison M.Boyce Skeletal disorders and Mineral Homeostasis Section National Institute of Dental and Craniofacial ResearchNational Institutes of HealthBethesdaMDUSA Section on Membrane Biology Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNational Institutes of HealthBethesdaMDUSA Metabolic Bone disorders Unit National Institute of Dental and Craniofacial ResearchNational Institutes of HealthBethesdaMDUSA Department of Plastic and Reconstructive Surgery The Johns Hopkins Medical InstitutionsBaltimoreMDUSA Department of Pathology and Laboratory Medicine University of Rochester Medical CenterRochesterNYUSA NIDCR Genomics and Computational Biology Core National Institute of Dental and Craniofacial ResearchNational Institutes of HealthBethesdaMDUSA

Fibrous dysplasia(FD)is a rare,disabling skeletal disease for which there are no established *** evidence supports inhibiting the osteoclastogenic factor receptor activator of nuclear kappa-B ligand(RANKL)as a potential treatment *** this study,we investigated the mechanisms underlying RANKL inhibition in FD tissue and its likely indirect effects on osteoprogenitors by evaluating human FD tissue pre-and post-treatment in a phase 2 clinical trial of denosumab(NCT03571191)and in murine in vivo and ex vivo preclinical *** analysis of human and mouse tissue demonstrated increased osteogenic maturation,reduced cellularity,and reduced expression of the pathogenic Gαs variant in FD lesions after RANKL *** sequencing of human and mouse tissue supported these *** interaction between osteoclasts and mutant osteoprogenitors was further assessed in an ex vivo lesion model,which indicated that the proliferation of abnormal FD osteoprogenitors was dependent on *** results from this study demonstrated that,in addition to its expected antiosteoclastic effect,denosumab reduces FD lesion activity by decreasing FD cell proliferation and increasing osteogenic maturation,leading to increased bone formation within *** findings highlight the unappreciated role of cellular crosstalk between osteoclasts and preosteoblasts/osteoblasts as a driver of FD pathology and demonstrate a novel mechanism of action of denosumab in the treatment of bone disease.

关键词： dysplasia treatment finding

The Application of Extended Reality in Treating Children with Autism Spectrum Disorder

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Neuroscience Bulletin 2024年第8期40卷 1189-1204页

作者： Weijia Zhao Song Xu Yanan Zhang Dandan Li Chunyan Zhu Kai Wang First Clinical Medical College Anhui Medical UniversityHefei 230032China School of Biomedical Engineering Anhui Medical UniversityHefei 230032China School of Mental Health and Psychological Sciences Anhui Medical UniversityChinaHefei 230032China Research Center for Translational Medicine The Second Hospital of Anhui Medical UniversityHefei 230000China Department of Neurology The First Affiliated Hospital of Anhui Medical UniversityHefei 230032China Collaborative Innovation Center of Neuropsychiatric disorders and Mental Health Hefei 230032China Institute of Artificial Intelligence Hefei Comprehensive National Science CenterHefei 230088China Anhui Province Key Laboratory of Cognition and Neuropsychiatric disorders Hefei 230032China

Autism Spectrum Disorder(ASD)is a common neurodevelopmental disorder in children,characterized by social interaction,communication difficulties,and repetitive and stereotyped *** intervention methods have limitations,such as requiring long treatment periods and needing to be more convenient to *** Reality(XR)technology offers a virtual environment to enhance children's social,communication,and self-regulation *** paper compares XR theoretical models,application examples,and intervention *** study reveals that XR intervention therapy is mainly based on cognitive rehabilitation,teaching,and social-emotional learning *** utilizes algorithms,models,artificial intelligence(AI),eye-tracking,and other technologies for interaction,achieving diverse intervention *** showed effective improvement in competency barriers using XR-based multimodal interactive ***,Mixed Reality(MR)technology still requires further *** research should explore multimsodal interaction technologies combining XR and AI,optimize models,prioritize the development of MR intervention scenarios,and sustain an optimal intervention level.

关键词： Autism spectrum disorde Extended reality Multimodal interaction technologies Intervention model Treatment effectiveness evaluation

Lysophosphatidylcholine binds α-synuclein and prevents its pathological aggregation

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National Science Review 2024年第6期11卷 119-128页

作者： Chunyu Zhao Jia Tu Chuchu Wang Wenbin Liu Jinge Gu Yandong Yin Shengnan Zhang Dan Li Jiajie Diao Zheng-Jiang Zhu Cong Liu Interdisciplinary Research Center on Biology and Chemistry Shanghai Institute of Organic Chemistry Chinese Academy of Sciences University of Chinese Academy of Sciences Bio-X Institutes Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders Ministry of Education Shanghai Jiao Tong University Zhangjiang Institute for Advanced Study Shanghai Jiao Tong University Department of Cancer Biology University of Cincinnati College of Medicine

Accumulation of aggregated α-synuclein(α-syn) in Lewy bodies is the pathological hallmark of Parkinson's disease(PD). Genetic mutations in lipid metabolism are causative for a subset of patients with Parkinsonism. The role of α-syn's lipid interactions in its function and aggregation is recognized, yet the specific lipids involved and how lipid metabolism issues trigger α-syn aggregation and neurodegeneration remain unclear. Here, we found that α-syn shows a preference for binding to lysophospholipids(LPLs),particularly targeting lysophosphatidylcholine(LPC) without relying on electrostatic interactions. LPC is capable of maintaining α-syn in a compact conformation, significantly reducing its propensity to aggregate both in vitro and within cellular environments. Conversely, a reduction in the production of cellular LPLs is associated with an increase in α-syn accumulation. Our work underscores the critical role of LPLs in preserving the natural conformation of α-syn to inhibit improper aggregation, and establishes a potential connection between lipid metabolic dysfunction and α-syn aggregation in PD.

关键词： α-synuclein Parkinson's disease lysophosphatidylcholine, aggregation