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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

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Role of lysosomal trafficking regulator in autophagic lysosome reformation in neurons:a disease perspective

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Neural Regeneration research 2024年第5期19卷 957-958页

作者： Prashant Sharma Jenny Serra-Vinardell Wendy J.Introne May Christine V.Malicdan NIH Undiagnosed Diseases Program Common FundOffice of the DirectorNational Institutes of HealthBethesdaMDUSA Human Biochemical Genetics Section Medical Genetics BranchNational Human Genome Research InstituteNational Institutes of HealthBethesdaMDUSA(Serra-Vinardell JIntrone)

Lysosomes are discrete organelles that act as recycling centers for extracellular and intracellular materials,playing a pivotal role in maintaining cellular *** acidic environment,maintained by numerous hydrolytic enzymes,facilitates substrate *** in lysosomal processes can lead to abnormal substrate degradation,significantly impacting cellular *** energy-demanding cells,such as post-mitotic neurons,are especially vulnerable to these changes,often resulting in neurological ***,a conserved catabolic process,requires extensive lysosomal *** plays a key role in removing unnecessary intracellular components,ensuring cellular homeostasis,and promoting cell survival during stress conditions such as starvation,infection,or cellular damage.

关键词： homeostasis lysosomal removing

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Peripheral Mechanism of Cancer-Induced Bone Pain

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Neuroscience Bulletin 2024年第6期40卷 815-830页

作者： Yachen Yang Wei Yang Ruofan Zhang Yanqing Wang Department of Integrative Medicine and Neurobiology School of Basic Medical SciencesShanghai Medical CollegeInstitute of Acupuncture ResearchInstitutes of Integrative MedicineFudan UniversityShanghai200032China Shanghai Key Laboratory of Acupuncture Mechanism and Acupoint Function Shanghai Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain ScienceInstitutes of Brain ScienceFudan UniversityShanghai200032China Zhongshan-Fudan Joint Innovation Center Zhongshan528437China

Cancer-induced bone pain(CIBP)is a type of ongoing or breakthrough pain caused by a primary bone tumor or bone *** constitutes a specific pain state with distinct characteristics;however,it shares similarities with inflammatory and neuropathic *** present,although various therapies have been developed for this condition,complete relief from CIBP in patients with cancer is yet to be ***,it is urgent to study the mechanism underlying CIBP to develop efficient analgesic ***,we focused on the peripheral mechanism associated with the initiation of CIBP,which involves tissue injury in the bone and changes in the tumor microenvironment(TME)and dorsal root *** nerve–cancer and cancer–immunocyte cross-talk in the TME creates circumstances that promote tumor growth and metastasis,ultimately leading to *** peripheral mechanism of CIBP and current treatments as well as potential therapeutic targets are discussed in this review.

关键词： Cancer-induced bone pain Peripheral mechanism Tumor microenvironment Sensory nerve Immunocytes

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Anti-epileptic and Neuroprotective Effects of Ultra-low Dose NADPH Oxidase Inhibitor Dextromethorphan on Kainic Acid-induced Chronic Temporal Lobe Epilepsy in Rats

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Neuroscience Bulletin 2024年第5期40卷 577-593页

作者： Jing-Jing Yang Ying-Xin Liu Yan-Fang Wang Bi-Ying Ge Ying Wang Qing-Shan Wang Sheng Li Jian-Jie Zhang Ling-Ling Jin Jau-Shyong Hong Sheng-Ming Yin Jie Zhao College of Basic medical Sciences Dalian Medical UniversityDalian116044China Department of Neurology The First Affiliated Hospital of Dalian Medical UniversityDalian116011China National and Local Joint Engineering research Center for Drug research and Development of Neurodegenerative Diseases Dalian116044China School of Public Health Dalian Medical UniversityDalian116044China Neurobiology Laboratory National Institute of Environmental Health SciencesNational Institutes of HealthResearch Triangle ParkDurhamNC27709USA

Neuroinflammation mediated by microglia and oxidative stress play pivotal roles in the development of chronic temporal lobe epilepsy(TLE).We postulated that kainic acid(KA)-Induced status epilepticus triggers microglia-dependent inflammation,leading to neuronal damage,a lowered seizure threshold,and the emergence of spontaneous recurrent seizures(SRS).Extensive evidence from our laboratory suggests that dextromethorphan(DM),even in ultra-low doses,has anti-inflammatory and neuroprotective effects in many animal models of neurodegenerative *** results showed that administration of DM(10 ng/kg per day;subcutaneously via osmotic minipump for 4 weeks)significantly mitigated the residual effects of KA,including the frequency of SRS and seizure *** addition,DM-treated rats showed improved cognitive function and reduced hippocampal neuronal *** found suppressed microglial activation-mediated neuroinflammation and decreased expression of hippocampal gp91^(phox) and p47^(phox) proteins in KA-induced chronic TLE ***,even after discontinuation of DM treatment,ultra-low doses of DM continued to confer long-term anti-seizure and neuroprotective effects,which were attributed to the inhibition of microglial NADPH oxidase 2 as revealed by mechanistic studies.

关键词： Temporal lobe epilepsy Dextromethorphan NADPH oxidase Ultra-low dose

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New glucocerebrosidase antibodies can advance research in the field of neurodegenerative disorders

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Neural Regeneration research 2025年第4期20卷 1085-1086页

作者： Charis Ma Krystyna Rytel Yu Chen Ellen Sidransky medical Genetics Branch National Human Genome Research InstituteNational Institutes of HealthBethesdaMDUSA

In medical research,there are times when the introduction of a new tool can launch scientific discovery in new *** antibody development may be considered mundane,in the field of glucocerebrosidase(GCase)research,the dearth of validated antibodies for different applications has impeded progress in studies of disease pathogenesis and therapeutic *** recent introduction of new,rigorously evaluated antibodies can now propel research into the link between glucocerebrosidase and Parkinson’s disease(PD)as well as aspects of the pathobiology of Gaucher disease(Jong et al.,2024).

关键词： antibodies cerebro

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Transcranial Magneto-Acoustic Stimulation Attenuates Synaptic Plasticity Impairment through the Activation of Piezo1 in Alzheimer’s Disease Mouse Model

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research 2024年第1期2023卷 81-95页

作者： Fangxuan Chu Ruxin Tan Xin Wang Xiaoqing Zhou Ren Ma Xiaoxu Ma Ying Li Ruixu Liu Chunlan Zhang Xu Liu Tao Yin Zhipeng Liu Institute of Biomedical Engineering Chinese Academy of Medical Sciences and Peking Union Medical CollegeTianjin300192China Tianjin institutes of Health Science Tianjin301600China Neuroscience Center Chinese Academy of Medical Science&Peking Union Medical CollegeBeijing100730China

The neuropathological features of Alzheimer’s disease include amyloid *** emerging evidence suggests that Piezo1,a mechanosensitive cation channel,plays a critical role in transforming ultrasound-related mechanical stimuli through its trimeric propeller-like structure,but the importance of Piezo1-mediated mechanotransduction in brain functions is less ***,apart from mechanical stimulation,Piezo1 channels are strongly modulated by *** assume that Piezo1 may play a role in converting mechanical and electrical signals,which could induce the phagocytosis and degradation of Aβ,and the combined effect of mechanical and electrical stimulation is superior to single mechanical ***,we design a transcranial magneto-acoustic stimulation(TMAS)system,based on transcranial ultrasound stimulation(TUS)within a magnetic field that combines a magnetoacoustic coupling effect electric field and the mechanical force of ultrasound,and applied it to test the above hypothesis in 5xFAD *** tests,in vivo electrophysiological recordings,Golgi–Cox staining,enzyme-linked immunosorbent assay,immunofluorescence,immunohistochemistry,real-time quantitative PCR,Western blotting,RNA sequencing,and cerebral blood flow monitoring were used to assess whether TMAS can alleviate the symptoms of AD mouse model by activating Piezo1.

关键词： stimulation Alzheimer Piezo1

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Targeting carnitine palmitoyl transferase 1A(CPT1A)induces ferroptosis and synergizes with immunotherapy in lung cancer

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Signal Transduction and Targeted Therapy 2024年第4期9卷 1675-1689页

作者： Lei Ma Chong Chen Chunxing Zhao Tong Li Lingyu Ma Jiayu Jiang Zhaojun Duan Qin Si Tsung-Hsien Chuang Rong Xiang Yunping Luo Department of Immunology Institute of Basic Medical SciencesChinese Academy of Medical SciencesSchool of Basic MedicinePeking Union Medical CollegeBeijing 100005China Collaborative Innovation Center for Biotherapy Institute of Basic Medical SciencesChinese Academy of Medical SciencesSchool of Basic MedicinePeking Union Medical CollegeBeijing 100005China Department of Lung Cancer Surgery Tianjin Medical University General HospitalTianjin 300052China Immunology research Center National Health Research InstitutesZhunanMiaoliTaiwanROC Department of Immunology Nankai UniversityTianjin 300071China

Despite the successful application of immune checkpoint therapy,no response or recurrence is typical in lung *** stem cells(CSCs)have been identified as a crucial player in immunotherapy-related ***,a form of cell death driven by iron-dependent lipid peroxidation,is highly regulated by cellular metabolism remolding and has been shown to have synergistic effects when combined with *** adaption of CsCs drives tumor resistance,yet the mechanisms of their ferroptosis defense in tumor immune evasion remain ***,through metabolomics,transcriptomics,a lung epithelialspecific Cptla-knockout mouse model,and clinical analysis,we demonstrate that CPT1A,a key rate-limiting enzyme of fatty acid oxidation,acts with L-carnitine,derived from tumor-associated macrophages to drive ferroptosis-resistance and CD8^(+)T cells inactivation in lung ***,CPT1A restrains ubiquitination and degradation of c-Myc,while c-Myc transcriptionally activates CPT1A *** CPT1A/c-Myc positive feedback loop further enhances the cellular antioxidant capacity by activating the NRF2/GPX4 system and reduces the amount of phospholipid polyunsaturated fatty acids through ACSL4 downregulating,thereby suppressing ferroptosis in ***,targeting CPT1A enhances immune checkpoint blockadeinduced anti-tumor immunity and tumoral ferroptosis in tumor-bearing *** results illustrate the potential of a mechanismguided therapeutic strategy by targeting a metabolic vulnerability in the ferroptosis of CsCs to improve the efficacy of lung cancer immunotherapy.

关键词： immunotherapy metabolism peroxidation

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Effects of Curcumin on Neuroinflammation and the Nrf2/HO-1 Pathway in Rat Brains Following Gas Explosion

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Biomedical and Environmental Sciences 2024年第8期37卷 943-947页

作者： Xinwen Dong Yaguang Su Zheng Luo Lyufei Deng Xiaofeng Han Yifang Liang Sanqiao Yao Weidong Wu Jia Cao Linqiang Tian Yichun Bai Wenjie Ren Health School of Public Health Xinxiang Medical UniversityXinxiang 453003HenanChina Toxicology research Institute PLA Army Medical UniversityChongqing 400038China Institute of Trauma and Orthopaedics Xinxiang Medical UniversityXinxiang 453003HenanChina institutes of Health Central Plains Xinxiang Medical UniversityXinxiang 453003HenanChina

Gas explosions,a major occupational hazard in China’s coal industry,endanger the lives and health of *** explosions cause a specific type of traumatic brain injury with complex mechanisms,leading to disability and death.A study by Zhao et *** magnetic resonance imaging on 49 gas explosion survivors revealed significant damage to brain regions like the hippocampus and cerebral cortex.

关键词： damage Nrf2 cerebral

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Role of cancer stem cell ecosystem on breast cancer metastasis and related mouse models

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Zoological research 2024年第3期45卷 506-517页

作者： Xilei Peng Haonan Dong Lixing Zhang Suling Liu Fudan University Shanghai Cancer Center&institutes of Biomedical Sciences/State Key Laboratory of Genetic Engineering/Cancer institutes/Department of Oncology/Key Laboratory of Breast Cancer in Shanghai/Shanghai Key Laboratory of medical Epigenetics/Shanghai Key Laboratory of Radiation Oncology/International Co-laboratory of medical Epigenetics and Metabolism Ministry of Science and Technology/Shanghai Medical College/Fudan UniversityShanghai 200032China

Breast cancer metastasis is responsible for most breast cancer-related deaths and is influenced by many factors within the tumor ecosystem,including tumor cells and *** cancer stem cells(BCSCs)constitute a small population of cancer cells with unique characteristics,including their capacity for self-renewal and *** have shown that BCSCs not only drive tumorigenesis but also play a crucial role in promoting metastasis in breast *** tumor microenvironment(TME),composed of stromal cells,immune cells,blood vessel cells,fibroblasts,and microbes in proximity to cancer cells,is increasingly recognized for its crosstalk with BCSCs and role in BCSC survival,growth,and dissemination,thereby influencing metastatic ***,a thorough understanding of BCSCs and the TME is critical for unraveling the mechanisms underlying breast cancer *** this review,we summarize current knowledge on the roles of BCSCs and the TME in breast cancer metastasis,as well as the underlying regulatory ***,we provide an overview of relevant mouse models used to study breast cancer metastasis,as well as treatment strategies and clinical trials addressing BCSC-TME interactions during ***,this study provides valuable insights for the development of effective therapeutic strategies to reduce breast cancer metastasis.

关键词： Breast cancer Metastasis Cancer stem cell Ecosystem Tumor microenvironment Mouse model

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Towards a blood ecosystem approach to dissect systemic diseases

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Science China(Life Sciences) 2024年第7期67卷 1528-1531页

作者： Hong Wang Tao Cheng State Key Laboratory of Experimental Hematology Haihe Laboratory of Cell EcosystemNational Clinical Research Center for Blood DiseasesInstitute of Hematology&Blood Diseases HospitalChinese Academy of Medical Sciences&Peking Union Medical CollegeTianjin 300020China Tianjin institutes of Health Science Tianjin 301600China

Systemic diseases,in contrast to localized ailments,exert widespread effects and can impact the entire *** of systemic diseases encompass autoimmune disorders,infectious diseases,metabolic disorders,and chronic conditions like *** diseases often entail intricate interactions among diverse organs,tissues,and physiological systems,influenced by a myriad of factors.

关键词： diseases organs autoimmune

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