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Boosting synergism of chemo- and immunotherapies via switching paclitaxel-induced apoptosis to mevalonate metabolism-triggered ferroptosis by bisphosphonate coordination lipid nanogranules

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Acta Pharmaceutica Sinica B 2024年第2期14卷 836-853页

作者： Ge Song Minghui li Shumin Fan Mengmeng Qin Bin Shao Wenbing dai Hua Zhang Xueqing Wang Bing He qiang Zhang Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems School of Pharmaceutical SciencesPeking UniversityBeijing 100191China State Key Laboratory of Natural and Biomimetic Drugs School of Pharmaceutical SciencesPeking UniversityBeijing 100191China Department of Medical Oncology Key Laboratory of Carcinogenesis and Translational Research(Ministry of Education)Peking University Cancer HospitalBeijing 100142China

Conventional chemotherapy based on cytotoxic drugs is facing tough challenges recently following the advances of monoclonal antibodies and molecularly targeted *** is critical to inspire new potential to remodel the value of this classical therapeutic ***,we fabricate bisphosphonate coordination lipid nanogranules(BC-LNPs)and load paclitaxel(PTX)to boost the chemo-and immuno-therapeutic synergism of cytotoxic *** in BC-LNPs@PTX,a bisphosphonate to block mevalonate metabolism,works as both the structure and drug constituent in nanogranules,where alendronate coordinated with calcium ions to form the particle *** synergy of alendronate enhances the efficacy of paclitaxel,suppresses tumor metastasis,and alters the cytotoxic *** from the paclitaxel-induced apoptosis,the involvement of alendronate inhibits the mevalonate metabolism,changes the mitochondrial morphology,disturbs the redox homeostasis,and causes theaccumulation of mitochondrial ROS and lethal lipid peroxides(LPO).These factors finally trigger the ferroptosis of tumor cells,an immunogenic cell death mode,which remodels the suppressive tumor immune microenvironment and synergizes with ***,by switching paclitaxel-induced apoptosis to mevalonate metabolism-triggered ferroptosis,BC-LNPs@PTX provides new insight into the development of cytotoxic drugs and highlights the potential of metabolism regulation in cancer therapy.

关键词： Bisphosphonate coordinationlipid nanogranules Ferroptosis Mevalonatemetabolism Mitochondrial metabolism Nano-systematic biology

SH2B1 Tunes Hippocampal ERK Signaling to Influence Fluid Intelligence in Humans and Mice

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Research 2024年第3期2023卷 369-389页

作者： Xiujuan Du Yuhua Yan Juehua Yu Tailin Zhu Chu-Chung Huang lingli Zhang Xingyue Shan Ren li Yuan dai Hui LV Xiao-Yong Zhang Jianfeng Feng Wei-Guang li qiang Luo Fei li Developmental and Behavioral Pediatric Department Brain and Behavioral Research Unit of Shanghai Institute for Pediatric Research and Ministry of Education-Shanghai Key Laboratory for Children's Environmental HealthXinhua Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai 200092China Developmental and Behavioral Pediatric Department Shanghai Xinhua Children's HospitalShanghai 200092China National Clinical Research Center for Aging and Medicine at Huashan Hospital Institute of Science and Technology for Brain-lnspired IntelligenceMinistry of Education-Key Laboratory of Computational Neuroscience and Brain-lnspired IntelligenceFudan UniversityShanghai 200433China State Key Laboratory of Medical Neurobiology and Ministry of Education Frontiers Center for Brain Science Institutes of Brain Science and Human Phenom InstituteFudan UniversityShanghai 200032China Shanghai Key Laboratory of Brain Functional Genomics(Ministry of Education) School of Life SciencesEast China Normal UniversityShanghai 200062China Department of Rehabilitation Medicine Huashan HospitalInstitute for Translational Brain ResearchState Key Laboratory of Medical Neurobiology and Ministry of Education Frontiers Center for Brain ScienceFudan UniversityShanghai 200032China Center for Experimental Studies and Research The First Affliated Hospital of Kunming Medical UniversityKunming 650032China Shanghai Research Center for Brain Science and Brain-lnspired Intelligence Shanghai201210China Institute of Cognitive Neuroscience School of Psychology and Cognitive ScienceEast China Normal UniversityShanghai 200062China.

Fluid intelligence is a cognitive domain that encompasses general reasoning, pattern recognition, and problem-solving abilities independent of task-specific experience. Understanding its genetic and neural underpinnings is critical yet challenging for predicting human development, lifelong health, and well-being. One approach to address this challenge is to map the network of correlations between intelligence and other constructs. In the current study, we performed a genome-wide association study using fluid intelligence quotient scores from the UK Biobank to explore the genetic architecture of the associations between obesity risk and fluid intelligence. Our results revealed novel common genetic loci (SH2B1, TUFM, ATP2A1, and FOXO3) underlying the association between fluid intelligence and body metabolism. Surprisingly, we demonstrated that SH2B1 variation influenced fluid intelligence independently of its effects on metabolism but partially mediated its association with bilateral hippocampal volume. Consistently, selective genetic ablation of Sh2b1 in the mouse hippocampus, particularly in inhibitory neurons, but not in excitatory neurons, significantly impaired working memory, short-term novel object recognition memory, and behavioral flexibility, but not spatial learning and memory, mirroring the human intellectual performance. Single-cell genetic profiling of Sh2B1-regulated molecular pathways revealed that Sh2b1 deletion resulted in aberrantly enhanced extracellular signal-regulated kinase (ERK) signaling, whereas pharmacological inhibition of ERK signaling reversed the associated behavioral impairment. Our cross-species study thus provides unprecedented insight into the role of SH2B1 in fluid intelligence and has implications for understanding the genetic and neural underpinnings of lifelong mental health and well-being.

关键词： metabolism impaired reversed

A seismic elastic moduli module for the measurements of low-frequency wave dispersion and attenuation of fluid-saturated rocks under different pressures

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Petroleum Science 2024年第1期21卷 162-181页

作者： Yan-Xiao He Shang-Xu Wang Gen-Yang Tang Chao Sun Hong-Bing li San-Yi Yuan Xian Wei li-Deng Gan Xiao-Feng dai qiang Ge Peng-Peng Wei Hui-Qing Zhang National Key Laboratory of Petroleum Resources and Engineering CNPC Key Lab of Geophysical ExplorationCollege of GeophysicsChina University of Petroleum(Beijing)Beijing102249China School of Resources and Geosciences China University of Mining and TechnologyXuzhou221116JiangsuChina Research Institute of Petroleum Exploration and Development CNPCBeijing100083China Beijing Vocational College of Labour and Social Security Beijing100029China PetroChina Dagang Oilfield Exploration and Development Research Institute CNPCTianjin300280China

Knowledge about the seismic elastic modulus dispersion,and associated attenuation,in fluid-saturated rocks is essential for better interpretation of seismic observations taken as part of hydrocarbon identification and time-lapse seismic surveillance of both conventional and unconventional reservoir and overburden performances.A Seismic Elastic Moduli Module has been developed,based on the forced-oscillations method,to experimentally investigate the frequency dependence of Young's modulus and Poisson's ratio,as well as the inferred attenuation,of cylindrical samples under different confining pressure *** with three standard samples showed that the measured elastic moduli were consistent with the published data,indicating that the new apparatus can operate reliably over a wide frequency range of f∈[1-2000,10^(6)]*** Young's modulus and Poisson's ratio of the shale and the tight sandstone samples were measured under axial stress oscillations to assess the frequency-and pressure-dependent *** dry condition,both samples appear to be nearly frequency independent,with weak pressure dependence for the shale and significant pressure dependence for the *** particular,it was found that the tight sandstone with complex pore microstructure exhibited apparent dispersion and attenuation under brine or glycerin saturation conditions,the levels of which were strongly influenced by the increased effective *** addition,the measured Young's moduli results were compared with the theoretical predictions from a scaled poroelastic model with a reasonably good agreement,revealing that the combined fluid flow mechanisms at both mesoscopic and microscopic scales possibly responsible for the measured dispersion.

关键词： Low-frequency measurements Dispersion and attenuation Rock physics Fluid flow

Exosomes derived from microglia overexpressing miR-124-3p alleviate neuronal endoplasmic reticulum stress damage after repetitive mild traumatic brain injury

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Neural Regeneration Research 2024年第9期19卷 2010-2018页

作者： Yan Wang dai li Lan Zhang Zhenyu Yin Zhaoli Han Xintong Ge Meimei li Jing Zhao Shishuang Zhang Yan Zuo Xiangyang Xiong Han Gao qiang liu Fanglian Chen Ping Lei Department of Geriatrics Tianjin Medical University General HospitalTianjinChina Tianjin Geriatrics Institute Tianjin Medical University General HospitalTianjinChina Tianjin Neurological Institute Tianjin Medical University General HospitalTianjinChina

We previously reported that miR-124-3p is markedly upregulated in microglia-derived exosomes following repetitive mild traumatic brain ***,its impact on neuronal endoplasmic reticulum stress following repetitive mild traumatic brain injury remains *** this study,we first used an HT22 scratch injury model to mimic traumatic brain injury,then co-cultured the HT22 cells with BV2 microglia expressing high levels of *** found that exosomes containing high levels of miR-124-3p attenuated apoptosis and endoplasmic reticulum ***,luciferase reporter assay analysis confirmed that miR-124-3p bound specifically to the endoplasmic reticulum stress-related protein IRE1α,while an IRE1αfunctional salvage experiment confirmed that miR-124-3p targeted IRE1αand reduced its expression,thereby inhibiting endoplasmic reticulum stress in injured ***,we delivered microglia-derived exosomes containing miR-124-3p intranasally to a mouse model of repetitive mild traumatic brain injury and found that endoplasmic reticulum stress and apoptosis levels in hippocampal neurons were significantly *** findings suggest that,after repetitive mild traumatic brain injury,miR-124-3 can be transferred from microglia-derived exosomes to injured neurons,where it exerts a neuroprotective effect by inhibiting endoplasmic reticulum ***,microglia-derived exosomes containing miR-124-3p may represent a novel therapeutic strategy for repetitive mild traumatic brain injury.

关键词： apoptosis C/EBP homologous protein endoplasmic reticulum stress exosome inositol-requiring enzyme 1α microglia miR-124-3p neuron repetitive mild traumatic brain injury X-box binding protein 1

3 - 62 Influence of Scan Step on Monitor Calibration in Spot Scanning with Carbon Ions

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IMP & HIRFL Annual Report 2010年第1期 160-160页

作者： dai zhongying li qiang liu Xinguo Huang Qiyan