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Overcoming adaptive resistance in AML by synergistically targeting FOXO3A-GNG7-mTOR axis with FOXO3A inhibitor Gardenoside and rapamycin

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Genes & Diseases 2024年第1期11卷 397-412页

作者： Zhe chen Qian Guo Shichen Huang Lei Li Feng Wu Zhilong Liu Zhigang Li Tao chen Guanbin Song Shuangnian Xu Jieping chen Yu Hou Department of Hematology Southwest HospitalThird Military Medical University(Army Medical University)Chongqing 400038China Institute of Life Sciences Chongqing Medical UniversityChongqing 400016China Key Laboratory of Biorheological Science and Technology Ministry of EducationCollege of BioengineeringChongqing UniversityChongqing 400044China chongqing Foreign Language School Chongqing 400039China

Therapeutic targeting FOxO3A(a forkhead transcription factor)represents a prom-ising strategy to suppress acute myeloid leukemia(AML).However,the effective inhibitors that target FOXO3A are lacking and the adaptive response signaling weakens the cytotoxic effect of FOxO3A depletion on AML cells.Here,we show that FOxO3A deficiency induces a compensa-tory response involved in the reactive activation of mTOR that leads to signaling rebound and adaptive resistance.Mitochondrial metabolism acts downstream of mTOR to provoke activa-tion of JNK/c-JUN via reactive oxygen species(ROS).At the molecular level,FOXO3A directly binds to the promoter of G protein gamma subunit 7(GNG7)and preserves its expression,while GNG7 interacts with mTOR and restricts phosphorylated activation of mTOR.consequently,combinatorial inhibition of FOXO3A and mTOR show a synergistic cytotoxic effect on AML cells and prolongs survival in a mouse model of AML.Through a structure-based virtual screening,we report one potent small-molecule FOxO3A inhibitor(Gardenoside)that exhibits a strong effect of anti-FOXO3A DNA binding.Gardenoside synergizes with rapamycin to substantially reduce tumor burden and extend survival in AML patient-derived xenograft model.These results demonstrate that mTOR can mediate adaptive resistance to FOxO3A inhibition and validate a combinatorial approach for treating AML.

关键词： AML combinatorial inhibition FOXO3A GNG7 mTOR

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Gd-EOB-DTPA增强MRI T1图评价非酒精性脂肪肝疾病的有效性

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国际医学放射学杂志 2014年第3期 306-306页

作者： Y.Ding S.X.Rao T.Meng c.chen R.Li M.S.Zeng 唐光健 Department of Radiology Zhongshan/Hospital of Fudan University

摘要目的本研究评价了Gd-EOB-DTPA增强MRI T1值测量用于非酒精性脂肪肝疾病(NAFLD)动物模型的诊断与分期价值。方法 34只兔子分为对照组(n=10)与NAFLD

关键词：非酒精性脂肪肝 Gd-EOB-DTPA MRI T1 NAFLD DTPA 疾病

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Durable Ru Nanocrystal with HfO_(2)Modification for Acidic Overall Water Splitting

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Nano-Micro Letters 2024年第9期16卷 462-477页

作者： Xiangkai Kong Jie Xu Zhicheng Ju changle chen School of Materials and Physics China University of Mining and TechnologyXuzhou 221116JiangsuPeople’s Republic of China Anhui Province Key Laboratory of Pollutant Sensitive Materials and Environmental Remediation Huaibei Normal UniversityHuaibei 235000AnhuiPeople’s Republic of China School of chemistry and Materials Science University of Science and Technology of ChinaHefei 230026AnhuiPeople’s Republic of China School of chemistry and chemical Engineering Nanjing UniversityNanjing 210023JiangsuPeople’s Republic of China

Durable and efficient bi-functional catalyst,that is capable of both oxygen evolution reaction and hydrogen evolution reaction under acidic condition,are highly desired for the commercialization of proton exchange membrane water electrolysis.Herein,we report a robust L-Ru/HfO_(2)heterostructure constructed via confining crystalline Ru nanodomains by HfO_(2)matrix.When assembled with a proton exchange membrane,the bi-functional L-Ru/HfO_(2)catalyst-based electrolyzer presents a voltage of 1.57 and 1.67 V to reach 100 and 300 mA cm^(-2)current density,prevailing most of previously reported Ru-based materials as well as commercial Pt/c||RuO_(2)electrolyzer.It is revealed that the synergistic effect of HfO_(2)modification and small crystalline domain formation significantly alleviates the over-oxidation of Ru.More importantly,this synergistic effect facilitates a dual-site oxide path during the oxygen evolution procedure via optimization of the binding configurations of oxygenated adsorbates.As a result,the Ru active sites maintain the metallic state along with reduced energy barrier for the rate-determining step(*O→*OOH).Both of water adsorption and dissociation(Volmer step)are strengthened,while a moderate hydrogen binding is achieved to accelerate the hydrogen desorption procedure(Tafel step).consequently,the activity and stability of acidic overall water splitting are simultaneously enhanced.

关键词： Ruthenium Hafnium dioxide Oxygen evolution catalysis Anti-oxidation

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Serum 25-hydroxyvitamin D, genetic susceptibility, and the risk of incident type 2 diabetes: A prospective cohort in East china

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中华医学杂志(英文版) 2024年第8期137卷 972-979页

作者： Sun Ying Zhang Haojie Wang Bin Wang Yuying chen chi chen Yi Lu Yingli Wang Ningjian West china Hospital Sichuan University chengdu Sichuan 610041 Department of Endocrinology Shuguang Hospital Affiliated to Shanghai University of Traditional chinese Medicine Shanghai 201203 Institute and Department of Endocrinology and Metabolism Shanghai Ninth People’s Hospital Shanghai JiaoTong University School of Medicine Shanghai 200011 china Department of Endocrinology and Metabolism and Department of Guideline and Rapid Recommendation cochrane china center MAGIc china center chinese Evidence-Based Medicine center

Background: The serum vitamin D level varies widely by population, and studies have linked vitamin D levels with the risk of type 2 diabetes mellitus (T2DM). However, the relationship is inconsistent and the impact of vitamin D on T2DM among East chinese adults is unclear. The study aimed to investigate the association between serum 25-hydroxyvitamin D (25[OH]D) levels and the risk of T2DM and evaluated whether the association is modified by genetic predisposition.Methods: In the Survey on Prevalence in East china for Metabolic Diseases and Risk Factors (SPEcT-china) cohort, 1862 participants free of T2DM at baseline were included. A weighted genetic risk score was calculated with 28 variants associated with T2DM. Hierarchical logistic models were used to examine the association of serum 25(OH)D and genetic risk with T2DM.Results: After a 5-year follow-up, 132 cases of T2DM were documented. We observed no significant association between quartiles of serum 25(OH)D and T2DM risk after multivariable adjustment (χ2 = 0.571,Pfor trend = 0.426). compared to those in the lowest quartile of 25(OH)D, the odds ratios (ORs) (95% confidence interval [cI]) for participants with increased quartiles were 1.29 (0.74-2.25), 1.35 (0.77-2.36), and 1.27 (0.72-2.24), respectively. We observed a positive association of glycated hemoglobin (HbA1c) with 25(OH)D at baseline (β = 1.752,P = 0.001) and after follow-up (β = 1.385,P = 0.003), and a negative association of ln conversion homeostasis model assessment (HOMA)-β with 25(OH)D at baseline (β = -0.982,P = 0.021). There was no significant interaction between 25(OH)D and diabetes genetic predisposition on the risk of T2DM (χ2 = 2.710,Pfor interaction = 0.100). The lowest OR (95% cI) of T2DM was among participants with low genetic risk and the highest quartile of 25(OH)D (0.17 [0.05–0.62]).conclusion: Serum 25(OH)D may be irrelevant to the risk of incident T2DM among East chinese adults regardless of genetic predisposition.

关键词： Vitamin D Diabetes mellitus, Type 2 Genetic predisposition to disease Prospective cohort Glycated hemoglobin SPEcT-china

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Aberrant epithelial cell interaction promotes esophageal squamous-cell carcinoma development and progression

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Signal Transduction and Targeted Therapy 2024年第1期9卷 279-294页

作者： Liping chen Shihao Zhu Tianyuan Liu Xuan Zhao Tao Xiang Xiao Hu chen Wu Dongxin Lin Department of Etiology and carcinogenesis National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China Key Laboratory of cancer Genomic Biology Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China collaborative Innovation center for cancer Personalized Medicine Nanjing Medical UniversityNanjing 211166China cAMS Oxford Institute Chinese Academy of Medical SciencesBeijing 100006China Sun Yat-sen University cancer center State Key Laboratory of Oncology in South ChinaGuangzhou 510060China

Epithelial-mesenchymal transition(EMT)and proliferation play important roles in epithelial cancer formation and progression,but what molecules and how they trigger EMT is largely unknown.Here we performed spatial transcriptomic and functional analyses on samples of multistage esophageal squamous-cell carcinoma(EScc)from mice and humans to decipher these critical issues.By investigating spatiotemporal gene expression patterns and cell–cell interactions,we demonstrated that the aberrant epithelial cell interaction via EFNB1-EPHB4 triggers EMT and cell cycle mediated by downstream SRc/ERK/AKT signaling.The aberrant epithelial cell interaction occurs within the basal layer at early precancerous lesions,which expands to the whole epithelial layer and strengthens along the cancer development and progression.Functional analysis revealed that the aberrant EFNB1-EPHB4 interaction is caused by overexpressedΔNP63 due to TP53 mutation,the culprit in human EScc tumorigenesis.Our results shed new light on the role of TP53-TP63/ΔNP63-EFNB1-EPHB4 axis in EMT and cell proliferation in epithelial cancer formation.

关键词： esophageal TP53 squamous

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On the half-quantized Hall conductance of massive surface electrons in magnetic topological insulator films

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Science china(Physics,Mechanics & Astronomy) 2024年第6期67卷 127-136页

作者： Rui chen Shun-Qing Shen Department of Physics The University of Hong KongHong Kong 999077China Department of Physics Hubei UniversityWuhan 430062China

In topological insulators,massive surface states resulting from local symmetry breaking were thought to exhibit a half-quantized Hall conductance,obtained from the low-energy effective model in an infinite Brillouin zone.In a lattice model,the surface band is composed of a combination of surface states and bulk states.The massive surface states alone may not be enough to support an exact one-half quantized surface Hall conductance in a finite Brillouin zone and the whole surface band always gives an integer quantized Hall conductance as enforced by the TKNN theorem.To explore this,we investigate the band structures of a lattice model describing the magnetic topological insulator film that supports the axion insulator,chern insulator,and semi-magnetic topological insulator phases.We reveal that the gapped and gapless surface bands in the three phases are characterized by an integer-quantized Hall conductance and a half-quantized Hall conductance,respectively.We propose an effective model to describe the three phases and show that the low-energy dispersion of the surface bands inherits from the surface Dirac fermions.The gapped surface band manifests a nearly half-quantized Hall conductance at low energy near the center of Brillouin zone,but is compensated by another nearly half-quantized Hall conductance at high energy near the boundary of Brillouin zone because a single band can only have an integer-quantized Hall conductance.The gapless band hosts a zero Hall conductance at low energy but is compensated by another half-quantized Hall conductance at high energy,and thus the half-quantized Hall conductance can only originate from the gapless band.Moreover,we calculate the layer-resolved Hall conductance of the system.The conclusion suggests that the individual gapped surface band alone does not support the half-quantized surface Hall effect in a lattice model.

关键词： magnetic topological insulator Dirac equation half-quantized Hall conductance

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cu_(2)Se@c thin film with three-dimensional braided structure as a cathode material for enhanced cu^(2+) storage

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chinese chemical Letters 2024年第5期35卷 523-528页

作者： Wenhao chen Muxuan Wu Han chen Lue Mo Yirong Zhu college of Materials and Advanced Manufacturing Hunan University of TechnologyZhuzhou 412007China Hunan Key of Laboratory of Applied Environmental Photocatalysis Changsha UniversityChangsha 410022China

In the face of multiple challenges brought by the changes of global climate and environment,developing clean energy and updating green energy storage equipment are important ways to achieve carbon peak and carbon neutrality.Aqueous batteries have become a research hotspot due to their advantages of using the multivalent charge carrier,high ionic conductivity,environmental friendliness and cost effectiveness.In this work,the cu_(2)Se@c(cu_(2)Se coated on carbon clothes)thin film with a three-dimensional braided structure is fabricated by a simple electrochemical deposition method for cu^(2+)storage for the first time.compared with the commercial cu_(2)Se powder,the well-designed cu_(2)Se@c film shows enhanced specific capacity(640 mAh/g at 0.5 A/g)and rate performance(542 mAh/g at 5 A/g)as well as superior cycling stability(82.7%capacity retention after 1000 cycles at 1 A/g).The cu^(2+)storage mechanism of the cu_(2)Se@c electrode is based on a reversible phase transition process of cu_(2)Se←→cu_(2-x)Se←→cuSe←→cuSe_(2).In kinetic characteristic analysis,the cu_(2)Se@c electrode demonstrates faster cu^(2+)diffusion in discharge process than charge process resulting from the phase transition and the variation of interplanar spacing.This work highlights a facile one-piece design strategy and opens a new gateway for the exploration of advanced aqueous energy storage systems.

关键词： cu_(2)Se@c cu^(2+)storage conversion mechanism Kinetic characteristic Flexible energy storage

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Single-cell transcriptomics reveals the ameliorative effect of rosmarinic acid on diabetic nephropathy-induced kidney injury by modulating oxidative stress and inflammation

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Acta Pharmaceutica Sinica B 2024年第4期14卷 1661-1676页

作者： Junhui chen Qian Zhang Jinan Guo Di Gu Jing Liu Piao Luo Yunmeng Bai Jiayun chen Xinzhou Zhang Sheng Nie chunbo chen Yulin Feng Jigang Wang National Pharmaceutical Engineering center for Solid Preparation of chinese Herbal Medicine Jiangxi University of Chinese MedicineNanchang 330006China Department of Pulmonary and critical care Medicine Shenzhen Institute of Respiratory Diseasesand Shenzhen Clinical Research Centre for GeriatricsShenzhen People's HospitalFirst Affiliated Hospital of Southern University of Science and TechnologySecond Clinical Medical College of Jinan UniversityShenzhen 518020China School of Traditional chinese Medicine and School of Pharmaceutical Sciences Southern Medical UniversityGuangzhou 510515China Department of Urology and Shenzhen Clinical Research Centre for GeriatricsShenzhen People's Hospitalthe First Affiliated HospitalSouthern University of Science and TechnologyShenzhen 518020China Department of Urology the First Affiliated Hospital of Guangzhou Medical UniversityGuangzhou 510230China Department of Nephrology Shenzhen Key Laboratory of Kidney Diseasesand Shenzhen Clinical Research Centre for GeriatricsShenzhen People's Hospitalthe First Affiliated HospitalSouthern University of Science and TechnologyShenzhen 518020China Department of Nephrology Nanfang Hospitalthe First Affiliated Hospital of Southern Medical UniversityGuangzhou 510515China Department of critical care Medicine Shenzhen People's Hospital(the Second Clinical Medical CollegeJinan Universitythe First Affiliated HospitalSouthern University of Science and Technology)Shenzhen 518020China State Key Laboratory for Quality Esurance and Sustainable Use of Dao-di Herbs Artemisinin Research Centerand Institute of Chinese Materia MedicaChina Academy of Chinese Medical SciencesBeijing 100700China Department of Oncology the Affiliated Hospital of Southwest Medical UniversityLuzhou 646000China

Diabetic nephropathy(DN)is a severe complication of diabetes,characterized by changes in kidney structure and function.The natural product rosmarinic acid(RA)has demonstrated therapeutic effects,including anti-inflammation and anti-oxidative-stress,in renal damage or dysfunction.In this study,we characterized the heterogeneity of the cellular response in kidneys to DN-induced injury and RA treatment at single cell levels.Our results demonstrated that RA significantly alleviated renal tubular epithelial injury,particularly in the proximal tubular S1 segment and on glomerular epithelial cells known as podocytes,while attenuating the inflammatory response of macrophages,oxidative stress,and cytotox-icity of natural killer cells.These findings provide a comprehensive understanding of the mechanisms by which RA alleviates kidney damage,oxidative stress,and inflammation,offering valuable guidance for the clinical application of RA in the treatment of DN.

关键词： Rosmarinic acid Diabetic nephropathy scRNA sequencing Injury Oxidative stress Infiammation Proteomics

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Microglial glutaminase 1 mediates chronic restraint stress-induced depression-like behaviors and synaptic damages

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Signal Transduction and Targeted Therapy 2024年第1期9卷 40-43页

作者： Huili chen Shengyang Fu Xiangyu Li Meng Shi Jiazhen Qian Shu Zhao Ping Yuan Lu Ding Xiaohuan Xia Jialin c.Zheng center for Translational Neurodegeneration and Regenerative Therapy Tongji Hospital affiliated to Tongji University School of Medicine200065 ShanghaiChina Department of cardio-Pulmonary circulation Shanghai Pulmonary HospitalSchool of MedicineTongji UniversityShanghaiChina Translational Research Institute of Brain and Brain-Like Intelligence Shanghai Fourth People’s Hospital affiliated to Tongji University School of Medicine200434 ShanghaiChina

Dear Editor,Major depressive disorder(MDD)is one of the most common psychiatric illnesses that significantly increase the risk of suicide.1 Stress-triggered dysfunctions of microglia have been identified as a commonly occurred pathological feature of MDD.1–3 Microglial dysfunction contributes to the pathogenesis of MDD via immunoresponses/neuroinflammation-mediated neural damage and pathological synapse loss-mediated neural circuit disruption.1 Although the involvement of microglia in MDD has been widely investigated,the molecular mechanisms underlying microglial dysfunction remain largely unknown.Recently,we identified glutaminase 1(Gls1)as one key protein that participates in microglial dysfunction.4–6 Gls1 catalyzes the hydrolysis of glutamine to produce glutamate in the brain.4 Besides its well-known role in excitatory neurotoxicity,we found Gls1 up-regulation in microglia in animal models of Alzheimer’s disease and ischemic stroke.4,7 Gls1 activates microglia to overproduce cytokines and release inflammatory extracellular vesicles,therefore leading to neuroinflammation in animal models of Alzheimer’s disease and ischemic stroke.4–6 More importantly,Gls1 has been found to be up-regulated in the brains of MDD patients,and microglial Gls1 deficiency mitigated LPS-induced depression-like behaviors.8 However,LPS exposure is not an appropriate model to mimic MDD phenotypes,leaving the involvement of Gls1 in MDD an undetermined question.

关键词： involvement inflammation media

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Blood pressure targets in patients with chronic kidney disease:comments and controversies

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chinese Medical Journal 2024年第3期137卷 270-272页

作者： Ying Zheng Guangyan cai Xiangmei chen Department of Nephrology First Medical Center of Chinese PLA General HospitalNational Key Laboratory of Kidney DiseasesNational Clinical Research Center for Kidney DiseasesBeijing Key Laboratory of Kidney Disease ResearchBeijing 100853China

According to the Global Burden of Disease Study 2017,there are 132 million patients with chronic kidney disease(cKD)in china,^([1])and the prevalence of hypertension in chinese patients with cKD(67.3%)is significantly higher than that in the general population(23.2%).^([2,3])cKD is both a cause and a consequence of hypertension,and these two conditions form a vicious cycle that leads to the high prevalence rate of hypertension in patients with cKD.Uncontrolled hypertension accelerates the deterioration of renal function,which significantly increases the risk of developing end-stage renal disease(ESRD),as well as cardiovascular and cerebrovascular diseases,leading to poor patient outcomes.

关键词： patients Blood hypertension

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