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NF-κB in biology and targeted therapy:new insights and translational implications

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Signal Transduction and Targeted Therapy 2024年第4期9卷 1322-1358页

作者： Qing Guo Yizi Jin Xinyu Chen Xiaomin Ye Xin Shen Mingxi Lin cheng zeng Teng Zhou Jian Zhang Department of Medical Oncology Fudan University Shanghai Cancer CenterNo.270Dong'an RoadShanghai 200032China Department of Oncology Shanghai Medical CollegeFudan UniversityShanghaiChina State Key Laboratory of Oncogenes and Related Genes Renj-Med-X Stem Cell Research CenterShanghai Cancer Institute&Department of UrologyRen Ji HospitalSchool of Medicine and School of Biomedical EngineeringShanghai Jiao Tong UniversityShanghai 200127PR China Department of Cardiology the First Affiliated Hospital of Sun Yat-Sen University58 Zhongshan 2nd RoadGuangzhou 510080China Department of Neurology Rujin HospitalShanghai JiaoTong University Schoolof MedicineShanghaiChina

NF-κB signaling has been discovered for nearly 40 years.Initially,NF-κB signaling was identified as a pivotal pathway in mediating inflammatory responses.However,with extensive and in-depth investigations,researchers have discovered that its role can be expanded to a variety of signaling mechanisms,biological processes,human diseases,and treatment options.In this review,we first scrutinize the research process of NF-κB signaling,and summarize the composition,activation,and regulatory mechanism of NF-κB signaling.We investigate the interaction of NF-κB signaling with other important pathways,including PI3K/AKT,MAPK,JAK-STAT,TGF-β,Wnt,Notch,Hedgehog,and TLR signaling.The physiological and pathological states of NF-κB signaling,as well as its intricate involvement in inflammation,immune regulation,and tumor microenvironment,are also explicated.Additionally,we illustrate how NF-κB signaling is involved in a variety of human diseases,including cancers,inflammatory and autoimmune diseases,cardiovascular diseases,metabolic diseases,neurological diseases,and covID-19.Further,we discuss the therapeutic approaches targeting NF-κB signaling,including IKK inhibitors,monoclonal antibodies,proteasome inhibitors,nuclear translocation inhibitors,DNA binding inhibitors,TKls,non-coding RNAs,immunotherapy,and CAR-T.Finally,we provide an outlook for research in the field of NF-κB signaling.We hope to present a stereoscopic,comprehensive NF-κB signaling that will inform future research and clinical practice.

关键词： PI3K/AKT diseases involvement

ERβ-activated LINC01018 promotes endometriosis development by regulating the CDC25C/CDK1/CyclinB1 pathway

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Journal of Genetics and Genomics 2024年第6期51卷 617-629页

作者： Ruihui Lu Jingwen Zhu Xin Li cheng zeng Yan Huang Chao Peng Yingfang Zhou Qing Xue Department of Obstetrics and Gynecology Peking University First HospitalBeijing 100034China

Endometriosis refers to as an estrogen-dependent disease.Estrogen receptorβ(ERB),the main estrogen receptor subtype which is encoded by the estrogen receptor 2(ESR2)gene,can mediate the action of estrogen in endometriosis.Although selective estrogen receptor modulators can target the ERβ,they are not specific due to the wide distribution of ERβ.Recently,long noncoding RNAs have been implicated in endometriosis.Therefore,we aim to explore and validate the downstream regulatory mechanism of ERβ,and to investigate the potential role of long intergenic noncoding RNA 1018(LINC01018)as a nonhormonal treatment for endometriosis.Our study demonstrates that the expression levels of ESR2 and LINCo1018 are increased in ectopic endometrial tissues and reveals a significant positive correlation between the ESR2 and LINCo1018 expression.Mechanistically,ERβdirectly binds to an estrogen response element located in the LINCO1018 promoter region and activates LINC01018 transcription.Functionally,ERβcan regulate the CDC25C/CDK1/CyclinB1 pathway and promote ectopic endometrial stromal cell proliferation via LINC01018 in vitro.Consistent with these findings,the knockdown of LINC01018 inhibits endometriotic lesion proliferation in vivo.In summary,our study demonstrates that the ERβ/LINC01018/CDC25C/CDK1/CyclinB1 signaling axis regulates endometriosis progression.

关键词： Estrogen receptorβ Long intergenic noncoding RNA 1018 (LINC01018) Endometriosis Cell cycle Proliferation

A back analysis scheme for refined soil stratification based on integrating borehole and CPT data

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Geoscience Frontiers 2024年第1期15卷 1-16页

作者： Jiawei Xie cheng zeng Jinsong Huang Yuting Zhang Jianlin Lu Discipline of Civil Surveying&Environmental EngineeringPriority Research Centre for Geotechnical Science&EngineeringThe University of NewcastleCallaghanNSW 2308Australia

Utilizing both borehole and Cone Penetration Testing(CPT)data in soil stratification helps to get more convincing soil stratification results.However,the soil classification results revealed by borehole(Unified Soil Classification System,USCS)and CPT tests(soil behavior type,SBT)are commonly not con-sistent.This study proposes a feasible solution to integrate the borehole and CPT data with the tree-based method.The tree-based method is naturally suitable for soil stratification tasks as it aims to divide the subsurface space into several clusters based on the similarities of the soil types.A novel boundary dic-tionary method is proposed to enhance the model performance on complex soil layer conditions.A prob-abilistic mapping matrix between the USCS-SBT system is built based on a collected municipal database with collocated borehole and CPT data.The optimal soil stratification results can be selected based on considering multiple borehole information and pruning the structure of trees.The structure of the trees can be optimized in a back analysis perspective with the Sequential Model-Based Global Optimization(SMBO)algorithm which aims to maximize the possibility of observing the borehole information based on the USCS-SBT probabilistic mapping matrix.The uncertainties of the optimal soil stratification results can be estimated based on a weighted Gini index method.The performance of the proposed method is validated based on a real case in New Zealand with a cross-validation method.The results indicate that the proposed method is robust and effective.

关键词： Soil stratification Data integration Borehole CPT Tree-based method

Targeted and activatable nanosystem for fluorescent and optoacoustic imaging of immune-mediated inflammatory diseases and therapy via inhibiting NF-κB/NLRP3 pathways

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Bioactive Materials 2022年第4期7卷 79-92页

作者： Lihe Sun Juan Ouyang Zhuo zeng cheng zeng Yunqing Ma Fang zeng Shuizhu Wu Biomedical Division State Key Laboratory of Luminescent Materials and DevicesGuangdong Provincial Key Laboratory of Luminescence from Molecular AggregatesCollege of Materials Science and EngineeringSouth China University of TechnologyGuangzhou510640China

Immune-mediated inflammatory diseases(IMIDs)represent a diverse group of diseases and challenges remain for the current medications.Herein,we present an activatable and targeted nanosystem for detecting and imaging IMIDs foci and treating them through blocking NF-κB/NLRP3 pathways.A ROS-activatable prodrug BH-EGCG is synthesized by coupling a near-infrared chromophore with the NF-κB/NLRP3 inhibitor epigallocatechin-3-gallate(EGCG)through boronate bond which serves as both the fluorescence quencher and ROS-responsive moiety.BH-EGCG molecules readily form stable nanoparticles in aqueous medium,which are then coated with macrophage membrane to ensure the actively-targeting capability toward inflammation sites.Additionally,an antioxidant precursor N-acetylcysteine is co-encapsulated into the coated nanoparticles to afford the nanosystem BH-EGCG&NAC@MM to further improve the anti-inflammatory efficacy.Benefiting from the inflammation-homing effect of the macrophage membrane,the nanosystem delivers payloads(diagnostic probe and therapeutic drugs)to inflammatory lesions more efficiently and releases a chromophore and two drugs upon being triggered by the overexpressed in-situ ROS,thus exhibiting better theranostic performance in the autoimmune hepatitis and hind paw edema mouse models,including more salient imaging signals and better therapeutic efficacy via inhibiting NF-κB pathway and suppressing NLRP3 inflammasome activation.This work may provide perceptions for designing other actively-targeting theranostic nanosystems for various inflammatory diseases.

关键词： Actively-targeting nanosystem Immune-mediated inflammatory disease Two-mode imaging NF-κB/NLRP3 pathways

Opening the“Black Box”:How Out-of-Class Use of Duolingo Impacts Chinese Junior High School Students'Intrinsic Motivation for English

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ECNU Review of Education 2024年第2期7卷 283-307页

作者：曾成 Linda Fisher 184 Hills Road Cambridge CB28PQUK

Purpose:Mobile-assisted language learning(MALL)apps such as Duolingo have great potential for promoting learners'motivation to learn a second language(L2).However,little research has investigated how this motivational impact takes place.Additionally,despite the flexibility of mobile learning,most existing studies are conducted in classroom settings,with less attention paid to out-of-school technology usage.Design/Approach/Methods:To address these gaps,we present a model based on self-determination theory and propose the idea of“motivational transfer”to explain the psychological mechanism underpinning the impact of technology.To examine the model,we conducted a case study with 20 Year 8 Chinese junior school students who used Duolingo to learn English as a foreign language(EFL)after school for 6 weeks.Findings:Questionnaire and group interview data support our hypothesized mechanism:learners'activity-specific intrinsic motivation(IM)for using Duolingo and their underlying psychological need for autonomy and competence can be transferred to a more general level,thereby enhancing learners'global IMforL2.OriginalityValue:The proposed theoretical model expands our understanding of how digital technology stimulates learners'L2 motivation;it can help L2 educators design better technological affordances to promote learners'motivation both in and outside the classroom.

关键词： Digital game-based learning L2 motivation MALL self-determination theory

The p21-activated kinases in neural cytoskeletal remodeling and related neurological disorders

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Protein & Cell 2022年第1期13卷 6-25页

作者： Kaifan Zhang Yan Wang Tianda Fan cheng zeng Zhong Sheng Sun Beijing Institutes of Life Science Chinese Academy of SciencesBeijing 100101China Institute of Genomic Medicine Wenzhou Medical UniversityWenzhou 325000China CAS Center for Excellence in Biotic Interactions University of Chinese Academy of SciencesBeijing 100049China State Key Laboratory of Integrated Management of Pest Insects and Rodents Chinese Academy of SciencesBeijing 100101China

The serine/threonine p21-activated kinases(PAKs),as main effectors of the Rho GTPases Cdc42 and Rac,represent a group of important molecular switches linking the complex cytoskeletal networks to broad neural activity.PAKs show wide expression in the brain,but they differ in specific cell types,brain regions,and developmental stages.PAKs play an essential and differential role in controlling neural cytoskeletal remodeling and are related to the development and fate of neurons as well as the structural and functional plasticity of dendritic spines.PAK-mediated actin signaling and interacting functional networks represent a common pathway frequently affected in multiple neurodevelopmental and neurodegenerative disorders.Considering specific small-molecule agonists and inhibitors for PAKs have been developed in cancer treatment,comprehensive knowledge about the role of PAKs in neural cytoskeletal remodeling will promote our understanding of the complex mechanisms underlying neurological diseases,which may also represent potential therapeutic targets of these diseases.

关键词： p21-activated kinases expression pattern synaptic cytoskeletal remodeling neuronal function neurological diseases

Bioinspired design of integral molded Janus silk fibroin-MXene evaporator for efficient solar vapor generation

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Nano Research 2024年第4期17卷 2824-2835页

作者： Ling-Qing Kong Zhi-cheng zeng Guang-Zong Min Zhao-Hui Meng Guo-Qing Meng Xiao-Xiao Guo Nai-Bo Lin Xiang-Yang Liu The Higher Educational Key Laboratory for Biomedical Engineering of Fujian Province Research Center of Biomedical Engineering of XiamenDepartment of BiomaterialsCollege of MaterialsXiamen UniversityXiamen 361005China The State Key Laboratory of Marine Environmental Science(MEL) College of Ocean and Earth SciencesXiamen UniversityXiamen 361005China

Solar vapor generation is a promising sustainable technology that uses solar distillation to produce fresh water from seawater and wastewater,helping relieve global water resource shortage.Here,inspired by naturally grown integrally molded mulberry leaves with a Janus hydrophilic and hydrophobic structure,a novel,simple,and efficient integrated molding method is proposed to break through the limitations of the traditional split manufacturing strategy and realizes the integrated formation of Janus evaporator.Based on the spontaneous sedimentation characteristics of MXene in silk fibroin solution and its regulation of mesoscopic structure and hydrophilicity of silk fibroin,layered structures with different compositions and hydrophilicities were obtained in one step.Meanwhile,ethanol and glutaraldehyde were added to construct a physical crystallization-chemical crosslinking dual stabilization structure in silk fibroin.Our evaporator has the evaporation rate of 3.07 kg·m^(-2)·h^(-1) and the efficiency of 86.8%under 1 sun and maintains high evaporation performance under various extreme test conditions including vigorous washing,repeated compression,and high-intensity ultraviolet(UV)irradiation.Additionally,the evaporator performs well in practical application scenarios,its evaporation rate in the simulated Dead Sea seawater exceeds 2.13 kg·m^(-2)·h^(-1),and more than 99.9%of the salt,heavy metal ions,oil pollution,and dyes are purified.

关键词： silk fibroin MXene bioinspired integrated molding Janus structure solar vapor generation

金属有机框架负载小干扰RNA克服乳腺癌的基质屏障

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中华肿瘤杂志 2024年第5期46卷 409-418页

作者：曾铖张剑复旦大学附属肿瘤医院肿瘤内科复旦大学上海医学院肿瘤学系上海200032

目的开发一种新型递送策略,利用金属有机框架(MOF)负载针对整合素αv(ITGAV)的小干扰RNA siITGAV,以克服基质屏障,进而增强乳腺癌内药物递送及免疫可及性。方法构建MOF@siITGAV颗粒,对其进行材料表征。通过细胞摄取实验观察乳腺癌4T1细... 详细信息

目的开发一种新型递送策略,利用金属有机框架(MOF)负载针对整合素αv(ITGAV)的小干扰RNA siITGAV,以克服基质屏障,进而增强乳腺癌内药物递送及免疫可及性。方法构建MOF@siITGAV颗粒,对其进行材料表征。通过细胞摄取实验观察乳腺癌4T1细胞对MOF@siITGAV的摄取情况,细胞计数试剂盒8法检测MOF@siITGAV的细胞毒性。设空白对照组、游离siITGAV组和MOF@siITGAV组,采用实时荧光定量聚合酶链反应检测各组4T1细胞中ITGAV mRNA的表达,采用Western blot检测ITGAV蛋白的表达,采用酶联免疫吸附试验检测TGF-β1的含量。采用3D球体穿透实验观察MOF@siITGAV穿透4T1细胞球的能力。建立三阴性乳腺癌小鼠模型,观察MOF@siITGAV对移植瘤生长及小鼠心、肝、脾、肺、肾等主要脏器的影响,采用免疫组化染色检测肿瘤组织中Ⅰ型胶原蛋白和CD8的表达。结果成功构建MOF@siITGAV颗粒,粒径为(198.0±3.3)nm,电位为-(20.2±0.4)mV。4T1细胞能有效摄取MOF@siITGAV,并触发siRNA的有效释放,MOF@siITGAV组细胞中ITGAV mRNA和蛋白表达水平、TGF-β1的表达水平均显著下调[相对于空白对照组,游离siITGAV组和MOF@siITGAV组4T1细胞中ITGAV mRNA相对表达水平分别为(109.9±19.0)%和(46.5±11.3)%;空白对照组、MOF@siNC组和MOF@siITGAV组TGF-β1浓度分别为(474.5±34.4)pg/ml、(437.2±16.5)pg/ml和(388.4±14.4)pg/ml]。MOF@siITGAV在4T1细胞球中的穿透能力更强,对4T1细胞无明显杀伤效应,0、10、20、40、80和160μg/ml MOF@siITGAV分别处理4T1细胞24 h,细胞活性分别为(99.7±3.5)%、(98.2±5.2)%、(97.3±6.6)%、(92.1±8.1)%和(92.4±4.1)%。MOF@siITGAV能有效抑制小鼠乳腺癌移植瘤的生长,给药15 d后,空白对照组、MOF@siNC组和MOF@siITGAV组小鼠的肿瘤体积分别为(691.1±193.0)mm^(3)、(652.7±306.5)mm^(3)和(135.3±41.9)mm^(3),MOF@siITGAV组小鼠的肿瘤体积小于空白对照组(P=0.025)。与空白对照组和MOF@siNC组相比,MOF@siITGAV组小鼠肿瘤组织中Ⅰ型胶原蛋白的含量明显减少,CD8阳性细胞明显增多,心、肝、脾、肺、肾等主要脏器未见明显异常。结论ITGAV可以破坏乳腺癌的ECM,改善药物瘤内递送,促进免疫细胞浸润。

关键词：乳腺肿瘤金属有机框架整合素αv 基因转染小干扰RNA 细胞外基质

Impact of depth ratio on flow structure and turbulence characteristics of compound open channel flows

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Water Science and Engineering 2022年第3期15卷 265-272页

作者： Shao-wei Ding cheng zeng Jie Zhou Ling-ling Wang Chen Chen College of Water Conservancy and Hydropower Engineering Hohai UniversityNanjing 210098China College of Mechanics and Materials Hohai UniversityNanjing 211100China

Compound open channel flows appear in most natural rivers are of great importance in river management and flood control.In this study,large eddy simulations were carried out to simulate the compound open channel flows with four different depth ratios(hr=0.10,0.25,0.50,and 0.75).The main flow velocity,secondary flow,Reynolds stress,and bed shear stress were obtained from numerical simulations.The depth-averaged stream wise momentum equation was used to quantify the lateral momentum exchange between the main channel and floodplain.The instantaneous coherent structures were presented by the Q criterion method.The impact of hr on flow structure and turbulence charac-teristics was analyzed.The results showed that with the increase of hr,the high velocity area in the main channel shifted to the floodplain,and the dip phenomenon became more obvious;the Reynolds stress largely contributed to the lateral momentum exchange within the flows near the side walls of floodplain;and the vortex structures were found to significantly increase in the floodplain region.

关键词： Large eddy simulation Compound open channel Depth ratio Flow structure Turbulence characteristics