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Ferroptosis inhibitors reduce celastrol toxicity and preserve its insulin sensitizing effects in insulin resistant HepG2 cells

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Journal of Integrative Medicine 2024年第3期22卷 286-294页

作者： jia-jia liu Xue Zhang Bang-lan Cai Man-man Qi Yong-bin Chi Bin Peng Deng-hai Zhang School of Medicine Shanghai UniversityShanghai 200444China Shanghai Health Commission Key Lab of Artificial Intelligence-Based Management of Inflammation and Chronic Diseases Shanghai Pudong Gongli HospitalSecondary Military Medical UniversityShanghai 200135China School of Basic Medicine Ningxia Medical UniversityYinchuan 750004Ningxia Hui Autonomous RegionChina

Objective:Research has shown that celastrol can effectively treat a variety of diseases,yet when passing a certain dosage threshold,celastrol becomes toxic,causing complications such as liver and kidney damage and erythrocytopenia,among others.With this dichotomy in mind,it is extremely important to find ways to preserve celastrol’s efficacy while reducing or preventing its toxicity.Methods:In this study,insulin-resistant Hep G2(IR-Hep G2)cells were prepared using palmitic acid and used for in vitro experiments.IR-Hep G2 cells were treated with celastrol alone or in combination with Nacetylcysteine(NAC)or ferrostatin-1(Fer-1)for 12,24 or 48 h,at a range of doses.Cell counting kit-8assay,Western blotting,quantitative reverse transcription-polymerase chain reaction,glucose consumption assessment,and flow cytometry were performed to measure celastrol’s cytotoxicity and whether the cell death was linked to ferroptosis.Results:Celastrol treatment increased lipid oxidation and decreased expression of anti-ferroptosis proteins in IR-Hep G2 cells.Celastrol downregulated glutathione peroxidase 4(GPX4)m RNA.Molecular docking models predicted that solute carrier family 7 member 11(SLC7A11)and GPX4 were covalently bound by celastrol.Importantly,we found for the first time that the application of ferroptosis inhibitors(especially NAC)was able to reduce celastrol’s toxicity while preserving its ability to improve insulin sensitivity in IR-Hep G2 cells.Conclusion:One potential mechanism of celastrol’s cytotoxicity is the induction of ferroptosis,which can be alleviated by treatment with ferroptosis inhibitors.These findings provide a new strategy to block celastrol’s toxicity while preserving its therapeutic effects.

关键词： Celastrol Insulin resistance Ferroptosis N-Acetylcysteine Palmitic acid Molecular docking

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A prognostic four-gene signature and a therapeutic strategy for hepatocellular carcinoma:Construction and analysis of a circRNA-mediated competing endogenous RNA network

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Hepatobiliary & Pancreatic Diseases International 2024年第3期23卷 272-287页

作者： Hai-Yan Zhang jia-Jie Zhu Zong-Ming liu Yu-Xuan Zhang jia-jia Chen Ke-Da Chen Zhejiang Chinese Medical University Hangzhou 310053China Shulan International Medical College Zhejiang Shuren UniversityHangzhou 310015China State Key Laboratory for Diagnosis and Treatment of Infectious Diseases National Clinical Research Center for Infectious DiseasesNational Medical Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalZhejiang University School of MedicineHangzhou 310009China

Background:Hepatocellular carcinoma(HCC)has a poor long-term prognosis.The competition of circular RNAs(circRNAs)with endogenous RNA is a novel tool for predicting HCC prognosis.Based on the alterations of circRNA regulatory networks,the analysis of gene modules related to HCC is feasible.Methods:Multiple expression datasets and RNA element targeting prediction tools were used to construct a circRNA-microRNA-mRNA network in HCC.Gene function,pathway,and protein interaction analyses were performed for the differentially expressed genes(DEGs)in this regulatory network.In the proteinprotein interaction network,hub genes were identified and subjected to regression analysis,producing an optimized four-gene signature for prognostic risk stratification in HCC patients.Anti-HCC drugs were excavated by assessing the DEGs between the low-and high-risk groups.A circRNA-microRNA-hub gene subnetwork was constructed,in which three hallmark genes,KIF4A,CCNA2,and PBK,were subjected to functional enrichment analysis.Results:A four-gene signature(KIF4A,CCNA2,PBK,and ZWINT)that effectively estimated the overall survival and aided in prognostic risk assessment in the The Cancer Genome Atlas(TCGA)cohort and International Cancer Genome Consortium(ICGC)cohort was developed.CDK inhibitors,PI3K inhibitors,HDAC inhibitors,and EGFR inhibitors were predicted as four potential mechanisms of drug action(MOA)in high-risk HCC patients.Subsequent analysis has revealed that PBK,CCNA2,and KIF4A play a crucial role in regulating the tumor microenvironment by promoting immune cell invasion,regulating microsatellite instability(MSI),and exerting an impact on HCC progression.Conclusions:The present study highlights the role of the circRNA-related regulatory network,identifies a four-gene prognostic signature and biomarkers,and further identifies novel therapy for HCC.

关键词： Hepatocellular carcinoma circRNA-related ceRNA network Biomarker Least absolute shrinkage and selection operator Bioinformatics

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Anti-OX40 Antibody Combined with HBc VLPs Delays Tumor Growth in a Mouse Colon Cancer Model

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Biomedical and Environmental Sciences 2024年第2期37卷 187-195页

作者： liu jia jia SU Qiu Dong YI Yao SHEN Li Ping BI Sheng Li National Institute for Viral Disease Control and Prevention Chinese Center for Disease Control and PreventionBeijing 102206China

Objective Combination immunotherapy strategies targeting OX40,a co-stimulatory molecule that can enhance antitumor immunity by modulating the proliferation,differentiation,and effector function of tumor-infiltrating T cells,have attracted much attention for their excellent therapeutic effects.In this study,we aimed to evaluate the antitumor efficacy of combined anti-OX40 and hepatitis B core viruslike particles(HBc VLPs)therapy using a mouse colon cancer model.Methods Humanized B-h OX40 mice were injected subcutaneously with MC38 colon tumor cells and treated with HBc VLPs+anti-h OX40 antibody.Tumor growth was monitored.Flow cytometric analysis was performed to evaluate the populations of T cell subsets in the tumors.Results The combination of anti-OX40 with HBc VLPs resulted in a significant delay in tumor growth,suggesting that a potent antitumor immunity was induced by the combination therapy.Further studies revealed that HBc VLPs+anti-OX40 treatment induced a significant increase in effector T cells(Teffs)and a significant decrease in regulatory T cells(Tregs)in the tumor microenvironment(TME),which accounted for the synergistic antitumor effect of anti-OX40 in combination with HBc VLPs.Conclusion Combination therapy of anti-h OX40 and HBc VLPs provides synergistic antitumor activity in colon cancer-bearing mice,which may represent a potential design strategy for cancer immunotherapy.

关键词： Anti-OX40 antibody Hepatitis B core virus-like particles Tumor Combination therapy

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Design Strategies for Aqueous Zinc Metal Batteries with High Zinc Utilization: From Metal Anodes to Anode-Free Structures

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Nano-Micro Letters 2024年第4期16卷 305-349页

作者： Xianfu Zhang Long Zhang Xinyuan jia Wen Song Yongchang liu School of Materials Science and Engineering University of Science and Technology Beijing30 College RoadBeijing 100083People’s Republic of China Beijing Advanced Innovation Center for Materials Genome Engineering Institute for Advanced Materials and TechnologyState Key Laboratory for Advanced Metals and MaterialsUniversity of Science and Technology BeijingBeijing 100083People’s Republic of China

Aqueous zinc metal batteries(AZMBs)are promising candidates for next-generation energy storage due to the excellent safety, environmental friendliness, natural abundance, high theoretical specific capacity, and low redox potential of zinc(Zn) metal. However,several issues such as dendrite formation, hydrogen evolution, corrosion, and passivation of Zn metal anodes cause irreversible loss of the active materials. To solve these issues, researchers often use large amounts of excess Zn to ensure a continuous supply of active materials for Zn anodes. This leads to the ultralow utilization of Zn anodes and squanders the high energy density of AZMBs. Herein, the design strategies for AZMBs with high Zn utilization are discussed in depth, from utilizing thinner Zn foils to constructing anode-free structures with theoretical Zn utilization of 100%, which provides comprehensive guidelines for further research. Representative methods for calculating the depth of discharge of Zn anodes with different structures are first summarized. The reasonable modification strategies of Zn foil anodes, current collectors with pre-deposited Zn, and anode-free aqueous Zn metal batteries(AF-AZMBs) to improve Zn utilization are then detailed. In particular, the working mechanism of AF-AZMBs is systematically introduced. Finally, the challenges and perspectives for constructing high-utilization Zn anodes are presented.

关键词： Aqueous zinc metal batteries Zinc anodes High zinc utilization Depth of discharge Anode-free structures

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Weakly Polarized Organic Cation-Modified Hydrated Vanadium Oxides for High-Energy Efficiency Aqueous Zinc-Ion Batteries

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Nano-Micro Letters 2024年第7期16卷 169-186页

作者： Xiaoxiao jia Chaofeng liu Zhi Wang Di Huang Guozhong Cao Department of Materials Science and Engineering University of WashingtonSeattleWA 98195USA School of Materials Science and Engineering Tongji UniversityShanghai 201804People’s Republic of China

Vanadium oxides,par-ticularly hydrated forms like V_(2)O_(5)·nH_(2)O(VOH),stand out as promising cathode candidates for aqueous zinc ion batteries due to their adjustable layered structure,unique electronic characteristics,and high theoretical capacities.However,challenges such as vanadium dissolution,sluggish Zn^(2+)diffusion kinetics,and low operating voltage still hinder their direct application.In this study,we present a novel vanadium oxide([C_(6)H_(6)N(CH_(3))_(3)]_(1.08)V_(8)O_(20)·0.06H_(2)O,TMPA-VOH),developed by pre-inserting trimethylphenylammonium(TMPA+)cations into VOH.The incorporation of weakly polarized organic cations capitalizes on both ionic pre-intercalation and molecular pre-intercalation effects,resulting in a phase and morphology transition,an expansion of the interlayer distance,extrusion of weakly bonded interlayer water,and a substantial increase in V^(4+)content.These modifications synergistically reduce the electrostatic interactions between Zn^(2+)and the V-O lattice,enhancing structural stability and reaction kinetics during cycling.As a result,TMPA-VOH achieves an elevated open circuit voltage and operation voltage,exhibits a large specific capacity(451 mAh g^(-1)at 0.1 A g^(-1))coupled with high energy efficiency(89%),the significantly-reduced battery polarization,and outstanding rate capability and cycling stability.The concept introduced in this study holds great promise for the development of high-performance oxide-based energy storage materials.

关键词： Zinc-ion battery Vanadium oxide V_(2)O_(5)·nH_(2)O Pre-intercalation Interlayer engineering

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Changes in Spring Snow Cover over the Eastern and Western Tibetan Plateau and Their Associated Mechanism

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Advances in Atmospheric Sciences 2024年第5期41卷 959-973页

作者： Fangchi liu Xiaojing jia Wei DONG Key Laboratory of Geoscience Big Data and Deep Resource of Zhejiang Province School of Earth SciencesZhejiang UniversityHangzhouZhejiang 310058China

The spring snow cover(SC)over the western Tibetan Plateau(TP)(TPSC)(W_TPSC)and eastern TPSC(E_TPSC)have displayed remarkable decreasing and increasing trends,respectively,during 1985–2020.The current work investigates the possible mechanisms accounting for these distinct TPSC changes.Our results indicate that the decrease in W_TPSC is primarily attributed to rising temperatures,while the increase in E_TPSC is closely linked to enhanced precipitation.Local circulation analysis shows that the essential system responsible for the TPSC changes is a significant anticyclonic system centered over the northwestern TP.The anomalous descending motion and adiabatic heating linked to this anticyclone leads to warmer temperatures and consequent snowmelt over the western TP.Conversely,anomalous easterly winds along the southern flank of this anticyclone serve to transport additional moisture from the North Pacific,leading to an increase in snowfall over the eastern TP.Further analysis reveals that the anomalous anticyclone is associated with an atmospheric wave pattern that originates from upstream regions.Springtime warming of the subtropical North Atlantic(NA)sea surface temperature(SST)induces an atmospheric pattern resembling a wave train that travels eastward across the Eurasian continent before reaching the TP.Furthermore,the decline in winter sea ice(SIC)over the Barents Sea exerts a persistent warming influence on the atmosphere,inducing an anomalous atmospheric circulation that propagates southeastward and strengthens the northwest TP anticyclone in spring.Additionally,an enhancement of subtropical stationary waves has resulted in significant increases in easterly moisture fluxes over the coastal areas of East Asia,which further promotes more snowfall over eastern TP.

关键词： snow cover Tibetan Plateau long-term changes spring

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Comparison of electrochemical behaviors of Ti-5Al-2Sn-4Zr-4Mo-2Cr-1Fe and Ti-6Al-4V titanium alloys in NaNO_(3) solution

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International Journal of Minerals,Metallurgy and Materials 2024年第4期31卷 750-763页

作者： jia liu Shuanglu Duan Xiaokang Yue Ningsong Qu College of Mechanical and Electrical Engineering Nanjing University of Aeronautics and AstronauticsNanjing 210016China

The Ti-5Al-2Sn-4Zr-4Mo-2Cr-1Fe(β-CEZ)alloy is considered as a potential structural material in the aviation industry due to its outstanding strength and corrosion resistance.Electrochemical machining(ECM)is an efficient and low-cost technology for manufacturing theβ-CEZ alloy.In ECM,the machining parameter selection and tool design are based on the electrochemical dissolution behavior of the materials.In this study,the electrochemical dissolution behaviors of theβ-CEZ and Ti-6Al-4V(TC4)alloys in NaNO3solution are discussed.The open circuit potential(OCP),Tafel polarization,potentiodynamic polarization,electrochemical impedance spectroscopy(EIS),and current efficiency curves of theβ-CEZ and TC4 alloys are analyzed.The results show that,compared to the TC4 alloy,the passivation film structure is denser and the charge transfer resistance in the dissolution process is greater for theβ-CEZ alloy.Moreover,the dissolved surface morphology of the two titanium-based alloys under different current densities are analyzed.Under low current densities,theβ-CEZ alloy surface comprises dissolution pits and dissolved products,while the TC4 alloy surface comprises a porous honeycomb structure.Under high current densities,the surface waviness of both the alloys improves and the TC4 alloy surface is flatter and smoother than theβ-CEZ alloy surface.Finally,the electrochemical dissolution models ofβ-CEZ and TC4 alloys are proposed.

关键词： electrochemical machining dissolution behavior β-CEZ titanium alloy polarization curve current efficiency

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Design method and experimental study of a cathode tool with an extremely high leveling ratio for electrochemical machining of blisk

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Chinese Journal of Aeronautics 2024年第4期37卷 593-608页

作者： Moqi SHEN jia liu Jingtao WANG Di ZHU College of Mechanical and Electrical Engineering Nanjing University of Aeronautics and AstronauticsNanjing 210016China

To obtain final parts with the desired dimensional accuracy and repeatability via electrochemical machining(ECM), the machining process must enter an ECM balanced state. However,for the ECM processing of blisk, a key component of aerospace engines, the surface of the blade blank often has an uneven allowance distribution due to the narrow passage of the cascade. It is difficult to remedy this issue in subsequent processing steps, which is necessary to ensure the dimensional accuracy and repeatability of the final blade profile. To solve this problem, electrolytic machining must be preceded by electrolytic shaping, which requires cathode tools with large leveling ratios to quickly homogenize the blank surface of the blade. In this study, to obtain a cathode tool with an extremely high leveling ratio, a design method based on the variation in the electrode gap in the non-equilibrium electrolytic state is proposed, and a dissolution model based on the nonequilibrium state is established. In this design method, the allowance on the blank to be machined is first divided into many discrete allowances with the normal direction. The initial machining clearance, feed rate, and total machining time are then calculated using classical ECM equilibrium state theory based on the maximum allowance. Meanwhile, the point coordinates of the cathode tool at maximum allowance can be determined. The non-equilibrium model can then be used to calculate the relative coordinate positions corresponding to the remaining discrete allowances. Finally, the entire cathode tool profile is designed. Simulations, fundamental experiments, and blisk unit workpiece experiments were carried out to validate the design approach. In the simulated processing of the plane workpiece, the leveling ratio of the cathode tool designed by the proposed method(0.77)was 83% higher than that of the cathode tool designed using the traditional method. The simulation results were confirmed by processing experiments. In the machining of blisk unit workpieces with compl

关键词： Electrochemical machining(ECM) Non-equilibrium machining Large leveling ratios Cathode design Finite element simulation Blisk

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Climatic impacts induced by winter wheat irrigation over North China simulated by the nonhydrostatic RegCM4.7

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Advances in Climate Change Research 2024年第2期15卷 197-210页

作者： jia WU Zhen-Yu HAN Xue-Jie GAO Zheng-jia liu National Climate Centre China Meteorological AdministrationBeijing 100081China Key Laboratory for Climate Studies China Meteorological AdministrationBeijing 100081China Climate Change Research Center Institute of Atmospheric PhysicsChinese Academy of SciencesBeijing 100029China Collaborative Innovation Center on Forecast and Evaluation of Meteorological Disasters Nanjing University of Information Science and TechnologyNanjing 210044China Institute of Geographic Sciences and Natural Resources Research Chinese Academy of SciencesBeijing 100101China

Quantification of the impact of winter wheat irrigation on the climate and the occurrence of extreme climatic events over North China is crucial for regional adaptation planning.Previous related studies mainly focused on the impact on surface processes;however,few focused on the effects of extreme events using high-resolution nonhydrostatic regional climate models.Here,the 9-km-resolution nonhydrostatic RegCM4.7 was coupled with a crop irrigation scheme and an updated winter wheat irrigation dataset to better simulate irrigation effects.Two experiments were conducted with and without winter wheat irrigation to isolate the effects of irrigation.Results showed that irrigation simulation reduces the model biases in temperature,precipitation,latent heat flux,soil moisture,sensitive heat flux,and top-layer soil moisture.Moreover,it also reduces the bias and increases the correlation with observations obtained in irrigated areas,especially in summer,indicating better representation of irrigation schemes.Winter wheat irrigation tends to cause substantial cooling of the local surface maximum,minimum,and mean air temperatures(by-1.68,-0.34,and-0.79℃,respectively)over irrigated areas of North China,with the largest changes observed in relation to maximum temperature.Additionally,precipitation is found to increase during spring and summer,which is strongly related to water vapor transport in the lower levels of the atmosphere.Further analyses indicated that the number of annual mean hot days decrease(-13.9 d),whereas the number of both comfort days(+10.2 d)and rainy days(days with total precipitation greater than 1 mm:+6.6 d)increase over irrigated areas,demonstrating beneficial feedback to human perception and agriculture.Fortunately,although the heat wave risk increases(number of annual mean heat wave days:+5.8 d),the impact is limited to small areas within irrigated region.Additionally,no notable change was found in terms of heavy rainfall events and precipitation intensity,which might be an undereastimation caused by th

关键词： Nonhydrostatic regional climate model Irrigation effect Extreme events North China

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Emerging clinical relevance of microbiome in cancer:promising biomarkers and therapeutic targets

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Protein & Cell 2024年第4期15卷 239-260页

作者： jia-Hao Dai Xi-Rong Tan Han Qiao Na liu State Key Laboratory of Oncology in South China Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and TherapyGuangdong Provincial Clinical Research Center for CancerSun Yat-sen University Cancer CenterGuangzhou 510050China

The profound influence of microbiota in cancer initiation and progression has been under the spotlight for years,leading to numerous researches on cancer microbiome entering clinical evaluation.As promising biomarkers and therapeutic targets,the critical involvement of microbiota in cancer clinical practice has been increasingly appreciated.Here,recent progress in this field is reviewed.We describe the potential of tumor-associated microbiota as effective diagnostic and prognostic biomarkers,respectively.In addition,we highlight the relationship between microbiota and the therapeutic efficacy,toxicity,or side effects of commonly utilized treatments for cancer,including chemotherapy,radiotherapy,and immunotherapy.Given that microbial factors influence the cancer treatment outcome,we further summarize some dominating microbial interventions and discuss the hidden risks of these strategies.This review aims to provide an overview of the applications and advancements of microbes in cancer clinical relevance.

关键词： microbiome cancer diagnosis prognosis therapy

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