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Phosphatidic acid-enabled MKL1 contributes to liver regeneration:Translational implication in liver failure

Acta Pharmaceutica Sinica B 2024年第1期14卷 256-272页

作者： jiawen Zhou Xinyue Sun Xuelian Chen Huimin Liu Xiulian Miao Yan Guo Zhiwen fan Jie Li Yong Xu Zilong Li State Key Laboratory of Natural Medicines Department of PharmacologyChina Pharmaceutical UniversityNanjing 211198China Institute of Biomedical Research Liaocheng UniversityLiaocheng 252200China Department of Pathology Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical SchoolNanjing 210008China Department of Infectious Diseases Nanjing Drum Tower Hospital Affiliated with Nanjing University Medical SchoolNanjing 210008China Institute of Viruses and Infectious Diseases Nanjing UniversityNanjing 210008China

Liver regeneration following injury aids the restoration of liver mass and the recovery of liver function.In the present study we investigated the contribution of megakaryocytic leukemia 1(MKL1),a transcriptional modulator,to liver regeneration.We report that both MKL1 expression and its nuclear translocation correlated with hepatocyte proliferation in cell and animal models of liver regeneration and in liver failure patients.Mice with MKL1 deletion exhibited defective regenerative response in the liver.Transcriptomic analysis revealed that MKL1 interacted with E2F1 to program pro-regenerative transcription.MAPKAPK2 mediated phosphorylation primed MKL1 for its interaction with E2F1.Of interest,phospholipase d2 promoted MKL1 nuclear accumulation and liver regeneration by catalyzing production of phosphatidic acid(PA).PA administration stimulated hepatocyte proliferation and enhanced survival in a MKL1-dependent manner in a pre-clinical model of liver failure.Finally,PA levels was detected to be positively correlated with expression of pro-regenerative genes and inversely correlated with liver injury in liver failure patients.In conclusion,our data reveal a novel mechanism whereby MKL1 contributes to liver regeneration.Screening for small-molecule compounds boosting MKL1 activity may be considered as a reasonable approach to treat acute liver failure.

关键词： Liver failure Liver regeneration Transcription regulation Transcription factor Hepatocytes Phosphatidic acid Phospholipase d2 Translational medicine

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A metal-organic framework-based redox homeostasis disruptor selectively potentiate the cytotoxicity of dihydroartemisinin for cancer therapy

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Nano Research 2023年第5期16卷 7489-7495页

作者： jiawen fan Xinchen Liu Qishun Wang Huan Wang Hao Liu Deming Han Jinsong Ren School of Life Science and Technology Changchun University of Science and TechnologyChangchun 130022China State Key Laboratory of Rare Earth Resources Utilization and Laboratory of Chemical Biology Changchun Institute of Applied ChemistryChinese Academy of SciencesChangchun 130022China Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling Hospital of StomatologyJilin UniversityChangchun 130021China Department of Chemistry Tsinghua UniversityBeijing 100084China

Artemisinin and its derivatives have emerged as promising therapeutic agents for cancer therapy by endogenous iron-mediated generation of free radicals.However,the enhanced antioxidant defense systems in cancer cells provide them with resistance to oxidative damage,greatly antagonizing the therapeutic efficacy that relies on inducing oxidative stress.Herein,a metal-organic framework(MOF)-based nanoplatform(CMD)is constructed to disrupt the cellular redox homeostasis and selectively potentiate the cytotoxicity of dihydroartemisinin for cancer therapy.In cancer cells,the copper(II)sites in the MOF nanocarrier of CMD can efficiently weaken the cellular antioxidant capacity by depleting the overexpressed glutathione,simultaneously leading to the decomposition of the framework structure and the release of the encapsulated dihydroartemisinin.As a result,the damaged antioxidant defense system of cancer cells reduces its effect on oxidative stress alleviation and strengthens the therapeutic efficacy of dihydroartemisinin.On contrast,the low concentration of cellular glutathione in normal cells protects them from dihydroartemisinin-induced cytotoxicity by decelerating the drug release.In vivo results demonstrate that CMD could completely suppress the tumor growth in mice and show no evidence of toxicity,providing an effective strategy for the practical usage of dihydroartemisinin in cancer therapy.

关键词： metal-organic framework dihydroartemisinin selective cancer therapy redox homeostasis disruptor glutathione depletion

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经济政策不确定性会促进企业数字化转型吗

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现代经济探讨 2024年第6期 85-93页

作者：冯帆许嘉文浙江大学民营经济研究中心杭州310063 南京大学商学院南京210093 江苏新时代自贸研究院南京210093

企业数字化转型被视为提高企业运行效率,实现企业高质量发展的重要途径。以2013-2022年沪深两市A股上市公司为研究样本,实证考察了经济政策不确定性对企业数字化转型的影响及其机制。研究结果表明:经济政策不确定性对企业数字化转型具... 详细信息

企业数字化转型被视为提高企业运行效率,实现企业高质量发展的重要途径。以2013-2022年沪深两市A股上市公司为研究样本,实证考察了经济政策不确定性对企业数字化转型的影响及其机制。研究结果表明:经济政策不确定性对企业数字化转型具有显著的正向促进作用;机制检验结果表明经济政策不确定性提升可以通过促进研发投入和优化人力资本两种渠道对企业数字化转型产生正向作用;异质性分析结果表明当企业拥有高政府补贴、处于高科技行业时,经济政策不确定性对其数字化转型的正向效应更大。这为经济政策不确定性与企业数字化转型之间的关系提供了新的经验证据。

关键词：经济政策不确定性数字化转型研发投入人力资本

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BAALC-AS1/G3BP2/c-Myc feedback loop promotes cell proliferation in esophageal squamous cell carcinoma

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Cancer Communications 2021年第3期41卷 240-257页

作者： Hongyue Zhang Yan Wang Weimin Zhang Qingnan Wu jiawen fan Qimin Zhan Key Laboratory of Carcinogenesis and Translational Research(Ministry of Education/Beijing) Laboratory of Molecular OncologyPeking University Cancer Hospital&InstituteBeijing 100142P.R.China Shenzhen Bay Laboratory ShenzhenGuangdong 518132P.R.China

Background:Long non-codingRNAs(lncRNAs)have been found to be involved in the development of many cancers.In this study,we aimed to identify the molecular mechanisms of lncRNA BAALC antisense RNA 1(BAALC-AS1)in regulating the malignancy of esophageal squamous cell carcinoma(ESCC).Methods:The expression of BAALC-AS1 in cancer patients was analyzed using a tissue microarray.The protein and RNA levels of BAALC-AS1 were determined by Western blotting analysis and quantitative reverse transcription-PCR(RT-qPCR),respectively.The cell proliferation was determined by cell viability assays,bromodeoxyuridine incorporation,and flow cytometry.The relationships among BAALC-AS1,RasGAPSH3 domain-binding protein 2(G3BP2),and c-Myc were determined using RNA immunoprecipitation,RNA pull-down assays,and luciferase assays.Results:The expression of BAALC-AS1 was highly up-regulated and associated with malignant phenotypes in ESCC tissues and cell lines.In vivo and in vitro assays showed that BAALC-AS1 promoted ESCC cell proliferation,migration,and invasion.BAALC-AS1 directly interacted with G3BP2,and thereby inhibited the degradation of c-Myc RNA 3’-UTR by G3BP2,thus leading to the accumulation of c-Myc expression.Additionally,c-Myc acted as a transcription factor that can induce the expression of BAALC-AS1 by directly binding to its promoter region.Conclusions:BAALC-AS1/G3BP2/c-Myc feedback loop plays a critical role in the development of ESCC,which might provide a novel therapeutic target and facilitate the development of new therapeutic strategies for the treatment of ESCC.

关键词： esophageal squamous cell carcinoma proliferation migration invasion long non-codingRNA BAALC-AS1 lncFZD6 G3BP2 c-Myc

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Chrysin serves as a novel inhibitor of DGKα/FAK interaction to suppress the malignancy of esophageal squamous cell carcinoma(ESCC)

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Acta Pharmaceutica Sinica B 2021年第1期11卷 143-155页

作者： Jie Cheny Yan Wangy Di Zhao Lingyuan Zhang Weimin Zhang jiawen fan Jinting Li Qimin Zhan Key Laboratory of Carcinogenesis and Translational Research(Ministry of Education/Beijing) Laboratory of Molecular OncologyPeking University Cancer Hospital&InstituteBeijing 100142China

Among current novel druggable targets,proteineprotein interactions(PPIs)are of considerable and growing interest.Diacylglycerol kinase a(DGKα)interacts with focal adhesion kinase(FAK)band 4.1-ezrin-radixin-moesin(FERM)domain to induce the phosphorylation of FAK Tyr397 site and promotes the malignant progression of esophageal squamous cell carcinoma(ESCC)cells.Chrysin is a multi-functional bioactive flavonoid,and possesses potential anticancer activity,whereas little is known about the anticancer activity and exact molecular mechanisms of chrysin in ESCC treatment.In this study,we found that chrysin significantly disrupted the DGKα/FAK signalosome to inhibit FAKcontrolled signaling pathways and the malignant progression of ESCC cells both in vitro and in vivo,whereas produced no toxicity to the normal cells.Molecular validation specifically demonstrated that Asp435 site in the catalytic domain of DGKαcontributed to chrysin-mediated inhibition of the assembly of DGKα/FAK complex.This study has illustrated DGKα/FAK complex as a target of chrysin for the first time,and provided a direction for the development of natural products-derived PPIs inhibitors in tumor treatment.

关键词： Chrysin Esophageal squamous cell carcinoma DGKα FAK Proteineprotein interactions

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Membranous NOX5-derived ROS oxidizes and activates local Src to promote malignancy of tumor cells

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Signal Transduction and Targeted Therapy 2020年第1期5卷 1111-1122页

作者： Jie Chen Yan Wang Weimin Zhang Di Zhao Lingyuan Zhang jiawen fan Jinting Li Qimin Zhan Key laboratory of Carcinogenesis and Translational Research(Ministry of Education/Beijing) Laboratory of Molecular OncologyPeking University Cancer Hospital&Institute100142 BeijingChina

Reactive oxygen species(ROS)localized at the precise subcellular compartments are essential for regulating the activity of signaling proteins.Furthermore,ROS are master regulators of tumor malignant progression that respond to a diverse set of environmental stress,especially hypoxia.NADPH oxidases(NOXs)appear to be activated within discrete subcellular compartments to facilitate local ROS production.However,the subcellular function of NOXs in hypoxic tumor is still unclear.In this study,we demonstrated that NOX5 was greatly upregulated in clinical esophageal squamous cell carcinoma(ESCC)tumors,ESCC cell lines or primary ESCC cells,and elevated NOX5 was correlated to malignancy of ESCC tumors and poor prognosis.NOX5 induced the malignant progression of ESCC by activating Src,especially under hypoxic condition.Mechanistically,we showed that hypoxia promoted the interaction between NOX5 and Pyk2 on cell membrane via facilitating Ca^(2+)-mediated Pyk2 Tyr^(402)site phosphorylation.Subsequently,Pyk2 acted as a scaffold for c-Abl phosphorylating the catalytic domain of NOX5 Tyr^(476/478)sites,which in turn upregulated hydrogen peroxide(H_(2)O_(2))inside the Pyk2/NOX5 complex to oxidize and activate local Src.These findings provide insights into the biological significance of NOX5 in the development of ESCC.

关键词： malignancy elevated esophageal

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矿山救援钻孔中井涌井漏事故预警预测

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煤田地质与勘探 2024年第3期52卷 144-152页

作者：陈卫明王家文凡东郝世俊赵江鹏邱雨中国地质大学(武汉)工程学院湖北武汉430074 中国地质大学(武汉)自然灾害风险防控与应急管理实验室湖北武汉430074 陕西省煤矿水害防治技术重点实验室陕西西安710077 中煤科工西安研究院(集团)有限公司陕西西安710077

为解决矿山应急救援钻孔作业过程中井涌井漏事故预警预测困难等问题,建立了基于机器学习的钻进过程井涌井漏事故预警预测模型。首先对井涌井漏事故发生初期时的钻进参数进行事故表征参数分析;其次对事故表征参数进行数据清洗处理,在此... 详细信息

为解决矿山应急救援钻孔作业过程中井涌井漏事故预警预测困难等问题,建立了基于机器学习的钻进过程井涌井漏事故预警预测模型。首先对井涌井漏事故发生初期时的钻进参数进行事故表征参数分析;其次对事故表征参数进行数据清洗处理,在此基础上,通过XGBoost事故诊断预警模型对井涌井漏事故进行早期诊断识别;随后建立PSO-LSTM事故发展预测模型,对事故发生后的孔底压力参数发展趋势进行预测,提前掌握钻进事故发展状态;最后通过实际钻进数据对预警预测模型的有效性进行验证。结果表明:XGBoost事故诊断预警模型能根据总池体积、立管压力、出入口流量差和动力头负荷这4种钻进参数的异常变化,快速准确诊断钻进过程中的井涌井漏事故;PSO-LSTM事故发展状态预测模型能充分学习孔底压力参数发展规律,综合EMAP、EMA、ERMS、R2这4项误差评价指标,PSO-LSTM模型相较于BP、RNN、SVM模型的预测性能最佳,能准确预测事故发生之后的孔底压力发展趋势,提前掌握井涌井漏事故的严重程度和发展态势。研究结果丰富了钻进过程井涌井漏事故预警预测方法,提高了矿山事故地面救援的可靠性,对矿山应急救援钻孔作业过程中事故控制有着借鉴与指导作用。

关键词：矿山救援钻进过程预警预测 XGBoost PSO-LSTM 机器学习井涌井漏

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miR-362-3p调控垂体肿瘤转化基因1抑制口腔鳞状细胞癌侵袭及增殖的研究

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华西口腔医学杂志 2024年第1期42卷 46-55页

作者：丁啸陈嘉雯曲鹏宇孙晨雨李洪利胡温庭范欣潍坊医学院附属医院口腔科潍坊261000 潍坊医学院口腔医学院潍坊261053 潍坊医学院医学研究实验中心潍坊261053

目的探讨垂体肿瘤转化基因1(PTTG1)在miR-362-3p作用下对口腔鳞状细胞癌(OSCC)细胞Cal-27、HN-30侵袭以及增殖能力的影响。方法生物信息学在线数据库查询PTTG1在头颈部鳞状细胞癌(HNSCC)中的表达。蛋白质印迹法(Western blot)实验检测PT... 详细信息

目的探讨垂体肿瘤转化基因1(PTTG1)在miR-362-3p作用下对口腔鳞状细胞癌(OSCC)细胞Cal-27、HN-30侵袭以及增殖能力的影响。方法生物信息学在线数据库查询PTTG1在头颈部鳞状细胞癌(HNSCC)中的表达。蛋白质印迹法(Western blot)实验检测PTTG1在Cal-27、HN-30以及HOK细胞系中的表达。划痕愈合实验、Transwell侵袭实验及5-乙炔基-2’脱氧尿嘧啶核苷(EdU)细胞增殖实验检测PTTG1对Cal-27、HN-30细胞迁移、侵袭、增殖的影响。生物信息学在线数据库预测PTTG1的上游miRNA,双荧光素酶实验检测结合情况,实时荧光定量聚合酶链反应(qRT-PCR)检测该miRNA在组织中的表达。结果ENCORI数据库结果显示PTTG1在OSCC组织中表达上调;Western blot实验显示Cal-27、HN-30细胞中PTTG1表达量较HOK细胞中高。转染Si-PTTG1质粒的Cal-27、HN-30细胞的迁移能力、侵袭能力和细胞增殖能力均较对照组降低(P<0.05)。通过网站预测出PTTG1的上游miRNA为miR-362-3p,双荧光素酶实验检测出PTTG1与miR-362-3p存在结合位点;qRT-PCR检测结果显示miR-362-3p在OSCC肿瘤组织中相对于正常组织表达下调(P<0.05);并且敲低miR-362-3p的表达后能够促进敲低PTTG1后的Cal-27、HN-30侵袭和增殖。结论miR-362-3p可通过靶向PTTG1抑制Cal-27、HN-30细胞侵袭、增殖。

关键词：口腔鳞状细胞癌垂体肿瘤转化基因1 微小RNA 侵袭增殖

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Defect of SLC38A3 promotes epithelial-mesenchymal transition and predicts poor prognosis in esophageal squamous cell carcinoma

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Chinese Journal of Cancer Research 2020年第5期32卷 547-563页

作者： Rui Liu Ruoxi Hong Yan Wang Ying Gong Danna Yeerken Di Yang Jinting Li jiawen fan Jie Chen Weimin Zhang Qimin Zhan Key Laboratory of Carcinogenesis and Translational Research(Ministry of Education/Beijing) Laboratory of Molecular OncologyPeking University Cancer Hospital&InstituteBeijing 100142China State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer MedicineSun Yat-sen University Cancer CenterGuangzhou 510060China

Objective: Solute carrier family 38(SLC38 s) transporters play important roles in amino acid transportation and signaling transduction. However, their genetic alterations and biological roles in tumors are still largely unclear.This study aimed to elucidate the genetic signatures of SLC38 s transporters and their implications in esophageal squamous cell carcinoma(ESCC).Methods: Analyses on somatic mutation and copy number alterations(CNAs) of SLC38 A3 were performed as described. Immunohistochemistry(IHC) assay and Western blot assay were used to detect the protein expression level. MTS assay, colony formation assay, transwell assay and wound healing assay were used to explore the malignant phenotypes of ESCC cells. Immunofluorescence assay was used to verify the colocalization of two indicated proteins and immunopreciptation assay was performed to confirm the interaction of proteins.Results: Our findings revealed that SLC38 s family was significantly disrupted in ESCC, with high frequent CNAs and few somatic mutations. SLC38 A3 was the most frequent loss gene among them and was linked to poor survival and lymph node metastasis. The expression of SLC38 A3 was lower in tumor tissues compared to that in normal tissues, which was also significantly associated with worse clinical outcome. Further experiments revealed that depletion of SLC38 A3 could promote EMT in ESCC cell lines, and the interaction of SLC38 A3 and SETDB1 might lead to the reduced transcription of Snail. Pharmacogenomic analyses demonstrated that fifteen inhibitors were showed significantly correlated with SLC38 A3 expression.Conclusions: Our investigations have provided insights that SLC38 A3 could act as a suppressor in EMT pathway and serve as a prognostic factor and predictor of differential drug sensitivities in ESCC.

关键词： Amino acid transporter esophageal squamous cell carcinoma epithelial-mesenchymal transition genomic alterations SLC38A3 SETDB1 Snail

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Engineering DNA logic systems with non-canonical DNA-nanostructures:basic principles,recent developments and bio-applications

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Science China Chemistry 2022年第2期65卷 284-297页

作者： Daoqing fan Jun Wang jiawen Han Erkang Wang Shaojun Dong State Key Laboratory of Electroanalytical Chemistry Changchun Institute of Applied ChemistryChinese Academy of SciencesChangchun 130022China Key Laboratory of Marine Drugs Ministry of EducationSchool of Medicine and PharmacyOcean University of China Laboratory for Marine Drugs and Bioproducts Pilot National Laboratory for Marine Science and TechnologyQ

Engineering DNA logic systems is considered as one of the most promising strategies for next-generation molecular computers.Owing to the inherent features of DNA,such as low cost,easy synthesis,and controllable hybridization,various DNA logic devices with different functions have been developed in the recent decade.Besides,a variety of logic-programmed biological applications are also explored,which initiates a new chapter for DNA logic computing.Although this field has gained rapid developments,a systematical review that could not only elaborate the logic principles of diverse DNA logic devices but also outline recent representative works is urgently needed.In this review,we first elaborate the general classification and logical principle of diverse DNA logic devices,in which the operating strategy of these devices and representative examples are selectively presented.Then,we review state-of-the-art advancements in DNA computing based on different non-canonical DNA-nanostructures during the past decade,in which some classical works are summarized.After that,the innovative applications of DNA computing to logic-controlled bioanalysis,cell imaging,and drug load/delivery are selectively presented.Finally,we analyze current obstacles and suggest appropriate prospects for this area.

关键词： DNA logic systems molecular logic non-canonical DNA-nanostructures arithmetic/non-arithmetic functions logical bio-applications

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