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Echinatin inhibits tumor growth and synergizes with chemotherapeutic agents against human bladder cancer cells by activating p38 and suppressing Wnt/β-catenin pathways

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Genes & Diseases 2024年第2期11卷 1050-1065页

作者： Xiaoxuan Wang Lijuan Luo Jingtao Xu Qiuping Lu Haichao Xia Yanran Huang Lulu Zhang Liping Xie Habu Jiwa Shiqiong Liang Xiaoji Luo Jinyong Luo key laboratory of Diagnostic Medicine designated By the chinese ministry of education School of Laboratory MedicineChongqing Medical UniversityChongqing 400016China Department of Orthopedics The First Affiliated Hospital of Chongqing Medical UniversityChongqing 400042China

Bladder cancer (BC) is one of the most common malignant tumors in the urinary system.Due to the poor prognosis and high mortality rate of the disease,it is urgent to develop new drugs with high efficacy and low toxicity to treat BC.Echinatin (Ecn) is a bioactive natural flavonoid oflicorice that has attracted special attention for its promising anti-tumor potential.Herein,we explored the inhibitory effects of Echinatin on BC cells and probed the possible molecular mechanism.We found that Ecnin vitro inhibited the proliferation,migration,and invasion,arrested the cell cycle at the G2/M phase,and promoted apoptosis in BC cells.Besides,Ecn had no notable cytotoxicity towards human normal cells.We subsequently confirmed that Ecn restrained xenograft tumor growth and metastasis of BC cells in vivo .Mechanistically,Ecn activated the p38 signaling pathway but inactivated the Wnt/β-catenin signaling pathway,while over-expression of β-catenin and the p38 inhibitor both attenuated the inhibitory effects of Ecn on BC cells.Remarkably,Ecn combined with cisplatin (DDP) or gemcitabine (Gem) had synergistic inhibitory effects on BC cells.In summary,our results validate that Ecn inhibits the tumor growth of human BC cells via p38 and Wnt/β-catenin signaling pathways.More meaningfully,our results suggest a potential strategy to enhance DDP- or Gem-induced inhibitory effects on BC cells by combining with Ecn.

关键词： Bladder cancer Combination chemotherapy Echinatin p38 Wnt/β-catenin

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PDK1 promotes breast cancer progression by enhancing the stability and transcriptional activity of HIF-1α

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Genes & Diseases 2024年第4期11卷 353-367页

作者： Yu Wei Dian Zhang He Shi Husun Qian Hongling Chen Qian Zeng Fangfang Jin Yan Ye Zuli Ou Minkang Guo Bianqin Guo Tingmei Chen key laboratory of Clinical laboratory diagnostics(ministry of education) College of Laboratory MedicineChongqing Medical UniversityChongqing 400016China Chongqing key laboratory of Translational Research for Cancer Metastasis and Individualized Treatment Chongqing University Cancer HospitalChongqing 400030China

Pyruvate dehydrogenase kinase 1(PDK1)phosphorylates the pyruvate dehydroge-nase complex,which inhibits its activity.Inhibiting pyruvate dehydrogenase complex inhibits the tricarboxylic acid cycle and the reprogramming of tumor cell metabolism to glycolysis,which plays an important role in tumor progression.This study aims to elucidate how PDK1 pro-motes breast cancer progression.We found that PDK1 was highly expressed in breast cancer tissues,and PDK1 knockdown reduced the proliferation,migration,and tumorigenicity of breast cancer cells and inhibited the HIF-1α(hypoxia-inducible factor 1a)pathway.Further investigation showed that PDK1 promoted the protein stability of HIF-1αby reducing the level of ubiquitination of HIF-1a.The HIF-1αprotein levels were dependent on PDK1 kinase activity.Furthermore,HIF-1a phosphorylation at serine 451 was detected in wild-type breast cancer cells but not in PDK1 knockout breast cancer cells.The phosphorylation of HIF-1αat Ser 451 stabilized its protein levels by inhibiting the interaction of HIF-1a with von Hippel-Lindau and prolyl hydroxylase domain.We also found that PDK1 enhanced HIF-1αtranscriptional ac-tivity.In summary,PDK1 enhances HIF-1αprotein stability by phosphorylating HIF-1a at Ser451 and promotes HIF-1αtranscriptional activity by enhancing the binding of HIF-1αto P300.PDK1 and HIF-1a form a positive feedback loop to promote breast cancer progression.

关键词： Breast cancer HIF-1α PDK1 Protein phosphorylation Transcriptional activity

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Early Growth Response Gene-1 Deficiency Interrupts TGFβ1 Signaling Activation and Aggravates Neurodegeneration in Experimental Autoimmune Encephalomyelitis Mice

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Neuroscience Bulletin 2024年第3期40卷 283-292页

作者： Yunyi Lan Xinyan Han Fei Huang Hailian Shi Hui Wu Liu Yang Zhibi Hu Xiaojun Wu Shanghai key laboratory of Compound chinese Medicines The Ministry of Education Key Laboratory for Standardization of Chinese MedicinesThe State Administration of TCM Key Laboratory for New Resources and Quality Evaluation of Chinese MedicineInstitute of Chinese Materia MedicaShanghai University of Traditional Chinese MedicineShanghai201203China Central laboratory Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese MedicineShanghai200021China

Early growth response protein 1(Egr-1)triggers the transcription of many genes involved in cell growth,differentiation,synaptic plasticity,and neurogenesis.However,its mechanism in neuronal survival and degeneration is still poorly understood.This study demonstrated that Egr-1 was down-regulated at mRNA and protein levels in the central nervous system(CNS)of experimental autoimmune encephalomyelitis(EAE)mice.Egr-1 knockout exacerbated EAE progression in mice,as shown by increased disease severity and incidence;it also aggravated neuronal apoptosis,which was associated with weakened activation of the BDNF/TGFβ1/MAPK/Akt signaling pathways in the CNS of EAE mice.Consistently,Egr-1 siRNA promoted apoptosis but mitigated the activation of BDNF/TGFβ1/MAPK/Akt signaling in SH-SY5Y cells.Our results revealed that Egr-1 is a crucial regulator of neuronal survival in EAE by regulating TGFβ1-mediated signaling activation,implicating the important role of Egr-1 in the pathogenesis of multiple sclerosis as a potential novel therapy target.

关键词： Early growth response protein 1 Transforming growth factor-beta 1 Multiple sclerosis Experimental autoimmune encephalomyelitis Neurodegeneration

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27-Hydroxycholesterol/liver X receptor/apolipoprotein E mediates zearalenone-induced intestinal immunosuppression:A key target potentially linking zearalenone and cancer

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Journal of Pharmaceutical Analysis 2024年第3期14卷 371-388页

作者： Haonan Ruan Jing Zhang Yunyun Wang Ying Huang Jiashuo Wu Chunjiao He Tongwei Ke Jiaoyang Luo Meihua Yang key laboratory of Bioactive Substances and Resources Utilization of chinese Herbal Medicine Ministry of EducationInstitute of Medicinal Plant DevelopmentChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing100193China

Zearalenone(ZEN)is a mycotoxin that extensively contaminates food and feed,posing a significant threat to public health.However,the mechanisms behind ZEN-induced intestinal immunotoxicity remain unclear.In this study,Sprague-Dawley(SD)rats were exposed to ZEN at a dosage of 5 mg/kg/day b.***.for a duration of 14 days.The results demonstrated that ZEN exposure led to notable pathological alterations and immunosuppression within the intestine.Furthermore,ZEN exposure caused a significant reduction in the levels of apolipoprotein E(ApoE)and liver X receptor(LXR)(P<0.05).Conversely,it upregulated the levels of myeloid-derived suppressor cells(MDSCs)markers(P<0.05)and decreased the presence of 27-hydroxycholesterol(27-HC)in the intestine(P<0.05).It was observed that ApoE or LXR agonists were able to mitigate the immunosuppressive effects induced by ZEN.Additionally,a bioinformatics analysis highlighted that the downregulation of ApoE might elevate the susceptibility to colorectal,breast,and lung cancers.These findings underscore the crucial role of the 27-HC/LXR/ApoE axis disruption in ZEN-induced MDSCs proliferation and subsequent inhibition of T lymphocyte activation within the rat intestine.Notably,ApoE may emerge as a pivotal target linking ZEN exposure to cancer development.

关键词： Zearalenone Intestinal immunosuppression Apolipoprotein E Bioinformatics analysis Cancer

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Robust, breathable, and chemical-resistant polytetrafluoroethylene (PTFE) films achieved by novel in-situ fibrillation strategy for highperformance triboelectric nanogenerators

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Nano Research 2024年第3期17卷 1942-1951页

作者： Jialong Chai Guilong Wang Jinchuan Zhao Guizhen Wang Chao Wei Aimin Zhang Guoqun Zhao laboratory for Liquid-Solid Structural Evolution and Processing of Materials(ministry of education) Shandong UniversityJinan 250061China key laboratory of chinese education ministry for Tropical Biological Resources Hainan UniversityHaikou 570228China

In the era of advanced wearable electronic devices,the triboelectric nanogenerators(TENGs)as energy harvesting and self-powered sensing units hold great promise.Selecting appropriate triboelectric material is the crucial factor to optimize the performance of TENG,while polytetrafluoroethylene(PTFE)stands out as a highly versatile option among the various materials.In this study,we present an ultrafine nanofibrous PTFE(NF-PTFE)films prepared by novel in-situ fibrillation strategy as the triboelectric material in TENG devices.The innovative processing methodology facilely addresses the dilemma between high porosity and fine pore size of traditional porous PTFE films,meanwhile achieves exceptional mechanical strength,hydrophobicity,air permeability,and chemical resistance of the films.With the integration of nanofibrous PTFE films into contact-separation mode TENG and droplet-based TENG,these devices realize the peak electrical output of 131 V/10.8μA and 54 V/14μA with great durability,which surpass the performance of TENGs using traditional expanded PTFE films.Furthermore,a smart glove capable of recognizing hand gestures is proposed,which demonstrates the versatility,flexibility,and practicality of this material for potential use in smart devices.This reported NF-PTFE film provides insights for the design of high-performance TENG device for advanced wearable electrical applications.

关键词： polytetrafluoroethylene(PTFE) nanofibrous film hydrophobic triboelectric nanogenerator self-powered sensor

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Total-factor energy efficiency of ten major global energy-consuming countries

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Journal of Environmental Sciences 2024年第3期137卷 41-52页

作者： Xuan Wang Yonglong Lu Chunci Chen Xiaojie Yi Haotian Cui State key laboratory of Urban and Regional Ecology Research Centre for Eco-Environmental SciencesChinese Academy of SciencesBeijing 100085China State key laboratory of Marine Environmental Science and key laboratory of the ministry of education for Coastal Wetland Ecosystems College of the Environment and EcologyXiamen UniversityFujian 361102China University of chinese Academy of Sciences Beijing 100049China

Improving energy efficiency is regarded as a key path to tackling global warming and achieving the Sustainable Development Goals(SDGs).In 2020,the energy consumption of the world's ten major energy-consuming countries accounted for 66.8%of the global total.This paper applied data envelopment analysis(DEA)to calculate these ten major energyconsuming countries'total-factor energy efficiency(TFEE)at national and sectoral levels from 2001-2020,and explored the infuencing factors of total-factor energy efficiency with the Tobit regression model.The results showed significant difference in the ten countries'energy efficiency.The United States and Germany topped the list for total-factor energy efficiency,while China and India were at the bottom.Meanwhile,the energy efficiency of the industrial subsector has increased significantly over the past two decades,while that of the other subsectors has been relatively fat.The industrial structure upgrading,per capita GDP,energy consumption structure,and foreign direct investment had significant impacts on energy efficiency with national heterogeneity.Energy consumption structure and GDP per capita were determinative factors of energy efficiency.

关键词： Total-factor energy efficiency SBM-UN model Major energy-consuming country Carbon emission reduction

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Selective type II TRK inhibitors overcome xDFG mutation mediated acquired resistance to the second-generation inhibitors selitrectinib and repotrectinib

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Acta Pharmaceutica Sinica B 2024年第2期14卷 517-532页

作者： Shuang Xiang Xiaoyun Lu International Cooperative laboratory of Traditional chinese Medicine Modernization and Innovative Drug Discovery of chinese ministry of education(MOE) Guangdong Provincial Key Laboratory of New Drug Design and EvaluationGuangzhou City Key Laboratory of Precision Chemical Drug DevelopmentSchool of PharmacyJinan UniversityGuangzhou 510632China

Neurotrophic receptor kinase(NTRK) fusions are actionable oncogenic drivers of multiple pediatric and adult solid tumors,and tropomyosin receptor kinase(TRK) has been considered as an attractive therapeutic target for "pan-cancer" harboring these fusions.Currently,two generations TRK inhibitors have been developed.The representative second-generation inhibitors selitrectinib and repotrectinib were designed to overcome clinic acquired resistance of the first-generation inhibitors larotrectinib or entrectinib resulted from solvent-front and gatekeeper on-target mutations.However,xDFG(TRKAG667C/A/S,homologous TRKCG696C/A/S) and some double mutations still confer resistance to selitrectinib and repotrectinib,and overcoming these resistances represents a major unmet clinical need.In this review,we summarize the acquired resistance mechanism of the first-and second-generation TRK inhibitors,and firstly put forward the emerging selective type Ⅱ TRK inhibitors to overcome xDFG mutations mediated resistance.Additionally,we concluded our perspectives on new challenges and future directions in this field.

关键词： NTRK fusions TRK kinase Clinical resistance xDFG mutations Selective type II inhibitors

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Establishment of a humanized ST6GAL1 mouse model for influenza research

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Animal Models and Experimental Medicine 2024年第3期7卷 337-346页

作者： Lyu Chao Han Feng Gao Qian Lv Limin Lu Ziwei Lu Shuangshuang Li Xiaoyan Hu Yuechao Yang Mengjie Zhao Yingze Liu Jun Lu Xuancheng Duo Shuguang National key laboratory of Intelligent Tracking and Forecasting for Infectious Diseases Chinese Center for Disease Control and PreventionBeijingChina Institute of Zoology Chinese Academy of SciencesBeijingChina NHC key laboratory of Biosafety National Key Laboratory of Intelligent Tracking and Forecasting for Infectious DiseasesNational Institute for Viral Disease Control and PreventionChinese Center for Disease Control and PreventionBeijingChina Zhejiang Provincial key laboratory of medical Genetics Key Laboratory of Laboratory MedicineMinistry of EducationSchool of Laboratory Medicine and Life SciencesWenzhou Medical UniversityWenzhouChina

Background:This study aimed to construct and characterize a humanized influenza mouse model expressing hST6GAL1.Methods:Humanized fragments,consisting of the endothelial cell-specific K18 promoter,human ST6GAL1-encoding gene,and luciferase gene,were microinjected into the fertilized eggs of mice.The manipulated embryos were transferred into the oviducts of pseudopregnant female mice.The offspring were identified using PCR.Mice exhibiting elevated expression of the hST6GAL1 gene were selectively bred for propagation,and in vivo analysis was performed for screening.Expression of the humanized gene was tested by performing immunohistochemical(IHC)analysis.Hematologic and biochemical analyses using the whole blood and serum of humanized hST6GAL1 mice were performed.Results:Successful integration of the human ST6GAL1 gene into the mouse genome led to the overexpression of human SiaT ST6GAL1.Seven mice were identified as carrying copies of the humanized gene,and the in vivo analysis indicated that hST6GAL1gene expression in positive mice mirrored influenza virus infection characteristics.The IHC results revealed that hST6GAL1 was expressed in the lungs of humanized mice.Moreover,the hematologic and biochemical parameters of the positive mice were within the normal range.Conclusion:A humanized influenza mouse model expressing the hST6GAL1 gene was successfully established and characterized.

关键词： hST6GAL1 humanized mice influenza animal model

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Recent advances in protein conformation sampling by combining machine learning with molecular simulation

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chinese Physics B 2024年第3期33卷 80-87页

作者：唐一鸣杨中元姚逸飞周运谈圆王子超潘瞳熊瑞孙俊力韦广红 Department of Physics State Key Laboratory of Surface Physicsand Key Laboratory for Computational Physical Sciences (Ministry of Education)Shanghai 200438China

The rapid advancement and broad application of machine learning(ML)have driven a groundbreaking revolution in computational biology.One of the most cutting-edge and important applications of ML is its integration with molecular simulations to improve the sampling efficiency of the vast conformational space of large biomolecules.This review focuses on recent studies that utilize ML-based techniques in the exploration of protein conformational landscape.We first highlight the recent development of ML-aided enhanced sampling methods,including heuristic algorithms and neural networks that are designed to refine the selection of reaction coordinates for the construction of bias potential,or facilitate the exploration of the unsampled region of the energy landscape.Further,we review the development of autoencoder based methods that combine molecular simulations and deep learning to expand the search for protein conformations.Lastly,we discuss the cutting-edge methodologies for the one-shot generation of protein conformations with precise Boltzmann weights.Collectively,this review demonstrates the promising potential of machine learning in revolutionizing our insight into the complex conformational ensembles of proteins.

关键词： machine learning molecular simulation protein conformational space enhanced sampling

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Multi-omics analysis of adamantinomatous craniopharyngiomas reveals distinct molecular subgroups with prognostic and treatment response significance

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中华医学杂志(英文版) 2024年第7期137卷 859-870页

作者： Wang Xianlong Zhao Chuan Lin Jincheng Liu Hongxing Zeng Qiuhong Chen Huadong Wang Ye Xu Dapeng Chen Wen Xu Moping Zhang En Lin Da Lin Zhixiong Sanbo Brain Hospital Capital medical University Beijing 100093 Department of Bioinformatics School of medical Technology and Engineering key laboratory of medical Bioinformatics key laboratory of ministry of education for Gastrointestinal Cancer Fujian medical University Fuzhou Fujian 350122 China Department of Neurosurgery

Background: Adamantinomatous craniopharyngioma (ACP) is the commonest pediatric sellar tumor. No effective drug is available and interpatient heterogeneity is prominent. This study aimed to identify distinct molecular subgroups of ACP based on the multi-omics profiles, imaging findings, and histological features, in order to predict the response to anti-inflammatory treatment and immunotherapies.Methods: Totally 142 chinese cases diagnosed with craniopharyngiomas were profiled, including 119 ACPs and 23 papillary craniopharyngiomas. Whole-exome sequencing (151 tumors, including recurrent ones), RNA sequencing (84 tumors), and DNA methylome profiling (95 tumors) were performed. Consensus clustering and non-negative matrix factorization were used for subgrouping, and Cox regression were utilized for prognostic evaluation, respectively.Results: Three distinct molecular subgroups were identified: WNT, ImA, and ImB. The WNT subgroup showed higher Wnt/β-catenin pathway activity, with a greater number of epithelial cells and more predominantly solid tumors. The ImA and ImB subgroups had activated inflammatory and interferon response pathways, with enhanced immune cell infiltration and more predominantly cystic tumors. Mitogen-activated protein kinases (MEK/MAPK) signaling was activated only in ImA samples, while IL-6 and epithelial-mesenchymal transition biomarkers were highly expressed in the ImB group, mostly consisting of children. The degree of astrogliosis was significantly elevated in the ImA group, with severe finger-like protrusions at the invasive front of the tumor. The molecular subgrouping was an independent prognostic factor, with the WNT group having longer event-free survival than ImB (Cox,P = 0.04). ImA/ImB cases were more likely to respond to immune checkpoint blockade (ICB) therapy than the WNT group (P <0.01). In the preliminary screening of subtyping markers, CD38 was significantly downregulated in WNT compared with ImA and ImB (P = 0.01).Conclusions: ACP comprises three molecular subtypes with disti

关键词： Craniopharyngioma Central nervous system tumor Precision medicine beta Catenin Proto-Oncogene Proteins B-raf

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