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Simultaneously targeting extracellular vesicle trafficking and TGF-β receptor kinase activity blocks signaling hyperactivation and metastasis

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Signal Transduction and Targeted Therapy 2024年第1期9卷 308-325页

作者： Adilson Fonseca Teixeira Yanhong Wang Josephine Iaria Peter ten Dijke Hong-Jian Zhu Department of Surgery(The Royal Melbourne Hospital) The University of MelbourneParkvilleVICAustralia Huagene Institute Kecheng Science and Technology ParkPukou DistrictNanjingJiangsuChina Department of Cell and Chemical biology Oncode InstituteLeiden University Medical CenterLeidenThe Netherlands

Metastasis is the leading cause of cancer-related *** growth factor beta(TGF-β)signaling drives metastasis and is strongly enhanced during cancer ***,the use of on-target TGF-βsignaling inhibitors in the treatment of cancer patients remains unsuccessful,highlighting a gap in the understanding of TGF-βbiology that limits the establishment of efficient anti-metastatic ***,we show that TGF-βsignaling hyperactivation in breast cancer cells is required for metastasis and relies on increased small extracellular vesicle(sEV)*** sEV’s unique role,TGF-βsignaling levels induced by sEVs exceed the activity of matching concentrations of soluble ligand TGF-β.Further,genetic disruption of sEV secretion in highlymetastatic breast cancer cells impairs cancer cell aggressiveness by reducing TGF-βsignaling to nearly-normal ***,TGF-βsignaling activity in non-invasive breast cancer cells is inherently low,but can be amplified by sEVs,enabling invasion and metastasis of poorly-metastatic breast cancer *** the translational potential of inhibiting sEV trafficking in advanced breast cancers,treatment with dimethyl amiloride(DMA)decreases sEV secretion,TGF-βsignaling activity,and breast cancer progression in *** both the sEV trafficking and TGF-βsignaling by combining DMA and SB431542 at suboptimal doses potentiated this effect,normalizing the TGF-βsignaling in primary tumors to potently reduce circulating tumor cells,metastasis,and tumor ***,this study establishes sEVs as critical elements in TGF-βbiology,demonstrating the feasibility of inhibiting sEV trafficking as a new therapeutic approach to impair metastasis by normalizing TGF-βsignaling levels in breast cancer cells.

关键词： metastasis doses invasion

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Messing with cancer therapy:how the melanoma phenotype predicts checkpoint inhibitor response

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Signal Transduction and Targeted Therapy 2024年第5期9卷 1784-1785页

作者： Svenja Meierjohann Corine Bertolotto Institute of Pathology University of WürzburgWürzburgGermany University Côte d’Azur InsermBiology and Pathologies of melanocytesteam1Equipe labellisée Ligue 2020Centre Méditerranéen de Médecine MoléculaireNiceFrance

In a study published in Cell,Pozniak et *** the spectrum of the phenotypic cell states of human metastatic melanomas in their tumor microenvironment before and early during immune checkpoint inhibitor(ICI)therapy and identified an enrichment of mesenchymal-like(MES)state melanoma cells in non-responders to ICI.1 These findings offer valuable insights into the factors contributing to the refractoriness of certain melanoma patients to ICI,while also unveiling novel molecular targets that hold promise for improving their treatment outcomes.

关键词： melanoma al. therapy

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Systemic analysis of metabolome reconfiguration in Arabidopsis after abiotic stressors uncovers metabolites that modulate defense against pathogens

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Plant Communications 2024年第1期5卷 55-68页

作者： Antoni Garcia-Molina Victoria Pastor centre for Research in Agricultural Genomics(CRAG)CSIC-IRTA-UAB-UB C/Vall MorontaEdifici CRAG08193 Bellaterra(Cerdanyola del Valles)BarcelonaSpain Department of biology Biochemistryand Natural SciencesSchool of Technology and Experimental SciencesUniversitat Jaume I12006 Castellode la PlanaSpain

Understanding plant immune responses is complex because of the high interdependence among biological processes in homeostatic ***,the integration of environmental cues causes network rewiring that interferes with defense ***,plants retain molecular signatures configured under abiotic stress periods to rapidly respond to recurrent stress,and these can alter *** changes imposed by abiotic stressors are persistent,although their impact on defense remains to be *** this study,we profiled metabolomes of Arabidopsis plants under several abiotic stress treatments applied individually or simultaneously to capture temporal trajectories in metabolite composition during adverse conditions and *** systemic analysis was performed to address the relevance of me-tabolome changes and extract central features to be tested in *** results demonstrate irreversibility in major fractions of metabolome changes as a general pattern in response to abiotic stress ***-tionalanalysisofmetabolomesandco-abundancenetworkspoints toconvergence inthereconfigurationof organic acid and secondary metabolite *** mutant lines for components related to these metabolic pathways showed altered defense capacities against different ***,our data suggest that sustained metabolome changes configured in adverse environments can act as mod-ulators of immune responses and provide evidence for a new layer of regulation in plant defense.

关键词： abiotic stress Arabidopsis biotic stress combinatorial stress metabolomics systems biology

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Self-assembly of differentiated dental pulp stem cells facilitates spheroid human dental organoid formation and prevascularization

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World Journal of Stem Cells 2024年第3期16卷 287-304页

作者： Fei Liu Jing Xiao Lei-Hui Chen Yu-Yue Pan Jun-Zhang Tian Zhi-Ren Zhang Xiao-Chun Bai School of Basic medical Sciences Southern Medical UniversityGuangzhou 510515Guangdong ProvinceChina Department of Health Management Guangdong Second Provincial General HospitalGuangzhou 510317Guangdong ProvinceChina Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment Zhuhai People’s Hospital Affiliated with Jinan UniversityZhuhai 519000Guangdong ProvinceChina centre of Reproduction Development and AgingFaculty of Health SciencesUniversity of MacaoMacao 999078China Department of Stomatology Guangdong Second Provincial General HospitalGuangzhou 510317Guangdong ProvinceChina Zhuhai Institute of Translational Medicine Zhuhai Hospital Affiliated with Jinan UniversityZhuhai 519000Guangdong ProvinceChina Department of Cell biology School of Basic Medical SciencesSouthern Medical UniversityGuangzhou 510515Guangdong ProvinceChina

BACKGROUND The self-assembly of solid organs from stem cells has the potential to greatly expand the applicability of regenerative *** cells can self-organise into microsized organ units,partially modelling tissue function and *** pulp organoids have been used to recapitulate the processes of tooth development and related ***,the lack of vasculature limits the utility of dental pulp *** To improve survival and aid in recovery after stem cell transplantation,we demonstrated the three-dimensional(3D)self-assembly of adult stem cell-human dental pulp stem cells(hDPSCs)and endothelial cells(ECs)into a novel type of spheroid-shaped dental pulp organoid in vitro under hypoxia and conditioned medium(CM).METHODS During culture,primary hDPSCs were induced to differentiate into ECs by exposing them to a hypoxic environment and *** hypoxic pretreated hDPSCs were then mixed with ECs at specific ratios and conditioned in a 3D environment to produce prevascularized dental pulp *** biological characteristics of the organoids were analysed,and the regulatory pathways associated with angiogenesis were *** The combination of these two agents resulted in prevascularized human dental pulp organoids(Vorganoids)that more closely resembled dental pulp tissue in terms of morphology and ***-cell RNA sequencing of dental pulp tissue and RNA sequencing of Vorganoids were integrated to analyse key regulatory pathways associated with *** biomarkers forkhead box protein O1 and fibroblast growth factor 2 were identified to be involved in the regulation of *** In this innovative study,we effectively established an in vitro model of Vorganoids and used it to elucidate new mechanisms of angiogenesis during regeneration,facilitating the development of clinical treatment strategies.

关键词： Human dental pulp stem cells Prevascularized organoids Integrated analyses Angiogenesis Forkhead box protein O1

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Advances in oral mesenchymal stem cell-derived extracellular vesicles in health and disease

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Genes & Diseases 2024年第1期11卷 346-357页

作者： Huanyu Luo Anahid Ahmadi Birjandi Feilong Ren Tianmeng Sun Paul T.Sharpe Hongchen Sun Zhengwen An Department of Oral biology Jilin Provincial Key Laboratory of Tooth Development and Bone RemodelingSchool and Hospital of StomatologyJilin UniversityChangchunJilin 130021China Faculty of Dentistry Oral&Craniofacial SciencesCentre for Craniofacial and Regenerative BiologyKing's College LondonLondonSE19RTUK Department of Oral Pathology Jilin Provincial Key Laboratory of Tooth Development and Bone RemodelingSchool and Hospital of StomatologyJilin UniversityChangchunJilin 130021China

Extracellular vesicles(EVs)are nano-size vesicles secreted naturally by all cells into the extracellular space and have been recognized as important cell-cell mediators in multicel-lular *** contain nucleic acids,proteins,lipids,and other cellular components,regulating many basic biological processes and playing an important role in regenerative med-icine and *** can be traced to their cells of origin and exhibit a similar ***,EVs demonstrate low immunogenicity,good biocompatibility,and fewer side ef-fects,compared to their parent *** stem cells(MsCs)are one of the most important resource cells for EVs,with a great capacity for self-renewal and multipotent differ-entiation,and play an essential role in stem cell *** mechanism of MsC therapy was thought to be attributed to the differentiation of MsCs after targeted migration,as previously ***,emerging evidence shows the previously unknown role of MsC-derived para-crine factors in stem cell *** EVs derived from oral tissue MSCs(OMSC-EVs),show more advantages than those of all other MsCs in tissue repair and regeneration,due to their lower invasiveness and easier accessibility for sample ***,we systematically review the biogenesis and biological characteristics of OMSC-EVs,as well as the role of OMsC-EVs in intercellular ***,we discuss the potential therapeutic roles of OMSC-EVs in oral and systemic *** highlight the current challenges and future directions of OMSC-EVs to focus more attention on clinical *** aim to provide valuable insights for the explorative clinical application of OMSC-EVs.

关键词： Disease Extracellular vesicles Oral tissue MSC Therapeutic application Tissue regeneration

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Sexual dimorphism in the antitumor immune responses elicited by the combination of fasting and chemotherapy

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Cancer Communications 2024年第4期44卷 508-513页

作者： Andrés Pastor-Fernández Manuel Montero Gómez de las Heras Jose Ignacio Escrig-Larena Marta Barradas Cristina Pantoja Adrian Plaza Jose Luis Lopez-Aceituno Esther Durán Alejo Efeyan Maria Mittelbrunn Lola Martinez Pablo Jose Fernandez-Marcos Metabolic Syndrome Group(BIOPROMET) Madrid Institute for Advanced Studies(IMDEA)FoodE28049MadridSpain Molecular biology Center Severo Ochoa(CBMSO) Spanish National Research Council(CSIC)Madrid Autonoma University(UAM)MadridSpain Department of Basic medical Sciences Institute of Applied Molecular MedicineSchool of MedicineUniversity Studies Center(CEU)-San Pablo UniversityMadridSpain Metabolism and Cell Signaling Laboratory Spanish National Cancer Research centre(CNIO) MadridSpain 5Flow Cytometry UnitBiotechnology ProgrammeSpanish National Cancer Research Centre(CNIO)MadridSpain

Fasting reduces chemotherapy toxicity[1],enhances immunogenic tumor cell death[2,3]and increases CD8^(+)T cell infiltration in tumors,particularly when combined with chemotherapy[2,3]or immunotherapy[4].More-over,fast... 详细信息

关键词： chemotherapy fasting immune

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General anesthetic agents induce neurotoxicity through astrocytes

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Neural Regeneration Research 2024年第6期19卷 1299-1307页

作者： Yanchang Yang Tiantian Liu Jun Li Dandan Yan Yuhan Hu Pin Wu Fuquan Fang Patrick M.McQuillan Wenxin Hang Jianhang Leng Zhiyong Hu Department of Anesthesiology The First Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang ProvinceChina Department of Anesthesiology Ningbo Women and Children’s HospitalNingboZhejiang ProvinceChina Department of Anesthesiology Shulan(Hangzhou)Hospital Affiliated to Zhejiang Shuren University Shulan International Medical CollegeHangzhouZhejiang ProvinceChina Cell biology Department Yale UniversityNew HavenCTUSA Department of Anesthesiology Penn State Hershey Medical CentrePenn State College of MedicineHersheyPAUSA Department of Central Laboratory Affiliated Hangzhou First People’s HospitalZhejiang University School of MedicineHangzhouZhejiang ProvinceChina

Neuroscientists have recognized the importance of astrocytes in regulating neurological function and their influence on the release of glial *** studies,however,have focused on the effects of general anesthetic agents on neuroglia or *** can also be an important target of general anesthetic agents as they exert not only sedative,analgesic,and amnesic effects but also mediate general anesthetic-induced neurotoxicity and postoperative cognitive ***,we analyzed recent advances in understanding the mechanism of general anesthetic agents on astrocytes,and found that exposure to general anesthetic agents will destroy the morphology and proliferation of astrocytes,in addition to acting on the receptors on their surface,which not only affect Ca^(2+)signaling,inhibit the release of brain-derived neurotrophic factor and lactate from astrocytes,but are even involved in the regulation of the pro-and anti-inflammatory processes of *** would obviously affect the communication between astrocytes as well as between astrocytes and neighboring neurons,other neuroglia,and vascular *** this review,we summarize how general anesthetic agents act on neurons via astrocytes,and explore potential mechanisms of action of general anesthetic agents on the nervous *** hope that this review will provide a new direction for mitigating the neurotoxicity of general anesthetic agents.

关键词： astrocytes brain-derived neurotrophic factor general anesthetic agents neuron neurotoxicity N-methyl-D-aspartate receptor perioperative neurocognition Toll-like receptor γ-aminobutyric acid receptor

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Exceptional Early Jurassic fossils with leathery eggs shed light on dinosaur reproductive biology

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National Science Review 2024年第6期11卷 146-158页

作者： Fenglu Han Yilun Yu Shukang Zhang Rong Zeng Xinjin Wang Huiyang Cai Tianzhuang Wu Yingfeng Wen Sifu Cai Chun Li Rui Wu Qi Zhao Xing Xu School of Earth Sciences China University of Geosciences (Wuhan) Key Laboratory of Vertebrate Evolution and Human Origins Institute of Vertebrate Paleontology and PaleoanthropologyChinese Academy of Sciences University of Chinese Academy of Sciences Guizhou Provincial Museum Guizhou Provincial Institute of Cultural Relics and Archaeology Pingba Institute of Cultural Relics Administration centre for Vertebrate Evolutionary biology Yunnan University

Our understanding of pre-Cretaceous dinosaur reproduction is hindered by a scarcity of evidence within fossil records. Here we report three adult skeletons and five clutches of embryo-containing eggs of a new sauropodomorph from the Lower Jurassic of southwestern China, displaying several significant reproductive features that are either unknown or unlike other early-diverging sauropodomorphs, such as relatively large eggs with a relatively thick calcareous shell formed by prominent mammillary cones, synchronous hatching and a transitional prehatching posture between the crocodilians and living birds. Most significantly,these Early Jurassic fossils provide strong evidence for the earliest known leathery eggs. Our comprehensive quantitative analyses demonstrate that the first dinosaur eggs were probably leathery, elliptical and relatively small, but with relatively long eggshell units, and that along the line to living birds, the most significant change in reptilian egg morphology occurred early in theropod evolution rather than near the origin of Aves.

关键词： dinosaur sauropodomorph Jurassic embryo egg evolution reproductive behavior

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Maslinic acid supplementation prevents di(2-ethylhexyl)phthalate-induced apoptosis via PRDX6 in peritubular myoid cells of Chinese forest musk deer

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Journal of Environmental Sciences 2024年第9期143卷 47-59页

作者： Heran Cao Zhenpeng Li Tianqi Jin Shuyang He Shujuan Liu Long Li Yang Wang Ye Gong Gang Wang Fangxia Yang Wuzi Dong College of Animal Science and Technology Northwest A&F UniversityShaanxi 712100China College of Forestry Northwest A&F UniversityShaanxi 712100China biology Research centre of Qin-Mountains Wildlife Northwest A&F UniversityShaanxi 712100China Shaanxi Qiyuan-Times Agri-Tech Development Co.Ltd. Shaanxi 725000China

Chinese forest musk deer(FMD),an endangered species,have exhibited low reproductive rates even in captivity due to stress *** revealed the presence of di(2-ethylhexyl)phthalate(DEHP),an environmental endocrine disruptor,in the serum and skin of captive *** FMDs with maslinic acid(MA)has been observed to alleviate the stress response and improve reproductive rates,although the precise molecular mechanisms remain ***,this study aims to investigate the molecular mechanisms underlying the alleviation of DEHP-induced oxidative stress and cell apoptosis in primary peritubular myoid cells(PMCs)through MA *** PMCs were isolated and exposed to DEHP in *** results demonstrated that DEHP significantly suppressed antioxidant levels and promoted cell apoptosis in primary ***,interfering with the expression of PRDX6 was found to induce excessive reactive oxygen species(ROS)production and cell apoptosis in primary *** with MA significantly upregulated the expression of PRDX6,thereby attenuating DEHP-induced oxidative stress and cell apoptosis in primary *** findings provide a theoretical foundation for mitigating stress levels and enhancing reproductive capacity of in captive FMDs.

关键词： Maslinic acid Forest musk deer Di(2-ethylhexyl)phthalate Peritubular myoid cells PRDX6

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Host cyclophilin A facilitates SARS-CoV-2 infection by binding and stabilizing spike on virions

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Signal Transduction and Targeted Therapy 2024年第1期9卷 36-39页

作者： Xiangpeng Sheng Fang Zhu Hong Peng Fan Yang Yi Yang Cong Yang Zhen Wang Wei Chen Deyin Guo Ronggui Hu State Key Laboratory of Molecular biology Center for Excellence in Molecular Cell ScienceShanghai Institute of Biochemistry and Cell BiologyUniversity of Chinese Academy of SciencesChinese Academy of SciencesShanghaiChina MOE Key Laboratory of Tropical Disease Control Centre for Infection and Immunity StudySchool of MedicineSun Yat-sen UniversityShenzhenChina ICU Longhua Hospital Shanghai University of Traditional Chinese MedicineShanghaiChina

Dear Editor,The novel coronavirus SARS-CoV-2 rapidly evolutes to increase its infectivity and transmissibility,facilitates its immune escape,impairs vaccine efficacy,and currently causes repeated infections in human,which is mainly determined by the accumulated mutations in spike(S).1 Transmembrane S is a heavily glycosylated protein on the surface of the virion as homotrimer,responsible for binding to human angiotensin-converting enzyme 2(hACE2)receptor.2 While the architecture of S trimers has been well studied,how the stability of S is regulated by potential host factors remains unknown.

关键词： ACE2 vaccine infection

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