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microvesicles with mitochondrial content are increased in patients with sepsis and associated with inflammatory responses

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World Journal of Clinical Cases 2023年第2期11卷 342-356页

作者： Hai-Jun Zhang Jin-Yi Li Chao Wang Guo-Qiang Zhong Department of Cardiology The First Affiliated Hospital of Guangxi Medical UniversityNanning 530000Guangxi Zhuang Autonomous RegionChina Department of Cardiology The First Affiliated HospitalHengyang Medical SchoolUniversity of South ChinaHengyang 421000Hunan ProvinceChina Department of Cardiology The Affiliated Hospital of Guilin Medical UniversityGuilin 541000Guangxi Zhuang Autonomous RegionChina

BACKGROUND Endothelial activation plays an important role in sepsis-mediated inflammation,but the triggering factors have not been fully elucidated.microvesicles carrying mitochondrial content(mitoMVs)have been implicated in several diseases and shown to induce endothelial activation.AIM To explore whether mitoMVs constitute a subset of MVs isolated from plasma of patients with sepsis and contribute to endothelial activation.METHODS MVs were isolated from human plasma and characterized by confocal microscopy and flow cytometry.Proinflammatory cytokines,including interleukin(IL)-6,IL-8 and tumour necrosis factor(TNF)-α,and soluble vascular cell adhesion molecule(sVCAM)-1 were detected by ELISA.Human umbilical vein endothelial cells(HUVECs)were stimulated with the circulating MVs to evaluate their effect on endothelial activation.RESULTS MitoMVs were observed in plasma from patients with sepsis.Compared with those in healthy controls,expression of MVs,mitoMVs,proinflammatory cytokines and sVCAM-1 was increased.The number of mitoMVs was positively associated with TNF-αand sVCAM-1.In vitro,compared with MVs isolated from the plasma of healthy controls,MVs isolated from the plasma of patients with sepsis induced expression of OAS2,RSAD2,and CXCL10 in HUVECs.MitoMVs were taken up by HUVECs,and sonication of MVs significantly reduced the uptake of mitoMVs by HUVECs and expression of the above three type I IFNdependent genes.CONCLUSION MitoMVs are increased in the plasma of patients with sepsis,which induces elevated expression of type I IFN-dependent genes.This suggests that circulating mitoMVs activate the type I IFN signalling pathway in endothelial cells and lead to endothelial activation.

关键词： Sepsis microvesicles Mitochondria microvesicles carrying mitochondrial content

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Immune modulatory function of abundant immune-related microRNAs in microvesicles from bovine colostrum

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Protein & Cell 2013年第3期4卷 197-210页

作者： Qi Sun Xi Chen Jianxiong Yu Ke Zen Chen-Yu Zhang Liang Li Jiangsu Engineering Research Center for microRNA Biology and Biotechnology State Key Laboratory of Pharmaceutical BiotechnologyNanjing University School of Life SciencesNanjing 210093China Department of Virology University of California School of Public HealthBerkeleyCA 94720USA

Colostrum provides essential nutrients and immunologically active factors that are beneficial to newborns.Our previous work demonstrated that milk contains large amounts of miRNA that is largely stored in milk-derived microvesicles(MVs).In the present study,we found that the MVs from colostrum contain signifi cantly higher levels of several immune-related miRNAs.We hypothesized that the colostrum MVs may transfer the immune-related miR-NAs into cells,which contribute to its immune modulatory feature.We isolated colostrum MVs by ultracentrifugation and demonstrated several immune modulation features associated with miRNAs.We also provide evidence that the physical structure of milk-derived MVs is essential for transfer miRNAs and following immune modulation effect.Moreover,we found that colostrum powder-derived MVs also contains higher levels of immune-related miRNAs that display similar immune modulation effects.Taken together,these results show that MV-containing immunerelated miRNAs may be a novel mechanism by which co-lostrum modulates body immune response.

关键词： colostrum miRNAs microvesicles immune modulation

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Glutamine metabolic microenvironment drives M2 macrophage polarization tomediate trastuzumab resistance in HER2-positive gastric cancer

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Cancer Communications 2023年第8期43卷 909-937页

作者： Xingbin Hu Zhenfeng Ma Beibei Xu Shulong Li Zhiqi Yao Bishan Liang Jiao Wang Wangjun Liao Li Lin Chunling Wang Siting Zheng Qijing Wu Qiong Huang Le Yu Fenghua Wang Min Shi Department of Oncology Nanfang HospitalSouthern Medical UniversityGuangzhouGuangdongP.R.China School of Biomedical Engineering Southern Medical UniversityGuangzhouGuangdongP.R.China School of Pharmaceutical Sciences Southern Medical UniversityGuangzhouGuangdongP.R.China Department of Medical Oncology Sun Yat-sen University Cancer CenterState Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineGuangzhouGuangdongP.R.China

Background:Trastuzumab is a first-line targeted therapy for human epidermal growth factor receptor-2(HER2)-positive gastric cancer.However,the inevitable occurrence of acquired trastuzumab resistance limits the drug benefit,and there is currently no effective reversal measure.Existing researches on the mechanism of trastuzumab resistance mainly focused on tumor cells themselves,while the understanding of the mechanisms of environment-mediated drug resistance is relatively lacking.This study aimed to further explore the mechanisms of trastuzumab resistance to identify strategies to promote survival in these patients.Methods:Trastuzumab-sensitive and trastuzumab-resistant HER2-positive tumor tissues and cells were collected for transcriptome sequencing.Bioinformatics were used to analyze cell subtypes,metabolic pathways,and molecular signaling pathways.Changes in microenvironmental indicators(such as macrophage,angiogenesis,and metabolism)were verified by immunofluorescence(IF)and immunohistochemical(IHC)analyses.Finally,a multi-scale agent-based model(ABM)was constructed.The effects of combination treatment were further validated in nude mice to verify these effects predicted by the ABM.Results:Based on transcriptome sequencing,molecular biology,and in vivo experiments,we found that the level of glutamine metabolism in trastuzumabresistant HER2-positive cells was increased,and glutaminase 1(GLS1)was significantly overexpressed.Meanwhile,tumor-derived GLS1 microvesicles drove M2macrophage polarization.Furthermore,angiogenesis promoted trastuzumab resistance.IHC showed high glutamine metabolism,M2 macrophage polarization,and angiogenesis in trastuzumab-resistant HER2-positive tumor tissues from patients and nudemice.Mechanistically,the cell division cycle 42(CDC42)promoted GLS1 expression in tumor cells by activating nuclear factor kappa-B(NF-κB)p65 and drove GLS1microvesicle secretion through IQmotif-containing GTPase-activating protein 1(IQGAP1).Based on the ABM and in vivo experiments,we confirmed that the combin

关键词： Gastric cancer glutamine metabolism macrophage mathematical model microvesicles trastuzumab

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Designer cell-self-implemented labeling of microvesicles in situ with the intracellular-synthesized quantum dots

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Science China Chemistry 2020年第4期63卷 448-453页

作者： Ling-Hong Xiong Jia-Wei Tu Ya-Nan Zhang Ling-Ling Yang Ran Cui Zhi-Ling Zhang Dai-Wen Pang College of Chemistry and Molecular Sciences State Key Laboratory of VirologyInstitute for Advanced Studiesand Wuhan Institute of BiotechnologyWuhan UniversityWuhan 430072China State Key Laboratory of Medicinal Chemical Biology Tianjin Key Laboratoryof Biosensing and Molecular RecognitionResearch Center for Analytical Sciencesand College of ChemistryNankai UniversityTianjin 300071China

Cell-derived microvesicles(MVs) are secreted from almost all kinds of mammalian cells into the extracellular space, and play crucial roles in intercellular communication and transporting biomolecules between cells. However, there is a great challenge for visualizing and monitoring of MVs’ bio-behaviors due to the limitations of existing labeling methods. Herein, we report the first paradigm of designer cell-self-implemented labeling of MVs secreted from living mammalian MCF-7 cells in situ using the intracellular-synthesized fluorescent quantum dots(QDs) during the formation of MVs. By elaborately coupling intracellular biochemical reactions and metabolism pathways, the MCF-7 cells can be illuminated brightly by intracellular-biosynthesized fluorescent CdSe QDs. Simultaneously, intracellular-synthesized QDs can be in situ encapsulated by the secreted MVs budding from the plasma membrane of the fluorescing cells to label the MVs with an efficiency of up to 89.9%. The whole labeling process skillfully combines designer precise cell-tuned intricate synthesis of CdSe QDs with mild in-situ labeling via cell-selfimplementation just after feeding the cell with suitable chemicals, which is structure-or function-nondestructive and much more straightforward and milder than those by chemical conjugation or indirect encapsulation with conventional fluorogenic labels.

关键词： in situ labeling live cell synthesis cell-derived microvesicles quantum dot cell-self-implementation

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microvesicles in Gliomas and Medulloblastomas: An Overview

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Journal of Cancer Therapy 2014年第2期5卷 182-191页

作者： Muhammad Nawaz Farah Fatima Bruna Riedo Zanetti Isabela de Lima Martins Nathalia Lopes Schiavotelo Niele Dias Mendes Renata Nacasaki Silvestre Luciano Neder Department of Pathology and Forensic Medicine Faculty of Medicine of Ribeirao Preto University of Sao Paulo Sao Paulo Brazil

microvesicles (MVs) or shedding membrane vesicles have recently been described as a novel model of intercellular communication. Previously, MVs were considered as unnecessary or secreted cellular debris, but MVs have lately been described as having roles in a variety of biological functions, such as cell homeostasis and the cellular processes involved in the oncogenesis of many types of tumors. Carrying several key molecules that contribute to tumor development and progression, similar to mRNAs, microRNAs and other non-coding RNAs, DNA and even small proteins, MVs can be considered as a ubiquitous form of novel cell communication that is present in most somatic cells. Although tumor-derived MVs have been demonstrated in different types of cancers, the literature data on MVs in primary central nervous system (CNS) tumors are relatively scarce. In this review, we address the involvement of MVs in diffuse astrocytomas, particularly glioblastomas, as well as oligodendrogliomas and medulloblastomas. We placed particular focus on the cellular crosstalk between tumor and “normal” cells, the putative mechanisms how the tumor microenvironment is modulated and the spread of aggressive phenotypes. Additionally, a better understanding of the participation of tumor-derived MVs in the regulation of key cancer pathways will offer new insights into tumor pathogenesis and the mechanisms of multidrug resistance, and may help to develop new strategies for novel therapies against these infiltrative CNS tumors.

关键词： microvesicles Exosomes Microparticles Gliomas Glioblastomas Medulloblastomas Oligodendrogliomas Review

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Take-over:multiple mechanisms of inter-adipocyte communication

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分子细胞生物学报:英文版 2011年第2期3卷 81-90页

作者： Gunter Muller Department Biology I Genetics MartinsriedBiocenterLudwig-Maximilians-University MunichMunichGermany

Adipose tissue mass in mammals is thought to expand with an increase in both volume and total number of the adipocytes.Recent findings suggest that in normal-weight as well as obese individuals,the adipocyte number is set during adolescence prior to adulthood,whereas the subsequent increase in size predominantly drives obesity.The simultaneous existence of large and small adipocytes and their unsynchronized growth,even within the same adipose tissue depot,argues against simple filling-up of emerging adipocytes with lipids and lipid droplets(LDs).Consequently,it is tempting to speculate about signals sent by large adipocytes to order small adipocytes the take-over of the burden of lipid loading.Currently there is experimental evidence for three distinct types of inter-adipocyte signals,i.***.cell-to-cell contacts,adipokines,and other soluble factors and microvesicles.Very recently,microvesicles have been shown(i)to harbour the glycosylphosphatidylinositol-anchored(c)AMP-degrading phosphodiesterase Gce1 and 5′-nucleotidase CD73,(ii)to be released from large adipocytes,(iii)to interact with small adipocytes,and(iv)to transfer Gce1 and CD73 to plasma membranes and LDs of small adipocytes where they degrade(c)AMP.This sequence of events leads to the up-regulation of lipid storage in small adipocytes in response to the microvesicle-encoded‘take-over’signal from large adipocytes.A model is proposed for the maturation of small adipocytes driven by large ones along a gradient of those inter-adipocyte signals.Pharmacological modulation of inter-adipocyte communication and thereby adipocyte maturation may be useful for the therapy of metabolic diseases.

关键词： adipokines fat cells glycosylphosphatidylinositol lipid droplets lipid metabolism microvesicles obesity type 2 diabetes

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Extracellular vesicles in the diagnosis and treatment of central nervous system diseases

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Neural Regeneration Research 2020年第4期15卷 586-596页

作者： Alisa A.Shaimardanova Valeriya V.Solovyeva Daria S.Chulpanova Victoria James Kristina V.Kitaeva Albert A.Rizvanov Institute of Fundamental Medicine and Biology Kazan Federal UniversityKazanRussia Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry The Russian Academy of SciencesMoscowRussia School of Veterinary Medicine and Science University of NottinghamSutton Bonington CampusLeicestershireUK

Extracellular vesicles,including exosomes and microvesicles,play a fundamental role in the activity of the nervous system,participating in signal transmission between neurons and providing the interaction of central nervous system with all body systems.In many neurodegenerative diseases,neurons pack toxic substances into vesicles and release them into the extracellular space,which leads to the spread of misfolded neurotoxic proteins.The contents of neuron-derived extracellular vesicles may indicate pathological changes in the central nervous system,and the analysis of extracellular vesicle molecular content contributes to the development of non-invasive methods for the diagnosis of many central nervous system diseases.Extracellular vesicles of neuronal origin can be isolated from various biological fluids due to their ability to cross the blood-brain barrier.Today,the diagnostic potential of almost all toxic proteins involved in nervous system disease pathogenesis,specificallyα-synuclein,tau protein,superoxide dismutase 1,FUS,leucine-rich repeat kinase 2,as well as some synaptic proteins,has been well evidenced.Special attention is paid to extracellular RNAs mostly associated with extracellular vesicles,which are important in the onset and development of many neurodegenerative diseases.Depending on parental cell type,extracellular vesicles may have different therapeutic properties,including neuroprotective,regenerative,and anti-inflammatory.Due to nano size,biosafety,ability to cross the blood-brain barrier,possibility of targeted delivery and the lack of an immune response,extracellular vesicles are a promising vehicle for the delivery of therapeutic substances for the treatment of neurodegenerative diseases and drug delivery to the brain.This review describes modern approaches of diagnosis and treatment of central nervous system diseases using extracellular vesicles.

关键词： biomarkers cell-mediated therapy central nervous system diseases diagnosis exosomes extracellular RNAs extracellular vesicles microRNAs microvesicles neurodegenerative diseases

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Extracellular vesicles and reproduction-promotion of successful pregnancy

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Cellular & Molecular Immunology 2014年第6期11卷 548-563页

作者： Dionne TannettaI Rebecca Dragovic Zahraa Alyahyaei Jennifer Southcombe Nuffield Department of Obstetrics and Gynaecology University of Oxford John Radcliffe Hospital Oxford UK

Extracellular vesicles （EVs） are membrane-bound complexes secreted from cells under both physiological and pathological conditions. They contain proteins, nucleic acids and lipids and act as messengers for cell-cell communication and signalling, particularly between immune cells. EV research is a rapidly evolving and expanding field, and it appears that all biological fluids contain very large numbers of EVs; they are produced from all cells that have been studied to date, and are known to have roles in several reproductive processes. This review analyses the evidence for the role of EVs throughout human reproduction, starting with the paternal and maternal gametes, followed by the establishment and continuation of successful pregnancies, with specific focus, where possible, on the interaction of EVs with the maternal immune system. Importantly, variations within the EV populations are identified in various reproductive disorders, such as pre-term labour and pre-eclampsia.

关键词： Extracellular vesicles pregnancy microvesicles exosomes nanoparticle tracking analysis pre-eclampsia

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Detection of Microvesicle miRNA Expression in ALL Subtypes and Analysis of Their Functional Roles

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Journal of Huazhong University of Science and Technology(Medical Sciences) 2014年第5期34卷 640-645页

作者：李雯英陈小梅熊薇郭冬梅卢力李慧玉 Center for Stem Cell Research and Application Institute of HematologyUnion HospitalTongji Medical CollegeHuazhong University of Science and Technology Neonatal Screening Center Zhuzhou Women and Children Medical Care Center

microvesicles （MVs） are the heterogeneous mixtures of vesicles. MVs released by leukemia cells constitute an important part of the leukemia microenvironment. MVs might act as important reser- voirs of microRNAs （miRNAs）. It is worth evaluating whether MVs possess some unique miRNA con- tents that are valuable in understanding the pathogenesis. In this study, we investigated the miRNA ex- pression patterns of Nalm-6-derived MVs, Jurkat-derived MVs and normal cell-derived MVs using miRNA microarrays. The potential target genes regulated by differentially expressed miRNAs were also predicted and analyzed. Results demonstrated that 182 miRNAs and 166 miRNAs were differentially expressed in Nalm-6-MVs and Jurkat-MVs, respectively. Many oncogenes, tumor suppressors and sig- nal pathway genes were targeted by these aberrantly expressed miRNAs, which might contribute to the development of B-ALL or T-ALL. Our findings expanded the potential diagnostic markers of ALL and provided useful information for ALL pathogenesis.

关键词： microvesicles miRNA expression profiles acute lymphoblastic leukemia subtypes

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Defining lung cancer stem cells exosomal payload of miRNAs in clinical perspective

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World Journal of Stem Cells 2020年第6期12卷 406-421页

作者： Beatrice Aramini Valentina Masciale Khawaja Husnain Haider Department of Medical and Surgical Sciences University of Modena and Reggio EmiliaModena 41124Italy MPharm PhDSulaiman AlRajhi UniveristyAlQaseem 52736Saudi Arabia

Since the first publication regarding the existence of stem cells in cancer[cancer stem cells(CSCs)]in 1994,many studies have been published providing in-depth information about their biology and function.This research has paved the way in terms of appreciating the role of CSCs in tumour aggressiveness,progression,recurrence and resistance to cancer therapy.Targeting CSCs for cancer therapy has still not progressed to a sufficient degree,particularly in terms of exploring the mechanism of dynamic interconversion between CSCs and non-CSCs.Besides the CSC scenario,the problem of cancer dissemination has been analyzed indepth with the identification and isolation of microRNAs(miRs),which are now considered to be compelling molecular markers in the diagnosis and prognosis of tumours in general and specifically in patients with non-small cell lung cancer.Paracrine release of miRs via“exosomes”(small membrane vesicles(30-100 nm),the derivation of which lies in the luminal membranes of multi-vesicular bodies)released by fusion with the cell membrane is gaining popularity.Whether exosomes play a significant role in maintaining a dynamic equilibrium state between CSCs and non-CSCs and their mechanism of activity is as yet unknown.Future studies on CSC-related exosomes will provide new perspectives for precision-targeted treatment strategies.

关键词： Cancer Cancer stem cells Exosomes Lungs miRNA microvesicles Nonsmall cell lung cancer

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