Optimized Cholesterol-siRNA Chemistry Improves Productive Loading onto Extracellular Vesicles

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Intercellular Communication by Extracellular Vesicles and Their MicroRNAs in Asthma

Purpose

Extracellular vesicles (EVs) such as exosomes and microvesicles are phospholipid bilayer–enclosed vesicles that are recognized as novel tools for intercellular communications and as biomarkers for several diseases. They contain various DNAs, proteins, mRNAs, and microRNAs (miRNAs) that have potential diagnostic and therapeutic purposes. Their biological roles have attracted significant interest in the pulmonary field because their vesicle composition and miRNA content have the ability to transfer biological information to recipient cells and play an important role in pulmonary inflammatory and allergic diseases. Asthma is a chronic inflammatory disease of the airways, and it is characterized by variable and recurring symptoms and reversible airflow obstruction. The purpose of this review was to discuss the function of EVs and their miRNAs in asthma, with a focus on the biological properties and biogenesis of EVs, their pathophysiologic roles, and their potential use as biomarkers and therapies for asthma.

Methods

We review the findings from several articles on EVs and their miRNAs in asthma and provide illustrative references.

Findings

A few studies have reported on the biological function of bronchoalveolar lavage fluid–derived EVs in asthmatic progression. In the lungs, EVs might regulate airway inflammation and allergic reactions through their paracrine effects. Furthermore, circulating miRNAs have been found to be associated with EVs.

Implication

EV-mediated miRNAs can be used as biomarkers in asthma.     

Red blood cell extracellular vesicles deliver therapeutic siRNAs to skeletal muscles for treatment of cancer cachexia

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Extracellular vesicles: From bone development to regenerative orthopedics

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Diagnostic and Prognostic Potential of Extracellular Vesicles in Peripheral Blood

Purpose

Extracellular vesicles (EVs) are small, membrane-enclosed entities released from cells in many different biological systems. These vesicles play an important role in cellular communication by virtue of their protein, RNA, and lipid content, which can be transferred among cells. The complement of biomolecules reflects the parent cell, and their characterization may provide information about the presence of an aberrant process. Peripheral blood is a rich source of circulating EVs, which are easily accessible through a blood sample. An analysis of EVs in peripheral blood could provide access to unparalleled amounts of biomarkers of great diagnostic and prognostic value. The objectives of this review are to briefly present the current knowledge about EVs and to introduce a toolbox of selected techniques, which can be used to rapidly characterize clinically relevant properties of EVs from peripheral blood.

Methods

Several techniques exist to characterize the different features of EVs, including size, enumeration, RNA cargo, and protein phenotype. Each technique has a number of advantages and pitfalls. However, with the techniques presented in this review, a possible platform for EV characterization in a clinical setting is outlined.

Findings

Although EVs have great diagnostic and prognostic potential, a lack of standardization regarding EV analysis hampers the full use of this potential. Nevertheless, the analysis of EVs in peripheral blood has several advantages compared with traditional analyses of many soluble molecules in blood.

Implications

Overall, the use of EV analysis as a diagnostic and prognostic tool has prodigious clinical potential.     

Extracellular vesicles from human saliva promote hemostasis by delivering coagulant tissue factor to activated platelets

Essentials

• Human salivary extracellular vesicles (EVs) expose coagulant tissue factor (TF).
• Salivary EVs expose CD24, a ligand of P‐selectin.
• CD24 and coagulant TF co‐localize on salivary EVs.
• TF⁺/CD24⁺ salivary EVs bind to activated platelets and trigger coagulation.

Summary

Background

Extracellular vesicles (EVs) from human saliva expose coagulant tissue factor (TF). Whether such TF‐exposing EVs contribute to hemostasis, however, is unknown. Recently, in a mice model, tumor cell‐derived EVs were shown to deliver coagulant TF to activated platelets at a site of vascular injury via interaction between P‐selectin glycoprotein ligand‐1 (PSGL‐1) and P‐selectin.

Objectives

We hypothesized that salivary EVs may deliver coagulant TF to activated platelets via interaction with P‐selectin.

Methods

We investigated the presence of two ligands of P‐selectin on salivary EVs, PSGL‐1 and CD24.

Results

Salivary EVs expose CD24 but PSGL‐1 was not detected. Immune depletion of CD24‐exposing EVs completely abolished the TF‐dependent coagulant activity of cell‐free saliva, showing that coagulant TF and CD24 co‐localize on salivary EVs. In a whole blood perfusion model, salivary EVs accumulated at the surface of activated platelets and promoted fibrin generation, which was abolished by an inhibitory antibody against human CD24.

Conclusions

A subset of EVs in human saliva expose coagulant TF and CD24, a ligand of P‐selectin, suggesting that such EVs may facilitate hemostasis at a site of skin injury where the wound is licked in a reflex action.     

Extracellular vesicles in neuroinflammation: Pathogenesis,diagnosis, and therapy

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Extracellular vesicles can act as a potent immunomodulators of human microglial cells

Functional impairments of microglia have been recently associated with several neurological conditions. Therefore, modulation of anti‐inflammatory and phagocytic properties of microglial cells could represent a novel therapeutic approach. In the present study, we investigated the effects of extracellular vesicles (EVs) derived from stem cells from the dental pulp of human exfoliated deciduous teeth (SHEDs) on the inflammatory response and functional properties of immortalized human microglial cells. NFκB reporter assays demonstrated that EVs suppressed LPS‐induced activation of NFκB signalling pathway in human microglial cells. The effect was similar to that obtained with anti‐TLR4 blocking antibody. We also show that EVs differentially affected phagocytic activity of unpolarized (M0) and polarized (M1 and M2) microglial cells. EVs induced significant upregulation of phagocytic activity in M0 cells (by 39%), slight decrease in M1 cells, and moderate increase (by 21%) in M2 cells. The Seahorse XF Glycolysis Stress Test revealed that EVs induced an immediate and sustained increase of glycolytic activity in M0, M1, and M2 cells. Interestingly, EVs acted in an inverse dose‐dependent manner. These findings indicate that EVs can induce glycolytic reprogramming of unpolarized and polarized human microglial cells. In conclusion, our pilot study demonstrates that EVs derived from SHEDs can act as a potent immunomodulators of human microglial cells. These findings could be potentially exploited for the development of new therapeutic strategies targeting neuroinflammatory microglia.     

Extracellular vesicles: The next generation in gene therapy delivery

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Extracellular communication between brain cells through functional transfer of Cre mRNA mediated by extracellular vesicles

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Urinary Extracellular Vesicles Carrying Klotho Improve the Recovery of Renal Function in an Acute Tubular Injury Model

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KIM-1 augments hypoxia-induced tubulointerstitial inflammation through uptake of small extracellular vesicles by tubular epithelial cells

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基于生物合成气囊的影像造影剂的研究进展

气囊是一种遗传编码的、自然稳定的纳米结构,可以自由渗透周围介质中的气体,使其具有独特的声学、磁化率、光学特性,可作为多种成像方式的造影剂。通过对气囊基因的修饰,可制备出用于肿瘤诊断和治疗的复合材料,将气囊开发为声学报告基因具有巨大潜力。本文就基于气囊的影像造影剂的研究进展进行综述。     

Iron as spirit of life to share under monopoly

Any independent life requires iron to survive. Whereas iron deficiency causes oxygen insufficiency, excess iron is a risk for cancer, generating a double-edged sword. Iron metabolism is strictly regulated via specific systems, including iron-responsive element (IRE)/iron regulatory proteins (IRPs) and the corresponding ubiquitin ligase FBXL5. Here we briefly reflect the history of bioiron research and describe major recent advancements. Ferroptosis, a newly coined Fe(II)-dependent regulated necrosis, is providing huge impact on science. Carcinogenesis is a process to acquire ferroptosis-resistance and ferroptosis is preferred in cancer therapy due to immunogenicity. Poly(rC)-binding proteins 1/2 (PCBP1/2) were identified as major cytosolic Fe(II) chaperone proteins. The mechanism how cells retrieve stored iron in ferritin cores was unraveled as ferritinophagy, a form of autophagy. Of note, ferroptosis may exploit ferritinophagy during the progression. Recently, we discovered that cellular ferritin secretion is through extracellular vesicles (EVs) escorted by CD63 under the regulation of IRE/IRP system. Furthermore, this process was abused in asbestos-induced mesothelial carcinogenesis. In summary, cellular iron metabolism is tightly regulated by multi-system organizations as surplus iron is shared through ferritin in EVs among neighbor and distant cells in need. However, various noxious stimuli dramatically promote cellular iron uptake/storage, which may result in ferroptosis.     

胞外囊泡miRNA在乳腺癌中的研究进展

胞外囊泡微小RNAs(microRNAs,miRNAs)是一类19~25个核苷酸的短链非编码RNA,有多效生物学功能,显著调控靶基因表达,影响细胞增殖和凋亡及其他生物学作用。现如今乳腺癌的标志物,如CA125,CA153,CEA,ER,PR,Her2/neu,BRCA1/BRCA2等越来越满足不了临床的需求。因此,对于乳腺癌的早期诊断、治疗和预后等亟需新的生物标志物。胞外囊泡miRNA在肿瘤发生发展、侵袭转移、增殖凋亡、血管生成等过程中均发挥重要作用,对乳腺癌特异性miRNA的鉴定和检出可为早期乳腺癌患者的诊断和减轻疾病负担提供较好的帮助。     

sEVs from tonsil-derived mesenchymal stromal cells alleviate activation of hepatic stellate cells and liver fibrosis through miR-486-5p

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