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Aug 23, 2016

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EV literature (RSS feed from PubMed)

Search terms: exosomes OR "extracellular vesicles" OR microvesicles OR microparticles. Direct link to the PubMed search here.

A Critical Assessment of Exosomes in the Pathogenesis and Stratification of Parkinson's Disease.

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A Critical Assessment of Exosomes in the Pathogenesis and Stratification of Parkinson's Disease.

J Parkinsons Dis. 2017 Sep 11;:

Authors: Tofaris GK

Abstract
Extracellular vesicles including exosomes are released by a variety of cell types including neurons and exhibit molecular profiles that reflect normal and disease states. As their content represents a snapshot of the intracellular milieu, they could be exploited as biomarkers of the otherwise inaccessible brain microenvironment. In addition they may contribute to the progression of neurodegenerative disorders by facilitating the spread of misfolded proteins at distant sites or activating immune cells. This review summarizes recent advances in the study of exosomes in Parkinson's disease pathophysiology and their potential as disease biomarkers.

PMID: 28922170 [PubMed - as supplied by publisher]

Self-Assembly of Mesoscale Artificial Clathrin Mimics.

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Self-Assembly of Mesoscale Artificial Clathrin Mimics.

ACS Nano. 2017 Sep 18;:

Authors: Kong Y, Hanna MS, Zhuo D, Chang KG, Bozorg-Grayeli T, Melosh NA

Abstract
Fluidic control and sampling in complex environments is an important process in biotechnology, materials synthesis, and microfluidics. An elegant solution to this problem has evolved in nature through cellular endocytosis, where the dynamic recruitment, self-assembly, and spherical budding of clathrin proteins allows cells to sample their external environment. Yet despite the importance and utility of endocytosis, artificial systems which can replicate this dynamic behavior have not been developed. Guided by clathrin's unusual structure, we created simplified metallic microparticles that capture the three-legged shape, particle curvature, and interfacial attachment characteristics of clathrin. These Artificial Clathrin Mimics (ACMs) successfully recreate biomimetic analogs of clathrin's recruitment, assembly, and budding, ultimately forming extended networks at fluid interfaces and invaginating immiscible phases into spheres under external fields. Particle curvature was discovered to be a critical structural motif, greatly limiting irreversible aggregation and inducing the legs' selective tip-to-tip attraction. This architecture provides a template for a class of active self-assembly units to drive structural and dimensional transformations of liquid-liquid interfaces and microscale fluidic sampling.

PMID: 28921943 [PubMed - as supplied by publisher]

In a randomized trial in prostate cancer patients, dietary protein restriction modifies markers of leptin and insulin signaling in plasma extracellular vesicles.

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In a randomized trial in prostate cancer patients, dietary protein restriction modifies markers of leptin and insulin signaling in plasma extracellular vesicles.

Aging Cell. 2017 Sep 17;:

Authors: Eitan E, Tosti V, Suire CN, Cava E, Berkowitz S, Bertozzi B, Raefsky SM, Veronese N, Spangler R, Spelta F, Mustapic M, Kapogiannis D, Mattson MP, Fontana L

Abstract
Obesity, metabolic syndrome, and hyperleptinemia are associated with aging and age-associated diseases including prostate cancer. One experimental approach to inhibit tumor growth is to reduce dietary protein intake and hence levels of circulating amino acids. Dietary protein restriction (PR) increases insulin sensitivity and suppresses prostate cancer cell tumor growth in animal models, providing a rationale for clinical trials. We sought to demonstrate that biomarkers derived from plasma extracellular vesicles (EVs) reflect systemic leptin and insulin signaling and respond to dietary interventions. We studied plasma samples from men with prostate cancer awaiting prostatectomy who participated in a randomized trial of one month of PR or control diet. We found increased levels of leptin receptor in the PR group in total plasma EVs and in a subpopulation of plasma EVs expressing the neuronal marker L1CAM. Protein restriction also shifted the phosphorylation status of the insulin receptor signal transducer protein IRS1 in L1CAM+ EVs in a manner suggestive of improved insulin sensitivity. Dietary PR modifies indicators of leptin and insulin signaling in circulating EVs. These findings are consistent with improved insulin and leptin sensitivity in response to PR and open a new window for following physiologic responses to dietary interventions in humans.

PMID: 28921841 [PubMed - as supplied by publisher]

Technical Note: A Simulation Study on the Feasibility of Radiotherapy Dose Enhancement with Calcium Tungstate and Hafnium Oxide Nano- and Microparticles.

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Technical Note: A Simulation Study on the Feasibility of Radiotherapy Dose Enhancement with Calcium Tungstate and Hafnium Oxide Nano- and Microparticles.

Med Phys. 2017 Sep 18;:

Authors: Sherck NJ, Won YY

Abstract
PURPOSE: To assess the radiotherapy dose enhancement (RDE) potential of calcium tungstate (CaWO4 ) and hafnium oxide (HfO2 ) nano- and microparticles (NPs). A Monte Carlo simulation study was conducted to gauge their respective RDE potentials relative to that of the broadly studied gold (Au) NP. The study was warranted due to the promising clinical and preclinical studies involving both CaWO4 and HfO2 NPs as RDE agents in the treatment of various types of cancers. The study provides a baseline RDE to which future experimental RDE trends can be compared to.
METHODS: All three materials were investigated in silico with the software Penetration and Energy Loss of Positrons and Electrons (PENELOPE 2014) developed by Francesc Salvat and distributed in the United States by the Radiation Safety Information Computational Center (RSICC) at Oak Ridge National Laboratory. The work utilizes the extensively studied Au NP as the "gold standard" for a baseline. The key metric used in the evaluation of the materials was the local dose enhancement factor (DEFloc ). An additional metric used, termed the relative enhancement ratio (RER), evaluates material performance at the same mass concentrations.
RESULTS: The results of the study indicate that Au has the strongest RDE potential using the DEFloc metric. HfO2 and CaWO4 both underperformed relative to Au with lower DEFloc of 2-3× and 4-100×, respectively.
CONCLUSIONS: The computational investigation predicts the RDE performance ranking to be: Au > HfO2 > CaWO4 . This article is protected by copyright. All rights reserved.

PMID: 28921536 [PubMed - as supplied by publisher]

Human Endothelial Progenitor Cell-Derived Exosomes Increase Proliferation and Angiogenesis in Cardiac Fibroblasts by Promoting the Mesenchymal-Endothelial Transition and Reducing High Mobility Group Box 1 Protein B1 Expression.

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Human Endothelial Progenitor Cell-Derived Exosomes Increase Proliferation and Angiogenesis in Cardiac Fibroblasts by Promoting the Mesenchymal-Endothelial Transition and Reducing High Mobility Group Box 1 Protein B1 Expression.

DNA Cell Biol. 2017 Sep 18;

Authors: Ke X, Yang D, Liang J, Wang X, Wu S, Wang X, Hu C

Abstract
Myocardial fibrosis is a characteristic feature of cardiomyopathies. However, no effective strategies to attenuate cardiac fibrosis are currently available. Late-stage endothelial progenitor cells (EPCs) are precursors of endothelial cells (ECs) that repair the heart through a paracrine mechanism. In the present study, we tested whether EPC-derived exosomes regulate the differentiation of fibroblasts into ECs. We isolated late-stage EPCs from human peripheral blood (PB) and used immunofluorescence and flow cytometry to confirm their identity. Next, we isolated exosomes from the EPCs and characterized their morphology using electron microscopy and confirmed the expression of exosome-specific marker proteins using Western blots. We then investigated the in vitro effects of exosomes on the proliferation and angiogenesis of cardiac fibroblasts (CFs) and on the expression of the mesenchymal-endothelial transition (MEndT)-related genes and the myocardial fibrosis-regulated protein, high mobility group box 1 protein B1 (HMGB1). We found that human PB-EPC-derived exosomes enhanced the proliferation and angiogenesis of CFs in vitro. Furthermore, CFs stimulated with these exosomes showed increased expression of the EC-specific markers, like cluster of differentiation 31 and vascular endothelial growth factor receptor 2, and decreased expression of proteins involved in fibrosis, like alpha-smooth muscle actin, vimentin, collagen I, transforming growth factor-beta, and tumor necrosis factor-alpha. In addition, CFs stimulated with human PB-EPC-derived exosomes, inhibited the expression of HMGB1. Taken together, our study demonstrated that EPC-derived exosomes promote the proliferation and angiogenesis of CFs by inhibiting MEndT and decreasing the expression of HMGB1.

PMID: 28920705 [PubMed - as supplied by publisher]

Magnetic nanoparticle-enhanced surface plasmon resonance biosensor for extracellular vesicle analysis.

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Magnetic nanoparticle-enhanced surface plasmon resonance biosensor for extracellular vesicle analysis.

Analyst. 2017 Sep 18;:

Authors: Reiner AT, Ferrer NG, Venugopalan P, Lai RC, Lim SK, Dostálek J

Abstract
The sensitive analysis of small lipid extracellular vesicles (EVs) by using a grating-coupled surface plasmon resonance (GC-SPR) biosensor has been reported. In order to enable the analysis of trace amounts of EVs present in complex liquid samples, the target analyte is pre-concentrated on the sensor surface by using magnetic nanoparticles and its affinity binding is probed by wavelength interrogation of SPR. The GC-SPR has been demonstrated to allow for the implementation of efficient pulling of EVs to the sensor surface by using magnetic nanoparticles and an external magnetic field gradient applied through the sensor chip. This approach overcomes slow diffusion-limited mass transfer and greatly enhances the measured sensor response. The specific detection of different EV populations secreted from mesenchymal stem cells is achieved with a SPR sensor chip modified with antibodies against the surface marker CD81 and magnetic nanoparticles binding the vesicles via annexin V and cholera toxin B chain.

PMID: 28920599 [PubMed - as supplied by publisher]

ANNALS EXPRESS: Association of subcutaneous and visceral fat with circulating microRNAs in a middle-aged Japanese population.

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ANNALS EXPRESS: Association of subcutaneous and visceral fat with circulating microRNAs in a middle-aged Japanese population.

Ann Clin Biochem. 2017 Jan 01;:4563217735124

Authors: Munetsuna E, Yamada H, Ando Y, Yamazaki M, Tsuboi Y, Kondo M, Mizuno G, Ishikawa H, Sugimoto K, Osakabe K, Ichino N, Ohashi K, Hamajima N, Suzuki K

Abstract
Purpose It has been demonstrated that circulating microRNA (miRNA) profiles are affected by physiological conditions. Several studies have demonstrated that miRNAs play important roles in the regulation of adiposity. However, few have investigated the relationship between circulating miRNAs and obesity, which has become a major public health problem worldwide. Current study investigated the association between circulating miRNAs and obesity in a Japanese population. Methods Obesity parameters, such as subcutaneous (SAT) and visceral fat (VAT) adipose tissue, body fat percentage, and body mass index (BMI) were assessed in a cross-sectional sample of 526 participants who attended health examinations in Yakumo, Japan. In addition, five circulating miRNAs (miR-20a, -21, -27a, -103a and -320), which are involved in adipocyte proliferation and differentiation, were quantified using real-time polymerase chain reaction amplification. Results We compared the circulating miRNA levels in a percentile greater than 75th (high) with below the value (low) of SAT, VAT, BMI and percent body fat. In high group in VAT, significant decrease miR-320 expression level was observed. Also, significant change of miR-20a, 103a, and 320 expression levels were also observed in high group in BMI. Multiple linear regression analysis demonstrated that circulating levels of some miRNA such as miR-27a were significantly associated with SAT, VAT and BMI. Conclusions Our findings support the need for further studies to determine whether such changes are consistent across different populations and whether the identified miRNAs may represent novel biomarkers to predict the susceptibility and progression of obesity-related disorders. Keywords Circulating miRNA · Biomarker · Extracellular vesicles · Visceral fat adipose tissue · Subcutaneous fat adipose tissue · General population.

PMID: 28920467 [PubMed - as supplied by publisher]

Human tumor-derived exosomes (TEX) regulate Treg functions via cell surface signaling rather than uptake mechanisms.

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Human tumor-derived exosomes (TEX) regulate Treg functions via cell surface signaling rather than uptake mechanisms.

Oncoimmunology. 2017;6(8):e1261243

Authors: Muller L, Simms P, Hong CS, Nishimura MI, Jackson EK, Watkins SC, Whiteside TL

Abstract
Tumor-derived exosomes (TEX) are ubiquitously present in the tumor microenvironment and plasma of cancer patients. TEX carry a cargo of multiple stimulatory and inhibitory molecules and deliver them to recipient cells, serving as a communication network for the tumor. The mechanisms TEX use for delivering messages to recipient cells were evaluated using PKH26-labeled TEX produced by cultured human tumor cells, exosomes produced by dendritic cells-derived exosomes (DEX), or exosomes isolated from plasma of cancer patients (EXO). Human T-cell subsets, B cells, NK cells, and monocytes were co-incubated with TEX, DEX, or EXO and binding or internalization of labeled vesicles was evaluated by confocal microscopy and/or Amnis-based flow cytometry. Vesicle-induced Ca(2+) influx in recipient T cells was monitored, and TEX-induced inosine production in Treg was determined by mass spectrometry. In contrast to B cells, NK cells or monocytes, conventional T cells did not internalize labeled vesicles. Minimal exosome uptake was only evident in Treg following prolonged co-incubation with TEX. All exosomes induced Ca(2+) influx in T cells, with TEX and EXO isolated from cancer patients' plasma delivering the strongest, sustained signaling to Treg. Such sustained signaling resulted in the significant upregulation of the conversion of extracellular ATP to inosine (adenosine metabolite) by Treg, suggesting that TEX signaling could have functional consequences in these recipient cells. Thus, modulation of Treg suppressor functions by TEX is mediated by mechanisms dependent on cell surface signaling and does not require TEX internalization by recipient cells.

PMID: 28919985 [PubMed]

Cellular uptake of extracellular vesicles is mediated by clathrin-independent endocytosis and macropinocytosis.

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Cellular uptake of extracellular vesicles is mediated by clathrin-independent endocytosis and macropinocytosis.

J Control Release. 2017 Sep 14;:

Authors: Verdera HC, Gitz-Francois JJ, Schiffelers RM, Vader P

Abstract
Recent evidence has established that extracellular vesicles (EVs), including exosomes and microvesicles, form an endogenous transport system through which biomolecules, including proteins and RNA, are exchanged between cells. This endows EVs with immense potential for drug delivery and regenerative medicine applications. Understanding the biology underlying EV-based intercellular transfer of cargo is of great importance for the development of EV-based therapeutics. Here, we sought to characterize the cellular mechanisms involved in EV uptake. Internalization of fluorescently-labeled EVs was evaluated in HeLa cells, in 2D (monolayer) cell culture as well as 3D spheroids. Uptake was assessed using flow cytometry and confocal microscopy, using chemical as well as RNA interference-based inhibition of key proteins involved in individual endocytic pathways. Experiments with chemical inhibitors revealed that EV uptake depends on cholesterol and tyrosine kinase activity, which are implicated in clathrin-independent endocytosis, and on Na+/H+ exchange and phosphoinositide 3-kinase activity, which are important for macropinocytosis. Furthermore, EV internalization was inhibited by siRNA-mediated knockdown of caveolin-1, flotillin-1, RhoA, Rac1 and Pak1, but not clathrin heavy chain. Together, these results suggest that EVs enter cells predominantly via clathrin-independent endocytosis and macropinocytosis. Identification of EV components that promote their uptake via pathways that lead to functional cargo transfer might allow development of more efficient therapeutics through EV-inspired engineering.

PMID: 28919558 [PubMed - as supplied by publisher]

Exosomes derived from human umbilical cord blood mesenchymal stem cells stimulates rejuvenation of human skin.

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Exosomes derived from human umbilical cord blood mesenchymal stem cells stimulates rejuvenation of human skin.

Biochem Biophys Res Commun. 2017 Sep 14;:

Authors: Kim YJ, Yoo SM, Park HH, Lim HJ, Kim YL, Lee S, Kang KS, Seo KW

Abstract
Human umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs) play an important role in cutaneous wound healing, and recent studies suggested that MSC-derived exosomes activate several signaling pathways, which are conducive in wound healing and cell growth. In this study, we investigated the roles of exosomes that are derived from USC-CM (USC-CM Exos) in cutaneous collagen synthesis and permeation. We found that USC-CM has various growth factors associated with skin rejuvenation. Our in vitro results showed that USC-CM Exos integrate in Human Dermal Fibroblasts (HDFs) and consequently promote cell migration and collagen synthesis of HDFs. Moreover, we evaluated skin permeation of USC-CM Exos by using human skin tissues. Results showed that Exo-Green labeled USC-CM Exos approached the outermost layer of the epidermis after 3 h and gradually approached the epidermis after 18 h. Moreover, increased expressions of Collagen type 1 and Elastin were found after 3 days of treatment on human skin. The results showed that USC-CM Exos is absorbed into human skin, it promotes collagen and elastin synthesis in the skin, which are essential to skin rejuvenation and shows the potential of USC-CM integration with the cosmetics or therapeutics.

PMID: 28919421 [PubMed - as supplied by publisher]

Endothelial microparticle-promoted inhibition of vascular remodeling is abrogated under hyperglycaemic conditions.

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Endothelial microparticle-promoted inhibition of vascular remodeling is abrogated under hyperglycaemic conditions.

J Mol Cell Cardiol. 2017 Sep 14;:

Authors: Jansen F, Zietzer A, Stumpf T, Flender A, Schmitz T, Nickenig G, Werner N

Abstract
BACKGROUND: Endothelial microparticles (EMPs) inhibit vascular remodeling by transferring functional microRNA (miRNA) into target vascular smooth muscle cells (VSMCs). Because EMPs are increased in diabetic patients and potentially linked to vascular complications in diabetes mellitus, we sought to determine whether effects of EMPs generated under high glucose concentration on vascular remodeling might differ from EMPs derived from untreated cells.
METHODS AND RESULTS: EMPs were generated from human coronary endothelial cells (HCAEC) exposed to high glucose concentrations in order to mimic diabetic conditions. These EMPs were defined as 'hyperglycaemic' EMPs (hgEMPs) and their miRNA transfer capacity and functional effects were compared with EMPs generated from 'healthy' untreated HCAECs. In vitro, the intercellular transfer of antiproliferative miRNA-126-3p from ECs to VSMCs via EMPs was significantly reduced under hyperglycaemic conditions. Additionally, EMP-mediated inhibition of the miRNA-126-3p target LRP6 and of VSMC migration and proliferation was abrogated, when hgEMPs were used. In vivo, the inhibitory effect of EMPs on neointima formation, VSMC proliferation and macrophage infiltration was abolished in mice treated with hgEMPs.
CONCLUSION: Pathological hyperglycaemic conditions weaken potentially protective intercellular communication mechanisms by affecting EMP content and function.

PMID: 28919327 [PubMed - as supplied by publisher]

A Link between Linearmycin Biosynthesis and Extracellular Vesicle Genesis Connects Specialized Metabolism and Bacterial Membrane Physiology.

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A Link between Linearmycin Biosynthesis and Extracellular Vesicle Genesis Connects Specialized Metabolism and Bacterial Membrane Physiology.

Cell Chem Biol. 2017 Aug 24;:

Authors: Hoefler BC, Stubbendieck RM, Josyula NK, Moisan SM, Schulze EM, Straight PD

Abstract
Specialized metabolites support bacterial competitive fitness as antibiotics, signals, pigments, and metal scavengers. Little is known about how specialized metabolites are processed and trafficked for their diverse competitive functions. Linearmycins A and B are linear polyketides with antifungal and antibacterial activity but are colony-localized in imaging mass spectrometry of Streptomyces sp. Mg1 (S. sp. Mg1). To decipher a connection between colony localization and antibiotic activity, we identified the linearmycin gene cluster and investigated linearmycin production and distribution by S. sp. Mg1. Our results uncover a large family of variant linearmycins with limited solubility in aqueous solution. We hypothesized that extracellular vesicles may traffic the lipid-like linearmycins. We found that vesicles isolated from culture supernatants contained linearmycins. Surprisingly, abolishing production of linearmycins in S. sp. Mg1 also diminished extracellular vesicle production. Our results reveal integration of linearmycin biosynthesis with production of extracellular vesicles, suggesting a deep connection between specialized metabolism and bacterial membrane physiology.

PMID: 28919037 [PubMed - as supplied by publisher]

End stage renal disease-induced hypercalcemia may promote aortic valve calcification via Annexin VI enrichment of valve interstitial cell derived-matrix vesicles.

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End stage renal disease-induced hypercalcemia may promote aortic valve calcification via Annexin VI enrichment of valve interstitial cell derived-matrix vesicles.

J Cell Physiol. 2017 Nov;232(11):2985-2995

Authors: Cui L, Rashdan NA, Zhu D, Milne EM, Ajuh P, Milne G, Helfrich MH, Lim K, Prasad S, Lerman DA, Vesey AT, Dweck MR, Jenkins WS, Newby DE, Farquharson C, Macrae VE

Abstract
Patients with end-stage renal disease (ESRD) have elevated circulating calcium (Ca) and phosphate (Pi), and exhibit accelerated progression of calcific aortic valve disease (CAVD). We hypothesized that matrix vesicles (MVs) initiate the calcification process in CAVD. Ca induced rat valve interstitial cells (VICs) calcification at 4.5 mM (16.4-fold; p < 0.05) whereas Pi treatment alone had no effect. Ca (2.7 mM) and Pi (2.5 mM) synergistically induced calcium deposition (10.8-fold; p < 0.001) in VICs. Ca treatment increased the mRNA of the osteogenic markers Msx2, Runx2, and Alpl (p < 0.01). MVs were harvested by ultracentrifugation from VICs cultured with control or calcification media (containing 2.7 mM Ca and 2.5 mM Pi) for 16 hr. Proteomics analysis revealed the marked enrichment of exosomal proteins, including CD9, CD63, LAMP-1, and LAMP-2 and a concomitant up-regulation of the Annexin family of calcium-binding proteins. Of particular note Annexin VI was shown to be enriched in calcifying VIC-derived MVs (51.9-fold; p < 0.05). Through bioinformatic analysis using Ingenuity Pathway Analysis (IPA), the up-regulation of canonical signaling pathways relevant to cardiovascular function were identified in calcifying VIC-derived MVs, including aldosterone, Rho kinase, and metal binding. Further studies using human calcified valve tissue revealed the co-localization of Annexin VI with areas of MVs in the extracellular matrix by transmission electron microscopy (TEM). Together these findings highlight a critical role for VIC-derived MVs in CAVD. Furthermore, we identify calcium as a key driver of aortic valve calcification, which may directly underpin the increased susceptibility of ESRD patients to accelerated development of CAVD.

PMID: 28369848 [PubMed - indexed for MEDLINE]

 

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