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

Exosome-mediated RNAi of PAK4 prolongs survival of pancreatic cancer mouse model after loco-regional treatment.

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Exosome-mediated RNAi of PAK4 prolongs survival of pancreatic cancer mouse model after loco-regional treatment.

Biomaterials. 2020 Sep 10;264:120369

Authors: Xu L, Faruqu FN, Lim YM, Lim KY, Liam-Or R, Walters AA, Lavender P, Fear D, Wells CM, Tzu-Wen Wang J, Al-Jamal KT

Abstract
With a dismal survival rate, pancreatic cancer (PC) remains one of the most aggressive and devastating malignancies, predominantly due to the absence of a valid biomarker for diagnosis and limited therapeutic options for advanced diseases. Exosomes (Exo) as cell-derived vesicles, are widely used as natural nanocarriers for drug delivery. P21-activated kinase 4 (PAK4) is oncogenic when overexpressed, promoting cell survival, migration and anchorage-independent growth. Herein we validated PAK4 as a therapeutic target in an in vivo PC tumour mouse model using Exo-mediated RNAi following intra-tumoural administration. PC derived Exo were firstly isolated by ultracentrifugation on sucrose cushion and characterised for their surface marker expression, size, number, purity and morphology. SiRNA was encapsulated into Exo via electroporation and dual uptake of Exo and siRNA was investigated by flow cytometry and confocal microscopy. In vitro siPAK4 silencing in PC cells following uptake was assessed by flow cytometry, western blotting, and in vitro scratch assay. In vivo efficacy (tumour growth delay and mouse survival) of siPAK4 was evaluated in PC bearing NSG mouse model. Ex vivo tumours were examined using Haematoxylin and eosin (H&E) staining and immunohistochemistry. Results showed high quality PC-derived PANC-1 Exo were obtained. SiRNA was incorporated in Exo with 16.5% encapsulation efficiency. In vitro imaging confirmed Exo and siRNA co-localisation in cells. PAK4 knockdown was successful with 30 nM Exo-siPAK4 at 24 h post incubation in vitro. Intra-tumoural administration of Exo-siPAK4 (0.03 mg/kg siPAK4 and 6.1 × 1011 Exo, each dose, two doses) reduced PC tumour growth in vivo and enhanced mice survival (p < 0.001), with minimal toxicity observed compared to polyethylenimine (PEI) used as a commercial transfection reagent. H&E staining of tumours showed significant tissue apoptosis in siPAK4 treated groups. PAK4 knockdown prolongs survival of PC-bearing mice suggesting its potential as a new therapeutic target for PC. PANC-1 Exo demonstrated comparable efficacy but safer profile than PEI as in vivo RNAi transfection reagent.

PMID: 32977209 [PubMed - as supplied by publisher]

Detachable microfluidic device implemented with electrochemical aptasensor (DeMEA) for sequential analysis of cancerous exosomes.

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Detachable microfluidic device implemented with electrochemical aptasensor (DeMEA) for sequential analysis of cancerous exosomes.

Biosens Bioelectron. 2020 Sep 17;169:112622

Authors: Kashefi-Kheyrabadi L, Kim J, Chakravarty S, Park S, Gwak H, Kim SI, Mohammadniaei M, Lee MH, Hyun KA, Jung HI

Abstract
The quantification of cancer-derived exosomes has a strong potential for minimally invasive diagnosis of cancer during its initial stage. As cancerous exosomes form a small fraction of all the exosomes present in blood, ultra-sensitive detection is a prerequisite for the development of exosome-based cancer diagnostics. Herein, a detachable microfluidic device implemented with an electrochemical aptasensor (DeMEA) is introduced for highly sensitive and in-situ quantification of cancerous exosomes. To fabricate the aptasensor, a nanocomposite was applied on the electrode surface followed by electroplating of gold nanostructures. Subsequently, an aptamer against an epithelial cell adhesion molecule is immobilized on the electrode surface to specifically detect cancer-specific exosomes. A microfluidic vortexer is then constructed and implemented in the sensing system to increase the collision between the exosomes and sensing surface using hydrodynamically generated transverse flow. The microfluidic vortexer was integrated with the aptasensor via a 3D printed magnetic housing. The detachable clamping of the two different devices provides an opportunity to subsequently harvest the exosomes for downstream analysis. The DeMEA has high sensitivity and specificity with an ultra-low limit of detection of 17 exosomes/μL over a wide dynamic range (1 × 102 to 1 × 109) exosomes/μL in a short period. As proof of the concept, the aptasensor can be separated from the 3D printed housing to harvest and analyze the exosomes by real-time polymerase chain reaction. Moreover, the DeMEA quantifies the exosomes from plasma samples of patients with breast cancer at different stages of the disease. The DeMEA provides a bright horizon for the application of microfluidic integrated biosensors for the early detection of cancerous biomarkers.

PMID: 32977087 [PubMed - as supplied by publisher]

Extracellular vesicles as natural therapeutic agents and innate drug delivery systems for cancer treatment: Recent advances, current obstacles, and challenges for clinical translation.

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Extracellular vesicles as natural therapeutic agents and innate drug delivery systems for cancer treatment: Recent advances, current obstacles, and challenges for clinical translation.

Semin Cancer Biol. 2020 Sep 22;:

Authors: Pirisinu M, Pham TC, Zhang DX, Hong TN, Nguyen LT, Le MT

Abstract
As cancer poses a significant threat to the well-being of humans on a global scale, many researchers have embarked on the search for effective anticancer therapeutic agents. In recent years, many drugs have been shown to have extraordinary anticancer effects. However, in a lot of cases the treatment is accompanied by undesirable side effects due to some intrinsic properties linked to the therapeutic agents, such as poor targeting selectivity and short half-life in the circulation. In this regard, extracellular vesicles (EVs), a diverse family of natural cell-derived vesicles, steal the show as potential anticancer immunotherapy or delivery vectors of anticancer agents since they are an innate mechanism of intercellular communication. Here, we describe some of the most hotly-debated issues regarding the use of EVs as anticancer therapeutics. First, we review the biology of EVs providing the most up-to-date definition of EVs as well as highlighting their circulation kinetics and homing properties. Next, we share our views on popular methods reported for EV isolation, characterization, and functional analysis. Pioneering and innovative reports along with emerging challenges in the field of EV imaging and EV drug loading strategies are then discussed. Finally, we examine in detail the therapeutic application of EVs in cancer treatment, including their role in cancer immunotherapy and as natural delivery systems for anticancer agents including natural compounds such as paclitaxel and doxorubicin. We consider standardised protocols and proper analytical approaches to be crucial in improving the reproducibility and rigor in EV research and ensuring the successful translation of EVs as anticancer therapeutics.

PMID: 32977006 [PubMed - as supplied by publisher]

Caveolin-1 derived from brain microvascular endothelial cells inhibits neuronal differentiation of neural stem/progenitor cells in vivo and in vitro.

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Caveolin-1 derived from brain microvascular endothelial cells inhibits neuronal differentiation of neural stem/progenitor cells in vivo and in vitro.

Neuroscience. 2020 Sep 22;:

Authors: Li Y, Zhao Y, Gao C, Wu M, So KF, Tong Y, Shen J

Abstract
Caveolin-1 (Cav-1) is an important modulator for adult neurogenesis in post stroke brain repair but its underlying mechanisms are largely unknown. In the present study, we report that endothelial Cav-1 inhibits neuronal differentiation of neural stem/progenitor cells (NSCs/NPCs) in post ischemic brain via regulating vascular endothelial growth factor (VEGF) and NeuroD1 signaling pathway. We first investigated the dynamic change of Cav-1 and its impact on neuronal differentiation in rat and mouse models of 2h transient middle cerebral artery occlusion (MCAO) plus 1, 7, 14, 21 and 28 day of reperfusion. We then studied the roles of endothelial Cav-1 in modulating the neuronal differentiation of NPCs which were co-cultured with brain microvascular endothelial cells (BMVECs) under 2 h oxygen-glucose deprivation plus 5 days reoxygenation (OGD/R). The major discoveries include: (1) Cav-1 expression in the hippocampal dentate gyrus was down-regulated on day 1 after 2 h cerebral ischemia, and gradually recovered with reperfusion time, accompanied with transient increased but gradually reduced neuronal differentiation of NPCs marked by doublecortin (DCX). (2) Cav-1 knockout mice exhibited the increased DCX and VEGF at the granular cell layers of hippocampal dentate gyrus in post-ischemic brains. (3) Co-cultured with BMVECs, NPCs had remarkably decreased neuronal differentiation under OGD/R. Knockdown of Cav-1 in the BMVECs increased VEGF secretion into the medium and NeuroD1+ cells, and rescued the neuronal differentiation of NPCs without affecting astroglial and oligodendroglial differentiation. (4) Cav-1 exosomes released from BMVECs inhibited neuronal differentiation of NPCs via decreasing the expression of VEGF, p44/42MAPK phosphorylation and NeuronD1 upon OGD/R insults. Taken together, endothelial Cav-1 serves as a niche regulator to inhibit neuronal differentiation via negatively modulating VEGF, p44/42MAPK phosphorylation and NeuronD1 signaling pathway.

PMID: 32976986 [PubMed - as supplied by publisher]

How to implement research studies on extracellular vesicle administration in myocardial infarction?

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How to implement research studies on extracellular vesicle administration in myocardial infarction?

Trends Cardiovasc Med. 2020 Sep 22;:

Authors: Sciarretta S, Schirone L, Sadoshima J

PMID: 32976978 [PubMed - as supplied by publisher]

Delivery of ionizable hydrophilic drugs based on pharmaceutical formulation of ion pairs and ionic liquids.

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Delivery of ionizable hydrophilic drugs based on pharmaceutical formulation of ion pairs and ionic liquids.

Eur J Pharm Biopharm. 2020 Sep 22;:

Authors: Gamboa A, Hecht N, Soto-Bustamante E, Romero-Hasler P, Meinel L, Morales JO

Abstract
New therapeutics such as antisense oligonucleotides, small interfering RNA and peptide-drug conjugates are taking great relevance in the pharmaceutical industry due to their specificity of action and their improved safety profile. However, they could present bioavailability issues due to their hydrophilic nature, such as BCS class III drugs. Therefore, the formation of ion pairs of these type of molecules allows modifying their physicochemical characteristics such as polarity and lipophilicity leading to improved permeability. By carrying out a tailored synthesis, it is possible to obtain complexes with greater stability and better performance in vitro and in vivo, where their correlation with physicochemical properties continues to be a growing field of research. Moreover, ionic liquids (IL), which are substances that melt below 100 °C, have enabled modifying various drug properties, showing promising results in vitro-in vivo, especially when they are included in suitable drug delivery systems, such as nanoparticles, microparticles, self-emulsifying drug delivery systems, and transdermal patches, among others. The drug-IL is formed from the therapeutic agent and a counterion, mainly by ionic interactions, and resulting in a wide variety of derivatives with different properties. However, the pharmaceutical field is limited to the use of some excipients or GRAS (generally recognized as safe) substances, so the search for new counterions is of great interest. In this article, we have compiled key indexes that can be obtained from databases to guide the search for suitable counterions, together with different drug delivery system strategies to choose the most appropriate formulation according to the non-parenteral route of administration selected. Intellectual property advancements in the field are also presented and analyzed.

PMID: 32976927 [PubMed - as supplied by publisher]

Deciphering piRNA biogenesis through cytoplasmic granules, mitochondria and exosomes.

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Deciphering piRNA biogenesis through cytoplasmic granules, mitochondria and exosomes.

Arch Biochem Biophys. 2020 Sep 22;:108597

Authors: Pippadpally S, Venkatesh T

Abstract
RNA systems biology is marked by a myriad of cellular processes mediated by small and long non-coding RNAs. Small non-coding RNAs include siRNAs (small interfering RNAs), miRNAs (microRNAs), tRFs(tRNA derived fragments), and piRNAs (PIWI-interacting RNAs). piRNAs are vital for the maintenance of the germ-line integrity and repress the transposons either transcriptionally or post-transcriptionally. Studies based on model organisms have shown that defects in the piRNA pathway exhibit impaired gametogenesis and loss of fertility. piRNA biogenesis is marked by transcription of precursor molecules and their subsequent processing in the cytoplasm to generate mature piRNAs. Their biogenesis is unique and complex, which involves non-canonical transcription and self-amplification mechanisms such as the ping-pong cycle. piRNA biogenesis is different in somatic and germ cells and involves the role of cytoplasmic granules in addition to mitochondria. In this review, we discuss the biogenesis and maturation of piRNAs in various cytoplasmic granules such as Yb and nuage bodies. Also, we review the role of P bodies, stress granules, and P granules, and membrane-bound compartments such as mitochondria and exosomes in piRNA biogenesis.

PMID: 32976825 [PubMed - as supplied by publisher]

Tumor-derived microparticles in tumor immunology and immunotherapy.

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Tumor-derived microparticles in tumor immunology and immunotherapy.

Eur J Immunol. 2020 Sep 25;:

Authors: Ma J, Zhang H, Tang K, Huang B

Abstract
Microvesicles or microparticles, a type of cytoplasm membrane-derived extracellular vesicles, can be released by cancer cells or normal cell types. Alteration of F-actin cytoskeleton by various signals may lead to the cytoplasm membrane encapsulating cellular contents to form microparticles, which contain various messenger molecules, including enzymes, RNAs and even DNA fragments, and are released to extracellular space. The release of microparticles by tumor cells (T-MPs) is a very common event in tumor microenvironments. As a result, T-MPs not only influence tumor cell biology but also profoundly forge tumor immunology. Moreover, T-MPs can act as a natural vehicle that delivers therapeutic drugs to tumor cells and immune cells, thus remodeling tumor microenvironments and resetting antitumor immune responses, thus conferring T-MPs a potential role in tumor immunotherapies and tumor vaccines. In this review, we focus on the double-edged sword role of T-MPs in tumor immunology, specifically in TAMs and DCs, and emphasize the application of drug-packaging T-MPs in cancer patients. We aim to provide a new angle to understand immuno-oncology and new strategies for cancer immunotherapy. This article is protected by copyright. All rights reserved.

PMID: 32976623 [PubMed - as supplied by publisher]

Molecular characterization of the co-produced extracellular vesicles in HEK293 during virus-like particle production.

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Molecular characterization of the co-produced extracellular vesicles in HEK293 during virus-like particle production.

J Proteome Res. 2020 Sep 25;:

Authors: Lavado-García J, González-Domínguez I, Cervera L, Jorge I, Vázquez J, Gòdia F

Abstract
Vaccine therapies based on virus-like particles (VLPs) are currently in the spotlight due to their potential for generating high immunogenic responses while presenting fewer side effects than conventional vaccines. These self-assembled nanostructures resemble the native conformation of the virus but lack genetic material. They are becoming a promising platform for vaccine candidates against several diseases due to the ability of modifying their membrane with antigens from different viruses. The coproduction of extracellular vesicles (EVs) when producing VLPs is a key phenomenon currently still under study. In order to characterize this extracellular environment, a quantitative proteomics approach has been carried out. Three conditions were studied: non-transfected, transfected with an empty plasmid as control and with a plasmid coding for HIV-1 Gag polyprotein. A shift in EV biogenesis has been detected upon transfection, changing the production from large to small EVs. Another remarkable trait found was the presence of DNA being secreted within vesicles smaller than 200 nm. Studying the protein profile of these biological nanocarriers, it was observed that EVs were reflecting an overall energy homeostasis disruption via mitochondrial proteins deregulation. Also, immunomodulatory proteins like ITGB1, ENO3 and PRDX5 were identified and quantified in VLPs and EVs fractions. These findings provide an insight on the nature of VLP extracellular environment defining the characteristics and protein profile of EVs, with potential to develop new downstream separation strategies or using them as adjuvants in viral therapies.

PMID: 32975947 [PubMed - as supplied by publisher]

Extracellular Vesicles in Spontaneous Preterm Birth.

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Extracellular Vesicles in Spontaneous Preterm Birth.

Am J Reprod Immunol. 2020 Sep 25;:e13353

Authors: Menon R, Shahin H

Abstract
Feto-maternal communication helps to maintain pregnancy and contributes to parturition at term and preterm. Endocrine and immune factor are well reported communication mediators. Recent advances in extracellular vesicle (EV) biology has introduced them as major communication channels between the mother and fetus. EVs are round structures with a lipid bilayer membrane. EVs are generally categorized based on their size and mode of biogenesis. The most commonly reported EVs are exosomes with a size range of 30 -160 nm that are formed inside the intraluminal vesicles of multivesicular body. Microvesicles (MVs) are larger than > 200nm and formed by outward budding of plasma membrane. Vesicles are released from all cells and carry various factors that reflect the physiologic state of cell at the time of their release. Analysis of vesicle provides a snapshot of origin cell. Recent studies in perinatal medicine has shown that exosomes are key communicators between feto-maternal units, and they can cross placenta. Fetal derived exosomes released under term labor associated conditions can cause parturition associated changes in maternal uterine tissues. Exosomes carrying inflammatory cargo can cause preterm birth in animal models suggesting their functional role in parturition. A few reports have profiled differences between exosome cargos from term and preterm pregnancies and indicated their biomarker potential to predict high risk pregnancy status. There are hardly any reports on MVs and their functional roles in reproduction. Herein, we review of EVs and MVs, their characteristics, function, and usefulness predicting adverse pregnancy complications such as preterm birth.

PMID: 32975858 [PubMed - as supplied by publisher]

The Potential of Liquid Biopsy of the Brain Using Blood Extracellular Vesicles: The First Step Toward Effective Neuroprotection Against Neurodegenerative Diseases.

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The Potential of Liquid Biopsy of the Brain Using Blood Extracellular Vesicles: The First Step Toward Effective Neuroprotection Against Neurodegenerative Diseases.

Mol Diagn Ther. 2020 Sep 25;:

Authors: Abdel-Haq H

Abstract
Early diagnosis and biomarker-based ante-mortem tests are essential in efforts against the development of neurodegenerative diseases and can be considered primary neuroprotective measures. Blood is the ideal biofluid for a routine ante-mortem screening test. However, biomarker discovery in the blood is particularly difficult because of interference from factors both intrinsic and extrinsic to blood with the detection of hallmark neurodegenerative biomarkers, such as the pathological prion protein, amyloid-β, and others. Blood extracellular vesicles (EVs), such as exosomes, are cell-derived vesicles released into the blood from all parts of the body (including the brain and spinal cord). They are an enriched source of neural-derived EVs containing neurodegenerative biomarkers that mirror (in the blood) the condition present in the brain. The feasibility of using, and the reliability of, neural-derived blood EVs (NDBEVs) as a method of diagnosing Alzheimer disease and other neurodegenerative diseases has been assessed in strong proof-of-concept studies. Results from these studies strongly suggest that NDBEVs might represent the right strategy for specific, reliable, and early diagnosis of neurodegenerative diseases. Based on these results, NDBEVs might enable the creation of an ante-mortem blood test (liquid biopsy of the brain) for neurodegenerative diseases. This would enormously accelerate the therapy of neurodegenerative diseases. This review highlights the powerful potential of liquid biopsy of the brain using NDBEVs for early diagnosis and treatment of neurodegenerative diseases, and the challenges and limitations related to the identification of clinically applicable EV (exosomal) biomarkers using blood are discussed.

PMID: 32975732 [PubMed - as supplied by publisher]

Solanine Attenuated Hepatocarcinoma Migration and Invasion Induced by Acetylcholine.

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Solanine Attenuated Hepatocarcinoma Migration and Invasion Induced by Acetylcholine.

Integr Cancer Ther. 2020 Jan-Dec;19:1534735420909895

Authors: Lin LT, Choong CY, Tai CJ

Abstract
AIM: Evidence has provided an explanation of the correlation between the nervous system and the tumor microenvironment. Neurotransmitters may be involved in different aspects of cancer progression. The glycoalkaloid solanine has been reported to suppress neural signaling pathways and exists in numerous plants, including Solanum nigrum, which have been demonstrated to inhibit cancer cell proliferation.
METHODS: We evaluated the potentials of solanine on inhibiting acetylcholine-induced cell proliferation and migration in hepatocellular carcinoma cells.
RESULTS: The results indicated that solanine markedly attenuated cell proliferation and migration via inhibiting epithelial-mesenchymal transition and matrix metalloproteinases in acetylcholine-treated Hep G2 cells. In addition, exosomes derived from acetylcholine-treated Hep G2 cells were isolated, and solanine showed inhibiting effects of extrahepatic metastasis on blocking cell proliferation in exosome-treated A549 lung carcinoma cells through regulating microRNA-21 expression.
CONCLUSION: Solanine has strong potential for application in integrative cancer therapy.

PMID: 32975458 [PubMed - as supplied by publisher]

Drying Kinetics and Particle Formation from Dilute Colloidal Suspensions in Aerosol Droplets.

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Drying Kinetics and Particle Formation from Dilute Colloidal Suspensions in Aerosol Droplets.

Langmuir. 2020 Sep 25;:

Authors: Archer J, Walker J, Gregson FKA, Hardy DA, Reid JP

Abstract
Industrial processes such as spray drying of pharmaceutical and food products often involve the drying of aerosol droplets containing colloidal suspensions into powdered microparticles of desired properties. The morphology and surface properties of the final dry products/microparticles obtained after the drying process are strongly influenced by the parameters of the initial aerosol droplet composition and the drying conditions. In particular, the final dry microparticle morphology can be dependent on the dimensionless Péclet number (Pe), which expresses the relative competition between the diffusion of the dispersed particles within the droplet and the rate of solvent loss via evaporation. In this work, we examine how control over the gas phase drying conditions and initial aerosol droplet composition can be used to influence the aerosol droplet drying kinetics in the gas phase for a range of Péclet numbers. We used a single-particle levitation instrument, the electrodynamic balance, to measure the drying kinetics of colloidal silica droplets (0.10 - 0.60 % v/v) under controlled gas phase drying conditions of temperature (263 - 326 K) and relative humidity (0 - 90 %) and obtained Péclet numbers ranging from 4.05 - 184.5 We demonstrate that, for aerosol droplets with initially low feed colloid concentrations and within the constant evaporation regime, the starting composition does not strongly influence the solvent evaporation rate with the included nanoparticles (NPs) acting as spectators. However, the gas phase drying conditions, temperature, and relative humidity, directly influence the droplet drying kinetics and the final dry microparticle properties. With a priori knowledge of the droplet drying kinetics from the single droplet measurements, we further demonstrate the possibility of tailoring the morphology of the dried microparticles. Dried silica microparticles collected at Pe = 23.8 had dense spherical morphologies whiles those at the highest Pe = 180.0 had crumpled surface morphologies with a transition in morphology between these limiting Pe values. Our results extend the fundamental understanding of the mechanisms controlling the drying of aerosol droplets in colloidal suspensions across a wide range of application areas extending from spray drying, to the drying of respiratory fluid droplets containing bacteria and viruses, and the drying of atmospheric aerosol droplets.

PMID: 32975425 [PubMed - as supplied by publisher]

TAF1 Transcripts and Neurofilament Light Chain as Biomarkers for X-Linked Dystonia-Parkinsonism.

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TAF1 Transcripts and Neurofilament Light Chain as Biomarkers for X-Linked Dystonia-Parkinsonism.

Mov Disord. 2020 Sep 25;:

Authors: Al Ali J, Vaine CA, Shah S, Campion L, Hakoum A, Supnet ML, Acuña P, Aldykiewicz G, Multhaupt-Buell T, Ganza NGM, Lagarde JBB, De Guzman JK, Go C, Currall B, Trombetta B, Webb PK, Talkowski M, Arnold SE, Cheah PS, Ito N, Sharma N, Bragg DC, Ozelius L, Breakefield XO

Abstract
BACKGROUND: X-linked dystonia-parkinsonism is a rare neurological disease endemic to the Philippines. Dystonic symptoms appear in males at the mean age of 40 years and progress to parkinsonism with degenerative pathology in the striatum. A retrotransposon inserted in intron 32 of the TAF1 gene leads to alternative splicing in the region and a reduction of the full-length mRNA transcript.
OBJECTIVES: The objective of this study was to discover cell-based and biofluid-based biomarkers for X-linked dystonia-parkinsonism.
METHODS: RNA from patient-derived neural progenitor cells and their secreted extracellular vesicles were used to screen for dysregulation of TAF1 expression. Droplet-digital polymerase chain reaction was used to quantify the expression of TAF1 mRNA fragments 5' and 3' to the retrotransposon insertion and the disease-specific splice variant TAF1-32i in whole-blood RNA. Plasma levels of neurofilament light chain were measured using single-molecule array.
RESULTS: In neural progenitor cells and their extracellular vesicles, we confirmed that the TAF1-3'/5' ratio was lower in patient samples, whereas TAF1-32i expression is higher relative to controls. In whole-blood RNA, both TAF1-3'/5' ratio and TAF1-32i expression can differentiate patient (n = 44) from control samples (n = 18) with high accuracy. Neurofilament light chain plasma levels were significantly elevated in patients (n = 43) compared with both carriers (n = 16) and controls (n = 21), with area under the curve of 0.79.
CONCLUSIONS: TAF1 dysregulation in blood serves as a disease-specific biomarker that could be used as a readout for monitoring therapies targeting TAF1 splicing. Neurofilament light chain could be used in monitoring neurodegeneration and disease progression in patients. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC. on behalf of International Parkinson and Movement Disorder Society.

PMID: 32975318 [PubMed - as supplied by publisher]

[The Effect of Exosomes Secreted by Astrocytes on the Vitality of Neural Stem Cells].

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[The Effect of Exosomes Secreted by Astrocytes on the Vitality of Neural Stem Cells].

Sichuan Da Xue Xue Bao Yi Xue Ban. 2020 Sep;51(5):605-610

Authors: Zhou ST, Zhao J, Xu DS

Abstract
Objective: To investigate the effects of exosomes of mouse astrocytes on the viability of neural stem cells.
Methods: Cultured and isolated the mouse astrocytes, and collected the cell supernatant for obtain the exosomes by ultracentrifugation. Neural stem cells that primary cultured for 2 nd to 6 th generation were obtained and treated with medium contained 0, 20, 40, 60 μg/mL of exosomes respectively. Screening the optimal exosome concentration for culturing neural stem cells by CCK-8 method. The optimal exosome concentration for neural stem cells was 40 μg/mL according to CCK-8 results. Then cells were intervened with 40 μg/mL of exosome in experimental group for 72 h, and the control group was added with the same volume of PBS. After intervention, the positive stem cells were labeled with EdU kit. Using the Transwell model, the number of nucleus stained by DAPI in the lower chamber in 40 μg/mL exosome treatment group and the control group were counted under a fluorescence microscope.
Results: ① Identification of astrocyte exosomes: The successful obtain of exosomes of cell supernatant were confirmed by techniques such as electron microscopy, Western blot, exosome concentration and particle size measurement. ② CCK8 experiment: As the increasement of the concentration of exosomes, cell proliferation of primary neural stem cells gradually increased. Compared with the control group, proliferation of the cells in 40 μg/mL and 60 μg/mL exosome treatment groups was significantly enhanced, but there was no significant difference between the two groups. So, 40 μg/mL was selected as the best intervention concentration. ③ EdU detection: Number of EdU positive labeled cells in the 40 μg/mL exosome group was higher than that in the control group (P<0.05). ④ Transwell experiment: In the Transwell model, more neural stem cells in the 40 μg/mL exosome group migrated from the upper layer to the lower layer of the Transwell membrane, and the number was higher than that of the control group (P<0.05).
Conclusion: Mouse astrocyte exosomes can improve the viability of neural stem cells.

PMID: 32975072 [PubMed - in process]

[Bone Marrow Mesenchymal Stem Cell Exosomes Promote Brain Microvascular Endothelial Cell Proliferation and Migration in Rats].

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[Bone Marrow Mesenchymal Stem Cell Exosomes Promote Brain Microvascular Endothelial Cell Proliferation and Migration in Rats].

Sichuan Da Xue Xue Bao Yi Xue Ban. 2020 Sep;51(5):599-604

Authors: Li XT, Zhao J, Xu DS, Zhang Y, Zhou ST

Abstract
Objective: To study the effect of bone marrow mesenchyml stem cell (BMSC) exosomes (Exo) on the proliferation and migration of brain microvascular endothelial cells in rats.
Methods: BMSCs were extracted from rats and identified. The BMSCs were co-cultured with bEnd.3 cells in Transwell chamber for 24 h (BMSCs group). Extracted and identified the BMSCs exosomes (BMSC-Exo). Observed and qualitatively evaluated the cells' abilities on swallowing the BMSC-Exo under a fluorescence microscope. The optimal work concentration of BMSC-Exo was selected by detecting the cell vitality under different BMSC-Exo concentrations by CCK8 method. bEnd.3 cells were co-cultured with BMSC-Exo for 24 h (BMSC-Exo group). bEnd.3 cells cultured alone was set as control group. The proliferation and migration of bEnd.3 cells in the three groups were respectively detected by EDU and cell scratching experiment after 24 h of culture.
Results: Flow cytometry showed that P3 BMSCs were CD90 and CD29 positive and CD45 negative, with osteogenic differentiation and adipogenesis differentiation, indicating the extracted BMSCs high purity. The BMSC-Exo under transmission electron microscopy was round-shaped with a diameter of about 100 nm; NTA analysis found the diameter distribution of BMSC-Exo ranged from 50 to 600 nm, with a peak size of 150 nm. Immunofluorescence showed that the endothelial cells could swallow BMSC-Exo. CCK8 showed that supplement of 20 μg/mL BMSC-Exo had the best effect on cell proliferation. EDU results showed that BMSCs group and BMSC-Exo group could promote the proliferation of bEnd.3 cells compared with the control group (P<0.05), and there was no difference between BMSCs group and BMSC-Exo group (P>0.05). Cell scratch test showed that the cell mobility of the BMSC-Exo group was higher than that of the control group (P<0.05), but there was no significant difference between the BMSC-Exo group and the BMSCs group (P>0.05).
Conclusion: BMSC-Exo can replace BMSCs in effectively promoting the proliferation and migration of cerebral microvascular endothelial cells, which provide a new potential treatment for angiogenesis after stroke.

PMID: 32975071 [PubMed - in process]

Long-chain polyunsaturated omega-3 fatty acids reduce multiple myeloma exosome-mediated suppression of NK cell cytotoxicity.

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Long-chain polyunsaturated omega-3 fatty acids reduce multiple myeloma exosome-mediated suppression of NK cell cytotoxicity.

Daru. 2020 Sep 24;:

Authors: Moloudizargari M, Redegeld F, Asghari MH, Mosaffa N, Mortaz E

Abstract
BACKGROUND: Despite the advances in the treatment of multiple myeloma (MM), complete remission is usually challenging. The interactions between tumor and host cells, in which exosomes (EXs) play critical roles, have been shown to be among the major deteriorative tumor-promoting factors herein. Therefore, any endeavor to beneficially target these EX-mediated interactions could be of high importance.
OBJECTIVES: a) To investigate the effects of myeloma EXs on natural killer (NK) cell functions. b) To check whether treatment of myeloma cells with eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA), two polyunsaturated omega-3 fatty acids with known anti-cancer effects, can modify myeloma EXs in terms of their effects on natural killer functions.
METHODS: L363 cells were treated with either EPA or DHA or left untreated and the released EXs (designated as E-EX, D-EX and C-EX, respectively) were used to treat NK cells for functional studies.
RESULTS: Myeloma EXs (C-EXs) significantly reduced NK cytotoxicity against K562 cells (P ≤ 0.05), while the cytotoxicity suppression was significantly lower (P ≤ 0.05) in the (E-EX)- and (D-EX)-treated NK cells compared to the (C-EX)-treated cells. The expression of the activating NK receptor NKG2D and NK degranulation, after treatment with the EXs, were both altered following the same pattern. However, C-EXs could increase IFN-γ production in NK cells (P < 0.01), which was not significantly affected by EPA/DHA treatment. This indicates a dual effect of myeloma EXs on NK cells functions.
CONCLUSION: Our observations showed that myeloma EXs have both suppressive and stimulatory effects on different NK functions. Treatment of myeloma cells with EPA/DHA can reduce the suppressive effects of myeloma EXs while maintaining their stimulatory effects. These findings, together with the previous findings on the anti-cancer effects of EPA/DHA, provide stronger evidence for the repositioning of the currently existing EPA/DHA supplements to be used in the treatment of MM as an adjuvant treatment. EXs released from L363 (myeloma) cells in their steady state increase IFN-γ production of NK cells, while reduce their cytotoxicity against the K562 cell line (right blue trace). EXs from L363 cells pre-treated with either EPA or DHA are weaker stimulators of IFN-γ production. These EXs also increase NK cytotoxicity and NKG2D expression (left brown trace) compared to the EXs obtained from untreated L363 cells. Based on these findings, myeloma EXs have both suppressive and stimulatory effects on different NK functions depending on the properties of their cells of origin, which can be exploited in the treatment of myeloma.

PMID: 32974883 [PubMed - as supplied by publisher]

Treatment Response Biomarkers in Anxiety Disorders: From Neuroimaging to Neuronally-Derived Extracellular Vesicles and Beyond.

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Treatment Response Biomarkers in Anxiety Disorders: From Neuroimaging to Neuronally-Derived Extracellular Vesicles and Beyond.

Biomark Neuropsychiatry. 2020 Dec;3:

Authors: Strawn JR, Levine A

Abstract
Multiple and diverse psychotherapeutic or psychopharmacologic treatments effectively reduce symptoms for many patients with anxiety disorders, but the trajectory and magnitude of response vary considerably. This heterogeneity of treatment response has invigorated the search for biomarkers of treatment response in anxiety disorders, across the lifespan. In this review, we summarize evidence for biomarkers of treatment response in children, adolescents and adults with generalized, separation and social anxiety disorders as well as panic disorder. We then discuss the relationship between these biomarkers of treatment response and the pathophysiology of anxiety disorders. Finally, we provide context for treatment response biomarkers of the future, including neuronally-derived extracellular vesicles in anxiety disorders and discuss challenges that must be overcome prior to the debut of treatment response biomarkers in the clinic. A number of promising treatment response biomarkers have been identified, although there is an urgent need to replicate findings and to identify which biomarkers might guide clinicians in selecting from available treatments rather than just simply identifying patients who may be less likely to respond to a given intervention.

PMID: 32974615 [PubMed]

The Delivery of Extracellular Vesicles Loaded in Biomaterial Scaffolds for Bone Regeneration.

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The Delivery of Extracellular Vesicles Loaded in Biomaterial Scaffolds for Bone Regeneration.

Front Bioeng Biotechnol. 2020;8:1015

Authors: Yan HC, Yu TT, Li J, Qiao YQ, Wang LC, Zhang T, Li Q, Zhou YH, Liu DW

Abstract
Extracellular vesicles (EVs) are heterogeneous nanoparticles actively released by cells that comprise highly conserved and efficient systems of intercellular communication. In recent years, numerous studies have proven that EVs play an important role in the field of bone tissue engineering (BTE) due to several advantages, such as good biosafety, stability and efficient delivery. However, the application of EVs therapies in bone regeneration has not been widely used. One of the major challenges for the application of EVs is the lack of sufficient scaffolds to load and control the release of EVs. Thus, in this review, we describe the most advanced current strategies for delivering EVs with various biomaterials for the use in bone regeneration, the role of EVs in bone regeneration, the distribution of EVs mediated by biomaterials and common methods of promoting EVs delivery efficacy with a focus on biomaterial properties.

PMID: 32974327 [PubMed]

Extracellular Vesicle-Dependent Cross-Talk in Cancer-Focus on Pancreatic Cancer.

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Extracellular Vesicle-Dependent Cross-Talk in Cancer-Focus on Pancreatic Cancer.

Front Oncol. 2020;10:1456

Authors: Nannan L, Oudart JB, Monboisse JC, Ramont L, Brassart-Pasco S, Brassart B

Abstract
Extracellular vesicles (EVs) like exosomes and shed microvesicles are generated by many different cells. However, among all the cells, cancer cells are now recognized to secrete more EVs than healthy cells. Tumor-derived EVs can be isolated from biofluids such as blood, urine, ascitic fluid, and saliva. Their numerous components (nucleic acids, proteins, and lipids) possess many pleiotropic functions involved in cancer progression. The tumor-derived EVs generated under the influence of tumor microenvironment play distant roles and promote cellular communication by directly interacting with different cells. Moreover, they modulate extracellular matrix remodeling and tumor progression. Tumor-derived EVs are involved in pre-metastatic niche formation, dependent on the EV-associated protein receptors, and in cancer chemoresistance as they transfer drug-resistance-related genes to recipient cells. Recent advances in preclinical and clinical fields suggest their potential use as biomarkers for diagnosis and prognosis as well as for drug delivery in cancer. In this Review, we discuss EV characteristics and pro-tumor capacities, and highlight the future crucial impact of tumor-derived EVs in pancreatic cancer diagnosis and prognosis.

PMID: 32974169 [PubMed]

MiR-124a Regulates Extracellular Vesicle Release by Targeting GTPase Rabs in Lung Cancer.

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MiR-124a Regulates Extracellular Vesicle Release by Targeting GTPase Rabs in Lung Cancer.

Front Oncol. 2020;10:1454

Authors: Romano G, Nigita G, Calore F, Saviana M, Le P, Croce CM, Acunzo M, Nana-Sinkam P

Abstract
Lung cancer is the leading cause of cancer mortality worldwide. Increased understanding of the molecular mechanisms of the disease has led to the development of novel therapies and improving outcomes. Recently, extracellular vesicles (EVs) have emerged as vehicles for the transfer of genetic information between tumors and their microenvironment and have been implicated in lung cancer initiation, progression, and response to therapy. However, the mechanisms that drive the biogenesis and selective packaging of EVs remain poorly understood. Rab family guanosine triphosphates (GTPases) and their regulators are important membrane trafficking organizers. In this study, we investigated the role of select Rab GTPases on the regulation of EV release. We found that microRNAs target Rab GTPases to regulate EV release from lung cancer cell lines. In particular, Rab32 is a target of miR-124a, and siRNA and miRNA mediated inhibition of Rab32 leads to impaired EV secretion. The downstream implications for microRNA-based regulation of EV release are currently under investigation.

PMID: 32974168 [PubMed]

Importance of Crosstalk Between Chronic Lymphocytic Leukemia Cells and the Stromal Microenvironment: Direct Contact, Soluble Factors, and Extracellular Vesicles.

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Importance of Crosstalk Between Chronic Lymphocytic Leukemia Cells and the Stromal Microenvironment: Direct Contact, Soluble Factors, and Extracellular Vesicles.

Front Oncol. 2020;10:1422

Authors: Dubois N, Crompot E, Meuleman N, Bron D, Lagneaux L, Stamatopoulos B

Abstract
Chronic lymphocytic leukemia (CLL) is caused by the accumulation of malignant B cells due to a defect in apoptosis and the presence of small population of proliferating cells principally in the lymph nodes. The abnormal survival of CLL B cells is explained by a plethora of supportive stimuli produced by the surrounding cells of the microenvironment, including follicular dendritic cells (FDCs), and mesenchymal stromal cells (MSCs). This crosstalk between malignant cells and normal cells can take place directly by cell-to-cell contact (assisted by adhesion molecules such as VLA-4 or CD100), indirectly by soluble factors (chemokines such as CXCL12, CXCL13, or CCL2) interacting with their receptors or by the exchange of material (protein, microRNAs or long non-coding RNAs) via extracellular vesicles. These different communication methods lead to different activation pathways (including BCR and NFκB pathways), gene expression modifications (chemokines, antiapoptotic protein increase, prognostic biomarkers), chemotaxis, homing in lymphoid tissues and survival of leukemic cells. In addition, these interactions are bidirectional, and CLL cells can manipulate the normal surrounding stromal cells in different ways to establish a supportive microenvironment. Here, we review this complex crosstalk between CLL cells and stromal cells, focusing on the different types of interactions, activated pathways, treatment strategies to disrupt this bidirectional communication, and the prognostic impact of these induced modifications.

PMID: 32974152 [PubMed]

Soluble HLA-G and HLA-G Bearing Extracellular Vesicles Affect ILT-2 Positive and ILT-2 Negative CD8 T Cells Complementary.

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Soluble HLA-G and HLA-G Bearing Extracellular Vesicles Affect ILT-2 Positive and ILT-2 Negative CD8 T Cells Complementary.

Front Immunol. 2020;11:2046

Authors: Schwich E, Hò GT, LeMaoult J, Bade-Döding C, Carosella ED, Horn PA, Rebmann V

Abstract
Tumor immune escape is associated with both, the expression of immune checkpoint molecules on peripheral immune cells and soluble forms of the human leukocyte antigen-G (HLA-G) in the blood, which are consequently discussed as clinical biomarker for disease status and outcome of cancer patients. HLA-G preferentially interacts with the inhibitory receptor immunoglobulin-like transcript (ILT) receptor-2 in the blood and can be secreted as free soluble molecules (sHLA-G) or via extracellular vesicles (EV). To investigate the contribution of these two forms to the expression of checkpoint molecules in peripheral blood, we primed peripheral blood mononuclear cells with purified soluble sHLA-G1 protein, or EV preparations derived from SUM149 cells transfected with membrane-bound HLA-G1 or control vector prior to anti-CD3/CD28 T cell activation. Our study demonstrated that priming of PBMC with sHLA-G1 protein prior to 48 h activation resulted in enhanced frequencies of ILT-2 expressing CD8+ T cells, and in an upregulation of immune checkpoint molecules CTLA-4, PD-1, TIM-3, and CD95 exclusively on ILT-2 positive CD8+ T cells. In contrast, when PBMC were primed with EV (containing HLA-G1 or not) upregulation of CTLA-4, PD-1, TIM-3, and CD95 occurred exclusively on ILT-2 negative CD8+ T cells. Taken together, our data suggest that priming with sHLA-G forms induces a pronounced immunosuppressive/exhausted phenotype and that priming with sHLA-G1 protein or EV derived from HLA-G1 positive or negative SUM149 cells affects CD8+ T cells complementary by targeting either the ILT-2 positive or negative subpopulation, respectively, after T cell activation.

PMID: 32973812 [PubMed - in process]

Immunomodulatory Effects of Mesenchymal Stem Cells and Mesenchymal Stem Cell-Derived Extracellular Vesicles in Rheumatoid Arthritis.

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Immunomodulatory Effects of Mesenchymal Stem Cells and Mesenchymal Stem Cell-Derived Extracellular Vesicles in Rheumatoid Arthritis.

Front Immunol. 2020;11:1912

Authors: Liu H, Li R, Liu T, Yang L, Yin G, Xie Q

Abstract
Rheumatoid arthritis (RA) is a chronic autoimmune disease that affects the joints and other organs for which there is currently no effective treatment. Mesenchymal stem cells (MSCs) have therapeutic potential due to their immunomodulatory and differentiation effects. While extensive experimental studies and clinical trials have demonstrated the effects of MSCs in various diseases, MSCs have been found to cause abnormal differentiation and tumor formation. Therefore, extracellular vesicles derived from MSCs (MSC-EVs) are more effective, less toxic, and more stable than the parental cells. MSC-EVs transfer various nucleic acids, proteins, and lipids from parent cells to recipient cells, and thus participate in chronic inflammatory and immune processes. In this review, we summarize the properties and biological functions of MSCs and MSC-EVs in RA. Improvement in our understanding of the mechanisms underlying MSC and MSC-EVs in RA provides an insight into potential biomarkers and therapeutic strategies for RA.

PMID: 32973792 [PubMed - in process]

HAuCl4, Putative General Aquaporins Blocker, Reduces Platelet Spreading, Filopodia Formation, Procoagulant Response, and Thrombus Formation Under Flow.

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HAuCl4, Putative General Aquaporins Blocker, Reduces Platelet Spreading, Filopodia Formation, Procoagulant Response, and Thrombus Formation Under Flow.

Front Physiol. 2020;11:1025

Authors: Misztal T, Golaszewska A, Branska-Januszewska J, Marcinczyk N, Chabielska E, Tomasiak M, Rusak T

Abstract
Background: Recent studies indicate that aquaporin (AQP) water channels have a regulatory function in human platelet secretion and in procoagulant response of murine platelets. However, the engagement of AQPs in morphological changes, procoagulant response, and thrombus formation in human blood has never been investigated. Methods: Confocal microscopy was used to study platelet spreading, filopodia formation, ballooning, and thrombus formation under flow. Flow cytometry was utilized to assess platelet phosphatidylserine (PS) exposure and microparticles shedding. Kinetics of clot formation in vitro was evaluated by thromboelastometry. Mouse model of ferric chloride (III) (FeCl3)-induced thrombosis was used to investigate thrombus formation in vivo. Results: We found that chloroauric(III) acid (HAuCl4), a classical AQP inhibitor (10-100 μM), reduced spreading of human platelets on collagen-coated surfaces and inhibited filopodia formation in a fluid phase. Under flow conditions, HAuCl4 (100 μM) attenuated thrombi growth on collagen, platelet secretion, and PS exposure. Thrombus formation was restored by the addition of exogenous adenosine diphosphate (ADP). Collagen-evoked platelet procoagulant response (evaluated as PS exposure, shedding of microparticles, platelet-dependent thrombin generation, and membrane ballooning) was distinctly reduced by HAuCl4 (25-200 μM), as well as the dynamics of clot formation. In mouse model of thrombosis, reduction of surface of PS-positive cells within thrombus was observed in the presence of HAuCl4 (1-10 mg/kg). Conclusion: These results suggest that in human platelets AQPs are crucial for agonist-evoked morphological changes, thrombus formation under flow, and in development of procoagulant response. Antithrombotic effect in vivo suggests that nontoxic inhibitors of AQPs may be considered as potential candidates for a novel class of antiplatelet drugs.

PMID: 32973556 [PubMed]

Bicuspid Aortic Valve and Endothelial Dysfunction: Current Evidence and Potential Therapeutic Targets.

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Bicuspid Aortic Valve and Endothelial Dysfunction: Current Evidence and Potential Therapeutic Targets.

Front Physiol. 2020;11:1015

Authors: Antequera-González B, Martínez-Micaelo N, Alegret JM

Abstract
Bicuspid aortic valve (BAV), the most frequent congenital heart malformation, is characterized by the presence of a two-leaflet aortic valve instead of a three-leaflet one. BAV disease progression is associated with valvular dysfunction (in the form of stenosis or regurgitation) and aortopathy, which can lead to aneurysm and aortic dissection. This morphological abnormality modifies valve dynamics and promotes eccentric blood flow, which gives rise to alterations of the flow pattern and wall shear stress (WSS) of the ascending aorta. Recently, evidence of endothelial dysfunction (ED) in BAV disease has emerged. Different studies have addressed a reduced endothelial functionality by analyzing various molecular biomarkers and cellular parameters in BAV patients. Some authors have found impaired functionality of circulating endothelial progenitors in these patients, associating it with valvular dysfunction and aortic dilation. Others focused on systemic endothelial function by measuring artery flow-mediated dilation (FMD), showing a reduced FMD in BAV individuals. Novel biomarkers like increased endothelial microparticles (EMP), which are related to ED, have also been discovered in BAV patients. Finally, latest studies indicate that in BAV, endothelial-to-mesenchymal transition (EndoMT) may also be de-regulated, which could be caused by genetic, hemodynamic alterations, or both. Different hypothesis about the pathology of ED in BAV are nowadays being debated. Some authors blamed this impaired functionality just on genetic abnormalities, which could lead to a pathological aorta. Nevertheless, thanks to the development of new and high-resolution imaging techniques like 4D flow MRI, hemodynamics has gained great attention. Based on latest studies, alterations in blood flow seem to cause proper modification of the endothelial cells (ECs) function and morphology. It also seems to be associated with aortic dilation and decreased vasodilators expression, like nitric oxide (NO). Although nowadays ED in BAV has been reported by many, it is not clear which its main cause may be. Comprehending the pathways that promote ED and its relevance in BAV could help further understand and maybe prevent the serious consequences of this disease. This review will discuss the ED present in BAV, focusing on the latest evidence, biomarkers for ED and potential therapeutic targets (Figure 1).

PMID: 32973551 [PubMed]

Synergy between 15-lipoxygenase and secreted PLA2 promotes inflammation by formation of TLR4 agonists from extracellular vesicles.

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Synergy between 15-lipoxygenase and secreted PLA2 promotes inflammation by formation of TLR4 agonists from extracellular vesicles.

Proc Natl Acad Sci U S A. 2020 Sep 24;:

Authors: Ha VT, Lainšček D, Gesslbauer B, Jarc-Jovičić E, Hyötyläinen T, Ilc N, Lakota K, Tomšič M, van de Loo FAJ, Bochkov V, Petan T, Jerala R, Manček-Keber M

Abstract
Damage-associated endogenous molecules induce innate immune response, thus making sterile inflammation medically relevant. Stress-derived extracellular vesicles (stressEVs) released during oxidative stress conditions were previously found to activate Toll-like receptor 4 (TLR4), resulting in expression of a different pattern of immune response proteins in comparison to lipopolysaccharide (LPS), underlying the differences between pathogen-induced and sterile inflammation. Here we report that synergistic activities of 15-lipoxygenase (15-LO) and secreted phospholipase A2 (sPLA2) are needed for the formation of TLR4 agonists, which were identified as lysophospholipids (lysoPLs) with oxidized unsaturated acyl chain. Hydroxy, hydroperoxy, and keto products of 2-arachidonoyl-lysoPI oxidation by 15-LO were identified by mass spectrometry (MS), and they activated the same gene pattern as stressEVs. Extracellular PLA2 activity was detected in the synovial fluid from rheumatoid arthritis and gout patients. Furthermore, injection of sPLA2 promoted K/BxN serum-induced arthritis in mice, whereby ankle swelling was partially TLR4 dependent. Results confirm the role of oxidized lysoPL of stressEVs in sterile inflammation that promotes chronic diseases. Both 15-LO and sPLA2 enzymes are induced during inflammation, which opens the opportunity for therapy without compromising innate immunity against pathogens.

PMID: 32973091 [PubMed - as supplied by publisher]

Unveiling the potential of purinergic signaling in schistosomiasis treatment.

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Unveiling the potential of purinergic signaling in schistosomiasis treatment.

Curr Top Med Chem. 2020 Sep 24;:

Authors: Oliveira NF, Silva CLM

Abstract
Schistosomiasis is a neglected tropical disease. It is related to long-lasting granulomatous fibrosis and inflammation of target organs, and current sub-optimal pharmacological treatment awakens global public health concerns. Intravascular worms and eggs release antigens and extracellular vesicles that target host endothelial cells, modulate the immune system, and stimulate the release of damage-associated molecular patterns (DAMPs). ATP, one of the most studied DAMP, triggers a cascade of autocrine and paracrine actions through purinergic P2X and P2Y receptors, which are shaped by ectonucleotidases (CD39). Both P2 receptor families, and in particular P2Y1, P2Y2, P2Y12, and P2X7 receptors, have been attracting increasing interest in several inflammatory diseases and drug development. Current data obtained in the murine model unveil a CD39-ADP-P2Y1/P2Y12 receptors signaling pathway linked to liver and mesenteric exacerbations of schistosomal inflammation. Therefore, we propose that members of this purinergic signaling could be putative pharmacological targets to reduce schistosomal morbidity.

PMID: 32972342 [PubMed - as supplied by publisher]

Exosome as a Natural Gene Delivery Vector for Cancer Treatment.

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Exosome as a Natural Gene Delivery Vector for Cancer Treatment.

Curr Cancer Drug Targets. 2020 Sep 24;:

Authors: Pofali P, Mondal A, Londhe V

Abstract
BACKGROUND: Current gene therapy vectors are viral vectors, non-viral vectors and bacterial vectors which are used for cancer treatment, but there are certain safety concerns and stability issues of these conventional vectors. Exosomes are the vesicles of size 40-100 nm secreted from multivesicular bodies into the extracellular environment by most of the cell types in-vivo and in-vitro. As a natural nanocarrier, exosomes are immunologically inert, biocompatible and can cross biological barriers like blood-brain barrier, intestinal barrier, and placental barrier.
OBJECTIVE: This review focusses on the role of exosome as a carrier to efficiently deliver a gene for cancer treatment and diagnosis. The methods for loading of nucleic acids onto the exosomes, advantages of exosomes as a smart intercellular shuttle for gene delivery and therapeutic applications as a gene delivery vector for siRNA, miRNA, and Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and also the limitations of exosomes as a gene carrier.
METHODS: Mostly electroporation and chemical transfection are used to prepare gene loaded exosomes.
RESULTS: Exosome-mediated delivery is highly promising and advantageous in comparison to the current delivery methods for systemic gene therapy. Targeted exosomes, loaded with therapeutic nucleic acids, can efficiently promote reduction of tumor proliferation without any adverse effects.
CONCLUSION: In the near future exosomes can become an efficient gene carrier for delivery and a biomarker for the diagnosis and treatment of cancer.

PMID: 32972340 [PubMed - as supplied by publisher]

Characterization of blood-derived exosomal proteins after exercise.

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Characterization of blood-derived exosomal proteins after exercise.

J Int Med Res. 2020 Sep;48(9):300060520957541

Authors: Xiang H, Chen S, Zhou J, Guo J, Zhou Q, Zhou Q

Abstract
OBJECTIVE: To assess changes in plasma exosome levels and protein content in mice after long-term exercise.
METHODS: We subjected 9-month-old adult C57BL/6J mice to daily treadmill running exercise for 4 weeks prior to the isolation of blood-derived exosomes. Exosomal proteins were identified using mass spectrometry.
RESULTS: Extracellular bodies were successfully isolated from mouse blood. Protein levels were altered in blood-derived exosomes after chronic treadmill exercise. Levels of the secretagogue secretogranin 2 were markedly elevated in exercise-induced exosomes.
CONCLUSION: Our data suggest that levels of secretogranin 2 were increased in mouse exosomes following chronic treadmill exercise. We conclude that exercise increases exocrine secretion of secretogranin 2.

PMID: 32972266 [PubMed - in process]

[Research advances on the roles of exosomes derived from vascular endothelial progenitor cells in wound repair].

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[Research advances on the roles of exosomes derived from vascular endothelial progenitor cells in wound repair].

Zhonghua Shao Shang Za Zhi. 2020 Sep 20;36(9):883-886

Authors: Pan MC, Lin XY, Wang H, Chen YF, Leng M

Abstract
Angiogenesis is the core step of wound repair, and vascular endothelial progenitor cells (EPC) play an extremely important role during wound repair. Recent studies have shown that vascular EPC-derived exosomes (EPC-Exo) can protect vessels, promote the proliferation and migration of vascular endothelial cells, and have anti-inflammatory, anti-oxidant and anti-apoptotic effects on vascular endothelial cells. This article reviews the mechanism of vascular EPC-Exo in angiogenesis and its potential applications in wound repair in recent years.

PMID: 32972078 [PubMed - in process]

MiRNA Profiles of Extracellular Vesicles Secreted by Mesenchymal Stromal Cells-Can They Predict Potential Off-Target Effects?

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MiRNA Profiles of Extracellular Vesicles Secreted by Mesenchymal Stromal Cells-Can They Predict Potential Off-Target Effects?

Biomolecules. 2020 Sep 22;10(9):

Authors: Nazari-Shafti TZ, Neuber S, Duran AG, Exarchos V, Beez CM, Meyborg H, Krüger K, Wolint P, Buschmann J, Böni R, Seifert M, Falk V, Emmert MY

Abstract
The cardioprotective properties of extracellular vesicles (EVs) derived from mesenchymal stromal cells (MSCs) are currently being investigated in preclinical studies. Although microRNAs (miRNAs) encapsulated in EVs have been identified as one component responsible for the cardioprotective effect of MSCs, their potential off-target effects have not been sufficiently characterized. In the present study, we aimed to investigate the miRNA profile of EVs isolated from MSCs that were derived from cord blood (CB) and adipose tissue (AT). The identified miRNAs were then compared to known targets from the literature to discover possible adverse effects prior to clinical use. Our data show that while many cardioprotective miRNAs such as miR-22-3p, miR-26a-5p, miR-29c-3p, and miR-125b-5p were present in CB- and AT-MSC-derived EVs, a large number of known oncogenic and tumor suppressor miRNAs such as miR-16-5p, miR-23a-3p, and miR-191-5p were also detected. These findings highlight the importance of quality assessment for therapeutically applied EV preparations.

PMID: 32971982 [PubMed - in process]

Complement Properdin Regulates the Metabolo-Inflammatory Response to a High Fat Diet.

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Complement Properdin Regulates the Metabolo-Inflammatory Response to a High Fat Diet.

Medicina (Kaunas). 2020 Sep 22;56(9):

Authors: Thomas RC, Kheder R, Alaridhee H, Martin N, Stover CM

Abstract
Background and objectives: Overnutrition leads to a metabolic and inflammatory response that includes the activation of Complement. Properdin is the only amplifier of complement activation and increases the provision of complement activation products. Its absence has previously been shown to lead to increased obesity in mice on a high fat diet. The aim of this study was to determine ways in which properdin contributes to a less pronounced obese phenotype. Materials and Methods: Wild type (WT) and properdin deficient mice (KO) were fed a high-fat diet (HFD) for up to 12 weeks. Results: There was a significant increase in liver triglyceride content in the KO HFD group compared to WT on HFD. WT developed steatosis. KO had an additional inflammatory component (steatohepatitis). Analysis of AKT signalling by phosphorylation array supported a decrease in insulin sensitivity which was greater for KO than WT in liver and kidney. There was a significant decrease of C5L2 in the fat membranes of the KO HFD group compared to the WT HFD group. Circulating microparticles in KO HFD group showed lower presence of C5L2. Expression of the fatty acid transporter CD36 in adipose tissue was increased in KO on HFD and was also significantly increased in plasma of KO HFD mice compared to WT on HFD. CD36 was elevated on microparticles from KO on HFD. Ultrastructural changes consistent with obesity-associated glomerulopathy were observed for both HFD fed genotypes, but tubular strain was greater in KO. Conclusion: Our work demonstrates that complement properdin is a dominant factor in limiting the severity of obesity-associated conditions that impact on liver and kidney. The two receptors, C5L2 and CD36, are downstream of the activity exerted by properdin.

PMID: 32971872 [PubMed - in process]

Exosome release and neuropathology induced by α-synuclein: new insights into protective mechanisms of Drp1 inhibition.

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Exosome release and neuropathology induced by α-synuclein: new insights into protective mechanisms of Drp1 inhibition.

Acta Neuropathol Commun. 2019 11 19;7(1):184

Authors: Fan RZ, Guo M, Luo S, Cui M, Tieu K

Abstract
Targeting alpha-synuclein (α-syn) as a therapeutic strategy for Parkinson's disease (PD) has been intensively pursued largely due to its well-recognized pathogenic role. Since its discovery as the first familial link to PD over two decades ago, this protein has been associated with multiple neurotoxic mechanisms, such as mitochondrial dysfunction and impaired autophagic flux. We report here that blocking dynamin-related protein 1 (Drp1) improved both mitochondrial function and autophagic flux in experimental models of α-syn. Using rat dopaminergic neuronal cells with inducible wild-type human α-syn, we observed excessive mitochondrial fragmentation and increased Drp1 levels 48 h after gene induction. Functionally, these cells exhibited lower mitochondrial membrane potential, reduced ATP production rate and mitochondrial spare respiratory capacity, as well as increased levels of mitochondrial reactive oxygen species. To evaluate the protective role of Drp1 inhibition, we used three complementary approaches: gene silencing mediated by siRNA, overexpression of Drp1-dominant negative and the small molecule mitochondrial division inhibitor-1 (mdivi-1). Both morphological and functional defects induced by α-syn were attenuated by these strategies. Importantly, Drp1 inhibition reduced proteinase K-resistant α-syn aggregates. Based on that observation, we investigated the involvement of autophagy. Through a combination of stable autophagy reporter cells and immunoreactivity for LC3 and p62 in neuronal cells with either α-syn overexpression or treatment of human α-syn preformed fibrils (PFF), we observed that Drp1 inhibition abolished autophagic impairment induced by α-syn. Consistent with its role in improving autophagy function, Drp1 inhibition reduced exosome release and spread of α-syn pathology from neurons to neurons and from microglia to neurons. In summary, this study highlights new insights that Drp1 inhibition confers neuroprotection through both mitochondrial and autophagy-lysosomal pathways, further strengthening the therapeutic potential of targeting Drp1.

PMID: 31744532 [PubMed - indexed for MEDLINE]

 

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