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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.

Extracellular microvesicles promote microglia-mediated pro-inflammatory responses to ethanol.

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Extracellular microvesicles promote microglia-mediated pro-inflammatory responses to ethanol.

J Neurosci Res. 2021 Feb 20;:

Authors: Crews FT, Zou J, Coleman LG

Abstract
Alcohol use disorder (AUD) pathology features pro-inflammatory gene induction and microglial activation. The underlying cellular processes that promote this activation remain unclear. Previously considered cellular debris, extracellular vesicles (EVs) have emerged as mediators of inflammatory signaling in several disease states. We investigated the role of microvesicles (MVs, 50 nm-100 µm diameter EVs) in pro-inflammatory and microglial functional gene expression using primary organotypic brain slice culture (OBSC). Ethanol caused a unique immune gene signature that featured: temporal induction of pro-inflammatory TNF-α and IL-1β, reduction of homeostatic microglia state gene Tmem119, progressive increases in purinergic receptor P2RY12 and the microglial inhibitory fractalkine receptor CX3CR1, an increase in the microglial presynaptic gene C1q, and a reduction in the phagocytic gene TREM2. MV signaling was implicated in this response as reduction of MV secretion by imipramine blocked pro-inflammatory TNF-α and IL-1β induction by ethanol, and ethanol-conditioned MVs (EtOH-MVs) reproduced the ethanol-associated immune gene signature in naïve OBSC slices. Depletion of microglia prior to ethanol treatment prevented pro-inflammatory activity of EtOH-MVs, as did incubation of EtOH-MVs with the HMGB1 inhibitor glycyrrhizin. Ethanol caused HMGB1 secretion from cultured BV2 microglia in MVs through activation of PI3 kinase. In summary, these studies find MVs modulate pro-inflammatory gene induction and microglial activation changes associated with ethanol. Thus, MVs may represent a novel therapeutic target to reduce neuroinflammation in the setting of alcohol abuse or other diseases that feature a neuroimmune component.

PMID: 33611821 [PubMed - as supplied by publisher]

Identification and structural elucidation of a new cetrorelix methylene dimer impurity in cetrorelix acetate by using LC-MS/MS.

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Identification and structural elucidation of a new cetrorelix methylene dimer impurity in cetrorelix acetate by using LC-MS/MS.

J Pharm Biomed Anal. 2021 Feb 03;197:113946

Authors: Li M, Li H, Huang H, Li Y, Qin L, Xu X, Zheng Q, Wang D, Zhang M, Sun Y, Yang Q

Abstract
Cetrorelix, a potent third generation of luteinizing hormone releasing hormone (LHRH) antagonist, is a synthetic decapeptide used for treatment of infertility, prostatic hypertrophy and sexual hormone-dependent tumors. The approved drug of cetrorelix (Cetrotide, Asta Medica AG, Frankfurt, Germany.), was used for prevention of premature ovulation in patients undergoing a controlled ovarian stimulation (COS), followed by oocyte pick-up and assisted reproductive techniques, and has been shown safe and effective in controlled ovarian stimulation. Nevertheless, the study of aggregation products of cetrorelix was rarely reported. A simple liquid chromatography mass spectrometry (LC-MS/MS) method was developed for separation, identification and characterization of a new cetrorelix methylene dimer impurity in cetrorelix. The chromatographic separation was achieved on an XSelect Peptide CSH ™C18 column (150 × 4.6 mm, 3.5 μm particle size) using gradient elution with a mobile phase of ammonium formate buffer (pH 3.0, 20 mM), acetonitrile at a flow rate 1.0 mL min-1, and an ultraviolet detection wavelength of 226 nm. The new cetrorelix methylene dimer impurity was characterized by LC-MS/MS and it characteristic fragment ions were summarized. A simple, fast and accurate method was established for the determination of the molecular weight and structure of the new cetrorelix methylene dimer impurity. In this study, the results showed that the cetrorelix was highly unstable in formaldehyde conditions. In addition, it is proposed that the impact of formaldehyde in the environment on the quality of cetrorelix acetate for Injection should be evaluated during the production process.

PMID: 33611089 [PubMed - as supplied by publisher]

Effects of antithrombotic drugs on the prothrombotic state in patients with atrial fibrillation: The west Birmingham atrial fibrillation project.

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Effects of antithrombotic drugs on the prothrombotic state in patients with atrial fibrillation: The west Birmingham atrial fibrillation project.

Thromb Res. 2021 Feb 09;200:149-155

Authors: Voukalis C, Lip GYH, Shantsila E

Abstract
BACKGROUND: Direct oral anticoagulants (DOACs) are known to prevent thrombosis but there is limited information about their activity on the clot formation and lysis cascade.
OBJECTIVES: This study assesses the role of apixaban, one of the four licenced DOACs, on clot dynamics in patients with atrial fibrillation (AF).
METHODS: We compared haemostatic and clot lysis characteristics between a group of patients with AF (n = 47) and a "disease control" group with ischaemic heart disease but in sinus rhythm (n = 39). Subsequently, we conducted clot structure studies in 3 groups of patients with AF on different antithrombotic drugs: warfarin (n = 60), apixaban (n = 60) or antiplatelets (n = 62) and in patients with AF naïve to oral anticoagulants before and after 3-months treatment with apixaban (n = 32). Haemostasis was investigated by a viscoelastic, whole blood technique (Thromboelastography/TEG), a "microplate-reader based", citrated plasma technique (microplate assay), immunoassays to determine plasma concentrations of plasminogen activator inhibitor-1 (PAI-1), tissue-Plasminogen Activator (t-PA), D-dimer and finally platelet derived and apoptotic microparticles.
RESULTS: Patients with AF have more potent thrombogenesis based on microplate assay indices [Rate of clot formation (p = 0.03, ƞ2 = 0.06), Maximum optical density (p < 0.001, ƞ2 = 0.05)] and delayed fibrinolysis [Rate of clot dissolution (p = 0.005, ƞ2 = 0.17)] with increased levels of apoptotic microparticles (p = 0.02, ƞ2 = 0.06) compared with the 'disease control' group. Apixaban was more effective in attenuating prothrombotic characteristics assessed by TEG {R (ε2 = 0.21), K (ε2 = 0.16) and angle [mean difference (MD), 95% Confidence Intervals (CI), vs warfarin 5, 0.96-8.6 and 8, 3.8-11.4 vs antiplatelets], (p < 0.001 for all indices)} compared with the other treatment groups. Patients on apixaban had lower D-dimer (p < 0.001, ε2 = 0.17) and tPA (p = 0.03, MD 90, 95%CI 6-150 vs warfarin and MD 90, 95% CI 4-150 vs antiplatelets) levels. From the microplate assay analysis, warfarin and apixaban demonstrated comparable activity based on multiple indices, both superior to antiplatelets. However, warfarin was associated with reduced fibrin network robustness (Max. optical density p < 0.001, ε2 = 0.1). Apixaban inhibited thrombosis, amplified fibrinolysis and decreased D-dimer (p = 0.001, r = 0.4) levels in the follow up study.
CONCLUSIONS: Patients with AF have impaired haemostasis and elevated levels of apoptotic microparticles. Apixaban appears to affect plasma prothrombotic characteristics in a distinctive manner compared with warfarin and to reduce biomarkers associated with adverse cardiovascular events.

PMID: 33610887 [PubMed - as supplied by publisher]

Bovine milk exosomes attenuate the alteration of purine metabolism and energy status in IEC-6 cells induced by hydrogen peroxide.

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Bovine milk exosomes attenuate the alteration of purine metabolism and energy status in IEC-6 cells induced by hydrogen peroxide.

Food Chem. 2021 Feb 01;350:129142

Authors: Wang L, Wang X, Shi Z, Shen L, Zhang J, Zhang J

Abstract
Evidence suggests that dietary depletion of bovine milk exosomes and their cargos causes a loss of circulating microRNAs and a series of health problems. The aim of the current study was to determine whether bovine milk exosomes affect purine nucleotide metabolism and energy metabolism in oxidatively stressed intestinal crypt epithelial cells (IEC-6). Cells were pretreated with exosomes, followed by H2O2 to induce oxidative stress. Reactive oxidative species (ROS) levels, purine nucleotides, purine metabolic key enzyme activities, cell energy status, and AMPK protein expression were analysed. Exosome pretreatment reduced ROS level and the activities of adenosine deaminase and xanthine oxidase induced by H2O2 in cells. Total adenine nucleotides and energy charge were increased with exosome pretreatment, while the AMPK phosphorylation level was downregulated. The results indicated that bovine milk exosomes could attenuate purine nucleotide catabolism and improve energy status in oxidatively stressed IEC-6 cells and exerted protective effects against oxidative stress.

PMID: 33610842 [PubMed - as supplied by publisher]

Exosome-mediated delivery of RNA and DNA for gene therapy.

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Exosome-mediated delivery of RNA and DNA for gene therapy.

Cancer Lett. 2021 Feb 18;:

Authors: Munagala R, Aqil F, Jeyabalan J, Kandimalla R, Wallen M, Tyagi N, Wilcher S, Yan J, Schultz DJ, Spencer W, Gupta RC

Abstract
Gene therapy promises to revolutionize biomedicine and personalized medicine by modulating or compensating the expression of abnormal genes. The biggest obstacle for clinical application is the lack of an effective, non-immunogenic delivery system. We show that bovine colostrum exosomes and polyethyleneimine matrix (EPM) delivers short interfering RNA (siRNA) or plasmid DNA (pDNA) for effective gene therapy. KRAS, a therapeutic focus for many cancers, was targeted by EPM-delivered KRAS siRNA (siKRAS) and inhibited lung tumor growth (>70%) and reduced KRAS expression (50%-80%). Aberrant p53 is another therapeutic focus for many cancers. EPM-mediated introduction of wild-type (WT) p53 pDNA (pcDNA-p53) resulted in p53 expression in p53-null H1299 cells in culture subcutaneous lung tumor, and tissues of p53-knockout mice. Additionally, chemo-sensitizing effects of paclitaxel were restored by exogenous WT p53 in lung cancer cells. Together, this novel EPM technology represents an effective 'platform' for delivery of therapeutic nucleic acids to treat human disease.

PMID: 33610731 [PubMed - as supplied by publisher]

Extracellular miRNAs and Cell-Cell Communication: Problems and Prospects.

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Extracellular miRNAs and Cell-Cell Communication: Problems and Prospects.

Trends Biochem Sci. 2021 Feb 17;:

Authors: Makarova J, Turchinovich A, Shkurnikov M, Tonevitsky A

Abstract
miRNAs are short RNA molecules regulating multiple cellular processes through post-transcriptional gene silencing. Over the past decade, miRNAs have been found in the extracellular space and have been consistently shown to mediate functional communication between cells. While it remains widely accepted that miRNA transfer between cells occurs via extracellular vesicles (EVs), multiple other carriers of cell-free miRNA have been described. In addition, some studies have demonstrated that both miRNAs and their binding partners, Argonaute proteins, remain hardly detectable in common isolates of EVs. In this Opinion article, we summarize the state-of-the-art mechanisms of miRNA sorting and secretion, discuss methodological challenges associated with extracellular miRNA research, and suggest experimental steps to resolve current inconsistencies in the field of miRNA-mediated cell-cell communication.

PMID: 33610425 [PubMed - as supplied by publisher]

 

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