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

Downregulation of Microparticle Release and Pro-Inflammatory Properties of Activated Human Polymorphonuclear Neutrophils by LMW Fucoidan.

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Downregulation of Microparticle Release and Pro-Inflammatory Properties of Activated Human Polymorphonuclear Neutrophils by LMW Fucoidan.

J Innate Immun. 2018 Dec 17;:1-17

Authors: Moraes JA, Frony AC, Barcellos-de-Souza P, Menezes da Cunha M, Brasil Barbosa Calcia T, Benjamim CF, Boisson-Vidal C, Barja-Fidalgo C

Abstract
Exposition of neutrophils (polymorphonuclear neutrophils, PMNs) to bacterial products triggers exacerbated activation of these cells, increasing their harmful effects on host tissues. We evaluated the possibility of interfering with the classic immune innate responses of human PMNs exposed to bacterial endotoxin (lipopolysaccharide, LPS), and further stimulated with bacterial formyl peptide (N-formyl-methionine-leucine-phenylalanine, fMLP). We showed that the low- molecular-weight fucoidan (LMW-Fuc), a polysaccharide extracted from brown algae, attenuated the exacerbated activation induced by fMLP on LPS-primed PMNs, in vitro, impairing chemotaxis, NET formation, and the pro-survival and pro-oxidative effects. LMW-Fuc also inhibited the activation of canonical signaling pathways, AKT, bad, p47phox and MLC, activated by the exposition of PMN to bacterial products. The activation of PMN by sequential exposure to LPS and fMLP induced the release of L-selectin+ microparticles, which were able to trigger extracellular reactive oxygen species production by fresh PMNs and macrophages. Furthermore, we observed that LMW-Fuc inhibited microparticle release from activated PMN. In vivo experiments showed that circulating PMN-derived microparticles could be detected in mice exposed to bacterial products (LPS/fMLP), being downregulated in animals treated with LMW-Fuc. The data highlight the autocrine and paracrine role of pro-inflammatory microparticles derived from activated PMN and demonstrate the anti-inflammatory effects of LMW-Fuc on these cells.

PMID: 30557873 [PubMed - as supplied by publisher]

Extracellular vesicles enhance the targeted delivery of immunogenic oncolytic adenovirus and paclitaxel in immunocompetent mice.

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Extracellular vesicles enhance the targeted delivery of immunogenic oncolytic adenovirus and paclitaxel in immunocompetent mice.

J Control Release. 2018 Dec 14;:

Authors: Garofalo M, Villa A, Rizzi N, Kuryk L, Rinner B, Cerullo V, Yliperttula M, Mazzaferro V, Ciana P

Abstract
Extracellular vesicles (EVs), are naturally occurring cargo delivery tools with the potential to be used as drug vehicles of single agents or combination therapies. We previously demonstrated that human lung cancer cell-derived EVs could be used for the systemic delivery of oncolytic virus (OVs) and chemotherapy drugs such as paclitaxel (PTX), leading to enhanced anti-tumor effects in nude mice. In the current work, we evaluated the biodistribution of EVs by using bioluminescence and fluorescence imaging technologies, thus proving the ability of these EVs-formulations to specifically target the neoplasia, while leaving other body tissues unaffected. Moreover, in vivo imaging of NFκB activation in an immunocompetent reporter mouse model allowed to demonstrate the selective ability of EVs to induce tumor-associated inflammatory reactions, which are characterized by immunogenic cell death and CD3+/CD4+/CD8+ T-cell infiltration. While EVs have the potential to induce a systemic immune reaction by pro-inflammatory cytokines, our study provides compelling evidences of a localized inflammatory effect in the peritumoral area. Collectively, our findings strongly support the systemic administration of EVs formulations with OVs alone or in combination with chemotherapy agents as a novel strategy aimed at treating primary and metastatic cancers.

PMID: 30557650 [PubMed - as supplied by publisher]

Alginate/Chitosan microparticles for gastric passage and intestinal release of therapeutic protein nanoparticles.

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Alginate/Chitosan microparticles for gastric passage and intestinal release of therapeutic protein nanoparticles.

J Control Release. 2018 Dec 14;:

Authors: Ling K, Wu H, Neish AS, Champion JA

Abstract
Enzymes with intracellular activity have significant potential to treat diseases. Protein nanoparticles (NPs) considerably enhance intracellular delivery of enzymes. We have previously shown that a Salmonella effector enzyme, AvrA, delivered by NPs is capable of modulating inflammatory signals in a murine dextran sulfate sodium (DSS) colitis model. The NPs were instilled intrarectally, limiting delivery to the distal colon. Localized intestinal delivery of protein therapeutics via the oral route is a highly attractive alternative approach. However, the harsh conditions in the gastrointestinal tract can severely reduce protein function. The approach described here is to deliver therapeutic protein NPs encapsulated within gastro-protective microparticles (MPs) made from alginate and chitosan that would subsequently release NPs in the small intestine and colon. A flow focusing microfluidic device was used to form alginate droplets encapsulating protein NPs. Droplets were then simultaneously crosslinked with calcium and coated with chitosan. Protein NPs encapsulated within crosslinked alginate/chitosan MPs were protected and retained their activity after incubation in simulated gastric fluid (SGF). Subsequent incubation in simulated intestinal fluid (SIF) induced release of bioactive protein NPs. Oral administration of AvrA NPs encapsulated in alginate/chitosan MPs delivered protein to intestinal epithelia and reduced clinical and histological scores of inflammation in a murine DSS-induced colitis model. Altogether, NPs in alginate/chitosan MPs are a potential oral delivery vehicle for protein therapeutics.

PMID: 30557649 [PubMed - as supplied by publisher]

CSF extracellular vesicles and neurofilament light protein as biomarkers of CNS injury in HIV-infected patients on antiretroviral therapy.

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CSF extracellular vesicles and neurofilament light protein as biomarkers of CNS injury in HIV-infected patients on antiretroviral therapy.

AIDS. 2018 Dec 14;:

Authors: Guha D, Mukerji SS, Chettimada S, Misra V, Lorenz DR, Morgello S, Gabuzda D

Abstract
OBJECTIVE: The relationship of cerebrospinal fluid (CSF) extracellular vesicles (EVs) to neurocognitive impairment (NCI) in HIV-infected individuals is unclear. Here, we characterize CSF EVs and their association with CNS injury-related biomarkers (neurofilament light [NFL], S100B, neopterin) and NCI in HIV+ subjects on combination antiretroviral therapy (cART).
DESIGN: Cross-sectional and longitudinal study of CSF samples from HIV+ subjects on cART.
METHODS: NFL, S100B, and neopterin were measured by ELISA in 190 CSF samples from 112 subjects (67 HIV+ and 45 HIV-). CSF EVs were isolated and characterized by electron microscopy, nanoparticle tracking analysis, immunoblotting for exosome markers (CD9, CD63, CD81, FLOT-1), and ELISA for HLA-DR.
RESULTS: HIV+ subjects had median age 52 years, 67% with suppressed plasma viral load (< 50 copies/ml), median CD4 nadir 66 cells/μl and CD4 count 313 cells/μl. CSF NFL, S100B, and neopterin levels were higher in HIV+ vs. HIV- subjects, and nonsuppressed vs. suppressed HIV+ subjects. While CSF NFL and S100B levels were higher in NCI vs. unimpaired HIV+ subjects (p < 0.05), only NFL was associated with NCI in adjusted models (p < 0.05). CSF EVs were increased in HIV+ vs. HIV- subjects, and NCI vs. unimpaired HIV+ subjects (p < 0.001), and correlated positively with NFL (p < 0.001). HLA-DR was enriched in CSF EVs from HIV+ subjects with NCI (p < 0.05), suggesting myeloid cells are a potential source of CSF EVs during HIV infection.
CONCLUSIONS: Increased CSF EVs correlate with neuronal injury biomarker NFL in cART-treated HIV+ individuals with neurocognitive impairment, suggesting potential applications as novel biomarkers of CNS injury.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0.

PMID: 30557159 [PubMed - as supplied by publisher]

What's wrong with neutrophils in lupus?

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What's wrong with neutrophils in lupus?

Clin Exp Rheumatol. 2018 Nov 19;

Authors: Tsai CY, Li KJ, Hsieh SC, Liao HT, Yu CL

Abstract
Polymorphonuclear neutrophils (PMNs) act by promoting phagocytosis, and are regarded as the first line of defense against pathogen invasion. However, recent investigations have revealed that they have many previously unknown functions. These functions include mitogen-induced cell-mediated cytotoxicity, production of cytokines/chemokines/growth factors, and release of neutrophil extracellular traps (NETs) and ectosomes/exosomes. Membrane exchange (trogocytosis) is also noted following direct cell-cell contact with other immune cells for modulating innate and adaptive immune responses. These observations strongly suggest that neutrophils may play an important role in the immune network. Systemic lupus erythematosus (SLE) is a prototype of systemic autoimmune diseases characterised by the production of diverse antigen-driven autoantibodies against intra- and extracellular molecules. Multiple immune dysfunctions have been reported in SLE patients. These include excessive interferon alpha (IFN-α) expression, aberrant cytokine/chemokine/growth factor production, skewing of T cell immune responses toward Th2 and Th17 pathways, polyclonal B cell activation, increased apoptosis and NET formation, defective clearance of cell debris and NET-related molecules, and abnormal ectosome/exosome release in the plasma. We have demonstrated that SLE-PMNs per se exhibit aberrant cytokine/chemokine expression, defective glucose metabolism, and increased mitochondrial DNA D310 heteroplasmy with reduced redox capacity. Our data also indicate that autoantibodies purified from SLE sera disrupt PMN functions. In the present review, we discuss these abnormalities in detail and attempt to elucidate the potential roles of disrupted PMN functions in lupus pathogenesis.

PMID: 30557133 [PubMed - as supplied by publisher]

Japanese Encephalitis Virus-induced let-7a/b interacted with the NOTCH-TLR7 pathway in microglia and facilitated neuronal death via caspase activation.

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Japanese Encephalitis Virus-induced let-7a/b interacted with the NOTCH-TLR7 pathway in microglia and facilitated neuronal death via caspase activation.

J Neurochem. 2018 Dec 17;:

Authors: Mukherjee S, Akbar I, Kumari B, Vrati S, Basu A, Banerjee A

Abstract
MicroRNAs (miRNAs) released from the activated microglia upon neurotropic virus infection may exacerbate the neuronal damage. Here, we identified let-7a and let-7b (let-7a/b) as one of the essential miRNAs overexpressed upon Japanese Encephalitis virus (JEV) infection and released in the culture supernatant of the JEV-infected microglial cells through extracellular vesicles. The let-7a/b were previously reported to modulate inflammation in microglial cells through Toll-like receptor 7 (TLR7) pathways; though their role in accelerating JEV pathogenesis remain unexplored. Therefore, we studied the role of let-7a/b in modulating microglia-mediated inflammation during JEV infection and investigated the effect of let-7a/b containing exosomes on primary neurons. To the end, we examined let-7a/b and NOTCH signaling pathway in TLR7 knockdown (KD) mice. We observed that TLR7 KD or inhibition of let-7a/b suppressed the JEV induced NOTCH activation possibly via NF-κB dependent manner and subsequently, attenuated JEV induced TNFα production in microglial cells. Further, exosomes secreted from let-7a/b overexpressed microglia when transferred to uninfected mice brain induced caspase activation. Exosomes secreted from virus-infected or let-7a/b overexpressed microglia when co-incubated with mouse neuronal (Neuro2a) cells or primary cortical neurons also facilitated caspase activation leading to neuronal death. Thus, our results provide evidence for the multifaceted role of let-7a/b miRNAs in JEV pathogenesis. Let-7a/b can interact with TLR7 and NOTCH signaling pathway and enhance TNFα release from microglia. On the other hand, exosomes secreted by JEV-infected microglia can activate caspases in uninfected neuronal cells which possibly contribute to bystander neuronal death. This article is protected by copyright. All rights reserved.

PMID: 30556910 [PubMed - as supplied by publisher]

Genome-wide interrogation of extracellular vesicle biology using barcoded miRNAs.

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Genome-wide interrogation of extracellular vesicle biology using barcoded miRNAs.

Elife. 2018 Dec 17;7:

Authors: Lu A, Wawro P, Morgens DW, Portela F, Bassik MC, Pfeffer SR

Abstract
Extracellular vesicles mediate transfer of biologically active molecules between neighboring or distant cells, and these vesicles may play important roles in normal physiology and the pathogenesis of multiple disease states including cancer. However, the underlying molecular mechanisms of their biogenesis and release remain unknown. We designed artificially barcoded, exosomal microRNAs (bEXOmiRs) to monitor extracellular vesicle release quantitatively using deep sequencing. We then expressed distinct pairs of CRISPR guide RNAs and bEXOmiRs, enabling identification of genes influencing bEXOmiR secretion from Cas9-edited cells. This approach uncovered genes with unrecognized roles in multivesicular endosome exocytosis, including critical roles for Wnt signaling in extracellular vesicle release regulation. Coupling bEXOmiR reporter analysis with CRISPR-Cas9 screening provides a powerful and unbiased means to study extracellular vesicle biology and for the first time, to associate a nucleic acid tag with individual membrane vesicles.

PMID: 30556811 [PubMed - as supplied by publisher]

Controlling the Internal Morphology of Aqueous Core-PLGA Shell Microcapsules: Promoting the Internal Phase Separation via Alcohol Addition.

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Controlling the Internal Morphology of Aqueous Core-PLGA Shell Microcapsules: Promoting the Internal Phase Separation via Alcohol Addition.

Pharm Dev Technol. 2018 Dec 17;:1-33

Authors: Abulateefeh SR, Al-Adhami GK, Alkawareek MY, Alkilany AM

Abstract
The ability to control the internal core architecture of polymeric microcapsules has a direct impact on their applications. However, this task, especially to produce microcapsules with a high percentage of mononuclear aqueous cores, proved to be challenging. In this work, and in continuation to our previous studies, we report a facile protocol to prepare poly(D,L-lactide-co-glycolide) (PLGA) microcapsules with unprecedented percentage (almost 100%) of mononuclear aqueous cores by the internal phase separation method via adding alcohols. Different types of alcohols (methanol, ethanol, propanol, isopropanol, butanol and octanol) were incorporated into the internal phase solution and then emulsified into mineral oil. In situ monitoring of emulsion droplets was performed by phase contrast microscopy at different time points and the percentage of mononuclear droplets was measured. While alcohol-free formulation ended up with only around 51% of mononuclear microcapsules, incorporating alcohols resulted in the formation of more than 90% of mononuclear microcapsules. Octanol, in particular, exhibited an outstanding performance as its incorporation led to an immediate (at 0 h) formation of almost entirely mononuclear microcapsules. Final microcapsules exhibited spherical shape with mean particle size in the range of 1-2 µm as depicted by scanning electron microscopy and dynamic light scattering analysis.

PMID: 30556763 [PubMed - as supplied by publisher]

RAB27A promotes melanoma cell invasion and metastasis via regulation of pro-invasive exosomes.

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RAB27A promotes melanoma cell invasion and metastasis via regulation of pro-invasive exosomes.

Int J Cancer. 2018 Dec 17;:

Authors: Guo D, Lui GYL, Lai SL, Wilmott JS, Tikoo S, Jackett LA, Quek C, Brown DL, Sharp DM, Kwan RYQ, Chacon D, Wong JH, Beck D, van Geldermalsen M, Holst J, Thompson JF, Mann GJ, Scolyer RA, Stow JL, Weninger W, Haass NK, Beaumont KA

Abstract
Despite recent advances in targeted and immune-based therapies, advanced stage melanoma remains a clinical challenge with a poor prognosis. Understanding the genes and cellular processes that drive progression and metastasis is critical for identifying new therapeutic strategies. Here, we found that the GTPase RAB27A was overexpressed in a subset of melanomas, which correlated with poor patient survival. Loss of RAB27A expression in melanoma cell lines inhibited 3D spheroid invasion and cell motility in vitro, and spontaneous metastasis in vivo. The reduced invasion phenotype was rescued by RAB27A-replete exosomes, but not RAB27A-knockdown exosomes, indicating that RAB27A is responsible for the generation of pro-invasive exosomes. Furthermore, while RAB27A loss did not alter the number of exosomes secreted, it did change exosome size and altered the composition and abundance of exosomal proteins, some of which are known to regulate cancer cell movement. Our data suggest that RAB27A promotes the biogenesis of a distinct pro-invasive exosome population. These findings support RAB27A as a key cancer regulator, as well as a potential prognostic marker and therapeutic target in melanoma. This article is protected by copyright. All rights reserved.

PMID: 30556600 [PubMed - as supplied by publisher]

Latent, Immunosuppressive Nature of Poly(lactic-co-glycolic acid) Microparticles.

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Latent, Immunosuppressive Nature of Poly(lactic-co-glycolic acid) Microparticles.

ACS Biomater Sci Eng. 2018 Mar 12;4(3):900-918

Authors: Allen RP, Bolandparvaz A, Ma JA, Manickam VA, Lewis JS

Abstract
Use of biomaterials to spatiotemporally control the activation of immune cells is at the forefront of biomedical engineering research. As more biomaterial strategies are employed for immunomodulation, understanding the immunogenicity of biodegradable materials and their byproducts is paramount in tailoring systems for immune activation or suppression. Poly(D,L-lactic-co-glycolic acid) (PLGA), one of the most commonly studied polymers in tissue engineering and drug delivery, has been previously described on one hand as an immune adjuvant, and on the other as a nonactivating material. In this study, the effect of PLGA microparticles (MPs) on the maturation status of murine bone marrow-derived dendritic cells (DCs), the primary initiators of adaptive immunity, was investigated to decipher the immunomodulatory properties of this biomaterial. Treatment of bone marrow-derived DCs from C57BL/6 mice with PLGA MPs led to a time dependent decrease in the maturation level of these cells, as quantified by decreased expression of the positive stimulatory molecules MHCII, CD80, and CD86 as well as the ability to resist maturation following challenge with lipopolysaccharide (LPS). Moreover, this immunosuppression was dependent on the molecular weight of the PLGA used to fabricate the MPs, as higher molecular weight polymers required longer incubation to produce comparable dampening of maturation molecules. These phenomena were correlated to an increase in lactic acid both intracellularly and extracellularly during DC/PLGA MP coculture, which is postulated to be the primary agent behind the observed immune inhibition. This hypothesis is supported by our results demonstrating that resistance to LPS stimulation may be due to the ability of PLGA MP-derived lactic acid to inhibit the phosphorylation of TAK1 and therefore prevent NF-κB activation. This work is significant as it begins to elucidate how PLGA, a prominent biomaterial with broad applications ranging from tissue engineering to pharmaceutics, could modulate the local immune environment and offers insight on engineering PLGA to exploit its evolving immunogenicity.

PMID: 30555893 [PubMed]

Exosome mediated multidrug resistance in cancer.

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Exosome mediated multidrug resistance in cancer.

Am J Cancer Res. 2018;8(11):2210-2226

Authors: Yousafzai NA, Wang H, Wang Z, Zhu Y, Zhu L, Jin H, Wang X

Abstract
Extracellular vesicles (EVs), named as exosomes, were recently found to play important roles in cell-cell communication by transducing various biochemical and genetic information. Exosomes, secreted from either tumor cells or stromal cells including immune cells, can eventually remodel tumor environment to promote tumor progression such as metastasis and multidrug resistance (MDR). Therefore, the detection or targeting of biochemical and genetic cargos like proteins, lipids, metabolites and various types of RNAs or DNAs are believed to be valuable for the diagnosis and treatment of human cancer. In this review, we will summarize recent progresses in the research of exosomes especially its biological and clinical relevance to MDR. By doing so, we hope it could be valuable for the prevention, detection and intervention of MDR which is one of the major challenges for the clinical management of human cancers.

PMID: 30555739 [PubMed]

Exosomes in cancer therapy: a novel experimental strategy.

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Exosomes in cancer therapy: a novel experimental strategy.

Am J Cancer Res. 2018;8(11):2165-2175

Authors: Gao D, Jiang L

Abstract
Exosomes are small membrane vesicles of endocytic origin secreted by most cell types. They play important roles in intercellular communications and many physiological processes. DCs-derived exosomes can prime naïve T cells and activate NK cells to shrink the tumor. Tumor-derived exosomes carry a variety of tumor antigens that trigger the robust tumor antigen-specific immune response. Tumor-derived exosomes also contain metastasis or invasive-related molecules, which maybe potential targets for cancer immunotherapy. Effector T cells-derived exosomes possess cytotoxic activity of their original cells, thus cause tumor cells lysis. In this review, we summarized the recent advances on the biogenesis and composition of exosomes, the functions of anti-tumor immune response, and the promising applications on cancer immunotherapy of exosomes from different origins. Exosomes schlep efficient targets homing to tumor sites and tend to be a promising new tool of immunotherapy to fight cancer in a cell-free system.

PMID: 30555736 [PubMed]

Exosomal microRNA-21 derived from bronchial epithelial cells is involved in aberrant epithelium-fibroblast cross-talk in COPD induced by cigarette smoking.

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Exosomal microRNA-21 derived from bronchial epithelial cells is involved in aberrant epithelium-fibroblast cross-talk in COPD induced by cigarette smoking.

Theranostics. 2018;8(19):5419-5433

Authors: Xu H, Ling M, Xue J, Dai X, Sun Q, Chen C, Liu Y, Zhou L, Liu J, Luo F, Bian Q, Liu Q

Abstract
Rationale: Aberrant bronchial epithelium-fibroblast communication is essential for the airway remodeling that contributes to chronic obstructive pulmonary disease (COPD). Exosomes have emerged as novel mediators of intercellular communication, but their role in cigarette smoke (CS)-induced COPD is unknown. Here, we investigated the role of exosomal miR-21 in the dysfunctional epithelium-fibroblast cross-talk caused by CS. Methods: Normal or CS extract (CSE)-treated human bronchial epithelial (HBE) cells were co-cultured with bronchial fibroblasts (MRC-5 cells). Exosomes were obtained from culture media or serum by use of commercial kits. The size distribution and concentration of exosomes were analyzed by nanoparticle tracking analysis using a ZetaView particle tracker from ParticleMetrix. Inhibition of miR-21 levels by tail vein injection of antagomir-21 into mice exposed to CS was used to demonstrate the role of miR-21 in airway remodeling leading to COPD in animals. Results: For MRC-5 cells, co-culture with CSE-treated HBE cells or with exosomes derived from CSE-treated HBE cells resulted in the myofibroblast differentiation phenotype. Exosomal miR-21 was responsible for myofibroblast differentiation through hypoxia-inducible factor 1α (HIF-1α) signaling by targeting the von Hippel-Lindau protein (pVHL); HIF-1α transcriptionally regulated the α-SMA gene. For mice, downregulation of miR-21 prevented CS-induced airway remodeling. The levels of exosomal miR-21 were high in sera of smokers and COPD patients and inversely correlated with FEV1/FVC. Conclusion: We demonstrate that CS triggers the modification of exosome components and identify miR-21 derived from bronchial epithelial cells as a mediator of myofibroblast differentiation through the pVHL/HIF-1α signaling pathway, which has potential value for diagnosis and treatment of COPD.

PMID: 30555555 [PubMed - in process]

Extracellular Vesicle-Mediated Immune Regulation of Tissue Remodeling and Angiogenesis After Myocardial Infarction.

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Extracellular Vesicle-Mediated Immune Regulation of Tissue Remodeling and Angiogenesis After Myocardial Infarction.

Front Immunol. 2018;9:2799

Authors: Sánchez-Alonso S, Alcaraz-Serna A, Sánchez-Madrid F, Alfranca A

Abstract
Myocardial ischemia-related disorders constitute a major health problem, being a leading cause of death in the world. Upon ischemia, tissue remodeling processes come into play, comprising a series of inter-dependent stages, including inflammation, cell proliferation and repair. Neovessel formation during late phases of remodeling provides oxygen supply, together with cellular and soluble components necessary for an efficient myocardial reconstruction. Immune system plays a central role in processes aimed at repairing ischemic myocardium, mainly in inflammatory and angiogenesis phases. In addition to cellular components and soluble mediators as chemokines and cytokines, the immune system acts in a paracrine fashion through small extracellular vesicles (EVs) release. These vesicular structures participate in multiple biological processes, and transmit information through bioactive cargoes from one cell to another. Cell therapy has been employed in an attempt to improve the outcome of these patients, through the promotion of tissue regeneration and angiogenesis. However, clinical trials have shown variable results, which put into question the actual applicability of cell-based therapies. Paracrine factors secreted by engrafted cells partially mediate tissue repair, and this knowledge has led to the hypothesis that small EVs may become a useful tool for cell-free myocardial infarction therapy. Current small EVs engineering strategies allow delivery of specific content to selected cell types, thus revealing the singular properties of these vesicles for myocardial ischemia treatment.

PMID: 30555478 [PubMed - in process]

Exosome-encapsulated antibiotic against intracellular infections of methicillin-resistant Staphylococcus aureus.

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Exosome-encapsulated antibiotic against intracellular infections of methicillin-resistant Staphylococcus aureus.

Int J Nanomedicine. 2018;13:8095-8104

Authors: Yang X, Shi G, Guo J, Wang C, He Y

Abstract
Background: Staphylococcus aureus survival inside phagocytes is considered to provide a reservoir of bacteria that are relatively protected from antibiotics, thus enabling long-term colonization of the host and explaining clinical failures and relapses after antibiotic therapy.
Purpose: The objective of this study was to develop a nanovesicle using exosomes loaded with linezolid to overcome intracellular infections by pathogenic bacteria.
Methods: Exosomes were collected from the culture supernatants of RAW 264.7 cells. Their size distribution and zeta potential were characterized by dynamic light scattering, their morphology was characterized by transmission electron microscopy, and their protein content (CD63 and Flotillin 1) was assessed by Western blotting. Linezolid was incorporated into exosomes by co-incubation at 37°C and it's accumulation in RAW264.7 cells and release in vitro were determined by high performance liquid chromatography. The intracellular bactericidal effect was evaluated in methicillin-resistant S. aureus (MRSA)-infected macrophages in vitro and MRSA peritonitis model in vivo.
Results: We prepared a nanoformulation of the antibiotic linezolid using exosomes harvested from mouse RAW264.7 macrophages. The exosomal formulation of linezolid was more effective against intracellular MRSA infections in vitro and in vivo than the free linezolid. Our data also showed no signs of cytotoxicity in macrophages.
Conclusion: Exosomes provide an effective alternative for intracellular antibiotic delivery of antibiotic that is efficacious, cost-effective, and safe. This regimen can be viewed as a potential antimicrobial agent for use against intracellular infections.

PMID: 30555228 [PubMed - in process]

Microparticles from Endothelial Cells and Immune Cells in Patients with Takayasu Arteritis.

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Microparticles from Endothelial Cells and Immune Cells in Patients with Takayasu Arteritis.

J Atheroscler Thromb. 2018 Dec 15;:

Authors: Cheng X, Dang A, Lv N, Zhao T

Abstract
AIM: This study was designed to analyze microparticles (MPs) from endothelial cells (EMPs) and immune cells from healthy individuals and paitents with Takayasu arteritis (TA), and any possible relationships between MPs and TA acitivity.
METHODS: MPs derived from the plasma of 51 subjects were analyzed, including 32 patients with TA and 19 healthy individuals. Flow cytometry was performed with Annexin (Anx)-V and antibodies against surface markers of endothelial cells (CD144), T cells (CD3), B cells (CD19), and monocytes (CD14).
RESULTS: The concentrations of total EMPs, AnxV+ EMPs and AnxV- EMPs were significantly increased when comparing patients with TA and healthy controls (54×103 vs. 32×103 MPs /ml, P=0.0004; 22×103 vs. 12×103 MPs /ml, P=0.0006; and 31×103 vs. 19×103 MPs /ml, P=0.0005), and comparing active TA patients with remission ones (85×103 vs. 45×103 MPs /ml, P=0.016; 39×103 vs. 14×103 MPs /ml, P=0.0092; and 47×103 vs.29×103 MPs /ml, P=0.0371). In addition, the concentrations of total EMPs (odds ratio [OR]=1.024, 95% confidence interval [CI]: 1.001 to 1.048, P=0.037), AnxV+(OR=1.089, 95%CI: 1.011 to 1.172, P=0.024), and AnxV- EMPs (OR=1.029, 95% CI: 1.002 to 1.056, P=0.034) were positively related to TA activity. With multiple linear regression analysis, platelet was associated with both total and AnxV- EMP concentrations independently, while erythrocyte sedimentation rate was independently correlated with AnxV+EMPs.
CONCLUSION: Concentrations of endothelial microparticles are correlated with inflammation in Takayasu arteritis and may be useful markers to assess disease activity.

PMID: 30555130 [PubMed - as supplied by publisher]

Highly efficient siRNA transfection in macrophages using apoptotic body-mimic Ca-PS lipopolyplex.

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Highly efficient siRNA transfection in macrophages using apoptotic body-mimic Ca-PS lipopolyplex.

Int J Nanomedicine. 2018;13:6603-6623

Authors: Lai Y, Xu X, Zhu Z, Hua Z

Abstract
Background: The discovery and development of RNA interference has made a tremendous contribution to the biochemical and biomedical field. However, liposomal transfection protocols to deliver siRNAs to certain types of cells, eg, immune cells, are not viable due to exceedingly low transfection efficiency. While viral delivery and electroporation are two widely adopted approaches to transfect immune cells, they are associated with certain drawbacks such as complexity of preparation, biosafety issues, and high cytotoxicity. We believe amendments can be made to liposomal formulas and protocols to achieve a highly efficient knockdown of genes by liposome-loaded siRNAs.
Aim: The aim of this study was to use the apoptotic-mimic Ca-PS lipopolyplex to achieve highly efficient siRNA knockdown of genes in the hard-to-transfect macrophages with reduced cytotoxicity and more efficient cellular uptake.
Results: We devised an anionic liposomal formula containing phosphatidylserine to mimic the apoptotic body, the Ca-PS lipopolyplex. Ca-PS lipopolyplex was proven to be capable of delivering and effecting efficient gene knockdown in multiple cell lines at lowered cytotoxicity. Among the two types of macrophages, namely Ana-1 and bone-marrow derived macrophages, Ca-PS lipopolyplex showed an improvement in knockdown efficiency, as high as 157%, over Lipo2000. Further investigations revealed that Ca-PS promotes increased cellular uptake, lysosomal escape and localization of siRNAs to the perinuclear regions in macrophages. Lastly, transfection by Ca-PS lipopolyplex did not induce spontaneous polarization of macrophages.
Conclusion: The apoptotic body-mimic Ca-PS lipopolyplex is a stable, non-cytotoxic liposomal delivery system for siRNAs featuring vastly improved potency for macrophages and lowered cytotoxicity. It is speculated that Ca-PS lipopolyplex can be applied to other immune cells such as T cells and DC cells, but further research efforts are required to explore its promising potentials.

PMID: 30425477 [PubMed - indexed for MEDLINE]

Colorectal Cancer Cell Line SW480 and SW620 Released Extravascular Vesicles: Focus on Hypoxia-induced Surface Proteome Changes.

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Colorectal Cancer Cell Line SW480 and SW620 Released Extravascular Vesicles: Focus on Hypoxia-induced Surface Proteome Changes.

Anticancer Res. 2018 Nov;38(11):6133-6138

Authors: Nakurte I, Jekabsons K, Rembergs R, Zandberga E, Abols A, Linē A, Muceniece R

Abstract
BACKGROUND/AIM: Extravascular vesicle (EV) proteome closely reflects the proteome of the cell of origin. Therefore, cancer cell-derived EV proteomic analysis could help in identifying cancer biomarkers. This study's goal was to investigate hypoxia-induced proteomic changes in EV released from hypoxic human isogenic non-metastatic colorectal cancer cells SW480 and metastatic colorectal cancer cells SW620.
MATERIALS AND METHODS: EV were characterized by western blot, transmission electron microscopy, proteomic analysis using liquid chromatography time-of-flight-mass spectrometry and quantified by an label-free intensity-based absolute quantitation (iBAQ) approach.
RESULTS: A total of 16 proteins in hypoxic EV exceeded normoxic EV protein levels in SW480 EV. Of them, 15 were also found in EV of hypoxic SW620 cells. The expression levels of proteins differed quantitatively: iBAQ (log 10) scores of the levels of five proteins in SW620 EV exceeded those in hypoxic SW480 EV and levels of 11 proteins in SW480 EV exceeded those of SW620 EV.
CONCLUSION: Under hypoxia, colorectal cancer cells release EV that qualitatively and quantitatively change the surface proteome. In the future, the specific hypoxia-induced proteins could be developed as new biomarkers for non-invasive assessment of tumour hypoxia.

PMID: 30396929 [PubMed - indexed for MEDLINE]

Distinct and evolutionary conserved structural features of the human nuclear exosome complex.

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Distinct and evolutionary conserved structural features of the human nuclear exosome complex.

Elife. 2018 07 26;7:

Authors: Gerlach P, Schuller JM, Bonneau F, Basquin J, Reichelt P, Falk S, Conti E

Abstract
The nuclear RNA exosome complex mediates the processing of structured RNAs and the decay of aberrant non-coding RNAs, an important function particularly in human cells. Most mechanistic studies to date have focused on the yeast system. Here, we reconstituted and studied the properties of a recombinant 14-subunit human nuclear exosome complex. In biochemical assays, the human exosome embeds a longer RNA channel than its yeast counterpart. The 3.8 Å resolution cryo-EM structure of the core complex bound to a single-stranded RNA reveals that the RNA channel path is formed by two distinct features of the hDIS3 exoribonuclease: an open conformation and a domain organization more similar to bacterial RNase II than to yeast Rrp44. The cryo-EM structure of the holo-complex shows how obligate nuclear cofactors position the hMTR4 helicase at the entrance of the core complex, suggesting a striking structural conservation from lower to higher eukaryotes.

PMID: 30047866 [PubMed - indexed for MEDLINE]

FtsA reshapes membrane architecture and remodels the Z-ring in Escherichia coli.

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FtsA reshapes membrane architecture and remodels the Z-ring in Escherichia coli.

Mol Microbiol. 2018 02;107(4):558-576

Authors: Conti J, Viola MG, Camberg JL

Abstract
Cell division in prokaryotes initiates with assembly of the Z-ring at midcell, which, in Escherichia coli, is tethered to the inner leaflet of the cytoplasmic membrane through a direct interaction with FtsA, a widely conserved actin homolog. The Z-ring is comprised of polymers of tubulin-like FtsZ and has been suggested to provide the force for constriction. Here, we demonstrate that FtsA exerts force on membranes causing redistribution of membrane architecture, robustly hydrolyzes ATP and directly engages FtsZ polymers in a reconstituted system. Phospholipid reorganization by FtsA occurs rapidly and is mediated by insertion of a C-terminal membrane targeting sequence (MTS) into the bilayer and further promoted by a nucleotide-dependent conformational change relayed to the MTS. FtsA also recruits FtsZ to phospholipid vesicles via a direct interaction with the FtsZ C-terminus and regulates FtsZ assembly kinetics. These results implicate the actin homolog FtsA in establishment of a Z-ring scaffold, while directly remodeling the membrane and provide mechanistic insight into localized cell wall remodeling, invagination and constriction at the onset of division.

PMID: 29280220 [PubMed - indexed for MEDLINE]

Amino acid deprivation and central carbon metabolism regulate the production of outer membrane vesicles and tubes by Francisella.

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Amino acid deprivation and central carbon metabolism regulate the production of outer membrane vesicles and tubes by Francisella.

Mol Microbiol. 2018 02;107(4):523-541

Authors: Sampath V, McCaig WD, Thanassi DG

Abstract
Francisella tularensis is a highly virulent Gram-negative bacterial pathogen that causes the zoonotic disease tularemia. F. novicida, a model tularemia strain, produces spherical outer membrane vesicles (OMV), as well as novel tubular vesicles and extensions of the cell surface. These OMV and tubes (OMV/T) are produced in a regulated manner and contain known virulence factors. Mechanisms by which bacterial vesicles are produced and regulated are not well understood. We performed a genetic screen in F. novicida to decipher the molecular basis for regulated OMV/T formation, and identified both hypo- and hyper-vesiculating mutants. Mutations in fumA and tktA, involved in central carbon metabolism, and in FTN_0908 and FTN_1037, of unknown function, resulted in severe defects in OMV/T production. Cysteine deprivation was identified as the signal that triggers OMV/T formation in F. novicida during growth in rich medium. We also found that fully virulent F. tularensis produces OMV/T in a similarly regulated manner. Further analysis revealed that OMV/T production is responsive to deprivation of essential amino acids in addition to cysteine, and that the hypo-vesiculating mutants are defective in responding to this signal. Thus, amino acid starvation, such as encountered by Francisella during host cell invasion, regulates the production of membrane-derived structures.

PMID: 29240272 [PubMed - indexed for MEDLINE]

Endovascular shedding markers in patients with heart failure with reduced ejection fraction: Results from a single-center exploratory study.

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Endovascular shedding markers in patients with heart failure with reduced ejection fraction: Results from a single-center exploratory study.

Microcirculation. 2018 02;25(2):

Authors: Nijst P, Cops J, Martens P, Swennen Q, Dupont M, Tang WHW, Mullens W

Abstract
BACKGROUND: Endothelial glycocalyx degradation has been associated with multiple pathophysiological processes in cardiovascular disease.
AIMS: To explore the role of glycocalyx shedding markers in pathophysiology of HFrEF.
METHODS: In 123 HFrEF patients, the concentration, prognostic value, and association of glycocalyx shedding markers with other disease processes were investigated.
RESULTS: Median HA levels and syndecan-1 levels in HFrEF patients were, respectively, 29.4 (10.7;61.6) ng/mL and 48.5 (33.6;80.8) ng/mL. Overall, HA-levels were significantly higher in HFrEF patients compared to healthy subjects, but only 31% of HFrEF patients had HA-levels above the cutoff of normal. There was no significant difference among HFrEF patients and healthy subjects regarding syndecan-1 levels. HFrEF patients with elevated HA-levels had a significantly worse outcome (log rank = 0.01) which remained significant after correction for established risk factors (HR 2.53 (1.13-5.69); P = .024). There was no significant relation between levels of shedding markers and neurohumoral activation (PRA, serum aldosterone, NT-proBNP), myocardial injury (HS-trop), inflammation (CRP), or other baseline characteristics.
CONCLUSIONS: The glycocalyx shedding marker HA is significantly elevated in a subgroup of HFrEF patients and an independent predictor for worse clinical outcome. Glycocalyx shedding might be an additional factor in the pathophysiology of HF which warrants further investigation.

PMID: 29210138 [PubMed - indexed for MEDLINE]

Tiny but mighty: bacterial membrane vesicles in food biotechnological applications.

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Tiny but mighty: bacterial membrane vesicles in food biotechnological applications.

Curr Opin Biotechnol. 2018 02;49:179-184

Authors: Liu Y, Alexeeva S, Defourny KA, Smid EJ, Abee T

Abstract
Membrane vesicle (MV) production is observed in all domains of life. Evidence of MV production accumulated in recent years among bacterial species involved in fermentation processes. These studies revealed MV composition, biological functions and properties, which made us recognize the potential of MVs in food applications as delivery vehicles of various compounds to other bacteria or the human host. Moreover, MV producing strains can deliver benefits as probiotics or starters in fermentation processes. Next to the natural production of MVs, we also highlight possible methods for artificial generation of bacterial MVs and cargo loading to enhance their applicability. We believe that a more in-depth understanding of bacterial MVs opens new avenues for their exploitation in biotechnological applications.

PMID: 28985542 [PubMed - indexed for MEDLINE]

 

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