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

MicroRNA-15b in extracellular vesicles from arsenite-treated macrophages promotes the progression of hepatocellular carcinomas by blocking the LATS1-mediated Hippo pathway.

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MicroRNA-15b in extracellular vesicles from arsenite-treated macrophages promotes the progression of hepatocellular carcinomas by blocking the LATS1-mediated Hippo pathway.

Cancer Lett. 2020 Oct 17;:

Authors: Li J, Xue J, Ling M, Sun J, Xiao T, Dai X, Sun Q, Cheng C, Xia H, Wei Y, Chen F, Liu Q

Abstract
Arsenic, a human carcinogen, causes various human cancers, including those of the skin, lung, and liver. Hepatocellular carcinomas (HCCs), which have high mortality, are common malignancies worldwide. Tumor-associated macrophages (TAMs), which are considered to be similar to M2-polarized macrophages, promote tumor invasion and progression. Small non-coding RNAs (miRNAs) regulate expression of genes involved in progression of various malignancies. Extracellular vesicles (EVs), as mediators of cell communication, pass specific miRNAs directly from TAMs to tumor cells, promoting tumor pathogenesis and metastasis. In HCCs, large tumor suppressor kinase 1 (LATS1), functions as a tumor suppressor. However, the molecular mechanism by which miRNA modulates LATS1 expression in HCCs remains unclear. The results show that exposure to arsenite, increased miR-15b levels and induced M2 polarization of THP-1 cells. Elevated levels of miR-15b were transferred from arsenite-treated-THP-1 (As-THP-1) cells to HCC cells via miR-15b in EVs inhibited activation of the Hippo pathway by targeting LATS1, and was involved in promoting the proliferation, migration, and invasion of HCC cells. In conclusion, miR-15b in EVs from As-THP-1 cells is transferred to HCC cells, in which it targets and downregulates LATS1 expression and promotes the proliferation, migration, and invasion of HCC cells.

PMID: 33080309 [PubMed - as supplied by publisher]

Activation of multiple receptors stimulates extracellular vesicle release from trophoblast cells.

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Activation of multiple receptors stimulates extracellular vesicle release from trophoblast cells.

Physiol Rep. 2020 Oct;8(20):e14592

Authors: Conrad KP, Tuna KM, Mestre CT, Banwatt ES, Alli AA

Abstract
Reports of the stimulated release of extracellular vesicles (EVs) are few, and the mechanisms incompletely understood. To our knowledge, the possibility that the activation of any one of the multitudes of G-protein-coupled receptors (GPCRs) expressed by a single cell-type might increase EV release has not been explored. Recently, we identified the expression of cholecystokinin (CCK), gastrin, gastrin/cholecystokinin types A and/or B receptors (CCKAR and/or -BR), and the bitter taste receptor, TAS2R14 in the human and mouse placenta. specifically, trophoblast. These GPCR(s) were also expressed in four different human trophoblast cell lines. The current objective was to employ two of these cell lines-JAR choriocarcinoma cells and HTR-8/SVneo cells derived from first-trimester human villous trophoblast-to investigate whether CCK, TAS2R14 agonists, and other GPCR ligands would each augment EV release. EVs were isolated from the cell-culture medium by filtration and ultracentrifugation. The preparations were enriched in small EVs (<200 nm) as determined by syntenin western blot before and after sucrose gradient purification, phycoerythrin (PE)-ADAM10 antibody labeling, and electron microscopy. Activation of TAS2R14, CCKBR, cholinergic muscarinic 1 & 3, and angiotensin II receptors, each increased EV release by 4.91-, 2.79-, 1.87-, and 3.11-fold, respectively (all p < .05 versus vehicle controls), without significantly changing EV diameter. A progressive increase of EV concentration in conditioned medium was observed over 24 hr consistent with the release of preformed EVs and de novo biogenesis. Compared to receptor-mediated stimulation, EV release by the calcium ionophore, A23187, was less robust (1.63-fold, p = .08). Diphenhydramine, a TAS2R14 agonist, enhanced EV release in JAR cells at a concentration 10-fold below that required to increase intracellular calcium. CCK activation of HTR-8/SVneo cells, which did not raise intracellular calcium, increased EV release by 2.06-fold (p < .05). Taken together, these results suggested that other signaling pathways may underlie receptor-stimulated EV release besides, or in addition to, calcium. To our knowledge, the finding that the activation of multiple GPCRs can stimulate EV release from a single cell-type is unprecedented and engenders a novel thesis that each receptor may orchestrate intercellular communication through the release of EVs containing a subset of unique cargo, thus mobilizing a specific integrated physiological response by a network of neighboring and distant cells.

PMID: 33080118 [PubMed - as supplied by publisher]

Exosomes and Extracellular Vesicles as Liquid Biopsy Biomarkers in Diffuse Large B-cell Lymphoma (DLBCL): Current State of the Art and Unmet Clinical Needs.

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Exosomes and Extracellular Vesicles as Liquid Biopsy Biomarkers in Diffuse Large B-cell Lymphoma (DLBCL): Current State of the Art and Unmet Clinical Needs.

Br J Clin Pharmacol. 2020 Oct 20;:

Authors: Ofori K, Bhagat G, Rai AJ

Abstract
Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin's lymphoma, constituting biologically heterogeneous entities. Standard first line therapies cure ~60% of patients, the rest being either refractory or experiencing relapse. Currently, there are no robust predictive biomarkers of therapeutic response. Heterogeneity of DLBCL is partly explained by the cell of origin (COO), i.e. germinal center B cell (GCB) or activated B cell (ABC), with the latter exhibiting worse prognosis. While gene expression profiling (GEP) is the gold standard for determining COO, surrogate immunohistochemical algorithms are used clinically, but show significant discordance with GEP. Recently, additional subgroups with different prognoses have been reported. However, the tools/expertise required for analysis prohibit widespread deployment. Liquid biopsy-based assays show promise in providing clinically actionable information, are non-invasive and facilitate serial sampling to assess mechanisms of therapy resistance. Circulating, cell free DNA analysis has shown enhanced sensitivity, however, this modality cannot provide information on signaling pathways. Exosomes are endosomally derived vesicles, are found in high abundance in body fluids, and readily isolated using a variety of methods. Tumor derived exosomes contain genetic information and can reveal details for diagnostic, prognostic and therapeutic purposes in DLBCL. At present, standardized techniques for isolating exosomes are lacking and discriminating exosomes from neoplastic or normal B cells is challenging. Refinements in isolation procedures are required to realize their full potential as precision medicine tools to provide comprehensive information on disease subtypes, identify prognostic factors, allow real time monitoring of therapy response and to delineate drug targets.

PMID: 33080045 [PubMed - as supplied by publisher]

Biological Characteristics and Roles of Noncoding RNAs in Milk-Derived Extracellular Vesicles.

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Biological Characteristics and Roles of Noncoding RNAs in Milk-Derived Extracellular Vesicles.

Adv Nutr. 2020 Oct 20;:

Authors: Zeng B, Chen T, Luo JY, Zhang L, Xi QY, Jiang QY, Sun JJ, Zhang YL

Abstract
Extracellular vesicles (EVs) have diverse roles in the transport of proteins, lipids, and nucleic acids between cells, and they serve as mediators of intercellular communication. Noncoding RNAs (ncRNAs) that are present in EVs, including microRNAs, long noncoding RNAs, and circular RNAs, have been found to participate in complex networks of interactions and regulate a wide variety of genes in animals. Milk is an important source of nutrition for humans and other mammals. Evidence suggests that milk-derived EVs contain abundant ncRNAs, which are stable and can be transported to the offspring and other consumers. Current data suggest a strong link between milk EV ncRNAs and many biological processes, and these ncRNAs have been drawing increasing attention and might play an epigenetic regulatory role in recipients, though further research is still necessary to understand their precise roles. The present review introduces basic information about milk EV ncRNAs, summarizes their expression profiles, biological characteristics, and functions based on current knowledge, and discusses their biological roles, indeterminate issues, and perspectives. Our goal is to provide a deeper understanding of the physiological effects of milk EV ncRNAs on offspring and to provide a reference for future research in this field.

PMID: 33080010 [PubMed - as supplied by publisher]

Differential immunological signature at the culprit site distinguishes acute coronary syndrome with intact from acute coronary syndrome with ruptured fibrous cap: results from the prospective translational OPTICO-ACS study.

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Differential immunological signature at the culprit site distinguishes acute coronary syndrome with intact from acute coronary syndrome with ruptured fibrous cap: results from the prospective translational OPTICO-ACS study.

Eur Heart J. 2020 Oct 20;:

Authors: Leistner DM, Kränkel N, Meteva D, Abdelwahed YS, Seppelt C, Stähli BE, Rai H, Skurk C, Lauten A, Mochmann HC, Fröhlich G, Rauch-Kröhnert U, Flores E, Riedel M, Sieronski L, Kia S, Strässler E, Haghikia A, Dirks F, Steiner JK, Mueller DN, Volk HD, Klotsche J, Joner M, Libby P, Landmesser U

Abstract
AIMS : Acute coronary syndromes with intact fibrous cap (IFC-ACS), i.e. caused by coronary plaque erosion, account for approximately one-third of ACS. However, the underlying pathophysiological mechanisms as compared with ACS caused by plaque rupture (RFC-ACS) remain largely undefined. The prospective translational OPTICO-ACS study programme investigates for the first time the microenvironment of ACS-causing culprit lesions (CL) with intact fibrous cap by molecular high-resolution intracoronary imaging and simultaneous local immunological phenotyping.
METHODS AND RESULTS : The CL of 170 consecutive ACS patients were investigated by optical coherence tomography (OCT) and simultaneous immunophenotyping by flow cytometric analysis as well as by effector molecule concentration measurements across the culprit lesion gradient (ratio local/systemic levels). Within the study cohort, IFC caused 24.6% of ACS while RFC-ACS caused 75.4% as determined and validated by two independent OCT core laboratories. The IFC-CL were characterized by lower lipid content, less calcification, a thicker overlying fibrous cap, and largely localized near a coronary bifurcation as compared with RFC-CL. The microenvironment of IFC-ACS lesions demonstrated selective enrichment in both CD4+ and CD8+ T-lymphocytes (+8.1% and +11.2%, respectively, both P < 0.05) as compared with RFC-ACS lesions. T-cell-associated extracellular circulating microvesicles (MV) were more pronounced in IFC-ACS lesions and a significantly higher amount of CD8+ T-lymphocytes was detectable in thrombi aspirated from IFC-culprit sites. Furthermore, IFC-ACS lesions showed increased levels of the T-cell effector molecules granzyme A (+22.4%), perforin (+58.8%), and granulysin (+75.4%) as compared with RFC plaques (P < 0.005). Endothelial cells subjected to culture in disturbed laminar flow conditions, i.e. to simulate coronary flow near a bifurcation, demonstrated an enhanced adhesion of CD8+T cells. Finally, both CD8+T cells and their cytotoxic effector molecules caused endothelial cell death, a key potential pathophysiological mechanism in IFC-ACS.
CONCLUSIONS : The OPTICO-ACS study emphasizes a novel mechanism in the pathogenesis of IFC-ACS, favouring participation of the adaptive immune system, particularly CD4+ and CD8+ T-cells and their effector molecules. The different immune signatures identified in this study advance the understanding of coronary plaque progression and may provide a basis for future development of personalized therapeutic approaches to ACS with IFC.
TRIAL REGISTRATION: The study was registered at clinicalTrials.gov (NCT03129503).

PMID: 33080003 [PubMed - as supplied by publisher]

Multidimensional Anisotropic Architectures on Polymeric Microparticles.

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Multidimensional Anisotropic Architectures on Polymeric Microparticles.

Small. 2020 Oct 20;:e2004691

Authors: Agusil JP, Arjona MI, Duch M, Fusté N, Plaza JA

Abstract
Next generation life science technologies will require the integration of building blocks with tunable physical and chemical architectures at the microscale. A central issue is to govern the multidimensional anisotropic space that defines these microparticle attributes. However, this control is limited to one or few dimensions due to profound fabrication tradeoffs, a problem that is exacerbated by miniaturization. Here, a vast number of anisotropic dimensions are integrated combining SU-8 photolithography with (bio)chemical modifications via soft-lithography. Microparticles in a 15-D anisotropic space are demonstrated, covering branching, faceting, fiducial, topography, size, aspect ratio, stiffness, (bio)molecular and quantum dot printing, top/bottom surface coverage, and quasi-0D, 1D, 2D, and 3D surface patterning. The strategy permits controlled miniaturization on physical dimensions below 1 µm and molecular patterns below 1 µm2 . By combining building blocks, anisotropic microparticles detect pH changes, form the basis for a DNA-assay recognition platform, and obtain an extraordinary volumetric barcoding density up to 1093 codes µm-3 in a 3 × 12 × 0.5 µm3 volume.

PMID: 33079486 [PubMed - as supplied by publisher]

Rapid capture of biomolecules from blood via stimuli-responsive elastomeric particles for acoustofluidic separation.

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Rapid capture of biomolecules from blood via stimuli-responsive elastomeric particles for acoustofluidic separation.

Analyst. 2020 Oct 20;:

Authors: Li L, Shields CW, Huang J, Zhang Y, Ohiri KA, Yellen BB, Chilkoti A, López GP

Abstract
The detection of biomarkers in blood often requires extensive and time-consuming sample preparation to remove blood cells and concentrate the biomarker(s) of interest. We demonstrate proof-of-concept for a chip-based, acoustofluidic method that enables the rapid capture and isolation of a model protein biomarker (i.e., streptavidin) from blood for off-chip quantification. Our approach makes use of two key components - namely, soluble, thermally responsive polypeptides fused to ligands for the homogeneous capture of biomarkers from whole blood and silicone microparticles functionalized with similar, tethered, thermally responsive polypeptides. When the two components are mixed together and subjected to a mild thermal trigger, the thermally responsive moieties undergo a phase transition, causing the untethered (soluble) polypeptides to co-aggregate with the particle-bound polypeptides. The mixture is then diluted with warm buffer and injected into a microfluidic channel supporting a bulk acoustic standing wave. The biomarker-bearing particles migrate to the pressure antinodes, whereas blood cells migrate to the pressure node, leading to rapid separation with efficiencies exceeding 90% in a single pass. The biomarker-bearing particles can then be analyzed via flow cytometry, with a limit of detection of 0.75 nM for streptavidin spiked in blood plasma. Finally, by cooling the solution below the solubility temperature of the polypeptides, greater than 75% of the streptavidin is released from the microparticles, offering a unique approach for downstream analysis (e.g., sequencing or structural analysis). Overall, this methodology has promise for the detection, enrichment and analysis of some biomarkers from blood and other complex biological samples.

PMID: 33079081 [PubMed - as supplied by publisher]

Mechanisms of COVID-19-induced cardiovascular disease: Is sepsis or exosome the missing link?

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Mechanisms of COVID-19-induced cardiovascular disease: Is sepsis or exosome the missing link?

J Cell Physiol. 2020 Oct 20;:

Authors: Patil M, Singh S, Henderson J, Krishnamurthy P

Abstract
Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has reached a pandemic level, spreading across the globe by affecting over 33 million people and causing over 1,009,270 deaths. SARS-CoV-2 is highly infectious with a high basic reproduction number (R0 ) of 2.2-5.7 that has led to its exponential spread. Besides, very little is known about it in terms of immunogenicity and its molecular targets. SARS-CoV-2 causes acute respiratory distress syndrome, followed by multiple organ failure and death in a small percentage of individuals. Cardiac injury has emerged as another dreaded outcome of COVID-19 complications. However, a thorough understanding of the pathogenesis of SARS-CoV-2 is lacking. In this review, we discuss the virus, possible mechanisms of COVID-19-induced cardiac injury, and potential therapeutic strategies, and we explore if exosomes could be targeted to treat symptoms of COVID-19. Furthermore, we discussed the virus-induced sepsis, which may be the cause of multiple organ failure, including myocardial injury.

PMID: 33078408 [PubMed - as supplied by publisher]

Hematopoietic stem and progenitor cell signaling in the niche.

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Hematopoietic stem and progenitor cell signaling in the niche.

Leukemia. 2020 Oct 19;:

Authors: Hurwitz SN, Jung SK, Kurre P

Abstract
Hematopoietic stem and progenitor cells (HSPCs) are responsible for lifelong maintenance of hematopoiesis through self-renewal and differentiation into mature blood cell lineages. Traditional models hold that HSPCs guard homeostatic function and adapt to regenerative demand by integrating cell-autonomous, intrinsic programs with extrinsic cues from the niche. Despite the biologic significance, little is known about the active roles HSPCs partake in reciprocally shaping the function of their microenvironment. Here, we review evidence of signals emerging from HSPCs through secreted autocrine or paracrine factors, including extracellular vesicles, and via direct contact within the niche. We also discuss the functional impact of direct cellular interactions between hematopoietic elements on niche occupancy in the context of leukemic infiltration. The aggregate data support a model whereby HSPCs are active participants in the dynamic adaptation of the stem cell niche unit during development and homeostasis, and under inflammatory stress, malignancy, or transplantation.

PMID: 33077865 [PubMed - as supplied by publisher]

Exosome-mediated metabolic reprogramming: the emerging role in tumor microenvironment remodeling and its influence on cancer progression.

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Exosome-mediated metabolic reprogramming: the emerging role in tumor microenvironment remodeling and its influence on cancer progression.

Signal Transduct Target Ther. 2020 Oct 19;5(1):242

Authors: Yang E, Wang X, Gong Z, Yu M, Wu H, Zhang D

Abstract
Metabolic reprogramming is reported to be one of the hallmarks of cancer, which is an adaptive mechanism by which fast-growing cancer cells adapt to their increasing energy demands. Recently, extracellular vesicles (EVs) known as exosomes have been recognized as crucial signaling mediators in regulating the tumor microenvironment (TME). Meanwhile, the TME is a highly heterogeneous ecosystem incorporating cancer cells, fibroblasts, adipocytes, endothelial cells, mesenchymal stem cells, and extracellular matrix. Accumulated evidence indicates that exosomes may transfer biologically functional molecules to the recipient cells, which facilitate cancer progression, angiogenesis, metastasis, drug resistance, and immunosuppression by reprogramming the metabolism of cancer cells and their surrounding stromal cells. In this review, we present the role of exosomes in the TME and the underlying mechanism of how exosomes exacerbate tumor development through metabolic reprogramming. In addition, we will also discuss the potential role of exosomes targeting metabolic process as biomarkers for tumor diagnosis and prognosis, and exosomes-mediated metabolic reprogramming as potential targets for cancer therapy. Furthermore, a better understanding of the link between exosomes and metabolic reprogramming, and their impact on cancer progression, would provide novel insights for cancer prevention and treatment in the future.

PMID: 33077737 [PubMed - in process]

Correction for Wu et al., Isolation of exosomes from whole blood by integrating acoustics and microfluidicss.

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Correction for Wu et al., Isolation of exosomes from whole blood by integrating acoustics and microfluidicss.

Proc Natl Acad Sci U S A. 2020 Oct 19;:

Authors:

PMID: 33077606 [PubMed - as supplied by publisher]

Visualization of extracellular vesicles in the regenerating caudal fin blastema of zebrafish using in vivo electroporation.

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Visualization of extracellular vesicles in the regenerating caudal fin blastema of zebrafish using in vivo electroporation.

Biochem Biophys Res Commun. 2020 Oct 17;:

Authors: Ohgo S, Sakamoto T, Nakajima W, Matsunaga S, Wada N

Abstract
Zebrafish have high regenerative ability in several organs including the fin. Although various mechanisms underlying fin regeneration have been revealed, some mechanisms remain to be elucidated. Recently, extracellular vesicles (EVs) have been the focus of research with regard to their role in cell-to-cell communication. It has been suggested that cells in regenerating tissues communicate using EVs. In this study, we examined the involvement of EVs in the caudal fin regeneration of zebrafish using an in vivo electroporation method. The process of regeneration appeared normal after in vivo electroporation, and the transferred plasmid showed mosaic expression in the blastema. We took advantage of this mosaic expression to observe the distribution of exosomal markers in the blastema. We transferred exosomal markers by in vivo electroporation and identified EVs in the regenerating caudal fin. The results suggest that blastemal cells communicate with other cells via EVs during caudal fin regeneration.

PMID: 33077180 [PubMed - as supplied by publisher]

Novel drug delivery systems targeting oxidative stress in chronic obstructive pulmonary disease: a review.

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Novel drug delivery systems targeting oxidative stress in chronic obstructive pulmonary disease: a review.

J Nanobiotechnology. 2020 Oct 19;18(1):145

Authors: Xu Y, Liu H, Song L

Abstract
Oxidative stress is significantly involved in the pathogenesis and progression of chronic obstructive pulmonary disease (COPD). Combining antioxidant drugs or nutrients results in a noteworthy therapeutic value in animal models of COPD. However, the benefits have not been reproduced in clinical applications, this may be attributed to the limited absorption, concentration, and half-life of exogenous antioxidants. Therefore, novel drug delivery systems to combat oxidative stress in COPD are needed. This review presents a brief insight into the current knowledge on the role of oxidative stress and highlights the recent trends in novel drug delivery carriers that could aid in combating oxidative stress in COPD. The introduction of nanotechnology has enabled researchers to overcome several problems and improve the pharmacokinetics and bioavailability of drugs. Large porous microparticles, and porous nanoparticle-encapsulated microparticles are the most promising carriers for achieving effective pulmonary deposition of inhaled medication and obtaining controlled drug release. However, translating drug delivery systems for administration in pulmonary clinical settings is still in its initial phases.

PMID: 33076918 [PubMed - in process]

Applications of Exosomes in Targeted Drug Delivery for the Treatment of Parkinson's Disease: A Review of Recent Advances and Clinical Challenges.

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Applications of Exosomes in Targeted Drug Delivery for the Treatment of Parkinson's Disease: A Review of Recent Advances and Clinical Challenges.

Curr Top Med Chem. 2020 Oct 19;:

Authors: Kumar B, Pandey M, Fayaz F, Izneid TA, Pottoo FH, Manchanda S, Sharma A, Sahoo PK

Abstract
Parkinson's disease (PD) is one of the most prevalent and severe neurodegenerative disease affecting more than 6.1 million people globally. It is characterized by age-related progressive deterioration of neurological functions caused by neuronal damage or neuronal death. During PD the dopamine producing-cells in the substantia nigra region of the brain degenerate, which leads to symptoms like resting tremors and rigidity. Treatment of PD is very challenging due to the blood brain barrier, which restricts the drug from reaching the brain. Conventional drug delivery systems possess limited capacity to cross the blood barrier, leading to low bioavailability and high toxicity (due to off-site drug release). Therefore, it becomes necessary to accelerate the development of novel drug delivery systems including nanoparticles, microemulsions, matrix systems, solid dispersions, liposomes, and solid lipid nanoparticles for the treatment of PD. Exosomes are biological lipid bilayer membrane vesicles produced by nearly all mammalian cells. The characteristics of vesicles are unique to their cell of origin and are primarily involved in intracellular communication. Exosomes due to their nanoscale size could easily permeate across the central nervous system, which makes them ideal for targeting the neurons in the substantia nigra. Exosomes could be efficient drug carrier systems for brain targeting, which can increase the efficacy of the drug and minimize the side effects. The review aims at providing a broad updated view of exosomes and their application in the treatment of PD.

PMID: 33076810 [PubMed - as supplied by publisher]

Targeting Vesicular LGALS3BP by an Antibody-Drug Conjugate as Novel Therapeutic Strategy for Neuroblastoma.

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Targeting Vesicular LGALS3BP by an Antibody-Drug Conjugate as Novel Therapeutic Strategy for Neuroblastoma.

Cancers (Basel). 2020 Oct 15;12(10):

Authors: Capone E, Lamolinara A, Pastorino F, Gentile R, Ponziani S, Di Vittorio G, D'Agostino D, Bibbò S, Rossi C, Piccolo E, Iacobelli V, Lattanzio R, Panella V, Sallese M, De Laurenzi V, Giansanti F, Sala A, Iezzi M, Ponzoni M, Ippoliti R, Iacobelli S, Sala G

Abstract
Neuroblastoma is the most common extra-cranial solid tumor in infants and children, which accounts for approximately 15% of all cancer-related deaths in the pediatric population. New therapeutic modalities are urgently needed. Antibody-Drug Conjugates (ADC)s-based therapy has been proposed as potential strategy to treat this pediatric malignancy. LGALS3BP is a highly glycosylated protein involved in tumor growth and progression. Studies have shown that LGALS3BP is enriched in extracellular vesicles (EV)s derived by most neuroblastoma cells, where it plays a critical role in preparing a favorable tumor microenvironment (TME) through direct cross talk between cancer and stroma cells. Here, we describe the development of a non-internalizing LGALS3BP ADC, named 1959-sss/DM3, which selectively targets LGALS3BP expressing neuroblastoma. 1959-sss/DM3 mediated potent therapeutic activity in different types of neuroblastoma models. Notably, we found that treatments were well tolerated at efficacious doses that were fully curative. These results offer preclinical proof-of-concept for an ADC targeting exosomal LGALS3BP approach for neuroblastomas.

PMID: 33076448 [PubMed]

Extracellular Vesicle Isolation Yields Increased by Low-Temperature Gaseous Plasma Treatment of Polypropylene Tubes.

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Extracellular Vesicle Isolation Yields Increased by Low-Temperature Gaseous Plasma Treatment of Polypropylene Tubes.

Polymers (Basel). 2020 Oct 15;12(10):

Authors: Resnik M, Kovač J, Štukelj R, Kralj-Iglič V, Humpolíček P, Junkar I

Abstract
Novel Extracellular Vesicles (EVs) based diagnostic techniques are promising non-invasive procedures for early stage disease detection which are gaining importance in the medical field. EVs are cell derived particles found in body liquids, especially blood, from which they are isolated for further analysis. However, techniques for their isolation are not fully standardized and require further improvement. Herein modification of polypropylene (PP) tubes by cold Atmospheric Pressure Plasma Jet (APPJ) is suggested to minimize the EVs to surface binding and thus increase EVs isolation yields. The influence of gaseous plasma treatment on surface morphology was studied by Atomic Force Microscopy (AFM), changes in surface wettability by measuring the Water Contact Angle (WCA), while surface chemical changes were analyzed by X-Ray Photoelectron Spectroscopy (XPS). Moreover, PP tubes from different manufacturers were compared. The final isolation yields of EVs were evaluated by flow cytometry. The results of this study suggest that gaseous plasma treatment is an intriguing technique to uniformly alter surface properties of PP tubes and improve EVs isolation yields up to 42%.

PMID: 33076317 [PubMed]

Aptamer-based CRISPR/Cas12a assay for the ultrasensitive detection of extracellular vesicle proteins.

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Aptamer-based CRISPR/Cas12a assay for the ultrasensitive detection of extracellular vesicle proteins.

Talanta. 2021 Jan 01;221:121670

Authors: Li H, Xing S, Xu J, He Y, Lai Y, Wang Y, Zhang G, Guo S, Deng M, Zeng M, Liu W

Abstract
Tumor-derived extracellular vesicles (TEVs) have emerged as promising sources of diagnostic and prognostic biomarkers for nasopharyngeal carcinoma (NPC). However, the lack of high-sensitivity analytic methods for ultratrace membrane proteins on TEVs hamper their clinical application of TEVs. Herein, by combining aptamers that specifically bind to protein targets on TEVs, PCR-based exponential amplification and CRISPR/Cas12a real-time DNA detection, we developed a novel technique, termed the aptamer-CRISPR/Cas12a assay, to detect CD109+ and EGFR+ TEVs from cell lines and complex biofluids. The platform enables highly sensitive detection of CD109+ and EGFR+ TEVs at as low as 100 particles/mL with a linear range spanning 6 orders of magnitude (102-108 particles/mL), which was found to be sufficient to effectively detect TEV proteins directly in low-volume (50 μl) samples. Furthermore, clinical serum sample analysis verified that the combination of serum CD109+ and EGFR+ TEV levels yielded high diagnostic accuracy, with an AUC of 0.934 (95% CI: 0.868-1.000), a sensitivity of 84.1% and a specificity of 85.0%, in discriminating NPC from healthy controls. Moreover, the dramatic decrease in both biomarkers in responders after radiotherapy indicated their potential roles in radiotherapy surveillance. Given that the aptamer-CRISPR/Cas12a assay rapidly and conveniently detects ultralow concentrations of CD109+ and EGFR+ TEVs directly in serum, it could be useful in NPC diagnosis and prognosis.

PMID: 33076176 [PubMed - in process]

Horseradish peroxidase-encapsulated DNA nanoflowers: An innovative signal-generation tag for colorimetric biosensor.

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Horseradish peroxidase-encapsulated DNA nanoflowers: An innovative signal-generation tag for colorimetric biosensor.

Talanta. 2021 Jan 01;221:121600

Authors: Zeng R, Wang J, Wang Q, Tang D, Lin Y

Abstract
Herein a versatile colorimetric biosensing platform was designed for sensitive, specific, and rapid screening of cancer-derived exosomes (HepG2 cell-derived) by introducing horseradish peroxidase -encapsulated DNA nanoflowers (HRP-DF) as the biorecognition elements and signal-generation tags. HRP was concurrently associated with the growing ultralong-chain DNA and the magnesium pyrophosphate crystals (Mg2PPi) during the rolling circle amplification (RCA), thereby ultimately leading to the direct fixation of HRP in DFs. For demonstration, a linear DNA circular molecule encoding the complementary sequence of CD63 aptamer (a nucleic acid sequence that can highly bind to exosomes) was used as a starting amplification template to obtain HRP-DF with the high biorecognition ability of exosomes. Upon addition of target exosomes, a sandwiched reaction was carried out between the cholesterol-modified DNA probes-conjugated magnetic bead (MB) and the HRP-DFs, accompanying formation of ternary complexes (MB-exosomes-HRP-DF). After simple magnetic separation, the HRP carried on the ternary complexes (MB-exosomes-HRP-DF) initiated oxidation of 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS, nearly colorless) into green-colored oxidized ABTS in the presence of hydrogen peroxide (H2O2). The obvious color change (from nearly colorless to dark green) of ABTS-H2O2 system can be easily observed with the naked eye and accurately monitored by UV-visible spectrometry, which was also proportional to the concentration of exosomes. Impressively, HRP-DF-based biosensing platform exhibited satisfactory colorimetric responses toward target exosomes within the working range from 5.0 × 103 to 5.0 × 106 particles/μL at a low detection limit of 3.32 × 103 particles/μL. Combined with a one-step sandwich reaction, magnetic separation and HRP-DF-based color-changing, this system had the advantages of acceptable accuracy, strong anti-interference ability and good reproducibility.

PMID: 33076131 [PubMed - in process]

Rapid isolation and proteome analysis of urinary exosome based on double interactions of Fe3O4@TiO2-DNA aptamer.

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Rapid isolation and proteome analysis of urinary exosome based on double interactions of Fe3O4@TiO2-DNA aptamer.

Talanta. 2021 Jan 01;221:121571

Authors: Zhang N, Sun N, Deng C

Abstract
There are accumulating evidence that proteins carried by exosomes in urine are most possibly used as biomarkers or therapeutic carriers for certain diseases. The isolation of exosomes is therefore highly desirable for aiding the downstream protein analysis. Particularly, urine is a dynamic biological fluid changing within a short time, resulting in that the separation of urinary exosome requires more efficient technology. Here, a new biocompatible material (denoted as Fe3O4@TiO2-CD63 aptamer) is designed and synthesized for rapid exosome isolation from human urine, depending on the double interactions of TiO2 with phosphate groups as well as aptamers with specific exosome proteins. Moreover, within 10 min, 92.6% exosomes with intact structure are captured from urine by Fe3O4@TiO2-CD63 aptamers, from which 999 proteins are detected through LC-MS/MS.

PMID: 33076118 [PubMed - in process]

Exploring carbon particle type and plasma treatment to improve electrochemical properties of stencil-printed carbon electrodes.

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Exploring carbon particle type and plasma treatment to improve electrochemical properties of stencil-printed carbon electrodes.

Talanta. 2021 Jan 01;221:121553

Authors: Kava AA, Henry CS

Abstract
Stencil-printing conductive carbon inks has revolutionized the development of inexpensive, disposable and portable electrochemical sensors. However, stencil-printed carbon electrodes (SPCEs) typically suffer from poor electrochemical properties. While many surface pretreatments and modifications have been tested to improve the electrochemical activity of SPCEs, the bulk composition of the inks used for printing has been largely ignored. Recent studies of other carbon composite electrode materials show significant evidence that the conductive carbon particle component is strongly related to electrochemical performance. However, such a study has not been carried out with SPCEs. In this work, we perform a systematic characterization of SPCEs made with different carbon particle types including graphite particles, glassy carbon microparticles and carbon black. The relationship between carbon particle characteristics including particle size, particle purity, and particle morphology as well as particle mass loading on the fabrication and electrochemical properties of SPCEs is studied. SPCEs were plasma treated for surface activation and the electrochemical properties of both untreated and plasma treated SPCEs are also compared. SPCEs displayed distinct analytical utilities characterized through solvent window and double layer capacitance. Cyclic voltammetry (CV) of several standard redox probes, FcTMA+, ferri/ferrocyanide, and pAP was used to establish the effects of carbon particle type and plasma treatment on electron transfer kinetics of SPCEs. CV of the biologically relevant molecules uric acid, NADH and dopamine was employed to further illustrate the differences in sensing and fouling characteristics of SPCEs fabricated with different carbon particle types. SEM imaging revealed significant differences in the SPCE surface microstructures. This systematic study demonstrates that the electrochemical properties of SPCEs can be tuned and significantly improved through careful selection of carbon particle type and plasma cleaning with a goal toward the development of better performing electrochemical point-of-need sensors.

PMID: 33076109 [PubMed - in process]

Analysis of microplastics in consumer products by single particle-inductively coupled plasma mass spectrometry using the carbon-13 isotope.

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Analysis of microplastics in consumer products by single particle-inductively coupled plasma mass spectrometry using the carbon-13 isotope.

Talanta. 2021 Jan 01;221:121486

Authors: Laborda F, Trujillo C, Lobinski R

Abstract
Single particle inductively coupled plasma mass spectrometry (SP-ICP-MS) has become a well-established technique for the detection, size characterization and quantification of inorganic nanoparticles but its use for the analysis of micro- and nanoparticles composed of carbon has been scarce. Here, the analysis of a microplastic suspensions by ICP-MS operated in single particle mode using microsecond dwell times is comprehensively discussed. The detection of polystyrene microparticles down to 1.2 μm was achieved by monitoring the 13C isotope. Plastic microparticles of up to 5 μm were completely volatized and their components atomized, which allowed the detection of microplastics, their quantification using aqueous dissolved carbon standards, and the measurement of the size-distribution of the detected particles. Limits of detection of 100 particles per milliliter were achieved for an acquisition time of 5 min. The method developed was applied to the screening of microplastics in personal care products and released from food packagings. The chemical identity of the detected microplastics was confirmed by attenuated total reflectance Fourier-transform infrared spectroscopy.

PMID: 33076096 [PubMed - in process]

Ultrasensitive electrochemiluminescence biosensor for the detection of tumor exosomes based on peptide recognition and luminol-AuNPs@g-C3N4 nanoprobe signal amplification.

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Ultrasensitive electrochemiluminescence biosensor for the detection of tumor exosomes based on peptide recognition and luminol-AuNPs@g-C3N4 nanoprobe signal amplification.

Talanta. 2021 Jan 01;221:121379

Authors: Liu X, Wang Q, Chen J, Chen X, Yang W

Abstract
Highly sensitive determination of tumor exosomes is significant for early diagnosis of cancers and precision therapy. Herein, a sandwich peptide-based electrochemiluminescence (ECL) biosensor was developed for determination of phosphatidylserine (PS)-positive exosomes, a promising biomarker for early diagnosis of ovarian malignancy. A PS-specific binding peptide with high affinity was immobilized on Au nanoflowers (AuNFs) modified biosensing interface for recognition and capture of exosomes. Meanwhile, g-C3N4 nanosheet loaded with luminol capped AuNPs (Lum-AuNPs@g-C3N4) nanocomposite was used as the ECL signal nanoprobe. The g-C3N4 nanosheets with large surface area were not only utilized as the carrier to immobilize more peptides for recognition of exosomes but also used to catalyze co-reactant H2O2 decomposition to achieve the ECL signal amplification of luminol-H2O2 system. Under optimal conditions, the biosensor showed superior performances compared with most currently available methods, including wider linear range across 5 orders of magnitude and a lower detection limit (LOD) down to 39 particles μL-1. Moreover, the biosensor could be applicable for determination of exosomes in complex biological samples. This study indicates the combination of peptide recognition with nanoprobe as a label for signal amplification in sandwich ECL biosensing is a great promising strategy for sensitive and cost-effective determination of exosomes.

PMID: 33076050 [PubMed - in process]

DEFA1B inhibits ZIKV replication and retards cell cycle progression through interaction with ORC1.

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DEFA1B inhibits ZIKV replication and retards cell cycle progression through interaction with ORC1.

Life Sci. 2020 Oct 16;:118564

Authors: Li S, Zhu A, Ren K, Li S, Chen L

Abstract
AIMS: Zika virus (ZIKV) infection causes a public health concern because of its potential association with the development of microcephaly. During viral infections, the host innate immune response is mounted quickly to produce some endogenous functional molecules to limit virus replication and spread. Exosomes contain molecules from their cell of origin following virus infection and can enter recipient cells for intercellular communication. Here, we aim to clarify whether ZIKV-induced exosomes can regulate viral pathogenicity by transferring specific RNAs.
MAIN METHODS: In this study, exosomes were isolated from the supernatants of A549 cells with or without ZIKV infection. Human transcriptome array (HTA) was performed to analyze the profiling of RNAs wrapped in exosomes. Then qPCR, western blotting and ELISA were used to determine ZIKV replication. CCK-8 and flow cytometry were used to test the cell proliferation and cell cycles. Co-culture assay was used to analyze the effect of exosomes on the cell cycles of recipient cells.
KEY FINDINGS: Through human transcriptome array (HTA) we found the defensin alpha 1B (DEFA1B) expression was significantly increased within exosomes isolated from ZIKV infected A549 cells. Additionally, we found that the extracellular DEFA1B exerts significant anti-ZIKV activity, mainly before ZIKV entering host cells. Interestingly, up-regulated DEFA1B retards the cell cycle of host cells. Further studies demonstrated that DEFA1B interacted with the origin recognition complex 1 (ORC1) which is required to initiate DNA replication during the cell cycle and increased DEFA1B expression decreased the ORC1 level in the cell nuclei. Accordingly, DEFA1B-containing exosomes can be internalized by the recipient cells to retard their cell cycles.
SIGNIFICANCE: Together, our results demonstrated that the anti-ZIKV activity of DEFA1B can be mediated by exosomes, and DEFA1B interacts with ORC1 to retard cell cycles. Our study provides a novel concept that DEFA1B not only acts as an antiviral molecule during ZIKV infection but also may correlate with cell proliferation by retarding the progression of cell cycles.

PMID: 33075374 [PubMed - as supplied by publisher]

A novel approach to correlate the salivary exosomes and their protein cargo in the progression of cognitive impairment into Alzheimer's disease.

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A novel approach to correlate the salivary exosomes and their protein cargo in the progression of cognitive impairment into Alzheimer's disease.

J Neurosci Methods. 2020 Oct 16;:108980

Authors: Rani K, Rastogi S, Vishwakarma P, Bharti PS, Sharma V, Renu K, Modi GP, Vishnu VY, Chatterjee P, Dey AB, Nikolajeff F, Kumar S

Abstract
BACKGROUND: Cognition is the ability of a person to think, remember, and interconnect ideas from various dimensions to strive for solutions. Cognitive defects accompany all forms of dementia and the decline in cognition is a most feared aspect. Mild cognitive impairment is considered as a transitional phase and the progressive loss in cognition can finally lead to Alzheimer's disease.
NEW METHOD: In this study, we demonstrated a novel method based on nanoparticle tracking analysis (NTA) technique to directly correlate salivary exosomes concentration with the progression of cognitive impairment (CI) in Alzheimer's disease (AD).This could open up the possibility for an early and cost-effective screening of Alzheimer's disease.
RESULTS: Using our novel method, the total salivary exosomes concentration was measured by NTA technique, followed by validation of key exosomal cargo proteins through an automated western blot analyzer. We observed significant differences in salivary exosomes concentration among the groups of cognitively impaired and Alzheimer's disease patients (p = 0.0023) compared to the healthy control cohort. The method was validated through CD63 (exosomes surface marker) fluorescent antibody based quantification, which yielded a similar outcome (p = 0.0286). We further corroborated our findings with the expression level of oligomeric amyloid-beta, phosphorylated-tau protein from salivary exosomes. The Aβ oligomer/fibril abundance (p = 0.0291), phospho-tau (p = 0.0325) and Aβ protein abundance (p = 0.0198) was significantly higher in Alzheimer's and cognitively impaired patients in comparison to the healthy controls.
COMPARISON WITH EXISTING METHOD(S): There are few molecular biomarkers available to differentiate between various stages of cognitive impairment. Moreover, the current methodologies utilizing the few biomarkers available are either invasive or expensive; also, for a patient with mild cognitive complains, it is impractical to use these as a screening tool.
CONCLUSION: Our initial results indicate that the salivary exosomes concentration based on the nano-tracking technique has the potential to be used as a cost-effective screening method for early disease detection.

PMID: 33075328 [PubMed - as supplied by publisher]

M2 macrophage-derived exosomal-miR-590-3p attenuates DSS-induced mucosal damage and promotes epithelial repair via the LATS1/YAP/β-catenin signalling axis.

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M2 macrophage-derived exosomal-miR-590-3p attenuates DSS-induced mucosal damage and promotes epithelial repair via the LATS1/YAP/β-catenin signalling axis.

J Crohns Colitis. 2020 Oct 19;:

Authors: Deng F, Yan J, Lu J, Luo M, Xia P, Liu S, Wang X, Zhi F, Liu D

Abstract
BACKGROUND AND AIMS: M2 phenotype macrophages are involved in the resolution of inflammation and intestinal repair. Exosomes are emerging as important mediators of intercellular communication in the mucosal microenvironment.
METHODS: M2 macrophages were transfected with or without miR-590-3p. Exosomes derived from M2 macrophages were isolated and identified. Proliferation and wound healing were tested in vitro and compared between groups. The mechanism involving LATS1, and activation of YAP and β-catenin signalling was investigated by using plasmid transfection, western blotting, immunofluorescence, and luciferase reporter assays. The effect of exosomes in vivo was detected in DSS-induced murine colitis.
RESULTS: First, we demonstrated that M2 macrophages promoted colonic epithelial cell proliferation in an exosome-dependent manner. Epithelial YAP mediated the effect of M2 macrophage-derived exosomes (M2-exos) in epithelial proliferation. Moreover, miR-590-3p, which was significantly enriched in M2-exos, could be transferred from macrophages into epithelial cells, resulting in the enhanced proliferation and wound healing of epithelial cells. Mechanistically, miR-590-3p suppressed the expression of LATS1 by binding to its coding sequence and subsequently activated the YAP/β-catenin-modulated transcription process to improve epithelial cell wound-healing ability. MiR-590-3p also inhibited the induction of pro-inflammatory cytokines including TNF-α, IL-1β, and IL-6. More importantly, repression miR-590-3p in M2-exos resulted with severer mucosal damage and impaired colon repair of mice compared with those in M2-exo-treated mice after DSS-induced colitis.
CONCLUSION: M2 macrophage-derived exosomal miR-590-3p reduces inflammatory signals and promotes epithelial regeneration by targeting LATS1 and subsequently activating YAP/β-catenin-regulated transcription, which could offer a new opportunity for clinical therapy for ulcerative colitis (UC).

PMID: 33075119 [PubMed - as supplied by publisher]

A non-enveloped arbovirus released in lysosome-derived extracellular vesicles induces super-infection exclusion.

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A non-enveloped arbovirus released in lysosome-derived extracellular vesicles induces super-infection exclusion.

PLoS Pathog. 2020 Oct 19;16(10):e1009015

Authors: Labadie T, Roy P

Abstract
Recent developments on extracellular vesicles (EVs) containing multiple virus particles challenge the rigid definition of non-enveloped viruses. However, how non-enveloped viruses hijack cell machinery to promote non-lytic release in EVs, and their functional roles, remain to be clarified. Here we used Bluetongue virus (BTV) as a model of a non-enveloped arthropod-borne virus and discovered that the majority of viruses are released in EVs. Based on the cellular proteins detected in these EVs, and use of inhibitors targeting the cellular degradation process, we demonstrated that these extracellular vesicles are derived from secretory lysosomes, in which the acidic pH is neutralized upon the infection. Moreover, we report that secreted EVs are more efficient than free-viruses for initiating infections, but that they trigger super-infection exclusion that only free-viruses can overcome.

PMID: 33075107 [PubMed - as supplied by publisher]

Glass Fiber-Supported Hybrid Monolithic Spin Tip for Enrichment of Phosphopeptides from Urinary Extracellular Vesicles.

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Glass Fiber-Supported Hybrid Monolithic Spin Tip for Enrichment of Phosphopeptides from Urinary Extracellular Vesicles.

Anal Chem. 2020 Oct 19;:

Authors: Zhang H, Deng Y, Liu X, Sun J, Ma L, Ding Y, Zhan Z, Zhang H, Yang Y, Gu Y, Iliuk AB, Yang C, Tao WA

Abstract
Extracellular vesicles (EVs) are attracting increasing interest with their intriguing role in intercellular communications. Protein phosphorylation in EVs is of great importance for understanding intercellular signaling processes. However, the study of EV phosphoproteomics is impeded by their relatively low amount in limited clinical sample volumes, and it is necessary to have a sensitive and efficient enrichment method for EV phosphopeptides. Herein, a novel Ti(IV)-functionalized and glass fiber-supported hybrid monolithic spin tip, termed PhosTip, was prepared for enriching phosphopeptides from urinary EVs. Glass fiber as the stationary phase positions the hybrid monolith in a standard pipet tip and prevents the monolith from distortion during experiments. The preparation procedure for the new PhosTip is simple and time-saving. The hybrid monolithic PhosTip provides excellent enrichment efficiency of low-abundance phosphopeptides from cell digests and urinary EVs with minimum contamination and sample loss. Using the PhosTip, we demonstrate that 5373 and 336 unique phosphopeptides were identified from 100 and 1 μg of cell lysates, while 3919 and 217 unique phosphopeptides were successfully identified from 10 and 1 mL of urinary samples, respectively. The PhosTip was finally applied to enrich phosphopeptides in urine EVs from prostate cancer patients and healthy controls and quantify 118 up-regulated proteins with phosphosites in prostate cancer samples. These results demonstrated that the PhosTip could be a simple and convenient tool for enriching phosphopeptides from clinical samples and for broader applications in biomarker discovery.

PMID: 33074658 [PubMed - as supplied by publisher]

Characterization of stanniocalcin-1 expression in macrophage differentiation.

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Characterization of stanniocalcin-1 expression in macrophage differentiation.

Transl Oncol. 2020 Oct 15;14(1):100881

Authors: Leung CCT, Wong CKC

Abstract
Human stanniocalcin-1 (STC1) is a paracrine factor associated with inflammation and carcinogenesis. The role of STC1 in the pro- and anti-inflammatory functions of differentiating macrophage, however, is not clear. In this study, our data showed that phorbol 12-myristate 13-acetate (PMA) treatment induced human leukemia monocytic cells (ThP-1) differentiation to M0 macrophages. The differentiation was accompanied by a significant increase in the mRNA expression levels of STC1, the pro-inflammatory cytokine TNFα, and anti-inflammatory markers, CD163 & CD206. An intermitted removal of PMA treatment reduced the mRNA levels of STC1 and TNFα but had no noticeable effects on the anti-inflammatory markers. The correlation in the expression of STC1 and pro-inflammatory markers in differentiating macrophages was investigated, using siRNASTC1-transfected PMA-induced cells. Consistently, the transcripts levels of TNFα and IL-6 were significantly reduced. Moreover, LPS/IFNγ-induced M1-polarization showed remarkably higher expression levels of STC1 than IL-4/IL-13-induced M2-macrophages and PMA-induced M0-macrophages. Transcriptomic analysis of siRNASTC1-transfected M1-polarized cells revealed an upregulation of TBC1 domain family member 3 (TBC1D3G). The gene regulates the payload of macrophage-released extracellular vesicles to mediate inflammation. The conditioned media from siRNASTC1-transfected M1-polarized cells were found to reduce Hep3B cell motility. The data suggest that the expression of STC1 were associated with macrophage differentiation, but preferentially to M1 polarization.

PMID: 33074126 [PubMed - as supplied by publisher]

Extracellular Vesicles of GMSCs Alleviate Aging-Related Cell Senescence.

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Extracellular Vesicles of GMSCs Alleviate Aging-Related Cell Senescence.

J Dent Res. 2020 Oct 17;:22034520962463

Authors: Shi HZ, Zeng JC, Shi SH, Giannakopoulos H, Zhang QZ, Le AD

Abstract
Healthy aging is a complex biological process with progressive accumulation of senescent cells characterized by stable cell cycle arrest, resulting in impaired homeostasis, regenerative potential, and gradual functional decline in multiple tissues and organs, whereby the aberrant activation of mammalian target of rapamycin (mTOR) signaling networks plays a central role. Herein, we explored the effects of extracellular vesicles (EVs) released by gingiva-derived mesenchymal stem cells (GMSC-EVs) on oxidative stress-induced cellular senescence in human endothelial cells and skin fibroblasts and their antiaging potentials. Our results showed that GMSC-EVs robustly abrogated oxidative stress-induced upregulation in the expression of cellular senescence-related genes, such as β-galactosidase, p21, p53, and γH2AX, and mTOR/pS6 signaling pathway, in human umbilical vein endothelial cells (HUVECs) and skin fibroblasts. Meanwhile, GMSC-EVs restored oxidative stress-induced impairment in proliferation and tube formation by HUVECs. Systemic administration of GMSC-EVs attenuated aging-associated elevation in the expression levels of p21, mTOR/pS6, interleukin 6, and tumor necrosis factor α in skin and heart tissues of aged mice. These findings suggest that GMSC-EVs could be a potential alternative source of cell-free product for attenuation of aging-related skin and vascular dysfunctions due to their potent inhibitory effects on oxidative stress-induced cellular senescence in endothelial cells and skin fibroblasts.

PMID: 33073684 [PubMed - as supplied by publisher]

Liquid biopsy and their application progress in head and neck cancer: focus on biomarkers CTCs, cfDNA, ctDNA and EVs.

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Liquid biopsy and their application progress in head and neck cancer: focus on biomarkers CTCs, cfDNA, ctDNA and EVs.

Biomark Med. 2020 Oct 19;:

Authors: Meng Y, Bian L, Zhang M, Bo F, Lu X, Li D

Abstract
Head and neck cancer (HNC) is the sixth leading cause of cancer death worldwide. Due to the low early diagnosis rate of HNC, local recurrence and high distant metastasis rate are the main reasons for treatment failure. Therefore, it is important to establish a method of diagnosis and monitoring, which is convenient, safe, reproducible, sensitive and specific. Compared with tissue biopsy, liquid biopsy is an emerging biopsy technique, which has the advantages of re-sampling, noninvasive, cost-effective and has shown good diagnostic and prognostic value in studies for various types of malignant solid tumors. This review introduces liquid biopsy, its research progress and prospects in HNC including early diagnosis, staging, grading, prognosis assessment and disease surveillance.

PMID: 33073579 [PubMed - as supplied by publisher]

Combination Treatment with Human Adipose Tissue Stem Cell-derived Exosomes and Fractional CO2 Laser for Acne Scars: A 12-week Prospective, Double-blind, Randomized, Split-face Study.

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Combination Treatment with Human Adipose Tissue Stem Cell-derived Exosomes and Fractional CO2 Laser for Acne Scars: A 12-week Prospective, Double-blind, Randomized, Split-face Study.

Acta Derm Venereol. 2020 Oct 19;:

Authors: Kwon HH, Yang SH, Lee J, Park BC, Park KY, Jung JY, Bae Y, Park GH

Abstract
A variety of applications of human adipose tissue stem cell-derived exosomes have been suggested as novel cell-free therapeutic strategies in the regenerative and aesthetic medical fields. This study evaluated the clinical efficacy and safety of adipose tissue stem cell-derived exosomes as an adjuvant therapy after application of fractional CO2 laser for acne scars. A 12-week prospective, double-blind, randomized, split-face trial was performed. A total of 25 patients received 3 consecutive treatment sessions of fractional CO2 laser to the whole face, with a follow-up evaluation. Post-laser treatment regimens were applied; for each patient, one side of the face was treated with adipose tissue stem cell-derived exosomes gel and the other side was treated with control gel. Adipose tissue stem cell-derived exosomes-treated sides had achieved a significantly greater improvement than the control sides at the final follow-up visit (percentage reduction in échelle d'évaluation clinique des cicatrices d'acné (ECCA) scores: 32.5 vs 19.9%, p < 0.01). Treatment-related erythema was milder, and post-treatment downtime was shorter on the applications of human adipose tissue stem cell-derived exosomes-treated side.

PMID: 33073298 [PubMed - as supplied by publisher]

Roles of Macrophages and Exosomes in Liver Diseases.

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Roles of Macrophages and Exosomes in Liver Diseases.

Front Med (Lausanne). 2020;7:583691

Authors: Shen M, Shen Y, Fan X, Men R, Ye T, Yang L

Abstract
Exosomes are small discoid extracellular vesicles (EVs) originating from endosomes that are 30-150 nm in diameter and have a double lipid layer. They participate in the immune response, cell migration, cell differentiation, and tumor invasion and mediate intercellular communication, regulating the biological activity of receptor cells through the proteins, nucleic acids, and lipids that they carry. Exosomes also play vital roles in the diagnosis and treatment of liver diseases. Macrophages, which show unique phenotypes and functions in complex microenvironments, can be divided into M1 and M2 subtypes. M1 macrophages function in immune surveillance, and M2 macrophages downregulate the immune response. Recent studies have shown that macrophages are involved in non-alcoholic fatty liver disease, liver fibrosis, and hepatocellular carcinoma. Moreover, several studies have demonstrated that liver diseases are associated with exosomes derived from or transferred to macrophages. This review focuses on the participation of macrophages and exosomes in liver diseases.

PMID: 33072790 [PubMed]

Secreted MicroRNA to Predict Embryo Implantation Outcome: From Research to Clinical Diagnostic Application.

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Secreted MicroRNA to Predict Embryo Implantation Outcome: From Research to Clinical Diagnostic Application.

Front Cell Dev Biol. 2020;8:586510

Authors: Zhou W, Dimitriadis E

Abstract
Embryo implantation failure is considered a leading cause of infertility and a significant bottleneck for in vitro fertilization (IVF) treatment. Confirmed factors that lead to implantation failure involve unhealthy embryos, unreceptive endometrium, and asynchronous development and communication between the two. The quality of embryos is further dependent on sperm parameters, oocyte quality, and early embryo development after fertilization. The extensive involvement of such different factors contributes to the variability of implantation potential across different menstrual cycles. An ideal approach to predict the implantation outcome should not compromise embryo implantation. The use of clinical material, including follicular fluid, cumulus cells, sperm, seminal exosomes, spent blastocyst culture medium, blood, and uterine fluid, that can be collected relatively non-invasively without compromising embryo implantation in a transfer cycle opens new perspectives for the diagnosis of embryo implantation potential. Compositional comparison of these samples between fertile women and women or couples with implantation failure has identified both quantitative and qualitative differences in the expression of microRNAs (miRs) that hold diagnostic potential for implantation failure. Here, we review current findings of secreted miRs that have been identified to potentially be useful in predicting implantation outcome using material that can be collected relatively non-invasively. Developing non-invasive biomarkers of implantation potential would have a major impact on implantation failure and infertility.

PMID: 33072767 [PubMed]

Circulating Mitochondrial-Derived Vesicles, Inflammatory Biomarkers and Amino Acids in Older Adults With Physical Frailty and Sarcopenia: A Preliminary BIOSPHERE Multi-Marker Study Using Sequential and Orthogonalized Covariance Selection - Linear Discriminant Analysis.

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Circulating Mitochondrial-Derived Vesicles, Inflammatory Biomarkers and Amino Acids in Older Adults With Physical Frailty and Sarcopenia: A Preliminary BIOSPHERE Multi-Marker Study Using Sequential and Orthogonalized Covariance Selection - Linear Discriminant Analysis.

Front Cell Dev Biol. 2020;8:564417

Authors: Marzetti E, Guerra F, Calvani R, Marini F, Biancolillo A, Gervasoni J, Primiano A, Coelho-Júnior HJ, Landi F, Bernabei R, Bucci C, Picca A

Abstract
Physical frailty and sarcopenia (PF&S) is a prototypical geriatric condition characterized by reduced physical function and low muscle mass. The multifaceted pathophysiology of this condition recapitulates all hallmarks of aging making the identification of specific biomarkers challenging. In the present study, we explored the relationship among three processes that are thought to be involved in PF&S (i.e., systemic inflammation, amino acid dysmetabolism, and mitochondrial dysfunction). We took advantage of the well-characterized cohort of older adults recruited in the "BIOmarkers associated with Sarcopenia and Physical frailty in EldeRly pErsons" (BIOSPHERE) study to preliminarily combine in a multi-platform analytical approach inflammatory biomolecules, amino acids and derivatives, and mitochondrial-derived vesicle (MDV) cargo molecules to evaluate their performance as possible biomarkers for PF&S. Eleven older adults aged 70 years and older with PF&S and 10 non-sarcopenic non-frail controls were included in the analysis based on the availability of the three categories of biomolecules. A sequential and orthogonalized covariance selection-linear discriminant analysis (SO-CovSel-LDA) approach was used for biomarkers selection. Of the 75 analytes assayed, 16 had concentrations below the detection limit. Within the remaining 59 biomolecules, So-CovSel-LDA selected a set comprising two amino acids (phosphoethanolamine and tryptophan), two cytokines (interleukin 1 receptor antagonist and macrophage inflammatory protein 1β), and MDV-derived nicotinamide adenine dinucleotide reduced form:ubiquinone oxidoreductase subunit S3 as the best predictors for discriminating older people with and without PF&S. The evaluation of these biomarkers in larger cohorts and their changes over time or in response to interventions may unveil specific pathogenetic pathways of PF&S and identify new biological targets for drug development.

PMID: 33072749 [PubMed]

Peptidylarginine Deiminase Inhibition Abolishes the Production of Large Extracellular Vesicles From Giardia intestinalis, Affecting Host-Pathogen Interactions by Hindering Adhesion to Host Cells.

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Peptidylarginine Deiminase Inhibition Abolishes the Production of Large Extracellular Vesicles From Giardia intestinalis, Affecting Host-Pathogen Interactions by Hindering Adhesion to Host Cells.

Front Cell Infect Microbiol. 2020;10:417

Authors: Gavinho B, Sabatke B, Feijoli V, Rossi IV, da Silva JM, Evans-Osses I, Palmisano G, Lange S, Ramirez MI

Abstract
Giardia intestinalis is a microaerophilic protozoan that is an important etiologic agent of diarrhea worldwide. There is evidence that under diverse conditions, the parasite is capable of shedding extracellular vesicles (EVs) which modulate the physiopathology of giardiasis. Here we describe new features of G. intestinalis EV production, revealing its capacity to shed two different enriched EV populations: large (LEV) and small extracellular vesicles (SEV) and identified relevant adhesion functions associated with the larger population. Proteomic analysis revealed differences in proteins relevant for virulence and host-pathogen interactions between the two EV subsets, such as cytoskeletal and anti-oxidative stress response proteins in LEVS. We assessed the effect of two recently identified inhibitors of EV release in mammalian cells, namely peptidylarginine deiminase (PAD) inhibitor and cannabidiol (CBD), on EV release from Giardia. The compounds were both able to effectively reduce EV shedding, the PAD-inhibitor specifically affecting the release of LEVs and reducing parasite attachment to host cells in vitro. Our results suggest that LEVs and SEVs have a different role in host-pathogen interaction, and that treatment with EV-inhibitors may be a novel treatment strategy for recurrent giardiasis.

PMID: 33072615 [PubMed - in process]

Exosome-Derived LncRNAs in Lung Cancer.

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Exosome-Derived LncRNAs in Lung Cancer.

Front Oncol. 2020;10:1728

Authors: Fan T, Sun N, He J

Abstract
As extracellular vesicles, exosomes are released from most cells to perform cell-cell communication. Recent studies have shown that exosomes could be released into tumor microenvironment and blood to promote tumor progression through packaging and transmitting various bioactive molecules, such as cholesterol, proteins, lipids, miRNAs, mRNAs, and long non-coding RNAs (lncRNAs) to distant cells. LncRNAs have emerged as a major class of non-coding transcripts. A lot of LncRNAs have been discovered during the past few years of research on genomics. They have been proven to participate in various biological functions and disease processes through multiple mechanisms. In this review, we analyzed the role of exosome-derived lncRNAs in lung carcinogenesis and metastasis. We also highlight opportunities for the clinical potential of exosomes with specific lncRNAs as biomarkers and therapeutic intervention in lung cancer.

PMID: 33072553 [PubMed]

Regenerative Medicine and Angiogenesis; Challenges and Opportunities.

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Regenerative Medicine and Angiogenesis; Challenges and Opportunities.

Adv Pharm Bull. 2020 Sep;10(4):490-501

Authors: Jahani M, Rezazadeh D, Mohammadi P, Abdolmaleki A, Norooznezhad A, Mansouri K

Abstract
Blood vessel development is one of the most prominent steps in regenerative medicine due to the restoration of blood flow to the ischemic tissues and providing the rapid vascularization in clinical-sized tissue-engineered grafts. However, currently tissue engineering technique is restricted because of the inadequate in vitro/in vivo tissue vascularization. Some challenges like as transportation in large scale, distribution of the nutrients and poor oxygen diffusion limit the progression of vessels in smaller than clinically relevant dimensions as well in vivo integration. In this regard, the scholars attempted to promote the vascularization process relied on the stem cells (SCs), growth factors as well as exosomes and interactions of biomaterials with all of them to enable the emergence of ideal microenvironment which is needed for treatment of unhealthy organs or tissue regeneration and formation of new blood vessels. Thus, in the present review we aim to describe these approaches, advances, obstacles and opportunities as well as their application in regeneration of heart as a prominent angiogenesis-dependent organ.

PMID: 33072530 [PubMed]

Role of Extracellular Vesicles in Autoimmune Pathogenesis.

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Role of Extracellular Vesicles in Autoimmune Pathogenesis.

Front Immunol. 2020;11:579043

Authors: Wu WC, Song SJ, Zhang Y, Li X

Abstract
Autoimmune diseases are conditions that emerge from abnormal immune responses to natural parts of the body. Extracellular vesicles (EVs) are membranous structures found in almost all types of cells. Because EVs often transport "cargo" between cells, their ability to crosstalk may be an important communication pathway within the body. The pathophysiological role of EVs is increasingly recognized in autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome, Type 1 diabetes, and autoimmune thyroid disease. EVs are considered as biomarkers of these diseases. This article outlines existing knowledge on the biogenesis of EVs, their role as messegers in cellular communication and the function in T/B cell differentiation and maturation, and focusing on their potential application in autoimmune diseases.

PMID: 33072123 [PubMed - in process]

The Cell Biology of Tau Secretion.

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The Cell Biology of Tau Secretion.

Front Mol Neurosci. 2020;13:569818

Authors: Merezhko M, Uronen RL, Huttunen HJ

Abstract
The progressive accumulation and spread of misfolded tau protein in the nervous system is the hallmark of tauopathies, progressive neurodegenerative diseases with only symptomatic treatments available. A growing body of evidence suggests that spreading of tau pathology can occur via cell-to-cell transfer involving secretion and internalization of pathological forms of tau protein followed by templated misfolding of normal tau in recipient cells. Several studies have addressed the cell biological mechanisms of tau secretion. It now appears that instead of a single mechanism, cells can secrete tau via three coexisting pathways: (1) translocation through the plasma membrane; (2) membranous organelles-based secretion; and (3) ectosomal shedding. The relative importance of these pathways in the secretion of normal and pathological tau is still elusive, though. Moreover, glial cells contribute to tau propagation, and the involvement of different cell types, as well as different secretion pathways, complicates the understanding of prion-like propagation of tauopathy. One of the important regulators of tau secretion in neuronal activity, but its mechanistic connection to tau secretion remains unclear and may involve all three secretion pathways of tau. This review article summarizes recent advancements in the field of tau secretion with an emphasis on cell biological aspects of the secretion process and discusses the role of neuronal activity and glial cells in the spread of pathological forms of tau.

PMID: 33071756 [PubMed]

Evaluation and implementation of commercial antibodies for improved nanoparticle-based immunomagnetic separation and real-time PCR for faster detection of Listeria monocytogenes.

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Evaluation and implementation of commercial antibodies for improved nanoparticle-based immunomagnetic separation and real-time PCR for faster detection of Listeria monocytogenes.

J Food Sci Technol. 2020 Nov;57(11):4143-4151

Authors: Garrido-Maestu A, Azinheiro S, Carvalho J, Espiña B, Prado M

Abstract
L. monocytogenes continues to be a major health issue in Europe, as well as worldwide. Faster methods, not only for detection, but also for sample preparation are of great interest particularly for this slow-growing pathogen. Immunomagnetic separation has been previously reported to be an effective way to concentrate bacteria, and remove inhibitors. In the present study, different commercial antibodies were evaluated to select the most appropriate one, in order to develop a highly specific method. Additionally, magnetic nanoparticles, instead of microparticles, were selected due to their reported advantages (higher surface-volume ration and faster kinetics). Finally, the separation protocol, with a calculated capture efficiency of 95%, was combined with real-time PCR for highly sensitive detection of the concentrated bacteria. The optimized IMS-qPCR allowed to reduce hands-on time in the sample treatment, without affecting the overall performance of the method as a very low limit of detection was still obtained (9.7 CFU/ 25 g) with values for sensitivity, specificity, accuracy, positive and negative predictive values of 100%, resulting in a kappa index of concordance of 1.00. These results were obtained in spiked food samples of different types (chicken, fish, milk, hard and fresh cheese), further demonstrating the applicability of the optimized methodology presented.

PMID: 33071335 [PubMed]

Gene therapies targeting the liver.

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Gene therapies targeting the liver.

J Hepatol. 2020 Oct 15;:

Authors: Cozmescu AC, Counsell J, Gissen P

PMID: 33071009 [PubMed - as supplied by publisher]

Commentary: The dilemma of donor heart cold storage: Are stem cell extracellular vesicles the answer?

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Commentary: The dilemma of donor heart cold storage: Are stem cell extracellular vesicles the answer?

J Thorac Cardiovasc Surg. 2020 Sep 18;:

Authors: Balsam LB

PMID: 33070942 [PubMed - as supplied by publisher]

Catalytic hairpin assembly-triggered DNA walker for electrochemical sensing of tumor exosomes sensitized with Ag@C core-shell nanocomposites.

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Catalytic hairpin assembly-triggered DNA walker for electrochemical sensing of tumor exosomes sensitized with Ag@C core-shell nanocomposites.

Anal Chim Acta. 2020 Oct 23;1135:55-63

Authors: Guo Y, Cao Q, Feng Q

Abstract
The detection of a small number of exosomes provides the possibility for early cancer diagnosis and prognosis. Here, a multi-signal amplified electrochemical sensing platform was explored for the ultrasensitive detection of tumor exosomes relying on catalytic hairpin assembly-triggered DNA walker, entropy beacon-based DNA assembly and Ag@C core-shell nanocomposites. In this work, the utilization of Ag@C nanocomposites as electrode interface effectively enhanced functional active sites and electron transfer capability. By designing a target-assisted entropy beacon-based DNA assembly, single exosome initiated the release of multiple special DNA sequences, which could be separated conveniently by magnet and then hybridize with the blocking DNA to liberate swing arm. DNA walker was activated with the assistance of catalytic hairpin assembly, introducing extensive electroactive methylene blue (MB) to electrode surface. Thus, the detection of exosomes was transferred into the measurement of the MB current, with a good liner range from 100 to 75 000 particles/μL. Furthermore, this constructed sensing system displayed acceptable reproducibility, long-term stability, favorable selectivity, and highlighting application potential in real samples.

PMID: 33070859 [PubMed - in process]

A new approach for COVID-19 treatment by micro-RNA.

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A new approach for COVID-19 treatment by micro-RNA.

Med Hypotheses. 2020 Oct;143:110203

Authors: El-Nabi SH, Elhiti M, El-Sheekh M

Abstract
MicroRNAs (miRNAs) naturally occur in plants and all living organisms. They play an important role in gene regulation through binding toa specific region in open reading frames (ORFs) and/or untranslated regions (UTRs) to block the translation processes through either degrading or blocking mRNA resulting in knocking down or suppression of targeted genes. Plants and many organisms protect themselves from viruses through the production of miRNAs, which are complementary to 3UTR of viruses resulting in degrading the viral mRNA or block the translation on ribosomes. As pandemic, COVID-19, and its consequences on the global economy, we hypothesized a new approach for the treatment of COVID-19 paints. This approach includes designing a mix of miRNAs targeting several regions on COVID-19 open reading frame (ORF) and 3 UTR and suitable delivery system targeting respiratory system tissues. These synthesized miRNAs may be delivered to humansinnon-viral delivery systems such as liposomes like exosome (extracellular vesicle), polymer-based carriers, or inorganic nanoparticles, which are considered to be more suitable for human use.

PMID: 33017912 [PubMed - indexed for MEDLINE]

Hybrid cellular membrane nanovesicles amplify macrophage immune responses against cancer recurrence and metastasis.

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Hybrid cellular membrane nanovesicles amplify macrophage immune responses against cancer recurrence and metastasis.

Nat Commun. 2020 09 30;11(1):4909

Authors: Rao L, Wu L, Liu Z, Tian R, Yu G, Zhou Z, Yang K, Xiong HG, Zhang A, Yu GT, Sun W, Xu H, Guo J, Li A, Chen H, Sun ZJ, Fu YX, Chen X

Abstract
Effectively activating macrophages against cancer is promising but challenging. In particular, cancer cells express CD47, a 'don't eat me' signal that interacts with signal regulatory protein alpha (SIRPα) on macrophages to prevent phagocytosis. Also, cancer cells secrete stimulating factors, which polarize tumor-associated macrophages from an antitumor M1 phenotype to a tumorigenic M2 phenotype. Here, we report that hybrid cell membrane nanovesicles (known as hNVs) displaying SIRPα variants with significantly increased affinity to CD47 and containing M2-to-M1 repolarization signals can disable both mechanisms. The hNVs block CD47-SIRPα signaling axis while promoting M2-to-M1 repolarization within tumor microenvironment, significantly preventing both local recurrence and distant metastasis in malignant melanoma models. Furthermore, by loading a stimulator of interferon genes (STING) agonist, hNVs lead to potent tumor inhibition in a poorly immunogenic triple negative breast cancer model. hNVs are safe, stable, drug loadable, and suitable for genetic editing. These properties, combined with the capabilities inherited from source cells, make hNVs an attractive immunotherapy.

PMID: 32999291 [PubMed - indexed for MEDLINE]

Editorial Comment.

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Editorial Comment.

J Urol. 2020 10;204(4):700

Authors: Helfand BT, Glaser AP

PMID: 32898984 [PubMed - indexed for MEDLINE]

'The Double-Edged Sword' - An hypothesis for Covid-19-induced salivary biomarkers.

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'The Double-Edged Sword' - An hypothesis for Covid-19-induced salivary biomarkers.

Med Hypotheses. 2020 Oct;143:110124

Authors: Adeoye J, Thomson P

Abstract
Utilising biomarkers for COVID-19 diagnosis, prediction of treatment response and overall prognostication have been investigated recently. However, these ventures have only considered the use of blood-based molecular markers. Saliva is another biofluid that warrants being applied in similar fashion with major advantages that centres on its non-invasive and repeatable collection as well as cost-efficiency. To this end, this article presents a hypothesis for the sources of biomarkers useful clinically for COVID-19 disease outcome estimation and identify the likely implications of their detection in saliva.

PMID: 32721813 [PubMed - indexed for MEDLINE]

The RNA exosome shapes the expression of key protein-coding genes.

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The RNA exosome shapes the expression of key protein-coding genes.

Nucleic Acids Res. 2020 09 04;48(15):8509-8528

Authors: Wu M, Karadoulama E, Lloret-Llinares M, Rouviere JO, Vaagensø CS, Moravec M, Li B, Wang J, Wu G, Gockert M, Pelechano V, Jensen TH, Sandelin A

Abstract
The ribonucleolytic exosome complex is central for nuclear RNA degradation, primarily targeting non-coding RNAs. Still, the nuclear exosome could have protein-coding (pc) gene-specific regulatory activities. By depleting an exosome core component, or components of exosome adaptor complexes, we identify ∼2900 transcription start sites (TSSs) from within pc genes that produce exosome-sensitive transcripts. At least 1000 of these overlap with annotated mRNA TSSs and a considerable portion of their transcripts share the annotated mRNA 3' end. We identify two types of pc-genes, both employing a single, annotated TSS across cells, but the first type primarily produces full-length, exosome-sensitive transcripts, whereas the second primarily produces prematurely terminated transcripts. Genes within the former type often belong to immediate early response transcription factors, while genes within the latter are likely transcribed as a consequence of their proximity to upstream TSSs on the opposite strand. Conversely, when genes have multiple active TSSs, alternative TSSs that produce exosome-sensitive transcripts typically do not contribute substantially to overall gene expression, and most such transcripts are prematurely terminated. Our results display a complex landscape of sense transcription within pc-genes and imply a direct role for nuclear RNA turnover in the regulation of a subset of pc-genes.

PMID: 32710631 [PubMed - indexed for MEDLINE]

Editorial Comment.

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Editorial Comment.

J Urol. 2020 09;204(3):474-475

Authors: Helfand B

PMID: 32579042 [PubMed - indexed for MEDLINE]

Identification and characterization of outer membrane vesicles from the fish pathogen Vibrio ordalii.

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Identification and characterization of outer membrane vesicles from the fish pathogen Vibrio ordalii.

J Fish Dis. 2020 May;43(5):621-629

Authors: Echeverría-Bugueño M, Espinosa-Lemunao R, Irgang R, Avendaño-Herrera R

Abstract
Vibriosis outbreaks due to Vibrio ordalii occur globally, but Chilean salmon aquaculture, in particular, has suffered significant monetary losses in the last 15 years. Little is known about the virulence mechanisms employed by V. ordalii. However, most Vibrio pathogens (e.g., Vibrio anguillarum, a very close taxonomic species) present outer membrane vesicles (OMVs) that are released extracellularly and implicated in the delivery of virulence factors to host cells. This study provides the first reported evidence of the fish pathogen V. ordalii producing and releasing OMVs under normal growth conditions. Analyses were conducted with the V. ordalii strain Vo-LM-18 and the type strain ATCC 33509T . For comparative purposes, the reference strain V. anguillarum ATCC 43307 was employed. The average size for the three Vibrio strains was 0.215 ± 0.6 µm (via scanning electron microscopy) or between 0.19 and 1.8 µm (via dynamic light scattering), with each bacterium presenting a wide range. SDS-PAGE revealed similarities in OMV patterns, but neither total nor external proteins were identical. Comparing V. ordalii ATCC 33509T and Vo-LM-18, bands were most evident in the total proteins, and the greatest degree of similarity in OMV profiles was between 37 and 50 kDa. The purified OMVs demonstrated haemolytic enzyme activity, which could play a role during V. ordalii infection. These data represent an initial step towards gaining new insights into this virulence factor, of which a lot is known in other pathogenic microorganisms.

PMID: 32293041 [PubMed - indexed for MEDLINE]

Microvesicle-containing miRNA-153-3p induces the apoptosis of proximal tubular epithelial cells and participates in renal interstitial fibrosis.

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Microvesicle-containing miRNA-153-3p induces the apoptosis of proximal tubular epithelial cells and participates in renal interstitial fibrosis.

Eur Rev Med Pharmacol Sci. 2019 Nov;23(22):10065-10071

Authors: Zhang XF, Yang Y, Zhang J, Cao W

Abstract
OBJECTIVE: To uncover the role of microvesicle-containing (MV-containing) miRNA-153-3p in inducing the apoptosis of proximal tubular epithelial cells and RIF (renal interstitial fibrosis), and its potential mechanism.
MATERIALS AND METHODS: Mice were subjected to unilateral ureteral obstruction (UUO) to establish the in vivo RIF model. MVs were extracted from the obstructed kidney tissues of mice, to further isolate the RNAs. MiRNA-153-3p levels in RIF mice and MVs were determined. In vitro RIF model was constructed by TGF-β1 induction in NRK-52E and NRK-49F cells. The regulatory effect of miRNA-153-3p on the apoptosis of tubular epithelial cells was examined. Subsequently, potential target gene of miRNA-153-3p was predicted and identified. Rescue experiments were finally carried out to uncover the role of miRNA-153-3p/Bcl-2 in influencing RIF.
RESULTS: MiRNA-153-3p was upregulated in mice undergoing UUO, MVs extracted from obstructed kidney tissues of mice and TGF-β1-induced NRK-52E and NRK-49F cells. The overexpression of miRNA-153-3p remarkably induced apoptosis in tubular epithelial cells. Bcl-2 was verified to be the target gene of miRNA-153-3p, and the Bcl-2 level was negatively regulated by miRNA-153-3p. Overexpression of Bcl-2 reversed the effect of miRNA-153-3p on inducing cell apoptosis.
CONCLUSIONS: MV-containing miRNA-153-3p released by tubulointerstitial fibroblasts transmits to the proximal tubular epithelial cells via the damaged tubule basement membrane. It induces the apoptosis of proximal tubular epithelial cells by inhibiting Bcl-2 level and further aggravates RIF.

PMID: 31799677 [PubMed - indexed for MEDLINE]

Citrullinome of Porphyromonas gingivalis Outer Membrane Vesicles: Confident Identification of Citrullinated Peptides.

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Citrullinome of Porphyromonas gingivalis Outer Membrane Vesicles: Confident Identification of Citrullinated Peptides.

Mol Cell Proteomics. 2020 01;19(1):167-180

Authors: Larsen DN, Mikkelsen CE, Kierkegaard M, Bereta GP, Nowakowska Z, Kaczmarek JZ, Potempa J, Højrup P

Abstract
Porphyromonas gingivalis is a key pathogen in chronic periodontitis and has recently been mechanistically linked to the development of rheumatoid arthritis via the activity of peptidyl arginine deiminase generating citrullinated epitopes in the periodontium. In this project the outer membrane vesicles (OMV) from P. gingivalis W83 wild-type (WT), a W83 knock-out mutant of peptidyl arginine deiminase (ΔPPAD), and a mutant strain expressing PPAD with the active site cysteine mutated to alanine (C351A), have been analyzed using a two-dimensional HFBA-based separation system combined with LC-MS. For optimal and positive identification and validation of citrullinated peptides and proteins, high resolution mass spectrometers and strict MS search criteria were utilized. This may have compromised the total number of identified citrullinations but increased the confidence of the validation. A new two-dimensional separation system proved to increase the strength of validation, and along with the use of an in-house build program, Citrullia, we establish a fast and easy semi-automatic (manual) validation of citrullinated peptides. For the WT OMV we identified 78 citrullinated proteins having a total of 161 citrullination sites. Notably, in keeping with the mechanism of OMV formation, the majority (51 out of 78) of citrullinated proteins were predicted to be exported via the inner membrane and to reside in the periplasm or being translocated to the bacterial surface. Citrullinated surface proteins may contribute to the pathogenesis of rheumatoid arthritis. For the C351A-OMV a single citrullination site was found and no citrullinations were identified for the ΔPPAD-OMV, thus validating the unbiased character of our method of citrullinated peptide identification.

PMID: 31754044 [PubMed - indexed for MEDLINE]

Marrow Fat-Secreted Factors as Biomarkers for Osteoporosis.

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Marrow Fat-Secreted Factors as Biomarkers for Osteoporosis.

Curr Osteoporos Rep. 2019 12;17(6):429-437

Authors: Herrmann M

Abstract
PURPOSE OF REVIEW: The age-related accumulation of bone marrow adipose tissue (BMAT) negatively impacts bone metabolism and hematopoiesis. This review provides an overview about BMAT-secreted factors as biomarkers for BMAT accumulation and osteoporosis risk.
RECENT FINDINGS: The adipokines leptin and adiponectin are regulators of BMAT. It remains to be clarified if locally produced adipokines substantially contribute to their peripheral serum levels and if they influence bone metabolism beyond that of extraosseous adipokine production. Existing data also suggests that BMAT disturbs bone metabolism primarily through palmitate-mediated toxic effects on osteoblasts and osteocytes, including dysregulated autophagy and apoptosis. BMAT-secreted factors are important modulators of bone metabolism. However, the majority of our understanding about MAT-secreted factors and their paracrine and endocrine effects is derived from in vitro studies and animal experiments. Therefore, more research is needed before BMAT-secreted biomarkers can be applied in medical practice.

PMID: 31734905 [PubMed - indexed for MEDLINE]

Immunoregulatory role of melatonin in cancer.

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Immunoregulatory role of melatonin in cancer.

J Cell Physiol. 2020 02;235(2):745-757

Authors: Moradkhani F, Moloudizargari M, Fallah M, Asghari N, Heidari Khoei H, Asghari MH

Abstract
Melatonin is a ubiquitous indole amine that plays a fundamental role in the regulation of the biological rhythm. Disrupted circadian rhythm alters the expression of clock genes and deregulates oncogenes, which finally promote tumor development and progression. An evidence supporting this notion is the higher risk of developing malignancies among night shift workers. Circadian secretion of the pineal hormone also synchronizes the immune system via a reciprocal association that exists between the immune system and melatonin. Immune cells are capable of melatonin biosynthesis in addition to the expression of its receptors. Melatonin induces big changes in different immune cell proportions, enhances their viability and improves immune cell metabolism in the tumor microenvironment. These effects might be directly mediated by melatonin receptors or indirectly through alterations in hormonal and cytokine release. Moreover, melatonin induces apoptosis in tumor cells via the intrinsic and extrinsic pathways of apoptosis, while it protectsthe immune cells. In general, melatonin has a profound impact on immune cell trafficking, cytokine production and apoptosis induction in malignant cells. On such a basis, using melatonin and resynchronization of sleep cycle may have potential implications in immune function enhancement against malignancies, which will be the focus of the present paper.

PMID: 31270813 [PubMed - indexed for MEDLINE]

Sulfate depletion triggers overproduction of phospholipids and the release of outer membrane vesicles by Neisseria meningitidis.

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Sulfate depletion triggers overproduction of phospholipids and the release of outer membrane vesicles by Neisseria meningitidis.

Sci Rep. 2019 03 18;9(1):4716

Authors: Gerritzen MJH, Martens DE, Uittenbogaard JP, Wijffels RH, Stork M

Abstract
Outer membrane vesicles (OMVs) produced by bacteria are interesting vaccine candidates. OMVs are nanoparticles that contain many immunogenic components, are self-adjuvating, and non-replicative. Despite recent insights in the biogenesis of OMVs, there is no consensus on a conserved mechanism of OMV release and the OMV yield from bacterial cultures remains low. For Neisseria meningitidis, a Gram-negative human pathogen causing meningitis and sepsis, a feasible OMV production method based on triggering OMV release by cysteine depletion has been described. In this study, we investigated the mechanism behind this external trigger for OMV release to improve the production process. Since enhanced OMV release upon cysteine depletion was associated with oxidative stress and redox responses, we investigate the influence of more oxidized sulfur sources on OMV release. We show that N. meningitidis grows similarly on sulfate, the most oxidized sulfur source, and OMV release is triggered by sulfur depletion in general. Sulfate depletion induced increased release of OMVs over cysteine depletion. Proteomics showed that sulfur depletion resulted in oxidative stress responses and upregulated phospholipid and LPS biosynthesis. Furthermore, OMVs produced by sulfur depletion were enriched in phospholipids. Mechanistically, we hypothesize that sulfur depletion results in overproduction of phospholipids causing increased bulging of the outer membrane and subsequent OMV release.

PMID: 30886228 [PubMed - indexed for MEDLINE]