scholarly journals Joint Reconstituted Signaling of the IL-6 Receptor via Extracellular Vesicles

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1307 ◽  
Author(s):  
Philipp Arnold ◽  
Wiebke Lückstädt ◽  
Wenjia Li ◽  
Inga Boll ◽  
Juliane Lokau ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Biological Functions ◽  
Pathological Conditions ◽  
Stat3 Phosphorylation ◽  
Attractive Therapeutic Target ◽  
Anti Inflammatory ◽  
Β Receptor ◽  
Almost All ◽  
Transcription 3 ◽  
Regulatory Event

Interleukin-6 (IL-6) signaling is a crucial regulatory event important for many biological functions, such as inflammation and tissue regeneration. Accordingly, several pathological conditions are associated with dysregulated IL-6 activity, making it an attractive therapeutic target. For instance, blockade of IL-6 or its α-receptor (IL-6R) by monoclonal antibodies has been successfully used to treat rheumatoid arthritis. However, based on different signaling modes, IL-6 function varies between pro- and anti-inflammatory activity, which is critical for therapeutic intervention. So far, three modes of IL-6 signaling have been described, the classic anti-inflammatory signaling, as well as pro-inflammatory trans-signaling, and trans-presentation. The IL-6/IL-6R complex requires an additional β-receptor (gp130), which is expressed on almost all cells of the human body, to induce STAT3 (signal transducer and activator of signal transcription 3) phosphorylation and subsequent transcriptional regulation. In contrast, the IL-6R is expressed on a limited number of cells, including hepatocytes and immune cells. However, the proteolytic release of the IL-6R enables trans-signaling on cells expressing gp130 only. Here, we demonstrate a fourth possibility of IL-6 signaling that we termed joint reconstituted signaling (JRS). We show that IL-6R on extracellular vesicles (EVs) can also be transported to and fused with other cells that lack the IL-6R on their surface. Importantly, JRS via EVs induces delayed STAT3 phosphorylation compared to the well-established trans-signaling mode. EVs isolated from human serum were already shown to carry the IL-6R, and thus this new signaling mode should be considered with regard to signal intervention.

scholarly journals Extracellular Vesicles: Novel Roles in Neurological Disorders

2021 ◽  
Vol 2021 ◽  
pp. 1-16
Author(s):  
Qian Jin ◽  
Peipei Wu ◽  
Xinru Zhou ◽  
Hui Qian ◽  
Wenrong Xu
Keyword(s):  
Central Nervous System ◽  
Extracellular Vesicles ◽  
Neurological Disorders ◽  
Unique Feature ◽  
Cns Development ◽  
Diagnostic Biomarkers ◽  
Pathological Conditions ◽  
The Central Nervous System ◽  
Therapeutic Tools ◽  
Almost All

Exosomes are small extracellular vesicles (EVs) secreted by almost all cells, which have been recognized as a novel platform for intercellular communication in the central nervous system (CNS). Exosomes are capable of transferring proteins, nucleic acids, lipids, and metabolites between neurons and glial cells, contributing to CNS development and maintenance of homeostasis. Evidence shows that exosomes originating from CNS cells act as suppressors or promoters in the initiation and progression of neurological disorders. Moreover, these exosomes have been shown to transfer molecules associated with diseases through the blood-brain barrier (BBB) and thus can be detected in blood. This unique feature enables exosomes to act as potential diagnostic biomarkers for neurological disorders. In addition, a substantial number of researches have indicated that exosomes derived from mesenchymal stem cells (MSCs) have repair effects on neurological disorders. Herein, we briefly introduce the roles of exosomes under physiological and pathological conditions. In particular, novel roles of exosomes as potential diagnostic biomarkers and therapeutic tools for neurological disorders are highlighted.

scholarly journals CIGAR-seq, a CRISPR/Cas-based method for unbiased screening of novel mRNA modification regulators

2020 ◽  
Author(s):  
Liang Fang ◽  
Wen Wang ◽  
Guipeng Li ◽  
Li Zhang ◽  
Jun Li ◽  
...  
Keyword(s):  
Bisulfite Sequencing ◽  
Rna Modification ◽  
Biological Functions ◽  
Cellular Functions ◽  
Chemical Modifications ◽  
Pathological Conditions ◽  
High Throughput Method ◽  
Crispr Screen ◽  
Almost All ◽  
Modification Rate

AbstractCellular RNA is decorated with over 170 types of chemical modifications. Many modifications in mRNA, including m6A and m5C, have been associated with critical cellular functions under physiological and/or pathological conditions. To understand the biological functions of these modifications, it is vital to identify the regulators that modulate the modification rate. However, a high-throughput method for unbiased screening of these regulators is so far lacking. Here, we report such a method combining pooled CRISPR screen and reporters with RNA modification readout, termed CRISPR integrated gRNA and reporter sequencing (CIGAR-seq). Using CIGAR-seq, we discovered NSUN6 as a novel mRNA m5C methyltransferase. Subsequent mRNA bisulfite sequencing in HAP1 cells without or with NSUN6 and/or NSUN2 knockout showed that NSUN6 and NSUN2 worked on non-overlapping subsets of mRNA m5C sites, and together contributed to almost all the m5C modification in mRNA. Finally, using m1A as an example, we demonstrated that CIGAR-seq can be easily adapted for identifying regulators of other mRNA modification.

scholarly journals Extracellular Vesicles in Viral Infections of the Nervous System

Viruses ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 700 ◽  
Author(s):  
Naseer A. Kutchy ◽  
Eric S. Peeples ◽  
Susmita Sil ◽  
Ke Liao ◽  
Ernest T. Chivero ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Viral Infections ◽  
Virus Particles ◽  
Pathological Conditions ◽  
Current Review ◽  
Membrane Bound ◽  
Mediate Cell ◽  
Almost All ◽  
Hiv 1

Almost all types of cells release extracellular vesicles (EVs) into the extracellular space. EVs such as exosomes and microvesicles are membrane-bound vesicles ranging in size from 30 to 1000 nm in diameter. Under normal conditions, EVs mediate cell to cell as well as inter-organ communication via the shuttling of their cargoes which include RNA, DNA and proteins. Under pathological conditions, however, the number, size and content of EVs are found to be altered and have been shown to play crucial roles in disease progression. Emerging studies have demonstrated that EVs are involved in many aspects of viral infection-mediated neurodegenerative diseases. In the current review, we will describe the interactions between EV biogenesis and the release of virus particles while also reviewing the role of EVs in various viral infections, such as HIV-1, HTLV, Zika, CMV, EBV, Hepatitis B and C, JCV, and HSV-1. We will also discuss the potential uses of EVs and their cargoes as biomarkers and therapeutic vehicles for viral infections.

scholarly journals Vaccinium Species (Ericaceae): From Chemical Composition to Bio-Functional Activities

2021 ◽  
Vol 11 (12) ◽  
pp. 5655
Author(s):  
Rosa Tundis ◽  
Maria C. Tenuta ◽  
Monica R. Loizzo ◽  
Marco Bonesi ◽  
Federica Finetti ◽  
...  
Keyword(s):  
Public Health ◽  
Functional Food ◽  
Bioactive Molecules ◽  
Biological Functions ◽  
Functional Activities ◽  
Pathological Conditions ◽  
Biological Studies ◽  
Cellular Pathways ◽  
Anti Inflammatory ◽  
Different Cultures

The genus Vaccinium L. (Ericaceae) includes more than 450 species, which mainly grow in cooler areas of the northern hemisphere. Vaccinium species have been used in traditional medicine of different cultures and the berries are widely consumed as food. Indeed, Vaccinium supplement-based herbal medicine and functional food, mainly from V. myrtillus and V. macrocarpon, are used in Europe and North America. Biological studies support traditional uses since, for many Vaccinium components, important biological functions have been described, including antioxidant, antitumor, anti-inflammatory, antidiabetic and endothelium protective activities. Vaccinium components, such as polyphenols, anthocyanins and flavonoids, are widely recognized as modulators of cellular pathways involved in pathological conditions, thus indicating that Vaccinium may be an important source of bioactive molecules. This review aims to better describe the bioactivity of Vaccinium species, focusing on anti-inflammatory and endothelial protective cellular pathways, modulated by their components, to better understand their importance for public health.

scholarly journals Opposite Effects of Chronic Central Leptin Infusion on Activation of Insulin Signaling Pathways in Adipose Tissue and Liver Are Related to Changes in the Inflammatory Environment

Biomolecules ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 1734
Author(s):  
Vicente Barrios ◽  
Ana Campillo-Calatayud ◽  
Santiago Guerra-Cantera ◽  
Sandra Canelles ◽  
Álvaro Martín-Rivada ◽  
...  
Keyword(s):  
Insulin Signaling ◽  
Inflammatory Cytokine ◽  
Stat3 Phosphorylation ◽  
Cytokine Levels ◽  
Relevant Role ◽  
Inflammatory Pattern ◽  
Anti Inflammatory ◽  
And Control ◽  
Transcription 3 ◽  
Anti Inflammatory Cytokine

Leptin modulates insulin signaling and this involves the Akt pathway, which is influenced by changes in the inflammatory environment and with leptin regulating cytokine synthesis. We evaluated the association between activation of the insulin-signaling pathway and alterations in pro- and anti-inflammatory cytokine levels in inguinal fat and liver of chronic central leptin infused (L), pair-fed (PF), and control rats. Signal transducer and activator of transcription 3 (STAT3) phosphorylation was increased in inguinal fat and reduced in liver of L rats. Phosphorylation of c-Jun N-terminal kinase (JNK) and nuclear factor kappa B (NFkB) was increased in inguinal fat of L rats, together with a pro-inflammatory cytokine profile, while in the liver activation of JNK and NFkB were reduced and an anti-inflammatory pattern was found. Phosphorylation of the insulin receptor, Akt and mechanistic target of rapamycin was decreased in inguinal fat and increased in liver of L rats. There was a direct relationship between pSTAT3 and JNK and a negative correlation of Akt with pSTAT3 and JNK in both tissues. These results indicate that the effects of chronically increased leptin on insulin-related signaling are tissue-specific and suggest that inflammation plays a relevant role in the crosstalk between leptin and insulin signaling.

scholarly journals Biological Functions Driven by mRNAs Carried by Extracellular Vesicles in Cancer

2021 ◽  
Vol 9 ◽  
Author(s):  
Marta Prieto-Vila ◽  
Yusuke Yoshioka ◽  
Takahiro Ochiya
Keyword(s):  
Nucleic Acids ◽  
Tumor Progression ◽  
Extracellular Vesicles ◽  
Migration And Invasion ◽  
Messenger Rnas ◽  
Biological Functions ◽  
Cancer Cell Growth ◽  
Premetastatic Niche ◽  
Pathological Conditions ◽  
Potential Use

Extracellular vesicles (EVs), including exosomes and microvesicles, are extracellular nanovesicles released by most cells. EVs play essential roles in intercellular communication via the transport of a large variety of lipids, proteins, and nucleic acids to recipient cells. Nucleic acids are the most commonly found molecules inside EVs, and due to their small size, microRNAs and other small RNAs are the most abundant nucleic acids. However, longer molecules, such as messenger RNAs (mRNAs), have also been found. mRNAs encapsulated within EVs have been shown to be transferred to recipient cells and translated into proteins, altering the behavior of the cells. Secretion of EVs is maintained not only through multiple normal physiological conditions but also during aberrant pathological conditions, including cancer. Recently, the mRNAs carried by EVs in cancer have attracted great interest due to their broad roles in tumor progression and microenvironmental remodeling. This review focuses on the biological functions driven by mRNAs carried in EVs in cancer, which include supporting tumor progression by activating cancer cell growth, migration, and invasion; inducing microenvironmental remodeling via hypoxia, angiogenesis, and immunosuppression; and promoting modulation of the microenvironment at distant sites for the generation of a premetastatic niche, collectively inducing metastasis. Furthermore, we describe the potential use of mRNAs carried by EVs as a noninvasive diagnostic tool and novel therapeutic approach.

scholarly journals Anti-Inflammatory Potential of Cow, Donkey and Goat Milk Extracellular Vesicles as Revealed by Metabolomic Profile

Nutrients ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2908
Author(s):  
Samanta Mecocci ◽  
Federica Gevi ◽  
Daniele Pietrucci ◽  
Luca Cavinato ◽  
Francesco R. Luly ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Metabolic Pathways ◽  
Biological Fluid ◽  
Biological Effects ◽  
Goat Milk ◽  
Cell Types ◽  
Inflammatory Conditions ◽  
Anti Inflammatory ◽  
Ultrahigh Performance Liquid Chromatography ◽  
Almost All

In recent years, extracellular vesicles (EVs), cell-derived micro and nano-sized structures enclosed in a double-layer membrane, have been in the spotlight for their high potential in diagnostic and therapeutic applications. Indeed, they act as signal mediators between cells and/or tissues through different mechanisms involving their complex cargo and exert a number of biological effects depending upon EVs subtype and cell source. Being produced by almost all cell types, they are found in every biological fluid including milk. Milk EVs (MEVs) can enter the intestinal cells by endocytosis and protect their labile cargos against harsh conditions in the intestinal tract. In this study, we performed a metabolomic analysis of MEVs, from three different species (i.e., bovine, goat and donkey) by mass spectroscopy (MS) coupled with Ultrahigh-performance liquid chromatography (UHPLC). Metabolites, both common or specific of a species, were identified and enriched metabolic pathways were investigated, with the final aim to evaluate their anti-inflammatory and immunomodulatory properties in view of prospective applications as a nutraceutical in inflammatory conditions. In particular, metabolites transported by MEVs are involved in common pathways among the three species. These metabolites, such as arginine, asparagine, glutathione and lysine, show immunomodulating effects. Moreover, MEVs in goat milk showed a greater number of enriched metabolic pathways as compared to the other kinds of milk.

scholarly journals The Immuno-Modulation Effect of Macrophage-Derived Extracellular Vesicles in Chronic Inflammatory Diseases

2021 ◽  
Vol 12 ◽  
Author(s):  
Yi Xing ◽  
Xun Sun ◽  
Yiming Dou ◽  
Min Wang ◽  
Yanmei Zhao ◽  
...  
Keyword(s):  
Immune Responses ◽  
Extracellular Vesicles ◽  
Inflammatory Diseases ◽  
Gastrointestinal Disease ◽  
Biological Functions ◽  
Modulation Effect ◽  
Chronic Inflammatory Diseases ◽  
Pathological Conditions ◽  
Potential Applications ◽  
Regulatory Effects

As natural nanocarriers and intercellular messengers, extracellular vesicles (EVs) control communication among cells. Under physiological and pathological conditions, EVs deliver generic information including proteins and nucleic acids to recipient cells and exert regulatory effects. Macrophages help mediate immune responses, and macrophage-derived EVs may play immunomodulatory roles in the progression of chronic inflammatory diseases. Furthermore, EVs derived from various macrophage phenotypes have different biological functions. In this review, we describe the pathophysiological significance of macrophage-derived extracellular vesicles in the development of chronic inflammatory diseases, including diabetes, cancer, cardiovascular disease, pulmonary disease, and gastrointestinal disease, and the potential applications of these EVs.

The size of extracellular vesicles secreted by different types of stem cells

2018 ◽  
pp. 38-42
Author(s):  
И.Б. Алчинова ◽  
М.В. Полякова ◽  
И.Н. Сабурина ◽  
М.Ю. Карганов
Keyword(s):  
Stem Cells ◽  
Extracellular Vesicles ◽  
Culture Media ◽  
Living Organism ◽  
Isolation And Characterization ◽  
Transmission Electron ◽  
Study Results ◽  
Multipotent Mesenchymal Stem Cells ◽  
Rat Adipose Tissue ◽  
Almost All

Механизм терапевтического действия мультипотентных мезенхимных стволовых клеток (ММСК) на облученный организм в последнее время вызывает повышенный интерес исследователей. В качестве активного участника паракринного механизма реализации этого эффекта предлагают рассматривать внеклеточные везикулы, секретируемые практически всеми клетками живого организма. Цель работы: выделить и охарактеризовать внеклеточные везикулы, продуцируемые стволовыми клетками различной природы. Материалы и методы. Суспензии внеклеточных везикул, выделенных по модифицированному протоколу дифференциального центрифугирования из культуральных жидкостей от культур ММСК костного мозга человека 2-го пассажа и ММСК жировой ткани крысы 4-го пассажа, были проанализированы методом просвечивающей электронной микроскопии и методом анализа траекторий наночастиц. Результаты. Исследование показало наличие в обоих образцах микрочастиц размерами до и около 100 нм, однако процентное содержание частиц разных размеров в суспензии различалось для двух анализируемых типов клеток. Заключение. Полученные результаты могут свидетельствовать о специфике секреции, обусловленной клеточным типом. A mechanism of the therapeutic effect of multipotent mesenchymal stem cells (MMSC) on irradiated body has recently arisen much interest of researchers. Extracellular vesicles (EVs) secreted by almost all cells of a living organism were suggested to actively contribute to the paracrine mechanism of this effect. The aim of the study was isolation and characterization of extracellular vesicles produced by various types of stem cells. Materials and methods. Suspensions of EVs were isolated from culture media of passage 2 human bone marrow-derived MMSC and passage 4 rat adipose tissue-derived MMSC using a modified protocol of differential centrifugation and then studied using transmission electron microscopy and nanoparticle tracking analysis. Results. The study showed the presence of microparticles with a size of >100 nm in the examined samples. However, the percent content of particles with different sizes in the suspension was different in two analyzed types of cell culture. Conclusion. The study results might reflect a specificity of secretion determined by the cell type.

scholarly journals Angiopoietin-Like Growth Factor Involved in Leptin Signaling in the Hypothalamus

2021 ◽  
Vol 22 (7) ◽  
pp. 3443
Author(s):  
Yunseon Jang ◽  
Jun Young Heo ◽  
Min Joung Lee ◽  
Jiebo Zhu ◽  
Changjun Seo ◽  
...  
Keyword(s):  
Growth Factor ◽  
Brain Regions ◽  
Whole Body ◽  
Signal Transducers ◽  
Leptin Signaling ◽  
Stat3 Phosphorylation ◽  
Hypothalamic Regulation ◽  
Induced Signal ◽  
Body Energy ◽  
Transcription 3

The hypothalamic regulation of appetite governs whole-body energy balance. Satiety is regulated by endocrine factors including leptin, and impaired leptin signaling is associated with obesity. Despite the anorectic effect of leptin through the regulation of the hypothalamic feeding circuit, a distinct downstream mediator of leptin signaling in neuron remains unclear. Angiopoietin-like growth factor (AGF) is a peripheral activator of energy expenditure and antagonizes obesity. However, the regulation of AGF expression in brain and localization to mediate anorectic signaling is unknown. Here, we demonstrated that AGF is expressed in proopiomelanocortin (POMC)-expressing neurons located in the arcuate nucleus (ARC) of the hypothalamus. Unlike other brain regions, hypothalamic AGF expression is stimulated by leptin-induced signal transducers and activators of transcription 3 (STAT3) phosphorylation. In addition, leptin treatment to hypothalamic N1 cells significantly enhanced the promoter activity of AGF. This induction was abolished by the pretreatment of ruxolitinib, a leptin signaling inhibitor. These results indicate that hypothalamic AGF expression is induced by leptin and colocalized to POMC neurons.

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