scholarly journals Extracellular vesicles as mediators and markers of acute organ injury: current concepts

2021 ◽  
Author(s):  
Birte Weber ◽  
Niklas Franz ◽  
Ingo Marzi ◽  
Dirk Henrich ◽  
Liudmila Leppik
Keyword(s):  
Extracellular Vesicles ◽  
Inflammatory Diseases ◽  
Organ Injury ◽  
Isolation And Characterization ◽  
Communication Processes ◽  
Incidence And Mortality ◽  
New Biomarkers ◽  
And Function

AbstractDue to the continued high incidence and mortality rate worldwide, there is a need to develop new strategies for the quick, precise, and valuable recognition of presenting injury pattern in traumatized and poly-traumatized patients. Extracellular vesicles (EVs) have been shown to facilitate intercellular communication processes between cells in close proximity as well as distant cells in healthy and disease organisms. miRNAs and proteins transferred by EVs play biological roles in maintaining normal organ structure and function under physiological conditions. In pathological conditions, EVs change the miRNAs and protein cargo composition, mediating or suppressing the injury consequences. Therefore, incorporating EVs with their unique protein and miRNAs signature into the list of promising new biomarkers is a logical next step. In this review, we discuss the general characteristics and technical aspects of EVs isolation and characterization. We discuss results of recent in vitro, in vivo, and patients study describing the role of EVs in different inflammatory diseases and traumatic organ injuries. miRNAs and protein signature of EVs found in patients with acute organ injury are also debated.

scholarly journals Alcohol-and-HIV-Induced Lysosomal Dysfunction Regulates Extracellular Vesicles Secretion in Vitro and in Liver-Humanized Mice

Biology ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 29
Author(s):  
Raghubendra Singh Dagur ◽  
Moses New-Aaron ◽  
Murali Ganesan ◽  
Weimin Wang ◽  
Svetlana Romanova ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Extracellular Vesicles ◽  
Treated Group ◽  
Human Hepatocytes ◽  
In Vivo Studies ◽  
People Living With Hiv ◽  
Humanized Mouse Model ◽  
And Function

Background: Alcohol abuse is common in people living with HIV-1 and dramaticallyenhances the severity of HIV-induced liver damage by inducing oxidative stress and lysosomaldysfunction in the liver cells. We hypothesize that the increased release of extracellular vesicles(EVs) in hepatocytes and liver humanized mouse model is linked to lysosome dysfunction. Methods:The study was performed on primary human hepatocytes and human hepatoma RLWXP-GFP (Huh7.5 cells stably transfected with CYP2E1 and XPack-GFP) cells and validated on ethanol-fed liverhumanizedfumarylacetoacetate hydrolase (Fah)-/-, Rag2-/-, common cytokine receptor gamma chainknockout (FRG-KO) mice. Cells and mice were infected with HIV-1ADA virus. Results: We observedan increase in the secretion of EVs associated with a decrease in lysosomal activity and expressionof lysosomal-associated membrane protein 1. Next-generation RNA sequencing of primary humanhepatocytes revealed 63 differentially expressed genes, with 13 downregulated and 50 upregulatedgenes in the alcohol–HIV-treated group. Upstream regulator analysis of differentially expressedgenes through Ingenuity Pathway Analysis identified transcriptional regulators affecting downstreamgenes associated with increased oxidative stress, lysosomal associated disease, and function andEVs biogenesis. Our in vitro findings were corroborated by in vivo studies on human hepatocytetransplantedhumanized mice, indicating that intensive EVs’ generation by human hepatocytes andtheir secretion to serum was associated with increased oxidative stress and reduction in lysosomalactivities triggered by HIV infection and ethanol diet. Conclusion: HIV-and-ethanol-metabolisminducedEVs release is tightly controlled by lysosome status in hepatocytes and participates in thedevelopment of double-insult-induced liver injury.

scholarly journals Extracellular Vesicles: Intercellular Communication Mediators in Antiphospholipid Syndrome

2021 ◽  
Author(s):  
Ula Štok ◽  
Saša Čučnik ◽  
Snežna Sodin-Šemrl ◽  
Polona Žigon
Keyword(s):  
Extracellular Vesicles ◽  
Antiphospholipid Syndrome ◽  
Intercellular Communication ◽  
Systemic Autoimmune Disease ◽  
In Vivo Models ◽  
Isolation And Characterization ◽  
Increased Risk ◽  
Insight Into

Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by thrombosis, obstetric complications and the presence of antiphospholipid antibodies (aPL) that cause endothelial injury and thrombophilia. Extracellular vesicles are involved in endothelial and thrombotic pathologies and may therefore have an influence on the prothrombotic status of APS patients. Intercellular communication and connectivity are important mechanisms of interaction between healthy and pathologically altered cells. Despite well-characterized in vitro and in vivo models of APS pathology, the field of extracellular vesicles is still largely unexplored and could therefore provide an insight into the APS mechanism and possibly serve as a biomarker to identify patients at increased risk. The analysis of EVs poses a challenge due to the lack of standardized technology for their isolation and characterization. Recent findings in the field of EVs offer promising aspects that may explain their role in the pathogenesis of various diseases, including APS.

scholarly journals α-Melanocyte Stimulating Hormone Prevents Lipopolysaccharide-Induced Vasculitis by Down-Regulating Endothelial Cell Adhesion Molecule Expression

Endocrinology ◽  
2003 ◽  
Vol 144 (1) ◽  
pp. 360-370 ◽  
Author(s):  
T. E. Scholzen ◽  
C. Sunderkötter ◽  
D.-H. Kalden ◽  
T. Brzoska ◽  
M. Fastrich ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Inflammatory Diseases ◽  
Nuclear Factor Κb ◽  
Vascular Damage ◽  
Adhesion Assay ◽  
Melanocyte Stimulating Hormone ◽  
And Function ◽  
Stimulating Hormone

Abstract The neuroendocrine hormone α-melanocyte stimulating hormone (MSH) has profound antiinflammatory and immunomodulating properties. Here we have examined the possibility that α-MSH may interfere with the expression and function of cell adhesion molecules (CAMs) expressed by human dermal microvascular endothelial cells (HDMECs) in response to lipopolysaccharide (LPS) or TNFα in vitro and in vivo. In HDMEC, α-MSH (10−8/10−12m) profoundly reduced the mRNA and protein expression of E-selectin, vascular CAM (VCAM)-1, and intercellular CAM (ICAM)-1 induced by LPS or TNFα as determined by semiquantitative RT-PCR, ELISA, and fluorescence-activated cell sorter analysis. In addition, α-MSH significantly impaired the LPS-induced ICAM-1 and VCAM-1-mediated adhesion of lymphocytes to HDMEC monolayer in a functional adhesion assay. Likewise, α-MSH effectively inhibited the transcription factor nuclear factor-κB activation in HDMEC, which is required for CAM gene expression. Importantly in vivo, in murine LPS-induced cutaneous vasculitis (local Shwartzman reaction), a single ip injection of α-MSH significantly suppressed the deleterious vascular damage and hemorrhage by inhibiting the sustained expression of vascular E-selectin and VCAM-1. This persistent expression has been implicated in the dysregulation of diapedesis and activation of leukocytes, which subsequently leads to hemorrhagic vascular damage. Our findings indicate that α-MSH may have an important therapeutical potential for the treatment of vasculitis, sepsis, and inflammatory diseases.

scholarly journals hERG1 Potassium Channels: Novel Biomarkers in Human Solid Cancers

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Elena Lastraioli ◽  
Tiziano Lottini ◽  
Lapo Bencini ◽  
Marco Bernini ◽  
Annarosa Arcangeli
Keyword(s):  
Potassium Channels ◽  
Health Problem ◽  
Tumor Therapy ◽  
Major Health Problem ◽  
Major Health ◽  
Incidence And Mortality ◽  
Novel Biomarkers ◽  
New Biomarkers

Because of their high incidence and mortality solid cancers are a major health problem worldwide. Although several new biomarkers and potential targets for therapy have been identified through biomolecular research in the last years, the effects on patients’ outcome are still unsatisfactory. Increasing evidence indicates that hERG1 potassium channels are overexpressed in human primary cancers of different origin and several associations between hERG1 expression and clinicopathological features and/or outcome are emerging. Aberrant hERG1 expression may be exploited either for early diagnosis (especially in those cancers where it is expressed in the initial steps of tumor progression) or for therapy purposes. Indeed, hERG1 blockage impairs tumor cell growth bothin vitroandin vivoin preclinical mouse model. hERG1-based tumor therapy in humans, however, encounters the major hindrance of the potential cardiotoxicity that many hERG1 blockers exert. In this review we focus on recent advances in translational research in some of the most frequent human solid cancers (breast, endometrium, ovary, pancreas, esophagus, stomach, and colorectum) that have been shown to express hERG1 and that are a major health problem.

scholarly journals Chronic inhalation of e-cigarette vapor containing nicotine disrupts airway barrier function and induces systemic inflammation and multiorgan fibrosis in mice

2018 ◽  
Vol 314 (6) ◽  
pp. R834-R847 ◽  
Author(s):  
Laura E. Crotty Alexander ◽  
Christopher A. Drummond ◽  
Mark Hepokoski ◽  
Denzil Mathew ◽  
Alex Moshensky ◽  
...  
Keyword(s):  
Barrier Function ◽  
Organ Damage ◽  
Organ Injury ◽  
Human Airway Epithelium ◽  
Inflammatory Protein ◽  
Proinflammatory Responses ◽  
Inflammatory State ◽  
And Function

Electronic (e)-cigarettes theoretically may be safer than conventional tobacco. However, our prior studies demonstrated direct adverse effects of e-cigarette vapor (EV) on airway cells, including decreased viability and function. We hypothesize that repetitive, chronic inhalation of EV will diminish airway barrier function, leading to inflammatory protein release into circulation, creating a systemic inflammatory state, ultimately leading to distant organ injury and dysfunction. C57BL/6 and CD-1 mice underwent nose only EV exposure daily for 3–6 mo, followed by cardiorenal physiological testing. Primary human bronchial epithelial cells were grown at an air-liquid interface and exposed to EV for 15 min daily for 3–5 days before functional testing. Daily inhalation of EV increased circulating proinflammatory and profibrotic proteins in both C57BL/6 and CD-1 mice: the greatest increases observed were in angiopoietin-1 (31-fold) and EGF (25-fold). Proinflammatory responses were recapitulated by daily EV exposures in vitro of human airway epithelium, with EV epithelium secreting higher IL-8 in response to infection (227 vs. 37 pg/ml, respectively; P < 0.05). Chronic EV inhalation in vivo reduced renal filtration by 20% ( P = 0.017). Fibrosis, assessed by Masson’s trichrome and Picrosirius red staining, was increased in EV kidneys (1.86-fold, C57BL/6; 3.2-fold, CD-1; P < 0.05), heart (2.75-fold, C57BL/6 mice; P < 0.05), and liver (1.77-fold in CD-1; P < 0.0001). Gene expression changes demonstrated profibrotic pathway activation. EV inhalation altered cardiovascular function, with decreased heart rate ( P < 0.01), and elevated blood pressure ( P = 0.016). These data demonstrate that chronic inhalation of EV may lead to increased inflammation, organ damage, and cardiorenal and hepatic disease.

scholarly journals Circulating CD3+HLA-DR+Extracellular Vesicles as a Marker for Th1/Tc1-Type Immune Responses

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Ryutaro Oba ◽  
Motomichi Isomura ◽  
Akira Igarashi ◽  
Kinya Nagata
Keyword(s):  
T Cells ◽  
T Cell ◽  
Extracellular Vesicles ◽  
Inflammatory Diseases ◽  
Cell Subset ◽  
Activated T Cells ◽  
Ebv Infection ◽  
Hla Dr

Extracellular vesicles (EVs) are known to contain unique proteins that reflect the cells of origins. Activated T cells are reported to secrete various EVs. To establish T cell subset-specific biomarkers, we performed proteomic analysis with Th1- and Th2-derived EVs and identified HLA-DR as a Th1-dominated EV membrane protein. We designed a measurement system for CD3+CD4+, CD3+CD8+, and CD3+HLA-DR+EVs to specifically determine EV subpopulations derived from CD4+, CD8+, and Th1-type T cells, respectively.In vitroanalysis showed that CD3+CD4+EVs and CD3+CD8+EVs were selectively secreted from activated CD4+and CD8+T cells, respectively, and that CD3+HLA-DR+EVs were actively secreted from not only Th1 but also activated CD8+T (probably mostly Tc1) cells. To evaluate the clinical usefulness of these EVs, we measured the serum levels in patients with inflammatory diseases, including Epstein-Barr virus (EBV,n=13) infection, atopic dermatitis (AD,n=10), rheumatoid arthritis (RA,n=20), and osteoarthritis (OA,n=20) and compared the levels with those of healthy adults (n=20). CD3+CD4+EVs were significantly higher in all of EBV infection, AD, RA, and OA while CD3+CD8+EVs were higher in EBV infection, lower in RA, and not different in AD and OA relative to the control. The levels of CD3+HLA-DR+EVs were markedly higher in EBV infection and significantly lower in AD. The results suggest that these EV subpopulations reflectin vivoactivation status of total CD4+, total CD8+, and Th1/Tc1-type T cells, respectively, and may be helpful in T cell-related clinical settings, such as cancer immunotherapy and treatment of chronic infection, autoimmune diseases, and graft-versus-host disease.

scholarly journals Molecular Crosstalk Between Macrophages and Mesenchymal Stromal Cells

2020 ◽  
Vol 8 ◽  
Author(s):  
Hazel Y. Stevens ◽  
Annie C. Bowles ◽  
Carolyn Yeago ◽  
Krishnendu Roy
Keyword(s):  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Inflammatory Diseases ◽  
The Body ◽  
Alternative Activation ◽  
Molecular Alterations ◽  
Preclinical Trials ◽  
And Function

Mesenchymal stromal cells (MSCs) have been widely investigated for regenerative medicine applications, from treating various inflammatory diseases as a cell therapy to generating engineered tissue constructs. Numerous studies have evaluated the potential effects of MSCs following therapeutic administration. By responding to their surrounding microenvironment, MSCs may mediate immunomodulatory effects through various mechanisms that directly (i.e., contact-dependent) or indirectly (i.e., paracrine activity) alter the physiology of endogenous cells in various disease pathologies. More specifically, a pivotal crosstalk between MSCs and tissue-resident macrophages and monocytes (TMφ) has been elucidated using in vitro and in vivo preclinical studies. An improved understanding of this crosstalk could help elucidate potential mechanisms of action (MOAs) of therapeutically administered MSCs. TMφ, by nature of their remarkable functional plasticity and prevalence within the body, are uniquely positioned as critical modulators of the immune system – not only in maintaining homeostasis but also during pathogenesis. This has prompted further exploration into the cellular and molecular alterations to TMφ mediated by MSCs. In vitro assays and in vivo preclinical trials have identified key interactions mediated by MSCs that polarize the responses of TMφ from a pro-inflammatory (i.e., classical activation) to a more anti-inflammatory/reparative (i.e., alternative activation) phenotype and function. In this review, we describe physiological and pathological TMφ functions in response to various stimuli and discuss the evidence that suggest specific mechanisms through which MSCs may modulate TMφ phenotypes and functions, including paracrine interactions (e.g., secretome and extracellular vesicles), nanotube-mediated intercellular exchange, bioenergetics, and engulfment by macrophages. Continued efforts to elucidate this pivotal crosstalk may offer an improved understanding of the immunomodulatory capacity of MSCs and inform the development and testing of potential MOAs to support the therapeutic use of MSCs and MSC-derived products in various diseases.

Exploiting Anti-Inflammation Effects of Flavonoids in Chronic Inflammatory Diseases

2020 ◽  
Vol 26 (22) ◽  
pp. 2610-2619 ◽  
Author(s):  
Tarique Hussain ◽  
Ghulam Murtaza ◽  
Huansheng Yang ◽  
Muhammad S. Kalhoro ◽  
Dildar H. Kalhoro
Keyword(s):  
Oxidative Stress ◽  
Chronic Diseases ◽  
Inflammatory Diseases ◽  
Therapeutic Option ◽  
Cellular Level ◽  
Antiinflammatory Drugs ◽  
Suitable Alternative ◽  
Chronic Inflammatory Diseases

Background: Inflammation is a complex response of the host defense system to different internal and external stimuli. It is believed that persistent inflammation may lead to chronic inflammatory diseases such as, inflammatory bowel disease, neurological and cardiovascular diseases. Oxidative stress is the main factor responsible for the augmentation of inflammation via various molecular pathways. Therefore, alleviating oxidative stress is effective a therapeutic option against chronic inflammatory diseases. Methods: This review article extends the knowledge of the regulatory mechanisms of flavonoids targeting inflammatory pathways in chronic diseases, which would be the best approach for the development of suitable therapeutic agents against chronic diseases. Results: Since the inflammatory response is initiated by numerous signaling molecules like NF-κB, MAPK, and Arachidonic acid pathways, their encountering function can be evaluated with the activation of Nrf2 pathway, a promising approach to inhibit/prevent chronic inflammatory diseases by flavonoids. Over the last few decades, flavonoids drew much attention as a potent alternative therapeutic agent. Recent clinical evidence has shown significant impacts of flavonoids on chronic diseases in different in-vivo and in-vitro models. Conclusion: Flavonoid compounds can interact with chronic inflammatory diseases at the cellular level and modulate the response of protein pathways. A promising approach is needed to overlook suitable alternative compounds providing more therapeutic efficacy and exerting fewer side effects than commercially available antiinflammatory drugs.

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