Untargeted Metabolic Profiling of Extracellular Vesicles of SARS-CoV-2-Infected Patients Shows Presence of Potent Anti-Inflammatory Metabolites

Extracellular vesicles (EVs) carry important biomolecules, including metabolites, and contribute to the spread and pathogenesis of some viruses. However, to date, limited data are available on EV metabolite content that might play a crucial role during infection with the SARS-CoV-2 virus. Therefore, this study aimed to perform untargeted metabolomics to identify key metabolites and associated pathways that are present in EVs, isolated from the serum of COVID-19 patients. The results showed the presence of antivirals and antibiotics such as Foscarnet, Indinavir, and lymecycline in EVs from patients treated with these drugs. Moreover, increased levels of anti-inflammatory metabolites such as LysoPS, 7-α,25-Dihydroxycholesterol, and 15-d-PGJ2 were detected in EVs from COVID-19 patients when compared with controls. Further, we found decreased levels of metabolites associated with coagulation, such as thromboxane and elaidic acid, in EVs from COVID-19 patients. These findings suggest that EVs not only carry active drug molecules but also anti-inflammatory metabolites, clearly suggesting that exosomes might play a crucial role in negotiating with heightened inflammation during COVID-19 infection. These preliminary results could also pave the way for the identification of novel metabolites that might act as critical regulators of inflammatory pathways during viral infections.

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Nucleosides and Nucleoside Analogues as Emerging Antiviral Drugs

Mini-Reviews in Organic Chemistry ◽

10.2174/1570193x17999200820163234 ◽

2020 ◽

Vol 17 ◽

Author(s):

Mohamed Ibrahim Elzagheid

Keyword(s):

Significant Role ◽

Mode Of Action ◽

Crucial Role ◽

Viral Infections ◽

Antiviral Drugs ◽

Review Article ◽

Nucleoside Analogues ◽

The Past ◽

Nucleoside Drugs

: Nucleosides and their analogues have been in use for many years and have become essential for treating patients with viral infections. Many additional nucleoside drugs have been approved over the past decades. This strongly demonstrates how important these compounds are and the crucial role they play. Given that a significant amount of research and literature has been documented regarding nucleoside analogues, this review article mainly focuses the discussion on nucleosides and nucleoside analogous that have proven to play significant role or be emerging in the treatment of known viral infections. This covers the names, structures, applications, toxicity, and mode of action of relevant nucleoside analogues.

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C-type lectins and extracellular vesicles in virus-induced NETosis

Journal of Biomedical Science ◽

10.1186/s12929-021-00741-7 ◽

2021 ◽

Vol 28 (1) ◽

Author(s):

Pei-Shan Sung ◽

Shie-Liang Hsieh

Keyword(s):

Extracellular Vesicles ◽

Viral Infections ◽

Multiple Organ ◽

Intercellular Adhesion Molecule ◽

Inflammatory Reactions ◽

Intravascular Coagulopathy ◽

Encephalomyelitis Virus ◽

Toll Like Receptor 2 ◽

Lectin Family ◽

Virus Spreading

AbstractDysregulated formation of neutrophil extracellular traps (NETs) is observed in acute viral infections. Moreover, NETs contribute to the pathogenesis of acute viral infections, including those caused by the dengue virus (DV) and severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Furthermore, excessive NET formation (NETosis) is associated with disease severity in patients suffering from SARS-CoV-2-induced multiple organ injuries. Dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) and other members of C-type lectin family (L-SIGN, LSECtin, CLEC10A) have been reported to interact with viral glycans to facilitate virus spreading and exacerbates inflammatory reactions. Moreover, spleen tyrosine kinase (Syk)-coupled C-type lectin member 5A (CLEC5A) has been shown as the pattern recognition receptor for members of flaviviruses, and is responsible for DV-induced cytokine storm and Japanese encephalomyelitis virus (JEV)-induced neuronal inflammation. Moreover, DV activates platelets via CLEC2 to release extracellular vesicles (EVs), including microvesicles (MVs) and exosomes (EXOs). The DV-activated EXOs (DV-EXOs) and MVs (DV-MVs) stimulate CLEC5A and Toll-like receptor 2 (TLR2), respectively, to enhance NET formation and inflammatory reactions. Thus, EVs from virus-activated platelets (PLT-EVs) are potent endogenous danger signals, and blockade of C-type lectins is a promising strategy to attenuate virus-induced NETosis and intravascular coagulopathy.

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Extracellular Vesicles Do Not Mediate the Anti-Inflammatory Actions of Mouse-Derived Adipose Tissue Mesenchymal Stem Cells Secretome

International Journal of Molecular Sciences ◽

10.3390/ijms22031375 ◽

2021 ◽

Vol 22 (3) ◽

pp. 1375

Author(s):

María Carmen Carceller ◽

María Isabel Guillén ◽

María Luisa Gil ◽

María José Alcaraz

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Adipose Tissue ◽

Extracellular Vesicles ◽

Nuclear Factor Κb ◽

Peritoneal Macrophages ◽

Toll Like Receptor 4 ◽

Anti Inflammatory ◽

Phagocytic Response

Adipose tissue represents an abundant source of mesenchymal stem cells (MSC) for therapeutic purposes. Previous studies have demonstrated the anti-inflammatory potential of adipose tissue-derived MSC (ASC). Extracellular vesicles (EV) present in the conditioned medium (CM) have been shown to mediate the cytoprotective effects of human ASC secretome. Nevertheless, the role of EV in the anti-inflammatory effects of mouse-derived ASC is not known. The current study has investigated the influence of mouse-derived ASC CM and its fractions on the response of mouse-derived peritoneal macrophages against lipopolysaccharide (LPS). CM and its soluble fraction reduced the release of pro-inflammatory cytokines, adenosine triphosphate and nitric oxide in stimulated cells. They also enhanced the migration of neutrophils or monocytes, in the absence or presence of LPS, respectively, which is likely related to the presence of chemokines, and reduced the phagocytic response. The anti-inflammatory effect of CM may be dependent on the regulation of toll-like receptor 4 expression and nuclear factor-κB activation. Our results demonstrate the anti-inflammatory effects of mouse-derived ASC secretome in mouse-derived peritoneal macrophages stimulated with LPS and show that they are not mediated by EV.

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ITS2 ribotyping, in vitro anti-inflammatory screening, and metabolic profiling of fungal endophytes from the Mexican species Crescentia alata Kunth

South African Journal of Botany ◽

10.1016/j.sajb.2019.12.030 ◽

2020 ◽

Vol 134 ◽

pp. 213-224

Author(s):

Rosario del Carmen Flores-Vallejo ◽

Jorge Luis Folch-Mallol ◽

Ashutosh Sharma ◽

Alexandre Cardoso-Taketa ◽

Laura Alvarez-Berber ◽

...

Keyword(s):

Metabolic Profiling ◽

Fungal Endophytes ◽

Anti Inflammatory ◽

Mexican Species

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Human umbilical cord mesenchymal stem cell-derived extracellular vesicles attenuate experimental autoimmune encephalomyelitis via regulating pro and anti-inflammatory cytokines

Scientific Reports ◽

10.1038/s41598-021-91291-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Samira Ahmadvand Koohsari ◽

Abdorrahim Absalan ◽

Davood Azadi

Keyword(s):

Spinal Cord ◽

Body Weight ◽

Extracellular Vesicles ◽

Inflammatory Cytokines ◽

Clinical Score ◽

Human Umbilical Cord ◽

Therapeutic Effects ◽

Leukocyte Infiltration ◽

Anti Inflammatory ◽

Pro Inflammatory Cytokines

AbstractThe therapeutic effects of mesenchymal stem cells-extracellular vesicles have been proved in many inflammatory animal models. In the current study, we aimed to investigate the effect of extracellular vesicles (EVs) derived from human umbilical cord-MSC (hUCSC-EV) on the clinical score and inflammatory/anti-inflammatory cytokines on the EAE mouse model. After induction of EAE in C57Bl/6 mice, they were treated intravenously with hUCSC-EV or vehicle. The clinical score and body weight of all mice was registered every day. On day 30, mice were sacrificed and splenocytes were isolated for cytokine assay by ELISA. Cytokine expression of pro-/anti-inflammatory cytokine by real-time PCR, leukocyte infiltration by hematoxylin and eosin (H&E) staining, and the percent of glial fibrillary acidic protein (GFAP) and myelin basic protein (MBP) positive cells by immunohistochemistry were assessed in the spinal cord. Our results showed that hUCSC-EV-treated mice have lower maximum mean clinical score (MMCS), pro-inflammatory cytokines, and inflammatory score in comparison to the control mice. We also showed that hUCSC-EV administration significantly improved body weight and increased the anti-inflammatory cytokines and the frequency of Treg cells in the spleen. There was no significant difference in the percent of GFAP and MBP positive cells in the spinal cord of experimental groups. Finally, we suggest that intravenous administration of hUCSC-EV alleviate induce-EAE by reducing the pro-inflammatory cytokines, such as IL-17a, TNF-α, and IFN-γ, and increasing the anti-inflammatory cytokines, IL-4 and IL-10, and also decrease the leukocyte infiltration in a model of MS. It seems that EVs from hUC-MSCs have the same therapeutic effects similar to EVs from other sources of MSCs, such as adipose or bone marrow MSCs.

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Acute Myopericarditis in a Pediatric Patient after First Dose of Pfizer BioNTech COVID - 19 Vaccination: First Case Report in the Kingdom of Bahrain

Journal of the Bahrain Medical Society ◽

10.26715/jbms.33_2021_4_7 ◽

2021 ◽

Vol 33 (4) ◽

pp. 29-32

Author(s):

Ghada Al Qassim ◽

Vimalarani Arulselvam ◽

Suad R Al Amer ◽

Salah Al Ghanem ◽

Neale Nicola Kalis

Keyword(s):

Case Report ◽

Adverse Events ◽

Pediatric Patient ◽

Task Force ◽

Limited Data ◽

First Case ◽

National Task ◽

Inflammatory Drugs ◽

Anti Inflammatory

Coronavirus disease 201 9 (COVID - 1 9 ) vaccination for children over 12 years of age began on May 2021 in the kingdom of Bahrain. Very limited data is available regarding the adverse events related to COVID -19 vaccination in children. This is a case report of a 12-year-old previously healthy boy with acute myopericarditis who presented on day 5 after the first dose of Pfizer COVID - 19 vaccination. Other causes of acute myopericarditis were ruled out. He was treated with non - steroidal anti-inflammatory drugs and recovered fully. This case of vaccine-induced myocarditis was reported to the national task force of Bahrain for combating COVID - 19.

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Extracellular Vesicles in the Pathogenesis of Viral Infections in Humans

Viruses ◽

10.3390/v12101200 ◽

2020 ◽

Vol 12 (10) ◽

pp. 1200 ◽

Cited By ~ 1

Author(s):

Allen Caobi ◽

Madhavan Nair ◽

Andrea D. Raymond

Keyword(s):

Extracellular Vesicles ◽

Viral Infections ◽

Membrane Vesicles ◽

Response Modulation ◽

Viral Spread ◽

Neurotropic Viruses ◽

Immunodeficiency Virus ◽

Immune Response Modulation ◽

Potential Use

Most cells can release extracellular vesicles (EVs), membrane vesicles containing various proteins, nucleic acids, enzymes, and signaling molecules. The exchange of EVs between cells facilitates intercellular communication, amplification of cellular responses, immune response modulation, and perhaps alterations in viral pathogenicity. EVs serve a dual role in inhibiting or enhancing viral infection and pathogenesis. This review examines the current literature on EVs to explore the complex role of EVs in the enhancement, inhibition, and potential use as a nanotherapeutic against clinically relevant viruses, focusing on neurotropic viruses: Zika virus (ZIKV) and human immunodeficiency virus (HIV). Overall, this review’s scope will elaborate on EV-based mechanisms, which impact viral pathogenicity, facilitate viral spread, and modulate antiviral immune responses.

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Clinical Applications of Mesenchymal Stem/Stromal Cell Derived Extracellular Vesicles: Therapeutic Potential of an Acellular Product

Diagnostics ◽

10.3390/diagnostics10120999 ◽

2020 ◽

Vol 10 (12) ◽

pp. 999

Author(s):

Margherita Massa ◽

Stefania Croce ◽

Rita Campanelli ◽

Carlotta Abbà ◽

Elisa Lenta ◽

...

Keyword(s):

Extracellular Vesicles ◽

Large Scale ◽

Therapeutic Potential ◽

Ischemia Reperfusion ◽

Clinical Stage ◽

Kidney Injury ◽

Scale Production ◽

Bioactive Lipids ◽

Anti Inflammatory ◽

Signaling Receptors

In the last decade, the secreting activity of mesenchymal stem/stromal cells (MSCs) has been widely investigated, due to its possible therapeutic role. In fact, MSCs release extracellular vesicles (EVs) containing relevant biomolecules such as mRNAs, microRNAs, bioactive lipids, and signaling receptors, able to restore physiological conditions where regenerative or anti-inflammatory actions are needed. An actual advantage would come from the therapeutic use of EVs with respect to MSCs, avoiding the possible immune rejection, the lung entrapment, improving the safety, and allowing the crossing of biological barriers. A number of concerns still have to be solved regarding the mechanisms determining the beneficial effect of MSC-EVs, the possible alteration of their properties as a consequence of the isolation/purification methods, and/or the best approach for a large-scale production for clinical use. Most of the preclinical studies have been successful, reporting for MSC-EVs a protecting role in acute kidney injury following ischemia reperfusion, a potent anti-inflammatory and anti-fibrotic effects by reducing disease associated inflammation and fibrosis in lung and liver, and the modulation of both innate and adaptive immune responses in graft versus host disease (GVHD) as well as autoimmune diseases. However, the translation of MSC-EVs to the clinical stage is still at the initial phase. Herein, we discuss the therapeutic potential of an acellular product such as MSC derived EVs (MSC-EVs) in acute and chronic pathologies.

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Extracellular vesicles from human cardiovascular progenitors trigger a reparative immune response in infarcted hearts

Cardiovascular Research ◽

10.1093/cvr/cvaa028 ◽

2020 ◽

Cited By ~ 8

Author(s):

Bruna Lima Correa ◽

Nadia El Harane ◽

Ingrid Gomez ◽

Hocine Rachid Hocine ◽

José Vilar ◽

...

Keyword(s):

Immune Response ◽

Extracellular Vesicles ◽

Inflammatory Cytokines ◽

Nk Cell ◽

Inflammatory Monocytes ◽

Ifn Γ ◽

Anti Inflammatory ◽

Pro Inflammatory Cytokines

Abstract Aims The cardioprotective effects of human induced pluripotent stem cell-derived cardiovascular progenitor cells (CPC) are largely mediated by the paracrine release of extracellular vesicles (EV). We aimed to assess the immunological behaviour of EV-CPC, which is a prerequisite for their clinical translation. Methods and results Flow cytometry demonstrated that EV-CPC expressed very low levels of immune relevant molecules including HLA Class I, CD80, CD274 (PD-L1), and CD275 (ICOS-L); and moderate levels of ligands of the natural killer (NK) cell activating receptor, NKG2D. In mixed lymphocyte reactions, EV-CPC neither induced nor modulated adaptive allogeneic T cell immune responses. They also failed to induce NK cell degranulation, even at high concentrations. These in vitro effects were confirmed in vivo as repeated injections of EV-CPC did not stimulate production of immunoglobulins or affect the interferon (IFN)-γ responses from primed splenocytes. In a mouse model of chronic heart failure, intra-myocardial injections of EV-CPC, 3 weeks after myocardial infarction, decreased both the number of cardiac pro-inflammatory Ly6Chigh monocytes and circulating levels of pro-inflammatory cytokines (IL-1α, TNF-α, and IFN-γ). In a model of acute infarction, direct cardiac injection of EV-CPC 2 days after infarction reduced pro-inflammatory macrophages, Ly6Chigh monocytes, and neutrophils in heart tissue as compared to controls. EV-CPC also reduced levels of pro-inflammatory cytokines IL-1α, IL-2, and IL-6, and increased levels of the anti-inflammatory cytokine IL-10. These effects on human macrophages and monocytes were reproduced in vitro; EV-CPC reduced the number of pro-inflammatory monocytes and M1 macrophages, while increasing the number of anti-inflammatory M2 macrophages. Conclusions EV-CPC do not trigger an immune response either in in vitro human allogeneic models or in immunocompetent animal models. The capacity for orienting the response of monocyte/macrophages towards resolution of inflammation strengthens the clinical attractiveness of EV-CPC as an acellular therapy for cardiac repair.

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