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1.
Int J Environ Res Public Health ; 18(16)2021 08 05.
Article in English | MEDLINE | ID: covidwho-1376804

ABSTRACT

Humans on earth inhabit a wide range of environmental conditions and some environments are more challenging for human survival than others. However, many living beings, including humans, have developed adaptive mechanisms to live in such inhospitable, harsh environments. Among different difficult environments, high-altitude living is especially demanding because of diminished partial pressure of oxygen and resulting chronic hypobaric hypoxia. This results in poor blood oxygenation and reduces aerobic oxidative respiration in the mitochondria, leading to increased reactive oxygen species generation and activation of hypoxia-inducible gene expression. Genetic mechanisms in the adaptation to high altitude is well-studied, but there are only limited studies regarding the role of epigenetic mechanisms. The purpose of this review is to understand the epigenetic mechanisms behind high-altitude adaptive and maladaptive phenotypes. Hypobaric hypoxia is a form of cellular hypoxia, which is similar to the one suffered by critically-ill hypoxemia patients. Thus, understanding the adaptive epigenetic signals operating in in high-altitude adjusted indigenous populations may help in therapeutically modulating signaling pathways in hypoxemia patients by copying the most successful epigenotype. In addition, we have summarized the current information about exosomes in hypoxia research and prospects to use them as diagnostic tools to study the epigenome of high-altitude adapted healthy or maladapted individuals.


Subject(s)
Exosomes , Exposome , Adaptation, Physiological/genetics , Altitude , Epigenesis, Genetic , Exosomes/genetics , Humans , Hypoxia/genetics
2.
Signal Transduct Target Ther ; 6(1): 300, 2021 08 11.
Article in English | MEDLINE | ID: covidwho-1351933

ABSTRACT

Elderly people and patients with comorbidities are at higher risk of COVID-19 infection, resulting in severe complications and high mortality. However, the underlying mechanisms are unclear. In this study, we investigate whether miRNAs in serum exosomes can exert antiviral functions and affect the response to COVID-19 in the elderly and people with diabetes. First, we identified four miRNAs (miR-7-5p, miR-24-3p, miR-145-5p and miR-223-3p) through high-throughput sequencing and quantitative real-time PCR analysis, that are remarkably decreased in the elderly and diabetic groups. We further demonstrated that these miRNAs, either in the exosome or in the free form, can directly inhibit S protein expression and SARS-CoV-2 replication. Serum exosomes from young people can inhibit SARS-CoV-2 replication and S protein expression, while the inhibitory effect is markedly decreased in the elderly and diabetic patients. Moreover, three out of the four circulating miRNAs are significantly increased in the serum of healthy volunteers after 8-weeks' continuous physical exercise. Serum exosomes isolated from these volunteers also showed stronger inhibitory effects on S protein expression and SARS-CoV-2 replication. Our study demonstrates for the first time that circulating exosomal miRNAs can directly inhibit SARS-CoV-2 replication and may provide a possible explanation for the difference in response to COVID-19 between young people and the elderly or people with comorbidities.


Subject(s)
COVID-19/genetics , Diabetes Mellitus/genetics , MicroRNAs/genetics , Spike Glycoprotein, Coronavirus/genetics , Adult , Age Factors , Aged , COVID-19/blood , COVID-19/pathology , COVID-19/virology , China , Circulating MicroRNA/blood , Circulating MicroRNA/genetics , Cohort Studies , Diabetes Mellitus/blood , Diabetes Mellitus/pathology , Diabetes Mellitus/virology , Exercise , Exosomes/genetics , Exosomes/metabolism , Exosomes/virology , Female , Gene Expression Regulation , HEK293 Cells , Host-Pathogen Interactions/genetics , Humans , Male , MicroRNAs/blood , Middle Aged , SARS-CoV-2/genetics , SARS-CoV-2/growth & development , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/blood , Virus Replication
3.
Mol Neurobiol ; 58(10): 5356-5368, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1326854

ABSTRACT

The pandemic of novel coronavirus 2 (SARS-CoV-2) has made global chaos for normal human living. Despite common COVID-19 symptoms, variability in clinical phenotypes was reported worldwide. Reports on SARS-CoV-2 suggest causing neurological manifestation. In addition, the susceptibility of SARS-CoV-2 in patients with neurodegenerative diseases and its complexity are largely unclear. Here, we aimed to demonstrate the possible transport of exosome from SARS-CoV-2-infected lungs to the brain regions associated with neurodegenerative diseases using multiple transcriptome datasets of SARS-CoV-2-infected lungs, RNA profiles from lung exosome, and gene expression profiles of the human brain. Upon transport, the transcription factors localized in the exosome regulate genes at lateral substantia nigra, medial substantia nigra, and superior frontal gyrus regions of Parkinson's disease (PD) and frontal cortex, hippocampus, and temporal cortex of Alzheimer's disease (AD). On SARS-CoV-2 infection, BCL3, JUND, MXD1, IRF2, IRF9, and STAT1 transcription factors in the exosomes influence the neuronal gene regulatory network and accelerate neurodegeneration. STAT1 transcription factor regulates 64 PD genes at lateral substantia nigra, 65 at superior frontal gyrus, and 19 at medial substantia nigra. Similarly, in AD, STAT1 regulates 74 AD genes at the temporal cortex, 40 genes at the hippocampus, and 16 genes at the frontal cortex. We further demonstrate that dysregulated neuronal genes showed involvement in immune response, signal transduction, apoptosis, and stress response process. In conclusion, SARS-CoV-2 may dysregulate neuronal gene regulatory network through exosomes that attenuate disease severity of neurodegeneration.


Subject(s)
Brain/metabolism , COVID-19/metabolism , Exosomes/metabolism , Lung/metabolism , Neurons/metabolism , Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Databases, Factual , Exosomes/genetics , Humans , Parkinson Disease/genetics , Parkinson Disease/metabolism , Transcriptome
4.
Biomolecules ; 10(10)2020 09 27.
Article in English | MEDLINE | ID: covidwho-1295752

ABSTRACT

Acute and chronic skin wounds due to burns, pressure injuries, and trauma represent a substantial challenge to healthcare delivery with particular impacts on geriatric, paraplegic, and quadriplegic demographics worldwide. Nevertheless, the current standard of care relies extensively on preventive measures to mitigate pressure injury, surgical debridement, skin flap procedures, and negative pressure wound vacuum measures. This article highlights the potential of adipose-, blood-, and cellulose-derived products (cells, decellularized matrices and scaffolds, and exosome and secretome factors) as a means to address this unmet medical need. The current status of this research area is evaluated and discussed in the context of promising avenues for future discovery.


Subject(s)
Burns/therapy , Exosomes/transplantation , Hydrogels/therapeutic use , Wound Healing/genetics , Burns/pathology , Cell- and Tissue-Based Therapy/trends , Cellulose/therapeutic use , Exosomes/genetics , Humans , Hydrogels/chemistry , Mesenchymal Stem Cell Transplantation/trends , Mesenchymal Stem Cells/cytology , Skin/growth & development , Skin/injuries , Skin/metabolism
5.
Signal Transduct Target Ther ; 6(1): 189, 2021 05 12.
Article in English | MEDLINE | ID: covidwho-1226420

ABSTRACT

Since the outbreak of coronavirus disease 2019 (COVID-19), it has become a global pandemic. The spike (S) protein of etiologic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) specifically recognizes human angiotensin-converting enzyme 2 (hACE2) as its receptor, which is recently identified as an interferon (IFN)-stimulated gene. Here, we find that hACE2 exists on the surface of exosomes released by different cell types, and the expression of exosomal hACE2 is increased by IFNα/ß treatment. In particular, exosomal hACE2 can specifically block the cell entry of SARS-CoV-2, subsequently inhibit the replication of SARS-CoV-2 in vitro and ex vivo. Our findings have indicated that IFN is able to upregulate a viral receptor on the exosomes which competitively block the virus entry, exhibiting a potential antiviral strategy.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Exosomes/metabolism , Interferon-alpha/pharmacology , Interferon-beta/pharmacology , SARS-CoV-2/physiology , Virus Internalization/drug effects , Virus Replication/drug effects , Angiotensin-Converting Enzyme 2/genetics , Animals , Chlorocebus aethiops , Exosomes/genetics , Exosomes/virology , HEK293 Cells , Humans , Mice , Mice, Transgenic , Vero Cells
6.
Front Immunol ; 12: 656700, 2021.
Article in English | MEDLINE | ID: covidwho-1211815

ABSTRACT

SARS-CoV-2, the novel coronavirus infection has consistently shown an association with neurological anomalies in patients, in addition to its usual respiratory distress syndrome. Multi-organ dysfunctions including neurological sequelae during COVID-19 persist even after declining viral load. We propose that SARS-CoV-2 gene product, Spike, is able to modify the host exosomal cargo, which gets transported to distant uninfected tissues and organs and can initiate a catastrophic immune cascade within Central Nervous System (CNS). SARS-CoV-2 Spike transfected cells release a significant amount of exosomes loaded with microRNAs such as miR-148a and miR-590. microRNAs gets internalized by human microglia and suppress target gene expression of USP33 (Ubiquitin Specific peptidase 33) and downstream IRF9 levels. Cellular levels of USP33 regulate the turnover time of IRF9 via deubiquitylation. Our results also demonstrate that absorption of modified exosomes effectively regulate the major pro-inflammatory gene expression profile of TNFα, NF-κB and IFN-ß. These results uncover a bystander pathway of SARS-CoV-2 mediated CNS damage through hyperactivation of human microglia. Our results also attempt to explain the extra-pulmonary dysfunctions observed in COVID-19 cases when active replication of virus is not supported. Since Spike gene and mRNAs have been extensively picked up for vaccine development; the knowledge of host immune response against spike gene and protein holds a great significance. Our study therefore provides novel and relevant insights regarding the impact of Spike gene on shuttling of host microRNAs via exosomes to trigger the neuroinflammation.


Subject(s)
COVID-19/metabolism , Exosomes/metabolism , Interferon-Stimulated Gene Factor 3, gamma Subunit/metabolism , MicroRNAs/metabolism , Microglia/metabolism , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Ubiquitin Thiolesterase/metabolism , COVID-19/genetics , COVID-19/physiopathology , COVID-19/virology , Cell Line , Central Nervous System/immunology , Central Nervous System/physiopathology , Central Nervous System/virology , Endopeptidases/metabolism , Exosomes/genetics , Exosomes/pathology , Humans , Inflammation/immunology , Inflammation/virology , Interferon-beta/metabolism , MicroRNAs/genetics , Microglia/pathology , NF-kappa B/metabolism , Protein Stability , Tumor Necrosis Factor-alpha/metabolism
7.
Int J Mol Sci ; 22(6)2021 Mar 20.
Article in English | MEDLINE | ID: covidwho-1143521

ABSTRACT

SARS-CoV-2 infection can cause cytokine storm and may overshoot immunity in humans; however, it remains to be determined whether virus-induced soluble mediators from infected cells are carried by exosomes as vehicles to distant organs and cause tissue damage in COVID-19 patients. We took an unbiased proteomic approach for analyses of exosomes isolated from plasma of healthy volunteers and COVID-19 patients. Our results revealed that tenascin-C (TNC) and fibrinogen-ß (FGB) are highly abundant in exosomes from COVID-19 patients' plasma compared with that of healthy normal controls. Since TNC and FGB stimulate pro-inflammatory cytokines via the Nuclear factor-κB (NF-κB) pathway, we examined the status of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and C-C motif chemokine ligand 5 (CCL5) expression upon exposure of hepatocytes to exosomes from COVID-19 patients and observed significant increase compared with that from healthy subjects. Together, our results demonstrate that TNC and FGB are transported through plasma exosomes and potentially trigger pro-inflammatory cytokine signaling in cells of distant organ.


Subject(s)
COVID-19/blood , Exosomes/chemistry , Exosomes/genetics , Fibrinogen/metabolism , Inflammation/metabolism , Tenascin/metabolism , Aged , COVID-19/complications , Cell Line , Chemokine CCL5/metabolism , Exosomes/metabolism , Exosomes/ultrastructure , Female , Hepatocytes/metabolism , Humans , Inflammation/etiology , Interleukin-6/metabolism , Male , Mass Spectrometry , Microscopy, Electron, Transmission , Middle Aged , NF-kappa B/metabolism , Protein Interaction Maps , Proteome/metabolism , Tumor Necrosis Factor-alpha/metabolism
8.
Cells ; 10(3)2021 03 07.
Article in English | MEDLINE | ID: covidwho-1143461

ABSTRACT

The novel coronavirus severe acute respiratory syndrome-CoV-2 (SARS-CoV-2) is responsible for COVID-19 infection. The COVID-19 pandemic represents one of the worst global threats in the 21st century since World War II. This pandemic has led to a worldwide economic recession and crisis due to lockdown. Biomedical researchers, pharmaceutical companies, and premier institutes throughout the world are claiming that new clinical trials are in progress. During the severe phase of this disease, mechanical ventilators are used to assist in the management of outcomes; however, their use can lead to the development of pneumonia. In this context, mesenchymal stem cell (MSC)-derived exosomes can serve as an immunomodulation treatment for COVID-19 patients. Exosomes possess anti-inflammatory, pro-angiogenic, and immunomodulatory properties that can be explored in an effort to improve the outcomes of SARS-CoV-2-infected patients. Currently, only one ongoing clinical trial (NCT04276987) is specifically exploring the use of MSC-derived exosomes as a therapy to treat SARS-CoV-2-associated pneumonia. The purpose of this review is to provide insights of using exosomes derived from mesenchymal stem cells in management of the co-morbidities associated with SARS-CoV-2-infected persons in direction of improving their health outcome. There is limited knowledge of using exosomes in SARS-CoV-2; the clinicians and researchers should exploit exosomes as therapeutic regime.


Subject(s)
COVID-19/therapy , Exosomes/metabolism , Extracellular Vesicles/metabolism , Immunomodulation , Mesenchymal Stem Cells/metabolism , Pneumonia, Viral/therapy , COVID-19/complications , COVID-19/metabolism , COVID-19/pathology , Cytokines/metabolism , Cytokines/pharmacology , Exosomes/chemistry , Exosomes/genetics , Humans , Inflammation/immunology , Inflammation/therapy , Inflammation/virology , Mesenchymal Stem Cells/immunology , Neovascularization, Physiologic/immunology , Pneumonia, Viral/complications , Pneumonia, Viral/virology , Respiratory Tract Infections/complications , Respiratory Tract Infections/therapy , Respiratory Tract Infections/virology
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