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1.
Int J Mol Med ; 49(2)2022 02.
Article in English | MEDLINE | ID: covidwho-1594678

ABSTRACT

The pathophysiology of coronavirus disease 2019 (COVID­19) is mainly dependent on the underlying mechanisms that mediate the entry of severe acute respiratory syndrome coronavirus 2 (SARS­CoV­2) into the host cells of the various human tissues/organs. Recent studies have indicated a higher order of complexity of the mechanisms of infectivity, given that there is a wide­repertoire of possible cell entry mediators that appear to co­localise in a cell­ and tissue­specific manner. The present study provides an overview of the 'canonical' SARS­CoV­2 mediators, namely angiotensin converting enzyme 2, transmembrane protease serine 2 and 4, and neuropilin­1, expanding on the involvement of novel candidates, including glucose­regulated protein 78, basigin, kidney injury molecule­1, metabotropic glutamate receptor subtype 2, ADAM metallopeptidase domain 17 (also termed tumour necrosis factor­α convertase) and Toll­like receptor 4. Furthermore, emerging data indicate that changes in microRNA (miRNA/miR) expression levels in patients with COVID­19 are suggestive of further complexity in the regulation of these viral mediators. An in silico analysis revealed 160 candidate miRNAs with potential strong binding capacity in the aforementioned genes. Future studies should concentrate on elucidating the association between the cellular tropism of the SARS­CoV­2 cell entry mediators and the mechanisms through which they might affect the clinical outcome. Finally, the clinical utility as a biomarker or therapeutic target of miRNAs in the context of COVID­19 warrants further investigation.


Subject(s)
COVID-19/metabolism , MicroRNAs/metabolism , Receptors, Virus/metabolism , SARS-CoV-2/metabolism , Virus Internalization , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/genetics , COVID-19/virology , /metabolism , Gene Expression Regulation , Host-Pathogen Interactions , Humans , Membrane Proteins/genetics , Membrane Proteins/metabolism , MicroRNAs/genetics , Neuropilin-1/genetics , Neuropilin-1/metabolism , Receptors, Virus/genetics , SARS-CoV-2/physiology , Serine Endopeptidases/genetics , Serine Endopeptidases/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Toll-Like Receptor 4/genetics , Toll-Like Receptor 4/metabolism , Viral Tropism
2.
Microrna ; 10(4): 226-228, 2021.
Article in English | MEDLINE | ID: covidwho-1594371

ABSTRACT

Despite their biological simplicity, microRNA-based organisms, such as RNA viruses, are currently shown to be unexpected threats to mammals, including humans. This situation is exemplified by the COVID-19 pandemic triggered by the spread of SARS-CoV-2. RNA viruses are older than DNA viruses. Indeed, from an evolutionary standpoint, RNA is an older molecule than DNA. The strength of RNA viruses, compared to DNA viruses, resides in their simplicity and instability. The instability of RNA viruses, such as human immunodeficiency virus (HIV) and flu viruses, generates mutants to escape the host's defense mechanisms. A formidable combination of lethality and infectivity was recently achieved by SARS-CoV-2. Complex DNAbased defense systems use Toll-like receptors to intercept viral RNA inside a cell. Activation of Toll-like receptors triggers inflammation and activates lymphocytes and monocytes, causing thromboxane release. In the case of SARS-CoV-2 infection, this process results in cytokine storms and lung thromboembolism. The ongoing pandemic can be envisioned as a struggle between highly evolved complex DNA organisms, i.e., humans, and poorly evolved simple RNA organisms, i.e., SARS-CoV-2 virus. Quite surprisingly, the complex organism has a serious problem defeating the simplistic organism. However, humans are finally developing a new effective weapon in fighting the SARS-CoV-2 virus, paradoxically, RNA-based vaccines. These considerations underscore the relevance of microRNAs as powerful tools in therapeutic and preventive medicine.


Subject(s)
COVID-19 , MicroRNAs , Animals , Humans , MicroRNAs/genetics , Pandemics , SARS-CoV-2
3.
Cells ; 10(12)2021 12 11.
Article in English | MEDLINE | ID: covidwho-1572377

ABSTRACT

The SARS-CoV-2 (COVID-19) pandemic has caused millions of deaths worldwide. Early risk assessment of COVID-19 cases can help direct early treatment measures that have been shown to improve the prognosis of severe cases. Currently, circulating miRNAs have not been evaluated as canonical COVID-19 biomarkers, and identifying biomarkers that have a causal relationship with COVID-19 is imperative. To bridge these gaps, we aim to examine the causal effects of miRNAs on COVID-19 severity in this study using two-sample Mendelian randomization approaches. Multiple studies with available GWAS summary statistics data were retrieved. Using circulating miRNA expression data as exposure, and severe COVID-19 cases as outcomes, we identified ten unique miRNAs that showed causality across three phenotype groups of COVID-19. Using expression data from an independent study, we validated and identified two high-confidence miRNAs, namely, hsa-miR-30a-3p and hsa-miR-139-5p, which have putative causal effects on developing cases of severe COVID-19. Using existing literature and publicly available databases, the potential causative roles of these miRNAs were investigated. This study provides a novel way of utilizing miRNA eQTL data to help us identify potential miRNA biomarkers to make better and early diagnoses and risk assessments of severe COVID-19 cases.


Subject(s)
COVID-19/genetics , Circulating MicroRNA/genetics , MicroRNAs/genetics , Patient Acuity , SARS-CoV-2/genetics , Biomarkers/blood , COVID-19/blood , Circulating MicroRNA/blood , Genome-Wide Association Study , Humans , Mendelian Randomization Analysis , MicroRNAs/blood , SARS-CoV-2/metabolism
4.
Int J Mol Sci ; 22(24)2021 Dec 07.
Article in English | MEDLINE | ID: covidwho-1554804

ABSTRACT

In the last few years, microRNA-mediated regulation has been shown to be important in viral infections. In fact, viral microRNAs can alter cell physiology and act on the immune system; moreover, cellular microRNAs can regulate the virus cycle, influencing positively or negatively viral replication. Accordingly, microRNAs can represent diagnostic and prognostic biomarkers of infectious processes and a promising approach for designing targeted therapies. In the past 18 months, the COVID-19 infection from SARS-CoV-2 has engaged many researchers in the search for diagnostic and prognostic markers and the development of therapies. Although some research suggests that the SARS-CoV-2 genome can produce microRNAs and that host microRNAs may be involved in the cellular response to the virus, to date, not enough evidence has been provided. In this paper, using a focused bioinformatic approach exploring the SARS-CoV-2 genome, we propose that SARS-CoV-2 is able to produce microRNAs sharing a strong sequence homology with the human ones and also that human microRNAs may target viral RNA regulating the virus life cycle inside human cells. Interestingly, all viral miRNA sequences and some human miRNA target sites are conserved in more recent SARS-CoV-2 variants of concern (VOCs). Even if experimental evidence will be needed, in silico analysis represents a valuable source of information useful to understand the sophisticated molecular mechanisms of disease and to sustain biomedical applications.


Subject(s)
MicroRNAs/genetics , SARS-CoV-2/genetics , Virus Replication/genetics , COVID-19/genetics , Computational Biology/methods , DNA Viruses/genetics , Gene Expression/genetics , Gene Expression Regulation, Viral/genetics , Genome, Viral/genetics , Host-Pathogen Interactions/genetics , RNA, Viral/genetics , Sequence Homology
5.
Int J Mol Sci ; 22(19)2021 Sep 30.
Article in English | MEDLINE | ID: covidwho-1463706

ABSTRACT

In hearts, calcium (Ca2+) signaling is a crucial regulatory mechanism of muscle contraction and electrical signals that determine heart rhythm and control cell growth. Ca2+ signals must be tightly controlled for a healthy heart, and the impairment of Ca2+ handling proteins is a key hallmark of heart disease. The discovery of microRNA (miRNAs) as a new class of gene regulators has greatly expanded our understanding of the controlling module of cardiac Ca2+ cycling. Furthermore, many studies have explored the involvement of miRNAs in heart diseases. In this review, we aim to summarize cardiac Ca2+ signaling and Ca2+-related miRNAs in pathological conditions, including cardiac hypertrophy, heart failure, myocardial infarction, and atrial fibrillation. We also discuss the therapeutic potential of Ca2+-related miRNAs as a new target for the treatment of heart diseases.


Subject(s)
Atrial Fibrillation/genetics , Calcium Signaling/genetics , Calcium/metabolism , Heart Failure/genetics , MicroRNAs/genetics , Myocardial Infarction/genetics , Animals , Atrial Fibrillation/metabolism , Atrial Fibrillation/therapy , Gene Expression Regulation , Heart Failure/metabolism , Heart Failure/therapy , Humans , Myocardial Contraction/genetics , Myocardial Infarction/metabolism , Myocardial Infarction/therapy
6.
Int J Mol Med ; 47(5)2021 05.
Article in English | MEDLINE | ID: covidwho-1448967

ABSTRACT

Circular RNAs (circRNAs) are a class of non­coding RNAs with a circular, covalent structure that lack both 5' ends and 3' poly(A) tails, which are stable and specific molecules that exist in eukaryotic cells and are highly conserved. The role of circRNAs in viral infections is being increasingly acknowledged, since circRNAs have been discovered to be involved in several viral infections (such as hepatitis B virus infection and human papilloma virus infection) through a range of circRNA/microRNA/mRNA regulatory axes. These findings have prompted investigations into the potential of circRNAs as targets for the diagnosis and treatment of viral infection­related diseases. The aim of the present review was to systematically examine and discuss the role of circRNAs in several common viral infections, as well as their potential as diagnostic markers and therapeutic targets.


Subject(s)
MicroRNAs/genetics , RNA, Circular/physiology , RNA, Messenger/genetics , Virus Diseases/genetics , Biomarkers/analysis , Humans , RNA, Circular/genetics , Virus Diseases/diagnosis , Virus Diseases/therapy , Virus Diseases/virology
7.
Biomed Pharmacother ; 144: 112247, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1446461

ABSTRACT

COVID-19 is a pneumonia-like disease with highly transmittable and pathogenic properties caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which infects both animals and humans. Although many efforts are currently underway to test possible therapies, there is no specific FDA approved drug against SARS-CoV-2 yet. miRNA-directed gene regulation controls the majority of biological processes. In addition, the development and progression of several human diseases are associated with dysregulation of miRNAs. In this regard, it has been shown that changes in miRNAs are linked to severity of COVID-19 especially in patients with respiratory diseases, diabetes, heart failure or kidney problems. Therefore, targeting these small noncoding-RNAs could potentially alleviate complications from COVID-19. Here, we will review the roles and importance of host and RNA virus encoded miRNAs in COVID-19 pathogenicity and immune response. Then, we focus on potential miRNA therapeutics in the patients who are at increased risk for severe disease.


Subject(s)
Antiviral Agents/administration & dosage , COVID-19/therapy , Genetic Therapy/methods , MicroRNAs/administration & dosage , Animals , Antiviral Agents/immunology , COVID-19/genetics , COVID-19/immunology , Drug Delivery Systems/methods , Humans , MicroRNAs/genetics , MicroRNAs/immunology
8.
PLoS One ; 16(9): e0257878, 2021.
Article in English | MEDLINE | ID: covidwho-1443847

ABSTRACT

Extracellular microRNAs (miRNAs) have been proposed to function in cross-kingdom gene regulation. Among these, plant-derived miRNAs of dietary origin have been reported to survive the harsh conditions of the human digestive system, enter the circulatory system, and regulate gene expression and metabolic function. However, definitive evidence supporting the presence of plant-derived miRNAs of dietary origin in mammals has been difficult to obtain due to limited sample sizes. We have developed a bioinformatics pipeline (ePmiRNA_finder) that provides strident miRNA classification and applied it to analyze 421 small RNA sequencing data sets from 10 types of human body fluids and tissues and comparative samples from carnivores and herbivores. A total of 35 miRNAs were identified that map to plants typically found in the human diet and these miRNAs were found in at least one human blood sample and their abundance was significantly different when compared to samples from human microbiome or cow. The plant-derived miRNA profiles were body fluid/tissue-specific and highly abundant in the brain and the breast milk samples, indicating selective absorption and/or the ability to be transported across tissue/organ barriers. Our data provide conclusive evidence for the presence of plant-derived miRNAs as a consequence of dietary intake and their cross-kingdom regulatory function within human circulating system.


Subject(s)
Computational Biology/methods , MicroRNAs/genetics , Plants/genetics , Sequence Analysis, RNA/methods , Animal Feed/analysis , Animals , Brain Chemistry , Carnivora/genetics , Diet , Female , Herbivory/genetics , Humans , Milk, Human/chemistry , Organ Specificity , RNA, Plant/genetics , Sample Size
9.
Naunyn Schmiedebergs Arch Pharmacol ; 394(11): 2187-2195, 2021 11.
Article in English | MEDLINE | ID: covidwho-1442084

ABSTRACT

Millions of people around the world are involved with COVID-19 due to infection with SARS-CoV-2. Virological features of SARS-CoV-2, including its genomic sequence, have been identified but the mechanisms governing COVID-19 immunopathogenesis have remained uncertain. miR-223 is a hematopoietic cell-derived miRNA that is implicated in regulating monocyte-macrophage differentiation, neutrophil recruitment, and pro-inflammatory responses. The miR-223 controls inflammation by targeting a variety of factors, including TRAF6, IKKα, HSP-70, FOXO1, TLR4, PI3K/AKT, PARP-1, HDAC2, ITGB3, CXCL2, CCL3, IL-6, IFN-I, STMN1, IL-1ß, IL-18, Caspase-1, NF-κB, and NLRP3. The key role of miR-223 in regulating the inflammatory process and its antioxidant and antiviral role can suggest this miRNA as a potential regulatory factor in the process of COVID-19 immunopathogenesis.


Subject(s)
COVID-19/genetics , COVID-19/pathology , Inflammasomes/genetics , Inflammation/genetics , Inflammation/pathology , MicroRNAs/genetics , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , Animals , COVID-19/immunology , Humans , Inflammasomes/immunology , Inflammation/immunology
10.
Sci Rep ; 11(1): 19161, 2021 09 27.
Article in English | MEDLINE | ID: covidwho-1440480

ABSTRACT

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is associated with fatal pulmonary fibrosis. Small interfering RNAs (siRNAs) can be developed to induce RNA interference against SARS-CoV-2, and their susceptible target sites can be inferred by Argonaute crosslinking immunoprecipitation sequencing (AGO CLIP). Here, by reanalysing AGO CLIP data in RNA viruses, we delineated putative AGO binding in the conserved non-structural protein 12 (nsp12) region encoding RNA-dependent RNA polymerase (RdRP) in SARS-CoV-2. We utilised the inferred AGO binding to optimise the local RNA folding parameter to calculate target accessibility and predict all potent siRNA target sites in the SARS-CoV-2 genome, avoiding sequence variants. siRNAs loaded onto AGO also repressed seed (positions 2-8)-matched transcripts by acting as microRNAs (miRNAs). To utilise this, we further screened 13 potential siRNAs whose seed sequences were matched to known antifibrotic miRNAs and confirmed their miRNA-like activity. A miR-27-mimicking siRNA designed to target the nsp12 region (27/RdRP) was validated to silence a synthesised nsp12 RNA mimic in lung cell lines and function as an antifibrotic miR-27 in regulating target transcriptomes related to TGF-ß signalling. siRNA sequences with an antifibrotic miRNA-like activity that could synergistically treat COVID-19 are available online ( http://clip.korea.ac.kr/covid19 ).


Subject(s)
Argonaute Proteins/genetics , COVID-19/prevention & control , MicroRNAs/genetics , RNA, Small Interfering/genetics , SARS-CoV-2/genetics , A549 Cells , Argonaute Proteins/metabolism , Base Sequence , Binding Sites/genetics , COVID-19/virology , Cell Line , Coronavirus RNA-Dependent RNA Polymerase/genetics , Coronavirus RNA-Dependent RNA Polymerase/metabolism , Gene Expression Profiling/methods , HeLa Cells , Humans , Pulmonary Fibrosis/genetics , Pulmonary Fibrosis/metabolism , RNA Interference , RNA-Seq/methods , SARS-CoV-2/physiology , Sequence Homology, Nucleic Acid
11.
Cell Rep ; 37(3): 109839, 2021 10 19.
Article in English | MEDLINE | ID: covidwho-1439921

ABSTRACT

MicroRNAs (miRNAs) are small non-coding RNAs involved in post-transcriptional gene regulation that have a major impact on many diseases and provide an exciting avenue toward antiviral therapeutics. From patient transcriptomic data, we determined that a circulating miRNA, miR-2392, is directly involved with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) machinery during host infection. Specifically, we show that miR-2392 is key in driving downstream suppression of mitochondrial gene expression, increasing inflammation, glycolysis, and hypoxia, as well as promoting many symptoms associated with coronavirus disease 2019 (COVID-19) infection. We demonstrate that miR-2392 is present in the blood and urine of patients positive for COVID-19 but is not present in patients negative for COVID-19. These findings indicate the potential for developing a minimally invasive COVID-19 detection method. Lastly, using in vitro human and in vivo hamster models, we design a miRNA-based antiviral therapeutic that targets miR-2392, significantly reduces SARS-CoV-2 viability in hamsters, and may potentially inhibit a COVID-19 disease state in humans.


Subject(s)
COVID-19/genetics , COVID-19/immunology , MicroRNAs/genetics , SARS-CoV-2/genetics , Adult , Aged , Aged, 80 and over , Animals , Antiviral Agents/pharmacology , Biomarkers/metabolism , COVID-19/drug therapy , Cricetinae , Female , Ferrets , Gene Expression Regulation , Glycolysis , Healthy Volunteers , Humans , Hypoxia , Inflammation , Male , Mice , Middle Aged , Proteomics/methods , ROC Curve , Rats
12.
Int J Mol Sci ; 22(19)2021 Sep 26.
Article in English | MEDLINE | ID: covidwho-1438630

ABSTRACT

A high incidence of thromboembolic events associated with high mortality has been reported in severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infections with respiratory failure. The present study characterized post-transcriptional gene regulation by global microRNA (miRNA) expression in relation to activated coagulation and inflammation in 21 critically ill SARS-CoV-2 patients. The cohort consisted of patients with moderate respiratory failure (n = 11) and severe respiratory failure (n = 10) at an acute stage (day 0-3) and in the later course of the disease (>7 days). All patients needed supplemental oxygen and severe patients were defined by the requirement of positive pressure ventilation (intubation). Levels of D-dimers, activated partial thromboplastin time (aPTT), C-reactive protein (CRP), and interleukin (IL)-6 were significantly higher in patients with severe compared with moderate respiratory failure. Concurrently, next generation sequencing (NGS) analysis demonstrated increased dysregulation of miRNA expression with progression of disease severity connected to extreme downregulation of miR-320a, miR-320b and miR-320c. Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis revealed involvement in the Hippo signaling pathway, the transforming growth factor (TGF)-ß signaling pathway and in the regulation of adherens junctions. The expression of all miR-320 family members was significantly correlated with CRP, IL-6, and D-dimer levels. In conclusion, our analysis underlines the importance of thromboembolic processes in patients with respiratory failure and emphasizes miRNA-320s as potential biomarkers for severe progressive SARS-CoV-2 infection.


Subject(s)
COVID-19/complications , COVID-19/genetics , MicroRNAs/genetics , Respiratory Insufficiency/etiology , Respiratory Insufficiency/genetics , Aged , Aged, 80 and over , Blood Coagulation , COVID-19/blood , Disease Progression , Down-Regulation , Female , Humans , Inflammation/blood , Inflammation/etiology , Inflammation/genetics , Male , MicroRNAs/blood , Middle Aged , Respiratory Insufficiency/blood , SARS-CoV-2/isolation & purification , Severity of Illness Index
13.
Cell Biol Int ; 45(10): 2045-2053, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1404545

ABSTRACT

Coronavirus disease 2019 (COVID-19) is the seventh member of the bat severe acute respiratory syndrome family. COVID-19 can fuse their envelopes with the host cell membranes and deliver their genetic material. COVID-19 attacks the respiratory system and stimulates the host inflammatory responses, enhances the recruitment of immune cells, and promotes angiotensin-converting enzyme 2 activities. Patients with confirmed COVID-19 may have experienced fever, dry cough, headache, dyspnea, acute kidney injury, acute respiratory distress syndrome, and acute heart injury. Several strategies such as oxygen therapy, ventilation, antibiotic or antiviral therapy, and renal replacement therapy are commonly used to decrease COVID-19-associated mortality. However, these approaches may not be good treatment options. Therefore, the search for an alternative-novel therapy is urgently important to prevent the disease progression. Recently, microRNAs (miRNAs) have emerged as a promising strategy for COVID-19. The design of oligonucleotide against the genetic material of COVID-19 might suppress virus RNA translation. Several previous studies have shown that host miRNAs play an antiviral role and improve the treatment of patients with COVID-19. miRNAs by binding to the 3'-untranslated region (UTR) or 5'-UTR of viral RNA play an important role in COVID-19-host interplay and viral replication. miRNAs interact with multiple pathways and reduce inflammatory biomarkers, thrombi formation, and tissue damage to accelerate the patient outcome. The information in this review provides a summary of the current clinical application of miRNAs for the treatments of patients with COVID-19.


Subject(s)
COVID-19/genetics , COVID-19/therapy , MicroRNAs/therapeutic use , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Humans , MicroRNAs/genetics , SARS-CoV-2/pathogenicity , Virus Replication/drug effects , Virus Replication/genetics
14.
Viruses ; 13(1)2021 Jan 16.
Article in English | MEDLINE | ID: covidwho-1389525

ABSTRACT

Our recent study identified seven key microRNAs (miR-8066, 5197, 3611, 3934-3p, 1307-3p, 3691-3p, 1468-5p) similar between SARS-CoV-2 and the human genome, pointing at miR-related mechanisms in viral entry and the regulatory effects on host immunity. To identify the putative roles of these miRs in zoonosis, we assessed their conservation, compared with humans, in some key wild and domestic animal carriers of zoonotic viruses, including bat, pangolin, pig, cow, rat, and chicken. Out of the seven miRs under study, miR-3611 was the most strongly conserved across all species; miR-5197 was the most conserved in pangolin, pig, cow, bat, and rat; miR-1307 was most strongly conserved in pangolin, pig, cow, bat, and human; miR-3691-3p in pangolin, cow, and human; miR-3934-3p in pig and cow, followed by pangolin and bat; miR-1468 was most conserved in pangolin, pig, and bat; while miR-8066 was most conserved in pangolin and pig. In humans, miR-3611 and miR-1307 were most conserved, while miR-8066, miR-5197, miR-3334-3p and miR-1468 were least conserved, compared with pangolin, pig, cow, and bat. Furthermore, we identified that changes in the miR-5197 nucleotides between pangolin and human can generate three new miRs, with differing tissue distribution in the brain, lung, intestines, lymph nodes, and muscle, and with different downstream regulatory effects on KEGG pathways. This may be of considerable importance as miR-5197 is localized in the spike protein transcript area of the SARS-CoV-2 genome. Our findings may indicate roles for these miRs in viral-host co-evolution in zoonotic hosts, particularly highlighting pangolin, bat, cow, and pig as putative zoonotic carriers, while highlighting the miRs' roles in KEGG pathways linked to viral pathogenicity and host responses in humans. This in silico study paves the way for investigations into the roles of miRs in zoonotic disease.


Subject(s)
Biological Coevolution , MicroRNAs/genetics , SARS-CoV-2/genetics , Animals , COVID-19/transmission , COVID-19/virology , Chickens , Gene Regulatory Networks , Genome/genetics , Host Specificity , Humans , Mammals , MicroRNAs/chemistry , MicroRNAs/metabolism , SARS-CoV-2/pathogenicity , SARS-CoV-2/physiology , Sequence Alignment , Tissue Distribution , Zoonoses/transmission , Zoonoses/virology
15.
Arch Virol ; 166(1): 271-274, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-1384460

ABSTRACT

Viral RNAs can perturb the miRNA regulatory network, competing with host RNAs as part of their infective process. An in silico competing endogenous RNA (ceRNA) analysis has been carried on SARS-CoV-2. The results suggest that, in humans, the decrease of microRNA activity caused by viral RNAs can lead to a perturbation of vesicle trafficking and the inflammatory response, in particular by enhancing KLF10 activity. The results suggest also that, during the study of the mechanics of viral infections, it could be of general interest to investigate the competition of viral RNA with cellular transcripts for shared microRNAs.


Subject(s)
Gene Regulatory Networks/genetics , RNA, Messenger/genetics , RNA, Viral/genetics , SARS-CoV-2/genetics , A549 Cells , COVID-19/pathology , Cell Line, Tumor , Early Growth Response Transcription Factors/genetics , Early Growth Response Transcription Factors/metabolism , Humans , Kruppel-Like Transcription Factors/genetics , Kruppel-Like Transcription Factors/metabolism , MicroRNAs/genetics
16.
Int J Mol Sci ; 22(3)2021 Jan 31.
Article in English | MEDLINE | ID: covidwho-1383877

ABSTRACT

Extracellular vesicles (EVs), such as exosomes, are newly recognized fundamental, universally produced natural nanoparticles of life that are seemingly involved in all biologic processes and clinical diseases. Due to their universal involvements, understanding the nature and also the potential therapeutic uses of these nanovesicles requires innovative experimental approaches in virtually every field. Of the EV group, exosome nanovesicles and larger companion micro vesicles can mediate completely new biologic and clinical processes dependent on the intercellular transfer of proteins and most importantly selected RNAs, particularly miRNAs between donor and targeted cells to elicit epigenetic alterations inducing functional cellular changes. These recipient acceptor cells are nearby (paracrine transfers) or far away after distribution via the circulation (endocrine transfers). The major properties of such vesicles seem to have been conserved over eons, suggesting that they may have ancient evolutionary origins arising perhaps even before cells in the primordial soup from which life evolved. Their potential ancient evolutionary attributes may be responsible for the ability of some modern-day exosomes to withstand unusually harsh conditions, perhaps due to unique membrane lipid compositions. This is exemplified by ability of the maternal milk exosomes to survive passing the neonatal acid/enzyme rich stomach. It is postulated that this resistance also applies to their durable presence in phagolysosomes, thus suggesting a unique intracellular release of their contained miRNAs. A major discussed issue is the generally poorly realized superiority of these naturally evolved nanovesicles for therapies when compared to human-engineered artificial nanoparticles, e.g., for the treatment of diseases like cancers.


Subject(s)
Cell- and Tissue-Based Therapy , Exosomes/metabolism , Extracellular Vesicles/metabolism , MicroRNAs/genetics , Neoplasms/therapy , Humans , Nanoparticles/therapeutic use
17.
Int J Mol Sci ; 21(13)2020 Jul 07.
Article in English | MEDLINE | ID: covidwho-1389380

ABSTRACT

The SARS-CoV-2 virus is a recently-emerged zoonotic pathogen already well adapted to transmission and replication in humans. Although the mutation rate is limited, recently introduced mutations in SARS-CoV-2 have the potential to alter viral fitness. In addition to amino acid changes, mutations could affect RNA secondary structure critical to viral life cycle, or interfere with sequences targeted by host miRNAs. We have analysed subsets of genomes from SARS-CoV-2 isolates from around the globe and show that several mutations introduce changes in Watson-Crick pairing, with resultant changes in predicted secondary structure. Filtering to targets matching miRNAs expressed in SARS-CoV-2-permissive host cells, we identified ten separate target sequences in the SARS-CoV-2 genome; three of these targets have been lost through conserved mutations. A genomic site targeted by the highly abundant miR-197-5p, overexpressed in patients with cardiovascular disease, is lost by a conserved mutation. Our results are compatible with a model that SARS-CoV-2 replication within the human host is constrained by host miRNA defences. The impact of these and further mutations on secondary structures, miRNA targets or potential splice sites offers a new context in which to view future SARS-CoV-2 evolution, and a potential platform for engineering conditional attenuation to vaccine development, as well as providing a better understanding of viral tropism and pathogenesis.


Subject(s)
Betacoronavirus/genetics , Genome, Viral , MicroRNAs/metabolism , RNA, Viral/chemistry , 3' Untranslated Regions , Base Sequence , COVID-19 , Coronavirus Infections/pathology , Coronavirus Infections/virology , Databases, Genetic , Humans , MicroRNAs/chemistry , MicroRNAs/genetics , Mutation , Nucleic Acid Conformation , Pandemics , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , RNA Splice Sites , RNA Splicing , SARS-CoV-2 , Sequence Alignment , Viral Nonstructural Proteins/genetics , Viral Proteins/chemistry , Viral Proteins/genetics , Viral Proteins/metabolism
18.
Biomed Res Int ; 2021: 8112783, 2021.
Article in English | MEDLINE | ID: covidwho-1378089

ABSTRACT

Long noncoding RNAs (lncRNAs) have been reported to participate in regulating many biological processes, including immune response to influenza A virus (IAV). However, the association between lncRNA expression profiles and influenza infection susceptibility has not been well elucidated. Here, we analyzed the expression profiles of lncRNAs, miRNAs, and mRNAs among IAV-infected adult rat (IAR), normal adult rat (AR), IAV-infected junior rat (IJR), and normal junior rat (JR) by RNA sequencing. Compared with differently expressed lncRNAs (DElncRNAs) between AR and IAR, 24 specific DElncRNAs were found between IJR and JR. Then, based on the fold changes and P value, the top 5 DElncRNAs, including 3 upregulated and 2 downregulated lncRNAs, were chosen to establish a ceRNA network for further disclosing their regulatory mechanisms. To visualize the differentially expressed genes in the ceRNA network, GO and KEGG pathway analysis was performed to further explore their roles in influenza infection of junior rats. The results showed that the downregulated DElncRNA-target genes were mostly enriched in the IL-17 signaling pathway. It indicated that the downregulated lncRNAs conferred the susceptibility of junior rats to IAV via mediating the IL-17 signaling pathway.


Subject(s)
Influenza A virus/pathogenicity , MicroRNAs/genetics , Orthomyxoviridae Infections/genetics , RNA, Long Noncoding/genetics , RNA, Messenger/genetics , Animals , Disease Models, Animal , Disease Susceptibility , Gene Expression Profiling , Influenza A virus/isolation & purification , Interleukin-17/genetics , Interleukin-17/immunology , MicroRNAs/immunology , Orthomyxoviridae Infections/immunology , Orthomyxoviridae Infections/pathology , Orthomyxoviridae Infections/virology , RNA, Long Noncoding/immunology , RNA, Messenger/immunology , Rats , Rats, Sprague-Dawley
19.
Adv Clin Exp Med ; 30(8): 839-848, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1359472

ABSTRACT

BACKGROUND: Long non-coding RNAs (lncRNAs) are involved in the development of many cancers, including colorectal cancer (CRC). FEZ family zinc finger 1 antisense RNA 1 (FEZF1-AS1) is a key lncRNA in the regulation of CRC progression, but its potential molecular mechanisms need to be further explored. OBJECTIVES: To investigate the mechanism of lncRNA FEZF1-AS1 in the progression of CRC. MATERIAL AND METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to measure FEZF1-AS1 and miR-363-3p expression. Cell proliferation, migration and invasion were analyzed using Cell Counting Kit-8 (CCK-8) and transwell assays. Protein expression of epithelial-mesenchymal transformation (EMT)-related markers and paired-related homeobox 1 (PRRX1) were determined using western blot analysis. The interactions among FEZF1-AS1, miR-363-3p and PRRX1 were verified with dual-luciferase reporter assay. A xenograft model was constructed in vivo to confirm the role of FEZF1-AS1 in CRC tumor growth. RESULTS: We demonstrated that FEZF1-AS1 expression was upregulated in CRC, and its silencing reduced CRC cell proliferation, migration, invasion, and EMT. MiR-363-3p could be inhibited by FEZF1-AS1, which inhibitor could reverse the suppressive effect of FEZF1-AS1 silencing on CRC progression. Paired-related homeobox 1 could be targeted by miR-363-3p, and the inhibitory effect of FEZF1-AS1 knockdown on CRC progression could also be eliminated by PRRX1 overexpression. Furthermore, interference of FEZF1-AS1 reduced the tumor growth of CRC in vivo. CONCLUSIONS: Our data demonstrate that FEZF1-AS1 regulated PRRX1 expression to promote CRC progression via inhibition of miR-363-3p.


Subject(s)
Colorectal Neoplasms , MicroRNAs , RNA, Long Noncoding , Cell Proliferation , Colorectal Neoplasms/genetics , Epithelial-Mesenchymal Transition , Homeodomain Proteins , Humans , MicroRNAs/genetics , RNA, Long Noncoding/genetics , Repressor Proteins
20.
Viruses ; 13(8)2021 08 11.
Article in English | MEDLINE | ID: covidwho-1355047

ABSTRACT

Cleavage of double-stranded RNA is described as an evolutionary conserved host defense mechanism against viral infection. Small RNAs are the product and triggers of post transcriptional gene silencing events. Up until now, the relevance of this mechanism for SARS-CoV-2-directed immune responses remains elusive. Herein, we used high throughput sequencing to profile the plasma of active and convalescent COVID-19 patients for the presence of small circulating RNAs. The existence of SARS-CoV-2 derived small RNAs in plasma samples of mild and severe COVID-19 cases is described. Clusters of high siRNA abundance were discovered, homologous to the nsp2 3'-end and nsp4 virus sequence. Four virus-derived small RNA sequences have the size of human miRNAs, and a target search revealed candidate genes associated with ageusia and long COVID symptoms. These virus-derived small RNAs were detectable also after recovery from the disease. The additional analysis of circulating human miRNAs revealed differentially abundant miRNAs, discriminating mild from severe cases. A total of 29 miRNAs were reduced or absent in severe cases. Several of these are associated with JAK-STAT response and cytokine storm.


Subject(s)
COVID-19/blood , COVID-19/virology , Cell-Free Nucleic Acids/blood , MicroRNAs/blood , RNA, Viral/blood , SARS-CoV-2/genetics , COVID-19/complications , COVID-19/genetics , Female , Genome, Viral , High-Throughput Nucleotide Sequencing , Humans , Male , MicroRNAs/genetics , RNA, Viral/genetics , Severity of Illness Index , Viral Nonstructural Proteins/genetics
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