Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 20 de 11.273
Filter
1.
Molecules ; 27(11)2022 May 26.
Article in English | MEDLINE | ID: covidwho-1866459

ABSTRACT

Dipyridamole, apart from its well-known antiplatelet and phosphodiesterase inhibitory activities, is a promising old drug for the treatment of pulmonary fibrosis. However, dipyridamole shows poor pharmacokinetic properties with a half-life (T1/2) of 7 min in rat liver microsomes (RLM). To improve the metabolic stability of dipyridamole, a series of pyrimidopyrimidine derivatives have been designed with the assistance of molecular docking. Among all the twenty-four synthesized compounds, compound (S)-4h showed outstanding metabolic stability (T1/2 = 67 min) in RLM, with an IC50 of 332 nM against PDE5. Furthermore, some interesting structure-activity relationships (SAR) were explained with the assistance of molecular docking.


Subject(s)
Dipyridamole , Idiopathic Pulmonary Fibrosis , Animals , Dipyridamole/pharmacology , Dipyridamole/therapeutic use , Idiopathic Pulmonary Fibrosis/drug therapy , Idiopathic Pulmonary Fibrosis/metabolism , Microsomes, Liver/metabolism , Molecular Docking Simulation , Molecular Structure , Rats , Structure-Activity Relationship
2.
Cell Physiol Biochem ; 56(3): 254-269, 2022 Jun 07.
Article in English | MEDLINE | ID: covidwho-1879823

ABSTRACT

BACKGROUND/AIMS: Quantitative and qualitative alterations in the sense of smell are well established symptoms of COVID-19. Some reports have shown that non-neuronal supporting (also named sustentacular) cells of the human olfactory epithelium co-express ACE2 and TMPRSS2 necessary for SARS-CoV-2 infection. In COVID-19, syncytia were found in many tissues but were not investigated in the olfactory epithelium. Some studies have shown that syncytia in some tissues are formed when SARS-CoV-2 Spike expressed at the surface of an infected cell binds to ACE2 on another cell, followed by activation of the scramblase TMEM16F (also named ANO6) which exposes phosphatidylserine to the external side of the membrane. Furthermore, niclosamide, an approved antihelminthic drug, inhibits Spike-induced syncytia by blocking TMEM16F activity. The aim of this study was to investigate if proteins involved in Spike-induced syncytia formation, i.e., ACE2 and TMEM16F, are expressed in the human olfactory epithelium. METHODS: We analysed a publicly available single-cell RNA-seq dataset from human nasal epithelium and performed immunohistochemistry in human nasal tissues from biopsies. RESULTS: We found that ACE2 and TMEM16F are co-expressed both at RNA and protein levels in non-neuronal supporting cells of the human olfactory epithelium. CONCLUSION: Our results provide the first evidence that TMEM16F is expressed in human olfactory supporting cells and indicate that syncytia formation, that could be blocked by niclosamide, is one of the pathogenic mechanisms worth investigating in COVID-19 smell loss.


Subject(s)
COVID-19 , SARS-CoV-2 , Angiotensin-Converting Enzyme 2/genetics , Anosmia , Giant Cells , Humans , Lipids , Niclosamide , Olfactory Mucosa/metabolism
3.
Stud Health Technol Inform ; 290: 694-698, 2022 Jun 06.
Article in English | MEDLINE | ID: covidwho-1879417

ABSTRACT

The COVID-19 pandemic has caused millions of infections and deaths worldwide in an ongoing pandemic. With the passage of time, several variants of this virus have surfaced. Machine learning methods and algorithms have been very useful in understanding the virus and its implications so far. In this paper, we have studied a set of novelty detection algorithms and applied it to the problem of detecting COVID-19 variants. Our results show accuracies of 79.64% and 82.43% on the B.1.1.7 and B.1.351 variants respectively on ProtVec unaligned COVID-19 spike protein sequences using One Class SVM with fine-tuned parameters. We believe that a system for automated and timely detection of variants will help countries formulate mitigation measures and study remedies in terms of medicines and vaccines that can protect against the new variants.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , Pandemics/prevention & control , Spike Glycoprotein, Coronavirus/metabolism
4.
PLoS One ; 17(6): e0268919, 2022.
Article in English | MEDLINE | ID: covidwho-1879310

ABSTRACT

The appearance of new variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the lack of effective antiviral therapeutics for coronavirus disease 2019 (COVID-19), a highly infectious disease caused by the virus, demands the search for alternative therapies. Most antiviral drugs known are passive defenders which must enter the cell to execute their function and suffer from concerns such as permeability and effectiveness, therefore in this current study, we aim to identify peptide inactivators that can act without entering the cells. SARS-CoV-2 spike protein is an essential protein that plays a major role in binding to the host receptor angiotensin-converting enzyme 2 and mediates the viral cell membrane fusion process. SARS vaccines and treatments have also been developed with the spike protein as a target. The virtual screening experiment revealed antiviral peptides which were found to be non-allergen, non-toxic and possess good water solubility. U-1, GST-removed-HR2 and HR2-18 exhibit binding energies of -47.8 kcal/mol, -43.01 kcal/mol, and -40.46 kcal/mol, respectively. The complexes between these peptides and spike protein were stabilized through hydrogen bonds as well as hydrophobic interactions. The stability of the top-ranked peptide with the drug-receptor is evidenced by 50-ns molecular dynamics (MD) simulations. The binding of U-1 induces conformational changes in the spike protein with alterations in its geometric properties such as increased flexibility, decreased compactness, the increased surface area exposed to solvent molecules, and an increase in the number of total hydrogen bonds leading to its probable inactivation. Thus, the identified antiviral peptides can be used as anti-SARS-CoV-2 candidates, inactivating the virus's spike proteins and preventing it from infecting host cells.


Subject(s)
COVID-19 , SARS-CoV-2 , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Humans , Molecular Docking Simulation , Peptides/metabolism , Peptides/pharmacology , Protein Binding , Spike Glycoprotein, Coronavirus/chemistry
5.
J Nanobiotechnology ; 20(1): 260, 2022 Jun 07.
Article in English | MEDLINE | ID: covidwho-1879240

ABSTRACT

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), seriously threatens human life and health. The correct folding and polymerization of the receptor-binding domain (RBD) protein of coronavirus in Escherichia coli may reduce the cost of SARS-CoV-2 vaccines. In this study, we constructed this nanopore by using the principle of ClyA porin polymerization triggered by the cell membrane. We used surfactants to "pick" the ClyA-RBD nanopore from the bacterial outer membrane. More importantly, the polymerized RBD displayed on the ClyA-RBD polymerized porin (RBD-PP) already displays some correct spatial conformational epitopes that can induce neutralizing antibodies. The nanostructures of RBD-PP can target lymph nodes and promote antigen uptake and processing by dendritic cells, thereby effectively eliciting the production of anti-SARS-CoV-2 neutralizing antibodies, systemic cellular immune responses, and memory T cells. We applied this PP-based vaccine platform to fabricate an RBD-based subunit vaccine against SARS-CoV-2, which will provide a foundation for the development of inexpensive coronavirus vaccines. The development of a novel vaccine delivery system is an important part of innovative drug research. This novel PP-based vaccine platform is likely to have additional applications, including other viral vaccines, bacterial vaccines, tumor vaccines, drug delivery, and disease diagnosis.


Subject(s)
COVID-19 Vaccines , COVID-19 , Antibodies, Neutralizing , Antibodies, Viral/metabolism , COVID-19/prevention & control , Humans , Polymerization , Porins , SARS-CoV-2 , Spike Glycoprotein, Coronavirus
6.
Blood Adv ; 6(11): 3367-3377, 2022 06 14.
Article in English | MEDLINE | ID: covidwho-1879216

ABSTRACT

Coagulation activation is a prominent feature of severe acute respiratory syndrome coronavirus 2 (COVID-19) infection. Activation of the contact system and intrinsic pathway has increasingly been implicated in the prothrombotic state observed in both sterile and infectious inflammatory conditions. We therefore sought to assess activation of the contact system and intrinsic pathway in individuals with COVID-19 infection. Baseline plasma levels of protease:serpin complexes indicative of activation of the contact and intrinsic pathways were measured in samples from inpatients with COVID-19 and healthy individuals. Cleaved kininogen, a surrogate for bradykinin release, was measured by enzyme-linked immunosorbent assay, and extrinsic pathway activation was assessed by microvesicle tissue factor-mediated factor Xa (FXa; MVTF) generation. Samples were collected within 24 hours of COVID-19 diagnosis. Thirty patients with COVID-19 and 30 age- and sex-matched controls were enrolled. Contact system and intrinsic pathway activation in COVID-19 was demonstrated by increased plasma levels of FXIIa:C1 esterase inhibitor (C1), kallikrein:C1, FXIa:C1, FXIa:α1-antitrypsin, and FIXa:antithrombin (AT). MVTF levels were also increased in patients with COVID-19. Because FIXa:AT levels were associated with both contact/intrinsic pathway complexes and MVTF, activation of FIX likely occurs through both contact/intrinsic and extrinsic pathways. Among the protease:serpin complexes measured, FIXa:AT complexes were uniquely associated with clinical indices of disease severity, specifically total length of hospitalization, length of intensive care unit stay, and extent of lung computed tomography changes. We conclude that the contact/intrinsic pathway may contribute to the pathogenesis of the prothrombotic state in COVID-19. Larger prospective studies are required to confirm whether FIXa:AT complexes are a clinically useful biomarker of adverse clinical outcomes.


Subject(s)
COVID-19 , Antithrombin III , Antithrombins , Blood Coagulation , COVID-19 Testing , Factor Xa , Humans , Kallikreins/metabolism
7.
Commun Biol ; 5(1): 542, 2022 06 03.
Article in English | MEDLINE | ID: covidwho-1878558

ABSTRACT

The well documented association between obesity and the severity of SARS-CoV-2 infection raises the question of whether adipose tissue (AT) is impacted during this infection. Using a model of SARS-CoV-2 infection in cynomolgus macaques, we detected the virus within subcutaneous AT (SCAT) but not in visceral AT (VAT) or epicardial AT on day 7 post-infection. We sought to determine the mechanisms responsible for this selective detection and observed higher levels of angiotensin-converting-enzyme-2 mRNA expression in SCAT than in VAT. Lastly, we evaluated the immunological consequences of SARS-CoV-2 infection on AT: both SCAT and VAT T cells showed a drastic reduction in CD69 expression, a standard marker of resident memory T cell in tissue, that is also involved in the migratory and metabolic properties of T cells. Our results demonstrate that in a model of mild infection, SCAT is selectively infected by SARS-CoV-2 although changes in the immune properties of AT are observed in both SCAT and VAT.


Subject(s)
COVID-19 , SARS-CoV-2 , Adipose Tissue , Animals , Homeostasis , Lymphocytes , Macaca , Subcutaneous Fat/metabolism
8.
J Antibiot (Tokyo) ; 75(6): 321-332, 2022 Jun.
Article in English | MEDLINE | ID: covidwho-1878523

ABSTRACT

Staphylococcus aureus is one of the most dangerous pathogens commonly associated with high levels of morbidity and mortality. Sortase A is considered as a promising molecular target for the development of antistaphylococcal agents. Using hybrid virtual screening approach and FRET analysis, we have identified five compounds able to decrease the activity of sortase A by more than 50% at the concentration of 200 µM. The most promising compound was 2-(2-amino-3-chloro-benzoylamino)-benzoic acid which was able to inhibit S. aureus sortase A at the IC50 value of 59.7 µM. This compound was selective toward sortase A compared to other four cysteine proteases - cathepsin L, cathepsin B, rhodesain, and the SARS-CoV2 main protease. Microscale thermophoresis experiments confirmed that this compound bound sortase A with KD value of 189 µM. Antibacterial and antibiofilm assays also confirmed high specificity of the hit compound against two standard and three wild-type, S. aureus hospital infection isolates. The effect of the compound on biofilms produced by two S. aureus ATCC strains was also observed suggesting that the compound reduced biofilm formation by changing the biofilm structure and thickness.


Subject(s)
COVID-19 , Staphylococcal Infections , Aminoacyltransferases , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Bacterial Proteins/metabolism , Biofilms , Cysteine Endopeptidases , Humans , Microbial Sensitivity Tests , RNA, Viral/pharmacology , SARS-CoV-2 , Staphylococcus aureus
9.
ACS Appl Bio Mater ; 5(5): 2307-2315, 2022 05 16.
Article in English | MEDLINE | ID: covidwho-1878485

ABSTRACT

Older people have been disproportionately vulnerable to the current SARS-CoV-2 pandemic, with an increased risk of severe complications and death compared to other age groups. A mix of underlying factors has been speculated to give rise to this differential infection outcome including changes in lung physiology, weakened immunity, and severe immune response. Our study focuses on the impact of biomechanical changes in lungs that occur as individuals age, that is, the stiffening of the lung parenchyma and increased matrix fiber density. We used hydrogels with an elastic modulus of 0.2 and 50 kPa and conventional tissue culture surfaces to investigate how infection rate changes with parenchymal tissue stiffness in lung epithelial cells challenged with SARS-CoV-2 Spike (S) protein pseudotyped lentiviruses. Further, we employed electrospun fiber matrices to isolate the effect of matrix density. Given the recent data highlighting the importance of alternative virulent strains, we included both the native strain identified in early 2020 and an early S protein variant (D614G) that was shown to increase the viral infectivity markedly. Our results show that cells on softer and sparser scaffolds, closer resembling younger lungs, exhibit higher infection rates by the WT and D614G variant. This suggests that natural changes in lung biomechanics do not increase the propensity for SARS-CoV-2 infection and that other factors, such as a weaker immune system, may contribute to increased disease burden in the elderly.


Subject(s)
COVID-19 , SARS-CoV-2 , Aged , Humans , Pandemics , Spike Glycoprotein, Coronavirus/metabolism
10.
Molecules ; 27(9)2022 May 02.
Article in English | MEDLINE | ID: covidwho-1875712

ABSTRACT

Hydroxylated polyphenols, also called flavonoids, are richly present in vegetables, fruits, cereals, nuts, herbs, seeds, stems, and flowers of numerous plants. They possess numerous medicinal properties such as antioxidant, anti-cancer, anti-microbial, neuroprotective, and anti-inflammation. Studies show that flavonoids activate antioxidant pathways that render an anti-inflammatory effect. They inhibit the secretions of enzymes such as lysozymes and ß-glucuronidase and inhibit the secretion of arachidonic acid, which reduces inflammatory reactions. Flavonoids such as quercetin, genistein, apigenin, kaempferol, and epigallocatechin 3-gallate modulate the expression and activation of a cytokine such as interleukin-1beta (IL-1ß), Tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-8 (IL-8); regulate the gene expression of many pro-inflammatory molecules such s nuclear factor kappa-light chain enhancer of activated B cells (NF-κB), activator protein-1 (AP-1), intercellular adhesion molecule-1 (ICAM), vascular cell adhesion molecule-1 (VCAM), and E-selectins; and also inhibits inducible nitric oxide (NO) synthase, cyclooxygenase-2, and lipoxygenase, which are pro-inflammatory enzymes. Understanding the anti-inflammatory action of flavonoids provides better treatment options, including coronavirus disease 2019 (COVID-19)-induced inflammation, inflammatory bowel disease, obstructive pulmonary disorder, arthritis, Alzheimer's disease, cardiovascular disease, atherosclerosis, and cancer. This review highlights the sources, biochemical activities, and role of flavonoids in enhancing human health.


Subject(s)
COVID-19 , Flavonoids , Anti-Inflammatory Agents/adverse effects , Antioxidants/adverse effects , Flavonoids/chemistry , Flavonoids/pharmacology , Flavonoids/therapeutic use , Humans , Inflammation/drug therapy , NF-kappa B/metabolism , Tumor Necrosis Factor-alpha/pharmacology
11.
Mar Drugs ; 20(5)2022 Apr 28.
Article in English | MEDLINE | ID: covidwho-1875691

ABSTRACT

Nowadays, the logarithmic production of existing well-known food materials is unable to keep up with the demand caused by the exponential growth of the human population in terms of the equality of access to food materials. Famous local food materials with treasury properties such as mangrove fruits are an excellent source to be listed as emerging food candidates with ethnomedicinal properties. Thus, this study reviews the nutrition content of several edible mangrove fruits and the innovation to improve the fruit into a highly economic food product. Within the mangrove fruit, the levels of primary metabolites such as carbohydrates, protein, and fat are acceptable for daily intake. The mangrove fruits, seeds, and endophytic fungi are rich in phenolic compounds, limonoids, and their derivatives as the compounds present a multitude of bioactivities such as antimicrobial, anticancer, and antioxidant. In the intermediary process, the flour of mangrove fruit stands as a supplementation for the existing flour with antidiabetic or antioxidant properties. The mangrove fruit is successfully transformed into many processed food products. However, limited fruits from species such as Bruguiera gymnorrhiza, Rhizophora mucronata, Sonneratia caseolaris, and Avicennia marina are commonly upgraded into traditional food, though many more species demonstrate ethnomedicinal properties. In the Middle East, A. marina is the dominant species, and the study of the phytochemicals and fruit development is limited. Therefore, studies on the development of mangrove fruits to functional for other mangrove species are demanding. The locally accepted mangrove fruit is coveted as an alternate food material to support the sustainable development goal of eliminating world hunger in sustainable ways.


Subject(s)
Fruit , Rhizophoraceae , Antioxidants/metabolism , Functional Food , Humans , Phytochemicals/analysis , Rhizophoraceae/metabolism
12.
Int J Mol Sci ; 23(10)2022 May 22.
Article in English | MEDLINE | ID: covidwho-1875645

ABSTRACT

Actinidia latifolia is one of the very few kiwifruit genotypes with extremely high ascorbic acid (AsA) content. However, a transcriptome atlas of this species is lacking. The accumulation of AsA during fruit development and ripening and the associated molecular mechanisms are still poorly understood. Herein, dynamic changes in AsA content at six different stages of A. latifolia fruit development and ripening were determined. AsA content of A. latifolia fruit reached 1108.76 ± 35.26 mg 100 g-1 FW at full maturity. A high-quality, full-length (FL) transcriptome of A. latifolia was successfully constructed for the first time using third-generation sequencing technology. The transcriptome comprises 326,926 FL non-chimeric reads, 15,505 coding sequences, 2882 transcription factors, 18,797 simple sequence repeats, 3328 long noncoding RNAs, and 231 alternative splicing events. The genes involved in AsA biosynthesis and recycling pathways were identified and compared with those in different kiwifruit genotypes. The correlation between the AsA content and expression levels of key genes in AsA biosynthesis and recycling pathways was revealed. LncRNAs that participate in AsA-related gene expression regulation were also identified. Gene expression patterns in AsA biosynthesis and metabolism exhibited a trend similar to that of AsA accumulation. Overall, this study paves the way for genetic engineering to develop kiwifruits with super-high AsA content.


Subject(s)
Actinidia , Actinidia/genetics , Actinidia/metabolism , Ascorbic Acid/metabolism , Fruit/metabolism , Gene Expression Regulation, Plant , Transcriptome
13.
Int J Mol Sci ; 23(10)2022 May 17.
Article in English | MEDLINE | ID: covidwho-1875644

ABSTRACT

The global utilization of single-use, non-biodegradable plastics, such as bottles made of polyethylene terephthalate (PET), has contributed to catastrophic levels of plastic pollution. Fortunately, microbial communities are adapting to assimilate plastic waste. Previously, our work showed a full consortium of five bacteria capable of synergistically degrading PET. Using omics approaches, we identified the key genes implicated in PET degradation within the consortium's pangenome and transcriptome. This analysis led to the discovery of a novel PETase, EstB, which has been observed to hydrolyze the oligomer BHET and the polymer PET. Besides the genes implicated in PET degradation, many other biodegradation genes were discovered. Over 200 plastic and plasticizer degradation-related genes were discovered through the Plastic Microbial Biodegradation Database (PMBD). Diverse carbon source utilization was observed by a microbial community-based assay, which, paired with an abundant number of plastic- and plasticizer-degrading enzymes, indicates a promising possibility for mixed plastic degradation. Using RNAseq differential analysis, several genes were predicted to be involved in PET degradation, including aldehyde dehydrogenases and several classes of hydrolases. Active transcription of PET monomer metabolism was also observed, including the generation of polyhydroxyalkanoate (PHA)/polyhydroxybutyrate (PHB) biopolymers. These results present an exciting opportunity for the bio-recycling of mixed plastic waste with upcycling potential.


Subject(s)
Microbial Consortia , Polyethylene Terephthalates , Bacteria/genetics , Bacteria/metabolism , Plasticizers , Plastics/metabolism
14.
Int J Mol Sci ; 23(10)2022 May 16.
Article in English | MEDLINE | ID: covidwho-1875642

ABSTRACT

Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is an overactivated inflammatory response caused by direct or indirect injuries that destroy lung parenchymal cells and dramatically reduce lung function. Although some research progress has been made in recent years, the pathogenesis of ALI/ARDS remains unclear due to its heterogeneity and etiology. MicroRNAs (miRNAs), a type of small noncoding RNA, play a vital role in various diseases. In ALI/ARDS, miRNAs can regulate inflammatory and immune responses by targeting specific molecules. Regulation of miRNA expression can reduce damage and promote the recovery of ALI/ARDS. Consequently, miRNAs are considered as potential diagnostic indicators and therapeutic targets of ALI/ARDS. Given that inflammation plays an important role in the pathogenesis of ALI/ARDS, we review the miRNAs involved in the inflammatory process of ALI/ARDS to provide new ideas for the pathogenesis, clinical diagnosis, and treatment of ALI/ARDS.


Subject(s)
Acute Lung Injury , MicroRNAs , Respiratory Distress Syndrome , Acute Lung Injury/metabolism , Humans , Inflammation/genetics , Lung/metabolism , MicroRNAs/genetics , Respiratory Distress Syndrome/genetics
15.
Cells ; 11(10)2022 May 11.
Article in English | MEDLINE | ID: covidwho-1875501

ABSTRACT

DEAD/H-box proteins are the largest family of RNA helicases in mammalian genomes, and they are present in all kingdoms of life. Since their discovery in the late 1980s, DEAD/H-box family proteins have been a major focus of study. They have been found to play central roles in RNA metabolism, gene expression, signal transduction, programmed cell death, and the immune response to bacterial and viral infections. Aberrant functions of DEAD/H-box proteins have been implicated in a wide range of human diseases that include cancer, neurodegeneration, and inherited genetic disorders. In this review, we provide a historical context and discuss the molecular functions of DEAD/H-box proteins, highlighting the recent discoveries linking their dysregulation to human diseases. We will also discuss the state of knowledge regarding two specific DEAD/H-box proteins that have critical roles in immune responses and programmed cell death, DDX3X and DDX58, also known as RIG-I. Given their importance in homeostasis and disease, an improved understanding of DEAD/H-box protein biology and protein-protein interactions will be critical for informing strategies to counteract the pathogenesis associated with several human diseases.


Subject(s)
DEAD-box RNA Helicases , RNA , Animals , Cell Death , Cell Differentiation , DEAD-box RNA Helicases/metabolism , DNA Helicases , Humans , Inflammation , Mammals/metabolism , RNA/metabolism
16.
Front Public Health ; 10: 914193, 2022.
Article in English | MEDLINE | ID: covidwho-1875442

ABSTRACT

Background: RNA N6-methyladenosine (m6A) regulators may be necessary for diverse viral infectious diseases, and serve pivotal roles in various physiological functions. However, the potential roles of m6A regulators in coronavirus disease 2019 (COVID-19) remain unclear. Methods: The gene expression profile of patients with or without COVID-19 was acquired from Gene Expression Omnibus (GEO) database, and bioinformatics analysis of differentially expressed genes was conducted. Random forest modal and nomogram were established to predict the occurrence of COVID-19. Afterward, the consensus clustering method was utilized to establish two different m6A subtypes, and associations between subtypes and immunity were explored. Results: Based on the transcriptional data from GSE157103, we observed that the m6A modification level was markedly enriched in the COVID-19 patients than those in the non-COVID-19 patients. And 18 essential m6A regulators were identified with differential analysis between patients with or without COVID-19. The random forest model was utilized to determine 8 optimal m6A regulators for predicting the emergence of COVID-19. We then established a nomogram based on these regulators, and its predictive reliability was validated by decision curve analysis. The consensus clustering algorithm was conducted to categorize COVID-19 patients into two m6A subtypes from the identified m6A regulators. The patients in cluster A were correlated with activated T-cell functions and may have a superior prognosis. Conclusions: Collectively, m6A regulators may be involved in the prevalence of COVID-19 patients. Our exploration of m6A subtypes may benefit the development of subsequent treatment modalities for COVID-19.


Subject(s)
COVID-19 , Adenosine/genetics , Adenosine/metabolism , COVID-19/epidemiology , Humans , Methylation , RNA/genetics , RNA/metabolism , Reproducibility of Results
17.
Genome Med ; 14(1): 46, 2022 05 03.
Article in English | MEDLINE | ID: covidwho-1875023

ABSTRACT

BACKGROUND: Natural killer (NK) cells are innate lymphoid cells that mediate antitumour and antiviral responses. However, very little is known about how ageing influences human NK cells, especially at the single-cell level. METHODS: We applied single-cell sequencing (scRNA-seq) to human lymphocytes and NK cells from 4 young and 4 elderly individuals and then analysed the transcriptome data using Seurat. We detected the proportion and phenotype of NK cell subsets in peripheral blood samples from a total of 62 young and 52 elderly healthy donors by flow cytometry. We also used flow cytometry to examine the effector functions of NK cell subsets upon IFN-α/IL-12+IL-15/K562/IL-2 stimulation in vitro in peripheral blood samples from a total of 64 young and 63 elderly healthy donors. We finally studied and integrated single-cell transcriptomes of NK cells from 15 young and 41 elderly COVID-19 patients with those from 12 young and 6 elderly healthy control individuals to investigate the impacts of ageing on NK cell subsets in COVID-19 disease. RESULTS: We discovered a memory-like NK subpopulation (NK2) exhibiting the largest distribution change between elderly and young individuals among lymphocytes. Notably, we discovered a unique NK subset that was predominantly CD52+ NK2 cells (NK2.1). These memory-like NK2.1 cells accumulated with age, exhibited proinflammatory characteristics, and displayed a type I interferon response state. Integrative analyses of a large-cohort COVID-19 dataset and our datasets revealed that NK2.1 cells from elderly COVID-19 patients are enriched for type I interferon signalling, which is positively correlated with disease severity in COVID-19. CONCLUSIONS: We identified a unique memory-like NK cell subset that accumulates with ageing and correlates with disease severity in COVID-19. Our results identify memory-like NK2.1 cells as a potential target for developing immunotherapies for infectious diseases and for addressing age-related dysfunctions of the immune system.


Subject(s)
COVID-19 , Transcriptome , Aged , Aging/genetics , Humans , Immunity, Innate , Killer Cells, Natural/metabolism , Severity of Illness Index
18.
J Clin Invest ; 132(10)2022 May 16.
Article in English | MEDLINE | ID: covidwho-1874936

ABSTRACT

Food addiction is characterized by a loss of behavioral control over food intake and is associated with obesity and other eating disorders. The mechanisms underlying this behavioral disorder are largely unknown. We aimed to investigate the changes in miRNA expression promoted by food addiction in animals and humans and their involvement in the mechanisms underlying the behavioral hallmarks of this disorder. We found sharp similitudes between miRNA signatures in the medial prefrontal cortex (mPFC) of our animal cohort and circulating miRNA levels in our human cohort, which allowed us to identify several miRNAs of potential interest in the development of this disorder. Tough decoy (TuD) inhibition of miRNA-29c-3p in the mouse mPFC promoted persistence of the response and enhanced vulnerability to developing food addiction, whereas miRNA-665-3p inhibition promoted compulsion-like behavior and also enhanced food addiction vulnerability. In contrast, we found that miRNA-137-3p inhibition in the mPFC did not lead to the development of food addiction. Therefore, miRNA-29c-3p and miRNA-665-3p could be acting as protective factors with regard to food addiction. We believe the elucidation of these epigenetic mechanisms will lead to advances toward identifying innovative biomarkers and possible future interventions for food addiction and related disorders based on the strategies now available to modify miRNA activity and expression.


Subject(s)
Food Addiction , MicroRNAs , Animals , Food Addiction/genetics , Humans , Mice , MicroRNAs/metabolism , Prefrontal Cortex/metabolism
19.
J Physiol Pharmacol ; 73(1)2022 Feb.
Article in English | MEDLINE | ID: covidwho-1876428

ABSTRACT

Coronavirus disease 2019 (COVID-19) causes cardiovascular damage in the acute period. Knowledge regarding cardiovascular damage after COVID-19 infection and during longer-term follow-up is currently limited. In our study, we aimed to compare cardiac and inflammatory markers and echocardiographic parameters between patients who had recovered from COVID-19 and control group. A total of 224 individuals were included, comprising 126 patients with a history of COVID-19 and 98 healthy controls. The demographic characteristics of the two groups were similar. Complete blood count, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), N-terminal pro-B type natriuretic peptide (NT-ProBNP), D-dimer, haemoglobin A1C, troponin T and creatine kinase myocardial band (CK-MB) levels were compared between both groups. The mean follow-up period of the COVID-19 group was 58.39 ± 39.1 days (range:10 - 180 days post-COVID-19). Red cell distribution width (RDW), ESR, CRP, NT-ProBNP, D-dimer and troponin T values were significantly higher in the COVID-19 group compared to the control group. Left ventricular ejection fraction (LVEF) was significantly lower in the COVID-19 group. Left ventricular diastolic diameter (LVDD) and incidence of pericardial effusion were higher in the COVID-19 group. For multivariate analysis, possible factors identified by univariate analysis were subjected to multivariate logistic regression analysis to determine independent predictors of COVID-19. Among these factors, RDW, CRP and LVEF were independently higher in the COVID-19 group than in the control group. We conclude that although the clinical and prognostic significance of cardiac and other inflammatory markers in the acute phase of COVID-19 is known, we found that these biomarkers and echocardiography parameters can also be used in the follow-up of cardiac injury for a mid-term period post-infection.


Subject(s)
COVID-19 , Heart Diseases , Biomarkers , C-Reactive Protein/metabolism , Echocardiography , Heart Diseases/diagnosis , Heart Diseases/virology , Humans , Stroke Volume , Troponin T , Ventricular Function, Left
20.
Viruses ; 14(5)2022 05 23.
Article in English | MEDLINE | ID: covidwho-1875812

ABSTRACT

This review is an accompaniment to a Special Issue on "Retroviral RNA Processing". It discusses post-transcriptional regulation of retroviruses, ranging from the ancient foamy viruses to more modern viruses, such as HIV-1, HTLV-1, Rous sarcoma virus, murine leukemia virus, mouse mammary tumor virus, and Mason-Pfizer monkey virus. This review is not comprehensive. However, it tries to address some of the major questions in the field with examples of how different retroviruses express their genes. It is amazing that a single primary RNA transcript can have so many possible fates: genomic RNA, unspliced mRNA, and up to 50 different alternatively spliced mRNAs. This review will discuss the sorting of RNAs for packaging or translation, RNA nuclear export mechanisms, splicing, translation, RNA modifications, and avoidance of nonsense-mediated RNA decay.


Subject(s)
RNA, Viral , Retroviridae , Active Transport, Cell Nucleus , Animals , Leukemia Virus, Murine/genetics , Mice , RNA Processing, Post-Transcriptional , RNA, Messenger/metabolism , RNA, Viral/genetics , RNA, Viral/metabolism , Retroviridae/genetics , Retroviridae/metabolism
SELECTION OF CITATIONS
SEARCH DETAIL