Background
Many arguments suggest that neutrophils could play a prominent role in COVID‐19. However, the role of key components of neutrophil innate immunity in severe forms of COVID‐19 has deserved ...insufficient attention. We aimed to evaluate the involvement of neutrophil elastase, histone‐DNA, and DNases in systemic and multi‐organ manifestations of COVID‐19.
Methods
We performed a multicenter study of markers of neutrophil innate immunity in 155 cases consecutively recruited in a screening center, local hospitals, and two regional university hospitals. The cases were evaluated according to clinical and biological markers of severity and multi‐organ manifestations and compared to 35 healthy controls.
Results
Blood neutrophil elastase, histone‐DNA, myeloperoxidase‐DNA, and free dsDNA were dramatically increased, and DNase activity was decreased by 10‐fold, compared with controls. Neutrophil elastase and histone‐DNA were associated with intensive care admission, body temperature, lung damage, and markers of cardiovascular outcomes, renal failure, and increased interleukin‐6 (IL‐6), IL‐8, and CXCR2. Neutrophil elastase was an independent predictor of the computed tomography score of COVID‐19 lung damage and the number of affected organs, in multivariate analyses. The increased blood concentrations of NE and neutrophil extracellular traps were related to exacerbation of neutrophil stimulation through IL‐8 and CXCR2 increased concentrations and increased serum DAMPs, and to impaired degradation of NETs as a consequence of the dramatic decrease in blood DNase activity.
Conclusion
Our results point out the key role of neutrophil innate immunity exacerbation in COVID‐19. Neutrophil elastase and DNase could be potential biomarkers and therapeutic targets of severe systemic manifestations of COVID‐19.
Blood levels of neutrophil elastase and histone‐DNA are associated with severe and systemic and multi‐organ manifestations of COVID‐19. Increased blood concentrations of neutrophil elastase and neutrophil extracellular traps are related to exacerbation of neutrophil stimulation through activated IL‐8/CXCR2 pathway. Neutrophil elastase and DNase could be potential biomarkers and therapeutic targets of severe systemic manifestations of COVID‐19.
Abbreviations: COVID‐19, coronavirus disease 2019; CXCR2, C‐X‐C motif chemokine receptor 2; ds, double‐stranded; NETs, neutrophil extracellular traps; NF, nuclear factor; SARS‐CoV‐2, severe acute respiratory syndrome coronavirus 2.
Convergent arguments suggest that innate immunity related to neutrophils, and in particular neutrophil extracellular traps (NETs), could play a key role in response to SARS-CoV-2 infection.
Background
Nonimmediate (delayed)‐allergic reactions to penicillins are common and some of them can be life‐threatening. The genetic factors influencing these reactions are unknown/poorly ...known/poorly understood. We assessed the genetic predictors of a delayed penicillin allergy that cover the HLA loci.
Methods
Using next‐generation sequencing (NGS), we genotyped the MHC region in 24 patients with delayed hypersensitivity compared with 20 patients with documented immediate hypersensitivity to penicillins recruited in Italy. Subsequently, we analyzed in silico Illumina Immunochip genotyping data that covered the HLA loci in 98 Spanish patients with delayed hypersensitivity and 315 with immediate hypersensitivity compared to 1,308 controls.
Results
The two alleles DRB3*02:02:01:02 and DRB3*02:02:01:01 were reported in twenty cases with delayed reactions (83%) and ten cases with immediate reactions (50%), but not in the Allele Frequency Net Database. Bearing at least one of the two alleles increased the risk of delayed reactions compared to immediate reactions, with an OR of 8.88 (95% CI, 3.37–23.32; p < .0001). The haplotype (ACAA) from rs9268835, rs6923504, rs6903608, and rs9268838 genetic variants of the HLA‐DRB3 genomic region was significantly associated with an increased risk of delayed hypersensitivity to penicillins (OR, 1.7; 95% CI: 1.06–1.92; p = .001), but not immediate hypersensitivity.
Conclusion
We showed that the HLA‐DRB3 locus is strongly associated with an increased risk of delayed penicillin hypersensitivity, at least in Southwestern Europe. The determination of HLA‐DRB3*02:02 alleles in the risk management of severe delayed hypersensitivity to penicillins should be evaluated further in larger population samples of different origins.
We demonstrate a strong association between HLA‐DRB3 locus and the risk of delayed hypersensitivity to penicillins. Bearing at least one of the two alleles DRB3*02:02:01:02 and DRB3*02:02:01:01 increases the risk of delayed reactions compared to immediate reactions. The HLA‐DRB3 ACAA haplotype is significantly associated with the risk of delayed hypersensitivity to penicillins.Abbreviations: Cl; confidence interval; HLA, human leukocyte antigen; NGS, next‐generation sequencing; OR, odds ratio; seq, sequencing
Folate and fetal programming: a play in epigenomics? Guéant, Jean-Louis; Namour, Fares; Guéant-Rodriguez, Rosa-Maria ...
Trends in endocrinology and metabolism,
06/2013, Letnik:
24, Številka:
6
Journal Article
Recenzirano
Folate plays a key role in the interactions between nutrition, fetal programming, and epigenomics. Maternal folate status influences DNA methylation, inheritance of the agouti phenotype, expression ...of imprinting genes, and the effects of mycotoxin FB1 on heterochromatin assembly in rodent offspring. Deficiency in folate and other methyl donors increases birth defects and produces visceral manifestations of fetal programming, including liver and heart steatosis, through imbalanced methylation and acetylation of PGC1-α and decreased SIRT1 expression, and produces persistent cognitive and learning disabilities through impaired plasticity and hippocampal atrophy. Maternal folate supplementation also produces long-term epigenomic effects in offspring, some beneficial and others negative. Deciphering these mechanisms will help understanding the discordances between experimental models and population studies of folate deficiency and supplementation.
Homocysteine (Hcy) is a non-protein forming amino acid which is the direct metabolic precursor of methionine. Increased concentration of serum Hcy is considered a risk factor for cardiovascular ...disease and is specifically linked to various diseases of the vasculature. Serum Hcy is associated with atherosclerosis, hypertension and aneurysms of the aorta in humans, though the precise mechanisms by which Hcy contributes to these conditions remain elusive. Results from clinical trials that successfully lowered serum Hcy without reducing features of vascular disease in cardiovascular patients have cast doubt on whether or not Hcy directly impacts the vasculature. However, studies in animals and in cell culture suggest that Hcy has a vast array of toxic effects on the vasculature, with demonstrated roles in endothelial dysfunction, medial remodeling and adventitial inflammation. It is hypothesized that rather than serum Hcy, tissue-bound Hcy and the incorporation of Hcy into proteins could underlie the toxic effects of Hcy on the vasculature. In this review, we present evidence for Hcy-associated vascular disease in humans, and we critically examine the possible mechanisms by which Hcy specifically impacts the endothelial, medial and adventitial layers of the arterial wall. Deciphering the mechanisms by which Hcy interacts with proteins in the arterial wall will allow for a better understanding of the pathomechanisms of hyperhomocysteinemia and will help to define a better means of prevention at the appropriate window of life.
Scope
Vitamin B12 and folate (methyl donors) deficiency is frequent during pregnancy. Experimental rat models with methyl donor deficit during pregnancy and lactation (Initial methyl donor deficit ...(iMDD)) produce impaired myocardium fatty acid oxidation and mitochondrial energy metabolism at weaning.
Methods and Results
The consequences of iMDD on heart of rat pups under normal diet after weaning and high fat diet (HF) between day (D) 50 and D185 are investigated. iMDD/HF induces increased histological fibrosis and increased B‐type natriuretic peptide blood level. Inflammation is evidenced by increased protein expression of NFkB, Caspase1, and IL1β and fibrosis by increased expression of αSMA, col1a1, and col1a2 in females, but not in males. Fibrosis is related to increased angiotensin at D50 and D185 and increased protein expression of TGFB1 and AT1 angiotensin receptors at D185. The limited fibrosis in males is consistent with increased expression of AT2, the antagonist receptor of AT1. The increased expression of GLUT4 and decreased expression of PGC1α and PPARα reflect a shift from fatty acid oxidation to glycolysis.
Conclusion
Developmental programming by iMDD produces cardiomyopathy in female offspring exposed to HF. The cardiomyopathy is linked to inflammation and fibrosis through angiotensin‐AT2 and TGFB1 pathways and alteration of energy metabolism.
A fetal programming of methyl donor deficiency during gestation and lactation (iMDD) is shown previously, with low birth weight and cardiac hypertrophy in rat offspring; it produced cardiomyopathy in day‐185 female offspring exposed to high‐fat diet since day‐50, with inflammation and fibrosis through angiotensin and TGFB1 pathways. The limited fibrosis in males is related to increased expression of angiotensin receptor AT2.
The worldwide obesity epidemic has been mainly attributed to lifestyle changes. However, who becomes obese in an obesity-prone environment is largely determined by genetic factors. In the last ...20 years, important progress has been made in the elucidation of the genetic architecture of obesity. In parallel with successful gene identifications, the number of gene-environment interaction (GEI) studies has grown rapidly. This paper reviews the growing body of evidence supporting gene-environment interactions in the field of obesity. Heritability, monogenic and polygenic obesity studies provide converging evidence that obesity-predisposing genes interact with a variety of environmental, lifestyle and treatment exposures. However, some skepticism remains regarding the validity of these studies based on several issues, which include statistical modelling, confounding, low replication rate, underpowered analyses, biological assumptions and measurement precision. What follows in this review includes (1) an introduction to the study of GEI, (2) the evidence of GEI in the field of obesity, (3) an outline of the biological mechanisms that may explain these interaction effects, (4) methodological challenges associated with GEI studies and potential solutions, and (5) future directions of GEI research. Thus far, this growing body of evidence has provided a deeper understanding of GEI influencing obesity and may have tremendous applications in the emerging field of personalized medicine and individualized lifestyle recommendations.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are the drugs most frequently involved in drug hypersensitivity reactions through mechanisms that may involve genetic predisposition. We performed a ...fine-mapping GWAS in patients with NSAID-induced hypersen-sitivity reactions with cross-intolerance belonging to the group of NSAID-induced urticaria, angioedema, and anaphylaxis (NIUAA) (2) and matched controls from South Spain, and we replicated the re-sults in patients and paired controls from central Spain. GNAI2 was a significant predictor of NSAID-induced hypersensitivity reactions. This association may reflect its influence on the activation of leukot-riene receptors and the recruitment of immune cells involved in the pathological mechanisms of NSAID hypersensitivity.
In patients with severe coronavirus disease 2019 (COVID-19), data are scarce and conflicting regarding whether chronic use of angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor ...blocker (ARB) influences disease outcomes. In patients with severe COVID-19, we assessed the association between chronic ACEI/ARB use and the occurrence of kidney, lung, heart, and liver dysfunctions and the severity of the inflammatory reaction as evaluated by biomarkers kinetics, and their association with disease outcomes.
We performed a retrospective longitudinal cohort study on consecutive patients with newly diagnosed severe COVID-19. Independent predictors were assessed through receiver operating characteristic analysis, time-series analysis, logistic regression analysis, and multilevel modeling for repeated measures.
On the 149 patients included in the study 30% (44/149) were treated with ACEI/ARB. ACEI/ARB use was independently associated with the following biochemical variations: phosphorus >40 mg/L (odds ratio OR, 3.35, 95% confidence interval CI, 1.83-6.14), creatinine >10.1 mg/L (OR, 3.22, 2.28-4.54), and urea nitrogen (UN) >0.52 g/L (OR, 2.65, 95% CI, 1.89-3.73). ACEI/ARB use was independently associated with acute kidney injury stage ≥1 (OR, 3.28, 95% CI, 2.17-4.94). The daily dose of ACEI/ARB was independently associated with altered kidney markers with an increased risk of +25 to +31% per each 10 mg increment of lisinopril-dose equivalent. In multivariable multilevel modeling, UN >0.52 g/L was independently associated with the risk of acute respiratory failure (OR, 3.54, 95% CI, 1.05-11.96).
Patients chronically treated with ACEI/ARB who have severe COVID-19 are at increased risk of acute kidney injury. In these patients, the increase in UN associated with ACEI/ARB use could predict the development of acute respiratory failure.
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