scholarly journals In plain sight: the role of alpha-1-antitrypsin in COVID-19 pathogenesis and therapeutics

2020 ◽  
Author(s):  
Kasopefoluwa Y Oguntuyo ◽  
Christian S Stevens ◽  
Mohammed NA Siddiquey ◽  
Robert M Schilke ◽  
Matthew D Woolard ◽  
...  
Keyword(s):  
Risk Factors ◽  
Protease Inhibitor ◽  
Viral Entry ◽  
Significant Inhibition ◽  
Regulatory Activity ◽  
Factors Associated ◽  
Virus Tropism ◽  
Alpha 1 Antitrypsin

ABSTRACTEntry of SARS-CoV-2 is facilitated by endogenous and exogenous proteases. These proteases proteolytically activate the SARS-CoV-2 spike glycoprotein and are key modulators of virus tropism. We show that SARS-CoV-2 naïve serum exhibits significant inhibition of SARS-CoV-2 entry. We identify alpha-1-antitrypsin (AAT) as the major serum protease inhibitor that potently restrict protease-mediated entry of SARS-CoV-2. AAT inhibition of protease-mediated SARS-CoV-2 entry in vitro occurs at concentrations far below what is present in serum and bronchoalveolar tissues, suggesting that AAT effects are physiologically relevant. Moreover, AAT deficiency affects up to 20% of the population and its symptomatic manifestations coincides with many risk factors associated with severe COVID-19 disease. In addition to the effects that AAT may have on viral entry itself, we argue that the anti-inflammatory and coagulation regulatory activity of AAT have implications for coronavirus disease 2019 (COVID-19) pathogenicity, SARS-CoV-2 tissue restriction, convalescent plasma therapies, and even potentially AAT therapy.

scholarly journals Role of β-Adrenergic Receptors and Nitric Oxide Signaling in Exercise-Mediated Cardioprotection

Physiology ◽  
2013 ◽  
Vol 28 (4) ◽  
pp. 216-224 ◽  
Author(s):  
John W. Calvert ◽  
David J. Lefer
Keyword(s):  
Nitric Oxide ◽  
Risk Factors ◽  
Adrenergic Receptors ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Nitric Oxide Signaling ◽  
Factors Associated ◽  
Cardioprotective Effects ◽  
Β Adrenergic Receptors

Exercise promotes cardioprotection in both humans and animals not only by reducing risk factors associated with cardiovascular disease but by reducing myocardial infarction and improving survival following ischemia. This article will define the role that nitric oxide and β-adrenergic receptors play in mediating the cardioprotective effects of exercise in the setting of ischemia-reperfusion injury.

scholarly journals Risk factors associated with delirium in a general ICU: role of S-100 protein

Critical Care ◽  
2008 ◽  
Vol 12 (Suppl 2) ◽  
pp. P513
Author(s):  
A Rubino ◽  
F Forfori ◽  
G Licitra ◽  
P Cosimini ◽  
F Foltran ◽  
...  
Keyword(s):  
Risk Factors ◽  
Factors Associated ◽  
S 100

scholarly journals ROLE OF VARIOUS RISK FACTORS ASSOCIATED WITH CARDIOVASCULAR DISEASES

2013 ◽  
Vol 4 (5) ◽  
pp. 44-50
Author(s):  
Pranay Wal ◽  
Ankita Wal ◽  
Nikita Saraswat ◽  
Shalini Singh ◽  
Shikha Bajpai
Keyword(s):  
Risk Factors ◽  
Cardiovascular Diseases ◽  
Factors Associated

scholarly journals The role of Neuropilin-1 in COVID-19

2021 ◽  
Vol 17 (1) ◽  
pp. e1009153
Author(s):  
Bindu S. Mayi ◽  
Jillian A. Leibowitz ◽  
Arden T. Woods ◽  
Katherine A. Ammon ◽  
Alphonse E. Liu ◽  
...  
Keyword(s):  
Immune Function ◽  
Viral Entry ◽  
Axonal Guidance ◽  
Cell Surface Receptor ◽  
Neuropilin 1 ◽  
Surface Receptor ◽  
The Central Nervous System

Neuropilin-1 (NRP-1), a member of a family of signaling proteins, was shown to serve as an entry factor and potentiate SARS Coronavirus 2 (SARS-CoV-2) infectivity in vitro. This cell surface receptor with its disseminated expression is important in angiogenesis, tumor progression, viral entry, axonal guidance, and immune function. NRP-1 is implicated in several aspects of a SARS-CoV-2 infection including possible spread through the olfactory bulb and into the central nervous system and increased NRP-1 RNA expression in lungs of severe Coronavirus Disease 2019 (COVID-19). Up-regulation of NRP-1 protein in diabetic kidney cells hint at its importance in a population at risk of severe COVID-19. Involvement of NRP-1 in immune function is compelling, given the role of an exaggerated immune response in disease severity and deaths due to COVID-19. NRP-1 has been suggested to be an immune checkpoint of T cell memory. It is unknown whether involvement and up-regulation of NRP-1 in COVID-19 may translate into disease outcome and long-term consequences, including possible immune dysfunction. It is prudent to further research NRP-1 and its possibility of serving as a therapeutic target in SARS-CoV-2 infections. We anticipate that widespread expression, abundance in the respiratory and olfactory epithelium, and the functionalities of NRP-1 factor into the multiple systemic effects of COVID-19 and challenges we face in management of disease and potential long-term sequelae.

scholarly journals Risk factors associated with the antimicrobial resistance of Staphylococcus aureus isolated from bovine mastitis

2014 ◽  
Vol 34 (10) ◽  
pp. 947-952 ◽  
Author(s):  
Daniele C. Beuron ◽  
Cristina S. Cortinhas ◽  
Bruno G. Botaro ◽  
Susana N. Macedo ◽  
Juliano L. Gonçalves ◽  
...  
Keyword(s):  
Risk Factors ◽  
Staphylococcus Aureus ◽  
Antimicrobial Resistance ◽  
Antimicrobial Susceptibility ◽  
Management Practices ◽  
Bovine Mastitis ◽  
Factors Associated ◽  
Milk Samples ◽  
Treatment Procedures

The objective of this study was to evaluate herd management practices and mastitis treatment procedures as risk factors associated with Staphylococcus aureus antimicrobial resistance. For this study, 13 herds were selected to participate in the study to evaluate the association between their management practices and mastitis treatment procedures and in vitro antimicrobial susceptibility. A total of 1069 composite milk samples were collected aseptically from the selected cows in four different periods over two years. The samples were used for microbiological culturing of S. aureus isolates and evaluation of their antimicrobial susceptibility. A total of 756 samples (70.7%) were culture-positive, and S. aureus comprised 27.77% (n=210) of the isolates. The S. aureus isolates were tested using the disk-diffusion susceptibility assay with the following antimicrobials: ampicillin 10mg; clindamycin 2μg; penicillin 1mg; ceftiofur 30μg; gentamicin 10mg; sulfa-trimethoprim 25μg; enrofloxacin 5μg; sulfonamide 300μg; tetracycline 30μg; oxacillin 1mg; cephalothin 30μg and erythromycin 5μg. The variables that were significantly associated with S. aureus resistance were as follows: the treatment of clinical mastitis for ampicillin (OR=2.18), dry cow treatment for enrofloxacin (OR=2.11) and not sending milk samples for microbiological culture and susceptibility tests, for ampicillin (OR=2.57) and penicillin (OR=4.69). In conclusion, the identification of risk factors for S. aureus resistance against various mastitis antimicrobials is an important information that may help in practical recommendations for prudent use of antimicrobial in milk production.

The Role of CXCR4 Inhibitors as Novel Antiangiogenesis Agents in Cancer Therapy.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1296-1296
Author(s):  
Irene M. Ghobrial ◽  
Michael M. Timm ◽  
Karen E. Hedin ◽  
Thomas E. Witzig
Keyword(s):  
Endothelial Cells ◽  
Map Kinase ◽  
Kinase Inhibitor ◽  
Negative Control ◽  
Model System ◽  
Significant Inhibition ◽  
Inhibitory Antibody ◽  
Inhibition Of Angiogenesis

Abstract Angiogenesis plays an important role in tumor growth. Endothelial cells express the chemokine receptor CXCR4, and interact with its ligand SDF-1/CXCL12. Previous studies have demonstrated that the ERK MAP kinase and the PI3Kinase pathways are activated in response to SDF-1 stimulation. In this study, we investigate the effect of the role of inhibitors of CXCR4, ERK MAP kinase and PI3Kinase on angiogenesis. The AngioKit (TCS Cellworks, U.K) is a 24 well plate in which human endothelial cells are co-cultured with other human myoblasts and fibroblasts in a specially designed medium. Control wells in the kit include media alone, VEGF (+control) and suramin (-control). Test samples were added on the day the kits arrive, then changed on days 4, 7, and 9, and stained on day 11 with CD31 (PECAM). The wells are then photographed and subjected to image analysis. The software measures angiogenesis as total tubule length per well in microns. Test samples can then be compared to the control wells to determine the drugs affect on angiogenesis in vitro. The following drugs were tested in this angiogenesis model system, a human CXCR4 neutralizing antibody (MAB 171, R&D systems, MN), SDF-1, the MAP kinase inhibitor PD098059, and the PI3Kinase inhibitor LY294002. Treatment with the CXCR4 inhibitory antibody, PD098059, and LY294002 caused marked decrease in angiogenesis (below the level of the negative control suramin). Inhibition of angiogenesis below the level of suramin was first detected at 1mg/ml CXCR4 antibody, and10mg/ml CXCR4 antibody resulted in complete inhibition of angiogenesis. The effect of PD098059 on angiogenesis was dependent on its concentration; 20mM PD098059 inhibited angiogenesis while lower concentrations did not. These results are consistent with the drug’s known concentration-dependent inhibition of MEK-1 and indicate that the MEK-1 inhibitor leads to angiostasis secondary to its specific inhibitory effect on MEK-1. The lowest level tested of 1μM LY294002 led to inhibition of angiogenesis, and 50μM of LY294002 led to complete abrogation of angiogenesis. SDF-1 has been reported to be angiogenic. In this model system, the effect of SDF-1 alone on angiogenesis was subtle. However, the endothelial cells used in this model system may be secreting endogenous SDF-1 leading to the saturation of the CXCR4 receptor and minimal effects of exogenous SDF-1 stimulation. This was demonstrated by the significant effect of the CXCR4 inhibitor on angiogenesis without the addition of exogenous SDF-1. These results indicate that CXCR4 inhibition and its downstream pathways PI3K and ERK MAP kinase lead to significant inhibition of angiogenesis, and suggest that selective inhibitors of CXCR4 may be useful agents to inhibit angiogenesis.

Risk factors associated with sensitive skin and potential role of lifestyle habits: a cross-sectional study

2017 ◽  
Vol 42 (6) ◽  
pp. 656-658 ◽  
Author(s):  
D. Falcone ◽  
R. J. H. Richters ◽  
N. E. Uzunbajakava ◽  
P. E. J. van Erp ◽  
P. C. M. van de Kerkhof
Keyword(s):  
Risk Factors ◽  
Potential Role ◽  
Cross Sectional Study ◽  
Sectional Study ◽  
Sensitive Skin ◽  
Lifestyle Habits ◽  
Cross Sectional ◽  
Factors Associated

scholarly journals Overexpressing PLA2G6 mutations cause symptoms of young–onset dystonia–parkinsonism type 14 and reduction in DHA levels in zebrafish model

2020 ◽  
Author(s):  
Tu-Hsueh Yeh ◽  
Han-Fang Liu ◽  
Mei-Ling Cheng ◽  
Yin-Cheng Huang ◽  
Ying-Zu Huang ◽  
...  
Keyword(s):  
Risk Factors ◽  
Dopaminergic Neurons ◽  
Molecular Mechanisms ◽  
Motor Disorder ◽  
Loss Of Function ◽  
Phospholipase Activity ◽  
Young Onset ◽  
Factors Associated ◽  
Metabolomics Analysis

Abstract Background: Parkinson’s disease (PD) is the most common neurodegenerative motor disorder, which is currently incurable. Mutations in many genes have been demonstrated to be the primary risk factors associated with the familial or idiopathic PD; however, the mechanisms underlying these genetic mutations resulting in parkinsonism remains unclear. Phospholipase A2 group VI (PLA2G6) has been shown to regulate lipid metabolism and homeostasis in the nervous system. Previous studies have shown that point mutations in PLA2G6 might be the risk factors associated with the young–onset of dystonia–parkinsonism type 14 (PARK14). However, limited information is available regarding its pathogenic role and the mechanism underlying its function. Methods: To study the role of PLA2G6 mutations in zebrafish PARK14 models, we injected different mutation constructs of human PLA2G6 genes and zebrafish pla2g6 deletion constructs in the zebrafish larvae. We analyzed the locomotion behavior, performed immunohistochemistry to examine the formation of dopaminergic neurons, and identified the defective metabolites affected by PLA2G6 mutations through metabolomics analysis. Results: Injection of human PLA2G6 mutations and zebrafish pla2g6 deletion constructs induced symptoms such as motility defects and reduced number of dopaminergic neurons, and these symptoms resembled those observed in PARK14. These phenotypes could be rescued by treatment with L-dopa. Furthermore, the injection of two PLA2G6 mutation constructs, D331Y and T572I, led to a decrease in the phospholipase activity of PLA2G6 and its lipid metabolites, indicating that these two mutations are the loss-of-function mutations. We further performed metabolomics analysis to identify which lipids are majorly affected by the overexpression of PLA2G6 and PLA2G6 mutants. We found that injecting D331Y or T572I mutation constructs led to higher phospholipid and lower DHA levels. Conclusions: D331Y and T572I injections in zebrafish were sufficient to create a PD phenotypes. In addition, D331Y and T572I are loss of function mutations and cause defective phospholipase activity and reduced the level of DHA. These results have helped us elucidate the role of PLA2G6 mutations in PARK14 and further led to a deeper understanding of the molecular mechanisms underlying PD. The results of this study may also facilitate the development of therapeutic strategies for PD.

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