Phenol-soluble modulins (PSMs), such as α-PSMs, β-PSMs, and δ-toxin, are virulence peptides secreted by different Staphylococcus aureus strains. PSMs are able to form amyloid fibrils, which may strengthen the biofilm matrix that promotes bacterial colonization of and extended growth on surfaces (e.g., cell tissue) and increases antibiotic resistance. Many components contribute to biofilm formation, including the human-produced highly sulfated glycosaminoglycan heparin. Although heparin promotes S. aureus infection, the molecular basis for this is unclear. Given that heparin is known to induce fibrillation of a wide range of proteins, we hypothesized that heparin aids bacterial colonization by promoting PSM fibrillation. Here, we address this hypothesis using a combination of thioflavin T-fluorescence kinetic studies, CD, FTIR, electron microscopy, and peptide microarrays to investigate the mechanism of aggregation, the structure of the fibrils, and identify possible binding regions. We found that heparin accelerates fibrillation of all α-PSMs (except PSMα2) and δ-toxin but inhibits β-PSM fibrillation by blocking nucleation or reducing fibrillation levels. Given that S. aureus secretes higher levels of α-PSM than β-PSM peptides, heparin is therefore likely to promote fibrillation overall. Heparin binding is driven by multiple positively charged lysine residues in α-PSMs and δ-toxins, the removal of which strongly reduced binding affinity. Binding of heparin did not affect the structure of the resulting fibrils, that is, the outcome of the aggregation process. Rather, heparin provided a scaffold to catalyze or inhibit fibrillation. Based on our findings, we speculate that heparin may strengthen the bacterial biofilm and therefore enhance colonization via increased PSM fibrillation.
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http://dx.doi.org/10.1016/j.jbc.2021.100953 | DOI Listing |
Pharmaceuticals (Basel)
November 2024
Independent Researcher, 5345 MT Oss, The Netherlands.
(1) Background: Danaparoid sodium is a heparinoid antithrombotic that has been used for over 40 years for prophylaxis of DVT in non-HIT patients and for the treatment of heparin-induced thrombocytopenia (HIT) with and without thrombosis. This update summarises current information on its pharmacology and reviews danaparoid dose management in a broad spectrum of clinical situations, including off-label indications. (2) Methods: Evidence from published clinical studies, case reports, compassionate use of danaparoid, and spontaneously reported serious adverse events is summarised and analysed by an interdisciplinary expert group to develop a consensus on dosing regimens of danaparoid for complex clinical situations, including vulnerable patient populations.
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Experimental Animals Application and Research Center, Duzce University, Duzce 81100, Türkiye.
: Subarachnoid hemorrhage (SAH) is a life-threatening cerebrovascular condition that triggers a robust inflammatory response and cerebral vasospasm. This study aimed to evaluate the effects of anakinra, an interleukin-1 receptor antagonist, and tocilizumab, an interleukin-6 receptor antagonist, on inflammation and vasospasm in an experimental rat SAH model. : Forty male Sprague Dawley rats (200-250 g) were randomly assigned to five groups: control, SAH, SAH + anakinra (ANA), SAH + tocilizumab (TCZ), and SAH + anakinra + tocilizumab (ANA+TCZ).
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December 2024
Department of Autoimmune Diseases, Reference Centre for Systemic Autoimmune Diseases (UEC/CSUR) of the Catalan and Spanish Health Systems-Member of ERNReCONNET, Hospital Clínic, University of Barcelona, 08036 Barcelona, Catalonia, Spain.
: The clinical and laboratory features of patients with non-criteria obstetric antiphospholipid syndrome (NC-OAPS), as well as their pregnancy outcomes and ideal treatment are not clearly determined. The aim of this study is to describe the characteristics and outcomes of pregnancies in NC-OAPS and compare them with an obstetric APS (OAPS) cohort. : This is a retrospective study conducted on a cohort of women referred to a high-risk obstetric unit of a tertiary hospital.
View Article and Find Full Text PDFJ Clin Med
December 2024
Division of Cardiology, Department of Medicine, NewYork-Presbyterian Hospital-Weill Cornell Medicine, New York, NY 10021, USA.
Thrombosis is an important cause of morbidity and mortality worldwide. Pregnancy is a hypercoagulable state, and thrombotic complications in pregnancy are a major cause of maternal and fetal morbidity and mortality. Current guidelines support the selective use of aspirin, heparin, and warfarin in pregnant women.
View Article and Find Full Text PDFJ Clin Med
December 2024
Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, 4650 Sunset Blvd, M/S #32, Los Angeles, CA 90027, USA.
N-terminal-proBNP (NT-proBNP) is a biomarker released into the blood in response to heart failure, reflecting the extent of cardiac stress and damage. QuidelOrtho Diagnostics released its latest reformulation of its NT-proBNP assay, the Vitros NT-proBNP II assay. This study aims to evaluate the analytical performance of the Vitros NT-proBNP II assay.
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