Molecular Mechanism of the Anti-Inflammatory Action of Heparin

Litov, L.; Petkov, P.; Rangelov, Miroslav; Ilieva, Nevena; Lilkova, Elena; Todorova, Nadezhda; Krachmarova, Elena; Malinova, Kristina; Gospodinov, Anastas; Hristova, Rumyana; Ivanov, Iván; Nacheva, Genoveva

doi:10.3390/ijms221910730

Cited by 26 publications

(15 citation statements)

References 88 publications

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“…Another cytokine, interleukin 10 (IL-10), which has a very similar structure to hIFN

[ 44 ] and its cellular receptor (IL-10R), is in the same receptor family as hIFNGR1 and was also found to bind with high affinity to the GAGs heparin and heparan sulfate [ 45 ]. Moreover, it was demonstrated that soluble sulfated GAGs, including H, HS, CS and dermatan sulfate, inhibit IL-10 activity, similar to results on hIFN

[ 46 ]. At the same time, inhibition of cell-surface sulfation by sodium chlorate led to a 60% decrease in the cytokine’s activity [ 45 ], which undergirds the hypothesis “that hIL-10 requires the presence of sulfated PG at the cell surface, which may in turn facilitate its interaction with high-affinity hIL-10 receptors on these cells”.…”

Section: Discussionmentioning

confidence: 80%

Heparan Sulfate Facilitates Binding of hIFNγ to Its Cell-Surface Receptor hIFNGR1

Miladinova

Lilkova

Krachmarova

et al. 2022

IJMS

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Human interferon-gamma (hIFNγ) is a crucial signaling molecule with an important role in the initialization and development of the immune response of the host. However, its aberrant activity is also associated with the progression of a multitude of autoimmune and other diseases, which determines the need for effective inhibitors of its activity. The development of such treatments requires proper understanding of the interaction of hIFNγ to its cell-surface receptor hIFNGR1. Currently, there is no comprehensive model of the mechanism of this binding process. Here, we employ molecular dynamics simulations to study on a microscopic level the process of hIFNγ–hIFNGR1 complex formation in different scenarios. We find that the two molecules alone fail to form a stable complex, but the presence of heparan-sulfate-like oligosaccharides largely facilitates the process by both demobilizing the highly flexible C-termini of the cytokine and assisting in the proper positioning of its globule between the receptor subunits. An antiproliferative-activity assay on cells depleted from cell-surface heparan sulfate (HS) sulfation together with the phosphorylation levels of the signal transducer and activator of transcription STAT1 confirms qualitatively the simulation-based multistage complex-formation model. Our results reveal the key role of HS and its proteoglycans in all processes involving hIFNγ signalling.

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“…Another cytokine, interleukin 10 (IL-10), which has a very similar structure to hIFN

Section: Discussionmentioning

confidence: 80%

Heparan Sulfate Facilitates Binding of hIFNγ to Its Cell-Surface Receptor hIFNGR1

Miladinova

Lilkova

Krachmarova

et al. 2022

IJMS

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“…Supercomputer simulations are crucial for development in a number of advanced areas. Examples are in silico molecular biology and medicine design [7,8], analysis of turbulent flows [9], non-destructive testing [10], 3D image processing [11], fluid dynamics [12] and many others.…”

Section: Overview Of Key Results In the Fieldmentioning

confidence: 99%

Composite Numerical Methods and Scalable Tile Algorithms

Slavchev¹

2022

BMC

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Numerical modeling is an important tool when studying various natural processes and phenomena. Fractional diffusion can be used for modeling many processes in biology, for example in silico experiments in molecular biology and medicine design, protein diffusion within cells, complex media geometry, etc. The problem is usually reduced to a system of linear algebraic equations and in many cases this system has a dense coefficient matrix. Numerically solving such problems with the traditional LU factorization is a computationally expensive endeavour - $O(n^3)$. In this paper we explore the use of a hierarchical compression method based on Hierarchical Semi-Separable compression and ULV-like factorization from the STRUctured Matrices PACKage (STRUMPACK) software library for a flow around airfoils problem discretized with Boundary Element Method and fractional diffusion problem discretized with the Finite Element Method. The HSS based method promises better overall computational complexity of $O(r^2n)$ for problems with suitable structure - low rank off-diagonal blocks. Here $r$ is the maximum rank of the off-diagonal blocks. We present analysis of the performance and accuracy of the HSS based method and compare it with the state of the art direct LU factorization solvers. This paper is based on the PhD thesis Composite Numerical Methods and Scalable Tile Algorithms of the author defended on 17.05.2022 in the Institute of Information and Communication Technologies at the Bulgarian Academy of Sciences.

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“…Furthermore, it influences the biological activity of IL-6 by binding either IL-6 or IL-6/IL-6Rα. These molecular interactions are likely the basis of the anti-inflammatory action of LMWH and better clarify its ability to favourably influence conditions such as COVID-19 characterized by overexpression of these chemical mediators [ 34 ] . More clinical evidence is without doubt required to better clarify these aspects related to heparin full-dose anticoagulation usage in hospitalized non critically ill COVID-19 patients.…”

Section: Discussionmentioning

confidence: 99%

Efficacy and safety of heparin full-dose anticoagulation in hospitalized non-critically ill COVID-19 patients: a meta-analysis of multicenter randomized controlled trials

Pilia

Belletti

Fresilli

et al. 2022

J Thromb Thrombolysis

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Arterial and venous thrombotic events in COVID-19 cause significant morbidity and mortality among patients. Although international guidelines agree on the need for anticoagulation, it is unclear whether full-dose heparin anticoagulation confers additional benefits over prophylactic-dose anticoagulation. This systematic review and meta-analysis aimed to investigate the efficacy and safety of heparin full-dose anticoagulation in hospitalized non-critically ill COVID-19 patients. We searched Pubmed/Medline, EMBASE, Clinicaltrials.gov, medRxiv.org and Cochrane Central Register of clinical trials dated up to April 2022. Randomized controlled trials (RCTs) comparing full-dose heparin anticoagulation to prophylactic-dose anticoagulation or standard treatment in hospitalized non-critically ill COVID-19 patients were included in our pooled analysis. The primary endpoint was the rate of major thrombotic events and the co-primary endpoint was the rate of major bleeding events. We identified 4 studies, all of them multicenter, randomizing 2926 patients. Major thrombotic events were 23/1524 (1.5%) in full-dose heparin anticoagulation versus 57/1402 (4.0%) in prophylactic-dose [relative risk (RR) 0.39; 95% confidence interval (CI) 0.25–0.62; p˂0.01; I 2 = 0%]. Clinical relevant bleeding events occurred in 1.7% (26/1524) among patients treated with heparin full anticoagulation dose compared to 1.1% (15/1403) in prophylactic-dose group (RR 1.60; 95% CI 0.85–3.03; p = 0.15; I 2 = 20%). Mortality was 6.6% (101/1524) versus 8.6% (121/1402) (RR 0.63; 95% CI 0.33–1.19; p = 0.15). In this meta-analysis of high quality multicenter randomized trials, full-dose anticoagulation with heparin was associated with lower rate of major thrombotic events without differences in bleeding risk and mortality in hospitalized non critically ill COVID-19 patients. Study registration PROSPERO, review no. CRD42022301874. Supplementary Information The online version contains supplementary material available at 10.1007/s11239-022-02681-x.

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Molecular Mechanism of the Anti-Inflammatory Action of Heparin

Cited by 26 publications

References 88 publications

Heparan Sulfate Facilitates Binding of hIFNγ to Its Cell-Surface Receptor hIFNGR1

Heparan Sulfate Facilitates Binding of hIFNγ to Its Cell-Surface Receptor hIFNGR1

Composite Numerical Methods and Scalable Tile Algorithms

Efficacy and safety of heparin full-dose anticoagulation in hospitalized non-critically ill COVID-19 patients: a meta-analysis of multicenter randomized controlled trials

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