Biology subjects

Bevers, S.

Publications and source records attributed to Bevers, S..

3 recordsLinked to original sources

bioRxiv2022

Heparins enhance C1 esterase inhibitor activity: a promising remedy for acute hereditary angioedema

RationaleHereditary angioedema (HAE) is a potentially life-threatening illness most commonly due to deficiency or dysfunction of C1-esterase inhibitor (C1-INH). While specific treatments are available to thwart acute exacerbations, they are extremely costly and some can be associated with rare but serious side effects. The heparins are long known to augment C1-INH activity and case reports / series have documented their efficacy in treating HAE. Objectiveto determine if unfractionated heparin and two low-molecular weight heparins (enoxaparin and nadroparin) can augment C1-INH activity ex vivo in the sera of patients with HAE and in an in vitro biochemical assay. MethodsC1-INH activity in the absence or presence of the heparin formulations were analyzed by two different methods. To measure C1-INH activity ex vivo, a commercially available assay was utilized with patient sera, excess amounts of C1s, and a substrate of C1s which, upon cleavage by C1s, produces a chromogenic product. To determine biochemically the C1-INH activity in vitro, a pharmacologic grade C1-INH, recombinant C1s (C1s-CCP12SP), and a peptide substrate of C1s were employed. Microscale thermophoresis was used to determine whether C1-INH binds to heparin. Main resultsin patient sera, nadroparin was superior to enoxaparin and unfractionated heparin in augmenting C1-INH activity, followed by enoxaparin and then unfractionated heparin. In the in vitro biochemical assay, all three heparins augmented C1-INH-C1s binding linearly in a dose-dependent fashion. Microscale thermophoresis assay demonstrated that nadroparin binds to C1-INH, providing a mechanism by which heparin facilitates the interaction between C1-INH and the proteases known to produce bradykinin, the mediator of HAE. Conclusionlow-molecular weight heparin augments C1-INH activity and should be studied as a potential treatment for acute HAE.

pharmacology and toxicology↗

bioRxiv2021

Binding of Monomeric and Polymeric Alzheimers Aβ peptides to Exosomes

Exosomes are secreted by every cell in our body under both physiological and pathological conditions. They travel in the blood, CSF, and all studied biofluids. Their biological roles have been reported to include delivery of important physiological cargo between organs and cells, clearance of toxic proteins; maintenance of cellular stasis, and the propagation of disease pathology. In the case of Alzheimers disease (AD) exosomes have been shown to carry pathological proteins such as amyloid, yet the specificity of this association of amyloid and exosomes is unclear. To address this deficiency, we utilized Isothermal Titration Calorimetry (ITC) to measure the binding of amyloid to exosomes. Here we report that A{beta}40 and A{beta}42 bind to exosomes in a saturable and endothermic manner, a phenomenon not observed with the scrambled versions of either peptide. This points to this interaction being more specific than previously understood, and to amyloid associated with exosomes as an important pool of this peptide in the plasma.

neuroscience↗

bioRxiv2021

Towards more accurate preclinical glioblastoma modelling: reverse translation of clinical standard of care in a glioblastoma mouse model.

IntroductionContrarily to clinical trials, where glioblastoma (GBM) patients are usually heavily pre-treated (surgery, radiotherapy (RT) and temozolomide (TMZ)) before receiving the experimental therapies, in preclinical GBM studies experimental treatments have mostly been administered as monotherapy or combined with a very limited part of the clinical standard of care. This discrepancy can explain the failed clinical translation of preclinically successful treatments. This study is aimed at evaluating the feasibility and survival impact of the clinical standard of care in glioma-bearing mice. Methods. Neurospheres CT-2A tumor-bearing mice were treated with fluorescence-guided tumor resection, focal RT and oral TMZ. ResultsThe implementation of postoperative intensive care treatment reduced surgical mortality by approximately 50% and increased experimental cost-effectiveness. Partial and total tumor resection significantly prolonged survival, the latter showing the strongest effect. Mice treated with surgery combined with RT or with RT and TMZ survived significantly longer than untreated controls. ConclusionsImplementing the current GBM clinical standard of care in preclinical research is feasible and it leads to results in line with those obtained in patients. Systematic preclinical evaluation of the efficacy of experimental therapies in combination with standard of care treatments could improve the translational impact of next generation GBM animal studies.

neuroscience↗