1,721,003 research outputs found
Formyl-peptide receptor is not involved in the protection afforded by annexin 1 in murine acute myocardial infarct
No full textAre formyl peptide receptors novel targets for therapeutic intervention in ischaemia-reperfusion injury?
Full text linkIschaemia–reperfusion (I/R) injury is a common feature of several diseases associated with high morbidity and mortality, such as stroke and myocardial infarction. The damaged tissue displays cardinal signs of inflammation and microvascular injury that, unless resolved, lead to long-term tissue damage with associated dysfunction. Current therapies are limited and are often associated with many side effects. Increasing evidence suggests that members of the formyl peptide receptor (FPR) family, in particular human FPR2/ALX, might have an important role in the pathophysiology of I/R injury. It was recently demonstrated that several peptides and non-peptidyl small-molecule compounds have anti-inflammatory and pro-resolving properties via their action on members of the FPR family. Here I review this evidence and suggest that FPR ligands, particularly in the brain, could be novel and exciting anti-inflammatory therapeutics for the treatment of a variety of clinical conditions, including stroke
The Resolution Mediator Annexin A1 Affords Protection Against Thromboinflammation
Full text linkMeeting poster 331.Thrombosis presented at the 63rd ASH Annual Meeting and Exposition, Atlanta, GA, USA, 11-14 December, 2021.Stroke is a leading cause of death and disability worldwide, with the majority (~85 %) being ischemic in origin. Age is the most important non-modifiable risk factor for acute ischemic stroke (AIS). While inflammation with ageing is a well-known complication of AIS, a new model is emerging in which ageing-associated thrombosis is being viewed as a multi-step, multi-cellular process driven by inflammatory stimuli and recruitment/activation of leukocytes. The ideal outcome of inflammation is resolution, an active process involving specific endogenous mediators (e.g. annexin A1 [AnxA1]) and related pathways (e.g. formyl peptide receptor-2 [Fpr2/ALX] pathway).[1,2] The development of therapies that temper inflammation and enhance resolution offer potential therapeutic strategies for the treatment and management of thromboinflammation associated with AIS. We have shown that the AnxA1 mimetic peptide AnxA1 Ac2-26 ameliorates thrombotic responses in thromboinflammatory conditions such as Sickle Cell Disease,[3] however, the role that AnxA1 plays in age-related thrombosis is currently unknown. Here we sought to comprehensively elucidate the functional significance of targeting the AnxA1/Fpr2/ALX pathway in age-related thrombosis. Initially, to evaluate the role of AnxA1, thrombosis in cerebral vessels was induced using the light/dye thrombosis model.[2] Male and female adult (10-14 weeks) and ageing (18-24 months) wild type (WT, C57/BL6) or AnxA1 knock-out (AnxA1 -/-) mice were used. WT mice received AnxA1 (1 µg/mouse), or saline vehicle injected 20 min before the onset of thrombus formation in cerebral pial vessels. Thrombogenesis and blood flow cessation times were quantified. AnxA1 treatment was able to prolong blood flow cessation times in both cerebral arterioles and venules, an effect which was more pronounced in ageing mice (p<0.05) via regulation of the FPR2/ALX-pathway. Next, to investigate the mechanism of action of AnxA1 in an inflammatory backdrop (i.e. lipopolysaccharide [LPS]), the effect of AnxA1 on platelet P‐selectin and αIIbβ3 receptor expression, following stimulation with the GPVI collagen receptor agonist convulxin (CVX), was performed. CVX treatment increased platelet activation, which was suppressed by AnxA1 co‐administration (100 ng. p<0.05). CVX+LPS increased platelet αIIbβ3 or P‐selectin levels, which were inhibited by the administration of AnxA1. Finally, to determine whether a deletion of AnxA1 impacts thrombosis, we performed the light/dye thrombosis model in AnxA1 −/− mice. These mice displayed accelerated cerebral microvascular thrombus formation (decrease in blood flow cessation time) compared to WT mice in both arterioles and venules (arterioles: 17.9 ± 2.3 vs 33.2 ± 1.9 min and venules: 13.2 ± 2.4 vs 20.9 ± 2.2 min. p<0.05). In conclusion, these results demonstrate the ability of AnxA1 to modify the thromboinflammatory environment, including reducing platelet activation under inflammatory conditions via GPVI. Collectively, these data show the importance of the AnxA1/Fpr2/ALX system in effecting the resolution of cerebral thromboinflammation in ageing and may provide a novel therapeutic strategy for AIS and other thromboinflammatory conditions. Disclosures No relevant conflicts of interest to declare.Royal Society Wolfson Fellowship ref: RSWF\R3\183001
Thromboinflammation in coronavirus disease 2019: The clot thickens
Full text linkData availability statement: No data have been shared.Linked articles: This article is part of a themed issue on The second wave: are we any closer to efficacious pharmacotherapy for COVID 19? (BJP 75th Anniversary). To view the other articles in this section visit https://onlinelibrary.wiley.com/doi/10.1111/bph.v179.10/issuetocSince the start of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, a disease that has become one of the world's greatest global health challenges, the role of the immune system has been at the forefront of scientific studies. The pathophysiology of coronavirus disease 2019 (COVID-19) is complex, which is evident in those at higher risk for poor outcome. Multiple systems contribute to thrombosis and inflammation seen in COVID-19 patients, including neutrophil and platelet activation, and endothelial dysfunction. Understanding how the immune system functions in different patient cohorts (particularly given recent emerging events with the Oxford/AstraZeneca vaccine) is vital to understanding the pathophysiology of this devastating disease and for the subsequent development of novel therapeutic targets and to facilitate possible drug repurposing strategies that could benefit society on a global scale.Royal Society Wolfson Foundation. Grant Number: RSWF\R3\18300
The Impact of Thrombo‐inflammation on the Cerebral Microcirculation
Full text linkCopyright © 2021 The Authors. The intertwined processes of thrombosis and inflammation (termed “thrombo-inflammation”) are significant drivers of cerebrovascular diseases, and as such, they represent prime targets for drug discovery programs focusing on treatment and management of cerebrovascular diseases. Most cerebrovascular events result from chronic systemic microcirculatory dysfunction due to underlying conditions, for example, hypertension, diabetes mellitus, coronary artery disease, dyslipidemia, and sickle cell disease. Immune cells especially neutrophils play a critical role in the onset and maintenance of neuroinflammatory responses in the microcirculation. Neutrophils have the ability to drive both inflammatory and anti-inflammatory/pro-resolution effects depending on the underlying vascular state (physiological vs. pathological). In this article, we highlight the pathophysiological role of neutrophils in stroke and discuss ongoing pharmacotherapeutic strategies that are focused on identifying potential therapeutic targets for enhancing neuroprotection, mitigating inflammatory pathways, and enabling resolution.The Royal Society Wolfson Foundation. Grant Number: RSWF\R3\18300
Surgical Approach for Middle Cerebral Artery Occlusion and Reperfusion Induced Stroke in Mice
Full text linkVideo Link:
The video component of this article can be found at https://www.jove.com/video/54302/Stroke is a leading cause of death worldwide and continues to be one of the major causes of long-term adult disabilities. About 87% of strokes are ischemic in origin and occur in the territory of the middle cerebral artery (MCA). Currently the only Food and Drug Administration (FDA) approved drug for the treatment of this devastating disease is tissue plasminogen activator (tPA). However, tPA has a small therapeutic window for administration (3 - 6 hr), and is only effective in 4% of the patients who actually receive it. Current research focuses on understanding the pathophysiology of stroke in order to find potential therapeutic targets. Thus, reliable models are crucial, and the MCA occlusion (MCAo) model (also termed the intraluminal filament or suture model) is deemed to be the most clinically relevant surgical model of ischemic stroke, and is fairly non-invasive and easily reproducible. Typically the MCAo model is used with rodents, especially with mice due to all the genetic variations available for this species. Here we describe (and present in the video) how to successfully perform the MCAo model (with reperfusion) in mice to generate reliable and reproducible data.This work was funded by the National Institute of Health, the National Heart Lung and Blood Institute (NIH and NHLBI; HL125572-01A1) and the LSUHSC-S start up fund to F.N.E. Gavins
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
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