Biology subjects

Yusuf, A. M.

Publications and source records attributed to Yusuf, A. M..

4 recordsLinked to original sources

bioRxiv2025

The nuclear receptor NR4A1 serves as a neutrophil-intrinsic regulator mitigating stroke severity

Ischemic stroke is accompanied by recruitment and activation of immune cells which play an important role in the progression of the brain damage. The nuclear receptor NR4A1 emerged as a key regulator within the inflammatory response of several immune diseases by regulating immune cell activation. In this study, we investigated the role of NR4A1 in the activation and recruitment of brain resident and peripheral immune cells after cerebral ischemia. Here, we show that NR4A1 mediates an anti-inflammatory and damage-limiting effect after stroke. This effect is largely mediated by neutrophil recruitment and importantly, NR4A1 activation with its ligand Cytosporone B improves functional outcome and reduces brain damage. Modulation of NR4A1 is therefore a promising therapeutic target for the treatment of the nuclear receptor NR4A1 in the activation and recruitment of peripheral and brain resident immune cells after cerebral ischemia and its consequences for stroke outcome. We demonstrate that NR4A1 ablation augments neutrophil activation and CNS recruitment within days after stroke thereby increasing infarct size, CNS inflammation, neuronal damage and deteriorating functional outcome. This effect is mediated via modulation of cell-intrinsic neutrophil function and maturation as illustrated by neutrophil-specific NR4A1 ablation and mixed bone-marrow chimera experiments. Notably, the NR4A1 agonist Cytosporone B reduced CNS neutrophil infiltration, infarct size and functional outcome after stroke in a bicentric preclinical stroke trial, demonstrating that NR4A1-mediated control of neutrophil reactivity is amenable to pharmacological modulation. In humans, NR4A1 expressing neutrophils are present in the peripheral blood of stroke patients and neutrophil NR4A1 expression correlates with improved long-term outcome after 3 months. Furthermore, NR4A1 expression in brain parenchyma neutrophils is negatively correlated with neuronal cell loss, illustrating a role of NR4A1 in regulating neutrophil mediated neuronal cell death in human stroke. Together our data reveal the nuclear factor NR4A1 as a brake of intrinsic neutrophil activity controlling neutrophil-mediated brain inflammation and neurotoxicity in stroke which may serve as a novel therapeutic target to limit inflammation-associated augmentation of ischemic damage after stroke.

neuroscience↗

bioRxiv2021

Cardiomyocyte GSK-3β deficiency induces cardiac progenitor cell proliferation in the ischemic heart through paracrine mechanisms

Cardiomyopathy is an irreparable loss and novel strategies are needed to induce resident cardiac progenitor cell (CPC) proliferation in situ to enhance the possibility of cardiac regeneration. Here we sought to identify the potential roles of glycogen synthase kinase-3{beta} (GSK-3{beta}), a critical regulator of cell proliferation and differentiation, in CPC proliferation post-myocardial infarction (MI). Cardiomyocyte-specific conditional GSK-3{beta} knockout (cKO) and littermate control mice were employed and challenged with MI. Though cardiac left ventricular chamber dimension (LVID) and contractile functions were comparable at two-week post-MI, cKO mice displayed significantly preserved LV chamber and contractile function vs. control mice at four-weeks post-MI. Consistent with protective phenotypes, an increased percentage of c-kit-positive cells (KPCs) were observed in the cKO hearts at four and six-weeks post-MI which was accompanied by increased levels of cardiomyocyte proliferation. Further analysis revealed that the observed increased number of KPCs in the ischemic cKO hearts was mainly from a cardiac lineage as the majority of identified KPCs were negative for the hematopoietic lineage marker, CD45. Mechanistically, cardiomyocyte-GSK-3{beta} profoundly suppresses the expression and secretion of growth factors, including basic-FGF angiopoietin-2, erythropoietin, stem cell factor (SCF), PDGF-BB, G-CSF, and VEGF, post-hypoxia. In conclusion, our findings strongly suggest that loss of cardiomyocyte-GSK-3{beta} promotes cardiomyocyte and resident CPC proliferation post-MI. The induction of cardiomyocyte and CPC proliferation in the ischemic cKO hearts is potentially regulated by autocrine and paracrine signaling governed by dysregulated growth factors post-MI. A strategy to inhibit cardiomyocyte GSK-3{beta} could be helpful for the promotion of in situ cardiac regeneration post-ischemic injury.

molecular biology↗

bioRxiv2021

Induction of soluble platelet activation markers and FXIII deficiency promote COVID-19 severity

IntroductionCoagulation dysfunction and thromboembolism emerge as strong comorbidity factors in severe COVID-19. However, it is unclear when particularly platelet activation markers and coagulation factors dysregulated during the pathogenesis of COVID-19. Here, we sought to assess the levels of coagulation and platelet activation markers at moderate and severe stages of COVID-19 to understand the pathogenesis. MethodsTo understand this, hospitalized COVID-19 patients with (severe cases that required intensive care) or without pneumonia (moderate cases) were recruited. Phenotypic and molecular characterizations were performed employing basic coagulation tests including PT, APTT, D-Dimer and TFPI. The flow cytometry-based multiplex assays were performed to assess FXI, anti-thrombin, prothrombin, fibrinogen, FXIII, P-selectin, sCD40L, plasminogen, tissue-plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1) and D-Dimer. ResultsThe investigations revealed induction of plasma P-selectin and CD40 ligand (sCD40L) in moderate COVID-19 cases which were significantly abolished with the progression of COVID-19 severity. Moreover, a profound reduction in plasma tissue factor pathway inhibitor (TFPI) and FXIII were identified particularly in the severe COVID-19. Further analysis revealed fibrinogen induction in both moderate and severe patients. Interestingly, an elevated PAI-1 more prominently in moderate, and tPA particularly in severe COVID-19 cases were observed. Particularly, the levels of fibrinogen and tPA directly correlated with the severity of the disease. ConclusionsIn summary, induction of soluble P-selectin, sCD40L, fibrinogen and PAI-1 in moderate COVID-19 cases suggests the activation of platelets and coagulation system before patients require intensive care. These findings would help in designing better thromboprophylaxis to limit the COVID-19 severity.

pathology↗

bioRxiv2021

Acid sphingomyelinase deactivation post-ischemia/ reperfusion promotes cerebral angiogenesis and brain remodeling via small extracellular vesicles

Functional inhibitors of acid sphingomyelinase are clinically used as anti-depressants since [~]60 years. Here, we show that acid sphingomyelinase inhibition by the antidepressants amitriptyline, fluoxetine and desipramine protects from ischemia/reperfusion and elicits a profound brain remodeling response with increased angiogenesis, improved blood-brain barrier integrity, reduced brain leukocyte infiltration and increased neuronal survival. Angiogenesis is promoted by small extracellular vesicles with bona fide characteristics of exosomes, which are released from endothelial cells and which constitute an elegant target for the amplification of stroke recovery.

neuroscience↗