Notch receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

The canonical Notch signalling pathway has four type I transmembrane Notch receptors (Notch1-4) and five ligands (DLL1, 2 and 3, and Jagged 1-2). Each member of this highly conserved receptor family plays a unique role in cell-fate determination during embryogenesis, differentiation, tissue patterning, proliferation and cell death [2]. As the Notch ligands are also membrane bound, cells have to be in close proximity for receptor-ligand interactions to occur. Cleavage of the intracellular domain (ICD) of activated Notch receptors by γ-secretase is required for downstream signalling and Notch-induced transcriptional modulation [15, 3, 11, 22]. This is why γ-secretase inhibitors can be used to downregulate Notch signalling and explains their anti-cancer action. One such small molecule is RO4929097 [8], although development of this compound has been terminated following an unsuccessful Phase II single agent clinical trial in metastatic colorectal cancer [19].Aberrant Notch signalling is implicated in a number of human cancers [12, 20, 6, 16], with demcizumab and tarextumab identified as antibody inhibitors of ligand:receptor binding [13]

Notch receptors in GtoPdb v.2021.2

Aberrant Notch signalling is implicated in a number of human cancers [18, 26, 13, 21], and there is intense pharmaceutical activity being directed towards achieving clinically effective Notch pathway inhibition [7, 16]

Intravenous immunoglobulin (IVIg) dampens neuronal toll-like receptor-mediated responses in ischemia

10.1186/s12974-015-0294-8Journal of Neuroinflammation12

The Homocysteine-inducible Endoplasmic Reticulum Stress Protein Counteracts Calcium Store Depletion and Induction of CCAAT Enhancer-binding Protein Homologous Protein in a Neurotoxin Model of Parkinson Disease

The endoplasmic reticulum (ER) is a key organelle regulating intracellular Ca(2+) homeostasis. Oxidants and mitochondria-derived free radicals can target ER-based Ca(2+) regulatory proteins and cause uncontrolled Ca(2+) release that may contribute to protracted ER stress and apoptosis. Several ER stress proteins have been suggested to counteract the deregulation of ER Ca(2+) homeostasis and ER stress. Here we showed that knockdown of Herp, an ubiquitin-like domain containing ER stress protein, renders PC12 and MN9D cells vulnerable to 1-methyl-4-phenylpyridinium-induced cytotoxic cell death by a mechanism involving up-regulation of CHOP expression and ER Ca(2+) depletion. Conversely, Herp overexpression confers protection by blocking 1-methyl-4-phenylpyridinium-induced CHOP upregulation, ER Ca(2+) store depletion, and mitochondrial Ca(2+) accumulation in a manner dependent on a functional ubiquitin-proteasomal protein degradation pathway. Deletion of the ubiquitin-like domain of Herp or treatment with a proteasomal inhibitor abolished the central function of Herp in ER Ca(2+) homeostasis. Thus, elucidating the underlying molecular mechanism(s) whereby Herp counteracts Ca(2+) disturbances will provide insights into the molecular cascade of cell death in dopaminergic neurons and may uncover novel therapeutic strategies to prevent and ameliorate Parkinson disease progression

Pathophysiology, treatment, and animal and cellular models of human ischemic stroke

Stroke is the world's second leading cause of mortality, with a high incidence of severe morbidity in surviving victims. There are currently relatively few treatment options available to minimize tissue death following a stroke. As such, there is a pressing need to explore, at a molecular, cellular, tissue, and whole body level, the mechanisms leading to damage and death of CNS tissue following an ischemic brain event. This review explores the etiology and pathogenesis of ischemic stroke, and provides a general model of such. The pathophysiology of cerebral ischemic injury is explained, and experimental animal models of global and focal ischemic stroke, and in vitro cellular stroke models, are described in detail along with experimental strategies to analyze the injuries. In particular, the technical aspects of these stroke models are assessed and critically evaluated, along with detailed descriptions of the current best-practice murine models of ischemic stroke. Finally, we review preclinical studies using different strategies in experimental models, followed by an evaluation of results of recent, and failed attempts of neuroprotection in human clinical trials. We also explore new and emerging approaches for the prevention and treatment of stroke. In this regard, we note that single-target drug therapies for stroke therapy, have thus far universally failed in clinical trials. The need to investigate new targets for stroke treatments, which have pleiotropic therapeutic effects in the brain, is explored as an alternate strategy, and some such possible targets are elaborated. Developing therapeutic treatments for ischemic stroke is an intrinsically difficult endeavour. The heterogeneity of the causes, the anatomical complexity of the brain, and the practicalities of the victim receiving both timely and effective treatment, conspire against developing effective drug therapies. This should in no way be a disincentive to research, but instead, a clarion call to intensify efforts to ameliorate suffering and death from this common health catastrophe. This review aims to summarize both the present experimental and clinical state-of-the art, and to guide future research directions

'Click' assembly of glycoclusters and discovery of a trehalose analogue that retards A(beta)40 aggregation and inhibits A(beta)40-induced neurotoxicity

Osmolytes have been proposed as treatments for neurodegenerative proteinopathies including Alzheimer's disease. However, for osmolytes to reach the clinic their efficacy must be improved. In this work, copper(I)-catalyzed azide-alkyne cycloaddition chemistry was used to synthesize glycoclusters bearing six copies of trehalose, lactose, galactose or glucose, with the aim of improving the potency of these osmolytes via multivalency. A trehalose glycocluster was found to be superior to monomeric trehalose in its ability to retard the formation of amyloid-beta peptide 40 (Aβ40) fibrils and protect neurons from Aβ40-induced cell death

IL-23 (Interleukin-23)-producing conventional dendritic cells control the detrimental IL-17 (Interleukin-17) response in stroke

Background and Purpose—Inflammatory mechanisms can exacerbate ischemic tissue damage and worsen clinical outcome in patients with stroke. Both αβ and γδ T cells are established mediators of tissue damage in stroke, and the role of dendritic cells (DCs) in inducing the early events of T cell activation and differentiation in stroke is not well understood. Methods—In a murine model of experimental stroke, we defined the immune phenotype of infiltrating DC subsets based on flow cytometry of surface markers, the expression of ontogenetic markers, and cytokine levels. We used conditional DC depletion, bone marrow chimeric mice, and IL-23 (interleukin-23) receptor-deficient mice to further explore the functional role of DCs. Results—We show that the ischemic brain was rapidly infiltrated by IRF4+/CD172a+ conventional type 2 DCs and that conventional type 2 DCs were the most abundant subset in comparison with all other DC subsets. Twenty-four hours after ischemia onset, conventional type 2 DCs became the major source of IL-23, promoting neutrophil infiltration by induction of IL-17 (interleukin-17) in γδ T cells. Functionally, the depletion of CD11c+ cells or the genetic disruption of the IL-23 signaling abrogated both IL-17 production in γδ T cells and neutrophil infiltration. Interruption of the IL-23/ IL-17 cascade decreased infarct size and improved neurological outcome after stroke. Conclusions—Our results suggest a central role for interferon regulatory factor 4-positive IL-23–producing conventional DCs in the IL-17–dependent secondary tissue damage in stroke

Circulating CD62E+ Microparticles and Cardiovascular Outcomes

BACKGROUND: Activated endothelial cells release plasma membrane submicron vesicles expressing CD62E (E-selectin) into blood, known as endothelial microparticles (EMPs). We studied whether the levels of endothelial microparticles expressing CD62E(+), CD31(+)/Annexin-V(+), or CD31(+)/CD42(-) predict cardiovascular outcomes in patients with stroke history. METHODS/PRINCIPAL FINDINGS: Patients with stroke history at least 3 months prior to enrolment were recruited. Peripheral blood EMP levels were measured by flow cytometry. Major cardiovascular events and death were monitored for 36 months. Three hundred patients were enrolled, of which 298 completed the study according to protocol. Major cardiovascular events occurred in 29 patients (9.7%). Nine patients died, five from cardiovascular causes. Cumulative event-free survival rates were lower in patients with high levels of CD62E(+) microparticles. Multivariate Cox regression analysis adjusted for cardiovascular risk factors, medications and stroke etiologic groups showed an association between a high CD62E(+) microparticle level and a risk of major cardiovascular events and hospitalization. Levels of other kinds of EMPs expressing CD31(+)/Annexin-V(+) or CD31(+)/CD42(-) markers were not predictive of cardiovascular outcomes. CONCLUSION: A high level of CD62E(+) microparticles is associated with cardiovascular events in patients with stroke history, suggesting that the systemic endothelial activation increases the risk for cardiovascular morbidities

Ribosomal S6 Kinase 2 (RSK2) Maintains Genomic Stability by Activating the Atm/p53-Dependent DNA Damage Pathway

10.1371/journal.pone.0074334PLoS ONE89-POLN