Search results for "Extracellular"

Intracellular ion signaling influences myelin basic protein synthesis in oligodendrocyte precursor cells

2016

Myelination in the central nervous system depends on axon-oligodendrocyte precursor cell (OPC) interaction. We suggest that myelin synthesis may be influenced by [Na+]i and [Ca2+]i signaling in OPCs. Experiments were performed in mouse cultured OPCs at day in vitro (DIV) 2-6 or acute slices of the corpus callosum at postnatal days (P) 10-30. Synthesis of Myelin Basic Protein (MBP), an "executive molecule of myelin", was used as readout of myelination. Immunohistological data revealed that MBP synthesis in cultured OPCs starts around DIV4. Transient elevations of resting [Ca2+]i and [Na+]i levels were observed in the same temporal window (DIV4-5). At DIV4, but not at DIV2, both extracellular…

Chemical probes to potently and selectively inhibit endocannabinoid cellular reuptake

2017

The extracellular effects of the endocannabinoids anandamide and 2-arachidonoyl glycerol are terminated by enzymatic hydrolysis after crossing cellular membranes by facilitated diffusion. The lack of potent and selective inhibitors for endocannabinoid transport has prevented the molecular characterization of this process, thus hindering its biochemical investigation and pharmacological exploitation. Here, we report the design, chemical synthesis, and biological profiling of natural product-derived N-substituted 2,4-dodecadienamides as a selective endocannabinoid uptake inhibitor. The highly potent (IC50 = 10 nM) inhibitor N-(3,4-dimethoxyphenyl)ethyl amide (WOBE437) exerted pronounced canna…

E2F1 interacts with BCL-xL and regulates its subcellular localization dynamics to trigger cell death

2018

International audience; E2F1 is the main pro-apoptotic effector of the pRB-regulated tumor suppressor pathway by promoting the transcription of various pro-apoptotic proteins. We report here that E2F1 partly localizes to mitochondria, where it favors mitochondrial outer membrane permeabilization. E2F1 interacts with BCL-xL independently from its BH3 binding interface and induces a stabilization of BCL-xL at mitochondrial membranes. This prevents efficient control of BCL-xL over its binding partners, in particular over BAK resulting in the induction of cell death. We thus identify a new, non-BH3-binding regulator of BCL-xL localization dynamics that influences its anti-apoptotic activity.

Extracellular histones disarrange vasoactive mediators reléase through COX-NOS interaction in human endothelial cells

2017

Abstract Extracellular histones are mediators of inflammation, tissue injury and organ dysfunction. Interactions between circulating histones and vascular endothelial cells are key events in histone‐mediated pathologies. Our aim was to investigate the implication of extracellular histones in the production of the major vasoactive compounds released by human endothelial cells (HUVECs), prostanoids and nitric oxide (NO). HUVEC exposed to increasing concentrations of histones (0.001 to 100 μg/ml) for 4 hrs induced prostacyclin (PGI2) production in a dose‐dependent manner and decreased thromboxane A2 (TXA2) release at 100 μg/ml. Extracellular histones raised cyclooxygenase‐2 (COX‐2) and prostac…

2017

Epidermal growth factor receptor (EGFR) and the mutant EGFRvIII are major focal points in current concepts of targeted cancer therapy for glioblastoma multiforme (GBM), the most malignant primary brain tumor. The receptors participate in the key processes of tumor cell invasion and tumor-related angiogenesis and their upregulation correlates with the poor prognosis of glioma patients. Glioma cell invasion and increased angiogenesis share mechanisms of the degradation of the extracellular matrix (ECM) through upregulation of ECM-degrading proteases as well as the activation of aberrant signaling pathways. This review describes the role of EGFR and EGFRvIII in those mechanisms which might off…

Phosphorylation of meprin β controls its cell surface abundance and subsequently diminishes ectodomain shedding

2021

Meprin β is a zinc-dependent metalloprotease exhibiting a unique cleavage specificity with strong preference for acidic amino acids at the cleavage site. Proteomic studies revealed a diverse substrate pool of meprin β including the interleukin-6 receptor (IL-6R) and the amyloid precursor protein (APP). Dysregulation of meprin β is often associated with pathological conditions such as chronic inflammation, fibrosis, or Alzheimer's disease (AD). The extracellular regulation of meprin β including interactors, sheddases, and activators has been intensively investigated while intracellular regulation has been barely addressed in the literature. This study aimed to analyze C-terminal phosphorylat…

Extracellular vesicles in food: Experimental evidence of their secretion in grape fruits

2017

In the last decade, the number of studies related with extracellular vesicles (EVs) has dramatically grown since their role as key part of intercellular communication has been confirmed. EVs, as transporter of distinct bioactive molecules, can take part in different physiological mechanisms and have been gaining attention as potential tools with a wide range of therapeutic effects. Whereas a high number of studies have been published related to mammalian derived EVs, including products as food source, the existence of EVs in plants still is controversial. Recent descriptions of vesicles derived from edible plants show that they might contain pharmacological active molecules. In this context…

Recovery from Toxic-Induced Demyelination Does Not Require the NG2 Proteoglycan

2016

NG2 cells are defined as CNS cells expressing chondroitin sulfate proteoglycan nerve/glia antigen. The vast majority of NG2-positive cells also express platelet-derived growth factor receptor alpha (PDGFRα) and are oligodendroglial progenitors (OPC). In addition a subpopulation of pericytes expresses NG2, but is positive for PDGF receptor beta (PDGFRβ) [1]. NG2-positive OPC comprise approximately 5% of the cells in the CNS where they are evenly distributed in grey and white matter [2, 3]. NG2-positive OPC form synapses with neurons [4–6] and react to brain injury with proliferation, as has been shown in several animal models as well as in human demyelinating and degenerative diseases [7–9].…

Extracellular vesicles: small bricks for tissue repair/regeneration

2017

Extracellular vesicles (EVs) are nano-sized membrane vesicles involved in intercellular communication. EVs have pleiotropic actions in physiological and pathological conditions. The ability of EVs to transports proteins, drugs and nucleic acid, to target specific cells and to increase the stability of therapeutic cargo, make EVs interesting as new devices for the treatment of human disease. In a recently published issue of European journal of pharmaceutical sciences, Silva and colleagues reviewed the ability of EVs to modulate tissue repair and regeneration, focusing on their roles and therapeutic potential as immunomodulatory messengers. In this perspective, we discussed the open questions…

A stiff extracellular matrix is associated with malignancy in peripheral neuroblastic tumors

2017

Purpose and objective Improved prognosis for patients with peripheral neuroblastic tumors (PNB) depends on enhanced pretreatment risk stratification combined with research into new therapeutic targets. This study investigated the potential contribution of extracellular matrix (ECM) elements toward this endeavor. Methods We characterized certain elements such as reticulin fibers, collagen type I fibers, and elastic fibers by digital pathology in almost 400 untreated PNB. Results A reticular and poorly porous ECM was identified in neuroblastomas (NBs) from patients with clinical and biological features associated with poor prognosis compared with a loose and permeable matrix found in NBs of t…