scholarly journals Proteolytic Processing of Neuregulin 2

2019 ◽  
Vol 57 (4) ◽  
pp. 1799-1813 ◽  
Author(s):  
Maria Czarnek ◽  
Joanna Bereta
Keyword(s):  
Immunohistochemical Staining ◽  
Hippocampal Neurons ◽  
Neuronal Cell ◽  
Brain Structures ◽  
Proteolytic Processing ◽  
Erbb Receptors ◽  
Ectodomain Shedding ◽  
Post Translational Modifications ◽  
Neuronal Cell Lines ◽  
Egf Family

AbstractNeuregulin 2 (NRG2) belongs to the EGF family of growth factors. Most of this family members require proteolytic cleavage to liberate their ectodomains capable of binding and activating their cognate ErbB receptors. To date, most of the studies investigating proteolytic processing of neuregulins focused on NRG1, which was shown to undergo ectodomain shedding by several ADAM proteases and BACE1 and the remaining fragment was further cleaved by γ-secretase. Recently, NRG2 attracted more attention due to its role in the neurogenesis and modulation of behaviors associated with psychiatric disorders. In this study, we used genetic engineering methods to identify proteases involved in proteolytic processing of murine NRG2. Using non-neuronal cell lines as well as cultures of primary hippocampal neurons, we demonstrated that the major proteases responsible for releasing NRG2 ectodomain are ADAM10 and BACE2. Co-expression of NRG2 and BACE2 in neurons of certain brain structures including medulla oblongata and cerebellar deep nuclei was confirmed via immunohistochemical staining. The cleavage of NRG2 by ADAM10 or BACE2 generates a C-terminal fragment that serves as a substrate for γ-secretase. We also showed that murine NRG2 is subject to post-translational modifications, substantial glycosylation of its extracellular part, and phosphorylation of the cytoplasmic tail.

scholarly journals Back signaling by the Nrg-1 intracellular domain

2003 ◽  
Vol 161 (6) ◽  
pp. 1133-1141 ◽  
Author(s):  
Jianxin Bao ◽  
Deon Wolpowitz ◽  
Lorna W. Role ◽  
David A. Talmage
Keyword(s):  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Extracellular Domain ◽  
Proteolytic Processing ◽  
Erbb Receptors ◽  
Intracellular Domain ◽  
Neuregulin 1 ◽  
Bidirectional Signaling ◽  
Receptor Dimers

Transmembrane isoforms of neuregulin-1 (Nrg-1), ligands for erbB receptors, include an extracellular domain with an EGF-like sequence and a highly conserved intracellular domain (ICD) of unknown function. In this paper, we demonstrate that transmembrane isoforms of Nrg-1 are bidirectional signaling molecules in neurons. The stimuli for Nrg-1 back signaling include binding of erbB receptor dimers to the extracellular domain of Nrg-1 and neuronal depolarization. These stimuli elicit proteolytic release and translocation of the ICD of Nrg-1 to the nucleus. Once in the nucleus, the Nrg-1 ICD represses expression of several regulators of apoptosis, resulting in decreased neuronal cell death in vitro. Thus, regulated proteolytic processing of Nrg-1 results in retrograde signaling that appears to mediate contact and activity-dependent survival of Nrg-1–expressing neurons.

scholarly journals Quantitative Analysis on the role ofRaffinose Synthasein Hippocampal Neurons

2017 ◽  
Author(s):  
Shatrunjai P. Singh ◽  
Vijendra P. Singh
Keyword(s):  
Oxidative Stress ◽  
Cell Lines ◽  
Hippocampal Neurons ◽  
Neuronal Cell ◽  
Biologically Active ◽  
Raffinose Synthase ◽  
Neuronal Cell Lines ◽  
Endogenous Antioxidant ◽  
Hpv 1 ◽  
Human And Mouse

1AbstractA diminished level of endogenous antioxidant in cells/tissues is associated with reduced resistance to oxidative stress. Raffinose synthase (RFS), a protective molecule regulates gene expression/function by controlling reactive oxygen species (ROS) levels, which has shown to be involved in a number of degenerative diseases. We confirmed the ubiquitous expression of this antioxidant protein in both human hippocampal neuron (HNN) and mouse hippocampal (HHPC-43) cell lines by an immunoblot and reverse transcriptase PCR (RT-PCR). Using a construct of RFS protein linked to CXCR-4, the transduction domain from HPV-1 CXCR-4 protein, we showed that RFS was transduced into both HNN, as well as HHPC-43 by the means of a western blot analysis. Further we proved that the protein was biologically active, and was shown to actively reduce the oxidative stress produced byparaquatand serum depletion in both human and mouse neuronal cell lines, increasing the viability of the cells. The results suggest that the intracellular delivery of RFS using CXCR-4 can be used to lower increased levels of ROS inside the cells and hence can be further investigated as a therapeutic tool in various ROS related neurodegenerative disorders.

scholarly journals Human Neuronal Cell Lines as An In Vitro Toxicological Tool for the Evaluation of Novel Psychoactive Substances

2021 ◽  
Vol 22 (13) ◽  
pp. 6785
Author(s):  
Valeria Sogos ◽  
Paola Caria ◽  
Clara Porcedda ◽  
Rafaela Mostallino ◽  
Franca Piras ◽  
...  
Keyword(s):  
Cell Death ◽  
Neuronal Cell ◽  
In Vitro Study ◽  
Dependent Manner ◽  
Novel Psychoactive Substances ◽  
Psychoactive Substances ◽  
Concentration Dependent Manner ◽  
Mechanisms Of Toxicity ◽  
Neuronal Cell Lines

Novel psychoactive substances (NPS) are synthetic substances belonging to diverse groups, designed to mimic the effects of scheduled drugs, resulting in altered toxicity and potency. Up to now, information available on the pharmacology and toxicology of these new substances is very limited, posing a considerable challenge for prevention and treatment. The present in vitro study investigated the possible mechanisms of toxicity of two emerging NPS (i) 4′-methyl-alpha-pyrrolidinoexanophenone (3,4-MDPHP), a synthetic cathinone, and (ii) 2-chloro-4,5-methylenedioxymethamphetamine (2-Cl-4,5-MDMA), a phenethylamine. In addition, to apply our model to the class of synthetic opioids, we evaluated the toxicity of fentanyl, as a reference compound for this group of frequently abused substances. To this aim, the in vitro toxic effects of these three compounds were evaluated in dopaminergic-differentiated SH-SY5Y cells. Following 24 h of exposure, all compounds induced a loss of viability, and oxidative stress in a concentration-dependent manner. 2-Cl-4,5-MDMA activates apoptotic processes, while 3,4-MDPHP elicits cell death by necrosis. Fentanyl triggers cell death through both mechanisms. Increased expression levels of pro-apoptotic Bax and caspase 3 activity were observed following 2-Cl-4,5-MDMA and fentanyl, but not 3,4-MDPHP exposure, confirming the different modes of cell death.

Neurotrophic Properties of Silexan, an Essential Oil from the Flowers of Lavender-Preclinical Evidence for Antidepressant-Like Properties

2020 ◽  
Vol 54 (01) ◽  
pp. 37-46
Author(s):  
Kristina Friedland ◽  
Giacomo Silani ◽  
Anita Schuwald ◽  
Carola Stockburger ◽  
Egon Koch ◽  
...  
Keyword(s):  
Essential Oil ◽  
Hippocampal Neurons ◽  
Day Treatment ◽  
Neuronal Cell ◽  
Antidepressant Activity ◽  
In Vivo Models ◽  
Antidepressant Effects ◽  
Primary Hippocampal Neurons

Abstract Background Silexan, a special essential oil from flowering tops of lavandula angustifolia, is used to treat subsyndromal anxiety disorders. In a recent clinical trial, Silexan also showed antidepressant effects in patients suffering from mixed anxiety-depression (ICD-10 F41.2). Since preclinical data explaining antidepressant properties of Silexan are missing, we decided to investigate if Silexan also shows antidepressant-like effects in vitro as well as in vivo models. Methods We used the forced swimming test (FST) in rats as a simple behavioral test indicative of antidepressant activity in vivo. As environmental events and other risk factors contribute to depression through converging molecular and cellular mechanisms that disrupt neuronal function and morphology—resulting in dysfunction of the circuitry that is essential for mood regulation and cognitive function—we investigated the neurotrophic properties of Silexan in neuronal cell lines and primary hippocampal neurons. Results The antidepressant activity of Silexan (30 mg/kg BW) in the FST was comparable to the tricyclic antidepressant imipramine (20 mg/kg BW) after 9-day treatment. Silexan triggered neurite outgrowth and synaptogenesis in 2 different neuronal cell models and led to a significant increase in synaptogenesis in primary hippocampal neurons. Silexan led to a significant phosphorylation of protein kinase A and subsequent CREB phosphorylation. Conclusion Taken together, Silexan demonstrates antidepressant-like effects in cellular as well as animal models for antidepressant activity. Therefore, our data provides preclinical evidence for the clinical antidepressant effects of Silexan in patients with mixed depression and anxiety.

Aflatoxin B1 Cytotoxicity in Neurons in Culture

1996 ◽  
Vol 24 (4) ◽  
pp. 533-540 ◽  
Author(s):  
Paola Bonsi ◽  
Maura Palmery ◽  
Gabriella Augusti-Tocco
Keyword(s):  
Motor Neurons ◽  
Aspergillus Parasiticus ◽  
Neuronal Cell ◽  
Cell Number ◽  
Human Brain Tissue ◽  
Proliferating Cells ◽  
Toxin Concentration ◽  
Lower Extent ◽  
Neuronal Cell Lines ◽  
Aflatoxin B

Aflatoxin B1 (AFB1), a metabolite produced by Aspergillus flavus and Aspergillus parasiticus, is mainly known for its strong hepatotoxic and hepatocarcinogenic actions. Acute and reversible effects due to exposure to aflatoxin and the presence of aflatoxins in various human tissues and organs have also been reported. In particular, aflatoxin M1 (a metabolite of AFB1) has been identified in human brain tissue, and a syndrome characterised by encephalopathy has been observed in humans poisoned by AFB1. As a first approach to the study of the neurotoxicity of AFB1, we used the human neuronal cell lines, SKNMC and SKNSH. The data reported show clearly that AFB1 is capable of interacting directly with neuronal cells and causing a decrease in cell number following the addition of toxin to the culture. Decrease in cell survival is dependent on the toxin concentration, on time of exposure, and on cell density. The cytotoxic response of these cells has been compared to the effects of AFB1 on hepatoma cells and spinal cord motor neurons. Postmitotic neurons are also susceptible to AFB1 toxicity, although to a lower extent than proliferating cells. A non-proliferating state thus appears to lower, but not destroy, neuron sensitivity to the toxin.

On the Application of Cultured Neuronal Cell Lines in Neurotoxicological Studies: Cytotoxicity of Acrylamide

1983 ◽  
Vol 11 (3) ◽  
pp. 135-145
Author(s):  
Erik Walum
Keyword(s):  
Cell Lines ◽  
Culture Medium ◽  
Neuroblastoma Cells ◽  
Neuronal Cell ◽  
Leucine Incorporation ◽  
Biochemical Process ◽  
Neurite Retraction ◽  
Mouse Neuroblastoma ◽  
Neuronal Cell Lines

Summary Acrylamide, a well known neurotoxic compound, was used in a first evaluation of cultured mouse neuroblastoma cells as an alternative to animal models for neurotoxicological studies. Hence, the effects of acrylamide on the growth, size, morphology and leucine incorporation of three neuroblastoma (41A3, N18 and N1E115), one neuroblastoma x glioma hybrid (NG108CC15), two glioma (138MG and C6) and two fibroblast (RLF and RMC) cell lines were studied. It was found that the concentration of acrylamide needed to inhibit the growth by 50% in 24 hr was similar in all cell lines, i.e. around 2 x 10-4g/ml culture medium. In the two cell lines, N1E115 and NG108CC15, acrylamide at this concentration caused neurite retraction and at higher concentrations (5 x 10-4g/ml) a decrease in cell viability. In a concentration range of 5 x 10-5 - 5 x 10-4g/ml acrylamide did not affect cell size, or at 2 x 10-4g/ml incorporation of leucine into trichloroacetic acid precipitable material. It is suggested that acrylamide interferes with a biochemical process common to all the tested cells, but of greater importance in differentiated nerve cells than in others. Whether this process is consistent with the in vivo target for the neurotoxic action of acrylamide remains to be unravelled.

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