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https://www.readbyqxmd.com/read/29061563/rescue-of-atxn3-neuronal-toxicity-in-c-elegans-by-chemical-modification-of-er-stress
#1
Yasmin Fardghassemi, Arnaud Tauffenberger, Sarah Gosselin, J Alex Parker
Background: Polyglutamine expansion diseases are a group of hereditary neurodegenerative disorders that develop when a CAG repeat in the causative genes are unstably expanded above a certain threshold. The expansion of trinucleotide CAG repeats cause hereditary adult-onset neurodegenerative disorders such as Huntington's disease, dentatorubral-pallidoluysian atrophy, spinobulbar muscular atrophy and multiple forms of spinocerebellar ataxia (SCA). The most common dominantly inherited spinocerebellar ataxia is the type 3 (SCA3) also known as Machado-Joseph disease (MJD), is an autosomal dominant, progressive neurological disorder...
October 23, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28953319/bergmann-glia-translocation-a-new-disease-marker-for-vanishing-white-matter-identifies-therapeutic-effects-of-guanabenz-treatment
#2
S Dooves, M Bugiani, L E Wisse, T E M Abbink, M S van der Knaap, V M Heine
AIM: Vanishing White Matter (VWM) is a devastating leucoencephalopathy without effective treatment options. Patients have mutations in the EIF2B1-5 genes, encoding the five subunits of eIF2B, a guanine exchange factor that is an important regulator of protein translation. We recently developed mouse models for VWM that replicate the human disease. To study disease improvement after treatment in these mice, it is essential to have sensitive biomarkers related to disease stage. The Bergmann glia of the cerebellum, an astrocytic subpopulation, translocate into the molecular layer in symptomatic VWM mice and patients...
May 13, 2017: Neuropathology and Applied Neurobiology
https://www.readbyqxmd.com/read/28801400/protein-misfolding-amyotrophic-lateral-sclerosis-and-guanabenz-protocol-for-a-phase-ii-rct-with-futility-design-promise-trial
#3
Eleonora Dalla Bella, Irene Tramacere, Giovanni Antonini, Giuseppe Borghero, Margherita Capasso, Claudia Caponnetto, Adriano Chiò, Massimo Corbo, Roberto Eleopra, Massimiliano Filosto, Fabio Giannini, Enrico Granieri, Vincenzo La Bella, Christian Lunetta, Jessica Mandrioli, Letizia Mazzini, Sonia Messina, Maria Rosaria Monsurrò, Gabriele Mora, Nilo Riva, Romana Rizzi, Gabriele Siciliano, Vincenzo Silani, Isabella Simone, Gianni Sorarù, Paolo Volanti, Giuseppe Lauria
INTRODUCTION: Recent studies suggest that endoplasmic reticulum stress may play a critical role in the pathogenesis of amyotrophic lateral sclerosis (ALS) through an altered regulation of the proteostasis, the cellular pathway-balancing protein synthesis and degradation. A key mechanism is thought to be the dephosphorylation of eIF2α, a factor involved in the initiation of protein translation. Guanabenz is an alpha-2-adrenergic receptor agonist safely used in past to treat mild hypertension and is now an orphan drug...
August 11, 2017: BMJ Open
https://www.readbyqxmd.com/read/28759048/decoding-the-selectivity-of-eif2%C3%AE-holophosphatases-and-ppp1r15a-inhibitors
#4
Marta Carrara, Anna Sigurdardottir, Anne Bertolotti
The reversible phosphorylation of proteins controls most cellular functions. Protein kinases have been popular drug targets, unlike phosphatases, which remain a drug discovery challenge. Guanabenz and Sephin1 are selective inhibitors of the phosphatase regulatory subunit PPP1R15A (R15A) that prolong the benefit of eIF2α phosphorylation, thereby protecting cells from proteostatic defects. In mice, Sephin1 prevents two neurodegenerative diseases, Charcot-Marie-Tooth 1B (CMT-1B) and SOD1-mediated amyotrophic lateral sclerosis (ALS)...
September 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28659918/guanabenz-prevents-d-galactosamine-lipopolysaccharide-induced-liver-damage-and-mortality
#5
Jessica Perego, Clarisse Bourbon, Lionel Chasson, Caroline Laprie, Lionel Spinelli, Voahirana Camosseto, Evelina Gatti, Philippe Pierre
Multi-organ failure in response to uncontrolled microbial infection is characterized by low blood pressure accompanied by a systemic over-inflammation state, caused by massive pro-inflammatory cytokines release and liver damage. Recently, the integrated stress response (ISR), characterized by eukaryotic translation initiation factor 2α (eIF2α) phosphorylation, was involved with controlling apoptosis in stressed hepatocytes and associated with poor survival to endotoxin challenge. Lipopolysaccharide (LPS) alone is able to induce the ISR in hepatocytes and can trigger massive liver damage along with tumor necrosis factor-alpha (TNF-α) expression...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28500648/bergmann-glia-translocation-a-new-disease-marker-for-vanishing-white-matter-identifies-therapeutic-effects-of-guanabenz-treatment
#6
Stephanie Dooves, Marianna Bugiani, Lisanne Wisse, Truus E M Abbink, Marjo S van der Knaap, Vivi M Heine
Vanishing White Matter (VWM) is a devastating leukoencephalopathy without effective treatment options. Patients have mutations in the EIF2B1-5 genes, encoding the five subunits of eIF2B, a guanine exchange factor that is an important regulator of protein translation. We recently developed mouse models for VWM that replicate the human disease. To study disease improvement after treatment in these mice it is essential to have sensitive biomarkers related to disease stage. The Bergmann glia of the cerebellum, an astrocytic subpopulation, translocate into the molecular layer in symptomatic VWM mice and patients...
May 13, 2017: Neuropathology and Applied Neurobiology
https://www.readbyqxmd.com/read/28447936/ppp1r15a-mediated-dephosphorylation-of-eif2%C3%AE-is-unaffected-by-sephin1-or-guanabenz
#7
Ana Crespillo-Casado, Joseph E Chambers, Peter M Fischer, Stefan J Marciniak, David Ron
Dephosphorylation of translation initiation factor 2 (eIF2α) terminates signalling in the mammalian integrated stress response (ISR) and has emerged as a promising target for modifying the course of protein misfolding diseases. The [(o-chlorobenzylidene)amino]guanidines (Guanabenz and Sephin1) have been proposed to exert protective effects against misfolding by interfering with eIF2α-P dephosphorylation through selective disruption of a PP1-PPP1R15A holophosphatase complex. Surprisingly, they proved inert in vitro affecting neither stability of the PP1-PPP1R15A complex nor substrate-specific dephosphorylation...
April 27, 2017: ELife
https://www.readbyqxmd.com/read/28323924/guanabenz-sensitizes-pancreatic-%C3%AE-cells-to-lipotoxic-endoplasmic-reticulum-stress-and-apoptosis
#8
Baroj Abdulkarim, Miriam Hernangomez, Mariana Igoillo-Esteve, Daniel A Cunha, Lorella Marselli, Piero Marchetti, Laurence Ladriere, Miriam Cnop
Deficient as well as excessive/prolonged endoplasmic reticulum (ER) stress signaling can lead to pancreatic β cell failure and the development of diabetes. Saturated free fatty acids (FFAs) such as palmitate induce lipotoxic ER stress in pancreatic β cells. One of the main ER stress response pathways is under the control of the protein kinase R-like endoplasmic reticulum kinase (PERK), leading to phosphorylation of the eukaryotic translation initiation factor 2 (eIF2α). The antihypertensive drug guanabenz has been shown to inhibit eIF2α dephosphorylation and protect cells from ER stress...
June 1, 2017: Endocrinology
https://www.readbyqxmd.com/read/28302022/glial-cell-a-potential-target-for-cellular-and-drug-based-therapy-in-various-cns-diseases
#9
Shakeeb Ahmed, Azka Gull, Tahir Khuroo, Mohd Aqil, Yasmin Sultana
Glial cells are integrated part of neurovascular unit of blood brain barrier (BBB). They undergo mitosis and mainly classified as astrocytes, oligodendrocytes, microglia, ependymal cells and nerve glial antigen 2 cells. Being a most versatile glial cell, astrocytes provide structural support to neurons, maintain brain homeostasis, take part in neuronal communication, and perform some housekeeping functions. Oligodendrocytes myelinate the neuronal axons for proper transmission of nerve impulse and microglia are brain immune cells...
2017: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/28237805/noradrenergic-regulation-of-plasticity-marker-expression-in-the-adult-rodent-piriform-cortex
#10
Krishna C Vadodaria, Sudhirkumar U Yanpallewar, Mayur Vadhvani, Devyani Toshniwal, L Cameron Liles, Karen S Rommelfanger, David Weinshenker, Vidita A Vaidya
The adult rodent piriform cortex has been reported to harbor immature neurons that express markers associated with neurodevelopment and plasticity, namely polysialylated neural cell adhesion molecule (PSA-NCAM) and doublecortin (DCX). We characterized the expression of PSA-NCAM and DCX across the rostrocaudal axis of the rat piriform cortex and observed higher numbers of PSA-NCAM and DCX positive cells in the posterior subdivision. As observed in the rat piriform cortex, Nestin-GFP reporter mice also revealed a similar gradient of GFP-positive cells with an increasing rostro-caudal gradient of expression...
March 22, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/28163699/a-systematic-review-of-in-vitro-and-in-vivo-activities-of-anti-toxoplasma-drugs-and-compounds-2006-2016
#11
REVIEW
Mahbobeh Montazeri, Mehdi Sharif, Shahabeddin Sarvi, Saeed Mehrzadi, Ehsan Ahmadpour, Ahmad Daryani
The currently available anti-Toxoplasma agents have serious limitations. This systematic review was performed to evaluate drugs and new compounds used for the treatment of toxoplasmosis. Data was systematically collected from published papers on the efficacy of drugs/compounds used against Toxoplasma gondii (T. gondii) globally during 2006-2016. The searched databases were PubMed, Google Scholar, Science Direct, ISI Web of Science, EBSCO, and Scopus. One hundred and eighteen papers were eligible for inclusion in this systematic review, which were both in vitro and in vivo studies...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/27992581/gadd34-keeps-the-mtor-pathway-inactivated-in-endoplasmic-reticulum-stress-related-autophagy
#12
Marianna Holczer, Gábor Bánhegyi, Orsolya Kapuy
The balance of protein synthesis and proteolysis (i.e. proteostasis) is maintained by a complex regulatory network in which mTOR (mechanistic target of rapamycin serine/threonine kinase) pathway and unfolded protein response are prominent positive and negative actors. The interplay between the two systems has been revealed; however the mechanistic details of this crosstalk are largely unknown. The aim of the present study was to investigate the elements of crosstalk during endoplasmic reticulum stress and to verify the key role of GADD34 in the connection with the mTOR pathway...
2016: PloS One
https://www.readbyqxmd.com/read/27416896/regulation-of-perk-eif2%C3%AE-signalling-by-tuberous-sclerosis-complex-1-controls-homoeostasis-and-survival-of-myelinating-oligodendrocytes
#13
Minqing Jiang, Lei Liu, Xuelian He, Haibo Wang, Wensheng Lin, Huimin Wang, Sung O Yoon, Teresa L Wood, Q Richard Lu
Tuberous sclerosis complex-1 or 2 (TSC1/2) mutations cause white matter abnormalities, including myelin deficits in the CNS; however, underlying mechanisms are not fully understood. TSC1/2 negatively regulate the function of mTOR, which is required for oligodendrocyte differentiation. Here we report that, unexpectedly, constitutive activation of mTOR signalling by Tsc1 deletion in the oligodendrocyte lineage results in severe myelination defects and oligodendrocyte cell death in mice, despite an initial increase of oligodendrocyte precursors during early development...
2016: Nature Communications
https://www.readbyqxmd.com/read/27234925/the-signaling-of-amitriptyline-induced-inhibitory-effect-on-electrical-field-stimulation-response-in-colon-smooth-muscle
#14
Tin Sandar Zaw, Phyu Phyu Khin, Uy Dong Sohn
Amitriptyline, a well-known antidepressant, exerts inhibitory effect on electrically stimulated rat colon smooth muscle contraction. In this study, we investigated the signaling pathway of amitriptyline-induced inhibitory effect. Changes in isometric force of colon muscle were recorded on polygraph, and data were analyzed by measuring the inhibitory extent induced by amitriptyline. Firstly, muscles were contracted by stimulation with electric field stimulation (EFS), and then, amitriptyline was added cumulatively to determine its influence effect on EFS...
September 2016: Naunyn-Schmiedeberg's Archives of Pharmacology
https://www.readbyqxmd.com/read/27164082/guanabenz-downregulates-inflammatory-responses-via-eif2%C3%AE-dependent-and-independent-signaling
#15
Shinya Takigawa, Andy Chen, Akinobu Nishimura, Shengzhi Liu, Bai-Yan Li, Akihiro Sudo, Hiroki Yokota, Kazunori Hamamura
Integrated stress responses (ISR) may lead to cell death and tissue degeneration via eukaryotic translation initiation factor 2 α (eIF2α)-mediated signaling. Alleviating ISR by modulating eIF2α phosphorylation can reduce the symptoms associated with various diseases. Guanabenz is known to elevate the phosphorylation level of eIF2α and reduce pro-inflammatory responses. However, the mechanism of its action is not well understood. In this study, we investigated the signaling pathway through which guanabenz induces anti-inflammatory effects in immune cells, in particular macrophages...
May 5, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/26965420/novel-dengue-virus-inhibitor-4-hpr-activates-atf4-independent-of-protein-kinase-r-like-endoplasmic-reticulum-kinase-and-elevates-levels-of-eif2%C3%AE-phosphorylation-in-virus-infected-cells
#16
J E Fraser, C Wang, K W K Chan, S G Vasudevan, D A Jans
Infections by dengue virus (DENV) are increasing worldwide, with an urgent need for effective anti-DENV agents. We recently identified N-(4-hydroxyphenyl) retinamide (4-HPR), an anti-DENV agent effective against all 4 serotypes of DENV in cell culture, and in a lethal mouse model for DENV infection (Fraser et al., 2014b). Although identified as an inhibitor of DENV non-structural protein 5 (NS5) recognition by host nuclear import proteins, the precise impact and mode of action of 4-HPR in effecting DENV clearance remains to be defined...
June 2016: Antiviral Research
https://www.readbyqxmd.com/read/26866051/data-on-na-k-atpase-in-primary-cultures-of-renal-proximal-tubule-cells-treated-with-catecholamines
#17
Mary Taub, Facundo Cutuli
This data article is concerned with chronic regulation of Na,K-ATPase by catecholamines. After a chronic treatment, inhibition of Na,K-ATPase activity was observed in cultures with dopamine, while a stimulation was observed in cultures treated with norepinephrine. Following a chronic incubation with guanabenz, an α adrenergic agonist, an increase in Na,K-ATPase α and β subunit mRNAs was observed. This data supports the research article entitled, "Renal proximal tubule Na, K-ATPase is controlled by CREB regulated transcriptional coactivators as well as salt inducible kinase 1" (Taub et al...
March 2016: Data in Brief
https://www.readbyqxmd.com/read/26744324/conserved-pharmacological-rescue-of-hereditary-spastic-paraplegia-related-phenotypes-across-model-organisms
#18
Carl Julien, Alexandra Lissouba, Surya Madabattula, Yasmin Fardghassemi, Cory Rosenfelt, Alaura Androschuk, Joel Strautman, Clement Wong, Andrew Bysice, Julia O'sullivan, Guy A Rouleau, Pierre Drapeau, J Alex Parker, François V Bolduc
Hereditary spastic paraplegias (HSPs) are a group of neurodegenerative diseases causing progressive gait dysfunction. Over 50 genes have now been associated with HSP. Despite the recent explosion in genetic knowledge, HSP remains without pharmacological treatment. Loss-of-function mutation of the SPAST gene, also known as SPG4, is the most common cause of HSP in patients. SPAST is conserved across animal species and regulates microtubule dynamics. Recent studies have shown that it also modulates endoplasmic reticulum (ER) stress...
March 15, 2016: Human Molecular Genetics
https://www.readbyqxmd.com/read/26400165/guanabenz-wytensin%C3%A2-selectively-enhances-uptake-and-efficacy-of-hydrophobically-modified-sirnas
#19
Maire F Osborn, Julia F Alterman, Mehran Nikan, Hong Cao, Marie C Didiot, Matthew R Hassler, Andrew H Coles, Anastasia Khvorova
One of the major obstacles to the pharmaceutical success of oligonucleotide therapeutics (ONTs) is efficient delivery from the point of injection to the intracellular setting where functional gene silencing occurs. In particular, a significant fraction of internalized ONTs are nonproductively sequestered in endo-lysosomal compartments. Here, we describe a two-step, robust assay for high-throughput de novo detection of small bioactive molecules that enhance cellular uptake, endosomal escape, and efficacy of ONTs...
October 15, 2015: Nucleic Acids Research
https://www.readbyqxmd.com/read/26328492/eif2%C3%AE-independent-inhibition-of-tnf-%C3%AE-triggered-nf-%C3%AE%C2%BAb-activation-by-salubrinal
#20
Shotaro Nakajima, Yuan Chi, Kun Gao, Koji Kono, Jian Yao
Salubrinal is a selective inhibitor of cellular complexes that dephosphorylate eukaryotic translation initiation factor 2α (eIF2α). In previous reports, salubrinal was shown to have the potential to inhibit the activation of nuclear factor-κB (NF-κB) by several stimuli. However, the effects of salubrinal on NF-κB signaling are largely unknown. In this study, we investigated whether and how salubrinal affects NF-κB activation induced by tumor necrosis factor (TNF)-α and interleukin (IL)-1β. We found that salubrinal selectively blocked TNF-α- but not IL-1β-induced activation of NF-κB...
2015: Biological & Pharmaceutical Bulletin
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