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Guanabenz

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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
#1
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
#2
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
#3
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...
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
#4
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
#5
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
#6
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
#7
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
#8
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
https://www.readbyqxmd.com/read/26303803/guanabenz-repurposed-as-an-antiparasitic-with-activity-against-acute-and-latent-toxoplasmosis
#9
Imaan Benmerzouga, Lisa A Checkley, Michael T Ferdig, Gustavo Arrizabalaga, Ronald C Wek, William J Sullivan
Toxoplasma gondii is a protozoan parasite that persists as a chronic infection. Toxoplasma evades immunity by forming tissue cysts, which reactivate to cause life-threatening disease during immune suppression. There is an urgent need to identify drugs capable of targeting these latent tissue cysts, which tend to form in the brain. We previously showed that translational control is critical during infections with both replicative and latent forms of Toxoplasma. Here we report that guanabenz, an FDA-approved drug that interferes with translational control, has antiparasitic activity against replicative stages of Toxoplasma and the related apicomplexan parasite Plasmodium falciparum (a malaria agent)...
November 2015: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/26303573/suppressed-invasive-and-migratory-behaviors-of-sw1353-chondrosarcoma-cells-through-the-regulation-of-src-rac1-gtpase-and-mmp13
#10
Wenxiao Xu, Qiaoqiao Wan, Sungsoo Na, Hiroki Yokota, Jing-Long Yan, Kazunori Hamamura
Chondrosarcoma is the second frequent type of primary bone cancer. In response to stress to the endoplasmic reticulum, activation of eIF2α-mediated signaling is reported to induce apoptosis. However, its effects on invasive and migratory behaviors of chondrosarcoma have not been understood. Focusing on potential roles of Src kinase, Rac1 GTPase, and MMP13, we investigated eIF2α-driven regulation of SW1353 chondrosarcoma cells. In particular, we employed two chemical agents (salubrinal, Sal; and guanabenz, Gu) that elevate the level of eIF2α phosphorylation...
December 2015: Cellular Signalling
https://www.readbyqxmd.com/read/26288094/guanabenz-treatment-accelerates-disease-in-a-mutant-sod1-mouse-model-of-als
#11
Fernando G Vieira, Qinggong Ping, Andy J Moreno, Joshua D Kidd, Kenneth Thompson, Bingbing Jiang, John M Lincecum, Monica Z Wang, Gerard S De Zutter, Valerie R Tassinari, Beth Levine, Theo Hatzipetros, Alan Gill, Steven Perrin
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by loss of motor neurons. The mechanisms leading to motor neuron degeneration in ALS are unclear. However, there is evidence for involvement of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) in ALS, notably in mutant SOD1 mediated models of ALS. Stress induced phosphorylation of the eIF2 alpha subunit by eukaryotic translation initiation factor 2-alpha kinase 3 Perk activates the UPR. Guanabenz is a centrally acting alpha2 adrenergic receptor agonist shown to interact with a regulatory subunit of the protein phosphatase, Pp1/Gadd34, and selectively disrupt the dephosphorylation of the alpha subunit of eukaryotic initiation factor 2 (eif2alpha)...
2015: PloS One
https://www.readbyqxmd.com/read/26265544/a-functional-tandem-between-transient-receptor-potential-canonical-channels-6-and-calcium-dependent-chloride-channels-in-human-epithelial-cells
#12
Johanna Bertrand, Luc Dannhoffer, Fabrice Antigny, Laura Vachel, Christophe Jayle, Clarisse Vandebrouck, Frédéric Becq, Caroline Norez
TRPC6 plays important human physiological functions, notably in artery and arterioles constriction, in regulation of vascular volume and in bronchial muscle constriction. It is implicated in pulmonary hypertension, cardiovascular disease, and focal segmental glomerulosclerosis and seems to play a role in cancer development. Previously, we identified Guanabenz, an α2-adrenergic agonist used for hypertension treatment (Wytensin®), as an activator of calcium-dependent chloride channels (CaCC) in human Cystic Fibrosis (CF) nasal epithelial cells by transiently increasing [Ca2+]i via an influx of extracellular Ca2+...
October 15, 2015: European Journal of Pharmacology
https://www.readbyqxmd.com/read/26005701/enhancement-of-osteoblastogenesis-and-suppression-of-osteoclastogenesis-by-inhibition-of-de-phosphorylation-of-eukaryotic-translation-initiation-factor-2-alpha
#13
Kazunori Hamamura, Andy Chen, Hiroki Yokota
The phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2α) is activated in response to various stresses such as viral infection, nutrient deprivation, and stress to the endoplasmic reticulum. Severe stress to the endoplasmic reticulum, for instance, induces an apoptotic pathway, while mild stress, on the contrary, leads to a pro-survival pathway. Little has been known about the elaborate role of eIF2α phosphorylation in the development of bone-forming osteoblasts and bone-resorbing osteoclasts...
2015: Receptors & Clinical Investigation
https://www.readbyqxmd.com/read/25977571/chondroprotective-effects-of-salubrinal-in-a-mouse-model-of-osteoarthritis
#14
K Hamamura, A Nishimura, T Iino, S Takigawa, A Sudo, H Yokota
OBJECTIVES: Salubrinal is a synthetic agent that elevates phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2α) and alleviates stress to the endoplasmic reticulum. Previously, we reported that in chondrocytes, Salubrinal attenuates expression and activity of matrix metalloproteinase 13 (MMP13) through downregulating nuclear factor kappa B (NFκB) signalling. We herein examine whether Salubrinal prevents the degradation of articular cartilage in a mouse model of osteoarthritis (OA)...
May 2015: Bone & Joint Research
https://www.readbyqxmd.com/read/25976385/neurodegenerative-disease-phosphatase-inhibitor-prevents-protein-misfolding-diseases
#15
COMMENT
Sarah Crunkhorn
No abstract text is available yet for this article.
June 2015: Nature Reviews. Drug Discovery
https://www.readbyqxmd.com/read/25859045/preventing-proteostasis-diseases-by-selective-inhibition-of-a-phosphatase-regulatory-subunit
#16
Indrajit Das, Agnieszka Krzyzosiak, Kim Schneider, Lawrence Wrabetz, Maurizio D'Antonio, Nicholas Barry, Anna Sigurdardottir, Anne Bertolotti
Protein phosphorylation regulates virtually all biological processes. Although protein kinases are popular drug targets, targeting protein phosphatases remains a challenge. Here, we describe Sephin1 (selective inhibitor of a holophosphatase), a small molecule that safely and selectively inhibited a regulatory subunit of protein phosphatase 1 in vivo. Sephin1 selectively bound and inhibited the stress-induced PPP1R15A, but not the related and constitutive PPP1R15B, to prolong the benefit of an adaptive phospho-signaling pathway, protecting cells from otherwise lethal protein misfolding stress...
April 10, 2015: Science
https://www.readbyqxmd.com/read/25843479/inhibition-of-eukaryotic-initiation-factor-2-alpha-phosphatase-reduces-tissue-damage-and-improves-learning-and-memory-after-experimental-traumatic-brain-injury
#17
Pramod K Dash, Michael J Hylin, Kimberly N Hood, Sara A Orsi, Jing Zhao, John B Redell, Andrey S Tsvetkov, Anthony N Moore
Patients who survive traumatic brain injury (TBI) are often faced with persistent memory deficits. The hippocampus, a structure critical for learning and memory, is vulnerable to TBI and its dysfunction has been linked to memory impairments. Protein kinase RNA-like ER kinase regulates protein synthesis (by phosphorylation of eukaryotic initiation factor 2 alpha [eIF2α]) in response to endoplasmic reticulum (ER) stressors, such as increases in calcium levels, oxidative damage, and energy/glucose depletion, all of which have been implicated in TBI pathophysiology...
October 15, 2015: Journal of Neurotrauma
https://www.readbyqxmd.com/read/25766071/pharmaceutical-integrated-stress-response-enhancement-protects-oligodendrocytes-and-provides-a-potential-multiple-sclerosis-therapeutic
#18
Sharon W Way, Joseph R Podojil, Benjamin L Clayton, Anita Zaremba, Tassie L Collins, Rejani B Kunjamma, Andrew P Robinson, Pedro Brugarolas, Robert H Miller, Stephen D Miller, Brian Popko
Oligodendrocyte death contributes to the pathogenesis of the inflammatory demyelinating disease multiple sclerosis (MS). Nevertheless, current MS therapies are mainly immunomodulatory and have demonstrated limited ability to inhibit MS progression. Protection of oligodendrocytes is therefore a desirable strategy for alleviating disease. Here we demonstrate that enhancement of the integrated stress response using the FDA-approved drug guanabenz increases oligodendrocyte survival in culture and prevents hypomyelination in cerebellar explants in the presence of interferon-γ, a pro-inflammatory cytokine implicated in MS pathogenesis...
2015: Nature Communications
https://www.readbyqxmd.com/read/25682812/approaches-for-discovering-anti-prion-compounds-lessons-learned-and-challenges-ahead
#19
REVIEW
Maria Laura Bolognesi, Giuseppe Legname
INTRODUCTION: Recent years have witnessed major advances in our understanding of the molecular bases of prion diseases. These studies not only highlight the protein misfolding as a potential initiator of a neurodegenerative process, they also provide a foundation for considering whether such a process can be common to many neurodegenerative diseases, including Alzheimer's disease. This makes prion diseases a sort of prototype of neurodegenerative disease, endowed with some intrinsic positive features in terms of drug development...
April 2015: Expert Opinion on Drug Discovery
https://www.readbyqxmd.com/read/25532480/prevention-of-glucocorticoid-induced-apoptosis-of-osteoblasts-and-osteocytes-by-protecting-against-endoplasmic-reticulum-er-stress-in-vitro-and-in-vivo-in-female-mice
#20
COMPARATIVE STUDY
Amy Y Sato, Xiaolin Tu, Kevin A McAndrews, Lilian I Plotkin, Teresita Bellido
Endoplasmic reticulum (ER) stress is associated with increased reactive oxygen species (ROS), results from accumulation of misfolded/unfolded proteins, and can trigger apoptosis. ER stress is alleviated by phosphorylation of eukaryotic translation initiation factor 2α (eIF2α), which inhibits protein translation allowing the ER to recover, thus promoting cell viability. We investigated whether osteoblastic cell apoptosis induced by glucocorticoids (GCs) is due to induction of ROS/ER stress and whether inhibition of eIF2α dephosphorylation promotes survival opposing the deleterious effects of GC in vitro and in vivo...
April 2015: Bone
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