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https://www.readbyqxmd.com/read/27902447/a-unique-type-of-gsk-3-inhibitor-brings-new-opportunities-to-the-clinic
#1
Avital Licht-Murava, Rom Paz, Lilach Vaks, Limor Avrahami, Batya Plotkin, Miriam Eisenstein, Hagit Eldar-Finkelman
Development of protein kinase inhibitors is a focus of many drug discovery programs. A major problem, however, is the limited specificity of the commonly used adenosine triphosphate-competitive inhibitors and the weak inhibition of the more selective substrate-competitive inhibitors. Glycogen synthase kinase-3 (GSK-3) is a promising drug target for treating neurodegenerative disorders, including Alzheimer's disease (AD), but most GSK-3 inhibitors have not reached the clinic. We describe a new type of GSK-3 inhibitor, L807mts, that acts through a substrate-to-inhibitor conversion mechanism that occurs within the catalytic site of the enzyme...
November 15, 2016: Science Signaling
https://www.readbyqxmd.com/read/27902446/science-signaling-podcast-for-15-november-2016-a-new-type-of-kinase-inhibitor
#2
Hagit Eldar-Finkelman, Annalisa M VanHook
This Podcast features an interview with Hagit Eldar-Finkelman, author of a Research Article that appears in the 15 November 2016 issue of Science Signaling, about a newly developed inhibitor of glycogen synthase kinase 3 (GSK-3). GSK-3 participates in several signaling networks and has been implicated in various pathologies, including neurodegenerative diseases, cognitive impairments, and cancer. Licht-Murava et al developed L807mts, a substrate-competitive peptide inhibitor that blocks GSK-3 activity through an unusual mechanism...
November 15, 2016: Science Signaling
https://www.readbyqxmd.com/read/27901086/glycycoumarin-inhibits-hepatocyte-lipoapoptosis-through-activation-of-autophagy-and-inhibition-of-er-stress-gsk-3-mediated-mitochondrial-pathway
#3
Enxiang Zhang, Shutao Yin, Xinhua Song, Lihong Fan, Hongbo Hu
Herbal medicine as an alternative approach in the treatment of disease has drawn growing attention. Identification of the active ingredient is needed for effective utilization of the herbal medicine. Licorice is a popular herbal plant that is widely used to treat various diseases including liver diseases. Glycycoumarin (GCM) is a representative of courmarin compounds isolated from licorice. In the present study, the protective effect of GCM on hepatocyte lipoapoptosis has been evaluated using both cell culture model of palmitate-induced lipoapoptosis and animal model of non-alcoholic steatohepatitis (NASH)...
November 30, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27900801/gsk-3-a-key-regulatory-target-for-ketamine-s-rapid-antidepressant-effects-mediated-by-enhanced-ampa-to-nmda%C3%A2-throughput
#4
Carlos A Zarate, Rodrigo Machado-Vieira
No abstract text is available yet for this article.
November 29, 2016: Bipolar Disorders
https://www.readbyqxmd.com/read/27875297/glycogen-synthase-kinase-3-gsk-3-mediated-phosphorylation-of-uracil-n-glycosylase-2-ung2-facilitates-repair-of-floxuridine-induced-dna-lesions-and-promotes-cell-survival
#5
Carly A Baehr, Catherine J Huntoon, Song-My Hoang, Calvin R Jerde, Larry M Karnitz
Uracil N-glycosylase 2 (UNG2), the nuclear isoform of UNG, catalyzes the removal of uracil or 5-fluorouracil lesions that accumulate in DNA following treatment with the anti-cancer agents 5-fluorouracil and 5-fluorodeoxyuridine (floxuridine), a 5-fluorouracil metabolite. By repairing these DNA lesions before they can cause cell death, UNG2 promotes cancer cell survival and is therefore critically involved in tumor resistance to these agents. However, the mechanisms by which UNG2 is regulated remain unclear...
November 14, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27864906/role-and-regulation-of-glycogen-synthase-kinase-3-beta-in-bovine-spermatozoa
#6
Michael Belenky, Haim Breitbart
The serine/threonine kinase Glycogen synthase kinase 3 (GSK-3) is a master switch that regulates a multitude of cellular pathways, including the acrosome reaction in sperm. In epididymal sperm cells, for example, GSK-3 activity correlates with inhibition of motility-yet no direct pathways connecting GSK-3 activation with loss of motility have been described. Indeed, the details of how GSK-3 is regulated during sperm capacitation and the acrosome reaction remains obscure. To this end, we addressed the involvement of the GSK-3 beta isoform in several known pathways that contribute to motility and the acrosome reaction...
November 19, 2016: Molecular Reproduction and Development
https://www.readbyqxmd.com/read/27828716/glycogen-synthase-kinase-3-gsk-3-inhibitors-a-patent-update-2014-2015
#7
Valle Palomo, Ana Martinez
Glycogen synthase kinase (GSK-3) is a serine/threonine kinase that phosphorylates more than one hundred different sequences within proteins in a variety of different pathways. It is a key component of a remarkably large number of cellular processes and diseases. Imbalance of GSK-3 activity is involved in various prevalent pathological diseases, such as diabetes, neurodegenerative diseases and cancer. Understanding its role in different disorders has been central in the last several decades and there has been a significantly large development of GSK-3 inhibitors, some of which, show promising results for the treatment of these devastating diseases...
November 21, 2016: Expert Opinion on Therapeutic Patents
https://www.readbyqxmd.com/read/27803315/inhibition-of-gsk-3%C3%AE-increases-trabecular-bone-volume-but-not-cortical-bone-volume-in-adenine-induced-uremic-mice-with-severe-hyperparathyroidism
#8
Narihito Tatsumoto, Masaki Arioka, Shunsuke Yamada, Fumi Takahashi-Yanaga, Masanori Tokumoto, Kazuhiko Tsuruya, Takanari Kitazono, Toshiyuki Sasaguri
Patients with chronic kidney disease (CKD) are at increased risk for bone fractures compared with the general population. Repression of the Wnt/β-catenin signaling pathway is associated with bone abnormalities. Inhibition of glycogen synthase kinase (GSK)-3β, a critical component of the Wnt/β-catenin signaling pathway, increases bone volume through accumulation of β-catenin. It remains unknown whether inhibition of GSK-3β increases bone volume in CKD The present in vivo study examined the effects of GSK-3β inhibition on bone volume in CKD mice...
November 2016: Physiological Reports
https://www.readbyqxmd.com/read/27801816/marine-fungi-as-producers-of-benzocoumarins-a-new-class-of-inhibitors-of-glycogen-synthase-kinase-3%C3%AE
#9
Jutta Wiese, Johannes F Imhoff, Tobias A M Gulder, Antje Labes, Rolf Schmaljohann
The glycogen-synthase-kinase 3 (GSK-3) is an important target in drug discovery. This enzyme is involved in the signaling pathways of type 2 diabetes, neurological disorders, cancer, and other diseases. Therefore, inhibitors of GSK-3 are promising drug candidates for the treatment of a broad range of diseases. Here we report pannorin (1), alternariol (2), and alternariol-9-methylether (3) to be promising inhibitors of the isoform GSK-3β showing sub-μM IC50 values. The in vitro inhibition is in the range of the known highly active GSK-3β inhibitor TDZD-8...
October 28, 2016: Marine Drugs
https://www.readbyqxmd.com/read/27793878/maf-protein-mediates-innate-resistance-to-proteasome-inhibition-therapy-in-multiple-myeloma
#10
Ya-Wei Qiang, Shiqiao Ye, Yu Chen, Amy F Buros, Ricky Edmonson, Frits Van Rhee, Bart Barlogie, Joshua Epstein, Gareth J Morgan, Faith E Davies
Multiple myeloma (MM) patients with the t(14;16) translocation have a poor prognosis, and unlike other molecular subgroups, their outcome has not improved with the introduction of bortezomib. The mechanism underlying innate resistance of MM to bortezomib is unknown. In the present study, we have investigated how MAF overexpression impacts resistance to proteasome inhibitor (PI) therapy (bortezomib and carfilzomib). High levels of MAF protein were found in t(14;16) cell lines, cell lines from the t(4;14) subgroup had intermediate levels, while cell lines from the other subgroups had low levels...
October 28, 2016: Blood
https://www.readbyqxmd.com/read/27789709/concerted-action-of-pgc-1-related-coactivator-prc-and-c-myc-in-the-stress-response-to-mitochondrial-dysfunction
#11
Natalie Gleyzer, Richard C Scarpulla
PGC-1-related coactivator (PRC) has a dual function in growth-regulated mitochondrial biogenesis and as a sensor of metabolic stress. PRC induction by mitochondrial inhibitors, intracellular ROS, or topoisomerase I inhibition orchestrates an inflammatory program associated with the adaptation to cellular stress. Activation of this program is accompanied by the coordinate expression of c-MYC, which is linked kinetically to that of PRC in response to multiple stress inducers. Here, we show that the c-MYC inhibitor 10058-F4 blocks the induction of c-MYC, PRC, and representative PRC-dependent stress genes by the respiratory chain uncoupler, carbonyl cyanide m-chlorophenyl hydrazine (CCCP)...
December 2, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27754361/plasma-25-hydroxyvitamin-d-is-related-to-protein-signaling-involved-in-glucose-homeostasis-in-a-tissue-specific-manner
#12
Lewan Parker, Itamar Levinger, Aya Mousa, Kirsten Howlett, Barbora de Courten
Vitamin D has been suggested to play a role in glucose metabolism. However, previous findings are contradictory and mechanistic pathways remain unclear. We examined the relationship between plasma 25-hydroxyvitamin D (25(OH)D), insulin sensitivity, and insulin signaling in skeletal muscle and adipose tissue. Seventeen healthy adults (Body mass index: 26 ± 4; Age: 30 ± 12 years) underwent a hyperinsulinemic-euglycemic clamp, and resting skeletal muscle and adipose tissue biopsies. In this cohort, the plasma 25(OH)D concentration was not associated with insulin sensitivity (r = 0...
October 13, 2016: Nutrients
https://www.readbyqxmd.com/read/27751939/inhibition-of-glycogen-synthase-kinase-3beta-ameliorates-triptolide-induced-acute-cardiac-injury-by-desensitizing-mitochondrial-permeability-transition
#13
Wenwen Wang, Yanqin Yang, Zhewen Xiong, Jiamin Kong, Xinlu Fu, Feihai Shen, Zhiying Huang
Triptolide (TP), a diterpene triepoxide, is a major active component of Tripterygium wilfordii extracts, which are prepared as tablets and has been used clinically for the treatment of inflammation and autoimmune disorders. However, TP's therapeutic potential is limited by severe adverse effects. In a previous study, we reported that TP induced mitochondria dependent apoptosis in cardiomyocytes. Glycogen synthase kinase-3β (GSK-3β) is a multifunctional serine/threonine kinase that plays important roles in the necrosis and apoptosis of cardiomyocytes...
December 15, 2016: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/27725131/diosmin-reduces-cerebral-a%C3%AE-levels-tau-hyperphosphorylation-neuroinflammation-and-cognitive-impairment-in-the-3xtg-ad-mice
#14
Darrell Sawmiller, Ahsan Habib, Song Li, Donna Darlington, Huayan Hou, Jun Tian, R Douglas Shytle, Adam Smith, Brian Giunta, Takashi Mori, Jun Tan
Naturally-occurring bioactive flavonoids such as diosmin significantly reduces amyloid beta (Aβ) associated pathology in Alzheimer's disease (AD) mouse models. In the present study, oral administration of diosmin reduced cerebral Aβ oligomer levels, tau-hyperphosphorylation and cognitive impairment in the 3xTg-AD mouse model through glycogen synthase kinase-3 (GSK-3) and transient receptor potential canonical 6-related mechanisms. Diosmetin, one major bioactive metabolite of diosmin, increased inhibitory GSK-3β phosphorylation, while selectively reducing γ-secretase activity, Aβ generation, tau hyperphosphorylation and pro-inflammatory activation of microglia in vitro, without altering Notch processing...
October 15, 2016: Journal of Neuroimmunology
https://www.readbyqxmd.com/read/27708215/dact2-silencing-by-promoter-cpg-methylation-disrupts-its-regulation-of-epithelial-to-mesenchymal-transition-and-cytoskeleton-reorganization-in-breast-cancer-cells
#15
Tingxiu Xiang, Yichao Fan, Chunhong Li, Lili Li, Ying Ying, Junhao Mu, Weiyan Peng, Yixiao Feng, Michael Oberst, Kathleen Kelly, Guosheng Ren, Qian Tao
Wnt signaling plays an important role in breast carcinogenesis. DAPPER2 (DACT2) functions as an inhibitor of canonical Wnt signaling and plays distinct roles in different cell contexts, with its role in breast tumorigenesis unclear. We investigated DACT2 expression in breast cancer cell lines and primary tumors, as well as its functions and molecular mechanisms. Results showed that DACT2 expression was silenced in 9/9 of cell lines. Promoter CpG methylation of DACT2 was detected in 89% (8/9) of cell lines, as well as in 73% (107/147) of primary tumors, but only in 20% (1/5) of surgical margin tissues and in none of normal breast tissues...
September 29, 2016: Oncotarget
https://www.readbyqxmd.com/read/27689729/natural-and-synthetic-bioactive-inhibitors-of-glycogen-synthase-kinase
#16
Imran Khan, Mushtaq A Tantray, Mohammad Sarwar Alam, Hinna Hamid
Glycogen synthase kinase-3 is a multi-functional serine-threonine kinase and is involved in diverse physiological processes, including metabolism, cell cycle, and gene expression by regulating a wide variety of known substrates like glycogen synthase, tau-protein and β-catenin. Aberrant GSK-3 has been involved in diabetes, inflammation, cancer, Alzheimer's and bipolar disorder. In this review, we present an overview of the involvement of GSK-3 in various signalling pathways, resulting in a number of adverse pathologies due to its dysregulation...
September 20, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27684957/%C3%AE-catenin-accumulation-is-associated-with-increased-expression-of-nanog-protein-and-predicts-maintenance-of-msc-self-renewal
#17
Sang-Jin Yu, Hyun-Je Kim, Eui Seok Lee, Chung-Gyu Park, Su Jin Cho, Soung-Hoo Jeon
Human mesenchymal stem cells (hMSCs) are self-renewing cells with ability to differentiate into organized, functional network of cells. Recent studies have revealed that activation of the Wnt/β-catenin pathway by a glycogen synthase kinase (GSK)-3-specific pharmacological inhibitor, Bio, results in the maintenance of self-renewal in both mouse and human ES cells. The molecular mechanism behind the maintenance of hMSCs by these factors, however, is not fully understood. We found that rEGF enhances level of β-catenin, a component of the Wnt/β-catenin signaling pathway...
September 27, 2016: Cell Transplantation
https://www.readbyqxmd.com/read/27668540/small-molecule-gsk-3-inhibitor-rescued-apoptosis-and-neurodegeneration-in-anesthetics-injured-dorsal-root-ganglion-neurons
#18
Tianchao Yu, Wanchun Lin
BACKGROUND: Application of general anesthetics may induce neurotoxicity in dorsal root ganglia (DRG) neurons. In this study, we examined the possible protective mechanism and associated signaling pathways of small-molecule glycogen synthase kinase-3 (GSK-3) inhibitor, SB216763, in bupivacaine-injured mouse DRG neurons in vitro. METHODS: In vitro DRG explant of 6-week old mice was treated with 5mM bupivacaine to induce neurotoxicity. The explants were also pre-treated with SB216763 for 72h...
September 23, 2016: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/27639185/valproic-acid-and-lithium-meditate-anti-inflammatory-effects-by-differentially-modulating-dendritic-cell-differentiation-and-function
#19
Sy-Jye Leu, Yi-Yuan Yang, Hsing-Cheng Liu, Chieh-Yu Cheng, Yu-Chen Wu, Ming-Chyi Huang, Yuen-Lun Lee, Chi-Ching Chen, Winston W Shen, Ko-Jiunn Liu
Valproic acid (VPA), with inhibition activity mainly towards histone deacetylase (HDAC) and Glycogen Synthase Kinase (GSK)-3, and lithium, with inhibition activity mainly toward GSK-3, are both prescribed in clinical as mood-stabilizers and anticonvulsants for the control of bipolar disorder. This study aims to compare the immuno-modulation activities of VPA and lithium, especially on the differentiation and functions of dendritic cells (DC). Our data show that treatment with VPA or lithium effectively alleviated the severity of collagen-induced arthritis triggered by LPS in mice...
September 17, 2016: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/27631495/small-gsk-3-inhibitor-shows-efficacy-in-a-motor-neuron-disease-murine-model-modulating-autophagy
#20
Estefanía de Munck, Valle Palomo, Emma Muñoz-Sáez, Daniel I Perez, Begoña Gómez-Miguel, M Teresa Solas, Carmen Gil, Ana Martínez, Rosa M Arahuetes
Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron degenerative disease that has no effective treatment up to date. Drug discovery tasks have been hampered due to the lack of knowledge in its molecular etiology together with the limited animal models for research. Recently, a motor neuron disease animal model has been developed using β-N-methylamino-L-alanine (L-BMAA), a neurotoxic amino acid related to the appearing of ALS. In the present work, the neuroprotective role of VP2.51, a small heterocyclic GSK-3 inhibitor, is analysed in this novel murine model together with the analysis of autophagy...
2016: PloS One
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