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Gsk3 Inhibitor

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https://www.readbyqxmd.com/read/29763624/the-gsk3-signaling-axis-regulates-adaptive-glutamine-metabolism-in-lung-squamous-cell-carcinoma
#1
Milica Momcilovic, Sean T Bailey, Jason T Lee, Michael C Fishbein, Daniel Braas, James Go, Thomas G Graeber, Francesco Parlati, Susan Demo, Rui Li, Tonya C Walser, Michael Gricowski, Robert Shuman, Julio Ibarra, Deborah Fridman, Michael E Phelps, Karam Badran, Maie St John, Nicholas M Bernthal, Noah Federman, Jane Yanagawa, Steven M Dubinett, Saman Sadeghi, Heather R Christofk, David B Shackelford
Altered metabolism is a hallmark of cancer growth, forming the conceptual basis for development of metabolic therapies as cancer treatments. We performed in vivo metabolic profiling and molecular analysis of lung squamous cell carcinoma (SCC) to identify metabolic nodes for therapeutic targeting. Lung SCCs adapt to chronic mTOR inhibition and suppression of glycolysis through the GSK3α/β signaling pathway, which upregulates glutaminolysis. Phospho-GSK3α/β protein levels are predictive of response to single-therapy mTOR inhibition while combinatorial treatment with the glutaminase inhibitor CB-839 effectively overcomes therapy resistance...
May 14, 2018: Cancer Cell
https://www.readbyqxmd.com/read/29758944/the-conundrum-of-gsk3-inhibitors-is-it-the-dawn-of-a-new-beginning
#2
Ratan V Bhat, Ulf Andersson, Shalini Andersson, Laurent Knerr, Udo Bauer, Anna Sundgren Andersson
Spanning over three decades of extensive drug discovery research, the efforts to develop a potent and selective GSK3 inhibitor as a therapeutic for the treatment of type 2 diabetes, Alzheimer's disease (AD), bipolar disorders and cancer have been futile. Since its initial discovery in 1980 and subsequent decades of research, one cannot underscore the importance of the target and the promise of a game changing disease modifier. Several pharmaceutical companies, biotech companies, and academic institutions raged in a quest to unravel the biology and discover potent and selective GSK3 inhibitors, some of which went through clinical trials...
May 11, 2018: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/29748581/leptin-increases-mitochondrial-opa1-via-gsk3-mediated-oma1-ubiquitination-to-enhance-therapeutic-effects-of-mesenchymal-stem-cell-transplantation
#3
Fan Yang, Rongrong Wu, Zhi Jiang, Jinghai Chen, Jinliang Nan, Sheng'an Su, Na Zhang, Chen Wang, Jing Zhao, Cheng Ni, Yingchao Wang, Wangxing Hu, Zhiru Zeng, Keyang Zhu, Xianbao Liu, Xinyang Hu, Wei Zhu, Hong Yu, Jinyu Huang, Jian'an Wang
Accumulating evidence revealed that mesenchymal stem cells (MSCs) confer cardioprotection against myocardial infarction (MI). However, the poor survival and engraftment rate of the transplanted cells limited their therapeutic efficacy in the heart. The enhanced leptin production associated with hypoxia preconditioning contributed to the improved MSCs survival. Mitochondrial integrity determines the cellular fate. Thus, we aimed to investigate whether leptin can enhance mitochondrial integrity of human MSCs (hMSCs) to protect against various stress...
May 10, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29725679/kinome-chemoproteomics-characterization-of-pyrrolo-3-4-c-pyrazoles-as-potent-and-selective-inhibitors-of-glycogen-synthase-kinase-3
#4
Martin Golkowski, Gayani K Perera, Venkata Narayana Vidadala, Kayode K Ojo, Wesley C Van Voorhis, Dustin J Maly, Shao-En Ong
Glycogen synthase kinase 3 has evolutionarily conserved roles in cell signaling and metabolism and is a recognized drug target in neurological pathologies, most prominently bipolar disorder. More recently it has been suggested that GSK3 may be a target for the treatment of trypanosomatid parasite infections, e.g. with T. brucei, due to the lethal phenotype observed in parasite GSK3 short RNAi knockdown experiments. Here we investigated the kinome selectivity of a library of pyrrolo[3,4-c]pyrazol inhibitors that were developed against T...
February 12, 2018: Molecular omics
https://www.readbyqxmd.com/read/29678905/phosphorylation-of-xiap-at-threonine-180-controls-its-activity-in-wnt-signaling
#5
Victoria H Ng, Brian I Hang, Leah M Sawyer, Leif R Neitzel, Emily E Crispi, Kristie L Rose, Tessa M Popay, Alison Zhong, Laura A Lee, William P Tansey, Stacey Huppert, Ethan Lee
X-linked Inhibitor of Apoptosis (XIAP) plays an important role in preventing apoptotic cell death. XIAP has been shown to participate in signaling pathways, including Wnt signaling. XIAP regulates Wnt signaling by promoting the monoubiquitination of the co-repressor Groucho/TLE, decreasing its affinity for TCF/Lef and allowing assembly of transcriptionally active β-catenin-TCF/Lef complexes. We now demonstrate that XIAP is phosphorylated by GSK3 at threonine 180 and that an alanine mutant (XIAPT180A ) exhibits decreased Wnt activity compared to wild-type XIAP in cultured human cells and in Xenopus embryos...
April 20, 2018: Journal of Cell Science
https://www.readbyqxmd.com/read/29653082/inhibition-of-glycogen-synthase-kinase-3-reduces-extension-of-the-axonal-leading-process-by-destabilizing-microtubules-in-cerebellar-granule-neurons
#6
Yoshihiro Inami, Mitsuru Omura, Kenta Kubota, Yoshiyuki Konishi
Recent studies have uncovered various molecules that play key roles in neuronal morphogenesis. Nevertheless, the mechanisms underlying the neuron-type-dependent regulation of morphogenesis remain unknown. We have previously reported that inhibition of glycogen synthase kinase-3 (GSK3) markedly reduced axonal length of cerebellar granule neurons (CGNs) in a neuron-type-dependent manner. In the present study, we investigated the mechanisms by which the growth of CGN axons was severely suppressed upon GSK3 inhibition...
April 10, 2018: Brain Research
https://www.readbyqxmd.com/read/29628506/zinc-finger-protein-746-promotes-colorectal-cancer-progression-via-c-myc-stability-mediated-by-glycogen-synthase-kinase-3%C3%AE-and-f-box-and-wd-repeat-domain-containing-7
#7
Ji Hoon Jung, Deok-Beom Jung, Hyunseok Kim, Hyemin Lee, Shi-Eun Kang, Sanjay K Srivastava, Miyong Yun, Sung-Hoon Kim
To elucidate the underlying oncogenic mechanism of zinc finger protein 746 (ZNF746), current study was conducted in colorectal cancers (CRCs). Herein, ZNF746 was overexpressed in HCT116, SW620, and SW480 cells, which was supported by CRC tissue microarray and TCGA analysis. Also, DNA microarray revealed the differentially expressed gene profile particularly related to cell cycle genes and c-Myc in ZNF746 depleted HCT116 cells. Furthermore, ZNF746 enhanced the stability of c-Myc via their direct binding through nuclear colocalization by immunoprecipitation and immunofluorescence, while ZNF746 and c-Myc exist mainly in nucleoplasm...
April 9, 2018: Oncogene
https://www.readbyqxmd.com/read/29603837/treatment-with-the-gsk3-beta-inhibitor-tideglusib-improves-hippocampal-development-and-memory-performance-in-juvenile-but-not-adult-cdkl5-knockout-mice
#8
Claudia Fuchs, Norma Fustini, Stefania Trazzi, Laura Gennaccaro, Roberto Rimondini, Elisabetta Ciani
Cyclin-dependent kinase-like 5 (CDKL5) disorder is a severe neurodevelopmental disorder characterized by early-onset epileptic seizures, severe developmental delay, and intellectual disability. To date, no effective pharmacological treatments are available to improve the neurological phenotype that is due to mutations in the CDKL5 gene. Murine models of CDKL5 disorder have recently been generated, making the preclinical testing of pharmacological interventions possible. Using a Cdkl5 knockout (KO) mouse model, we recently demonstrated that deficiency of Cdkl5 causes defects in postnatal hippocampal development and hippocampus-dependent learning and memory...
March 30, 2018: European Journal of Neuroscience
https://www.readbyqxmd.com/read/29579399/gsk3-activated-stat5-regulates-expression-of-sfrps-to-modulate-adipogenesis
#9
Li Wang, Yuan Wang, Yuan Meng, Chao Zhang, Lijun Di
Adipogenesis is a tightly regulated cellular process and is closely associated with obesity and its associated metabolic disorders, such as diabetes. Multiple transcription factors and signaling pathways are involved in the regulation of adipogenesis. Here, we report that glycogen synthase kinase (GSK3), which was reported to play an important role in many cellular processes, is essential to adipocyte differentiation at early and terminal differentiation phases. Mechanistically, GSK3 modulates adipogenesis through regulation of both canonical Wnt pathways, which involve Wnt/β-catenin signaling, and noncanonical Wnt pathways, which include JNK and Ras-related C3 botulinum toxin substrate signaling...
March 26, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/29574946/cyclic-amp-and-glycogen-synthase-kinase-3-form-a-regulatory-loop-in-spermatozoa
#10
Souvik Dey, Suranjana Goswami, Alaa Eisa, Rahul Bhattacharjee, Cameron Brothag, Douglas Kline, Srinivasan Vijayaraghavan
The multifaceted glycogen synthase kinase (GSK3) has an essential role in sperm and male fertility. Since cyclic AMP (cAMP) plays an important role in sperm function, we investigated whether GSK3 and cAMP pathways may be interrelated. We used GSK3 and soluble adenylyl cyclase (sAC) knockout mice and pharmacological modulators to examine this relationship. Intracellular cAMP levels were found to be significantly lower in sperm lacking GSK3α or GSK3β. A similar outcome was observed when sperm cells were treated with SB216763, a GSK3 inhibitor...
March 25, 2018: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/29515000/exploiting-an-asp-glu-switch-in-glycogen-synthase-kinase-3-to-design-paralog-selective-inhibitors-for-use-in-acute-myeloid-leukemia
#11
Florence F Wagner, Lina Benajiba, Arthur J Campbell, Michel Weïwer, Joshua R Sacher, Jennifer P Gale, Linda Ross, Alexandre Puissant, Gabriela Alexe, Amy Conway, Morgan Back, Yana Pikman, Ilene Galinsky, Daniel J DeAngelo, Richard M Stone, Taner Kaya, Xi Shi, Matthew B Robers, Thomas Machleidt, Jennifer Wilkinson, Olivier Hermine, Andrew Kung, Adam J Stein, Damodharan Lakshminarasimhan, Michael T Hemann, Edward Scolnick, Yan-Ling Zhang, Jen Q Pan, Kimberly Stegmaier, Edward B Holson
Glycogen synthase kinase 3 (GSK3), a key regulatory kinase in the wingless-type MMTV integration site family (WNT) pathway, is a therapeutic target of interest in many diseases. Although dual GSK3α/β inhibitors have entered clinical trials, none has successfully translated to clinical application. Mechanism-based toxicities, driven in part by the inhibition of both GSK3 paralogs and subsequent β-catenin stabilization, are a concern in the translation of this target class because mutations and overexpression of β-catenin are associated with many cancers...
March 7, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29482106/development-and-validation-of-an-lc-ms-ms-method-for-quantitative-determination-of-gs87-a-novel-antineoplastic-agent-in-mouse-plasma
#12
Sandeep R Kunati, Shuming Yang, David Wald, Yan Xu
GS87 is a novel, highly specific GSK3 inhibitor, which has shown to induce extensive differentiation of acute myeloid leukemia (AML) cells in early mouse studies and has great potential for therapeutic advancement. This work described the development and validation of an LC-MS/MS method for quantitative determination of GS87 in mouse plasma. In this method, GS87 and T6447952 (a structural analog used as internal standard) were extracted from plasma using hexane as extraction solvent, and separated isocratically on a Waters XTerra® MS C8 column (2...
May 10, 2018: Journal of Pharmaceutical and Biomedical Analysis
https://www.readbyqxmd.com/read/29472592/gsk3-is-a-negative-regulator-of-the-thermogenic-program-in-brown-adipocytes
#13
Lasse K Markussen, Sally Winther, Barton Wicksteed, Jacob B Hansen
Brown adipose tissue is a promising therapeutic target in metabolic disorders due to its ability to dissipate energy and improve systemic insulin sensitivity and glucose homeostasis. β-Adrenergic stimulation of brown adipocytes leads to an increase in oxygen consumption and induction of a thermogenic gene program that includes uncoupling protein 1 (Ucp1) and fibroblast growth factor 21 (Fgf21). In kinase inhibitor screens, we have identified glycogen synthase kinase 3 (GSK3) as a negative regulator of basal and β-adrenergically stimulated Fgf21 expression in cultured brown adipocytes...
February 22, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29452218/tnf%C3%AE-disrupts-blood-brain-barrier-integrity-to-maintain-prolonged-depressive-like-behavior-in-mice
#14
Yuyan Cheng, Sachi Desse, Ana Martinez, Ryan J Worthen, Richard S Jope, Eleonore Beurel
Recovery from major depressive disorder is difficult, particularly in patients who are refractory to antidepressant treatments. To examine factors that regulate recovery, we developed a prolonged learned helplessness depression model in mice. After the induction of learned helplessness, mice were separated into groups that recovered or did not recover within 4 weeks. Comparisons were made between groups in hippocampal proteins, inflammatory cytokines, and blood brain barrier (BBB) permeability. Compared with mice that recovered and control mice, non-recovered mice displaying prolonged learned helplessness had greater hippocampal activation of glycogen synthase kinase-3 (GSK3), higher levels of tumor necrosis factor-α (TNFα), interleukin-17A, and interleukin-23, increased permeability of the blood brain barrier (BBB), and lower levels of the BBB tight junction proteins occludin, ZO1, and claudin-5...
March 2018: Brain, Behavior, and Immunity
https://www.readbyqxmd.com/read/29452207/glycogen-synthase-kinase-3%C3%AE-promotes-liver-innate-immune-activation-by-restraining-amp-activated-protein-kinase-activation
#15
Haoming Zhou, Han Wang, Ming Ni, Shi Yue, Yongxiang Xia, Ronald W Busuttil, Jerzy W Kupiec-Weglinski, Ling Lu, Xuehao Wang, Yuan Zhai
BACKGROUND & AIMS: Glycogen synthase kinase 3β (Gsk3β [Gsk3b]) is a ubiquitously expressed kinase with distinctive functions in different types of cells. Although its roles in regulating innate immune activation and ischaemia and reperfusion injuries (IRIs) have been well documented, the underlying mechanisms remain ambiguous, in part because of the lack of cell-specific tools in vivo. METHODS: We created a myeloid-specific Gsk3b knockout (KO) strain to study the function of Gsk3β in macrophages in a murine liver partial warm ischaemia model...
February 13, 2018: Journal of Hepatology
https://www.readbyqxmd.com/read/29434052/in-vitro-and-in-vivo-antitumor-and-anti-inflammatory-capabilities-of-the-novel-gsk3-and-cdk9-inhibitor-abc1183
#16
Randy S Schrecengost, Cecelia L Green, Yan Zhuang, Staci N Keller, Ryan A Smith, Lynn W Maines, Charles D Smith
Glycogen synthase kinase-3s (GSK3 α and GSK3 β ) are constitutively active protein kinases that target over 100 substrates, incorporate into numerous protein complexes, and regulate such vital cellular functions as proliferation, apoptosis, and inflammation. Cyclin-dependent kinase 9 (CDK9) regulates RNA production as a component of positive transcription elongation factor b and promotes expression of oncogenic and inflammatory genes. Simultaneous inhibition of these signaling nodes is a promising approach for drug discovery, although previous compounds exhibit limited selectivity and clinical efficacy...
April 2018: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/29421539/salvianolic-acid-b-promotes-neural-differentiation-of-induced-pluripotent-stem-cells-via-pi3k-akt-gsk3%C3%AE-%C3%AE-catenin-pathway
#17
Tao Shu, Chang Liu, Mao Pang, Lei He, Bu Yang, Lei Fan, Shufan Zhang, Xuan Wang, Bin Liu, Limin Rong
Salvianolic acid B (Sal B), a water-soluble component mainly extracted from the traditional Chinese medicine Salvia miltiorrhiza, has potential anti-inflammatory, anti-oxidative and anti-apoptotic actions to protect neural cells. Here, we explore the effects and mechanisms of Sal B on the promotion of differentiation of induced pluripotent stem cells (iPSCs) into neural stem cells (NSCs), then further into neurons. During the processes of neural differentiation of iPSCs, Sal B or a phosphatidylinositide 3 kinase (PI3K) inhibitor (LY294002) were added to the medium...
April 3, 2018: Neuroscience Letters
https://www.readbyqxmd.com/read/29382851/gimap5-dependent-inactivation-of-gsk3%C3%AE-is-required-for-cd4-t-cell-homeostasis-and-prevention-of-immune-pathology
#18
Andrew R Patterson, Mehari Endale, Kristin Lampe, Halil I Aksoylar, Aron Flagg, Jim R Woodgett, David Hildeman, Michael B Jordan, Harinder Singh, Zeynep Kucuk, Jack Bleesing, Kasper Hoebe
GTPase of immunity-associated protein 5 (Gimap5) is linked with lymphocyte survival, autoimmunity, and colitis, but its mechanisms of action are unclear. Here, we show that Gimap5 is essential for the inactivation of glycogen synthase kinase-3β (GSK3β) following T cell activation. In the absence of Gimap5, constitutive GSK3β activity constrains c-Myc induction and NFATc1 nuclear import, thereby limiting productive CD4+ T cell proliferation. Additionally, Gimap5 facilitates Ser389 phosphorylation and nuclear translocation of GSK3β, thereby limiting DNA damage in CD4+ T cells...
January 30, 2018: Nature Communications
https://www.readbyqxmd.com/read/29328365/nuclear-gsk3%C3%AE-induces-dna-double-strand-break-repair-by-phosphorylating-53bp1-in-glioblastoma
#19
Yong Yang, Tiantian Lei, Suya Du, Rongsheng Tong, Hailian Wang, Jiao Yang, Juan Huang, Minghan Sun, Yi Wang, Zhi Dong
Glioblastoma is the most malignant and lethal subtype brain tumors with high risk of recurrence and therapeutic resistance. Emerging evidence has indicated that glycogen synthesis kinase 3 (GSK3)β plays oncogenic roles in multiple tumor types; however, the underlying mechanisms remain largely unknown. It has also been demonstrated that p53 binding protein 1 (53BP1) plays a central role in DNA double-strand break (DSB) repair. This study aimed to reveal the significance of GSK3β translocation from the cytoplasm to the nucleus, and to determine whether GSK3β induces DNA DSB repair in the nuclei of glioblastoma cells via phospho-53BP1...
March 2018: International Journal of Oncology
https://www.readbyqxmd.com/read/29316313/microrna-21-promotes-glioma-cell-proliferation-and-inhibits-senescence-and-apoptosis-by-targeting-spry1-via-the-pten-pi3k-akt-signaling-pathway
#20
Chang Chai, Lai-Jun Song, Shuang-Yin Han, Xi-Qing Li, Ming Li
AIMS: Our study aims to investigate the effect of microRNA-21 (miR-21) on the proliferation, senescence, and apoptosis of glioma cells by targeting SPRY1 via the PTEN/PI3K/AKT signaling pathway. METHODS: Glioma tissues and brain tissues were collected for this study after surgical decompression for traumatic brain injury. RT-qPCR was employed to measure mRNA levels of miR-21, SPRY1, PTEN, PI3K, and AKT, and Western blotting was conducted to determine protein levels of SPRY1, PTEN, PI3K, AKT, p-AKT, Caspase-3, Caspase-9, P53, GSK3, and p-GSK3...
January 5, 2018: CNS Neuroscience & Therapeutics
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