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Gsk3 Inhibitor

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
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...
February 19, 2018: Journal of Pharmaceutical and Biomedical Analysis
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
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...
February 13, 2018: Brain, Behavior, and Immunity
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) is a ubiquitously expressed kinase with distinctive functions in different types of cells. Although its roles in regulating innate immune activation and ischemia and reperfusion injuries (IRI) have been well documented, underlying mechanisms remain ambiguous, due in part to the lack of cell-specific tools in vivo. METHODS: We created a myeloid-specific Gsk3β KO strain to study its function in macrophages in a murine liver partial warm ischemia model...
February 13, 2018: Journal of Hepatology
Randy S Schrecengost, Cecelia L Green, Yan Zhuang, Staci N Keller, Ryan A Smith, Lynn W Maines, Charles D Smith
Glycogen synthase kinase-3s (GSK3α and GSK3β) are constitutively active protein kinases that target over 100 substrates, incorporate into numerous protein complexes, and regulate vital cellular functions such 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...
February 6, 2018: Journal of Pharmacology and Experimental Therapeutics
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...
February 5, 2018: Neuroscience Letters
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
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...
January 4, 2018: International Journal of Oncology
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
Hun Min Song, Gwang Hun Park, Su Bin Park, Hyun-Seok Kim, Ho-Jun Son, Yurry Um, Jin Boo Jeong
Viticis Fructus (VF) as the dried fruit from Vitex rotundifolia L. used as a traditional medicine for treating inflammation, headache, migraine, chronic bronchitis, eye pain, and gastrointestinal infections has been reported to have antiproliferative effects against various cancer cells, including breast, lung and colorectal cancer cells. However, the molecular mechanisms by which VF mediates the inhibitory effect of the proliferation of cancer cells have not been elucidated in detail. In this study, we investigated the molecular mechanism of VF on the down-regulation of cyclin D1 and CDK4 level associated with cancer cell proliferation...
January 3, 2018: American Journal of Chinese Medicine
Lisa Logie, Lidy Van Aalten, Axel Knebel, Thomas Force, C James Hastie, Hilary MacLauchlan, David G Campbell, Robert Gourlay, Alan Prescott, Jane Davidson, Will Fuller, Calum Sutherland
Glycogen synthase kinase-3 (GSK3) regulates many physiological processes through phosphorylation of a diverse array of substrates. Inhibitors of GSK3 have been generated as potential therapies in several diseases, however the vital role GSK3 plays in cell biology makes the clinical use of GSK3 inhibitors potentially problematic. A clearer understanding of true physiological and pathophysiological substrates of GSK3 should provide opportunities for more selective, disease specific, manipulation of GSK3. To identify kinetically favourable substrates we performed a GSK3 substrate screen in heart tissue...
December 15, 2017: Scientific Reports
Theun de Groot, Lars Damen, Leanne Kosse, Mohammad Alsady, Rosalinda Doty, Ruben Baumgarten, Susan Sheehan, Johan van der Vlag, Ron Korstanje, Peter M T Deen
Glycogen synthase kinase 3 (GSK3) plays an important role in the development of diabetes mellitus and renal injury. GSK3 inhibition increases glucose uptake in insulin-insensitive muscle and adipose tissue, while it reduces albuminuria and glomerulosclerosis in acute kidney injury. The effect of chronic GSK3 inhibition in diabetic nephropathy is not known. We tested the effect of lithium, the only clinical GSK3 inhibitor, on the development of diabetes mellitus and kidney injury in a mouse model of diabetic nephropathy...
2017: PloS One
Xiaofeng Han, Xinfeng Li, Guibin Zhong, Zude Liu
Bone marrow mesenchymal stem cells (BMSCs) are stem cells with multidirectional differentiation potential, which can be used as seed cells to repair and reconstruct many types of tissues and organs following injury or disease. Osteogenic differentiation involves a variety of pathway and factors, including cytokines, growth factors, and hormones. In the present study, we investigated the potential role of Dishevelled in osteogenic differentiation of BMSCs in induction medium containing the methyltransferase inhibitor 5-aza-2'-deoxycytidine...
2017: American Journal of Translational Research
Ata Ur Rahman Mohammed Abdul, Bhagya De Silva, Ronald K Gary
Lithium salt is a classic glycogen synthase kinase 3 (GSK3) inhibitor. Beryllium is a structurally related inhibitor that is more potent but relatively uncharacterized. This study examined the effects of these inhibitors on the phosphorylation of endogenous GSK3 substrates. In NIH-3T3 cells, both salts caused a decrease in phosphorylated glycogen synthase, as expected. GSK3 inhibitors produce enhanced phosphorylation of Ser9 of GSK3β via a positive feedback mechanism, and both salts elicited this enhancement...
January 26, 2018: Biology Open
Xi Chen, Ruizhe Wang, Xu Liu, Yongming Wu, Tao Zhou, Yujia Yang, Andrew Perez, Ying-Chu Chen, Liang Hu, Jean Paul Chadarevian, Amir Assadieskandar, Chao Zhang, Qi-Long Ying
Glycogen synthase kinase 3 (GSK3) plays a central role in diverse cellular processes. GSK3 has two mammalian isozymes, GSK3α and GSK3β, whose functions remain ill-defined because of a lack of inhibitors that can distinguish between the two highly homologous isozymes. Here, we show that GSK3α and GSK3β can be selectively inhibited in mouse embryonic stem cells (ESCs) using a chemical-genetic approach. Selective inhibition of GSK3β is sufficient to maintain mouse ESC self-renewal, whereas GSK3α inhibition promotes mouse ESC differentiation toward neural lineages...
December 4, 2017: Developmental Cell
Christina Wei, Lauren Stock, Leila Valanejad, Zachary A Zalewski, Rebekah Karns, Jack Puymirat, David Nelson, David Witte, Jim Woodgett, Nikolai A Timchenko, Lubov Timchenko
Myotonic dystrophy type 1 (DM1) is a progressive neuromuscular disease caused by expanded CUG repeats, which misregulate RNA metabolism through several RNA-binding proteins, including CUG-binding protein/CUGBP1 elav-like factor 1 (CUGBP1/CELF1) and muscleblind 1 protein. Mutant CUG repeats elevate CUGBP1 and alter CUGBP1 activity via a glycogen synthase kinase 3β (GSK3β)-cyclin D3-cyclin D-dependent kinase 4 (CDK4) signaling pathway. Inhibition of GSK3β corrects abnormal activity of CUGBP1 in DM1 mice [human skeletal actin mRNA, containing long repeats ( HSALR ) model]...
January 5, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Runsheng He, Besa Xhabija, Batool Al-Qanber, Benjamin L Kidder
Embryonic stem (ES) cell pluripotency is governed by OCT4-centric transcriptional networks. Conventional ES cells can be derived and maintained in vitro with media containing the cytokine leukemia inhibitory factor (LIF), which propagates the pluripotent state by activating STAT3 signaling, and simultaneous inhibition of glycogen synthase kinase-3 (GSK3) and MAP kinase/ERK kinase signaling. However, it is unclear whether overexpression of OCT4 is sufficient to overcome LIF-dependence. Here, we show that inducible expression of OCT4 (iOCT4) supports long-term LIF-independent self-renewal of ES cells cultured in media containing fetal bovine serum (FBS) and a glycogen synthase kinase-3 (GSK3) inhibitor, and in serum-free media...
November 27, 2017: Scientific Reports
Jinsoo Oh, Yongbo Kim, Lihua Che, Jeong Beom Kim, Gyeong Eon Chang, Eunji Cheong, Seok-Gu Kang, Yoon Ha
Glioma is the most malignant type of primary central nervous system tumors, and has an extremely poor prognosis. One potential therapeutic approach is to induce the terminal differentiation of glioma through the forced expression of pro-neural factors. Our goal is to show the proof of concept of the neuronal conversion of C6 glioma through the combined action of small molecules. We investigated the various changes in gene expression, cell-specific marker expression, signaling pathways, physiological characteristics, and morphology in glioma after combination treatment with two small molecules (CHIR99021, a glycogen synthase kinase 3 [GSK3] inhibitor and forskolin, a cyclic adenosine monophosphate [cAMP] activator)...
2017: PloS One
Elke Tatjana Aristizabal Prada, Christoph J Auernhammer
Molecular targeted therapy of advanced neuroendocrine tumours (NETs) of the gastroenteropancreatic (GEP) system currently encompasses approved therapy with the mTOR-inhibitor everolimus and the multi-tyrosinkinase inhibitor sunitinib. However clinical efficacy of these treatment strategies is limited by low objective response rates and limited progression free survival due to tumor resistance. Further novel strategies for molecular targeted therapy of NETs of the GEP-system are needed. This paper reviews preclinical research models and signaling pathways in NETs of the GEP-system...
November 16, 2017: Endocrine Connections
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