TY - JOUR. T1 - Inhibition of glycogen synthase kinase 3β activity with lithium in vitro attenuates sepsis-induced changes in muscle protein turnover. AU - Bertsch, Stephen. AU - Lang, Charles H.. AU - Vary, Thomas C.. N1 - Copyright: Copyright 2011 Elsevier B.V., All rights reserved.. PY - 2011/3. Y1 - 2011/3. N2 - Loss of lean body mass is a characteristic feature of the septic response, and the mechanisms responsible for this decrease and means of prevention have not been fully elucidated. The present study tested the hypothesis that in vitro treatment of skeletal muscle with lithium chloride (LiCl), a glycogen synthase kinase (GSK) 3 inhibitor, would reverse both the sepsis-induced increase in muscle protein degradation and inhibition of protein synthesis. Sepsis decreased GSK-3β phosphorylation and increased GSK-3β activity, under basal conditions. Sepsis increased muscle protein degradation, with a concomitant increase in atrogin 1 and MuRF1 mRNA and 26S proteosome activity. Incubation ...

In Saccharomyces cerevisiae, nutrient levels control multiple cellular processes. Cells lacking the SNF1 gene cannot express glucose-repressible genes and do not accumulate the storage polysaccharide glycogen. The impaired glycogen synthesis is due to maintenance of glycogen synthase in a hyperphosphorylated, inactive state. In a screen for second site suppressors of the glycogen storage defect of snf1 cells, we identified a mutant gene that restored glycogen accumulation and which was allelic with PHO85, which encodes a member of the cyclin-dependent kinase family. In cells with disrupted PHO85 genes, we observed hyperaccumulation of glycogen, activation of glycogen synthase, and impaired glycogen synthase kinase activity. In snf1 cells, glycogen synthase kinase activity was elevated. Partial purification of glycogen synthase kinase activity from yeast extracts resulted in the separation of two fractions by phenyl-Sepharose chromatography, both of which phosphorylated and inactivated glycogen ...

TY - JOUR. T1 - Multiple phosphorylation of rabbit muscle glycogen synthase by glycogen synthase kinase-1. Relationship between phosphorylation state and kinetic properties. AU - Salavert, Agustí. AU - Itarte, Emilio. AU - Massaguè, Joan. AU - Guinovart, Joan J.. PY - 1979/10/15. Y1 - 1979/10/15. U2 - https://doi.org/10.1016/0014-5793(79)80514-1. DO - https://doi.org/10.1016/0014-5793(79)80514-1. M3 - Article. VL - 106. SP - 279. EP - 283. ER - ...

Background Glycogen synthase kinase-3 (GSK-3) is a multifunctional serine/threonine kinase that has an important function in cancers tumorigenesis and development. at both mRNA and proteins levels. Conclusion Used together, our outcomes demonstrate the fact that GSK-3 inhibitor AZD1080 suppresses ovarian cancers development and for that reason may indicate a fresh path for ovarian cancers treatment. strong course=kwd-title Keywords: ovarian cancers, GSK-3 inhibitor, AZD1080, tumorigenesis, development Introduction Ovarian cancers may be the third most common feminine reproductive system cancer tumor. The ovarian cancers mortality rate may be the highest from the gynecological malignancies because of the insufficient effective early diagnostic strategies, its chemotherapy level of resistance, and its capability to metastasize and recurrence. The 5-calendar year survival rate is certainly 30%, rendering it as a significant threat to medical and lives of females.1,2 Ovarian cancers has many ...

Full Text - The rapid and efficient clearance of apoptotic germ cells (GCs) by Sertoli cells (SCs) is important for spermatogenesis. High mitochondrial activity in phagocytes is critical for continued clearance of apoptotic cells. However, the underlying molecular mechanism is poorly understood. Glycogen synthase kinase-3α (GSK3α) is a protein kinase that participates in the regulation of mitochondrial activity. Immunohistochemistry evidenced the predominant presence of the Ser21 phosphorylation GSK3α (inactivation) signal in SCs. Heat shock-induced apoptosis of GCs and dephosphorylation of GSK3α in SCs is a perfect model to investigate the role of GSK3α in phagocytic action. The number of apoptotic GCs was significantly lower in GSK3α inhibitor pre-treated mice with HS compared to normal control. In vitro phagocytosis assays shown that the phagocytic activity in GSK3α activated SCs was downregulated, while GSK3α inhibitor supplementation restored this process. Moreover, GSK3α activation

Cytoarchitectural abnormalities have been reported in the cortex in schizophrenia. These suggest a developmental origin for this disorder. The Wnt signalling pathway is involved in the regulation of brain development; disruption of this pathway may lead to abnormal cortical development. In this study levels of three components of the Wnt signalling pathway; glycogen synthase kinase-3beta(GSK-3beta), beta-catenin and dishevelled-2 (Dvl-2) were determined in the prefrontal cortex of ten schizophrenic and ten control individuals using immunoblotting. GSK-3beta levels were significantly reduced in the schizophrenic group, while levels of beta-catenin and Dvl-2 did not differ between groups. This provides further evidence for an abnormality of the Wnt signalling pathway in schizophrenia.

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Deprivation of oxygen and glucose is the main cause of neuronal cell death during cerebral infarction and can result in severe morbidity and mortality. In general, the neuroprotective therapies that are applied after ischemic stroke have been unsuccessful, despite many investigations. Acetyl-L-carnitine (ALCAR) plays an important role in mitochondrial metabolism and in modulating the coenzyme A (CoA)/acyl-CoA ratio. We investigated the protective effects of ALCAR against oxygen-glucose deprivation (OGD) in neural stem cells (NSCs). We measured cell viability, proliferation, apoptosis, and intracellular signaling protein levels after treatment with varying concentrations of ALCAR under OGD for 8 h. ALCAR protected NSCs against OGD by reducing apoptosis and restoring proliferation. Its protective effects are associated with increases in the expression of survival-related proteins, such as phosphorylated Akt (pAkt), phosphorylated glycogen synthase kinase 3b (pGSK3b), B cell lymphoma 2 (Bcl-2), and ...

Constitutively active protein kinase that acts as a negative regulator in the hormonal control of glucose homeostasis, Wnt signaling and regulation of transcription factors and microtubules, by phosphorylating and inactivating glycogen synthase (GYS1 or GYS2), CTNNB1/beta-catenin, APC and AXIN1. Requires primed phosphorylation of the majority of its substrates. Contributes to insulin regulation of glycogen synthesis by phosphorylating and inhibiting GYS1 activity and hence glycogen synthesis. Regulates glycogen metabolism in liver, but not in muscle. May also mediate the development of insulin resistance by regulating activation of transcription factors. In Wnt signaling, regulates the level and transcriptional activity of nuclear CTNNB1/beta-catenin. Facilitates amyloid precursor protein (APP) processing and the generation of APP-derived amyloid plaques found in Alzheimer disease. May be involved in the regulation of replication in pancreatic beta-cells. Is necessary for the establishment of neuronal

Li, Y., Hu, S-Q., & Han, Y. (2015). Preventing H2O2-induced toxicity in primary cerebellar granule neurons via activating the PI3-K/Akt/GSK3ß pathway by kukoamine from Lycii Cortex. Journal of Functional Foods, 17, 709 - 721 ...

Supplementary Materialsijms-20-05857-s001. = 7.4), Tf may bind two atoms of Fe3+ tightly. may be the receptor of can bind easily, and initiates Pyrithioxin dihydrochloride the clathrin-mediated endocytosis with the help of the TfR trafficking proteins [16]. Using the entry of protons, the pH in endosome filled with diferric Tf/TfR1 complicated decreases, producing a conformational alter in discharge and Tf of Fe3+ [17]. Subsequently, the apo-Tf/TfR complicated returns towards the cell surface area for another routine, whilst Fe3+ is normally decreased to Fe2+ by way of a reductase called six-transmembrane epithelial antigen from the prostate 3 ((PRV) over the hosts iron fat burning capacity [27], it really is of great importance to clarify the partnership between aquatic trojan infection as well as the iron fat burning capacity, which may donate to illuminating the antiviral iron-withholding strategies in aquatic pets and exploiting iron-related medications or feed chemicals for the avoidance ...

FIG. 7. Ser404 phosphorylation decreases GR function. (A and B) GR-null U-2 OS cells or those expressing WT-, S404A-, or S404D-GR were transiently transfected with pRL-Renilla and the GRE-luc (A) or MHC-luc NF-κB (B) luciferase reporters. Cells were then treated with Dex (0 to 100 nM) as indicated. After 20 h, the cells were lysed and analyzed for luciferase activity, which was normalized to the Renilla activity. Plotted are the normalized percentages of GRE transactivation or NF-κB transrepression by Dex (*, P , 0.05). (C) WT-GR-expressing U-2 OS cells were treated with the GSK-3α/β inhibitor BIO (5 μM) and Dex (100 nM) for 20 h. Cells were then lysed, analyzed by Western blotting, and probed with antibodies directed to the NF-κB regulated prosurvival genes Bcl-xL, c-IAP, and survivin. The protein band intensities were quantitated from three independent experiments and normalized to actin. (D) WT-and S404D-GR-expressing U-2 OS cells were treated with Dex for 20 h (100 nM), lysed, analyzed ...

Glycogen synthase kinase 3β (GSK-3β) actions are central in the canonical Wnt pathway, important in many biological processes and a potential drug target for treating several diseases. It is appreciated that a balanced Wnt canonical signaling is crucial for the maintenance of normal bone mass. In this study we investigated the effects of a potent orally active GSK-3 inhibitor, AZD2858, on bone mass in rats. Treatment (1μM) of human osteoblast cells with AZD2858 in vitro increased β-catenin levels after a short period of time. In rats, oral AZD2858 treatment caused a dose-dependent increase in trabecular bone mass compared to control after a two-week treatment with a maximum effect at a dose of 20mg/kg once daily (total BMC: 172% of control; p,0.001). A small but significant effect was also seen at cortical sites (total BMC: 111% of control; p,0.001). Biomechanical testing demonstrated an increase in both vertebral compression strength at a dose of 20mg/kg once daily (Load at failure: 370% of ...

Nuclear myosin 1c (NM1) mediates RNA polymerase I (pol I) transcription activation and cell cycle progression by facilitating PCAF-mediated H3K9 acetylation, but the molecular mechanism by which NM1 is regulated remains unclear. Here, we report that at early G1 the glycogen synthase kinase (GSK) 3β phosphorylates and stabilizes NM1, allowing for NM1 association with the chromatin. Genomic analysis by ChIP-Seq showed that this mechanism occurs on the rDNA as active GSK3β selectively occupies the gene. ChIP assays and transmission electron microscopy in GSK3β-/- mouse embryonic fibroblasts indicated that at G1 rRNA synthesis is suppressed due to decreased H3K9 acetylation leading to a chromatin state incompatible with transcription. We found that GSK3β directly phosphorylates the endogenous NM1 on a single serine residue (Ser-1020) located within the NM1 C-terminus. In G1 this phosphorylation event stabilizes NM1 and prevents NM1 polyubiquitination by the E3 ligase UBR5 and proteasome-mediated ...

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The phenotypes of the dwf12 mutants can be summarized by the statement that all organs are reduced in size. The specific characteristics examined in this research, such as plant height and the length of pedicels, siliques, petioles, hypocotyls, and roots, all are significantly shorter than wild type (Table I; Figs. 1 and 2). These morphological alterations are typical of BR biosynthetic or signaling mutants (Figs. 1 and 2). Thus, it is likely that the dwf12mutants are defective in BR biosynthesis or signaling. One interesting exception in dwf12 is a typical leaf curling in the abaxial direction. Downward curling leaves are often found in mutants that are defective in auxin signaling, such as axr1 andaxr2 (Lincoln et al., 1990; Timpte et al., 1992). These shared phenotypes between dwf12 and auxin mutants suggest that DWF12 also plays a role in auxin signaling in specific cell types.. Two lines of evidence strongly suggest that the dwf12mutants are BR insensitive. First, a BR biosynthetic ...

Glycogen synthase kinase 3 is a serine/threonine protein kinase that mediates the addition of phosphate molecules onto serine and threonine amino acid residues. First discovered in 1980 as a regulatory kinase for its namesake, Glycogen synthase, GSK-3 has since been identified as a kinase for over forty different proteins in a variety of different pathways. In mammals GSK-3 is encoded by two known genes, GSK-3 alpha (GSK3A) and GSK-3 beta (GSK3B). GSK-3 has recently been the subject of much research because it has been implicated in a number of diseases, including Type II diabetes (Diabetes mellitus type 2), Alzheimers Disease, inflammation, cancer, and bipolar disorder. GSK-3 functions by phosphorylating a serine or threonine residue on its target substrate. A positively charged pocket adjacent to the active site binds a priming phosphate group attached to a serine or threonine four residues C-terminal of the target phosphorylation site. The active site, at residues 181, 200, 97, and 85, ...

The glycogen synthase kinase 3/shaggy kinase (GSK3) is a serine/threonine kinase with important roles in animals. Although GSK3 genes have been studied for more than 30 years, plant GSK genes have been studied only since the last decade. Previous research has confirmed that plant GSK genes are involved in diverse processes, including floral development, brassinosteroid signaling, and responses to abiotic stresses. In this study, 20, 15 (including 5 different transcripts) and 10 GSK genes were identified in G. hirsutum, G. raimondii and G. arboreum, respectively. A total of 65 genes from Arabidopsis, rice, and cotton were classified into 4 clades. High similarities were found in GSK3 protein sequences, conserved motifs, and gene structures, as well as good concordance in gene pairwise comparisons (G. hirsutum vs. G. arboreum, G. hirsutum vs. G. raimondii, and G. arboreum vs. G. raimondii) were observed. Whole genome duplication (WGD) within At and Dt sub-genomes has been central to the expansion of the

Arteries isolated from hypertensive animals consistently demonstrate potentiated contractions to a variety of agonists, and recent evidence has underlined the importance of phosphatidylinositol 3-kinase (PI3K) activity in this potentiation.1-5 For example, Northcott et al5 have demonstrated that PI3K activity is elevated in aortae from rats with DOCA-salt hypertension and that the increased activity contributes to enhanced arterial reactivity.. To investigate the mechanisms involved in the PI3K-mediated contractile response seen in arteries from DOCA-salt hypertensive animals, we have focused on the downstream serine-threonine kinase, glycogen synthase kinase 3 (GSK-3). GSK-3 is a ubiquitously expressed kinase that was first characterized as a major regulator of glycogen synthase activity.6 GSK-3 is a direct substrate of PKB/Akt7 and functions in several signaling pathways, including the PI3K pathway, to affect protein synthesis, carbohydrate metabolism, gene transcription, and apoptosis.8 Of ...

The phosphorylation state of tau changes during neurodevelopment and highly phosphorylated tau accumulates in the paired helical filaments found in Alzheimers disease. In non-neuronal mammalian cells transiently expressed tau is predominantly not phosphorylated at sites known to be phosphorylated i …

The focus of this study was to identify signaling pathways and potential therapeutic agents that would allow reproducible stimulation of DNA synthesis, cell cycle progression, and proliferation in human β-cells. We found that glucose, mTOR activity, and inhibition of GSK-3 together stimulated these regenerative processes in a highly reproducible manner in adult human β-cells regardless of sex, age, BMI, or isolation center.. Both LiCl and 1-Akp significantly enhanced DNA synthesis above that of 8 mmol/l glucose, and LiCl-mediated DNA synthesis was more sensitive to rapamycin than 1-Akp. This finding suggested that a component of 1-Akp-stimulated DNA synthesis in human islets is mTOR independent. Although lithium at higher concentrations decreased DNA synthesis in human islets, this did not appear to be due to apoptosis because cell cycle analysis (Fig. 3A and B) failed to detect a significant degree of apoptosis under similar conditions. Mussmann et al. (18) reported that lithium produces ...

O-GlcNAc1 is a dynamically regulated post-translational modification (PTM), in which a β-N-acetylglucosamine moiety is attached to hydroxyl side chains of serine or threonine residues of proteins by O-GlcNAc-transferase (1) and removed by β-N-acetylglucosaminidase (O-GlcNAcase) (2). O-GlcNAc is ubiquitous on nuclear and cytoplasmic proteins in all multicellular eukaryotes (3). Dynamic O-GlcNAcylation plays critical roles in signal transduction (4), transcriptional control (5, 6), cell cycle regulation (7), protein degradation (8), neurodegeneration (9), and stress responses (10). Abnormally regulated O-GlcNAcylation has been found in diseases such as diabetes (11) and Alzheimer disease (12).. The role of O-GlcNAcylation in signal transduction is at least in part related to its competitive interplay with O-phosphorylation. Some of the known O-GlcNAc sites are the same as or adjacent to phosphorylation sites. For example, O-GlcNAc is reciprocal to O-phosphorylation on the C-terminal domain of ...

Research Question: Transforming growth factor beta (TGF-β) causes growth stimulation and transformation in fibroblasts, but growth inhibition/apoptosis in other cell types. Previously, TGF-β has been shown to activate the Smad signalling cascade in all cell types. Alternative signalling pathways have been described in response to TGF-β. To explain how TGF-β controls growth, we investigated a downstream target of phosphatidylinositol 3-kinase (PI3K) called Akt. Akt inactivates glycogen synthase kinase 3 beta (GSK-3β) and FOXO. We propose that PI3K signalling is partially responsible for the different phenotypic effects of TGF-β in mesenchymal and epithelial cells. -- Methods: Western blotting was used to describe temporal changes (0-3 hours) in PDK-1, Akt, GSK-3β and Cyclin Dl phosphorylation/protein levels with TGF-β2 stimulation of normal fibroblast and epithelial cell lines. Additionally, we blocked the effects of TGF-β on Akt/GSK-3β using PI3K/Akt specific inhibitors and TGF-β ...

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 ...

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Using a functional genetic screen for inhibitors of γ-secretase activity, researchers have identified an unusual gene that keeps a lid on both amyloid production and tau phosphorylation in mouse brain. The expressed protein, RPS23R1, activates the cAMP/protein kinase A pathway, which ends in inhibition of glycogen synthase kinase 3 (GSK3), an upstream regulator of Aβ processing and a major tau kinase. Although it is not clear whether the mouse gene has a human homolog, the findings open the possibility that targeting upstream events in the cAMP/PKA/GSK3 pathway might offer an approach to preventing both Aβ and tau pathology with a single drug. The work, from Huaxi Xu of the Burnham Institute for Medical Research in La Jolla, California; Limin Li of Functional Genetics, Inc., Gaithersburg, Maryland, and the Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; and collaborators appears in todays issue of Neuron.. In the study, the four first authors, Yun-wu ...

Recombinant Human Glycogen synthase 1/GYS1 protein is a Wheat germ Full length protein 1 to 737 aa range and validated in WB, ELISA.

ENGLISH ABSTRACT: INTRODUCTION: Glycogen synthase kinase-3 (GSK-3) is a serine-threonine protein kinase that was first discovered as a regulator of glycogen synthase thus playing a role in glycogen synthesis (Embi et al ...

Neurons are polarized cells with axons (the site of signal output) and dendrites (the sites of signal input). Not only are these functionally different parts of the cell, but the morphology of axons and dendrites is very different as well. Two groups report that glycogen synthase kinase 3β (GSK-3β) is at the center of a process that regulates the balance of axons and dendrites. Jiang et al. and Yoshimura et al. reported that when GSK-3β activity was increased by transfection of isolated embryonic hippocampal neurons with a constitutively active mutant, the number of cells that formed an axon or extended neurite was decreased, and when GSK-3β activity was inhibited, using multiple methods, the number of cells producing multiple axons increased. The overall number of neurites was unchanged. Inhibition of GSK-3β activity in cultured neurons before or after polarity had been established produced an increase in the number of cells with multiple axons, suggesting a role for GSK-3β in both ...

Glycogen synthase kinase 3 (GSK-3) was originally defined as a regulator of glycogen synthesis in mammals. lines exposed changes in sugars metabolism including improved levels of maltose the primary degradation item of starch in leaves. Vegetation over-expressing MsK4 demonstrated improved tolerance to sodium tension. Furthermore under high-salinity circumstances MsK4-over-expressing vegetation accumulated a lot more showed […]. ...

In eukaryotic cells, the modification and folding of membrane and secreted proteins occurs in the endoplasmic reticulum (ER). Agents that interfere with these processes cause such proteins to accumulate in the ER, leading to ER stress. Geoff Werstuck and colleagues now show that valproate, a branched-chain fatty acid used to treat epilepsy, protects cells from the lipid accumulation and apoptosis associated with ER stress (see p. 89). The authors report that, although valproate increases the expression of ER chaperones in the human hepatic cell line HepG2, it does not directly protect these cells from ER stress by increasing protein folding capacity. Instead, valproate protects the ER from the cellular complications induced by stress by inhibiting glycogen synthase kinase 3 (GSK3). Other GSK3 inhibitors have similar effects, indicating that GSK3 plays a central role in the cellular responses to ER stress. Thus, small-molecule drugs that inhibit GSK3 could provide new treatments for disorders in ...

Beta-catenin is a multifunctional protein involved both in cell adhesion and in activation of transcription. Calcium-dependent intercellular adhesion transmembrane glycoprotein E-cadherin interacts by its cytoplasmic domain with reciprocally bound alpha, beta and gamma catenin. Beta-catenin links this complex through alpha-actinin to the cytoskeleton. Functional cadherin-catenin system is important for invasiveness of tumour cells. Beta-catenin level in cytoplasm is controlled by glycogen synthase kinase-3 beta. When activity of this kinase is blocked (e.g. by excessive stimulation of Wnt signaling pathway), hypophosphorylated stable form of beta-catenin accumulates in the cytoplasm, translocates to the nucleus and activates transcription of genes including those that are involved in cell cycle control. As a result, cell division and neoplastic transformation are promoted ...

Data Availability StatementThe supplementary data could be accessed via links. leads to the accumulation of sarcomeric proteins and hypertrophic myotubes with a sophisticated fusion index. The elevated fusion in DNAJB6 KO myotubes correlates with reduced glycogen synthase kinase- (GSK3) activity. On the other hand, LGMD1D mutations in enhance GSK3 suppress and activation -catenin and NFAT3c signaling. GSK3 inhibition with lithium chloride improves muscle strength and size within an LGMD1D preclinical mouse super model tiffany livingston. Conclusions Our results suggest that DNAJB6 facilitates protein quality control and negatively regulates myogenic signaling. In addition, LGMD1D-associated mutations inhibit myogenic signaling through augmented GSK3 activity. GSK3 inhibition with lithium chloride may be a restorative option in LGMD1D. Protein chaperones, or warmth AZ32 shock proteins (HSPs), are progressively recognized as critical for skeletal muscle mass health.1 Recently, mutations in is ...

Alsterpaullone, also known as 9-Nitropaullone and NSC 705701, is a derivative of kenpaullone and an ATP-competitive inhibitor of several cyclin-dependent kinases (CDKs) as well as glycogen synthase kinase 3β (GSK3β). Alsterpaullone induces apoptosis by activation of caspase-9 due to perturbation in mitochondrial membrane potential. Alsterpaullone mediated toxicity in HeLa Cells through Apoptosis-Inducing Effect.

We found that 150 mM NaPO[4] with … FMB PowerMatrix slides was best. We prefer PowerMatrix substrates because they are cheaper and more robust.. Woodard C, Liao G, A Screen for Extracellular Signal-Regulated Kinase-Primed Glycogen Synthase Kinase 3 Substrates Identifies the p53 Inhibitor iASPP, Journal of Virology, 2015 89(18):9232-41 [PubMed]. Yang L, Wang J, Identification of serum biomarkers for gastric cancer diagnosis using a human proteome microarray, Molecular & Cellular Proteomics, 2015 Nov 23. pii: mcp.M115.051250 [PubMed]. Yauk CL, Williams A, et al.: Novel Design and Controls for Focused DNA Microarrays: Applications in Quality Assurance/Control and Normalization for the Health Canada ToxArrayä, BMC Genomics 2006, 7:266 ...

Buy GSK-3 beta Inhibitors from Santa Cruz. These inhibit GSK-3 beta and may affect a variety of other cell signaling and Alzheimers disease related proteins.

The work reported in this article illustrates the features and the advantages of the real-time RT-PCR technique. First, it allowed us to estimate the absolute level of transcripts of any type of genes studied, with either a very high or an extremely low level of expression. It is worth noting that no report about quantitative analysis of the SUP or MEA steady-state transcript levels had previously been published, and that genes such asAtMAP3Kε and AtMAP4Kα could not be analyzed quantitatively by another method so far. Second, this technique guaranties the specific detection of the gene studied, even when it belongs to a very conserved gene family. The microarray technology could be a powerful tool, especially when expression profiling is concerned. However, hybridization of chips loaded with full-sized cDNAs or even partial EST would not be suitable for the study of a gene family because of the lack of specificity of the targets. Conversely, due to its high cost, real-time RT-PCR has to remain ...

New treatment strategies with erythropoietin (EPO) offer exciting opportunities to prevent the onset and progression of neurodegenerative disorders that currently lack effective therapy and can progress to devastating disability in patients. EPO and its receptor are present in multiple systems of the body and can impact disease progression in the nervous, vascular, and immune systems that ultimately affect disorders such as Alzheimers disease, Parkinsons disease, retinal injury, stroke, and demyelinating disease. EPO relies upon wingless signaling with Wnt1 and an intimate relationship with the pathways of phosphoinositide 3-kinase (PI 3-K), protein kinase B (Akt), and mammalian target of rapamycin (mTOR). Modulation of these pathways by EPO can govern the apoptotic cascade to control b-catenin, glycogen synthase kinase-3b, mitochondrial permeability, cytochrome c release, and caspase activation. Yet, EPO and each of these downstream pathways require precise biological modulation to avert

Few things can be considered to be more important to a cell than its threshold for apoptotic cell death, which can be modulated up or down, but rarely in both directions, by a single enzyme. Therefore, it came as quite a surprise to find that one enzyme, glycogen synthase kinase-3 (GSK3), has the pe …

The widely used psychiatric drug lithium, and other agents that inhibit glycogen synthase kinase-3 (GSK3), have been mentioned as possible Alzheimers disease therapies for some time, primarily because GSK3 is one of several kinases known to phosphorylate tau.... ...

Dr. Mickie Bhatias group from McMaster University in Ontario, Canada has generated an approach that combines two previously developed techniques in order to promote direct conversion of adult human blood progenitor cells into neural progenitor cells - a blood to brain cell conversion!2 The first technique is OCT4-induced plasticity reprogramming.3 OCT4 is a transcription factor whose brief expression converts cells into a plastic state in which they have the ability to differentiate into other cell types, a process of which terminally differentiated cells are incapable. Unfortunately, this technique only serves to de-differentiate somatic cells, and does not commit them to a particular lineage. Bhatias group combined OCT4-induced plasticity reprogramming with previously identified small molecules that specifically induce neural potentiating cells. These molecules are chemical inhibitors of SMAD proteins and the enzyme glycogen synthase kinase-3 (GSK3). Previous studies4 show that ...

Glycogen Synthase antibody (glycogen synthase 1 (muscle)) for WB. Anti-Glycogen Synthase pAb (GTX50798) is tested in Human, Mouse, Rat samples. 100% Ab-Assurance.

pon:100452879 K00693 glycogen synthase [EC:2.4.1.11] , (RefSeq) GYS2; glycogen synthase 2 (A) MLRGRSLSVTSLGGLPQWEVEELPVEELLLFEVAWEVTNKVGGIYTVIQTKAKTTADEWG ENYFLIGPYFEHNMKTQVEQCEPVNDAVRRAVDAMNKHGCQVHFGRWLIEGSPYVVLFDI GYSAWNLDRWKGDLWEACSVGIPYHDREANDMLIFGSLTAWFLKEVTDHADGKHVIAQFH EWQAGIGLILSRARKLPIATIFTTHATLLGRYLCAASIDFYNHLDKFNIDKEAGERQIYH RYCMERASVHCAHVFTTVSEITAIEAEHMLKRKPDVVTPNGLNVKKFSAVHEFQNLHAMY KARIQDFVRGHFYGHLDFDLEKTLFLFIAGRYEFSNKGADIFLESLSRLNFLLRMHKSDV TVVVFFIMPAKTNNFNVETLKGQAVRKQLWDVAHSVKEKFGKKLYDALLRGEIPDMNNIL DRDDLTIMKRAIFSTQRQSLPPVTTHNMIDDSTDPILSTIRRIGLFNNRTDRVKVILHPE FLSSTSPLLPMDYEEFVRGCHLGVFPSYYEPWGYTPAECTVMGIPSVTTNLSGFGCFMQE HVADPTAYGIYIVDRRFRSPDDSCNQLTKFLYGFCKQSRRQRIIQRNRTERLSDLLDWRY LGRYYQHARHLTLSRAFPDKFHVELTSPPTTEGFKYPRPSSVPPSPSGSQASSPQSSDVE DEVEDERYDEEEEAERDRLNIKSPFSLSHIPHGKKKLHGEYKN ...

bfu:BC1G_11987 K00693 glycogen synthase [EC:2.4.1.11] , (RefSeq) glycogen synthase (A) MSGKTNRDVKNHFLFEIATEVANRVGGIYSVIKSKAPVTTAEYGDRYTLIGPLNRQSAAV EVEALTPTNPHLAATIEAMEERGIQMVYGRWLIEGAPRVLLIDTKSAYRFLDEWKADLWN TAGIPSPPGDDETNEAVVFGYLVAWFLGEFVAHEKEKAVIAHFHEWLSGVALPLCKKRRI DVTTIFTTHATLLGRYLCAGSVDFYNNLQWFDVDAEAGKRGIYHRYCIERAATHSCDVFT TVSHITAYESEHLLKRKPDGVLPNGLNVTKFSAMHEFQNLHQQAKEKIHDFVRGHFYGHN DFDPENTLYFFTAGRYEYRNKGVDMFIESLARLNHRLKSAGSKMTVVAFIIMPAQTQSLT VEALKGQAVIKSLRDTVDVIERGVGKRIFERALKWHEGEVMPDEKDLITSQDRILLRRRL FAMKRHGLPPIVTHNMANDSEDPILNQIRRVQLFNHPSDRVKVVFHPEFLNSANPVLPMD YDEFVRGTHLGVFSSYYEPWGYTPAECTVMGVPSITTNLSGFGCYMEELIENSTDYGIYI VDRRMKGVDDSVNQLTSYMFDFAGKSRRQRINQRNRTERLSDLLDWKRMGMEYVKARQLA LRRAYPASFDGEEEDDFIPGVEQKISRPFSVPGSPRDRTGMMTPGDFASLQEGREGLSTE DYVSWKLPEEEDPDEYPFPLTLRTKKPNGSQSPYGYGGAQSPSEYAITNGNGMK ...

Obsahem této práce je studium chirální separace enantiomerů omeprazolu. Pět různých monosubstituovaných derivátů α- a β-cyklodextrínů, z toho dva kationické a tři anionické, bylo použito jako chirální selektory v různých pufrech o různých pH. Byly studovány vlivy koncentrace CD a koncentrace pufru na chirální separaci. Všechna měření byla prováděna při napětí 25 kV s UV detekcí v rozmezí vlnových délek 202 - 303 nm a konstantní teplotě 20 řC. Koncentrace CD byla v rozmezí 0 - 7 mmol.l-1 . Jako separační byla využita křemenná kapilára o vnitřním průměru 50 µm, vnějším průměru 375 µm, celkové délce 48,5 cm a efektivní délce 40 cm. Koncentrace omeprazolu použitá při separacích byla 0,1 mmol.l-1 . Jako organické rozpouštědlo zásobního roztoku omeprazolu byl použit dimethylformamid, který sloužil zároveň jako indikátor EOF. Chirální separace omeprazolu proběhla úspěšně v 2-O- karboxymethyl-β-Cyklodextrínu ...

GSRd (.one, 1, and ten mM) markedly reduced SI/Rinduced mobile dying, respectively growing viability price to 59%sixty one.eight%, sixty three%sixty

AR-A014418 is a potent, selective and ATP-competitive GSK3β inhibitor with an IC50 of 104 nM。 - Mechanism of Action & Protocol.

Glycogen synthase (UDP-glucose-glycogen glucosyltransferase) is a key enzyme in glycogenesis, the conversion of glucose into glycogen. It is a glycosyltransferase (EC 2.4.1.11) that catalyses the reaction of UDP-glucose and (1,4-α-D-glucosyl)n to yield UDP and (1,4-α-D-glucosyl)n+1. In other words, this enzyme combines excess glucose residues one by one into a polymeric chain for storage as glycogen. Glycogen synthase concentration is highest in the bloodstream 30 to 60 minutes following intense exercise. Much research has been done on glycogen degradation through studying the structure and function of glycogen phosphorylase, the key regulatory enzyme of glycogen degradation. On the other hand, much less is known about the structure of glycogen synthase, the key regulatory enzyme of glycogen synthesis. The crystal structure of glycogen synthase from Agrobacterium tumefaciens, however, has been determined at 2.3 A resolution. In its asymmetric form, glycogen synthase is found as a dimer, whose ...

The cDNA for mouse brain glycogen synthase has been isolated by screening a mouse cerebral cortical astrocyte lambda ZAP II cDNA library. The mouse brain glycogen synthase cDNA is 3.5 kilobases in length and encodes a protein of 737 amino acids. The coding sequence of mouse brain glycogen synthase cDNA shares approximately 87% nucleotide identity and approximately 96% amino acid identity with the muscle isozyme, while the degree of identity is lower with the liver isozyme. The regional distribution of glycogen synthase mRNA determined by in situ hybridization in the mouse brain reveals a wide distribution throughout the central nervous system with highest densities observed in the cerebellum, hippocampus and olfactory bulb. At the cellular level the expression of brain glycogen synthase mRNA is localized both in astrocytes and neurons with, however, the higher levels observed in astrocytes. Vasoactive intestinal peptide and noradrenaline, two neurotransmitters previously shown to induce a glycogen

TY - JOUR. T1 - Dextromethorphan attenuates NADPH oxidase-regulated glycogen synthase kinase 3 and NF-B activation and reduces nitric oxide production in group a streptococcal infection. AU - Chen, Chia-Ling. AU - Cheng, Miao-Huei. AU - Kuo, Chih-Feng. AU - Cheng, Yi-Lin. AU - Li, Ming-Han. AU - Chang, Chih-Peng. AU - Wu, Jiunn-Jong. AU - Anderson, Robert. AU - Wang, Shuying. AU - Tsai, Pei-Jane. AU - Liu, Ching-Chuan. AU - Lin, Yee-Shin. N1 - Copyright © 2018 American Society for Microbiology.. PY - 2018/6/1. Y1 - 2018/6/1. N2 - Group A Streptococcus (GAS) is an important human pathogen that causes a wide spectrum of diseases, including necrotizing fasciitis and streptococcal toxic shock syndrome. Dextromethorphan (DM), an antitussive drug, has been demonstrated to efficiently reduce inflammatory responses, thereby contributing to an increased survival rate of GAS-infected mice. However, the anti-inflammatory mechanisms underlying DM treatment in GAS infection remain unclear. DM is known to ...

article: Dexmedetomidine reduces myocardial ischemia-reperfusion injury in rats through PI3K/AKT/GSK-3β signaling pathway - Minerva Cardioangiologica 2020 February;68(1):58-9 - Minerva Medica - Journals

The glycogen synthase kinase 3 (GSK3)/SHAGGY-like kinases (GSKs) are non-receptor serine/threonine protein kinases that are involved in a variety of biological processes. In contrast to the two members of the GSK3 family in mammals, plants appear to have a much larger set of divergent GSK genes. Plant GSKs are encoded by a multigene family; analysis of the Arabidopsis genome revealed the existence of 10 GSK genes that fall into four major groups. Here we characterized the structure of Arabidopsis and rice GSK genes and conducted the first broad phylogenetic analysis of the plant GSK gene family, covering a taxonomically diverse array of algal and land plant sequences. We found that the structure of GSK genes is generally conserved in Arabidopsis and rice, although we documented examples of exon expansion and intron loss. Our phylogenetic analyses of 139 sequences revealed four major clades of GSK genes that correspond to the four subgroups initially recognized in Arabidopsis. ESTs from basal angiosperms

Two cellular systems have been used to investigate the modulation of tau hyperphosphorylation. In the first system, the effects of the excitatory amino acid glutamate, the microtubule destabilising agent colchicine, and beta 25-35-amyloid peptide on tau phosphorylation were studied in rat cortical neurones in primary culture. Using immunocytochemistry and western blot analysis, we demonstrated that tau in these cultures is normally highly phosphorylated, but a proportion becomes rapidly dephosphorylated following treatment of the cultures with glutamate or colchicine. These changes in tau phosphorylation occurred prior to cell death. In the second system, the ability of p42 MAP and p44 MAP kinases, glycogen synthase kinases 3 alpha and 3 beta (GSK-3 alpha and GSK-3 beta) to phosphorylate tau in transfected COS cells was investigated. Both GSK-3 alpha and GSK-3 beta phosphorylated tau to produce a PHF-like state of phosphorylation but the MAP kinases failed to induce such a transformation in tau. These

We investigated the protective effect of tetramethylpyrazine (TMP) on injury related to acute myocardial ischemia (AMI) induced by isoproterenol (ISO). Rats were randomly assigned to five groups: control, ISO, ISO + propranolol (10 mg/kg), ISO + TMP (10 mg/kg) and ISO + TMP (20 mg/kg). The rats in the three ISO + groups were pretreated with propranolol or TMP, while the rats in the control and ISO groups were pretreated with an equal volume of saline. Afterwards, the rats in the four administration groups were subcutaneously injected with ISO for two consecutive days. The levels of creatine kinase (CK), lactate dehydrogenase (LDH), superoxide dismutase (SOD), malondialdehyde (MDA), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and IL-1β in the serum were measured using ELISA. The expressions of B-cell lymphoma-associated X-2 (Bax-2), B-cell lymphoma-2 (Bcl-2), phosphoinositide-3-kinase (PI3K), protein kinase B (Akt), glycogen synthase kinase 3β (GSK-3β), MDA5 and SOD1 were determined using

Postsynaptic scaffolding proteins ensure efficient neurotransmission by anchoring receptors and signaling molecules in synapse-specific subcellular domains. In turn, posttranslational modifications of scaffolding proteins contribute to synaptic plasticity by remodeling the postsynaptic apparatus. Though these mechanisms are operant in glutamatergic synapses, little is known about regulation of GABAergic synapses, which mediate inhibitory transmission in the CNS. Here, we focused on gephyrin, the main scaffolding protein of GABAergic synapses. We identify a unique phosphorylation site in gephyrin, Ser270, targeted by glycogen synthase kinase 3β (GSK3β) to modulate GABAergic transmission. Abolishing Ser270 phosphorylation increased the density of gephyrin clusters and the frequency of miniature GABAergic postsynaptic currents in cultured hippocampal neurons. Enhanced, phosphorylation-dependent gephyrin clustering was also induced in vitro and in vivo with lithium chloride. Lithium is a GSK3β ...

TY - JOUR. T1 - Chronic mild stress alters synaptic plasticity in the nucleus accumbens through GSK3β-dependent modulation of Kv4.2 channels. AU - Aceto, Giuseppe. AU - Colussi, Claudia. AU - Leone, Lucia. AU - Fusco, Salvatore. AU - Rinaudo, Marco. AU - Scala, Federico. AU - Green, Thomas A.. AU - Laezza, Fernanda. AU - DAscenzo, Marcello. AU - Grassi, Claudio. PY - 2020/4/7. Y1 - 2020/4/7. N2 - Although major depressive disorder (MDD) is highly prevalent, its pathophysiology is poorly understood. Recent evidence suggests that glycogen-synthase kinase 3β (GSK3β) plays a key role in memory formation, yet its role in mood regulation remains controversial. Here, we investigated whether GSK3β activity in the nucleus accumbens (NAc) is associated with depression-like behaviors and synaptic plasticity. We performed whole-cell patch-clamp recordings of medium spiny neurons (MSNs) in the NAc and determined the role of GSK3β in spike timing-dependent long-term potentiation (tLTP) in the chronic ...

Glu Asp Ser Ser Ser Val Ala Val Leu Asp Thr Ala 370 375 380Ala Gly Val Trp Cys Asp Thr Lys Ser Val Val Thr Ser Pro Arg Thr385 390 395 400Gly Arg Tyr Ser Ala Asp Ala Ala Gly Gly Asp Ala Ser Val Glu Leu 405 410 415Thr Arg Arg Cys Arg His Ala Ala Ala Ala Val Gly Asp Leu Ile Phe 420 425 430Ile Tyr Gly Gly Leu Arg Gly Gly Val Leu Leu Asp Asp Leu Leu Val 435 440 445Ala Glu Asp Leu Ala Ala Ala Glu Thr Thr Tyr Ala Ala Ser His Ala 450 455 460Ala Ala Ala Ala Ala Thr Asn Ser Pro Pro Gly Arg Leu Pro Gly Arg465 470 475 480Tyr Gly Phe Ser Asp Glu Arg Asn Arg Glu Leu Ser Glu Ser Ala Ala 485 490 495Asp Gly Ala Val Val Leu Gly Ser Pro Val Ala Pro Pro Val Asn Gly 500 505 510Asp Met His Thr Asp Ile Ser Pro Glu Asn Ala Leu Leu Pro Gly Thr 515 520 525Arg Arg Thr Asn Lys Gly Val Glu Tyr Leu Val Glu Ala Ser Ala Ala 530 535 540Glu Ala Glu Ala Ile Ser Ala Thr Leu Ala Ala Ala Lys Ala Arg Gln545 550 555 560Val Asn Gly Glu Val Glu Leu Pro Asp Arg Asp Cys Gly Ala Glu Ala 565 570 575Thr Pro Ser Gly Lys Pro Thr Phe Ser Leu ...

© the author(s), publisher and licensee Libertas Academica Ltd. Here we show by western blotting that transcriptionally active isoforms of p63 (p63α and p63γ) induce the phosphorylation of human 2N4R tau at the tau-1/AT8 epitope in HEK293a cells; a phospho-epitope increased in Alzheimers disease. Confocal microscopy shows that tau and p63α are spatially separated intracellularly. Tau was found in the cytoskeletal compartment, whilst p63α was located in the nucleus, indicating that the effects of p63 on tau phosphorylation are indirectly mediated. Tau phosphorylation occurred independently of the known tau kinases, protein kinase C delta (PKCδ), c-Jun N-terminal kinase (JNK), extracellular-signal-regulated kinase (ERK), p38 mitogen-activated protein kinase (p38), glycogen synthase kinase 3 (GSK3), v-akt murine thymoma viral oncogene homolog (AKT) and cyclin-dependent kinase 5 (Cdk5) and the tau protein phosphatases (PP), PP1 and PP2A-Aαa/β. Considering that p63 and tau are both associated with

Background Rosai-Dorfman disease (RDD) is a rare form of histiocytosis characterized by histiocyte proliferation within lymph nodes and extranodal tissue. in size of all lesions, resolution of systemic symptoms, and normalization of blood tests. Conclusion RDD is generally considered a benign and self-limiting type of histiocytosis, generally connected with favorable prognosis. Nevertheless, complications arent infrequent and fatal situations were reported also in children. Initiatives should be designed to establish the very best therapeutic technique for this disease, as no well-defined suggestions can be found. Finally, RDD ought to be contained in differential medical diagnosis BIRB-796 kinase activity assay of lymphadenopathy and parotid swelling also in babies and toddlers. Electronic supplementary materials The web version of the article (doi:10.1186/s12887-016-0595-9) contains supplementary materials, which is open to certified users. and simply because keywords and selecting all of the ...

Alzheimers disease (AD) is the most common cause of dementia worldwide. One of the main pathological changes that occurs in AD is the intracellular accumulation of hyperphosphorylated Tau protein in neurons. Cyclin-dependent kinase 5 (CDK5) is one of the major kinases involved in Tau phosphorylation, directly phosphorylating various residues and simultaneously regulating various substrates such as kinases and phosphatases that influence Tau phosphorylation in a synergistic and antagonistic way. It remains unknown how the interaction between CDK5 and its substrates promotes Tau phosphorylation, and systemic approaches are needed that allow an analysis of all the proteins involved. In this review, the role of the CDK5 signaling pathway in Tau hyperphosphorylation is described, an in silico model of the CDK5 signaling pathway is presented. The relationship among these theoretical and computational models shows that the regulation of Tau phosphorylation by PP2A and glycogen synthase kinase 3β (GSK3β) is

Chemotherapy resistance of pancreatic cancer has been previously associated with hyperactivity of NF-κB [7, 11, 19, 33]. The discovery that GSK-3 regulates NF-κB [26], and that its inhibition has anti-inflammatory and growth inhibitory effects, holds promise to resolve the problem of drug resistance in cancers with inflammatory origin including pancreatic cancer [26, 28, 34]. In this paper, using a panel of six genetically distinct pancreatic cancer cell lines we confirmed previous reports that pharmacological inhibition of GSK-3 suppresses NF-κB transcriptional activity and is toxic to pancreatic cancer cells in a dose- and time-dependent manner [28]. We also show for the first time that GSK-3 inhibition potently reduces the clonogenic survival of pancreatic cancer cells. However, contrary to our hypothesis GSK-3/NF-κB inhibition did not sensitize to gemcitabine chemotherapy.. GSK-3 is a kinase involved in many cellular processes including energy metabolism, transcriptional regulation, cell ...

Akt-regulated pathways enhance cell division and cell survival. Metabolic regulation through Akt and its targets is important for insulin and insulin-like growth factor I-coupled responses. Inhibition of glycogen synthase kinase-3 by Akt-dependent phosphorylation promotes accumulation of β-catenin, which forms complexes with T-cell factor/lymphoid enhancer factor transcription factors and transcriptionally up-regulates cyclin D1, Myc, and other positive growth regulators. Cyclin D1 is also inhibited by glycogen synthase kinase-3 through effects on stability and localization (7) . Concomitantly, Akt phosphorylation of cyclin-dependent protein kinase inhibitors p21Cip1 and p27Kip1 interferes with negative growth regulation (3 , 8) .. Phosphorylation of Mdm2 by Akt enhances nuclear entry, which promotes ubiquitin-dependent proteolysis of p53, and impedes p53-dependent growth suppression and apoptosis (9) . Akt directly forestalls apoptosis by phosphorylation of proapoptotic Bad and caspase-9, ...

The data presented here indicate that GSK-3, a kinase that is active in resting epithelial cells (Papkoff and Aikawa, 1998; Murray et al., 1999), is a critical determinant of epithelial structure and a suppressor of the EMT. This finding implies that epithelial cells must sustain activation of a specific kinase to prevent an EMT, a mechanism distinct from that suggested by previous studies, which have shown that activation of kinases such as Akt (Grille et al., 2003) and ILK (Oloumi et al., 2004) can promote an EMT. An important implication of our findings is that endogenous suppressors of GSK-3, such as Wnt and PI3-kinase, which are frequently activated in carcinoma cells (Woodgett, 2001), may also inhibit E-cadherin transcription and promote an EMT. Our observation that inhibition of both GSK-3α and GSK-3β isoforms increased Snail expression in epithelial cells (Fig. 2 A), whereas inhibition of either isoform alone had no effect on Snail levels (not depicted), indicates that these isoforms ...

A quantitative structure-activity relationship study on 6-aryl-pyrazolo (3,4-b) pyridines was performed to gain structural insight into the binding mode of the molecules to the glycogen synthase kinase -3α, an enzyme phosphorylate and inhibit Glycogen Synthase (GS) which is the rate limiting enzyme in the glycogen biosynthesis. The molecular modeling studies were performed using CS Chem. Office 2001 molecular modeling software version 6.0. Allinger`s MM2 force field by fixing Root Mean Square Gradient (RMS) to 0.1 Kcal mol-1 and semiemperical AM1 Hamiltonian method (MOPAC module) were used to minimize the energy and calculate descriptors. The thermodynamic and steric features of 6-aryl-pyrazolo (3,4-b) pyridines are highly correlated with GSK-3α inhibitory activity. The results of the study suggests that introduction of bulky groups at C-5 position of the pyrazolopyridine ring will increase the GSK-3α inhibitory potency as it may involve in hydrophobic interaction with the ATP binding site of ...

Neurons rely on microtubule (MT) motor proteins such as kinesin-1 and dynein to transport essential cargos between the cell body and axon terminus. Defective axonal transport causes abnormal axonal cargo accumulations and is connected to neurodegenerative diseases, including Alzheimers disease (AD). Glycogen synthase kinase 3 (GSK-3) has been proposed to be a central player in AD and to regulate axonal transport by the MT motor protein kinesin-1. Using genetic, biochemical and biophysical approaches in Drosophila melanogaster, we ?nd that endogenous GSK-3 is a required negative regulator of both kinesin-1-mediated and dynein-mediated axonal transport of the amyloid precursor protein (APP), a key contributor to AD pathology. GSK-3 also regulates transport of an unrelated cargo, embryonic lipid droplets. By measuring the forces motors generate in vivo, we ?nd that GSK-3 regulates transport by altering the activity of kinesin-1 motors but not their binding to the cargo. These ?ndings reveal a new ...

Glycogen synthase kinase 3 (GSK3) has long been known as a signaling component in insulin regulation of metabolism and, more recently, as a key part of the Wnt signaling pathway regulating cell proliferation, cell fate, and other processes during development. Unlike most other kinases, GSK3 is constitutively active and is regulated by inhibition. Full expression of this constitutive activity in the mammalian enzyme appears to require phosphorylation of a tyrosine residue in the activation loop of GSK3, which the enzyme accomplishes by intramolecular autophosphorylation, even though the kinase phosphorylates strictly serine and threonine residues on its exogenous substrates. Lochhead et al. explored the mechanism by which this switch in residue specificity is possible. Tagged GSK-3β synthesized in a rabbit reticulocyte lysate translation system showed rapid autophosphorylation that was inhibited by inhibitors of the molecular chaperone protein Hsp90. This chaperone-assisted tyrosine kinase ...

The (Adenomatous Polyposis Coli) APC protein normally builds a destruction complex with glycogen synthase kinase 3-alpha and or beta (GSK-3α/β) and axin via interactions with the 20 AA and SAMP repeats[citation needed]. This complex is then able to bind β-catenins in the cytoplasm, that have dissociated from adherens contacts between cells. With the help of casein kinase 1 (CK1), which carries out an initial phosphorylation of β-catenin, GSK-3β is able to phosphorylate β-catenin a second time. This targets β-catenin for ubiquitination and degradation by cellular proteasomes. This prevents it from translocating into the nucleus, where it acts as a transcription factor for proliferation genes. APC is also thought to be targeted to microtubules via the PDZ binding domain, stabilizing them[citation needed]. The deactivation of the APC protein can take place after certain chain reactions in the cytoplasm are started, e.g. through the Wnt signals that destroy the conformation of the ...

Extracellular signals transduced by both RTKs and GPCRs converge upon the activation of a family of PI3Ks. Activation of these lipid kinases by GPCRs is thought to be dependent on the direct binding of Gβγ subunits and Ras to PI3Ks [88]. PI3K activation initiates a phosphorylation cascade leading to the activation of Akt (also termed protein kinase B) and its downstream kinases phosphoinositide-dependant kinase 1 (PDK1), glycogen synthase kinase 3 (GSK3), p70 ribosomal protein S6 kinase (p70S6K), mammalian target of rapamycin (mTOR) and others [89]. In addition, we have already seen how GPCRs can activate PI3K pathways via RTK or integrin transactivation [41,42,66]. Following direct or indirect GPCR-induced PI3K activation, cell cycle progression is regulated by the effect of PI3K-activated kinases on the expression and stability of cell cycle proteins, or by the modulation of the activity of other signal transduction pathways. For example, somatostatin SST2 receptors expressed in Chinese ...

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. Compounds 1-3 have a highly oxygenated benzocoumarin core structure in common, which suggests that this may be a new structural feature for efficient GSK-3β inhibition.

Glycogen synthase kinase-3 (GSK-3) is a widely expressed and highly conserved serine/threonine protein kinase encoded by 2 genes, GSK3A and GSK3B. GSK-3 is thought to be involved in tissue repair and fibrogenesis, but its role in these processes is currently unknown. To investigate the function of GSK-3β in fibroblasts, we generated mice harboring a fibroblast-specific deletion of Gsk3b and evaluated their wound-healing and fibrogenic responses. We have shown that Gsk3b-conditional-KO mice (Gsk3b-CKO mice) exhibited accelerated wound closure, increased fibrogenesis, and excessive scarring compared with control mice. In addition, Gsk3b-CKO mice showed elevated collagen production, decreased cell apoptosis, elevated levels of profibrotic α-SMA, and increased myofibroblast formation during wound healing. In cultured Gsk3b-CKO fibroblasts, adhesion, spreading, migration, and contraction were enhanced. Both Gsk3b-CKO mice and fibroblasts showed elevated expression and production of endothelin-1 ...

Glycogen synthase kinase-3 (GSK-3) is a widely expressed and highly conserved serine/threonine protein kinase encoded by 2 genes, GSK3A and GSK3B. GSK-3 is thought to be involved in tissue repair and fibrogenesis, but its role in these processes is currently unknown. To investigate the function of GSK-3β in fibroblasts, we generated mice harboring a fibroblast-specific deletion of Gsk3b and evaluated their wound-healing and fibrogenic responses. We have shown that Gsk3b-conditional-KO mice (Gsk3b-CKO mice) exhibited accelerated wound closure, increased fibrogenesis, and excessive scarring compared with control mice. In addition, Gsk3b-CKO mice showed elevated collagen production, decreased cell apoptosis, elevated levels of profibrotic α-SMA, and increased myofibroblast formation during wound healing. In cultured Gsk3b-CKO fibroblasts, adhesion, spreading, migration, and contraction were enhanced. Both Gsk3b-CKO mice and fibroblasts showed elevated expression and production of endothelin-1 ...

OBJECTIVES: Wnt/β-catenin signalling plays important roles in regeneration, particularly in hard tissues such as bone and teeth, and can be regulated by small molecule antagonists of glycogen synthase kinase 3 (GSK3); however, small molecules can be difficult to deliver clinically. Lithium (Li) is also a GSK3 antagonist and can be incorporated into bioactive glasses (BG),

GPC3 is a proteoglycan downregulated in breast cancer cells. We previously demonstrated that GPC3 reexpression inhibits in vivo metastatic potential of LM3 murine mammary adenocarcinoma cells. This event was associated in vitro with a lower motility and an increased aggregation, as well as with an enhanced senescence and apoptosis. We have previous evidence indicating that the canonical Wnt pathway is inhibited in LM3-GPC3 cells. The aim of this work was to validate the inhibition of canonical Wnt signaling in GPC3 reexpressing cells and to investigate whether differences in cell behavior are due to the regulation of GPC3 on this pathway. By means of western blots (WB) we established that LM3-GPC3 cells have 5-10 folds less phosphorylated GSK3B. Using cytoplasmic protein extracts and WB we also determined that GPC3 reexpressing cells present lower levels of cytoplasmic B-Catenin. This was further studied by immunofluorescence (IF), where it was found that while LM3-vector cells show positive ...

Regulation of hematopoietic stem and progenitor cell (HSPC) steady-state egress from the bone marrow (BM) to the circulation is poorly understood. While glycogen synthase kinase-3β (GSK3β) is known to participate in HSPC proliferation, we revealed an unexpected role in the preferential regulation of CXCL12-induced migration and steady-state egress of murine HSPCs, including long-term repopulating HSCs, over mature leukocytes. HSPC egress, regulated by circadian rhythms of CXCL12 and CXCR4 levels, correlated with dynamic expression of GSK3β in the BM. Nevertheless, GSK3β signaling was CXCL12/CXCR4 independent, suggesting that synchronization of both pathways is required for HSPC motility. Chemotaxis of HSPCs expressing higher levels of GSK3β compared with mature cells was selectively enhanced by stem cell factor-induced activation of GSK3β. Moreover, HSPC motility was regulated by norepinephrine and insulin-like growth factor-1 (IGF-1), which increased or reduced, respectively, GSK3β ...

What D Bunker is NOT: D Bunker is Not African American. D Bunker is Not Hispanic American. D Bunker is Not a Jewish American. D Bunker is Not a Gay American. D Bunker is an American, Period. And this POd American has had 10 times more than twice too much of enough of Anyone claiming special rights for themselves over Anyone else. Far too many good men and women of all races, creeds and colors have given Everything and more to establish that None of Us are better than the Next of Us, AS LAW, to allow Any Ideology, especially one which is Wholly Smoke and Mirrors, to rule and ruin the lives of Any of us ...

4ACG: Discovery of Novel Potent and Highly Selective Glycogen Synthase Kinase-3Beta (Gsk3Beta) Inhibitors for AlzheimerS Disease: Design, Synthesis, and Characterization of Pyrazines.

Koeck, E.S., Iordanskaia, T., Sevilla, S., Ferrante, S.C., Hubal, M.J. et al. (2014). Adipocyte exosomes induce transforming growth factor beta pathway dysregulation in hepatocytes: A novel paradigm for obesity-related liver disease. Journal of Surgical Research, 192(2), 268-275.. ...

Tytuł projektu: Rozbudowa i przekształcenie bibliograficznej bazy danych AGRO w bazę bibliograficzno-abstraktową z wykorzystaniem oprogramowania YADDA. Nr umowy: POIG 02.03.02-00-031/09 (okres realizacji 2009-2013 ...

A lot of people are beginning to realize that the MHRA and GSK are perhaps way too close for comfort... Some very interesting views lately on my blog. The Webstats can tell you quite a bit of information, about who is viewing the blog etc. I noticed today that GSK and the MHRA were both…

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GSK778 is a potent and selective inhibitor of bromodomain (BRD) BD1 and offers a super survival advantage in the aggressive MLL-AF9 AML model.