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glycogen synthase kinase

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https://www.readbyqxmd.com/read/28543747/oxazolo-4-5-b-pyridine-based-piperazinamides-as-gsk-3%C3%AE-inhibitors-with-potential-for-attenuating-inflammation-and-suppression-of-pro-inflammatory-mediators
#1
Mushtaq A Tantray, Imran Khan, Hinna Hamid, Mohammad Sarwar Alam, Abhijeet Dhulap, Ajaz Ahmad Ganai
Recent studies reveal that glycogen synthase kinase-3β (GSK-3β) acts as a pro-inflammatory enzyme, and by inhibiting this kinase, inflammation can be controlled. In this regard, a series of 17 piperazine-linked oxazolo[4,5-b]pyridine-based derivatives was synthesized and evaluated for in vitro GSK-3β inhibitory and in vivo anti-inflammatory activity. The compounds 7d, 7e, 7g, and 7c displayed the best GSK-3β inhibitory activity among all the synthesized compounds, with corresponding IC50 values of 0.34, 0...
May 22, 2017: Archiv der Pharmazie
https://www.readbyqxmd.com/read/28539358/protein-kinase-c-%C3%AE%C2%B5-stabilizes-%C3%AE-catenin-and-regulates-its-subcellular-localization-in-podocytes
#2
Michelle Duong, Xuejiao Yu, Beina Teng, Patricia Schroder, Hermann Haller, Susanne Eschenburg, Mario Schiffer
Kidney disease has been linked to dysregulated signaling via protein kinase C (PKC) in kidney cells such as podocytes. PKCα is a conventional isoform of PKC and a well-known binding partner of β-catenin, which promotes its degradation. β-Catenin is the main effector of the canonical Wnt pathway and is critical in cell adhesion. However, whether other PKC isoforms interact with β-catenin has not been studied systematically. Here we demonstrate that PKCε-deficient mice, which develop proteinuria and glomerulosclerosis, display a lower β-catenin expression compared to PKC wildtype mice, consistent with an altered phenotype of podocytes in culture...
May 24, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28536263/axodendritic-sorting-and-pathological-missorting-of-tau-is-isoform-specific-and-determined-by-axon-initial-segment-architecture
#3
Hans Zempel, Frank Dennissen, Yatender Kumar, Julia Luedtke, Jacek Biernat, Eva-Maria Mandelkow, Eckhard Mandelkow
Subcellular mislocalization of the microtubule-associated protein Tau is a hallmark of Alzheimer disease (AD) and other tauopathies. Six Tau isoforms, differentiated by the presence or absence of a second repeat or of N-terminal inserts, exist in the human CNS but their physiological and pathological differences have long remained remain elusive. Here, we investigated the properties and distributions of human and rodent Tau isoforms in primary forebrain rodent neurons. We found that the Tau-Diffusion-Barrier (TDB), located within the Axon-Initial-Segment (AIS), controls retrograde (axon-to-soma) and anterograde (soma-to-axon) traffic of Tau...
May 23, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28536070/cotinine-improves-visual-recognition-memory-and-decreases-cortical-tau-phosphorylation-in-the-tg6799-mice
#4
J Alex Grizzell, Sagar Patel, George E Barreto, Valentina Echeverria
Alzheimer's disease (AD) is associated with the progressive aggregation of hyperphosphorylated forms of the microtubule associated protein Tau in the central nervous system. Cotinine, the main metabolite of nicotine, reduced working memory deficits, synaptic loss, and amyloid β peptide aggregation into oligomers and plaques as well as inhibited the cerebral Tau kinase, glycogen synthase 3β (GSK3β) in the transgenic (Tg)6799 (5XFAD) mice. In this study, the effect of cotinine on visual recognition memory and cortical Tau phosphorylation at the GSK3β sites Serine (Ser)-396/Ser-404 and phospho-CREB were investigated in the Tg6799 and non-transgenic (NT) littermate mice...
May 20, 2017: Progress in Neuro-psychopharmacology & Biological Psychiatry
https://www.readbyqxmd.com/read/28534956/effects-of-octreotide-on-hepatic-glycogenesis-in-rats-with-high-fat-diet%C3%A2-induced-obesity
#5
Xiao-Xia Wang, Ting Ye, Mao Li, Xian Li, Ou Qiang, Cheng-Wei Tang, Rui Liu
Reduced hepatic glycogenesis is one of the most important causes of metabolic abnormalities in non‑alcoholic fatty liver disease. Octreotide, a somatostatin analogue, has been demonstrated to promote weight loss and improve metabolic disorders in mice with high fat diet (HFD)‑induced obesity. However, whether octreotide affects hepatic glycogenesis is unknown. The aim of the present study was to verify the effects of octreotide on hepatic glycogenesis in rats with HFD‑induced obesity. Male Sprague‑Dawley rats were fed a standard diet or a HFD for 24 weeks...
May 16, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28534931/leucine-rich-glioma-inactivated-3-integrative-analyses-support-its-role-in-the-cytokine-network
#6
Hyun A Kim, Nyoun Soo Kwon, Kwang Jin Baek, Dong-Seok Kim, Hye-Young Yun
Leucine-rich glioma inactivated (LGI)3 is a secreted protein member of LGI family. We previously repo-rted that LGI3 was upregulated in adipose tissues from obese mice and suppressed adipogenesis through its receptor, a disintegrin and metalloproteinase domain-containing protein 23 (ADAM23). We demonstrated that LGI3 regulated tumor necrosis factor-α and adiponectin, and proposed that LGI3 may be a pro-inflammatory adipokine involved in adipose tissue inflammation. In this study, we analyzed adipokine and cytokine profiles in LGI3 knockout mice and demonstrated that multiple factors were increased or decreased in the adipose tissues and plasma of the LGI3 knockout mice...
May 15, 2017: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/28524001/brain-derived-neurotrophic-factor-promotes-growth-of-neurons-and-neural-stem-cells-possibly-by-triggering-the-phosphoinositide-3-kinase-akt-glycogen-synthase-kinase-3%C3%AE-%C3%AE-catenin-pathway
#7
Jin-Wei Yang, Zhang Liang, Shi-Kang Deng Deng, Wei Ma, Xian-Bin Wang, Xing-Tong Li, Tong-Tong Wang, Yun-Fei Dai, Jian-Hui Guo, Li-Yan Li
BACKGROUND: Brain-derived neurotrophic factor (BDNF) plays a crucial role in promoting survival and differentiation of neurons and neural stem cells (NSCs), but the downstream regulating mechanisms remain poorly understood. OBJECTIVE: We investigated whether BDNF exerts its effect by triggering the phosphoinositide 3-kinase (PI3K), protein kinase B, PKB (AKT), glycogen synthase kinase-3β (GSK-3β) and β-catenin signaling pathway in cultured neurons and NSCs derived from the rat embryonic spinal cord...
May 18, 2017: CNS & Neurological Disorders Drug Targets
https://www.readbyqxmd.com/read/28506637/thiamine-and-benfotiamine-prevent-stress-induced-suppression-of-hippocampal-neurogenesis-in-mice-exposed-to-predation-without-affecting-brain-thiamine-diphosphate-levels
#8
Julie Vignisse, Margaux Sambon, Anna Gorlova, Dmitrii Pavlov, Nicolas Caron, Brigitte Malgrange, Elena Shevtsova, Andrey Svistunov, Daniel C Anthony, Natalyia Markova, Natalyia Bazhenova, Bernard Coumans, Bernard Lakaye, Pierre Wins, Tatyana Strekalova, Lucien Bettendorff
Thiamine is essential for normal brain function and its deficiency causes metabolic impairment, specific lesions, oxidative damage and reduced adult hippocampal neurogenesis (AHN). Thiamine precursors with increased bioavailability, especially benfotiamine, exert neuroprotective effects not only for thiamine deficiency (TD), but also in mouse models of neurodegeneration. As it is known that AHN is impaired by stress in rodents, we exposed C57BL6/J mice to predator stress for 5 consecutive nights and studied the proliferation (number of Ki67-positive cells) and survival (number of BrdU-positive cells) of newborn immature neurons in the subgranular zone of the dentate gyrus...
May 12, 2017: Molecular and Cellular Neurosciences
https://www.readbyqxmd.com/read/28504720/a-clinical-drug-library-screen-identifies-clobetasol-propionate-as-an-nrf2-inhibitor-with-potential-therapeutic-efficacy-in-keap1-mutant-lung-cancer
#9
E-J Choi, B-J Jung, S-H Lee, H-S Yoo, E-A Shin, H-J Ko, S Chang, S-Y Kim, S-M Jeon
The Kelch-like ECH-associated protein 1 (KEAP1)-nuclear factor E2-related factor 2 (NRF2)pathway has a central role in cellular antioxidant defense. NRF2 activation due to KEAP1 or NRF2 mutations occurs frequently in many cancers, suggesting that NRF2 inhibition could be a promising therapeutic strategy. However, no potent NRF2 inhibitors are clinically available to date. To develop potent NRF2 inhibitors for therapeutic purpose, we screened ~4000 clinical compounds and determined clobetasol propionate (CP) as the most potent NRF2 inhibitor...
May 15, 2017: Oncogene
https://www.readbyqxmd.com/read/28503524/treadmill-exercise-improves-motor-and-memory-functions-in-cerebral-palsy-rats-through-activation-of-pi3k-akt-pathway
#10
Sun-Young Jung, Dae-Young Kim
Cerebral palsy (CP) is a chronic disorder characterized by physical disability and disruption of brain function. We evaluated the effects of treadmill exercise on motor and memory functions in relation with phosphatidylinositol 3-kinase (PI3K)-Akt pathway using CP rat model. Rota-rod test, step-down avoidance task, 5-bromo-2'-deoxyuridine (BrdU) immunohistochemistry, and western blot for synapsin I, postsynaptic density-95 (PSD-95), PI3K, Akt, and glycogen synthase kinase-3β (GSK-3β) were performed. CP was induced by maternal lipopolysaccharide (LPS)-injection with sensorimotor restriction...
April 2017: Journal of Exercise Rehabilitation
https://www.readbyqxmd.com/read/28502066/ebselen-ameliorates-%C3%AE-amyloid-pathology-tau-pathology-and-cognitive-impairment-in-triple-transgenic-alzheimer-s-disease-mice
#11
Yongli Xie, Yibin Tan, Youbiao Zheng, Xiubo Du, Qiong Liu
Alzheimer's disease (AD) is a progressive neurodegenerative disease which is clinically characterized by memory loss and cognitive decline caused by protein misfolding and aggregation. Imbalance between free radicals and the antioxidant system is a prominent and early feature in the neuropathology of AD. Selenium (Se), a vital trace element with excellent antioxidant potential, is preferentially retained in the brain in Se-limited conditions and has been reported to provide neuroprotection through resisting oxidative damage...
May 13, 2017: Journal of Biological Inorganic Chemistry: JBIC
https://www.readbyqxmd.com/read/28501501/anti-tumor-effects-of-differentiation-inducing-factor-1-in-malignant-melanoma-gsk-3-mediated-inhibition-of-cell-proliferation-and-gsk-3-independent-suppression-of-cell-migration-and-invasion
#12
Masaki Arioka, Fumi Takahashi-Yanaga, Momoko Kubo, Kazunobu Igawa, Katsuhiko Tomooka, Toshiyuki Sasaguri
Differentiation-inducing factor-1 (DIF-1) isolated from Dictyostelium discoideum strongly inhibits the proliferation of various mammalian cells through the activation of glycogen synthase kinase-3 (GSK-3). To evaluate DIF-1 as a novel anti-cancer agent for malignant melanoma, we examined whether DIF-1 has anti-proliferative, anti-migratory, and anti-invasive effects on melanoma cells using in vitro and in vivo systems. DIF-1 reduced the expression levels of cyclin D1 and c-Myc by facilitating their degradation via GSK-3 in mouse (B16BL6) and human (A2058) malignant melanoma cells, and thereby strongly inhibited their proliferation...
May 10, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28499784/gsk-3-as-a-novel-prognostic-indicator-in-leukemia
#13
REVIEW
Peter P Ruvolo
While leukemias represent a diverse set of diseases with malignant cells derived from myeloid or lymphoid origin, a common feature is the dysregulation of signal transduction pathways that influence leukemogeneisis, promote drug resistance, and favor leukemia stem cells. Mutations in PI3K, PTEN, RAS, or other upstream regulators can activate the AKT kinase which has central roles in supporting cell proliferation and survival. A major target of AKT is Glycogen Synthase Kinase 3 (GSK3). GSK3 has two isoforms (alpha and beta) that were studied as regulators of metabolism but emerged as central players in cancer in the early 1990s...
May 8, 2017: Advances in Biological Regulation
https://www.readbyqxmd.com/read/28488766/brief-isoflurane-anesthesia-regulates-striatal-akt-gsk3%C3%AE-signaling-and-ameliorates-motor-deficits-in-a-rat-model-of-early-stage-parkinson-s-disease
#14
Juuso V Leikas, Samuel Kohtala, Wiebke Theilmann, Aaro J Jalkanen, Markus M Forsberg, Tomi Rantamäki
Parkinson's disease (PD) is a progressive neurodegenerative movement disorder primarily affecting the nigrostriatal dopaminergic system. The link between heightened activity of glycogen synthase kinase 3β (GSK3β) and neurodegenerative processes has encouraged investigation into the potential disease modifying effects of novel GSK3β inhibitors in experimental models of PD. Therefore, the intriguing ability of several anesthetics to readily inhibit GSK3β within the cortex and hippocampus led us to investigate the effects of brief isoflurane anesthesia on striatal GSK3β signaling in naïve rats and in a rat model of early-stage PD...
May 10, 2017: Journal of Neurochemistry
https://www.readbyqxmd.com/read/28485728/adenosine-a2a-receptor-inactivation-alleviates-early-onset-cognitive-dysfunction-after-traumatic-brain-injury-involving-an-inhibition-of-tau-hyperphosphorylation
#15
Z-A Zhao, Y Zhao, Y-L Ning, N Yang, Y Peng, P Li, X-Y Chen, D Liu, H Wang, X Chen, W Bai, J-F Chen, Y-G Zhou
Tau is a microtubule-associated protein, and the oligomeric and hyperphosphorylated forms of tau are increased significantly after neurotrauma and considered important factors in mediating cognitive dysfunction. Blockade of adenosine A2A receptors, either by caffeine or gene knockout (KO), alleviates cognitive dysfunction after traumatic brain injury (TBI). We postulated that A2AR activation exacerbates cognitive impairment via promoting tau hyperphosphorylation. Using a mouse model of moderate controlled cortical impact, we showed that TBI induced hyperphosphorylated tau (p-tau) in the hippocampal dentate gyrus and spatial memory deficiency in the Morris water maze test at 7 days and 4 weeks after TBI...
May 9, 2017: Translational Psychiatry
https://www.readbyqxmd.com/read/28485573/radiosynthesis-and-in-vivo-evaluation-of-11-c-a1070722-a-high-affinity-gsk-3-pet-tracer-in-primate-brain
#16
Jaya Prabhakaran, Francesca Zanderigo, Kiran Kumar Solingapuram Sai, Harry Rubin-Falcone, Matthew J Jorgensen, Jay R Kaplan, Akiva Mintz, J John Mann, J S Dileep Kumar
Dysfunction of glycogen synthase kinase 3 (GSK-3) is implicated in the etiology of Alzheimer's disease, Parkinson's disease, diabetes, pain, and cancer. A radiotracer for functional positron emission tomography (PET) imaging could be used to study the kinase in brain disorders and to facilitate the development of small molecule inhibitors of GSK-3 for treatment. At present, there is no target-specific or validated PET tracer available for the in vivo monitoring of GSK-3. We radiolabeled the small molecule inhibitor [(11)C]1-(7-methoxy- quinolin-4-yl)-3-(6-(trifluoromethyl)pyridin-2-yl)urea ([(11)C]A1070722) with high affinity to GSK-3 (Ki = 0...
May 17, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28484287/mir-135b-plays-a-neuroprotective-role-by-targeting-gsk3%C3%AE-in-mpp-intoxicated-sh-sy5y-cells
#17
Jianlei Zhang, Wei Liu, Yabo Wang, Shengnan Zhao, Na Chang
miR-135a-5p was reported to play a crucial role in the protective effects of hydrogen sulfide against Parkinson's disease (PD) by targeting rho-associated protein kinase 2 (ROCK2). However, the role of another member of miR-135 family (miR-135b) and the underlying mechanism in PD are still unclear. qRT-PCR and western blot showed that miR-135 was downregulated and glycogen synthase kinase 3β (GSK3β) was upregulated at mRNA and protein levels in MPP(+)-intoxicated SH-SY5Y cells in a dose- and time-dependent manner...
2017: Disease Markers
https://www.readbyqxmd.com/read/28483921/lack-of-liver-glycogen-causes-hepatic-insulin-resistance-and-steatosis-in-mice
#18
Jose M Irimia, Catalina M Meyer, Dyann M Segvich, Sneha Surendran, Anna A DePaoli-Roach, Nuria Morral, Peter J Roach
Disruption of the Gys2 gene that encodes the liver isoform of glycogen synthase generates a mouse (LGSKO mouse) with an almost complete lack of hepatic glycogen, impaired glucose disposal and a pre-disposition to enter the fasted state. This study explores how the lack of liver glycogen increases fat accumulation and the development of liver insulin resistance. Insulin signaling in LGSKO mice is reduced in liver, but not in muscle, suggesting an organ specific defect. Phosphorylation of several components of the hepatic insulin signaling pathway, IRS1, Akt, and GSK3, were decreased in LGSKO mice and, after insulin stimulation, their responses were significantly suppressed, both temporally and in an insulin dose response...
May 8, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28483667/effect-of-brain-derived-neurotrophic-factor-bdnf-on-hepatocyte-metabolism
#19
Yoni Genzer, Nava Chapnik, Oren Froy
Brain-derived neurotrophic factor (BDNF) plays crucial roles in the development, maintenance, plasticity and homeostasis of the central and peripheral nervous systems. Perturbing BDNF signaling in mouse brain results in hyperphagia, obesity, hyperinsulinemia and hyperglycemia. Currently, little is known whether BDNF affects liver tissue directly. Our aim was to determine the metabolic signaling pathways activated after BDNF treatment in hepatocytes. Unlike its effect in the brain, BDNF did not lead to activation of the liver AKT pathway...
May 5, 2017: International Journal of Biochemistry & Cell Biology
https://www.readbyqxmd.com/read/28482409/-protective-effect-of-glycogen-synthase-kinase-3%C3%AE-inhibition-via-peroxisome-proliferator-activated-receptor-alpha-activation-in-mice-with-acute-liver-failure
#20
H B Shi, H L Shi, X Y Zhang, D X Chen, Z P Duan, F Ren
Objective: To investigate the role of the glycogen synthase kinase 3β (GSK3β) and the peroxisome proliferator-activated receptor alpha (PPARα) signaling pathway in acute liver failure and related mechanisms in a mouse model of acute liver failure induced by D-galactosamine/lipopolysaccharide (D-GalN/LPS). Methods: C57BL/6 mice were given intraperitoneal injection of D-GalN/LPS to establish a mouse model of acute liver failure. SB216763 was used to inhibit the activity of GSK3β and PPARα siRNA was used to inhibit the expression of PPARα...
March 20, 2017: Zhonghua Gan Zang Bing za Zhi, Zhonghua Ganzangbing Zazhi, Chinese Journal of Hepatology
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