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https://www.readbyqxmd.com/read/28734998/oxidative-stress-with-tau-hyperphosphorylation-in-memory-impaired-1-2-diacetylbenzene-treated-mice
#1
Sin-Woo Kang, Sung Jin Kim, Min-Sun Kim
Long-term exposure to organic solvent may be related to the incidence of neuronal diseases, such as, Alzheimer's disease, depression, multiple sclerosis, dementia, Parkinson's disease. Previously, the authors reported 1,2-diacetylbenzene (DAB; a neurotoxic metabolite of 1,2-diethylbenzene) causes central and peripheral neuropathies that lead to motor neuronal deficits. Furthermore, it is known DAB increases oxidative stress and protein adduct levels and impairs hippocampal neurogenesis in mice. The authors examined the relevance of oxidative stress and tau hyperphosphorylation in the hippocampus...
July 19, 2017: Toxicology Letters
https://www.readbyqxmd.com/read/28732374/the-protective-effect-of-pft%C3%AE-on-alcohol-induced-osteonecrosis-of-the-femoral-head
#2
Yi-Xuan Chen, Dao-Yu Zhu, Jun-Hui Yin, Wen-Jing Yin, Yue-Lei Zhang, Hao Ding, Xiao-Wei Yu, Jiong Mei, You-Shui Gao, Chang-Qing Zhang
Epidemiologic studies have shown alcohol plays a pivotal role in the development of osteonecrosis of the femoral head (ONFH). The aim of this study was to explore the underlying mechanism of alcohol-induced ONFH and the protective effect of pifithrin-α (PFTα). In vitro, we found ethanol treatment significantly activated p53, suppressed Wnt/β-catenin signaling and inhibited osteogenic-related proteins. Furthermore, by separating the cytoplasmic and nuclear proteins, we found ethanol inhibited osteogenesis by impairing the accumulation of β-catenin in both the cytoplasm and nucleus in human bone mesenchymal stem cells (hBMSCs), which resulted from activating glycogen synthase kinase-3β (GSK-3β)...
July 11, 2017: Oncotarget
https://www.readbyqxmd.com/read/28731198/gsk-3%C3%AE-inhibition-suppresses-instability-induced-osteolysis-by-a-dual-action-on-osteoblast-and-osteoclast-differentiation
#3
Mehdi Amirhosseini, Rune Vinther Madsen, K Jane Escott, Mathias Bostrom, F Patrick Ross, Anna Fahlgren
Currently, there are no medications available to treat aseptic loosening of orthopedic implants. Using osteoprotegerin fusion protein (OPG-Fc), we previously blocked instability-induced osteoclast differentiation and peri-prosthetic osteolysis. Wnt/β-catenin signaling, which regulates OPG secretion from osteoblasts, also modulates the bone tissue response to mechanical loading. We hypothesized that activating Wnt/β-catenin signaling by inhibiting glycogen synthase kinase-3β (GSK-3β) would reduce instability-induced bone loss through regulation of both osteoblast and osteoclast differentiation...
July 21, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/28731148/molecular-genetics-and-targeted-therapy-of-wnt-related-human-diseases-review
#4
Masuko Katoh, Masaru Katoh
Canonical WNT signaling through Frizzled and LRP5/6 receptors is transduced to the WNT/β-catenin and WNT/stabilization of proteins (STOP) signaling cascades to regulate cell fate and proliferation, whereas non-canonical WNT signaling through Frizzled or ROR receptors is transduced to the WNT/planar cell polarity (PCP), WNT/G protein-coupled receptor (GPCR) and WNT/receptor tyrosine kinase (RTK) signaling cascades to regulate cytoskeletal dynamics and directional cell movement. WNT/β-catenin signaling cascade crosstalks with RTK/SRK and GPCR-cAMP-PKA signaling cascades to regulate β-catenin phosphorylation and β-catenin-dependent transcription...
July 19, 2017: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/28729116/convergence-of-glycogen-synthase-kinase-3%C3%AE-and-gr-signaling-in-response-to-fluoxetine-treatment-in-chronically-stressed-female-and-male-rats
#5
Milos Mitic, Zeljka Brkic, Iva Lukic, Miroslav Adzic
Accumulating evidence strongly suggest that impaired glucocorticoid receptor (GR) signaling is involved in stress-related mood disorders, and nominate GR as a potential target for antidepressants (ADs). It is known that different classes of ADs affects the GR action via modifying its phosphorylation, while the mechanism through which ADs alter GR phosphorylation targeted by GSK3β, a kinase modulated via serotonin neurotransmission, are unclear. On this basis, we investigated whether GSK3β-GR signaling could be a convergence point of fluoxetine action on brain function and behavior, by examining its effect on GSK3β targeted-GR phosphorylation on threonine 171 (pGR171), and expression of GR-regulated genes in the hippocampus of female and male rats exposed to chronic isolation stress...
July 17, 2017: Behavioural Brain Research
https://www.readbyqxmd.com/read/28726150/inhibition-mechanism-of-cdk-2-and-gsk-3%C3%AE-by-a-sulfamoylphenyl-derivative-of-indoline-a-molecular-dynamics-study
#6
Przemysław Czeleń
A good understanding of the inhibition mechanism of enzymes exhibiting high levels of similarity is the first step to the discovery of new drugs with selective potential. Examples of such proteins include glycogen synthase kinase-3 (GSK-3β) and cyclin-dependent kinase 2 (CDK-2). This article reports the mechanism of such enzyme inhibition as analyzed by an indoline sulfamylophenyl derivative (CHEMBL410072). Previous work has shown that such compounds exhibit selective properties towards their biological targets...
August 2017: Journal of Molecular Modeling
https://www.readbyqxmd.com/read/28720858/gsk-3%C3%AE-deletion-in-dentate-gyrus-excitatory-neuron-impairs-synaptic-plasticity-and-memory
#7
Enjie Liu, Ao-Ji Xie, Qiuzhi Zhou, Mengzhu Li, Shujuan Zhang, Shihong Li, Weijin Wang, Xiaochuan Wang, Qun Wang, Jian-Zhi Wang
Increasing evidence suggests that glycogen synthase kinase-3β (GSK-3β) plays a crucial role in neurodegenerative/psychiatric disorders, while pan-neural knockout of GSK-3β also shows detrimental effects. Currently, the function of GSK-3β in specific type of neurons is elusive. Here, we infused AAV-CaMKII-Cre-2A-eGFP into GSK-3β(lox/lox) mice to selectively delete the kinase in excitatory neurons of hippocampal dentate gyrus (DG), and studied the effects on cognitive/psychiatric behaviors and the molecular mechanisms...
July 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28716393/combine-effect-of-chondroitinase-abc-and-low-level-laser-660nm-on-spinal-cord-injury-model-in-adult-male-rats
#8
Atousa Janzadeh, Arash Sarveazad, Mahmoud Yousefifard, Sima Dameni, Fazel Sahraneshin Samani, Kobra Mokhtarian, Farinaz Nasirinezhad
After spinal cord injury (SCI) there are many recoveries inhibiting factors such as chondroitin sulfate proteoglycan (CSPG) and inflammation. The present study investigated the combinational effect of low level laser therapy (LLLT) as anti-inflammatory agent and Chondroitinase ABC (ChABC) enzyme as CSPG digesting factor on spinal cord after injury. This study performed on 44 male Wistar rats, spinal cord injury induced by a clip compression injury. Animals received two-weeks treatment of 660nm low level laser (LLL) and intraspinal injection of 1μg ChABC...
July 14, 2017: Neuropeptides
https://www.readbyqxmd.com/read/28714566/gsk-3%C3%AE-activation-index-is-a-potential-indicator-for-recurrent-inflammation-of-chronic-rhinosinusitis-without-nasal-polyps
#9
Haiyu Hong, Fenghong Chen, Yongkang Qiao, Yan Yan, Rongkai Zhang, Zhe Zhu, Huabin Li, Yunping Fan, Geng Xu
Chronic rhinosinusitis without nasal polyps (CRSsNP) is one of the most common otorhinolaryngologic diseases worldwide. However, the underlying mechanism remains unclear. In this study, the expression of glycogen synthase kinase 3 (GSK-3) was quantitatively evaluated in patients with CRSsNP (n = 20) and healthy controls (n = 20). The mRNA levels of GSK-3α and GSK-3β were examined by qPCR, the immunoreactivities of GSK-3β and nuclear factor-κB (NF-κB) were examined by immunohistochemistry (IHC) staining, and the protein levels of GSK-3β, phospho-GSK-3β (p-GSK-3β, s9) and NF-κB were examined using Western blot analysis...
July 17, 2017: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/28714403/gsk3-inhibitors-in-the-therapeutic-development-of-diabetes-cancer-and-neurodegeneration-past-present-and-future
#10
Mudasir Maqbool, Nasimul Hoda
GSK3 has gained a considerable attention of researchers in the late 1970s as an inevitable drug target to treat diabetes. Furthermore, it was found to have a key role in the development of diseases like cancer and neurodegeneration (ND). A broad spectrum of GSK3 inhibitors have been discovered from time to time in order to curb these diseases. Inhibition of GSK3 by insulin boosts the dephosphorylation of glycogen synthase, hence its activation to convert UDP glucose into glycogen. Lack of insulin and insulin-resistance is supposed to be the cause of type 2 diabetes (Diabetes mellitus)...
July 14, 2017: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/28712708/discovery-of-novel-2-3-phenylpiperazin-1-yl-pyrimidin-4-ones-as-glycogen-synthase-kinase-3%C3%AE-inhibitors
#11
Yoshihiro Usui, Fumiaki Uehara, Shinsuke Hiki, Kazutoshi Watanabe, Hiroshi Tanaka, Aya Shouda, Satoshi Yokoshima, Keiichi Aritomo, Takashi Adachi, Kenji Fukunaga, Shinji Sunada, Mika Nabeno, Ken-Ichi Saito, Jun-Ichi Eguchi, Keiji Yamagami, Shouichi Asano, Shinji Tanaka, Satoshi Yuki, Narihiko Yoshii, Masatake Fujimura, Takashi Horikawa
We herein describe the results of further evolution of glycogen synthase kinase (GSK)-3β inhibitors from our promising compounds containing a 2-phenylmorpholine moiety. Transformation of the morpholine moiety into a piperazine moiety resulted in potent GSK-3β inhibitors. SAR studies focused on the phenyl moiety revealed that a 4-fluoro-2-methoxy group afforded potent inhibitory activity toward GSK-3β. Based on docking studies, new hydrogen bonding between the nitrogen atom of the piperazine moiety and the oxygen atom of the main chain of Gln185 has been indicated, which may contribute to increased activity compared with that of the corresponding phenylmorpholine analogues...
July 5, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28712706/discovery-of-novel-2-4-aryl-2-methylpiperazin-1-yl-pyrimidin-4-ones-as-glycogen-synthase-kinase-3%C3%AE-inhibitors
#12
Toshiyuki Kohara, Kazuki Nakayama, Kazutoshi Watanabe, Shin-Ichi Kusaka, Daiki Sakai, Hiroshi Tanaka, Kenji Fukunaga, Shinji Sunada, Mika Nabeno, Ken-Ichi Saito, Jun-Ichi Eguchi, Akiko Mori, Shinji Tanaka, Tomoko Bessho, Keiko Takiguchi-Hayashi, Takashi Horikawa
We herein describe the results of further evolution of glycogen synthase kinase (GSK)-3β inhibitors from our promising compounds containing a 3-methylmorpholine moiety. Transformation of the morpholine moiety into a piperazine moiety resulted in potent GSK-3β inhibitors. SAR studies focused on the nitrogen atom of the piperazine moiety revealed that a phenyl group afforded potent inhibitory activity toward GSK-3β. Docking studies indicated that the phenyl group on the piperazine nitrogen atom and the methyl group on the piperazine make cation-π and CH-π interactions with GSK-3β respectively...
July 5, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28712664/gsk3-and-its-interactions-with-the-pi3k-akt-mtor-signalling-network
#13
REVIEW
Miguel A Hermida, J Dinesh Kumar, Nick R Leslie
Glycogen Synthase Kinase-3 (GSK3 or GSK-3) is a promiscuous protein kinase and its phosphorylation of its diverse substrates has major influences on many areas of physiology and pathology, including cellular metabolism, lineage commitment and neuroscience. GSK3 was one of the first identified substrates of the heavily studied oncogenic kinase AKT, phosphorylation by which inhibits GSK3 activity via the formation of an autoinhibitory pseudosubstrate sequence. This has led to investigation of the role of GSK3 inhibition as a key component of the cellular responses to growth factors and insulin, which stimulate the class I PI 3-Kinases and in turn AKT activity and GSK3 phosphorylation...
June 27, 2017: Advances in Biological Regulation
https://www.readbyqxmd.com/read/28710530/proteomic-characterisation-reveals-active-wnt-signalling-by-human-multipotent-stromal-cells-as-a-key-regulator-of-beta-cell-survival-and-proliferation
#14
Miljan Kuljanin, Gillian I Bell, Stephen E Sherman, Gilles A Lajoie, David A Hess
AIMS/HYPOTHESIS: Novel strategies to stimulate the expansion of beta cell mass in situ are warranted for diabetes therapy. The aim of this study was to elucidate the secretome of human bone marrow (BM)-derived multipotent stromal cells (MSCs) with documented islet regenerative paracrine function. We hypothesised that regenerative MSCs will secrete a unique combination of protein factors that augment islet regeneration. METHODS: Human BM-derived MSCs were examined for glucose-lowering capacity after transplantation into streptozotocin-treated NOD/severe combined immunodeficiency (SCID) mice and segregated into samples with regenerative (MSC(R)) vs nonregenerative (MSC(NR)) capacity...
July 14, 2017: Diabetologia
https://www.readbyqxmd.com/read/28701865/processed-panax-ginseng-sun-ginseng-inhibits-the-differentiation-and-proliferation-of-3t3-l1-preadipocytes-and-fat-accumulation-in-caenorhabditis-elegans
#15
Hyejin Lee, Jinhee Kim, Jun Yeon Park, Ki Sung Kang, Joeng Hill Park, Gwi Seo Hwang
BACKGROUND: Heat-processed ginseng, sun ginseng (SG), has been reported to have improved therapeutic properties compared with raw forms, such as increased antidiabetic, anti-inflammatory, and antihyperglycemic effects. The aim of this study was to investigate the antiobesity effects of SG through the suppression of cell differentiation and proliferation of mouse 3T3-L1 preadipocyte cells and the lipid accumulation in Caenorhabditis elegans. METHODS: To investigate the effect of SG on adipocyte differentiation, levels of stained intracellular lipid droplets were quantified by measuring the oil red O signal in the lipid extracts of cells on differentiation Day 7...
July 2017: Journal of Ginseng Research
https://www.readbyqxmd.com/read/28699113/protective-role-of-naringenin-against-a%C3%AE-25-35-caused-damage-via-er-and-pi3k-akt-mediated-pathways
#16
Ning Zhang, Zhonghua Hu, Zhibo Zhang, Guoliang Liu, Yeqiu Wang, Yandong Ren, Xiuhong Wu, Fang Geng
Senile plaque accumulation and neurofibrillary tangles are primary characteristics of Alzheimer's disease. We aimed to assess the protective functions of naringenin against β-amyloid protein fragment 25-35 (Aβ25-35)-caused nerve damage in differentiated PC12 cells, and study the potential mechanisms. We evaluated cell viability and apoptosis using the 3-(4, 5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) test and flow cytometry, respectively. Moreover, we measured protein kinase B (Akt), glycogen synthase kinase-3β (GSK-3β), and caspase-3 activity via western blotting and RT-PCR...
July 11, 2017: Cellular and Molecular Neurobiology
https://www.readbyqxmd.com/read/28698144/inhibiting-glycogen-synthase-kinase-3-and-transforming-growth-factor-%C3%AE-signaling-to-promote-epithelial-transition-of-human-adipose-mesenchymal-stem-cells
#17
Melina Setiawan, Xiao-Wei Tan, Tze-Wei Goh, Gary Hin-Fai Yam, Jodhbir S Mehta
BACKGROUND: This study was aimed to investigate the epithelial differentiation of human adipose-derived mesenchymal stem cells (ADSCs) by inhibiting glycogen synthase kinase-3 (GSK3) and transforming growth factor β (TGFβ) signaling. METHODS AND RESULTS: STEMPRO human ADSCs at passage 2 were treated with CHIR99021 (GSK3 inhibitor), E-616452 (TGFβ1 receptor kinase inhibitor), A-83-01 (TGFβ type 1 receptor inhibitor), valproic acid (histone deacetylase inhibitor), tranylcypromine (monoamine oxidase inhibitor) and all-trans retinoic acid for 72 h...
July 8, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28694190/non-canonical-pathway-induced-by-wnt3a-regulates-%C3%AE-catenin-via-pyk2-in-differentiating-human-neural-progenitor-cells
#18
Venkata Ajay Narendra Talabattula, Peter Morgan, Moritz J Frech, Adelinde M Uhrmacher, Ottmar Herchenröder, Brigitte M Pützer, Arndt Rolfs, Jiankai Luo
Wnt/β-catenin and Wnt/Ca(2+) pathways are involved in cellular processes during embryonic development and the interaction between them in the same cell decides the outcome of cellular functions. In this study, we showed that Wnt3a triggers the Wnt/Ca(2+) signaling pathway, indicated by an increase of cytosolic free calcium ([Ca(2+)]i) and activation of calmodulin dependent kinase II (CaMKII) during the differentiation of human neuronal progenitor cells (hNPCs). Wnt3a via the increase of [Ca(2+)]i activates proline-rich tyrosine kinase 2 (Pyk2), which subsequently regulates phosphorylation of glycogen synthase kinase 3β (GSK3β) and β-catenin stabilization...
July 7, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28693280/improved-antitumor-effect-of-ionizing-radiation-in-combination-with-rapamycin-for-treating-nasopharyngeal-carcinoma
#19
Di Wang, Lichen Gao, Xueting Liu, Chuang Yuan, Guihua Wang
The aim of the present study is to investigate if rapamycin is a radiosensitizer of nasopharyngeal carcinoma (NPC), and to identify which pathways are involved in radiation sensitization. In vitro, using untreated cells as the control, NPC cells were treated with rapamycin, ionizing radiation (IR) or both. Differences in the phosphorylation of ribosomal protein S6 and glycogen synthase kinase (GSK) 3β, expression of cyclin D1, clonogenic survival, number of phosphorylated histone subunit 2AX (γH2AX) foci, and cell cycle status between the study groups were compared...
July 2017: Oncology Letters
https://www.readbyqxmd.com/read/28689095/first-dual-ak-gsk-3%C3%AE-inhibitors-endowed-with-antioxidant-properties-as-multifunctional-potential-neuroprotective-agents
#20
Simone Brogi, Anna Ramunno, Lida Savi, Giulia Chemi, Gloria Alfano, Alessandra Pecorelli, Erika Pambianchi, Paola Galatello, Giulia Compagnoni, Federico Focher, Giuseppe Biamonti, Giuseppe Valacchi, Stefania Butini, Sandra Gemma, Giuseppe Campiani, Margherita Brindisi
The manuscript deals with the design, synthesis and biological evaluation of novel benzoxazinone-based and indole-based compounds as multifunctional neuroprotective agents. These compounds inhibit human adenosine kinase (hAK) and human glycogen synthase kinase 3 beta (hGSK-3β) enzymes. Computational analysis based on a molecular docking approach underlined the potential structural requirements for simultaneously targeting both proteins' allosteric sites. In silico hints drove the synthesis of appropriately decorated benzoxazinones and indoles (5a-s, and 6a-c) and biochemical analysis revealed their behavior as allosteric inhibitors of hGSK-3β...
June 9, 2017: European Journal of Medicinal Chemistry
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