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https://www.readbyqxmd.com/read/28328738/inhibition-of-hippocampal-long-term-potentiation-by-high-fat-diets-is-it-related-to-an-effect-of-palmitic-acid-involving-glycogen-synthase-kinase-3
#1
Ana Contreras, Danila Del Rio, Ana Martínez, Carmen Gil, Lidia Morales, Mariano Ruiz-Gayo, Nuria Del Olmo
High-fat diets (HFD) impair hippocampal-dependent learning and memory and produce important changes in synaptic transmission by enhancing glutamate uptake, decreasing synaptic efficacy, and inhibiting plasticity mechanisms such as N-methyl-D-aspartate-mediated long-term depression (LTD) within the hippocampus. Adolescent animals seem to be particularly susceptible to the detrimental effect of HFD as dietary treatments carried out between weaning and early adulthood are much more efficient in terms of hippocampal damage that those carried out during the adult period...
March 21, 2017: Neuroreport
https://www.readbyqxmd.com/read/28324067/gestational-protein-restriction-impairs-glucose-disposal-in-the-gastrocnemius-muscles-of-female-rats
#2
C S Blesson, V Chinnathambi, S Kumar, C Yallampalli
Gestational low protein (LP) diet causes hyperglycemia and insulin resistance in adult offspring but the mechanism is not clearly understood. In this study, we explored the role of insulin signaling in gastrocnemius muscles of gestational LP exposed female offspring. Pregnant rats were fed control (20% protein) or isocaloric LP (6%) diet from gestational day 4 until delivery. Normal diet was given to mothers after delivery and to pups after weaning until necropsy. Offspring were euthanized at 4 months and gastrocnemius muscles were treated with insulin ex vivo for 30 min...
January 30, 2017: Endocrinology
https://www.readbyqxmd.com/read/28324053/hepatic-insulin-resistance-and-altered-gluconeogenic-pathway-in-premature-baboons
#3
Lisa McGill-Vargas, Amalia Gastaldelli, Hanyu Liang, Diana Anzueto Guerra, Teresa Johnson-Pais, Steven Seidner, Donald McCurnin, Giovanna Muscogiuri, Ralph DeFronzo, Nicolas Musi, Cynthia Blanco
Premature infants have altered glucose regulation early in life and increased risk for diabetes in adulthood. Although prematurity leads to an increased risk of diabetes and metabolic syndrome in adult life, the role of hepatic glucose regulation and adaptation to an early extra-uterine environment in preterm infants remain unknown. The purpose of this study was to investigate developmental differences in glucose metabolism, hepatic protein content and gene expression of key insulin signaling/gluconeogenic molecules...
January 17, 2017: Endocrinology
https://www.readbyqxmd.com/read/28299185/recent-advances-in-understanding-the-cellular-roles-of-gsk-3
#4
REVIEW
Kevin W Cormier, James R Woodgett
Glycogen synthase kinase-3 (GSK-3) is a ubiquitously expressed protein kinase that sits at the nexus of multiple signaling pathways. Its deep integration into cellular control circuits is consummate to its implication in diseases ranging from mood disorders to diabetes to neurodegenerative diseases and cancers. The selectivity and insulation of such a promiscuous kinase from unwanted crosstalk between pathways, while orchestrating a multifaceted response to cellular stimuli, offer key insights into more general mechanisms of cell regulation...
2017: F1000Research
https://www.readbyqxmd.com/read/28288414/butyrate-induces-ros-mediated-apoptosis-by-modulating-mir-22-sirt-1-pathway-in-hepatic-cancer-cells
#5
Kishor Pant, Ajay K Yadav, Parul Gupta, Rakibul Islam, Anoop Saraya, Senthil K Venugopal
Butyrate is one of the short chain fatty acids, produced by the gut microbiota during anaerobic fermentation of dietary fibres. It has been shown that it can inhibit tumor progression via suppressing histone deacetylase and can induce apoptosis in cancer cells. However, the comprehensive pathway by which butyrate mediates apoptosis and growth arrest in cancer cells still remains unclear. In this study, the role of miR-22 in butyrate-mediated ROS release and induction of apoptosis was determined in hepatic cells...
March 7, 2017: Redox Biology
https://www.readbyqxmd.com/read/28283665/il-18-dependent-nkg2d-ligand-upregulation-on-accessory-cells-is-mediated-by-the-pi3k-gsk-3-pathway
#6
Joshua D Brandstadter, Huiyao Chen, Songfu Jiang, Xiaopei Huang, Yiping Yang
NK cells are critical for the control of viral infections. Studies have shown that efficient NK cell activation in response to infection with VV in vivo requires multiple pathways, including the NKG2D pathway. We have recently shown that IL-18 is necessary for the activation of NK cells through upregulation of the NKG2D ligand Rae-1 on DCs upon VV infection. However, how IL-18R signaling on the accessory cells contributes to Rae-1 up-regulation remains to be defined. In this study, we found IL-18-mediated Rae-1 up-regulation in accessory cells, including macrophages and DCs, to be dependent on the MyD88-PI3K pathway...
March 10, 2017: Journal of Leukocyte Biology
https://www.readbyqxmd.com/read/28281841/lncrna-nonratt021972-sirna-normalized-the-dysfunction-of-hepatic-glucokinase-through-akt-signaling-in-t2dm-rats
#7
Miaomiao Song, Lifang Zou, Lichao Peng, Shuangmei Liu, Bing Wu, Zhihua Yi, Yun Gao, Chunping Zhang, Hong Xu, Yurong Xu, Mengxia Tang, Shouyu Wang, Yun Xue, Tianyu Jia, Shanhong Zhao, Shangdong Liang, Guilin Li
Hepatic glucokinase (GK) expression and activity are decreased in type 2 diabetes mellitus (T2DM), and glycogen synthase kinase-3 (GSK-3) inhibits the synthesis of GK. In hepatocytes, the activation of the protein kinase B (PKB/AKT) signaling pathway enhances GK expression and inhibits the phosphorylation of GSK-3β. The dysfunction of certain long noncoding RNAs (lncRNAs) has been associated with a variety of diseases. AIMS: This study explored the effects of the lncRNA NONRATT021972 small interfering RNA (siRNA) on the dysfunction of hepatic GK through AKT signaling in T2DM rats...
March 10, 2017: Endocrine Research
https://www.readbyqxmd.com/read/28272406/o-glcnacylation-of-skn-1-modulates-the-lifespan-and-oxidative-stress-resistance-in-caenorhabditis-elegans
#8
Hongyuan Li, Xin Liu, Dan Wang, Liangping Su, Tingting Zhao, Zhongwei Li, Cong Lin, Yu Zhang, Baiqu Huang, Jun Lu, Xiaoxue Li
In C. elegans, the transcription factor skinhead-1 (SKN-1), the ortholog of human NF-E2-related factor 2 (Nrf-2), plays important roles in oxidative stress defense and aging processes. It has been documented that the activity of SKN-1 is regulated by its phosphorylation modification. However, whether other posttranslational modifications of SKN-1 affect its function remains unclear to date. Here we report, for the first time, that SKN-1 is O-GlcNAcylated at Ser470 and Thr493 by O-GlcNActransferase OGT-1. By generating the double mutations of Ser470/Thr493 in the wild type and skn-1(zu67) worms, respectively, we found that disruption of O-GlcNAc modification on SKN-1 repressed the accumulation of SKN-1 in the intestinal nuclei, and decreased the activities of SKN-1 in modulating lifespan and oxidative stress resistance...
March 8, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28256546/promoting-in-vivo-remyelination-with-small-molecules-a-neuroreparative-pharmacological-treatment-for-multiple-sclerosis
#9
Eva María Medina-Rodríguez, Ana Bribián, Amanda Boyd, Valle Palomo, Jesús Pastor, Alfonso Lagares, Carmen Gil, Ana Martínez, Anna Williams, Fernando de Castro
Multiple Sclerosis (MS) is a neurodegenerative disease where immune-driven demyelination occurs with inefficient remyelination, but therapies are limited, especially those to enhance repair. Here, we show that the dual phosphodiesterase (PDE)7- glycogen synthase kinase (GSK)3 inhibitor, VP3.15, a heterocyclic small molecule with good pharmacokinetic properties and safety profile, improves in vivo remyelination in mouse and increases both adult mouse and adult human oligodendrocyte progenitor cell (OPC) differentiation, in addition to its immune regulatory action...
March 3, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28253732/the-indirubin-derivative-6-bromoindirubin-3-oxime-6bio-activates-proteostatic-modules-reprograms-cellular-bioenergetics-pathways-and-exerts-anti-aging-effects
#10
Eleni Tsakiri, Nicolas Gaboriaud-Kolar, Kalliopi Iliaki, Job Tchoumtchoua, Eleni-Dimitra Papanagnou, Sofia Chatzigeorgiou, Konstantinos Tallas, Emmanuel Mikros, Maria Halabalaki, Alexios-Leandros Skaltsounis, Ioannis P Trougakos
AIMS: Organismal aging can be delayed by mutations that either activate stress responses or reduce the nutrients sensing pathways signaling; thus, by using Drosophila melanogaster as an in vivo experimental screening platform we searched for compounds that modulate these pathways. RESULTS: We noted that oral administration of the glycogen synthase kinase 3 (Gsk-3) inhibitor 6-bromoindirubin-3'-oxime (6BIO) in Drosophila flies extended healthy lifespan. 6BIO is not metabolized in flies' tissues; modulated bioenergetic pathways, decreased lipid and glucose tissues' load, activated antioxidant and proteostatic modules and enhanced resistance to stressors...
March 2, 2017: Antioxidants & Redox Signaling
https://www.readbyqxmd.com/read/28253260/direct-keap1-nrf2-disruption-as-a-potential-therapeutic-target-for-alzheimer-s-disease
#11
Fiona Kerr, Oyinkan Sofola-Adesakin, Dobril K Ivanov, Jemma Gatliff, Beatriz Gomez Perez-Nievas, Hélène C Bertrand, Pedro Martinez, Rebecca Callard, Inge Snoeren, Helena M Cochemé, Jennifer Adcott, Mobina Khericha, Jorge Iván Castillo-Quan, Geoffrey Wells, Wendy Noble, Janet Thornton, Linda Partridge
Nrf2, a transcriptional activator of cell protection genes, is an attractive therapeutic target for the prevention of neurodegenerative diseases, including Alzheimer's disease (AD). Current Nrf2 activators, however, may exert toxicity and pathway over-activation can induce detrimental effects. An understanding of the mechanisms mediating Nrf2 inhibition in neurodegenerative conditions may therefore direct the design of drugs targeted for the prevention of these diseases with minimal side-effects. Our study provides the first in vivo evidence that specific inhibition of Keap1, a negative regulator of Nrf2, can prevent neuronal toxicity in response to the AD-initiating Aβ42 peptide, in correlation with Nrf2 activation...
March 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28236969/glycogen-synthase-kinase-3-a-kinase-for-all-pathways
#12
Prital Patel, James R Woodgett
Glycogen synthase kinase-3 (GSK-3) is an unusual protein-serine kinase in that it is primarily regulated by inhibition and lies downstream of multiple cell signaling pathways. This raises a variety of questions in terms of its physiological role(s), how signaling specificity is maintained and why so many eggs have been placed into one basket. There are actually two baskets, as there are two isoforms, GSK-3α and β, that are highly related and largely redundant. Their many substrates range from regulators of cellular metabolism to molecules that control growth and differentiation...
2017: Current Topics in Developmental Biology
https://www.readbyqxmd.com/read/28186681/skin-derived-precursors-as-a-source-of-progenitors-for-corneal-endothelial-regeneration
#13
Emi Inagaki, Shin Hatou, Kazunari Higa, Satoru Yoshida, Shinsuke Shibata, Hideyuki Okano, Kazuo Tsubota, Shigeto Shimmura
Corneal blindness is the fourth leading cause of blindness in the world. Current treatment is allogenic corneal transplantation, which is limited by shortage of donors and immunological rejection. Skin-derived precursors (SKPs) are postnatal stem cells, which are self-renewing, multipotent precursors that can be isolated and expanded from the dermis. Facial skin may therefore be an accessible autologous source of neural crest derived cells. SKPs were isolated from facial skin of Wnt1-Cre/Floxed EGFP mouse. After inducing differentiation with medium containing retinoic acid and GSK 3-β inhibitor, SKPs formed polygonal corneal endothelial-like cells (sTECE)...
March 2017: Stem Cells Translational Medicine
https://www.readbyqxmd.com/read/28140405/the-impact-of-disrupted-in-schizophrenia-1-disc1-on-the-dopaminergic-system-a-systematic-review
#14
REVIEW
T Dahoun, S V Trossbach, N J Brandon, C Korth, O D Howes
Disrupted-in-Schizophrenia 1 (DISC1) is a gene known as a risk factor for mental illnesses possibly associated with dopamine impairments. DISC1 is a scaffold protein interacting with proteins involved in the dopamine system. Here we summarise the impact of DISC1 disruption on the dopamine system in animal models, considering its effects on presynaptic dopaminergic function (tyrosine hydroxylase levels, dopamine transporter levels, dopamine levels at baseline and after amphetamine administration) and postsynaptic dopaminergic function (dopamine D1 and D2 receptor levels, dopamine receptor-binding potential and locomotor activity after amphetamine administration)...
January 31, 2017: Translational Psychiatry
https://www.readbyqxmd.com/read/28130417/phosphorylation-of-clustered-serine-residues-in-the-n-terminus-of-bps-domain-negatively-regulates-formation-of-the-complex-between-human-grb14-and-insulin-receptor
#15
Junichi Taira, Yutaka Kida, Kohei Inatomi, Hideyuki Komatsu, Yuichiro Higashimoto, Hiroshi Sakamoto
Growth factor receptor-bound protein 14 (Grb14) is a negative regulator of insulin receptor (IR) and is involved in a negative feedback mechanism of insulin signaling. Grb14 associates with IR and inhibits its tyrosine kinase activity through the between pleckstrin homology and Src homology-2 (BPS) domain. We previously reported that the pharmacological inhibition and knockdown of glycogen synthase kinase-3 (GSK-3) facilitates the insulin-induced complex formation of human Grb14 (hGrb14) and IR, suggesting that GSK-3 suppresses hGrb14 recruitment to IR...
January 27, 2017: Journal of Biochemistry
https://www.readbyqxmd.com/read/28129131/6bio-enhances-oligonucleotide-activity-in-cells-a-potential-combinatorial-anti-androgen-receptor-therapy-in-prostate-cancer-cells
#16
Xiaowei Zhang, Daniela Castanotto, Sangkil Nam, David Horne, Cy Stein
Approximately 15%-25% of men diagnosed with prostate cancer do not survive their disease. The American Cancer Society estimated that for the year 2016 the number of prostate cancer deaths will be 26,120. Thus, there is a critical need for novel approaches to treat this deadly disease. Using high-throughput small-molecule screening, we found that the small molecule 6-bromo-indirubin-3'-oxime (6BIO) significantly improves the targeting of antisense oligonucleotides (ASOs) delivered by gymnosis (i.e., in the absence of any transfection reagents) in both the cell cytoplasm and the nucleus...
January 4, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28119025/synthesis-of-carbon-11-labeled-isonicotinamides-as-new-potential-pet-agents-for-imaging-of-gsk-3-enzyme-in-alzheimer-s-disease
#17
Mingzhang Gao, Min Wang, Qi-Huang Zheng
The authentic standards 2-(cyclopropanecarboxamido)-N-(4-methoxypyridin-3-yl)isonicotinamide (4a) and 2-(cyclopropanecarboxamido)-N-(4-(4-methoxyphenyl)pyridin-3-yl)isonicotinamide (7a), and their corresponding precursors 2-(cyclopropanecarboxamido)-N-(4-hydroxypyridin-3-yl)isonicotinamide (4b) and 2-(cyclopropanecarboxamido)-N-(4-(4-hydroxyphenyl)pyridin-3-yl)isonicotinamide (7b) were synthesized from methyl 2-aminoisonicotinate and cyclopropanecarbonyl chloride with overall chemical yield 47% in three steps, 22% in four steps, 40% in three steps, and 17% in four steps, respectively...
January 16, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28114834/small-molecules-targeting-glycogen-synthase-kinase-3-as-potential-drug-candidates-for-the-treatment-of-retinitis-pigmentosa
#18
Miguel Marchena, Beatriz Villarejo-Zori, Josefa Zaldivar-Diez, Valle Palomo, Carmen Gil, Catalina Hernández-Sánchez, Ana Martínez, Enrique J de la Rosa
Retinitis pigmentosa (RP) is an inherited retinal dystrophy that courses with progressive degeneration of retinal tissue and loss of vision. Currently, RP is an unpreventable, incurable condition. We propose glycogen synthase kinase 3 (GSK-3) inhibitors as potential leads for retinal cell neuroprotection, since the retina is also a part of the central nervous system and GSK-3 inhibitors are potent neuroprotectant agents. Using a chemical genetic approach, diverse small molecules with different potency and binding mode to GSK-3 have been used to validate and confirm GSK-3 as a pharmacological target for RP...
December 2017: Journal of Enzyme Inhibition and Medicinal Chemistry
https://www.readbyqxmd.com/read/28108896/pharmacophore-based-screening-and-drug-repurposing-exemplified-on-glycogen-synthase-kinase-3-inhibitors
#19
Luminita Crisan, Sorin Avram, Liliana Pacureanu
The current study was conducted to elaborate a novel pharmacophore model to accurately map selective glycogen synthase kinase-3 (GSK-3) inhibitors, and perform virtual screening and drug repurposing. Pharmacophore modeling was developed using PHASE on a data set of 203 maleimides. Two benchmarking validation data sets with focus on selectivity were assembled using ChEMBL and PubChem GSK-3 confirmatory assays. A drug repurposing experiment linking pharmacophore matching with drug information originating from multiple data sources was performed...
January 21, 2017: Molecular Diversity
https://www.readbyqxmd.com/read/28106616/lymphocyte-phospho-ser-9-gsk-3%C3%AE-total-gsk-3%C3%AE-protein-levels-ratio-is-not-affected-by-chronic-lithium-or-valproate-treatment-in-euthymic-patients-with-bipolar-disorder
#20
Abed N Azab, Ella Vainer, Galila Agam, Yuly Bersudsky
BACKGROUND: Glycogen synthase kinase-3 (GSK-3) inhibition by lithium has been well established in vitro, but proof that this biochemical effect mediates lithium's beneficial action in patients with bipolar disorder is lacking. We studied whether lymphocyte GSK-3β activity measured indirectly in lithium- or valproate (VPA)-treated euthymic patients with bipolar disorder is different from controls. METHODS: Lymphocyte total and Ser-9-phospho-GSK-3β (inactive) levels were measured by Western blotting...
January 19, 2017: Journal of Clinical Psychopharmacology
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