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Lithium AND GSK3

Shuo Yang, Shuo Yu, Xinli Liu, Jinyi Yu, Xiaosheng Zhang, Hong Lu
PURPOSE: To evaluate the anti-inflammatory effect of lithium chloride in endotoxin-induced uveitis. METHODS: A total of 200 Wistar rats were randomly divided into four groups: a control group; EIU group; LiCl-treated control group; and LiCl-treated lipopolysaccharide group. Clinical score, slit-lamp photography, hematoxylin and eosin (H&E) staining were used to determine the degree of inflammatory reaction. Level of glycogen synthase kinase3-beta and nuclear factor-kappa B p65 in iris-ciliary body was examined by western blot and RT-PCR...
January 12, 2017: Ocular Immunology and Inflammation
P-M Martin, R E Stanley, A P Ross, A E Freitas, C E Moyer, A C Brumback, J Iafrati, K S Stapornwongkul, S Dominguez, S Kivimäe, K A Mulligan, M Pirooznia, W R McCombie, J B Potash, P P Zandi, S M Purcell, S J Sanders, Y Zuo, V S Sohal, B N R Cheyette
Mice lacking DIX domain containing-1 (DIXDC1), an intracellular Wnt/β-catenin signal pathway protein, have abnormal measures of anxiety, depression and social behavior. Pyramidal neurons in these animals' brains have reduced dendritic spines and glutamatergic synapses. Treatment with lithium or a glycogen synthase kinase-3 (GSK3) inhibitor corrects behavioral and neurodevelopmental phenotypes in these animals. Analysis of DIXDC1 in over 9000 cases of autism, bipolar disorder and schizophrenia reveals higher rates of rare inherited sequence-disrupting single-nucleotide variants (SNVs) in these individuals compared with psychiatrically unaffected controls...
October 18, 2016: Molecular Psychiatry
Dhiana Efani Dahari, Raifana Mohamad Salleh, Fauze Mahmud, Lee Ping Chin, Noor Embi, Hasidah Mohd Sidek
Exploiting natural resources for bioactive compounds is an attractive drug discovery strategy in search for new anti-malarial drugs with novel modes of action. Initial screening efforts in our laboratory revealed two preparations of soil-derived actinomycetes (H11809 and FH025) with potent anti-malarial activities. Both crude extracts showed glycogen synthase kinase 3β (GSK3β)-inhibitory activities in a yeast-based kinase assay. We have previously shown that the GSK3 inhibitor, lithium chloride (LiCl), was able to suppress parasitaemia development in a rodent model of malarial infection...
August 2016: Tropical Life Sciences Research
Antonina Luca, Carmela Calandra, Maria Luca
Objective. To discuss the link between glycogen synthase kinase-3 (GSK3) and the main biological alterations demonstrated in bipolar disorder (BD), with special attention to the redox status and the evidence supporting the efficacy of lithium (a GSK3 inhibitor) in the treatment of BD. Methods. A literature research on the discussed topics, using Pubmed and Google Scholar, has been conducted. Moreover, a manual selection of interesting references from the identified articles has been performed. Results. The main biological alterations of BD, pertaining to inflammation, oxidative stress, membrane ion channels, and circadian system, seem to be intertwined...
2016: Oxidative Medicine and Cellular Longevity
Myriam Fezai, Musaab Ahmed, Zohreh Hosseinzadeh, Florian Lang
BACKGROUND/AIMS: The pleotropic functions of the large conductance Ca2+-activated K+ channels (maxi K+ channel or BK channels) include regulation of neuronal excitation and cell volume. Kinases participating in those functions include the glycogen synthase kinase GSK3 ß which is under negative control of protein kinase B (PKB/Akt). GSK3ß is inhibited by the antidepressant Lithium. The present study thus explored whether GSK3ß modifies the activity of BK channels. METHODS: cRNA encoding the Ca2+ insensitive BK channel mutant BKM513I+Δ899-903 was injected into Xenopus laevis oocytes without or with additional injection of cRNA encoding wild-type GSK3ß, inactive K85RGSK3ß, or wild-type GSK3ß with wild-type PKB...
2016: Cellular Physiology and Biochemistry
M Kouwenberg, C W M Jacobs, J van der Vlag, L B Hilbrands
INTRODUCTION: Tolerogenic dendritic cells (DCs) have the potential to prolong graft survival after transplantation. Tolerogenic DCs are in general characterized by a low expression of co-stimulatory molecule and a high IL-10:IL-12 production ratio. Based on promising results with earlier used alternatively activated DCs, we aimed to generate in culture potentially tolerogenic DC by simultaneously blocking GSK3 by lithium chloride (LiCl) and stimulating TLR2 by PAM3CysSerLys4. MATERIALS AND METHODS: Bone marrow-derived LiClPAM3 DCs were generated by the addition of LiCl 24 hours before harvesting, and one hour later PAM3CysSerLys4...
2016: PloS One
Eduardo Mulato do Vale, Cecília Coelho Xavier, Brenda Gomes Nogueira, Bruna Caldas Campos, Pedro Everson Alexandre de Aquino, Roberta Oliveira da Costa, Luzia Kalyne Almeida Moreira Leal, Silvânia Maria Mendes de Vasconcelos, Kelly Rose Tavares Neves, Glauce Socorro de Barros Viana
Ketamine (KET), a NMDA antagonist, exerts an antidepressant effect at subanaesthetic doses and possesses analgesic and anti-inflammatory activities. We evaluated the involvement of KET antinociceptive and anti-inflammatory effects with its antidepressant action. Male Swiss mice were subjected to formalin, carrageenan-induced paw oedema and forced swimming tests, for assessing antinociceptive, anti-inflammatory and antidepressant effects. The treatment groups were as follows: control, KET (2, 5 and 10 mg/kg), lithium (LI: 5 mg/kg) and KET2 + LI5 combination...
December 2016: Basic & Clinical Pharmacology & Toxicology
Anne S Jacoby, Klaus Munkholm, Maj Vinberg, Helena Gp Joaquim, Leda L Talib, Wagner F Gattaz, Lars V Kessing
OBJECTIVES: The enzyme glycogen synthase kinase-3β (GSK3β) is involved in the mechanisms of action of lithium and may play a role in relation to affective states in bipolar disorder. The objectives of the present study were to compare the activity of GSK-3β (measured as levels of phosphorylated GSK-3β [p-GSK-3β]) between patients with bipolar disorder in the euthymic state and healthy control subjects, and to investigate whether GSK-3β activity varies with affective states in patients with bipolar I disorder...
June 2016: Bipolar Disorders
Yuichi Uwai, Tatsuya Kawasaki, Tomohiro Nabekura
Lithium, which is used in the treatment of and prophylaxis for bipolar disease, inhibits glycogen synthase kinase-3β (GSK3β) by producing its phosphorylated form (p-GSK3β). GSK3β plays a role in apoptosis and some kinds of acute kidney injuries, and the formation of p-GSK3β is considered to contribute to protection against acute kidney injury. We previously reported that the sodium-phosphate cotransporter NaPi-IIa (SLC34A1) mediated the reabsorption of lithium in the rat kidney. In the present study, the phosphorylation status of GSK3β in the kidney cortex of rats administered lithium chloride and foscarnet, a typical inhibitor of NaPi-IIa, was examined using Western blotting...
June 2016: Drug Metabolism and Pharmacokinetics
Yong-Xia Li, Yun Huang, Song Liu, Yan Mao, Cheng-Yan Yuan, Xiao Yang, Li-Jun Yao
AIM: Glycogen synthase kinase 3 (GSK3) regulates urine concentration by mediating the vasopressin-induced aquaporin 2 expression and water permeability, although it is unknown whether GSK3 also mediates the accumulation of the urea transporter A1 (UT-A1). The aim of this study is to investigate the effect of GSK3 on UT-A1 distribution. METHODS: Mouse inner medullary collecting duct 3 cells were transfected with UT-A1-GFP construct. The stable transfected cells were cultured under hypertonic conditions, treated with GSK3 inhibitor lithium chloride, GSK3 activator, lysosome or proteasome inhibitor...
2016: Nephron
Hong Chen, Abul Fajol, Miriam Hoene, Bingbing Zhang, Erwin D Schleicher, Yun Lin, Carsten Calaminus, Bernd J Pichler, Cora Weigert, Hans U Häring, Florian Lang, Michael Föller
Metabolic syndrome is characterized by insulin resistance, obesity, and dyslipidemia. It is the consequence of an imbalance between caloric intake and energy consumption. Adiponectin protects against metabolic syndrome. Insulin-induced signaling includes activation of PI3 kinase and protein kinase B (PKB)/Akt. PKB/Akt in turn inactivates glycogen synthase kinase (GSK) 3, a major regulator of metabolism. Here, we studied the significance of PI3K-dependent GSK3 inactivation for adiponectin formation in diet-induced metabolic syndrome...
May 17, 2016: Proceedings of the National Academy of Sciences of the United States of America
Florence F Wagner, Joshua A Bishop, Jennifer P Gale, Xi Shi, Michelle Walk, Joshua Ketterman, Debasis Patnaik, Doug Barker, Deepika Walpita, Arthur J Campbell, Shannon Nguyen, Michael Lewis, Linda Ross, Michel Weïwer, W Frank An, Andrew R Germain, Partha P Nag, Shailesh Metkar, Taner Kaya, Sivaraman Dandapani, David E Olson, Anne-Laure Barbe, Fanny Lazzaro, Joshua R Sacher, Jaime H Cheah, David Fei, Jose Perez, Benito Munoz, Michelle Palmer, Kimberly Stegmaier, Stuart L Schreiber, Edward Scolnick, Yan-Ling Zhang, Stephen J Haggarty, Edward B Holson, Jen Q Pan
The mood stabilizer lithium, the first-line treatment for bipolar disorder, is hypothesized to exert its effects through direct inhibition of glycogen synthase kinase 3 (GSK3) and indirectly by increasing GSK3's inhibitory serine phosphorylation. GSK3 comprises two highly similar paralogs, GSK3α and GSK3β, which are key regulatory kinases in the canonical Wnt pathway. GSK3 stands as a nodal target within this pathway and is an attractive therapeutic target for multiple indications. Despite being an active field of research for the past 20 years, many GSK3 inhibitors demonstrate either poor to moderate selectivity versus the broader human kinome or physicochemical properties unsuitable for use in in vitro systems or in vivo models...
July 15, 2016: ACS Chemical Biology
Jorge Iván Castillo-Quan, Li Li, Kerri J Kinghorn, Dobril K Ivanov, Luke S Tain, Cathy Slack, Fiona Kerr, Tobias Nespital, Janet Thornton, John Hardy, Ivana Bjedov, Linda Partridge
The quest to extend healthspan via pharmacological means is becoming increasingly urgent, both from a health and economic perspective. Here we show that lithium, a drug approved for human use, promotes longevity and healthspan. We demonstrate that lithium extends lifespan in female and male Drosophila, when administered throughout adulthood or only later in life. The life-extending mechanism involves the inhibition of glycogen synthase kinase-3 (GSK-3) and activation of the transcription factor nuclear factor erythroid 2-related factor (NRF-2)...
April 19, 2016: Cell Reports
Alexander L Houck, Félix Hernández, Jesús Ávila
Tau proteins play a role in the stabilization of microtubules, but in pathological conditions, tauopathies, tau is modified by phosphorylation and can aggregate into aberrant aggregates. These aggregates could be toxic to cells, and different cell models have been used to test for compounds that might prevent these tau modifications. Here, we have used a cell model involving the overexpression of human tau in human embryonic kidney 293 cells. In human embryonic kidney 293 cells expressing tau in a stable manner, we have been able to replicate the phosphorylation of intracellular tau...
2016: Journal of Experimental Neuroscience
Lijun Gan, Hong Wu, Dapeng Wu, Zhanfang Zhang, Zhengfei Guo, Na Yang, Kai Xia, Xie Zhou, Keimei Oh, Makoto Matsuoka, Denny Ng, Changhua Zhu
Lamina joint inclination or leaf angle (the angle between the leaf blade and vertical culm) is a major trait of rice plant architecture. The plant hormone brassinosteroid (BR) is the main regulator of this trait, while other plant hormones, including ethylene, gibberellin, and auxin, also influence leaf angle. In this study, we found that methyl jasmonate (MeJA) also participates in regulating lamina joint inclination. MeJA decreased lamina joint inclination and inhibited the BR-induced increase in lamina joint inclination...
December 2015: Plant Science: An International Journal of Experimental Plant Biology
S Suhaini, S Z Liew, J Norhaniza, P C Lee, G Jualang, N Embi, M S Hasidah
Gleichenia truncata is a highland fern from the Gleicheniaceae family known for its traditional use among indigenous communities in Asia to treat fever. The scientific basis of its effect has yet to be documented. A yeast-based kinase assay conducted in our laboratory revealed that crude methanolic extract (CME) of G. truncata exhibited glycogen synthase kinase-3 (GSK3)-inhibitory activity. GSK3β is now recognized to have a pivotal role in the regulation of inflammatory response during bacterial infections...
September 2015: Tropical Biomedicine
Serena Guidotti, Manuela Minguzzi, Daniela Platano, Luca Cattini, Giovanni Trisolino, Erminia Mariani, Rosa Maria Borzì
INTRODUCTION: Recent evidence suggests that GSK3 activity is chondroprotective in osteoarthritis (OA), but at the same time, its inactivation has been proposed as an anti-inflammatory therapeutic option. Here we evaluated the extent of GSK3β inactivation in vivo in OA knee cartilage and the molecular events downstream GSK3β inactivation in vitro to assess their contribution to cell senescence and hypertrophy. METHODS: In vivo level of phosphorylated GSK3β was analyzed in cartilage and oxidative damage was assessed by 8-oxo-deoxyguanosine staining...
2015: PloS One
Xunxian Liu, Xinyue Lu, Kaimei Song, Marc R Blackman
Belonging to the PLIN family, PLIN2 associates with lipid storage droplets (LSDs), but other functions of PLIN2 remain unclear. Here, we suggest that PLIN2 mediates Wnt signaling because PLIN2 small interfering RNA (siRNA) suppresses activation of Wnt/coreceptor pathways. The mediation in the Wnt/Frizzled pathway seems to occur from Dishevelleds to axin/glycogen synthase kinase 3(GSK3)/β-catenin complexes (AGβC) as Wnt decreases Dishevelled/PLIN2 but increases AGβC/PLIN2 associations. Augmenting cellular LSDs that affect PLIN2 associations with these proteins, oleic acid (OA) treatment inhibits Wnt-increased AGβC/PLIN2 associations and β-catenin T-cell factor signaling (β-CTS)...
November 23, 2015: Molecular and Cellular Biology
Maria Antonietta Ajmone-Cat, Maria Cristina D'Urso, Giorgia di Blasio, Maria Stefania Brignone, Roberta De Simone, Luisa Minghetti
Repeated stimulation of TLR4 signaling by lipopolysaccharide (LPS) in microglia induces a state of tolerance/sensitization consisting in the reprogramming of the expression of pro-inflammatory genes in favor of anti-inflammatory ones. The molecular mechanisms underlying this adaptive response are far to be elucidated. Glycogen synthase kinase 3 (GSK3) has emerged as crucial regulator of TLR signaling, mediating the balance between pro- and anti-inflammatory functions in both periphery and central nervous system...
July 2016: Brain, Behavior, and Immunity
Thomas Del' Guidice, Jean-Martin Beaulieu
Mood stabilizers are a heterogeneous class of drugs having antidepressant and anti-manic effects in bipolar disorders, depression and schizophrenia. Despite wide clinical applications, the mechanisms underlying their shared actions and therapeutic specificity are unknown. Here, we examine the effects of the structurally unrelated mood stabilizers lamotrigine, lithium and valproate on G protein and beta-arrestin-dependent components of dopamine D2 receptor signaling and assess their contribution to the behavioral effects of these drugs...
June 2015: Journal of Receptor and Signal Transduction Research
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