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GSK3 AND Aging

Xunxian Liu, Zemin Yao
Loss of cellular response to hormonal regulation in maintaining metabolic homeostasis is common in the process of aging. Chronic over-nutrition may render cells insensitive to such a hormonal regulation owing to overstimulation of certain signaling pathways, thus accelerating aging and causing diseases. The glycogen synthase kinase 3 (GSK3) plays a pivotal role in relaying various extracellular and intracellular regulatory signals critical to cell growth, survival, regeneration, or death. The main signaling pathway regulating GSK3 activity through serine-phosphorylation is the phosphoinositide 3-kinase (PI3K)/phosphoinositide-dependent kinase-1 (PDK1)/Akt relay that catalyzes serine-phosphorylation and thus inactivation of GSK3...
2016: Nutrition & Metabolism
Yini Zhang, Zhao Zhang, Haitang Wang, Nan Cai, Shuang Zhou, Yaoping Zhao, Xue Chen, Shaoqiang Zheng, Qi Si, Wei Zhang
Ginsenoside Rg1 is the primary active substance in ginseng, and it has multiple pharmacological actions. Investigations on the pharmacologic action of ginsenoside Rg1 have developed, with a particular focus on the regulation of metabolism. The present study hypothesized that the neuroprotective effects of ginsenoside Rg1 prevent cognitive impairment induced by isoflurane anesthesia via antioxidant, anti‑inflammatory and anti‑apoptotic effects, mediated by the phosphoinositide 3‑kinase (PI3K)/AKT/glycogen synthase kinase‑3β (GSK‑3β) pathway in aged rats...
September 2016: Molecular Medicine Reports
Bo Xing, Yan-Chun Li, Wen-Jun Gao
Schizophrenia (SZ) is a neurodevelopmental disorder in which the emergence of cognitive symptoms occurs during early adolescence. Glycogen synthase kinase-3β (GSK3β) plays a critical role in synaptic plasticity during development and is highly implicated in the etiology of SZ. However, how GSK3β activity affects synaptic plasticity and working memory function in the prefrontal cortex (PFC) during development remains unknown. Here we show a GSK3β hyperactivity during the early postnatal period in a neurodevelopmental rat SZ model that receives gestational exposure (E17) to the neurotoxin, methylazoxymethanol (MAM)...
June 29, 2016: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
Benjamin Kolisnyk, Mohammed Al-Onaizi, Lilach Soreq, Shahar Barbash, Uriya Bekenstein, Nejc Haberman, Geula Hanin, Maxine T Kish, Jussemara Souza da Silva, Margaret Fahnestock, Jernej Ule, Hermona Soreq, Vania F Prado, Marco A M Prado
The relationship between long-term cholinergic dysfunction and risk of developing dementia is poorly understood. Here we used mice with deletion of the vesicular acetylcholine transporter (VAChT) in the forebrain to model cholinergic abnormalities observed in dementia. Whole-genome RNA sequencing of hippocampal samples revealed that cholinergic failure causes changes in RNA metabolism. Remarkably, key transcripts related to Alzheimer's disease are affected. BACE1, for instance, shows abnormal splicing caused by decreased expression of the splicing regulator hnRNPA2/B1...
June 16, 2016: Cerebral Cortex
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
Carolina S Martinez, Verónica G Piazza, Lorena González, Yimin Fang, Andrzej Bartke, Danie Turynl, Johanna G Miquet, Ana I Sotelo
Growth hormone (GH) is a pleiotropic hormone that triggers STATs, ERK1/2 and Akt signaling, related to cell growth and proliferation. Transgenic mice overexpressing GH present increased body size, with a disproportionate liver enlargement due to hypertrophy and hyperplasia of the hepatocytes. We had described enhanced mitogenic signaling in liver of young adult transgenic mice. We now evaluate the activation of these signaling cascades during the growth period and relate them to the morphological alterations found...
2016: Cell Cycle
Amal Houssaini, Shariq Abid, Geneviève Derumeaux, Feng Wan, Aurélien Parpaleix, Dominique Rideau, Elisabeth Marcos, Kanny Kebe, Gabor Czibik, Daigo Sawaki, Caroline Treins, Jean-Luc Dubois-Randé, Zhenlin Li, Valérie Amsellem, Larissa Lipskaia, Mario Pende, Serge Adnot
Constitutive activation of the mammalian target of rapamycin (mTOR) complexes mTORC1 and mTORC2 is associated with pulmonary hypertension (PH) and sustained growth of pulmonary artery (PA) smooth muscle cells (SMCs). We investigated whether selective mTORC1 activation in SMCs induced by deleting the negative mTORC1 regulator tuberous sclerosis complex 1 gene (TSC1) was sufficient to produce PH in mice. Mice expressing Cre recombinase under SM22 promoter control were crossed with TSC1(LoxP/LoxP) mice to generate SM22-TSC1(-/-) mice...
September 2016: American Journal of Respiratory Cell and Molecular Biology
Himanshu K Mishra, Iryna Prots, Steven Havlicek, Zacharias Kohl, Francesc Perez-Branguli, Tom Boerstler, Lukas Anneser, Georgia Minakaki, Holger Wend, Martin Hampl, Marina Leone, Martina Brückner, Jochen Klucken, Andre Reis, Leah Boyer, Gerhard Schuierer, Jürgen Behrens, Angelika Lampert, Felix B Engel, Fred H Gage, Jürgen Winkler, Beate Winner
OBJECTIVE: Mutations in the Spastic Paraplegia Gene11 (SPG11), encoding spatacsin, cause the most frequent form of autosomal recessive (AR) complex hereditary spastic paraplegia (HSP) and juvenile onset amyotrophic lateral sclerosis (ALS5). When SPG11 is mutated, patients frequently present with spastic paraparesis, a thin corpus callosum, and cognitive impairment. We previously delineated a neurodegenerative phenotype in neurons of these patients. In the current study, we recapitulated early developmental phenotypes of SPG11 and outlined their cellular and molecular mechanisms in patient-specific induced pluripotent stem cell (iPSC) derived cortical neural progenitor cells (NPCs)...
March 11, 2016: Annals of Neurology
N Slutsky, M Vatarescu, Y Haim, N Goldstein, B Kirshtein, I Harman-Boehm, Y Gepner, I Shai, N Bashan, M Blüher, A Rudich
BACKGROUND/OBJECTIVES: Adipose tissue (AT) autophagy gene expression is elevated in human obesity, correlating with increased metabolic risk, but mechanistic links between the two remain unclear. Thus, the objective of this study was to assess whether elevated autophagy may cause AT endocrine dysfunction, emphasizing the putative role of adiponectin in fat-liver endocrine communication. SUBJECTS/METHODS: We utilized a large (N=186) human AT biobank to assess clinical associations between human visceral AT autophagy genes, adiponectin and leptin, by multivariate models...
June 2016: International Journal of Obesity: Journal of the International Association for the Study of Obesity
Abul Fajol, Hong Chen, Anja T Umbach, L Darryl Quarles, Florian Lang, Michael Föller
Glycogen synthase kinase (GSK)-3 is a ubiquitously expressed kinase inhibited by insulin-dependent Akt/PKB/SGK. Mice expressing Akt/PKB/SGK-resistant GSK3α/GSK3β (gsk3(KI)) exhibit enhanced sympathetic nervous activity and phosphaturia with decreased bone density. Hormones participating in phosphate homeostasis include fibroblast growth factor (FGF)-23, a bone-derived hormone that inhibits 1,25-dihydroxyvitamin D3 (1,25(OH)2D3; calcitriol) formation and phosphate reabsorption in the kidney and counteracts vascular calcification and aging...
February 2016: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Clarissa B Haas, Eduardo Kalinine, Eduardo R Zimmer, Gisele Hansel, Andressa W Brochier, Jean P Oses, Luis V Portela, Alexandre P Muller
Aging is a major risk factor for cognitive deficits and neurodegenerative disorders, and impaired brain insulin receptor (IR) signaling is mechanistically linked to these abnormalities. The main goal of this study was to investigate whether brain insulin infusions improve spatial memory in aged and young rats. Aged (24 months) and young (4 months) male Wistar rats were intracerebroventricularly injected with insulin (20 mU) or vehicle for five consecutive days. The animals were then assessed for spatial memory using a Morris water maze...
October 26, 2015: Molecular Neurobiology
Xiao-Yong Man, Xi-Bei Chen, Wei Li, Lilla Landeck, Ting-Ting Dou, Jia-Qi Chen, Jiong Zhou, Sui-Qing Cai, Min Zheng
Psoriasis is similar to endpoints of epithelial-mesenchymal transition (EMT), a process of epithelial cells transformed into fibroblast-like cells. The molecular epithelial and mesenchymal markers were analysed in psoriatic keratinocytes. No obvious alteration of epithelial markers E-cadherin (E-cad), keratin 10 (K10), K14 and K16 was detected in psoriatic keratinocytes. However, significantly increased expression of Vim, FN, plasminogen activator inhibitor 1 (PAI-1) and Slug was seen. IL-17A and IL-13 at 50 ng ml(-1) strongly decreased expression of K10, Vim and FN...
August 2015: Open Biology
Jemeen Sreedharan, Lukas J Neukomm, Robert H Brown, Marc R Freeman
The RNA-processing protein TDP-43 is central to the pathogenesis of amyotrophic lateral sclerosis (ALS), the most common adult-onset motor neuron (MN) disease. TDP-43 is conserved in Drosophila, where it has been the topic of considerable study, but how TDP-43 mutations lead to age-dependent neurodegeneration is unclear and most approaches have not directly examined changes in MN morphology with age. We used a mosaic approach to study age-dependent MN loss in the adult fly leg where it is possible to resolve single motor axons, NMJs and active zones, and perform rapid forward genetic screens...
August 17, 2015: Current Biology: CB
Timothy J Hohman, Lori Chibnik, William S Bush, Angela L Jefferson, Phillip L De Jaeger, Tricia A Thornton-Wells, David A Bennett, Julie A Schneider
Glyocogen synthase kinase 3 (GSK3) plays an important role in the pathophysiology of Alzheimer's disease (AD) through the phosphorylation of tau. Recent work has suggested that GSK3β also plays a role in the amyloid pathway of AD through genetic interactions with APP and APBB2 on in vivo measures of amyloid. This project extends the previously identified genotype interactions to an autopsy measure of amyloid, while also testing the same interactions leveraging gene expression data quantified in the prefrontal cortex...
October 2015: Neurotoxicity Research
Nagesha Guthalu Kondegowda, Rafael Fenutria, Ilana R Pollack, Michael Orthofer, Adolfo Garcia-Ocaña, Josef M Penninger, Rupangi C Vasavada
Diabetes results from a reduction of pancreatic β-cells. Stimulating replication could normalize β-cell mass. However, adult human β-cells are recalcitrant to proliferation. We identified osteoprotegerin, a bone-related decoy receptor, as a β-cell mitogen. Osteoprotegerin was induced by and required for lactogen-mediated rodent β-cell replication. Osteoprotegerin enhanced β-cell proliferation in young, aged, and diabetic mice. This resulted in increased β-cell mass in young mice and significantly delayed hyperglycemia in diabetic mice...
July 7, 2015: Cell Metabolism
Christian Griñan-Ferré, David Pérez-Cáceres, Sofía Martínez Gutiérrez-Zetina, Antoni Camins, Verónica Palomera-Avalos, Daniel Ortuño-Sahagún, M Teresa Rodrigo, M Pallàs
The environment in which organisms live can greatly influence their development. Consequently, environmental enrichment (EE) is progressively recognized as an important component in the improvement of brain function and development. It has been demonstrated that rodents raised under EE conditions exhibit favorable neuroanatomical effects that improve their learning, spatial memory, and behavioral performance. Here, by using senescence-accelerated prone mice (SAMP8) and these as a model of adverse genetic conditions for brain development, we determined the effect of EE by raising these mice during early life under favorable conditions...
May 2016: Molecular Neurobiology
Andrew N Clarkson, Kim Parker, Michael Nilsson, F Rohan Walker, Emma K Gowing
Cerebral ischemia results in damage to neuronal circuits and lasting impairment in function. We have previously reported that stimulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors with the ampakine, CX1837, increases brain-derived neurotrophic factor (BDNF) levels and affords significant motor recovery after stroke in young mice. Here, we investigated whether administration of CX1837 in aged (24 months old) mice was equally effective. In a model of focal ischemia, administration of CX1837 from 5 days after stroke resulted in a small gain of motor function by week 6 after stroke...
August 2015: Journal of Cerebral Blood Flow and Metabolism
Kwangsik Nho, Vijay K Ramanan, Emrin Horgusluoglu, Sungeun Kim, Mark H Inlow, Shannon L Risacher, Brenna C McDonald, Martin R Farlow, Tatiana M Foroud, Sujuan Gao, Christopher M Callahan, Hugh C Hendrie, Alexander B Niculescu, Andrew J Saykin
Depressive symptoms are common in older adults and are particularly prevalent in those with or at elevated risk for dementia. Although the heritability of depression is estimated to be substantial, single nucleotide polymorphism-based genome-wide association studies of depressive symptoms have had limited success. In this study, we performed genome-wide gene- and pathway-based analyses of depressive symptom burden. Study participants included non-Hispanic Caucasian subjects (n = 6,884) from three independent cohorts, the Alzheimer's Disease Neuroimaging Initiative (ADNI), the Health and Retirement Study (HRS), and the Indiana Memory and Aging Study (IMAS)...
2015: Journal of Alzheimer's Disease: JAD
Lion Shahab, Florian Plattner, Elaine E Irvine, Damian M Cummings, Frances A Edwards
Glycogen synthase kinase-3 (GSK3), particularly the isoform GSK3β, has been implicated in a wide range of physiological systems and neurological disorders including Alzheimer's Disease. However, the functional importance of GSK3α has been largely untested. The multifunctionality of GSK3 limits its potential as a drug target because of inevitable side effects. Due to its greater expression in the CNS, GSK3β rather than GSK3α has also been assumed to be of primary importance in synaptic plasticity. Here, we investigate bidirectional long-term synaptic plasticity in knockin mice with a point mutation in GSK3α or GSK3β that prevents their inhibitory regulation...
December 2014: Hippocampus
Franc Llorens, Saima Zafar, Belén Ansoleaga, Mohsin Shafiq, Rosi Blanco, Marga Carmona, Oriol Grau-Rivera, Carlos Nos, Ellen Gelpí, José Antonio Del Río, Inga Zerr, Isidre Ferrer
AIMS: Creutzfeldt-Jakob disease (CJD) is a rapid progressive neurological disease leading to dementia and death. Prion biomarkers are altered in the cerebrospinal fluid (CSF) of CJD patients, but the pathogenic mechanisms underlying these alterations are still unknown. The present study examined prion biomarker levels in the brain and CSF of sporadic CJD (sCJD) cases and their correlation with neuropathological lesion profiles. METHODS: The expression levels of 14-3-3, Tau, phospho-Tau and α-synuclein were measured in the CSF and brain of sCJD cases in a subtype- and region-specific manner...
August 2015: Neuropathology and Applied Neurobiology
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