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https://www.readbyqxmd.com/read/28648896/inhibition-of-cdk5-alleviates-the-cardiac-phenotypes-in-timothy-syndrome
#1
LouJin Song, Seon-Hye E Park, Yehuda Isseroff, Kumi Morikawa, Masayuki Yazawa
L-type calcium channel CaV1.2 plays an essential role in cardiac function. The gain-of-function mutations in CaV1.2 have been reported to be associated with Timothy syndrome, a disease characterized by QT prolongation and syndactyly. Previously we demonstrated that roscovitine, a cyclin-dependent kinase (CDK) inhibitor, could rescue the phenotypes in induced pluripotent stem cell-derived cardiomyocytes from Timothy syndrome patients. However, exactly how roscovitine rescued the phenotypes remained unclear. Here we report a mechanism potentially underlying the therapeutic effects of roscovitine on Timothy syndrome cardiomyocytes...
June 21, 2017: Stem Cell Reports
https://www.readbyqxmd.com/read/28646794/dexibuprofen-prevents-neurodegeneration-and-cognitive-decline-in-appswe-ps1de9-through-multiple-signaling-pathways
#2
Miren Ettcheto, Elena Sánchez-López, Laura Pons, Oriol Busquets, Jordi Olloquequi, Carlos Beas-Zarate, Merce Pallas, Maria Luisa García, Carme Auladell, Jaume Folch, Antoni Camins
The aim of the present study is to elucidate the neuronal pathways associated to NSAIDs causing a reduction of the risk and progression of Alzheimer's disease. The research was developed administering the active enantiomer of ibuprofen, dexibuprofen (DXI), in order to reduce associated gastric toxicity. DXI was administered from three to six-month-old female APPswe/PS1dE9 mice as a model of familial Alzheimer's disease. DXI treatment reduced the activation of glial cells and the cytokine release involved in the neurodegenerative process, especially TNFα...
June 15, 2017: Redox Biology
https://www.readbyqxmd.com/read/28641077/inhibition-of-early-growth-response-1-in-the-hippocampus-alleviates-neuropathology-and-improves-cognition-in-an-alzheimer-model-with-plaques-and-tangles
#3
Xike Qin, Yunling Wang, Hemant K Paudel
A sporadic form of Alzheimer disease (AD) and vascular dementia share many risk factors, and their pathogenic mechanisms are suggested to be related. Transcription factor early growth response 1 (Egr-1) regulates various vascular pathologies and is up-regulated in both AD brains and AD mouse models; however, its role in AD pathogenesis is unclear. Herein, we report that silencing of Egr-1 in the hippocampus by shRNA reduces tau phosphorylation, amyloid-β (Aβ) pathology, and improves cognition in the 3xTg-AD mouse model...
June 19, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28640256/microrna-26a-cyclin-dependent-kinase-5-axis-controls-proliferation-apoptosis-and-in-vivo-tumor-growth-of-diffuse-large-b-cell-lymphoma-cell-lines
#4
Floriana Maria Farina, Alessandra Inguscio, Paolo Kunderfranco, Alice Cortesi, Leonardo Elia, Manuela Quintavalle
Diffuse large B-cell lymphoma (DLBCL) is the most frequent type of non-Hodgkin lymphoma. Despite a favorable therapeutic response to first-line chemo-immunotherapy, still 30-40% of patients is refractory, or relapse after this treatment. Thus, alternative strategies must be sought. Previous studies have indicated that cyclin-dependent kinase 5 (CDK5), a serine/threonine protein kinase, is involved in tumor development and progression, and it may represent a potential therapeutic target. However, its role in modulating DLBCL growth and progression remains largely unexplored...
June 22, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28639593/synaptic-roles-of-cyclin-dependent-kinase-5-its-implications-in-epilepsy
#5
REVIEW
Aparna Banerjee Dixit, Jyotirmoy Banerjee, Manjari Tripathi, Chitra Sarkar, P Sarat Chandra
There is an urgent need to understand the molecular mechanisms underlying epilepsy to find novel prognostic/diagnostic biomarkers to prevent epilepsy patients at risk. Cyclin-dependent kinase 5 (CDK5) is involved in multiple neuronal functions and plays a crucial role in maintaining homeostatic synaptic plasticity by regulating intracellular signalling cascades at synapses. CDK5 deregulation is shown to be associated with various neurodegenerative diseases such as Alzheimer's disease. The association between chronic loss of CDK5 and seizures has been reported in animal models of epilepsy...
February 2017: Indian Journal of Medical Research
https://www.readbyqxmd.com/read/28637871/phosphorylation-at-serine-31-targets-tyrosine-hydroxylase-to-vesicles-for-transport-along-microtubules
#6
Ana Jorge-Finnigan, Rune Kleppe, Kunwar Jung-Kc, Ming Ying, Michael Marie, Ivan Rios-Mondragon, Michael F Salvatore, Jaakko Saraste, Aurora Martinez
Tyrosine hydroxylase (TH) catalyzes the conversion of L-tyrosine into L-Dopa, which is the rate-limiting step in the synthesis of catecholamines, particularly dopamine in dopaminergergic neurons. Low dopamine levels and death of the dopaminergic neurons are hallmarks of Parkinson's disease (PD), where α-synuclein is also a key player. TH is highly regulated, notably by phosphorylation of several Ser/Thr residues in the N-terminal tail. However, the functional role of TH phosphorylation at the Ser31 site (THpSer31) remains unclear...
June 21, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28637746/early-protection-to-stress-mediated-by-cdk-dependent-pi3-5p2-signaling-from-the-vacuole-lysosome
#7
Natsuko Jin, Yui Jin, Lois S Weisman
Adaptation to environmental stress is critical for cell survival. Adaptation generally occurs via changes in transcription and translation. However, there is a time lag before changes in gene expression, which suggests that more rapid mechanisms likely exist. In this study, we show that in yeast, the cyclin-dependent kinase Pho85/CDK5 provides protection against hyperosmotic stress and acts before long-term adaptation provided by Hog1. This protection requires the vacuolar/endolysosomal signaling lipid PI3,5P2 We show that Pho85/CDK5 directly phosphorylates and positively regulates the PI3P-5 kinase Fab1/PIKfyve complex and provide evidence that this regulation is conserved in mammalian cells...
June 21, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28634862/effect-of-gapt-extract-on-expression-of-tau-protein-and-its-phosphorylation-related-enzymes-in-hippocampal-neurons-of-appv717i-transgenic-mice
#8
Jing-Nian Ni, Jing Shi, Xue-Kai Zhang, Yi-Chang Yang, Xiao-Meng Liu, Ming-Qing Wei, Ting Li, Peng-Wen Wang, Jin-Zhou Tian, Yong-Yan Wang
OBJECTIVE: To investigate the effect of GAPT, an extract mixture from Radix Ginseng, Rhizoma Acor tatarinowii, Radix Polygalae and Radix Curcuma (containing ingredient of turmeric), etc. on expression of tau protein and its phosphorylation related enzyme in hippocampal neurons of APPV717I transgenic mice. METHODS: Sixty three-month-old APPV717I transgenic mice were randomly divided into model group, donepezil group [0.92 mg/(kg d)], the low, medium and high dosage of GAPT groups [0...
June 20, 2017: Chinese Journal of Integrative Medicine
https://www.readbyqxmd.com/read/28627448/opiate-exposure-state-controls-dopamine-d3-receptor-and-cdk5-calcineurin-signaling-in-the-basolateral-amygdala-during-reward-and-withdrawal-aversion-memory-formation
#9
Laura G Rosen, Walter J Rushlow, Steven R Laviolette
The dopamine (DA) D3 receptor (D3R) is highly expressed in the basolateral nucleus of the amygdala (BLA), a neural region critical for processing opiate-related reward and withdrawal aversion-related memories. Functionally, D3R transmission is linked to downstream Cdk5 and calcineurin signaling, both of which regulate D3R activity states and play critical roles in memory-related synaptic plasticity. Previous evidence links D3R transmission to opiate-related memory processing, however little is known regarding how chronic opiate exposure may alter D3R-dependent memory mechanisms...
June 14, 2017: Progress in Neuro-psychopharmacology & Biological Psychiatry
https://www.readbyqxmd.com/read/28595035/n-methyl-d-aspartate-receptors-mediate-epilepsy-induced-axonal-impairment-and-tau-phosphorylation-via-activating-glycogen-synthase-kinase-3%C3%AE-and-cyclin-dependent-kinase-5
#10
Xi Liu, Shu Ou, Maojia Yin, Tao Xu, Teng Wang, Ying Liu, Xueying Ding, Xinyuan Yu, Jinxian Yuan, Hao Huang, Xiuhang Zhang, Xinjie Tan, Lifen Chen, Yangmei Chen
The mechanism of epilepsy-induced axonal impairment is poorly understood. N-methyl-D-aspartate receptors (NMDARs) play important roles in epilepsy and mediate structural and functional axonal impairment. GSK-3β and Cdk5 affect axons and are regulated by NMDARs, while their roles in epilepsy-induced axonal impairment are unclear. We demonstrated that axonal impairment is characterized by neurofilament heavy (NFH) reduction, amyloid precursor protein (APP) accumulation, and increased tau phosphorylation accompanied by a decrease of total tau in temporal lobe epilepsy (TLE) patients and pentylenetetrazol (PTZ)-kindled rats...
April 2017: Discovery Medicine
https://www.readbyqxmd.com/read/28589675/cdk5-activity-is-required-for-purkinje-cell-dendritic-growth-in-cell-autonomous-and-non-cell-autonomous-manners
#11
Bozong Xu, Ayumi Kumazawa, Shunsuke Kobayashi, Shin-Ichi Hisanaga, Takafumi Inoue, Toshio Ohshima
Cyclin-dependent kinase 5 (Cdk5) is recognized as a unique member among other Cdks due to its versatile roles in many biochemical processes in the nervous system. The proper development of neuronal dendrites is required for the formation of complex neural networks providing the physiological basis of various neuronal functions. We previously reported that sparse dendrites were observed on cultured Cdk5-null Purkinje cells and Purkinje cells in Wnt1(cre) -mediated Cdk5 conditional knockout (KO) mice. In the present study, we generated L7(cre) -mediated p35; p39 double KO (L7(cre) -p35(f/f) ; p39(-/-) ) mice whose Cdk5 activity was eliminated specifically in Purkinje cells of the developing cerebellum...
June 7, 2017: Developmental Neurobiology
https://www.readbyqxmd.com/read/28583208/mir199a-3p-regulates-p53-by-targeting-cables1-in-mouse-cardiac-c-kit-cells-to-promote-proliferation-and-inhibit-apoptosis-through-a-negative-feedback-loop
#12
Jingjin Liu, Yongshun Wang, Jinjin Cui, Meng Sun, Zhongyue Pu, Chao Wang, Wenjuan Du, Xinxin Liu, Jian Wu, Jingbo Hou, Shuo Zhang, Bo Yu
BACKGROUND: MicroRNAs (miRNAs) have emerged as crucial factors that regulate proliferation and apoptosis of cardiac c-kit(+) cells. Although much is known about their role in maintaining cardiac c-kit(+) cell pluripotency, the mechanisms by which they affect cell fate decisions that are an essential part of the repair of heart failure remain poorly understood. METHODS: Cardiac c-kit(+) cells were obtained from Balb/c mice and cultured in vitro. Lentiviral vectors of miR199a-3p, its corresponding anti-miRNA, or short hairpin RNA against Cables1 were transfected into cells...
June 5, 2017: Stem Cell Research & Therapy
https://www.readbyqxmd.com/read/28580384/genetic-risk-score-based-on-the-prevalence-of-vertebral-fracture-in-japanese-women-with-osteoporosis
#13
Heying Zhou, Seijiro Mori, Tatsuro Ishizaki, Atsushi Takahashi, Koichi Matsuda, Yukihiro Koretsune, Shiro Minami, Masahiko Higashiyama, Shinji Imai, Kozo Yoshimori, Minoru Doita, Akira Yamada, Satoshi Nagayama, Kazuo Kaneko, Satoshi Asai, Masaki Shiono, Michiaki Kubo, Hideki Ito
A genetic risk score (GRS) was developed for predicting fracture risk based on the prevalence of vertebral fractures in 441 Japanese females with osteoporosis. A total of 979 (858 nonsynonymous and 121 silent) single-nucleotide polymorphisms (SNPs) located in 74 osteoporosis-susceptibility genes were genotyped and evaluated for their association with fracture prevalence. Four SNPs (protein kinase domain containing, cytoplasmic [PKDCC; rs4952590], CDK5-regulatory subunit-associated protein 1-like 1 [CDKAL1; rs4712556], wingless-type MMTV-integration site family member 16 [WNT16; rs2707466], and G-patch domain-containing gene 1 [GPATCH1; rs10416265]) showed a significant association (p < 0...
December 2016: Bone Reports
https://www.readbyqxmd.com/read/28559121/calpain-2-p35-p25-cdk5-pathway-is-involved-in-the-neuronal-apoptosis-induced-by-polybrominated-diphenyl-ether-153
#14
Hongmei Zhang, Lijun Chang, Huajun Zhang, Jisheng Nie, Zhihong Zhang, Xiaorong Yang, Ann M Vuong, Zemin Wang, Aimin Chen, Qiao Niu
Polybrominated diphenyl ethers (PBDEs) have been demonstrated to induce neurotoxicity in experimental rats and mice, with neuronal apoptosis as one of the major mechanisms, however, the mechanisms underlying PBDEs-induced neuronal apoptosis remain unclear. In this study, we aimed to investigate the role of calpain/p35-p25/Cdk5 pathway in BDE-153-induced neuronal apoptosis in the hippocampus and primary neurons in rats. Results showed that compared to the controls, neuronal apoptosis was significantly increased in vivo and ex vivo, as manifested by the increased hippocampus TUNEL-positive cell rates, apoptotic neurons in Hoechst and AO/EB staining, and the increased LDH activity and percentage of Annexin V-positive cells in rat hippocampus and primary neurons...
May 27, 2017: Toxicology Letters
https://www.readbyqxmd.com/read/28553339/tibolone-modulates-neuronal-plasticity-through-regulating-tau-gsk3%C3%AE-akt-pi3k-pathway-and-cdk5-p35-p25-complexes-in-the-hippocampus-of-aged-male-mice
#15
Teresa Neri-Gómez, Judith Espinosa-Raya, Sofía Díaz-Cintra, Julia Segura-Uribe, Sandra Orozco-Suárez, Juan Manuel Gallardo, Christian Guerra-Araiza
Aging is a key risk factor for cognitive decline and age-related neurodegenerative disorders. Also, an age-related decrease in sex steroid hormones may have a negative impact on the formation of neurofibrillary tangles (NFTs); these hormones can regulate Tau phosphorylation and the principal kinase GSK3β involved in this process. Hormone replacement therapy decreases NFTs, but it increases the risk of some types of cancer. However, other synthetic hormones such as tibolone (TIB) have been used for hormone replacement therapy...
April 2017: Neural Regeneration Research
https://www.readbyqxmd.com/read/28552936/tau-secretion-is-correlated-to-an-increase-of-golgi-dynamics
#16
Nguyen-Vi Mohamed, Alexandre Desjardins, Nicole Leclerc
Tau protein can be released by neurons, an event linked to the propagation of Tau pathology in Alzheimer'disease (AD). Neuronal hyperexcitability was shown to significantly increase Tau release by neurons. We confirmed this in the present study. In a previous study, it was demonstrated that hyperexcitability induces Golgi apparatus dynamics resulting in its fragmentation. Our present results revealed that the increase of Tau secretion upon hyperexcitability could be significantly reduced by preventing Golgi dynamics through the inactivation of cdk5...
2017: PloS One
https://www.readbyqxmd.com/read/28528366/cdk5-mediated-phosphorylation-dependent-ubiquitination-and-degradation-of-e3-ubiquitin-ligases-gp78-accelerates-neuronal-death-in-parkinson-s-disease
#17
Qingzhi Wang, Fengjuan Jiao, Pei Zhang, Jianguo Yan, Zheng Zhang, Feng He, Qian Zhang, Zexi Lv, Xiang Peng, Hongwei Cai, Bo Tian
The molecular mechanisms responsible for the loss of dopaminergic neurons in Parkinson's disease (PD) remain obscure. Loss of function of E3 ubiquitin ligases is associated with mitochondria dysfunction, dysfunction of protein degradation, and α-synuclein aggregation, which are major contributors to neurodegeneration in PD. Recent research has thus focused on E3 ubiquitin ligase glycoprotein 78 (GP78); however, the role of GP78 in PD pathogenesis remains unclear. Notably, cyclin-dependent kinase 5 (CDK5) controls multiple cellular events in postmitotic neurons, and CDK5 activity has been implicated in the pathogenesis of PD...
May 20, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28526617/cyclin-dependent-kinase-5-a-novel-avenue-for-alzheimer-s-disease
#18
REVIEW
Anisha S Bhounsule, Lokesh Kumar Bhatt, Kedar S Prabhavalkar, Manisha Oza
Alzheimer's disease (AD) is one of the most frequently encountered diseases in adults with progressive loss of memory and behavioral changes. Inspite of there being an intense research in the field of AD, only a few chemical entities exhibiting anti-AD activity make it through the clinical trials and it is thus need of an hour to develop new drugs or repurpose the existing ones for better management of Alzheimer's disease. Novel therapeutic targets can influence drug discovery in the field of AD. Cyclin Dependent Kinase 5 (Cdk5) which is a serine/threonine kinase can prove to be an upcoming beneficial target to be studied for treating AD...
May 17, 2017: Brain Research Bulletin
https://www.readbyqxmd.com/read/28502042/tale-of-the-good-and-the-bad-cdk5-remodeling-of-the-actin-cytoskeleton-in-the-brain
#19
REVIEW
Kavita Shah, Sandra Rossie
Cdk5 kinase, a cyclin-dependent kinase family member, is a key regulator of cytoskeletal remodeling in the brain. Cdk5 is essential for brain development during embryogenesis. After birth, it is essential for numerous neuronal processes such as learning and memory formation, drug addiction, pain signaling, and long-term behavior changes, all of which rely on rapid alterations in the cytoskeleton. Cdk5 activity is deregulated in various brain disorders including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and ischemic stroke, resulting in profound remodeling of the neuronal cytoskeleton, loss of synapses, and ultimately neurodegeneration...
May 13, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28498462/loss-of-reelin-suppresses-cell-survival-and-mobility-in-non-hodgkin-lymphoma
#20
Aixia Dou, Zhilun Wang, Ni Zhang, Junli Liu
Reelin, a secreted glycoprotein, was recently demonstrated to be involved in the pathogenesis of cancer. However, its oncogenic activities in non-Hodgkin lymphoma (NHL) remain unclear. Therefore, we aimed to evaluate the functional role of reelin in NHL, and the underlying molecular mechanisms. In the present study, we analyzed reelin expression in lymphoma tissues and cell lines using immunohistochemistry, immunofluorescence staining, qRT-PCR and western blotting. Then, the expression of Reelin was silenced with short hairpin RNA (shRNA)-expressing plasmid in the NHL cell line A20...
May 4, 2017: Oncology Reports
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