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Xiang He, Ling Jiang, Qi-Qin Dan, Qiang Lv, Yue Hu, Jia Liu, Ting-Hua Wang, Shu-Fen Wang
Collapsin response mediator protein 2 (CRMP2), an important protein involved in axonal growth and the maintenance of neuronal membrane integrity, has proved to be altered in nervous system diseases. This study was aimed to investigate the role of CRMP2 in bone marrow stromal cells (BMSCs) treating rats with cerebral ischemia. BMSCs were isolated from shaft of the femurs, tibiae, and humeri and was intra-carotid administrated immediately after middle cerebral artery occlusion (MCAO). Modified Neurological Severity Scores (mNSS) was conducted at 3, 7, 14 dpo and the electrophysiologic evaluation was evaluated at 14 dpo...
October 17, 2016: Behavioural Brain Research
Andrea Becerra-Calixto, Gloria Patricia Cardona-Gómez
Cerebral ischemia is a cerebrovascular episode that generates a high incidence of death and physical and mental disabilities worldwide. Excitotoxicity, release of free radicals, and exacerbated immune response cause serious complications in motor and cognitive areas during both short and long time frames post-ischemia. CDK5 is a kinase that is widely involved in the functions of neurons and astrocytes, and its over-activation is implicated in neurodegenerative processes. In this study, we evaluated the brain parenchymal response to the transplantation of CDK5-knockdown astrocytes into the somatosensory cortex after ischemia in rats...
October 15, 2016: Molecular Neurobiology
Kangmin Zhuang, Juchang Zhang, Man Xiong, Xianfei Wang, Xiaobei Luo, Lu Han, Yan Meng, Yali Zhang, Wenting Liao, Side Liu
Abnormal expression of cyclin-dependent kinase 5 (CDK5) has been found in several human cancers, whereas the role of CDK5 in the malignant development of colorectal cancer (CRC) has not been well characterized. Here we investigated the role of CDK5 in CRC and found that its expression was much higher in CRC tissues than that in normal tissues with a higher expression level of CDK5 closely correlating to advanced American Joint Committee on Cancer (AJCC) stage, poor differentiation, increased tumor size and poor prognosis of CRC...
October 13, 2016: Cell Death & Disease
Lei Zhang, Lu Huang, Kangrong Lu, Yutong Liu, Genghong Tu, Mengjuan Zhu, Li Ying, Jinlan Zhao, N Liu, Fukun Guo, Lin Zhang, Lu Zhang
Synaptic plasticity plays a critical role in cocaine addiction. The dopamine D1 and D3 receptors differentially regulate the cocaine-induced gene expression, structural remodeling and behavioral response. However, how these two receptors coordinately mediate the ultra-structural changes of synapses after cocaine exposure and whether these changes are behaviorally relevant are still not clear. Here, using quantitative electron microscopy, we show that D1 and D3 receptors have distinct roles in regulating cocaine-induced ultra-structural changes of synapses in the nucleus accumbens and caudoputamen...
October 12, 2016: Addiction Biology
Guo-Qiang Wang, Cheng Cen, Chong Li, Shuai Cao, Ning Wang, Zheng Zhou, Xue-Mei Liu, Yu Xu, Na-Xi Tian, Ying Zhang, Jun Wang, Li-Ping Wang, Yun Wang
No abstract text is available yet for this article.
October 10, 2016: Nature Communications
Zhong-Hao Zhang, Chen Chen, Qiu-Yan Wu, Rui Zheng, Yao Chen, Qiong Liu, Jia-Zuan Ni, Guo-Li Song
Olfactory dysfunction is an early and common symptom in Alzheimer's disease (AD) and is reported to be related to several pathologic changes, including the deposition of Aβ and hyperphosphorylated tau protein as well as synaptic impairment. Selenomethionine (Se-Met), the major form of selenium in animals and humans, may be a promising therapeutic option for AD as it decreases the deposition of Aβ and tau hyperphosphorylation in a triple transgenic mouse model of AD (3× Tg-AD). In this study, 4-month-old AD mice were treated with 6 µg/mL Se-Met in drinking water for 12 weeks and the effect of Se-Met on neuropathological deficits in olfactory bulb (OB) of 3× Tg-AD mice was investigated...
2016: International Journal of Molecular Sciences
Christophe Labrière, Olivier Lozach, Mélina Blairvacq, Laurent Meijer, Catherine Guillou
Starting from a known compound, identified as the first inhibitor of the kinesin MKLP-2 and named Paprotrain, we have investigated its reactivity to produce through photochemistry a potent nanomolar inhibitor of the kinase DYRK1A. Using similar and different chemical pathways, we have designed several families of compounds that have been screened on a panel of five protein kinases: CK1δ/ε, CDK5/p25, GSK3α/β, DYRK1A and CLK1, all involved in neurodegenerative disorders such as Alzheimer's disease. We have identified a first group of multi-targeted compounds, a second group of dual inhibitors of DYRK1A & CLK1 and a last group of selective inhibitors of CLK1...
August 31, 2016: European Journal of Medicinal Chemistry
Wen-Hui Fang, Shant Kumar, Garry McDowell, David Smith, Jurek Krupinski, Peter Olah, Raid Saleem Al-Baradie, Mohammad Othman Al-Rukban, Eugene Bogdan Petcu, Mark Slevin
The potential use of stem cells as therapeutics in disease has gained momentum over the last few years and recently phase-I clinical trials have shown favourable results in treatment of a small cohort of acute stroke patients. Similarly, they have been used in preclinical models drug-loaded for the effective treatment of solid tumours. Here we have characterized uptake and release of a novel p5-cyclin-dependent kinase 5 (CDK5) inhibitory peptide by mesenchymal stem cells and showed release levels capable of blocking aberrant cyclin-dependent kinase 5 (CDK5) signaling pathways, through phosphorylation of cyclin-dependent kinase 5 (CDK5) and p53...
2016: Stem Cells International
Taeko Kimura, Tomohisa Hosokawa, Masato Taoka, Koji Tsutsumi, Kanae Ando, Koichi Ishiguro, Masato Hosokawa, Masato Hasegawa, Shin-Ichi Hisanaga
Tau is hyperphosphorylated in the brains of patients with tauopathies, such as Alzheimer's disease and frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). However, neither the mechanism of hyperphosphorylation nor its contribution to pathogenesis is known. We applied Phos-tag SDS-PAGE, a phosphoaffinity electrophoresis, to the analysis of tau phosphorylation in vitro by Cdk5, in cultured cells and in mouse brain. Here, we found that Cdk5-p25 phosphorylated tau in vitro at Ser404, Ser235, Thr205 and Ser202 in this order...
2016: Scientific Reports
Niranjana D Amin, Yali Zheng, Binukumar Bk, Varsha Shukla, Susan Skuntz, Philip Grant, Joseph Steiner, Manju Bhaskar, Harish C Pant
In a series of studies, we have identified TFP5, a truncated fragment of p35, the Cdk5 kinase regulatory protein, that inhibits Cdk5/p35 and the hyperactive Cdk5/p25 activities in test tube experiments. In cortical neurons, however, and in vivo in AD model mice, the peptide specifically inhibits the Cdk5/p25 complex and not the endogenous Cdk5/p35. To account for the selective inhibition of Cdk5/p25 activity, we propose that the "p10" N-terminal domain of p35, absent in p25, spares Cdk5/p35 because p10 binds to macromolecules (e...
September 14, 2016: Molecular Biology of the Cell
Isabella Salzer, Fatma Asli Erdem, Wei-Qiang Chen, Seok Heo, Xaver Koenig, Klaus W Schicker, Helmut Kubista, Gert Lubec, Stefan Boehm, Jae-Won Yang
The function of numerous ion channels is tightly controlled by G protein-coupled receptors (GPCRs). The underlying signalling mechanisms may involve phosphorylation of channel proteins and participation of phosphatidylinositol-4,5-bisphosphate (PIP2 ). Although the roles of both mechanisms were investigated extensively, thus far only little has been reported on their interaction in channel modulation. GPCRs govern Kv7 channels, which latter play a major role in the regulation of neuronal excitability, by determining the levels of PIP2 and through phosphorylation...
September 13, 2016: Journal of Physiology
Mei-Yin Chien, Cheng-Hung Chuang, Chang-Ming Chern, Kou-Tong Liou, Der-Zen Liu, Yu-Chang Hou, Yuh-Chiang Shen
Salvianolic acid A (SalA), a chemical type of caffeic acid trimer, has drawn great attention for its potent bioactivities against ischemia-induced injury both in vitro and in vivo. In this study, we evaluated SalA's protective effects against acute ischemic stroke by inducing middle cerebral artery occlusion/reperfusion (MCAO) injuries in mice. Treatment of the mice with SalA (50 and 100μg/kg, i.v.) at 2h after MCAO enhanced their survival rate, improved their moving activity, and ameliorated the severity of brain infarction and apoptosis seen in the mice by diminishing pathological changes such as the extensive breakdown of the blood-brain barrier (BBB), nitrosative stress, and the activation of an inflammatory transcriptional factor p65 nuclear factor-kappa B (NF-κB) and a pro-apoptotic kinase p25/Cdk5...
September 5, 2016: Free Radical Biology & Medicine
Susan A Austin, Zvonimir S Katusic
RATIONALE: Alzheimer's disease (AD) has an unknown etiology; however, cardiovascular risk factors are associated with a higher incidence of AD. A defining feature of endothelial dysfunction induced by cardiovascular risk factors is reduced bioavailable endothelial nitric oxide (NO). We previously demonstrated endothelial NO acts as an important signaling molecule in neuronal tissue. OBJECTIVE: We sought to determine the relationship between the loss of endothelial nitric oxide synthase (eNOS) and tau phosphorylation in neuronal tissue...
September 6, 2016: Circulation Research
M Durán Aguilar, S I Román Ponce, F J Ruiz López, E González Padilla, C G Vásquez Peláez, A Bagnato, M G Strillacci
Mastitis, the most common and expensive disease in dairy cows, implies significant losses in the dairy industry worldwide. Many efforts have been made to improve genetic mastitis resistance in dairy populations, but low heritability of this trait made this process not as effective as desired. The purpose of this study was to identify genomic regions explaining genetic variation of somatic cell count using copy number variations (CNVs) as markers in the Holstein population, genotyped with the Illumina BovineHD BeadChip...
August 30, 2016: Journal of Animal Breeding and Genetics, Zeitschrift Für Tierzüchtung und Züchtungsbiologie
Miren Ettcheto, Dmitry Petrov, Ignacio Pedrós, Norma Alva, Teresa Carbonell, Carlos Beas-Zarate, Merce Pallas, Carme Auladell, Jaume Folch, Antoni Camins
Alzheimer's disease (AD) is currently an incurable aging-related neurodegenerative disorder. Recent studies give support to the hypotheses that AD should be considered as a metabolic disease. The present study aimed to explore the relationship between hippocampal neuropathological amyloid-β (Aβ) plaque formation and obesity at an early presymptomatic disease stage (3 months of age). For this purpose, we used APPswe/PS1dE9 (APP/PS1) transgenic mice, fed with a high-fat diet (HFD) in order to investigate the potential molecular mechanisms involved in both disorders...
July 14, 2016: Journal of Alzheimer's Disease: JAD
B K Binukumar, Steven L Pelech, Catherine Sutter, Varsha Shukla, Niranjana D Amin, Philip Grant, Manju Bhaskar, Suzanne Skuntz, Joseph Steiner, Harish C Pant
Cyclin-dependent kinase 5 (CDK5) is a multifunctional serine/threonine kinase that regulates a large number of neuronal processes essential for nervous system development and function with its activator p35 CDK5R1. Upon neuronal insults, p35 is proteolyzed and cleaved to p25 producing deregulation and hyperactivation of CDK5 (CDK5/p25), implicated in tau hyperphosphorylation, a pathology in some neurodegenerative diseases. A truncated, 24 amino acid peptide, p5, derived from p35 inhibits the deregulated CDK5 phosphotransferase activity and ameliorates Alzheimer's disease (AD) phenotypes in AD model mice...
September 6, 2016: Journal of Alzheimer's Disease: JAD
Thomas Koed Doktor, Yimin Hua, Henriette Skovgaard Andersen, Sabrina Brøner, Ying Hsiu Liu, Anna Wieckowska, Maja Dembic, Gitte Hoffmann Bruun, Adrian R Krainer, Brage Storstein Andresen
Spinal Muscular Atrophy (SMA) is a neuromuscular disorder caused by insufficient levels of the Survival of Motor Neuron (SMN) protein. SMN is expressed ubiquitously and functions in RNA processing pathways that include trafficking of mRNA and assembly of snRNP complexes. Importantly, SMA severity is correlated with decreased snRNP assembly activity. In particular, the minor spliceosomal snRNPs are affected, and some U12-dependent introns have been reported to be aberrantly spliced in patient cells and animal models...
August 23, 2016: Nucleic Acids Research
Fuling Zhou, Ming Li, Yongchang Wei, Kevin Lin, Yue Lu, Jianjun Shen, Gary L Johanning, Feng Wang-Johanning
Human endogenous retrovirus type K (HERV-K) Env protein was previously demonstrated to be overexpressed in human breast cancer (BC) cells and tissues. However, the molecular pathways driving the specific alterations are unknown. We now show that knockdown of its expression with an shRNA (shRNAenv) blocked BC cell proliferation, migration, and invasion. shRNAenv transduction also attenuated the ability of BC cells to form tumors, and notably prevented metastasis. Mechanistically, downregulation of HERV-K blocked expression of tumor-associated genes that included Ras, p-RSK, and p-ERK...
August 20, 2016: Oncotarget
Luyi Zhou, Wei-Lun Sun, Karen Weierstall, Ana Christina Minerly, Jan Weiner, Shirzad Jenab, Vanya Quinones-Jenab
Previous studies have shown sex different patterns in behavioral responses to cocaine. Here, we used between-subject experiment design to study whether sex differences exist in the development of behavioral sensitization and tolerance to repeated cocaine, as well as the role of protein kinase A (PKA) signaling cascade in this process. Ambulatory and rearing responses were recorded in male and female rats after 1 to 14 days of administration of saline or cocaine (15 mg/kg; ip). Correspondent PKA-associated signaling in the nucleus accumbens (NAc) and caudate-putamen (CPu) was measured at each time point...
October 2016: Psychopharmacology
Alexey V Danilov, Shanhu Hu, Bernardo Orr, Kristina Godek, Lisa Maria Mustachio, David Sekula, Xi Liu, Masanori Kawakami, Faye M Johnson, Duane A Compton, Sarah J Freemantle, Ethan Dmitrovsky
Despite advances in targeted therapy, lung cancer remains the most common cause of cancer-related mortality in the United States. Chromosomal instability is a prominent feature in lung cancer and because it rarely occurs in normal cells, it represents a potential therapeutic target. Our prior work discovered that lung cancer cells undergo anaphase catastrophe in response to inhibition of cyclin-dependent kinase 2 (CDK2), followed by apoptosis and reduced tumor cell growth. In this study, the effects and mechanisms of the multi-CDK inhibitor dinaciclib on lung cancer cells were investigated...
August 22, 2016: Molecular Cancer Therapeutics
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