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https://www.readbyqxmd.com/read/29788780/isoform-selectivity-of-harmine-conjugated-1-2-3-triazoles-against-human-monoamine-oxidase
#1
Saqlain Haider, Manal Alhusban, Narayan D Chaurasiya, Babu L Tekwani, Amar G Chittiboyina, Ikhlas A Khan
AIM: There is little information available on the monoamine oxidase isoform selectivity of N-alkyl harmine analogs, which exhibit a myriad of activities including monoamine oxidase isoform A (MAO-A), tyrosine-phosphorylation-regulated kinase (DYRK1A) and cytotoxicity to several select cancer cell lines. RESULTS: Compounds 3e and 4c exhibited an IC50 of 0.83 ± 0.03 and 0.43 ± 0.002 μM against MAO-A and an IC50 of 0.26 ± 0.04 and 0.36 ± 0.001 μM against MAO-B, respectively...
May 23, 2018: Future Medicinal Chemistry
https://www.readbyqxmd.com/read/29773344/lncrna-oip5-as1-regulates-radioresistance-by-targeting-dyrk1a-through-mir-369-3p-in-colorectal-cancer-cells
#2
Yanmei Zou, Shuo Yao, Xiuqiong Chen, Dian Liu, Jianhua Wang, Xun Yuan, Jie Rao, Huihua Xiong, Shiying Yu, Xianglin Yuan, Feng Zhu, Guohong Hu, Yihua Wang, Hua Xiong
OBJECT: This study aimed to investigate the role of lncRNA OIP5-AS1 in regulating radioresistance of colorectal cancer (CRC) cells. METHODS: Microarray analysis was used to screen out lncRNAs differentially expressed in radio-resistant CRC cell lines. Expression levels of OIP5-AS1, miR-369-3p and DYRK1A in CRC cell lines were measured by qRT-PCR. Protein expression of DYRK1A was determined by western blot. The target relationships among OIP5-AS1, miR-369-3p and DYRK1A were validated by dual luciferase reporter assay...
April 14, 2018: European Journal of Cell Biology
https://www.readbyqxmd.com/read/29764512/mutational-analysis-of-two-residues-in-the-dyrk-homology-box-of-the-protein-kinase-dyrk1a
#3
Esti Wahyu Widowati, Simone Bamberg-Lemper, Walter Becker
OBJECTIVE: Dual specificity tyrosine phosphorylation-regulated kinases (DYRK) contain a characteristic sequence motif (DYRK homology box, DH box) that is located N-terminal of the catalytic domain and supports the autophosphorylation of a conserved tyrosine during maturation of the catalytic domain. Two missense mutations in the DH box of human DYRK1B were recently identified as causative of a rare familiar form of metabolic syndrome. We have recently shown that these amino acid exchanges impair maturation of the kinase domain...
May 15, 2018: BMC Research Notes
https://www.readbyqxmd.com/read/29746474/analysis-of-motor-dysfunction-in-down-syndrome-reveals-motor-neuron-degeneration
#4
Sheona Watson-Scales, Bernadett Kalmar, Eva Lana-Elola, Dorota Gibbins, Federica La Russa, Frances Wiseman, Matthew Williamson, Rachele Saccon, Amy Slender, Anna Olerinyova, Radma Mahmood, Emma Nye, Heather Cater, Sara Wells, Y Eugene Yu, David L H Bennett, Linda Greensmith, Elizabeth M C Fisher, Victor L J Tybulewicz
Down Syndrome (DS) is caused by trisomy of chromosome 21 (Hsa21) and results in a spectrum of phenotypes including learning and memory deficits, and motor dysfunction. It has been hypothesized that an additional copy of a few Hsa21 dosage-sensitive genes causes these phenotypes, but this has been challenged by observations that aneuploidy can cause phenotypes by the mass action of large numbers of genes, with undetectable contributions from individual sequences. The motor abnormalities in DS are relatively understudied-the identity of causative dosage-sensitive genes and the mechanism underpinning the phenotypes are unknown...
May 10, 2018: PLoS Genetics
https://www.readbyqxmd.com/read/29742440/dyrk1a-kinase-positively-regulates-angiogenic-responses-in-endothelial-cells
#5
Esteban J Rozen, Julia Roewenstrunk, María José Barallobre, Chiara Di Vona, Carole Jung, Ana F Figueiredo, Jeroni Luna, Cristina Fillat, Maria L Arbonés, Mariona Graupera, Miguel A Valverde, Susana de la Luna
Angiogenesis is a highly regulated process essential for organ development and maintenance, and its deregulation contributes to inflammation, cardiac disorders, and cancer. The Ca2+ /nuclear factor of activated T cells (NFAT) signaling pathway is central to endothelial cell angiogenic responses, and it is activated by stimuli like vascular endothelial growth factor (VEGF) A. NFAT phosphorylation by dual-specificity tyrosine phosphorylation-regulated kinases (DYRKs) is thought to be an inactivating event. Contrary to expectations, we show that the DYRK family member DYRK1A positively regulates VEGF-dependent NFAT transcriptional responses in primary endothelial cells...
May 8, 2018: Cell Reports
https://www.readbyqxmd.com/read/29742358/application-of-integrated-drug-screening-kinome-analysis-to-identify-inhibitors-of-gemcitabine-resistant-pancreatic-cancer-cell-growth
#6
Linas J Krulikas, Ian M McDonald, Benjamin Lee, Denis O Okumu, Michael P East, Thomas S K Gilbert, Laura E Herring, Brian T Golitz, Carrow I Wells, Allison D Axtman, William J Zuercher, Timothy M Willson, Dmitri Kireev, Jen Jen Yeh, Gary L Johnson, Antonio T Baines, Lee M Graves
Continuous exposure of a pancreatic cancer cell line MIA PaCa-2 (MiaS ) to gemcitabine resulted in the formation of a gemcitabine-resistant subline (MiaR ). In an effort to discover kinase inhibitors that inhibited MiaR growth, MiaR cells were exposed to kinase inhibitors (PKIS-1 library) in a 384-well screening format. Three compounds (UNC10112721A, UNC10112652A, and UNC10112793A) were identified that inhibited the growth of MiaR cells by more than 50% (at 50 nM). Two compounds (UNC10112721A and UNC10112652A) were classified as cyclin-dependent kinase (CDK) inhibitors, whereas UNC10112793A was reported to be a PLK inhibitor...
May 1, 2018: SLAS Discovery
https://www.readbyqxmd.com/read/29700199/functional-characterization-of-dyrk1a-missense-variants-associated-with-a-syndromic-form-of-intellectual-deficiency-and-autism
#7
Esti Wahyu Widowati, Sabrina Ernst, Ralf Hausmann, Gerhard Müller-Newen, Walter Becker
Haploinsufficiency of DYRK1A is a cause of a neurodevelopmental syndrome termed mental retardation autosomal dominant 7 (MRD7). Several truncation mutations, microdeletions and missense variants have been identified and result in a recognizable phenotypic profile, including microcephaly, intellectual disability, epileptic seizures, autism spectrum disorder and language delay. DYRK1A is an evolutionary conserved protein kinase which achieves full catalytic activity through tyrosine autophosphorylation. We used a heterologous mammalian expression system to explore the functional characteristics of pathogenic missense variants that affect the catalytic domain of DYRK1A...
April 26, 2018: Biology Open
https://www.readbyqxmd.com/read/29698690/alzheimer-s-disease-susceptibility-genes-modify-the-risk-of-parkinson-disease-and-parkinson-s-disease-associated-cognitive-impairment
#8
Lu Fang, Bei-Sha Tang, Kuan Fan, Chang-Min Wan, Xin-Xiang Yan, Ji-Feng Guo
The pathogenic mechanism underlying Parkinson's disease (PD) and PD- Cognitive impairment (CI) remains elusive. Its potential link to the risk factors in Alzheimer's disease (AD) is unclear. In this study, we analyzed 16 CE-associated single nucleotide polymorphisms (SNPs) in twelve genes in a Chinese cohort of 450 PD cases and 449 controls. Among our 298 cases clinically evaluated for CI, 113 cases did not show CI signs (PD-NC), 86 cases had mildly cognitive impairment (PD-MCI) and 99 cases had dementia (PD-D)...
April 24, 2018: Neuroscience Letters
https://www.readbyqxmd.com/read/29661714/microrna-155-up-regulation-in-the-cns-is-strongly-correlated-to-down-s-syndrome-dementia
#9
Esmerina Tili, Louisa Mezache, Jean-Jacques Michaille, Vicky Amann, James Williams, Paige Vandiver, Maria Quinonez, Paolo Fadda, Adel Mikhail, Gerard Nuovo
This study examined the molecular correlates of Down's dementia. qRTPCR for chromosome 21 microRNAs was correlated with in situ hybridization, immunohistochemistry for microRNA targets, mRNAs located on chromosome 21, and neurofibrillary tangles in human and the Ts65 dn mouse Down's model. qRTPCR for the microRNAs on the triplicated chromosome showed miR-155 dominance in brain tissues (14.3 fold increase, human and 24.2 fold increase, mouse model) that co-expressed with hyperphosphorylated tau protein. miR-155 was not elevated in Alzheimer's disease or neonates with Downs' syndrome...
March 26, 2018: Annals of Diagnostic Pathology
https://www.readbyqxmd.com/read/29514186/cc-401-promotes-%C3%AE-cell-replication-via-pleiotropic-consequences-of-dyrk1a-b-inhibition
#10
Yassan Abdolazimi, Sooyeon Lee, Haixia Xu, Paul Allegretti, Timothy M Horton, Benjamin Yeh, Hannah P Moeller, Robert J Nichols, David McCutcheon, Aryaman Shalizi, Mark Smith, Neali A Armstrong, Justin P Annes
Pharmacologic expansion of endogenous β-cells is a promising therapeutic strategy for diabetes. To elucidate the molecular pathways that control β-cell growth we screened ∼2,400 bioactive compounds for rat β-cell replication-modulating activity. Numerous hit compounds impaired or promoted rat β-cell replication, including CC-401, an advanced clinical candidate previously characterized as a c-Jun N-terminal kinase (JNK) inhibitor. Surprisingly, CC-401 induced rodent (in vitro and in vivo) and human (in vitro) β-cell replication via dual specificity tyrosine-phosphorylation-regulated kinases (DYRK1A/B) inhibition...
March 5, 2018: Endocrinology
https://www.readbyqxmd.com/read/29495936/mnb-dyrk1a-orchestrates-a-transcriptional-network-at-the-transition-from-self-renewing-neurogenic-progenitors-to-postmitotic-neuronal-precursors
#11
Mirja N Shaikh, Francisco J Tejedor
The Down syndrome and microcephaly related gene Mnb/Dyrk1A encodes an evolutionary conserved protein kinase subfamily that plays important roles in neurodevelopment. minibrain (mnb) mutants of Drosophila melanogaster (Dm) exhibit reduced adult brains due to neuronal deficits generated during larval development. These deficits are the consequence of the apoptotic cell death of numerous neuronal precursors that fail to properly exit the cell cycle and differentiate. We have recently found that in both the Dm larval brain and the embryonic vertebrate central nervous system (CNS), a transient expression of Mnb/Dyrk1A promotes the cell cycle exit of newborn neuronal precursors by upregulating the expression of the cyclin-dependent kinase inhibitor p27kip1 (called Dacapo in Dm)...
March 2018: Journal of Neurogenetics
https://www.readbyqxmd.com/read/29434250/dyrk1a-inhibition-and-cognitive-rescue-in-a-down-syndrome-mouse-model-are-induced-by-new-fluoro-dandy-derivatives
#12
Fernanda Neumann, Stéphanie Gourdain, Christelle Albac, Alain D Dekker, Linh Chi Bui, Julien Dairou, Isabelle Schmitz-Afonso, Nathalie Hue, Fernando Rodrigues-Lima, Jean M Delabar, Marie-Claude Potier, Jean-Pierre Le Caër, David Touboul, Benoît Delatour, Kevin Cariou, Robert H Dodd
Inhibition of DYRK1A kinase, produced by chromosome 21 and consequently overproduced in trisomy 21 subjects, has been suggested as a therapeutic approach to treating the cognitive deficiencies observed in Down syndrome (DS). We now report the synthesis and potent DYRK1A inhibitory activities of fluoro derivatives of 3,5-di(polyhydroxyaryl)-7-azaindoles (F-DANDYs). One of these compounds (3-(4-fluorophenyl)-5-(3,4-dihydroxyphenyl)-1H-pyrrolo[2,3-b]pyridine, 5a) was selected for in vivo studies of cognitive rescuing effects in a standard mouse model of DS (Ts65Dn line)...
February 12, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29423924/timing-of-prenatal-exposure-to-trauma-and-altered-placental-expressions-of-hypothalamic-pituitary-adrenal-axis-genes-and-genes-driving-neurodevelopment
#13
W Zhang, Q Li, M Deyssenroth, L Lambertini, J Finik, J Ham, Y Huang, K J Tsuchiya, P Pehme, J Buthmann, S Yoshida, J Chen, Y Nomura
Prenatal maternal stress increases the risk for negative developmental outcomes in offspring; however, the underlying biological mechanisms remain largely unexplored. In the present study, alterations in placental gene expression associated with maternal stress were examined to clarify the potential underlying epi/genetic mechanisms. Expression levels of 40 selected genes involved in regulating foetal hypothalamic-pituitary-adrenal axis and neurodevelopment were profiled in placental tissues collected from a birth cohort established around the time of Superstorm Sandy...
April 2018: Journal of Neuroendocrinology
https://www.readbyqxmd.com/read/29394516/ca1-pyramidal-neuron-gene-expression-mosaics-in-the-ts65dn-murine-model-of-down-syndrome-and-alzheimer-s-disease-following-maternal-choline-supplementation
#14
Melissa J Alldred, Helen M Chao, Sang Han Lee, Judah Beilin, Brian E Powers, Eva Petkova, Barbara J Strupp, Stephen D Ginsberg
Although there are changes in gene expression and alterations in neuronal density and afferent inputs in the forebrain of trisomic mouse models of Down syndrome (DS) and Alzheimer's disease (AD), there is a lack of systematic assessments of gene expression and encoded proteins within individual vulnerable cell populations, precluding translational investigations at the molecular and cellular level. Further, no effective treatment exists to combat intellectual disability and basal forebrain cholinergic neurodegeneration seen in DS...
April 2018: Hippocampus
https://www.readbyqxmd.com/read/29364148/indole-3-carbonitriles-as-dyrk1a-inhibitors-by-fragment-based-drug-design
#15
Rosanna Meine, Walter Becker, Hannes Falke, Lutz Preu, Nadège Loaëc, Laurent Meijer, Conrad Kunick
Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is a potential drug target because of its role in the development of Down syndrome and Alzheimer's disease. The selective DYRK1A inhibitor 10-iodo-11 H -indolo[3,2- c ]quinoline-6-carboxylic acid (KuFal194), a large, flat and lipophilic molecule, suffers from poor water solubility, limiting its use as chemical probe in cellular assays and animal models. Based on the structure of KuFal194, 7-chloro-1 H -indole-3-carbonitrile was selected as fragment template for the development of smaller and less lipophilic DYRK1A inhibitors...
January 24, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/29223763/dyrk1a-haploinsufficiency-in-mice-causes-autistic-like-features-and-febrile-seizures
#16
Matthieu Raveau, Atsushi Shimohata, Kenji Amano, Hiroyuki Miyamoto, Kazuhiro Yamakawa
Mutations and copy number variants affecting DYRK1A gene encoding the dual-specificity tyrosine phosphorylation-regulated kinase 1A are among the most frequent genetic causes of neurodevelopmental disorders including autism spectrum disorder (ASD) associated with microcephaly, febrile seizures and severe speech acquisition delay. Here we developed a mouse model harboring a frame-shift mutation in Dyrk1a resulting in a protein truncation and elimination of its kinase activity site. Dyrk1a+/- mice showed significant impairments in cognition and cognitive flexibility, communicative ultrasonic vocalizations, and social contacts...
February 2018: Neurobiology of Disease
https://www.readbyqxmd.com/read/29221819/cerebellar-alterations-in-a-model-of-down-syndrome-the-role-of-the-dyrk1a-gene
#17
Susana García-Cerro, Verónica Vidal, Sara Lantigua, Maria Teresa Berciano, Miguel Lafarga, Pedro Ramos-Cabrer, Daniel Padro, Noemí Rueda, Carmen Martínez-Cué
Down syndrome (DS) is characterized by a marked reduction in the size of the brain and cerebellum. These changes play an important role in the motor alterations and cognitive disabilities observed in this condition. The Ts65Dn (TS) mouse, the most commonly used model of DS, reflects many DS phenotypes, including alterations in cerebellar morphology. One of the genes that is overexpressed in both individuals with DS and TS mice is DYRK1A/Dyrk1A (dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A), which has been implicated in the altered cerebellar structural and functional phenotypes observed in both populations...
February 2018: Neurobiology of Disease
https://www.readbyqxmd.com/read/29186912/computer-aided-drug-design-applied-to-marine-drug-discovery-meridianins-as-alzheimer-s-disease-therapeutic-agents
#18
Laura Llorach-Pares, Alfons Nonell-Canals, Melchor Sanchez-Martinez, Conxita Avila
Computer-aided drug discovery/design (CADD) techniques allow the identification of natural products that are capable of modulating protein functions in pathogenesis-related pathways, constituting one of the most promising lines followed in drug discovery. In this paper, we computationally evaluated and reported the inhibitory activity found in meridianins A-G, a group of marine indole alkaloids isolated from the marine tunicate Aplidium , against various protein kinases involved in Alzheimer's disease (AD), a neurodegenerative pathology characterized by the presence of neurofibrillary tangles (NFT)...
November 27, 2017: Marine Drugs
https://www.readbyqxmd.com/read/29179659/dyrk1a-is-a-regulator-of-s-phase-entry-in-hepatic-progenitor-cells
#19
Hedwig S Kruitwagen, Bart Westendorp, Cornelia S Viebahn, Krista Post, Monique E van Wolferen, Loes A Oosterhoff, David A Egan, Jean-Maurice Delabar, Mathilda J Toussaint, Baukje A Schotanus, Alain de Bruin, Jan Rothuizen, Louis C Penning, Bart Spee
Hepatic progenitor cells (HPCs) are adult liver stem cells that act as second line of defense in liver regeneration. They are normally quiescent, but in case of severe liver damage, HPC proliferation is triggered by external activation mechanisms from their niche. Although several important proproliferative mechanisms have been described, it is not known which key intracellular regulators govern the switch between HPC quiescence and active cell cycle. We performed a high-throughput kinome small interfering RNA (siRNA) screen in HepaRG cells, a HPC-like cell line, and evaluated the effect on proliferation with a 5-ethynyl-2'-deoxyuridine (EdU) incorporation assay...
January 15, 2018: Stem Cells and Development
https://www.readbyqxmd.com/read/29127398/overexpression-of-dyrk1a-a-down-syndrome-candidate-gene-impairs-primordial-germ-cells-maintenance-and-migration-in-zebrafish
#20
Yanyan Liu, Ziyuan Lin, Mingfeng Liu, He Wang, Huaqin Sun
DYRK1A, located on chromosome 21, is a major candidate gene of Down syndrome (DS, trisomy21), and its overexpression is associated with abnormal phenotype of Down syndrome patients. The defects of gonads and germ cells in Down Syndrome suggest that overexpression of DYRK1A has potential effect on primordial germ cells (PGCs) development. Human and zebrafish DYRK1A protein sequence possess 75.6% similarity and same function domains, suggesting the evolutional conservation. Here, we used zebrafish model to detect the definite role of excessive expression of DYRK1A in PGCs development during embryogenesis...
November 10, 2017: Scientific Reports
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