keyword
https://read.qxmd.com/read/38163507/identification-of-selective-dual-specificity-tyrosine-phosphorylation-regulated-kinase-1a-dyrk1a-inhibitors-and-their-effects-on-tau-and-microtubule
#21
JOURNAL ARTICLE
Yi-Wen Wu, Wei-Chun HuangFu, Tony Eight Lin, Chao-Hiang Peng, Huang-Ju Tu, Ting-Yi Sung, Tzu-Ying Sung, Shih-Chung Yen, Shiow-Lin Pan, Kai-Cheng Hsu
The overexpression of dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), commonly observed in neurodegenerative diseases like Alzheimer's disease (AD) and Down syndrome (DS), can induce the formation of neurofibrillary tangles (NFTs) and amyloid plaques. Hence, designing a selective DYRK1A inhibitor would result in a promising small molecule for treating neurodegenerative diseases. Developing selective inhibitors for DYRK1A has been a difficult challenge due to the highly preserved ATP-binding site of protein kinases...
December 30, 2023: International Journal of Biological Macromolecules
https://read.qxmd.com/read/38147409/inhibition-of-dyrk1a-attenuates-vascular-remodeling-in-pulmonary-arterial-hypertension-via-suppressing-stat3-pim-1-nfat-pathway
#22
JOURNAL ARTICLE
Cong Lan, Guangyao Fang, Chenming Qiu, Xiuchuan Li, Fengyuan Yang, Yongjian Yang
Pulmonary arterial hypertension (PAH) is characterized by progressive vascular remodeling caused by the excessive proliferation and survival of pulmonary artery smooth muscle cells (PASMCs). Dual-specificity tyrosine regulated kinase 1A (DYRK1A) is a pleiotropic kinase involved in the regulation of multiple biological functions, including cell proliferation and survival. However, the role and underlying mechanisms of DYRK1A in PAH pathogenesis remain unclear. We found that DYRK1A was upregulated in PASMCs in response to hypoxia, both in vivo and in vitro ...
December 31, 2024: Clinical and Experimental Hypertension: CHE
https://read.qxmd.com/read/38117886/haploid-genetic-screening-of-trophectoderm-specification-identifies-dyrk1a-as-a-repressor-of-totipotent-like-status
#23
JOURNAL ARTICLE
Wenhao Zhang, Shengyi Sun, Qing Wang, Xu Li, Mei Xu, Qian Li, Yiding Zhao, Keli Peng, Chunmeng Yao, Yuna Wang, Ying Chang, Yan Liu, Xudong Wu, Qian Gao, Ling Shuai
Trophectoderm (TE) and the inner cell mass are the first two lineages in murine embryogenesis and cannot naturally transit to each other. The barriers between them are unclear and fascinating. Embryonic stem cells (ESCs) and trophoblast stem cells (TSCs) retain the identities of inner cell mass and TE, respectively, and, thus, are ideal platforms to investigate these lineages in vitro. Here, we develop a loss-of-function genetic screening in haploid ESCs and reveal many mutations involved in the conversion of TSCs...
December 22, 2023: Science Advances
https://read.qxmd.com/read/38114583/de-novo-variants-underlying-monogenic-syndromes-with-intellectual-disability-in-a-neurodevelopmental-cohort-from-india
#24
JOURNAL ARTICLE
Shruti Pande, Purvi Majethia, Karthik Nair, Lakshmi Priya Rao, Selinda Mascarenhas, Namanpreet Kaur, Michelle C do Rosario, Kausthubham Neethukrishna, Ankur Chaurasia, Bhagesh Hunakunti, Nalesh Jadhav, Sruthy Xavier, Jeevan Kumar, Vivekananda Bhat, Gandham SriLakshmi Bhavani, Dhanya Lakshmi Narayanan, B L Yatheesha, Siddaramappa J Patil, Sheela Nampoothiri, Nutan Kamath, Shrikiran Aroor, Ramesh Bhat Y, Leslie E Lewis, Suvasini Sharma, Shruti Bajaj, Naveen Sankhyan, Shahyan Siddiqui, Shalini S Nayak, Stephanie Bielas, Katta Mohan Girisha, Anju Shukla
The contribution of de novo variants as a cause of intellectual disability (ID) is well established in several cohorts reported from the developed world. However, the genetic landscape as well as the appropriate testing strategies for identification of de novo variants of these disorders remain largely unknown in low-and middle-income countries like India. In this study, we delineate the clinical and genotypic spectrum of 54 families (55 individuals) with syndromic ID harboring rare de novo variants. We also emphasize on the effectiveness of singleton exome sequencing as a valuable tool for diagnosing these disorders in resource limited settings...
December 20, 2023: European Journal of Human Genetics: EJHG
https://read.qxmd.com/read/38106192/chromothripsis-orchestrates-leukemic-transformation-in-blast-phase-mpn-through-targetable-amplification-of-dyrk1a
#25
C K Brierley, B H Yip, G Orlando, H Goyal, S Wen, J Wen, M F Levine, G M Jakobsdottir, A Rodriguez-Meira, A Adamo, M Bashton, A Hamblin, S A Clark, J O'Sullivan, L Murphy, A A Olijnik, A Cotton, S Narina, S M Pruett-Miller, A Enshaei, C Harrison, M Drummond, S Knapper, A Tefferi, I Antony-Debré, S Thongjuea, D C Wedge, S Constantinescu, E Papaemmanuil, B Psaila, J D Crispino, A J Mead
Chromothripsis, the process of catastrophic shattering and haphazard repair of chromosomes, is a common event in cancer. Whether chromothripsis might constitute an actionable molecular event amenable to therapeutic targeting remains an open question. We describe recurrent chromothripsis of chromosome 21 in a subset of patients in blast phase of a myeloproliferative neoplasm (BP-MPN), which alongside other structural variants leads to amplification of a region of chromosome 21 in ∼25% of patients ('chr21amp')...
December 10, 2023: bioRxiv
https://read.qxmd.com/read/38099687/dyrk1a-is-a-multifunctional-host-factor-that-regulates-coronavirus-replication-in-a-kinase-independent-manner
#26
JOURNAL ARTICLE
Zhen Fu, Yixin Xiang, Yanan Fu, Zhelin Su, Yubei Tan, Mengfang Yang, Yuanyuan Yan, Hakimeh Baghaei Daemi, Yuejun Shi, Shengsong Xie, Limeng Sun, Guiqing Peng
Coronaviruses, like other positive-sense RNA viruses, can remodel the host membrane to form double-membrane vesicles (DMVs) as their replication organelles. Currently, host factors involved in DMV formation are not well defined. In this study, we used transmissible gastroenteritis virus (TGEV) as a virus model to investigate the regulatory mechanism of dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) on coronavirus. Results showed that DYRK1A significantly inhibited TGEV replication in a kinase-independent manner...
December 15, 2023: Journal of Virology
https://read.qxmd.com/read/38063330/spermatogonial-depletion-and-a-spermatogenesis-defect-in-the-dp-16-1yey-mouse-model-of-down-syndrome
#27
JOURNAL ARTICLE
Rodolphe Dard, Anastasia Tutunaru, Malek Bouassida, Aissatu Balde Camara, Estelle Parizot, Nadim Kassis, Joanne Fortemps, Céline Cierniewski, Chrystèle Racine, Nathalie di Clemente, Francois Vialard, Nathalie Janel
Down syndrome (DS), or Trisomy 21, is the most common chromosomal disorder in humans. Men with DS are infertile. The DYRK1A gene on Hsa21 is involved in several features of DS. Overexpression of the homolog dyrk1A disrupts primordial germ cell migration in zebrafish, and overexpression of Dyrk1A impairs gonadotropic axis function and the early stages of spermatogenesis in the mouse. Other genes on Hsa21 might be involved in the pathogenesis of infertility in DS. We investigated the Dp(16)1Yey mouse model of DS, which features segmental duplication of chromosome Mmu16 (orthologous to a large part of Hsa21 and carrying Dyrk1A and 112 other genes)...
December 1, 2023: Reproduction
https://read.qxmd.com/read/38051674/chemical-biochemical-cellular-and-physiological-characterization-of-leucettinib-21-a-down-syndrome-and-alzheimer-s-disease-drug-candidate
#28
JOURNAL ARTICLE
Mattias F Lindberg, Emmanuel Deau, Frédéric Miege, Marie Greverie, Didier Roche, Nicolas George, Pascal George, Laura Merlet, Julie Gavard, Sander J T Brugman, Edwin Aret, Paul Tinnemans, René de Gelder, Jan Sadownik, Eva Verhofstad, Dennis Sleegers, Sara Santangelo, Julien Dairou, Álvaro Fernandez-Blanco, Mara Dierssen, Andreas Krämer, Stefan Knapp, Laurent Meijer
Leucettinibs are substituted 2-aminoimidazolin-4-ones (inspired by the marine sponge natural product Leucettamine B) developed as pharmacological inhibitors of DYRK1A (dual-specificity, tyrosine phosphorylation-regulated kinase 1A), a therapeutic target for indications such as Down syndrome and Alzheimer's disease. Leucettinib-21 was selected as a drug candidate following extensive structure/activity studies and multiparametric evaluations. We here report its physicochemical properties (X-ray powder diffraction, differential scanning calorimetry, stability, solubility, crystal structure) and drug-like profile...
December 5, 2023: Journal of Medicinal Chemistry
https://read.qxmd.com/read/38010470/discovery-of-novel-harmine-derivatives-as-gsk-3%C3%AE-dyrk1a-dual-inhibitors-for-alzheimer-s-disease-treatment
#29
JOURNAL ARTICLE
Jingsong Qiu, Xiangling Feng, Huanhua Chen, Wenwu Liu, Wenjie Liu, Limeng Wu, Xudong Gao, Yanfang Liu, Yaoguang Huang, Hao Gong, Yiming Qi, Zihua Xu, Qingchun Zhao
Multitarget-directed ligands (MTDLs) have recently attracted significant interest due to their superior effectiveness in multifactorial Alzheimer's disease (AD). Combined inhibition of two important AD targets, glycogen synthase kinase-3β (GSK-3β) and dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), may be a breakthrough in the treatment of AD. Based on our previous work, we have designed and synthesized a series of novel harmine derivatives, investigated their inhibition of GSK-3β and DYRK1A, and evaluated a variety of biological activities...
November 27, 2023: Archiv der Pharmazie
https://read.qxmd.com/read/37997361/deficits-in-neuronal-architecture-but-not-over-inhibition-are-main-determinants-of-reduced-neuronal-network-activity-in-a-mouse-model-of-overexpression-of-dyrk1a
#30
JOURNAL ARTICLE
Linus Manubens-Gil, Meritxell Pons-Espinal, Thomas Gener, Inmaculada Ballesteros-Yañez, María Martínez de Lagrán, Mara Dierssen
In this study, we investigated the impact of Dual specificity tyrosine-phosphorylation-regulated kinase 1A (Dyrk1A) overexpression, a gene associated with Down syndrome, on hippocampal neuronal deficits in mice. Our findings revealed that mice overexpressing Dyrk1A (TgDyrk1A; TG) exhibited impaired hippocampal recognition memory, disrupted excitation-inhibition balance, and deficits in long-term potentiation (LTP). Specifically, we observed layer-specific deficits in dendritic arborization of TG CA1 pyramidal neurons in the stratum radiatum...
November 23, 2023: Cerebral Cortex
https://read.qxmd.com/read/37992782/sex-specific-developmental-alterations-in-dyrk1a-expression-in-the-brain-of-a-down-syndrome-mouse-model
#31
JOURNAL ARTICLE
Laura E Hawley, Megan Stringer, Abigail J Deal, Andrew Folz, Charles R Goodlett, Randall J Roper
Aberrant neurodevelopment in Down syndrome (DS)-caused by triplication of human chromosome 21-is commonly attributed to gene dosage imbalance, linking overexpression of trisomic genes with disrupted developmental processes, with DYRK1A particularly implicated. We hypothesized that regional brain DYRK1A protein overexpression in trisomic mice varies over development in sex-specific patterns that may be distinct from Dyrk1a transcription, and reduction of Dyrk1a copy number from 3 to 2 in otherwise trisomic mice reduces DYRK1A, independent of other trisomic genes...
January 2024: Neurobiology of Disease
https://read.qxmd.com/read/37952278/dnak-promotes-autophosphorylation-of-dyrk1a-and-its-family-kinases-in-escherichia-coli-based-cell-free-protein-expression
#32
JOURNAL ARTICLE
Mizuki Aoyama, Ninako Kimura, Masato Yamakawa, Sora Suzuki, Koji Umezawa, Isao Kii
Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is one of the drug target kinases involved in neurological disorders. DYRK1A phosphorylates substrate proteins related to disease progression in an intermolecular manner. Meanwhile, DYRK1A intramolecularly phosphorylates its own residues on key segments during folding process, which is required for its activation and stabilization. To reproduce the autophosphorylation in vitro, DYRK1A was expressed in Escherichia coli-based cell-free protein synthesis system...
November 8, 2023: Biochemical and Biophysical Research Communications
https://read.qxmd.com/read/37951194/harmine-and-kaempferol-treatment-enhances-nfatc1-and-foxp3-mediated-regulatory-t-cells-suppressive-capacity-in-generalized-vitiligo
#33
JOURNAL ARTICLE
Prashant S Giri, Ankit H Bharti, Jyoti Kode, Rasheedunnisa Begum, Mitesh Dwivedi
BACKGROUND: Generalized vitiligo (GV) is an autoimmune disease characterized by the progressive loss of melanocytes. OBJECTIVES: Current study was undertaken to assess in-vitro therapeutic potential of Harmine and Kaempferol for GV. METHODS: Calcium, calcineurin, NFATC1 levels, cell proliferation were assessed by various kits and ORAI1, PEIZO1, Calcineurin, GSK3B, DYRK1A transcripts and IFN-γ,IL-10,TGF-β protein levels were assessed by qPCR and ELISA in blood and skin biopsy samples from Tregs of 52 patients and 50 controls...
November 9, 2023: International Immunopharmacology
https://read.qxmd.com/read/37944876/pancreatic-beta-cell-regenerative-potential-of-zanthoxylum-chalybeum-engl-aqueous-stem-bark-extract
#34
JOURNAL ARTICLE
Clare Njoki Kimani, Helmuth Reuter, Sanet Henriët Kotzé, Pieter Venter, Pritika Ramharack, Christo John Frederick Muller
ETHNOPHARMACOLOGICAL RELEVANCE: Zanthoxylum chalybeum Engl. is endemic to Africa and has been used traditionally to treat diabetes mellitus. Moreover, its pharmacological efficacy has been confirmed experimentally using in vitro and in vivo models of diabetes. However, the effects of Z. chalybeum extracts and its major constituent compounds on beta cell and islet regeneration are not clear. Further, the mechanisms associated with observed antidiabetic effects at the beta cell level are not fully elucidated...
November 7, 2023: Journal of Ethnopharmacology
https://read.qxmd.com/read/37926156/hsc70-phosphorylation-patterns-and-calmodulin-regulate-ap2-ccv-life-span-for-cell-adhesion-protein-transport
#35
JOURNAL ARTICLE
G F Sengül, R Mishra, E Candiello, P Schu
AP2 forms AP2 CCV with clathrin and over 60 additional coat proteins. Due to this complexity, we have a limited understanding of CCV life cycle regulation. Synapses contain canonical AP2 CCV, canCCV, and more stable, thereby longer lived, AP2 CCV. The more stable AP2 CCV can be distinguished from canCCV due to the stable binding of Hsc70 to clathrin. The AP1/σ1B complex knockout leads to impaired synaptic vesicle recycling and altered endosomal protein sorting. This causes as a secondary phenotype the twofold upregulation of endocytosis by canCCV and by more stable AP2 CCV...
November 3, 2023: Biochimica et Biophysica Acta. Molecular Cell Research
https://read.qxmd.com/read/37906251/synergistic-roles-of-dyrk1a-and-gata1-in-trisomy-21-megakaryopoiesis
#36
JOURNAL ARTICLE
Ying Ting Sit, Kaoru Takasaki, Hyun Hyung An, Yan Xiao, Christian Hurtz, Peter Gearhart, Zhe Zhang, Paul Gadue, Deborah French, Stella T Chou
Patients with Down syndrome (DS, trisomy 21, T21) are at increased risk of transient abnormal myelopoiesis (TAM) and acute megakaryoblastic leukemia (ML-DS). Both TAM and ML-DS require prenatal somatic mutations in GATA1, resulting in the truncated isoform GATA1s. The mechanism by which individual chromosome 21 (HSA21) genes synergize with GATA1s for leukemic transformation is challenging to study, in part due to limited human cell models with wild type GATA1 or GATA1s. HSA21-encoded DYRK1A is overexpressed in ML-DS and may be a therapeutic target...
October 31, 2023: JCI Insight
https://read.qxmd.com/read/37900285/insights-from-the-protein-interaction-universe-of-the-multifunctional-goldilocks-kinase-dyrk1a
#37
REVIEW
Varsha Ananthapadmanabhan, Kathryn H Shows, Amanda J Dickinson, Larisa Litovchick
Human Dual specificity tyrosine (Y)-Regulated Kinase 1A (DYRK1A) is encoded by a dosage-dependent gene located in the Down syndrome critical region of human chromosome 21. The known substrates of DYRK1A include proteins involved in transcription, cell cycle control, DNA repair and other processes. However, the function and regulation of this kinase is not fully understood, and the current knowledge does not fully explain the dosage-dependent function of this kinase. Several recent proteomic studies identified DYRK1A interacting proteins in several human cell lines...
2023: Frontiers in Cell and Developmental Biology
https://read.qxmd.com/read/37872245/binding-mechanism-and-biological-effects-of-flavone-dyrk1a-inhibitors-for-the-design-of-new-antidiabetics
#38
JOURNAL ARTICLE
Katarzyna Pustelny, Przemyslaw Grygier, Agata Barzowska, Barbara Pucelik, Alex Matsuda, Krzysztof Mrowiec, Emilia Slugocka, Grzegorz M Popowicz, Grzegorz Dubin, Anna Czarna
The selective inhibition of kinases from the diabetic kinome is known to promote the regeneration of beta cells and provide an opportunity for the curative treatment of diabetes. The effect can be achieved by carefully tailoring the selectivity of inhibitor toward a particular kinase, especially DYRK1A, previously associated with Down syndrome and Alzheimer's disease. Recently DYRK1A inhibition has been shown to promote both insulin secretion and beta cells proliferation. Here, we show that commonly available flavones are effective inhibitors of DYRK1A...
October 23, 2023: Scientific Reports
https://read.qxmd.com/read/37864462/truncated-dyrk1a-aggravates-neuronal-apoptosis-by-inhibiting-asf-mediated-bcl-x-exon-2b-inclusion
#39
JOURNAL ARTICLE
Shuqiang Zhang, Junjie Zhong, Lian Xu, Yue Wu, Jie Xu, Jianhua Shi, Zhikai Gu, Xiaoyu Li, Nana Jin
AIM: Aggravated neuronal loss, caused mainly by neuronal apoptosis, is observed in the brain of patients with Alzheimer's disease (AD) and animal models of AD. A truncated form of Dual-specific and tyrosine phosphorylation-regulated protein kinase 1A (Dyrk1A) plays a vital role in AD pathogenesis. Downregulation of anti-apoptotic Bcl-xL is tightly correlated with neuronal loss in AD. However, the molecular regulation of neuronal apoptosis and Bcl-x expression by Dyrk1A in AD remains largely elusive...
October 21, 2023: CNS Neuroscience & Therapeutics
https://read.qxmd.com/read/37841687/glutamatergic-synaptic-deficits-in-the-prefrontal-cortex-of-the-ts65dn-mouse-model-for-down-syndrome
#40
JOURNAL ARTICLE
Aurore Thomazeau, Olivier Lassalle, Olivier J Manzoni
Down syndrome (DS), the most prevalent cause of intellectual disability, stems from a chromosomal anomaly resulting in an entire or partial extra copy of chromosome 21. This leads to intellectual disability and a range of associated symptoms. While there has been considerable research focused on the Ts65Dn mouse model of DS, particularly in the context of the hippocampus, the synaptic underpinnings of prefrontal cortex (PFC) dysfunction in DS, including deficits in working memory, remain largely uncharted territory...
2023: Frontiers in Neuroscience
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