keyword
https://read.qxmd.com/read/38479168/imidazo-1-2-b-pyridazines-as-inhibitors-of-dyrk-kinases
#1
JOURNAL ARTICLE
Scott H Henderson, Fiona J Sorrell, James M Bennett, Oleg Fedorov, Marcus T Hanley, Paulo H Godoi, Roberta Ruela de Sousa, Sean Robinson, Iva Hopkins Navratilova, Jonathan M Elkins, Simon E Ward
Selective inhibitors of DYRK1A are of interest for the treatment of cancer, Type 2 diabetes and neurological disorders. Optimization of imidazo [1,2-b]pyridazine fragment 1 through structure-activity relationship exploration and in silico drug design efforts led to the discovery of compound 17 as a potent cellular inhibitor of DYRK1A with selectivity over much of the kinome. The binding mode of compound 17 was elucidated with X-ray crystallography, facilitating the rational design of compound 29, an imidazo [1,2-b]pyridazine with improved kinase selectivity with respect to closely related CLK kinases...
March 7, 2024: European Journal of Medicinal Chemistry
https://read.qxmd.com/read/38474215/gene-expression-studies-in-down-syndrome-what-do-they-tell-us-about-disease-phenotypes
#2
REVIEW
Laura R Chapman, Isabela V P Ramnarine, Dan Zemke, Arshad Majid, Simon M Bell
Down syndrome is a well-studied aneuploidy condition in humans, which is associated with various disease phenotypes including cardiovascular, neurological, haematological and immunological disease processes. This review paper aims to discuss the research conducted on gene expression studies during fetal development. A descriptive review was conducted, encompassing all papers published on the PubMed database between September 1960 and September 2022. We found that in amniotic fluid, certain genes such as COL6A1 and DSCR1 were found to be affected, resulting in phenotypical craniofacial changes...
March 4, 2024: International Journal of Molecular Sciences
https://read.qxmd.com/read/38461326/microrna-221-3p-inhibits-the-inflammatory-response-of-keratinocytes-by-regulating-the-dyrk1a-stat3-signaling-pathway-to-promote-wound-healing-in-diabetes
#3
JOURNAL ARTICLE
Keyan Hu, Lei Liu, Songtao Tang, Xin Zhang, Hongfeng Chang, Wenyang Chen, Taotao Fan, Lesha Zhang, Bing Shen, Qiu Zhang
Diabetic foot ulcer (DFU), a serious complication of diabetes, remains a clinical challenge. MicroRNAs affect inflammation and may have therapeutic value in DFU. Here, we find that an miR-221-3p mimic reduces the inflammatory response and increases skin wound healing rates in a mouse model of diabetes, whereas miR-221-3p knockout produced the opposite result. In human keratinocytes cells, miR-221-3p suppresses the inflammatory response induced by high glucose. The gene encoding DYRK1A is a target of miR-221-3p...
March 9, 2024: Communications Biology
https://read.qxmd.com/read/38447464/synthesis-and-evaluation-of-novel-n1-acylated-5-4-pyridinyl-indazole-derivatives-as-potent-and-selective-haspin-inhibitors
#4
JOURNAL ARTICLE
Mona M Shawky, Mennatallah Abdallah, Hend Khalifa, Youssef Aboushady, Ashraf H Abadi, Matthias Engel, Mohammad Abdel-Halim
Protein kinase dysregulation was strongly linked to cancer pathogenesis. Moreover, histone alterations were found to be among the most important post-translational modifications that could contribute to cancer growth and development. In this context, haspin, an atypical serine/threonine kinase, phosphorylates histone H3 at threonine-3 and is notably overexpressed in various common cancer types. Herein, we report novel 5-(4-pyridinyl)indazole derivatives as potent and selective haspin inhibitors. Amide coupling at N1 of the indazole ring with m-hydroxyphenyl acetic acid yielded compound 21 with an IC50 value of 78 nM against haspin...
February 20, 2024: Bioorganic Chemistry
https://read.qxmd.com/read/38438741/dyrk1a-causes-heart-defects-in-down-syndrome
#5
JOURNAL ARTICLE
Alexandra Le Bras
No abstract text is available yet for this article.
March 2024: Lab Animal
https://read.qxmd.com/read/38434732/corrigendum-gut-and-spleen-anomalies-associated-with-dyrk1a-syndrome
#6
I Infantino, F Tocchioni, M Ghionzoli, R Coletta, F Morini, A Morabito
[This corrects the article DOI: 10.3389/fped.2022.936732.].
2024: Frontiers in Pediatrics
https://read.qxmd.com/read/38426275/efficacy-of-dyrk1a-inhibitors-in-novel-models-of-down-syndrome-acute-lymphoblastic-leukemia
#7
JOURNAL ARTICLE
Shannon L Carey-Smith, Maryam H Simad, Kunjal Panchal, Carlos Aya-Bonilla, Hannah Smolders, Sang Lin, Jesse D Armitage, Vivien T Nguyen, Kathryn Bentley, Jette Ford, Sajla Singh, Joyce Oommen, Anouchka P Laurent, Thomas Mercher, John D Crispino, Andrew P Montgomery, Michael Kassiou, Thierry Besson, Emmanuel Deau, Laurent Meijer, Laurence C Cheung, Rishi S Kotecha, Sébastien Malinge
Not available.
February 29, 2024: Haematologica
https://read.qxmd.com/read/38382213/generation-of-a-human-induced-pluripotent-stem-cell-line-fdchi012-a-from-a-patient-with-dyrk1a-related-intellectual-disability-syndrome-carrying-dyrk1a-mutation-c-1024g%C3%A2-%C3%A2-t
#8
JOURNAL ARTICLE
Yanzhuang Ge, Yan Cheng, Tingting Yin, Xingsheng Peng, Zhongmeng Xiong, Bingbing Wu, Huijun Wang, Man Xiong, Wenhao Zhou
DYRK1A haploinsufficiency causes a neurodevelopmental syndrome termed DYRK1A-related intellectual disability syndrome which is associated with a range of symptoms including microcephaly, epileptic seizures, and autism spectrum disorder. Here, we generated an induced Pluripotent Stem Cell (iPSC) line with a de novo missense mutation (DYRKIA c.1024G > T) from the peripheral blood mononuclear cells of a patient with DYRK1A-related intellectual disability syndrome. This iPSC line showed normal karyotype, exhibited pluripotency, and has three embryonic germ layers differentiation capacity...
February 11, 2024: Stem Cell Research
https://read.qxmd.com/read/38326439/dyrk1a-gene-linked-to-heart-defects-in-down-syndrome
#9
JOURNAL ARTICLE
Irene Fernández-Ruiz
No abstract text is available yet for this article.
February 7, 2024: Nature Reviews. Cardiology
https://read.qxmd.com/read/38300844/naturally-occurring-caffeic-acid-phenethyl-ester-from-chestnut-honey-based-propolis-and-virtual-screening-towards-dyrk1a
#10
JOURNAL ARTICLE
Idris Arslan
Neurodegenerative diseases (NDDs) are disorders with dysfunction and ongoing loss of neurons, glial cells and the neural networks in the brain and spinal cord. DYRK1A protein was reported to modulate to the cytoskeletal fraction in human and mouse brain, and the remaining protein is located in the cytosolic and nuclear fractions. Caffeic acid phenethyl ester (CAPE) is a natural derivative of caffeic acid and found in propolis, a bee product. In this study, we focused on isolation and characterisation of CAPE from chestnut honey-based propolis by HPLC-MS/MS technique and virtual screening of CAPE towards DYRK1A by molecular docking methods...
February 1, 2024: Natural Product Research
https://read.qxmd.com/read/38298296/a-rare-cause-of-intellectual-disability
#11
Íris Oliveira, Andreia Fernandes, Mafalda Pereira, Márcia Rodrigues, Noémia Silva, Carla Mendonça
A seven-year-old female was followed in a developmental clinic from the age of nine months due to delayed psychomotor development. The first physical examination showed a newborn with irritability and a large anterior fontanelle. A transfontanellar ultrasound was performed, revealing mild enlargement of the lateral and third ventricles. Head circumference remained below the third percentile until the age of five months, then rose to the third percentile. Developmental milestones were globally delayed, with expressive language being more severely affected and axial hypotonia with appendicular hypertonia on neurological examination...
January 2024: Curēus
https://read.qxmd.com/read/38283191/systems-biology-approach-to-identify-biomarkers-and-therapeutic-targets-for-colorectal-cancer
#12
JOURNAL ARTICLE
Niloufar Sadat Kalaki, Mozhgan Ahmadzadeh, Mohammad Najafi, Meysam Mobasheri, Hossein Ajdarkosh, Mohammad Hadi Karbalaie Niya
BACKGROUND: Colorectal cancer (CRC), is the third most prevalent cancer across the globe, and is often detected at advanced stage. Late diagnosis of CRC, leave the chemotherapy and radiotherapy as the main options for the possible treatment of the disease which are associated with severe side effects. In the present study, we seek to explore CRC gene expression data using a systems biology framework to identify potential biomarkers and therapeutic targets for earlier diagnosis and treatment of the disease...
March 2024: Biochemistry and Biophysics Reports
https://read.qxmd.com/read/38276744/asymmetric-schottky-barrier-generated-mos-2-wte-2-fet-biosensor-based-on-a-rectified-signal
#13
JOURNAL ARTICLE
Xinhao Zhang, Shuo Chen, Heqi Ma, Tianyu Sun, Xiangyong Cui, Panpan Huo, Baoyuan Man, Cheng Yang
Field-effect transistor (FET) biosensors can be used to measure the charge information carried by biomolecules. However, insurmountable hysteresis in the long-term and large-range transfer characteristic curve exists and affects the measurements. Noise signal, caused by the interference coefficient of external factors, may destroy the quantitative analysis of trace targets in complex biological systems. In this report, a "rectified signal" in the output characteristic curve, instead of the "absolute value signal" in the transfer characteristic curve, is obtained and analyzed to solve these problems...
January 20, 2024: Nanomaterials
https://read.qxmd.com/read/38266108/increased-dosage-of-dyrk1a-leads-to-congenital-heart-defects-in-a-mouse-model-of-down-syndrome
#14
JOURNAL ARTICLE
Eva Lana-Elola, Rifdat Aoidi, Miriam Llorian, Dorota Gibbins, Callan Buechsenschuetz, Claudio Bussi, Helen Flynn, Tegan Gilmore, Sheona Watson-Scales, Marie Haugsten Hansen, Darryl Hayward, Ok-Ryul Song, Véronique Brault, Yann Herault, Emmanuel Deau, Laurent Meijer, Ambrosius P Snijders, Maximiliano G Gutierrez, Elizabeth M C Fisher, Victor L J Tybulewicz
Down syndrome (DS) is caused by trisomy of human chromosome 21 (Hsa21). DS is a gene dosage disorder that results in multiple phenotypes including congenital heart defects. This clinically important cardiac pathology is the result of a third copy of one or more of the approximately 230 genes on Hsa21, but the identity of the causative dosage-sensitive genes and hence mechanisms underlying this cardiac pathology remain unclear. Here, we show that hearts from human fetuses with DS and embryonic hearts from the Dp1Tyb mouse model of DS show reduced expression of mitochondrial respiration genes and cell proliferation genes...
January 24, 2024: Science Translational Medicine
https://read.qxmd.com/read/38260562/dyrk1a-is-required-for-craniofacial-development-in-xenopus-laevis
#15
H Katherine Johnson, Stacy E Wahl, Fatmata Sesay, Larisa Litovchick, Amanda Jg Dickinson
Loss of function mutations in the dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) gene are associated with craniofacial malformations in humans. Here we characterized the effects of deficient DYRK1A in craniofacial development using a developmental model, Xenopus laevis . Dyrk1a mRNA and protein was expressed throughout the developing head and was enriched in the branchial arches which contribute to the face and jaw. Consistently, reduced Dyrk1a function, using dyrk1a morpholinos and pharmacological inhibitors, resulted in orofacial malformations including hypotelorism, altered mouth shape, slanted eyes, and narrower face accompanied by smaller jaw cartilage and muscle...
January 14, 2024: bioRxiv
https://read.qxmd.com/read/38254631/loss-of-the-dyrk1a-protein-kinase-results-in-the-reduction-in-ribosomal-protein-gene-expression-ribosome-mass-and-reduced-translation
#16
JOURNAL ARTICLE
Chiara Di Vona, Laura Barba, Roberto Ferrari, Susana de la Luna
Ribosomal proteins (RPs) are evolutionary conserved proteins that are essential for protein translation. RP expression must be tightly regulated to ensure the appropriate assembly of ribosomes and to respond to the growth demands of cells. The elements regulating the transcription of RP genes (RPGs) have been characterized in yeast and Drosophila , yet how cells regulate the production of RPs in mammals is less well understood. Here, we show that a subset of RPG promoters is characterized by the presence of the palindromic TCTCGCGAGA motif and marked by the recruitment of the protein kinase DYRK1A...
December 25, 2023: Biomolecules
https://read.qxmd.com/read/38245602/inherent-genome-instability-underlies-trisomy-21-associated-myeloid-malignancies
#17
JOURNAL ARTICLE
Chun-Chin Chen, Rebecca E Silberman, Duanduan Ma, Jennifer A Perry, Delan Khalid, Yana Pikman, Angelika Amon, Michael T Hemann, R Grant Rowe
Constitutional trisomy 21 (T21) is a state of aneuploidy associated with high incidence of childhood acute myeloid leukemia (AML). T21-associated AML is preceded by transient abnormal myelopoiesis (TAM), which is triggered by truncating mutations in GATA1 generating a short GATA1 isoform (GATA1s). T21-associated AML emerges due to secondary mutations in hematopoietic clones bearing GATA1s. Since aneuploidy generally impairs cellular fitness, the paradoxically elevated risk of myeloid malignancy in T21 is not fully understood...
January 20, 2024: Leukemia
https://read.qxmd.com/read/38212778/identification-of-potential-biomarkers-and-therapeutic-targets-related-to-post-traumatic-stress-disorder-due-to-traumatic-brain-injury
#18
JOURNAL ARTICLE
Peng Qi, Mengjie Huang, Xuewen Ren, Yongzhi Zhai, Chen Qiu, Haiyan Zhu
BACKGROUND: Post-traumatic stress disorder (PTSD), a disease state that has an unclear pathogenesis, imposes a substantial burden on individuals and society. Traumatic brain injury (TBI) is one of the most significant triggers of PTSD. Identifying biomarkers associated with TBI-related PTSD will help researchers to uncover the underlying mechanism that drives disease development. Furthermore, it remains to be confirmed whether different types of traumas share a common mechanism of action...
January 11, 2024: European Journal of Medical Research
https://read.qxmd.com/read/38195774/gr-ahi1-regulates-wdr68-dyrk1a-binding-and-mediates-cognitive-impairment-in-prenatally-stressed-offspring
#19
JOURNAL ARTICLE
Bin Wei, Haixia Shi, Xi Yu, Yajun Shi, Hongtao Zeng, Yan Zhao, Zejun Zhao, Yueyang Song, Miao Sun, Bin Wang
Accumulating research shows that prenatal exposure to maternal stress increases the risk of behavioral and mental health problems for offspring later in life. However, how prenatal stress affects offspring behavior remains unknown. Here, we found that prenatal stress (PNS) leads to reduced Ahi1, decreased synaptic plasticity and cognitive impairment in offspring. Mechanistically, Ahi1 and GR stabilize each other, inhibit GR nuclear translocation, promote Ahi1 and WDR68 binding, and inhibit DYRK1A and WDR68 binding...
January 10, 2024: Cellular and Molecular Life Sciences: CMLS
https://read.qxmd.com/read/38171148/egcg-like-non-competitive-inhibitor-of-dyrk1a-rescues-cognitive-defect-in-a-down-syndrome-model
#20
JOURNAL ARTICLE
Jean M Delabar, Marco Antônio G B Gomes, Marta Fructuoso, Nadège Sarrazin, Nicolas George, Nadia Fleary-Roberts, Hua Sun, Linh Chi Bui, Fernando Rodrigues-Lima, Nathalie Janel, Julien Dairou, Edmilson J Maria, Robert H Dodd, Kevin Cariou, Marie-Claude Potier
Overexpression of the chromosome 21 DYRK1A gene induces morphological defects and cognitive impairments in individuals with Down syndrome (DS) and in DS mice models. Aging neurons of specific brain regions of patients with Alzheimer's disease, DS and Pick's disease have increased DYRK1A immunoreactivity suggesting a possible association of DYRK1A with neurofibrillary tangle pathology. Epigallocatechin-3-gallate (EGCG) displays appreciable inhibition of DYRK1A activity and, contrary to all other published inhibitors, EGCG is a non-competitive inhibitor of DYRK1A...
January 1, 2024: European Journal of Medicinal Chemistry
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