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https://www.readbyqxmd.com/read/29649626/novel-compounds-tad-1822-7-f2-and-f5-inhibited-hela-cells-growth-through-the-jak-stat-signaling-pathway
#1
Tianfeng Yang, Xianpeng Shi, Yuan Kang, Man Zhu, Mengying Fan, Dongdong Zhang, Yanmin Zhang
Cervical carcinoma remains the second most common malignancy with a high mortality rate among women worldwide. TAD-1822-7-F2 (F2) and TAD-1822-7-F5 (F5) are novel compounds synthesized on the chemical structure of taspine derivatives, and show an effective suppression for HeLa cells. Our study aims to confirm the potential targets of F2 and F5, and investigate the underlying mechanism of the inhibitory effect on HeLa cells. In this study, Real Time Cell Analysis and crystal violet staining assay were conducted to investigate the effect of F2 and F5 on HeLa cells proliferation...
April 9, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/29589523/an-update-on-jak-inhibitors
#2
Francesca Musumeci, Chiara Greco, Ilaria Giacchell, Anna Lucia Fallacara, Munjed M Ibrahim, Giancarlo Grossi, Chiara Brullo, Silvia Schenone
Janus kinases (JAKs) are a family of non-receptor tyrosine kinases, composed by four members, JAK1, JAK2, JAK3 and TYK2. JAKs are involved in different inflammatory and autoimmune diseases, as well as in malignancies, through the activation of the JAK/STAT signalling pathway. Furthermore, the V617F mutation in JAK2 was identified in patients affected by myeloproliferative neoplasms. This knowledge prompted researchers from academia and pharmaceutical companies to investigate this field in order to discover small molecule JAK inhibitors...
March 26, 2018: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/29588471/discovery-of-a-highly-selective-jak3-inhibitor-for-the-treatment-of-rheumatoid-arthritis
#3
Heying Pei, Linhong He, Mingfeng Shao, Zhuang Yang, Yan Ran, Dan Li, Yuanyuan Zhou, Minghai Tang, Taijin Wang, Yanqiu Gong, Xiaoxin Chen, Shengyong Yang, Mingli Xiang, Lijuan Chen
Janus tyrosine kinase 3 (JAK3) is expressed in lymphoid cells and is involved in the signalling of T cell functions. The development of a selective JAK3 inhibitor has been shown to have a potential benefit in the treatment of autoimmune disorders. In this article, we developed the 4-aminopiperidine-based compound RB1, which was highly selective for JAK3 inhibition, with an IC50 of value of 40 nM, but did not inhibit JAK1, JAK2 or tyrosine kinase 2 (TYK2) at concentrations up to 5 µM. Furthermore, RB1 also exhibited favourable selectivity against a panel of representative kinases...
March 27, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29541669/dataset-on-characterization-of-recombinant-interleukin-23%C3%AE-il-12p40-and-il-23-complex-protein-which-activates-jak-stat-signaling-pathway-in-chicken-cell-lines-using-immunocytochemical-staining
#4
Anh Duc Truong, Cong Thanh Hoang, Yeojin Hong, Janggeun Lee, Kyungbaek Lee, Hyun S Lillehoj, Yeong Ho Hong
The data herein is related to the research article entitled "Functional analyses of the interaction of chicken interleukin 23 subunit p19 with IL-12 subunit p40 to form the IL-23 complex" [1] where we demonstrated that the chicken interleukin (IL)-23α, IL-12p40, and IL-23 complex regulates Th1, Th17, and Treg cytokine production through heterodimer receptors as well as a homodimer receptor consisting of IL-12Rβ1 and IL-23R, and activates the JAK/STAT signaling pathways. Here, we evaluated the effects of the recombinant chicken IL-23α, IL-12p40, and IL-23 complex protein on cell proliferation and nitric oxide (NO) production in chicken macrophage (HD11) and CU91 T cell lines...
February 2018: Data in Brief
https://www.readbyqxmd.com/read/29504848/signalling-pathways-identified-in-salivary-glands-from-primary-sj%C3%A3-gren-s-syndrome-patients-reveal-enhanced-adipose-tissue-development
#5
Lara A Aqrawi, Janicke Liaaen Jensen, Gunnvor Øijordsbakken, Ann-Kristin Ruus, Ståle Nygård, Marit Holden, Roland Jonsson, Hilde Kanli Galtung, Kathrine Skarstein
A characteristic feature of primary Sjögren's syndrome (pSS) is the destruction of salivary and lacrimal glands mediated by mononuclear cell infiltration. Adipocytes can also occupy a large portion of the salivary gland (SG) tissue area, although little is known about their significance in pSS. We have previously investigated adipose tissue infiltration in SG biopsies from pSS patients and non-SS sicca controls. Our findings indicated the distinct incidence of adipose tissue replacement in pSS patients, where adipocytes were detected in interleukin (IL) 6 rich regions...
March 5, 2018: Autoimmunity
https://www.readbyqxmd.com/read/29475858/the-stat4-sle-risk-allele-rs7574865-t-is-associated-with-increased-il-12-induced-ifn-%C3%AE-production-in-t-cells-from-patients-with-sle
#6
Niklas Hagberg, Martin Joelsson, Dag Leonard, Sarah Reid, Maija-Leena Eloranta, John Mo, Magnus K Nilsson, Ann-Christine Syvänen, Yenan T Bryceson, Lars Rönnblom
OBJECTIVES: Genetic variants in the transcription factor STAT4 are associated with increased susceptibility to systemic lupus erythematosus (SLE) and a more severe disease phenotype. This study aimed to clarify how the SLE-associated intronic STAT4 risk allele rs7574865[T] affects the function of immune cells in SLE. METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from 52 genotyped patients with SLE. Phosphorylation of STAT4 (pSTAT4) and STAT1 (pSTAT1) in response to interferon (IFN)-α, IFN-γ or interleukin (IL)-12, total levels of STAT4, STAT1 and T-bet, and frequency of IFN-γ+ cells on IL-12 stimulation were determined by flow cytometry in subsets of immune cells before and after preactivation of cells with phytohaemagglutinin (PHA) and IL-2...
February 23, 2018: Annals of the Rheumatic Diseases
https://www.readbyqxmd.com/read/29455109/dysregulation-of-jak-stat-genes-by-vasoactive-intestinal-peptide-vip-in-salmonella-infected-monocytes-may-inhibit-its-therapeutic-potential-in-human-sepsis
#7
Hiba Ibrahim, Basim Askar, Paul Barrow, Neil Foster
Murine/LPS models of Gram negative sepsis indicate that vasoactive intestinal peptide (VIP) has therapeutic potential. We investigated the unknown effect of VIP on JAK/STAT proteins and genes in human monocytes infected with Salmonella Typhimurium 14028. S. Typhimurium 14028 increased expression of both IL-6 receptor (IL-6R) and interferon gamma receptor 1 (IFNγR1) on monocytes but co-culture of infected monocytes with VIP (10-7 M) only decreased expression of IFNγR1 (P < 0.05). In contrast, S. Typhimurium 14028 infection or co-culture with VIP had no effect on IL-10 receptor expression on the monocyte surface...
February 15, 2018: Cytokine
https://www.readbyqxmd.com/read/29454012/immunologic-effects-of-chronic-administration-of-tofacitinib-a-janus-kinase-inhibitor-in-cynomolgus-monkeys-and-rats-comparison-of-juvenile-and-adult-responses
#8
Mark Collinge, Douglas J Ball, Christopher J Bowman, Andrea L Nilson, Zaher A Radi, W Mark Vogel
Tofacitinib, an oral Janus kinase (JAK) inhibitor for treatment of rheumatoid arthritis, targets JAK1, JAK3, and to a lesser extent JAK2 and TYK2. JAK1/3 inhibition impairs gamma common chain cytokine receptor signaling, important in lymphocyte development, homeostasis and function. Adult and juvenile cynomolgus monkey and rat studies were conducted and the impact of tofacitinib on immune parameters (lymphoid tissues and lymphocyte subsets) and function (T-dependent antibody response (TDAR), mitogen-induced T cell proliferation) assessed...
February 14, 2018: Regulatory Toxicology and Pharmacology: RTP
https://www.readbyqxmd.com/read/29452839/development-of-selective-inhibitors-for-the-treatment-of-rheumatoid-arthritis-r-3-3-methyl-7h-pyrrolo-2-3-d-pyrimidin-4-yl-amino-pyrrolidin-1-yl-3-oxopropanenitrile-as-a-jak1-selective-inhibitor
#9
Chieyeon Chough, Misuk Joung, Sunmin Lee, Jaemin Lee, Jong Hoon Kim, B Moon Kim
A series of 3(R)-aminopyrrolidine derivatives were designed and synthesized for JAK1-selective inhibitors through the modification of tofacitinib's core structure, (3R,4R)-3-amino-4-methylpiperidine. From the new core structures, we selected (R)-N-methyl-N-(pyrrolidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine as a scaffold for further SAR studies. From biochemical enzyme assays and liver microsomal stability tests, (R)-3-(3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)-3-oxopropanenitrile (6) was chosen for further in vivo test through oral administration...
February 3, 2018: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/29434279/oncogenic-activation-of-jak3-stat-signaling-confers-clinical-sensitivity-to-prn371-a-novel-selective-and-potent-jak3-inhibitor-in-natural-killer-t-cell-lymphoma
#10
M -L Nairismägi, M E Gerritsen, Z M Li, G C Wijaya, B K H Chia, Y Laurensia, J Q Lim, K W Yeoh, X S Yao, W L Pang, A Bisconte, R J Hill, J M Bradshaw, D Huang, T L L Song, C C Y Ng, V Rajasegaran, T Tang, Q Q Tang, X J Xia, T B Kang, B T Teh, S T Lim, C K Ong, J Tan
Aberrant activation of the JAK3-STAT signaling pathway is a characteristic feature of many hematological malignancies. In particular, hyperactivity of this cascade has been observed in natural killer/T-cell lymphoma (NKTL) cases. Although the first-in-class JAK3 inhibitor tofacitinib blocks JAK3 activity in NKTL both in vitro and in vivo, its clinical utilization in cancer therapy has been limited by the pan-JAK inhibition activity. To improve the therapeutic efficacy of JAK3 inhibition in NKTL, we have developed a highly selective and durable JAK3 inhibitor PRN371 that potently inhibits JAK3 activity over the other JAK family members JAK1, JAK2, and TYK2...
February 2, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/29351919/high-yield-of-pathogenic-germline-mutations-causative-or-likely-causative-of-the-cancer-phenotype-in-selected-children-with-cancer
#11
Illja J Diets, Esmé Waanders, Marjolijn J Ligtenberg, Diede A G van Bladel, Eveline J Kamping, Peter M Hoogerbrugge, Saskia Hopman, Maran J Olderode-Berends, Erica H Gerkes, David A Koolen, Carlo Marcelis, Gijs W Santen, Martine J van Belzen, Dylan Mordaunt, Lesley McGregor, Elizabeth Thompson, Antonis Kattamis, Agata Pastorczak, Wojciech Mlynarski, Denisa Ilencikova, Anneke Vulto- van Silfhout, Thatjana Gardeitchik, Eveline S de Bont, Jan Loeffen, Anja Wagner, Arjen R Mensenkamp, Roland P Kuiper, Nicoline Hoogerbrugge, Marjolijn C Jongmans
Purpose: In many children with cancer and characteristics suggestive of a genetic predisposition syndrome, the genetic cause is still unknown. We studied the yield of pathogenic mutations by applying whole-exome sequencing on a selected cohort of children with cancer. Experimental Design: To identify mutations in known and novel cancer-predisposing genes, we performed trio-based whole-exome sequencing on germline DNA of 40 selected children and their parents. These children were diagnosed with cancer and had at least one of the following features: (1) intellectual disability and/or congenital anomalies, (2) multiple malignancies, (3) family history of cancer, or (4) an adult type of cancer...
April 1, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29340620/delivery-of-tapasin-modified-ctl-epitope-peptide-via-cytoplasmic-transduction-peptide-induces-ctls-by-jak-stat-signaling-pathway-in-vivo
#12
Shanshan Wu, Xiaohua Chen, Yuyan Tang, Yi Zhang, Dan Li, Jie Chen, Jieling Wang, Zhenghao Tang, Guoqing Zang, Yongsheng Yu
Hepatitis B virus (HBV)-specific cytotoxic T lymphocytes (CTLs) play a vital role in viral control and clearance. Recent studies have elucidated that Tapasin, an endoplasmic reticulum chaperone, is a well-known molecule that appears to be essential in peptide-loading process. The Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway plays an important role in immune response regulation and cytokines secretion. We have previously verified that fusion protein CTP-HBcAg18-27-Tapasin could facilitate the maturation of bone marrow derived dendritic cells and enhance specific CTLs responses in vitro, which might be associated with the activation of JAK/STAT signaling pathway...
February 1, 2018: Acta Biochimica et Biophysica Sinica
https://www.readbyqxmd.com/read/29316631/psoriasis-a-stat3-centric-view
#13
REVIEW
Enzo Calautti, Lidia Avalle, Valeria Poli
Signal Transducer and Activator of Transcription (STAT)3 has recently emerged as a key player in the development and pathogenesis of psoriasis and psoriatic-like inflammatory conditions. Indeed, STAT3 hyperactivation has been reported in virtually every cell type involved in disease initiation and maintenance, and this factor mediates the signal of most cytokines that are involved in disease pathogenesis, including the central Interleukin (IL)-23/IL-17/IL-22 axis. Despite the recent availability of effective biological agents (monoclonal antibodies) against IL-17 and IL-23, which have radically changed the current standard of disease management, the possibility of targeting either STAT3 itself or, even better, the family of upstream activators Janus kinases (JAK1, 2, 3, and TYK2) offers additional therapeutic options...
January 6, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29304122/comprehensive-analysis-of-three-tyk2-gene-variants-in-the-susceptibility-to-chagas-disease-infection-and-cardiomyopathy
#14
Daniel A Leon Rodriguez, Marialbert Acosta-Herrera, F David Carmona, Nuria Dolade, Sofia Vargas, Luis Eduardo Echeverría, Clara Isabel González, Javier Martin
Tyrosine kinase 2 (TYK2) is a member of the Janus kinases family implicated in the signal transduction of type I interferons and several interleukins. It has been described that genetic mutations within TYK2 lead to multiple deleterious effects in the immune response. In this work, we have analyzed three functional independent variants from the frequency spectrum on the TYK2 gene (common and low-frequency variants) suggested to reduce the function of the gene in mediating cytokine signaling and the susceptibility to infections by Trypanosoma cruzi and/or the development of Chagas cardiomyopathy in the Colombian population...
2018: PloS One
https://www.readbyqxmd.com/read/29298069/identification-of-n-cis-3-methyl-7h-pyrrolo-2-3-d-pyrimidin-4-yl-amino-cyclobutyl-propane-1-sulfonamide-pf-04965842-a-selective-jak1-clinical-candidate-for-the-treatment-of-autoimmune-diseases
#15
Michael L Vazquez, Neelu Kaila, Joseph W Strohbach, John D Trzupek, Matthew F Brown, Mark E Flanagan, Mark J Mitton-Fry, Timothy A Johnson, Ruth E TenBrink, Eric P Arnold, Arindrajit Basak, Steven E Heasley, Soojin Kwon, Jonathan Langille, Mihir D Parikh, Sarah H Griffin, Jeffrey M Casavant, Brian A Duclos, Ashley E Fenwick, Thomas M Harris, Seungil Han, Nicole Caspers, Martin E Dowty, Xin Yang, Mary Ellen Banker, Martin Hegen, Peter T Symanowicz, Li Li, Lu Wang, Tsung H Lin, Jason Jussif, James D Clark, Jean-Baptiste Telliez, Ralph P Robinson, Ray Unwalla
Janus kinases (JAKs) are intracellular tyrosine kinases that mediate the signaling of numerous cytokines and growth factors involved in the regulation of immunity, inflammation, and hematopoiesis. As JAK1 pairs with JAK2, JAK3, and TYK2, a JAK1-selective inhibitor would be expected to inhibit many cytokines involved in inflammation and immune function while avoiding inhibition of the JAK2 homodimer regulating erythropoietin and thrombopoietin signaling. Our efforts began with tofacitinib, an oral JAK inhibitor approved for the treatment of rheumatoid arthritis...
February 8, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29296813/oncogenic-role-and-therapeutic-targeting-of-abl-class-and-jak-stat-activating-kinase-alterations-in-ph-like-all
#16
Kathryn G Roberts, Yung-Li Yang, Debbie Payne-Turner, Wenwei Lin, Jacob K Files, Kirsten Dickerson, Zhaohui Gu, Jack Taunton, Laura J Janke, Taosheng Chen, Mignon L Loh, Stephen P Hunger, Charles G Mullighan
New therapies for Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) patients are urgently needed. The genetic landscape of Ph-like ALL is characterized by a diverse array of kinase-activating alterations (including rearrangements, sequence mutations, and copy number alterations), suggesting that patients with Ph-like ALL are candidates for targeted therapy, similar to BCR-ABL1 ALL. We sought to investigate the functional role and targetability of the spectrum of kinase-activating alterations identified in Ph-like ALL...
September 12, 2017: Blood Advances
https://www.readbyqxmd.com/read/29200018/the-diagnostic-and-prognostic-role-of-interleukin-12b-and-interleukin-6r-gene-polymorphism-in-patients-with-ankylosing-spondylitis
#17
Wen-Feng Ruan, Jiang-Tao Xie, Qi Jin, Wen-Da Wang, An-Song Ping
OBJECTIVES: Interleukin 23 (IL-23) pathway and IL-1 cluster genes play prominent role in the etiopathology of ankylosing spondylitis (AS). The aim of this study was to investigate the diagnostic and prognostic role of 5 single-nucleotide polymorphisms related to IL-23 pathway and IL-1 cluster genes in AS patients. METHODS: Four hundred thirty-one patients with AS and 206 age- and sex-matched healthy controls were recruited in this prospective cohort study. Five potential single-nucleotide polymorphisms (IL-23R [rs11209026], IL-12B [rs6871626], TYK2 [rs6511701], IL-6R [rs4129267], and IL-1R2 [rs2192752]) related to IL-23 pathway and IL-1 cluster genes by analyzing previous studies were genotyped...
January 2018: Journal of Clinical Rheumatology: Practical Reports on Rheumatic & Musculoskeletal Diseases
https://www.readbyqxmd.com/read/29162862/tyk2-induced-phosphorylation-of-y640-suppresses-stat3-transcriptional-activity
#18
Raffaele Mori, Joris Wauman, Laura Icardi, José Van der Heyden, Lode De Cauwer, Frank Peelman, Karolien De Bosscher, Jan Tavernier
STAT3 is a pleiotropic transcription factor involved in homeostatic and host defense processes in the human body. It is activated by numerous cytokines and growth factors and generates a series of cellular effects. Of the STAT-mediated signal transduction pathways, STAT3 transcriptional control is best understood. Jak kinase dependent activation of STAT3 relies on Y705 phosphorylation triggering a conformational switch that is stabilized by intermolecular interactions between SH2 domains and the pY705 motif...
November 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29157973/when-the-good-go-bad-mutant-npm1-in-acute-myeloid-leukemia
#19
REVIEW
Preethi Kunchala, Sudhakiranmayi Kuravi, Roy Jensen, Joseph McGuirk, Ramesh Balusu
Nucleophosmin 1 (NPM1) is a nucleolar phosphoprotein that performs diverse biological functions including molecular chaperoning, ribosome biogenesis, DNA repair, and genome stability. Acute myeloid leukemia (AML) is a heterogeneous disease, more than half of the AML cases exhibit normal karyotype (NK). Approximately 50-60 percent of patients with NK-AML carry NPM1 mutations which are characterized by cytoplasmic dislocation of the NPM1 protein. In AML, mutant NPM1 (NPM1c+) acts in a dominant negative fashion and also blocks the differentiation of myeloid cells through gain-of-function for the AML phenotype...
November 4, 2017: Blood Reviews
https://www.readbyqxmd.com/read/29157944/down-regulation-of-tyk2-cblb-and-lmp7-genes-expression-in-relapsing-remitting-multiple-sclerosis-patients-treated-with-interferon-beta
#20
Mehrdokht Mazdeh, Najmeh Moradi, Elnaz Khoshroo, Zahra Shayesteh, Mohammad Taheri, Arezou Sayad, Mir Davood Omrani, Mehrdad Hajilooi, Ghodratollah Roshanaei, Ghasem Solgi
This study aimed to examine the expression of TYK2, CBLB and LMP7 genes at both mRNA and protein levels in relapsing-remitting MS (RRMS) patients in compare with healthy controls. Seventy-eight RRMS patients treated with IFNβ-1a and 79 age- and ethnic-matched healthy subjects were studied. The mRNA expression levels of TYK2, CBLB and LMP7 in PBMCs were quantified by real-time PCR and plasma concentrations of three molecules were measured by ELISA. Results were compared between patients and controls, IFNβ-responders and non-responders...
January 15, 2018: Journal of Neuroimmunology
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