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https://www.readbyqxmd.com/read/29031523/6-hydroxy-3-o-methyl-kaempferol-6-o-glucopyranoside-potentiates-the-anti-proliferative-effect-of-interferon-%C3%AE-%C3%AE-by-promoting-activation-of-the-jak-stat-signaling-by-inhibiting-socs3-in-hepatocellular-carcinoma-cells
#1
Orawan Wonganan, Yu-Jiao He, Xiao-Fei Shen, Kanjana Wongkrajang, Apichart Suksamrarn, Guo-Lin Zhang, Fei Wang
Suppressor of cytokine signaling 3 (SOCS3) is a key negative regulator of type I interferon (IFN α/β) signaling. Inhibition of SOCS3 by small molecules may be a new strategy to enhance the efficacy of type I IFN and reduce its side effects. We established a cell-based screening assay using human hepatoma HepG2 cells stably transfected with a plasmid wherein the luciferase reporter activity was propelled by interferon α-stimulated response element (ISRE), which is a motif specifically recognized by type I IFN-induced activation of Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway...
October 11, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/29016674/re-evaluation-of-il-10-signaling-reveals-novel-insights-on-the-contribution-of-the-intracellular-domain-of-the-il-10r2-chain
#2
Ruud H P Wilbers, Debbie R van Raaij, Lotte B Westerhof, Jaap Bakker, Geert Smant, Arjen Schots
Interleukin-10 (IL-10) is an anti-inflammatory cytokine that plays a key role in maintaining immune homeostasis. IL-10-mediated responses are triggered upon binding to a heterodimeric receptor complex consisting of IL-10 receptor (IL-10R)1 and IL-10R2. Engagement of the IL-10R complex activates the intracellular kinases Jak1 and Tyk2, but the exact roles of IL-10R2 and IL-10R2-associated signaling via Tyk2 remain unclear. To elucidate the contribution of IL-10R2 and its signaling to IL-10 activity, we re-evaluated IL-10-mediated responses on bone marrow-derived dendritic cells, macrophages and mast cells...
2017: PloS One
https://www.readbyqxmd.com/read/28990043/%C3%AE-he-genetics-of-juvenile-idiopathic-arthritis-searching-for-new-susceptibility-loci
#3
Maria I Zervou, Despoina G Dimopoulou, Elias Eliopoulos, Maria Trachana, Polyxeni Pratsidou-Gkertsi, Athena Andreou, Prodromos Sidiropoulos, Demetrios A Spandidos, Alexandros Garyfallos, George N Goulielmos
Juvenile idiopathic arthritis (JIA) is an autoimmune disease that is characterized by persistent chronic arthritis and affected by genetic and environmental factors. Different genetic variations have been reported as risk factors for JIA. However, given that many results could not be replicated in individuals of different ancestral origin, it was assumed that heterogeneous genetic factors are involved in this disease. In the present study, we analyzed three single nucleotide polymorphisms (SNPs), namely PTPRC (rs10919563), TYK2 (rs34536443) and PRKCQ (rs4750316), which were found to be associated with JIA in previous studies...
October 5, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28973304/exome-wide-association-study-reveals-novel-psoriasis-susceptibility-locus-at-tnfsf15-and-rare-protective-alleles-in-genes-contributing-to-type-i-ifn-signalling
#4
Nick Dand, Sören Mucha, Lam C Tsoi, Satveer K Mahil, Philip E Stuart, Andreas Arnold, Hansjörg Baurecht, A David Burden, Kristina Callis Duffin, Vinod Chandran, Charles J Curtis, Sayantan Das, David Ellinghaus, Eva Ellinghaus, Charlotta Enerback, Tõnu Esko, Dafna D Gladman, Christopher E M Griffiths, Johann E Gudjonsson, Per Hoffman, Georg Homuth, Ulrike Hüffmeier, Gerald G Krueger, Matthias Laudes, Sang Hyuck Lee, Wolfgang Lieb, Henry W Lim, Sabine Löhr, Ulrich Mrowietz, Martina Müller-Nurayid, Markus Nöthen, Annette Peters, Proton Rahman, André Reis, Nick J Reynolds, Elke Rodriguez, Carsten O Schmidt, Sarah L Spain, Konstantin Strauch, Trilokraj Tejasvi, John J Voorhees, Richard B Warren, Michael Weichenthal, Stephan Weidinger, Matthew Zawistowski, Rajan P Nair, Francesca Capon, Catherine H Smith, Richard C Trembath, Goncalo R Abecasis, James T Elder, Andre Franke, Michael A Simpson, Jonathan N Barker
Psoriasis is a common inflammatory skin disorder for which multiple genetic susceptibility loci have been identified, but few resolved to specific functional variants. In this study we sought to identify common and rare psoriasis-associated gene-centric variation. Using exome arrays we genotyped four independent cohorts, totalling 11,861 psoriasis cases and 28,610 controls, aggregating the dataset through statistical meta-analysis. Single variant analysis detected a previously unreported risk locus at TNFSF15 (rs6478108; p = 1...
August 24, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28972016/philadelphia-chromosome-like-acute-lymphoblastic-leukemia
#5
Sarah K Tasian, Mignon L Loh, Stephen P Hunger
Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL; also referred to as BCR-ABL1-like ALL) is a high risk subset with a gene expression profile that shares significant overlap with that of Philadelphia chromosome positive (Ph(+)) ALL and is suggestive of activated kinase signaling. While Ph(+) ALL is defined by BCR-ABL1 fusion, Ph-like ALL cases contain a variety of genomic alterations that activate kinase and cytokine receptor signaling. These alterations can be grouped into major subclasses that include ABL-class fusions involving ABL1, ABL2, CSF1R, and PDGFRB that phenocopy BCR-ABL1, and alterations of CRLF2, JAK2, and EPOR that activate JAK/STAT signaling...
October 2, 2017: Blood
https://www.readbyqxmd.com/read/28916157/diabetes-the-tyk2-gene-and-the-interferon-response-in-search-for-environmental-causes
#6
Antonio Toniolo, Richard David Leslie
No abstract text is available yet for this article.
September 6, 2017: EBioMedicine
https://www.readbyqxmd.com/read/28883754/the-activation-of-%C3%AE-2-adrenergic-receptor-in-the-spinal-cord-lowers-sepsis-induced-mortality
#7
Sung-Su Kim, Soo-Hyun Park, Jae-Ryung Lee, Jun-Sub Jung, Hong-Won Suh
The effect of clonidine administered intrathecally (i.t.) on the mortality and the blood glucose level induced by sepsis was examined in mice. To produce sepsis, the mixture of D-galactosamine (GaLN; 0.6 g/10 ml)/lipopolysaccharide (LPS; 27 µg/27 µl) was treated intraperitoneally (i.p.). The i.t. pretreatment with clonidine (5 µg/5 µl) increased the blood glucose level and attenuated mortality induced by sepsis in a dose-dependent manner. The i.t. post-treatment with clonidine up to 3 h caused an elevation of the blood glucose level and protected sepsis-induced mortality, whereas clonidine post-treated at 6, 9, or 12 h did not affect...
September 2017: Korean Journal of Physiology & Pharmacology
https://www.readbyqxmd.com/read/28846454/glis3-and-tyk2-single-nucleotide-polymorphisms-are-not-associated-with-dermatomyositis-polymyositis-in-chinese-han-population
#8
Liubing Li, Si Chen, Qian Wang, Chanyuan Wu, Xiaoting Wen, Funing Yang, Chenxi Liu, Fengchun Zhang, Yongzhe Li
AIM: Racial differences and genetic overlap have been shown to be responsible for the difference in susceptibility to dermatomyositis (DM)/polymyositis (PM) in a variety of populations. Single nucleotide polymorphisms (SNPs) in the GLI-similar 3 (GLIS3) and tyrosine kinase 2 (TYK2) genes have been associated with various autoimmune diseases. The aim of this study was to investigate whether SNPs in GLIS3 (rs7020673, rs10758593, and rs10814916) and TYK2 (rs280519, rs2304256, rs17000730, and rs280501) were associated with an increase in susceptibility to DM/PM in a Chinese Han population...
September 2017: Genetic Testing and Molecular Biomarkers
https://www.readbyqxmd.com/read/28842327/genome-wide-analysis-of-protein-coding-variants-in-leprosy
#9
Hong Liu, Zhenzhen Wang, Yi Li, Gongqi Yu, Xi'an Fu, Chuan Wang, Wenting Liu, Yongxiang Yu, Fangfang Bao, Astrid Irwanto, Jian Liu, Tongsheng Chu, Anand Kumar Andiappan, Sebastian Maurer-Stroh, Vachiranee Limviphuvadh, Honglei Wang, Zihao Mi, Yonghu Sun, Lele Sun, Ling Wang, Chaolong Wang, Jiabao You, Jinghui Li, Jia Nee Foo, Herty Liany, Wee Yang Meah, Guiye Niu, Zhenhua Yue, Qing Zhao, Na Wang, Meiwen Yu, Wenjun Yu, Xiujun Cheng, Chiea Chuen Khor, Kar Seng Sim, Tin Aung, Ningli Wang, Deyun Wang, Li Shi, Yong Ning, Zhongyi Zheng, Rongde Yang, Jinlan Li, Jun Yang, Liangbin Yan, Jianping Shen, Guocheng Zhang, Shumin Chen, Jianjun Liu, Furen Zhang
Although genome-wide association studies (GWAS) have greatly advanced our understanding on the contribution of common non-coding variants to leprosy susceptibility, protein-coding variants have not been systematically investigated. We carried out a three-stage genome-wide association study of protein-coding variants in 7,048 leprosy patients and 14,398 healthy controls of Han Chinese. Seven to our knowledge previously unreported coding variants at exome-wide significance were discovered, including two rare variants: rs145562243 in NCKIPSD (P = 1...
August 22, 2017: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/28830649/identification-of-an-imidazopyridine-scaffold-to-generate-potent-and-selective-tyk2-inhibitors-that-demonstrate-activity-in-an-in-vivo-psoriasis-model
#10
Jun Liang, Anne Van Abbema, Mercedesz Balazs, Kathy Barrett, Leo Berezhkovsky, Wade S Blair, Christine Chang, Donnie Delarosa, Jason DeVoss, Jim Driscoll, Charles Eigenbrot, Simon Goodacre, Nico Ghilardi, Calum MacLeod, Adam Johnson, Pawan Bir Kohli, Yingjie Lai, Zhonghua Lin, Priscilla Mantik, Kapil Menghrajani, Hieu Nguyen, Ivan Peng, Amy Sambrone, Steven Shia, Jan Smith, Sue Sohn, Vickie Tsui, Mark Ultsch, Karen Williams, Lawren C Wu, Wenqian Yang, Birong Zhang, Steven Magnuson
Herein we report identification of an imidazopyridine class of potent and selective TYK2 inhibitors, exemplified by prototype 6, through constraint of the rotatable amide bond connecting the pyridine and aryl rings of compound 1. Further optimization led to generation of compound 30 that potently inhibits the TYK2 enzyme and the IL-23 pathway in cells, exhibits selectivity against cellular JAK2 activity, and has good pharmacokinetic properties. In mice, compound 30 demonstrated dose-dependent reduction of IL-17 production in a PK/PD model as well as in an imiquimod-induced psoriasis model...
September 15, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28826655/subtyping-of-type-1-diabetes-as-classified-by-anti-gad-antibody-ige-levels-and-tyrosine-kinase-2-tyk2-promoter-variant-in-the-japanese
#11
Keiichiro Mine, Kanako Hirakawa, Shiori Kondo, Masae Minami, Akira Okada, Nobutaka Tsutsu, Yasushi Yokogawa, Yumi Hibio, Fumiko Kojima, Shuji Fujimoto, Hironori Kurisaki, Keizo Anzai, Yasunobu Yoshikai, Seiho Nagafuchi
OBJECTIVE: Type 1 diabetes (T1D) is known to be caused by Th1 cell-dependent autoimmunity. Recently, we reported that TYK2 promoter variant serves as a putative virus-induced diabetes susceptibility gene associated with deteriorated interferon-dependent antiviral response. TYK2 is also related to HIES, that is, Th2 cell-dependent. Therefore, TYK2 promoter variant may be also associated with the pathogenesis of T1D, modulating Th1/Th2 balance. RESEARCH DESIGN AND METHODS: We assessed the association between anti- GAD Ab, IgE levels, and TYK2 promoter variant among 313 T1D patients, 184 T2D patients, and 264 YH controls in the Japanese...
September 2017: EBioMedicine
https://www.readbyqxmd.com/read/28790099/gsk2586184-a-jak1-selective-inhibitor-in-two-patients-with-ulcerative-colitis
#12
Leonie C S De Vries, Valerie J Ludbrook, Kirsty J Hicks, Geert R D'Haens
Tofacitinib, a non-selective Janus kinase (JAK) inhibitor, is effective in inducing clinical and endoscopic remission in patients with active ulcerative colitis (UC). Tofacitinib inhibits cytokine signalling through blockade of JAK1, JAK2, JAK3 and tyrosine kinase 2 (TYK2). Adverse events including neutropenia and anaemia resulting from JAK2 inhibition have been observed in actively treated patients. By selectively targeting JAK1, such adverse events could be expected to be avoided. This open label study was designed to enrol 15 patients with UC, however the trial was discontinued after two inclusions due to safety concerns with the agent in a parallel trial for systemic lupus erythematosus...
August 7, 2017: BMJ Case Reports
https://www.readbyqxmd.com/read/28759991/in-silico-prediction-of-ligand-binding-energies-in-multiple-therapeutic-targets-and-diverse-ligand-sets-a-case-study-on-bace1-tyk2-hsp90-and-perk-proteins
#13
Elizabeth Hatcher Frush, Sivakumar Sekharan, Shahar Keinan
We present here the use of QM/MM LIE (linear interaction energy) based binding free energy calculations that greatly improve the precision and accuracy of predicting experimental binding affinities, in comparison to most current binding free energy methodologies, while maintaining reasonable computational times. Calculations are done for four sets of ligand-protein complexes, chosen on the basis of diversity of protein types and availability of experimental data, totaling 140 ligands binding to therapeutic protein targets BACE1, TYK2, HSP90, and PERK...
August 17, 2017: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/28730475/characterization-of-ligand-binding-to-pseudokinases-using-a-thermal-shift-assay
#14
Isabelle S Lucet, James M Murphy
The protocol herein describes a robust and proven method for the measurement of pseudokinase-ligand interaction using a fluorescence-based thermal shift assay (TSA). Pseudokinases are kinase-like proteins that have recently emerged as crucial regulatory modules of signal transduction pathways and may well represent a novel class of drug targets. However, unlike kinases, the regulatory activity of pseudokinases is mainly conferred through protein-protein interactions. Understanding the mechanisms that underlie pseudokinase conformational changes through ligand binding and how such conformational changes can tune signaling pathways is a necessary step to unravel their biological functions...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28716895/ctla4-promotes-tyk2-stat3-dependent-b-cell-oncogenicity
#15
Andreas Herrmann, Christoph Lahtz, Toshikage Nagao, Joo Y Song, Wing C Chan, Heehyoung Lee, Chanyu Yue, Thomas Look, Ronja Mülfarth, Wenzhao Li, Kurt Jenkins, John Williams, Lihua E Budde, Stephen Forman, Larry Kwak, Thomas Blankenstein, Hua Yu
CTL-associated antigen 4 (CTLA4) is a well-established immune checkpoint for antitumor immune responses. The protumorigenic function of CTLA4 is believed to be limited to T-cell inhibition by countering the activity of the T-cell costimulating receptor CD28. However, as we demonstrate here, there are two additional roles for CTLA4 in cancer, including via CTLA4 overexpression in diverse B-cell lymphomas and in melanoma-associated B cells. CTLA4-CD86 ligation recruited and activated the JAK family member Tyk2, resulting in STAT3 activation and expression of genes critical for cancer immunosuppression and tumor growth and survival...
September 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/28705941/tyk2-as-a-target-for-immune-regulation-in-human-viral-bacterial-pneumonia
#16
Johanna Berg, Katja Zscheppang, Diana Fatykhova, Mario Tönnies, Torsten T Bauer, Paul Schneider, Jens Neudecker, Jens C Rückert, Stephan Eggeling, Maria Schimek, Achim D Gruber, Norbert Suttorp, Stefan Hippenstiel, Andreas C Hocke
The severity and lethality of influenza A virus (IAV) infections is frequently aggravated by secondary bacterial pneumonia. However, the mechanisms in human lung tissue that provoke this increase in fatality are unknown and therapeutic immune modulatory options are lacking.We established a human lung ex vivo co-infection model to investigate innate immune related mechanisms contributing to the susceptibility of secondary pneumococcal pneumonia.We revealed that type I and III interferon (IFN) inhibits Streptococcus pneumoniae-induced interleukin (IL)-1β release...
July 2017: European Respiratory Journal: Official Journal of the European Society for Clinical Respiratory Physiology
https://www.readbyqxmd.com/read/28704535/interferon-related-genetic-markers-of-necroinflammatory-activity-in-chronic-hepatitis-c
#17
Rosario López-Rodríguez, Ángel Hernández-Bartolomé, María Jesús Borque, Yolanda Rodríguez-Muñoz, Samuel Martín-Vílchez, Luisa García-Buey, Leticia González-Moreno, Yolanda Real-Martínez, Paloma Muñoz de Rueda, Javier Salmerón, José Ramón Vidal-Castiñeira, Carlos López-Larrea, Luis Rodrigo, Ricardo Moreno-Otero, Paloma Sanz-Cameno
INTRODUCTION: Chronic hepatitis C (CHC) is a major cause of liver disease worldwide which often leads to progressive liver inflammation, fibrosis, cirrhosis and hepatocellular carcinoma (HCC). CHC displays heterogeneous progression depending on a broad set of factors, some of them intrinsic to each individual such as the patient's genetic profile. This study aims to evaluate the contribution of certain genetic variants of crucial interferon alpha and lambda signaling pathways to the hepatic necroinflammatory activity (NIA) grade of CHC patients...
2017: PloS One
https://www.readbyqxmd.com/read/28687744/ccm111-the-water-extract-of-antrodia-cinnamomea-regulates-immune-related-activity-through-stat3-and-nf-%C3%AE%C2%BAb-pathways
#18
In-Yu Lin, Min-Hsiung Pan, Ching-Shu Lai, Ting-Ting Lin, Chiung-Tong Chen, Tao-Sheng Chung, Chien-Lung Chen, Chen-Huan Lin, Wu-Chang Chuang, Ming-Chung Lee, Ching-Che Lin, Nianhan Ma
Antrodia cinnamomea (AC) exhibits many bioactivities, including anti-inflammatory, anti-cancer, and hepatoprotection activities. Many researchers have studied the functions of the components or fractions of AC, but the functions of the original extractions of AC have not been studied. In addition, the detailed relationship between AC and immune-related signaling pathways is unclear. In this study, we screened the effects of CCM111, which is the extract of AC, on seven immune-related signaling pathways and further investigated whether CCM111 can influence inflammation...
July 7, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28668884/loss-of-tyrosine-kinase-2-does-not-affect-the-severity-of-jak2v617f-induced-murine-myeloproliferative-neoplasm
#19
Takumi Yamaji, Kotaro Shide, Takuro Kameda, Masaaki Sekine, Ayako Kamiunten, Tomonori Hidaka, Yoko Kubuki, Haruko Shimoda, Hiroo Abe, Tadashi Miike, Hisayoshi Iwakiri, Yoshihiro Tahara, Mitsue Sueta, Shojiro Yamamoto, Satoru Hasuike, Kenji Nagata, Kazuya Shimoda
BACKGROUND/AIM: In myeloproliferative neoplasms (MPN), Janus kinase 2 (JAK2) is activated by mutations including JAK2V617F (JAK2VF). It is unclear whether JAK kinases [i.e. JAK1, JAK2, JAK3, or tyrosine kinase 2 (TYK2)] other than JAK2 have cooperative actions such as enhancement or suppression of JAK2. If other kinases enhance activation, therapies that co-target them could have a therapeutic efficacy. We examined the role of TYK2 in Jak2VF-induced murine MPN. MATERIALS AND METHODS: We crossed Jak2VF transgenic mice and Tyk2-knockout (Tyk2KO) mice to generate Jak2VF/Tyk2KO mice...
July 2017: Anticancer Research
https://www.readbyqxmd.com/read/28539220/discovery-of-potent-and-efficacious-pyrrolopyridazines-as-dual-jak1-3-inhibitors
#20
John Hynes, Hong Wu, James Kempson, James J-W Duan, Zhonghui Lu, Bin Jiang, Sylwia Stachura, John S Tokarski, John S Sack, Javed A Khan, Jonathan S Lippy, Rosemary F Zhang, Sidney Pitt, Guoxiang Shen, Kate Gillooly, Kim McIntyre, Percy H Carter, Joel C Barrish, Steven G Nadler, Luisa M Salter-Cid, Aberra Fura, Gary L Schieven, William J Pitts, Stephen T Wrobleski
A series of potent dual JAK1/3 inhibitors have been developed from a moderately selective JAK3 inhibitor. Substitution at the C6 position of the pyrrolopyridazine core with aryl groups provided exceptional biochemical potency against JAK1 and JAK3 while maintaining good selectivity against JAK2 and Tyk2. Translation to in vivo efficacy was observed in a murine model of chronic inflammation. X-ray co-crystal structure determination confirmed the presumed inhibitor binding orientation in JAK3. Efforts to reduce hERG channel inhibition will be described...
July 15, 2017: Bioorganic & Medicinal Chemistry Letters
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