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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
#1
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...
August 12, 2017: EBioMedicine
https://www.readbyqxmd.com/read/28790099/gsk2586184-a-jak1-selective-inhibitor-in-two-patients-with-ulcerative-colitis
#2
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
#3
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 based on diversity of protein types and availability of experimental data, totaling 140 ligands binding to therapeutic protein targets BACE1, TYK2, HSP90 and PERK...
July 31, 2017: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/28730475/characterization-of-ligand-binding-to-pseudokinases-using-a-thermal-shift-assay
#4
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%C3%A2-tyk2-stat3-dependent-b-cell-oncogenecity
#5
Andreas Herrmann, Christoph Lahtz, Toshikage Nagao, Joo Y Song, Wing C Chan, Heehyoung Lee, Chanyu Yue, Thomas Look, Ronja Muelfarth, Wenzhao Li, Kurt Jenkins, John Williams, Lihua E Budde, Stephen J Forman, Larry W Kwak, Thomas Blankenstein, Hua Yu
Cytotoxic T lymphocyte-associated antigen 4 (CTLA4) is a well-established immune checkpoint for antitumor immune responses. The pro-tumorigenic function of CTLA4 is believed to be limited to T cell inhibition by countering the activity of the T cell co-stimulating 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...
July 17, 2017: Cancer Research
https://www.readbyqxmd.com/read/28705941/tyk2-as-a-target-for-immune-regulation-in-human-viral-bacterial-pneumonia
#6
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
#7
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
#8
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
#9
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
#10
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...
May 15, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28525837/differentially-expressed-jak-stat-signaling-pathway-genes-and-target-micrornas-in-the-spleen-of-necrotic-enteritis-afflicted-chicken-lines
#11
Anh Duc Truong, Deivendran Rengaraj, Yeojin Hong, Cong Thanh Hoang, Yeong Ho Hong, Hyun S Lillehoj
The JAK signal transducer and STAT signaling pathway is an important regulator of cell proliferation, differentiation, survival, motility, apoptosis, immune response, and development. In this study, we used RNA-Sequencing, qRT-PCR, and bioinformatics tools to investigate the differential expression of JAK-STAT pathway genes, their interactions, and regulators in the spleen of two genetically disparate chicken lines (Marek's disease-resistant line 6.3 and MD-susceptible line 7.2) induced necrotic enteritis (NE) disease by co-infection with Eimeria maxima and Clostridium perfringens...
May 13, 2017: Research in Veterinary Science
https://www.readbyqxmd.com/read/28496097/hepatitis-b-virus-e-antigen-activates-the-suppressor-of-cytokine-signaling-2-to-repress-interferon-action
#12
Yi Yu, Pin Wan, Yanhua Cao, Wei Zhang, Junbo Chen, Li Tan, Yan Wang, Zhichen Sun, Qi Zhang, Yushun Wan, Ying Zhu, Fang Liu, Kailang Wu, Yingle Liu, Jianguo Wu
Hepatitis B virus (HBV) infection causes acute hepatitis B (AHB), chronic hepatitis B (CHB), liver cirrhosis (LC), and eventually hepatocellular carcinoma (HCC). The presence of hepatitis B e antigen (HBeAg) in the serum generally indicates ongoing viral replication and disease progression. However, the mechanism by which HBeAg regulates HBV infection remains unclear. Interferons (IFNs) are pleiotropic cytokines that participate in host innate immunity. After binding to receptors, IFNs activate the JAK/STAT pathway to stimulate expression of IFN-stimulated genes (ISGs), leading to induction of antiviral responses...
May 11, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28494922/analysis-of-jak-stat-signaling-pathway-genes-and-their-micrornas-in-the-intestinal-mucosa-of-genetically-disparate-chicken-lines-induced-with-necrotic-enteritis
#13
Anh Duc Truong, Deivendran Rengaraj, Yeojin Hong, Cong Thanh Hoang, Yeong Ho Hong, Hyun S Lillehoj
The JAK-STAT signaling pathway plays a key role in cytokine and growth factor activation and is involved in several cellular functions and diseases. The main objective of this study was to investigate the expression of candidate JAK-STAT pathway genes and their regulators and interactors in the intestinal mucosal layer of two genetically disparate chicken lines [Marek's disease (MD)-resistant line 6.3 and MD-susceptible line 7.2] induced with necrotic enteritis (NE). Through RNA-sequencing, we investigated 116 JAK-STAT signaling pathway-related genes that were significant and differentially expressed between the intestinal mucosa of the two lines compared with respective uninfected controls...
May 2017: Veterinary Immunology and Immunopathology
https://www.readbyqxmd.com/read/28318222/selective-downregulation-of-jak2-and-jak3-by-an-atp-competitive-pan-jak-inhibitor
#14
S Denise Field, Jacob Arkin, Jing Li, Lyn H Jones
PF-956980 has been used previously as a JAK3-selective chemical probe in numerous cell-based experiments. Here, we report that not only is PF-956980 a pan-JAK ATP-competitive inhibitor but it also causes selective reduction of endogenous JAK2 and JAK3 protein levels in human primary immune cells (in a time-dependent manner), leaving the other JAK family members (JAK1 and TYK2) unchanged. We found that PF-956980 selectively downregulated JAK2 and JAK3 mRNA, corresponding to changes observed at the protein level...
March 22, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28295194/anti-leukaemic-activity-of-the-tyk2-selective-inhibitor-ndi-031301-in-t-cell-acute-lymphoblastic-leukaemia
#15
Koshi Akahane, Zhaodong Li, Julia Etchin, Alla Berezovskaya, Evisa Gjini, Craig E Masse, Wenyan Miao, Jennifer Rocnik, Rosana Kapeller, Jeremy R Greenwood, Hong Tiv, Takaomi Sanda, David M Weinstock, A Thomas Look
Activation of tyrosine kinase 2 (TYK2) contributes to the aberrant survival of T-cell acute lymphoblastic leukaemia (T-ALL) cells. Here we demonstrate the anti-leukaemic activity of a novel TYK2 inhibitor, NDI-031301. NDI-031301 is a potent and selective inhibitor of TYK2 that induced robust growth inhibition of human T-ALL cell lines. NDI-031301 treatment of human T-ALL cell lines resulted in induction of apoptosis that was not observed with the JAK inhibitors tofacitinib and baricitinib. Further investigation revealed that NDI-031301 treatment uniquely leads to activation of three mitogen-activated protein kinases (MAPKs), resulting in phosphorylation of ERK, SAPK/JNK and p38 MAPK coincident with PARP cleavage...
April 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28259699/chicken-il-26-regulates-immune-responses-through-the-jak-stat-and-nf-%C3%AE%C2%BAb-signaling-pathways
#16
Anh Duc Truong, Yeojin Hong, Cong Thanh Hoang, Janggeun Lee, Yeong Ho Hong
Chicken interleukin 26 (ChIL-26), a member of the IL-10 family, is expressed in T cells and can induce expression of proinflammatory cytokines. We examined the response of signal transduction pathways to ChIL-26 stimulation in the chicken T (CU91), macrophage (HD11), and fibroblast (OU2) cell lines. ChIL-26 activated JAK2 and TYK2 phosphorylation, as well as activation of STAT1, STAT3, and SHP2 via tyrosine/serine residues. We also showed that ChIL-26 activates the phosphorylation of NF-κB1, TAK1, and MyD88 kinase, which are key regulators of NF-κB signaling pathways...
March 2, 2017: Developmental and Comparative Immunology
https://www.readbyqxmd.com/read/28250121/porcine-deltacoronavirus-nsp5-antagonizes-type-i-interferon-signaling-by-cleaving-stat2
#17
Xinyu Zhu, Dang Wang, Junwei Zhou, Ting Pan, Jiyao Chen, Yuting Yang, Mengting Lv, Xu Ye, Guiqing Peng, Liurong Fang, Shaobo Xiao
Porcine deltacoronavirus (PDCoV) is an emerging swine enteropathogenic coronavirus. The first outbreak of PDCoV was announced from the United States in 2014, followed by reports in Asia. The nonstructural protein nsp5 is a 3C-like protease of coronavirus, and our previous study showed that PDCoV nsp5 inhibits type I interferon (IFN) production. In this study, we found that PDCoV nsp5 significantly inhibited IFN-stimulated response element (ISRE) promoter activity and transcription of IFN-stimulated genes (ISGs), suggesting that PDCoV nsp5 also suppresses IFN signaling...
May 15, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28228280/autocrine-loop-involving-il-6-family-member-lif-lif-receptor-and-stat4-drives-sustained-fibroblast-production-of-inflammatory-mediators
#18
Hung N Nguyen, Erika H Noss, Fumitaka Mizoguchi, Christine Huppertz, Kevin S Wei, Gerald F M Watts, Michael B Brenner
Fibroblasts are major contributors to and regulators of inflammation and dominant producers of interleukin-6 (IL-6) in inflammatory diseases like rheumatoid arthritis. Yet, compared to leukocytes, the regulation of inflammatory pathways in fibroblasts is largely unknown. Here, we report that analyses of genes coordinately upregulated with IL-6 pointed to STAT4 and leukemia inhibitory factor (LIF) as potentially linked. Gene silencing revealed that STAT4 was required for IL-6 transcription. STAT4 was recruited to the IL-6 promoter after fibroblast activation, and LIF receptor (LIFR) and STAT4 formed a molecular complex that, together with JAK1 and TYK2 kinases, controlled STAT4 activation...
February 21, 2017: Immunity
https://www.readbyqxmd.com/read/28224022/introduction-of-inflammatory-bowel-disease-biomarkers-panel-using-protein-protein-interaction-ppi-network-analysis
#19
Hamid Asadzadeh-Aghdaee, Shabnam Shahrokh, Mohsen Norouzinia, Mostafa Hosseini, Aliasghar Keramatinia, Mostafa Jamalan, Bijan Naghibzadeh, Ali Sadeghi, Somayeh Jahani Sherafat, Mohammad Reza Zali
AIM: In the present study, a protein-protein interaction network construction is conducted for IBD. BACKGROUND: Inflammatory bowel diseases as serious chronic gastrointestinal disorders attracted many molecular investigations. Diverse molecular information is present for IBD. However, these molecular findings are not highlighted based on interactome analysis. On the other hand, PPI network analysis is a powerful method for study of molecular interactions in the protein level that provide useful information for highlighting the desired key proteins...
December 2016: Gastroenterology and Hepatology From Bed to Bench
https://www.readbyqxmd.com/read/28214886/adenovirus-vector-harboring-the-hbcag-and-tripeptidyl-peptidase-ii-genes-induces-potent-cellular-immune-responses-in-vivo
#20
Quanhui Tan, Siyuan Ma, Jianjun Hu, Xiaohua Chen, Yongsheng Yu, Zhenghao Tang, Guoqin Zang
BACKGROUND: Chronic hepatitis B virus (HBV) infection is associated with a weak but specific cellular immune response of the host to HBV. Tripeptidyl peptidaseⅡ (TPPⅡ), an intracellular macromolecule and proteolytic enzyme, plays an important complementary and compensatory role for the proteasome during viral protein degradation and major histocompatibility complex class I antigen presentation by inducing a specific cellular immune response in vivo. Based on a previous study, we aimed to explore the role of MHC class I antigen presentation in vivo and the mechanisms that may be involved...
2017: Cellular Physiology and Biochemistry
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