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https://www.readbyqxmd.com/read/28318222/selective-downregulation-of-jak2-and-jak3-by-an-atp-competitive-pan-jak-inhibitor
#1
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 20, 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
#2
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...
March 14, 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
#3
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
#4
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...
March 1, 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
#5
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
#6
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
#7
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...
January 27, 2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/28184222/canonical-and-non-canonical-aspects-of-jak-stat-signaling-lessons-from-interferons-for-cytokine-responses
#8
REVIEW
Andrea Majoros, Ekaterini Platanitis, Elisabeth Kernbauer-Hölzl, Felix Rosebrock, Mathias Müller, Thomas Decker
Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signal transduction mediates cytokine responses. Canonical signaling is based on STAT tyrosine phosphorylation by activated JAKs. Downstream of interferon (IFN) receptors, activated JAKs cause the formation of the transcription factors IFN-stimulated gene factor 3 (ISGF3), a heterotrimer of STAT1, STAT2 and interferon regulatory factor 9 (IRF9) subunits, and gamma interferon-activated factor (GAF), a STAT1 homodimer. In recent years, several deviations from this paradigm were reported...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28182798/expression-of-genes-belonging-to-the-interacting-tlr-cascades-nadph-oxidase-and-mitochondrial-oxidative-phosphorylation-in-septic-patients
#9
Laura A Nucci, Sidnéia S Santos, Milena K C Brunialti, Narendra Kumar Sharma, Flavia R Machado, Murillo Assunção, Luciano C P de Azevedo, Reinaldo Salomao
BACKGROUND AND OBJECTIVES: Sepsis is a complex disease that is characterized by activation and inhibition of different cell signaling pathways according to the disease stage. Here, we evaluated genes involved in the TLR signaling pathway, oxidative phosphorylation and oxidative metabolism, aiming to assess their interactions and resulting cell functions and pathways that are disturbed in septic patients. MATERIALS AND METHODS: Blood samples were obtained from 16 patients with sepsis secondary to community acquired pneumonia at admission (D0), and after 7 days (D7, N = 10) of therapy...
2017: PloS One
https://www.readbyqxmd.com/read/28133881/towards-full-quantum-mechanics-based-protein-ligand-binding-affinities
#10
Stephan Ehrlich, Andreas H Göller, Stefan Grimme
Computational methods play a key role in modern drug design in pharmaceutical industry but are mostly based on force fields which are limited in accuracy when describing non-classical binding effects, proton transfer or metal coordination. Here, we propose a general fully quantum mechanical (QM) scheme for the computation of protein-ligand affinities. It works on a single protein cutout (of about 1000 atoms) and evaluates all contributions (interaction energy, solvation, thermostatistical) to absolute binding free energy on the highest feasible QM level...
January 29, 2017: Chemphyschem: a European Journal of Chemical Physics and Physical Chemistry
https://www.readbyqxmd.com/read/28087469/tofacitinib-ameliorates-inflammation-in-a-rat-model-of-airway-neutrophilia-induced-by-inhaled-lps
#11
Elena Calama, Isabel Ramis, Anna Domènech, Cristina Carreño, Jorge De Alba, Neus Prats, Montserrat Miralpeix
BACKGROUND AND PURPOSE: The Janus Kinase (JAK) family mediates the cytokine receptor-induced signalling pathways involved in inflammatory processes. The activation of the signal transducers and activators of transcription (STATs) by JAK kinases is a key point in these pathways. Four JAK proteins, JAK1, JAK2, JAK3 and tyrosine kinase 2 (Tyk2) associate with the intracellular domains of surface cytokine receptors are phosphorylating STATs and modulating gene expression. The aim of this study was to explore the role of JAK inhibition in an acute model of inhaled lipopolysaccharide (LPS)-induced airway inflammation in rats through evaluating the effects of tofacitinib, a marketed pan-JAK inhibitor...
January 10, 2017: Pulmonary Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28062922/interferon-%C3%AE-mediates-human-beta-cell-hla-class-i-overexpression-endoplasmic-reticulum-stress-and-apoptosis-three-hallmarks-of-early-human-type-1-diabetes
#12
Laura Marroqui, Reinaldo S Dos Santos, Anne Op de Beeck, Alexandra Coomans de Brachène, Lorella Marselli, Piero Marchetti, Decio L Eizirik
AIMS/HYPOTHESIS: Three hallmarks of the pancreatic islets in early human type 1 diabetes are overexpression of HLA class I, endoplasmic reticulum (ER) stress and beta cell apoptosis. The mediators of these phenomena remain to be defined. The type I interferon IFNα is expressed in human islets from type 1 diabetes patients and mediates HLA class I overexpression. We presently evaluated the mechanisms involved in IFNα-induced HLA class I expression in human beta cells and determined whether this cytokine contributes to ER stress and apoptosis...
January 6, 2017: Diabetologia
https://www.readbyqxmd.com/read/28024402/relative-binding-free-energy-calculations-applied-to-protein-homology-models
#13
Daniel Cappel, Michelle Lynn Hall, Eelke B Lenselink, Thijs Beuming, Jun Qi, James Bradner, Woody Sherman
A significant challenge and potential high-value application of computer-aided drug design is the accurate prediction of protein-ligand binding affinities. Free energy perturbation (FEP) using molecular dynamics (MD) sampling is among the most suitable approaches to achieve accurate binding free energy predictions, due to the rigorous statistical framework of the methodology, correct representation of the energetics, and thorough treatment of the important degrees of freedom in the system (including explicit waters)...
December 27, 2016: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/27976820/integration-of-expression-quantitative-trait-loci-and-pleiotropy-identifies-a-novel-psoriasis-susceptibility-gene-ptpn1
#14
Xianyong Yin, Yuan Lin, Changbing Shen, Ling Wang, Xianbo Zuo, Xiaodong Zheng, Sen Yang, Jianjun Liu, Kirk C Wilhelmsen, Xuejun Zhang
BACKGROUND: Psoriasis is a common inflammatory skin disease, whereas schizophrenia is a psychiatric disorder with substantial comorbidity. Although these two disorders manifest with apparently unrelated phenotypes, there is some evidence suggesting that they share common genetic factors. METHODS: We implemented a genetic analysis incorporating pleiotropy and annotation to genome-wide association summary statistics data for approximately 120 000 psoriasis and schizophrenia samples, as well as whole blood expression quantitative trait loci in 5311 samples...
January 2017: Journal of Gene Medicine
https://www.readbyqxmd.com/read/27965317/cell-specific-computational-modeling-of-the-pim-pathway-in-acute-myeloid-leukemia
#15
Dana Silverbush, Shaun Grosskurth, Dennis Wang, Francoise Powell, Berthold Gottgens, Jonathan Dry, Jasmin Fisher
Personalized therapy is a major goal of modern oncology, as patient responses vary greatly even within a histologically defined cancer subtype. This is especially true in acute myeloid leukemia (AML), which exhibits striking heterogeneity in molecular segmentation. When calibrated to cell-specific data, executable network models can reveal subtle differences in signaling that help explain differences in drug response. Furthermore, they can suggest drug combinations to increase efficacy and combat acquired resistance...
December 13, 2016: Cancer Research
https://www.readbyqxmd.com/read/27875628/clinical-genomic-profiling-identifies-tyk2-mutation-and-overexpression-in-patients-with-neurofibromatosis-type-1-associated-malignant-peripheral-nerve-sheath-tumors
#16
Angela C Hirbe, Madhurima Kaushal, Mukesh Kumar Sharma, Sonika Dahiya, Melike Pekmezci, Arie Perry, David H Gutmann
BACKGROUND: Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas that arise at an estimated frequency of 8% to 13% in individuals with neurofibromatosis type 1 (NF1). Compared with their sporadic counterparts, NF1-associated MPNSTs (NF1-MPNSTs) develop in young adults, frequently recur (approximately 50% of cases), and carry a dismal prognosis. As such, most individuals affected with NF1-MPNSTs die within 5 years of diagnosis, despite surgical resection combined with radiotherapy and chemotherapy...
April 1, 2017: Cancer
https://www.readbyqxmd.com/read/27815207/poly-i-c-facilitates-the-phosphorylation-of-ctenopharyngodon-idellus-type-i-ifn-receptor-subunits-and-jak-kinase
#17
Qunhao Hou, Ruiyue Gong, Xiancheng Liu, Huiling Mao, Xiaowen Xu, Dan Liu, Zao Dai, Haizhou Wang, Binhua Wang, Chengyu Hu
Members of the Janus kinase (JAK) family, JAK1 and TYK2 take part in JAK-STAT signaling pathway mediated by interferon in mammalian cells. Similar to the mammalian counterparts, fish JAK1 and TYK2 also perform their potential biological activities by phosphorylating cytokine receptors and STAT. In the present study, Ctenopharyngodon idellus JAK1 (CiJAK1) and TYK2 (CiTYK2) were cloned and identified. The full-length cDNA of CiJAK1 (KT724352.1) is 3829 bp, with an Open Reading Frame (ORF) of 3465 bp encoding a putative protein of 1154 amino acids...
November 1, 2016: Fish & Shellfish Immunology
https://www.readbyqxmd.com/read/27810495/psoriasis-risk-snps-and-their-association-with-hiv-1-control
#18
Joanne Nititham, Rashmi Gupta, Xue Zeng, Wendy Hartogensis, Douglas F Nixon, Steven G Deeks, Frederick M Hecht, Wilson Liao
Human evolution has resulted in selection for genetic polymorphisms beneficial in the defense against pathogens. However, such polymorphisms may have the potential to heighten the risk of autoimmune disease. Here, we investigated whether psoriasis-associated single nucleotide polymorphisms influence host control of HIV-1 infection. We studied psoriasis and viral immune response variants in three HIV-positive cohorts: (1) HIV-1 controllers and non-controllers in the Study of the Consequences of the Protease Inhibitor Era (SCOPE) cohort (n=366), (2) Individuals with primary HIV infection in the Options cohort (n=675), and (3) HIV-positive injection drug users from the Urban Health Study (UHS) (n=987)...
February 2017: Human Immunology
https://www.readbyqxmd.com/read/27807284/resolving-tyk2-locus-genotype-to-phenotype-differences-in-autoimmunity
#19
Calliope A Dendrou, Adrian Cortes, Lydia Shipman, Hayley G Evans, Kathrine E Attfield, Luke Jostins, Thomas Barber, Gurman Kaur, Subita Balaram Kuttikkatte, Oliver A Leach, Christiane Desel, Soren L Faergeman, Jane Cheeseman, Matt J Neville, Stephen Sawcer, Alastair Compston, Adam R Johnson, Christine Everett, John I Bell, Fredrik Karpe, Mark Ultsch, Charles Eigenbrot, Gil McVean, Lars Fugger
Thousands of genetic variants have been identified, which contribute to the development of complex diseases, but determining how to elucidate their biological consequences for translation into clinical benefit is challenging. Conflicting evidence regarding the functional impact of genetic variants in the tyrosine kinase 2 (TYK2) gene, which is differentially associated with common autoimmune diseases, currently obscures the potential of TYK2 as a therapeutic target. We aimed to resolve this conflict by performing genetic meta-analysis across disorders; subsequent molecular, cellular, in vivo, and structural functional follow-up; and epidemiological studies...
November 2, 2016: Science Translational Medicine
https://www.readbyqxmd.com/read/27802075/kinase-inactive-tyrosine-kinase-tyk2-supports-differentiation-of-brown-fat-cells
#20
Vidisha Raje, Marta Derecka, Marc Cantwell, Jeremy Meier, Karol Szczepanek, Jennifer D Sisler, Birgit Strobl, Ana Gamero, Thurl E Harris, Andrew C Larner
It has been known for decades that brown adipose tissue plays a central role in maintaining body temperature in hibernating animals, and human infants. Recently it has become evident that there are also depots of brown fat in adult humans, and the mass of brown fat is inversely correlated with body weight. There are a variety of transcription factors implicated in the differentiation of classical Myf5+ brown preadipocytes, one of the most important of which is PRDM16. We have recently identified that in addition to PRDM16, the tyrosine kinase Tyk2 and the STAT3 transcription factor are required for the differentiation of Myf5 positive brown preadipocytes both in cell culture and in mice...
November 1, 2016: Endocrinology
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