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https://www.readbyqxmd.com/read/27919027/phosphorylation-of-janus-kinase-1-jak1-by-amp-activated-protein-kinase-ampk-links-energy-sensing-to-anti-inflammatory-signaling
#1
Claire Rutherford, Claire Speirs, Jamie J L Williams, Marie-Ann Ewart, Sarah J Mancini, Simon A Hawley, Christian Delles, Benoit Viollet, Ana P Costa-Pereira, George S Baillie, Ian P Salt, Timothy M Palmer
Adenosine 5'-monophosphate-activated protein kinase (AMPK) is a pivotal regulator of metabolism at cellular and organismal levels. AMPK also suppresses inflammation. We found that pharmacological activation of AMPK rapidly inhibited the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway in various cells. In vitro kinase assays revealed that AMPK directly phosphorylated two residues (Ser(515) and Ser(518)) within the Src homology 2 domain of JAK1. Activation of AMPK enhanced the interaction between JAK1 and 14-3-3 proteins in cultured vascular endothelial cells and fibroblasts, an effect that required the presence of Ser(515) and Ser(518) and was abolished in cells lacking AMPK catalytic subunits...
November 8, 2016: Science Signaling
https://www.readbyqxmd.com/read/27917774/screening-for-calreticulin-mutations-in-a-cohort-of-patients-suspected-of-having-a-myeloproliferative-neoplasm
#2
A De Kock, C Booysen
BACKGROUND: The discovery of calreticulin (CALR) has shown it to be the second most frequent mutation after the Janus Kinase 2 (JAK2) mutation in myeloproliferative neoplasms (MPNs). Its structure indicates various functions, of which two are to ensure calcium homeostasis and proper folding of other target proteins. Over 36 types of CALR mutations have been identified, all causing a recurrent frameshift in the C-terminal domain affecting CALR's localisation and calcium-binding function...
December 1, 2016: South African Medical Journal, Suid-Afrikaanse Tydskrif Vir Geneeskunde
https://www.readbyqxmd.com/read/27917282/ginkgetin-induces-apoptosis-in-786-o-cell-line-via-suppression-of-jak2-stat3-pathway
#3
Yu Ren, Shuang-Shuang Huang, Xue Wang, Zhong-Guan Lou, Xu-Ping Yao, Guo-Bin Weng
OBJECTIVES: Renal cell carcinoma (RCC) is insensitive to conventional chemotherapy. Ginkgetin effectively treats several carcinoma cells. However, little is known about effects of Ginkgetin on RCC. In the present study, using 786-O cells, we evaluate whether Ginkgetin exerts anticancer effects against RCC. MATERIALS AND METHODS: 786-O cells suspended in the medium containing Ginkgetin were cultured for 24 hr to 72 hr, and then MTT assay was used to study cytotoxic effect of Ginkgetin...
November 2016: Iranian Journal of Basic Medical Sciences
https://www.readbyqxmd.com/read/27917175/nuclear-localization-of-suppressor-of-cytokine-signaling-1-regulates-local-immunity-in-the-lung
#4
Jana Zimmer, Michael Weitnauer, Sébastien Boutin, Günter Küblbeck, Sabrina Thiele, Patrick Walker, Felix Lasitschka, Lars Lunding, Zane Orinska, Christina Vock, Bernd Arnold, Michael Wegmann, Alexander Dalpke
Suppressor of cytokine signaling 1 (SOCS1) is a negative feedback inhibitor of cytoplasmic Janus kinase and signal transducer and activator of transcription (STAT) signaling. SOCS1 also contains a nuclear localization sequence (NLS), yet, the in vivo importance of nuclear translocation is unknown. We generated transgenic mice containing mutated Socs1ΔNLS that fails to translocate in the cell nucleus (MGL(tg) mice). Whereas mice fully deficient for SOCS1 die within the first 3 weeks due to excessive interferon signaling and multiorgan inflammation, mice expressing only non-nuclear Socs1ΔNLS (Socs1(-/-)MGL(tg) mice) were rescued from early lethality...
2016: Frontiers in Immunology
https://www.readbyqxmd.com/read/27916398/ruxolitinib-for-the-treatment-of-inadequately-controlled-polycythaemia-vera-without-splenomegaly-response-2-a-randomised-open-label-phase-3b-study
#5
Francesco Passamonti, Martin Griesshammer, Francesca Palandri, Miklos Egyed, Giulia Benevolo, Timothy Devos, Jeannie Callum, Alessandro M Vannucchi, Serdar Sivgin, Caroline Bensasson, Mahmudul Khan, Nadjat Mounedji, Guray Saydam
BACKGROUND: In the pivotal RESPONSE study, ruxolitinib, a Janus kinase (JAK)1 and JAK2 inhibitor, was superior to best available therapy at controlling haematocrit and improving splenomegaly and symptoms in patients with polycythaemia vera with splenomegaly who were inadequately controlled with hydroxyurea. In this study, we assessed the efficacy and safety of ruxolitinib in controlling disease in patients with polycythaemia vera without splenomegaly who need second-line therapy. METHODS: RESPONSE-2 is a randomised, open-label, phase 3b study assessing ruxolitinib versus best available therapy in patients with polycythaemia vera done in 48 hospitals or clinics across 12 countries in Asia, Australia, Europe, and North America...
December 1, 2016: Lancet Oncology
https://www.readbyqxmd.com/read/27916280/novel-targeted-therapies-for-inflammatory-bowel-disease
#6
REVIEW
Mehmet Coskun, Severine Vermeire, Ole Haagen Nielsen
Our growing understanding of the immunopathogenesis of inflammatory bowel disease (IBD) has opened new avenues for developing targeted therapies. These advances in treatment options targeting different mechanisms of action offer new hope for personalized management. In this review we highlight emerging novel and easily administered therapeutics that may be viable candidates for the management of IBD, such as antibodies against interleukin 6 (IL-6) and IL-12/23, small molecules including Janus kinase inhibitors, antisense oligonucleotide against SMAD7 mRNA, and inhibitors of leukocyte trafficking to intestinal sites of inflammation (e...
December 1, 2016: Trends in Pharmacological Sciences
https://www.readbyqxmd.com/read/27909955/suppressive-effects-of-dabrafenib%C3%A2-on-endothelial-protein-c-receptor-shedding
#7
Sae-Kwang Ku, Jongdoo Kim, Sang Chan Kim, Jong-Sup Bae
Beyond its role in the activation of protein C, the endothelial cell protein C receptor (EPCR) plays an important role in the cytoprotective pathway. EPCR can be shed from the cell surface, which is mediated by tumor necrosis factor-α converting enzyme (TACE). Dabrafenib (DAB) is a B-Raf inhibitor and initially used for the treatment of metastatic melanoma therapy. However, little is known about the effects of DAB on EPCR shedding. We investigated this issue by monitoring the effects of DAB on phorbol-12-myristate 13-acetate (PMA)-, tumor necrosis factor (TNF)-α-, interleukin (IL)-1β-induced EPCR shedding in human umbilical vein endothelial cells (HUVECs), and cecal ligation and puncture (CLP)-mediated EPCR shedding in mice and underlying mechanism...
December 1, 2016: Archives of Pharmacal Research
https://www.readbyqxmd.com/read/27909216/molecular-determinants-of-pathogenesis-and-clinical-phenotype-in-myeloproliferative-neoplasms
#8
Jacob Grinfeld, Jyoti Nangalia, Anthony R Green
The myeloproliferative neoplasms are a heterogeneous group of clonal disorders characterised by overproduction of mature cells in the peripheral blood, together with an increased risk of thrombosis and progression to acute myeloid leukemia. The majority of patients with Philadelphia-chromosome negative myeloproliferative neoplasms harbour somatic mutations in Janus kinase 2, leading to constitutive activation. Acquired mutations in calreticulin or myeloproliferative leukemia virus oncogene are found in a significant number of patients with essential thrombocythaemia or myelofibrosis, and mutations in numerous epigenetic regulators and spliceosome components are also seen...
December 1, 2016: Haematologica
https://www.readbyqxmd.com/read/27907269/remission-rates-with-tofacitinib-treatment-in-rheumatoid-arthritis-a-comparison-of-various-remission-criteria
#9
Josef S Smolen, Daniel Aletaha, David Gruben, Samuel H Zwillich, Sriram Krishnaswami, Charles Mebus
OBJECTIVE: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Throughout tofacitinib clinical studies, a 28-joint Disease Activity Score (DAS28)-based analysis was used to assess outcomes. In this study, remission rates by various remission criteria were evaluated across five Phase 3 randomized controlled studies. METHODS: Tofacitinib was dosed 5 or 10 mg twice daily (BID), either as monotherapy, or with background methotrexate or other conventional synthetic disease-modifying antirheumatic drugs (DMARDs)...
December 1, 2016: Arthritis & Rheumatology
https://www.readbyqxmd.com/read/27907166/vaccinia-virus-protein-c6-inhibits-type-i-ifn-signalling-in-the-nucleus-and-binds-to-the-transactivation-domain-of-stat2
#10
Jennifer H Stuart, Rebecca P Sumner, Yongxu Lu, Joseph S Snowden, Geoffrey L Smith
The type I interferon (IFN) response is a crucial innate immune signalling pathway required for defense against viral infection. Accordingly, the great majority of mammalian viruses possess means to inhibit this important host immune response. Here we show that vaccinia virus (VACV) strain Western Reserve protein C6, is a dual function protein that inhibits the cellular response to type I IFNs in addition to its published function as an inhibitor of IRF-3 activation, thereby restricting type I IFN production from infected cells...
December 2016: PLoS Pathogens
https://www.readbyqxmd.com/read/27906090/muscle-specific-deletion-of-socs3-increases-the-early-inflammatory-response-but-does-not-affect-regeneration-after-myotoxic-injury
#11
Kristy Swiderski, Savant S Thakur, Timur Naim, Jennifer Trieu, Annabel Chee, David I Stapleton, René Koopman, Gordon S Lynch
BACKGROUND: Muscles of old animals are injured more easily and regenerate poorly, attributed in part to increased levels of circulating pro-inflammatory cytokines. The Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling cascade is a key mediator of inflammatory cytokine action, and signaling via this pathway is increased in muscles with aging. As a negative regulator of JAK/STAT signaling, a key mediator of myogenic proliferation and differentiation, altered expression of suppressor of cytokine signaling (SOCS3) is likely to have important consequences for muscle regeneration...
October 24, 2016: Skeletal Muscle
https://www.readbyqxmd.com/read/27905994/the-role-of-il-10-in-mycobacterium-avium-subsp-paratuberculosis-infection
#12
REVIEW
Tariq Hussain, Syed Zahid Ali Shah, Deming Zhao, Srinand Sreevatsan, Xiangmei Zhou
Mycobacterium avium subsp. paratuberculosis (MAP) is an intracellular pathogen and is the causative agent of Johne's disease of domestic and wild ruminants. Johne's disease is characterized by chronic granulomatous enteritis leading to substantial economic losses to the livestock sector across the world. MAP persistently survives in phagocytic cells, most commonly in macrophages by disrupting its early antibacterial activity. MAP triggers several signaling pathways after attachment to pathogen recognition receptors (PRRs) of phagocytic cells...
December 1, 2016: Cell Communication and Signaling: CCS
https://www.readbyqxmd.com/read/27900042/antitumor-activity-of-7rh-a-discoidin-domain-receptor-1-inhibitor-alone-or-in-combination-with-dasatinib-exhibits-antitumor-effects-in-nasopharyngeal-carcinoma-cells
#13
Qiu-Ping Lu, Wen-Dan Chen, Jie-Ren Peng, Yao-Dong Xu, Qian Cai, Gong-Kan Feng, Ke Ding, Xiao-Feng Zhu, Zhong Guan
Dysregulation of the discoidin domain receptors (DDRs) has been implicated in the development of numerous types of tumors, including head and neck cancer, and nasopharyngeal, breast, ovarian and esophageal carcinomas. Furthermore, agents that inhibit DDR1 activity are hypothesized to be useful for the treatment of nasopharyngeal carcinoma (NPC). The aim of the present study was to evaluate the effect of the DDR1 inhibitory (3-(2-(pyrazolo(1,5-a)pyrimidin-6-yl)-ethynyl)benzamide compound, 7RH, in NPC cells both in vitro and in vivo, and its effect when used in combination with dasatinib, a SRC family kinase (SFK) inhibitor...
November 2016: Oncology Letters
https://www.readbyqxmd.com/read/27895800/a-novel-curcumin-analogue-is-a-potent-chemotherapy-candidate-for-human-hepatocellular-carcinoma
#14
Ji-An Zhao, Mei-Xiang Sang, Cui-Zhi Geng, Shi-Jie Wang, Bao-En Shan
Curcumin (CUR) has been demonstrated to protect against carcinogenesis and to prevent tumor development in cancer; however, the clinical application of CUR is limited by its instability and poor metabolic properties. The present study offers an strategy for a novel CUR analogue, (1E,4E)-1,5-bis(2-bromophenyl)penta-1,4-dien-3-one (GL63), to be used as a potential therapeutic agent for hepatocellular carcinoma (HCC) in vitro and in vivo. The current study demonstrated that GL63 exhibited more potent inhibition of proliferation of HCC cells than CUR...
November 2016: Oncology Letters
https://www.readbyqxmd.com/read/27895777/cryptotanshinone-inhibits-lung-tumor-growth-by-increasing-cd4-t-cell-cytotoxicity-through-activation-of-the-jak2-stat4-pathway
#15
Yonghong Man, Le Yang, Dongxian Zhang, Yongyi Bi
Cryptotanshinone is one of the fat-soluble phenanthrene quinone components. In vitro studies have shown that tanshinone compounds can inhibit the proliferation of various tumor cells and affect cell cycle distribution. The aim of the present study was to better understand the effect of cryptotanshinone on the inhibition of small cell lung cancer by cytotoxic cluster of differentiation (CD)4(+) T cells through activation of the Janus kinase 2/signal transducer and activator of transcription 4 (JAK2/STAT4) pathway...
November 2016: Oncology Letters
https://www.readbyqxmd.com/read/27894215/the-molecular-pathogenesis-of-mantle-cell-lymphoma
#16
Niklas Vogt, Beiying Dai, Tabea Erdmann, Wolfgang E Berdel, Georg Lenz
Mantle cell lymphoma (MCL) is characterized by the translocation t(11;14) leading to constitutive cyclin D1 overexpression. However, overexpression of cyclin D1 alone is insufficient to cause malignant transformation. Secondary genetic alterations and deregulated signaling pathways involved in DNA damage response, cell proliferation, and apoptosis are indispensable for MCL lymphomagenesis. Recent studies investigating the biology of MCL have revealed crucial importance of B-cell receptor (BCR), nuclear factor-kappa B (NF-κB), phosphoinositide 3-kinase (PI3K), and BCL2 signaling for the molecular pathogenesis of MCL...
November 28, 2016: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/27890175/malignancy-and-janus-kinase-inhibition
#17
REVIEW
Padmapriya Sivaraman, Stanley B Cohen
The use of biologics such as anti-tumor necrosis factor and oral Janus kinase inhibitors have revolutionized the treatment of rheumatoid arthritis (RA). The risk of malignancies such as lymphomas, lung cancer, and nonmelanoma skin cancers (NMSCs) is greater in patients with RA compared with the general population. The incidence of all malignancy (excluding NMSC) was similar in tofacitinib users compared with the general population. The rates of overall and site-specific malignancies in patients with RA treated with tofacitinib are similar to what is expected in the RA population and not different from disease-modifying antirheumatic drugs and biologics...
February 2017: Rheumatic Diseases Clinics of North America
https://www.readbyqxmd.com/read/27889755/prevalence-of-the-janus-kinase-2-v617f-mutation-in-patients-with-end-stage-renal-disease
#18
Axel Muendlein, Janine Ebner, Emanuel Zitt
No abstract text is available yet for this article.
November 26, 2016: Nephron
https://www.readbyqxmd.com/read/27889300/tofacitinib-versus-biologic-treatments-in-patients-with-active-rheumatoid-arthritis-who-have-had-an-inadequate-response-to-tumor-necrosis-factor-inhibitors-results-from-a-network-meta-analysis
#19
Maria-Cecilia Vieira, Samuel H Zwillich, Jeroen P Jansen, Brielan Smiechowski, Dean Spurden, Gene V Wallenstein
PURPOSE: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). This analysis compared the efficacy and safety of tofacitinib with biologic disease-modifying antirheumatic drugs in patients with RA and a prior inadequate response (IR) to tumor necrosis factor inhibitors (TNFi). METHODS: A systematic literature review identified 5 randomized placebo-controlled trials that evaluated tofacitinib or biologic disease-modifying antirheumatic drugs (bDMARDs) against placebo in patient populations with RA with a prior IR to TNFi...
November 23, 2016: Clinical Therapeutics
https://www.readbyqxmd.com/read/27886336/comparative-transcriptome-analysis-reveals-three-potential-antiviral-signaling-pathways-in-lymph-organ-tissue-of-the-red-swamp-crayfish-procambarus-clarkii
#20
Z-Q Du
The red swamp crayfish (Procambarus clarkii) is one of the most economically important farmed aquatic species in China. Compared with its relatively well-known antibacterial and antifungal mechanisms, the antiviral mechanism is still unclear. We used Illumina-based RNA sequencing and bioinformatic technology to obtain high-quality sequence reads from the crayfish lymph organ. A total of 5933 differentially expressed genes (DEGs) were identified between normal and white spot syndrome virus-challenged samples...
November 21, 2016: Genetics and Molecular Research: GMR
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