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https://www.readbyqxmd.com/read/28214951/inhibition-of-jak-stat-pathway-restrains-tslp-activated-dendritic-cells-mediated-inflammatory-t-helper-type-2-cell-response-in-allergic-rhinitis
#1
Zhaohui Shi, Weihong Jiang, Min Wang, Xiaocheng Wang, Xiaoyuan Li, Xiaodong Chen, Li Qiao
Thymic stromal lymphopoietin (TSLP) has recently been implicated as a key molecule for initiating allergic rhinitis (AR) at the cell-dendritic cell (DC) interface. Previous studies demonstrated that TSLP activated DCs to express more OX40 ligand (OX40L), which is associated with the initiation of T helper type 2 (Th2) cell responses. STAT phosphorylation has been reported to be promoted by TSLP. Thus, we investigated if the JAK/STAT pathway inhibitor CYT387 could affect TSLP-DC-mediated Th2 cell response in naive T cell and AR mice model...
February 18, 2017: Molecular and Cellular Biochemistry
https://www.readbyqxmd.com/read/28214593/jak-stat-pathway-directed-therapy-of-t-cell-leukemia-lymphoma-inspired-by-functional-and-structural-genomics
#2
REVIEW
Thomas A Waldmann
Abnormal activation of the γc cytokine JAK/STAT signaling pathway assessed by STAT3 or STAT5b phosphorylation was present in a proportion of many T-cell malignancies. Activating mutations of STAT3/STAT5b and JAK1/3 were present in some but not in all cases with constitutive signaling pathway activation. Using shRNA analysis pSTAT malignant T-cell lines were addicted to JAKs/STATs whether they were mutated or not. Activating JAK/STAT mutations were not sufficient to support leukemic cell proliferation but only augmented upstream pathway signals...
February 15, 2017: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/28202754/jak-stat-signaling-pathways-and-inhibitors-affect-reversion-of-envelope-mutated-hiv-1
#3
Yudong Quan, Hongtao Xu, Yingshan Han, Thibault Mesplède, Mark A Wainberg
HIV can spread by both cell-free and cell-to-cell transmission. Here, we show that numerous of the amino acid changes in Env that are close to the CD4 binding pocket can affect HIV replication. We generated a number of mutant viruses that were unable to infect T cells as cell-free viruses but were nevertheless able to infect certain T cell lines as cell-associated viruses, followed by reversion to wild type. However, the activation of JAK-STAT signaling pathways caused inhibition of such cell-to-cell infection as well as the reversion of multiple HIV Env mutants that displayed differences in ability to bind to the CD4 receptor...
February 15, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28193636/evaluation-of-jak3-biology-in-autoimmune-disease-using-a-highly-selective-irreversible-jak3-inhibitor
#4
Fiona Elwood, David Witter, Jennifer Piesvaux, Brian Kraybill, Nathan Bays, Carla Alpert, Peter Goldenblatt, Yujie Qu, Irena Ivanovska, Hyun-Hee Lee, Chi-Sung Chiu, Hao Tang, Mark E Scott, Sujal Deshmukh, Mark Zielstorff, Alan Byford, Kalyan Chakravarty, Lauren Dorosh, Alexy Rivkin, Joel Klappenbach, Bo-Sheng Pan, Ilona Kariv, Christopher Dinsmore, Deborah Slipetz, Peter Dandliker
Reversible Janus kinase (JAK) inhibitors such as Tofacitinib(Changelian, et al., 2003;Flanagan, et al., 2010) and Decernotinib(Farmer, et al., 2015;Mahajan, et al., 2015) block cytokine signaling and are efficacious in treating autoimmune diseases (Kremer, et al., 2009;Fleischmann, et al., 2015;Fleischmann, et al., 2015;Krueger, et al., 2016;Sandborn, et al., 2012). However therapeutic doses are limited due to inhibition of other JAK/STAT pathways associated with hematopoiesis, lipid biogenesis, infection and immune responses(Kahn C, 2012)...
February 13, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28186964/il-6-secreted-by-cancer-associated-fibroblasts-promotes-epithelial-mesenchymal-transition-and-metastasis-of-gastric-cancer-via-jak2-stat3-signaling-pathway
#5
Xiongyan Wu, Pan Tao, Quan Zhou, Jie Li, Zhenjia Yu, Xiaofeng Wang, Jiaanfang Li, Chen Li, Min Yan, Zhenggang Zhu, Bingya Liu, Liping Su
Cancer-associated fibroblasts (CAFs), as the activated fibroblasts in tumor stroma, are important modifiers of tumor progression. However, the molecular mechanisms underlying the tumor-promoting properties of CAFs in gastric cancer remain unclear. Here, we show that CAFs isolated from gastric cancer produce significant amounts of interleukin-6 (IL-6). CAFs enhances the migration and EMT of gastric cancer cells through the secretion of IL-6 that activates Janus kinase 2/signal transducers and activators of transcription (JAK2/STAT3) pathway in gastric cancer cells, while deprivation of IL-6 using a neutralizing antibody or inhibition of JAK/STAT3 pathway with specific inhibitor AG490 markedly attenuates these phenotypes in gastric cancer cells induced by CAFs...
February 6, 2017: Oncotarget
https://www.readbyqxmd.com/read/28182501/disorders-of-the-jak-stat-pathway-in-t-cell-lymphoma-pathogenesis-implications-for-immunotherapy
#6
Thomas A Waldmann, Jing Chen
Common gamma receptor-dependent cytokines and their JAK/STAT pathways play pivotal roles in T cell immunity. Abnormal activation of this system was pervasive in diverse T cell malignancies assessed by pSTAT3/pSTAT5 phosphorylation. Activating mutations were described in some but not all cases. JAK1 and STAT3 were required for proliferation and survival of these T cell lines whether or not JAKs or STATs were mutated. Activating JAK and STAT mutations were not sufficient to initiate leukemic cell proliferation but rather only augmented signals from upstream in the cytokine pathway...
February 9, 2017: Annual Review of Immunology
https://www.readbyqxmd.com/read/28179120/novel-therapeutic-approaches-for-disease-modification-of-epileptogenesis-for-curing-epilepsy
#7
REVIEW
Bryan L Clossen, Doodipala Samba Reddy
This article describes the recent advances in epileptogenesis and novel therapeutic approaches for the prevention of epilepsy, with a special emphasis on the pharmacological basis of disease-modification of epileptogenesis for curing epilepsy. Here we assess animal studies and human clinical trials of epilepsy spanning 1982-2016. Epilepsy arises from a number of neuronal factors that trigger epileptogenesis, which is the process by which a brain shifts from a normal physiologic state to an epileptic condition...
February 4, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28172803/dop076-a-phase-2b-multicenter-randomized-placebo-controlled-dose-ranging-trial-of-peficitinab-an-oral-jak-inhibitor-in-patients-with-moderately-to-severely-active-ulcerative-colitis
#8
B Sands, W Sandborn, B G Feagan, G Lichtenstein, H Zhang, P Szapary, J Panes, S Vermeire, C O'Brien, J Dewey, Z Yang, J Johanns, R Strauss, C Marano
No abstract text is available yet for this article.
February 1, 2017: Journal of Crohn's & Colitis
https://www.readbyqxmd.com/read/28169015/janus-kinase-inhibitors-in-dermatology-a-systematic-review
#9
REVIEW
Rony Shreberk-Hassidim, Yuval Ramot, Abraham Zlotogorski
BACKGROUND: Janus kinase (JAK) inhibitors are emerging as a promising new treatment modality for many inflammatory conditions. OBJECTIVE: Our aim was to systematically review the available data on the use of JAK inhibitors in cutaneous diseases. METHODS: This is a systematic review of PubMed and ClinicalTrials.gov. RESULTS: One hundred thirty-four articles matched our search terms, of which 78 were original articles and 12 reports on adverse events...
February 3, 2017: Journal of the American Academy of Dermatology
https://www.readbyqxmd.com/read/28164724/jak-inhibition-in-inflammatory-bowel-disease
#10
Pablo Olivera, Silvio Danese, Laurent Peyrin-Biroulet
Current available treatments for inflammatory bowel disease (IBD) have some limitations and new options are needed. Several new molecules are being tested for the treatment of IBD and other immune-mediated inflammatory diseases. Among them, Janus kinase (JAK) inhibitors seem to have the lead, since tofacitinib has received regulatory approval in 2012 for the treatment of rheumatoid arthritis, and also it has shown a favorable risk-benefit ratio in phase 3 studies for ulcerative colitis, both in anti-TNF naïve and anti-TNF experienced patients...
February 4, 2017: Expert Review of Clinical Immunology
https://www.readbyqxmd.com/read/28159736/myeloproliferative-neoplasm-stem-cells
#11
Adam J Mead, Ann Mullally
Myeloproliferative neoplasms (MPN) arise in the hematopoietic stem cell (HSC) compartment as a result of the acquisition of somatic mutations in a single HSC that provide a selective advantage to mutant HSC over normal HSC and promote myeloid differentiation to engender a myeloproliferative phenotype. This population of somatically mutated HSC, which initiate and sustain MPN, are termed MPN stem cells. In greater than 95% of cases, mutations that drive the development of an MPN phenotype occur in a mutually exclusive manner in one of three genes: JAK2, CALR or MPL The thrombopoietin receptor, MPL is the key cytokine receptor in MPN development and these mutations all activate MPL-JAK-STAT signaling in MPN stem cells...
February 3, 2017: Blood
https://www.readbyqxmd.com/read/28157215/identification-of-a-genetically-defined-ultra-high-risk-group-in-relapsed-pediatric-t-lymphoblastic-leukemia
#12
P Richter-Pechańska, J B Kunz, J Hof, M Zimmermann, T Rausch, O R Bandapalli, E Orlova, G Scapinello, J C Sagi, M Stanulla, M Schrappe, G Cario, R Kirschner-Schwabe, C Eckert, V Benes, J O Korbel, M U Muckenthaler, A E Kulozik
In the search for genes that define critical steps of relapse in pediatric T-cell acute lymphoblastic leukemia (T-ALL) and can serve as prognostic markers, we performed targeted sequencing of 313 leukemia-related genes in 214 patients: 67 samples collected at the time of relapse and 147 at initial diagnosis. As relapse-specific genetic events, we identified activating mutations in NT5C2 (P=0.0001, Fisher's exact test), inactivation of TP53 (P=0.0007, Fisher's exact test) and duplication of chr17:q11.2-24.3 (P=0...
February 3, 2017: Blood Cancer Journal
https://www.readbyqxmd.com/read/28154773/role-of-micrornas-in-inflammation-associated-liver-cancer
#13
Lin Huan, Lin-Hui Liang, Xiang-Huo He
Liver cancer, primarily hepatocellular carcinoma (HCC), is a major cause of cancer-related death worldwide. HCC is a suitable model of inflammation-induced cancer because more than 90% of HCC cases are caused by liver damage and chronic inflammation. Several inflammatory response pathways, such as NF-κB and JAK/STAT3 signaling pathways, play roles in the crosstalk between inflammation and HCC. MicroRNAs (miRNAs) are evolutionarily conserved, short endogenous, non-coding single-stranded RNAs that are involved in various biological and pathological processes by regulating gene expression and protein translation...
December 2016: Cancer Biology & Medicine
https://www.readbyqxmd.com/read/28149160/immune-characteristics-study-of-ag490-a-signal-pathway-inhibitor-in-eae-model-mice
#14
Zhihua Zhao, Zhifeng Mao, Junjie Yin, Yaqing Shu, Wei Qiu, Zhengqi Lu, Xueqiang Hu
Multiple sclerosis (MS) is an autoimmune disease characterized by demyelination, axonal damage and progressive neurologic dysfunction in central nervous system (CNS). Many evidences show that B cells play an important role in the pathogenesis of MS. Follicular helper T cells (Tfh) secrete IL-21 to prompt the proliferation and differentiation of B cells in germinal center (GC) through clonal proliferation, somatic hypermutation, antibody class switching, antibody affinity maturation process. AG490 is a synthetic inhibitor to JAK-STAT signal pathway, which has been studied in inflammatory, tumor and autoimmune diseases...
February 2017: Saudi Journal of Biological Sciences
https://www.readbyqxmd.com/read/28147353/anti-cytokine-strategies-beyond-anti-tumour-necrosis-factor-%C3%AE-therapy-pathophysiology-and-clinical-implications
#15
REVIEW
Gerhard Rogler, Luc Biedermann, Michael Scharl
Cytokines are small proteins produced by a broad range of cells important in cell signaling. They include interleukins, but also chemokines, interferons, and tumor necrosis factors (TNF). They play an important role for communication between cells of the innate and adaptive immune system. The cytokine network is complex and, therefore, therapeutic interventions are difficult. The first anti-cytokine strategy successfully introduced into IBD therapy was the neutralization of TNF by antibodies. Beyond targeting this cytokine anti-IL-23 strategies were demonstrated to be of therapeutic benefit in IBD...
2017: Digestive Diseases
https://www.readbyqxmd.com/read/28144028/current-and-emerging-therapeutic-targets-for-ibd
#16
REVIEW
Markus F Neurath
Various therapeutic advances have led to a paradigm shift in the clinical management of patients with IBD. The introduction of immunosuppressive (such as azathioprine) and biologic agents (such as TNF blockers) has markedly reduced the need to use corticosteroids for therapy. Furthermore, the α4β7 integrin blocker vedolizumab has been introduced for clinical IBD therapy. Moreover, various new inhibitors of cytokines (for example, IL-6-IL-6R and IL-12-IL-23 blockers or apremilast), modulators of cytokine signalling events (for example, JAK inhibitors or SMAD7 blocker), inhibitors of transcription factors (for example, GATA3 or RORγt) and new anti-adhesion and anti-T-cell-activation and migration strategies (for example, β7 integrin, sphingosine 1-phosphate receptors and MAdCAM1 inhibitors, regulatory T-cell therapy and stem cells) are currently being evaluated in controlled clinical trials...
February 1, 2017: Nature Reviews. Gastroenterology & Hepatology
https://www.readbyqxmd.com/read/28139931/design-of-a-janus-kinase-3-jak3-specific-inhibitor-1-2s-5r-5-7h-pyrrolo-2-3-d-pyrimidin-4-yl-amino-2-methylpiperidin-1-yl-prop-2-en-1-one-pf-06651600-allowing-for-the-interrogation-of-jak3-signaling-in-humans
#17
Atli Thorarensen, Martin E Dowty, Mary Ellen Banker, Brian Juba, Jason Jussif, Tsung Lin, Fabien Vincent, Robert M Czerwinski, Agustin Casimiro-Garcia, Ray Unwalla, John I Trujillo, Sidney Liang, Paul Balbo, Ye Che, Adam M Gilbert, Matthew F Brown, Matthew Hayward, Justin Montgomery, Louis Leung, Xin Yang, Sarah Soucy, Martin Hegen, Jotham Coe, Jonathan Langille, Felix Vajdos, Jill Chrencik, Jean-Baptiste Telliez
Significant work has been dedicated to the discovery of JAK kinase inhibitors resulting in several compounds entering clinical development and two FDA approved NMEs. However, despite significant effort during the past 2 decades, identification of highly selective JAK3 inhibitors has eluded the scientific community. A significant effort within our research organization has resulted in the identification of the first orally active JAK3 specific inhibitor, which achieves JAK isoform specificity through covalent interaction with a unique JAK3 residue Cys-909...
February 16, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28139263/jak-inhibitors-in-dermatology-the-promise-of-a-new-drug-class
#18
REVIEW
William Damsky, Brett A King
New molecularly targeted therapeutics are changing dermatologic therapy. Janus kinase-signal transducer and activator of transcription (JAK-STAT) is an intracellular signaling pathway upon which many different proinflammatory signaling pathways converge. Numerous inflammatory dermatoses are driven by soluble inflammatory mediators, which rely on JAK-STAT signaling, and inhibition of this pathway using JAK inhibitors might be a useful therapeutic strategy for these diseases. Growing evidence suggests that JAK inhibitors are efficacious in atopic dermatitis, alopecia areata, psoriasis, and vitiligo...
January 28, 2017: Journal of the American Academy of Dermatology
https://www.readbyqxmd.com/read/28131799/janus-kinase-inhibitors-display-broad-anti-itch-properties-a-possible-link-via-the-trpv1-receptor
#19
Tomoki Fukuyama, Joy Rachel Ganchingco, Santosh K Mishra, Thierry Olivry, Ignacy Rzagalinski, Dietrich A Volmer, Wolfgang Bäumer
The antipruritic effect of JAK inhibitors is fast and sustained in dogs with atopic dermatitis and in human patients with psoriasis. The inhibitory profiles of these molecules might be more related to their direct inhibition of TRPV1 rather than that of JAKs.
January 25, 2017: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/28131742/jak-stat-disruption-induces-immune-deficiency-rationale-for-the-development-of-jak-inhibitors-as-immunosuppressive-drugs
#20
Isabelle Cornez, Sowmya Parampalli Yajnanarayana, Anna Maria Wolf, Dominik Wolf
Cytokines are mediating immune cells responses through the activation of the JAK/STAT signaling pathway. Being critical for immune cells, a defective JAK/STAT signaling leads to various immune disorders, such as immunodeficiency. In contrast, hyperactivation of JAK/STAT signaling is linked to autoimmunity and cancer. Targeting the JAK/STAT proteins by small protein inhibitors impedes immune cell function by uncoupling cells from cytokine effects and by interfering with functional immune cell hallmarks, such as cell migration...
January 25, 2017: Molecular and Cellular Endocrinology
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