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Interleukin receptor associated kinase m

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https://www.readbyqxmd.com/read/29743719/inhibition-of-interleukin-1-receptor-associated-kinase-1-is-a-therapeutic-strategy-for-acute-myeloid-leukemia-subtypes
#1
Mona M Hosseini, Stephen E Kurtz, Sherif Abdelhamed, Shawn Mahmood, Monika A Davare, Andy Kaempf, Johannes Elferich, Jason E McDermott, Tao Liu, Samuel H Payne, Ujwal Shinde, Karin D Rodland, Motomi Mori, Brian J Druker, Jack W Singer, Anupriya Agarwal
Interleukin-1 receptor-associated kinase 1 (IRAK1), an essential mediator of innate immunity and inflammatory responses, is constitutively active in multiple cancers. We evaluated the role of IRAK1 in acute myeloid leukemia (AML) and assessed the inhibitory activity of multikinase inhibitor pacritinib on IRAK1 in AML. We demonstrated that IRAK1 is overexpressed in AML and provides a survival signal to AML cells. Genetic knockdown of IRAK1 in primary AML samples and xenograft model showed a significant reduction in leukemia burden...
March 29, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/29706963/protective-role-of-the-mer-tyrosine-kinase-via-efferocytosis-in-rheumatoid-arthritis-models
#2
Claire E J Waterborg, Silke Beermann, Mathijs G A Broeren, Miranda B Bennink, Marije I Koenders, Peter L E M van Lent, Wim B van den Berg, Peter M van der Kraan, Fons A J van de Loo
Objective: Rheumatoid arthritis (RA) is a chronic and progressive joint disease. It appears that anti-inflammatory feedback mechanisms that could restrain joint inflammation and restore homeostasis are insufficient to perform this control. In this study, we investigated the contribution of the MER tyrosine kinase-mediated anti-inflammatory response on arthritis and whether targeting MER could be a valid approach to treat RA. Methods: KRN serum transfer arthritis (KRN STA) was induced in either Mertk -deficient mice or in mice that adenovirally overexpressed Pros1 ...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29686383/the-il-33-pin1-irak-m-axis-is-critical-for-type-2-immunity-in-il-33-induced-allergic-airway-inflammation
#3
Morris Nechama, Jeahoo Kwon, Shuo Wei, Adrian Tun Kyi, Robert S Welner, Iddo Z Ben-Dov, Mohamed S Arredouani, John M Asara, Chun-Hau Chen, Cheng-Yu Tsai, Kyle F Nelson, Koichi S Kobayashi, Elliot Israel, Xiao Zhen Zhou, Linda K Nicholson, Kun Ping Lu
Interleukin 33 (IL-33) is among the earliest-released cytokines in response to allergens that orchestrate type 2 immunity. The prolyl cis-trans isomerase PIN1 is known to induce cytokines for eosinophil survival and activation by stabilizing cytokines mRNAs, but the function of PIN1 in upstream signaling pathways in asthma is unknown. Here we show that interleukin receptor associated kinase M (IRAK-M) is a PIN1 target critical for IL-33 signaling in allergic asthma. NMR analysis and docking simulations suggest that PIN1 might regulate IRAK-M conformation and function in IL-33 signaling...
April 23, 2018: Nature Communications
https://www.readbyqxmd.com/read/29683202/placental-inflammation-in-pre-eclampsia-by-nod-like-receptor-protein-nlrp-3-inflammasome-activation-in-trophoblasts
#4
G S Stødle, G B Silva, L H Tangerås, L M Gierman, I Nervik, U E Dahlberg, C Sun, M H Aune, L C V Thomsen, L Bjørge, A-C Iversen
Pre-eclampsia is associated with increased levels of cholesterol and uric acid and an inflamed placenta expressing danger-sensing pattern recognition receptors (PRRs). Crystalline cholesterol and uric acid activate the PRR Nod-like receptor protein (NLRP)3 inflammasome to release interleukin (IL)-1β and result in vigorous inflammation. We aimed to characterize crystal-induced NLRP3 activation in placental inflammation and examine its role in pre-eclampsia. We confirmed that serum total cholesterol and uric acid were elevated in pre-eclamptic compared to healthy pregnancies and correlated positively to high sensitivity C-reactive protein (hsCRP) and the pre-eclampsia marker soluble fms-like tyrosine kinase-1 (sFlt-1)...
April 23, 2018: Clinical and Experimental Immunology
https://www.readbyqxmd.com/read/29604293/immune-cell-production-of-interleukin-17-induces-stem-cell-features-of-pancreatic-intraepithelial-neoplasia-cells
#5
Yu Zhang, Michelle Zoltan, Erick Riquelme, Hanwen Xu, Ismet Sahin, Susana Castro-Pando, Maria Fernanda Montiel, Kyle Chang, Zhengyu Jiang, Jianhua Ling, Sonal Gupta, William Horne, Melissa Pruski, Huamin Wang, Shao-Cong Sun, Guillermina Lozano, Paul Chiao, Anirban Maitra, Steven D Leach, Jay K Kolls, Eduardo Vilar Sanchez, Timothy C Wang, Jennifer M Bailey, Florencia McAllister
BACKGROUND & AIMS: Little is known about how the immune system affects stem cell features of pancreatic cancer cells. Immune cells that produce interleukin 17 A (IL17A) in the chronically inflamed pancreas (chronic pancreatitis) contribute to PanIN initiation and progression. We investigated the effects of IL17A signaling exerts on pancreatic cancer progenitor cells and the clinical relevance of this phenomena. METHODS: We performed studies with Mist1Cre;LSLKras;Rosa26mTmG (KCiMist ;G) and Kras(G12D); Trp53(R172H); Pdx1-Cre (KPC) mice (which upon tamoxifen induction spontaneously develop pancreatic intraepithelial neoplasias, PanINs) and control littermates...
March 28, 2018: Gastroenterology
https://www.readbyqxmd.com/read/29601781/cardiac-fibroblast-specific-p38%C3%AE-map-kinase-promotes-cardiac-hypertrophy-via-a-putative-paracrine-interleukin-6-signaling-mechanism
#6
Sumia A Bageghni, Karen E Hemmings, Ngonidzashe Zava, Christopher P Denton, Karen E Porter, Justin F X Ainscough, Mark J Drinkhill, Neil A Turner
Recent studies suggest that cardiac fibroblast-specific p38α MAPK contributes to the development of cardiac hypertrophy, but the underlying mechanism is unknown. Our study used a novel fibroblast-specific, tamoxifen-inducible p38α knockout (KO) mouse line to characterize the role of fibroblast p38α in modulating cardiac hypertrophy, and we elucidated the mechanism. Myocardial injury was induced in tamoxifen-treated Cre-positive p38α KO mice or control littermates via chronic infusion of the β-adrenergic receptor agonist isoproterenol...
March 30, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/29534932/resveratrol-a-natural-polyphenol-prevents-chemotherapy-induced-cognitive-impairment-involvement-of-cytokine-modulation-and-neuroprotection
#7
Dong-Dong Shi, Celia M Dong, Leon C Ho, C T W Lam, Xi-Dan Zhou, Ed X Wu, Zhong-Jun Zhou, Xiao-Min Wang, Zhang-Jin Zhang
Chemotherapy-induced cognitive impairment, also known as "chemobrain," is a common side effect. The purpose of this study was to examine whether resveratrol, a natural polyphenol that has nootropic effects, could prevent chemobrain and its underlying mechanisms. Mice received three injections of docetaxel, adriamycin, and cyclophosphamide (DAC) in combination, a common chemotherapy regimen, at two-day intervals within one week. Resveratrol (50 and 100 mg/kg per day) was orally administered for three weeks, beginning one week before the DAC treatment...
June 2018: Neurobiology of Disease
https://www.readbyqxmd.com/read/29434744/interleukin-1-receptor-associated-kinase-3-downregulation-in-peripheral-blood-mononuclear-cells-attenuates-immunosuppression-in-sepsis
#8
Qin Xia, Yupin Zhou, Xi Wang, Shukun Fu
Sepsis is the leading cause of mortality in intensive care units due to complex inflammatory immune responses and immunosuppression. Recent studies have indicated that the negative regulator of toll like receptors, interleukin-1 receptor-associated kinase 3 (IRAK-3/IRAK-M), serves an important role in immunosuppression during sepsis. In the current study, a cecal ligation puncture model was established in mice using lipopolysaccharide secondary challenge to simulate immunosuppression in sepsis. Peripheral blood mononuclear cells (PBMCs) from this model were then used to evaluate the expression and function of IRAK-M...
February 2018: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/29429051/cilostazol-mediated-nurr1-and-autophagy-enhancement-neuroprotective-activity-in-rat-rotenone-pd-model
#9
Shireen A Hedya, Marwa M Safar, Ashraf K Bahgat
Nuclear receptor related 1 (Nurr1) orphan receptor has emerged as a promising contender in ameliorating Parkinson's disease; thus, finding a suitable activator of Nurr1 receptor is an attracting target for treating PD. Cilostazol, a phosphodiesterase-3 inhibitor, recently showed a favorable neuroprotective activity in multiple devastating central disorders, yet the possible antiparkinsonian activity of the drug has not been fully elucidated. Thus, the aim of this study is to explore the neuroprotective effect of cilostazol in rotenone-induced PD model in rats...
February 10, 2018: Molecular Neurobiology
https://www.readbyqxmd.com/read/29419652/chemotherapy-induced-pain-is-promoted-by-enhanced-spinal-adenosine-kinase-levels-through-astrocyte-dependent-mechanisms
#10
Carrie Wahlman, Timothy M Doyle, Joshua W Little, Livio Luongo, Kali Janes, Zhoumou Chen, Emanuela Esposito, Dilip K Tosh, Salvatore Cuzzocrea, Kenneth A Jacobson, Daniela Salvemini
Development of chemotherapy-induced neuropathic pain (CINP) compromises the use of chemotherapy and greatly impacts thousands of lives. Unfortunately, there are no Food and Drug Administration-approved drugs to prevent or treat CINP. Neuropathological changes within CNS, including neuroinflammation and increased neuronal excitability, are driven by alterations in neuro-glia communication; but, the molecular signaling pathways remain largely unexplored. Adenosine is a potent neuroprotective purine nucleoside released to counteract the consequences of these neuropathological changes...
February 6, 2018: Pain
https://www.readbyqxmd.com/read/29345428/traf3-regulation-of-inhibitory-signaling-pathways-in-b-and-t-lymphocytes-by-kinase-and-phosphatase-localization
#11
REVIEW
Alicia M Wallis, Gail A Bishop
This brief review presents current understanding of how the signaling adapter protein TRAF3 can both induce and block inhibitory signaling pathways in B and T lymphocytes, via association with kinases and phosphatases, and subsequent regulation of their localization within the cell. In B lymphocytes, signaling through the interleukin 6 receptor (IL-6R) induces association of TRAF3 with IL-6R-associated JAK1, to which TRAF3 recruits the phosphatase PTPN22 (protein tyrosine phosphatase number 22) to dephosphorylate JAK1 and STAT3, inhibiting IL-6R signaling...
January 17, 2018: Journal of Leukocyte Biology
https://www.readbyqxmd.com/read/29242937/paclitaxel-with-and-without-pazopanib-for-persistent-or-recurrent-ovarian-cancer-a-randomized-clinical-trial
#12
Debra L Richardson, Michael W Sill, Robert L Coleman, Anil K Sood, Michael L Pearl, Siobhan M Kehoe, Michael E Carney, Parviz Hanjani, Linda Van Le, Xun C Zhou, Angeles Alvarez Secord, Heidi J Gray, Lisa M Landrum, Heather A Lankes, Wei Hu, Carol Aghajanian
Importance: Ovarian cancer is the leading cause of gynecologic cancer deaths in the United States. Pazopanib is an oral, multitarget kinase inhibitor of vascular endothelial growth factor receptors 1, 2, and 3; platelet-derived growth factor receptors α and β; and proto-oncogene receptor tyrosine kinase (c-KIT). Objective: To estimate the progression-free survival (PFS) hazard ratio (HR) of weekly paclitaxel and pazopanib compared with weekly paclitaxel and placebo in women with recurrent ovarian cancer...
February 1, 2018: JAMA Oncology
https://www.readbyqxmd.com/read/29208712/crystal-structure-of-human-irak1
#13
Li Wang, Qi Qiao, Ryan Ferrao, Chen Shen, John M Hatcher, Sara J Buhrlage, Nathanael S Gray, Hao Wu
Interleukin 1 (IL-1) receptor-associated kinases (IRAKs) are serine/threonine kinases that play critical roles in initiating innate immune responses against foreign pathogens and other types of dangers through their role in Toll-like receptor (TLR) and interleukin 1 receptor (IL-1R) mediated signaling pathways. Upon ligand binding, TLRs and IL-1Rs recruit adaptor proteins, such as myeloid differentiation primary response gene 88 (MyD88), to the membrane, which in turn recruit IRAKs via the death domains in these proteins to form the Myddosome complex, leading to IRAK kinase activation...
December 19, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29208683/il-33-and-st2-mediate-fak-dependent-antitumor-immune-evasion-through-transcriptional-networks
#14
Bryan Serrels, Niamh McGivern, Marta Canel, Adam Byron, Sarah C Johnson, Henry J McSorley, Niall Quinn, David Taggart, Alex Von Kreigsheim, Stephen M Anderton, Alan Serrels, Margaret C Frame
Focal adhesion kinase (FAK) mediates tumor cell-intrinsic behaviors that promote tumor growth and metastasis. We previously showed that FAK also induces the expression of inflammatory genes that inhibit antitumor immunity in the microenvironment. We identified a crucial, previously unknown role for the dual-function cytokine interleukin-33 (IL-33) in FAK-dependent immune evasion. In murine squamous cell carcinoma (SCC) cells, specifically nuclear FAK enhanced the expression of the genes encoding IL-33, the chemokine CCL5, and the soluble, secreted form of the IL-33 receptor, called soluble ST2 (sST2)...
December 5, 2017: Science Signaling
https://www.readbyqxmd.com/read/29203859/interleukin-13-receptor-alpha-2-cooperates-with-egfrviii-signaling-to-promote-glioblastoma-multiforme
#15
Jennifer P Newman, Grace Y Wang, Kazuhiko Arima, Shou P Guan, Michael R Waters, Webster K Cavenee, Edward Pan, Edita Aliwarga, Siao T Chong, Catherine Y L Kok, Berwini B Endaya, Amyn A Habib, Tomohisa Horibe, Wai H Ng, Ivy A W Ho, Kam M Hui, Tomasz Kordula, Paula Y P Lam
The interleukin-13 receptor alpha2 (IL-13Rα2) is a cancer-associated receptor overexpressed in human glioblastoma multiforme (GBM). This receptor is undetectable in normal brain which makes it a highly suitable target for diagnostic and therapeutic purposes. However, the pathological role of this receptor in GBM remains to be established. Here we report that IL-13Rα2 alone induces invasiveness of human GBM cells without affecting their proliferation. In contrast, in the presence of the mutant EGFR (EGFRvIII), IL-13Rα2 promotes GBM cell proliferation in vitro and in vivo...
December 4, 2017: Nature Communications
https://www.readbyqxmd.com/read/29172502/discovery-and-optimization-of-pyrrolopyrimidine-inhibitors-of-interleukin-1-receptor-associated-kinase-4-irak4-for-the-treatment-of-mutant-myd88-l265p-diffuse-large-b-cell-lymphoma
#16
James S Scott, Sébastien L Degorce, Rana Anjum, Janet Culshaw, Robert D M Davies, Nichola L Davies, Keith S Dillman, James E Dowling, Lisa Drew, Andrew D Ferguson, Sam D Groombridge, Christopher T Halsall, Julian A Hudson, Scott Lamont, Nicola A Lindsay, Stacey K Marden, Michele F Mayo, J Elizabeth Pease, David R Perkins, Jennifer H Pink, Graeme R Robb, Alan Rosen, Minhui Shen, Claire McWhirter, Dedong Wu
Herein we report the optimization of a series of pyrrolopyrimidine inhibitors of interleukin-1 receptor associated kinase 4 (IRAK4) using X-ray crystal structures and structure based design to identify and optimize our scaffold. Compound 28 demonstrated a favorable physicochemical and kinase selectivity profile and was identified as a promising in vivo tool with which to explore the role of IRAK4 inhibition in the treatment of mutant MYD88L265P diffuse large B-cell lymphoma (DLBCL). Compound 28 was shown to be capable of demonstrating inhibition of NF-κB activation and growth of the ABC subtype of DLBCL cell lines in vitro at high concentrations but showed greater effects in combination with a BTK inhibitor at lower concentrations...
December 28, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29144391/antimicrobial-peptide-epinecidin-1-modulates-myd88-protein-levels-via-the-proteasome-degradation-pathway
#17
Bor-Chyuan Su, Jyh-Yih Chen
The cationic antimicrobial peptide epinecidin-1 was identified from Epinephelus coioides and possesses multiple biological functions, including antibacterial, antifungal, anti-tumor, and immunomodulatory effects. In addition, epinecidin-1 suppresses lipopolysaccharide (LPS)-induced inflammation by neutralizing LPS and ameliorating LPS/Toll-like receptor (TLR)-4 internalization. However, it is unclear whether the actions of epinecidin-1 depend on the regulation of TLR adaptor protein MyD88 or endogenous TLR signaling antagonists, which include A20, interleukin-1 receptor associated kinase (IRAK)-M, and suppressor of cytokine signaling (SOCS)-1...
November 16, 2017: Marine Drugs
https://www.readbyqxmd.com/read/29142418/-marantodes-pumilum-blume-kuntze-inhibited-secretion-of-lipopolysaccharide-and-monosodium-urate-crystal-stimulated-cytokines-and-plasma-prostaglandin-e-2
#18
Eldiza Puji Rahmi, Jamia Azdina Jamal, Endang Kumolosasi, Juriyati Jalil, Nor-Ashila Aladdin
Background: Marantodes pumilum is traditionally used for dysentery, gonorrhea, and sickness in the bones. Previous studies revealed its antibacterial and xanthine oxidase inhibitory activities. Objective: To evaluate the inhibitory effects of three M. pumilum varieties on the secretion of lipopolysaccharide (LPS)- and monosodium urate crystal (MSU)-induced cytokines and plasma prostaglandin E2 (PGE2 ) in vitro . Materials and Methods: The leaves and roots of M...
October 2017: Pharmacognosy Magazine
https://www.readbyqxmd.com/read/29059216/protective-effect-of-dexamethasone-on-5-fu-induced-oral-mucositis-in-hamsters
#19
Susana Barbosa Ribeiro, Aurigena Antunes de Araújo, Raimundo Fernandes de Araújo Júnior, Gerly Anne de Castro Brito, Renata Carvalho Leitão, Maisie Mitchele Barbosa, Vinicius Barreto Garcia, Aldo Cunha Medeiros, Caroline Addison Carvalho Xavier de Medeiros
Oral mucositis (OM) is an important side effect of cancer treatment, characterized by ulcerative lesions in the mucosa of patients undergoing radiotherapy or chemotherapy, which has marked effects on patient quality of life and cancer therapy continuity. Considering that few protocols have demonstrated efficacy in preventing this side effect, the aim of this study was to examine the effect of dexamethasone (DEX) on OM induced by 5-fluorouracil (5-FU) in hamsters by studying signaling pathways. OM was induced in hamsters by 5-FU followed by mechanical trauma (MT) on day 4...
2017: PloS One
https://www.readbyqxmd.com/read/29037857/exploring-the-role-of-il-32-in-hiv-related-kaposi-sarcoma
#20
George Semango, Bas Heinhuis, Theo S Plantinga, Willeke A M Blokx, Gibson Kibiki, Tolbert Sonda, Daudi Mavura, Elisante J Masenga, Mramba Nyindo, Andre J A M van der Ven, Leo A B Joosten
The intracellular proinflammatory mediator IL-32 is associated with tumor progression; however, the mechanisms remain unknown. We studied IL-32 mRNA expression as well as expression of other proinflammatory cytokines and mediators, including IL-1α, IL-1β, IL-6, IL-8, tumor necrosis factor (TNF)-α, the proangiogenic and antiapoptotic enzyme cyclooxygenase-2, the IL-8 receptor C-X-C chemokine receptor (CXCR) 1, and the intracellular kinase focal adhesion kinase-1. The interaction of IL-32 expression with expression of IL-6, TNF-α, IL-8, and cyclooxygenase-2 was also investigated...
January 2018: American Journal of Pathology
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