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Interleukin receptor associated kinase m

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https://www.readbyqxmd.com/read/28685413/telluric-acid-ameliorates-endotoxemic-kidney-injury-in-mice-involvement-of-tlr4-nrf2-and-pi3k-akt-signaling-pathways
#1
Ahmed F Mohamed, Marwa M Safar, Hala F Zaki, Helmy M Sayed
Being one of the most abundant trace elements in the human body, the therapeutic potential of tellurium-based compounds has been a target of interest. Recent reports denoted their redox-modulating and anti-inflammatory activities in experimental endotoxemia. However, their potential nephroprotective effect against endotoxemic kidney injury is yet to be elucidated. This study investigated the possible renoprotective effect of telluric acid (TEL) against lipopolysaccharide (LPS)-induced acute kidney injury (AKI) in mice, targeting toll-like receptor 4 (TLR4), phosphoinositide 3-kinase (PI3K)/Akt, and nuclear factor-erythroid 2-related factor-2 (Nrf2) pathways as possible mechanistic contributors to TEL's effect...
July 6, 2017: Inflammation
https://www.readbyqxmd.com/read/28684999/mechanism-of-action-of-selective-inhibitors-of-il-6-induced-stat3-pathway-in-head-and-neck-cancer-cell-lines
#2
Malabika Sen, Paul A Johnston, Netanya I Pollock, Kara DeGrave, Sonali C Joyce, Maria L Freilino, Yun Hua, Daniel P Camarco, David A Close, Donna M Huryn, Peter Wipf, Jennifer R Grandis
Studies indicate that elevated interleukin-6 (IL-6) levels engage IL6Rα-gp130 receptor complexes to activate signal transducer and activator of transcription 3 (STAT3) that is hyperactivated in many cancers including head and neck squamous cell carcinoma (HNSCC). Our previous HCS campaign identified several hits that selectively blocked IL-6-induced STAT3 activation. This study describes our investigation of the mechanism(s) of action of three of the four chemical series that progressed to lead activities: a triazolothiadiazine (864669), amino alcohol (856350), and an oxazole-piperazine (4248543)...
July 2017: Journal of Chemical Biology
https://www.readbyqxmd.com/read/28619064/protective-effect-of-rutin-supplementation-against-cisplatin-induced-nephrotoxicity-in-rats
#3
Ali R Alhoshani, Mohamed M Hafez, Sufia Husain, Abdel Malek Al-Sheikh, Moureq R Alotaibi, Salim S Al Rejaie, Musaad A Alshammari, Mashal M Almutairi, Othman A Al-Shabanah
BACKGROUND: Cisplatin (CP) is commonly used in the treatment of different types of cancer but nephrotoxicity has been a major limiting factor. Therefore, the present study aimed to study the possible protective effect of rutin against nephrotoxicity induced by cisplatin in rats. METHODS: Forty male Wistar albino rats were randomly divided into 4 groups. Rats of group 1 control group intraperitoneal (i.p.) received 2.5 ml/kg, group 2 CP group received single dose 5 mg/kg cisplatin i...
June 15, 2017: BMC Nephrology
https://www.readbyqxmd.com/read/28609207/protection-of-lipopolysaccharide-lps-preconditioning-against-endotoxin-induced-uveitis-eiu-in-rats-is-associated-with-overexpression-of-interleukin-1-receptor-associated-kinase-m-irak-m
#4
Shuo Yu, Xinli Liu, Nan Zhang, Shuo Yang, Cui Mao, Shilan Feng, Hong Lu
PURPOSE: To investigate the protective effect of LPS preconditioning against EIU in rats. METHODS: EIU in Wistar rats was developed by subcutaneous injection of LPS (200 μg). Lower dose of LPS (0.1 mg/kg, intraperitoneally) or its carrier was injected daily for five days before EIU induction. Twenty-four hours after EIU, eyes were examined and then enucleated. The degree of inflammatory reaction was determined by routine histological examinations. Real-time RT-PCR and Western blot were used to determine the activation of NF-kB and expression of IRAK-1, IRAK-4, and IRAK-M Results: Repeated pre-administration of LPS induced a significant reduction in ocular inflammation and the expression of NF-κb p65 in neurons...
June 13, 2017: Ocular Immunology and Inflammation
https://www.readbyqxmd.com/read/28559019/il6-is-associated-with-response-to-dasatinib-and-cetuximab-phase-ii-clinical-trial-with-mechanistic-correlatives-in-cetuximab-resistant-head-and-neck-cancer
#5
L P Stabile, A M Egloff, M K Gibson, W E Gooding, J Ohr, P Zhou, N J Rothenberger, L Wang, J L Geiger, J T Flaherty, J R Grandis, J E Bauman
OBJECTIVE: Src family kinase (SFK) activation circumvents epidermal growth factor receptor (EGFR) targeting in head and neck squamous cell carcinoma (HNSCC); dual SFK-EGFR targeting could overcome cetuximab resistance. PATIENTS AND METHODS: We conducted a Simon two-stage, phase II trial of the SFK inhibitor, dasatinib, and cetuximab in biomarker-unselected patients with cetuximab-resistant, recurrent/metastatic HNSCC. Pre- and post-treatment serum levels of interleukin-6 (IL6) were measured by ELISA...
June 2017: Oral Oncology
https://www.readbyqxmd.com/read/28536249/bronchial-inflammation-and-bacterial-load-in-stable-copd-is-associated-with-tlr4-overexpression
#6
Antonino Di Stefano, Fabio L M Ricciardolo, Gaetano Caramori, Ian M Adcock, Kian Fan Chung, Peter J Barnes, Paola Brun, Andrea Leonardi, Filippo Andò, Davide Vallese, Isabella Gnemmi, Luisella Righi, Francesco Cappello, Bruno Balbi
Toll-like receptors (TLRs) and nucleotide-binding oligomerisation domain (NOD)-like receptors (NLRs) are two major forms of innate immune sensors but their role in the immunopathology of stable chronic obstructive pulmonary disease (COPD) is incompletely studied. Our objective here was to investigate TLR and NLR signalling pathways in the bronchial mucosa in stable COPD.Using immunohistochemistry, the expression levels of TLR2, TLR4, TLR9, NOD1, NOD2, CD14, myeloid differentiation primary response gene 88 (MyD88), Toll-interleukin-1 receptor domain-containing adaptor protein (TIRAP), and the interleukin-1 receptor-associated kinases phospho-IRAK1 and IRAK4 were measured in the bronchial mucosa of subjects with stable COPD of different severity (n=34), control smokers (n=12) and nonsmokers (n=12)...
May 2017: European Respiratory Journal: Official Journal of the European Society for Clinical Respiratory Physiology
https://www.readbyqxmd.com/read/28498658/discovery-of-clinical-candidate-1-2s-3s-4s-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl-methoxy-7-methoxyisoquinoline-6-carboxamide-pf-06650833-a-potent-selective-inhibitor-of-interleukin-1-receptor-associated-kinase-4-irak4-by-fragment-based-drug-design
#7
Katherine L Lee, Catherine M Ambler, David R Anderson, Brian P Boscoe, Andrea G Bree, Joanne I Brodfuehrer, Jeanne S Chang, Chulho Choi, Seungwon Chung, Kevin J Curran, Jacqueline E Day, Christoph M Dehnhardt, Ken Dower, Susan E Drozda, Richard K Frisbie, Lori K Gavrin, Joel A Goldberg, Seungil Han, Martin Hegen, David Hepworth, Heidi R Hope, Satwik Kamtekar, Iain C Kilty, Arthur Lee, Lih-Ling Lin, Frank E Lovering, Michael D Lowe, John P Mathias, Heidi M Morgan, Elizabeth A Murphy, Nikolaos Papaioannou, Akshay Patny, Betsy S Pierce, Vikram R Rao, Eddine Saiah, Ivan J Samardjiev, Brian M Samas, Marina W H Shen, Julia H Shin, Holly H Soutter, Joseph W Strohbach, Peter T Symanowicz, Jennifer R Thomason, John D Trzupek, Richard Vargas, Fabien Vincent, Jiangli Yan, Christoph W Zapf, Stephen W Wright
Through fragment-based drug design focused on engaging the active site of IRAK4 and leveraging three-dimensional topology in a ligand-efficient manner, a micromolar hit identified from a screen of a Pfizer fragment library was optimized to afford IRAK4 inhibitors with nanomolar potency in cellular assays. The medicinal chemistry effort featured the judicious placement of lipophilicity, informed by co-crystal structures with IRAK4 and optimization of ADME properties to deliver clinical candidate PF-06650833 (compound 40)...
June 14, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28432060/toll-like-receptor-2-tlr2-dominance-over-tlr4-in-stressful-conditions-for-its-detrimental-role-in-the-heart
#8
Ashim K Bagchi, Gauri Akolkar, Soma Mandal, Prathapan Ayyappan, Xi Yang, Pawan K Singal
It has been suggested that toll-like receptor 4 (TLR4) promotes interleukin-10 (IL-10)-mediated cardiac cell survival while another receptor, TLR2, from the same family is detrimental. Here we examined the interactive role of these two innate signaling molecules under stressful conditions including interleukin-10 knockout (IL-10(-/-)) mice, global ischemia/reperfusion (I/R) injury in rat hearts and in-vitro shRNA experimental models in presence or absence of IL-10 (10ng/ml). Circulating and myocardial levels of tumor necrosis factor-α (TNF-α) as well as apoptosis and fibrosis were higher in IL-10(-/-) mice...
April 21, 2017: American Journal of Physiology. Heart and Circulatory Physiology
https://www.readbyqxmd.com/read/28422768/mechanisms-involved-in-secondary-cardiac-dysfunction-in-animal-models-of-trauma-and-haemorrhagic-shock
#9
Nick M Wilson, Johanna Wall, Veena Naganathar, Karim Brohi, Henry D De'Ath
Clinical evidence reveals the existence of a trauma induced secondary cardiac injury (TISCI) which is associated with poor patient outcomes. The mechanisms leading to TISCI in injured patients are uncertain. Conversely, animal models of trauma haemorrhage have repeatedly demonstrated significant cardiac dysfunction following injury, and highlighted mechanisms through which this might occur. The aim of this review was to provide an overview of the animal studies describing TISCI and its pathophysiology.Basic science models of trauma show evidence of innate immune system activation via Toll-Iike receptors (TLRs), the exact protagonists of which remain unclear...
April 18, 2017: Shock
https://www.readbyqxmd.com/read/28350111/melittin-inhibits-osteoclast-formation-through-the-downregulation-of-the-rankl-rank-signaling-pathway-and-the-inhibition-of-interleukin-1%C3%AE-in-murine-macrophages
#10
Jung-Yoon Choe, Seong-Kyu Kim
Melittin is a major toxic component of bee venom (Apis mellifera). It is not known whether melittin is involved in bone metabolism and osteoclastogenesis. The aim of this study was to determine the role of melittin in the regulation of osteoclastogenesis. In vitro osteoclastogenesis assays were performed using mouse RAW 264.7 cells and bone marrow-derived macrophages (BMMs) treated with receptor activator of nuclear factor-κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF). Morphologic and functional analyses for osteoclast-like multinucleated cells (MNCs) were performed by tartrate-resistant acid phosphatase (TRAP) staining, F-actin staining and pit formation methods...
February 3, 2017: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/28333195/genome-wide-genetic-analyses-highlight-mitogen-activated-protein-kinase-mapk-signaling-in-the-pathogenesis-of-endometriosis
#11
Outi Uimari, Nilufer Rahmioglu, Dale R Nyholt, Katy Vincent, Stacey A Missmer, Christian Becker, Andrew P Morris, Grant W Montgomery, Krina T Zondervan
Study question: Do genome-wide association study (GWAS) data for endometriosis provide insight into novel biological pathways associated with its pathogenesis? Summary answer: GWAS analysis uncovered multiple pathways that are statistically enriched for genetic association signals, analysis of Stage A disease highlighted a novel variant in MAP3K4, while top pathways significantly associated with all endometriosis and Stage A disease included several mitogen-activated protein kinase (MAPK)-related pathways...
April 1, 2017: Human Reproduction
https://www.readbyqxmd.com/read/28314411/small-molecule-inhibition-of-interleukin-1-receptor-associated-kinase-4-irak4
#12
N E Genung, K M Guckian
In recent years, interleukin-1 receptor-associated kinase 4, IRAK4, has become an attractive target for many medicinal chemistry programmes. Target inhibition is of potential therapeutic value in areas including autoimmune disorders, cancer, inflammatory diseases, and possibly neurodegenerative diseases. Results from high-throughput screening efforts have led, in conjunction with structure-based drug design, to the identification of highly potent and selective small molecule IRAK4 inhibitors from many diverse chemical series...
2017: Progress in Medicinal Chemistry
https://www.readbyqxmd.com/read/28295231/deficiency-in-irak4-activity-attenuates-manifestations-of-murine-lupus
#13
Michael Murphy, Goutham Pattabiraman, Tissa T Manavalan, Andrei E Medvedev
Interleukin-1 receptor-associated kinase (IRAK) 4 mediates host defense against infections. As an active kinase, IRAK4 elicits full spectra of myeloid differentiation primary response protein (MyD) 88-dependent responses, while kinase-inactive IRAK4 induces a subset of cytokines and negative regulators whose expression is not regulated by mRNA stability. IRAK4 kinase activity is critical for resistance against Streptococcus pneumoniae, but its involvement in autoimmunity is incompletely understood. In this study, we determined the role of IRAK4 kinase activity in murine lupus...
May 2017: European Journal of Immunology
https://www.readbyqxmd.com/read/28288918/increased-carbon-dioxide-levels-stimulate-neutrophils-to-produce-microparticles-and-activate-the-nucleotide-binding-domain-like-receptor-3-inflammasome
#14
Stephen R Thom, Veena M Bhopale, JingPing Hu, Ming Yang
We hypothesized that elevations of carbon dioxide (CO2) commonly found in modern buildings will stimulate leukocytes to produce microparticles (MPs) and activate the nucleotide-binding domain-like receptor 3 (NLRP3) inflammasome due to mitochondrial oxidative stress. Human and murine neutrophils generate MPs with high interleukin-1β (IL-1β) content when incubated ex vivo in buffer equilibrated with 0.1-0.4% additional CO2. Enhanced MPs production requires mitochondrial reactive oxygen species production, which is mediated by activities of pyruvate carboxylase and phosphoenolpyruvate carboxykinase...
March 10, 2017: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/28283553/genome-wide-association-study-of-sepsis-in-extremely-premature-infants
#15
Lakshmi Srinivasan, Grier Page, Haresh Kirpalani, Jeffrey C Murray, Abhik Das, Rosemary D Higgins, Waldemar A Carlo, Edward F Bell, Ronald N Goldberg, Kurt Schibler, Beena G Sood, David K Stevenson, Barbara J Stoll, Krisa P Van Meurs, Karen J Johnson, Joshua Levy, Scott A McDonald, Kristin M Zaterka-Baxter, Kathleen A Kennedy, Pablo J Sánchez, Shahnaz Duara, Michele C Walsh, Seetha Shankaran, James L Wynn, C Michael Cotten
OBJECTIVE: To identify genetic variants associated with sepsis (early-onset and late-onset) using a genome-wide association (GWA) analysis in a cohort of extremely premature infants. STUDY DESIGN: Previously generated GWA data from the Neonatal Research Network's anonymised genomic database biorepository of extremely premature infants were used for this study. Sepsis was defined as culture-positive early-onset or late-onset sepsis or culture-proven meningitis. Genomic and whole-genome-amplified DNA was genotyped for 1...
March 10, 2017: Archives of Disease in Childhood. Fetal and Neonatal Edition
https://www.readbyqxmd.com/read/28213090/glycyrrhetinic-acid-attenuates-lipopolysaccharide-induced-fulminant-hepatic-failure-in-d-galactosamine-sensitized-mice-by-up-regulating-expression-of-interleukin-1-receptor-associated-kinase-m
#16
Xinru Yin, Xia Gong, Li Zhang, Rong Jiang, Ge Kuang, Bin Wang, Xinyu Chen, Jingyuan Wan
Glycyrrhetinic acid (GA), the main active ingredient of licorice, reportedly has anti-inflammatory and hepatoprotective properties, but its molecular mechanisms remain be elusive. In the present study, Balb/c mice were pretreated with GA (10, 30, or 100mg/kg) 1h before lipopolysaccharide (LPS)/d-galactosamine (D-GalN) administration. In other in vitro experiment, RAW264.7 macrophages were pretreated with GA before LPS exposure. The mortality, hepatic tissue histology, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were analyzed...
April 1, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28204822/melittin-inhibits-osteoclast-formation-through-the-downregulation-of-the-rankl-rank-signaling-pathway-and-the-inhibition-of-interleukin-1%C3%AE-in-murine-macrophages
#17
Jung-Yoon Choe, Seong-Kyu Kim
Melittin is a major toxic component of bee venom (Apis mellifera). It is not known whether melittin is involved in bone metabolism and osteoclastogenesis. The aim of this study was to determine the role of melittin in the regulation of osteoclastogenesis. In vitro osteoclastogenesis assays were performed using mouse RAW 264.7 cells and bone marrow-derived macrophages (BMMs) treated with receptor activator of nuclear factor-κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF). Morphologic and functional analyses for osteoclast-like multinucleated cells (MNCs) were performed by tartrate-resistant acid phosphatase (TRAP) staining, F-actin staining and pit formation methods...
March 2017: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/28123588/y-box-binding-protein-1-contributes-to-il-7-mediated-survival-signaling-in-b-cell-precursor-acute-lymphoblastic-leukemia
#18
Amina Kariminia, Sabine M Ivison, Vivian M Leung, Susanna Sung, Nicole Couto, Jacob Rozmus, Nina Rolf, Aru Narendran, Sandra E Dunn, Gregor S D Reid, Kirk R Schultz
Y-box-binding protein 1 (YB-1) is a regulatory protein that is associated with drug resistance and relapse in solid tumors. As YB-1 mediates some of its activity through growth factor receptor signaling dysregulation, the present study compared the expression of YB-1 and interleukin 7 (IL-7) receptor α (IL-7Rα) in pediatric B-cell precursor (BCP) acute lymphoblastic leukemia (ALL) and normal BCP cells. The expression levels of IL-7Rα and YB-1 were higher in relapsed vs. diagnostic samples of primary BCP ALL; however, co-expression was also observed in a minor BCP cell population in samples from healthy donors...
January 2017: Oncology Letters
https://www.readbyqxmd.com/read/28098138/scimp-is-a-transmembrane-non-tir-tlr-adaptor-that-promotes-proinflammatory-cytokine-production-from-macrophages
#19
Lin Luo, Nilesh J Bokil, Adam A Wall, Ronan Kapetanovic, Natalie M Lansdaal, Faustine Marceline, Belinda J Burgess, Samuel J Tong, Zhong Guo, Kirill Alexandrov, Ian L Ross, Margaret L Hibbs, Jennifer L Stow, Matthew J Sweet
Danger signals activate Toll-like receptors (TLRs), thereby initiating inflammatory responses. Canonical TLR signalling, via Toll/Interleukin-1 receptor domain (TIR)-containing adaptors and proinflammatory transcription factors such as NF-κB, occurs in many cell types; however, additional mechanisms are required for specificity of inflammatory responses in innate immune cells. Here we show that SCIMP, an immune-restricted, transmembrane adaptor protein (TRAP), promotes selective proinflammatory cytokine responses by direct modulation of TLR4...
January 18, 2017: Nature Communications
https://www.readbyqxmd.com/read/28095323/pattern-recognitions-receptors-in-immunodeficiency-disorders
#20
Esameil Mortaz, Ian M Adcock, Payam Tabarsi, Ilad Alavi Darazam, Masoud Movassaghi, Johan Garssen, Hamidreza Jamaati, Aliakbar Velayati
Pattern recognition receptors (PRRs) recognize common microbial or host-derived macromolecules and have important roles in early activation and response of the immune system. Initiation of the innate immune response starts with the recognition of microbial structures called pathogen associated molecular patterns (PAMPs). Recognition of PAMPs is performed by germline-encoded receptors expressed mainly on immune cells termed pattern recognition receptors (PRRs). Several classes of pattern recognition receptors (PRRs) are involved in the pathogenesis of diseases, including Toll-like receptors (TLRs), C-type lectin receptors (CLRs), and Nod-like receptors (NLRs)...
August 5, 2017: European Journal of Pharmacology
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