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https://www.readbyqxmd.com/read/29797599/expression-of-micrornas-and-irak1-pathway-genes-are-altered-in-gastric-cancer-patients-with-helicobacter-pylori-infection
#1
Reza Ranjbar, AmirReza Hesari, Faezeh Ghasemi, Amirhossein Sahebkar
Gastric cancer (GC) is among the most common cancer types in the world and one of the most lethal gastrointestinal cancers. MicroRNAs (miRNAs) can be of great importance in the early detection of GC. This study aimed to investigate some miRNAs and the genes involved in IRAK1 pathways in the serum of GC patients with Helicobacter pylori (H. pylori) infections compared to the control group. Total RNA was extracted from the serum of GC patients with H. pylori infection and healthy volunteers. The expression levels of miRNAs and the genes were assessed using Real time RT-PCR with specific primers...
May 24, 2018: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/29784900/irak-inhibitor-protects-the-intestinal-tract-of-necrotizing-enterocolitis-by-inhibiting-the-toll-like-receptor-tlr-inflammatory-signaling-pathway-in-rats
#2
Yu Hou, Xin Lu, Yueju Zhang
BACKGROUND The aim of this study was to assess the effects of interleukin-1 (IL-1) receptor associated kinase (IRAK) inhibitors on intestinal injury induced by necrotizing enterocolitis (NEC) in neonatal rats and its regulation on the intestinal Toll-like receptor (TLR) inflammatory signaling pathway. MATERIAL AND METHODS The neonatal rat models of NEC were established though hypoxia-cold stimulation. All rats were divided into 3 groups: an NEC model group (NEC group), an IRAK inhibitor group (IRAKI group), and a normal control group (NC group)...
May 22, 2018: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
https://www.readbyqxmd.com/read/29778672/defective-myd88-and-irak4-but-not-tlr-2-expression-in-hiv-individuals-with-latent-tuberculosis-infection
#3
Kamakshi Prudhula Devalraju, Venkata Sanjeev Kumar Neela, Ramulu Gaddam, Arunabala Chaudhury, Abhinav Van, Siva Sai Krovvidi, Ramakrishna Vankayalapati, Vijaya Lakshmi Valluri
HIV infection markedly increases the likelihood of latent tuberculosis infection progressing to active TB. Information on expression of TLR-2, myeloid differentiation factor (MyD88), IL-1R- associated kinase-4 (IRAK4) and nuclear factor kappa B (NF-kB) in HIV+LTBI+ and HIV+ patients with active TB disease is limited. We found significantly higher percentages of CD14+TLR2+ cells in PBMCs of HIV+LTBI+ patients compared to HIV-LTBI+ individuals. γ-irradiated Mtb was unable to induce MyD88, IRAK4 expression and IL-1β, MCP-1, IP-10 production in HIV+LTBI+ patients...
May 17, 2018: Cytokine
https://www.readbyqxmd.com/read/29749650/irak4-activity-controls-immune-responses-to-intracellular-bacteria-listeria-monocytogenes-and-mycobacterium-smegmatis
#4
Goutham Pattabiraman, Michael Murphy, Federica Agliano, Keaton Karlinsey, Andrei E Medvedev
IL-1 receptor-associated kinase (IRAK) 4 is a central enzyme of the TLR pathways. This study tested the hypothesis that IRAK4 kinase activity is prerequisite for regulating innate immunity during infections with intracellular bacteria. To this end, we analyzed responses of macrophages obtained from mice expressing wild-type (WT) IRAK4 or its kinase-inactive K213M mutant (IRAK4KI ) upon infection with intracellular bacteria Listeria monocytogenes or Mycobacterium smegmatis. In contrast to robust induction of cytokines by macrophages expressing kinase-sufficient IRAK4, IRAK4KI macrophages expressed decreased TNF-α, IL-6, IL-1β, and C-C motif chemokine ligand 5 upon infection with L...
May 11, 2018: Journal of Leukocyte Biology
https://www.readbyqxmd.com/read/29739813/interleukin-1-%C3%AE-activates-a-myc-dependent-metabolic-switch-in-kidney-stromal-cells-necessary-for-progressive-tubulointerstitial-fibrosis
#5
Dario R Lemos, Michael McMurdo, Gamze Karaca, Julia Wilflingseder, Irina A Leaf, Navin Gupta, Tomoya Miyoshi, Koichiro Susa, Bryce G Johnson, Kirolous Soliman, Guanghai Wang, Ryuji Morizane, Joseph V Bonventre, Jeremy S Duffield
Background Kidney injury is characterized by persisting inflammation and fibrosis, yet mechanisms by which inflammatory signals drive fibrogenesis remain poorly defined. Methods RNA sequencing of fibrotic kidneys from patients with CKD identified a metabolic gene signature comprising loss of mitochondrial and oxidative phosphorylation gene expression with a concomitant increase in regulators and enzymes of glycolysis under the control of PGC1 α and MYC transcription factors, respectively. We modeled this metabolic switch in vivo , in experimental murine models of kidney injury, and in vitro in human kidney stromal cells (SCs) and human kidney organoids...
May 8, 2018: Journal of the American Society of Nephrology: JASN
https://www.readbyqxmd.com/read/29733298/snasp-inhibits-tlr-signaling-to-regulate-immune-response-in-sepsis
#6
Feng-Ming Yang, Yong Zuo, Wei Zhou, Chuan Xia, Bumsuk Hahm, Mark Sullivan, Jinke Cheng, Hui-Ming Chang, Edward Th Yeh
Many Toll-like receptors (TLRs) signal through TNF receptor-associated factor 6 (TRAF6) to activate innate immune responses. Here, we show that somatic nuclear autoantigenic sperm protein (sNASP) binds to TRAF6 to prevent TRAF6 autoubiquitination in unstimulated macrophages. Following LPS stimulation, a complex consisting of sNASP, TRAF6, IRAK4, and casein kinase 2 (CK2) is formed. CK2 phosphorylates sNASP at serine 158, allowing sNASP to dissociate from TRAF6. Free TRAF6 is then autoubiquitinated, followed by activation of downstream signaling pathways...
May 7, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29728508/small-molecule-mimetics-of-%C3%AE-helical-domain-of-irak2-attenuate-the-proinflammatory-effects-of-il-33-in-asthma-like-mouse-models
#7
Jinghong Li, Kunio Saruta, Justin P Dumouchel, Jenna M Magat, Joanna L Thomas, Dariush Ajami, Mitra Rebek, Julius Rebek, Timothy D Bigby
IL-33 and its receptor ST2 play important roles in airway inflammation and contribute to asthma onset and exacerbation. The IL-33/ST2 signaling pathway recruits adapter protein myeloid differentiation primary response 88 (MyD88) to transduce intracellular signaling. MyD88 forms a complex with IL-R-associated kinases (IRAKs), IRAK4 and IRAK2, called the Myddosome (MyD88-IRAK4-IRAK2). The myddosome subsequently activates downstream NF-κB and MAPKs p38 and JNK. We established an asthma-like mouse model by intratracheal administration of IL-33...
May 4, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29531937/corrigendum-irak4-deficiency-in-a-patient-with-recurrent-pneumococcal-infections-case-report-and-review-of-the-literature
#8
Karina S Gobin, Mary Hintermeyer, Bertrand Boisson, Maya Chrabieh, Pegah Ghandil, Anne Puel, Capucine Picard, Jean-Laurent Casanova, John Routes, James Verbsky
[This corrects the article on p. 83 in vol. 5, PMID: 28503543.].
2018: Frontiers in Pediatrics
https://www.readbyqxmd.com/read/29483095/irak1-augments-cancer-stemness-and-drug-resistance-via-the-ap-1-akr1b10-signaling-cascade-in-hepatocellular-carcinoma
#9
Bowie Y Cheng, Eunice Y Lau, Hoi-Wing Leung, Carmen Oi-Ning Leung, Nicole P Ho, Shilpa Gurung, Lily K Cheng, Chi Ho Lin, Regina Cheuk-Lam Lo, Stephanie Ma, Irene Oi-Lin Ng, Terence K Lee
Frequent relapse and drug resistance in patients with hepatocellular carcinoma (HCC) can be attributed to the existence of tumor-initiating cells (TIC) within the tumor bulk. Therefore, targeting liver TICs may improve the prognosis of these patients. From transcriptome sequencing of 16 pairs of clinical HCC samples, we report that interleukin-1 receptor-associated kinase 1 (IRAK1) in the TLR/IRAK pathway is significantly upregulated in HCC. IRAK1 overexpression in HCC was further confirmed at the mRNA and protein levels and correlated with advanced tumor stages and poor patient survival...
May 1, 2018: Cancer Research
https://www.readbyqxmd.com/read/29482609/microrna-302b-negatively-regulates-il-1%C3%AE-production-in-response-to-msu-crystals-by-targeting-irak4-and-epha2
#10
Teng Ma, Xiao Liu, Zhifu Cen, Chuan Xin, Mingfeng Guo, Chaoyu Zou, Wenpeng Song, Rou Xie, Kailun Wang, Hong Zhou, Jun Zhang, Zhen Wang, Ce Bian, Kaijun Cui, Jiong Li, Yu-Quan Wei, Jing Li, Xikun Zhou
BACKGROUND: Interleukin-1β (IL-1β) is a pivotal proinflammatory cytokine that is strongly associated with the inflammation of gout. However, the underlying mechanism through which the production of IL-1β is regulated has not been fully elucidated. Our previous work identified that miR-302b had an important immune regulatory role in bacterial lung infections. This study was conducted to evaluate the function of miR-302b on monosodium urate (MSU) crystal-induced inflammation and its mechanism...
February 26, 2018: Arthritis Research & Therapy
https://www.readbyqxmd.com/read/29468521/identification-of-a-constitutively-active-mutant-mouse-irak2-by-retroviral-expression-screening
#11
Yanmei Liu, Weilan Yin, Lingqing Xu, Helin Zhang, Qian Liu, Weiguo Yin
To identify the importance of IRAK2 kinase activity in TLR-mediated signaling pathways, we constructed a retroviral vector harboring either a mouse IRAK2 gene (IRAK2-WT) or with its mutant with loss of function of its ATP-binding site (IRAK2-KD). Further, we comparatively analyzed for the gain of function and modulations in TLR-mediated signaling pathways in IRAK2 knockout (IRAK2-KO) macrophages upon introduction of the IRAK2-WT retroviral constructs. The pBS/IRAK2-KD with the ATP-binding site mutation in IRAK2 was obtained by using site-specific mutagenesis...
April 2018: Molecular Biotechnology
https://www.readbyqxmd.com/read/29400698/clonally-expanded-%C3%AE-%C3%AE-t-cells-protect-against-staphylococcus-aureus-skin-reinfection
#12
Carly A Dillen, Bret L Pinsker, Alina I Marusina, Alexander A Merleev, Orly N Farber, Haiyun Liu, Nathan K Archer, Da B Lee, Yu Wang, Roger V Ortines, Steven K Lee, Mark C Marchitto, Shuting S Cai, Alyssa G Ashbaugh, Larissa S May, Steven M Holland, Alexandra F Freeman, Loren G Miller, Michael R Yeaman, Scott I Simon, Joshua D Milner, Emanual Maverakis, Lloyd S Miller
The mechanisms that mediate durable protection against Staphylococcus aureus skin reinfections are unclear, as recurrences are common despite high antibody titers and memory T cells. Here, we developed a mouse model of S. aureus skin reinfection to investigate protective memory responses. In contrast with WT mice, IL-1β-deficient mice exhibited poor neutrophil recruitment and bacterial clearance during primary infection that was rescued during secondary S. aureus challenge. The γδ T cells from skin-draining LNs utilized compensatory T cell-intrinsic TLR2/MyD88 signaling to mediate rescue by trafficking and producing TNF and IFN-γ, which restored neutrophil recruitment and promoted bacterial clearance...
March 1, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29398441/optimization-of-permeability-in-a-series-of-pyrrolotriazine-inhibitors-of-irak4
#13
Sébastien L Degorce, Rana Anjum, Keith S Dillman, Lisa Drew, Sam D Groombridge, Christopher T Halsall, Eva M Lenz, Nicola A Lindsay, Michele F Mayo, Jennifer H Pink, Graeme R Robb, James S Scott, Stephen Stokes, Yafeng Xue
We have developed a series of orally efficacious IRAK4 inhibitors, based on a scaffold hopping strategy and using rational structure based design. Efforts to tackle low permeability and high efflux in our previously reported pyrrolopyrimidine series (Scott et al., 2017) led to the identification of pyrrolotriazines which contained one less formal hydrogen bond donor and were intrinsically more lipophilic. Further optimisation of substituents on this pyrrolotriazine core culminated with the discovery of 30 as a promising in vivo probe to assess the potential of IRAK4 inhibition for the treatment of MyD88 mutant DLBCL in combination with a BTK inhibitor...
February 15, 2018: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/29363544/tumor-stroma-il1%C3%AE-irak4-feedforward-circuitry-drives-tumor-fibrosis-chemoresistance-and-poor-prognosis-in-pancreatic-cancer
#14
Daoxiang Zhang, Lin Li, Hongmei Jiang, Qiong Li, Andrea Wang-Gillam, Jinsheng Yu, Richard Head, Jingxia Liu, Marianna B Ruzinova, Kian-Huat Lim
Targeting the desmoplastic stroma of pancreatic ductal adenocarcinoma (PDAC) holds promise to augment the effect of chemotherapy, but success in the clinic has thus far been limited. Preclinical mouse models suggest that near-depletion of cancer-associated fibroblasts (CAF) carries a risk of accelerating PDAC progression, underscoring the need to concurrently target key signaling mechanisms that drive the malignant attributes of both CAF and PDAC cells. We previously reported that inhibition of IL1 receptor-associated kinase 4 (IRAK4) suppresses NFκB activity and promotes response to chemotherapy in PDAC cells...
April 1, 2018: Cancer Research
https://www.readbyqxmd.com/read/29341132/acanthoic-acid-suppresses-lipin1-2-via-tlr4-and-irak4-signalling-pathways-in-etoh-and-lipopolysaccharide-induced-hepatic-lipogenesis
#15
Jian Song, Xin Han, You-Li Yao, Ya-Mei Li, Jing Zhang, Dan-Yang Shao, Li-Shuang Hou, Ying Fan, Shun-Zong Song, Li-Hua Lian, Ji-Xing Nan, Yan-Ling Wu
OBJECTIVES: In alcoholic liver disease, alcohol and lipopolysaccharide (LPS) are major stimulation factors of hepatic lipogenesis. Our objective was to determine the protective mechanism of acanthoic acid (AA) in EtOH- and LPS-induced hepatic lipogenesis. METHODS: HSC-T6 cells were treated with ethanol (200 mm) plus LPS (1 μg/ml) for 1 h, followed by AA (10 or 20 μm) for another 6 h. C57BL/6 mice were pretreated with of AA (20 and 40 mg/kg) or equal volume of saline and then exposed to three doses of ethanol (5 g/kg body weight) within 24 h...
January 17, 2018: Journal of Pharmacy and Pharmacology
https://www.readbyqxmd.com/read/29242191/the-inducible-microrna-203-in-fish-represses-the-inflammatory-responses-to-gram-negative-bacteria-by-targeting-il-1-receptor-associated-kinase-4
#16
Tianjun Xu, Qing Chu, Junxia Cui, Xueyan Zhao
Innate immune responses are the first defense against pathogenic invaders. Activation and termination of these immune responses are regulated by several mechanisms. MicroRNAs (miRNAs), a group of small non-coding RNAs, have been implicated in the regulation of a spectrum of both physiological and pathological conditions, including immune responses. Although the immune regulatory miRNA networks in higher vertebrates have been well described, regulation of these responses in fish species is poorly understood...
January 26, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29208712/crystal-structure-of-human-irak1
#17
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/29177859/examining-myddosome-formation-by-luminescence-based-mammalian-interactome-mapping-lumier
#18
Olaf-Oliver Wolz, Manfred Koegl, Alexander N R Weber
Recent structural, biochemical, and functional studies have led to the notion that many of the post-receptor signaling complexes in innate immunity have a multimeric, multi-protein architecture whose hierarchical assembly is vital for function. The Myddosome is a post-receptor complex in the cytoplasmic signaling of Toll-like receptors (TLR) and the Interleukin-1 receptor (IL-1R), involving the proteins MyD88, IL-1R-associated kinase 4 (IRAK4), and IRAK2. Its importance is strikingly illustrated by the fact that rare germline mutations in MYD88 causing high susceptibility to infections are characterized by failure to assemble Myddosomes; conversely, gain-of-function MYD88 mutations leading to oncogenic hyperactivation of NF-κB show increased Myddosome formation...
2018: Methods in Molecular Biology
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
#19
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/29142761/-aeromonas-hydrophila-utilizes-tlr4-topology-for-synchronous-activation-of-myd88-and-trif-to-orchestrate-anti-inflammatory-responses-in-zebrafish
#20
Nidhi Srivastava, Asha Shelly, Manmohan Kumar, Archana Pant, Bhabatosh Das, Tanmay Majumdar, Shibnath Mazumder
Toll-like receptor 4 (TLR4) plays a critical role in host immunity against Gram-negative bacteria. It transduces signals through two distinct TIR-domain-containing adaptors, MyD88 and TRIF, which function at the plasma membrane and endosomes, respectively. Using zebrafish Aeromonas hydrophila infection model, we demonstrate that synchronization of MyD88 and TRIF dependent pathways is critical for determining the fate of infection. Zebrafish were infected with A. hydrophila, and bacterial recovery studies suggested its effective persistence inside the host...
2017: Cell Death Discovery
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