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Daoxiang Zhang, Lin Li, Hongmei Jiang, Brett Knolhoff, Albert C Lockhart, Andrea Wang-Gillam, David DeNardo, Marianna B Ruzinova, Kian-Huat Lim
PURPOSE: Aberrant activation of the NF-κB transcription factors underlies the aggressive behavior and poor outcome of pancreatic ductal adenocarcinoma (PDAC). However, clinically effective and safe NF-κB inhibitors are not yet available. Because NF-κB transcription factors can be activated by the Interleukin-1 Receptor-Associated Kinase (IRAK) downstream of the Toll-like receptors (TLRs), but has not been explored in PDAC, we sought to investigate the role of IRAK in the pathobiology of PDAC...
October 4, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Hua Zhou, Erin Harberts, Rita Fishelevich, Anthony A Gaspari
UVR-induced apoptosis in cutaneous antigen presenting cells (APC) causes systemic immune suppression and is dependent on TLR4/MyD88 signaling, but the apoptotic signaling pathways have not been defined. Macrophages pre-treated with lipopolysaccharide (LPS) were unresponsive to subsequent LPS treatment; however, but were susceptible to UVR-induced apoptosis. Macrophage survival and apoptotic events after UVR were also unaffected by treatment with TLR4 antagonists, a blocking IgG or a TLR4 analog antagonist, suggesting that UVR cell death is independent of a soluble ligand...
September 27, 2016: Experimental Dermatology
Li Xia He, Xiaoyun Tong, Jing Zeng, Yuanqing Tu, Saicun Wu, Manping Li, Huaming Deng, Miaomiao Zhu, Xiucun Li, Hong Nie, Li Yang, Feng Huang
In this work, we assessed the anti-inflammatory effects of paeonol (PAE) in LPS-activated N9 microglia cells, as well as its underlying molecular mechanisms. PAE had no adverse effect on the viability of murine microglia N9 cell line within a broad range (0.12∼75 μM). When N9 cell line was activated by LPS, PAE (0.6, 3, 15 μM) significantly suppressed the release of proinflammatory products, such as nitric oxide (NO), interleukin-1β (IL-1β), and prostaglandin E2 (PGE2), demonstrated by the ELISA assay...
September 13, 2016: Inflammation
Marie Willems, Nadège Dubois, Lucia Musumeci, Vincent Bours, Pierre A Robe
IκBζ, an atypical member of the nuclear IκB family of proteins, is expressed at low levels in most resting cells, but is induced upon stimulation of Toll-like/IL-1 receptors through an IRAK1/IRAK4/NFκB-dependent pathway. Like its homolog Bcl3, IκBζ can regulate the transcription of a set of inflamatory genes through its association with the p50 or p52 subunits of NF-κB. Long studied as a key component of the immune response, IκBζ emerges as an important regulator of inflammation, cell proliferation and survival...
August 26, 2016: Oncotarget
Jennifer Hanisak, W Michael Seganish, William T McElroy, Haiquin Tang, Rui Zhang, Hon-Chung Tsui, Theirry Fischmann, Deen Tulshian, James Tata, Christopher Sondey, Kristine Devito, James Fossetta, Charles G Garlisi, Daniel Lundell, Xiaoda Niu
IRAK4 has been identified as potential therapeutic target for inflammatory and autoimmune diseases. Herein we report the identification and initial SAR studies of a new class of pyrazole containing IRAK4 inhibitors designed to expand chemical diversity and improve off target activity of a previously identified series. These compounds maintain potent IRAK4 activity and desirable ligand efficiency. Rat clearance and a variety of off target activities were also examined, resulting in encouraging data with tractable SAR...
September 1, 2016: Bioorganic & Medicinal Chemistry Letters
Bart Ferwerda, Mercedes Valls Serón, Aldo Jongejan, Aeilko H Zwinderman, Madelijn Geldhoff, Arie van der Ende, Frank Baas, Matthijs C Brouwer, Diederik van de Beek
Pneumococcal meningitis is the most common and severe form of bacterial meningitis. Early recognition of the pathogen and subsequent innate immune response play a vital role in disease susceptibility and outcome. Genetic variations in innate immune genes can alter the immune response and influence susceptibility and outcome of meningitis disease. Here we conducted a sequencing study of coding regions from 46 innate immune genes in 435 pneumococcal meningitis patients and 416 controls, to determine the role of genetic variation on pneumococcal meningitis susceptibility and disease outcome...
August 2016: EBioMedicine
W Michael Seganish
INTRODUCTION: IRAK4 is located proximal to TLR/IL-1 receptors, and in preclinical studies, inhibits downstream signaling from these receptors. The development of novel small molecule inhibitors of this kinase has the potential to lead to new therapeutics to treat diseases such as rheumatoid arthritis, lupus, and lymphomas. AREAS COVERED: The aim of this review is to summarize the recent patent literature (2012-2015) surrounding small molecule inhibitors of IRAK4...
August 2016: Expert Opinion on Therapeutic Patents
Minakshi Rana, Amit Kumar, Rajiv Lochan Tiwari, Vishal Singh, Tulika Chandra, Madhu Dikshit, Manoj Kumar Barthwal
Interleukin-1 receptor-associated kinase-1 (IRAK1) is linked to the pathogenesis of atherosclerosis; however, its role in macrophage foam cell formation is not known. Therefore, the present study investigated the role of IRAK1 in lipid uptake, biosynthesis, and efflux in THP-1 derived macrophages and human monocyte-derived macrophages (HMDMs). Ox-LDL (40 μg/mL, 15 minutes-48 hours) treatment induced time-dependent increase in IRAK1, IRAK4, and Stat1 activation in THP-1 derived macrophages. IRAK1/4 inhibitor (INH) or IRAK1 siRNA significantly attenuated cholesterol accumulation, DiI-Ox-LDL binding, and uptake while cholesterol efflux to apoAI and HDL was enhanced in THP-1 derived macrophages and HMDMs...
July 2016: BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology
Lin-Lin Kang, Dong-Mei Zhang, Chun-Hua Ma, Jian-Hua Zhang, Ke-Ke Jia, Jia-Hui Liu, Rong Wang, Ling-Dong Kong
Fructose consumption induces metabolic syndrome to increase cardiovascular disease risk. Cinnamaldehyde and allopurinol possess anti-oxidative and anti-inflammatory activity to relieve heart injury in metabolic syndrome. But the mechanisms of fructose-induced cardiac injury, and cardioprotective effects of cinnamaldehyde and allopurinol are not completely understood. In this study, fructose-fed rats displayed metabolic syndrome with elevated serum ox-LDL, cardiac oxidative stress, inflammation and fibrosis...
2016: Scientific Reports
Alexander Asmussen, Katrin Fink, Hans-Jörg Busch, Thomas Helbing, Natascha Bourgeois, Christoph Bode, Sebastian Grundmann
BACKGROUND: Whole body ischemia-reperfusion injury (IRI) after cardiopulmonary resuscitation (CPR) induces a generalized inflammatory response which contributes to the development of post-cardiac arrest syndrome (PCAS). Recently, pattern recognition receptors (PRRs), such as toll-like receptors (TLRs) and inflammasomes, have been shown to mediate the inflammatory response in IRI. In this study we investigated monocyte PRR signaling and function in PCAS. METHODS: Blood samples were drawn in the first 12 hours, and at 24 and 48 hours following return of spontaneous circulation in 51 survivors after cardiac arrest...
2016: Critical Care: the Official Journal of the Critical Care Forum
Yan Yan Wang, Chun Fang Hu, Juan Li, Xiang You, Feng Guang Gao
Cross-presentation by dendritic cells (DCs) requires surface molecules such as lectin, CD40, langerin, heat shock protein, mannose receptor, mediated endocytosis, the endosomal translocation of internalized antigen, and the relocation of transporter associated with antigen processing (TAP). Although the activation of α7 nicotinic acetylcholine receptor (α7 nAchR) up-regulate surface molecule expression, augment endocytosis, and enhance cross-presentation, the molecular mechanism of α7 nAchR activation-increased cross-presentation is still poorly understood...
May 20, 2016: Oncotarget
Yu-fan Shen, Xue Zhang, Ying Wang, Fan-fan Cao, Georges Uzan, Bin Peng, Deng-hai Zhang
OBJECTIVE: Celastrol has been established as a nuclear factor-κB (NF-κB) activation inhibitor; however, the exact mechanism behind this action is still unknown. Using text-mining technology, the authors predicted that interleukin-1 receptor-associated kinases (IRAKs) are potential celastrol targets, and hypothesized that targeting IRAKs might be one way that celastrol inhibits NF-κB. This is because IRAKs are key molecules for some crucial pathways to activate NF-κB (e.g., the interleukin-1 receptor (IL-1R)/Toll-like receptor (TLR) superfamily)...
May 2016: Journal of Integrative Medicine
Lijuan Cao, Defeng Pan, Dongye Li, Yanbin Zhang, Qiuping Chen, Tongda Xu, Wenhua Li, Wanling Wu
Deregulation of phenotypic modulation in VSMCs is the initial stage of atherosclerosis, especially in diabetes. Functional deficiency of IRAK4 inhibits the formation of vascular lesions in ApoE-/- mice. Therefore, in this study, we examined the functions of IRAK4 in the regulation of VSMCs differentiation and phenotypic modulation at the levels of transcription and translation in T2D rats. The T2D rat model was generated by feeding a high-fat diet and injecting a low dose of streptozotocin intraperitoneally...
2016: American Journal of Translational Research
Li Deng, Peng Pang, Ke Zheng, Jiao Nie, Huachong Xu, Sizhi Wu, Jia Chen, Xiaoyin Chen
OBJECTIVE: The objective of this study was to observe the effects of forsythoside A on controlling influenza A virus (IAV) infection and improving the prognosis of IAV infection. METHODS: Forty-eight SPF C57BL/6j mice were randomly divided into the following four groups: Group A: normal control group (normal con); Group B: IAV control group (V con); Group C: IAV+ oseltamivir treatment group (V oseltamivir; 0.78 mg/mL, 0.2 mL/mouse/day); Group D: IAV+ forsythoside A treatment group (V FTA; 2 μg/mL, 0...
2016: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Jianjian Ji, Jingjing Xu, Fanlin Li, Xiaojing Li, Wei Gong, Yuxian Song, Huan Dou, Yayi Hou
Myeloid dendritic cells (DCs) can produce B-cell-activating factor (BAFF) that modulates survival and differentiation of B cells and plays a pivotal role in the pathogenesis of systemic lupus erythematosus (SLE). Toll-like receptor 4 (TLR4) signaling has important functions in the process of BAFF production. Our previous study showed that a benzenediamine derivate FC-99 possesses anti-inflammation activity and directly interacts with interleukin-1 receptor-associated kinase 4 (IRAK4), which was a pivotal molecule in TLR4 signaling...
May 2016: Acta Biochimica et Biophysica Sinica
Congcong Guo, Liju Zhang, Lihong Nie, Na Zhang, Di Xiao, Xingguang Ye, Meiling Ou, Yang Liu, Baohuan Zhang, Man Wang, Hansheng Lin, Guang Yang, Chunxia Jing
Type 2 diabetes mellitus (T2DM) has been linked to a state of low-grade inflammation resulting from abnormalities in the innate immune pathway. MyD88 is an essential adaptor protein for TLR signaling, which is involved in activating NF-κB through IRAK4 and TRAF6. To investigate the effects of the MyD88, IRAK4 and TRAF6 polymorphisms in the susceptibility of T2DM and diabetic vascular complications, eight SNPs were analyzed in 553 T2DM patients and 553 matched healthy controls. Gene-gene interactions and haplotype associations were also evaluated...
July 5, 2016: Molecular and Cellular Endocrinology
Lin Zhuang, Ye Fan, Ling Lu, Wenbin Ding, Chuangye Ni, Xuehao Wang, Feng Zhang, Jianhua Rao
Ischemic preconditioning (IP) has been shown to protect hepatic tissue from liver ischemia-reperfusion injury (IRI). TGR5, as a new-type bile acid receptor, has been shown protective roles in several liver diseases. However, the relationship between TGR5 and IP is still unknown. This study investigated effects of IP on TGR5 as well as the roles of TGR5 on hepatic tissue lesions and apoptosis in liver IRI. We showed that TGR5 was significantly upregulated in liver tissues after IP. To further analyzed effects of the TGR5 on liver IRI, wild type and TGR5 knockout mice were used to establish the liver IRI model...
May 13, 2016: Biochemical and Biophysical Research Communications
Toshiyuki Nishikido, Jun-ichi Oyama, Aya Shiraki, Hiroshi Komoda, Koichi Node
BACKGROUND: An excessive inflammatory response after myocardial infarction (MI) increases myocardial injury. The toll-like receptor (TLR)-4 is activated by the recognition of endogenous ligands and is proinflammatory when there is myocardial tissue injury. The apoptosis inhibitor of the macrophage (AIM) is known to provoke an efflux of saturated free fatty acids (FFA) due to lipolysis, which causes inflammation via the TLR-4 pathway. Therefore, this study investigated the hypothesis that AIM causes a proinflammatory response after MI...
April 2016: Journal of the American Heart Association
Sudipta Biswas, Liang Xin, Soumya Panigrahi, Alejandro Zimman, Hua Wang, Valentin P Yakubenko, Tatiana V Byzova, Robert G Salomon, Eugene A Podrez
A prothrombotic state and increased platelet reactivity are common in dyslipidemia and oxidative stress. Lipid peroxidation, a major consequence of oxidative stress, generates highly reactive products, including hydroxy-ω-oxoalkenoic acids that modify autologous proteins generating biologically active derivatives. Phosphatidylethanolamine, the second most abundant eukaryotic phospholipid, can also be modified by hydroxy-ω-oxoalkenoic acids. However, the conditions leading to accumulation of such derivatives in circulation and their biological activities remain poorly understood...
May 26, 2016: Blood
Yan-Ni Lv, Ai-Jun Ou-Yang, Long-Sheng Fu
microRNA, a family of small non-coding RNA, plays significant roles in regulating gene expression, mainly via binding to the 3'-untranslated region of target genes. Although the role of miRNA in regulating neuroinflammation via the innate immune pathway has been studied, its role in the production of inflammatory mediators during microglial activation is poorly understood. In this study, we investigated the effect of miR-27a on lipopolysaccharide (LPS)-induced microglial inflammation. miR-27a expression was found to be rapidly decreased in microglia by real-time polymerase chain reaction (real-time PCR) after LPS stimulation...
March 12, 2016: Cellular and Molecular Neurobiology
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