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Search results for: ML130

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#31956962   2020/01/19 To Up

Activation of the pattern recognition receptor NOD1 augments colon cancer metastasis.

While emerging data suggest nucleotide oligomerization domain receptor 1 (NOD1), a cytoplasmic pattern recognition receptor, may play an important and complementary role in the immune response to bacterial infection, its role in cancer metastasis is entirely unknown. Hence, we sought to determine the effects of NOD1 on metastasis. NOD1 expression in paired human primary colon cancer, human and murine colon cancer cells were determined using immunohistochemistry and immunoblotting (WB). Clinical significance of NOD1 was assessed using TCGA survival data. A series of in vitro and in vivo functional assays, including adhesion, migration, and metastasis, was conducted to assess the effect of NOD1. C12-iE-DAP, a highly selective NOD1 ligand derived from gram-negative bacteria, was used to activate NOD1. ML130, a specific NOD1 inhibitor, was used to block C12-iE-DAP stimulation. Stable knockdown (KD) of NOD1 in human colon cancer cells (HT29) was constructed with shRNA lentiviral transduction and the functional assays were thus repeated. Lastly, the predominant signaling pathway of NOD1-activation was identified using WB and functional assays in the presence of specific kinase inhibitors. Our data demonstrate that NOD1 is highly expressed in human colorectal cancer (CRC) and human and murine CRC cell lines. Clinically, we demonstrate that this increased NOD1 expression negatively impacts survival in patients with CRC. Subsequently, we identify NOD1 activation by C12-iE-DAP augments CRC cell adhesion, migration and metastasis. These effects are predominantly mediated via the p38 mitogen activated protein kinase (MAPK) pathway. This is the first study implicating NOD1 in cancer metastasis, and thus identifying this receptor as a putative therapeutic target.
Henry Y Jiang, Sara Najmeh, Guy Martel, Elyse MacFadden-Murphy, Raquel Farias, Paul Savage, Arielle Leone, Lucie Roussel, Jonathan Cools-Lartigue, Stephen Gowing, Julie Berube, Betty Giannias, France Bourdeau, Carlos H F Chan, Jonathan D Spicer, Rebecca McClure, Morag Park, Simon Rousseau, Lorenzo E Ferri

2745 related Products with: Activation of the pattern recognition receptor NOD1 augments colon cancer metastasis.



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#29849500   2018/04/05 To Up

Anti-Inflammatory Effect of Columbianetin on Lipopolysaccharide-Stimulated Human Peripheral Blood Mononuclear Cells.

Dysregulated inflammation is increasingly considered as the main cause of many diseases on which NOD1/NF-B pathway plays an important role. Columbianetin (CBT) is derived from the root of the Chinese herb for treating inflammatory diseases. Although the anti-inflammatory effect of CBT has been reported, its anti-inflammatory mechanism was poorly studied. In this study, we explored the anti-inflammatory pathway of CBT in lipopolysaccharide- (LPS-) stimulated human peripheral blood mononuclear cell (PBMC) model. Inflammatory cytokine production in culture supernatant was assessed using ELISA assay, and the possible anti-inflammatory pathway of CBT was screened using qPCR array and enrichment analysis with DAVID6.8. To further confirm the targeted pathway of CBT, we pretreated PBMC with the selective NOD1 inhibitor ML130 and then measured the protein levels of the pathway by Western blotting. The result showed that CBT effectively suppressed the expressions of TNF-, IL-6, MCP-1, and IL-1 in a dose-dependent manner and significantly downregulated 19 out of 32 differentially expressed genes, most of which were involved in the NOD1/NF-B pathway, and also showed that CBT remarkably inhibited LPS-induced NOD1, RIP2, and NF-B activation. Furthermore, the inhibitory effects of CBT on NOD1/NF-B pathways were blocked by ML130. These findings indicated that CBT inhibits the production of inflammatory cytokines induced by LPS involved in the downregulation of NOD1/NF-B pathways.
Junying Lu, Keyong Fang, Shiji Wang, Lingxin Xiong, Chao Zhang, Zhongmin Liu, Xuewa Guan, Ruipeng Zheng, Guoqiang Wang, Jingtong Zheng, Fang Wang

2772 related Products with: Anti-Inflammatory Effect of Columbianetin on Lipopolysaccharide-Stimulated Human Peripheral Blood Mononuclear Cells.

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#28813514   2017/08/15 To Up

The Helicobacter pylori type IV secretion system promotes IL-8 synthesis in a model of pediatric airway epithelium via p38 MAP kinase.

Epidemiologic studies have reported an inverse relationship between childhood Helicobacter pylori infection and development of allergic asthma. Because lung epithelium plays an important role in allergic asthma pathogenesis, we hypothesized that H. pylori may directly influence airway epithelial cell innate immune function, particularly in early childhood. To test our hypothesis, we established an in vitro H. pylori infection model using primary tracheobronchial epithelial cell cultures derived from infant, juvenile and adult rhesus monkeys. Airway epithelial cell cultures were infected with wild-type or cag pathogenicity island mutant H. pylori strains, followed by evaluation of IL-8 and IL-6 protein synthesis. We found that H. pylori primarily increased IL-8 synthesis in a MOI and age-dependent fashion, with a greater than 4-fold induction in infant versus adult cultures. H. pylori-induced IL-8 synthesis in infant and juvenile cultures was significantly reduced by cag pathogenicity island mutants, indicating a requirement for the type IV secretion system. Although peptidoglycan recognition of nucleotide binding oligomerization domain-containing protein 1 (NOD1) and NF-kappaB have been implicated as key cytokine signaling molecules for H. pylori infection in gastric epithelium, NOD1 (ML130) or NF-kappaB (JSH-23) inhibitors minimally affected IL-8 synthesis in airway epithelial cell cultures following H. pylori infection. In contrast, inhibition of the p38 MAP kinase pathway (SB203580) resulted in almost complete suppression of H. pylori-induced IL-8 synthesis. Collectively, these results indicate that H. pylori can preferentially elicit IL-8 synthesis in a model of pediatric airway epithelium using the type IV secretion system via p38 MAP kinase.
Myra G Dela Pena-Ponce, Monica T Jimenez, Lori M Hansen, Jay V Solnick, Lisa A Miller

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#27856764   2016/11/16 To Up

Role of nucleotide-binding oligomerization domain 1 (NOD1) and its variants in human cytomegalovirus control in vitro and in vivo.

Induction of nucleotide-binding oligomerization domain 2 (NOD2) and downstream receptor-interacting serine/threonine-protein kinase 2 (RIPK2) by human cytomegalovirus (HCMV) is known to up-regulate antiviral responses and suppress virus replication. We investigated the role of nucleotide-binding oligomerization domain 1 (NOD1), which also signals through RIPK2, in HCMV control. NOD1 activation by Tri-DAP (NOD1 agonist) suppressed HCMV and induced IFN-β. Mouse CMV was also inhibited through NOD1 activation. NOD1 knockdown (KD) or inhibition of its activity with small molecule ML130 enhanced HCMV replication in vitro. NOD1 mutations displayed differential effects on HCMV replication and antiviral responses. In cells overexpressing the E56K mutation in the caspase activation and recruitment domain, virus replication was enhanced, but in cells overexpressing the E266K mutation in the nucleotide-binding domain or the wild-type NOD1, HCMV was inhibited, changes that correlated with IFN-β expression. The interaction of NOD1 and RIPK2 determined the outcome of virus replication, as evidenced by enhanced virus growth in NOD1 E56K mutant cells (which failed to interact with RIPK2). NOD1 activities were executed through IFN-β, given that IFN-β KD reduced the inhibitory effect of Tri-DAP on HCMV. Signaling through NOD1 resulting in HCMV suppression was IKKα-dependent and correlated with nuclear translocation and phosphorylation of IRF3. Finally, NOD1 polymorphisms were significantly associated with the risk of HCMV infection in women who were infected with HCMV during participation in a glycoprotein B vaccine trial. Collectively, our data indicate a role for NOD1 in HCMV control via RIPK2- IKKα-IRF3 and suggest that its polymorphisms predict the risk of infection.
Yi-Hsin Fan, Sujayita Roy, Rupkatha Mukhopadhyay, Arun Kapoor, Priya Duggal, Genevieve L Wojcik, Robert F Pass, Ravit Arav-Boger

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#27387722   2016/02/19 To Up

Role of the NOD1/NF-κB pathway on bovine neutrophil responses to crude lipopolysaccharide.

Cytosolic nucleotide oligomerisation domain (NOD)-like receptors play an important role in host defence against infection. Reduced NOD1 expression has been observed in dysfunctional neutrophils derived from periparturient cattle known to be most susceptible to coliform mastitis. However, whether impairment of NOD1 suppresses the immune responses of bovine neutrophils during bacterial infections remains unknown. Crude (phenol extracted) lipopolysaccharide (cLPS), which often contains other immunostimulatory molecules, including NOD1 agonist, is known to induce almost the whole bacterial response. This study was conducted to explore the role of NOD1/nuclear factor (NF)-κB pathway in the cytokine and functional responses of bovine neutrophils challenged with Escherichia coli-derived cLPS. Freshly isolated blood neutrophils from healthy heifers were pre-incubated for 2 h with ML130, a selective inhibitor of NOD1/NF-κB pathway. Cells were then exposed to cLPS for additional 4 h. Inhibition of the NOD1/NF-κB pathway resulted in a decrease in cLPS-induced phosphorylation of the inhibitor of NF-κBα (IκBα) in neutrophils. Impairment of the NOD1/NF-κB pathway tended to down-regulate mRNA levels of pro-inflammatory cytokines interleukin (IL)-1β and tumour necrosis factor (TNF)-α, chemokines IL-8 and C-X-C motif ligand 2 (CXCL2), and adhesion molecules CD11b and CD62L, in cLPS-challenged cells. Functional analyses showed that blocking the NOD1/NF-κB pathway inhibited neutrophil migration and phagocytic killing capacity, and promoted neutrophil death upon cLPS stimulation. The data presented here demonstrate that activation of NOD1/NF-κB pathway contributes to the functional responses of neutrophils to cLPS.
Liang-Jun Wei, Xun Tan, Guo-Juan Fan, Ya-Nan Jiang, Qurban A Shah

1024 related Products with: Role of the NOD1/NF-κB pathway on bovine neutrophil responses to crude lipopolysaccharide.

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#27169686   2016/05/11 To Up

High Glucose and Lipopolysaccharide Activate NOD1- RICK-NF-κB Inflammatory Signaling in Mesangial Cells.

Systemic and local low-grade inflammation and release of proinflammatory cytokines are implicated in the development and progression of diabetes mellitus (DM) and diabetic nephropathy (DN). The TLR2, TLR4, and NLRP3 inflammasomes of the innate immune system produce various proinflammatory cytokines and are critically involved in inflammatory responses in kidney tissues. The NOD-like receptor (NLR) NOD1 is involved in the NF-κB inflammatory signaling pathway and has an important role in the development of insulin resistance. Extracellular stimuli such as high glucose or lipopolysaccharide (LPS) can induce NOD1-RICK to activate NF-κB, which is associated with diabetes and other chronic inflammatory conditions. It is currently unknown whether NOD1-RICK-mediated NF-κB signaling is involved in DN pathogenesis. In this study, expression of NOD1, RICK, IκBα, NF-κB and IL-1β was detected in cultured rat glomerular mesangial cells (rGMCs) stimulated with high concentrations of glucose and LPS. ML130, a NOD1 inhibitor, was used to investigate the role of the NOD1 signaling pathway in DN inflammation. Our results showed that high glucose or LPS increased the protein and mRNA expression of NOD1, RICK,NF-κBp65 and IL-1β, but attenuated IκBα expression (<0.05). These changes were synergistically enhanced by stimulating with high glucose and LPS. However, pretreatment with the NOD1 inhibitor ML130 significantly reversed these changes (<0.05). These combined results support the hypothesis that high glucose and LPS can activate the NOD1-RICK-NF-κB inflammatory signaling pathway via the NOD1 receptor, and may participate in the development of DN.
W Huang, F Gou, Y Long, Y Li, H Feng, Q Zhang, C Gao, G Chen, Y Xu

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#26321220   2015/08/19 To Up

Effector responses of bovine blood neutrophils against Escherichia coli: Role of NOD1/NF-κB signalling pathway.

Neutrophils use a broad array of pattern recognition receptors to sense and respond to invading pathogens and are important in the early control of acute bacterial infections. Nucleotide-binding oligomerizing domain-1 (NOD1) is a cytoplasmic receptor involved in recognizing bacterial peptidoglycan. Reduced neutrophil NOD1 expression has been reported in periparturient dairy cows. The aim of this study was to investigate the role of NOD1 signalling in the early responses of bovine neutrophils to bacterial infections. Blood neutrophils from healthy heifers were preincubated for 2h with ML130, a selective inhibitor of NOD1-dependent nuclear factor-κB (NF-κB) activation. Thereafter, cells were cultured with live Escherichia coli for additional 30 min or subjected to Boyden chamber cell migration assay with E. coli in the lower chamber. Results showed that ML130 inhibited E. coli-induced NF-κB nuclear translocation. There was an indication, although not significant, that ML130 down-regulated gene expression of proinflammatory cytokines interleukin (IL)-1β and tumour necrosis factor (TNF)-α, chemokines IL-8 and C-X-C motif ligand 2 (CXCL2), and adhesion molecule CD62L, in E. coli-challenged neutrophils. Flow cytometry-based Annexin V staining revealed a considerable increase in neutrophil survival upon E. coli infection, an effect that was attenuated in the presence of ML130. Additionally, inhibition of NOD1/NF-κB signalling resulted in reduced migration of neutrophils to E. coli, and impaired phagocytosis, intracellular bacterial killing and reactive oxygen species production by neutrophils. These results indicate that NOD1/NF-κB pathway plays a crucial role in modulating neutrophil responses that are important for early control of infections. Approaches aiming at restoring neutrophil NOD1 function could be beneficial for prevention or treatment of coliform mastitis.
Xun Tan, Liang-Jun Wei, Guo-Juan Fan, Ya-Nan Jiang, Xu-Ping Yu

1168 related Products with: Effector responses of bovine blood neutrophils against Escherichia coli: Role of NOD1/NF-κB signalling pathway.

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#23766805   2013/05/08 To Up

Synthesis and physicochemical characterization of novel phenotypic probes targeting the nuclear factor-kappa B signaling pathway.

Activation of nuclear factor-kappa B (NF-κB) and related upstream signal transduction pathways have long been associated with the pathogenesis of a variety of inflammatory diseases and has recently been implicated in the onset of cancer. This report provides a synthetic and compound-based property summary of five pathway-related small-molecule chemical probes identified and optimized within the National Institutes of Health-Molecular Libraries Probe Center Network (NIH-MLPCN) initiative. The chemical probes discussed herein represent first-in-class, non-kinase-based modulators of the NF-κB signaling pathway, which were identified and optimized through either cellular phenotypic or specific protein-target-based screening strategies. Accordingly, the resulting new chemical probes may allow for better fundamental understanding of this highly complex biochemical signaling network and could advance future therapeutic translation toward the clinical setting.
Paul M Hershberger, Satyamaheshwar Peddibhotla, E Hampton Sessions, Daniela B Divlianska, Ricardo G Correa, Anthony B Pinkerton, John C Reed, Gregory P Roth

2893 related Products with: Synthesis and physicochemical characterization of novel phenotypic probes targeting the nuclear factor-kappa B signaling pathway.

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#22450316   2012/03/17 To Up

TNFα and IL-1β are mediated by both TLR4 and Nod1 pathways in the cultured HAPI cells stimulated by LPS.

A growing body of evidence recently suggests that glial cell activation plays an important role in several neurodegenerative diseases and neuropathic pain. Microglia in the central nervous system express toll-like receptor 4 (TLR4) that is traditionally accepted as the primary receptor of lipopolysaccharide (LPS). LPS activates TLR4 signaling pathways to induce the production of proinflammatory molecules. In the present studies, we verified the LPS signaling pathways using cultured highly aggressively proliferating immortalized (HAPI) microglial cells. We found that HAPI cells treated with LPS upregulated the expression of TLR4, phospho-JNK (pJNK) and phospho-NF-κB (pNF-κB), TNFα and IL-1β. Silencing TLR4 with siRNA reduced the expression of pJNK, TNFα and IL-1β, but not pNF-κB in the cells. Inhibition of JNK with SP600125 (a JNK inhibitor) decreased the expression of TNFα and IL-1β. Unexpectedly, we found that inhibition of Nod1 with ML130 significantly reduced the expression of pNF-κB. Inhibition of NF-κB also reduced the expression of TNFα and IL-1β. Nod1 ligand, DAP induced the upregulation of pNF-κB which was blocked by Nod1 inhibitor. These data indicate that LPS-induced pJNK is TLR4-dependent, and that pNF-κB is Nod1-dependent in HAPI cells treated with LPS. Either TLR4-JNK or Nod1-NF-κB pathways is involved in the expression of TNFα and IL-1β.
Wenwen Zheng, Xuexing Zheng, Shue Liu, Hongsheng Ouyang, Roy C Levitt, Keith A Candiotti, Shuanglin Hao

1129 related Products with: TNFα and IL-1β are mediated by both TLR4 and Nod1 pathways in the cultured HAPI cells stimulated by LPS.

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#22003428   2011/08/05 To Up

Identification of Inhibitors of NOD1-Induced Nuclear Factor-κB Activation.

NOD1 (nucleotide-binding oligomerization domain 1) protein is a member of the NLR (NACHT and leucine rich repeat domain containing proteins) protein family, which plays a key role in innate immunity as a sensor of specific microbial components derived from bacterial peptidoglycans and induction of inflammatory responses. Mutations in NOD proteins have been associated with various inflammatory diseases that affect NF-κB (nuclear factor κB) activity, a major signaling pathway involved in apoptosis, inflammation, and immune response. A luciferase-based reporter gene assay was utilized in a high-throughput screening program conducted under the NIH-sponsored Molecular Libraries Probe Production Center Network program to identify the active scaffolds. Herein, we report the chemical synthesis, structure-activity relationship studies, downstream counterscreens, secondary assay data, and pharmacological profiling of the 2-aminobenzimidazole lead (compound 1c, ML130) as a potent and selective inhibitor of NOD1-induced NF-κB activation.
Pasha M Khan, Ricardo G Correa, Daniela B Divlianska, Satyamaheshwar Peddibhotla, E Hampton Sessions, Gavin Magnuson, Brock Brown, Eigo Suyama, Hongbin Yuan, Arianna Mangravita-Novo, Michael Vicchiarelli, Ying Su, Stefan Vasile, Layton H Smith, Paul W Diaz, John C Reed, Gregory P Roth

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