NOD1 rs2075820 (p.E266K) polymorphism is associated with gastric cancer among individuals infected with cagPAI-positive H. pylori

BACKGROUND: Helicobacter pylori is detected by pathogen recognition receptors including toll-like receptors (TLR) and nucleotide-binding oligomerization domain (NOD)-like receptors, eliciting an innate immune response against this bacteria. The aim of this study was to assess if polymorphisms of TLR2, TLR4, TLR5, NOD1 and NOD2 genes are associated with gastric cancer, in particular in individuals infected with H. pylori. RESULTS: A case-control study of 297 gastric cancer patients and 300 controls was performed to assess the association of 17 polymorphisms. Analyses performed under the allele model did not find association with gastric cancer. However, NOD1 rs2075820 (p.E266K) showed association with intestinal-type gastric cancer among H. pylori infected subjects (OR = 2.69, 95% CI 1.41-5.13, p = 0.0026). The association was not statistically significant in diffuse-type gastric cancer cases (OR = 1.26, 95% CI 0.63-2.52, p = 0.51). When the analyses were performed in patients carrying H. pylori strains harboring the cag pathogenicity island (cagPAI), we noticed significant association with NOD1 rs2075820 (OR = 4.90, 95% CI 1.80-3.36, p = 0.0019), in particular for intestinal-type gastric cancer cases (OR = 7.16, 95% CI 2.40-21.33, p = 4.1 × 10- 4) but not among diffuse-type gastric cancer cases (OR = 3.39, 95% CI 1.13-0.10, p = 0.03). CONCLUSIONS: NOD1 rs2075820 increases the risk of intestinal-type gastric cancer among individuals infected with H. pylori, particularly in those harboring the cagPAI.

Nucleotide-binding oligomerization domain 1 is dispensable for host immune responses against pulmonary infection of Acinetobacter baumannii in mice / 한국실험동물학회지

Nucleotide-binding domain 1 (Nod1) is a cytosolic receptor that is responsible for the recognition of a bacterial peptidoglycan motif containing meso-diaminophimelic acid. In this study, we sought to identify the role of Nod1 in host defense in vivo against pulmonary infection by multidrug resistant Acinetobacter baumannii. Wildtype (WT) and Nod1-deficient mice were intranasally infected with 3×107 CFU of A. baumannii and sacrificed at 1 and 3 days post-infection (dpi). Bacterial CFUs, cytokines production, histopathology, and mouse β-defensins (mBD) in the lungs of infected mice were evaluated. The production of cytokines in response to A. baumannii was also measured in WT and Nod1-deficient macrophages. The bacterial clearance in the lungs was not affected by Nod1 deficiency. Levels of IL-6, TNF-α, and IL-1β in the lung homogenates were comparable at days 1 and 3 between WT and Nod1-deficient mice, except the TNF-α level at day 3, which was higher in Nod1-deficient mice. There was no significant difference in lung pathology and expression of mBDs (mBD1, 2, 3, and 4) between WT and Nod1-deficient mice infected with A. baumannii. The production of IL-6, TNF-α, and NO by macrophages in response to A. baumannii was also comparable in WT and Nod1-deficient mice. Our results indicated that Nod1 does not play an important role in host immune responses against A. baumannii infection.

The roles of NOD1 and NOD2 in tumorigenesis and development / 中国生化药物杂志

Theinnate immunity system of human body has more and more attention for its antibacterial, antiviral, maintainingimmunehemostasis and promoting tissue damage and repair and other physiological functions.As members of NOD-like receptors(NLRs), NOD1 and NOD2 receptors are identified as intracellular pattern recognition receptors(PRRs), can be identified with molecular damage endogenous(damage-associated molecular patterns, DAMPs)and exogenous injury-molecular pathogen associated molecular(pathogen-associated molecular patterns, PAMPs), and initiation of innate and specific immune response, maintain the steady balance of body.Recently, a bunch of evidence have demonstrated that the importance of NOD1 receptor and NOD2 receptor is not limited in field of anti-infection, and the insulin resistance, kidney and liver damage recovery, cardiovascular disease and tumorigenesis are also closely related with these two receptors.So the aim of this article is to interpret the NOD1 and NOD2 general structure and function, and summarize the link between these two PRRs and tumorigenesis and finally make a clue for cancer immunotherapy.

Nucleotide Binding Oligomerization Domain 1 Is an Essential Signal Transducer in Human Epithelial Cells Infected with Helicobacter pylori That Induces the Transepithelial Migration of Neutrophils

BACKGROUND/AIMS: The cytosolic host protein nucleotide binding oligomerization domain 1 (Nod1) has emerged as a key pathogen recognition molecule for innate immune responses in epithelial cells. The purpose of the study was to elucidate the mechanism by which Helicobacter pylori infection leads to transepithelial neutrophil migration in a Nod1-mediated manner. METHODS: Human epithelial cell lines AGS and Caco-2 were grown and infected with H. pylori. Interleukin (IL)-8 mRNA expression and IL-8 secretion were assessed, and nuclear factor kappaB (NF-kappaB) activation was determined. Stable transfections of AGS and Caco-2 cells with dominant negative Nod1 were generated. Neutrophil migration across the monolayer was quantified. RESULTS: Cytotoxin-associated gene pathogenicity island (cagPAI)(+) H. pylori infection upregulated IL-8 mRNA expression and IL-8 secretion in AGS and Caco-2 cells compared with controls. NF-kappaB activation, IL-8 mRNA expression and IL-8 secretion by cagPAI knockdown strains were reduced compared with those infected with the wild-type strain. NF-kappaB activation, IL-8 mRNA expression and IL-8 secretion in dominant-negative (DN)-Nod1 stably transfected cells were reduced compared with the controls. The transepithelial migration of neutrophils in DN-Nod1 stably transfected cells was reduced compared with that in controls. CONCLUSIONS: Signaling through Nod1 plays an essential role in neutrophil migration induced by the upregulated NF-kappaB activation and IL-8 expression in H. pylori-infected human epithelial cells.

Helicobacter pylori induces NOD1/NF-κB activation and IFN-βand IP-10 production in gastrics of mice / 中国免疫学杂志

Objective:To construct the Helicobacter pylori infected C57BL/6 mice model to observe the activation of NOD1/NF-κB signaling pathways in the gastric tissues,and study its roles in inflammatory response during Hp infection.Methods:6-8 week-old C57BL/6 mice were randomly divided into two groups,the Hp infection group and the control group,and mice were given by gavage every 48 h for five times with Hp or PBS,respectively.All the animals were sacrificed at different time point and the gastric tissue were stained with hematoxylin-eosin( HE);The mRNA expression of NOD1 and RIP2 in gastric tissues were examined by RT-PCR;Levels of IFN-βand IP-10 in mice serum were assessed by ELISA;Nuclear translocation of p65 in gastric tissue was detected by Western blot.Results:Hp infection elicits an inflammatory cell response,glands in gastric tissue were reduced or atrophic,as compared with that in the control group.The levels of IP-10 and IFN-βincreased in the model group, and peaked at 16 weeks after Hp infection.Hp infection increased the mRNA expression of NOD1 and the p65 content in nuclear between 24-120 h(P<0.05),and the highest level at 48 h,subsequently the expression levels were began to decrease.The mRNA expression level of RIP2 was up-regulated after Hp was administrated, peaked at 48 h and declined after 72 h.However, the expression levels would rise again at 120 h.Conclusion: Hp infection can activate the NOD1/NF-κB signaling pathways and induce the production of IFN-βand IP-10 in gastrics of mice.

NOD1 and NOD2 receptors in mrigal (Cirrhinus mrigala): Inductive expression and downstream signalling in ligand stimulation and bacterial infections.

Nucleotide binding and oligomerization domain (NOD)1 and NOD2 are important cytoplasmic pattern recognition receptors (PRRs) and key members of the NOD-like receptor (NLR) family. They sense a wide range of bacteria or their products and play a key role in inducing innate immunity. This report describes the role of NOD1 and NOD2 receptors signalling in innate immunity in the Indian major carp, mrigal (Cirrhinus mrigala). Tissue-specific expression analysis of NOD1 and NOD2 genes by quantitative real-time PCR (qRT-PCR) revealed their wide distribution in various organs/tissues. In the untreated fish, the highest expression of NOD1 and NOD2 was detected in liver and blood, respectively. Stimulation with NOD1- and NOD2-specific ligands, i.e. iE-DAP and MDP, activated NOD1 and NOD2 receptor signalling in vivo and in vitro resulting in significant (p<0.05) induction of downstream signalling molecule RICK, and the effector molecules IL-1β, IL-8 and IFN-γ in the treated group as compared to their controls. In response to both Gram-positive and Gram-negative bacterial infections, NOD1 and NOD2 receptors signalling were activated and IL-1β, IL-8 and IFN-γ were induced. These findings highlight the important role of NOD receptors in eliciting innate immune response during the pathogenic invasion to the fish.

Effect of remifentanil on nucleotide-binding oligomerization domain 1 mRNA expression in rats with renal ischemia-reperfusion injury / 中华麻醉学杂志

Objective To investigate the effect of remifentanil on nucleotide-binding oligomerization domain 1 (NOD1) mRNA expression in rats with renal ischemia-reperfusion (I/R) injury.Methods Sixty male Sprague-Dawley rats,weighing 220-250 g,were randomly divided into 3 groups (n =20 each):sham operation group (S group),I/R group and remifentanil group (R group).Renal ischemia was induced by occlusion of bilateral renal arteries for 45 min followed by 24 h reperfusion in groups I/R and R.Remifentanil 1.0 μg· kg-1 · min-1 was infused until 30 min of reperfusion starting from 15 min before ischemia in group R,while the equal volume of normal saline was given instead in S and I/R groups.The animals were sacrificed at 15 min before ischemia and at 3,6,24 h of reperfusion and the kidneys were removed for microscopic examination and polymorphonuclear leukocyte (PMN) count and for measurement of NOD1 mRNA expression (by RT-PCR).The apoptotic rate was determined by flow cytometry double staining method.Results Compared with group S,NOD1 mRNA expression was up-regulated,and the apoptotic rate and PMN count were significantly increased at each time point during reperfusion in group I/R,and the apoptotic rate and PMN count were significantly increased at each time point during reperfusion,and NOD1 mRNA expression was up-regulated at 6 and 24 h of reperfusion in group R (P ＜ 0.01).Compared with I/R group,NOD1 mRNA expression was down-regulated,and the apoptotic rate and PMN count were significantly decreased at each time point during reperfusion (P ＜ 0.05 or 0.01),and the pathological changes were significantly attenuated in group R.Conclusion Remifentanil can reduce the renal I/R injury by down-regulating the expression of NOD1 mRNA and inhibiting inflammatory response and apoptosis.