Ripk2

RIPK2 is an essential adaptor for NOD signalling and its kinase domain is a drug target for NOD-related diseases, such as inflammatory bowel disease. However, recent work indicates that the phosphorylation activity of RIPK2 is dispensable for signalling and that inhibitors of both RIPK2 activity and RIPK2 ubiquitination prevent the essential interaction between RIPK2 and the BIR2 domain of XIAP, the key RIPK2 ubiquitin E3 ligase. Moreover, XIAP BIR2 antagonists also block this interaction. To reveal the molecular mechanisms involved, we combined native mass spectrometry, NMR, and cryo-electron microscopy to determine the structure of the RIPK2 kinase BIR2 domain complex and validated the interface with in cellulo assays...

Receptor-interacting protein kinases 2 and 3 (RIPK2 and RIPK3) are considered attractive therapeutic enzyme targets for the treatment of a multitude of inflammatory diseases and cancers. In this study, we developed three interrelated series of novel quinazoline-based derivatives to investigate the effects of extensive modifications of positions 6 and 7 of the central core on the inhibitory activity and the selectivity against these RIPKs. The design of the derivatives was inspired by analyses of available literary knowledge on both RIPK2 and RIPK3 in complex with known quinazoline or quinoline inhibitors...

Ten hexahydropyrimido[4,5-d]pyrimidine derivatives have been synthesized by using a green and time-efficient microwave method. The synthesized motifs were evaluated for their anticancer activity, antimicrobial activity, molecular docking, drug likeliness and ADMET studies. Comparatively, the hetero-aromatic pyrazole substituted compound 4a exhibited the highest anticancer activity [Mean growth percent: 35.57], while EDG [-N(CH3 )2 ] substituted compound 4i indicated very good activity [Mean growth percent: 60...

Receptor-interacting protein kinase 2 (RIPK2) belongs to the receptor-interacting protein family (RIPs), which is mainly distributed in the cytoplasm. RIPK2 is widely expressed in human tissues, and its mRNA level is highly expressed in the spleen, leukocytes, placenta, testis, and heart. RIPK2 is a dual-specificity kinase with multiple domains, which can interact with tumor necrosis factor receptor (TNFR), and participate in the Toll-like receptor (TLR) and nucleotide-binding oligomerization domain (NOD) signaling pathways...

The human Nod-like receptor (NLR) protein NOD1 is a well described pattern-recognition receptor with diverse functions. NOD1 associates with F-actin, and its protein levels are upregulated in metastatic cancer cells. A hallmark of cancer cells is their ability to migrate, which involves actin remodelling. Using chemotaxis and wound healing assays, we show that NOD1 expression correlated with the migration rate and chemotactic index in the cervical carcinoma cell line HeLa. The effect of NOD1 in cell migration was independent of the downstream kinase RIPK2 and NF-ĸB activity...

Pyrazolo[4,3- e ]tetrazolo[1,5- b ][1,2,4]triazine sulfonamides ( MM -compounds) are a relatively new class of heterocyclic compounds that exhibit a wide variety of biological actions, including anticancer properties. Here, we used caspase enzyme activity assays, flow cytometry analysis of propidium iodide (PI)-stained cells, and a DNA laddering assay to investigate the mechanisms of cell death triggered by the MM -compounds ( MM134 , -6 , -7 , and -9 ). Due to inconsistent results in caspase activity assays, we have performed a bromodeoxyuridine (BrdU) incorporation assay, colony formation assay, and gene expression profiling...

Antibody-mediated rejection (AMR) remains a refractory rejection after donor-specific antibody (DSA)-positive or blood-type incompatible liver transplantation (LT), even in the era of pre-transplant rituximab desensitization. This is due to the lack of not only effective post-transplant treatments but also robust animal models to develop/validate new interventions. Orthotopic LT from male Dark Agouti (DA) to male Lewis (LEW) rats was used to develop a rat LT-AMR model. LEW were pre-sensitized by a preceding skin transplantation from DA 4-6 weeks before LT ( Group-PS ), while sham procedure was performed in non-sensitized controls ( Group-NS )...

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The interleukin-1 family members, IL-1β and IL-18, are processed into their biologically active forms by multi-protein complexes, known as inflammasomes. Although the inflammasome pathways that mediate IL-1β processing in myeloid cells have been defined, those involved in IL-18 processing, particularly in non-myeloid cells, are still not well understood. Here we report that the host defence molecule NOD1 regulates IL-18 processing in mouse epithelial cells in response to the mucosal pathogen, Helicobacter pylori...

As an essential mediator of inflammation and innate immunity, the receptor-interacting serine/threonine-protein kinase-2 (RIPK2) is responsible for transducing signaling downstream of the intracellular peptidoglycan sensors nucleotide oligomerization domain (NOD)-like receptors 1 and 2 (NOD1/2), which will further activate nuclear factor kappa-B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways, leading to the transcription activation of pro-inflammatory cytokines and productive inflammatory response...

Nucleotide-binding oligomerization domain-containing protein 1 and 2 (NOD 1/2) are important cytosolic pattern recognition receptors that initiate host immune response. The dysregulation of NOD signaling is highly associated with inflammatory bowel disease (IBD) that needs novel treatment options. Receptor-interacting protein kinase 2 (RIPK2) is a critical mediator of NOD signaling and considered a promising therapeutic target for IBD treatment. However, there are currently no RIPK2 inhibitors available for clinical use...

Although the immunomodulatory potency of bacterial membrane vesicles (MVs) is widely acknowledged, their interactions with host cells and the underlying signaling pathways have not been well studied. Herein, we provide a comparative analysis of the proinflammatory cytokine profile secreted by human intestinal epithelial cells exposed to MVs derived from 32 gut bacteria. In general, outer membrane vesicles (OMVs) from Gram-negative bacteria induced a stronger proinflammatory response than MVs from Gram-positive bacteria...

Gut microbiota influence host immunity and metabolism during obesity. Bacterial sensors of the innate immune system relay signals from specific bacterial components (i.e., postbiotics) that can have opposing outcomes on host metabolic inflammation. NOD-like receptors (NLRs) such as Nod1 and Nod2 both recruit receptor-interacting protein kinase 2 (RIPK2) but have opposite effects on blood glucose control. Nod1 connects bacterial cell wall-derived signals to metabolic inflammation and insulin resistance, whereas Nod2 can promote immune tolerance, insulin sensitivity, and better blood glucose control during obesity...

Selenium-enriched Cardamine violifolia (SEC), a cruciferous plant, exerts excellent antioxidant and anti-inflammatory capacity, but its effect on hepatic function is unclear. This study investigated the effect and potential mechanism of SEC on hepatic injury induced by lipopolysaccharide (LPS). Twenty-four weaned piglets were randomly allotted to treatment with SEC (0.3 mg/kg Se) and/or LPS (100 μg/kg). After 28 days of the trial, pigs were injected with LPS to induce hepatic injury. These results indicated that SEC supplementation attenuated LPS-induced hepatic morphological injury and reduced aspartate aminotransferase (AST) and alkaline phosphatase (ALP) activities in plasma...

Colon cancer is a cancer with high morbidity and mortality worldwide. Receptor interacting serine/threonine kinase 2 (RIPK2) has been identified as a proto-oncogene, but its role in colon cancer is largely unknown. Herein, we found that RIPK2 interference could inhibit the proliferation and invasion of colon cancer cells, and promote apoptosis. Baculoviral IAP repeat containing 3 (BIRC3) is an E3 ubiquitin ligase, which was found highly expressed in colon cancer cells. Co-immunoprecipitation (Co-IP) experiments showed that RIPK2 could directly bind with BIRC3...

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) and chronic kidney disease (CKD) are both highly prevalent worldwide. Studies have confirmed the association between them, but the underlying pathophysiological mechanisms are not clear yet. This study aims to identify the genetic and molecular mechanisms influencing both diseases through a bioinformatics approach. RESULTS: Fifty-four overlapping differentially expressed genes associated with NAFLD and CKD were obtained by analysis of microarray datasets GSE63067 and GSE66494 downloaded from Gene Expression Omnibus...

Purpose: The long-term prognosis and survival rate of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) are poor, although the identification of specific biomarkers that reveal its nature and aggressiveness has improved it. Growth-related oncogene alpha (Groα) and NOD1 (nucleotide-binding oligomerization domain 1) can be used as prognosis markers to identify subgroups of HNSCC patients with low survival rates and as potential therapeutic targets for HNSCC patients. However, the mechanism associated with the Groα-mediated NOD pathway in HNSCC progression remains unclear...

The natural product family of the fusicoccanes (FCs) has been shown to display anti-cancer activity, especially when combined with established therapeutic agents. FCs stabilize 14-3-3 protein-protein interactions (PPIs). Here, we tested combinations of a small library of FCs with interferon α (IFNα) on different cancer cell lines and report a proteomics approach to identify the specific 14-3-3 PPIs that are induced by IFNα and stabilized by FCs in OVCAR-3 cells. Among the identified 14-3-3 target proteins are THEMIS2, receptor interacting protein kinase 2 (RIPK2), EIF2AK2, and several members of the LDB1 complex...

BACKGROUND: Obesity and diabetes are associated with elevated free fatty acids like palmitic acid (PA), which promote chronic inflammation and impaired inflammation resolution associated with cardiometabolic disorders. Long noncoding RNAs (lncRNAs) are implicated in inflammatory processes; however, their roles in PA-regulated inflammation and resolution are unclear. METHODS: We performed RNA-sequencing analysis to identify PA-regulated coding genes and novel lncRNAs in CD14+ monocytes from healthy volunteers...

OBJECTIVE: Inflammation and oxidation brought on by myocardial ischemia-reperfusion (MI/R) injury lead to cardiomyocyte apoptosis and necrosis. The receptor interacting serine/threonine kinase 2 (RIPK2) plays significant roles in oxidative stress and excessive inflammation. The purpose of this research is to examine the roles of RIPK2 in MI/R injury. METHODS: The in vivo animal model was constructed by acute coronary I/R, and the in vitro cell model was established by oxygen and glucose deprivation/reperfusion (OGD/R)-stimulated cardiomyocyte injury...