Delving into the Latest Updates on NOD1 antagonist (Tsinghua University) with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Compound 66

Target

NOD1

Action

antagonists

Mechanism

NOD1 antagonists(Nucleotide-binding oligomerization domain-containing protein 1 antagonists)

Therapeutic Areas

Infectious Diseases

Active Indication

Helicobacter pylori infection

Inactive Indication-

Originator Organization

Tsinghua University

Active Organization

Tsinghua University

Inactive Organization-

License Organization-

Drug Highest PhaseDiscovery

First Approval Date-

Regulation-

Helicobacter pylori (H. pylori) infection is characterized by the complex interplay between H. pylori and gastric disorders. It has been established that NOD1 can be activated by the peptidoglycan (PGN) present in the cell wall of H. pylori, serving as a key mediator of inflammation and initiating the RIP2/NF-κB and MAPK inflammatory signaling pathways. In this article, we reported on the development of a 2-chloroquinazolin-4-ol derivative 66 as a potent and selective antagonist of both human and mouse NOD1, which effectively inhibited the expression of inflammatory cytokines (IL-6, TNF-α) and chemokines (CXCL1, CXCL8) in immune and epithelial cells, as well as inflammatory cytokines (KC, IL-6) in a H. pylori-induced murine model of gastritis following oral administration. This study laid a foundation for treating gastritis induced by H. pylori infection.

01 Dec 2022·Cell proliferation

Activation of the pattern recognition receptor NOD1 in periodontitis impairs the osteogenic capacity of human periodontal ligament stem cells via p38/MAPK signalling

Article

Author: Shujuan Zou ; Li Zhu ; Yuying He ; Chenchen Zhou ; Sirui Chen ; Jing Xie ; Jiahe Wang ; Zuping Wu

Abstract:

Objectives:

Nucleotide oligomerization domain receptor 1 (NOD1) mediates host recognition of pathogenic bacteria in periodontium. However, the specific role of NOD1 in regulating osteogenesis is unclear. Therefore, this study focused on the activation status of NOD1 in periodontitis and its effect on the osteogenic capacity of human periodontal ligament stem cells (hPDLSCs) as well as the underlying mechanism.

Methods:

Histological staining and Western blot were utilized to assess NOD1 expression in the periodontium of people with or without periodontitis. HPDLSCs were cultured under NOD1 agonist or antagonist treatment. Q‐PCR and Western blot were employed to assess the expression of osteogenic marker genes and proteins. Alizarin red staining and alkaline phosphatase staining were used to determine the osteogenic capability of hPDLSCs. The activation of downstream signalling was determined and specific inhibitors were utilized to confirm the signalling pathway in NOD1‐regulated osteogenesis.

Results:

NOD1 expression is significantly elevated in periodontitis. With NOD1 activated by particular agonist tri‐DAP, the osteogenic potential of hPDLSCs was impaired. NOD1 antagonist co‐incubation partially restored the decreased osteogenesis in hPDLSCs. P38/MAPK was phosphorylated in tri‐DAP‐induced NOD1 activation. The inhibitor of p38 rescued the suppression of osteogenesis induced by tri‐DAP in hPDLSCs.

Conclusions:

Our study revealed the expression status of NOD1 in periodontitis. Its activation greatly decreased the osteogenic capacity of hPDLSCs which was mediated by the phosphorylation of p38 downstream signalling.

01 Jun 2019·Journal of hepatology

Nucleotide-binding oligomerization domain 1 (NOD1) modulates liver ischemia reperfusion through the expression adhesion molecules

Article

Author: Patrice Maboudou ; Didier Betbeder ; Natascha Leleu-Chavain ; Laurent Dubuquoy ; Viviane Gnemmi ; Massih Ningarhari ; Philippe Mathurin ; Florent Artru ; Sébastien Dharancy ; Rodolphe Carpentier ; Emilie Gantier ; Mohamed Bou Saleh ; Benjamin Bertin ; Alexandre Louvet ; Céline Gheeraert ; François Maggiotto ; Guillaume Lassailly

BACKGROUND & AIMS:

In liver transplantation, organ shortage leads to the use of marginal grafts that are more susceptible to ischemia-reperfusion (IR) injury. We identified nucleotide-binding oligomerization domain 1 (NOD1) as an important modulator of polymorphonuclear neutrophil (PMN)-induced liver injury, which occurs in IR. Herein, we aimed to elucidate the role of NOD1 in IR injury, particularly focusing on its effects on the endothelium and hepatocytes.

METHOD:

Nod1 WT and KO mice were treated with NOD1 agonists and subjected to liver IR. Expression of adhesion molecules was analyzed in total liver, isolated hepatocytes and endothelial cells. Interactions between PMNs and hepatocytes were studied in an ex vivo co-culture model using electron microscopy and lactate dehydrogenase levels. We generated NOD1 antagonist-loaded nanoparticles (np ALINO).

RESULTS:

NOD1 agonist treatment increased liver injury, PMN tissue infiltration and upregulated ICAM-1 and VCAM-1 expression 20 hours after reperfusion. NOD1 agonist treatment without IR increased expression of adhesion molecules (ICAM-1, VCAM-1) in total liver and more particularly in WT hepatocytes, but not in Nod1 KO hepatocytes. This induction is dependent of p38 and ERK signaling pathways. Compared to untreated hepatocytes, a NOD1 agonist markedly increased hepatocyte lysis in co-culture with PMNs as shown by the increase of lactate dehydrogenase in supernatants. Interaction between hepatocytes and PMNs was confirmed by electron microscopy. In a mouse model of liver IR, treatment with np ALINO significantly reduced the area of necrosis, aminotransferase levels and ICAM-1 expression.

CONCLUSION:

NOD1 regulates liver IR injury through induction of adhesion molecules and modulation of hepatocyte-PMN interactions. NOD1 antagonist-loaded nanoparticles reduced liver IR injury and provide a potential approach to prevent IR, especially in the context of liver transplantation.

LAY SUMMARY:

Nucleotide-binding oligomerization domain 1 (NOD1) is as an important modulator of polymorphonuclear neutrophil (PMN)-induced liver injury, which occurs in ischemia-reperfusion. Here, we show that the NOD1 pathway targets liver adhesion molecule expression on the endothelium and on hepatocytes through p38 and ERK signaling pathways. The early increase of adhesion molecule expression after reperfusion emphasizes the importance of adhesion molecules in liver injury. In this study we generated nanoparticles loaded with NOD1 antagonist. These nanoparticles reduced liver necrosis by reducing PMN liver infiltration and adhesion molecule expression.

100 Deals associated with NOD1 antagonist (Tsinghua University)

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