AZD-9056

Regulated cell death plays a very important role in atherosclerosis (AS). Despite a large number of studies, there is a lack of literature on immunogenic cell death (ICD) in AS.

Carotid atherosclerotic plaque single-cell RNA (scRNA) sequencing data were analyzed to define involved cells and determine their transcriptomic characteristics. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, CIBERSORT, ESTIMATE and ssGSEA (Gene Set Enrichment Analysis), consensus clustering analysis, random forest (RF), Decision Curve Analysis (DCA), and the Drug-Gene Interaction and DrugBank databases were applied for bulk sequencing data. All data were downloaded from Gene Expression Omnibus (GEO).

mDCs and CTLs correlated obviously with AS occurrence and development (k²(mDCs) = 48.333, P < 0.001; k²(CTL) = 130.56, P < 0.001). In total, 21 differentially expressed genes were obtained for the bulk transcriptome; KEGG enrichment analysis results were similar to those for differentially expressed genes in endothelial cells. Eleven genes with a gene importance score > 1.5 were obtained in the training set and validated in the test set, resulting in 8 differentially expressed genes for ICD. A model to predict occurrence of AS and 56 drugs that may be used to treat AS were obtained with these 8 genes.

Immunogenic cell death occurs mainly in endothelial cells in AS. ICD maintains chronic inflammation in AS and plays a crucial role in its occurrence and development. ICD related genes may become drug-targeted genes for AS treatment.

Visceral pain is a prominent feature of various gastrointestinal diseases. The P2X7 receptor is expressed by multiple cell types including dorsal root ganglion satellite glial cells, macrophages, and spinal microglia, all of which have been implicated in nociceptive sensitization. We have used the selective and CNS penetrant P2X7 receptor antagonist Lu AF27139 to explore this receptor's role in distinct rat models of inflammatory and visceral hypersensitivity. Rats injected with CFA in the hindpaw displayed a marked reduction in hindpaw mechanical threshold, which was dose-dependently reversed by Lu AF27139 (3-30 mg/kg, p.o.). In rats injected with TNBS in the proximal colon, the colorectal distension threshold measured distally was significantly lower than sham treated rats at 7 days post-injection (P < 0.001), indicative of a marked central sensitization. Colonic hypersensitivity was also reversed by Lu AF27139 (10-100 mg/kg) and by the κ-opioid receptor agonist U-50,488H (3 mg/kg, s.c.). Moreover, both Lu AF27139 and U-50,488H prevented a TNBS-induced increase in spinal and brain levels of PGE2 and LTB4, as well as an increase in brain levels of PGF2α and TXB2. Lu AF27139 was well tolerated as revealed by a lack of significant effect on rotarod motor function and coordination at all doses tested up to 300 mg/kg. Thus, P2X7 receptor antagonism is efficacious in a rat model of visceral pain, via a mechanism which potentially involves attenuation of microglial function within spinal and/or supraspinal pain circuits, albeit a peripheral site of action cannot be excluded.