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Nociceptin/orphanin FQ opioid receptor selective ligand MCOPPB as a potent senolytic drug

ABSTRACT: Nociceptin/orphanin FQ opioid receptor selective ligand MCOPPB as a potent senolytic drug

PROVIDER: PRJNA678239 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR13054011_1.fastq.gz	Fastqsanger.gz
	SRR13054011_2.fastq.gz	Fastqsanger.gz
	SRR13054012_1.fastq.gz	Fastqsanger.gz
	SRR13054012_2.fastq.gz	Fastqsanger.gz
	SRR13054013_1.fastq.gz	Fastqsanger.gz

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Nociceptin/orphanin FQ opioid receptor selective ligand MCOPPB as a potent senolytic drug

Project description:Here we used RNA-Seq to gain deep mechanistic insight into the effects of the drug MCOPPB on C57BL6J mice that were fed with chow diet or that received a low dose of a carcinogen (25 mg/kg diethynitrosamine, DEN) and then fed with high fat diet (HFD). Only in a second step we decided to focus exclusevely on the groups under chow diet. Heatmap analysis of the differentially expressed genes between the two groups revealed a difference in transcriptomic profile of MCOPPB-treated mice compared to the control condition. Genes were considered differentially expressed between groups if their expression values significantly differed by >4 fold. Statistical differences in gene expression were assessed by the ANOVA test. Correction for multiple test was achieved by the Benjamini-Hochberg procedure. The significance threshold was set to 0.05. Significantly enriched transcripts over-represented in MCOPPB compared to control were implicated in a number of functions and diseases. Specifically,Ingenuity pathway analysis (IPA) identified differences in hepatic fibrosis, oxidative stress,Ephrin A signaling, GP6 signaling pathway, Ephrin B signaling and others categories between MCOPPB versus CTL. These data suggested a slight pro-fibrotic effect in the liver of MCOPPB.

2020-11-14 | GSE161412 | GEO

Nociceptin/orphanin FQ opioid receptor (NOP) selective ligand MCOPPB links anxiolytic and senolytic effects.

Project description:Accumulation of senescent cells may drive age-associated alterations and pathologies. Senolytics are promising therapeutics that can preferentially eliminate senescent cells. Here, we performed a high-throughput automatized screening (HTS) of the commercial LOPAC®Pfizer library on aphidicolin-induced senescent human fibroblasts, to identify novel senolytics. We discovered the nociceptin receptor FQ opioid receptor (NOP) selective ligand 1-[1-(1-methylcyclooctyl)-4-piperidinyl]-2-[(3R)-3-piperidinyl]-1H-benzimidazole (MCOPPB, a compound previously studied as potential anxiolytic) as the best scoring hit. The ability of MCOPPB to eliminate senescent cells in in vitro models was further tested in mice and in C. elegans. MCOPPB reduced the senescence cell burden in peripheral tissues but not in the central nervous system. Mice and worms exposed to MCOPPB also exhibited locomotion and lipid storage changes. Mechanistically, MCOPPB treatment activated transcriptional networks involved in the immune responses to external stressors, implicating Toll-like receptors (TLRs). Our study uncovers MCOPPB as a NOP ligand that, apart from anxiolytic effects, also shows tissue-specific senolytic effects.

| S-EPMC8612119 | biostudies-literature

B cell-derived nociceptin/orphanin FQ contributes to impaired glucose tolerance and insulin resistance in obesity

Project description:B cells play a significant, yet underexplored, role in modulating immune responses in obesity and type 2 diabetes. In this study, we investigate the impact of B cell-derived nociceptin/orphanin FQ (N/OFQ) on metabolic function and inflammation in the context of obesity. Using a B cell-specific Pnoc knockout mouse model (PnocΔCD19), we demonstrate that loss of N/OFQ expression in B cells improves insulin sensitivity and glucose tolerance, particularly in the context of high-fat diet (HFD)-induced obesity. PnocΔCD19 mice exhibit a marked reduction in immune cell migration markers and macrophage recruitment in liver and adipose tissue. Mechanistically, we demonstrate that N/OFQ facilitates macrophage migration, contributing to the glucose intolerance and insulin resistance associated with obesity. Overall, the immunomodulatory properties exhibited by the N/OFQ-NOP system render it a compelling therapeutic target for metabolic inflammation.

2025-05-12 | GSE281815 | GEO

B cell-derived nociceptin/orphanin FQ contributes to impaired glucose tolerance and insulin resistance in obesity [THP1]

2025-05-12 | GSE281913 | GEO

B cell-derived nociceptin/orphanin FQ contributes to impaired glucose tolerance and insulin resistance in obesity [liver]

2025-05-12 | GSE281911 | GEO

[Dmt1]N/OFQ(1-13)-NH2: a potent nociceptin/orphanin FQ and opioid receptor universal agonist.

Project description:Background and purposeIntrathecally (i.t.) administered nociceptin/orphanin FQ (N/OFQ) evokes antinociceptive effects in rodents. Recent studies in monkeys demonstrated that i.t. co-application of N/OFQ and morphine elicits synergistic antinociceptive actions suggesting mixed N/OFQ peptide (NOP) and μ opioid receptor agonists as innovative spinal analgesics. Thus, novel N/OFQ related peptides were synthesized in order to identify and pharmacologically characterize a mixed NOP/ μ opioid receptor agonist.Experimental approachThe following in vitro assays were used: calcium mobilization in cells expressing the human NOP or classical opioid receptors and chimeric G proteins, receptor and [(35)S]-GTPγS binding, [(35)S]-GTPγS binding in rat spinal cord membranes, guinea pig ileum bioassay. In vivo experiments were performed in monkeys using the tail withdrawal assay.Key resultsFrom calcium mobilization studies [Dmt(1)]N/OFQ(1-13)-NH(2) was selected as the most potent and least selective compound. The mixed NOP/opioid full agonist activity and high affinity of [Dmt(1)]N/OFQ(1-13)-NH(2) was confirmed at human recombinant receptors in receptor binding, calcium mobilization and/or [(35)S]-GTPγS binding studies, at rat spinal cord receptors in [(35)S]-GTPγS binding experiments, and at guinea pig receptors inhibiting neurogenic contractions in the ileum. In vivo in the tail withdrawal assay in monkeys i.t. [Dmt(1) ]N/OFQ(1-13)-NH(2) was able to elicit robust and long-lasting antinociceptive effects.Conclusions and implicationsCollectively, these results demonstrate that [Dmt(1)]N/OFQ(1-13)-NH(2) behaves as NOP/opioid receptor universal agonist and substantiate the suggestion that such mixed ligands are worthy of development as innovative spinal analgesics.

| S-EPMC3570011 | biostudies-literature

B cell-derived nociceptin/orphanin FQ contributes to impaired glucose tolerance and insulin resistance in obesity

Project description:B cell-derived nociceptin/orphanin FQ contributes to impaired glucose tolerance and insulin resistance in obesity

| PRJNA1185752 | ENA

B cell-derived nociceptin/orphanin FQ contributes to impaired glucose tolerance and insulin resistance in obesity [liver]

Project description:B cell-derived nociceptin/orphanin FQ contributes to impaired glucose tolerance and insulin resistance in obesity [liver]

| PRJNA1186167 | ENA

B cell-derived nociceptin/orphanin FQ contributes to impaired glucose tolerance and insulin resistance in obesity [THP1]

Project description:B cell-derived nociceptin/orphanin FQ contributes to impaired glucose tolerance and insulin resistance in obesity [THP1]

| PRJNA1186168 | ENA

RiboTag enrichment of aBNST nociceptin neurons

Project description:We report the differential expression of genes in aBNST nociceptin neurons in comparison to the whole aBNST in mice