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Inosine monophosphate and inosine differentially regulate endotoxemia and bacterial sepsis

ABSTRACT: Inosine monophosphate and inosine differentially regulate endotoxemia and bacterial sepsis

PROVIDER: PRJNA762272 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR15836381_1.fastq.gz	Fastqsanger.gz
	SRR15836381_2.fastq.gz	Fastqsanger.gz
	SRR15836382_1.fastq.gz	Fastqsanger.gz
	SRR15836382_2.fastq.gz	Fastqsanger.gz
	SRR15836383_1.fastq.gz	Fastqsanger.gz

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Inosine monophosphate and inosine differentially regulate endotoxemia and bacterial sepsis

Project description:Inosine monophosphate (IMP) plays a central role in intracellular purine metabolism. How IMP regulates inflammation induced by bacterial products or bacteria is unknown. In this study, we demonstrate that IMP fundamentally alters gene expression in the liver.To assess how IMP affects inflammatory cell activation in vivo, we subjected liver, the organ containing the highest numbers of macrophages in the body, to RNAseq analyses. High quality RNA was isolated from the livers of 3 vehicle- and 3 IMP-treated endotoxemic mice and submitted for RNAseq analysis. Our analysis identified 105 genes that were differentially expressed, determined by adjusted p values (42 downregulated, 63 upregulated; padj ≤ 0.05).

2021-09-12 | GSE183880 | GEO

Inosine monophosphate and inosine differentially regulate endotoxemia and bacterial sepsis.

Project description:Inosine monophosphate (IMP) is the intracellular precursor for both adenosine monophosphate and guanosine monophosphate and thus plays a central role in intracellular purine metabolism. IMP can also serve as an extracellular signaling molecule, and can regulate diverse processes such as taste sensation, neutrophil function, and ischemia-reperfusion injury. How IMP regulates inflammation induced by bacterial products or bacteria is unknown. In this study, we demonstrate that IMP suppressed tumor necrosis factor (TNF)-α production and augmented IL-10 production in endotoxemic mice. IMP exerted its effects through metabolism to inosine, as IMP only suppressed TNF-α following its CD73-mediated degradation to inosine in lipopolysaccharide-activated macrophages. Studies with gene targeted mice and pharmacological antagonism indicated that A2A , A2B, and A3 adenosine receptors are not required for the inosine suppression of TNF-α production. The inosine suppression of TNF-α production did not require its metabolism to hypoxanthine through purine nucleoside phosphorylase or its uptake into cells through concentrative nucleoside transporters indicating a role for alternative metabolic/uptake pathways. Inosine augmented IL-β production by macrophages in which inflammasome was activated by lipopolysaccharide and ATP. In contrast to its effects in endotoxemia, IMP failed to affect the inflammatory response to abdominal sepsis and pneumonia. We conclude that extracellular IMP and inosine differentially regulate the inflammatory response.

| S-EPMC9812230 | biostudies-literature

Differential effects of inosine monophosphate dehydrogenase (IMPDH/GuaB) inhibition in Acinetobacter baumannii and Escherichia coli

Project description:Inosine 5’-monophosphate dehydrogenase (IMPDH) catalyzes the rate-limiting step in the de novo guanine biosynthesis and is conserved from humans to bacteria, where it is called GuaB. We developed a series of potent inhibitors that selectively target GuaB over its human homolog. Here we show that these GuaB inhibitors are bactericidal, generate phenotypic signatures that are distinct from other antibiotics, and elicit different time-kill kinetics and regulatory responses in two important gram-negative pathogens: Acinetobacter baumannii and Escherichia coli. Specifically, the GuaB inhibitor G6 rapidly kills A. baumannii but only kills E. coli after 24 hours. After exposure to G6, the expression of genes involved in purine biosynthesis and stress responses change in opposite directions while siderophore biosynthesis is downregulated in both species. Our results suggest that different species respond to GuaB inhibition using distinct regulatory programs, and possibly explain the different bactericidal kinetics upon GuaB inhibition. The comparison highlights opportunities for developing GuaB inhibitors as novel antibiotics.

2024-08-25 | GSE275261 | GEO

Differential effects of inosine monophosphate dehydrogenase (IMPDH/GuaB) inhibition in Acinetobacter baumannii and Escherichia coli

Project description:Differential effects of inosine monophosphate dehydrogenase (IMPDH/GuaB) inhibition in Acinetobacter baumannii and Escherichia coli

| PRJNA1150140 | ENA

Small non-coding RNA expression in whole blood leukocytes of healthy subjects, critically-ill patients with sepsis or non-infectious etiology and human endotoxemia

Project description:Genome-wide gene expression profiling of whole blood leukocytes in critically ill patients with sepsis or non-infectious disease has been used extensively in search of diagnostic biomarkers, as well as prognostic signatures reflecting diseases severity and outcome. Through technological advances in genomics it has become clear that transcription is not limited to protein-coding regions of the genome. Here, we describe a comprehensive analysis of small non-coding RNA expression in blood leukocytes of critically ill patients with sepsis, a non-infectious condition, healthy subjects and experimental human endotoxemia

2021-01-11 | GSE134358 | GEO

Single-cell RNA sequencing of liver nonparenchymal cells from murine model of endotoxemia

Project description:Liver has a crucial role in the regulation of immune defense in systemic infections. During endotoxemia, the liver transits from an immune-tolerant towards an immune-active state and forms the first line of defense against invading microorganisms. the role of liver nonparenchymal cells in endotoxemia remains unintelligible. To characterize the liver nonparenchymal cells in endotoxemia liver, we performed single-cell RNA sequencing of liver nonparenchymal cells from healthy C57BL/6J mice and murine model of endotoxemia at early or late stage. The single-cell RNA-seq analyses revealed the heterogeneity of liver nonparenchymal cells in endotoxemia liver.

2023-02-28 | GSE186558 | GEO

Single-cell RNA sequencing of liver parenchymal cells from murine model of endotoxemia

Project description:Liver has a crucial role in the regulation of immune defense in systemic infections. During endotoxemia, the liver transits from an immune-tolerant towards an immune-active state and forms the first line of defense against invading microorganisms. the role of liver parenchymal cells in endotoxemia remains unintelligible. To characterize the liver parenchymal cells in endotoxemia liver, we performed single-cell RNA sequencing of liver parenchymal cells from healthy C57BL/6J mice and murine model of endotoxemia at early or late stage. The single-cell RNA-seq analyses revealed the heterogeneity of liver parenchymal cells in endotoxemia liver.

2022-04-06 | GSE186554 | GEO

Inosine enhances mitochondria respiration to promote cancer survival under starvation

Project description:To investigate mechanism of inosine promotes the survival and metabolism of MDA-MB-231 cells under starvation conditions, MDA-MB-231 cells were treated with inosine and glucose for 12h under starvation conditions. We then performed gene expression profiling analysis using data obtained from RNA-seq of MDA-MB-231 cells under three different treatments（-G-Q,Inosine,Glucose）.

2023-07-17 | GSE225643 | GEO

Inhibiting tumor cell-intrinsic UBA6 by inosine augments tumor immunogenicity

Project description:Metabolic alteration influences cancer immunity. However, the role and mechanism of metabolic adaption on immune checkpoint blockade (ICB) responses remains ill-defined. Here, metabolomic profiling in mouse tumor models and cancer patients treated with ICB was performed. We found that metabolite inosine was associated with ICB sensitivity in mice and humans, and overcame ICB resistance in several mouse tumor models. Notably, inosine sensitized tumor cells to T cell-mediated cytotoxicity by amplifying tumor-intrinsic immunogenicity. Chemical proteomics further identified that inosine directly bound and inhibited ubiquitin-activating enzyme UBA6. Tumor intrinsic UBA6 loss augmented tumor immunogenicity and substituted the synergistic effect of inosine in combination with ICB. Clinically, tumor UBA6 expression negatively correlated with ICB response in cancer patients. Thus, we reveal an unappreciated function of inosine on tumor-intrinsic immunogenicity and UBA6 as a candidate target for immunotherapy.

2022-08-04 | GSE210225 | GEO

Oxanosine Monophosphate Is a Covalent Inhibitor of Inosine 5'-Monophosphate Dehydrogenase.

Project description:Reactive nitrogen species (RNS) are produced during infection and inflammation, and the effects of these agents on proteins, DNA, and lipids are well recognized. In contrast, the effects of RNS damaged metabolites are less appreciated. 5-Amino-3-β-(d-ribofuranosyl)-3 H-imidazo-[4,5- d][1,3]oxazine-7-one (oxanosine) and its nucleotides are products of guanosine nitrosation. Here we demonstrate that oxanosine monophosphate (OxMP) is a potent reversible competitive inhibitor of IMPDH. The value of Ki varies from 50 to 340 nM among IMPDHs from five different organisms. UV spectroscopy and X-ray crystallography indicate that OxMP forms a ring-opened covalent adduct with the active site Cys (E-OxMP*). Unlike the covalent intermediate of the normal catalytic reaction, E-OxMP* does not hydrolyze, but instead recyclizes to OxMP. IMPDH inhibitors block proliferation and can induce apoptosis, so the inhibition of IMPDH by OxMP presents another potential mechanism for RNS toxicity.

| S-EPMC6467267 | biostudies-literature

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