DFMO effect on Th17 and iTreg cells (ATAC-Seq)
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE165088 | GEO | 2021/07/06
REPOSITORIES: GEO
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Project description:We studied the effects of polyamine pathway inhibitors on differentiation of pathogenic and nonpathogenic Th17 cells in vitro. Here, we used difluoromethylornithine (DFMO), an irreversible inhibitor of ODC1, the enzyme that catalyzes the conversion of ornithine to putrescine.
2021-07-06 | GSE162300 | GEO
Project description:We studied the effects of polyamine pathway inhibitors on differentiation of Th17 cells in vitro. Here, we used difluoromethylornithine (DFMO), an irreversible inhibitor of ODC1, the enzyme that catalyzes the conversion of ornithine to putrescine, against a genetic background of WT or Jmjd3-deficient cells.
2021-07-06 | GSE162382 | GEO
Project description:Inhibition of polyamine biosynthesis using α-difluoromethylornithine (DFMO), an inhibitor of ornithine decarboxylase (ODC), reduces β-cell stress and type 1 diabetes (T1D) incidence in preclinical models. However, underlying cellular and molecular mechanisms and the tolerability and effectiveness of polyamine depletion by DFMO in humans with T1D remain unknown. Transcriptomics and proteomics of cytokine-stressed human islets treated with DFMO reveal alterations in mRNA translation, nascent protein transport, and secretion. Collectively, our data suggest that inhibition of polyamine biosynthesis may preserve β-cell function in T1D via islet cell-autonomous responses to stress.
2023-03-12 | GSE226888 | GEO
Project description:Diffuse intrinsic pontine glioma (DIPG) is an incurable malignant childhood brain tumour, with no active systemic therapies and a 5-year survival of less than 1%. Polyamines are small organic polycations that are essential for DNA replication, translation and cell proliferation. Ornithine decarboxylase 1 (ODC1), the rate limiting enzyme in polyamine synthesis, is irreversibly inhibited by difluoromethylornithine (DFMO). Herein we show that polyamine synthesis is upregulated in DIPG, leading to sensitivity to DFMO. DIPG cells compensate for ODC1 inhibition by upregulation of the polyamine transporter SLC3A2. Treatment with the polyamine transporter inhibitor AMXT 1501 reduced uptake of polyamines in DIPG cells, and co-administration of AMXT 1501 and DFMO led to potent in vitro activity, and significant extension of survival in three aggressive DIPG orthotopic animal models. Collectively, these results demonstrate the potential of dual targeting of polyamine synthesis and uptake as a therapeutic strategy for incurable DIPG.
| EGAS00001004905 | EGA
Project description:Streptococcus pneumoniae (Spn), a Gram-positive bacterium, poses a significant threat to human health, causing mild respiratory infections to severe invasive conditions. Despite availability of vaccines, challenges persist due to serotype replacement and antibiotic resistance, emphasizing the need for alternative therapeutic strategies. This study explores the intriguing role of polyamines, ubiquitous, small organic cations, in modulating virulence factors, especially the capsule, a crucial determinant of Spn's pathogenicity. Utilizing chemical inhibitors, difluoromethylornithine (DFMO) and AMXT 1501, this research unveils distinct regulatory effects on the gene expression of Spn D39 serotype in response to altered polyamine homeostasis. DFMO inhibits polyamine biosynthesis, disrupting pathways associated with glucose import and interconversion of sugars. In contrast, AMXT 1501, targeting polyamine transport, enhances the expression of polyamine and glucose biosynthesis genes, presenting a novel avenue for regulating the capsule independent of glucose availability. Despite ample glucose availability, AMXT 1501 treatment downregulates glycolytic pathway, fatty acid synthesis and ATP synthase, crucial for energy production while upregulating two-component systems responsible for stress management. This suggests a potential shutdown of energy production and capsule biosynthesis, redirecting resources towards stress management. Following DFMO and AMXT 1501 treatments, countermeasures such as upregulation of stress response genes and ribosomal protein were observed but appear to be insufficient to overcome the deleterious effects on capsule production. This study highlights the complexity of polyamine-mediated regulation in S. pneumoniae, particularly, capsule biosynthesis. Our findings offer valuable insights into potential therapeutic targets for modulation of capsule in a polyamine dependent manner, a promising avenue for intervention against S. pneumoniae infections.
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Project description:Group 3 innate lymphoid cells (ILC3s) are RORγT+ lymphocytes that are predominately enriched in mucosal tissues and produce IL-22 and IL-17A. They are the innate counterparts of Th17. While Th17 lymphocytes utilize unique metabolic pathways in their differentiation program, it is unknown whether ILC3s make similar metabolic adaptations. We employed single-cell RNA sequencing and metabolomic profiling of intestinal ILC subsets to identify an enrichment of polyamine biosynthesis in ILC3s, converging on the rate-limiting enzyme ornithine decarboxylase (ODC1). In vitro and in vivo studies demonstrated that exogenous supplementation with the polyamine putrescine or its biosynthetic substrate, ornithine, enhanced ILC3 production of IL-22. Conditional deletion of ODC1 in ILC3s impaired mouse antibacterial defense against C. rodentium infection, which was associated with a decrease in anti-microbial peptide production by the intestinal epithelium. Furthermore, in a model of anti-CD40 colitis, deficiency of ODC1 in ILC3s markedly reduced the production of IL-22 and severity of inflammatory colitis. We conclude that cell-intrinsic polyamine biosynthesis facilitates efficient defense against enteric pathogens as well as augments autoimmune colitis, thus representing an attractive target to modulate ILC3 function in intestinal disease.
2022-10-06 | GSE214152 | GEO
Project description:Type 1 diabetes (T1D) is an autoimmune disease leading to dysfunction and loss of insulin-secreting β cells. In β cells, polyamines have been implicated in causing cellular stress and dysfunction. An inhibitor of polyamine biosynthesis, difluoromethylornithine (DFMO), has been shown to delay T1D in mouse models and preserve β cell function in humans with recent-onset T1D. Another small molecule, N1,N11-diethylnorspermine (DENSpm), both inhibits polyamine biosynthesis and accelerates polyamine metabolism and is currently being tested for efficacy in cancer clinical trials. In this study, we show that DENSpm depletes intracellular polyamines as effectively as DFMO in mouse β cells. RNA sequencing analysis, however, suggests that the cellular reponses to DENSpm and DFMO differ, with the two sharing similar effects on cellular proliferation, but the latter showing greater effects on mRNA translation and protein folding pathways. In the low-dose streptozotocin-induced mouse model of T1D, DENSpm administration did not prevent or delay diabetes outcome, but did result in improvements in glucose tolerance and reductions in islet oxidative stress. In non-obese diabetic (NOD) mice, short-term DENSpm administration resulted in slight reduction in insulitis and proinflammatory Th1 cells in the pancreatic lymph nodes. Longer term treatment resulted in a dose-dependent increase in mortality. Notwithstanding the efficacy of both DFMO and DENSpm in reducing potentially toxic polyamine levels in β cells, our results highlight the discordant T1D outcomes that result from differing mechanisms of polyamine depletion and, more importantly, that toxic effects of DENSpm may limit its utility in T1D treatment.
2024-01-01 | GSE242725 | GEO
Project description:Pancreatic ductal adenocarcinoma (PDA) cells have a distinct dependence on de novo ornithine synthesis from glutamine via ornithine aminotransferase (OAT), which supports polyamine synthesis and is required for tumor growth. This directional OAT activity is normally largely restricted to infancy and contrasts with the reliance of most adult normal tissues and other cancer types on arginase (ARG) to generate arginine-derived ornithine, the substrate for polyamine synthesis. This dependence associates with arginine depletion in PDA tumor microenvironment, and is driven by mutant KRAS, which induces the expression of OAT and polyamine synthesis enzymes, including the rate-limiting enzyme ornithine decarboxylase-1 (ODC1). Loss of OAT, but not ARG2, largely mimics loss of ODC1, altering the transcriptional profiles in PDA cells, which in turn correlate with alterations in open chromatin states.
2023-01-01 | GSE193411 | GEO
Project description:Polyamines are absolutely required for cell growth and proliferation. While polyamine depletion results in reversible cell cycle arrest, the actual mechanism of growth inhibition is still obscure. This work aimed at determining the cellular processes affected by reduction in the intracellular polyamine levels In order to reveal the general transcriptional responses to polyamine depletion in mammalian cells, NIH3T3 mouse fibroblasts were treated with 1mM L-Difluoromethylornithine (DFMO), G1 cellular fractions were collected by sorting at 0,12, 24, 48 and 96 hours upon addition of the reagent, total RNA was extracted, reverse-transcribed, fragmented, labeled and hybridized to Affymetrix MoGene 1.0 ST DNA array.
2012-09-11 | E-GEOD-36445 | biostudies-arrayexpress
Project description:Polyamines are absolutely required for cell growth and proliferation. While polyamine depletion results in reversible cell cycle arrest, the actual mechanism of growth inhibition is still obscure. This experiment aimed at determining the cellular processes elicited by re-addition of polyamines to polyamine-depleted (growth arrested) cells. In order to reveal the general transcriptional responses to polyamine re-addition, NIH3T3 mouse fibroblasts were first treated with 1mM L-Difluoromethylornithine (DFMO) for 96 hours and then growth stimulated by spermidine. Cells were collected at 0, 30, 60, 120, 240, 360, 480 and 600 min upon addition of spermidine to polyamine-depleted (growth arrested) cells. Total RNA was isolated, reverse-transcribed, fragmented, labeled and hybridized to Affymetrix MoGene 1.0 ST DNA array.
2012-09-11 | E-GEOD-36664 | biostudies-arrayexpress