Differential effects of polyamine depletion by DENSpm and DFMO on beta cell stress reponses and type 1 diabetes outcomes in mice
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ABSTRACT:
PROVIDER: PRJNA1014421 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25956336_1.fastq.gz | Fastqsanger.gz | |||
| SRR25956336_2.fastq.gz | Fastqsanger.gz | |||
| SRR25956337_1.fastq.gz | Fastqsanger.gz | |||
| SRR25956337_2.fastq.gz | Fastqsanger.gz | |||
| SRR25956338_1.fastq.gz | Fastqsanger.gz |
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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: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
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:We studied the effects of polyamine pathway inhibitors on differentiation of nonpathogenic Th17 cellsin vitro. Here, we used difluoromethylornithine (DFMO), an irreversible inhibitor of ODC1, the enzyme that catalyzes the conversion of ornithine to putrescine.
2021-07-06 | GSE165088 | GEO
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: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: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.
2024-02-28 | GSE252370 | 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: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: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.
2012-09-11 | GSE36664 | GEO