bims-polyam Biomed News
on Polyamines
Issue of 2024–11–17
eight papers selected by
Sebastian J. Hofer, University of Graz
  1. Conservation of the Polyamines Pathway in Ustilaginomycetes A Genomic and Experimental Approach.
  2. Post-fast refeeding: rise of intestinal stemness and mutagen-induced cancer risk through polyamine metabolism.
  3. Spermidine limits diabetes by modulating RIPK1-mediated cell death and inflammation.
  4. Spermine oxidase promotes Helicobacter pylori-mediated gastric carcinogenesis through acrolein production.
  5. eIF5A controls mitoprotein import by relieving ribosome stalling at TIM50 translocase mRNA.
  6. Probiotics and their metabolite spermidine enhance IFN-γ+CD4+ T cell immunity to inhibit hepatitis B virus.
  7. Spermidine mediates acetylhypusination of RIPK1 to suppress diabetes onset and progression.
  8. Effects of Target of Rapamycin and Phosphatidylinositol 3-Kinase Inhibitors and Other Autophagy-Related Supplements on Life Span in y w Male Drosophila melanogaster.
  1. J Basic Microbiol. 2024 Nov 11. e2400561
    Conservation of the Polyamines Pathway in Ustilaginomycetes A Genomic and Experimental Approach.
    Domingo Martínez-Soto, Albo J Hernández-Rojas, Laura Valdés-Santiago, Luis F García-Ortega, Adriana Ramírez-Martínez, Elías Trujillo-Esquivel, Fernando Pérez-Rodríguez, Lucila Ortiz-Castellanos, Claudia G León-Ramírez, Edgardo Ulises Esquivel-Naranjo, José Ruiz-Herrera, José Antonio Cervantes-Chávez.
      Polyamines are organic and aliphatic molecules essential for the growth, development, and survival of both eukaryotes and prokaryotes. In fungi, polyamines play a crucial role in cellular differentiation and pathogenesis. Since fungi and animals are closely related evolutionarily, and fungi can be easily genetically manipulated in the lab, they serve as excellent models for studying polyamine metabolism and the molecular mechanisms controlled by these biomolecules. Although the metabolism of polyamines has been extensively studied in model fungi such as Saccharomyces cerevisiae and Ustilago maydis, the conservation of the polyamine biosynthesis pathway in other Ustilaginomycetes, a class of fungi that includes phytopathogens, saprophytes, mutualists, and mycorrhizae, has not been thoroughly investigated. In this study, using a genomic and bioinformatics approach, we analyzed the conservation of the polyamine biosynthesis pathway in Ustilaginomycetes. Additionally, we confirmed the functional conservation of ornithine decarboxylase (Odc), which is involved in the synthesis of putrescine, one of the most important polyamines in fungi and complex multicellular eukaryotic organisms, using genetics and molecular biology tools. Moreover, we identified the differentially regulated genes by this polyamine in U. maydis. This research provides insights into the similarities and differences in the conservation of the polyamine biosynthesis pathway in fungi, and it expands our understanding of the role of polyamines and the mechanisms regulated by these molecules in eukaryotes.
    Keywords:  Ustilaginomycetes; basidiomycota; fungi; genes regulated by putrescine; ornithine decarboxylase; polyamine mutant; putrescine
    DOI:  https://doi.org/10.1002/jobm.202400561
  2. Signal Transduct Target Ther. 2024 Nov 11. 9(1): 317
    Post-fast refeeding: rise of intestinal stemness and mutagen-induced cancer risk through polyamine metabolism.
    Sarah Brunner, Klaus-Peter Janssen, Josef Ecker.
      
    DOI:  https://doi.org/10.1038/s41392-024-02038-1
  3. Nat Cell Biol. 2024 Nov 07.
    Spermidine limits diabetes by modulating RIPK1-mediated cell death and inflammation.
      
    DOI:  https://doi.org/10.1038/s41556-024-01542-4
  4. Oncogene. 2024 Nov 10.
    Spermine oxidase promotes Helicobacter pylori-mediated gastric carcinogenesis through acrolein production.
    Kara M McNamara, Johanna C Sierra, Yvonne L Latour, Caroline V Hawkins, Mohammad Asim, Kamery J Williams, Daniel P Barry, Margaret M Allaman, Irene Zagol-Ikapitte, Paula B Luis, Claus Schneider, Alberto G Delgado, M Blanca Piazuelo, Regina N Tyree, Kate S Carson, Yash A Choksi, Lori A Coburn, Alain P Gobert, Keith T Wilson.
      Helicobacter pylori is the primary cause of gastric cancer, and there is a need to discover new molecular targets for therapeutic intervention in H. pylori disease progression. We have previously shown that spermine oxidase (SMOX), the enzyme that catabolizes the back-conversion of the polyamine spermine to spermidine, is upregulated during infection and is associated with increased cancer risk in humans. We sought to determine the direct role of SMOX in gastric carcinogenesis during H. pylori infection. In this study, we demonstrate that transgenic FVB/N insulin-gastrin (INS-GAS) mice that develop gastric carcinoma with H. pylori infection were protected from cancer development with Smox deletion. RNA sequencing revealed that genes associated with the immune system and cancer were downregulated in the infected Smox-/- mice. Furthermore, there was a decrease in cell proliferation and DNA damage in infected Smox-/- animals. There was significant generation of adducts of the highly reactive electrophile acrolein, a byproduct of SMOX activity, in gastric tissues from H. pylori-infected humans and wild-type, but not Smox-/- mice. Genetic deletion of Smox in murine organoids or chemical inhibition of SMOX in human gastric epithelial cells significantly reduced generation of acrolein induced by H. pylori. Additionally, acrolein-induced DNA damage in gastric epithelial cells was ablated with the electrophile scavenger 2-hydroxybenzylamine (2-HOBA). Gastric acrolein adduct levels were attenuated in infected INS-GAS mice treated with 2-HOBA, which exhibit reduced gastric carcinoma. These findings implicate SMOX and acrolein in H. pylori-induced carcinogenesis, thus indicating their potential as therapeutic targets.
    DOI:  https://doi.org/10.1038/s41388-024-03218-7
  5. J Cell Biol. 2024 Dec 02. pii: e202404094. [Epub ahead of print]223(12):
    eIF5A controls mitoprotein import by relieving ribosome stalling at TIM50 translocase mRNA.
    Marina Barba-Aliaga, Vanessa Bernal, Cynthia Rong, Madeleine E Volfbeyn, Keguang Zhang, Brian M Zid, Paula Alepuz.
      Efficient import of nuclear-encoded proteins into mitochondria is crucial for proper mitochondrial function. The conserved translation factor eIF5A binds ribosomes, alleviating stalling at polyproline-encoding sequences. eIF5A impacts mitochondrial function across species, though the precise molecular mechanism is unclear. We found that eIF5A depletion in yeast reduces the translation and levels of the TCA cycle and oxidative phosphorylation proteins. Loss of eIF5A causes mitoprotein precursors to accumulate in the cytosol and triggers a mitochondrial import stress response. We identify an essential polyproline protein as a direct target of eIF5A: the mitochondrial inner membrane protein and translocase component Tim50. Thus, eIF5A controls mitochondrial protein import by alleviating ribosome stalling along Tim50 mRNA at the mitochondrial surface. Removal of polyprolines from Tim50 partially rescues the mitochondrial import stress response and translation of oxidative phosphorylation genes. Overall, our findings elucidate how eIF5A impacts the mitochondrial function by promoting efficient translation and reducing ribosome stalling of co-translationally imported proteins, thereby positively impacting the mitochondrial import process.
    DOI:  https://doi.org/10.1083/jcb.202404094
  6. Cell Rep Med. 2024 Nov 07. pii: S2666-3791(24)00593-7. [Epub ahead of print] 101822
    Probiotics and their metabolite spermidine enhance IFN-γ+CD4+ T cell immunity to inhibit hepatitis B virus.
    Tixiao Wang, Yuchen Fan, Siyu Tan, Zehua Wang, Mengzhen Li, Xiaowei Guo, Xiangguo Yu, Qinghai Lin, Xiaojia Song, Leiqi Xu, Lixiang Li, Shiyang Li, Lifen Gao, Xiaohong Liang, Chunyang Li, Chunhong Ma.
      The therapeutic potential of commensal microbes and their metabolites is promising in the functional cure of chronic hepatitis B virus (HBV) infection, which is defined as hepatitis B surface antigen (HBsAg) loss. Here, using both specific-pathogen-free and germ-free mice, we report that probiotics significantly promote the decline of HBsAg and inhibit HBV replication by enhancing intestinal homeostasis and provoking intrahepatic interferon (IFN)-γ+CD4+ T cell immune response. Depletion of CD4+ T cells or blockage of IFN-γ abolishes probiotics-mediated HBV inhibition. Specifically, probiotics-derived spermidine accumulates in the gut and transports to the liver, where it exhibits a similar anti-HBV effect. Mechanistically, spermidine enhances IFN-γ+CD4+ T cell immunity by autophagy. Strikingly, administration of probiotics in HBV patients reveals a preliminary trend to accelerate the decline of serum HBsAg. In conclusion, probiotics and their derived spermidine promote HBV clearance via autophagy-enhanced IFN-γ+CD4+ T cell immunity, highlighting the therapeutic potential of probiotics and spermidine for the functional cure of HBV patients.
    Keywords:  IFN-γ(+)CD4(+) T cell; autophagy; fecal microbiota transplantation; gut microbiota; hepatitis B virus; probiotics; spermidine
    DOI:  https://doi.org/10.1016/j.xcrm.2024.101822
  7. Nat Cell Biol. 2024 Nov 07.
    Spermidine mediates acetylhypusination of RIPK1 to suppress diabetes onset and progression.
    Tian Zhang, Weixin Fu, Haosong Zhang, Jianlong Li, Beizi Xing, Yuping Cai, Mengmeng Zhang, Xuheng Liu, Chunting Qi, Lihui Qian, Xinbo Hu, Hua Zhu, Shuailong Yang, Min Zhang, Jianping Liu, Ganquan Li, Yang Li, Rong Xiang, Zhengqiang Qi, Junhao Hu, Ying Li, Chengyu Zou, Qin Wang, Xia Jin, Rui Pang, Peiying Li, Junli Liu, Yaoyang Zhang, Zhaoyin Wang, Zheng-Jiang Zhu, Bing Shan, Junying Yuan.
      It has been established that N-acetyltransferase (murine NAT1 (mNAT1) and human NAT2 (hNAT2)) mediates insulin sensitivity in type 2 diabetes. Here we show that mNAT1 deficiency leads to a decrease in cellular spermidine-a natural polyamine exhibiting health-protective and anti-ageing effects-but understanding of its mechanism is limited. We identify that mNAT1 and hNAT2 modulate a type of post-translational modification involving acetylated spermidine, which we name acetylhypusination, on receptor-interacting serine/threonine-protein kinase 1 (RIPK1)-a key regulator of inflammation and cell death. Spermidine supplementation decreases RIPK1-mediated cell death and diabetic phenotypes induced by NAT1 deficiency in vivo. Furthermore, insulin resistance and diabetic kidney disease mediated by vascular pathology in NAT1-deficient mice can be blocked by inhibiting RIPK1. Finally, we demonstrate a decrease in spermidine and activation of RIPK1 in the vascular tissues of human patients with diabetes. Our study suggests a role for vascular pathology in diabetes onset and progression and identifies the inhibition of RIPK1 kinase as a potential therapeutic approach for the treatment of type 2 diabetes.
    DOI:  https://doi.org/10.1038/s41556-024-01540-6
  8. Int J Mol Sci. 2024 Oct 26. pii: 11504. [Epub ahead of print]25(21):
    Effects of Target of Rapamycin and Phosphatidylinositol 3-Kinase Inhibitors and Other Autophagy-Related Supplements on Life Span in y w Male Drosophila melanogaster.
    Aaron A Bearden, Emily M Stewart, Candace C Casher, Meredith A Shaddix, Amber C Nobles, Robin J Mockett.
      Various dietary supplements have been shown to extend the life span of Drosophila melanogaster, including several that promote autophagy, such as rapamycin and spermidine. The goal of the study presented here was to test numerous additional potential anti-aging supplements, primarily inhibitors of the target of rapamycin (TOR) and/or phosphatidylinositol 3-kinase (PI3K). Using a single, comparatively long-lived y w test strain, screening was performed in male flies supplemented either throughout adulthood or, in a few cases, beginning in middle or late adult life, with concentrations spanning 4-6 orders of magnitude in most cases. Supplementation with PP242 and deferiprone, an iron chelator, beginning in late adult life had no positive effect on life span. Lifelong supplementation with Ku-0063794, LY294002, PX-866-17OH, Torin2 and WYE-28 had no effect at any dose. Rapamycin, spermidine and wortmannin all had significant life-shortening effects at the highest doses tested. AZD8055, PI-103 hydrochloride and WYE-132 yielded slight beneficial effects at 1-2 doses, but only 100 nM AZD8055 was confirmed to have a minor (1.3%) effect in a replicate experiment, which was encompassed by other control groups within the same study. These compounds had no effect on fly fecundity (egg laying) or fertility (development of progeny to adulthood), but equivalent high doses of rapamycin abolished fertility. The solvent DMSO had no significant effect on life span at the concentrations used to solubilize most compounds in the fly medium, but it drastically curtailed both survival and fertility at higher concentrations. 2-Hydroxypropyl-β-cyclodextrin also failed to extend the life span when provided throughout adulthood or beginning in mid-adult life. Collectively, the results suggest that inhibition of the TOR/PI3K pathway and autophagy through dietary intervention is not a straightforward anti-aging strategy in Drosophila and that further extension of life is difficult in comparatively long-lived flies.
    Keywords:  Drosophila; TOR inhibition; aging; life span; rapamycin
    DOI:  https://doi.org/10.3390/ijms252111504
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