bims-polyam Biomed News
on Polyamines
Issue of 2021–04–18
seven papers selected by
Sebastian J. Hofer, University of Graz
  1. Dietary spermidine improves cognitive function.
  2. eIF5A hypusination, boosted by dietary spermidine, protects from premature brain aging and mitochondrial dysfunction.
  3. Inverse regulation of Vibrio cholerae biofilm dispersal by polyamine signals.
  4. Spermidine at supraphysiological doses induces oxidative stress and granulosa cell apoptosis in mouse ovaries.
  5. Effect of thermospermine on expression profiling of different gene using massive analysis of cDNA ends (MACE) and vascular maintenance in Arabidopsis.
  6. Structure of the E. coli agmatinase, SPEB.
  7. Berberine, a potential prebiotic to indirectly promote Akkermansia growth through stimulating gut mucin secretion.
  1. Cell Rep. 2021 Apr 13. pii: S2211-1247(21)00299-0. [Epub ahead of print]35(2): 108985
    Dietary spermidine improves cognitive function.
    Sabrina Schroeder, Sebastian J Hofer, Andreas Zimmermann, Raimund Pechlaner, Christopher Dammbrueck, Tobias Pendl, G Mark Marcello, Viktoria Pogatschnigg, Martina Bergmann, Melanie Müller, Verena Gschiel, Selena Ristic, Jelena Tadic, Keiko Iwata, Gesa Richter, Aitak Farzi, Muammer Üçal, Ute Schäfer, Michael Poglitsch, Philipp Royer, Ronald Mekis, Marlene Agreiter, Regine C Tölle, Péter Sótonyi, Johann Willeit, Barbara Mairhofer, Helga Niederkofler, Irmgard Pallhuber, Gregorio Rungger, Herbert Tilg, Michaela Defrancesco, Josef Marksteiner, Frank Sinner, Christoph Magnes, Thomas R Pieber, Peter Holzer, Guido Kroemer, Didac Carmona-Gutierrez, Luca Scorrano, Jörn Dengjel, Tobias Madl, Simon Sedej, Stephan J Sigrist, Bence Rácz, Stefan Kiechl, Tobias Eisenberg, Frank Madeo.
      Decreased cognitive performance is a hallmark of brain aging, but the underlying mechanisms and potential therapeutic avenues remain poorly understood. Recent studies have revealed health-protective and lifespan-extending effects of dietary spermidine, a natural autophagy-promoting polyamine. Here, we show that dietary spermidine passes the blood-brain barrier in mice and increases hippocampal eIF5A hypusination and mitochondrial function. Spermidine feeding in aged mice affects behavior in homecage environment tasks, improves spatial learning, and increases hippocampal respiratory competence. In a Drosophila aging model, spermidine boosts mitochondrial respiratory capacity, an effect that requires the autophagy regulator Atg7 and the mitophagy mediators Parkin and Pink1. Neuron-specific Pink1 knockdown abolishes spermidine-induced improvement of olfactory associative learning. This suggests that the maintenance of mitochondrial and autophagic function is essential for enhanced cognition by spermidine feeding. Finally, we show large-scale prospective data linking higher dietary spermidine intake with a reduced risk for cognitive impairment in humans.
    Keywords:  Pink1; aging; autophagy; cognitive function; dietary spermidine; memory; mitochondria; mitophagy
    DOI:  https://doi.org/10.1016/j.celrep.2021.108985
  2. Cell Rep. 2021 Apr 13. pii: S2211-1247(21)00255-2. [Epub ahead of print]35(2): 108941
    eIF5A hypusination, boosted by dietary spermidine, protects from premature brain aging and mitochondrial dysfunction.
    YongTian Liang, Chengji Piao, Christine B Beuschel, David Toppe, Laxmikanth Kollipara, Boris Bogdanow, Marta Maglione, Janine Lützkendorf, Jason Chun Kit See, Sheng Huang, Tim O F Conrad, Ulrich Kintscher, Frank Madeo, Fan Liu, Albert Sickmann, Stephan J Sigrist.
      Mitochondrial function declines during brain aging and is suspected to play a key role in age-induced cognitive decline and neurodegeneration. Supplementing levels of spermidine, a body-endogenous metabolite, has been shown to promote mitochondrial respiration and delay aspects of brain aging. Spermidine serves as the amino-butyl group donor for the synthesis of hypusine (Nε-[4-amino-2-hydroxybutyl]-lysine) at a specific lysine residue of the eukaryotic translation initiation factor 5A (eIF5A). Here, we show that in the Drosophila brain, hypusinated eIF5A levels decline with age but can be boosted by dietary spermidine. Several genetic regimes of attenuating eIF5A hypusination all similarly affect brain mitochondrial respiration resembling age-typical mitochondrial decay and also provoke a premature aging of locomotion and memory formation in adult Drosophilae. eIF5A hypusination, conserved through all eukaryotes as an obviously critical effector of spermidine, might thus be an important diagnostic and therapeutic avenue in aspects of brain aging provoked by mitochondrial decline.
    Keywords:  CG8005; brain aging; deoxyhypusine synthase; eIF5A; eIF5A hypusination; learning and memory; locomotion; longevity; mitochondrial respiration; spermidine
    DOI:  https://doi.org/10.1016/j.celrep.2021.108941
  3. Elife. 2021 Apr 15. pii: e65487. [Epub ahead of print]10
    Inverse regulation of Vibrio cholerae biofilm dispersal by polyamine signals.
    Andrew A Bridges, Bonnie L Bassler.
      The global pathogen Vibrio cholerae undergoes cycles of biofilm formation and dispersal in the environment and the human host. Little is understood about biofilm dispersal. Here, we show that MbaA, a periplasmic polyamine sensor, and PotD1, a polyamine importer, regulate V. cholerae biofilm dispersal. Spermidine, a commonly produced polyamine, drives V. cholerae dispersal, whereas norspermidine, an uncommon polyamine produced by vibrios, inhibits dispersal. Spermidine and norspermidine differ by one methylene group. Both polyamines control dispersal via MbaA detection in the periplasm and subsequent signal relay. Our results suggest that dispersal fails in the absence of PotD1 because endogenously produced norspermidine is not reimported, periplasmic norspermidine accumulates, and it stimulates MbaA signaling. These results suggest that V. cholerae uses MbaA to monitor environmental polyamines, blends of which potentially provide information about numbers of 'self' and 'other'. This information is used to dictate whether or not to disperse from biofilms.
    Keywords:  infectious disease; microbiology
    DOI:  https://doi.org/10.7554/eLife.65487
  4. Theriogenology. 2021 Apr 03. pii: S0093-691X(21)00120-5. [Epub ahead of print]168 25-32
    Spermidine at supraphysiological doses induces oxidative stress and granulosa cell apoptosis in mouse ovaries.
    Dongmei Jiang, Yilong Jiang, Shiyun Long, Ziyu Chen, Yanling Li, Guilin Mo, Lin Bai, Xiaoxia Hao, Yanhong Yan, Liang Li, Chunchun Han, Shenqiang Hu, Hua Zhao, Bo Kang.
      Given that spermidine is associated with aging-related diseases and it is a potential target for delaying aging, functional studies on supraphysiological levels of spermidine are required. Our previous studies showed that the granulosa layer arranged irregular and the follicular oocytes were shrunk in female mice injected intraperitoneally with spermidine at 150 mg/kg (Body weight) after 24 h. It indicated that supraphysiological levels of spermidine induced ovarian damage in female mice. The objective of this study was to investigate the effect of acute administration of supraphysiological spermidine on the ovary and granulosa cells in mice. The results showed that treatment with spermidine at 150 mg/kg (intraperitoneal) significantly increased the levels of both H2O2 and malondialdehyde and reduced total antioxidant capacity and the activities of catalase and superoxide dismutase in mouse ovaries. The contents of putrescine and spermine increased significantly in the ovaries of mice treated with spermidine. Treatment with spermidine at 150 mg/kg increased the apoptotic rate and reactive oxygen species levels of granulosa cells in mouse ovaries. Furthermore, the protein expression of P53, CASPASE 8 (Cleaved/Pro), CASPASE 9 (Cleaved/Pro) and CASPASE 3 (Cleaved/Pro) in granulosa cells of mice treated with spermidine were significantly upregulated, while BCL2 expression was significantly downregulated. In summary, our study demonstrates for the first time that spermidine at supraphysiological doses causes ovarian oxidative stress and induces granulosa cell apoptosis via the P53 and/or BCL2-CASPASEs pathway.
    Keywords:  Apoptosis; Granulosa cell; Mouse; Ovary; Oxidative stress; Spermidine
    DOI:  https://doi.org/10.1016/j.theriogenology.2021.03.026
  5. Physiol Mol Biol Plants. 2021 Mar;27(3): 577-586
    Effect of thermospermine on expression profiling of different gene using massive analysis of cDNA ends (MACE) and vascular maintenance in Arabidopsis.
    G H M Sagor, Stefan Simm, Dong Wook Kim, Masaru Niitsu, Tomonobu Kusano, Thomas Berberich.
      Arabidopsis thaliana polyamine oxidase 5 gene (AtPAO5) functions as a thermospermine (T-Spm) oxidase. Aerial growth of its knock-out mutant (Atpao5-2) was significantly repressed by low dose(s) of T-Spm but not by other polyamines. To figure out the underlying mechanism, massive analysis of 3'-cDNA ends was performed. Low dose of T-Spm treatment modulates more than two fold expression 1,398 genes in WT compared to 3186 genes in Atpao5-2. Cell wall, lipid and secondary metabolisms were dramatically affected in low dose T-Spm-treated Atpao5-2, in comparison to other pathways such as TCA cycle-, amino acid- metabolisms and photosynthesis. The cell wall pectin metabolism, cell wall proteins and degradation process were highly modulated. Intriguingly Fe-deficiency responsive genes and drought stress-induced genes were also up-regulated, suggesting the importance of thermospermi'ne flux on regulation of gene network. Histological observation showed that the vascular system of the joint part between stem and leaves was structurally dissociated, indicating its involvement in vascular maintenance. Endogenous increase in T-Spm and reduction in H2O2 contents were found in mutant grown in T-Spm containing media. The results indicate that T-Spm homeostasis by a fine tuned balance of its synthesis and catabolism is important for maintaining gene regulation network and the vascular system in plants.
    Keywords:  Gene expression; MACE; Polyamine; Polyamine oxidase; Thermospermine
    DOI:  https://doi.org/10.1007/s12298-021-00967-7
  6. PLoS One. 2021 ;16(4): e0248991
    Structure of the E. coli agmatinase, SPEB.
    Iva Chitrakar, Syed Fardin Ahmed, Andrew T Torelli, Jarrod B French.
      Agmatine amidinohydrolase, or agmatinase, catalyzes the conversion of agmatine to putrescine and urea. This enzyme is found broadly across kingdoms of life and plays a critical role in polyamine biosynthesis and the regulation of agmatine concentrations. Here we describe the high-resolution X-ray crystal structure of the E. coli agmatinase, SPEB. The data showed a relatively high degree of pseudomerohedral twinning, was ultimately indexed in the P31 space group and led to a final model with eighteen chains, corresponding to three full hexamers in the asymmetric unit. There was a solvent content of 38.5% and refined R/Rfree values of 0.166/0.216. The protein has the conserved fold characteristic of the agmatine ureohydrolase family and displayed a high degree of structural similarity among individual protomers. Two distinct peaks of electron density were observed in the active site of most of the eighteen chains of SPEB. As the activity of this protein is known to be dependent upon manganese and the fold is similar to other dinuclear metallohydrolases, these peaks were modeled as manganese ions. The orientation of the conserved active site residues, in particular those amino acids that participate in binding the metal ions and a pair of acidic residues (D153 and E274 in SPEB) that play a role in catalysis, are similar to other agmatinase and arginase enzymes and is consistent with a hydrolytic mechanism that proceeds via a metal-activated hydroxide ion.
    DOI:  https://doi.org/10.1371/journal.pone.0248991
  7. Biomed Pharmacother. 2021 Apr 13. pii: S0753-3322(21)00380-2. [Epub ahead of print]139 111595
    Berberine, a potential prebiotic to indirectly promote Akkermansia growth through stimulating gut mucin secretion.
    Chaoran Dong, Jiaqi Yu, Yanan Yang, Fang Zhang, Wenquan Su, Qinhua Fan, Chongming Wu, Shengxian Wu.
       BACKGROUND: Akkermansia spp. plays important roles in maintenance of host health. Increasing evidence reveals that berberine (BBR) may exert its pharmacological effects via, at least partially, promotion of Akkermansia spp. However, how BBR stimulates Akkermansia remains largely unknown.
    PURPOSE: In this study, we investigated the mechanism underlying the Akkermansia-promoting effect of BBR.
    MATERIALS AND METHODS: The effect of BBR on Akkermansia was assessed in BBR-gavaged mice and direct incubation. The influence of BBR on intestinal mucin production was determined by alcian-blue staining and real-time PCR. The feces were analysis by gas chromatography-time-of-flight mass spectrometry (GC-TOF/MS) metabolomics. The role of polyamines in BBR-elicited mucin secretion and Akkermansia growth was evaluated by administration of difluoromethylornithine (DFMO) in mice.
    RESULTS: Gavage of BBR dose-dependently and time-dependently increased the abundance of Akkermansia in mice. However, it did not stimulate Akkermansia growth in direct incubation, suggesting that BBR may promote Akkermansia in a host-dependent way. Oral administration of BBR significantly increased the transcription of mucin-producing genes and mucin secretion in colon. Untargeted metabolomics analysis showed that BBR increased polyamines production in feces which are known to stimulate goblet cell proliferation and differentiation, but treatment with eukaryotic polyamine synthase inhibitor DFMO did not abolish the stimulating effect of BBR on mucin secretion and Akkermansia growth, indicating that the gut bacteria-derived but not the host-derived polyamines may involve in the BBR-promoted Akkermansia growth.
    CONCLUSIONS: Our results reveal that BBR is a promising prebiotic for Akkermansia, and it promotes Akkermansia growth via stimulating mucin secretion in colon.
    Keywords:  Akkermansia muciniphila; Berberine; Mucin secretion; Polyamine
    DOI:  https://doi.org/10.1016/j.biopha.2021.111595
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