bims-polyam Biomed News
on Polyamines
Issue of 2024–03–03
seven papers selected by
Sebastian J. Hofer, University of Graz
  1. Preventing Cancer by Inhibiting Ornithine Decarboxylase: A Comparative Perspective on Synthetic vs. Natural Drugs.
  2. Dietary polyamines promote intestinal adaptation in an experimental model of short bowel syndrome.
  3. Polyamine Inhibitor SAM486A Augments Cytarabine Cytotoxicity in Methylthioadenosine Phosphorylase-deficient Leukemia Cells.
  4. New Insights into Identification, Distribution, and Health Benefits of Polyamines and Their Derivatives.
  5. PA YEAST SC-1, Polyamine-Rich Saccharomyces cerevisiae, Induces Muscle Hypertrophy in C2C12 Myotubes.
  6. Synergistic effect of spermidine and ciprofloxacin against Alzheimer's disease in male rat via ferroptosis modulation.
  7. Enzymatic-related network of catalysis, polyamine, and tumors for acetylpolyamine oxidase: from calculation to experiment.
  1. Chem Biodivers. 2024 Feb 25. e202302067
    Preventing Cancer by Inhibiting Ornithine Decarboxylase: A Comparative Perspective on Synthetic vs. Natural Drugs.
    Preeti Nanda Sahu, Anik Sen.
      This perspective explores synthetic and natural inhibitors, their inhibition patterns, and the efficacy of recently employed natural compounds as inhibitors for Ornithine decarboxylase enzyme which targets the MYC oncogene, and links polyamine metabolism to oncogenesis in normal and cancer cells. ODC activation and heightened polyamine activity are associated with tumor development in numerous cancers and fluctuations in ODC protein levels exert a profound influence on cellular activity for inhibition or suppressing tumor cells. This perspective outlines efforts to develop novel drugs, evaluate natural compounds, and identify promising inhibitors to address gaps in cancer prevention, highlighting the potential of newly designed synthetic moieties and natural flavonoids as alternatives. It also discusses natural compounds with potential as enhanced inhibitors.
    Keywords:  Comparison; Molecular Docking; Natural inhibitors; ODC enzyme; synthetic inhibitors
    DOI:  https://doi.org/10.1002/cbdv.202302067
  2. Sci Rep. 2024 02 26. 14(1): 4605
    Dietary polyamines promote intestinal adaptation in an experimental model of short bowel syndrome.
    Naoya Kasahara, Takumi Teratani, Shinichiro Yokota, Yasunaru Sakuma, Hideki Sasanuma, Yasuhiro Fujimoto, Tetsuo Ijichi, Taizen Urahashi, Hideyuki Yoshitomi, Joji Kitayama, Naohiro Sata.
      Intestinal adaptation does not necessarily recover absorptive capacity in short bowel syndrome (SBS), sometimes resulting in intestinal failure-associated liver disease (IFALD). Additionally, its therapeutic options remain limited. Polyamines (spermidine and spermine) are known as one of the autophagy inducers and play important roles in promoting the weaning process; however, their impact on intestinal adaptation is unknown. The aim of this study was to investigate the impact of polyamines ingestion on adaptation and hepatic lipid metabolism in SBS. We performed resection of two-thirds of the small intestine in male Lewis rats as an SBS model. They were allocated into three groups and fed different polyamine content diets (0%, 0.01%, 0.1%) for 30 days. Polyamines were confirmed to distribute to remnant intestine, whole blood, and liver. Villous height and number of Ki-67-positive cells in the crypt area increased with the high polyamine diet. Polyamines increased secretory IgA and mucin content in feces, and enhanced tissue Claudin-3 expression. In contrast, polyamines augmented albumin synthesis, mitochondrial DNA copy number, and ATP storage in the liver. Moreover, polyamines promoted autophagy flux and activated AMP-activated protein kinase with suppression of lipogenic gene expression. Polyamines ingestion may provide a new therapeutic option for SBS with IFALD.
    DOI:  https://doi.org/10.1038/s41598-024-55258-4
  3. Anticancer Res. 2024 Mar;44(3): 981-991
    Polyamine Inhibitor SAM486A Augments Cytarabine Cytotoxicity in Methylthioadenosine Phosphorylase-deficient Leukemia Cells.
    Rie Nishi, Kei Fujita, Yasufumi Matsuda, Naoyuki Kamatani, Takahiro Yamauchi.
       BACKGROUND/AIM: Methionine metabolism contributes to supplying sulfur-containing amino acids, controlling the methyl group transfer reaction, and producing polyamines in cancer cells. Polyamines play important roles in various cellular functions. Methylthioadenosine phosphorylase (MTAP), the key enzyme of the methionine salvage pathway, is reported to be deficient in 15-62% of cases of hematological malignancies. MTAP-deficient cancer cells accumulate polyamines, resulting in enhanced cell proliferation. The aim of this study was to investigate the combined effects of the polyamine synthesis inhibitor SAM486A and the anticancer antimetabolite cytarabine in MTAP-deficient leukemic cells in vitro.
    MATERIALS AND METHODS: The leukemia cell line U937 and the subline, U937/MTAP(-), in which MTAP was knocked down by shRNA, were used. The experiments were performed in media supplemented with 20% methionine (low methionine), which was the minimum concentration for maintaining cellular viability.
    RESULTS: The knockdown efficiency test confirmed a 70% suppression of the expression of the MTAP gene in U937/MTAP(-) cells. Even in the media with low methionine, the intracellular methionine concentration was not reduced in U937/MTAP(-) cells, suggesting that the minimum supply of methionine was sufficient to maintain intracellular levels of methionine. Both U937/MTAP(+) and U937/MTAP(-) cells were comparably sensitive to anticancer drugs (cytarabine, methotrexate, clofarabine and 6-thioguanine). The combination of SAM486A and cytarabine was demonstrated to have synergistic cytotoxicity in U937/MTAP(-) cells with regard to cell growth inhibition and apoptosis induction, but not in U937/MTAP(+) cells. Mechanistically, SAM486A altered the intracellular polyamine concentrations and reduced the antiapoptotic proteins.
    CONCLUSION: Methionine metabolism and polyamine synthesis can be attractive therapeutic targets in leukemia.
    Keywords:  Acute leukemia; MTAP; SAM486A; cytarabine (ara-C); methionine; methylthioadenosine phosphorylase; polyamines; sardomozide dihydrochloride
    DOI:  https://doi.org/10.21873/anticanres.16893
  4. J Agric Food Chem. 2024 Feb 28.
    New Insights into Identification, Distribution, and Health Benefits of Polyamines and Their Derivatives.
    Jiangtao Qiao, Wenwen Cai, Kai Wang, Eric Haubruge, Jie Dong, Hesham R El-Seedi, Xiang Xu, Hongcheng Zhang.
      Polyamines and their derivatives are ubiquitously present in free or conjugated forms in various foods from animal, plant, and microbial origins. The current knowledge of free polyamines in foods and their contents is readily available; furthermore, conjugated polyamines generate considerable recent research interest due to their potential health benefits. The structural diversity of conjugated polyamines results in challenging their qualitative and quantitative analysis in food. Herein, we review and summarize the knowledge published on polyamines and their derivatives in foods, including their identification, sources, quantities, and health benefits. Particularly, facing the inherent challenges of isomer identification in conjugated polyamines, this paper provides a comprehensive overview of conjugated polyamines' structural characteristics, including the cleavage patterns and characteristic ion fragments of MS/MS for isomer identification. Free polyamines are present in all types of food, while conjugated polyamines are limited to plant-derived foods. Spermidine is renowned for antiaging properties, acclaimed as antiaging vitamins. Conjugated polyamines highlight their anti-inflammatory properties and have emerged as the mainstream drugs for antiprostatitis. This paper will likely help us gain better insight into polyamines and their derivatives to further develop functional foods and personalized nutraceuticals.
    Keywords:  conjugated polyamines; functional properties; nutraceuticals; spermidine
    DOI:  https://doi.org/10.1021/acs.jafc.3c08556
  5. J Nutr Sci Vitaminol (Tokyo). 2024 ;70(1): 53-60
    PA YEAST SC-1, Polyamine-Rich Saccharomyces cerevisiae, Induces Muscle Hypertrophy in C2C12 Myotubes.
    Yasukiyo Yoshioka, Keigo Onishi, Kensuke Yasui, Noriyuki Miyoshi.
      Maintenance of appropriate muscle mass is necessary for good quality of life as skeletal muscles play critical roles in locomotion, metabolic homeostasis, and thermogenesis. Polyamines are essential metabolites that regulate several important cellular functions. In C57BL6 mice who underwent sciatic nerve transection of the hind limb, compensatory muscle hypertrophy is enhanced by the administration of polyamines. However, the action mechanisms of polyamines in muscle hypertrophy remain unclear. Here, we isolated PA YEAST SC-1, a polyamine-rich Saccharomyces cerevisiae, from Baker's yeast. We examined whether PA YEAST SC-1 induces muscle hypertrophy and elucidated the underlying action mechanisms of polyamines and the active ingredients in PA YEAST SC-1 using C2C12 myotubes. PA YEAST SC-1 at 1 mg/mL increased myosin heavy chain expression in C2C12 myotubes. Mechanistically, PA YEAST SC-1 induced the activation of Akt/mechanistic target of rapamycin kinase/p70S6K signaling. Furthermore, PA YEAST SC-1 decreased the expression levels of the ubiquitin ligases, atrogin-1 and muscle RING finger-1, via forkhead box O1 phosphorylation. These findings suggest PA YEAST SC-1 as an effective food ingredient for the treatment of muscle hypertrophy.
    Keywords:  C2C12 myotubes; PA YEAST SC-1; food ingredient; muscle hypertrophy; polyamine
    DOI:  https://doi.org/10.3177/jnsv.70.53
  6. Int J Biol Macromol. 2024 Feb 23. pii: S0141-8130(24)01190-5. [Epub ahead of print]263(Pt 2): 130387
    Synergistic effect of spermidine and ciprofloxacin against Alzheimer's disease in male rat via ferroptosis modulation.
    Menna Allah M Youssef, Tarek M Mohamed, Azza A Bakry, Mai M El-Keiy.
      Alzheimer's disease (AD) is a prevalent form of neurodegenerative disease with a complex pathophysiology that remains not fully understood, and the exact mechanism of neurodegeneration is uncertain. Ferroptosis has been linked to the progression of degenerative diseases observed in AD models. The present study is designed to investigate the protective effects of spermidine, a potent antioxidant and iron chelator, and its synergistic interactions with ciprofloxacin, another iron chelator, in modulating ferroptosis and mitigating AD progression in rats. This study investigated AD-related biomarkers like neurotoxic amyloid beta (Aβ), arginase I, and serotonin. Spermidine demonstrated an anti-ferroptotic effect in the AD model, evident from the modulation of ferroptosis parameters such as hippocampus iron levels, reduced protein expression of transferrin receptor 1 (TFR1), and arachidonate 15-lipoxygenase (ALOX15). Additionally, the administration of spermidine led to a significant increase in protein expression of phosphorylated nuclear factor erythroid 2-related factor 2 (p-Nrf2) and upregulation of Cystine/glutamate transporter (SLC7A11) gene expression. Moreover, spermidine notably decreased p53 protein levels, acrolein, and gene expression of spermidine/spermine N1-acetyltransferase 1 (SAT1). Overall, our findings suggest that spermidine and/or ciprofloxacin may offer potential benefits against AD by modulating ferroptosis. Furthermore, spermidine enhanced the antioxidant efficacy of ciprofloxacin and reduced its toxic effects.
    Keywords:  Alzheimer's disease; Antioxidant effects; Ferroptosis; Oxidative stress; Spermidine
    DOI:  https://doi.org/10.1016/j.ijbiomac.2024.130387
  7. Chem Sci. 2024 Feb 22. 15(8): 2867-2882
    Enzymatic-related network of catalysis, polyamine, and tumors for acetylpolyamine oxidase: from calculation to experiment.
    Dong Fang, Zhiyang Zhang, Jihang Zhai, Baolin Guo, Pengfei Li, Xiaoyuan Liu, Jinshuai Song, Songqiang Xie, Ruibo Wu, Yuan Zhao, Chaojie Wang.
      The regulation of enzymes and development of polyamine analogs capable of controlling the dynamics of endogenous polyamines to achieve anti-tumor effects is one of the biggest challenges in polyamine research. However, the root of the problem remains unsolved. This study represents a significant milestone as it unveils, for the first time, the comprehensive catalytic map of acetylpolyamine oxidase that includes chemical transformation and product release kinetics, by utilizing multiscale simulations with over six million dynamical snapshots. The transportation of acetylspermine is strongly exothermic, and high binding affinity of enzyme and reactant is observed. The transfer of hydride from polyamine to FAD is the rate-limiting step, via an H-shift coupled electron transfer mechanism. The two products are released in a detour stepwise mechanism, which also impacts the enzymatic efficiency. Inspired by these mechanistic insights into enzymatic catalysis, we propose a novel strategy that regulates the polyamine level and catalytic progress through the action of His64. Directly suppressing APAO by mutating His64 further inhibited growth and migration of tumor cells and tumor tissue in vitro and in vivo. Therefore, the network connecting microcosmic and macroscopic scales opens up new avenues for designing polyamine compounds and conducting anti-tumor research in the future.
    DOI:  https://doi.org/10.1039/d3sc06037c
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