bims-polyam Biomed News
on Polyamines
Issue of 2024–01–28
twelve papers selected by
Sebastian J. Hofer, University of Graz
  1. Polyamine Metabolism for Drug Intervention in Trypanosomatids.
  2. Functionalized Polyamine Synthesis with Photoredox Catalysis.
  3. Spermidine or spermine pretreatment regulates organic metabolites and ions homeostasis in favor of white clover seed germination against salt toxicity.
  4. Exogenous Spermidine and Amino-Ethoxyvinylglycine Improve Nutritional Quality via Increasing Amino Acids in Rice Grains.
  5. Hypusine Signaling Promotes Pulmonary Vascular Remodeling in Pulmonary Arterial Hypertension.
  6. Polyamine Signal through HCC Microenvironment: A Key Regulator of Mitochondrial Preservation and Turnover in TAMs.
  7. Molecular Insights into the Synergistic Effects of Putrescine and Ammonium on Dinoflagellates.
  8. Polyamines in Edible and Medicinal Fungi from Serbia: A Novel Perspective on Neuroprotective Properties.
  9. Reprogramming neuroblastoma by diet-enhanced polyamine depletion.
  10. Effect of spermidine on long non-coding RNAs MALAT1 in a rotenone induced-rat model of Parkinson's disease.
  11. Anti-inflammatory effect of pepper extract with high polyamine levels; inhibition of ERK/MAPK pathway in mice.
  12. Toxoplasma gondii eIF-5A Modulates the Immune Response of Murine Macrophages In Vitro.
  1. Pathogens. 2024 Jan 16. pii: 79. [Epub ahead of print]13(1):
    Polyamine Metabolism for Drug Intervention in Trypanosomatids.
    Yolanda Pérez-Pertejo, Carlos García-Estrada, María Martínez-Valladares, Sankaranarayanan Murugesan, Rosa M Reguera, Rafael Balaña-Fouce.
      Neglected tropical diseases transmitted by trypanosomatids include three major human scourges that globally affect the world's poorest people: African trypanosomiasis or sleeping sickness, American trypanosomiasis or Chagas disease and different types of leishmaniasis. Different metabolic pathways have been targeted to find antitrypanosomatid drugs, including polyamine metabolism. Since their discovery, the naturally occurring polyamines, putrescine, spermidine and spermine, have been considered important metabolites involved in cell growth. With a complex metabolism involving biosynthesis, catabolism and interconversion, the synthesis of putrescine and spermidine was targeted by thousands of compounds in an effort to produce cell growth blockade in tumor and infectious processes with limited success. However, the discovery of eflornithine (DFMO) as a curative drug against sleeping sickness encouraged researchers to develop new molecules against these diseases. Polyamine synthesis inhibitors have also provided insight into the peculiarities of this pathway between the host and the parasite, and also among different trypanosomatid species, thus allowing the search for new specific chemical entities aimed to treat these diseases and leading to the investigation of target-based scaffolds. The main molecular targets include the enzymes involved in polyamine biosynthesis (ornithine decarboxylase, S-adenosylmethionine decarboxylase and spermidine synthase), enzymes participating in their uptake from the environment, and the enzymes involved in the redox balance of the parasite. In this review, we summarize the research behind polyamine-based treatments, the current trends, and the main challenges in this field.
    Keywords:  Chagas disease; S-adenosylmethionine decarboxylase; eflornithine (DFMO); leishmaniasis; neglected tropical diseases; ornithine decarboxylase; polyamines; sleeping sickness; trypanosomatids; trypanothione
    DOI:  https://doi.org/10.3390/pathogens13010079
  2. Chemistry. 2024 Jan 24. e202304374
    Functionalized Polyamine Synthesis with Photoredox Catalysis.
    Yuta Makihara, Bumpei Maeda, Ryohei Akiyoshi, Daisuke Tanaka, Kei Murakami.
      Polyamines, such as putrescine and spermidine, are pivotal in various biological processes across living organisms. Despite their significance, structurally modified polyamines offer a less-explored avenue for discovering bioactive compounds. The limitation is attributed to the synthetic difficulty of accessing functionalized polyamines. In this study, we accomplished photoredox-catalyzed functionalization of polyamines to diversify their structure. The rapid functionalization allows attaching fluorophores to the target polyamine, facilitating the development of molecular probes for advancing chemical biology studies.
    Keywords:  photoredox catalyst polyamine alkylation
    DOI:  https://doi.org/10.1002/chem.202304374
  3. Plant Physiol Biochem. 2024 Jan 20. pii: S0981-9428(24)00047-0. [Epub ahead of print]207 108379
    Spermidine or spermine pretreatment regulates organic metabolites and ions homeostasis in favor of white clover seed germination against salt toxicity.
    Bizhen Cheng, Muhammad Jawad Hassan, Dandan Peng, Ting Huang, Yan Peng, Zhou Li.
      White clover is widely cultivated as a leguminous forage or ground cover plant worldwide. However, soil salinization decreases its yield and quality. Aims of the present experiment were to elucidate the impact of seed pretreatment with spermidine (Spd) or spermine (Spm) on amylolysis, Na+/K+ accumulation, and metabolic homeostasis during germination. Seed was soaked in distilled water (control), Spd or Spm solution and then germinated under optimal or salt stress conditions for 7 days. Results showed that germination vigor, germination percentage, or seed vigour index of seeds pretreatment with Spd increased by 7%, 11%, or 70% when compared with water-pretreated seeds under salt stress, respectively. Germination percentage or seed vigour index of seeds pretreatment with Spm increased by 17% or 78% than water-pretreated seeds under saline condition, respectively. In response to salt stress, accelerated amylolysis via activation of β-amylase activity was induced by Spd or Spm pretreatment. Spd or Spm pretreatment also significantly enhanced accumulation of diverse amino acids, organic acids, sugars, and other metabolites (putrescine, myo-inositol, sorbitol, daidzein etc.) associated with enhanced osmotic adjustment, antioxidant capacity, and energy supply during germination under salt stress. In addition, Spd or Spm pretreatment not only significantly reduced salt-induced K+ loss and overaccumulation of Na+, but also improved the ratio of K+ to Na+, contributing to Na+ and K+ balance in seedlings. In response to salt stress, seeds pretreatment with Spd or Spm up-regulated transcription level of NHX2 related to enhancement in compartmentation of Na+ from cytoplasm to vacuole, thus reducing Na+ toxicity in cytoplasm. Spm priming also uniquely up-regulated transcription levels of SKOR, HKT1, and HAL2 associated with K+ and Na + homeostasis and decline in cytotoxicity under salt stress.
    Keywords:  Gene expression; Ionic equilibrium; Metabolome; Organic metabolites; Salinity; Starch metabolism
    DOI:  https://doi.org/10.1016/j.plaphy.2024.108379
  4. Plants (Basel). 2024 Jan 20. pii: 316. [Epub ahead of print]13(2):
    Exogenous Spermidine and Amino-Ethoxyvinylglycine Improve Nutritional Quality via Increasing Amino Acids in Rice Grains.
    Ying Liu, Yi Jiang, Xiaohan Zhong, Chaoqing Li, Yunji Xu, Kuanyu Zhu, Weilu Wang, Junfei Gu, Hao Zhang, Zhiqin Wang, Lijun Liu, Jianhua Zhang, Weiyang Zhang, Jianchang Yang.
      Polyamines and ethylene are key regulators of the growth and development, quality formation, and stress response of cereal crops such as rice. However, it remains unclear whether the application of these regulators could improve the nutritional quality via increasing amino acids in rice grains. This study examined the role of exogenous polyamines and ethylene in regulating amino acid levels in the milled rice of earlier-flowered superior grain (SG) and later-flowered inferior grain (IG). Two rice varieties were field grown, and either 1 mmol L-1 spermidine (Spd) or 50 μmol L-1 amino-ethoxyvinylglycine (AVG) was applied to panicles at the early grain-filling stage. The control check (CK) was applied with deionized water. The results showed that the Spd or AVG applications significantly increased polyamine (spermine (Spm) and Spd) contents and decreased ethylene levels in both SG and IG and significantly increased amino acid levels in the milled rice of SG and IG relative to the CK. Collectively, the application of Spd or AVG can increase amino acid-based nutritional quality and grain yield via increasing polyamine (Spm and Spd) contents and reducing ethylene levels in both SG and IG of rice.
    Keywords:  amino acid; ethylene; inferior grains; polyamine; rice; superior grains
    DOI:  https://doi.org/10.3390/plants13020316
  5. Am J Respir Crit Care Med. 2024 Jan 23.
    Hypusine Signaling Promotes Pulmonary Vascular Remodeling in Pulmonary Arterial Hypertension.
    Sarah-Eve Lemay, Yann Grobs, Charlotte Romanet, Sandra Martineau, Mabrouka Salem, Tsukasa Shimauchi, Sandra Breuils-Bonnet, Alice Bourgeois, Charlie Théberge, Andréanne Pelletier, François Potus, Steeve Provencher, Sébastien Bonnet, Olivier Boucherat.
       RATIONALE: The ubiquitous polyamine spermidine is essential for cell survival and proliferation. One important function of spermidine is to serve as a substrate for hypusination, a post-translational modification process that occurs exclusively on eukaryotic translation factor 5A (eIF5A) and ensures efficient translation of various gene products. Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by progressive obliteration of the small pulmonary arteries (PAs) due to excessive proliferation of PA smooth muscle cells (PASMCs) and suppressed apoptosis.
    OBJECTIVES: To characterize the role of hypusine signaling in PAH.
    METHODS: Molecular, genetic, and pharmacological approaches were used both in vitro and in vivo to investigate the role of hypusine signaling in pulmonary vascular remodeling.
    MEASUREMENTS AND MAIN RESULTS: Hypusine forming enzymes (deoxyhypusine synthase, DHPS and deoxyhypusine hydroxylase, DOHH) and hypusinated eIF5A are overexpressed in distal PAs and isolated PASMCs from PAH patients and animal models. In vitro, inhibition of DHPS using GC7 or short hairpin RNA resulted in a decrease in PAH-PASMC resistance to apoptosis and proliferation. In vivo, inactivation of one allele of Dhps targeted to smooth muscle cells alleviates PAH in mice and that its pharmacological inhibition significantly decreases pulmonary vascular remodeling and improves hemodynamics and cardiac function in two rat models of established PAH. Using mass spectrometry, we show that hypusine signaling promotes the expression of a broad array of proteins involved in oxidative phosphorylation, thus supporting the bioenergetic requirements of cell survival and proliferation.
    CONCLUSIONS: These findings support inhibiting hypusine signaling as a potential treatment for PAH.
    Keywords:  DHPS; hypusine; right ventricular failure; smooth muscle cells; spermidine
    DOI:  https://doi.org/10.1164/rccm.202305-0909OC
  6. Int J Mol Sci. 2024 Jan 13. pii: 996. [Epub ahead of print]25(2):
    Polyamine Signal through HCC Microenvironment: A Key Regulator of Mitochondrial Preservation and Turnover in TAMs.
    Qingqing Liu, Xiaoyu Yan, Runyuan Li, Yuan Yuan, Jian Wang, Yuanxin Zhao, Jiaying Fu, Jing Su.
      Hepatocellular carcinoma (HCC) is the most common primary liver cancer, and, with increasing research on the tumor immune microenvironment (TIME), the immunosuppressive micro-environment of HCC hampers further application of immunotherapy, even though immunotherapy can provide survival benefits to patients with advanced liver cancer. Current studies suggest that polyamine metabolism is not only a key metabolic pathway for the formation of immunosuppressive phenotypes in tumor-associated macrophages (TAMs), but it is also profoundly involved in mitochondrial quality control signaling and the energy metabolism regulation process, so it is particularly important to further investigate the role of polyamine metabolism in the tumor microenvironment (TME). In this review, by summarizing the current research progress of key enzymes and substrates of the polyamine metabolic pathway in regulating TAMs and T cells, we propose that polyamine biosynthesis can intervene in the process of mitochondrial energy metabolism by affecting mitochondrial autophagy, which, in turn, regulates macrophage polarization and T cell differentiation. Polyamine metabolism may be a key target for the interactive dialog between HCC cells and immune cells such as TAMs, so interfering with polyamine metabolism may become an important entry point to break intercellular communication, providing new research space for developing polyamine metabolism-based therapy for HCC.
    Keywords:  EVs; TME; mitochondria; polyamine; spermidine
    DOI:  https://doi.org/10.3390/ijms25020996
  7. Int J Mol Sci. 2024 Jan 21. pii: 1306. [Epub ahead of print]25(2):
    Molecular Insights into the Synergistic Effects of Putrescine and Ammonium on Dinoflagellates.
    Yanfei Wang, Kathryn J Coyne.
      Ammonium and polyamines are essential nitrogen metabolites in all living organisms. Crosstalk between ammonium and polyamines through their metabolic pathways has been demonstrated in plants and animals, while no research has been directed to explore this relationship in algae or to investigate the underlying molecular mechanisms. Previous research demonstrated that high concentrations of ammonium and putrescine were among the active substances in bacteria-derived algicide targeting dinoflagellates, suggesting that the biochemical inter-connection and/or interaction of these nitrogen compounds play an essential role in controlling these ecologically important algal species. In this research, putrescine, ammonium, or a combination of putrescine and ammonium was added to cultures of three dinoflagellate species to explore their effects. The results demonstrated the dose-dependent and species-specific synergistic effects of putrescine and ammonium on these species. To further explore the molecular mechanisms behind the synergistic effects, transcriptome analysis was conducted on dinoflagellate Karlodinium veneficum treated with putrescine or ammonium vs. a combination of putrescine and ammonium. The results suggested that the synergistic effects of putrescine and ammonium disrupted polyamine homeostasis and reduced ammonium tolerance, which may have contributed to the cell death of K. veneficum. There was also transcriptomic evidence of damage to chloroplasts and impaired photosynthesis of K. veneficum. This research illustrates the molecular mechanisms underlying the synergistic effects of the major nitrogen metabolites, ammonium and putrescine, in dinoflagellates and provides direction for future studies on polyamine biology in algal species.
    Keywords:  algicide; amine; ammonium; dinoflagellate; harmful algae; nitrogen; polyamine; putrescine
    DOI:  https://doi.org/10.3390/ijms25021306
  8. J Fungi (Basel). 2023 Dec 28. pii: 21. [Epub ahead of print]10(1):
    Polyamines in Edible and Medicinal Fungi from Serbia: A Novel Perspective on Neuroprotective Properties.
    Milena Rašeta, Marko Kebert, Jovana Mišković, Milana Rakić, Saša Kostić, Eleonora Čapelja, Maja Karaman.
      The therapeutic effectiveness of current neurodegenerative disease treatments is still under debate because of problems with bioavailability and a range of side effects. Fungi, which are increasingly recognized as sources of natural antioxidants and acetylcholinesterase (AChE) enzyme inhibitors, may thus serve as potent neuroprotective agents. Previous studies have associated the anti-AChE and antioxidant activities of fungi mostly with polysaccharides and phenolic compounds, while other secondary metabolites such as polyamines (PAs) have been neglected. This study aimed to investigate eight edible and medicinal fungi from Serbia, marking the initial investigation into the neuroprotective capabilities of Postia caesia, Clitocybe odora, Clitopilus prunulus, and Morchella elata. Neuroprotective activity was examined using the Ellman assay, while the antioxidant capacity was tested by conducting DPPH, NO, ABTS, and FRAP tests. PA levels were determined by high-performance liquid chromatography (HPLC) coupled with fluorescent detection. Ganoderma applanatum and Lepista nuda exhibited the most robust anti-AChE (98.05 ± 0.83% and 99.94 ± 3.10%, respectively) and antioxidant activities, attributed to the synergistic effects of the total protein, total phenolic, and PA levels. Furthermore, P. caesia displayed significant AChE inhibition (88.21 ± 4.76%), primarily linked to the elevated spermidine (SPD) (62.98 ± 3.19 mg/kg d.w.) and putrescine (PUT) levels (55.87 ± 3.16 mg/kg d.w.). Our results highlight the need for thorough research to comprehend the intricate relationships between distinct fungus species and AChE inhibition. However, it is important to recognize that more research is required to identify the precise substances causing the reported inhibitory effects.
    Keywords:  G. applanatum; L. nuda; anti-acetylcholinesterase; antioxidant; phenolics; polyamines; synergism
    DOI:  https://doi.org/10.3390/jof10010021
  9. bioRxiv. 2024 Jan 08. pii: 2024.01.07.573662. [Epub ahead of print]
    Reprogramming neuroblastoma by diet-enhanced polyamine depletion.
    Sarah Cherkaoui, Lifeng Yang, Matthew McBride, Christina S Turn, Wenyun Lu, Caroline Eigenmann, George E Allen, Olesya O Panasenko, Lu Zhang, Annette Vu, Kangning Liu, Yimei Li, Om H Gandhi, Lea Surrey, Michael Wierer, Eileen White, Joshua D Rabinowitz, Michael D Hogarty, Raphael J Morscher.
      Neuroblastoma is a highly lethal childhood tumor derived from differentiation-arrested neural crest cells 1,2 . Like all cancers, its growth is fueled by metabolites obtained from either circulation or local biosynthesis 3,4 . Neuroblastomas depend on local polyamine biosynthesis, with the inhibitor difluoromethylornithine showing clinical activity 5 . Here we show that such inhibition can be augmented by dietary restriction of upstream amino acid substrates, leading to disruption of oncogenic protein translation, tumor differentiation, and profound survival gains in the TH- MYCN mouse model. Specifically, an arginine/proline-free diet decreases the polyamine precursor ornithine and augments tumor polyamine depletion by difluoromethylornithine. This polyamine depletion causes ribosome stalling, unexpectedly specifically at adenosine-ending codons. Such codons are selectively enriched in cell cycle genes and low in neuronal differentiation genes. Thus, impaired translation of these codons, induced by the diet-drug combination, favors a pro-differentiation proteome. These results suggest that the genes of specific cellular programs have evolved hallmark codon usage preferences that enable coherent translational rewiring in response to metabolic stresses, and that this process can be targeted to activate differentiation of pediatric cancers.
    Highlights: - Extra-tumoral conversion of arginine feeds tumor ornithine via uptake from circulation in MYCN-neuroblastoma.- A proline and arginine free diet enhances pharmacological polyamine depletion via reduced ornithine substrate availability.- Polyamine depletion disrupts oncogenic translation to induce a pro-differentiation proteome causing neuroblast differentiation and prolonged survival in the TH-MYCN mouse model.- Genes of specific cellular programs have evolved codon usage preferences that enable coherent translational rewiring in response to metabolic stress, such as polyamine depletion.
    DOI:  https://doi.org/10.1101/2024.01.07.573662
  10. Fundam Clin Pharmacol. 2024 Jan 26.
    Effect of spermidine on long non-coding RNAs MALAT1 in a rotenone induced-rat model of Parkinson's disease.
    Noha Mohamed Badae, Doaa A Abdelmonsif, Rania Gaber Aly, Amira M Omar, Mai S Shoela, Eman M Omar.
       BACKGROUND: Spermidine is a natural biologically active substance that has widespread influences on the body.
    OBJECTIVE: This study aims to enhance our understanding of the potential effect of spermidine on long non-coding RNA MALAT1 and explore the underlying mechanism in the rotenone-induced rat model of Parkinson's disease.
    METHODS: Rats were sacrificed after locomotor behavioral testing. Striatal tissues were used to assess the expression of MALAT1, oxidative stress markers, and autophagy markers.
    RESULTS: Our study found that treatment with spermidine for 2 weeks during the induction of the model significantly improved behavioral assessment, dopamine levels, and attenuated the histopathological changes that occurred in PD in comparison to the non-treated group.
    CONCLUSION: Our preliminary study supports the protective effect of spermidine on the activation of autophagy and its antioxidant properties. Part of the antioxidant activity is due to the inhibition of MALAT1. However, MALAT1 does not correlate with the spermidine-induced autophagy pathway.
    Keywords:  MALAT1; autophagy; oxidative stress; rotenone; spermidine
    DOI:  https://doi.org/10.1111/fcp.12986
  11. Food Sci Biotechnol. 2024 Feb;33(3): 677-687
    Anti-inflammatory effect of pepper extract with high polyamine levels; inhibition of ERK/MAPK pathway in mice.
    Sun Hyeon So, Jae Hoon Lee, Hee Woong Kim, Hae Ik Rhee, Deug Chan Lee.
      Polyamines have been reported to have cell proliferative and anti-inflammatory effects on normal metabolism in the body. This study aimed to investigate polyamine content of AIG01 pepper and the anti-inflammatory effect of AIG01 pepper extract (PAE) in mice. Polyamine content was analyzed by HPLC after acid hydrolysis of peppers with different acidic solvents. AIG01 pepper has the highest total polyamine content at about 1.5 mg/g. In LPS-stimulated RAW264.7, PAE inhibits nitric oxide production in a concentration-dependent manner and decreased the levels of pro-inflammatory cytokines. PAE has been shown to inhibit phosphorylation of MAPK/ERK. In TPA-stimulated Balb/C, PAE treatment showed tissue-level reductions in pro-inflammatory cytokines, reductions in ear thickness, and inhibition of neutrophil invasion. The polyamine content, polyamine extraction efficiency and anti-inflammatory effect of AIG01 obtained in this study suggest that it is useful as a raw material for the treatment of inflammatory diseases.
    Supplementary Information: The online version contains supplementary material available at 10.1007/s10068-023-01333-x.
    Keywords:  Acid hydrolysis extraction; Anti-inflammatory; Pepper; Polyamine; TPA-induced mouse model
    DOI:  https://doi.org/10.1007/s10068-023-01333-x
  12. Vaccines (Basel). 2024 Jan 19. pii: 101. [Epub ahead of print]12(1):
    Toxoplasma gondii eIF-5A Modulates the Immune Response of Murine Macrophages In Vitro.
    Xinchao Liu, Xiaoyu Li, Chunjing Li, Mingmin Lu, Lixin Xu, Ruofeng Yan, Xiaokai Song, Xiangrui Li.
      Toxoplasma gondii (T. gondii) is an obligate intracellular protozoan that can elicit a robust immune response during infection. Macrophage cells have been shown to play an important role in the immune response against T. gondii. In our previous study, the eukaryotic translation initiation factor 5A (eIF-5A) gene of T. gondii was found to influence the invasion and replication of tachyzoites. In this study, the recombinant protein of T. gondii eIF-5A (rTgeIF-5A) was incubated with murine macrophages, and the regulatory effect of TgeIF-5A on macrophages was characterized. Immunofluorescence assay showed that TgeIF-5A was able to bind to macrophages and partially be internalized. The Toll-like receptor 4 (TLR4) level and chemotaxis of macrophages stimulated with TgeIF-5A were reduced. However, the phagocytosis and apoptosis of macrophages were amplified by TgeIF-5A. Meanwhile, the cell viability experiment indicated that TgeIF-5A can promote the viability of macrophages, and in the secretion assays, TgeIF-5A can induce the secretion of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and nitric oxide (NO) from macrophages. These findings demonstrate that eIF-5A of T. gondii can modulate the immune response of murine macrophages in vitro, which may provide a reference for further research on developing T. gondii vaccines.
    Keywords:  Toxoplasma gondii; eukaryotic translation initiation factor 5A; immune response; in vitro; macrophages
    DOI:  https://doi.org/10.3390/vaccines12010101
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