bims-polyam Biomed News
on Polyamines
Issue of 2024–06–30
ten papers selected by
Sebastian J. Hofer, University of Graz
  1. Spermidine Synthase Localization in Retinal Layers: Early Age Changes.
  2. In vitro and in vivo studies on exogenous polyamines and α-difluoromethylornithine to enhance bone formation and suppress osteoclast differentiation.
  3. Spider and Wasp Acylpolyamines: Venom Components and Versatile Pharmacological Leads, Probes, and Insecticidal Agents.
  4. Hepatitis C Virus Dysregulates Polyamine and Proline Metabolism and Perturbs the Urea Cycle.
  5. Unveiling the hidden players: noncoding RNAs orchestrating polyamine metabolism in disease.
  6. Evolution of polyamine resistance in Staphylococcus aureus through modulation of potassium transport.
  7. A risk score based on polyamine metabolism and chemotherapy-related genes predicts prognosis and immune cells infiltration of lung adenocarcinoma.
  8. Mitigation of salinity stress in yarrow (Achillea millefolium L.) plants through spermidine application.
  9. Structural Insights into the Mechanisms Underlying Polyaminopathies.
  10. The Polyamine Analogue Ivospemin Increases Chemotherapeutic Efficacy in Murine Ovarian Cancer.
  1. Int J Mol Sci. 2024 Jun 12. pii: 6458. [Epub ahead of print]25(12):
    Spermidine Synthase Localization in Retinal Layers: Early Age Changes.
    Astrid Zayas-Santiago, Christian J Malpica-Nieves, David S Ríos, Amanda Díaz-García, Paola N Vázquez, José M Santiago, David E Rivera-Aponte, Rüdiger W Veh, Miguel Méndez-González, Misty Eaton, Serguei N Skatchkov.
      Polyamine (PA) spermidine (SPD) plays a crucial role in aging. Since SPD accumulates in glial cells, particularly in Müller retinal cells (MCs), the expression of the SPD-synthesizing enzyme spermidine synthase (SpdS) in Müller glia and age-dependent SpdS activity are not known. We used immunocytochemistry, Western blot (WB), and image analysis on rat retinae at postnatal days 3, 21, and 120. The anti-glutamine synthetase (GS) antibody was used to identify glial cells. In the neonatal retina (postnatal day 3 (P3)), SpdS was expressed in almost all progenitor cells in the neuroblast. However, by day 21 (P21), the SpdS label was pronouncedly expressed in multiple neurons, while GS labels were observed only in radial Müller glial cells. During early cell adulthood, at postnatal day 120 (P120), SpdS was observed solely in ganglion cells and a few other neurons. Western blot and semi-quantitative analyses of SpdS labeling showed a dramatic decrease in SpdS at P21 and P120 compared to P3. In conclusion, the redistribution of SpdS with aging indicates that SPD is first synthesized in all progenitor cells and then later in neurons, but not in glia. However, MCs take up and accumulate SPD, regardless of the age-associated decrease in SPD synthesis in neurons.
    Keywords:  glial cell compartments; glial cells; nervous system; neurons; polyamines; retina; spermidine; spermidine synthase
    DOI:  https://doi.org/10.3390/ijms25126458
  2. Amino Acids. 2024 Jun 27. 56(1): 43
    In vitro and in vivo studies on exogenous polyamines and α-difluoromethylornithine to enhance bone formation and suppress osteoclast differentiation.
    Chien-Ching Lee, Chia-Chun Chuang, Chung-Hwan Chen, Yuan-Pin Huang, Chiao-Yi Chang, Pei-Yi Tung, Mon-Juan Lee.
      Exogenous polyamines, including putrescine (PUT), spermidine (SPD), and spermine (SPM), and the irreversible inhibitor of the rate-limiting enzyme ornithine decarboxylase (ODC) of polyamine biosynthesis, α-difluoromethylornithine (DFMO), are implicated as stimulants for bone formation. We demonstrate in this study the osteogenic potential of exogenous polyamines and DFMO in human osteoblasts (hOBs), murine monocyte cell line RAW 264.7, and an ovariectomized rat model. The effect of polyamines and DFMO on hOBs and RAW 264.7 cells was studied by analyzing gene expression, alkaline phosphatase (ALP) activity, tartrate-resistant acid phosphatase (TRAP) activity, and matrix mineralization. Ovariectomized rats were treated with polyamines and DFMO and analyzed by micro computed tomography (micro CT). The mRNA level of the early onset genes of osteogenic differentiation, Runt-related transcription factor 2 (Runx2) and ALP, was significantly elevated in hOBs under osteogenic conditions, while both ALP activity and matrix mineralization were enhanced by exogenous polyamines and DFMO. Under osteoclastogenic conditions, the gene expression of both receptor activator of nuclear factor-κB (RANK) and nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1) was reduced, and TRAP activity was suppressed by exogenous polyamines and DFMO in RAW 264.7 cells. In an osteoporotic animal model of ovariectomized rats, SPM and DFMO were found to improve bone volume in rat femurs, while trabecular thickness was increased in all treatment groups. Results from this study provide in vitro and in vivo evidence indicating that polyamines and DFMO act as stimulants for bone formation, and their osteogenic effect may be associated with the suppression of osteoclastogenesis.
    Keywords:  Osteoclastogenic differentiation; Osteogenic differentiation; Osteoporosis; Ovariectomized rat; Polyamines; α-difluoromethylornithine (DFMO)
    DOI:  https://doi.org/10.1007/s00726-024-03403-8
  3. Toxins (Basel). 2024 May 21. pii: 234. [Epub ahead of print]16(6):
    Spider and Wasp Acylpolyamines: Venom Components and Versatile Pharmacological Leads, Probes, and Insecticidal Agents.
    Gandhi Rádis-Baptista, Katsuhiro Konno.
      Polyamines (PAs) are polycationic biogenic amines ubiquitously present in all life forms and are involved in molecular signaling and interaction, determining cell fate (e.g., cell proliferation, dif-ferentiation, and apoptosis). The intricate balance in the PAs' levels in the tissues will determine whether beneficial or detrimental effects will affect homeostasis. It's crucial to note that endoge-nous polyamines, like spermine and spermidine, play a pivotal role in our understanding of neu-rological disorders as they interact with membrane receptors and ion channels, modulating neuro-transmission. In spiders and wasps, monoamines (histamine, dopamine, serotonin, tryptamine) and polyamines (spermine, spermidine, acyl polyamines) comprise, with peptides and other sub-stances, the low molecular weight fraction of the venom. Acylpolyamines are venom components exclusively from spiders and a species of solitary wasp, which cause inhibition chiefly of iono-tropic glutamate receptors (AMPA, NMDA, and KA iGluRs) and nicotinic acetylcholine receptors (nAChRs). The first venom acylpolyamines ever discovered (argiopines, Joro and Nephila toxins, and philanthotoxins) have provided templates for the design and synthesis of numerous analogs. Thus far, analogs with high potency exert their effect at nanomolar concentrations, with high se-lectivity toward their ionotropic and ligand receptors. These potent and selective acylpolyamine analogs can serve biomedical purposes and pest control management. The structural modification of acylpolyamine with photolabile and fluorescent groups converted these venom toxins into use-ful molecular probes to discriminate iGluRs and nAchRs in cell populations. In various cases, the linear polyamines, like spermine and spermidine, constituting venom acyl polyamine backbones, have served as cargoes to deliver active molecules via a polyamine uptake system on diseased cells for targeted therapy. In this review, we examined examples of biogenic amines that play an essential role in neural homeostasis and cell signaling, contributing to human health and disease outcomes, which can be present in the venom of arachnids and hymenopterans. With an empha-sis on the spider and wasp venom acylpolyamines, we focused on the origin, structure, derivatiza-tion, and biomedical and biotechnological application of these pharmacologically attractive, chemically modular venom components.
    Keywords:  acylpolyamines; biogenic amines; bioinsecticide; ionotropic glutamate receptors; molecular probes; polyamine therapeutics; polyamine transport system; polyamines; spider venom; wasp venom
    DOI:  https://doi.org/10.3390/toxins16060234
  4. Cells. 2024 Jun 14. pii: 1036. [Epub ahead of print]13(12):
    Hepatitis C Virus Dysregulates Polyamine and Proline Metabolism and Perturbs the Urea Cycle.
    Natalia F Zakirova, Olga A Khomich, Olga A Smirnova, Jennifer Molle, Sarah Duponchel, Dmitry V Yanvarev, Vladimir T Valuev-Elliston, Lea Monnier, Boyan Grigorov, Olga N Ivanova, Inna L Karpenko, Mikhail V Golikov, Cedric Bovet, Barbara Rindlisbacher, Alex R Khomutov, Sergey N Kochetkov, Birke Bartosch, Alexander V Ivanov.
      Hepatitis C virus (HCV) is an oncogenic virus that causes chronic liver disease in more than 80% of patients. During the last decade, efficient direct-acting antivirals were introduced into clinical practice. However, clearance of the virus does not reduce the risk of end-stage liver diseases to the level observed in patients who have never been infected. So, investigation of HCV pathogenesis is still warranted. Virus-induced changes in cell metabolism contribute to the development of HCV-associated liver pathologies. Here, we studied the impact of the virus on the metabolism of polyamines and proline as well as on the urea cycle, which plays a crucial role in liver function. It was found that HCV strongly suppresses the expression of arginase, a key enzyme of the urea cycle, leading to the accumulation of arginine, and up-regulates proline oxidase with a concomitant decrease in proline concentrations. The addition of exogenous proline moderately suppressed viral replication. HCV up-regulated transcription but suppressed protein levels of polyamine-metabolizing enzymes. This resulted in a decrease in polyamine content in infected cells. Finally, compounds targeting polyamine metabolism demonstrated pronounced antiviral activity, pointing to spermine and spermidine as compounds affecting HCV replication. These data expand our understanding of HCV's imprint on cell metabolism.
    Keywords:  antiviral agents; hepatitis C virus; polyamines; proline metabolism; urea cycle
    DOI:  https://doi.org/10.3390/cells13121036
  5. Cell Biosci. 2024 Jun 25. 14(1): 84
    Unveiling the hidden players: noncoding RNAs orchestrating polyamine metabolism in disease.
    Marianna Nicoletta Rossi, Cristian Fiorucci, Paolo Mariottini, Manuela Cervelli.
      Polyamines (PA) are polycations with pleiotropic functions in cellular physiology and pathology. In particular, PA have been involved in the regulation of cell homeostasis and proliferation participating in the control of fundamental processes like DNA transcription, RNA translation, protein hypusination, autophagy and modulation of ion channels. Indeed, their dysregulation has been associated to inflammation, oxidative stress, neurodegeneration and cancer progression. Accordingly, PA intracellular levels, derived from the balance between uptake, biosynthesis, and catabolism, need to be tightly regulated. Among the mechanisms that fine-tune PA metabolic enzymes, emerging findings highlight the importance of noncoding RNAs (ncRNAs). Among the ncRNAs, microRNA, long noncoding RNA and circRNA are the most studied as regulators of gene expression and mRNA metabolism and their alteration have been frequently reported in pathological conditions, such as cancer progression and brain diseases. In this review, we will discuss the role of ncRNAs in the regulation of PA genes, with a particular emphasis on the changes of this modulation observed in health disorders.
    Keywords:  Gene expression; Noncoding RNA; Polyamine metabolism; Polyamines
    DOI:  https://doi.org/10.1186/s13578-024-01235-3
  6. bioRxiv. 2024 Jun 15. pii: 2024.06.15.599172. [Epub ahead of print]
    Evolution of polyamine resistance in Staphylococcus aureus through modulation of potassium transport.
    Killian Campbell, Caitlin H Kowalski, Kristin M Kohler, Matthew F Barber.
      Microbes must adapt to diverse biotic and abiotic factors encountered in host environments. Polyamines are an abundant class of aliphatic molecules that play essential roles in fundamental cellular processes across the tree of life. Surprisingly, the bacterial pathogen Staphylococcus aureus is highly sensitive to polyamines encountered during infection, and acquisition of a polyamine resistance locus has been implicated in spread of the prominent USA300 methicillin-resistant S. aureus lineage. At present, alternative pathways of polyamine resistance in staphylococci are largely unknown. Here we applied experimental evolution to identify novel mechanisms and consequences of S. aureus adaption when exposed to increasing concentrations of the polyamine spermine. Evolved populations of S. aureus exhibited striking evidence of parallel adaptation, accumulating independent mutations in the potassium transporter genes ktrA and ktrD . Mutations in either ktrA or ktrD are sufficient to confer polyamine resistance and function in an additive manner. Moreover, we find that ktr mutations provide increased resistance to multiple classes of unrelated cationic antibiotics, suggesting a common mechanism of resistance. Consistent with this hypothesis, ktr mutants exhibit alterations in cell surface charge indicative of reduced affinity and uptake of cationic molecules. Finally, we observe that laboratory-evolved ktr mutations are also present in diverse natural S. aureus isolates, suggesting these mutations may contribute to antimicrobial resistance during human infections. Collectively this study identifies a new role for potassium transport in S. aureus polyamine resistance with consequences for susceptibility to both host-derived and clinically-used antimicrobials.
    DOI:  https://doi.org/10.1101/2024.06.15.599172
  7. J Cell Mol Med. 2024 Jun;28(12): e18387
    A risk score based on polyamine metabolism and chemotherapy-related genes predicts prognosis and immune cells infiltration of lung adenocarcinoma.
    Minjun Du, Xiangzhi Meng, Boxuan Zhou, Weijian Song, Jianwei Shi, Mei Liang, Yicheng Liang, Yushun Gao.
      We aimed to explore whether the genes associated with both platinum-based therapy and polyamine metabolism could predict the prognosis of LUAD. We searched for the differential expression genes (DEGs) associated with platinum-based therapy, then we interacted them with polyamine metabolism-related genes to obtain hub genes. Subsequently, we analysed the main immune cell populations in LUAD using the scRNA-seq data, and evaluated the activity of polyamine metabolism of different cell subpopulations. The DEGs between high and low activity groups were screened to identify key DEGs to establish prognostic risk score model. We further elucidated the landscape of immune cells, mutation and drug sensitivity analysis in different risk groups. Finally, we got 10 hub genes associated with both platinum-based chemotherapy and polyamine metabolism, and found that these hub genes mainly affected signalling transduction pathways. B cells and mast cells with highest polyamine metabolism activity, while NK cells were found with lowest polyamine metabolism activity based on scRNA-seq data. DEGs between high and low polyamine metabolism activity groups were identified, then 6 key genes were screened out to build risk score, which showed a good predictive power. The risk score showed a universal negative correlation with immunotherapy checkpoint genes and the cytotoxic T cells infiltration. The mutation rates of EGFR in low-risk group was significantly higher than that of high-risk group. In conclusion, we developed a risk score based on key genes associated with platinum-based therapy and polyamine metabolism, which provide a new perspective for prognosis prediction of LUAD.
    Keywords:  immune infiltration; lung adenocarcinoma; platinum‐based chemotherapy; polyamine metabolism; prognosis
    DOI:  https://doi.org/10.1111/jcmm.18387
  8. PLoS One. 2024 ;19(6): e0304831
    Mitigation of salinity stress in yarrow (Achillea millefolium L.) plants through spermidine application.
    Sajedeh Alijani, Mohammad-Reza Raji, Zohreh Emami Bistgani, Abdollah Ehtesham Nia, Mostafa Farajpour.
      This study investigated the mitigating effects of spermidine on salinity-stressed yarrow plants (Achillea millefolium L.), an economically important medicinal crop. Plants were treated with four salinity levels (0, 30, 60, 90 mM NaCl) and three spermidine concentrations (0, 1.5, 3 μM). Salinity induced electrolyte leakage in a dose-dependent manner, increasing from 22% at 30 mM to 56% at 90 mM NaCl without spermidine. However, 1.5 μM spermidine significantly reduced leakage across salinities by 1.35-11.2% relative to untreated stressed plants. Photosynthetic pigments (chlorophyll a, b, carotenoids) also exhibited salinity- and spermidine-modulated responses. While salinity decreased chlorophyll a, both spermidine concentrations increased chlorophyll b and carotenoids under most saline conditions. Salinity and spermidine synergistically elevated osmoprotectants proline and total carbohydrates, with 3 μM spermidine augmenting proline and carbohydrates up to 14.4% and 13.1% at 90 mM NaCl, respectively. Antioxidant enzymes CAT, POD and APX displayed complex regulation influenced by treatment factors. Moreover, salinity stress and spermidine also influenced the expression of linalool and pinene synthetase genes, with the highest expression levels observed under 90 mM salt stress and the application of 3 μM spermidine. The findings provide valuable insights into the responses of yarrow plants to salinity stress and highlight the potential of spermidine in mitigating the adverse effects of salinity stress.
    DOI:  https://doi.org/10.1371/journal.pone.0304831
  9. Int J Mol Sci. 2024 Jun 07. pii: 6340. [Epub ahead of print]25(12):
    Structural Insights into the Mechanisms Underlying Polyaminopathies.
    Bing Wu, Sen Liu.
      Polyamines are ubiquitous in almost all biological entities and involved in various crucial physiological processes. They are also closely associated with the onset and progression of many diseases. Polyaminopathies are a group of rare genetic disorders caused by alterations in the function of proteins within the polyamine metabolism network. Although the identified polyaminopathies are all rare diseases at present, they are genetically heritable, rendering high risks not only to the carriers but also to their descendants. Meanwhile, more polyaminopathic patients might be discovered with the increasing accessibility of gene sequencing. This review aims to provide a comprehensive overview of the structural variations of mutated proteins in current polyaminopathies, in addition to their causative genes, types of mutations, clinical symptoms, and therapeutic approaches. We focus on analyzing how alterations in protein structure lead to protein dysfunction, thereby facilitating the onset of diseases. We hope this review will offer valuable insights and references for the future clinical diagnosis and precision treatment of polyaminopathies.
    Keywords:  Bachmann–Bupp syndrome; Faundes–Banka syndrome; Snyder–Robinson syndrome; deoxyhypusine hydroxylase disorder; deoxyhypusine synthase disorder; polyamine
    DOI:  https://doi.org/10.3390/ijms25126340
  10. Biomedicines. 2024 May 23. pii: 1157. [Epub ahead of print]12(6):
    The Polyamine Analogue Ivospemin Increases Chemotherapeutic Efficacy in Murine Ovarian Cancer.
    Cassandra E Holbert, Jackson R Foley, Robert A Casero, Tracy Murray Stewart.
      Polyamines are small polycationic alkylamines that are absolutely required for the continual growth and proliferation of cancer cells. The polyamine analogue ivospemin, also known as SBP-101, has shown efficacy in slowing pancreatic and ovarian tumor progression in vitro and in vivo and has demonstrated encouraging results in early pancreatic cancer clinical trials. We sought to determine if ivospemin was a viable treatment option for the under-served platinum-resistant ovarian cancer patient population by testing its efficacy in combination with commonly used chemotherapeutics. We treated four ovarian adenocarcinoma cell lines in vitro and found that each was sensitive to ivospemin regardless of cisplatin sensitivity. Next, we treated patients with ivospemin in combination with four commonly used chemotherapeutics and found that ivospemin increased the toxicity of each; however, only gemcitabine and topotecan combination treatments were more effective than ivospemin alone. Using the VDID8+ murine ovarian cancer model, we found that the addition of ivospemin to either topotecan or gemcitabine increased median survival over untreated animals alone, delayed tumor progression, and decreased the overall tumor burden. Our results indicate that the combination of ivospemin and chemotherapy is a worthwhile treatment option to further explore clinically in ovarian cancer.
    Keywords:  SBP-101; chemotherapy; ivospemin; ovarian cancer; platinum resistance; polyamine; polyamine analogue
    DOI:  https://doi.org/10.3390/biomedicines12061157
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