bims-polyam Biomed News
on Polyamines
Issue of 2024–10–20
eight papers selected by
Sebastian J. Hofer, University of Graz



  1. Nutr Res. 2024 Sep 19. pii: S0271-5317(24)00126-X. [Epub ahead of print]132 1-14
      This study represents the first investigation into the safety of a novel, high-purity spermidine trihydrochloride supplement (hpSPD) in humans. Spermidine, a natural compound found in various foods, has demonstrated potential health benefits in animal and epidemiological studies. However, evidence from clinical trials and safety evaluations of spermidine supplements is limited because pure spermidine for human administration has not been available. In this randomized, double-blind, within-subject and placebo-controlled trial, 37 healthy men (age 50-70 years; body mass index, 18.5-28 kg/m2) were administered either hpSPD or a placebo. We hypothesized that 7-day and 28-day dosing of 40 mg/day of hpSPD would have minimal effects on safety, although metabolic and polyamine homeostasis has not previously been examined at this dosage level. Consistent with our hypothesis, 40 mg/day hpSPD did not result in any significant changes in clinical, lipids, chemistry, or hematological parameters compared to placebo. Compliance was high, and no study product-related adverse events were reported. Substantial changes in serum and urine polyamine concentrations were not observed following hpSPD supplementation, suggesting effective homeostatic control of full-dose highly purified spermidine supplements with no evidence of adaptation of spermidine metabolism at 40 mg/day. These findings suggest that hpSPD at 40 mg/day for up to 28 days is safe and well-tolerated in healthy older men. The study is consistent with preclinical results and provides important evidence supporting the safety of high-purity spermidine supplementation, enabling further research with single-molecule spermidine to investigate its potential biology for improving human health. This trial was registered at clinicaltrials.gov (NCT05459961).
    Keywords:  Antiaging; Autophagy; Cardiovascular; Human dose; Longevity; Natural; Safety; Spermidine
    DOI:  https://doi.org/10.1016/j.nutres.2024.09.012
  2. Int J Mol Sci. 2024 Oct 01. pii: 10596. [Epub ahead of print]25(19):
      Polyamines modulate cellular proliferation and function. Their dysregulation results in inflammatory and oncological repercussions. This study aims to map the current literature and provide an overview of polyamines in dysbiotic oral conditions among older adults. English publications indexed in MEDLINE, Scopus, and Web of Science from January 2000 to May 2024 were screened. Eligibility criteria included clinical and laboratory studies using samples from adults aged 65 or above. This scoping review identified 2725 publications and included 19 publications. Ten studies detected that older adults with oral carcinoma had increased levels of polyamines such as spermidine in saliva and tumour-affected tissues. Eight studies reported older adults suffering from periodontal infection had increased levels of polyamines such as putrescine in saliva, gingival crevicular fluid, and biofilm from the gingival crevice. Two studies showed polyamine levels could reflect the success of periodontal therapy. Three studies found older adults with halitosis had increased levels of polyamines such as cadaverine in saliva and tongue biofilm. Polyamines were suggested as biomarkers for these oral conditions. In conclusion, certain polyamine levels are elevated in older adults with oral cancer, periodontal infections, and halitosis. Polyamines may be used as a simple and non-invasive tool to detect dysbiotic oral conditions and monitor treatment progress in older adults (Open Science Framework registration).
    Keywords:  biomarkers; elderly; halitosis; older adults; oral cancer; oral health; periodontal; polyamines; prevention
    DOI:  https://doi.org/10.3390/ijms251910596
  3. Clin Psychopharmacol Neurosci. 2024 Nov 30. 22(4): 624-634
       Objective: Major depressive disorder (MDD) is common in childhood, but its etiopathogenesis is still unclear. Published neurochemical studies mostly focus on monoaminergic system, however, the pathophysiology of MDD cannot be explained by monoamine hypothesis only, medications that have effect on monoamines cannot have effect needed in all patients. We aimed to investigate the poliamine pathway of L-arginine metabolism which is proceeding by way of agmatine in adolescents with MDD.
    Methods: Our study involved 45 patients with MDD (case group), and 44 healthy controls (control group) between the ages of 13-17. Sociodemographic data form, Schedule for Affective Disorders and Schizophrenia for School Age Children-Present and Lifetime Version-DSM-5-Turkish, Beck Depression Inventory (BDI), Spielberger's State-Trait Anxiety Inventory were applied to all subjects. All subjects were evaluated in terms of the levels of serum agmatine, putrescine, spermidine, and spermine.
    Results: The levels of agmatine and spermine were significantly higher and putrescine and spermidine were significantly lower in case group compared with healthy controls. There was significant negative correlation with the levels of putrescine and spermidine between BDI scores, and there was significant positive correlation between the levels of spermine and BDI scores. No correlation found between the levels of agmatine and BDI scores.
    Conclusion: These differences that the levels of agmatine and polyamines in the MDD group seem to be a field that worth researching. In the future, the evaluation of the arginine/polyamine metabolism in MDD with larger sample and longitudinal studies is going to capable to contribute to a better understanding of the disorder.
    Keywords:  Adolescent; Agmatine; Major depressive disorder; Putrescine; Spermidine; Spermine
    DOI:  https://doi.org/10.9758/cpn.24.1176
  4. Cell Commun Signal. 2024 Oct 15. 22(1): 499
       BACKGROUND: Spermidine (SPD) is an intermediate compound in the polyamine metabolism which takes critical part in a variety of cellular processes. In particular, it has been reported to exert anti-aging effects, suppress the age-related diseases, and extend lifespan across species. However, whether it has the favorable influence on the quality of postovulatory aged oocytes remains elusive.
    METHODS: Immunostaining and fluorescence intensity measurement were used to evaluate the effects of postovulatory aging and SPD supplementation on the oocyte fragmentation, spindle/chromosome structure, actin polymerization, dynamics of cortical granules (CGs) and ovastacin, mitochondrial distribution and function, as well as autophagy levels. In addition, in vitro sperm binding assay and in vitro fertilization (IVF) experiment were applied to assess the impacts of postovulatory aging and SPD supplementation on the sperm binding ability and fertilization capacity of oocytes.
    RESULTS: Here, we showed that supplementation of SPD during postovulatory aging could relieve the deterioration of porcine oocytes. Specifically, we found that postovulatory aging impaired the oocyte quality by damaging the morphological integrity of oocytes, maintenance of spindle/chromosome structure, and dynamics of actin cytoskeleton. Postovulatory aging also weakened the sperm binding ability and fertilization capacity of oocytes by compromising the distribution pattern of CGs and their content ovastacin. Notably, supplementation of SPD attenuated these defects in postovulatory aged porcine oocytes via strengthening mitochondrial function, eliminating excessive reactive oxygen species (ROS), inhibiting apoptosis, and enhancing autophagy levels.
    CONCLUSION: Altogether, our findings demonstrate that SPD supplementation is a feasible approach to ameliorate the quality of postovulatory aged oocytes, which can be potentially applied to the human assisted reproductive technology (ART) and in vitro production of animal embryos.
    Keywords:  Apoptosis; Autophagy; Oocyte quality; Postovulatory aging; ROS; Spermidine
    DOI:  https://doi.org/10.1186/s12964-024-01881-7
  5. Adv Exp Med Biol. 2024 ;1463 279-284
      Gap junctions are channels between adjacent cells, contributing to the unhindered exchange of metabolites, second messengers, nucleotides, and other molecules. The functional status of gap junctions in brain tumours is underinvestigated. One avenue of research focuses on exploring the expression of polyamines and their co-localisation with the Connexin 43 (Cx43) in the growth zones of glioblastoma multiforme (GBM). The aim of this work was to analyse the expression of Cx43 and spermine in human GBM to reveal their roles in neuro-oncogenesis. Human GBM sample sections were used for the immunochemistry [glial fibrillary acidic protein (GFAP), Cx43, and spermine], confocal laser scanning microscopy, and electron immunohistochemistry. Immunofluorescent analysis revealed that the more extensive processes of GBM cells exhibit GFAP. All GBM samples (n = 10) exhibited positive Cx43 signals in the form of variously sized dots and lines. Cx43 formed dotted lines around cell bodies with segmented transformed nuclei, which were also present in the gliovascular complexes. Furthermore, spermine was overexpressed in all tumour samples (cytoplasm and large and thin tumour processes), including the areas of Cx43 localisation. Merging the Cx43 and spermine signals showed co-expression in the same regions: the membranes of individual cells and individual points on processes in the tumour tissue. Therefore, we established the staining of the co-localisation of Cx43 and the polyamine spermine within glioblastoma, revealing that tumour processes housing the polyamine indeed form gap junctions, suggesting their potential joint interaction. This finding indicates that glioma cells can integrate into the surrounding neural networks, potentially serving as a mechanism to release glycolysis products, relying on gap junction activity facilitated by spermine. Cx43 exhibits sensitivity to polyamines, which play a role in opening gap junctional channels. Furthermore, polyamines have been observed to eliminate the blockades caused by hydrogen ions and calcium, which is crucial for cellular physiology.
    Keywords:  Confocal laser; Electron microscopy; Glial tumours; Polyamines; Proteins of astrocytic gap junctions
    DOI:  https://doi.org/10.1007/978-3-031-67458-7_46
  6. ACS Med Chem Lett. 2024 Oct 10. 15(10): 1715-1723
      Histone deacetylase 10 (HDAC10) is unique among the greater HDAC family due to its unusually narrow substrate specificity as a polyamine deacetylase, specifically as an N 8-acetylspermidine hydrolase. Polyamines are essential for cell growth and proliferation; consequently, inhibition of polyamine deacetylation represents a possible strategy for cancer chemotherapy. In this work, we have designed six acetylated phenylthioketone inhibitors of HDAC10 containing positively charged para- and meta-substituted amino groups designed to target interactions with E274, the gatekeeper that recognizes the positively charged ammonium group of the substrate N 8-acetylspermidine. We prepared each of these inhibitors through a short synthetic route of six steps. By adapting a low-cost colorimetric activity assay, we measured low-micromolar IC50 values for these compounds against a humanized construct of zebrafish HDAC10 (A24E-D94A HDAC10). Selected inhibitors were cocrystallized with A24E-D94A zebrafish HDAC10 and zebrafish HDAC6 to provide insight into class IIb isozyme affinity and selectivity.
    DOI:  https://doi.org/10.1021/acsmedchemlett.4c00293
  7. Front Immunol. 2024 ;15 1462777
       Introduction: Osteoarthritis (OA) is a prevalent chronic degenerative disease, marked by a complex interplay of mechanical stress, inflammation, and metabolic imbalances. Recent studies have highlighted the potential of spermidine (SPD), a naturally occurring polyamine known for its anti-inflammatory and antioxidant properties, as a promising therapeutic agent for OA. This study delves into the therapeutic efficacy and mechanistic pathways of SPD in mitigating OA symptoms.
    Methods: Forty Sprague-Dawley rats were randomly assigned to four groups, including the CG (sham operation), model (anterior cruciate ligament transection [ACLT], and treatment (ACLT + two different doses of SPD) groups. In vivo, correlations between OA severity and different interventions were assessed by ELISA, X-rays, CT imaging, histological staining, and immunohistochemistry. In vitro, IL-1β was used to trigger chondrocyte inflammation, and SPD's cytotoxicity was assessed in primary rat chondrocytes. Next, inflammatory markers, extracellular matrix (ECM) proteins, and pathway marker proteins were detected in chondrocytes administered IL-1β alone, SPD, or aryl hydrocarbon receptor (AhR) silencing, by qRT-PCR, Griess reaction, ELISA, Western blot, and immunofluorescence. Morphological alterations and pyroptosis in chondrocytes were examined by transmission electron microscopy (TEM) and flow cytometry.
    Results: Our research reveals that SPD exerts significant anti-inflammatory and antipyroptotic effects on IL-1β-treated chondrocytes and in anterior cruciate ligament transection (ACLT) rat models of OA, primarily through interaction with the Aryl hydrocarbon receptor (AhR). Specifically, SPD's binding to AhR plays a crucial role in modulating the inflammatory response and cellular pyroptosis by inhibiting both the AhR/NF-κB and NLRP3/caspase-1/GSDMD signaling pathways. Furthermore, the knockdown of AhR was found to negate the beneficial effects of SPD, underscoring the centrality of the AhR pathway in SPD's action mechanism. Additionally, SPD was observed to promote the preservation of cartilage integrity and suppress ECM degradation, further supporting its potential as an effective intervention for OA.
    Discussion: Collectively, our findings propose SPD as a novel therapeutic approach for OA treatment, targeting the AhR pathway to counteract the disease's progression and highlighting the need for further clinical evaluation to fully establish its therapeutic utility.
    Keywords:  aromatic hydrocarbon receptor; inflammation; osteoarthritis; pyroptosis; spermidine
    DOI:  https://doi.org/10.3389/fimmu.2024.1462777
  8. Pharmacol Rev. 2024 Oct 15. pii: PHARMREV-AR-2024-001271. [Epub ahead of print]
      Arginase catalyzes the hydrolysis of L-arginine into L-ornithine and urea. The two existing isoforms Arg1 and Arg2 show different cellular localizations and metabolic functions. Arginase activity is crucial for nitrogen detoxification in the urea cycle, synthesis of polyamines, and control of l-arginine bioavailability and nitric oxide production. Despite significant progress in the understanding of the biochemistry and function of arginases, several open questions remain. Recent studies have revealed that the regulation and function of Arg1 and Arg2 are cell-type-specific, species-specific, and profoundly different in mice and humans. The main differences were found in the distribution and function of Arg1 and Arg2 in immune and erythroid cells. Contrary to what was previously thought, Arg1 activity appears to be only partially related to vascular NO signaling under homeostatic conditions in the vascular wall, but its expression is increased under disease conditions and may be targeted by treatment with arginase inhibitors. Arg2 appears to be mainly a catabolic enzyme involved in the synthesis of L-ornithine, polyamine, and proline but may play a putative role in blood pressure control, at least in mice. The immunosuppressive role of arginase-mediated arginine depletion is a promising target for cancer treatment. This review critically revises and discusses the biochemistry, pharmacology, and in vivo function of arginase, focusing on the insights gained from the analysis of cell-specific Arg1 and Arg2 knockout mice and human studies using arginase inhibitors or pegylated recombinant arginase. Significance Statement The review emphasizes the need for further research to deepen our understanding of the regulation of Arg1 and Arg 2 in different cell types under consideration of their localization, species-specificity, and multiple biochemical and physiological roles. This could lead to better pharmacological strategies to target arginase activity in liver, cardiovascular, hematological, immune/infection diseases and cancer.
    Keywords:  L-arginine; animal models; cancer; cardiovascular disease; immunopharmacology; liver disease; nitric oxide synthase
    DOI:  https://doi.org/10.1124/pharmrev.124.001271