bims-polyam 2025-03-09 papers

Issue of 2025–03–09
six papers selected by
Sebastian J. Hofer, University of Graz

Front Immunol. 2025 ;16 1529337

Polyamine metabolism and anti-tumor immunity.

Jing-Yi Wu, Yan Zeng, Yu-Yang You, Qi-Yue Chen.

Growing attention has been directed toward the critical role of polyamines in the tumor microenvironment and immune regulation. Polyamines, primarily comprising putrescine, spermidine, and spermine, are tightly regulated through coordinated biosynthesis, catabolism, and transport, with distinct metabolic patterns between normal and cancerous tissues. Emerging evidence highlights the pivotal role of polyamine metabolism in tumor initiation, progression, and metastasis. This review aims to elucidate the differences in polyamine biosynthesis, transport, and catabolism between normal and cancerous tissues, as well as the associated alterations in tumor epigenetic modifications and resistance to immune checkpoint blockade driven by polyamine metabolism. Polyamine metabolism influences both tumor cells and the tumor microenvironment by modulating immune cell phenotypes-shifting them towards either tumor suppression or immune evasion within the tumor immune microenvironment. Additionally, polyamine metabolism impacts immunotherapy through its regulation of key enzymes. This review also explores potential therapeutic targets and summarizes the roles of polyamine inhibitors in combination with immunotherapy for cancer treatment, offering a novel perspective on therapeutic strategies.

Keywords: metabolism; polyamine; polyamine combination therapeutic strategies; tumor microenvironment; tumorigenesis

DOI: https://doi.org/10.3389/fimmu.2025.1529337

Cardiorenal Med. 2025 Mar 04. 1-20

Association of Serum Polyamines with Cardiovascular Events and All-Cause Mortality in Chronic Kidney Disease.

Zijin Chen, Shaobo Wang, Li Liu, Liangyu Yin, Xinli Xu, Jiachuan Xiong, Jinghong Zhao.

BACKGROUND: Emerging evidence indicates that serum polyamines, including putrescine, spermidine, and spermine, may serve as potential biomarkers for chronic kidney disease (CKD) and its progression. However, the association between serum polyamine levels, cardiovascular events, and mortality in CKD patients remains poorly understood.
METHODS: A retrospective cohort study was conducted, involving 297 adult patients with CKD at stages 1-5 from March 2015 to September 2018, with follow-up until May 2023. Serum polyamine levels were quantified using high-performance liquid chromatography and subsequently categorized into quartiles. The Kaplan-Meier curve was employed to assess the survival probabilities of CV events and overall mortality in relation to serum polyamine levels. The relationship between serum polyamines and the risk of CVD and overall mortality was explored using univariate and multivariate Cox regression analyses. Furthermore, we conducted a competing-risk analysis to investigate the link between serum polyamines and CV events, with mortality as the competing event.
RESULTS: Over a median follow-up of 6.11 years, our findings revealed a negative correlation between putrescine levels and estimated glomerular filtration rate (eGFR), while spermidine and spermine levels were positively correlated with eGFR. The Kaplan-Meier curve demonstrated that serum polyamines were significantly associated with risk of CV events and all-cause mortality. Moreover, Cox regression analyses showed that, in multivariate Cox model, patients in the highest quartile of putrescine displayed a significantly higher risk of CV events (hazard ratio [HR] 6.972, 95% confidence interval [CI] 2.520-19.242, p＜0.001) compared to those in the lowest quartile. Conversely, higher levels of spermidine were associated with a lower risk of CV events (HR= 0.077, 95% CI 0.022-0.274, p＜0.001), and higher levels of spermine also appeared to reduce the risk of CV events (HR= 0.180, 95% CI 0.061-0.530, p=0.002). The relationship between serum polyamines and CVD remained robust in the competing risk models. Additionally, in the multivariate model, spermidine and spermine showed a significant protective effect on the risk of overall mortality; however, the protective effect was diminished upon the inclusion of eGFR as a covariate.
CONCLUSIONS: Our study demonstrates significant disruption in serum polyamine levels among CKD patients, which correlates with eGFR. Altered polyamine levels are linked to an increased risk of CV events and overall mortality. Thus, serum polyamines may be considered valuable prognostic indicators for CKD patients.

DOI: https://doi.org/10.1159/000545054

Atherosclerosis. 2025 Feb 27. pii: S0021-9150(25)00047-4. [Epub ahead of print]403 119150

Plasma polyamines levels and post-stroke depression in ischemic stroke patients: A multicenter prospective study.

Yu He, Xinyue Chang, Yi Liu, Jiawen Fei, Xiaoli Qin, Beiping Song, Quan Yu, Pinni Yang, Mengyao Shi, Daoxia Guo, Yanbo Peng, Jing Chen, Aili Wang, Tan Xu, Jiang He, Yonghong Zhang, Zhengbao Zhu.

BACKGROUND AND AIMS: Polyamines have been suggested to implicated in inflammation, ischemic stroke, and mental disorders, but the associations of polyamines with post-stroke depression (PSD) remain unclear. We aimed to prospectively investigate the associations of plasma putrescine, spermidine and spermine with PSD among ischemic stroke patients in a multicenter cohort study.
METHODS: We measured plasma putrescine, spermidine and spermine levels at baseline among 635 ischemic stroke patients from a preplanned ancillary study of the CATIS (China Antihypertensive Trial in Acute Ischemic Stroke). The study outcome was depression (Hamilton Depression Rating Scale score ≥8) at 3-month follow-up after ischemic stroke.
RESULTS: Plasma putrescine and spermidine were positively associated with the risk of PSD. The adjusted odds ratios of PSD for the highest versus lowest tertile of putrescine and spermidine were 1.77 (95 % CI, 1.13-2.78; ptrend = 0.014) and 1.77 (95 % CI, 1.11-2.82; ptrend = 0.013), respectively. Multivariable-adjusted spline regression analyses showed linear associations of plasma putrescine (p = 0.002 for linearity) and spermidine (p = 0.008 for linearity) with PSD. In addition, plasma putrescine (continuous net reclassification improvement [NRI]: 26.33 %, p = 0.002; integrated discrimination improvement [IDI]: 1.06 %, p = 0.009) and spermidine (continuous NRI: 20.72 %, p = 0.013; IDI: 1.04 %, p = 0.010) could significantly improve the risk reclassification of PSD beyond the established risk factors.
CONCLUSIONS: High plasma putrescine and spermidine levels were associated with increased risk of PSD among ischemic stroke patients. Our findings suggest that plasma polyamines should be implicated in the pathophysiologic processes of PSD and may be the potential intervention targets for PSD.

Keywords: Depression; Ischemic stroke; Polyamines; Prognosis; Risk factors

DOI: https://doi.org/10.1016/j.atherosclerosis.2025.119150

Ideggyogy Sz. 2025 Jan 30. 78(1-2): 19-25

A case-control study of spermidine in obstructive sleep apnea.

Gurbuz Edanur, Saruhan Ercan, Bek Semai, Kutlu Gulnihal.

Background and purpose: Obstructive sleep apnea (OSA) is a common sleep dis-order. Despite many studies, its etiology is not clearly known. Polyamines are ubiquitous positively charged amines found in all or-ga-nisms and one of the polyamines types is spermidine. In the literature, some articles demonstrate relationship between sleep dis-orders and polyamines. The common point of OSA and polyamines is oxidative stress. This study aimed to determine the serum levels of spermidine in patients with OSA and compare the results with healthy subjects.
Methods: This cross-sectional case-cont-rol study was designed with 69 subjects. Sub-jects were selected from people who were referred to polysomnography due to complaints of sleep disturbance and snoring. They were divided into two groups according to their Apnea Hypopnea Index (AHI) scores: control (n=29; AHI<5), and OSA (n=40; AHI≥5). Spermidine levels were determined in serum samples by using an enzyme-linked immunosorbent assay (ELISA) kit.
Results: After adjusting for age, body mass index (BMI), and gender, there was no significant difference in spermidine levels between OSA and controls (p=0.063, p=0.063, and p=0.818, respectively). There was no correlation between AHI and spermidine levels (rho=-0.063; p=0.698). The area under the Receiver Operating Characteristic (ROC) curve (AUC) was found to be 0.635 for spermidine.
Conclusion: These results demonstrated that decreased levels of spermidine in OSA patients was related to age, BMI, and gender. The relationship between OSA and the polyamines pathway should be the subject of future studies with more homogenous groups to understand the roles of polyamines in OSA pathogenesis.

Keywords: biomolecules; pathophysiology; polyamines; sleep disorders; spermidine

DOI: https://doi.org/10.18071/isz.78.0019

J Inherit Metab Dis. 2025 Mar;48(2): e70015

Spermidine Treatment Improves GRIN2B Loss-Of-Function, A Primary Disorder of Glutamatergic Neurotransmission.

A Santos-Gómez, N Juliá-Palacios, A Rejano-Bosch, R Marí-Vico, F Miguez-Cabello, M Masana, D Soto, M Olivella, À García-Cazorla, X Altafaj.

GRIN-related disorders (GRD) developmental and epileptic encephalopathies (DEEs) display a clinical spectrum including developmental delay, hypotonia, intellectual disability, epilepsy, and autistic traits. The presence of de novo pathogenic variants in the GRIN genes alters the N-methyl D-aspartate receptor (NMDAR) function, with a genotype-phenotype relationship. Despite recent advances to elucidate GRD pathophysiological mechanisms and to find treatments, to date, GRD therapeutic arms are still scarce and with limited efficacy. Herein, we investigated whether the natural polyamine spermine-positive allosteric modulators of GluN2B subunit-containing NMDARs-or its precursor spermidine might rescue NMDAR hypofunctionality. In heterologous cell systems, administration of spermine potentiated wild-type and loss-of-function (LoF) NMDAR-mediated currents and attenuated synaptic density deficits. Functionally, the putative therapeutic benefit of spermidine (spermine precursor) was assessed in constitutive Grin2b+/- heterozygous mice, a GRIN2B-LoF genetic murine model recapitulating GRD-like synaptic, motor, and cognitive alterations. Chronic spermidine administration in young adult Grin2b+/- mice partially rescued hippocampal long-term potentiation deficits in hippocampal slices of Grin2b+/- mice, supporting the cognitive improvement observed in behavioral phenotyping. Based on these preclinical findings, a case study was conducted in two pediatric patients harboring mild GRIN2B-LoF variants. Importantly, in line with preclinical findings, 18 months of spermidine treatment resulted in the amelioration of adaptive behavior (notably in the younger treated patient), with the absence of noticeable side effects. Overall, our findings provide both preclinical and clinical data supporting the benefit of spermidine for the treatment of GRD in individuals harboring GRIN2B-LoF variants.

Keywords: NMDA receptor; developmental encephalopathies; glutamatergic neurotransmission; metabolic treatment; precision medicine; spermidine

DOI: https://doi.org/10.1002/jimd.70015

J Med Chem. 2025 Mar 04.

Design, Synthesis, and Biological Activity of Novel Ornithine Decarboxylase (ODC) Inhibitors.

Chad R Schultz, Bilal Aleiwi, X Edward Zhou, Kelly Suino-Powell, Karsten Melcher, Nuno M S Almeida, Angela K Wilson, Edmund L Ellsworth, André S Bachmann.

We here describe the design, synthesis, and biological activity of novel ornithine decarboxylase (ODC) inhibitors that show significantly higher potency in vitro than α-difluoromethylornithine (DFMO), a U.S. Food and Drug Administration (FDA) approved drug. We report two X-ray structures of ODC complexed with new ODC inhibitors, computational docking, molecular dynamics, and binding free energy calculations to validate the experimental models. The X-ray structures reveal that covalent adducts with pyridoxal phosphate (PLP) are formed in the active site of the human ODC enzyme, as verified by their preparation and enzymatic testing. Finally, we verified that the cellular activity of endogenous ODC was inhibited, and polyamine levels were reduced. Given that ODC is a clinically validated target, combined with the fact that DFMO is currently the only ODC inhibitor in clinical use for several indications, the further development of more potent ODC inhibitors with superior activity and physical properties is warranted.

DOI: https://doi.org/10.1021/acs.jmedchem.4c03120