bims-polyam 2025-01-19 papers

Issue of 2025–01–19
four papers selected by
Sebastian J. Hofer, University of Graz

Nutrients. 2025 Jan 04. pii: 186. [Epub ahead of print]17(1):

The Associations of Dietary Polyamines with Incident Type 2 Diabetes Mellitus: A Large Prospective Cohort Study.

Xiaohong Zhang, Mingxia Qian, Min Liu, Mengyao He, Fu-Rong Li, Liqiang Zheng.

OBJECTIVES: This study aimed to analyze the associations between dietary polyamine intake and incident T2DM.
METHODS: This prospective analysis included 168,137 participants from the UK Biobank who did not have T2DM at baseline. Dietary polyamines were calculated based on portion sizes of food items and a nutrient database. Incident T2DM was defined by hospital admissions with ICD10 codes E11-E14. Cox proportional hazard regression models and restricted cubic splines were used to examine the associations between dietary polyamine intake and incident T2DM.
RESULTS: During a median follow-up of 11.2 years (IQR, 11.8-13.2), 4422 (2.6%) participants developed T2DM. The average (SD) daily dietary intake was 10.5 (11.8) mg/day for spermidine, 4.3 (2.1) mg/day for spermine, and 12.7 (6.9) mg/day for putrescine. Compared to quintile 1, the multivariable-adjusted hazard ratios (95% CI) for quintiles 2-5 of dietary spermidine were 0.87 (0.79 to 0.96), 0.87 (0.79 to 0.96), 0.91 (0.82 to 0.99), and 0.96 (0.88 to 1.06); for dietary spermine, they were 1.01 (0.91 to 1.11), 1.03 (0.93 to 1.13), 1.07 (0.97 to 1.18), and 1.11 (1.01 to 1.23); and for dietary putrescine, they were 0.84 (0.76 to 0.92), 0.83 (0.79 to 0.91), 0.82 (0.74 to 0.90), and 0.87 (0.80 to 0.96).
CONCLUSIONS: Higher dietary spermidine and putrescine were associated with a lower risk of T2DM, while higher dietary spermine appeared to be associated with a higher risk of T2DM. These findings suggest optimal levels of dietary polyamine intake and indicate that polyamines may be promising targets for nutritional interventions in the prevention and management of T2DM.

Keywords: T2DM; cox proportional hazards model; nonlinear association; polyamines; prospective cohort study; putrescine; spermidine; spermine

DOI: https://doi.org/10.3390/nu17010186

J Am Heart Assoc. 2025 Jan 16. eJAHA2024037465T

High Plasma Polyamine Levels Are Associated With an Increased Risk of Poststroke Cognitive Impairment: A Multicenter Prospective Study From CATIS.

Yu He, Yiming Jia, Yi Liu, Xinyue Chang, Pinni Yang, Mengyao Shi, Daoxia Guo, Yanbo Peng, Jing Chen, Aili Wang, Tan Xu, Jiang He, Yonghong Zhang, Zhengbao Zhu.

BACKGROUND: Polyamines have been suggested to play pivotal roles in ischemic stroke and neurodegenerative disorders, but the associations of plasma polyamines with poststroke cognitive impairment (PSCI) remain unclear. We aimed to prospectively investigate the associations of plasma putrescine, spermidine, and spermine with PSCI among patients with ischemic stroke in a multicenter cohort study.
METHODS AND RESULTS: We measured plasma polyamine levels at baseline among 619 patients with ischemic stroke from a preplanned ancillary study of CATIS (China Antihypertensive Trial in Acute Ischemic Stroke). We used the Mini-Mental State Examination and Montreal Cognitive Assessment to evaluate cognitive function at 3-month follow-up after ischemic stroke, and PSCI was defined as Mini-Mental State Examination score <27 or Montreal Cognitive Assessment score <25. According to the Mini-Mental State Examination score, plasma polyamines were positively associated with PSCI. The adjusted odds ratios of PSCI for the highest versus lowest quartile of putrescine, spermidine, and spermine were 1.81 (95% CI, 1.09-3.00), 1.81 (95% CI, 1.09-3.01), and 1.92 (95% CI, 1.15-3.20), respectively. In addition, plasma putrescine (net reclassification improvement, 32.08%; P<0.001; integrated discrimination improvement, 1.62%; P=0.002), spermidine (net reclassification improvement, 25.29%; P=0.002; integrated discrimination improvement, 1.22%; P=0.006), and spermine (net reclassification improvement, 16.54%; P=0.045; integrated discrimination improvement, 1.36%; P=0.004) could significantly improve the risk reclassification of PSCI beyond established risk factors. There were similar significant relationships when PSCI was defined by Montreal Cognitive Assessment score.
CONCLUSIONS: Higher plasma polyamine levels were associated with increased risk of PSCI among patients with ischemic stroke. Our findings suggest that plasma polyamines should be implicated in the pathophysiologic processes of PSCI and may be the potential intervention targets for PSCI.
REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01840072.

Keywords: cognitive impairment; ischemic stroke; polyamines; prognosis; risk factors

DOI: https://doi.org/10.1161/JAHA.124.037465

Bioorg Chem. 2025 Jan 07. pii: S0045-2068(25)00015-X. [Epub ahead of print]155 108135

Spermidine synthase promotes liver cancer progression in a paracrine manner by altering the macrophage immunometabolic state.

Sihang Yu, Yuanxin Zhao, Qingqing Liu, Jian Wang, Jiaying Fu, Runyuan Li, Yuan Yuan, Xiaoyu Yan, Jing Su.

PURPOSE: Understanding the molecular mechanisms of adaptive regulation in the tumor microenvironment is crucial for precision therapy in hepatocellular carcinoma (HCC). We hypothesized that cargo proteins carried by extracellular vesicles (EVs) released in a hypoxic microenvironment might promote HCC progression by remodeling tumor-associated macrophages (TAMs).
METHODS: EV protein analysis by label-free proteomics mass spectrometry of HCC cell lines of different tumor grades was performed. The promotional effect if spermidine synthase（SRM） on M2 polarized TAMs was further investigated using various biological approaches.
RESULTS: SRM expression was positively correlated with liver cancer progression in HCC cell lines, liver cancer samples, and nude mouse models. In a mouse model, SRM expression was positively correlated with TAM infiltration and liver cancer progression. Pan-cancer dataset analysis confirmed that SRM overexpression in HCC tumors is correlated with poor patient prognosis. However, a hypoxic microenvironment is an internal driving factor for exosomal SRM that participates in microenvironmental modifications. Moreover, we defined a hitherto unknown pattern of microenvironmental crosstalk involving SRM in EVs, whereby macrophages complete the phenotypic fate of M2 tumor-associated macrophages through SRM uptake.
CONCLUSION: SRM regulation within the immune microenvironment is metabolically driven. By upregulating spermidine, which serves as a substrate for eIF5A hypusination, excessive oxidative phosphorylation (OXPHOS) assembly is achieved. This, in turn, leads to the expression of immunosuppressive marker molecules and ultimately promotes liver cancer progression. SRM, which is enriched in the EVs of HCC cells under hypoxic conditions, acts as a potent regulator linking polyamine and energy metabolism in TAMs, thereby promoting liver cancer progression.

Keywords: Biomarker; Exosome; Hepatocellular carcinoma; Hypusine; Macrophage; OXPHOS; Spermidine synthase; eIF5A

DOI: https://doi.org/10.1016/j.bioorg.2025.108135

Structure. 2025 Jan 09. pii: S0969-2126(24)00546-X. [Epub ahead of print]

The structural biology of deoxyhypusination complexes.

Elżbieta Wątor-Wilk, Piotr Wilk, Przemysław Grudnik.

Deoxyhypusination is the first rate-limiting step of the unique post-translational modification-hypusination-that is catalyzed by deoxyhypusine synthase (DHS) and deoxyhypusine hydroxylase (DOHH). This modification is essential for the activation of translation factor 5A in eukaryotes (eIF5A) and Archaea (aIF5A). This perspective focuses on the structural biology of deoxyhypusination complexes in eukaryotic and archaeal organisms. Based on recently published crystal and cryogenic electron microscopy (cryo-EM) structures of deoxyhypusination complexes from three different organisms, we compare the structural features and stoichiometries of DHS-IF5A complexes across different species. We discuss conserved elements in the active site architecture and binding interfaces as well as significant differences in their stoichiometry and regulation mechanisms. The structural insights provide a comprehensive understanding of the deoxyhypusination process and highlight evolutionary adaptations across the domains of life. Future research should focus on the regulatory mechanisms governing DHS activity and the functional implications of stoichiometric variations in different organisms.

Keywords: PTM; aIF5A; deoxyhypusination; deoxyhypusine synthase; eIF5A; hypusination; hypusine; translation

DOI: https://doi.org/10.1016/j.str.2024.12.011