bims-polyam 2023-09-10 papers

bims-polyam

Biomed News

on Polyamines

Issue of 2023–09–10
seven papers selected by
Sebastian J. Hofer, University of Graz

Inhibition of Polyamine Catabolism Reduces Cellular Senescence.
Polyamine-metabolizing enzymes are activated to promote the proper assembly of rice stripe mosaic virus in insect vectors.
Synergistic antitumor efficacy of gemcitabine and cisplatin to induce ferroptosis in pancreatic ductal adenocarcinoma via Sp1-SAT1-polyamine metabolism pathway.
Hypusination-induced DHPS/eIF5A pathway as a new therapeutic strategy for human diseases: A mechanistic review and structural classification of DHPS inhibitors.
Polyamine-producing bacteria inhibit the absorption of Cd by spinach and alter the bacterial community composition of rhizosphere soil.
The contribution of polyamine pathway to determinations of diagnosis for treatment-resistant depression: A metabolomic analysis.
From Monoamine Oxidase Inhibition to Antiproliferative Activity: New Biological Perspectives for Polyamine Analogs.

Int J Mol Sci. 2023 Aug 29. pii: 13397. [Epub ahead of print]24(17):

Inhibition of Polyamine Catabolism Reduces Cellular Senescence.

Takeshi Uemura, Miki Matsunaga, Yuka Yokota, Koichi Takao, Takemitsu Furuchi.

  The aging of the global population has necessitated the identification of effective anti-aging technologies based on scientific evidence. Polyamines (putrescine, spermidine, and spermine) are essential for cell growth and function. Age-related reductions in polyamine levels have been shown to be associated with reduced cognitive and physical functions. We have previously found that the expression of spermine oxidase (SMOX) increases with age; however, the relationship between SMOX expression and cellular senescence remains unclear. Therefore, we investigated the relationship between increased SMOX expression and cellular senescence using human-liver-derived HepG2 cells. Intracellular spermine levels decreased and spermidine levels increased with the serial passaging of cells (aged cells), and aged cells showed increased expression of SMOX. The levels of acrolein-conjugated protein, which is produced during spermine degradation, also increases. Senescence-associated β-gal activity was increased in aged cells, and the increase was suppressed by MDL72527, an inhibitor of acetylpolyamine oxidase (AcPAO) and SMOX, both of which are enzymes that catalyze polyamine degradation. DNA damage accumulated in aged cells and MDL72527 reduced DNA damage. These results suggest that the SMOX-mediated degradation of spermine plays an important role in cellular senescence. Our results demonstrate that cellular senescence can be controlled by inhibiting spermine degradation using a polyamine-catabolizing enzyme inhibitor.

Keywords:  acrolein; aging; polyamine metabolism; senescence; spermine oxidase

DOI:  https://doi.org/10.3390/ijms241713397
Stress Biol. 2022 Apr 15. 2(1): 10

Polyamine-metabolizing enzymes are activated to promote the proper assembly of rice stripe mosaic virus in insect vectors.

Dongsheng Jia, Huan Liu, Jian Zhang, Wenqiang Wan, Zongwen Wang, Xiaofeng Zhang, Qian Chen, Taiyun Wei.

  Both viruses and host cells compete for intracellular polyamines for efficient propagation. Currently, how the key polyamine-metabolizing enzymes, including ornithine decarboxylase 1 (ODC1) and its antizyme 1 (OAZ1), are activated to co-ordinate viral propagation and polyamine biosynthesis remains unknown. Here, we report that the matrix protein of rice stripe mosaic virus (RSMV), a cytorhabdovirus, directly hijacks OAZ1 to ensure the proper assembly of rigid bacilliform non-enveloped virions in leafhopper vector. Viral matrix protein effectively competes with ODC1 to bind to OAZ1, and thus, the ability of OAZ1 to target and mediate the degradation of ODC1 is significantly inhibited during viral propagation, which finally promotes polyamines production. Thus, OAZ1 and ODC1 are activated to synergistically promote viral persistent propagation and polyamine biosynthesis in viruliferous vectors. Our data suggest that it is a novel mechanism for rhabdovirus to exploit OAZ1 for facilitating viral assembly.

Keywords:  Insect vector; OAZ1; ODC1; Polyamines; Rhabdovirus; Rice stripe mosaic virus; Viral assembly

DOI:  https://doi.org/10.1007/s44154-021-00032-z
Cell Oncol (Dordr). 2023 Sep 09.

Synergistic antitumor efficacy of gemcitabine and cisplatin to induce ferroptosis in pancreatic ductal adenocarcinoma via Sp1-SAT1-polyamine metabolism pathway.

Wanhui Wei, Yuanyuan Lu, Qian Hu, Jinwen Yin, Youwei Wang, Heng Zhang, Qiu Zhao, Lan Liu.

   PURPOSE: The combination of cisplatin and gemcitabine-based chemotherapy has been recommended as a preferred regimen for pancreatic ductal adenocarcinoma (PDAC) patients with germline-based mutations. However, the underlying mechanism remains poorly elucidated. Therefore, our study aimed to explore the mechanistic basis of the cell-killing activity of gemcitabine plus cisplatin and identify potential therapeutic targets.
METHODS: First, we explored the synergistic cytotoxic effects of gemcitabine and cisplatin on PDAC through in vitro and in vivo experiments. Then, we investigated ferroptosis-related biomarkers, to assess the impact of the combination therapy on ferroptosis. Using bioinformatics methods, we identified SAT1 as a potential key mediator of ferroptosis induced by gemcitabine and cisplatin. We tested the polyamine levels in PDAC cells by LC-MS after overexpressed or knocked down SAT1, and explored the role of polyamines in ferroptosis using exogenous supplementation. Finally, we explored the regulatory effect of Sp1 on SAT1 through ChIP-qPCR and dual-luciferase reporter assay.
RESULTS: Gemcitabine plus cisplatin enhanced cell death and induced ferroptosis in PDAC. This combination upregulated SAT1 transcription by inhibiting Sp1. SAT1 activation promoted the catabolism of spermine and spermidine, leading to iron accumulation and lipid peroxide generation, ultimately resulting in ferroptosis.
CONCLUSIONS: In summary, our findings suggested the gemcitabine and cisplatin combination therapy induced ferroptosis in a GSH-independent manner in PDAC. The combined treatment inhibited Sp1 and upregulated SAT1 transcription, leading to the breakdown of spermine and spermidine. Therefore, targeting SAT1-induced polyamine metabolism may represent a promising therapeutic strategy for PDAC.

Keywords:  Chemotherapy; Ferroptosis; PDAC; Polyamine; SAT1

DOI:  https://doi.org/10.1007/s13402-023-00870-1
Biomed Pharmacother. 2023 Sep 06. pii: S0753-3322(23)01238-6. [Epub ahead of print]167 115440

Hypusination-induced DHPS/eIF5A pathway as a new therapeutic strategy for human diseases: A mechanistic review and structural classification of DHPS inhibitors.

Jing-Si Guo, Kai-Li Liu, Yu-Xi Qin, Lin Hou, Ling-Yan Jian, Yue-Hui Yang, Xin-Yang Li.

  The discovery of new therapeutic strategies for diseases is essential for drug research. Deoxyhypusine synthase (DHPS) is a critical enzyme that modifies the conversion of the eukaryotic translation initiation factor 5A (eIF5A) precursor into physiologically active eIF5A (eIF5A-Hyp). Recent studies have revealed that the hypusine modifying of DHPS on eIF5A has an essential regulatory role in human diseases. The hypusination-induced DHPS/eIF5A pathway has been shown to play an essential role in various cancers, and it could regulate immune-related diseases, glucose metabolism-related diseases, neurological-related diseases, and aging. In addition, DHPS has a more defined substrate and a well-defined structure within the active pocket than eIF5A. More and more researchers are focusing on the prospect of advanced development of DHPS inhibitors. This review summarizes the regulatory mechanisms of the hypusination-induced DHPS/eIF5A pathway in a variety of diseases in addition to the inhibitors related to this pathway; it highlights and analyzes the structural features and mechanisms of action of DHPS inhibitors and expands the prospects of future drug development using DHPS as an anticancer target.

Keywords:  Allosteric inhibitors; Deoxyhypusine synthase; Hypusine

DOI:  https://doi.org/10.1016/j.biopha.2023.115440
Ecotoxicol Environ Saf. 2023 Sep 04. pii: S0147-6513(23)00946-6. [Epub ahead of print]264 115442

Polyamine-producing bacteria inhibit the absorption of Cd by spinach and alter the bacterial community composition of rhizosphere soil.

Yonghong He, Nannan Su, Qingzhao Zhao, Jiaer Meng, Zhaojin Chen, Hui Han.

  Polyamines (PAs) are small aliphatic nitrogenous bases with strong biological activity that participate in plant stress response signaling and the alleviation of damage from stress. Herein, the effects of the PA-producing bacterium Bacillus megaterium N3 and PAs on the immobilization of Cd and inhibition of Cd absorption by spinach and the underlying mechanisms were studied. A solution test showed that strain N3 secreted spermine and spermidine in the presence of Cd. Both strain N3 and the PAs (spermine+spermidine) immobilized Cd and increased the pH of the solution. Untargeted metabolomics results showed that strain N3 secreted PAs, N1-acetylspermidine, 3-indolepropionic acid, indole-3-acetaldehyde, cysteinyl-gamma-glutamate, and choline, which correlated with plant growth promotion and Cd immobilization. A pot experiment showed that rhizosphere soil inoculation with strain N3 and PAs improved spinach dry weight and reduced spinach Cd absorption compared with the control. These positive effects were likely due to the increase in rhizosphere soil pH and NH4+-N and PA contents, which can be attributed primarily to Cd immobilization. Moreover, inoculation with strain N3 more effectively inhibited the absorption of Cd by spinach than spraying PAs, mainly because strain N3 enabled a better relative abundance of bacteria (Microvirga, Pedobacter, Bacillus, Brevundimonas, Pseudomonas, Serratia, Devosid, and Aminobacter), that have been reported to have the ability to resist heavy metals and produce PAs. Strain N3 regulated the structure of rhizosphere functional bacterial communities and inhibited Cd uptake by spinach. These results provide a theoretical basis for the prevention of heavy metal absorption by vegetables using PA-producing bacteria.

Keywords:  Bacterial community; Cadmium; Immobilization; Polyamine-producing bacteria; Polyamines

DOI:  https://doi.org/10.1016/j.ecoenv.2023.115442
Prog Neuropsychopharmacol Biol Psychiatry. 2023 Sep 01. pii: S0278-5846(23)00135-5. [Epub ahead of print]128 110849

The contribution of polyamine pathway to determinations of diagnosis for treatment-resistant depression: A metabolomic analysis.

Zerui You, Chengyu Wang, Xiaofeng Lan, Weicheng Li, Dewei Shang, Fan Zhang, Yanxiang Ye, Haiyan Liu, Yanling Zhou, Yuping Ning.

   OBJECTIVES: Approximately one-third of major depressive disorder (MDD) patients do not respond to standard antidepressants and develop treatment-resistant depression (TRD). We aimed to reveal metabolic differences and discover promising potential biomarkers in TRD.
METHODS: Our study recruited 108 participants including healthy controls (n = 40) and patients with TRD (n = 35) and first-episode drug-naive MDD (DN-MDD) (n = 33). Plasma samples were presented to ultra performance liquid chromatography-tandem mass spectrometry. Then, a machine-learning algorithm was conducted to facilitate the selection of potential biomarkers.
RESULTS: TRD appeared to be a distinct metabolic disorder from DN-MDD and healthy controls (HCs). Compared to HCs, 199 and 176 differentially expressed metabolites were identified in TRD and DN-MDD, respectively. Of all the metabolites that were identified, spermine, spermidine, and carnosine were considered the most promising biomarkers for diagnosing TRD and DN-MDD patients, with the resulting area under the ROC curve of 0.99, 0.99, and 0.93, respectively. Metabolic pathway analysis yielded compelling evidence of marked changes or imbalances in both polyamine metabolism and energy metabolism, which could potentially represent the primary altered pathways associated with MDD. Additionally, L-glutamine, Beta-alanine, and spermine were correlated with HAMD score.
CONCLUSIONS: A more disordered metabolism structure is found in TRD than in DN-MDD and HCs. Future investigations should prioritize the comprehensive analysis of potential roles played by these differential metabolites and disturbances in polyamine pathways in the pathophysiology of TRD and depression.

Keywords:  Biomarker; Machine learning; Metabolomics; Treatment-resistant depression

DOI:  https://doi.org/10.1016/j.pnpbp.2023.110849
Molecules. 2023 Aug 29. pii: 6329. [Epub ahead of print]28(17):

From Monoamine Oxidase Inhibition to Antiproliferative Activity: New Biological Perspectives for Polyamine Analogs.

Giulia Nordio, Francesco Piazzola, Giorgio Cozza, Monica Rossetto, Manuela Cervelli, Anna Minarini, Filippo Basagni, Elisa Tassinari, Lisa Dalla Via, Andrea Milelli, Maria Luisa Di Paolo.

  Monoamine oxidases (MAOs) are well-known pharmacological targets in neurological and neurodegenerative diseases. However, recent studies have revealed a new role for MAOs in certain types of cancer such as glioblastoma and prostate cancer, in which they have been found overexpressed. This finding is opening new frontiers for MAO inhibitors as potential antiproliferative agents. In light of our previous studies demonstrating how a polyamine scaffold can act as MAO inhibitor, our aim was to search for novel analogs with greater inhibitory potency for human MAOs and possibly with antiproliferative activity. A small in-house library of polyamine analogs (2-7) was selected to investigate the effect of constrained linkers between the inner amine functions of a polyamine backbone on the inhibitory potency. Compounds 4 and 5, characterized by a dianiline (4) or dianilide (5) moiety, emerged as the most potent, reversible, and mainly competitive MAO inhibitors (Ki < 1 μM). Additionally, they exhibited a high antiproliferative activity in the LN-229 human glioblastoma cell line (GI50 < 1 μM). The scaffold of compound 5 could represent a potential starting point for future development of anticancer agents endowed with MAO inhibitory activity.

Keywords:  LN-229 cells; antiproliferative activity; docking studies; inhibitors; monoamine oxidases; polyamine analogs

DOI:  https://doi.org/10.3390/molecules28176329