bims-polyam 2022-02-20 papers

bims-polyam

Biomed News

on Polyamines

Issue of 2022‒02‒20
twelve papers selected by
Sebastian J. Hofer
University of Graz

Development of Polyamine Lassos as Polyamine Transport Inhibitors.
PEDV infection affects the expression of polyamine-related genes inhibiting viral proliferation.
YAP/TAZ drives cell proliferation and tumour growth via a polyamine-eIF5A hypusination-LSD1 axis.
Polyamine Oxidase Triggers H2O2-Mediated Spermidine Improved Oxidative Stress Tolerance of Tomato Seedlings Subjected to Saline-Alkaline Stress.
Rebalance of the Polyamine Metabolism Suppresses Oxidative Stress and Delays Senescence in Nucleus Pulposus Cells.
The Potential Role of Spermine and Its Acetylated Derivative in Human Malignancies.
Physical Interaction between Embryonic Stem Cell-Expressed Ras (ERas) and Arginase-1 in Quiescent Hepatic Stellate Cells.
Cytoprotective Activity of Polyamines Is Associated with the Alternative Splicing of RAD51A Pre-mRNA in Normal Human CD4+ T Lymphocytes.
From Marine Metabolites to the Drugs of the Future: Squalamine, Trodusquemine, Their Steroid and Triterpene Analogues.
Role of eIF5A in Mitochondrial Function.
The effect of putrescine on the lysozyme activity and structure: Spectroscopic approaches and molecular dynamic simulation.
An mTOR siRNA-loaded Spermidine/DNA Tetrahedron Nanoplatform with a Synergistic Anti-Inflammatory Effect on Acute Lung Injury.

ACS Med Chem Lett. 2022 Feb 10. 13(2): 319-326

Development of Polyamine Lassos as Polyamine Transport Inhibitors.

Aiste Dobrovolskaite, Richard Andrew Gardner, Jean-Guy Delcros, Otto Phanstiel.

Nine- and twelve-membered triaza-macrocycles were appended to one end of homospermidine to make polyamine lassos. These compounds were shown to be potent polyamine transport inhibitors (PTIs) using pancreatic ductal adenocarcinoma L3.6pl cells, which have high polyamine transport activity. The smaller triazacyclononane-based lasso significantly reduced the uptake of a fluorescent polyamine probe and inhibited spermidine uptake and reduced intracellular polyamine levels in difluoromethylornithine (DFMO)-treated L3.6pl cells. Both designs were shown to be effective inhibitors of 3H-spermidine uptake, with the smaller lasso outperforming the larger lasso. When the smaller lasso was challenged to inhibit each of the three radiolabeled native polyamines, it had similar K i values as those of the known PTIs, Trimer44NMe and AMXT1501. Because of these promising properties, these materials may have future anticancer applications in polyamine blocking therapy, an approach that couples a polyamine biosynthesis inhibitor (DFMO) with a PTI to lower intracellular polyamines and suppress cell growth.

DOI: https://doi.org/10.1021/acsmedchemlett.1c00557
Virus Res. 2022 Feb 10. pii: S0168-1702(22)00036-3. [Epub ahead of print] 198708

PEDV infection affects the expression of polyamine-related genes inhibiting viral proliferation.

Hangao Xie, Qiangyun Ai, Tiezhu Tong, Ming Liao, Huiying Fan.

  Porcine epidemic diarrhea virus (PEDV) is an alpha-coronavirus that causes epidemic diarrhea in swines. The mortality of PEDV infection in one-week-old piglets is extremely high, which causes a huge significant economic loss to the global pig husbandry and blocks its healthy development. There was a lack of adequate studies to elucidate pathogenic mechanism associated with PEDV infection. In the present study, we detected the expression profiles of polyamine metabolism associated genes in Vero cells infected with PEDV by RT-qPCR. It is shown that PAOX(acetylpolyamine oxidase), SMOX(spermine oxidase), SAT1(spermidine-spermine acetyltransferase 1), ODC1(ornithine decarboxylase 1), DHPS(deoxyhypusine synthase) and EIF5A( eukaryotic initiation factor 5A) were significantly upregulated. Through intervening SAT1 level in PEDV-infected Vero cells, it is identified that overexpression of SAT1 inhibited PEDV replication by reducing polyamine levels. Furthermore, polyamine depletion and upregulation were found to regulate the proliferation of PEDV. PEDV infection in Vero cells did not result in a significant change in the protein level of eIF5A, and in addition, the activated eIF5A did not affect the proliferation of PEDV. Our results provided new insights into the influence of polyamine metabolism on the proliferation of PEDV.

Keywords:  Porcine epidemic diarrhea virus (PEDV); eukaryotic initiation factor 5A; polyamine; proliferation; spermidine-spermine acetyltransferase 1

DOI:  https://doi.org/10.1016/j.virusres.2022.198708
Nat Cell Biol. 2022 Feb 17.

YAP/TAZ drives cell proliferation and tumour growth via a polyamine-eIF5A hypusination-LSD1 axis.

Hongde Li, Bo-Kuan Wu, Mohammed Kanchwala, Jing Cai, Li Wang, Chao Xing, Yonggang Zheng, Duojia Pan.

Metabolic reprogramming is central to oncogene-induced tumorigenesis by providing the necessary building blocks and energy sources, but how oncogenic signalling controls metabolites that play regulatory roles in driving cell proliferation and tumour growth is less understood. Here we show that oncogene YAP/TAZ promotes polyamine biosynthesis by activating the transcription of the rate-limiting enzyme ornithine decarboxylase 1. The increased polyamine levels, in turn, promote the hypusination of eukaryotic translation factor 5A (eIF5A) to support efficient translation of histone demethylase LSD1, a transcriptional repressor that mediates a bulk of YAP/TAZ-downregulated genes including tumour suppressors in YAP/TAZ-activated cells. Accentuating the importance of the YAP/TAZ-polyamine-eIF5A hypusination-LSD1 axis, inhibiting polyamine biosynthesis or LSD1 suppressed YAP/TAZ-induced cell proliferation and tumour growth. Given the frequent upregulation of YAP/TAZ activity and polyamine levels in diverse cancers, our identification of YAP/TAZ as an upstream regulator and LSD1 as a downstream effector of the oncometabolite polyamine offers a molecular framework in which oncogene-induced metabolic and epigenetic reprogramming coordinately drives tumorigenesis, and suggests potential therapeutic strategies in YAP/TAZ- or polyamine-dependent human malignancies.

DOI: https://doi.org/10.1038/s41556-022-00848-5
Int J Mol Sci. 2022 Jan 30. pii: 1625. [Epub ahead of print]23(3):

Polyamine Oxidase Triggers H2O2-Mediated Spermidine Improved Oxidative Stress Tolerance of Tomato Seedlings Subjected to Saline-Alkaline Stress.

Jianyu Yang, Pengju Wang, Suzhi Li, Tao Liu, Xiaohui Hu.

  Saline-alkaline stress is one of several major abiotic stresses in crop production. Exogenous spermidine (Spd) can effectively increase tomato saline-alkaline stress resistance by relieving membrane lipid peroxidation damage. However, the mechanism through which exogenous Spd pre-treatment triggers the tomato antioxidant system to resist saline-alkaline stress remains unclear. Whether H2O2 and polyamine oxidase (PAO) are involved in Spd-induced tomato saline-alkaline stress tolerance needs to be determined. Here, we investigated the role of PAO and H2O2 in exogenous Spd-induced tolerance of tomato to saline-alkaline stress. Results showed that Spd application increased the expression and activities of superoxide dismutase (SOD), catalase (CAT), ascorbate peroxidase (APX), glutathione reductase (GR), and the ratio of reduced ascorbate (AsA) and glutathione (GSH) contents under saline-alkaline stress condition. Exogenous Spd treatment triggered endogenous H2O2 levels, SlPAO4 gene expression, as well as PAO activity under normal conditions. Inhibiting endogenous PAO activity by 1,8-diaminooctane (1,8-DO, an inhibitor of polyamine oxidase) significantly reduced H2O2 levels in the later stage. Moreover, inhibiting endogenous PAO or silencing the SlPAO4 gene increased the peroxidation damage of tomato leaves under saline-alkaline stress. These findings indicated that exogenous Spd treatment stimulated SlPAO4 gene expression and increased PAO activity, which mediated the elevation of H2O2 level under normal conditions. Consequently, the downstream antioxidant system was activated to eliminate excessive ROS accumulation and relieve membrane lipid peroxidation damage and growth inhibition under saline-alkaline stress. In conclusion, PAO triggered H2O2-mediated Spd-induced increase in the tolerance of tomato to saline-alkaline stress.

Keywords:  Solanum lycopersicum; hydrogen peroxide; polyamine oxidase; saline-alkaline stress; spermidine

DOI:  https://doi.org/10.3390/ijms23031625
Oxid Med Cell Longev. 2022 ;2022 8033353

Rebalance of the Polyamine Metabolism Suppresses Oxidative Stress and Delays Senescence in Nucleus Pulposus Cells.

Hui Che, Cheng Ma, He Li, Fenglei Yu, Yifan Wei, Hailong Chen, Jun Wu, Yongxin Ren.

Intervertebral disk degeneration (IDD) is a major cause of low back pain that becomes a prevalent age-related disease. However, the pathophysiological processes behind IDD are rarely known. Here, we used bioinformatics analysis based on the microarray datasets (GSE34095) to identify the differentially expressed genes (DEGs) as biomarkers and therapeutic targets in degenerated discs. From the previous studies, oxidative stress has been notified as a positive inducement of IDD, which causes DNA damage and accelerates cell senescence. Polyamine oxidase (PAOX), a member of the observed 1057 DEGs, is involved in polyamine metabolism and influences the oxidative balance in cells. However, it is uncertain if the IDD is implicated in the dysregulation of PAOX and polyamine metabolism. This study firstly verified the PAOX upregulation in human degenerated disc samples and applied an IL-1β-induced nucleus pulposus (NP) cell degeneration model to demonstrate that spermidine supplementation balanced polyamine metabolism and delayed NP cell senescence. Moreover, we confirmed that spermidine/N-acetylcysteine supplementation or Cdkn2a gene deletion stabilized the polyamine metabolism, suppressed oxidative stress, and therefore delayed the progress of IDD in older mice. Collectively, our study highlights the role of polyamine metabolism in IDD and foresees spermidine would be the advanced therapeutical drug for IDD.

DOI: https://doi.org/10.1155/2022/8033353
Int J Mol Sci. 2022 Jan 23. pii: 1258. [Epub ahead of print]23(3):

The Potential Role of Spermine and Its Acetylated Derivative in Human Malignancies.

Ryan Tsz-Hei Tse, Christine Yim-Ping Wong, Peter Ka-Fung Chiu, Chi-Fai Ng.

  Polyamines are essential biomolecules for normal cellular metabolism in humans. The roles of polyamines in cancer development have been widely discussed in recent years. Among all, spermine alongside with its acetylated derivative, N1, N12-Diacetylspermine, demonstrate a relationship with the diagnosis and staging of various cancers, including lung, breast, liver, colorectal and urogenital. Numerous studies have reported the level of spermine in different body fluids and organ tissues in patients with different types of cancers. Currently, the role and the underlying mechanisms of spermine in cancer development and progression are still under investigation. This review summarized the roles of spermine in cancer development and as a diagnostic, prognostic and therapeutic tool in various cancers.

Keywords:  cancer development; diacetylspermine; polyamines; spermine

DOI:  https://doi.org/10.3390/ijms23031258
Cells. 2022 Feb 01. pii: 508. [Epub ahead of print]11(3):

Physical Interaction between Embryonic Stem Cell-Expressed Ras (ERas) and Arginase-1 in Quiescent Hepatic Stellate Cells.

Silke Pudewell, Jana Lissy, Hossein Nakhaeizadeh, Mohamed S Taha, Mohammad Akbarzadeh, Soheila Rezaei Adariani, Saeideh Nakhaei-Rad, Junjie Li, Claus Kordes, Dieter Häussinger, Roland P Piekorz, Miriam M Cortese-Krott, Mohammad Reza Ahmadian.

  Embryonic stem cell-expressed Ras (ERas) is an atypical constitutively active member of the Ras family and controls distinct signaling pathways, which are critical, for instance, for the maintenance of quiescent hepatic stellate cells (HSCs). Unlike classical Ras paralogs, ERas has a unique N-terminal extension (Nex) with as yet unknown function. In this study, we employed affinity pull-down and quantitative liquid chromatography-tandem mass spectrometry (LC-MS/MS) analyses and identified 76 novel binding proteins for human and rat ERas Nex peptides, localized in different subcellular compartments and involved in various cellular processes. One of the identified Nex-binding proteins is the nonmitochondrial, cytosolic arginase 1 (ARG1), a key enzyme of the urea cycle and involved in the de novo synthesis of polyamines, such as spermidine and spermine. Here, we show, for the first time, a high-affinity interaction between ERas Nex and purified ARG1 as well as their subcellular colocalization. The inhibition of ARG1 activity strikingly accelerates the activation of HSCs ex vivo, suggesting a central role of ARG1 activity in the maintenance of HSC quiescence.

Keywords:  ARG1; ERas; L-arginine; L-ornithine; arginase 1; embryonic stem cell-expressed Ras; hepatic stellate cells; iNOS; polyamines; quiescence; spermidine; spermine; urea cycle

DOI:  https://doi.org/10.3390/cells11030508
Int J Mol Sci. 2022 Feb 07. pii: 1863. [Epub ahead of print]23(3):

Cytoprotective Activity of Polyamines Is Associated with the Alternative Splicing of RAD51A Pre-mRNA in Normal Human CD4+ T Lymphocytes.

Yulia A Gladilina, Lylia Bey, Abdullah Hilal, Ekaterina V Neborak, Varvara G Blinova, Dmitry D Zhdanov.

  Physiological polyamines are ubiquitous polycations with pleiotropic biochemical activities, including regulation of gene expression and cell proliferation as well as modulation of cell signaling. They can also decrease DNA damage and promote cell survival. In the present study, we demonstrated that polyamines have cytoprotective effects on normal human CD4+ T lymphocytes but not on cancer Jurkat or K562 cells. Pretreatment of lymphocytes with polyamines resulted in a significant reduction in cells with DNA damage induced by doxorubicin, cisplatin, or irinotecan, leading to an increase in cell survival and viability. The induction of RAD51A expression was in response to DNA damage in both cancer and normal cells. However, in normal cells, putrescin pretreatment resulted in alternative splicing of RAD51A and the switch of the predominant expression from the splice variant with the deletion of exon 4 to the full-length variant. Induction of RAD51A alternative splicing by splice-switching oligonucleotides resulted in a decrease in DNA damage and cell protection against cisplatin-induced apoptosis. The results of this study suggest that the cytoprotective activity of polyamines is associated with the alternative splicing of RAD51A pre-mRNA in normal human CD4+ T lymphocytes. The difference in the sensitivity of normal and cancer cells to polyamines may become the basis for the use of these compounds to protect normal lymphocytes during lymphoblastic chemotherapy.

Keywords:  DNA damage; alternative splicing; apoptosis; cytoprotection; polyamines

DOI:  https://doi.org/10.3390/ijms23031863
Int J Mol Sci. 2022 Jan 19. pii: 1075. [Epub ahead of print]23(3):

From Marine Metabolites to the Drugs of the Future: Squalamine, Trodusquemine, Their Steroid and Triterpene Analogues.

Oxana Kazakova, Gulnara Giniyatullina, Denis Babkov, Zdenek Wimmer.

  This review comprehensively describes the recent advances in the synthesis and pharmacological evaluation of steroid polyamines squalamine, trodusquemine, ceragenins, claramine, and their diverse analogs and derivatives, with a special focus on their complete synthesis from cholic acids, as well as an antibacterial and antiviral, neuroprotective, antiangiogenic, antitumor, antiobesity and weight-loss activity, antiatherogenic, regenerative, and anxiolytic properties. Trodusquemine is the most-studied small-molecule allosteric PTP1B inhibitor. The discovery of squalamine as the first representative of a previously unknown class of natural antibiotics of animal origin stimulated extensive research of terpenoids (especially triterpenoids) comprising polyamine fragments. During the last decade, this new class of biologically active semisynthetic natural product derivatives demonstrated the possibility to form supramolecular networks, which opens up many possibilities for the use of such structures for drug delivery systems in serum or other body fluids.

Keywords:  angiogenesis; antibiotic; ceragenine; claramine; diabetes; obesity; squalamine; triterpenoids; trodusquemine

DOI:  https://doi.org/10.3390/ijms23031075
Int J Mol Sci. 2022 Jan 24. pii: 1284. [Epub ahead of print]23(3):

Role of eIF5A in Mitochondrial Function.

Marina Barba-Aliaga, Paula Alepuz.

  The eukaryotic translation initiation factor 5A (eIF5A) is an evolutionarily conserved protein that binds ribosomes to facilitate the translation of peptide motifs with consecutive prolines or combinations of prolines with glycine and charged amino acids. It has also been linked to other molecular functions and cellular processes, such as nuclear mRNA export and mRNA decay, proliferation, differentiation, autophagy, and apoptosis. The growing interest in eIF5A relates to its association with the pathogenesis of several diseases, including cancer, viral infection, and diabetes. It has also been proposed as an anti-aging factor: its levels decay in aged cells, whereas increasing levels of active eIF5A result in the rejuvenation of the immune and vascular systems and improved brain cognition. Recent data have linked the role of eIF5A in some pathologies with its function in maintaining healthy mitochondria. The eukaryotic translation initiation factor 5A is upregulated under respiratory metabolism and its deficiency reduces oxygen consumption, ATP production, and the levels of several mitochondrial metabolic enzymes, as well as altering mitochondria dynamics. However, although all the accumulated data strongly link eIF5A to mitochondrial function, the precise molecular role and mechanisms involved are still unknown. In this review, we discuss the findings linking eIF5A and mitochondria, speculate about its role in regulating mitochondrial homeostasis, and highlight its potential as a target in diseases related to energy metabolism.

Keywords:  OXPHOS; TCA; eIF5A; mitochondria; mitochondrial respiration; spermidine; translation

DOI:  https://doi.org/10.3390/ijms23031284
Colloids Surf B Biointerfaces. 2022 Feb 08. pii: S0927-7765(22)00085-6. [Epub ahead of print]213 112402

The effect of putrescine on the lysozyme activity and structure: Spectroscopic approaches and molecular dynamic simulation.

Narges Ashrafi, Behzad Shareghi, Sadegh Farhadian, Mansoore Hosseini-Koupaei.

  The present research addressed the influence of polyamine (putrescine) on the compound as well as function of lysozyme; accordingly, UV- Visible, fluorescence spectroscopy and simulation method were applied to fulfill this goal. Lysozyme's structural variability was examined at various putrescine ‌concentrations; also, the putrescine binding to lysozyme was addressed using spectrofluorescence, circular dichroism (CD) and UV-Vis measurements. The obtained results indicated that with raising the putrescine concentration, the intrinsic quenching fluorescence of lysozyme was decreased based on the static mechanism. Analysis of thermodynamic parameters also indicated that van der Waals as well as hydrogen bond forces served a fundamental role in determining the resulting stability; this was in agreement with modeling studies. Measurement of UV absorption spectroscopy, fluorescence spectroscopy, and circular dichroism spectroscopy also demonstrated that lysozyme's second and tertiary structures were altered in a putrescine concentration-dependent manner. Putrescine inhibited lysozyme's enzymatic activity, displaying its affinity with the lysozyme's active site. Further, molecular simulation conducted revealed that putrescine could have spontaneous binding to lysozyme, changing its structure, thus further emphasizing the experimental results.

Keywords:  Circular dichroism; Enzymatic activity; Fluorescence spectroscopy; Lysozyme; UV-Vis

DOI:  https://doi.org/10.1016/j.colsurfb.2022.112402
Adv Healthc Mater. 2022 Feb 15. e2200008

An mTOR siRNA-loaded Spermidine/DNA Tetrahedron Nanoplatform with a Synergistic Anti-Inflammatory Effect on Acute Lung Injury.

Chaowang Huang, Qianyi You, Jing Xu, Di Wu, Huaping Chen, Yuhang Guo, Jiancheng Xu, Mingdong Hu, Hang Qian.

  Acute lung injury (ALI) is characterized by severe inflammation and damage to the lung air-blood barrier, resulting in respiratory function damage and life-threatening outcomes. Macrophage polarization plays an essential role in the occurrence, development, and outcome of ALI. As drug carriers, self-assembled DNA nanostructures can potentially overcome the drawbacks and limitations of traditional anti-inflammatory agents owing to their nontoxicity, programmability, and excellent structural control at the nanoscale. In this study, we proposed and constructed an siRNA and drug dual therapy nanoplatform to combat ALI. The nanoplatform consisted of a spermidine-assembled DNA tetrahedron and four mTOR siRNAs. Spermidine serves as a mediator of drug delivery vehicle synthesis and a drug that alters macrophage polarization. Both spermidine and siRNA exerted anti-inflammatory effects in vitro and in vivo by regulating the macrophage phenotype. More importantly, these factors exhibited a synergistic anti-inflammatory effect by promoting macrophage autophagy. For the first time, an anti-inflammatory dual therapy strategy that uses self-assembled DNA nanostructures as nontoxic, programmable delivery vehicles has been proposed and demonstrated through this work. Future work on utilizing DNA nanostructures for the treatment of noncancerous diseases such as ALI is highly promising and desirable. This article is protected by copyright. All rights reserved.

Keywords:  Acute lung injury; DNA nanostructure; mTOR siRNA; macrophage; spermidine

DOI:  https://doi.org/10.1002/adhm.202200008