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Polyamines in Aging and Disease

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: closed (30 July 2024) | Viewed by 28377

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Special Issue Editors

Dr. Takeshi Uemura

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Guest Editor

Department of Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, Josai University, Saitama 330-0295, Japan
Interests: polyamines; polyamine oxidase; ageing; spermine oxidase; brain stroke
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Yusuke Terui

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Guest Editor

Faculty of Pharmacy, Chiba Institute of Science, Chiba 288-0025, Japan
Interests: polyamine; cell proliferation; cell viability; Escherichia coli; spermine; eEF1A; biofilm; spermidine; Shine–Dalgarno sequence; oxidative stress; CR sequence; glutathione; SoxR; GshA; BMAL1; circadian rhythm; clock gene; bio-molecules; polyamine modulon; regulation of metabolic rhythm
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Polyamines are bioactive amines found in almost all living organisms and are essential for normal cellular functions. The number of polyamines in cells is tightly regulated by metabolism: biosynthesis, degradation, and transport. Recent studies have shown that disturbances in polyamine metabolism are associated with aging and disease. Age-related reductions in polyamines have been shown to lead to reduced cognitive and physical function. In cancer, on the other hand, high levels of polyamines have been suggested to lead to a worse prognosis. As the global population ages, there is a need for technologies to prevent and overcome aging and various diseases and to extend healthy life spans. The aim of this Special Issue is to deepen our knowledge of the relationship between polyamines and aging and disease. This Special Issue invites contributors to publish important work that will clarify the relationship between polyamines and aging and disease and extend the healthy life span by preventing and overcoming various diseases.

Dr. Takeshi Uemura
Prof. Dr. Yusuke Terui
Guest Editors

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Keywords

polyamines
bioactive amines
aging
senility
old people
spermine
spermidine
polyamine metabolism
polyamine oxidase
polyamine analogues
metabolic diseases in the elderly

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Published Papers (12 papers)

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Editorial

Jump to: Research, Review

3 pages, 151 KiB

Open AccessEditorial

Special Issue “Polyamines in Aging and Disease”

by Takeshi Uemura and Yusuke Terui

Int. J. Mol. Sci. 2024, 25(22), 11960; https://doi.org/10.3390/ijms252211960 - 7 Nov 2024

Viewed by 811

Abstract

Polyamines are bioactive amines found in almost all living organisms and are essential for normal cellular functions [...] Full article

(This article belongs to the Special Issue Polyamines in Aging and Disease)

Research

Jump to: Editorial, Review

14 pages, 2436 KiB

Open AccessArticle

Spermidine Synthase Localization in Retinal Layers: Early Age Changes

by Astrid Zayas-Santiago, Christian J. Malpica-Nieves, David S. Ríos, Amanda Díaz-García, Paola N. Vázquez, José M. Santiago, David E. Rivera-Aponte, Rüdiger W. Veh, Miguel Méndez-González, Misty Eaton and Serguei N. Skatchkov

Int. J. Mol. Sci. 2024, 25(12), 6458; https://doi.org/10.3390/ijms25126458 - 12 Jun 2024

Cited by 1 | Viewed by 1474

Abstract

Polyamine (PA) spermidine (SPD) plays a crucial role in aging. Since SPD accumulates in glial cells, particularly in Müller retinal cells (MCs), the expression of the SPD-synthesizing enzyme spermidine synthase (SpdS) in Müller glia and age-dependent SpdS activity are not known. We used immunocytochemistry, Western blot (WB), and image analysis on rat retinae at postnatal days 3, 21, and 120. The anti-glutamine synthetase (GS) antibody was used to identify glial cells. In the neonatal retina (postnatal day 3 (P3)), SpdS was expressed in almost all progenitor cells in the neuroblast. However, by day 21 (P21), the SpdS label was pronouncedly expressed in multiple neurons, while GS labels were observed only in radial Müller glial cells. During early cell adulthood, at postnatal day 120 (P120), SpdS was observed solely in ganglion cells and a few other neurons. Western blot and semi-quantitative analyses of SpdS labeling showed a dramatic decrease in SpdS at P21 and P120 compared to P3. In conclusion, the redistribution of SpdS with aging indicates that SPD is first synthesized in all progenitor cells and then later in neurons, but not in glia. However, MCs take up and accumulate SPD, regardless of the age-associated decrease in SPD synthesis in neurons. Full article

(This article belongs to the Special Issue Polyamines in Aging and Disease)

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17 pages, 10753 KiB

Open AccessArticle

In Silico and In Vitro Approach for Evaluation of the Anti-Inflammatory and Antioxidant Potential of Mygalin

by Abraham Espinoza-Culupú, Nayara Del Santos, Mariella Farfán-López, Elizabeth Mendes, Pedro Ismael da Silva Junior and Monamaris Marques Borges

Int. J. Mol. Sci. 2023, 24(23), 17019; https://doi.org/10.3390/ijms242317019 - 30 Nov 2023

Cited by 4 | Viewed by 2506

Abstract

There is a great interest in describing new molecules to be used as therapeutic targets in various diseases, particularly those that play a role in inflammatory responses and infection control. Mygalin is a synthetic analogue of spermidine, and previous studies have demonstrated its bactericidal effect against Escherichia coli, as well as its ability to modulate the inflammatory response of macrophages against lipopolysaccharide (LPS). However, the mechanisms through which mygalin regulates this inflammatory response remain poorly characterized. A set of platforms using molecular docking analysis was employed to analyze various properties of mygalin, including toxicity, biodistribution, absorption, and the prediction of its anti-inflammatory properties. In in vitro assays, we evaluated the potential of mygalin to interact with products of the inflammatory response, such as reactive oxygen species (ROS) and antioxidant activity, using the BMDM cell. The in silico analyses indicated that mygalin is not toxic, and can interact with proteins from the kinase group, and enzymes and receptors in eukaryotic cells. Molecular docking analysis showed interactions with key amino acid residues of COX-2, iNOS and 5-LOX enzymes. In vitro, assays demonstrated a significant reduction in the expression of iNOS and COX-2 induced by LPS, along with a decrease in the oxidative stress caused by the treatment with PMA, all without altering cell viability. Mygalin exhibited robust antioxidant activity in DPPH assays, regardless of the dose used, and inhibited heat-induced hemolysis. These studies suggest that mygalin holds promise for further investigation as a new molecule with anti-inflammatory and antioxidant properties. Full article

(This article belongs to the Special Issue Polyamines in Aging and Disease)

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9 pages, 2402 KiB

Open AccessArticle

Inhibition of Polyamine Catabolism Reduces Cellular Senescence

by Takeshi Uemura, Miki Matsunaga, Yuka Yokota, Koichi Takao and Takemitsu Furuchi

Int. J. Mol. Sci. 2023, 24(17), 13397; https://doi.org/10.3390/ijms241713397 - 29 Aug 2023

Cited by 6 | Viewed by 2676

Abstract

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. Full article

(This article belongs to the Special Issue Polyamines in Aging and Disease)

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11 pages, 1812 KiB

Open AccessArticle

Transient Receptor Potential Ankyrin 1 (TRPA1) Channel Mediates Acrolein Cytotoxicity in Human Lung Cancer Cells

by Akihiko Sakamoto, Yusuke Terui, Kazuei Igarashi and Keiko Kashiwagi

Int. J. Mol. Sci. 2023, 24(14), 11847; https://doi.org/10.3390/ijms241411847 - 24 Jul 2023

Cited by 6 | Viewed by 1955

Abstract

Transient receptor potential ankyrin 1 (TRPA1) is a nonselective ion channel implicated in thermosensation and inflammatory pain. It has been reported that expression of the TRPA1 channel is induced by cigarette smoke extract. Acrolein found in cigarette smoke is highly toxic and known as an agonist of the TRPA1 channel. However, the role of TRPA1 in the cytotoxicity of acrolein remains unclear. Here, we investigated whether the TRPA1 channel is involved in the cytotoxicity of acrolein in human lung cancer A549 cells. The IC₅₀ of acrolein in A549 cells was 25 μM, and acrolein toxicity increased in a concentration- and time-dependent manner. When the effect of acrolein on TRPA1 expression was examined, the expression of TRPA1 in A549 cells was increased by treatment with 50 μM acrolein for 24 h or 500 μM acrolein for 30 min. AP-1, a transcription factor, was activated in the cells treated with 50 μM acrolein for 24 h, while induction of NF-κB and HIF-1α was observed in the cells treated with 500 μM acrolein for 30 min. These results suggest that acrolein induces TRPA1 expression by activating these transcription factors. Overexpression of TRPA1 in A549 cells increased acrolein sensitivity and the level of protein-conjugated acrolein (PC-Acro), while knockdown of TRPA1 in A549 cells or treatment with a TRPA1 antagonist caused tolerance to acrolein. These findings suggest that acrolein induces the TRPA1 channel and that an increase in TRPA1 expression promotes the cytotoxicity of acrolein. Full article

(This article belongs to the Special Issue Polyamines in Aging and Disease)

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10 pages, 1715 KiB

Open AccessArticle

Levilactobacillus brevis with High Production of Putrescine Isolated from Blue Cheese and Its Application

by Yuta Ami, Narumi Kodama, Masahiro Umeda, Hanae Nakamura, Hideto Shirasawa, Takashi Koyanagi and Shin Kurihara

Int. J. Mol. Sci. 2023, 24(11), 9668; https://doi.org/10.3390/ijms24119668 - 2 Jun 2023

Cited by 4 | Viewed by 3141

Abstract

Polyamine intake has been reported to help extend the lifespan of animals. Fermented foods contain high concentrations of polyamines, produced by fermenting bacteria. Therefore, the bacteria, isolated from fermented foods that produce large amounts of polyamines, are potentially used as a source of polyamines for humans. In this study, the strain Levilactobacillus brevis FB215, which has the ability to accumulate approximately 200 µM of putrescine in the culture supernatant, was isolated from fermented foods, specifically the Blue Stilton cheese. Furthermore, L. brevis FB215 synthesized putrescine from agmatine and ornithine, which are known polyamine precursors. When cultured in the extract of Sakekasu, a byproduct obtained during the brewing of Japanese rice wine containing high levels of both agmatine and ornithine, L. brevis FB215 grew to OD₆₀₀ = 1.7 after 83 h of cultivation and accumulated high concentrations (~1 mM) of putrescine in the culture supernatant. The fermentation product also did not contain histamine or tyramine. The Sakekasu-derived ingredient fermented by the food-derived lactic acid bacteria developed in this study could contribute to increasing polyamine intake in humans. Full article

(This article belongs to the Special Issue Polyamines in Aging and Disease)

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Review

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12 pages, 1212 KiB

Open AccessReview

Polyamines in Dysbiotic Oral Conditions of Older Adults: A Scoping Review

by Stephanie Chu, Alice Kit Ying Chan and Chun Hung Chu

Int. J. Mol. Sci. 2024, 25(19), 10596; https://doi.org/10.3390/ijms251910596 - 1 Oct 2024

Cited by 1 | Viewed by 1313

Abstract

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). Full article

(This article belongs to the Special Issue Polyamines in Aging and Disease)

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24 pages, 6544 KiB

Open AccessReview

The Synergistic Benefit of Combination Strategies Targeting Tumor Cell Polyamine Homeostasis

by Ting-Ann Liu, Tracy Murray Stewart and Robert A. Casero, Jr.

Int. J. Mol. Sci. 2024, 25(15), 8173; https://doi.org/10.3390/ijms25158173 - 26 Jul 2024

Cited by 3 | Viewed by 1851

Abstract

Mammalian polyamines, including putrescine, spermidine, and spermine, are positively charged amines that are essential for all living cells including neoplastic cells. An increasing understanding of polyamine metabolism, its molecular functions, and its role in cancer has led to the interest in targeting polyamine metabolism as an anticancer strategy, as the metabolism of polyamines is frequently dysregulated in neoplastic disease. In addition, due to compensatory mechanisms, combination therapies are clinically more promising, as agents can work synergistically to achieve an effect beyond that of each strategy as a single agent. In this article, the nature of polyamines, their association with carcinogenesis, and the potential use of targeting polyamine metabolism in treating and preventing cancer as well as combination therapies are described. The goal is to review the latest strategies for targeting polyamine metabolism, highlighting new avenues for exploiting aberrant polyamine homeostasis for anticancer therapy and the mechanisms behind them. Full article

(This article belongs to the Special Issue Polyamines in Aging and Disease)

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13 pages, 656 KiB

Open AccessReview

The Many Faces of Hypusinated eIF5A: Cell Context-Specific Effects of the Hypusine Circuit and Implications for Human Health

by Shima Nakanishi and John L. Cleveland

Int. J. Mol. Sci. 2024, 25(15), 8171; https://doi.org/10.3390/ijms25158171 - 26 Jul 2024

Cited by 5 | Viewed by 2208

Abstract

The unique amino acid hypusine [N^ε-(4-amino-2-hydroxybutyl)lysine] is exclusively formed on the translational regulator eukaryotic initiation factor 5A (eIF5A) via a process coined hypusination. Hypusination is mediated by two enzymes, deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase (DOHH), and hypusinated eIF5A (eIF5A^Hyp) promotes translation elongation by alleviating ribosome pauses at amino acid motifs that cause structural constraints, and it also facilitates translation initiation and termination. Accordingly, eIF5A^Hyp has diverse biological functions that rely on translational control of its targets. Homozygous deletion of Eif5a, Dhps, or Dohh in mice leads to embryonic lethality, and heterozygous germline variants in EIF5A and biallelic variants in DHPS and DOHH are associated with rare inherited neurodevelopmental disorders, underscoring the importance of the hypusine circuit for embryonic and neuronal development. Given the pleiotropic effects of eIF5A^Hyp, a detailed understanding of the cell context-specific intrinsic roles of eIF5A^Hyp and of the chronic versus acute effects of eIF5A^Hyp inhibition is necessary to develop future strategies for eIF5A^Hyp-targeted therapy to treat various human health problems. Here, we review the most recent studies documenting the intrinsic roles of eIF5A^Hyp in different tissues/cell types under normal or pathophysiological conditions and discuss these unique aspects of eIF5A^Hyp-dependent translational control. Full article

(This article belongs to the Special Issue Polyamines in Aging and Disease)

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13 pages, 2559 KiB

Open AccessReview

Structural Insights into the Mechanisms Underlying Polyaminopathies

by Bing Wu and Sen Liu

Int. J. Mol. Sci. 2024, 25(12), 6340; https://doi.org/10.3390/ijms25126340 - 7 Jun 2024

Cited by 2 | Viewed by 1235

Abstract

Polyamines are ubiquitous in almost all biological entities and involved in various crucial physiological processes. They are also closely associated with the onset and progression of many diseases. Polyaminopathies are a group of rare genetic disorders caused by alterations in the function of proteins within the polyamine metabolism network. Although the identified polyaminopathies are all rare diseases at present, they are genetically heritable, rendering high risks not only to the carriers but also to their descendants. Meanwhile, more polyaminopathic patients might be discovered with the increasing accessibility of gene sequencing. This review aims to provide a comprehensive overview of the structural variations of mutated proteins in current polyaminopathies, in addition to their causative genes, types of mutations, clinical symptoms, and therapeutic approaches. We focus on analyzing how alterations in protein structure lead to protein dysfunction, thereby facilitating the onset of diseases. We hope this review will offer valuable insights and references for the future clinical diagnosis and precision treatment of polyaminopathies. Full article

(This article belongs to the Special Issue Polyamines in Aging and Disease)

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17 pages, 2315 KiB

Open AccessReview

The Molecular Role of Polyamines in Age-Related Diseases: An Update

by Guadalupe Elizabeth Jimenez Gutierrez, Fabiola V. Borbolla Jiménez, Luis G. Muñoz, Yessica Sarai Tapia Guerrero, Nadia Mireya Murillo Melo, José Melesio Cristóbal-Luna, Norberto Leyva Garcia, Joaquín Cordero-Martínez and Jonathan J. Magaña

Int. J. Mol. Sci. 2023, 24(22), 16469; https://doi.org/10.3390/ijms242216469 - 17 Nov 2023

Cited by 11 | Viewed by 4637

Abstract

Polyamines (Pas) are short molecules that exhibit two or three amine groups that are positively charged at a physiological pH. These small molecules are present in high concentrations in a wide variety of organisms and tissues, suggesting that they play an important role in cellular physiology. Polyamines include spermine, spermidine, and putrescine, which play important roles in age-related diseases that have not been completely elucidated. Aging is a natural process, defined as the time-related deterioration of the physiological functions; it is considered a risk factor for degenerative diseases such as cardiovascular, neurodegenerative, and musculoskeletal diseases; arthritis; and even cancer. In this review, we provide a new perspective on the participation of Pas in the cellular and molecular processes related to age-related diseases, focusing our attention on important degenerative diseases such as Alzheimerߣs disease, Parkinsonߣs disease, osteoarthritis, sarcopenia, and osteoporosis. This new perspective leads us to propose that Pas function as novel biomarkers for age-related diseases, with the main purpose of achieving new molecular alternatives for healthier aging. Full article

(This article belongs to the Special Issue Polyamines in Aging and Disease)

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15 pages, 1519 KiB

Open AccessReview

Polyamines in Ovarian Aging and Disease

by Bo Kang, Xin Wang, Xiaoguang An, Chengweng Ji, Weikang Ling, Yuxin Qi, Shuo Li and Dongmei Jiang

Int. J. Mol. Sci. 2023, 24(20), 15330; https://doi.org/10.3390/ijms242015330 - 18 Oct 2023

Cited by 8 | Viewed by 2966

Abstract

Ovarian aging and disease-related decline in fertility are challenging medical and economic issues with an increasing prevalence. Polyamines are a class of polycationic alkylamines widely distributed in mammals. They are small molecules essential for cell growth and development. Polyamines alleviate ovarian aging through various biological processes, including reproductive hormone synthesis, cell metabolism, programmed cell death, etc. However, an abnormal increase in polyamine levels can lead to ovarian damage and promote the development of ovarian disease. Therefore, polyamines have long been considered potential therapeutic targets for aging and disease, but their regulatory roles in the ovary deserve further investigation. This review discusses the mechanisms by which polyamines ameliorate human ovarian aging and disease through different biological processes, such as autophagy and oxidative stress, to develop safe and effective polyamine targeted therapy strategies for ovarian aging and the diseases. Full article

(This article belongs to the Special Issue Polyamines in Aging and Disease)

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