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Polyamine Metabolism in Health and Disease: Potential for Polyamine-Targeted Therapies...
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Polyamine Metabolism in Health and Disease: Potential for Polyamine-Targeted Therapies and Prevention

A special issue of Medical Sciences (ISSN 2076-3271). This special issue belongs to the section "Endocrinology and Metabolic Diseases".

Deadline for manuscript submissions: closed (31 July 2021) | Viewed by 40858

Special Issue Editor

Dr. Noriyuki Murai

E-Mail Website
Guest Editor
Department of Molecular Biology, The Jikei University School of Medicine, 3‐25‐8 Nishi‐shinbashi, Minato‐ku, Tokyo 105‐8461, Japan
Interests: polyamine metabolism; antizyme; ornithine decarboxylase; ubiquitin-independent protein degradation; proteasome; cancer biology; cancer metabolism

Special Issue Information

Dear Colleagues,

Polyamines are highly charged bioactive substances presented ubiquitously in species from bacteria to humans. Mammalian cells have three major polyamines—putrescine, spermidine, and spermine—at concentrations that range from micromolar to millimolar. Cellular polyamine concentration is highly regulated by polyamine-dependent negative feedback regulation of ornithine decarboxylase (ODC), a rate-limiting enzyme for polyamine biosynthesis. Polyamines are also taken up and exported through putative cellular membrane transporters. The functions of cellular polyamines are highly diversified, and they are involved in cell growth; cell division; apoptosis; autophagy; oxidative stress; ion channel activity; various diseases such as cancer, Alzheimer’s, and Parkinson’s diseases; stroke; and infectious diseases caused by viruses, bacteria, fungi, and parasites. In addition, recent reports suggest that spermidine exerts cardioprotective effects and that its supplementation extends the lifespan of mice through autophagy signaling. In cancer cells, polyamine concentrations are elevated in response to excessive growth signals resulting from amplification and/or abnormalities of oncogenes and/or tumor suppressor genes. Considering these tumor characteristics, difluoromethyl ornithine (DFMO), which is a suicide inhibitor of ODC, was used in clinical trials to suppress tumor growth; however, it had no effect on tumor growth alone. Nevertheless, used in combination with polyamine transport inhibitor, it is likely to be effective for reducing tumor progression. As represented by the Warburg effect, cancer cells have a distinctive metabolic flow compared with normal cells. Accordingly, detailed analysis on polyamine and polyamine-related metabolism, including energy metabolism, will be needed to clarify cancer cell biology and to search therapeutic targets and biomarkers. Recent comprehensive analysis of brain metabolites in patients for Parkinson’s disease suggest that N1, N8-diacetylspermidine levels have the potential to be diagnostic biomarkers of this disease. The aim of this Special Issue of Medical Sciences is to present the latest polyamine research in health and disease and to explore the potential for polyamine-targeted medical applications.

Dr. Noriyuki Murai
Guest Editor

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Keywords

  • Polyamine metabolism
  • Polyamines in cancer
  • Polyamines in health
  • Polyamines in disease
  • Polyamines in cancer therapy and prevention
  • Polyamines as a biomarker

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Published Papers (8 papers)

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Research

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9 pages, 1097 KiB  
Article
The Role of Spermidine Synthase (SpdS) and Spermine Synthase (Sms) in Regulating Triglyceride Storage in Drosophila
by Tahj S. Morales, Erik C. Avis, Elise K. Paskowski, Hamza Shabar, Shannon L. Nowotarski and Justin R. DiAngelo
Med. Sci. 2021, 9(2), 27; https://doi.org/10.3390/medsci9020027 - 2 May 2021
Cited by 6 | Viewed by 3112
Abstract
Polyamines are small organic cations that are important for several biological processes such as cell proliferation, cell cycle progression, and apoptosis. The dysregulation of intracellular polyamines is often associated with diseases such as cancer, diabetes, and developmental disorders. Although polyamine metabolism has been [...] Read more.
Polyamines are small organic cations that are important for several biological processes such as cell proliferation, cell cycle progression, and apoptosis. The dysregulation of intracellular polyamines is often associated with diseases such as cancer, diabetes, and developmental disorders. Although polyamine metabolism has been well studied, the effects of key enzymes in the polyamine pathway on lipid metabolism are not well understood. Here, we determined metabolic effects resulting from the absence of spermidine synthase (SpdS) and spermine synthase (Sms) in Drosophila. While SpdS mutants developed normally and accumulated triglycerides, Sms mutants had reduced viability and stored less triglyceride than the controls. Interestingly, when decreasing SpdS and Sms, specifically in the fat body, triglyceride storage increased. While there was no difference in triglycerides stored in heads, thoraxes and abdomen fat bodies, abdomen fat body DNA content increased, and protein/DNA decreased in both SpdS- and Sms-RNAi flies, suggesting that fat body-specific knockdown of SpdS and Sms causes the production of smaller fat body cells and triglycerides to accumulate in non-fat body tissues of the abdomen. Together, these data provide support for the role that polyamines play in the regulation of metabolism and can help enhance our understanding of polyamine function in metabolic diseases. Full article
(This article belongs to the Special Issue Polyamine Metabolism in Health and Disease: Potential for Polyamine-Targeted Therapies and Prevention)
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14 pages, 761 KiB  
Article
Polyamine-Rich Diet Elevates Blood Spermine Levels and Inhibits Pro-Inflammatory Status: An Interventional Study
by Kuniyasu Soda, Takeshi Uemura, Hidenori Sanayama, Kazuei Igarashi and Taro Fukui
Med. Sci. 2021, 9(2), 22; https://doi.org/10.3390/medsci9020022 - 29 Mar 2021
Cited by 27 | Viewed by 6200
Abstract
The Japanese diet and the Mediterranean diet are rich in polyamines (spermidine and spermine). Increased polyamine intake elevated blood spermine levels, inhibited aging-associated pro-inflammatory status (increases in lymphocyte function-associated antigen-1 (LFA-1) on immune cells), suppressed aberrant gene methylation and extended the lifespan of [...] Read more.
The Japanese diet and the Mediterranean diet are rich in polyamines (spermidine and spermine). Increased polyamine intake elevated blood spermine levels, inhibited aging-associated pro-inflammatory status (increases in lymphocyte function-associated antigen-1 (LFA-1) on immune cells), suppressed aberrant gene methylation and extended the lifespan of mice. To test the effects of increased polyamine intake by humans, 30 healthy male volunteers were asked to eat polyamine-rich and ready-to-eat traditional Japanese food (natto) for 12 months. Natto with high polyamine content was used. Another 27 male volunteers were asked not to change their dietary pattern as a control group. The volunteers’ age of intervention and control groups ranged from 40 to 69 years (median 48.9 ± 7.9). Two subjects in the control group subsequently dropped out of the study. The estimated increases in spermidine and spermine intakes were 96.63 ± 47.70 and 22.00 ± 9.56 µmol per day in the intervention group, while no changes were observed in the control group. The mean blood spermine level in the intervention group gradually rose to 1.12 ± 0.29 times the pre-intervention level after 12 months, and were significantly higher (p = 0.019) than those in the control group. Blood spermidine did not increase in either group. LFA-1 on monocytes decreased gradually in the intervention group, and there was an inverse association between changes in spermine concentrations relative to spermidine and changes in LFA-1 levels. Contingency table analysis revealed that the odds ratio to decrease LFA-1 by increased polyamine intake was 3.927 (95% CI 1.116–13.715) (p = 0.032) when the effect of acute inflammation was excluded. The results in the study were similar to those of our animal experiments. Since methylation changes of the entire genome are associated with aging-associated pathologies and our previous studies showed that spermine-induced LFA-1 suppression was associated with the inhibition of aberrant gene methylation, the results suggest that dietary polyamine contributes to human health and longevity. Full article
(This article belongs to the Special Issue Polyamine Metabolism in Health and Disease: Potential for Polyamine-Targeted Therapies and Prevention)
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19 pages, 4924 KiB  
Article
Effect of Yuzu (Citrus junos) Seed Limonoids and Spermine on Intestinal Microbiota and Hypothalamic Tissue in the Sandhoff Disease Mouse Model
by Mayumi Minamisawa, Takuma Suzumura, Sudeep Bose, Tetsuyuki Taniai, Gota Kawai, Kyoko Suzuki, Akira Yamaguchi and Shoji Yamanaka
Med. Sci. 2021, 9(1), 17; https://doi.org/10.3390/medsci9010017 - 11 Mar 2021
Cited by 4 | Viewed by 3781
Abstract
The effect of limonoids and spermine (Spm) extracted from yuzu (Citrus junos) seeds on the gut and the brain in a mouse model with Sandhoff disease (SD) was investigated. Wild-type and SD mice were fed a normal diet, or a diet [...] Read more.
The effect of limonoids and spermine (Spm) extracted from yuzu (Citrus junos) seeds on the gut and the brain in a mouse model with Sandhoff disease (SD) was investigated. Wild-type and SD mice were fed a normal diet, or a diet supplemented with limonoid, Spm, or limonoid + Spm for 14–18 weeks, and then 16S rRNA gene amplicon sequencing with extracted DNA from their feces was executed. For SD control mice, intestinal microbiota was mostly composed of Lactobacillus and linked to dysbiosis. For SD and wild-type mice fed with limonoids + Spm or limonoids alone, intestinal microbiota was rich in mucin-degrading bacteria, including Bacteroidetes, Verrucomicrobia, and Firmicutes, and displayed a higher production of short-chain fatty acids and immunoglobulin A. Additionally, SD mice fed with limonoids + Spm or limonoids alone had less inflammation in hypothalamic tissues and displayed a greater number of neurons. Administration of limonoids and/or Spm improved the proportions of beneficial intestinal microbiota to host health and reduced neuronal degeneration in SD mice. Yuzu seed limonoids and Spermine may help to maintain the homeostasis of intestinal microbiota and hypothalamic tissue in the SD mouse model. Full article
(This article belongs to the Special Issue Polyamine Metabolism in Health and Disease: Potential for Polyamine-Targeted Therapies and Prevention)
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8 pages, 621 KiB  
Communication
Development of an ELISA for Measurement of Urinary 3-Hydroxypropyl Mercapturic Acid (3-HPMA), the Marker of Stroke
by Akihiko Sakamoto, Takeshi Uemura, Yusuke Terui, Madoka Yoshida, Kazumasa Fukuda, Takao Nakamura, Keiko Kashiwagi and Kazuei Igarashi
Med. Sci. 2020, 8(3), 33; https://doi.org/10.3390/medsci8030033 - 16 Aug 2020
Cited by 3 | Viewed by 2749
Abstract
We previously observed an inverse correlation between stroke and urinary 3-hydroxypropyl mercapturic acid (3-HPMA), an acrolein-glutathione metabolite, through its measurement by liquid chromatography with tandem mass spectrometry (LC-MS/MS). However, the cost of equipment for LC-MS/MS and its maintenance fee is very expensive and [...] Read more.
We previously observed an inverse correlation between stroke and urinary 3-hydroxypropyl mercapturic acid (3-HPMA), an acrolein-glutathione metabolite, through its measurement by liquid chromatography with tandem mass spectrometry (LC-MS/MS). However, the cost of equipment for LC-MS/MS and its maintenance fee is very expensive and a cost-efficient method is required. In this study, we have developed a sensitive enzyme-linked immunosorbent assay (ELISA) system to measure 3-HPMA using a chicken antibody recognizing 3-HPMA-conjugated chicken albumin as antigen. Linearity to measure 3-HPMA was obtained from 0 to 10 μM, indicating that this ELISA system is useful for measurement of urine 3-HPMA. It was confirmed that 3-HPMA in urine of stroke patients decreased significantly compared with that of control subjects using the ELISA system. Using the ELISA kit, it became possible to evaluate the risk of brain stroke by not only plasma but also by urine. These results confirm that shortage of glutathione to detoxify acrolein is one of the major causes of stroke incidence. Our method contributes to maintenance of quality of life (QOL) of the elderly. Full article
(This article belongs to the Special Issue Polyamine Metabolism in Health and Disease: Potential for Polyamine-Targeted Therapies and Prevention)
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Review

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32 pages, 1739 KiB  
Review
Polyamine Metabolism in Leishmania Parasites: A Promising Therapeutic Target
by Nicola S. Carter, Yumena Kawasaki, Surbhi S. Nahata, Samira Elikaee, Sara Rajab, Leena Salam, Mohammed Y. Alabdulal, Kelli K. Broessel, Forogh Foroghi, Alyaa Abbas, Reyhaneh Poormohamadian and Sigrid C. Roberts
Med. Sci. 2022, 10(2), 24; https://doi.org/10.3390/medsci10020024 - 22 Apr 2022
Cited by 13 | Viewed by 4564
Abstract
Parasites of the genus Leishmania cause a variety of devastating and often fatal diseases in humans and domestic animals worldwide. The need for new therapeutic strategies is urgent because no vaccine is available, and treatment options are limited due to a lack of [...] Read more.
Parasites of the genus Leishmania cause a variety of devastating and often fatal diseases in humans and domestic animals worldwide. The need for new therapeutic strategies is urgent because no vaccine is available, and treatment options are limited due to a lack of specificity and the emergence of drug resistance. Polyamines are metabolites that play a central role in rapidly proliferating cells, and recent studies have highlighted their critical nature in Leishmania. Numerous studies using a variety of inhibitors as well as gene deletion mutants have elucidated the pathway and routes of transport, revealing unique aspects of polyamine metabolism in Leishmania parasites. These studies have also shed light on the significance of polyamines for parasite proliferation, infectivity, and host–parasite interactions. This comprehensive review article focuses on the main polyamine biosynthetic enzymes: ornithine decarboxylase, S-adenosylmethionine decarboxylase, and spermidine synthase, and it emphasizes recent discoveries that advance these enzymes as potential therapeutic targets against Leishmania parasites. Full article
(This article belongs to the Special Issue Polyamine Metabolism in Health and Disease: Potential for Polyamine-Targeted Therapies and Prevention)
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21 pages, 1544 KiB  
Review
Polyamines: Functions, Metabolism, and Role in Human Disease Management
by Narashans Alok Sagar, Swarnava Tarafdar, Surbhi Agarwal, Ayon Tarafdar and Sunil Sharma
Med. Sci. 2021, 9(2), 44; https://doi.org/10.3390/medsci9020044 - 9 Jun 2021
Cited by 93 | Viewed by 8901
Abstract
Putrescine, spermine, and spermidine are the important polyamines (PAs), found in all living organisms. PAs are formed by the decarboxylation of amino acids, and they facilitate cell growth and development via different cellular responses. PAs are the integrated part of the cellular and [...] Read more.
Putrescine, spermine, and spermidine are the important polyamines (PAs), found in all living organisms. PAs are formed by the decarboxylation of amino acids, and they facilitate cell growth and development via different cellular responses. PAs are the integrated part of the cellular and genetic metabolism and help in transcription, translation, signaling, and post-translational modifications. At the cellular level, PA concentration may influence the condition of various diseases in the body. For instance, a high PA level is detrimental to patients suffering from aging, cognitive impairment, and cancer. The levels of PAs decline with age in humans, which is associated with different health disorders. On the other hand, PAs reduce the risk of many cardiovascular diseases and increase longevity, when taken in an optimum quantity. Therefore, a controlled diet is an easy way to maintain the level of PAs in the body. Based on the nutritional intake of PAs, healthy cell functioning can be maintained. Moreover, several diseases can also be controlled to a higher extend via maintaining the metabolism of PAs. The present review discusses the types, important functions, and metabolism of PAs in humans. It also highlights the nutritional role of PAs in the prevention of various diseases. Full article
(This article belongs to the Special Issue Polyamine Metabolism in Health and Disease: Potential for Polyamine-Targeted Therapies and Prevention)
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17 pages, 577 KiB  
Review
Polyamine Homeostasis in Development and Disease
by Shima Nakanishi and John L. Cleveland
Med. Sci. 2021, 9(2), 28; https://doi.org/10.3390/medsci9020028 - 13 May 2021
Cited by 37 | Viewed by 4782
Abstract
Polycationic polyamines are present in nearly all living organisms and are essential for mammalian cell growth and survival, and for development. These positively charged molecules are involved in a variety of essential biological processes, yet their underlying mechanisms of action are not fully [...] Read more.
Polycationic polyamines are present in nearly all living organisms and are essential for mammalian cell growth and survival, and for development. These positively charged molecules are involved in a variety of essential biological processes, yet their underlying mechanisms of action are not fully understood. Several studies have shown both beneficial and detrimental effects of polyamines on human health. In cancer, polyamine metabolism is frequently dysregulated, and elevated polyamines have been shown to promote tumor growth and progression, suggesting that targeting polyamines is an attractive strategy for therapeutic intervention. In contrast, polyamines have also been shown to play critical roles in lifespan, cardiac health and in the development and function of the brain. Accordingly, a detailed understanding of mechanisms that control polyamine homeostasis in human health and disease is needed to develop safe and effective strategies for polyamine-targeted therapy. Full article
(This article belongs to the Special Issue Polyamine Metabolism in Health and Disease: Potential for Polyamine-Targeted Therapies and Prevention)
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8 pages, 4785 KiB  
Review
Health-Promoting Effects of Dietary Polyamines
by Rika Hirano, Hideto Shirasawa and Shin Kurihara
Med. Sci. 2021, 9(1), 8; https://doi.org/10.3390/medsci9010008 - 5 Feb 2021
Cited by 30 | Viewed by 5170
Abstract
The purpose of this paper is to summarize the latest information on the various aspects of polyamines and their health benefits. In recent years, attempts to treat cancer by reducing elevated polyamines levels in cancer cells have been made, with some advancing to [...] Read more.
The purpose of this paper is to summarize the latest information on the various aspects of polyamines and their health benefits. In recent years, attempts to treat cancer by reducing elevated polyamines levels in cancer cells have been made, with some advancing to clinical trials. However, it has been reported since 2009 that polyamines extend the healthy life span of animals by inducing autophagy, protecting the kidneys and liver, improving cognitive function, and inhibiting the progression of heart diseases. As such, there is conflicting information regarding the relationship between polyamines and health. However, attempts to treat cancer by decreasing intracellular polyamines levels are a coping strategy to suppress the proliferation-promoting effects of polyamines, and a consensus is being reached that polyamine intake does not induce cancer in healthy individuals. To provide further scientific evidence for the health-promoting effects of polyamines, large-scale clinical studies involving multiple groups are expected in the future. It is also important to promote basic research on polyamine intake in animals, including elucidation of the polyamine balance between food, intestinal bacteria, and biosynthesis. Full article
(This article belongs to the Special Issue Polyamine Metabolism in Health and Disease: Potential for Polyamine-Targeted Therapies and Prevention)
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