Papers - UEMURA Takeshi
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Correlation of polyamines, acrolein-conjugated lysine and polyamine metabolic enzyme levels with age in human liver. Reviewed International journal
Takeshi Uemura, Yoshihisa Akasaka, Hiroshi Ikegaya
Heliyon 6 ( 9 ) e05031 - e05031 2020.09
Authorship：Lead author, Corresponding author Language：English Publishing type：Research paper (scientific journal)
The polyamines spermidine, spermine and putrescine are essential for normal cellular functions. The contents of polyamines in tissue decreased in aged mice compared to young mice. In this study, the polyamine contents and their metabolic byproduct acrolein-conjugated lysine (Nε-(3-formyl-3,4-dehydropiperidino)-lysine, FDP-Lys) in human liver tissue were measured and analyzed the correlation with age of the subjects. The putrescine and FDP-Lys levels were significantly increased with age. On the other hand, spermine level was decreased with age. Spermidine did not significantly correlate with age. The relative amount of spermine oxidase (SMOX) significantly correlated with the age of subjects whereas ornithine decarboxylase (ODC) and adenosylmethionine decarboxylase (AMD1) significantly reduced by the age. Our results suggested that an increase in oxidation and reduction in polyamine synthesis may cause the change of polyamine profile in the elderly.
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A search for acrolein scavengers among food components Reviewed
Uemura T, Uchida M, Nakamura M, Shimekake M, Sakamoto A, Terui Y, Higashi K, Ishii I, Kashiwagi K, Igarashi K.
Amino Acids 2023.02
Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)
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Nα-(5-Fluoro-2,4-dinitrophenyl)-L-leucinamide-derivatized LC/MS/MS Analysis of Amino Acid Enantiomers in HepG2 Cells Reviewed
Takano Y, Takahashi M, Kobayashi M, Uemura T, Furuchi T.
Chromatography 42 ( 3 ) 143 - 149 2021
Language：English Publishing type：Research paper (scientific journal)
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Structural change and degradation of cytoskeleton due to the acrolein conjugation with vimentin and actin during brain infarction. Reviewed International journal
Takeshi Uemura, Takehiro Suzuki, Kenta Ko, Mizuho Nakamura, Naoshi Dohmae, Akihiko Sakamoto, Yusuke Terui, Toshihiko Toida, Keiko Kashiwagi, Kazuei Igarashi
Cytoskeleton (Hoboken, N.J.) 77 ( 10 ) 414 - 421 2020.10
Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)
We have found recently that dendritic spine extension is inhibited through acrolein conjugation with α- and β-tubulin proteins during brain infarction. In this current study, we looked for other acrolein-conjugated proteins in the 100,000g precipitate fraction, to clarify how cytoskeleton structure is modified by acrolein. Acrolein-conjugated proteins were sought from acrolein-treated mouse FM3A and Neuro2a cells and from tissues isolated from mouse brain infarction. It was found that vimentin was conjugated with acrolein, and the conjugated amino acid residue was Cys328, which is the only Cys residue in vimentin. It was also found that Cys207, 257, 285, and Lys118 in actin, another cytoskeleton protein, were conjugated with acrolein. The structure and localization of vimentin and actin filaments were changed greatly in infarct brain in photochemically induced thrombosis model mice and in acrolein-treated Neuro2a cells. In addition, degradation of cytoskeleton proteins was accelerated in the order vimentin > tubulin > actin in mouse brain infarction. These findings indicate that a dysfunction of the cytoskeleton by acrolein is strongly involved in the tissue damage during brain infarction, together with the apoptosis caused by glyceraldehyde-3-phosphate dehydrogenase and protein degradation by matrix metalloproteinase-9.
DOI： 10.1002/cm.21638
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Urinary Amino Acid-Conjugated Acrolein and Taurine as New Biomarkers for Detection of Dementia Reviewed
Yoshida M, Uemura T, Mizoi M, Waragai M, Sakamoto A, Terui Y, Kashiwagi K, Igarashi K.
J Alzheimers Dis. 2023.01
Authorship：Second author Language：English Publishing type：Research paper (scientific journal)
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Polyamine analysis of acidophiles, alkaliphiles, halophiles and thermophiles belonging to the bacterial phyla Actinobacteria, Aquificae, Bacterioidetes, Cyanobacteria, Desulfobacterota, Firmicutes, Tenericutes, and Thermotogae – Polyamine catalogue of bacterial and archaeal extremophiles – (XII) Reviewed
Koei Hamana, Hidenori Hayashi, Takemitsu Furuchi, Takeshi Uemura, Masaru Niitsu, Takashi Itoh, Mitsuo Sakamoto, and Moriya Okuma
Journal of Japanese Society for Extremophiles 2022
Language：English Publishing type：Research paper (scientific journal)
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Polyamines produced by an extreme thermophile are essential for cell growth at high temperature Reviewed
Akihiko Sakamoto, Masatada Tamakoshi, Toshiyuki Moriya, Tairo Oshima, Koichi Takao, Yoshiaki Sugita, Takemitsu Furuchi, Masaru Niitsu, Takeshi Uemura, Kazuei Igarashi, Keiko Kashiwagi, Yusuke Terui.
Journal of Biochemistry 172 ( 2 ) 109 - 115 2022
Language：English Publishing type：Research paper (scientific journal)
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The Polyamine Regulator AMD1 Upregulates Spermine Levels to Drive Epidermal Differentiation. Invited Reviewed International coauthorship International journal
Anisa B Rahim, Hui Kheng Lim, Christina Yan Ru Tan, Li Jia, Vonny Ivon Leo, Takeshi Uemura, Jonathan Hardman-Smart, John E A Common, Thiam Chye Lim, Sophie Bellanger, Ralf Paus, Kazuei Igarashi, Henry Yang, Leah A Vardy
The Journal of investigative dermatology 141 ( 9 ) 2178 - 2188.e6 2021.09
Language：English Publishing type：Research paper (scientific journal)
Maintaining tissue homeostasis depends on a balance between cell proliferation, differentiation, and apoptosis. Within the epidermis, the levels of the polyamines putrescine, spermidine, and spermine are altered in many different skin conditions, yet their role in epidermal tissue homeostasis is poorly understood. We identify the polyamine regulator, Adenosylmethionine decarboxylase 1 (AMD1), as a crucial regulator of keratinocyte (KC) differentiation. AMD1 protein is upregulated on differentiation and is highly expressed in the suprabasal layers of the human epidermis. During KC differentiation, elevated AMD1 promotes decreased putrescine and increased spermine levels. Knockdown or inhibition of AMD1 results in reduced spermine levels and inhibition of KC differentiation. Supplementing AMD1-knockdown KCs with exogenous spermidine or spermine rescued aberrant differentiation. We show that the polyamine shift is critical for the regulation of key transcription factors and signaling proteins that drive KC differentiation, including KLF4 and ZNF750. These findings show that human KCs use controlled changes in polyamine levels to modulate gene expression to drive cellular behavior changes. Modulation of polyamine levels during epidermal differentiation could impact skin barrier formation or can be used in the treatment of hyperproliferative skin disorders.
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Polyamine-Rich Diet Elevates Blood Spermine Levels and Inhibits Pro-Inflammatory Status: An Interventional Study. Reviewed International journal
Kuniyasu Soda, Takeshi Uemura, Hidenori Sanayama, Kazuei Igarashi, Taro Fukui
Medical sciences (Basel, Switzerland) 9 ( 2 ) 2021.03
Language：English Publishing type：Research paper (scientific journal)
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.
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A Raman algorithm to estimate human age from protein structural variations in autopsy skin samples: a protein biological clock. Reviewed International journal
Daisuke Miyamori, Takeshi Uemura, Wenliang Zhu, Kei Fujikawa, Takaaki Nakaya, Satoshi Teramukai, Giuseppe Pezzotti, Hiroshi Ikegaya
Scientific reports 11 ( 1 ) 5949 - 5949 2021.03
Language：English Publishing type：Research paper (scientific journal)
The recent increase of the number of unidentified cadavers has become a serious problem throughout the world. As a simple and objective method for age estimation, we attempted to utilize Raman spectrometry for forensic identification. Raman spectroscopy is an optical-based vibrational spectroscopic technique that provides detailed information regarding a sample's molecular composition and structures. Building upon our previous proof-of-concept study, we measured the Raman spectra of abdominal skin samples from 132 autopsy cases and the protein-folding intensity ratio, RPF, defined as the ratio between the Raman signals from a random coil an α-helix. There was a strong negative correlation between age and RPF with a Pearson correlation coefficient of r = 0.878. Four models, based on linear (RPF), squared (RPF2), sex, and RPF by sex interaction terms, were examined. The results of cross validation suggested that the second model including linear and squared terms was the best model with the lowest root mean squared error (11.3 years of age) and the highest coefficient of determination (0.743). Our results indicate that the there was a high correlation between the age and RPF and the Raman biological clock of protein folding can be used as a simple and objective forensic age estimation method for unidentified cadavers.
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Translational Regulation of Clock Genes BMAL1 and REV-ERBα by Polyamines. Reviewed International journal
Akihiko Sakamoto, Yusuke Terui, Takeshi Uemura, Kazuei Igarashi, Keiko Kashiwagi
International journal of molecular sciences 22 ( 3 ) 2021.01
Language：English Publishing type：Research paper (scientific journal)
Polyamines stimulate the synthesis of specific proteins at the level of translation, and the genes encoding these proteins are termed as the "polyamine modulon". The circadian clock generates daily rhythms in mammalian physiology and behavior. We investigated the role of polyamines in the circadian rhythm using control and polyamine-reduced NIH3T3 cells. The intracellular polyamines exhibited a rhythm with a period of about 24 h. In the polyamine-reduced NIH3T3 cells, the circadian period of circadian clock genes was lengthened and the synthesis of BMAL1 and REV-ERBα was significantly reduced at the translation level. Thus, the mechanism of polyamine stimulation of these protein syntheses was analyzed using NIH3T3 cells transiently transfected with genes encoding enhanced green fluorescent protein (EGFP) fusion mRNA with normal or mutated 5'-untranslated region (5'-UTR) of Bmal1 or Rev-erbα mRNA. It was found that polyamines stimulated BMAL1 and REV-ERBα synthesis through the enhancement of ribosomal shunting during the ribosome shunting within the 5'-UTR of mRNAs. Accordingly, the genes encoding Bmal1 and Rev-erbα were identified as the members of "polyamine modulon", and these two proteins are significantly involved in the circadian rhythm control.
DOI： 10.3390/ijms22031307
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The Polyamine Putrescine Promotes Human Epidermal Melanogenesis. Reviewed International journal
Aishwarya Sridharan, Meng Shi, Vonny Ivon Leo, Nagavidya Subramaniam, Thiam Chye Lim, Takeshi Uemura, Kazuei Igarashi, Steven Thng Tien Guan, Nguan Soon Tan, Leah A Vardy
The Journal of investigative dermatology 140 ( 10 ) 2032 - 2040.e1 2020.10
Language：English Publishing type：Research paper (scientific journal)
Hyperpigmentary conditions can arise when melanogenesis in the epidermis is misregulated. Understanding the pathways underlying melanogenesis is essential for the development of effective treatments. Here, we report that a group of metabolites called polyamines are important in the control of melanogenesis in human skin. Polyamines are cationic molecules present in all cells and are essential for cellular function. We report that polyamine regulator ODC1 is upregulated in melanocytes from melasma lesional skin. We report that the polyamine putrescine can promote pigmentation in human skin explants and primary normal human epidermal melanocytes through induction of tyrosinase which is rate-limiting for the synthesis of melanin. Putrescine supplementation on normal human epidermal melanocytes results in the activation of polyamine catabolism, which results in increased intracellular H2O2. Polyamine catabolism is also increased in human skin explants that have been treated with putrescine. We further report that inhibition of polyamine catabolism prevents putrescine-induced promotion of tyrosinase levels and pigmentation in normal human epidermal melanocytes, showing that polyamine catabolism is responsible for the putrescine induction of melanogenesis. Our data showing that putrescine promotes pigmentation has important consequences for hyperpigmented and hypopigmented conditions. Further understanding of how polyamines control epidermal pigmentation could open the door for the development of new therapeutics.
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Development of an ELISA for Measurement of Urinary 3-Hydroxypropyl Mercapturic Acid (3-HPMA), the Marker of Stroke. Reviewed International journal
Akihiko Sakamoto, Takeshi Uemura, Yusuke Terui, Madoka Yoshida, Kazumasa Fukuda, Takao Nakamura, Keiko Kashiwagi, Kazuei Igarashi
Medical sciences (Basel, Switzerland) 8 ( 3 ) 2020.08
Language：English Publishing type：Research paper (scientific journal)
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.
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Polyamines regulate gene expression by stimulating translation of histone acetyltransferase mRNAs. Reviewed International journal
Akihiko Sakamoto, Yusuke Terui, Takeshi Uemura, Kazuei Igarashi, Keiko Kashiwagi
The Journal of biological chemistry 295 ( 26 ) 8736 - 8745 2020.06
Language：English Publishing type：Research paper (scientific journal)
Polyamines regulate gene expression in Escherichia coli by translationally stimulating mRNAs encoding global transcription factors. In this study, we focused on histone acetylation, one of the mechanisms of epigenetic regulation of gene expression, to attempt to clarify the role of polyamines in the regulation of gene expression in eukaryotes. We found that activities of histone acetyltransferases in both the nucleus and cytoplasm decreased significantly in polyamine-reduced mouse mammary carcinoma FM3A cells. Although protein levels of histones H3 and H4 did not change in control and polyamine-reduced cells, acetylation of histones H3 and H4 was greatly decreased in the polyamine-reduced cells. Next, we used control and polyamine-reduced cells to identify histone acetyltransferases whose synthesis is stimulated by polyamines. We found that polyamines stimulate the translation of histone acetyltransferases GCN5 and HAT1. Accordingly, GCN5- and HAT1-catalyzed acetylation of specific lysine residues on histones H3 and H4 was stimulated by polyamines. Consistent with these findings, transcription of genes required for cell proliferation was enhanced by polyamines. These results indicate that polyamines regulate gene expression by enhancing the expression of the histone acetyltransferases GCN5 and HAT1 at the level of translation. Mechanistically, polyamines enhanced the interaction of microRNA-7648-5p (miR-7648-5p) with the 5'-UTR of GCN5 mRNA, resulting in stimulation of translation due to the destabilization of the dsRNA between the 5'-UTR and the ORF of GCN5 mRNA. Because HAT1 mRNA has a short 5'-UTR, polyamines may enhance initiation complex formation directly on this mRNA.
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Cytotoxic Mechanism of Excess Polyamines Functions through Translational Repression of Specific Proteins Encoded by Polyamine Modulon. Reviewed International journal
Akihiko Sakamoto, Junpei Sahara, Gota Kawai, Kaneyoshi Yamamoto, Akira Ishihama, Takeshi Uemura, Kazuei Igarashi, Keiko Kashiwagi, Yusuke Terui
International journal of molecular sciences 21 ( 7 ) 2020.03
Language：English Publishing type：Research paper (scientific journal)
Excessive accumulation of polyamines causes cytotoxicity, including inhibition of cell growth and a decrease in viability. We investigated the mechanism of cytotoxicity caused by spermidine accumulation under various conditions using an Escherichia coli strain deficient in spermidine acetyltransferase (SAT), a key catabolic enzyme in controlling polyamine levels. Due to the excessive accumulation of polyamines by the addition of exogenous spermidine to the growth medium, cell growth and viability were markedly decreased through translational repression of specific proteins [RMF (ribosome modulation factor) and Fis (rRNA transcription factor) etc.] encoded by members of polyamine modulon, which are essential for cell growth and viability. In particular, synthesis of proteins that have unusual locations of the Shine-Dalgarno (SD) sequence in their mRNAs was inhibited. In order to elucidate the molecular mechanism of cytotoxicity by the excessive accumulation of spermidine, the spermidine-dependent structural change of the bulged-out region in the mRNA at the initiation site of the rmf mRNA was examined using NMR analysis. It was suggested that the structure of the mRNA bulged-out region is affected by excess spermidine, so the SD sequence of the rmf mRNA cannot approach initiation codon AUG.
DOI： 10.3390/ijms21072406
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Assessing acrolein for determination of the severity of brain stroke, dementia, renal failure, and Sjögren's syndrome. Reviewed
Igarashi K, Uemura T, Kashiwagi K
Amino acids 52 ( 2 ) 119 - 127 2020.02
Language：English Publishing type：Research paper (scientific journal)
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蛋白質抱合アクロレイン、IL-6並びにCRP測定に基づく脳梗塞リスク評価による脳梗塞発症者数の減少 Reviewed
五十嵐一衛、植村武史、柏木敬子
未病と抗老化 29 30 - 34 2020
Authorship：Second author Language：Japanese Publishing type：Research paper (scientific journal)
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GSTΠ stimulates caveolin-1-regulated polyamine uptake via actin remodeling. Reviewed
Uemura T, Tsaprailis G, Gerner EW
Oncotarget 10 ( 55 ) 5713 - 5723 2019.10
Language：English Publishing type：Research paper (scientific journal)
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Inhibition of dendritic spine extension through acrolein conjugation with α-, β-tubulin proteins. Reviewed International journal
Uemura T, Suzuki T, Ko K, Watanabe K, Dohmae N, Sakamoto A, Terui Y, Toida T, Kashiwagi K, Igarashi K
The international journal of biochemistry & cell biology 113 58 - 66 2019.08
Language：English Publishing type：Research paper (scientific journal)
We have recently found that conjugation of acrolein with a 50 kDa protein(s) is strongly associated with tissue damage during brain infarction. In the current study, the identity and function of the 50 kDa protein(s) conjugated with acrolein during brain infarction were investigated. The 50 kDa protein(s) conjugated with acrolein were identified as α- and β-tubulins. Ten cysteine residues in α- and β-tubulins (Cys25, 295, 347 and 376 in α-tubulin and Cys12, 129, 211, 239, 303 and 354 in β-tubulin) were mainly conjugated with acrolein. Since two cysteine residues of α-tubulin (Cys347 and 376) and four cysteine residues of β-tubulin (Cys12, 129, 239 and 354) were located at the interaction site of α- and β-tubulins, association between α- and β-tubulins to form microtubules was strongly inhibited by conjugation with acrolein. Accordingly, dendritic spine extension consisting of microtubules was greatly inhibited in acrolein-treated Neuro2a cells. The results strongly suggest that acrolein contributes to the functional losses in brain signaling through its conjugation with α- and β-tubulins.
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Polyamine Regulator AMD1 Promotes Cell Migration in Epidermal Wound Healing. Reviewed International journal
Hui Kheng Lim, Anisa B Rahim, Vonny Ivon Leo, Shatarupa Das, Thiam Chye Lim, Takeshi Uemura, Kazuei Igarashi, John Common, Leah A Vardy
The Journal of investigative dermatology 138 ( 12 ) 2653 - 2665 2018.12
Language：English Publishing type：Research paper (scientific journal)
Wound healing is a dynamic process involving gene-expression changes that drive re-epithelialization. Here, we describe an essential role for polyamine regulator AMD1 in driving cell migration at the wound edge. The polyamines, putrescine, spermidine, and spermine are small cationic molecules that play essential roles in many cellular processes. We demonstrate that AMD1 is rapidly upregulated following wounding in human skin biopsies. Knockdown of AMD1 with small hairpin RNAs causes a delay in cell migration that is rescued by the addition of spermine. We further show that spermine can promote cell migration in keratinocytes and in human ex vivo wounds, where it significantly increases epithelial tongue migration. Knockdown of AMD1 prevents the upregulation of urokinase-type plasminogen activator/urokinase-type plasminogen activator receptor on wounding and results in a failure in actin cytoskeletal reorganization at the wound edge. We demonstrate that keratinocytes respond to wounding by modulating polyamine regulator AMD1 in order to regulate downstream gene expression and promote cell migration. This article highlights a previously unreported role for the regulation of polyamine levels and ratios in cellular behavior and fate.
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MINDY1 Is a Downstream Target of the Polyamines and Promotes Embryonic Stem Cell Self-Renewal. Reviewed International journal
Christina James, Tian Yun Zhao, Anisa Rahim, Parul Saxena, Nazreen Abdul Muthalif, Takeshi Uemura, Norihiro Tsuneyoshi, Sheena Ong, Kazuei Igarashi, Chin Yan Lim, Norris Ray Dunn, Leah A Vardy
Stem cells (Dayton, Ohio) 36 ( 8 ) 1170 - 1178 2018.08
Language：English Publishing type：Research paper (scientific journal)
Embryonic stem cells have the ability to self-renew or differentiate and these processes are under tight control. We previously reported that the polyamine regulator AMD1 is critical for embryonic stem cell self-renewal. The polyamines putrescine, spermidine, and spermine are essential organic cations that play a role in a wide array of cellular processes. Here, we explore the essential role of the polyamines in the promotion of self-renewal and identify a new stem cell regulator that acts downstream of the polyamines: MINDY1. MINDY1 protein levels are high in embryonic stem cells (ESCs) and are dependent on high polyamine levels. Overexpression of MINDY1 can promote ESC self-renewal in the absence of the usually essential cytokine Leukemia Inhibitory Factor (LIF). MINDY1 protein is prenylated and this modification is required for its ability to promote self-renewal. We go on to show that Mindy1 RNA is targeted for repression by mir-710 during Neural Precursor cell differentiation. Taken together, these data demonstrate that high polyamine levels are required for ESC self-renewal and that they function, in part, through promotion of high MINDY1 levels. Stem Cells 2018;36:1170-1178.
DOI： 10.1002/stem.2830
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Protective Effects of Brain Infarction by N-Acetylcysteine Derivatives. Reviewed International journal
Uemura T, Watanabe K, Ko K, Higashi K, Kogure N, Kitajima M, Takayama H, Takao K, Sugita Y, Sakamoto A, Terui Y, Toida T, Kashiwagi K, Igarashi K
Stroke 49 ( 7 ) 1727 - 1733 2018.07
Language：English Publishing type：Research paper (scientific journal)
BACKGROUND AND PURPOSE: We recently found that acrolein (CH2=CH-CHO) is more strongly involved in brain infarction compared with reactive oxygen species. In this study, we looked for acrolein scavengers with less side effects. METHODS: Photochemically induced thrombosis model mice were prepared by injection of Rose Bengal. Effects of N-acetylcysteine (NAC) derivatives on brain infarction were evaluated using the public domain National Institutes of Health image program. RESULTS: NAC, NAC ethyl ester, and NAC benzyl ester (150 mg/kg) were administered intraperitoneally at the time of induction of ischemia, or these NAC derivatives (50 mg/kg) were administered 3× at 24-h intervals before induction of ischemia and 1 more administration at the time of induction of ischemia. The size of brain infarction decreased in the order NAC benzyl ester>NAC ethyl ester>NAC in both experimental conditions. Detoxification of acrolein occurred through conjugation of acrolein with glutathione, which was catalyzed by glutathione S-transferases, rather than direct conjugation between acrolein and NAC derivatives. The level of glutathione S-transferases at the locus of brain infarction was in the order of administration of NAC benzyl ester>NAC ethyl ester>NAC>no NAC derivatives, suggesting that NAC derivatives stabilize glutathione S-transferases. CONCLUSIONS: The results indicate that detoxification of acrolein by NAC derivatives is caused through glutathione conjugation with acrolein catalyzed by glutathione S-transferases, which can be stabilized by NAC derivatives. This is a new concept of acrolein detoxification by NAC derivatives.
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Acrolein toxicity at advanced age: present and future Reviewed
Kazuei Igarashi, Takeshi Uemura, Keiko Kashiwagi
Amino Acids 50 ( 2 ) 217 - 228 2018.02
Language：English Publishing type：Research paper (scientific journal) Publisher：Springer-Verlag Wien
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Acrolein: An effective biomarker for tissue damage produced from polyamines Reviewed
Kazuei Igarashi, Takeshi Uemura, Keiko Kashiwagi
Methods in Molecular Biology 1694 459 - 468 2018
Language：English Publishing type：Research paper (scientific journal) Publisher：Humana Press Inc.
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加齢による脳梗塞悪化メカニズムと新規脳梗塞予防薬の探索 Invited Reviewed
植村武史、渡辺健太、柏木敬子、五十嵐一衛
未病と抗老化 27 39 - 43 2018
Authorship：Lead author Language：Japanese Publishing type：Research paper (scientific journal)
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Spermine oxidase promotes bile canalicular lumen formation through acrolein production Reviewed
Takeshi Uemura, Tomokazu Takasaka, Kazuei Igarashi, Hiroshi Ikegaya
SCIENTIFIC REPORTS 7 ( 1 ) 14841 - 14841 2017.11
Language：English Publishing type：Research paper (scientific journal)
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Determination of 3-hydroxypropylmercapturic acid in urine by three column-switching high-performance liquid chromatography with electrochemical detection using a diamond electrode Reviewed
Kyohei Higashi, Mana Shibasaki, Kyoshiro Kuni, Takeshi Uemura, Masaaki Waragai, Kenichi Uemura, Kazuei Igarashi, Toshihiko Toida
JOURNAL OF CHROMATOGRAPHY A 1517 79 - 85 2017.09
Language：English Publishing type：Research paper (scientific journal)
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Activation of MMP-9 activity by acrolein in saliva from patients with primary Sjogren's syndrome and its mechanism Reviewed
Takeshi Uemura, Takehiro Suzuki, Ryotaro Saiki, Naoshi Dohmae, Satoshi Ito, Hoyu Takahashi, Toshihiko Toida, Keiko Kashiwagi, Kazuei Igarashi
INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY 88 84 - 91 2017.07
Language：English Publishing type：Research paper (scientific journal)
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Time dependent transition of the levels of protein-conjugated acrolein (PC-Acro), IL-6 and CRP in plasma during stroke Reviewed
Madoka Yoshida, Naoki Kato, Takeshi Uemura, Mutsumi Mizoi, Mizuho Nakamura, Ryotaro Saiki, Keisuke Hatano, Kunitomo Sato, Shota Kakizaki, Aya Nakamura, Takuya Ishii, Tohru Terao, Yuichi Murayama, Keiko Kashiwagi, Kazuei Igarashi
eNeurologicalSci 7 18 - 24 2017.06
Language：English Publishing type：Research paper (scientific journal) Publisher：Elsevier B.V.
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Correlation between brain damage, associated biomarkers, and medication in psychiatric inpatients: A cross-sectional study Reviewed
Madoka Yoshida, Tetsuto Kanzaki, Mutsumi Mizoi, Mizuho Nakamura, Takeshi Uemura, Seisuke Mimori, Yoriyasu Uju, Keisuke Sekine, Yukihiro Ishii, Taro Yoshimi, Reiko Yasui, Asuka Yasukawa, Mamoru Sato, Seiko Okamoto, Tetsuya Hisaoka, Masafumi Miura, Shun Kusanishi, Kanako Murakami, Chieko Nakano, Yasuhiko Mizuta, Shunichi Mishima, Tatsuro Hayakawa, Kazumi Tsukada, Keiko Kashiwagi, Kazuei Igarashi
CLINICA CHIMICA ACTA 464 50 - 56 2017.01
Language：English Publishing type：Research paper (scientific journal)
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Decrease in acrolein toxicity based on the decline of polyamine oxidases Reviewed
Takeshi Uemura, Mizuho Nakamura, Akihiko Sakamoto, Takehiro Suzuki, Naoshi Dohmae, Yusuke Terui, Hideyuki Tomitori, Robert A. Casero, Keiko Kashiwagi, Kazuei Igarashi
INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY 79 151 - 157 2016.10
Language：English Publishing type：Research paper (scientific journal)
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Aggravation of brain infarction through an increase in acrolein production and a decrease in glutathione with aging Reviewed
Takeshi Uemura, Kenta Watanabe, Misaki Ishibashi, Ryotaro Saiki, Kyoshiro Kuni, Kazuhiro Nishimura, Toshihiko Toida, Keiko Kashiwagi, Kazuei Igarashi
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 473 ( 2 ) 630 - 635 2016.04
Language：English Publishing type：Research paper (scientific journal)
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Toxic acrolein production due to Ca2+ influx by the NMDA receptor during stroke Reviewed
Mizuho Nakamura, Takeshi Uemura, Ryotaro Saiki, Akihiko Sakamoto, Hyerim Park, Kazuhiro Nishimura, Yusuke Terui, Toshihiko Toida, Keiko Kashiwagi, Kazuei Igarashi
ATHEROSCLEROSIS 244 131 - 137 2016.01
Language：English Publishing type：Research paper (scientific journal)
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Increase in acrolein-conjugated immunoglobulins in saliva from patients with primary Sjogren's syndrome Reviewed
Tadao Hirose, Ryotaro Saiki, Takeshi Uemura, Takehiro Suzuki, Naoshi Dohmae, Satoshi Ito, Hoyu Takahashi, Itsuko Ishii, Toshihiko Toida, Keiko Kashiwagi, Kazuei Igarashi
CLINICA CHIMICA ACTA 450 184 - 189 2015.10
Language：English Publishing type：Research paper (scientific journal)
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Raman spectroscopy of human skin: Looking for a quantitative algorithm to reliably estimate human age Reviewed
Giuseppe Pezzotti, Marco Boffelli, Daisuke Miyamori, Takeshi Uemura, Yoshinori Marunaka, Wenliang Zhu, Hiroshi Ikegaya
Journal of Biomedical Optics 20 ( 6 ) 065008 - 065008 2015.06
Language：English Publishing type：Research paper (scientific journal) Publisher：SPIE
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Experimental studies of remarkable monoamine releases and neural resistance to the transient ischemia and reperfusion Reviewed
Kanji Yoshimoto, Akira Namera, Yousuke Arima, Takahiro Nagao, Hiroh Saji, Tomokazu Takasaka, Takeshi Uemura, Yoshihisa Watanabe, Shuichi Ueda, Masataka Nagao
Pathophysiology 21 ( 4 ) 309 - 316 2014.11
Language：English Publishing type：Research paper (scientific journal) Publisher：Elsevier
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Identification of Functional Amino Acid Residues Involved in Polyamine and Agmatine Transport by Human Organic Cation Transporter 2 Reviewed
Kyohei Higashi, Masataka Imamura, Satoshi Fudo, Takeshi Uemura, Ryotaro Saiki, Tyuji Hoshino, Toshihiko Toida, Keiko Kashiwagi, Kazuei Igarashi
PLOS ONE 9 ( 7 ) e102234 - e102234 2014
Language：English Publishing type：Research paper (scientific journal)
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Acetaldehyde-induced cytotoxicity involves induction of spermine oxidase at the transcriptional level Reviewed
Takeshi Uemura, Yuka Tanaka, Kyohei Higashi, Daisuke Miyamori, Tomokazu Takasaka, Tatsuo Nagano, Toshihiko Toida, Kanji Yoshimoto, Kazuei Igarashi, Hiroshi Ikegaya
TOXICOLOGY 310 1 - 7 2013.08
Language：English Publishing type：Research paper (scientific journal)
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Polyamine transport systems in mammalian cells and tissues. Reviewed
Uemura T, Gerner EW
Methods in molecular biology (Clifton, N.J.) 720 339 - 348 2011
Language：English Publishing type：Research paper (scientific journal)
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Identification and Functions of Amino Acid Residues in PotB and PotC Involved in Spermidine Uptake Activity Reviewed
Kyohei Higashi, Yoshiharu Sakamaki, Emiko Herai, Risa Demizu, Takeshi Uemura, Sunil D. Saroj, Risa Zenda, Yusuke Terui, Kazuhiro Nishimura, Toshihiko Toida, Keiko Kashiwagi, Kazuei Igarashi
JOURNAL OF BIOLOGICAL CHEMISTRY 285 ( 50 ) 39061 - 39069 2010.12
Language：English Publishing type：Research paper (scientific journal)
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Polyamine transport is mediated by both endocytic and solute carrier transport mechanisms in the gastrointestinal tract Reviewed
Takeshi Uemura, David E. Stringer, Karen A. Blohm-Mangone, Eugene W. Gerner
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY 299 ( 2 ) G517 - G522 2010.08
Language：English Publishing type：Research paper (scientific journal)
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Polyamine modulon in yeast-Stimulation of COX4 synthesis by spermidine at the level of translation Reviewed
Takeshi Uemura, Kyohei Higashi, Miki Takigawa, Toshihiko Toida, Keiko Kashiwagi, Kazuei Igarashi
INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY 41 ( 12 ) 2538 - 2545 2009.12
Language：English Publishing type：Research paper (scientific journal)
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Identification and characterization of a diamine exporter in colon epithelial cells Reviewed
Takeshi Uemura, Hagit F. Yerushalmi, George Tsaprailis, David E. Stringer, Kirk E. Pastorian, Leo Hawel, Craig V. Byus, Eugene W. Gerner
JOURNAL OF BIOLOGICAL CHEMISTRY 283 ( 39 ) 26428 - 26435 2008.09
Language：English Publishing type：Research paper (scientific journal)
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Identification of a spermidine excretion protein complex (MdtJl) in Escherichia coli Reviewed
Kyohei Higashi, Hiroyuki Ishigure, Risa Demizu, Takeshi Uemura, Kunihiko Nishino, Akihito Yamaguchi, Keiko Kashiwagi, Kazuei Igarashil
JOURNAL OF BACTERIOLOGY 190 ( 3 ) 872 - 878 2008.02
Language：English Publishing type：Research paper (scientific journal)
DOI： 10.1128/JB.01505-07
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Polyamine uptake by DUR3 and SAM3 in Saccharomyces cerevisiae Reviewed
Takeshi Uemura, Keiko Kashiwagi, Kazuei Igarashi
JOURNAL OF BIOLOGICAL CHEMISTRY 282 ( 10 ) 7733 - 7741 2007.03
Language：English Publishing type：Research paper (scientific journal)
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Identification of the cadaverine recognition site on the cadaverine-lysine antiporter CadB Reviewed
Waraporn Soksawatmaekhin, Takeshi Uemura, Natsuko Fukiwake, Keiko Kashiwagi, Kazuei Igarashi
JOURNAL OF BIOLOGICAL CHEMISTRY 281 ( 39 ) 29213 - 29220 2006.09
Language：English Publishing type：Research paper (scientific journal)
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Excretion of putrescine and spermidine by the protein encoded by YKL174c (TPO5) in Saccharomyces cerevisiae Reviewed
K Tachihara, T Uemura, K Kashiwagi, K Igarashi
JOURNAL OF BIOLOGICAL CHEMISTRY 280 ( 13 ) 12637 - 12642 2005.04
Language：English Publishing type：Research paper (scientific journal)
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Uptake of putrescine and spermidine by Gap1p on the plasma membrane in Saccharomyces cerevisiae Reviewed
T Uemura, K Kashiwagi, K Igarashi
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 328 ( 4 ) 1028 - 1033 2005.03
Language：English Publishing type：Research paper (scientific journal)
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Characteristics of the polyamine transporter TPO1 and regulation of its activity and cellular localization by phosphorylation Reviewed
T Uemura, K Tachihara, H Tomitori, K Kashiwagi, K Igarashi
JOURNAL OF BIOLOGICAL CHEMISTRY 280 ( 10 ) 9646 - 9652 2005.03
Language：English Publishing type：Research paper (scientific journal)
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Uptake of GABA and putrescine by UGA4 on the vacuolar membrane in Saccharomyces cerevisiae Reviewed
T Uemura, Y Tomonari, K Kashiwagi, K Igarashi
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 315 ( 4 ) 1082 - 1087 2004.03
Language：English Publishing type：Research paper (scientific journal)
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Intestinal luminal polyamines support the gut colonization of enteric bacterial pathogens by modulating flagellar motility and nitrate respiration. International journal
Tsuyoshi Miki, Shin Kurihara, Takeshi Uemura, Yuta Ami, Masahiro Ito, Takeshi Haneda, Takemitsu Furuchi, Nobuhiko Okada, Tohru Minamino, Yun-Gi Kim
mBio 16 ( 9 ) e0178625 2025.09
Language：English Publishing type：Research paper (scientific journal)
UNLABELLED: Salmonella enterica serovar Typhimurium (STm) is an etiological agent of common foodborne diseases and a major health concern worldwide. STm gastrointestinal infection induces intestinal inflammation, allowing STm outgrowth in the gut lumen by exploiting inflammation-induced host factors. Polyamines, including putrescine and spermidine, are crucial for both intestinal homeostasis and STm infectivity. However, our understanding of polyamines' role in STm infection remains incomplete. This study aimed to elucidate that role. We found that defects in polyamine uptake‒dependent homeostasis altered the expression profiles of genes involved in STm flagellar motility and nitrate respiration. Spermidine supplementation restored the expression of the nar and nap operons, which encode distinct nitrate reductases, in an STm mutant with impaired polyamine homeostasis. Thus, the polyamine homeostasis-defective STm mutant exhibited reduced nitrate respiration, which spermidine supplementation rescued. In contrast, both putrescine and spermidine partially reversed the impaired expression of flagellin in this mutant. Additionally, the mutant exhibited a higher proportion of nonmotile cells compared with the wild-type strain. Finally, we demonstrated that the reduced gut colonization of this mutant was due to decreased nitrate respiration and flagellar motility. Moreover, polyamine supplementation enhanced the luminal growth of STm and a pathobiont, Escherichia coli. Our findings reveal that intestinal luminal polyamines support the growth of enteric bacterial pathogens in the intestinal tract. IMPORTANCE: Microbiota-derived metabolites play crucial roles in gastrointestinal infections caused by enteric pathogens. One notable example is short-chain fatty acids, such as acetate, propionate, and butyrate, which are beneficial for health and protective against infection. This study highlights that the gut microbiota‒derived polyamine spermidine drives luminal growth of enteric bacterial pathogens. The findings suggest that higher luminal levels of polyamines may be a risk factor for enteric infections. Therefore, regulating luminal polyamines could represent a promising therapeutic intervention for gastrointestinal infections.
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NF-E2-related factor 1 suppresses the expression of a spermine oxidase and the production of highly reactive acrolein. International journal
Tomoaki Hirakawa, Megumi Taniuchi, Yoko Iguchi, Sudarma Bogahawaththa, Kiko Yoshitake, Shanika Werellagama, Takeshi Uemura, Tadayuki Tsujita
Scientific reports 15 ( 1 ) 12405 - 12405 2025.04
Language：English Publishing type：Research paper (scientific journal)
Polyamines (putrescine, spermidine, and spermine) are among the most abundant intracellular small molecular metabolites, with concentrations at the mM level. The ratios of these three molecules remain constant under physiological conditions. Stress (i.e. polyamine overload, oxidative stress, aging, infection, etc.) triggers the catabolic conversion of spermine to spermidine, ultimately yielding acrolein and hydrogen peroxide. The potential of acrolein to induce DNA damage and protein denaturation is 1,000 times greater than that of reactive oxygen species. We have shown that these polyamine metabolic pathways also involve the nuclear factor erythroid-2-related factor 1 (NRF1) transcription factor. In our chemically-inducible, liver-specific Nrf1-knockout mice, the polyamine catabolic pathway dominated the anabolic pathway, producing free acrolein and accumulating acrolein-conjugated proteins in vivo. This metabolic feature implicates SMOX as an important causative enzyme. Chromatin immunoprecipitation and reporter assays confirmed that NRF1 directly suppressed Smox expression. This effect was also observed in vitro. Ectopic overexpression of SMOX increased the accumulation of free acrolein and acrolein-conjugated proteins. SMOX knockdown reversed the accumulation of free acrolein and acrolein-conjugated proteins. Our results show that NRF1 typically suppresses Smox expression when NRF1 is downregulated, SMOX is upregulated, and polyamine metabolic pathways are altered, producing low molecular weight polyamines and acrolein.
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Polyamines enhance repeat-associated non-AUG translation from CCUG repeats by stabilizing the tertiary structure of RNA. International journal
Akihiro Oguro, Takeshi Uemura, Kodai Machida, Kanta Kitajiri, Ayasa Tajima, Takemitsu Furuchi, Gota Kawai, Hiroaki Imataka
The Journal of biological chemistry 301 ( 3 ) 108251 - 108251 2025.03
Language：English Publishing type：Research paper (scientific journal)
Repeat expansion disorders are caused by abnormal expansion of microsatellite repeats. Repeat-associated non-AUG (RAN) translation is one of the pathogenic mechanisms underlying repeat expansion disorders, but the exact molecular mechanism underlying RAN translation remains unclear. Polyamines are ubiquitous biogenic amines that are essential for cell proliferation and cellular functions. They are predominantly found in cells in complexes with RNA and influence many cellular events, but the relationship between polyamines and RAN translation is yet to be explored. Here, we show that, in both a cell-free protein synthesis system and cell culture, polyamines promote RAN translation of RNA-containing CCUG repeats. The CCUG-dependent RAN translation is suppressed when cells are depleted of polyamines but can be recovered by the addition of polyamines. Thermal stability analysis revealed that the tertiary structure of the CCUG-repeat RNA is stabilized by the polyamines. Spermine was the most effective polyamine for stabilizing CCUG-repeat RNA and enhancing RAN translation. These results suggest that polyamines, particularly spermine, modulate RAN translation of CCUG-repeat RNA by stabilizing the tertiary structure of the repeat RNA.
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Special Issue "Polyamines in Aging and Disease". International journal
Takeshi Uemura, Yusuke Terui
International journal of molecular sciences 25 ( 22 ) 2024.11
Language：English Publishing type：Research paper (scientific journal)
Polyamines are bioactive amines found in almost all living organisms and are essential for normal cellular functions [...].
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Salmonella Typhimurium exploits host polyamines for assembly of the type 3 secretion machinery. International journal
Tsuyoshi Miki, Takeshi Uemura, Miki Kinoshita, Yuta Ami, Masahiro Ito, Nobuhiko Okada, Takemitsu Furuchi, Shin Kurihara, Takeshi Haneda, Tohru Minamino, Yun-Gi Kim
PLoS biology 22 ( 8 ) e3002731 2024.08
Language：English Publishing type：Research paper (scientific journal)
Bacterial pathogens utilize the factors of their hosts to infect them, but which factors they exploit remain poorly defined. Here, we show that a pathogenic Salmonella enterica serovar Typhimurium (STm) exploits host polyamines for the functional expression of virulence factors. An STm mutant strain lacking principal genes required for polyamine synthesis and transport exhibited impaired infectivity in mice. A polyamine uptake-impaired strain of STm was unable to inject effectors of the type 3 secretion system into host cells due to a failure of needle assembly. STm infection stimulated host polyamine production by increasing arginase expression. The decline in polyamine levels caused by difluoromethylornithine, which inhibits host polyamine production, attenuated STm colonization, whereas polyamine supplementation augmented STm pathogenesis. Our work reveals that host polyamines are a key factor promoting STm infection, and therefore a promising therapeutic target for bacterial infection.
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Caldomycin, a new guanidopolyamine produced by a novel agmatine homocoupling enzyme involved in homospermidine biosynthesis. International journal
Teruyuki Kobayashi, Akihiko Sakamoto, Tamao Hisano, Keiko Kashiwagi, Kazuei Igarashi, Koichi Takao, Takeshi Uemura, Takemitsu Furuchi, Yoshiaki Sugita, Toshiyuki Moriya, Tairo Oshima, Yusuke Terui
Scientific reports 14 ( 1 ) 7566 - 7566 2024.03
Language：English Publishing type：Research paper (scientific journal)
An extreme thermophilic bacterium, Thermus thermophilus produces more than 20 unusual polyamines, but their biosynthetic pathways, including homospermidine, are not yet fully understood. Two types of homospermidine synthases have been identified in plants and bacteria, which use spermidine and putrescine or two molecules of putrescine as substrates. However, homospermidine synthases with such substrate specificity have not been identified in T. thermophilus. Here we identified a novel agmatine homocoupling enzyme that is involved in homospermidine biosynthesis in T. thermophilus. The reaction mechanism is different from that of a previously described homospermidine synthase, and involves conjugation of two molecules of agmatine, which produces a diamidino derivative of homospermidine (caldomycin) as an immediate precursor of homospermidine. We conclude that there is a homospermidine biosynthetic pathway from agmatine via caldomycin synthase followed by ureohydrolase in T. thermophilus. Furthermore, it is shown that caldomycin is a novel compound existing in nature.
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Inhibition of Polyamine Catabolism Reduces Cellular Senescence. International journal
Takeshi Uemura, Miki Matsunaga, Yuka Yokota, Koichi Takao, Takemitsu Furuchi
International journal of molecular sciences 24 ( 17 ) 2023.08
Language：English Publishing type：Research paper (scientific journal)
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.
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Whole Blood Spermine/Spermidine Ratio as a New Indicator of Sarcopenia Status in Older Adults. International journal
Hidenori Sanayama, Kiyonori Ito, Susumu Ookawara, Takeshi Uemura, Yoshio Sakiyama, Hitoshi Sugawara, Kaoru Tabei, Kazuei Igarashi, Kuniyasu Soda
Biomedicines 11 ( 5 ) 2023.05
Language：English Publishing type：Research paper (scientific journal)
Early diagnosis and therapeutic intervention improve the quality of life and prognosis of patients with sarcopenia. The natural polyamines spermine and spermidine are involved in many physiological activities. Therefore, we investigated blood polyamine levels as a potential biomarker for sarcopenia. Subjects were Japanese patients >70 years of age who visited outpatient clinics or resided in nursing homes. Sarcopenia was determined based on muscle mass, muscle strength, and physical performance according to the criteria of the Asian Working Group for Sarcopenia (2019). The analysis included 182 patients (male: 38%, age: 83 [76-90] years). Spermidine levels were higher (p = 0.002) and the spermine/spermidine ratio was lower (p < 0.001) in the sarcopenia group than in the non-sarcopenia group. Polyamine concentration analysis showed that the odds ratios for age and spermidine changed in parallel with sarcopenia progression, and the odds ratio for the spermine/spermidine ratio changed inversely with the degree of sarcopenia progression. Additionally, when the odds ratio was analyzed with spermine/spermidine instead of polyamine concentrations, only for spermine/spermidine, the odds ratio values varied in parallel with the progression of sarcopenia. Based on the present data, we believe that the blood spermine/spermidine ratio may be a diagnostic indicator of risk for sarcopenia.
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Putrescine Biosynthesis from Agmatine by Arginase (TtARG) in Thermus thermophilus. International journal
Teruyuki Kobayashi, Akihiko Sakamoto, Keiko Kashiwagi, Kazuei Igarashi, Koichi Takao, Takeshi Uemura, Toshiyuki Moriya, Tairo Oshima, Yusuke Terui
Journal of biochemistry 2023.03
Language：English Publishing type：Research paper (scientific journal)
In the three domains of life, three biosynthetic pathways are known for putrescine. The first route is conversion of ornithine to putrescine by ornithine decarboxylase (ODC: SpeC), the second route is the conversion of arginine to agmatine by arginine decarboxylase (ADC: SpeA), followed by the conversion of agmatine to putrescine by agmatine ureohydrolase (AUH: SpeB), and the third route is the conversion of agmatine to N-carbamoylputrescine by agmatine deiminase (agmatine iminohydrolase, AIH), followed by the conversion of N-carbamoylputrescine to putrescine by N-carbamoylputrescine amidohydrolase (NCPAH). An extreme thermophile, Thermus thermophilus produces putrescine, although this bacterium lacks homologs for putrescine synthesizing pathways such as ODC, AUH, AIH and NCPAH. To identify genes involved in putrescine biosynthesis in T. thermophilus, putrescine biosynthesis was examined by disruption of a predicted gene for agmatinase (agmatine ureohydrolase), or by using purified enzyme. It was found that arginase (TTHA1496) showed an agmatinase activity utilizing agmatine as a substrate. These results indicate that this bacterium can use arginase for putrescine biosynthesis. Arginase is a major contributor to putrescine biosynthesis under physiological conditions. The presence of an alternative pathway for converting agmatine into putrescine is functionally important for polyamine metabolism supporting survival at extreme environments.
DOI： 10.1093/jb/mvad026
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Positive Correlation between Relative Concentration of Spermine to Spermidine in Whole Blood and Skeletal Muscle Mass Index: A Possible Indicator of Sarcopenia and Prognosis of Hemodialysis Patients. International journal
Hidenori Sanayama, Kiyonori Ito, Susumu Ookawara, Takeshi Uemura, Sojiro Imai, Satoshi Kiryu, Miho Iguchi, Yoshio Sakiyama, Hitoshi Sugawara, Yoshiyuki Morishita, Kaoru Tabei, Kazuei Igarashi, Kuniyasu Soda
Biomedicines 11 ( 3 ) 2023.03
Language：English Publishing type：Research paper (scientific journal)
Several mechanisms strictly regulate polyamine concentration, and blood polyamines are excreted in urine. This indicates polyamine accumulation in renal dysfunction, and studies have shown increased blood polyamine concentrations in patients with renal failure. Hemodialysis (HD) may compensate for polyamine excretion; however, little is known about polyamine excretion. We measured whole-blood polyamine levels in patients on HD and examined the relationship between polyamine concentrations and indicators associated with health status. Study participants were 59 hemodialysis patients (median age: 70.0 years) at Minami-Uonuma City Hospital and 26 healthy volunteers (median age: 44.5 years). Whole-blood spermidine levels were higher and spermine/spermidine ratio (SPM/SPD) was lower in hemodialysis patients. Hemodialysis showed SPD efflux into the dialysate; however, blood polyamine levels were not altered by hemodialysis and appeared to be minimally excreted. The skeletal muscle mass index (SMI), which was positively correlated with hand grip strength and serum albumin level, was positively correlated with SPM/SPD. Given that sarcopenia and low serum albumin levels are reported risk factors for poor prognosis in HD patients, whole blood SPM/SPD in hemodialysis patients may be a new indicator of the prognosis and health status of HD patients.
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Urinary Amino Acid-Conjugated Acrolein and Taurine as New Biomarkers for Detection of Dementia. International journal
Madoka Yoshida, Takeshi Uemura, Mutsumi Mizoi, Masaaki Waragai, Akihiko Sakamoto, Yusuke Terui, Keiko Kashiwagi, Kazuei Igarashi
Journal of Alzheimer's disease : JAD 2023.01
Language：English Publishing type：Research paper (scientific journal)
BACKGROUND: Dementia, including Alzheimer's disease (AD), is one of the serious diseases at advanced age, and its early detection is important for maintaining quality of life (QOL). OBJECTIVE: In this study, we sought novel biomarkers for dementia in urine. METHODS: Samples of urine were collected from 57 control subjects without dementia, 62 mild cognitive impairment (MCI) patients, and 42 AD patients. Mini-Mental State Examination (MMSE) was evaluated when subjects were examined by medical doctors. Urinary amino acid (lysine)-conjugated acrolein (AC-Acro) was measured using N ɛ -(3-formyl-3, 4-dehydropiperidine) lysine (FDP-Lys) ELISA kit, and taurine content was measured using a taurine assay kit. Values were normalized by creatinine content which was measured with the colorimetric assay kit. RESULTS: We found that urinary amino acid (lysine)-conjugated acrolein (AC-Acro) and taurine negatively correlated with MMSE score and are significantly lower in dementia patients compared to the normal subjects. When AC-Acro and taurine were evaluated together with age using an artificial neural network model, median relative risk values for subjects with AD, subjects with mild cognitive impairment, and control subjects were 0.96, 0.53, and 0.06, respectively. CONCLUSION: Since urine is relatively easy to collect, our findings provide a novel biomarker for dementia without invasiveness.
DOI： 10.3233/JAD-220912
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蛋白質抱合アクロレイン、IL-6並びにCRP測定に基づく脳梗塞リスク評価による脳梗塞発症者数の減少 Reviewed
五十嵐一衛, 植村武史, 柏木敬子
未病と抗老化 2020.06
Language：Japanese
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Decrease of Patients with Brain Infarction through Evaluation of Relative Risk Value of Brain Infarction by Measurement of Protein-Conjugated Acrolein, IL-6 and CRP in Plasma Together with Age Reviewed
Takeshi Uemura, Tetsuto Kanzaki, Katsuhiko Ishizawa, Keiko Kashiwagi, Kazuei Igarashi
Biomark J 6 ( 1 ) 1 - 3 2020.02
Language：English Publishing type：Research paper (scientific journal)
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加齢による脳梗塞悪化メカニズムと新規脳梗塞予防薬の探索 Reviewed
植村武史, 渡辺健太, 柏木敬子, 五十嵐一衛
未病と抗老化 27 39 - 43 2018.11
Authorship：Lead author Language：Japanese Publishing type：Research paper (scientific journal)
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精神疾患患者における脳障害度、組織障害バイオマーカー及び薬物療法の関連
吉田 円, 神崎 哲人, 溝井 睦美, 中村 瑞穂, 植村 武史, 三森 盛亮, 鵜重 順康, 関根 慶輔, 石井 千博, 吉見 太朗, 安井 玲子, 安川 明香, 佐藤 護, 岡元 誠子, 久岡 哲也, 三浦 正史, 草西 俊, 村上 佳奈子, 中野 知恵子, 水田 康彦, 三島 修一, 早川 達郎, 塚田 和美, 柏木 敬子, 五十嵐 一衛
日本薬学会年会要旨集 137年会 ( 3 ) 71 - 71 2017.03
Language：Japanese Publisher：(公社)日本薬学会
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甲状腺穿刺吸引細胞診施行後に自宅で死亡した1剖検例 Reviewed
垣内 康宏, 赤坂 喜久, 間下 恭平, 井戸田 望, 宮森 大輔, 小林 正樹, 高坂 友和, 植村 武史, 一家 綱邦, 池谷 博
日本法医学雑誌 68 ( 2 ) 295 - 295 2014.12
Language：Japanese Publisher：(NPO)日本法医学会
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月経困難症治療薬を内服中の若年女性に生じた肺血栓塞栓症の一剖検例 Reviewed
井戸田 望, 宮森 大輔, 垣内 康宏, 小林 正樹, 高坂 友和, 植村 武史, 一家 綱邦, 赤坂 喜久, 間下 恭平, 池谷 博
日本法医学雑誌 68 ( 2 ) 293 - 294 2014.12
Language：Japanese Publisher：(NPO)日本法医学会
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羊水塞栓症による母体死亡の1例
宮森 大輔, 田中 由香, 赤坂 喜久, 石川 昂, 植村 武史, 池谷 博
日本法医学雑誌 67 ( 2 ) 170 - 170 2013.12
Language：Japanese Publisher：(NPO)日本法医学会
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解剖症例におけるアルコール関連死の検討
宮森 大輔, 池谷 博, 植村 武史, 高坂 友和, 安 炳文, 山畑 佳篤, 太田 凡
中毒研究 26 ( 3 ) 267 - 267 2013.09
Language：Japanese Publisher：(株)へるす出版
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アセトアルデヒドの肝細胞毒性には、スペルミンオキシダーゼが関与する
植村 武史, 高坂 友和, 宮森 大輔, 吉本 寛司, 池谷 博
日本法医学雑誌 67 ( 1 ) 88 - 88 2013.05
Language：Japanese Publisher：(NPO)日本法医学会
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Polyamine transport systems in yeast Reviewed
T Uemura, K Tachihara, K Kashiwagi, K Igarashi
YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN 125 58 - 59 2005