bims-polyam 2023-04-02 papers

bims-polyam

Biomed News

on Polyamines

Issue of 2023‒04‒02
twenty papers selected by
Sebastian J. Hofer
University of Graz

Ornithine aminotransferase supports polyamine synthesis in pancreatic cancer.
Cryo-EM structure of human eIF5A-DHS complex reveals the molecular basis of hypusination-associated neurodegenerative disorders.
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.
Spermidine enhances the efficacy of adjuvant in HBV vaccination in mice.
Spermidine ameliorates colitis via induction of anti-inflammatory macrophages and prevention of intestinal dysbiosis.
Putrescine Biosynthesis from Agmatine by Arginase (TtARG) in Thermus thermophilus.
More Than a Diamine Oxidase Inhibitor: L-Aminoguanidine Modulates Polyamine-Related Abiotic Stress Responses of Plants.
Chronic sleep loss sensitizes Drosophila melanogaster to nitrogen stress.
Reduction of Spermine Synthase Suppresses Tau Accumulation Through Autophagy Modulation in Tauopathy.
Exploration of the Antioxidant Effect of Spermidine on the Ovary and Screening and Identification of Differentially Expressed Proteins.
Understanding the Effects of Trenbolone Acetate, Polyamine Precursors, and Polyamines on Proliferation, Protein Synthesis Rates, and the Abundance of Genes Involved in Myoblast Growth, Polyamine Biosynthesis, and Protein Synthesis in Murine Myoblasts.
Nitric oxide promotes adventitious root formation in cucumber under cadmium stress through improving antioxidant system, regulating glycolysis pathway and polyamine homeostasis.
Putrescine supplementation shifts macrophage L-arginine metabolism related-genes reducing Leishmania amazonensis infection.
Spermidine Rescues Bioenergetic and Mitophagy Deficits Induced by Disease-Associated Tau Protein.
Analysis of gene expression related to polyamine concentration and dimorphism induced in ornithine decarboxylase (odc) and spermidine synthase (spd) Ustilago maydis mutants.
Putrescine transformation to other forms of polyamines in filling grain embryos functioned in enhancing the resistance of maize plants to drought stress.
Spermidine Synthase and Saccharopine Reductase Have Co-Expression Patterns Both in Basidiomycetes with Fusion Form and Ascomycetes with Separate Form.
The oncogenic properties of the EWSR1::CREM fusion gene are associated with polyamine metabolism.
α,ω-Diacyl-Substituted Analogues of Natural and Unnatural Polyamines: Identification of Potent Bactericides That Selectively Target Bacterial Membranes.
Polyamines inhibit abscisic acid-induced stomatal closure by scavenging hydrogen peroxide.

Nature. 2023 Mar 29.

Ornithine aminotransferase supports polyamine synthesis in pancreatic cancer.

Min-Sik Lee, Courtney Dennis, Insia Naqvi, Lucas Dailey, Alireza Lorzadeh, George Ye, Tamara Zaytouni, Ashley Adler, Daniel S Hitchcock, Lin Lin, Megan T Hoffman, Aladdin M Bhuiyan, Jaimie L Barth, Miranda E Machacek, Mari Mino-Kenudson, Stephanie K Dougan, Unmesh Jadhav, Clary B Clish, Nada Y Kalaany.

There is a need to develop effective therapies for pancreatic ductal adenocarcinoma (PDA), a highly lethal malignancy with increasing incidence1 and poor prognosis2. Although targeting tumour metabolism has been the focus of intense investigation for more than a decade, tumour metabolic plasticity and high risk of toxicity have limited this anticancer strategy3,4. Here we use genetic and pharmacological approaches in human and mouse in vitro and in vivo models to show that PDA has a distinct dependence on de novo ornithine synthesis from glutamine. We find that this process, which is mediated through ornithine aminotransferase (OAT), supports polyamine synthesis and is required for tumour growth. This directional OAT activity is usually largely restricted to infancy and contrasts with the reliance of most adult normal tissues and other cancer types on arginine-derived ornithine for polyamine synthesis5,6. This dependency associates with arginine depletion in the PDA tumour microenvironment and is driven by mutant KRAS. Activated KRAS induces the expression of OAT and polyamine synthesis enzymes, leading to alterations in the transcriptome and open chromatin landscape in PDA tumour cells. The distinct dependence of PDA, but not normal tissue, on OAT-mediated de novo ornithine synthesis provides an attractive therapeutic window for treating patients with pancreatic cancer with minimal toxicity.

DOI: https://doi.org/10.1038/s41586-023-05891-2
Nat Commun. 2023 Mar 27. 14(1): 1698

Cryo-EM structure of human eIF5A-DHS complex reveals the molecular basis of hypusination-associated neurodegenerative disorders.

Elżbieta Wątor, Piotr Wilk, Artur Biela, Michał Rawski, Krzysztof M Zak, Wieland Steinchen, Gert Bange, Sebastian Glatt, Przemysław Grudnik.

Hypusination is a unique post-translational modification of the eukaryotic translation factor 5A (eIF5A) that is essential for overcoming ribosome stalling at polyproline sequence stretches. The initial step of hypusination, the formation of deoxyhypusine, is catalyzed by deoxyhypusine synthase (DHS), however, the molecular details of the DHS-mediated reaction remained elusive. Recently, patient-derived variants of DHS and eIF5A have been linked to rare neurodevelopmental disorders. Here, we present the cryo-EM structure of the human eIF5A-DHS complex at 2.8 Å resolution and a crystal structure of DHS trapped in the key reaction transition state. Furthermore, we show that disease-associated DHS variants influence the complex formation and hypusination efficiency. Hence, our work dissects the molecular details of the deoxyhypusine synthesis reaction and reveals how clinically-relevant mutations affect this crucial cellular process.

DOI: https://doi.org/10.1038/s41467-023-37305-2
Biomedicines. 2023 Mar 01. pii: 746. [Epub ahead of print]11(3):

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.

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.

  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.

Keywords:  hemodialysis; polyamine; sarcopenia; spermidine; spermine

DOI:  https://doi.org/10.3390/biomedicines11030746
Hepatol Commun. 2023 04 01. pii: e0104. [Epub ahead of print]7(4):

Spermidine enhances the efficacy of adjuvant in HBV vaccination in mice.

Daisuke Ito, Hiroyasu Ito, Tatsuya Ando, Yasuhiro Sakai, Takayasu Ideta, Ken J Ishii, Tetsuya Ishikawa, Masahito Shimizu.

Background: Various vaccine adjuvants have been developed to eliminate HBV from patients with chronic HBV infection. In addition, spermidine (SPD), a type of polyamine, has been reported to enhance the activity of immune cells. In the present study, we investigated whether the combination of SPD and vaccine adjuvant enhances the HBV antigen-specific immune response to HBV vaccination. Methods: Wild-type and HBV-transgenic (HBV-Tg) mice were vaccinated 2 or 3 times. SPD was orally administered in drinking water. Cyclic guanosine monophosphate-AMP (cGAMP) and nanoparticulate CpG-ODN (K3-SPG) were used as the HBV vaccine adjuvants. The HBV antigen-specific immune response was evaluated by measuring the HBsAb titer in blood collected over time and the number of interferon-γ producing cells by enzyme-linked immunospot assay. Results: The administration of HBsAg + cGAMP + SPD or HBsAg + K3-SPG + SPD significantly enhanced HBsAg-specific interferon-γ production by CD8 T cells from wild-type and HBV-Tg mice. The administration of HBsAg, cGAMP, and SPD increased serum HBsAb levels in wild-type and HBV-Tg mice. In HBV-Tg mice, the administration of SPD + cGAMP or SPD + K3-SPG with HBV vaccination significantly reduced HBsAg levels in the liver and serum.CONCLUSIONS: These results indicate that the combination of HBV vaccine adjuvant and SPD induces a stronger humoral and cellular immune response through T-cell activation. These treatments may support the development of a strategy to completely eliminate HBV.

DOI: https://doi.org/10.1097/HC9.0000000000000104
J Crohns Colitis. 2023 Mar 30. pii: jjad058. [Epub ahead of print]

Spermidine ameliorates colitis via induction of anti-inflammatory macrophages and prevention of intestinal dysbiosis.

Anna Niechcial, Marlene Schwarzfischer, Marcin Wawrzyniak, Kirstin Atrott, Andrea Laimbacher, Yasser Morsy, Egle Katkeviciute, Janine Häfliger, Patrick Westermann, Cezmi A Akdis, Michael Scharl, Marianne R Spalinger.

  BACKGROUND AND AIMS: Exacerbated immune activation, intestinal dysbiosis, and a disrupted intestinal barrier are common features among inflammatory bowel disease (IBD) patients. The polyamine spermidine, which is naturally present in all living organisms, is an integral component of the human diet, and exerts beneficial effects in human diseases. Here, we investigated whether spermidine treatment ameliorates intestinal inflammation and offers therapeutic potential for IBD treatment.METHODS: We assessed the effect of oral spermidine administration on colitis severity in the T cell transfer colitis model in Rag2 -/- mice by analysis of endoscopy, histology, and molecular inflammation markers. The effects on the intestinal microbiome were determined by 16S sequencing of mouse feces. The impact on intestinal barrier integrity was evaluated in co-cultures of patient-derived macrophages with intestinal epithelial cells.
RESULTS: Spermidine administration protected mice from intestinal inflammation in a dose-dependent manner. While T helper cell subsets remained unaffected, spermidine promoted anti-inflammatory macrophages and prevented the microbiome shift from Firmicutes and Bacteroides to Proteobacteria, maintaining a healthy gut microbiome. Consistent with spermidine as a potent activator of the anti-inflammatory molecule protein tyrosine phosphatase non-receptor type 2 (PTPN2), its colitis-protective effect was dependent on PTPN2 in intestinal epithelial cells and in myeloid cells. The loss of PTPN2 in epithelial and myeloid cells, but not in T cells, abrogated the barrier-protective, anti-inflammatory effect of spermidine and prevented the anti-inflammatory polarization of macrophages.
CONCLUSION: Spermidine reduces intestinal inflammation by promoting anti-inflammatory macrophages, maintaining a healthy microbiome, and preserving epithelial barrier integrity in a PTPN2-dependent manner.

Keywords:  IBD; PTPN2; anti-inflammatory macrophages; dysbiosis; spermidine

DOI:  https://doi.org/10.1093/ecco-jcc/jjad058
J Biochem. 2023 Mar 31. pii: mvad026. [Epub ahead of print]

Putrescine Biosynthesis from Agmatine by Arginase (TtARG) in Thermus thermophilus.

Teruyuki Kobayashi, Akihiko Sakamoto, Keiko Kashiwagi, Kazuei Igarashi, Koichi Takao, Takeshi Uemura, Toshiyuki Moriya, Tairo Oshima, Yusuke Terui.

  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.

Keywords:   Thermus thermophilus ; Agmatine; Aminopropylagmatine ureohydrolase; Arginase; Polyamine metabolism; Putrescine

DOI:  https://doi.org/10.1093/jb/mvad026
Life (Basel). 2023 Mar 09. pii: 747. [Epub ahead of print]13(3):

More Than a Diamine Oxidase Inhibitor: L-Aminoguanidine Modulates Polyamine-Related Abiotic Stress Responses of Plants.

Zoltán Márton Köhler, Ágnes Szepesi.

  L-aminoguanidine (AG) is an inhibitor frequently used for investigating plant abiotic stress responses; however, its exact mode of action is not well understood. Many studies used this compound as a specific diamine oxidase inhibitor, whereas other studies used it for reducing nitric oxide (NO) production. Recent studies suggest its antiglycation effect; however, this remains elusive in plants. This review summarises our current knowledge about different targets of AG in plants. Our recommendation is to use AG as a modulator of polyamine-related mechanisms rather than a specific inhibitor. In the future overall investigation is needed to decipher the exact mechanisms of AG. More careful application of AG could give more insight into plant abiotic stress responses.

Keywords:  aminoguanidine; copper amine oxidase; nitric oxide synthase inhibitor; plant; polyamines

DOI:  https://doi.org/10.3390/life13030747
Curr Biol. 2023 Mar 20. pii: S0960-9822(23)00296-8. [Epub ahead of print]

Chronic sleep loss sensitizes Drosophila melanogaster to nitrogen stress.

Joseph L Bedont, Anna Kolesnik, Pavel Pivarshev, Dania Malik, Cynthia T Hsu, Aalim Weljie, Amita Sehgal.

  Chronic sleep loss profoundly impacts metabolic health and shortens lifespan, but studies of the mechanisms involved have focused largely on acute sleep deprivation.1,2 To identify metabolic consequences of chronically reduced sleep, we conducted unbiased metabolomics on heads of three adult Drosophila short-sleeping mutants with very different mechanisms of sleep loss: fumin (fmn), redeye (rye), and sleepless (sss).3,4,5,6,7 Common features included elevated ornithine and polyamines, with lipid, acyl-carnitine, and TCA cycle changes suggesting mitochondrial dysfunction. Studies of excretion demonstrate inefficient nitrogen elimination in adult sleep mutants, likely contributing to their polyamine accumulation. Increasing levels of polyamines, particularly putrescine, promote sleep in control flies but poison sleep mutants. This parallels the broadly enhanced toxicity of high dietary nitrogen load from protein in chronically sleep-restricted Drosophila, including both sleep mutants and flies with hyper-activated wake-promoting neurons. Together, our results implicate nitrogen stress as a novel mechanism linking chronic sleep loss to adverse health outcomes-and perhaps for linking food and sleep homeostasis at the cellular level in healthy organisms.

Keywords:  Drosophila; excretion; lifespan; lipid; metabolism; mitochondria; polyamine; protein; putrescine; sleep

DOI:  https://doi.org/10.1016/j.cub.2023.03.008
bioRxiv. 2023 Mar 18. pii: 2023.03.17.533015. [Epub ahead of print]

Reduction of Spermine Synthase Suppresses Tau Accumulation Through Autophagy Modulation in Tauopathy.

Xianzun Tao, Jiaqi Liu, Zoraida Diaz-Perez, Jackson R Foley, Tracy Murray Stewart, Robert A Casero, R Grace Zhai.

Tauopathy, including Alzheimer Disease (AD), is characterized by Tau protein accumulation and autophagy dysregulation. Emerging evidence connects polyamine metabolism with the autophagy pathway, however the role of polyamines in Tauopathy remains unclear. In the present study we investigated the role of spermine synthase (SMS) in autophagy regulation and tau protein processing in Drosophila and human cellular models of Tauopathy. Our previous study showed that Drosophila spermine synthase ( dSms ) deficiency impairs lysosomal function and blocks autophagy flux. Interestingly, partial loss-of-function of SMS in heterozygous dSms flies extends lifespan and improves the climbing performance of flies with human Tau (hTau) overexpression. Mechanistic analysis showed that heterozygous loss-of-function mutation of dSms reduces hTau protein accumulation through enhancing autophagic flux. Measurement of polyamine levels detected a mild elevation of spermidine in flies with heterozygous loss of dSms . SMS knock-down in human neuronal or glial cells also upregulates autophagic flux and reduces Tau protein accumulation. Proteomics analysis of postmortem brain tissue from AD patients showed a significant albeit modest elevation of SMS protein level in AD-relevant brain regions compared to that of control brains consistently across several datasets. Taken together, our study uncovers a correlation between SMS protein level and AD pathogenesis and reveals that SMS reduction upregulates autophagy, promotes Tau clearance, and reduces Tau protein accumulation. These findings provide a new potential therapeutic target of Tauopathy.

DOI: https://doi.org/10.1101/2023.03.17.533015
Int J Mol Sci. 2023 Mar 17. pii: 5793. [Epub ahead of print]24(6):

Exploration of the Antioxidant Effect of Spermidine on the Ovary and Screening and Identification of Differentially Expressed Proteins.

Dongmei Jiang, Yongni Guo, Chunyang Niu, Shiyun Long, Yilong Jiang, Zelong Wang, Xin Wang, Qian Sun, Weikang Ling, Xiaoguang An, Chengweng Ji, Hua Zhao, Bo Kang.

  Spermidine is a naturally occurring polyamine compound that has many biological functions, such as inducing autophagy and anti-inflammatory and anti-aging effects. Spermidine can affect follicular development and thus protect ovarian function. In this study, ICR mice were fed exogenous spermidine drinking water for three months to explore the regulation of ovarian function by spermidine. The results showed that the number of atretic follicles in the ovaries of spermidine-treated mice was significantly lower than that in the control group. Antioxidant enzyme activities (SOD, CAT, T-AOC) significantly increased, and MDA levels significantly decreased. The expression of autophagy protein (Beclin 1 and microtubule-associated protein 1 light chain 3 LC3 II/I) significantly increased, and the expression of the polyubiquitin-binding protein p62/SQSTM 1 significantly decreased. Moreover, we found 424 differentially expressed proteins (DEPs) were upregulated, and 257 were downregulated using proteomic sequencing. Gene Ontology and KEGG analyses showed that these DEPs were mainly involved in lipid metabolism, oxidative metabolism and hormone production pathways. In conclusion, spermidine protects ovarian function by reducing the number of atresia follicles and regulating the level of autophagy protein, antioxidant enzyme activity, and polyamine metabolism in mice.

Keywords:  antioxidant; autophagy; ovary; proteomics; spermidine

DOI:  https://doi.org/10.3390/ijms24065793
Biology (Basel). 2023 Mar 14. pii: 446. [Epub ahead of print]12(3):

Understanding the Effects of Trenbolone Acetate, Polyamine Precursors, and Polyamines on Proliferation, Protein Synthesis Rates, and the Abundance of Genes Involved in Myoblast Growth, Polyamine Biosynthesis, and Protein Synthesis in Murine Myoblasts.

Laura A Motsinger, Lillian L Okamoto, Nikole E Ineck, Brynne A Udy, Christopher L Erickson, Youssef Harraq, Caleb C Reichhardt, Gordon K Murdoch, Kara Jean Thornton.

  Research suggests that androgens increase skeletal muscle growth by modulating polyamine biosynthesis. As such, the objective of this study was to investigate effects of anabolic hormones, polyamine precursors, and polyamines relative to proliferation, protein synthesis, and the abundance of mRNA involved in polyamine biosynthesis, proliferation, and protein synthesis in C2C12 and Sol8 cells. Cultures were treated with anabolic hormones (trenbolone acetate and/or estradiol), polyamine precursors (methionine or ornithine), or polyamines (putrescine, spermidine, or spermine). Messenger RNA was isolated 0.5 or 1, 12, or 24 h post-treatment. The cell type had no effect (p > 0.10) on proliferation, protein synthesis, or mRNA abundance at any time point. Each treatment increased (p < 0.01) proliferation, and anabolic hormones increased (p = 0.04) protein synthesis. Polyamines increased (p < 0.05) the abundance of mRNA involved in polyamine biosynthesis, proliferation, and protein synthesis. Treatment with polyamine precursors decreased (p < 0.05) the abundance of mRNA involved in proliferation and protein synthesis. Overall, C2C12 and Sol8 myoblasts do not differ (p > 0.10) in proliferation, protein synthesis, or mRNA abundance at the time points assessed. Furthermore, anabolic hormones, polyamines, and polyamine precursors increase proliferation and protein synthesis, and polyamines and their precursors alter the abundance of mRNA involved in growth.

Keywords:  anabolic hormones; estradiol; myoblast; polyamine; proliferation; protein synthesis; skeletal muscle growth; trenbolone acetate

DOI:  https://doi.org/10.3390/biology12030446
Front Plant Sci. 2023 ;14 1126606

Nitric oxide promotes adventitious root formation in cucumber under cadmium stress through improving antioxidant system, regulating glycolysis pathway and polyamine homeostasis.

Lijuan Niu, Yunlai Tang, Bo Zhu, Zhenfu Huang, Dan Wang, Qiyang Chen, Jian Yu.

  Cadmium (Cd) as a potentially toxic heavy metal that not only pollutes the environment but also interferes with plant growth. Nitric oxide (NO) regulates plant growth and development as well as abiotic stress response. However, the mechanism underpinning NO-induced adventitious root development under Cd stress remains unclear. In this study, cucumber (Cucumis sativus 'Xinchun No. 4') was used as the experimental material to investigate the effect of NO on the development of adventitious roots in cucumber under Cd stress. Our results revealed that, as compared to Cd stress, 10 μM SNP (a NO donor) could considerably increase the number and length of adventitious roots by 127.9% and 289.3%, respectively. Simultaneously, exogenous SNP significantly increased the level of endogenous NO in cucumber explants under Cd stress. Our results revealed that supplementation of Cd with SNP significantly increased endogenous NO content by 65.6% compared with Cd treatment at 48 h. Furthermore, our study indicated that SNP treatment could improve the antioxidant capacity of cucumber explants under Cd stress by up-regulating the gene expression level of antioxidant enzymes, as well as reducing the levels of malondialdehyde (MDA), hydrogen peroxide (H2O2) and superoxide anion ( O 2    · - ) to alleviate oxidative damage and membrane lipid peroxidation. Application of NO resulted in a decrease of the O 2    · - , MDA, and H2O2 level by 39.6%, 31.4% and 60.8% as compared to Cd-alone treatment, respectively. Besides that, SNP treatment significantly increased the expression level of related genes involved in glycolysis processes and polyamine homeostasis. However, application of NO scavenger 2-(4-carboxy -2-phenyl)-4, 4, 5, 5-tetramethy limidazoline -1-oxyl -3-oxide (cPTIO) and the inhibitor tungstate significantly reversed the positive role of NO in promoting the adventitious root formation under Cd stress. These results suggest that exogenous NO can increase the level of endogenous NO, improve antioxidation ability, promote glycolysis pathway and polyamine homeostasis to enhance the occurrence of adventitious roots in cucumber under Cd stress. In summary, NO can effectively alleviate the damage of Cd stress and significantly promote the development of adventitious root of cucumber under Cd stress.

Keywords:  antioxidants; cadmium; glycolysis; nitric oxide; polyamine pathway; rooting response

DOI:  https://doi.org/10.3389/fpls.2023.1126606
PLoS One. 2023 ;18(3): e0283696

Putrescine supplementation shifts macrophage L-arginine metabolism related-genes reducing Leishmania amazonensis infection.

Jonathan Miguel Zanatta, Stephanie Maia Acuña, Yan de Souza Angelo, Camilla de Almeida Bento, Jean Pierre Schatzman Peron, Beatriz Simonsen Stolf, Sandra Marcia Muxel.

Leishmania is a protozoan that causes leishmaniasis, a neglected tropical disease with clinical manifestations classified as cutaneous, mucocutaneous, and visceral leishmaniasis. In the infection context, the parasite can modulate macrophage gene expression affecting the microbicidal activity and immune response. The metabolism of L-arginine into polyamines putrescine, spermidine, and spermine reduces nitric oxide (NO) production, favoring Leishmania survival. Here, we investigate the effect of supplementation with L-arginine and polyamines in infection of murine BALB/c macrophages by L. amazonensis and in the transcriptional regulation of genes involved in arginine metabolism and proinflammatory response. We showed a reduction in the percentage of infected macrophages upon putrescine supplementation compared to L-arginine, spermidine, and spermine supplementation. Unexpectedly, deprivation of L-arginine increased nitric oxide synthase (Nos2) gene expression without changes in NO production. Putrescine supplementation increased transcript levels of polyamine metabolism-related genes Arg2, ornithine decarboxylase (Odc1), Spermidine synthase (SpdS), and Spermine synthase (SpmS), but reduced Arg1 in L. amazonensis infected macrophages, while spermidine and spermine promoted opposite effects. Putrescine increased Nos2 expression without leading to NO production, while L-arginine plus spermine led to NO production in uninfected macrophages, suggesting that polyamines can induce NO production. Besides, L-arginine supplementation reduced Il-1b during infection, and L-arginine or L-arginine plus putrescine increased Mcp1 at 24h of infection, suggesting that polyamines availability can interfere with cytokine/chemokine production. Our data showed that putrescine shifts L-arginine-metabolism related-genes on BALB/c macrophages and affects infection by L. amazonensis.

DOI: https://doi.org/10.1371/journal.pone.0283696
Int J Mol Sci. 2023 Mar 10. pii: 5297. [Epub ahead of print]24(6):

Spermidine Rescues Bioenergetic and Mitophagy Deficits Induced by Disease-Associated Tau Protein.

Lauren H Fairley, Imane Lejri, Amandine Grimm, Anne Eckert.

  Abnormal tau build-up is a hallmark of Alzheimer's disease (AD) and more than 20 other serious neurodegenerative diseases. Mitochondria are paramount organelles playing a predominant role in cellular bioenergetics, namely by providing the main source of cellular energy via adenosine triphosphate generation. Abnormal tau impairs almost every aspect of mitochondrial function, from mitochondrial respiration to mitophagy. The aim of our study was to investigate the effects of spermidine, a polyamine which exerts neuroprotective effects, on mitochondrial function in a cellular model of tauopathy. Recent evidence identified autophagy as the main mechanism of action of spermidine on life-span prolongation and neuroprotection, but the effects of spermidine on abnormal tau-induced mitochondrial dysfunction have not yet been investigated. We used SH-SY5Y cells stably expressing a mutant form of human tau protein (P301L tau mutation) or cells expressing the empty vector (control cells). We showed that spermidine improved mitochondrial respiration, mitochondrial membrane potential as well as adenosine triphosphate (ATP) production in both control and P301L tau-expressing cells. We also showed that spermidine decreased the level of free radicals, increased autophagy and restored P301L tau-induced impairments in mitophagy. Overall, our findings suggest that spermidine supplementation might represent an attractive therapeutic approach to prevent/counteract tau-related mitochondrial impairments.

Keywords:  autophagy; bioenergetics; mitochondria; mitophagy; spermidine; tau

DOI:  https://doi.org/10.3390/ijms24065297
Fungal Genet Biol. 2023 Mar 28. pii: S1087-1845(23)00023-3. [Epub ahead of print] 103792

Analysis of gene expression related to polyamine concentration and dimorphism induced in ornithine decarboxylase (odc) and spermidine synthase (spd) Ustilago maydis mutants.

Fernando Pérez Rodríguez, Laura Valdés-Santiago, Jorge Noé García-Chávez, José Luis Castro-Guillén, José Ruiz-Herrera.

  Polyamines are ubiquitous small organic cations, and their roles as regulators of several cellular processes are widely recognized. They are implicated in the key stages of the fungal life cycle. Ustilago maydis is a phytopathogenic fungus, the causal agent of common smut of maize and a model system to understand dimorphism and virulence. U. maydis grows in yeast form at pH 7 and it can develop its mycelial form in vitro at pH 3. Δodc mutants that are unable to synthesize polyamines, grew as yeast at pH 3 with a low putrescine concentration, and to complete its dimorphic transition high putrescine concentration was required. Δspd mutants required spermidine to grow and cannot form mycelium at pH 3. In this work, the increased expression of the mating genes, mfa1 and mfa2, on Δodc mutants, was related to high putrescine concentration. Global gene expression analysis comparisons of Δodc and Δspd U. maydis mutants indicated that 2,959 genes were differentially expressed in the presence of exogenous putrescine at pH 7 and 475 genes at pH 3. While, in Δspd mutant, the expression of 1,426 genes was affected by exogenous spermine concentration at pH 7 and 11 genes at pH 3. Additionally, we identified 28 transcriptional modules with correlated expression during seven tested conditions: mutant genotype, morphology (yeast, and mycelium), pH, and putrescine or spermidine concentration. Furthermore, significant differences in transcript levels were noted for genes in modules relating to pH and genotype genes involved in ribosome biogenesis, mitochondrial oxidative phosphorylation, N-glycan synthesis, and Glycosylphosphatidylinositol (GPI)-anchor. In summary, our results offer a valuable tool for the identification of potential factors involved in phenomena related to polyamines and dimorphism.

Keywords:  dimorphism; microarray; phytopathogenic fungus; putrescine; spermidine

DOI:  https://doi.org/10.1016/j.fgb.2023.103792
Plant Physiol Biochem. 2023 Mar 22. pii: S0981-9428(23)00158-4. [Epub ahead of print]197 107654

Putrescine transformation to other forms of polyamines in filling grain embryos functioned in enhancing the resistance of maize plants to drought stress.

Ben-Xue Chen, Yan-Bing Li, Huai-Pan Liu, Ronald Kurtenbach.

  Polyamines (PAs), one of plant growth regulators, play an important role in the plant resistance to drought stress. However, the precise function of putrescine (Put) transformation to other forms of PAs is not clear in filling maize grain embryos. In this study, two maize (Zea mays L.) cultivars, Yedan No. 13 (drought-resistant) and Xundan No. 22 (drought-sensitive), were used as experimental materials. Maize was planted in big plastic basins during whole growth period, and from the 25th day after fertilization, the plants were treated with drought (-1.0 MPa), PAs and inhibitors for 12 d. The experiments were performed during three consecutive years. The changes in the levels of three main free PAs, Put, spermidine (Spd) and spermine (Spm), covalently conjugated PAs (perchloric acid-soluble), covalently bound PAs (perchloric acid-insoluble), the activities of arginine decarboxylase, S-adenosylmethionine decarboxylase, and transglutaminase were investigated in embryos of filling grains. During drought stress, free Put increased from 109 to 367 nmol g-1 FW and from 107 to 142 nmol g-1 FW in Xundan 22 and in Yedan 13, respectively. Meanwhile, free Spd, free Spm and bound Put increased 2.7, 3.0 and 4.2 times in Yedan 13, respectively, and they merely increased about 1.5 times in Xundan 22. These results suggested that free Spd/Spm and bound Put, which were transformed from free Put, were possibly involved in drought resistance. Exogenous Spd treatment enhanced the drought-induced increase in endogenous free Spd/Spm content in drought-sensitive Xundan 22, coupled with the increase in drought resistance, as judged by the decrease in ear leaf relative plasma membrane permeability and increases in ear leaf relative water content, 1000-grain weight and grain number per ear. The suggestion was further testified with methylglyoxal-bis guanylhydrazone and o-phenanthrolin treatments. Collectively, it could be inferred that transformation of free Put to free Spd/Spm and bound Put in filling grain embryos functioned in enhancing the resistance of maize plants to soil drought.

Keywords:  Bound polyamine; Conjugated polyamine; Free polyamine; Maize (Zea mays L.) filling grain embryo; Soil drought

DOI:  https://doi.org/10.1016/j.plaphy.2023.107654
J Fungi (Basel). 2023 Mar 14. pii: 352. [Epub ahead of print]9(3):

Spermidine Synthase and Saccharopine Reductase Have Co-Expression Patterns Both in Basidiomycetes with Fusion Form and Ascomycetes with Separate Form.

Yayong Yang, Lei Shi, Xinyu Xu, Jin Wen, Tianyue Xie, Hui Li, Xiaoyu Li, Mengyu Chen, Xinyi Dou, Chengjin Yuan, Hanbing Song, Baogui Xie, Yongxin Tao.

  Gene fusion is a process through which two or more distinct genes are fused into a single chimeric gene. Unlike most harmful fusion genes in cancer cells, in this study, we first found that spermidine synthetase- (SPDS, catalyst of spermidine biosynthesis) and saccharopine reductase- (SR, catalyst of the penultimate step of lysine biosynthesis) encoding genes form a natural chimeric gene, FfSpdsSr, in Flammulina filiformis. Through the cloning of full-length ORFs in different strains and the analysis of alternative splicing in developmental stages, FfSpdsSr has only one copy and unique transcript encoding chimeric SPDS-SR in F. filiformis. By an orthologous gene search of SpdsSr in more than 80 fungi, we found that the chimeric SpdsSr exists in basidiomycetes, while the two separate Spds and Sr independently exist in ascomycetes, chytridiomycetes, and oomycetes. Further, the transcript level of FfSpdsSr was investigated in different developmental stages and under some common environmental factors and stresses by RT-qPCR. The results showed that FfSpdsSr mainly up-regulated in the elongation stage and pileus development of F. filiformis, as well as under blue light, high temperature, H2O2, and MeJA treatments. Moreover, a total of 15 sets of RNA-Seq data, including 218 samples of Neurospora crassa, were downloaded from the GEO database and used to analyze the expression correlation of NcSpds and NcSr. The results showed that the separate NcSpds and NcSr shared highly similar co-expression patterns in the samples with different strains and different nutritional and environmental condition treatments. The chimeric SpdsSr in basidiomycetes and the co-expression pattern of the Spds and Sr in N. crassa indicate the special link of spermidine and lysine in fungi, which may play an important role in the growth and development of fruiting body and in response to the multiple environmental factors and abiotic stresses.

Keywords:  ascomycetes; basidiomycetes; chimeric gene; lysine; spermidine

DOI:  https://doi.org/10.3390/jof9030352
Sci Rep. 2023 Mar 25. 13(1): 4884

The oncogenic properties of the EWSR1::CREM fusion gene are associated with polyamine metabolism.

Heidi Kaprio, Arafat Siddiqui, Lotta Saustila, Vanina D Heuser, Maria Gardberg.

The EWSR1::CREM fusion gene, caused by a chromosomal translocation t(10;22)(p11;q12), has been discovered in divergent malignancies, ranging from low-grade to highly malignant cancers. The translocation gives rise to a chimeric protein, EWSR1::CREM. The molecular mechanisms behind the oncogenic properties of the EWSR1::CREM protein have not previously been systematically characterized. In this study, we performed transcriptional profiling of the melanoma cell line CHL-1, with depletion of endogenous EWSR1::CREM protein using siRNA mediated knockdown. We found that the expression of 712 genes was altered (Log2 fold-change ≥ 2). We performed pathway analysis to identify EWSR1::CREM mediated pathways and cell studies to examine functional differences brought upon by the knockdown. Altered pathways involved cell cycle and proliferation, this was further validated by the cell studies where cell migration was affected as well. Among the target genes with the greatest downregulation, we discovered ODC1-a well-established oncogenic enzyme that can be pharmacologically inhibited and is essential for polyamine synthesis. We found that the main effects seen upon EWSR1::CREM knockdown can be reproduced by directly silencing ODC1 expression. These findings provide novel insights into pathogenesis of tumors harboring a EWSR1::CREM fusion gene, hopefully facilitating the development of novel therapeutic strategies.

DOI: https://doi.org/10.1038/s41598-023-31576-x
Int J Mol Sci. 2023 Mar 20. pii: 5882. [Epub ahead of print]24(6):

α,ω-Diacyl-Substituted Analogues of Natural and Unnatural Polyamines: Identification of Potent Bactericides That Selectively Target Bacterial Membranes.

Dan Chen, Melissa M Cadelis, Florent Rouvier, Thomas Troia, Liam R Edmeades, Kyle Fraser, Evangelene S Gill, Marie-Lise Bourguet-Kondracki, Jean Michel Brunel, Brent R Copp.

  In this study, α-ω-disubstituted polyamines exhibit a range of potentially useful biological activities, including antimicrobial and antibiotic potentiation properties. We have prepared an expanded set of diarylbis(thioureido)polyamines that vary in central polyamine core length, identifying analogues with potent methicillin-resistant Staphylococcus aureus (MRSA), Escherichia coli, Acinetobacter baumannii and Candida albicans growth inhibition properties, in addition to the ability to enhance action of doxycycline towards Gram-negative bacterium Pseudomonas aeruginosa. The observation of associated cytotoxicity/hemolytic properties prompted synthesis of an alternative series of diacylpolyamines that explored aromatic head groups of varying lipophilicity. Examples bearing terminal groups each containing two phenyl rings (15a-f, 16a-f) were found to have optimal intrinsic antimicrobial properties, with MRSA being the most susceptible organism. A lack of observed cytotoxicity or hemolytic properties for all but the longest polyamine chain variants identified these as non-toxic Gram-positive antimicrobials worthy of further study. Analogues bearing either one or three aromatic-ring-containing head groups were either generally devoid of antimicrobial properties (one ring) or cytotoxic/hemolytic (three rings), defining a rather narrow range of head group lipophilicity that affords selectivity for Gram-positive bacterial membranes versus mammalian. Analogue 15d is bactericidal and targets the Gram-positive bacterial membrane.

Keywords:  antibiotic enhancement; antimicrobial activities; polyamine conjugates; thiourea

DOI:  https://doi.org/10.3390/ijms24065882
Physiol Plant. 2023 Apr 01. e13903

Polyamines inhibit abscisic acid-induced stomatal closure by scavenging hydrogen peroxide.

Xu-Dong Liu, Yuan-Yuan Zeng, Xia-Yi Zhang, Xue-Qian Tian, Md Mahadi Hasan, Guang-Qian Yao, Xiang-Wen Fang.

Stomatal closure is regulated by plant hormones and some small molecules to reduce water loss under stress conditions. Both abscisic acid (ABA) and polyamines alone induce stomatal closure; however, whether the physiological functions of ABA and polyamines are synergistic or antagonistic with respect to inducing stomatal closure is still unknown. Here, stomatal movement in response to ABA and/or polyamines was tested in Vicia faba and Arabidopsis thaliana, and the change in the signalling components under stomatal closure was analysed. We found that both polyamines and ABA could induce stomatal closure through similar signalling components, including the synthesis of hydrogen peroxide (H2 O2 ) and nitric oxide (NO) and the accumulation of Ca2+ . However, polyamines partially inhibited ABA-induced stomatal closure both in epidermal peels and in planta by activating antioxidant enzymes, including superoxide dismutase (SOD), peroxidase (POD) and catalase (CAT), to eliminate the ABA-induced increase in H2 O2 . These results strongly indicate that polyamines inhibit abscisic acid-induced stomatal closure, suggesting that polyamines could be used as potential plant growth regulators to increase photosynthesis under mild drought stress. This article is protected by copyright. All rights reserved.

DOI: https://doi.org/10.1111/ppl.13903