bims-polyam Biomed News
on Polyamines
Issue of 2019‒06‒16
thirteen papers selected by
Alexander Ivanov
Engelhardt Institute of Molecular Biology

  1. Medchemcomm. 2019 May 01. 10(5): 778-790
    Holshouser S, Dunworth M, Murray-Stewart T, Peterson YK, Burger P, Kirkpatrick J, Chen HH, Casero RA, Woster PM.
      We have previously described the synthesis and evaluation of 3,5-diamino-1,2,4-triazole analogues as inhibitors of the flavin-dependent histone demethylase LSD1. These compounds are potent inhibitors of LSD1 without activity against monoamine oxidases A and B, and promote the elevation of H3K4me2 levels in tumor cells in vitro. We now report that the cytotoxicity of these analogues in pancreatic tumor cells correlates with the overexpression of LSD1 in each tumor type. In addition, we show that a subset of these 3,5-diamino-1,2,4-triazole analogues inhibit a related flavin-dependent oxidase, the polyamine catabolic enzyme spermine oxidase (SMOX) in vitro.
  2. Front Plant Sci. 2019 ;10 692
    Majumdar R, Minocha R, Lebar MD, Rajasekaran K, Long S, Carter-Wientjes C, Minocha S, Cary JW.
      Polyamines (PAs) are ubiquitous polycations found in plants and other organisms that are essential for growth, development, and resistance against abiotic and biotic stresses. The role of PAs in plant disease resistance depends on the relative abundance of higher PAs [spermidine (Spd), spermine (Spm)] vs. the diamine putrescine (Put) and PA catabolism. With respect to the pathogen, PAs are required to achieve successful pathogenesis of the host. Maize is an important food and feed crop, which is highly susceptible to Aspergillus flavus infection. Upon infection, the fungus produces carcinogenic aflatoxins and numerous other toxic secondary metabolites that adversely affect human health and crop value worldwide. To evaluate the role of PAs in aflatoxin resistance in maize, in vitro kernel infection assays were performed using maize lines that are susceptible (SC212) or resistant (TZAR102, MI82) to aflatoxin production. Results indicated significant induction of both PA biosynthetic and catabolic genes upon A. flavus infection. As compared to the susceptible line, the resistant maize lines showed higher basal expression of PA metabolism genes in mock-inoculated kernels that increased upon fungal infection. In general, increased biosynthesis and conversion of Put to Spd and Spm along with their increased catabolism was evident in the resistant lines vs. the susceptible line SC212. There were higher concentrations of amino acids such as glutamate (Glu), glutamine (Gln) and γ-aminobutyric acid (GABA) in SC212. The resistant lines were significantly lower in fungal load and aflatoxin production as compared to the susceptible line. The data presented here demonstrate an important role of PA metabolism in the resistance of maize to A. flavus colonization and aflatoxin contamination. These results provide future direction for the manipulation of PA metabolism in susceptible maize genotypes to improve aflatoxin resistance and overall stress tolerance.
    Keywords:  Aspergillus flavus; amino acids; mycotoxin; polyamine oxidase; polyamine uptake; s-adenosylmethionine decarboxylase
  3. Amino Acids. 2019 Jun 13.
    Leonetti A, Baroli G, Fratini E, Pietropaoli S, Marcoli M, Mariottini P, Cervelli M.
      Several studies have demonstrated high polyamine levels in brain diseases such as epilepsy. Epilepsy is the fourth most common neurological disorder and affects people of all ages. Excitotoxic stress has been associated with epilepsy and it is considered one of the main causes of neuronal degeneration and death. The transgenic mouse line Dach-SMOX, with CD1 background, specifically overexpressing spermine oxidase in brain cortex, has been proven to be highly susceptible to epileptic seizures and excitotoxic stress induced by kainic acid. In this study, we analysed the effect of spermine oxidase over-expression in a different epileptic model, pentylenetetrazole. Behavioural evaluations of transgenic mice compared to controls showed a higher susceptibility towards pentylentetrazole. High-performance liquid chromatography analysis of transgenic brain from treated mice revealed altered polyamine content. Immunoistochemical analysis indicated a rise of 8-oxo-7,8-dihydro-2'-deoxyguanosine, demonstrating an increase in oxidative damage, and an augmentation of system x c - as a defence mechanism. This cascade of events can be initially linked to an increase in protein kinase C alpha, as shown by Western blot. This research points out the role of spermine oxidase, as a hydrogen peroxide producer, in the oxidative stress during epilepsy. Moreover, Dach-SMOX susceptibility demonstrated by two different epileptic models strongly indicates this transgenic mouse line as a potential animal model to study epilepsy.
    Keywords:  Excitotoxicity; Glutamate toxicity; Pentylentetrazole treatment; Polyamines; Spermine oxidase
  4. Front Plant Sci. 2019 ;10 601
    Zarza X, Shabala L, Fujita M, Shabala S, Haring MA, Tiburcio AF, Munnik T.
      Polyamines, such as putrescine (Put), spermidine (Spd), and spermine (Spm), are low-molecular-weight polycationic molecules found in all living organisms. Despite the fact that they have been implicated in various important developmental and adaptative processes, their mode of action is still largely unclear. Here, we report that Put, Spd, and Spm trigger a rapid increase in the signaling lipid, phosphatidic acid (PA) in Arabidopsis seedlings but also mature leaves. Using time-course and dose-response experiments, Spm was found to be the most effective; promoting PA responses at physiological (low μM) concentrations. In seedlings, the increase of PA occurred mainly in the root and partly involved the plasma membrane polyamine-uptake transporter (PUT), RMV1. Using a differential 32Pi-labeling strategy combined with transphosphatidylation assays and T-DNA insertion mutants, we found that phospholipase D (PLD), and in particular PLDδ was the main contributor of the increase in PA. Measuring non-invasive ion fluxes (MIFE) across the root plasma membrane of wild type and pldδ-mutant seedlings, revealed that the formation of PA is linked to a gradual- and transient efflux of K+. Potential mechanisms of how PLDδ and the increase of PA are involved in polyamine function is discussed.
    Keywords:  MIFE; lipid signaling; phosphatidic acid (PA); phospholipase D (PLD); phospholipids; polyamines (putrescine; spermidine; spermine)
  5. Carcinogenesis. 2019 Jun 12. pii: bgz115. [Epub ahead of print]
    Alexander ET, Mariner K, Borodyanskaya Y, Minton A, Gilmour SK.
      Tumor promotion is strongly associated with inflammation and increased polyamine levels. Our understanding of relevant mechanisms responsible for arsenic-induced cancer remains limited. Previous studies suggest that arsenic targets and dysregulates stem cell populations that remain dormant in the skin until promoted to be recruited out of the bulge stem cell region, thus giving rise to skin tumors. In this study we explored a possible mechanism by which increased keratinocyte polyamine biosynthesis promotes tumorsphere formation and invasiveness of arsenic-transformed HaCaT keratinocytes (As-HaCaT). Unlike parental HaCaT cells, As-HaCaT cells were tumorigenic in athymic nude mice, and the CD45negative epithelial tumor cells had enriched expression of TLR4, CD34, and CXCR4 as did As-HaCaT tumorsphere cultures compared to As-HaCaT monolayer cultures. Ornithine decarboxylase (ODC) overexpressing keratinocytes (Ker/ODC) release increased levels of the alarmin HMGB1. Ker/ODC conditioned medium (CM) stimulated As-HaCaT but not parental HaCaT tumorsphere formation, and this was inhibited by glycyrrhizin, an inhibitor of HMGB1, and by TAK242, an inhibitor of the HMGB1 receptor TLR4. Compared to parental HaCaT cells, As-HaCaT cells demonstrated greater invasiveness across a Matrigel-coated filter using either fibroblast CM or SDF-1α as chemoattractants. Addition of Ker/ODC CM or HMGB1 dramatically increased As-HaCaT invasiveness. Glycyrrhizin and TAK242 inhibited this Ker/ODC CM-stimulated invasion of As-HaCaT cells but not HaCaT cells. These results show that polyamine-dependent release of HMGB1 promotes the expansion of stem cell-like subpopulations in arsenic-transformed keratinocytes while also increasing their invasiveness, suggesting that polyamines may be a potential therapeutic target for the prevention and treatment of arsenic-initiated skin cancers.
    Keywords:  HMGB1; arsenic; keratinocytes; polyamines; stem cell
  6. J Inherit Metab Dis. 2019 Jun 08.
    Heibel SK, McGuire PJ, Haskins N, Majumdar HD, Rayavarapu S, Nagaraju K, Hathout Y, Brown K, Tuchman M, Caldovic L.
      Abundance of urea cycle enzymes in the liver is regulated by dietary protein intake. Although urea cycle enzyme levels rise in response to a high protein diet, signaling networks that sense dietary protein intake and trigger changes in expression of urea cycle genes have not been identified. The aim of this study was to identify signaling pathway(s) that respond to changes in protein intake and regulate expression of urea cycle genes in mice and human hepatocytes. Mice were adapted to either high (HP) or low (LP) protein diets followed by isolation of liver protein and mRNA and integrated analysis of the proteomic and transcriptomic data. HP diet led to increased expression of mRNA and enzymes in amino acid degradation pathways, and decreased expression of mRNA and enzymes in carbohydrate and fat metabolism, which implicated AMPK as a possible regulator. Primary human hepatocytes, treated with AICAR an activator of AMPK, were used to test whether AMPK regulates expression of urea cycle genes. The abundance of CPS1 and OTC mRNA increased in hepatocytes treated with AICAR, which supports a role for AMPK signaling in regulation of the urea cycle. Because AMPK is either a target of drugs used to treat type-2 diabetes, these drugs might increase the expression of urea cycle enzymes in patients with partial urea cycle disorders, which could be the basis of a new therapeutic approach. This article is protected by copyright. All rights reserved.
    Keywords:  AMPK signaling; SILAM; amino acids; dietary protein intake; gene expression; phosphorylation; proteome; regulation; signaling; transcriptome; urea cycle
  7. Amino Acids. 2019 Jun 13.
    Hou Y, He W, Hu S, Wu G.
      Dietary polyamines and amino acids (AAs) are crucial for human growth, development, reproduction, and health. However, the scientific literature shows large variations in polyamine and AA concentrations among major staple foods of plant origin, and there is a scarcity of information regarding their complete composition of AAs. To provide a much-needed database, we quantified polyamines, agmatine, and AAs in select plant-source foods. On the dry matter basis, total polyamines were most abundant in corn grains, followed by soybeans, sweet potatoes, pistachio nuts, potatoes, peanuts, wheat flour and white rice in descending order. Glutamine was the most abundant AA in pistachio nuts, wheat flour and white rice, arginine in peanuts, leucine in corn grains, glutamate in soybeans, and asparagine in potatoes and sweet potatoes. Glutamine was the second most abundant AA in corn grains, peanuts, potatoes, and soybeans, arginine in pistachio nuts, proline in wheat flour, and glutamate in sweet potatoes and white rice. Free AAs represented ≤ 3.1% of total AAs in corn grains, peanuts, pistachio nuts, soybeans, wheat flour and white rice, but 34.4% and 28.5% in potatoes and sweet potatoes, respectively. Asparagine accounted for 32.3%, 17.5%, and 19.4% of total free AAs in potatoes, sweet potatoes, and white rice, respectively. The content of histidine, glycine, lysine, tryptophan, methionine, cysteine, and threonine was relatively low in corn grains, potatoes, sweet potatoes, and white rice. All of the analyzed plant-source foods lacked taurine, creatine, carnosine and anserine (antioxidants that are abundant in meats and also present in milk), and contained little 4-hydroxyproline. Proper proportions of plant- and animal-source products are likely most desirable for optimizing human nutrition and health.
    Keywords:  Amino acids; Arginine; Humans; Methionine; Plant-source foods; Polyamines
  8. Int J Syst Evol Microbiol. 2019 Jun 14.
    Chen WM, Cai CY, Sheu SY.
      A bacterial strain designated FSY-15T was isolated from a freshwater mesocosm in Taiwan and characterised using a polyphasic taxonomic approach. Cells of strain FSY-15T were Gram-negative, aerobic, non-spore forming, non-motile rods and formed orange coloured colonies. Growth occurred at 20-30 °C (optimum, 25 °C), at pH 6-7.5 (optimum, pH 7) and with 0-0.5 % NaCl (optimum, 0 %). Phylogenetic analyses based on 16S rRNA gene sequences and coding sequences of 92 protein clusters indicated that strain FSY-15T formed a phylogenetic lineage in the the family Cytophagaceae. Strain FSY-15T was most closely related to the genera Pseudarcicella and Arcicella, and the levels of 16S rRNA gene sequence identity with respect to members of related genera are less than 94.1 %. Strain FSY-15T showed less than 68.8 % average nucleotide identity and less than 24.7 % digital DNA-DNA hybridisation identity compared to the type strains of related genera within the family Cytophagaceae. The predominant fatty acids were iso-C15 : 0, C16 : 1ω5c and the major hydroxyl fatty acid was iso-C15 : 0 3-OH. The major isoprenoid quinone was MK-7 and the DNA G+C content was 35.8 mol%. The major polar lipids were phosphatidylethanolamine and several uncharacterised aminophospholipid, aminolipid, phospholipid and lipid. The major polyamine was spermidine. On the basis of the genotypic and phenotypic data, strain FSY-15T represents a novel species of a new genus in the family Cytophagaceae, for which the name Sandaracinomonas limnophila gen. nov., sp. nov. is proposed. The type strain is FSY-15T (=BCRC 81011T =LMG 29732T =KCTC 52445T).
  9. Plant Cell Rep. 2019 Jun 07.
    Banerjee A, Roychoudhury A.
      KEY MESSAGE: Excessive bioaccumulation of fluoride in IR-64 caused low abscisic acid level, inhibition of polyamine biosynthesis and ascorbate-glutathione cycle but not in Gobindobhog which had higher antioxidant activity. The current study presents regulation of diverse metabolic and molecular defence pathways during fluoride stress in non-aromatic rice variety, IR-64 and aromatic rice variety, Gobindobhog (GB). Increasing concentration of fluoride affected fresh weight, dry weight, vigour index and relative water content to a lesser extent in GB compared to IR-64. GB exhibited lower methylglyoxal accumulation and lipoxygenase activity compared to IR-64 during stress. The level of osmolytes (proline, amino acids and glycine-betaine) increased in both the stressed varieties. The biosynthesis of higher polyamines was stimulated in stressed GB. IR-64 accumulated higher amount of putrescine due to degradation of higher polyamines as supported by gene expression analysis. Unlike IR-64, GB efficiently maintained the ascorbate-glutathione cycle due to much lower fluoride bioaccumulation, compared to IR-64. GB adapted to fluoride stress by strongly inducing guaiacol peroxidase, phenylalanine ammonia lyase and a novel isozyme of superoxide dismutase. While GB accumulated higher abscisic acid (ABA) level during stress, IR-64 exhibited slow ABA degradation which enabled induction of associated osmotic stress-responsive genes. Unlike GB, ABA-independent DREB2A was downregulated in stressed IR-64. The research illustrates varietal differences in the defence machinery of the susceptible variety, IR-64, and the well adapted cultivar, GB, on prolonged exposure to increasing concentrations of fluoride.
    Keywords:  Abscisic acid; Antioxidants; Defence mechanism; Fluoride; Injuries; Osmolytes; Rice
  10. Toxicon. 2019 Jun 07. pii: S0041-0101(19)30185-0. [Epub ahead of print]
    Querobino SM, Costa MS, Alberto-Silva C.
      The low molecular mass fraction from Bothrops jararaca snake venom contains proline-rich peptides (Bj-PROs), also known as bradykinin-potentiating peptides (BPPs), which were described as neuroprotective against H2O2-induced oxidative stress. Recently, we reported that the neuroprotective action of Bj-PRO-10c (<ENWPHPQIPP) is a result of an increase in the expression and activity of argininosuccinate synthase (AsS), thereby improving increase L-arginine synthesis. It is proposed that formation agmatine and polyamines from L-arginine metabolism are neuroprotective, reducing lipid peroxidation, oxidative stress, and maintenance of the mitochondrial membrane. In the present study, Bj-PRO-5a (<EKWAP), Bj-PRO-7a (<EDGPIPP), Bj-PRO-11e (<EARPPHPPIPP), and Bj-PRO-AP (<EARPPHPPIPPAP) - with different structure-activities, in particular on AsS expression and activity - were selected to study their protective properties on H2O2-induced oxidative stress in SH-SY5Y cells. Bj-PROs tested were neuroprotective, but Bj-PRO-5a and Bj-PRO-7a increased cell viability by more than 85% in the presence of H2O2 (450 μM) and reduced the oxidative stress markers. AsS, iNOS, and NF-ĸB expressions were not involved in the neuroprotective mechanism for both peptides, in contrast to Bj-PRO-10c, as reported in the literature. Bj-PRO-5a is a neuroprotector peptide that decreases ROS production, NO levels lipid peroxidation, and changes in mitochondrial membrane permeability caused by H2O2 exposition. The neuroprotective property of Bj-PRO-7a against H2O2 is also related to decreased ROS production and lipid peroxidation but without altering NO levels. These results show that the protective effects of different Bj-PROs against oxidative stress can be explained by distinct mechanisms independent of an increase in L-arginine bioavailability arising from AsS activity. Further studies are now needed to reveal the details of the neuroprotective mechanisms exerted by Bj-PROs.
    Keywords:  Argininosuccinate synthase; Bothrops jararaca; Bradykinin-potentiating peptides; Neuroprotective; Oxidative stress; Proline-rich peptides
  11. Anal Biochem. 2019 Jun 06. pii: S0003-2697(18)31000-5. [Epub ahead of print]
    Isobe K, Matsui D, Asano Y.
      l-Lysine is an essential amino acid important for maintaining human health. To date, many enzymatic methods for assay of l-lysine have been developed. The first method has been developed using l-lysine α-oxidase (L-LysOα). However, low specificity towards l-lysine of L-LysOα is a disadvantage inherent in this method. Recently, methods more specific to l-lysine were developed using newly discovered enzymes such as l-lysine ε-oxidase (L-LysOε), l-amino acid oxidase/monooxygenase (L-AAO/MOG) and l-lysine decarboxylase/oxidase (L-Lys-DC/OD). The present paper reviews recent enzymatic methods used for assay of l-lysine. These l-lysine selective assays rely on detecting and quantifying hydrogen peroxide, a product generated by the oxidase reaction of these enzymes. L-LysOε catalyzes the oxidative deamination of the ε-amino group of l-lysine, thus assays using this enzyme are more specific towards l-lysine than the ones using L-LysOα. The L-AAO/MOG has high substrate specificity towards l-lysine; however it exhibits l-lysine oxidase and monooxygenase activities. The sensitivity of L-AAO/MOG method was improved either by using its mutant, which has reduced monooxygenase activity, or by coupling with an aminoamide-oxidizing enzyme. The L-Lys-DC/OD exhibits both l-lysine decarboxylase and oxidase activities. The sensitivity of the L-Lys-DC/OD method was improved by using putrescine oxidase to oxidize the decarboxylation product of l-lysine.
    Keywords:  Aminoamide-oxidizing enzyme; L-lysine α-oxidase; Putrescine oxidase; l-amino acid oxidase/monooxygenase; l-lysine decarboxylase/oxidase; l-lysine ε-oxidase
  12. Biochem Biophys Res Commun. 2019 Jun 10. pii: S0006-291X(19)30815-0. [Epub ahead of print]
    Liu G, Mei H, Chen M, Qin S, Li K, Zhang W, Chen T.
      Hyperoxia-induced acute lung injury (HALI) is a kind of iatrogenic pulmonary dysfunction caused by the prolonged exposure to high concentrations of oxygen, which is commonly seen in the treatment of refractory hypoxemia. Agmatine (AGM), a biogenic amine metabolite of l-arginine, induces a variety of physiological and pharmacological effects in the body. In this study, we investigated the protective effect of AGM on hyperoxia-induced lung injury and explored the underlying mechanism. A series of methods were used including flow cytometry, tunnel assay, dual-luciferase reporter assay, qRT-PCR and Western blotting. The results indicate that AGM can protect hyperoxia-induced lung injury. Further studies suggest that AGM decreased the upregulated expression of lncRNA gadd7 caused by hyperoxia and due to the presence of the competitive binding of lncRNA gadd7 and MFN1 to miR-125a, AGM indirectly decreased MFN1 protein expression to inhibit the cells apoptosis. In conclusion, AGM protects hyperoxia-induced lung injury by decreasing the expression of lncRNA gadd7 to regulate MFN1 expression.
    Keywords:  Agmatine; Hyperoxia-induced acute lung injury; MFN1; lncRNA gadd7
  13. Molecules. 2019 Jun 10. pii: E2171. [Epub ahead of print]24(11):
    Datki Z, Galik-Olah Z, Bohar Z, Zadori D, Fulop F, Szatmari I, Galik B, Kalman J, Vecsei L.
      The in vivo investigation of kynurenic acid (KYNA) and its analogs is one of the recent exciting topics in pharmacology. In the current study we assessed the biological effects of these molecules on bdelloid rotifers (Philodina acuticornis and Adineta vaga) by monitoring changes in their survival and phenotypical characteristics. In addition to longitudinal (slowly changing) markers (survival, number of rotifers alive and body size index), some dynamic (quickly responding) ones (cellular reduction capacity and mastax contraction frequency) were measured as well. KYNA and its analogs increased longevity, reproduction and growth, whereas reduction capacity and energy-dependent muscular activity decreased conversely. We found that spermidine, a calorie restriction mimetic, exerted similar changes in the applied micro-invertebrates. This characterized systemic profile evoked by the above-mentioned compounds was named beneficial physiologic attenuation. In reference experiments, using a stimulator (cyclic adenosine monophosphate) and a toxin (sodium azide), all parameters changed in the same direction (positively or negatively, respectively), as expected. The currently described adaptive phenomenon in bdelloid rotifers may provide holistic perspectives in translational research.
    Keywords:  bdelloid rotifer; kynurenic acid; mastax; metabolism; physiology; survival