bims-polyam Biomed News
on Polyamines
Issue of 2019‒09‒08
sixteen papers selected by
Alexander Ivanov
Engelhardt Institute of Molecular Biology


  1. Cell Rep. 2019 Sep 03. pii: S2211-1247(19)31015-0. [Epub ahead of print]28(10): 2620-2633.e4
    Tate PM, Mastrodomenico V, Mounce BC.
      Common antivirals include nucleoside or nucleotide analogs with base prodrugs. The antiviral ribavirin, a US Food and Drug Administration (FDA)-approved nucleoside antimetabolite, halts guanine production, mutagenizes viral genomes, and activates interferon signaling. Here, we find that ribavirin induces spermidine-spermine N1-acetyltransferase (SAT1), a polyamine catabolic enzyme. Polyamines are small, positively charged molecules involved in cellular functions such as transcription and translation. Previous work showed that SAT1 activation and polyamine depletion interfere with RNA virus replication. We show ribavirin depletes polyamines via SAT1, in conjunction with its known mechanisms. SAT1 transcripts, protein, and activity are induced in a dose-dependent manner, which depletes polyamine levels and reduces viral titers. Inhibition of SAT1 activity, pharmacologically or genetically, reduces ribavirin's effectiveness against three virus infection models. Additionally, ribavirin-mediated polyamine depletion results from nucleotide pool depletion. These data demonstrate another mechanism of ribavirin that inform its clinical effectiveness, which may provide insight for improved therapies.
    DOI:  https://doi.org/10.1016/j.celrep.2019.07.099
  2. Mol Cell. 2019 Aug 26. pii: S1097-2765(19)30621-5. [Epub ahead of print]
    Zhang H, Alsaleh G, Feltham J, Sun Y, Napolitano G, Riffelmacher T, Charles P, Frau L, Hublitz P, Yu Z, Mohammed S, Ballabio A, Balabanov S, Mellor J, Simon AK.
      Failure to make adaptive immune responses is a hallmark of aging. Reduced B cell function leads to poor vaccination efficacy and a high prevalence of infections in the elderly. Here we show that reduced autophagy is a central molecular mechanism underlying immune senescence. Autophagy levels are specifically reduced in mature lymphocytes, leading to compromised memory B cell responses in old individuals. Spermidine, an endogenous polyamine metabolite, induces autophagy in vivo and rejuvenates memory B cell responses. Mechanistically, spermidine post-translationally modifies the translation factor eIF5A, which is essential for the synthesis of the autophagy transcription factor TFEB. Spermidine is depleted in the elderly, leading to reduced TFEB expression and autophagy. Spermidine supplementation restored this pathway and improved the responses of old human B cells. Taken together, our results reveal an unexpected autophagy regulatory mechanism mediated by eIF5A at the translational level, which can be harnessed to reverse immune senescence in humans.
    Keywords:  B cell; TFEB; aging; autophagy; eIF5A; spermidine
    DOI:  https://doi.org/10.1016/j.molcel.2019.08.005
  3. Antioxidants (Basel). 2019 Sep 01. pii: E358. [Epub ahead of print]8(9):
    Lokesh V, Manjunatha G, Hegde NS, Bulle M, Puthusseri B, Gupta KJ, Neelwarne B.
      Nitric oxide (NO) is known to antagonize ethylene by various mechanisms; one of such mechanisms is reducing ethylene levels by competitive action on S-adenosyl-L-methionine (SAM)-a common precursor for both ethylene and polyamines (PAs) biosynthesis. In order to investigate whether this mechanism of SAM pool diversion by NO occur towards PAs biosynthesis in banana, we studied the effect of NO on alterations in the levels of PAs, which in turn modulate ethylene levels during ripening. In response to NO donor sodium nitroprusside (SNP) treatment, all three major PAs viz. putrescine, spermidine and spermine were induced in control as well as ethylene pre-treated banana fruits. However, the gene expression studies in two popular banana varieties of diverse genomes, Nanjanagudu rasabale (NR; AAB genome) and Cavendish (CAV; AAA genome) revealed the downregulation of SAM decarboxylase, an intermediate gene involved in ethylene and PA pathway after the fifth day of NO donor SNP treatment, suggesting that ethylene and PA pathways do not compete for SAM. Interestingly, arginine decarboxylase belonging to arginine-mediated route of PA biosynthesis was upregulated several folds in response to the SNP treatment. These observations revealed that NO induces PAs via l-arginine-mediated route and not via diversion of SAM pool.
    Keywords:  Musa; SAM decarboxylase; arginine decarboxylase; ethylene; fruit ripening; ornithine decarboxylase
    DOI:  https://doi.org/10.3390/antiox8090358
  4. Plants (Basel). 2019 Sep 03. pii: E323. [Epub ahead of print]8(9):
    Toumi I, Pagoulatou MG, Margaritopoulou T, Milioni D, Roubelakis-Angelakis KA.
      The chaperones, heat shock proteins (HSPs), stabilize proteins to minimize proteotoxic stress, especially during heat stress (HS) and polyamine (PA) oxidases (PAOs) participate in the modulation of the cellular homeostasis of PAs and reactive oxygen species (ROS). An interesting interaction of HSP90s and PAOs was revealed in Arabidopsis thaliana by using the pLFY:HSP90RNAi line against the four AtHSP90 genes encoding cytosolic proteins, the T-DNA Athsp90-1 and Athsp90-4 insertional mutants, the Atpao3 mutant and pharmacological inhibitors of HSP90s and PAOs. Silencing of all cytosolic HSP90 genes resulted in several-fold higher levels of soluble spermidine (S-Spd), acetylated Spd (N8-acetyl-Spd) and acetylated spermine (N1-acetyl-Spm) in the transgenic Arabidopsis thaliana leaves. Heat shock induced increase of soluble-PAs (S-PAs) and soluble hydrolyzed-PAs (SH-PAs), especially of SH-Spm, and more importantly of acetylated Spd and Spm. The silencing of HSP90 genes or pharmacological inhibition of the HSP90 proteins by the specific inhibitor radicicol, under HS stimulatory conditions, resulted in a further increase of PA titers, N8-acetyl-Spd and N1-acetyl-Spm, and also stimulated the expression of PAO genes. The increased PA titers and PAO enzymatic activity resulted in a profound increase of PAO-derived hydrogen peroxide (H2O2) levels, which was terminated by the addition of the PAO-specific inhibitor guazatine. Interestingly, the loss-of-function Atpao3 mutant exhibited increased mRNA levels of selected AtHSP90 genes. Taken together, the results herein reveal a novel function of HSP90 and suggest that HSP90s and PAOs cross-talk to orchestrate PA acetylation, oxidation, and PA/H2O2 homeostasis.
    Keywords:  PA acetylation; PA back-conversion; PA oxidation; heat shock proteins; heat stress; hydrogen peroxide; polyamine oxidases; polyamines
    DOI:  https://doi.org/10.3390/plants8090323
  5. Sci Rep. 2019 Sep 04. 9(1): 12777
    Qin L, Zhang X, Yan J, Fan L, Rong C, Mo C, Zhang M.
      Flower bud formation in 'Fuji' apple (Malus domestica Borkh.) is difficult, which severely constrains commercial production. Spermidine (Spd) plays an important role in floral induction, but the mechanism of its action is incompletely understood. To investigate the effect of Spd on flowering, 6-year-old 'Fuji' apple trees were treated with 1 × 10-5 mol L-1 Spd to study the responses of polyamines [putrescine (Put), Spd and spermine (Spm)], hormones [gibberellins (GA3) and abscisic acid (ABA)], and polyamine-, hormone- and flowering-related genes. Spd application promoted flowering during floral induction by increasing MdGA2ox2 (gibberellin 2-oxidase) through GA3 reduction and increasing MdNCED1 and MdNCED3 (9-cis-epoxycarotenoid dioxygenase) through ABA enrichment during 60 to 80 days after full bloom. The flowering rate as well as the expressions of flower-related genes, except for MdLEY (LEAFY), also increased, thereby promoting flowering. In addition, spraying with Spd significantly increased the contents of endogenous polyamines except for Spm in terminal buds by increasing the expressions of polyamine-associated genes. We hypothesize that the contribution of Spd to flowering is related to crosstalk among polyamines, hormone signals, and related gene expressions, which suggests that Spd participates in the apple floral induction process.
    DOI:  https://doi.org/10.1038/s41598-019-49280-0
  6. Plants (Basel). 2019 Aug 30. pii: E315. [Epub ahead of print]8(9):
    Paschalidis K, Tsaniklidis G, Wang BQ, Delis C, Trantas E, Loulakakis K, Makky M, Sarris PF, Ververidis F, Liu JH.
      The interplay between polyamines (PAs) and nitrogen (N) is emerging as a key factor in plant response to abiotic and biotic stresses. The PA/N interplay in plants connects N metabolism, carbon (C) fixation, and secondary metabolism pathways. Glutamate, a pivotal N-containing molecule, is responsible for the biosynthesis of proline (Pro), arginine (Arg) and ornithine (Orn) and constitutes a main common pathway for PAs and C/N assimilation/incorporation implicated in various stresses. PAs and their derivatives are important signaling molecules, as they act largely by protecting and preserving the function/structure of cells in response to stresses. Use of different research approaches, such as generation of transgenic plants with modified intracellular N and PA homeostasis, has helped to elucidate a plethora of PA roles, underpinning their function as a major player in plant stress responses. In this context, a range of transgenic plants over-or under-expressing N/PA metabolic genes has been developed in an effort to decipher their implication in stress signaling. The current review describes how N and PAs regulate plant growth and facilitate crop acclimatization to adverse environments in an attempt to further elucidate the N-PAs interplay against abiotic and biotic stresses, as well as the mechanisms controlling N-PA genes/enzymes and metabolites.
    Keywords:  abiotic and biotic stress; antioxidant machinery; hydrogen peroxide; nitrogen metabolism; polyamines
    DOI:  https://doi.org/10.3390/plants8090315
  7. Transl Psychiatry. 2019 Sep 05. 9(1): 218
    Limon A, Delbruck E, Yassine A, Pandya D, Myers RM, Barchas JD, Lee F, Schatzberg , Watson SJ, Akil H, Bunney WE, Vawter MP, Sequeira A.
      Polyamines have fundamental roles in brain homeostasis as key modulators of cellular excitability. Several studies have suggested alterations in polyamine metabolism in stress related disorders, suicide, depression, and neurodegeneration, making the pharmacological modulation of polyamines a highly appealing therapeutic strategy. Polyamines are small aliphatic molecules that can modulate cationic channels involved in neuronal excitability. Previous indirect evidence has suggested that polyamines can modulate anionic GABAA receptors (GABAARs), which mediate inhibitory signaling and provide a direct route to reduce hyperexcitability. Here, we attempted to characterize the effect that spermine, the polyamine with the strongest reported effect on GABAARs, has on human postmortem native GABAARs. We microtransplanted human synaptic membranes from the dorsolateral prefrontal cortex of four cases with no history of mental or neurological disorders, and directly recorded spermine effects on ionic GABAARs responses on microtransplanted oocytes. We show that in human synapses, inhibition of GABAARs by spermine was better explained by alkalization of the extracellular solution. Additionally, spermine had no effect on the potentiation of GABA-currents by diazepam, indicating that even if diazepam binding is enhanced by spermine, it does not translate to changes in functional activity. Our results clearly demonstrate that while extracellular spermine does not have direct effects on human native synaptic GABAARs, spermine-mediated shifts of pH inhibit GABAARs. Potential spermine-mediated increase of pH in synapses in vivo may therefore participate in increased neuronal activity observed during physiological and pathological states, and during metabolic alterations that increase the release of spermine to the extracellular milieu.
    DOI:  https://doi.org/10.1038/s41398-019-0551-1
  8. In Vitro Cell Dev Biol Anim. 2019 Aug 19.
    Chirino-Galindo G, Hernández-Hernández DE, Reyes-Mateos LC, Mejía-Zepeda R, Martínez-García M, Palomar-Morales M.
      The frequency of congenital malformations is 3-5 times higher in mothers with pregestational diabetes mellitus than in general population. Apparently, this problem is due to change in the expression of apoptotic and antiapoptotic genes induced by the oxidative stress derived from the diabetes/hyperglycemia. One of these genes is Bcl-2, which is associated with the control and inhibition of apoptosis. The purpose of the present work was to study the effect of polyamine addition over expression of Bcl-2 gene in a model of diabetic embryopathy. For this, gestational day 10.5 (GD10.5) rat embryos were incubated at 37°C for 24 h in control medium, medium with high glucose, or medium with high glucose and supplemented with spermidine or spermine. Post-cultured embryos were harvested and observed to obtain morphological scores; some of them were subjected to molecular biology studies: DNA isolation plus conventional PCR or RNA isolation plus RT-PCR; other embryos were fixed with paraformaldehyde and used for immunohistochemical detection of Bcl-2 protein. Although Bcl-2 mRNA was similarly expressed in all rat embryo treatments, Bcl-2 protein was found only in control-incubated embryos. In conclusion, it seems that the inhibition of Bcl-2 gene expression induced by glucose was not reversed by polyamines.
    Keywords:  Bcl-2 expression; Cultured rat embryos; Polyamines
    DOI:  https://doi.org/10.1007/s11626-019-00400-0
  9. BMC Microbiol. 2019 Sep 05. 19(1): 209
    Fountain JC, Yang L, Pandey MK, Bajaj P, Alexander D, Chen S, Kemerait RC, Varshney RK, Guo B.
      BACKGROUND: The primary and secondary metabolites of fungi are critical for adaptation to environmental stresses, host pathogenicity, competition with other microbes, and reproductive fitness. Drought-derived reactive oxygen species (ROS) have been shown to stimulate aflatoxin production and regulate in Aspergillus flavus, and may function in signaling with host plants. Here, we have performed global, untargeted metabolomics to better understand the role of aflatoxin production in oxidative stress responses, and also explore isolate-specific oxidative stress responses over time.RESULTS: Two field isolates of A. flavus, AF13 and NRRL3357, possessing high and moderate aflatoxin production, respectively, were cultured in medium with and without supplementation with 15 mM H2O2, and mycelia were collected following 4 and 7 days in culture for global metabolomics. Overall, 389 compounds were described in the analysis which encompassed 9 biological super-pathways and 47 sub-pathways. These metabolites were examined for differential accumulation. Significant differences were observed in both isolates in response to oxidative stress and when comparing sampling time points.
    CONCLUSIONS: The moderately high aflatoxin-producing isolate, NRRL3357, showed extensive stimulation of antioxidant mechanisms and pathways including polyamines metabolism, glutathione metabolism, TCA cycle, and lipid metabolism while the highly aflatoxigenic isolate, AF13, showed a less vigorous response to stress. Carbohydrate pathway levels also imply that carbohydrate repression and starvation may influence metabolite accumulation at the later timepoint. Higher conidial oxidative stress tolerance and antioxidant capacity in AF13 compared to NRRL3357, inferred from their metabolomic profiles and growth curves over time, may be connected to aflatoxin production capability and aflatoxin-related antioxidant accumulation. The coincidence of several of the detected metabolites in H2O2-stressed A. flavus and drought-stressed hosts also suggests their potential role in the interaction between these organisms and their use as markers/targets to enhance host resistance through biomarker selection or genetic engineering.
    Keywords:  Aflatoxin; Aspergillus flavus; Drought stress; Metabolomics; Oxidative stress
    DOI:  https://doi.org/10.1186/s12866-019-1580-x
  10. Plant Physiol Biochem. 2019 Aug 30. pii: S0981-9428(19)30329-8. [Epub ahead of print]143 94-108
    Hu Y, Peuke AD, Zhao X, Yan J, Li C.
      During recent decades, the southern and eastern regions of Asia have experienced high levels of atmospheric N deposition. Excess N deposition is predicted to influence tree growth and species composition in the regions, but visual or physiological assessments alone are not sufficient to determine the real effects of atmospheric N deposition. In this study, we simulated atmospheric wet deposition of inorganic N by spraying a NO3- solution (20 mmol⋅L-1) or a mixture of NO3- (20 mmol⋅L-1) plus NO2- (100 or 300 μmol⋅L-1) on leaves of hybrid poplar (Populus alba × Populus berolinensis) seedlings and examined morphoanatomical traits and physiological processes. Leaves of seedlings sprayed with single or mixed N solutions developed marginal necrosis, curling, and small cracks on the adaxial surface. The silicon (Si)-rich crystals were larger (about 100% increase in crystal diameter compared to untreated seedlings) on the adaxial leaf surface, with a significant positive correlation between the atomic percentage of N and Si on the crystal areas of the surface. Leaves were sensitive to NO2- compared with NO3- even at a low concentration; water content, dry mass, and photochemical variables significantly declined and dark respiration increased only in leaves treated with mixed N form. Mixed N foliar applications significantly increased leaf concentrations of the free amino acids Glu, Gln, and Asn and organic acids oxaloacetic acid and citric acid. Besides, mixed N treatment stimulated leaf transamination, as indicated by significant increases in Ala and Asp concentrations and activities of glutamic oxalacetic transaminase and glutamic pyruvic transaminase. However, mixed N applications led to declines in leaf concentrations of putrescine (by 65%, p = 0.01) and spermine (by 53%, p = 0.01). A higher proportion of NO2- (300 μmol⋅L-1) in mixed N solution was inhibitory to key N-metabolic enzymes and N translocation via the phloem. Our results showed that wet deposition of airborne N pollutants modified surface properties and induced additional detrimental effects related to N-compound foliar absorption. Furthermore, our findings indicate that detoxification of reactive N is apparently related to N assimilation and export from the treated leaves via the phloem.
    Keywords:  Atmospheric nitrogen deposition; Crystal; Dark respiration; Free amino acid; Polyamine; Poplar
    DOI:  https://doi.org/10.1016/j.plaphy.2019.08.023
  11. J Anim Physiol Anim Nutr (Berl). 2019 Sep 04.
    Novak TE, Rodriguez-Zas SL, Southey BR, Starkey JD, Stockler RM, Alfaro GF, Moisá SJ.
      The transition from a high forage to a high concentrate diet is an important milestone for beef cattle moving from a stocker system to the feedlot. However, little is known about how this transition affects the rumen epithelial gene expression. This study assessed the effects of the transition from a high forage to a high concentrate diet as well as the transition from a high concentrate to a high forage diet on a variety of genes as well as ruminal papillae morphology in rumen fistulated Jersey steers. Jersey steers (n = 5) were fed either a high forage diet (80% forage and 20% grain) and transitioned to a high concentrate diet (20% forage and 80% grain) or a high concentrate diet (40% forage and 60% grain) and transitioned to a high forage diet (100% forage). Papillae from the rumen were collected for histology and RT-qPCR analysis. Body weight had a tendency for significant difference (p = .08). Histological analysis did not show changes in papillae length or width in steers transitioning from a high forage to a high concentrate diet or vice versa (p > .05). Genes related to cell membrane structure (CLDN1, CLDN4, DSG1), fatty acid metabolism (CPT1A, ACADSB), glycolysis (PFKL), ketogenesis (HMGCL, HMGCS2, ACAT1), lactate/pyruvate (LDHA), oxidative stress (NQO1), tissue growth (AKT3, EGFR, EREG, IGFBP5, IRS1) and the urea cycle (SLC14A1) were considered in this study. Overall, genes related to fatty acid metabolism (ACADSB) and growth and development (AKT3 and IGFBP5) had a tendency for a treatment × day on trial interaction effect. These profiles may be indicators of rumen epithelial adaptations in response to changes in diet. In conclusion, these results indicate that changes in the composition of the diet can alter the expression of genes with specific functions in rumen epithelial metabolism.
    Keywords:  bovine; diet change; gene expression; nutrigenomics; rumen epithelium
    DOI:  https://doi.org/10.1111/jpn.13189
  12. Adv Clin Chem. 2019 ;pii: S0065-2423(19)30027-7. [Epub ahead of print]92 59-103
    Phipps WS, Jones PM, Patel K.
      Inborn errors of metabolism (IEMs) are a large class of genetic disorders that result from defects in enzymes involved in energy production and metabolism of nutrients. For every metabolic pathway, there are defects that can occur and potentially result in an IEM. While some defects can go undetected in one's lifetime, some have moderate to severe clinical consequences. In the latter case, the biochemical defect leads to accumulation of metabolites and byproducts that are toxic or interfere with normal biological function. Disorders of amino acid metabolism, organic acid metabolism and the urea cycle comprise a large portion of IEMs. Two essential tools required for the diagnosis of these categories of disorders are amino acid and organic acid profiling. Most all clinical laboratories offering metabolic testing perform amino acid analysis, while organic acid profiling is restricted to more specialized pediatric hospitals and reference laboratories. In this chapter, we will provide an overview of various methodologies employed for amino acid and organic acid profiling as well as specific examples to demonstrate how these techniques are applied in clinical laboratories for the diagnosis of IEMs.
    Keywords:  Amino acid analysis; Amino acid derivatization; Inborn errors of metabolism; Inherited metabolic diseases; Liquid chromatography; Mass spectrometry; Newborn screening; Organic acid analysis
    DOI:  https://doi.org/10.1016/bs.acc.2019.04.001
  13. Curr Res Transl Med. 2019 Sep 03. pii: S2452-3186(19)30032-7. [Epub ahead of print]
    Wu G, Yan Y, Zhou Y, Wang X, Wei J, Chen X, Lin W, Ou C, Zhou J, Xu Z.
      Carbamoyl phosphate synthetase-1 (CPS1), the first rate-limiting mitochondrial enzyme in the urea cycle, regulates proliferation and differentiation during tumor progression. However, the detailed function of CPS1 in glioblastoma Multiforme (GBM) is still unclear. Here, we highlight mechanisms for CPS1 upregulation and the effects of upregulated CPS1 on GBM tumorigenesis. The transcriptome data from several public databases, such as Oncomine and GEPIA, revealed that CPS1 transcriptional level was significantly upregulated in GBM tissues and cells. Moreover, CPS1 was hypomethylated in GBM tissues. The Wanderer database, linked to the Cancer Genome Atlas (TCGA), showed the association between CPS1 expression or its methylation values and the clinicopathological parameters in GBM patients. Our work fully demonstrated that CPS1 expression was upregulated in GBM and this gene could be used as a potential diagnostic and prognosis indicator for GBM.
    Keywords:  CPS1; Diagnosis; Glioblastoma multiforme; TCGA
    DOI:  https://doi.org/10.1016/j.retram.2019.08.003
  14. Cancer Prev Res (Phila). 2019 Sep 04. pii: canprevres.0167.2019. [Epub ahead of print]
    Sinicrope FA, Velamala PR, Wong Kee Song LM, Viggiano TR, Bruining DH, Rajan E, Gostout C, Kriachley RE, Buttar NS, Schroeder KW, Kisiel JB, Larson MV, Sweetser SR, Sedlack RR, Sinicrope SN, Richmond E, Umar A, Della'Zanna G, Noaeill JS, Meyers J, Foster NR.
      Difluoromethylornithine (DFMO), an inhibitor of polyamine synthesis, was shown to act synergistically with a NSAID for chemoprevention of colorectal neoplasia. We determined the efficacy and safety of DFMO plus aspirin for prevention of colorectal adenomas and regression of rectal aberrant crypt foci (ACF) in patients with prior advanced adenomas or cancer. A double-blinded, placebo-controlled trial was performed in 104 subjects (age 46- 83) randomized (1:1) to receive daily DFMO (500 mg orally) plus aspirin (325 mg) or matched placebos for one year. All polyps were removed at baseline. Adenoma number (primary endpoint) and rectal ACF (index cluster and total) were evaluated at a one year colonoscopy. ACF were identified by chromoendoscopy. Toxicity was monitored, including audiometry. Eighty-seven subjects were evaluable for adenomas or ACF modulation (n=62). At one year of treatment, adenomas were detected in 16 (38.1%) subjects in the DFMO plus aspirin arm (n= 42) versus 18 (40.9%) in the placebo arm (n= 44; p=0.790); advanced adenomas were similar (n= 3/arm). DFMO plus aspirin was associated with a statistically significant reduction in the median number of rectal ACF compared to placebo (p= 0.036). Total rectal ACF burden was also reduced in the treatment versus the placebo arm relative to baseline (74% vs 45%, p=0.020). No increase in adverse events, including ototoxicity, was observed in the treatment versus placebo arms. While adenoma recurrence was not significantly reduced by one year of DFMO plus aspirin, the drug combination significantly reduced rectal ACF number consistent with a chemopreventive effect.
    DOI:  https://doi.org/10.1158/1940-6207.CAPR-19-0167
  15. Sci Rep. 2019 Sep 03. 9(1): 12669
    Bergin DH, Jing Y, Williams G, Mockett BG, Zhang H, Abraham WC, Liu P.
      Agmatine (decarboxylated arginine) exerts numerous central nervous system (CNS) dependent pharmacological effects and may potentially modulate altered neurochemistry seen in neurological disorders. In preclinical studies, injection has been the predominant route of systemic administration. However, a significant translational step would be the use of oral agmatine treatment at therapeutic doses and better understanding of L-arginine metabolic profiles in the CNS post-treatment. The present study systematically investigated the tolerability, safety and brain-plasma neurochemistry following daily oral agmatine sulfate treatment (via gavage) to wild-type (WT) mice up to 900 mg/kg for one week (Experiment 1) or WT and APPswe/PS1ΔE9 transgenic (Tg) mice at 300 mg/kg for fifteen weeks (Experiment 2). Agmatine treatment in both experiments was well tolerated with no marked behavioural impairments, and gross necropsy and organ histology revealed no pathological alterations after 15-week dosing. Moreover, oral treatment increased agmatine levels in the hippocampus and plasma of WT mice (Experiment 1), and in 6 brain regions examined (but not plasma) of WT and Tg mice (Experiment 2), at 30 minutes or 24 hours post-treatment respectively. This study provides fundamental pre-clinical evidence that daily oral delivery of agmatine sulfate to both WT and Tg mice is safe and well tolerated. Exogenous agmatine passes through the blood brain barrier and accumulates in the brain to a greater extent in Tg mice. Furthermore exogenous agmatine has differential actions in the brain and periphery, and its effect on brain putrescine appears to be dependent on the time post-treatment.
    DOI:  https://doi.org/10.1038/s41598-019-49078-0
  16. J Food Biochem. 2019 Sep 05. e13039
    Hagi T, Nakagawa H, Ohmori H, Sasaki K, Kobayashi M, Narita T, Nomura M.
      Fermented dairy products comprise many functional components. Our previous study using fermented milk showed that the γ-aminobutyric acid (GABA)-producing Lactococcus lactis 01-7 strain can produce unique metabolites such as antihypertensive peptides, whereas this study was designed to find the unique metabolites in GABA-rich cheese using the 01-7 strain. Metabolites between cheese ripening with the non-GABA-producing L. lactis 01-1 strain (control) and GABA-rich cheese ripening with a mixture of 01-1 and 01-7 strains were compared. GABA and ornithine were detected in GABA-rich cheese using an amino acid analyzer and citrate was detected in the control cheese using HPLC. Metabolome analysis using LC-MS showed that peptides with unknown function and those with antihypertensive activity were higher in the GABA-rich cheese than in the control cheese. Further analysis of the amount of the YLGY derivatives showed that the amount of YL in the GABA-rich cheese was lower than that in the control. PRACTICAL APPLICATIONS: Clarification of metabolites in cheese contributes to the improvement of cheese ripening, thereby providing consumers with unique cheese with good nutritional and functional characteristics. The use of the 01-7 strain as a cheese starter might provide a functional cheese with antihypertensive-, antioxidative-, and anxiolytic-like activities.
    Keywords:   Lactococcus lactis ; LC-MS; cheese; peptides; γ-aminobutyric acid
    DOI:  https://doi.org/10.1111/jfbc.13039