bims-polyam 2020-06-21 papers

on Polyamines

Issue of 2020–06–21
twelve papers selected by
Sebastian J. Hofer, University of Graz and Alexander Ivanov, Engelhardt Institute of Molecular Biology

Triethylenetetramine (trientine): a caloric restriction mimetic with a new mode of action.
Excessive Polyamine Generation in Keratinocytes Promotes Self-RNA Sensing by Dendritic Cells in Psoriasis.
COVID-19 infection alters kynurenine and fatty acid metabolism, correlating with IL-6 levels and renal status.
mRNA expression of ageing-associated genes in calorie reduction is subject to donor variability and can be induced by calorie restriction mimetics.
Identification of longevity compounds with minimized probabilities of side effects.
Malodorous biogenic amines in Escherichia coli-caused urinary tract infections in women-a metabolomics approach.
CRISPR/Cas9 knockout of human arylamine N-acetyltransferase 1 in MDA-MB-231 breast cancer cells suggests a role in cellular metabolism.
The miR-1908/SRM regulatory axis contributes to extracellular vesicle secretion in prostate cancer.
Mycorrhizal effector PaMiSSP10b alters polyamine biosynthesis in Eucalyptus root cells and promotes root colonization.
Ectopic expression of CsTGase enhances salt tolerance by regulating polyamine biosynthesis, antioxidant activities and Na+/K+ homeostasis in transgenic tobacco.
Spermine regulates water balance associated with Ca2+-dependent aquaporins (TrTIP2-1, TrTIP2-2, and TrPIP2-7) expression in plants under water stress.
The effects of putrescine pre-treatment on osmotic stress responses in drought-tolerant and drought-sensitive wheat seedlings.

Autophagy. 2020 Jun 16. 1-3

Triethylenetetramine (trientine): a caloric restriction mimetic with a new mode of action.

Federico Pietrocola, Francesca Castoldi, Frank Madeo, Guido Kroemer.

  Caloric restriction mimetics (CRMs) are nontoxic macroautophagy/autophagy enhancers that act through the stimulation of cytoplasmic protein deacetylation reactions. Thus far, three functional classes of CRMs have been described: inhibitors of acetyltransferases (such as spermidine), inhibitors of acetyl coenzyme (AcCoA) synthesis (such as hydroxycitrate) and activators of deacetylases/sirtuins (such as resveratrol). Triethylenetetramine (also called trientine, abbreviated TETA) is a synthetic polyamine with resemblance in its structure to spermidine, a natural polyamine reputed for its pro-autophagic, anti-obesity and anti-aging effects. TETA, which is approved for the treatment of Wilson disease, has no effects on the longevity of mice, yet does induce autophagy and reduces weight gain in mice fed a high-fat diet (HFD). Mechanistically, these effects of TETA involve an increased activity of the TETA-metabolizing enzyme, SAT1 (spermidine/spermine N1-acetyltransferase 1). SAT1 overactivation ultimately results in the depletion of intracellular AcCoA with a consequent de-acetylation of cytoplasmic proteins and induction of autophagy. Accordingly, TETA fails to induce autophagy or to control HFD-induced weight gain in SAT1-deficient mice. Altogether, these findings indicate that TETA induces autophagy through a novel mode of action, namely, by the activation of an AcCoA-depleting enzyme.

Keywords:  Acetylation; SAT1; aging; autophagy; copper; metabolomics; obesity; spermidine

DOI:  https://doi.org/10.1080/15548627.2020.1778293
Immunity. 2020 Jun 13. pii: S1074-7613(20)30234-X. [Epub ahead of print]

Excessive Polyamine Generation in Keratinocytes Promotes Self-RNA Sensing by Dendritic Cells in Psoriasis.

Fangzhou Lou, Yang Sun, Zhenyao Xu, Liman Niu, Zhikai Wang, Siyu Deng, Zhaoyuan Liu, Hong Zhou, Jing Bai, Qianqian Yin, Xiaojie Cai, Libo Sun, Hong Wang, Qun Li, Zhouwei Wu, Xiang Chen, Jun Gu, Yu-Ling Shi, Wufan Tao, Florent Ginhoux, Honglin Wang.

  Psoriasis is a chronic inflammatory disease whose etiology is multifactorial. The contributions of cellular metabolism to psoriasis are unclear. Here, we report that interleukin-17 (IL-17) downregulated Protein Phosphatase 6 (PP6) in psoriatic keratinocytes, causing phosphorylation and activation of the transcription factor C/EBP-β and subsequent generation of arginase-1. Mice lacking Pp6 in keratinocytes were predisposed to psoriasis-like skin inflammation. Accumulation of arginase-1 in Pp6-deficient keratinocytes drove polyamine production from the urea cycle. Polyamines protected self-RNA released by psoriatic keratinocytes from degradation and facilitated the endocytosis of self-RNA by myeloid dendritic cells to promote toll-like receptor-7 (TLR7)-dependent RNA sensing and IL-6 production. An arginase inhibitor improved skin inflammation in murine and non-human primate models of psoriasis. Our findings suggest that urea cycle hyperreactivity and excessive polyamine generation in psoriatic keratinocytes promote self-RNA sensation and PP6 deregulation in keratinocytes is a pivotal event that amplifies the inflammatory circuits in psoriasis.

Keywords:  ARG1; Protein Phosphatase 6 (PP6); arginase; dendritic cells; keratinocytes; polyamines; psoriasis; self-RNA; urea cycle

DOI:  https://doi.org/10.1016/j.immuni.2020.06.004
JCI Insight. 2020 Jun 19. pii: 140327. [Epub ahead of print]

COVID-19 infection alters kynurenine and fatty acid metabolism, correlating with IL-6 levels and renal status.

Tiffany Thomas, Davide Stefanoni, Julie A Reisz, Travis Nemkov, Lorenzo Bertolone, Richard O Francis, Krystalyn E Hudson, James C Zimring, Kirk C Hansen, Eldad A Hod, Steven L Spitalnik, Angelo D'Alessandro.

  Reprogramming of host metabolism supports viral pathogenesis by fueling viral proliferation, by providing, for example, free amino acids and fatty acids as building blocks. To investigate metabolic effects of SARS-COV-2 infection, we evaluated serum metabolites of COVID-19 patients (n = 33; diagnosed by nucleic acid testing), as compared to COVID-19-negative controls (n = 16). Targeted and untargeted metabolomics analyses identified altered tryptophan metabolism into the kynurenine pathway, which regulates inflammation and immunity. Indeed, these changes in tryptophan metabolism correlated with interleukin-6 (IL-6) levels. Widespread dysregulation of nitrogen metabolism was also seen in infected patients, with altered levels of most amino acids, along with increased markers of oxidant stress (e.g., methionine sulfoxide, cystine), proteolysis, and renal dysfunction (e.g., creatine, creatinine, polyamines). Increased circulating levels of glucose and free fatty acids were also observed, consistent with altered carbon homeostasis. Interestingly, metabolite levels in these pathways correlated with clinical laboratory markers of inflammation (i.e., IL-6 and C-reactive protein) and renal function (i.e., blood urea nitrogen). In conclusion, this initial observational study identified amino acid and fatty acid metabolism as correlates of COVID-19, providing mechanistic insights, potential markers of clinical severity, and potential therapeutic targets.

Keywords:  Amino acid metabolism; COVID-19; Intermediary metabolism; Metabolism

DOI:  https://doi.org/10.1172/jci.insight.140327
Nutr Health. 2020 Jun 18. 260106020932732

mRNA expression of ageing-associated genes in calorie reduction is subject to donor variability and can be induced by calorie restriction mimetics.

Katja Matt, Barbara Hochecker, Alica Schöller-Mann, Jörg Bergemann.

   BACKGROUND: Finding ways to a healthier ageing are increasingly becoming the focus of geriatric research. One way to accomplish this could be calorie restriction, as this is known to positively influence the ageing of model organisms.
AIM: The aim of this study was to investigate the influence of calorie reduction (F. X. Mayr therapy) and of the calorie restriction mimetics resveratrol and spermidine on the expression of ageing-associated genes.
METHODS: mRNA expression in peripheral blood mononuclear cells (PBMCs) of 18 participants taking part in an F. X. Mayr therapy was analysed. The PBMCs of one additional participant were treated ex vivo with spermidine or resveratrol. mRNA expression of SIRT1, SIRT3, FOXO3 and SOD2 was determined for these two calorie restriction mimetics. For the F. X. Mayr therapy samples, mRNA of XPA was analysed additionally.
RESULTS: mRNA expression of the ageing-associated genes showed a distinct donor variation during F. X. Mayr therapy, with a significant increase in mRNA expression of SIRT1. Expression of XPA was similar to SIRT1, with a significant correlation at the last time point tested. Spermidine treatment of PBMCs resulted in a significantly increased expression of all genes tested, whereas resveratrol treatment caused a significant increase of SIRT3, FOXO3 and SOD2 mRNA expression.
CONCLUSIONS: By increasing SIRT1 and XPA mRNA expression, calorie reduction in the form of F. X. Mayr therapy could contribute to a healthier ageing; however, the donor variability observed showed that not everyone benefited from this. Calorie restriction mimetics may be an option for promote healthier ageing for those who do not benefit from calorie reduction.

Keywords:  Calorie reduction; ageing; calorie restriction mimetics; human peripheral blood mononuclear cells; mRNA expression

DOI:  https://doi.org/10.1177/0260106020932732
Biogerontology. 2020 Jun 19.

Identification of longevity compounds with minimized probabilities of side effects.

Georges E Janssens, Riekelt H Houtkooper.

  It is hypothesized that treating the general aging population with compounds that slow aging, geroprotectors, could provide many benefits to society, including a reduction of age-related diseases. It is intuitive that such compounds should cause minimal side effects, since they would be distributed to otherwise healthy individuals for extended periods of time. The question therefore emerges of how we should prioritize geroprotectors discovered in model organisms for clinical testing in humans. In other words, which compounds are least likely to cause harm, while still potentially providing benefit? To systematically answer this question we queried the DrugAge database-containing hundreds of known geroprotectors-and cross-referenced this with a recently published repository of compound side effect predictions. In total, 124 geroprotectors were associated to 800 unique side effects. Geroprotectors with high risks of side effects, some even with risk for death, included lamotrigine and minocycline, while compounds with low side effect risks included spermidine and D-glucosamine. Despite their popularity as top geroprotector candidates for humans, sirolimus and metformin harbored greater risks of side effects than many other candidate geroprotectors, sirolimus being the more severe of the two. Furthermore, we found that a correlation existed between maximum lifespan extension in worms and the likelihood of causing a side effect, suggesting that extreme lifespan extension in model organisms should not necessarily be the priority when screening for novel geroprotectors. We discuss the implications of our findings for prioritizing geroprotectors, suggesting spermidine and D-glucosamine for clinical trials in humans.

Keywords:  D-Glucosamine; Geroprotectors; Hormesis; Side effects; Spermidine

DOI:  https://doi.org/10.1007/s10522-020-09887-7
Sci Rep. 2020 Jun 16. 10(1): 9703

Malodorous biogenic amines in Escherichia coli-caused urinary tract infections in women-a metabolomics approach.

Scarlett Puebla-Barragan, Justin Renaud, Mark Sumarah, Gregor Reid.

Many women suffer from urinary tract infections (UTIs). In addition to pain and increased urgency to urinate, malodour is a significant issue for these patients. The specific factors causing this malodour are unclear, and there are no targeted treatment options to counteract it effectively. We used a metabolomics approach to compare the chemical composition of metabolites in the urine of women with E. coli UTIs (n = 15) and those who are healthy (n = 10). The biogenic amines trimethylamine and putrescine, which cause malodour in other urogenital conditions, were significantly increased in UTI patients. Conversely, the precursor of trimethylamine, trimethylamine N-oxide, was lower. To further confirm the source of the malodorous compounds, in vitro experiments were conducted by incubating strains of uropathogenic E. coli in sterilized urine from healthy women. All tested strains accumulated trimethylamine and putrescine. Notably, cadaverine was also produced by E. coli strains in vitro; however, it was not significantly different between both groups. We confirmed that the malodorous amines TMA and putrescine are found in higher concentrations in the urine of patients with an E.coli-caused UTI.

DOI: https://doi.org/10.1038/s41598-020-66662-x
Sci Rep. 2020 Jun 17. 10(1): 9804

CRISPR/Cas9 knockout of human arylamine N-acetyltransferase 1 in MDA-MB-231 breast cancer cells suggests a role in cellular metabolism.

Samantha M Carlisle, Patrick J Trainor, Kyung U Hong, Mark A Doll, David W Hein.

Human arylamine N-acetyltransferase 1 (NAT1), present in all tissues, is classically described as a phase-II xenobiotic metabolizing enzyme but can also catalyze the hydrolysis of acetyl-Coenzyme A (acetyl-CoA) in the absence of an arylamine substrate using folate as a cofactor. NAT1 activity varies inter-individually and has been shown to be overexpressed in estrogen receptor-positive (ER+) breast cancers. NAT1 has also been implicated in breast cancer progression however the exact role of NAT1 remains unknown. The objective of this study was to evaluate the effect of varying levels of NAT1 N-acetylation activity in MDA-MB-231 breast cancer cells on global cellular metabolism and to probe for unknown endogenous NAT1 substrates. Global, untargeted metabolomics was conducted via ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) on MDA-MB-231 breast cancer cell lines constructed with siRNA and CRISPR/Cas9 technologies to vary only in NAT1 N-acetylation activity. Many metabolites were differentially abundant in NAT1-modified cell lines compared to the Scrambled parental cell line. N-acetylasparagine and N-acetylputrescine abundances were strongly positively correlated (r = 0.986 and r = 0.944, respectively) with NAT1 N-acetylation activity whereas saccharopine abundance was strongly inversely correlated (r = -0.876). Two of the most striking observations were a reduction in de novo pyrimidine biosynthesis and defective β-oxidation of fatty acids in the absence of NAT1. We have shown that NAT1 expression differentially affects cellular metabolism dependent on the level of expression. Our results support the hypothesis that NAT1 is not just a xenobiotic metabolizing enzyme and may have a role in endogenous cellular metabolism.

DOI: https://doi.org/10.1038/s41598-020-66863-4
Cancer Sci. 2020 Jun 18.

The miR-1908/SRM regulatory axis contributes to extracellular vesicle secretion in prostate cancer.

Fumihiko Urabe, Nobuyoshi Kosaka, Yurika Sawa, Kagenori Ito, Takahiro Kimura, Shin Egawa, Takahiro Ochiya, Yusuke Yamamoto.

  Targeting the extracellular vesicle (EV) secretion can have potential clinical implications for cancer therapy; however, the precise regulatory mechanisms of EV secretion are not fully understood. Recently, we have shown a novel pathway of EV biogenesis in PCa cell lines, PC3 and PC3M. However, since the characteristics of EVs were divergent even among PCa cell lines, we hypothesized that other pathways or common regulatory pathways of EV biogenesis still exist. Here, we performed quantitative high throughput screening to determine the key regulatory genes involved in EV biogenesis in 22Rv1 cells, which secreted a different type of EVs. A total of 1728 miRNAs were screened and miR-1908 was selected as the potential miRNA regulating the EV biogenesis in 22Rv1 cells. Subsequently, we investigated the target genes of miR-1908 by siRNA screening and identified that spermidine synthase (SRM) was the key regulator of EV secretion in 22Rv1 cells. The attenuation of the SRM expression significantly inhibited the secretion of EVs in 22Rv1 cells, and the overexpression of SRM was confirmed in PCa tissues. Furthermore, we found that the number of the endosome compartment was increased in cellular cytoplasm after the knockdown of the SRM gene. In conclusion, our results showed that the miR-1908-mediated regulation of SRM can control the secretion of EVs in PCa. In addition, these data suggested that EV secretion pathway was depending on the cellular character.

Keywords:  Extracellular vesicles; biogenesis of extracellular vesicles; high-throughput screening; prostate cancer

DOI:  https://doi.org/10.1111/cas.14535
New Phytol. 2020 Jun 20.

Mycorrhizal effector PaMiSSP10b alters polyamine biosynthesis in Eucalyptus root cells and promotes root colonization.

Jonathan M Plett, Krista L Plett, Johanna Wong-Bajracharya, Maíra de Freitas Pereira, Maurício Dutra Costa, Annegret Kohler, Francis Martin, Ian C Anderson.

  Pathogenic microbes are known to manipulate the defences of their hosts through the production of secreted effector proteins. More recently, mutualistic mycorrhizal fungi have also been described as using these secreted effectors to promote host colonization. Here we characterise a mycorrhiza-induced small secreted effector protein of 10 kDa produced by the ectomycorrhizal fungus Pisolithus albus, PaMiSSP10b. We demonstrate that PaMiSSP10b is secreted from fungal hyphae, enters the cells of its host, Eucalyptus grandis, and interacts with an S-adenosyl methionine decarboxylase (AdoMetDC) in the polyamine pathway. Plant polyamines are regulatory molecules integral to the plant immune system during microbial challenge. Using biochemical and transgenic approaches we show that expression of PaMiSSP10b influences levels of polyamines in the plant roots as it enhances the enzymatic activity of AdoMetDC and increases the biosynthesis of higher polyamines. This ultimately favours the colonization success of P. albus. These results identify a new mechanism by which mutualistic microbes are able to manipulate the host´s enzymatic pathways to favour colonization.

Keywords:   Pisolithus ; Plant-microbe interactions; ectomycorrhizal fungus; immunity; mutualistic symbiosis; nutrition

DOI:  https://doi.org/10.1111/nph.16759
Plant Sci. 2020 Jul;pii: S0168-9452(20)30094-7. [Epub ahead of print]296 110492

Ectopic expression of CsTGase enhances salt tolerance by regulating polyamine biosynthesis, antioxidant activities and Na+/K+ homeostasis in transgenic tobacco.

Min Zhong, Yu Wang, Sheng Shu, Jin Sun, Shirong Guo.

  Transglutaminases (TGases), mediators of the transamidation of specific proteins by polyamines (PA), play critical roles in PA metabolism in animals, but their functions and regulatory mechanisms are largely unknown in plants. In this study, we demonstrated that TGase from cucumber played a protective role in the regulation of PA metabolism under salt stress. The expression of TGase was induced by salt stress in cucumber. Ectopic overexpression of cucumber TGase in tobacco conferred enhanced tolerance to salt stress based on both external symptoms and membrane integrity. Overexpression lines maintained high levels of PAs under salt stress, suggesting that PAs played a vital role in TGase-induced salt tolerance. In contrast, the levels of Na+ content in the wild-type (WT) plants increased, while they decreased in the overexpression plants. The expression levels of several genes related to ion exchange enhanced, and the Na+/K+ ratio decreased by increased TGase activity under salt stress. The activities of the proton-pump ATPase (H+-ATPase), vacuolar H+-ATPase (V-ATPase) and vacuolar H+-pyrophosphatase (PPase) were higher in the overexpression lines than in WT plants under salt stress. Moreover, the malondialdehyde (MDA) and H2O2 contents were significantly lower in the overexpression lines than in WT plants, accompanied by increased antioxidant enzyme activity. Taken together, these findings demonstrate that TGase plays protective roles in response to salt stress, which may promote plant survival by regulating PA metabolism and the Na+/K+ balance under salt stress.

Keywords:  Antioxidant system; Cucumber; Ion homeostasis; Polyamine; Salt stress; TGase

DOI:  https://doi.org/10.1016/j.plantsci.2020.110492
Plant Cell Physiol. 2020 Jun 16. pii: pcaa080. [Epub ahead of print]

Spermine regulates water balance associated with Ca2+-dependent aquaporins (TrTIP2-1, TrTIP2-2, and TrPIP2-7) expression in plants under water stress.

Zhou Li, Jieru Hou, Yan Zhang, Weihang Zeng, Bizhen Cheng, Muhammad Jawad Hassan, Youzhi Zhang, Qi Pu, Yan Peng.

  Spermine (Spm) regulates water balance involved in water channel proteins aquaporins (AQPs) in plants. An increase in endogenous Spm content via exogenous Spm application significantly improved cell membrane stability, photosynthesis, osmotic adjustment (OA), and water use efficiency (WUE) contributing to enhanced tolerance to water stress in white clover. Spm up-regulated TrTIP2-1, TrTIP2-2, and TrPIP2-7 expression and also increased the abundance of TIP2 and PIP2-7 proteins in white clover under water stress. Spm quickly activated intracellular Ca2+ signaling and Spm-induced TrTIP2-2 and TrPIP2-7 expression could be blocked by Ca2+ channels blockers and the inhibitor of CDPK in leaves of white clover. TrSAMS in relation to Spm biosynthesis was firstly cloned from white clover and the TrSAMS was located in nucleus. Transgenic Arabidopsis overexpressing the TrSAMS had significantly higher endogenous Spm content and improved cell membrane stability, photosynthesis, OA, WUE, and transcript levels of AtSIP1-1, AtSIP1-2, AtTIP2-1, AtTIP2-2, AtPIP1-2, AtPIP2-1, and AtNIP2-1 than wild type in response to water stress. Current findings indicates that Spm regulates water balance via enhancement in OA, WUE, and water transport related to Ca2+-dependent AQPs expression in plants under water stress.

Keywords:   S-adenosylmethionine synthetases; drought tolerance; signal transduction; transgenosis; water channel proteins; white clover

DOI:  https://doi.org/10.1093/pcp/pcaa080
Physiol Plant. 2020 Jun 17.

The effects of putrescine pre-treatment on osmotic stress responses in drought-tolerant and drought-sensitive wheat seedlings.

Dilyana Doneva, Magda Pál, Liliana Brankova, Gabriella Szalai, Judit Tajti, Radwan Khalil, Beti Ivanovska, Violeta Velikova, Svetlana Misheva, Tibor Janda, Violeta Peeva.

Recent studies have demonstrated that exogenous polyamines have protective effects under various stress condition. A broader understanding of the role of the polyamine pool fine regulation and the alterations of polyamine-related physiological processes could be obtained by comparing the stress effects in different genotypes. In this study, the impact of pre-treatment with putrescine in response to osmotic stress was investigated in the drought-tolerant Katya and drought-sensitive Zora wheat (Triticum aestivum) cultivars. Photosynthetic performance, in vivo thermoluminescence emission from leaves, leaf temperature, polyamine and salicylic acid levels, contents of osmoprotectants, and activities of antioxidant enzymes in the leaves were investigated not only to reveal differences in the physiological processes associated to drought tolerance, but to highlight the modulating strategies of polyamine metabolism between a drought-tolerant and a drought-sensitive wheat genotype. Results showed that the tolerance of Katya under osmotic stress conditions was characterized by higher photosynthetic ability, stable charge separation across the thylakoid membrane in photosystem II, higher proline accumulation and antioxidant activity. Thermoluminescence also revealed differences between the two varieties - a downshift of the B band and an increase of the afterglow band under osmotic stress in Zora, providing original complementary information to leaf photosynthesis. Katya variety exhibited higher constitutive levels of the signaling molecules putrescine and salicylic acid compared to the sensitive Zora. However, responses to exogenous putrescine were more advantageous for the sensitive variety under PEG treatment, which may be in relation with the decreased catabolism of polyamines, suggesting the increased need for polyamine under stress conditions. This article is protected by copyright. All rights reserved.

DOI: https://doi.org/10.1111/ppl.13150