bims-polyam 2022-05-01 papers

bims-polyam

Biomed News

on Polyamines

Issue of 2022–05–01
ten papers selected by
Sebastian J. Hofer, University of Graz

Polyamines in cancer: integrating organismal metabolism and antitumour immunity.
Elevated spermidine serum levels in mild cognitive impairment, a potential biomarker of progression to Alzheimer dementia, a pilot study.
Involvement of Polyamines From Cardiac Mast Cells in Myocardial Remodeling Induced by Pressure Overload Through Mitochondrial Permeability Transition Pore Opening.
Gibberellic acid interacts with salt stress on germination, growth and polyamine gene expression in fennel (Foeniculum vulgare Mill.) seedlings.
Polyamine biosynthesis and eIF5A hypusination are modulated by the DNA tumor virus KSHV and promote KSHV viral infection.
Valorisation of the diterpene podocarpic acid - Antibiotic and antibiotic enhancing activities of polyamine conjugates.
Metabolic engineering of Aureobasidium melanogenum for the overproduction of putrescine by improved L-ornithine biosynthesis.
A comprehensive review of spermidine: Safety, health effects, absorption and metabolism, food materials evaluation, physical and chemical processing, and bioprocessing.
Spermine reduces the harmful effects of salt stress in Tropaeolum majus.
Serum Spermidine in Relation to Risk of Stroke: A Multilevel Study.

Nat Rev Cancer. 2022 Apr 27.

Polyamines in cancer: integrating organismal metabolism and antitumour immunity.

Cassandra E Holbert, Michael T Cullen, Robert A Casero, Tracy Murray Stewart.

The natural mammalian polyamines putrescine, spermidine and spermine are essential for both normal and neoplastic cell function and replication. Dysregulation of metabolism of polyamines and their requirements is common in many cancers. Both clinical and experimental depletion of polyamines have demonstrated their metabolism to be a rational target for therapy; however, the mechanisms through which polyamines can establish a tumour-permissive microenvironment are only now emerging. Recent data indicate that polyamines can play a major role in regulating the antitumour immune response, thus likely contributing to the existence of immunologically 'cold' tumours that do not respond to immune checkpoint blockade. Additionally, the interplay between the microbiota and associated tissues creates a tumour microenvironment in which polyamine metabolism, content and function can all be dramatically altered on the basis of microbiota composition, dietary polyamine availability and tissue response to its surrounding microenvironment. The goal of this Perspective is to introduce the reader to the many ways in which polyamines, polyamine metabolism, the microbiota and the diet interconnect to establish a tumour microenvironment that facilitates the initiation and progression of cancer. It also details ways in which polyamine metabolism and function can be successfully targeted for therapeutic benefit, including specifically enhancing the antitumour immune response.

DOI: https://doi.org/10.1038/s41568-022-00473-2
J Clin Neurosci. 2022 Apr 26. pii: S0967-5868(22)00186-2. [Epub ahead of print]100 169-174

Elevated spermidine serum levels in mild cognitive impairment, a potential biomarker of progression to Alzheimer dementia, a pilot study.

Zohara Sternberg, Rebecca Podolsky, Adam Nir, Jihnhee Yu, Raphael Nir, Stanley W Halvorsen, Joseph F Quinn, Jeffrey Kaye, Channa Kolb.

   BACKGROUND/AIMS: There is a close link between iron and polyamine biosynthesis and metabolism. In a recent study, we reported alterations in the serum levels of hepcidin and other iron-related proteins in Alzheimer's disease (AD) patients (Sternberg et al., 2017). Based on these findings, this pilot study compared serum levels of one of the polyamines, Spermidine, between AD, mild cognitive impairment (MCI), and control subjects, correlating the levels with the existing clinical and neuroimaging data.
METHODS: This cross-sectional study measured Spermidine levels in frozen serum samples of 43 AD patients, 12 MCI patients, and 21 age-matched controls, provided by the Oregon Alzheimer's Disease Center Bio-repository, using enzyme-linked immunosorbent assay.
RESULTS: MCI patients showed significantly higher mean Spermidine serum levels compared to controls (P = 0.01), with a non-significant trend for higher Spermidine serum levels in pure AD (P = 0.08) participants compared to controls. Spermidine serum levels correlated with the values of cognitive assessment tests including MMSE (r = -0.705, P = 0.003), CDR (r = 0.751, P = 0.002), and CDR-SOB (r = 0.704, P = 0.007), in "pure" AD subgroup, suggesting that higher Spermidine serum levels in MCI can be a potential biomarker of conversion to dementia in subjects with AD underlying pathology. Furthermore, Spermidine serum levels correlated with serum levels of the chief iron regulatory protein, hepcidin in AD participants with a more advanced disease stage, indicated by MMSE (strata of 8-19, P = 0.02), and CDR-SOB (strata of 6-12, P = 0.03).
CONCLUSION: Studies with larger cohort are warranted for defining the role of Spermidine in AD pathophysiology, and the utility of polyamines as biomarkers of progression of MCI to AD.

Keywords:  Iron homeostasis; Ornithine decarboxylase; Polyamine; Serum biomarker

DOI:  https://doi.org/10.1016/j.jocn.2022.04.028
Front Cardiovasc Med. 2022 ;9 850688

Involvement of Polyamines From Cardiac Mast Cells in Myocardial Remodeling Induced by Pressure Overload Through Mitochondrial Permeability Transition Pore Opening.

Xiaolan Xiong, Junming Li, Shizhong Zhang, Xiaoli Jia, Chao Xiao.

   Objective: Polyamines mainly contain spermine (SPM), spermidine (SPD), and putrescine (PUT). Many research results suggest that polyamines participate in cell proliferation, differentiation, and the regulation of gene expression, and have a close relationship with the occurrence and development of many diseases. However, the role and possible mechanisms of action of polyamines from cardiac mast cells in myocardial remodeling induced by pressure overload remain to be elucidated.
Methods: Pressure overload was induced by abdominal aortic constriction (AAC). Toluidine blue staining was used to visualize mast cells in cardiac tissue. The polyamine content of cardiac tissue was analyzed using high-performance liquid chromatography. Opening of the mitochondrial permeability transition pore (MPTP) was determined by the Ca2+-induced swelling of isolated cardiac mitochondria, measured as a reduction in A520.
Results: Compared with sham rats, the cardiac mast cell density, the polyamine content (PUT, SPB, and SPM), and myocardial MPTP opening in rats with AAC were significantly increased (P < 0.05), and were accompanied by increased myocardial fibrosis and heart weight/body weight ratio. Intraperitoneal injection of polyamines mimicked these results, and these effects were reversed by cromolyn sodium, a mast cell stabilizer (P < 0.05). Myocardial MPTP opening increased in rats with AAC (P < 0.05), and the three polyamines also increased myocardial MPTP opening (P < 0.05).
Conclusion: Mast cell-derived polyamines are involved in pressure overload-induced myocardial remodeling by increasing opening of the MPTP.

Keywords:  MPTP; cardiac remodeling; mast cell; polyamine; pressure overload

DOI:  https://doi.org/10.3389/fcvm.2022.850688
Physiol Mol Biol Plants. 2022 Mar;28(3): 607-622

Gibberellic acid interacts with salt stress on germination, growth and polyamine gene expression in fennel (Foeniculum vulgare Mill.) seedlings.

Houneida Attia, Khalid Alamer, Badreyah Algethami, Walid Zorrig, Kamel Hessini, Kamala Gupta, Bhaskar Gupta.

  This study aimed to rigorously investigate and integrate the underlying hypothesis that an enhancing effect of gibberellic acid (GA3, 3 µM) with increased growth actually leads to a modification of the physiological role of polyamines during salinity stress (NaCl, 100 mM) in fennel. These analyses concern both reserve tissues (cotyledons) and embryonic axes in growth. Physiological results indicate a restriction of germination, growth, mineral nutrition and damages to membranes of salt-treated seedlings. This was partially attenuated in seedlings treated with an interaction effect of GA3 and NaCl. Peroxidase and catalase activities showed a reduction or an augmentation according to the treatments and organs. The three main polyamines (PA): putrescine, spermidine and spermine were elevated in the salt-treated seedlings. Meanwhile, GA3 seed priming was extremely efficient in reducing PA levels in salt-stressed seedlings compared to the control. Response of PA genes to salinity was variable. Up-regulation was noted for SPMS1, ODC1, and ADC1 in hypocotyls and cotyledons (H + C) and down-regulation for SAMDC1 in the radicle. Interaction of salt/GA3 treatment showed different responses, only ODC1 in (H + C) and ADC1 in both radicle and (H + C) were overexpressed. Concerning other genes, no change in mRNA abundance was observed in both organs compared to the salt-treated seedlings. From these results, it could be inferred that the fennel seedlings were NaCl sensitive. This sensitivity was mitigated when GA3 applied for seed priming and applied in combination with NaCl, which resulted in a reduction of the PA content.
Supplementary Information: The online version contains supplementary material available at 10.1007/s12298-022-01140-4.

Keywords:  Antioxidant enzyme activity; Ion accumulation; Oxidative stress; Polyamines; Salt stress; Seed priming

DOI:  https://doi.org/10.1007/s12298-022-01140-4
PLoS Pathog. 2022 Apr 29. 18(4): e1010503

Polyamine biosynthesis and eIF5A hypusination are modulated by the DNA tumor virus KSHV and promote KSHV viral infection.

Guillaume N Fiches, Zhenyu Wu, Dawei Zhou, Ayan Biswas, Tai-Wei Li, Weili Kong, Maxime Jean, Netty G Santoso, Jian Zhu.

Polyamines are critical metabolites involved in various cellular processes and often dysregulated in cancers. Kaposi's sarcoma-associated Herpesvirus (KSHV), a defined human oncogenic virus, leads to profound alterations of host metabolic landscape to favor development of KSHV-associated malignancies. In our studies, we identified that polyamine biosynthesis and eIF5A hypusination are dynamically regulated by KSHV infection through modulation of key enzymes (ODC1 and DHPS) of these pathways. During KSHV latency, ODC1 and DHPS are upregulated along with increase of hypusinated eIF5A (hyp-eIF5A), while hyp-eIF5A is further induced along with reduction of ODC1 and intracellular polyamines during KSHV lytic reactivation. In return these metabolic pathways are required for both KSHV lytic reactivation and de novo infection. Further analysis unraveled that synthesis of critical KSHV latent and lytic proteins (LANA, RTA) depends on hypusinated-eIF5A. We also demonstrated that KSHV infection can be efficiently and specifically suppressed by inhibitors targeting these pathways. Collectively, our results illustrated that the dynamic and profound interaction of a DNA tumor virus (KSHV) with host polyamine biosynthesis and eIF5A hypusination pathways promote viral propagation, thus defining new therapeutic targets to treat KSHV-associated malignancies.

DOI: https://doi.org/10.1371/journal.ppat.1010503
Bioorg Med Chem. 2022 Apr 21. pii: S0968-0896(22)00154-7. [Epub ahead of print]64 116762

Valorisation of the diterpene podocarpic acid - Antibiotic and antibiotic enhancing activities of polyamine conjugates.

Steven A Li, Melissa M Cadelis, Rebecca C Deed, Hana Douafer, Marie-Lise Bourguet-Kondracki, Jean Michel Brunel, Brent R Copp.

  As part of our search for new antimicrobials and antibiotic adjuvants, a series of podocarpic acid-polyamine conjugates have been synthesized. The library of compounds made use of the phenolic and carboxylic acid moieties of the diterpene allowing attachment of polyamines (PA) of different lengths to afford a structurally-diverse set of analogues. Evaluation of the conjugates for intrinsic antimicrobial properties identified two derivatives of interest: a PA3-4-3 (spermine) amide-bonded variant 7a that was a non-cytotoxic, non-hemolytic potent growth inhibitor of Gram-positive Staphylococcus aureus (MRSA) and 9d, a PA3-8-3 carbamate derivative that was a non-toxic selective antifungal towards Cryptococcus neoformans. Of the compound set, only one example exhibited activity towards Gram-negative bacteria. However, in the presence of sub-therapeutic amounts of either doxycycline (4.5 µM) or erythromycin (2.7 μM) several analogues were observed to exhibit weak to modest antibiotic adjuvant properties against Pseudomonas aeruginosa and/or Escherichia coli. The observation of strong cytotoxicity and/or hemolytic properties for subsets of the library, in particular those analogues bearing methyl ester or n-pentylamide functionality, highlighted the fine balance of structural requirements and lipophilicity for antimicrobial activity as opposed to mammalian cell toxicity.

Keywords:  Antibiotic adjuvant; Antimicrobial activities; Diterpene polyamine conjugates; Podocarpic acid

DOI:  https://doi.org/10.1016/j.bmc.2022.116762
Microbiol Res. 2022 Apr 25. pii: S0944-5013(22)00081-7. [Epub ahead of print]260 127041

Metabolic engineering of Aureobasidium melanogenum for the overproduction of putrescine by improved L-ornithine biosynthesis.

Cun-Cui Kong, Xin Wei, Guang-Lei Liu, Zhen-Ming Chi, Zhe Chi.

  Aureobasidium melanogenum HN6.2 is a high siderophore-producing yeast-like fungal strain. After blocking siderophore biosynthesis and attenuating the expression of the ornithine carbamoyltransferase gene (the OTC gene), the obtained D-LCFAO-cre strain produced 2.1 ± 0.02 mg of intracellular L-ornithine per mg of the protein. The overexpression of the L-ornithine decarboxylase gene (the SPE1-S gene) from Saccharomyces cerevisiae in the mutant D-LCFAO-cre could make the transformant E-SPE1-S synthesize 3.6 ± 0.1 of intracellular ornithine per mg of protein and produce 10.5 g/L of putrescine. The further overexpression of the ArgB/C gene encoding bifunctional acetylglutamate kinase/N-acetyl-gamma-glutamyl-phosphate reductase in the transformant E-SPE1-S caused the transformant E-SPE1-S-ArgB/C to accumulate L-ornithine (4.2 mg/mg protein) and to produce 21.3 g/L of putrescine. During fed-batch fermentation, the transformant E-SPE1-S-ArgB/C could produce 33.4 g/L of putrescine, the yield was 0.96 g/g of glucose, and the productivity was 0.28 g/L/h. The putrescine titer was much higher than that produced by most engineered strains obtained thus far.

Keywords:  A. melanogenum; L-Ornithine; L-ornithine decarboxylase; Ornithine carbamoyltransferase; Putrescine

DOI:  https://doi.org/10.1016/j.micres.2022.127041
Compr Rev Food Sci Food Saf. 2022 Apr 27.

A comprehensive review of spermidine: Safety, health effects, absorption and metabolism, food materials evaluation, physical and chemical processing, and bioprocessing.

Dian Zou, Ziyue Zhao, Lu Li, Yu Min, Daiyuan Zhang, Anying Ji, Cong Jiang, Xuetuan Wei, Xian Wu.

  Spermidine, a natural autophagy inducer, has a variety of health effects, such as antitumor, antiaging, anti-inflammation, cardiovascular protection, and neuromodulation. It has been a hot topic in the field of food processing, and current research findings suggest that spermidine-rich foods may be used in intervention and prevention of age-related diseases. In this article, recent findings on the safety, health effects, absorption and metabolism of spermidine were reviewed, and advances in food processing, including the raw materials evaluation, physical and chemical processing, and biological processing of spermidine, were highlighted. In particular, the core metabolic pathways, key gene targets, and efficient metabolic engineering strategies involved in the biosynthesis of spermidine and its precursors were discussed. Moreover, limitations and future perspectives of spermidine research were proposed. The purpose of this review is to provide new insights on spermidine from its safety to its food processing, which will advance the commercial production and applications of spermidine-rich foods and nutraceuticals.

Keywords:  biosynthesis; food processing; health effects; metabolic engineering; safety; spermidine

DOI:  https://doi.org/10.1111/1541-4337.12963
Physiol Mol Biol Plants. 2022 Mar;28(3): 687-696

Spermine reduces the harmful effects of salt stress in Tropaeolum majus.

Toshik Iarley da Silva, Marlon Gomes Dias, Nícolas Oliveira de Araújo, Mirelle Nayana de Sousa Santos, Renata Ranielly Pedroza Cruz, Thiago Jardelino Dias, Wellington Souto Ribeiro, José Antonio Saraiva Grossi, José Geraldo Barbosa.

  Flowers, leaves, fruits and buds of Tropaeolum majus are used for ornamental, medicinal and food purposes. However, salt stress limits the development and productivity of T. majus due to biochemical, physiological and anatomical disturbances. Polyamine application is an alternative for mitigating the harmful effects of salt stress. Thus, the objective of this work was to evaluate the effects of spermine application in T. majus grown under salt stress. The experiment was carried out in a completely randomized design, in a 3 × 2 factorial scheme, with 0, 40 mM (moderate salt stress) and 80 mM (severe salt stress) NaCl, and 0 and 1 mM spermine, and with five replicates. Growth (plant height, stem diameter, number of leaves, number of flowers, number of buds, leaf dry mass, stem dry mass and flower dry mass), gas exchange (gs, A, E, Ci and WUE), relative water content, contents of free amino acids, phenolic compounds, reducing and non-reducing sugars, lipid peroxidation and enzymatic activities (CAT, POD and APX) were evaluated. Spermine application decreased the harmful effects of salt stress on the growth and gas exchange and increased flowering in T. majus. Furthermore, the relative water content of T. majus increased under severe salt stress conditions. Spermine application reduced the contents of total phenolic compounds, free amino acids, reducing sugars and non-reducing sugars on leaves of T. majus. Spermine application increased CAT and POD activities in plants under severe salt stress and POD and APX in plants under moderate salt stress.

Keywords:  Polyamine; Salinity; Tropaeolaceae; nasturtium

DOI:  https://doi.org/10.1007/s12298-022-01165-9
Front Nutr. 2022 ;9 843616

Serum Spermidine in Relation to Risk of Stroke: A Multilevel Study.

Liqiang Zheng, Yanxia Xie, Zhaoqing Sun, Rui Zhang, Yanan Ma, Jiahui Xu, Jia Zheng, Qianyi Xu, Zhao Li, Xiaofan Guo, Guozhe Sun, Fuguo Xing, Yingxian Sun, Deliang Wen.

  The relationship between serum spermidine levels and future cardiovascular disease risk has not yet been well elucidated in the general population based on community studies. Using a nested case-control study, we estimated the association between serum spermidine level and future stroke. New stroke cases had higher baseline levels of spermidine than controls [182.8 (141.8-231.5) vs. 152.0 (124.3-193.0), P < 0.001]. After multivariable adjustment, individuals with spermidine ≥ 205.9 nmol/L (T3) higher risks of stroke (HR 5.02, 95% CI 1.58-16.02) with the lowest quartile (< 136.9 nmol/L) as reference. The association between serum spermidine levels and risk of stroke seemed to be consistent and was reproducible in our cross-sectional studies. In addition, comparisons of the areas under receiver operator characteristics curves confirmed that a model including spermidine had better discrimination than without (0.755 vs. 0.715, P = 0.04). Here we report a close relationship exists between serum spermidine levels and risk of stroke.

Keywords:  cardiovascular disease; epidemiology; nested case-control study; spermidine; stroke

DOI:  https://doi.org/10.3389/fnut.2022.843616