bims-polyam Biomed News
on Polyamines
Issue of 2021–04–04
twelve papers selected by
Sebastian J. Hofer, University of Graz
  1. ATP13A2 Regulates Cellular α-Synuclein Multimerization, Membrane Association, and Externalization.
  2. The Impact of Polyamine Precursors, Polyamines, and Steroid Hormones on Temporal Messenger RNA Abundance in Bovine Satellite Cells Induced to Differentiate.
  3. Dual Inhibition of Ornithine Decarboxylase and A1 Adenosine Receptor Efficiently Suppresses Breast Tumor Cells.
  4. Arginine Decarboxylase Is Essential for Pneumococcal Stress Responses.
  5. Polyamine-Rich Diet Elevates Blood Spermine Levels and Inhibits Pro-Inflammatory Status: An Interventional Study.
  6. Effects of Spermine and Spermidine Supplemented Extenders on Post-thaw Spermatological Parameters in Stallion Semen Cryopreservation.
  7. AMD1 upregulates hepatocellular carcinoma cells stemness by FTO mediated mRNA demethylation.
  8. Emerging Role of ODC1 in Neurodevelopmental Disorders and Brain Development.
  9. Chromogenic Chemodosimeter Based on Capped Silica Particles to Detect Spermine and Spermidine.
  10. Application of gold and silver nanoparticles for selective assay of spermine in mixture with spermidine.
  11. Relationship between polyamines conjugated to mitochondrion membrane and mitochondrion conformation from developing wheat embryos under drought stress.
  12. Spermidine Prevents Ethanol and Lipopolysaccharide-Induced Hepatic Injury in Mice.
  1. Int J Mol Sci. 2021 Mar 07. pii: 2689. [Epub ahead of print]22(5):
    ATP13A2 Regulates Cellular α-Synuclein Multimerization, Membrane Association, and Externalization.
    Jianmin Si, Chris Van den Haute, Evy Lobbestael, Shaun Martin, Sarah van Veen, Peter Vangheluwe, Veerle Baekelandt.
      ATP13A2, a late endo-/lysosomal polyamine transporter, is implicated in a variety of neurodegenerative diseases, including Parkinson's disease and Kufor-Rakeb syndrome, an early-onset atypical form of parkinsonism. Loss-of-function mutations in ATP13A2 result in lysosomal deficiency as a consequence of impaired lysosomal export of the polyamines spermine/spermidine. Furthermore, accumulating evidence suggests the involvement of ATP13A2 in regulating the fate of α-synuclein, such as cytoplasmic accumulation and external release. However, no consensus has yet been reached on the mechanisms underlying these effects. Here, we aimed to gain more insight into how ATP13A2 is linked to α-synuclein biology in cell models with modified ATP13A2 activity. We found that loss of ATP13A2 impairs lysosomal membrane integrity and induces α-synuclein multimerization at the membrane, which is enhanced in conditions of oxidative stress or exposure to spermine. In contrast, overexpression of ATP13A2 wildtype (WT) had a protective effect on α-synuclein multimerization, which corresponded with reduced αsyn membrane association and stimulation of the ubiquitin-proteasome system. We also found that ATP13A2 promoted the secretion of α-synuclein through nanovesicles. Interestingly, the catalytically inactive ATP13A2 D508N mutant also affected polyubiquitination and externalization of α-synuclein multimers, suggesting a regulatory function independent of the ATPase and transport activity. In conclusion, our study demonstrates the impact of ATP13A2 on α-synuclein multimerization via polyamine transport dependent and independent functions.
    Keywords:  ATP13A2; Parkinson’s disease; spermine; α-synuclein; α-synuclein multimerization
    DOI:  https://doi.org/10.3390/ijms22052689
  2. Animals (Basel). 2021 Mar 10. pii: 764. [Epub ahead of print]11(3):
    The Impact of Polyamine Precursors, Polyamines, and Steroid Hormones on Temporal Messenger RNA Abundance in Bovine Satellite Cells Induced to Differentiate.
    Caleb C Reichhardt, Lillian L Okamoto, Laura A Motsinger, Brian P Griffin, Gordon K Murdoch, Kara J Thornton.
      Emerging research suggests that hormones found in anabolic implants interact with polyamine biosynthesis. The objective of this study was to determine the effects of steroidal hormones, polyamines and polyamine precursors on bovine satellite cell (BSC) differentiation and polyamine biosynthesis temporally. Primary BSCs were induced to differentiate in 3% horse serum (CON) and treated with 10 nM trenbolone acetate (TBA), 10 nM estradiol (E2), 10 nM TBA and 10 nM E2, 10 mM methionine, 8 mM ornithine, 2 mM putrescine, 1.5 mM spermidine, or 0.5 mM spermine. Total mRNA was isolated 0, 2, 4, 8, 12, 24, and 48 h post-treatment. Abundance of mRNA for genes associated with induction of BSC differentiation: paired box transcription factor 7, myogenic factor 5, and myogenic differentiation factor 1 and genes in the polyamine biosynthesis pathway: ornithine decarboxylase and S-adenosylmethionine-were analyzed. Overall, steroidal hormones did not impact (p > 0.05) mRNA abundance of genes involved in BSC differentiation, but did alter (p = 0.04) abundance of genes involved in polyamine biosynthesis. Polyamine precursors influenced (p < 0.05) mRNA of genes involved in BSC differentiation. These results indicate that polyamine precursors and polyamines impact BSC differentiation and abundance of mRNA involved in polyamine biosynthesis, while steroidal hormones altered the mRNA involved in polyamine biosynthesis.
    Keywords:  anabolic implants; beef; bovine satellite cells; polyamines; skeletal muscle
    DOI:  https://doi.org/10.3390/ani11030764
  3. Front Oncol. 2021 ;11 636373
    Dual Inhibition of Ornithine Decarboxylase and A1 Adenosine Receptor Efficiently Suppresses Breast Tumor Cells.
    Hongyan Ma, Qizhang Li, Jing Wang, Jing Pan, Zhengding Su, Sen Liu.
      Personized treatment of breast cancer is still a challenge, and more treatment options for breast cancer are warranted. Combination therapies have been a highly appreciated strategy for breast cancer treatment in recent years, and the development of new combination therapies could improve patient outcomes. Adenosine and polyamines are both endogenous metabolites with indispensable biological functions. Adenosine binds with the A1 adenosine receptor (A1AR) to downregulate cAMP concentration, and both low cAMP content and high polyamine levels stimulate the growth and proliferation of cancer cells. In this work, we initially used a polyamine synthesis inhibitor, DFMO (α-difluoromethylornithine), and an A1AR inhibitor, DPCPX (8-cyclopentyl-1,3-dipropylxanthine) to investigate if simultaneously inhibiting A1AR and polyamine synthesis has synergistical antitumor effects. Next, we investigated a dual inhibitor (ODC-MPI-2) of A1AR and ODC (ornithine decarboxylase 1), the rate-limiting enzyme in polyamine biosynthesis. We investigated if ODC-MPI-2 could inhibit the proliferation and growth of breast cancer cells. Our data showed that DFMO and DPCPX synergistically inhibit the growth and proliferation of MCF-7 cells. We also demonstrated that ODC-MPI-2 reduces cellular polyamine levels and elevates cAMP concentration. We further showed that ODC-MPI-2 inhibits the growth, proliferation, and migration/invasion of MCF-7 cells. Finally, ODC-MPI-2 showed a preference for inhibiting triple-negative breast cancer cells. The dual inhibition of ODC and A1AR is a new combination therapy strategy for treating breast cancer, and dual inhibitors of ODC and A1AR may be effective future drugs for treating breast cancer.
    Keywords:  A1AR; cyclic AMP (cAMP) pathway; dual inhibitor; ornithine decarboxylase 1 (ODC); polyamine pathway
    DOI:  https://doi.org/10.3389/fonc.2021.636373
  4. Pathogens. 2021 Mar 02. pii: 286. [Epub ahead of print]10(3):
    Arginine Decarboxylase Is Essential for Pneumococcal Stress Responses.
    Mary Frances Nakamya, Moses B Ayoola, Leslie A Shack, Mirghani Mohamed, Edwin Swiatlo, Bindu Nanduri.
      Polyamines such as putrescine, cadaverine, and spermidine are small cationic molecules that play significant roles in cellular processes, including bacterial stress responses and host-pathogen interactions. Streptococcus pneumoniae is an opportunistic human pathogen, which causes several diseases that account for significant morbidity and mortality worldwide. As it transits through different host niches, S. pneumoniae is exposed to and must adapt to different types of stress in the host microenvironment. We earlier reported that S. pneumoniae TIGR4, which harbors an isogenic deletion of an arginine decarboxylase (ΔspeA), an enzyme that catalyzes the synthesis of agmatine in the polyamine synthesis pathway, has a reduced capsule. Here, we report the impact of arginine decarboxylase deletion on pneumococcal stress responses. Our results show that ΔspeA is more susceptible to oxidative, nitrosative, and acid stress compared to the wild-type strain. Gene expression analysis by qRT-PCR indicates that thiol peroxidase, a scavenger of reactive oxygen species and aguA from the arginine deiminase system, could be important for peroxide stress responses in a polyamine-dependent manner. Our results also show that speA is essential for endogenous hydrogen peroxide and glutathione production in S. pneumoniae. Taken together, our findings demonstrate the critical role of arginine decarboxylase in pneumococcal stress responses that could impact adaptation and survival in the host.
    Keywords:  Streptococcus pneumoniae; acid stress; arginine decarboxylase; nitrosative stress; oxidative stress; polyamines
    DOI:  https://doi.org/10.3390/pathogens10030286
  5. Med Sci (Basel). 2021 Mar 29. pii: 22. [Epub ahead of print]9(2):
    Polyamine-Rich Diet Elevates Blood Spermine Levels and Inhibits Pro-Inflammatory Status: An Interventional Study.
    Kuniyasu Soda, Takeshi Uemura, Hidenori Sanayama, Kazuei Igarashi, Taro Fukui.
      The Japanese diet and the Mediterranean diet are rich in polyamines (spermidine and spermine). Increased polyamine intake elevated blood spermine levels, inhibited aging-associated pro-inflammatory status (increases in lymphocyte function-associated antigen-1 (LFA-1) on immune cells), suppressed aberrant gene methylation and extended the lifespan of mice. To test the effects of increased polyamine intake by humans, 30 healthy male volunteers were asked to eat polyamine-rich and ready-to-eat traditional Japanese food (natto) for 12 months. Natto with high polyamine content was used. Another 27 male volunteers were asked not to change their dietary pattern as a control group. The volunteers' age of intervention and control groups ranged from 40 to 69 years (median 48.9 ± 7.9). Two subjects in the control group subsequently dropped out of the study. The estimated increases in spermidine and spermine intakes were 96.63 ± 47.70 and 22.00 ± 9.56 µmol per day in the intervention group, while no changes were observed in the control group. The mean blood spermine level in the intervention group gradually rose to 1.12 ± 0.29 times the pre-intervention level after 12 months, and were significantly higher (p = 0.019) than those in the control group. Blood spermidine did not increase in either group. LFA-1 on monocytes decreased gradually in the intervention group, and there was an inverse association between changes in spermine concentrations relative to spermidine and changes in LFA-1 levels. Contingency table analysis revealed that the odds ratio to decrease LFA-1 by increased polyamine intake was 3.927 (95% CI 1.116-13.715) (p = 0.032) when the effect of acute inflammation was excluded. The results in the study were similar to those of our animal experiments. Since methylation changes of the entire genome are associated with aging-associated pathologies and our previous studies showed that spermine-induced LFA-1 suppression was associated with the inhibition of aberrant gene methylation, the results suggest that dietary polyamine contributes to human health and longevity.
    Keywords:  Natto; aging; high polyamine diet; spermidine; spermine
    DOI:  https://doi.org/10.3390/medsci9020022
  6. Cryobiology. 2021 Mar 29. pii: S0011-2240(21)00068-7. [Epub ahead of print]
    Effects of Spermine and Spermidine Supplemented Extenders on Post-thaw Spermatological Parameters in Stallion Semen Cryopreservation.
    Kemal Tuna Olğaç, Ergun Akçay.
      In this study, the effects of polyamines, Spermine and Spermidine, on long-term preservation and post-thaw spermatological parameters were evaluated. Moreover, determination of the most suitable polyamine and its dose that can be added to standard extenders were aimed. Four adult Arabian stallions were used in the study. Five ejaculates were collected from each of four stallions via artificial vagina two days interval. Each ejaculate was divided into 13 aliquots. INRA96 (95,5%), egg yolk (2%), and glycerol (2,5%) were used as a control extender. Extenders of experimental groups were prepared with different doses of Spermine and Spermidine (0,1 mg/ml; 0,2 mg/ml; 0,4 mg/ml; 1 mg/ml; 2 mg/ml; 4 mg/ml). Stallion semen that were cryopreserved with Control and experimental extenders were evaluated in terms of motility, progressive motility, plasma membrane integrity, capacitation index, acrosome integrity and DNA fragmentation index. At the end of the evaluations, it was determined that 0,2 mg/ml Spermine and 0,4 mg/ml Spermidine showed better motility and progressive motility, numerically. On the other hand, it was observed that 4 mg/ml Spermine and Spermidine had the lowest statistically significant values (p<0,001). While statistically similar differences were obtained between groups in terms of the plasma membrane and acrosome integrity, it was determined that all experimental groups had lower and statistically significant values in terms of capacitation and DNA fragmentation index (p<0,001). As result, it was observed that the stallion semen cryopreservation success can be increased by the addition of 1-2 mg/ml Spermine that had effective protection on capacitation and DNA fragmentation index without damaging other spermatological properties.
    Keywords:  Polyamine; Semen cryopreservation; Spermidine; Spermine; Stallion
    DOI:  https://doi.org/10.1016/j.cryobiol.2021.03.008
  7. Clin Transl Med. 2021 Mar;11(3): e352
    AMD1 upregulates hepatocellular carcinoma cells stemness by FTO mediated mRNA demethylation.
    Xinyu Bian, Dongmin Shi, Kailin Xing, Hongxin Zhou, Lili Lu, Dahai Yu, Weizhong Wu.
       BACKGROUND: S-adenosylmethionine decarboxylase proenzyme (AMD1) is a key enzyme involved in the synthesis of spermine (SPM) and spermidine (SPD), which are associated with multifarious cellular processes. It is also found to be an oncogene in multiple cancers and a potential target for tumor therapy. Nevertheless, the role AMD1 plays in hepatocellular carcinoma (HCC) is still unknown.
    METHODS: HCC samples were applied to detect AMD1 expression and evaluate its associations with clinicopathological features and prognosis. Subcutaneous and orthotopic tumor mouse models were constructed to analyze the proliferation and metastasis of HCC cells after AMD1 knockdown or overexpression. Drug sensitive and tumor sphere assay were performed to investigate the effect of AMD1 on HCC cells stemness. Real-time quantitative PCR (qRT-PCR), western blot, immunohistochemical (IHC) and m6A-RNA immunoprecipitation (Me-RIP) sequencing/qPCR were applied to explore the potential mechanisms of AMD1 in HCC. Furthermore, immunofluorescence, co-IP (Co-IP) assays, and mass spectrometric (MS) analyses were performed to verify the proteins interacting with AMD1.
    RESULTS: AMD1 was enriched in human HCC tissues and suggested a poor prognosis. High AMD1 level could promote SRY-box transcription factor 2 (SOX2), Kruppel like factor 4 (KLF4), and NANOG expression of HCC cells through obesity-associated protein (FTO)-mediated mRNA demethylation. Mechanistically, high AMD1 expression increased the levels of SPD in HCC cells, which could modify the scaffold protein, Ras GTPase-activating-like protein 1 (IQGAP1) and enhance the interaction between IQGAP1 and FTO. This interaction could enhance the phosphorylation and decrease the ubiquitination of FTO.
    CONCLUSIONS: AMD1 could stabilize the interaction of IQGAP1 with FTO, which then promotes FTO expression and increases HCC stemness. AMD1 shows prospects as a prognostic predictor and a therapeutic target for HCC.
    Keywords:  AMD1; FTO; IQGAP1; N6-methyladenosine; hepatocellular carcinoma; polyamination; stemness
    DOI:  https://doi.org/10.1002/ctm2.352
  8. Genes (Basel). 2021 Mar 25. pii: 470. [Epub ahead of print]12(4):
    Emerging Role of ODC1 in Neurodevelopmental Disorders and Brain Development.
    Jeremy W Prokop, Caleb P Bupp, Austin Frisch, Stephanie M Bilinovich, Daniel B Campbell, Daniel Vogt, Chad R Schultz, Katie L Uhl, Elizabeth VanSickle, Surender Rajasekaran, André S Bachmann.
      Ornithine decarboxylase 1 (ODC1 gene) has been linked through gain-of-function variants to a rare disease featuring developmental delay, alopecia, macrocephaly, and structural brain anomalies. ODC1 has been linked to additional diseases like cancer, with growing evidence for neurological contributions to schizophrenia, mood disorders, anxiety, epilepsy, learning, and suicidal behavior. The evidence of ODC1 connection to neural disorders highlights the need for a systematic analysis of ODC1 genotype-to-phenotype associations. An analysis of variants from ClinVar, Geno2MP, TOPMed, gnomAD, and COSMIC revealed an intellectual disability and seizure connected loss-of-function variant, ODC G84R (rs138359527, NC_000002.12:g.10444500C > T). The missense variant is found in ~1% of South Asian individuals and results in 2.5-fold decrease in enzyme function. Expression quantitative trait loci (eQTLs) reveal multiple functionally annotated, non-coding variants regulating ODC1 that associate with psychiatric/neurological phenotypes. Further dissection of RNA-Seq during fetal brain development and within cerebral organoids showed an association of ODC1 expression with cell proliferation of neural progenitor cells, suggesting gain-of-function variants with neural over-proliferation and loss-of-function variants with neural depletion. The linkage from the expression data of ODC1 in early neural progenitor proliferation to phenotypes of neurodevelopmental delay and to the connection of polyamine metabolites in brain function establish ODC1 as a bona fide neurodevelopmental disorder gene.
    Keywords:  neural development; ornithine decarboxylase; polyamine; rs138359527 (NP_002530.1:p.Gly84Arg); variant data integration
    DOI:  https://doi.org/10.3390/genes12040470
  9. Nanomaterials (Basel). 2021 Mar 23. pii: 818. [Epub ahead of print]11(3):
    Chromogenic Chemodosimeter Based on Capped Silica Particles to Detect Spermine and Spermidine.
    Mariana Barros, Alejandro López-Carrasco, Pedro Amorós, Salvador Gil, Pablo Gaviña, Margarita Parra, Jamal El Haskouri, Maria Carmen Terencio, Ana M Costero.
      A new hybrid organic-inorganic material for sensing spermine (Spm) and spermidine (Spd) has been prepared and characterized. The material is based on MCM-41 particles functionalized with an N-hydroxysuccinimide derivative and loaded with Rhodamine 6G. The cargo is kept inside the porous material due to the formation of a double layer of organic matter. The inner layer is covalently bound to the silica particles, while the external layer is formed through hydrogen and hydrophobic interactions. The limits of detection determined by fluorimetric titration are 27 µM and 45 µM for Spm and Spd, respectively. The sensor remains silent in the presence of other biologically important amines and is able to detect Spm and Spd in both aqueous solution and cells.
    Keywords:  detection; silica particles; spermidine; spermine
    DOI:  https://doi.org/10.3390/nano11030818
  10. Exp Oncol. 2021 03;43(1): 77-81
    Application of gold and silver nanoparticles for selective assay of spermine in mixture with spermidine.
    Yu V Yanish, S P Zaletok, N V Vityuk, Yu P Mukha.
       AIM: To assess the applicability of the novel technique based on the detection of spermine in solutions by spectrocolorimetric method using gold and silver colloidal nanoparticles.
    MATERIALS AND METHODS: Colloidal solution of gold nanoparticles were synthesized by chemical reduction of tetrachlorauric acid with trisodium citrate. Colloidal solution of silver nanoparticles was obtained by chemical reduction of silver nitrate with tryptophan. The absorption spectra of gold/silver metal colloids and their mixtures with polyamines were recorded.
    RESULTS: The increase of spermine concentration in solution caused the change in the intensity of the band of localized surface plasmon resonance that was not affected by the excess of spermidine. The color shift in colloidal gold due to its aggregation with spermine was registered spectrophotometrically.
    CONCLUSION: The principal possibility of selective quantification of spermine in the presence of spermidine in extremely high concentration using colloidal gold has been shown. This method can be used to assay selectively spermine in biological fluids.
  11. J Biosci. 2021 ;pii: 31. [Epub ahead of print]46
    Relationship between polyamines conjugated to mitochondrion membrane and mitochondrion conformation from developing wheat embryos under drought stress.
    D X Liu, H L Liu, H Y DU, H P Liu, R Kurtenbach.
      The mitochondrion conformation and the contents of conjugated polyamines were investigated using the embryos of developing wheat (Triticum aestivum L.) grains of two cultivars differing in drought tolerance as experiment materials. After drought stress treatment for 7 days, the relative water content of embryo and relative increase rate of embryo dry weight of the drought-sensitive Yangmai No. 9 cv. decreased more significantly than those of the drought-tolerant Yumai No. 18 cv. Furthermore, the changes in mitochondrion conformation of Yangmai No. 9 were more marked. Meanwhile, the increases of the contents of conjugated non-covalently spermidine (CNC-Spd) and conjugated covalently putrescine (CC-Put) of Yumai No. 18 were more obvious than those of Yangmai No. 9. Treatment with exogenous Spd not only alleviated the injury of drought stress to Yangmai No. 9, but also enhanced the increase of CNC-Spd content and inhibited the change in the mitochondrion conformation of this cultivar. The treatments of Yumai No. 18 with two inhibitors, methylglyoxyl-bis (guanylhydrazone) and phenanthrolin, significantly inhibited the drought stress-induced increases of CNC-Spd and CC-Put contents of the cultivar, respectively. Meanwhile, the treatments with the two inhibitors aggravated the injury of drought stress to Yumai No. 18 and enhanced the change in the mitochondrion conformation of this cultivar. These results mentioned above suggested that the CNC-Spd and CC-Put in embryo mitochondrion membrane isolated from developing grains could enhance the wheat tolerance to drought stress by maintaining the mitochondrion conformation.
  12. Molecules. 2021 Mar 22. pii: 1786. [Epub ahead of print]26(6):
    Spermidine Prevents Ethanol and Lipopolysaccharide-Induced Hepatic Injury in Mice.
    Raghabendra Adhikari, Ruchi Shah, Karina Reyes-Gordillo, Jaime Arellanes-Robledo, Ying Cheng, Joseph Ibrahim, Pamela L Tuma.
      To date, there is no effective treatment for alcoholic liver disease, despite its prevalence world-wide. Because alcohol consumption is associated with oxidative stress-induced liver injury and pro-inflammatory responses, naturally occurring antioxidants and/or anti-inflammatories may be potential therapeutics. Spermidine is an abundant, ubiquitous polyamine that has been found to display strong antioxidant and anti-inflammatory properties. To further investigate whether spermidine is an effective intervention for alcohol-induced liver disease, we examined its hepatoprotective properties using a two-hit, chronic ethanol and acute lipopolysaccharide (LPS)-induced mouse model of liver injury. We determined that spermidine administration prevented ethanol and LPS-induced increases in liver injury using plasma ALT as a readout. Furthermore, histological analysis of tissue from control and treated animals revealed that the pathology associated with ethanol and LPS treatment was prevented in mice additionally treated with spermidine. As predicted, spermidine also prevented ethanol and LPS-induced oxidative stress by decreasing the levels of both reactive oxygen species (ROS) and lipid peroxidation. We further determined that spermidine treatment prevented the nuclear translocation of nuclear factor κB (NFκB) by blocking the phosphorylation of the inhibitory protein, IκB, thereby preventing expression of pro-inflammatory cytokines. Finally, by measuring expression of known markers of hepatic stellate cell activation and monitoring collagen deposition, we observed that spermidine also prevented alcohol and LPS-induced hepatic fibrosis. Together, our results indicate that spermidine is an antioxidant thereby conferring anti-inflammatory and anti-fibrotic effects associated with alcoholic liver injury.
    Keywords:  alcoholic liver disease; fibrosis; hepatic stellate cell activation; oxidative stress; spermidine
    DOI:  https://doi.org/10.3390/molecules26061786
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