Correlation of polyamines, acrolein-conjugated lysine and polyamine metabolic enzyme levels with age in human liver
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ABSTRACT:
SUBMITTER: Uemura T
PROVIDER: S-EPMC7512001 | biostudies-literature | 2020 Sep
REPOSITORIES: biostudies-literature
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Project description:In plants, many of the enzymes in polyamine metabolism are encoded by multiple genes, whose expressions are differentially regulated under different physiological conditions. For comprehensive understanding of their regulation during the seedling growth stage, we examined the expression of polyamine metabolic genes in response to polyamines and stress-related plant hormones in Arabidopsis thaliana. While confirming previous findings such as induction of many of the genes by abscisic acid, induction of arginase genes and a copper amine oxidase gene, CuAOα3, by methyl jasmonate, that of an arginine decarboxylase gene, ADC2, and a spermine synthase gene, SPMS, by salicylic acid, and negative feedback regulation of thermospermine biosynthetic genes by thermospermine, our results showed that expressions of most of the genes are not responsive to exogenous polyamines. We thus examined expression of OsPAO6, which encodes an apoplastic polyamine oxidase and is strongly induced by polyamines in rice, by using the promoter-GUS fusion in transgenic Arabidopsis seedlings. The GUS activity was increased by treatment with methyl jasmonate but neither by polyamines nor by other plant hormones, suggesting a difference in the response to polyamines between Arabidopsis and rice. Our results provide a framework to study regulatory modules directing expression of each polyamine metabolic gene.
| S-EPMC8699553 | biostudies-literature
Project description:Objective:Measurement of plasma levels of protein-conjugated acrolein (PC-Acro) together with IL-6 and CRP can be used to identify silent brain infarction (SBI) with high sensitivity and specificity. The aim of this study was to determine how these biomarkers vary during stroke. Methods:Levels of PC-Acro, IL-6 and CRP in plasma were measured on day 0, 2, 7 and 14 after the onset of ischemic or hemorrhagic stroke. Results:After the onset of stroke, the level of PC-Acro in plasma was elevated corresponding to the size of stroke. It returned to near control levels by day 2, and remained similar through day 14. The degree of the decrease in PC-Acro on day 2 was greater when the size of brain infarction or hemorrhage was larger. An increase in IL-6 and CRP occurred after the increase in PC-Acro, and it was well correlated with the size of the injury following infarction or hemorrhage. The results suggest that acrolein becomes a trigger for the production of IL-6 and CRP, as previously observed in a mouse model of stroke and in cell culture systems. The increase in IL-6 and CRP was also correlated with poor outcome judging from mRS. Conclusion:The results indicate that the degree of the decrease in PC-Acro and the increase in IL-6 and CRP from day 0 to day 2 was correlated with the size of brain infarction, and the increase in IL-6 and CRP with poor outcome at discharge.
| S-EPMC5721576 | biostudies-literature
Project description:An acidic tumor microenvironment plays a critical role in tumor progression. However, understanding of metabolic reprogramming of tumors in response to acidic extracellular pH has remained elusive. Using comprehensive metabolomic analyses, we demonstrated that acidic extracellular pH (pH 6.8) leads to the accumulation of N1-acetylspermidine, a pro-tumor metabolite, through upregulation of the expression of spermidine/spermine acetyl transferase 1 (SAT1). Inhibition of SAT1 expression suppressed the accumulation of intra- and extracellular N1-acetylspermidine at acidic pH. Conversely, overexpression 3 of SAT1 increased intra- and extracellular N1-acetylspermidine levels, supporting the proposal that SAT1 is responsible for accumulation of N1-acetylspermidine. While inhibition of SAT1 expression only had a minor effect on cancer cell growth in vitro, SAT1 knockdown significantly decreased tumor growth in vivo, supporting a contribution of the SAT1-N1-acetylspermidine axis to pro-tumor immunity. Immune cell profiling revealed that inhibition of SAT1 expression decreased neutrophil recruitment to the tumor, resulting in impaired angiogenesis and tumor growth. We showed that anti-neutrophil neutralizing antibodies suppressed growth in control tumors to a similar extent to that seen in SAT1 knockdown tumors in vivo. Further, a SAT1 signature was found to be correlated with poor patient prognosis. Our findings demonstrate that extracellular acidity stimulates recruitment of pro-tumor neutrophils via the SAT1-N1-acetylspermidine axis, which may represent a novel target for anti-tumor immune therapy.
2023-08-14 | GSE239784 | GEO
Project description:Plant development and productivity are negatively regulated by adverse environmental conditions. The identification of stress-regulatory genes, networks, and signaling molecules should allow the development of novel strategies to obtain tolerant plants. Polyamines (PAs) are polycationic compounds with a recognized role in plant growth and development, as well as in abiotic and biotic stress responses. During the last years, knowledge on PA functions has been achieved using genetically modified plants with altered PA levels. In this review, we combine the information obtained from global transcriptome analyses in transgenic Arabidopsis plants with altered putrescine or spermine levels. Comparison of common and specific gene networks affected by elevation of endogenous PAs, support the view that these compounds actively participate in stress signaling through intricate crosstalks with abscisic acid (ABA), Ca(2+) signaling and other hormonal pathways in plant defense and development.
| S-EPMC3229227 | biostudies-literature
Project description:Expression of genes encoding polyamine transporters from plasmids and polyamine supplements increased furfural tolerance (growth and ethanol production) in ethanologenic Escherichia coli LY180 (in AM1 mineral salts medium containing xylose). This represents a new approach to increase furfural tolerance and may be useful for other organisms. Microarray comparisons of two furfural-resistant mutants (EMFR9 and EMFR35) provided initial evidence for the importance of polyamine transporters. Each mutant contained a single polyamine transporter gene that was upregulated over 100-fold (microarrays) compared to that in the parent LY180, as well as a mutation that silenced the expression of yqhD. Based on these genetic changes, furfural tolerance was substantially reconstructed in the parent, LY180. Deletion of potE in EMFR9 lowered furfural tolerance to that of the parent. Deletion of potE and puuP in LY180 also decreased furfural tolerance, indicating functional importance of the native genes. Of the 8 polyamine transporters (18 genes) cloned and tested, half were beneficial for furfural tolerance (PotE, PuuP, PlaP, and PotABCD). Supplementing AM1 mineral salts medium with individual polyamines (agmatine, putrescine, and cadaverine) also increased furfural tolerance but to a smaller extent. In pH-controlled fermentations, polyamine transporter plasmids were shown to promote the metabolism of furfural and substantially reduce the time required to complete xylose fermentation. This increase in furfural tolerance is proposed to result from polyamine binding to negatively charged cellular constituents such as nucleic acids and phospholipids, providing protection from damage by furfural.
| S-EPMC4178697 | biostudies-literature
Project description:Excessive accumulation of polyamines causes cytotoxicity, including inhibition of cell growth and a decrease in viability. We investigated the mechanism of cytotoxicity caused by spermidine accumulation under various conditions using an Escherichia coli strain deficient in spermidine acetyltransferase (SAT), a key catabolic enzyme in controlling polyamine levels. Due to the excessive accumulation of polyamines by the addition of exogenous spermidine to the growth medium, cell growth and viability were markedly decreased through translational repression of specific proteins [RMF (ribosome modulation factor) and Fis (rRNA transcription factor) etc.] encoded by members of polyamine modulon, which are essential for cell growth and viability. In particular, synthesis of proteins that have unusual locations of the Shine-Dalgarno (SD) sequence in their mRNAs was inhibited. In order to elucidate the molecular mechanism of cytotoxicity by the excessive accumulation of spermidine, the spermidine-dependent structural change of the bulged-out region in the mRNA at the initiation site of the rmf mRNA was examined using NMR analysis. It was suggested that the structure of the mRNA bulged-out region is affected by excess spermidine, so the SD sequence of the rmf mRNA cannot approach initiation codon AUG.
| S-EPMC7177335 | biostudies-literature
Project description:Lysine-specific demethylases 1 and 2 (LSD1 and LSD2) are flavoenzyme demethylases, and their inhibitors are considered as potential chemical tools and anticancer agents. Here we report polyamine-based inhibitors of LSD1 and LSD2. In the initial screening, partially constrained polyamine 2 which contains three trans-cyclopentane units with a total of six stereogenic centers, showed the most potent LSD1-inhibitory activity. We then prepared a set of optical isomers of 2 and evaluated their inhibitory activities toward LSD1, LSD2, monoamine oxidases A and B (MAO-A and MAO-B). Optical isomers of 2 showed LSD1-inhibitory activity with K i values of 2.2 to 6.4 μM, and LSD2-inhibitory activity with K i values of 4.4 to 39 μM; there was a general preference for LSD1 to LSD2. All of them showed weak to negligible inhibition of MAO-A and MAO-B. This selectivity seemed to reflect the differences in the size and shape of the catalytic cavity of target enzymes, and our strategy of employing a set of optical isomers appears to be an effective approach for exploring the structural features of this family of enzymes. Polyamine 9 showed most potent LSD1-inhibitory activity (K i = 2.2 μM in vitro), and it also inhibited the proliferation of HL-60 cells (IC50 = 49 μM). On the other hand, 12 was the most potent inhibitors of LSD2 with in vitro K i values of 4.4 μM.
| S-EPMC9088916 | biostudies-literature
Project description:Both single and multicellular organisms depend on anti-stress mechanisms that enable them to deal with sudden changes in the environment, including exposure to heat and oxidants. Central to the stress response are dynamic changes in metabolism, such as the transition from the glycolysis to the pentose phosphate pathway-a conserved first-line response to oxidative insults1,2. Here we report a second metabolic adaptation that protects microbial cells in stress situations. The role of the yeast polyamine transporter Tpo1p3-5 in maintaining oxidant resistance is unknown6. However, a proteomic time-course experiment suggests a link to lysine metabolism. We reveal a connection between polyamine and lysine metabolism during stress situations, in the form of a promiscuous enzymatic reaction in which the first enzyme of the polyamine pathway, Spe1p, decarboxylates lysine and forms an alternative polyamine, cadaverine. The reaction proceeds in the presence of extracellular lysine, which is taken up by cells to reach concentrations up to one hundred times higher than those required for growth. Such extensive harvest is not observed for the other amino acids, is dependent on the polyamine pathway and triggers a reprogramming of redox metabolism. As a result, NADPH-which would otherwise be required for lysine biosynthesis-is channelled into glutathione metabolism, leading to a large increase in glutathione concentrations, lower levels of reactive oxygen species and increased oxidant tolerance. Our results show that nutrient uptake occurs not only to enable cell growth, but when the nutrient availability is favourable it also enables cells to reconfigure their metabolism to preventatively mount stress protection.
| S-EPMC6774798 | biostudies-literature
Project description:Antibiotic resistance is a big threat to public health. How to improve the therapeutic efficacy of conventional antibiotics is an effective way to address this issue. In order to enhance the antibacterial activity of conventional antibiotic erythromycin (EM), EM is conjugated to positively charged ε-poly-l-lysine (EPL) to obtain EPL modified EM (EPL-EM). The grafting ratio of EM can be calculated from the 1H NMR spectrum. EPL-EM is stable in physiological environment, while EM can be readily released from EPL-EM upon incubating with esterase which can be secreted by most bacteria. Because of the presence of cationic EPL, EPL-EM showed much stronger antibacterial activity than free EM, with much lower minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC). Moreover, compared to free EM, the development of drug resistance can be slowed down if EPL-EM is used, which can be ascribed to the reduction of EM dosage. Meanwhile, EPL-EM cannot induce hemolysis and cytotoxicity, which indicates that EPL-EM exhibits excellent biocompatibility. The design of EPL-EM with enhanced antibacterial activity and excellent biocompatibility provides an innovative way to combat antibiotic resistance.
| S-EPMC10280332 | biostudies-literature
Project description:BackgroundAlzheimer's disease (AD) is caused by many intertwining pathologies involving metabolic aberrations. Patients with metabolic syndrome (MetS) generally show hyperglycemia and dyslipidemia, which can lead to the formation of aldehydic adducts such as acrolein on peptides in the brain and blood. However, the pathogenesis from MetS to AD remains elusive.MethodsAn AD cell model expressing Swedish and Indiana amyloid precursor protein (APP-Swe/Ind) in neuro-2a cells and a 3xTg-AD mouse model were used. Human serum samples (142 control and 117 AD) and related clinical data were collected. Due to the involvement of MetS in AD, human samples were grouped into healthy control (HC), MetS-like, AD with normal metabolism (AD-N), and AD with metabolic disturbance (AD-M). APP, amyloid-beta (Aß), and acrolein adducts in the samples were analyzed using immunofluorescent microscopy, histochemistry, immunoprecipitation, immunoblotting, and/or ELISA. Synthetic Aß1-16 and Aß17-28 peptides were modified with acrolein in vitro and verified using LC-MS/MS. Native and acrolein-modified Aß peptides were used to measure the levels of specific autoantibodies IgG and IgM in the serum. The correlations and diagnostic power of potential biomarkers were evaluated.ResultsAn increased level of acrolein adducts was detected in the AD model cells. Furthermore, acrolein adducts were observed on APP C-terminal fragments (APP-CTFs) containing Aß in 3xTg-AD mouse serum, brain lysates, and human serum. The level of acrolein adducts was correlated positively with fasting glucose and triglycerides and negatively with high-density lipoprotein-cholesterol, which correspond with MetS conditions. Among the four groups of human samples, the level of acrolein adducts was largely increased only in AD-M compared to all other groups. Notably, anti-acrolein-Aß autoantibodies, especially IgM, were largely reduced in AD-M compared to the MetS group, suggesting that the specific antibodies against acrolein adducts may be depleted during pathogenesis from MetS to AD.ConclusionsMetabolic disturbance may induce acrolein adduction, however, neutralized by responding autoantibodies. AD may be developed from MetS when these autoantibodies are depleted. Acrolein adducts and the responding autoantibodies may be potential biomarkers for not only diagnosis but also immunotherapy of AD, especially in complication with MetS.
| S-EPMC10286356 | biostudies-literature