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Molecules (Basel, Switzerland) Nov 2023Polyamines participate in the processes of cell growth and development. The degradation branch of their metabolism involves amine oxidases. The oxidation of spermine,... (Review)
Review
Polyamines participate in the processes of cell growth and development. The degradation branch of their metabolism involves amine oxidases. The oxidation of spermine, spermidine and putrescine releases hydrogen peroxide and the corresponding aminoaldehyde. Polyamine-derived aminoaldehydes have been found to be cytotoxic, and they represent the subject of this review. 3-aminopropanal disrupts the lysosomal membrane and triggers apoptosis or necrosis in the damaged cells. It is implicated in the pathogenesis of cerebral ischemia. Furthermore, 3-aminopropanal yields acrolein through the elimination of ammonia. This reactive aldehyde is also generated by the decomposition of aminoaldehydes produced in the reaction of serum amine oxidase with spermidine or spermine. In addition, acrolein is a common environmental pollutant. It causes covalent modifications of proteins, including carbonylation, the production of Michael-type adducts and cross-linking, and it has been associated with inflammation-related diseases. APAL and acrolein are detoxified by aldehyde dehydrogenases and other mechanisms. High-performance liquid chromatography, immunochemistry and mass spectrometry have been largely used to analyze the presence of polyamine-derived aminoaldehydes and protein modifications elicited by their effect. However, the main and still open challenge is to find clues for discovering clear linkages between aldehyde-induced modifications of specific proteins and the development of various diseases.
Topics: Polyamines; Acrolein; Spermidine; Spermine; Aldehydes
PubMed: 37959847
DOI: 10.3390/molecules28217429 -
Magnetic Resonance in Medicine May 2024Prostate tissue has a complex microstructure, mainly composed of epithelial and stromal cells, and of extracellular (acinar-luminal) spaces. Diffusion-weighted MR...
PURPOSE
Prostate tissue has a complex microstructure, mainly composed of epithelial and stromal cells, and of extracellular (acinar-luminal) spaces. Diffusion-weighted MR spectroscopy (DW-MRS) is ideally suited to explore complex microstructure in vivo with metabolites selectively distributed in different subspaces. To date, this technique has been applied to brain and muscle. This study presents the development and pioneering utilization of H-DW-MRS in the prostate, accompanied by in vitro studies to support interpretations of in vivo findings.
METHODS
Nine healthy volunteers underwent a prostate MR examination (mean age, 56 years; range, 31-66). Metabolic complexation was studied in vitro using solutions with major compounds found in prostatic fluid of the lumen. DW-MRS was performed at 3 T with a non-water-suppressed single-voxel sequence with metabolite-cycling to concurrently measure metabolite and water signals. The water signal was used in postprocessing as a reference in a motion-compensation scheme. The spectra were fitted simultaneously in the spectral and diffusion-weighting dimensions. Apparent diffusion coefficients (ADCs) were derived by fitting signal decays that were assumed to be mono-exponential for metabolites and biexponential for water.
RESULTS
DW-MRS of the prostate revealed relatively low ADCs for Cho and Cr compounds, aligning with their intracellular location and higher ADCs for citrate and spermine supporting their luminal origin. In vitro assessments of the ADCs of citrate and spermine demonstrated their complex formation and protein binding. Tissue concentrations of MRS-detectable metabolites were as expected for the voxel location.
CONCLUSIONS
This work successfully demonstrates the feasibility of H-DW-MRS of the prostate and its potential for providing valuable microstructural information.
PubMed: 38775024
DOI: 10.1002/mrm.30141 -
EMBO Molecular Medicine Nov 2023Snyder-Robinson syndrome (SRS) results from mutations in spermine synthase (SMS), which converts the polyamine spermidine into spermine. Affecting primarily males,...
Snyder-Robinson syndrome (SRS) results from mutations in spermine synthase (SMS), which converts the polyamine spermidine into spermine. Affecting primarily males, common manifestations of SRS include intellectual disability, osteoporosis, hypotonia, and seizures. Symptom management is the only treatment. Reduced SMS activity causes spermidine accumulation while spermine levels are reduced. The resulting exaggerated spermidine:spermine ratio is a biochemical hallmark of SRS that tends to correlate with symptom severity. Our studies aim to pharmacologically manipulate polyamine metabolism to correct this imbalance as a therapeutic strategy for SRS. Here we report the repurposing of 2-difluoromethylornithine (DFMO), an FDA-approved inhibitor of polyamine biosynthesis, in rebalancing spermidine:spermine ratios in SRS patient cells. Mechanistic in vitro studies demonstrate that, while reducing spermidine biosynthesis, DFMO also stimulates the conversion of spermidine into spermine in hypomorphic SMS cells and induces uptake of exogenous spermine, altogether reducing the aberrant ratios. In a Drosophila SRS model characterized by reduced lifespan, DFMO improves longevity. As nearly all SRS patient mutations are hypomorphic, these studies form a strong foundation for translational studies with significant therapeutic potential.
Topics: Male; Humans; Polyamines; Spermidine; Spermine; Eflornithine; Spermine Synthase
PubMed: 37702369
DOI: 10.15252/emmm.202317833 -
Frontiers in Immunology 2023Neuroblastoma(NB) is the most common extracranial solid tumor in childhood, and it is now believed that some patients with NB have an underlying genetic susceptibility,...
Neuroblastoma(NB) is the most common extracranial solid tumor in childhood, and it is now believed that some patients with NB have an underlying genetic susceptibility, which may be one of the reasons for the multiplicity of NB patients within a family line. Even within the same family, the samples show great variation and can present as ganglioneuroblastoma or even benign ganglioneuroma. The genomics of NB is still unclear and more in-depth studies are needed to reveal its key components. We first performed single-cell RNA sequencing(sc-RNAseq) analysis on clinical specimens of two family neuroblastoma(FNB) and four sporadic NB cases. A complete transcriptional profile of FNB was constructed from 18,394 cells from FNB, and we found that may be genetically associated with FNB and identified a prognostic related CAF subtype in FNB: Fib-4. Single-cell flux estimation analysis (scFEA) results showed that malignant cells were associated with arginine spermine, oxaloacetate and hypoxanthine, and that malignant cells metabolize lactate at lower levels than T cells. Our study provides new resources and ideas for the development of the genomics of family NB, and the mechanisms of cell-to-cell interactions and communication and the metabolic landscape will provide new therapeutic targets.
Topics: Humans; Transcriptome; Neuroblastoma; Ganglioneuroblastoma; Prognosis; Genetic Predisposition to Disease
PubMed: 37790931
DOI: 10.3389/fimmu.2023.1197773 -
Biomedicines Oct 2023The relationship between polyamines and healthy longevity has received much attention in recent years. However, conducting research without understanding the properties... (Review)
Review
The relationship between polyamines and healthy longevity has received much attention in recent years. However, conducting research without understanding the properties of polyamines can lead to unexpected pitfalls. The most fundamental consideration in conducting polyamine studies is that bovine serum used for cell culture contains bovine serum amine oxidase. Bovine serum amine oxidase, which is not inactivated by heat treatment, breaks down spermine and spermidine to produce the highly toxic aldehyde acrolein, which causes cell damage and activates autophagy. However, no such enzyme activity has been found in humans. Polyamine catabolism does not produce toxic aldehydes under normal conditions, but inflammation and some pathogens provoke an inducible enzyme, spermine oxidase, which only breaks down spermine to produce acrolein, resulting in cytotoxicity and the activation of autophagy. Therefore, spermine oxidase activation reduces spermine concentration and the ratio of spermine to spermidine, a feature recently reported in patients with age-related diseases. Spermine, which is increased by a long-term, continuous high polyamine diet, suppresses aberrant gene methylation and the pro-inflammatory status that progress with age and are strongly associated with the development of several age-related diseases and senescence. Changes in spermine concentration and the spermine/spermidine ratio should be considered as indicators of human health status.
PubMed: 37893199
DOI: 10.3390/biomedicines11102827 -
BMC Plant Biology Nov 2023Two spotted spider mite, Tetranychus urticae (Acari: Tetranychidae) is one of the most important plant pests in the world. Due to increased resistance of mites to...
BACKGROUND
Two spotted spider mite, Tetranychus urticae (Acari: Tetranychidae) is one of the most important plant pests in the world. Due to increased resistance of mites to acaricides, it is necessary to use other methods such as inducing resistance in plants by natural compounds for pests' management. Polyamins such as spermine are effective in increasing plant resistance to biotic and abiotic stressors. In this research, the effect of spermine treatments in cucumber plants on life table parameters of T. urticae was investigated. Also, top-down effect of spermine and T. urticae on cucumber biochemical parameters was measured. In the experiments, 1, 2 and 3 mM spermine concentrations were used.
RESULTS
Amongst the spermine treatments, those mites that fed on cucumbers which received 1 mM spermine showed the shortest protonymphal period and higher ovipositon period, fecundity, gross and net reproductive rates and life expectancy compare to control. Treatment with 2 mM spermine lead to the longest teleochrysalis period and shortest range of age-stage-specific fecundity period. In addition, 2 mM spermine lowered intrinsic and finite rate of population increase in T. urticae. The longest larval period of T. urticae was observed in 3 mM spermine. Feeding of T. urticae from cucumber plants increased hydrogen peroxide (HO), malondialdehyde (MDA) content, electrolyte leakage (EL) level and ascorbate peroxidase (APX) activity but inhibited catalase (CAT) activity in this plant. Infested cucumber plants treated with 2 mM spermine showed lower HO and MDA content and highest activity of APX and CAT on day 1 and 3 compare to the others. The 3 mM spermine increased HO content in infested plants during the whole experiment as well as non-infested plants in day 5 and 9 only. This treatment induced the highest MDA content and lowest catalase activity on day1, 3 and 5 of experiment in infested plants.
CONCLUSION
This study showed that 2 mM spermine was the only effective concentration that reduce cucumber sensitivity to T. urticae. The trend of changes in biochemical parameters, especially HO, in 3 mM spermine was abnormal, and this concentration could be considered toxic.
Topics: Animals; Cucumis sativus; Tetranychidae; Spermine; Hydrogen Peroxide; Catalase
PubMed: 37978429
DOI: 10.1186/s12870-023-04573-5 -
Pathogens (Basel, Switzerland) Jan 2024Neglected tropical diseases transmitted by trypanosomatids include three major human scourges that globally affect the world's poorest people: African trypanosomiasis or... (Review)
Review
Neglected tropical diseases transmitted by trypanosomatids include three major human scourges that globally affect the world's poorest people: African trypanosomiasis or sleeping sickness, American trypanosomiasis or Chagas disease and different types of leishmaniasis. Different metabolic pathways have been targeted to find antitrypanosomatid drugs, including polyamine metabolism. Since their discovery, the naturally occurring polyamines, putrescine, spermidine and spermine, have been considered important metabolites involved in cell growth. With a complex metabolism involving biosynthesis, catabolism and interconversion, the synthesis of putrescine and spermidine was targeted by thousands of compounds in an effort to produce cell growth blockade in tumor and infectious processes with limited success. However, the discovery of eflornithine (DFMO) as a curative drug against sleeping sickness encouraged researchers to develop new molecules against these diseases. Polyamine synthesis inhibitors have also provided insight into the peculiarities of this pathway between the host and the parasite, and also among different trypanosomatid species, thus allowing the search for new specific chemical entities aimed to treat these diseases and leading to the investigation of target-based scaffolds. The main molecular targets include the enzymes involved in polyamine biosynthesis (ornithine decarboxylase, S-adenosylmethionine decarboxylase and spermidine synthase), enzymes participating in their uptake from the environment, and the enzymes involved in the redox balance of the parasite. In this review, we summarize the research behind polyamine-based treatments, the current trends, and the main challenges in this field.
PubMed: 38251386
DOI: 10.3390/pathogens13010079 -
Cell Death & Disease May 2024Precise polyamine metabolism regulation is vital for cells and organisms. Mutations in spermine synthase (SMS) cause Snyder-Robinson intellectual disability syndrome...
Precise polyamine metabolism regulation is vital for cells and organisms. Mutations in spermine synthase (SMS) cause Snyder-Robinson intellectual disability syndrome (SRS), characterized by significant spermidine accumulation and autophagy blockage in the nervous system. Emerging evidence connects polyamine metabolism with other autophagy-related diseases, such as Tauopathy, however, the functional intersection between polyamine metabolism and autophagy in the context of these diseases remains unclear. Here, we altered SMS expression level to investigate the regulation of autophagy by modulated polyamine metabolism in Tauopathy in Drosophila and human cellular models. Interestingly, while complete loss of Drosophila spermine synthase (dSms) impairs lysosomal function and blocks autophagic flux recapitulating SRS disease phenotype, partial loss of dSms enhanced autophagic flux, reduced Tau protein accumulation, and led to extended lifespan and improved climbing performance in Tauopathy flies. Measurement of polyamine levels detected a mild elevation of spermidine in flies with partial loss of dSms. Similarly, in human neuronal or glial cells, partial loss of SMS by siRNA-mediated knockdown upregulated autophagic flux and reduced Tau protein accumulation. Importantly, proteomics analysis of postmortem brain tissue from Alzheimer's disease (AD) patients showed a significant albeit modest elevation of SMS level. Taken together, our study uncovers a functional correlation between polyamine metabolism and autophagy in AD: SMS reduction upregulates autophagy, suppresses Tau accumulation, and ameliorates neurodegeneration and cell death. These findings provide a new potential therapeutic target for AD.
Topics: Autophagy; Animals; tau Proteins; Humans; Spermine Synthase; Drosophila melanogaster; Drosophila Proteins; Tauopathies; Neurons; Alzheimer Disease; Spermidine; Disease Models, Animal; Lysosomes; Drosophila; Mental Retardation, X-Linked
PubMed: 38740758
DOI: 10.1038/s41419-024-06720-8 -
Cells Jul 2023Polyamines are simple yet critical molecules with diverse roles in numerous pathogenic and non-pathogenic organisms. Regulating polyamine concentrations affects the...
Polyamines are simple yet critical molecules with diverse roles in numerous pathogenic and non-pathogenic organisms. Regulating polyamine concentrations affects the transcription and translation of genes and proteins important for cell growth, stress, and toxicity. One way polyamine concentrations are maintained within the cell is via spermidine/spermine -acetyltransferases (SSATs) that acetylate intracellular polyamines so they can be exported. The bacterial SpeG enzyme is an SSAT that exhibits a unique dodecameric structure and allosteric site compared to other SSATs that have been previously characterized. While its overall 3D structure is conserved, its presence and role in different bacterial pathogens are inconsistent. For example, not all bacteria have encoded in their genomes; in some bacteria, the gene is present but has become silenced, and in other bacteria, it has been acquired on mobile genetic elements. The latter is the case for methicillin-resistant (MRSA) USA300, where it appears to aid pathogenesis. To gain a greater understanding of the structure/function relationship of SpeG from the MRSA USA300 strain (SaSpeG), we determined its X-ray crystal structure in the presence and absence of spermine. Additionally, we showed the oligomeric state of SaSpeG is dynamic, and its homogeneity is affected by polyamines and AcCoA. Enzyme kinetic assays showed that pre-incubation with polyamines significantly affected the positive cooperativity toward spermine and spermidine and the catalytic efficiency of the enzyme. Furthermore, we showed bacterial SpeG enzymes do not have equivalent capabilities to acetylate aminopropyl versus aminbutyl ends of spermidine. Overall, this study provides new insight that will assist in understanding the SpeG enzyme and its role in pathogenic and non-pathogenic bacteria at a molecular level.
Topics: Spermidine; Spermine; Methicillin-Resistant Staphylococcus aureus; Polyamines; Acetyltransferases
PubMed: 37508494
DOI: 10.3390/cells12141829 -
Prostate International Sep 2023To investigate the role of urine spermine and spermine risk score in predicting prostate cancer (PCa) diagnoses in combination with multiparametric magnetic resonance...
OBJECTIVES
To investigate the role of urine spermine and spermine risk score in predicting prostate cancer (PCa) diagnoses in combination with multiparametric magnetic resonance imaging (mpMRI).
METHODS
Three hundred forty seven consecutive men with elevated prostate-specific antigen (PSA) with mpMRI examination were prospectively enrolled in this study. In 265 patients with PSA levels between 4 and20 ng/ml, pre-biopsy urine samples were analyzed for spermine levels with ultra-high performance liquid chromatography (UPLC-MS/MS). Transperineal image-guided prostate biopsies with 16-18 cores were performed. Logistic regressions were used to form different models for the prediction of the PCa, and the performances were compared using the area under the curve (AUC).
RESULTS
The median serum PSA level and prostate volume were 7.4 ng/mL and 33.9 mL, respectively. PCa and high-grade PCa (ISUP group ≥2, HGPCa) were diagnosed in 66.0% (175/265) and 132/265 (49.8%) cases, respectively. The urine spermine levels were significantly lower in men with PCa (0.87 vs. 2.20, < 0.001). Multivariate analyses showed that age, PSA, PV, urine spermine level, and Prostate Imaging Reporting and Data System (PI-RADS) findings were independent predictors for PCa. The Spermine Risk Score is a multivariable model including PSA, age, prostate volume, and urine spermine. Adding the Spermine Risk Score to PI-RADS improved the AUC from 0.73 to 0.86 in PCa and from 0.72 to 0.83 in high grade PCa (HGPCa) prediction (both < 0.001). At 90% sensitivity for HGPCa prediction using Spermine Risk Score, 31.1% of unnecessary biopsies could be avoided. In men with equivocal MRI PI-RADS score 3, the AUC for HGPCa prediction was 0.58, 0.79, and 0.87 for PSA, PSA density, and Spermine Risk Score, respectively.
CONCLUSION
Urine Spermine Risk Score, including mpMRI could accurately identify men at high risk of HGPCa and reduce unnecessary prostate biopsies. Spermine Risk Score could more accurately predict HGPCa than PSA density in men with MRI showing equivocal PI-RADS 3 lesions.
PubMed: 37745906
DOI: 10.1016/j.prnil.2023.07.003