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Biomolecules Oct 2022Epilepsy is one of the most common neurological disorders and severely impacts the life quality of patients. Polyamines are ubiquitous, positively charged aliphatic... (Review)
Review
Epilepsy is one of the most common neurological disorders and severely impacts the life quality of patients. Polyamines are ubiquitous, positively charged aliphatic amines that are present at a relatively high level and help regulate the maintenance of cell membrane excitability and neuronal physiological functions in the central nervous system. Studies have shown abnormalities in the synthesis and catabolism of polyamines in patients with epilepsy and in animal models of epilepsy. The polyamine system seems to involve in the pathophysiological processes of epilepsy via several mechanisms such as the regulation of ion permeability via interaction with ion channels, involvement in antioxidation as hydroperoxide scavengers, and the induction of cell damage via the production of toxic metabolites. In this review, we try to describe the possible associations between polyamines and epilepsy and speculate that the polyamine system is a potential target for the development of novel strategies for epilepsy treatment.
Topics: Animals; Polyamines; Epilepsy; Central Nervous System; Neurons; Mental Disorders
PubMed: 36358946
DOI: 10.3390/biom12111596 -
Archives of Biochemistry and Biophysics Jun 2022The roles and molecular interactions of polyamines (PAs) in the nucleus are not fully understood. Here their effect on nucleosome stability, a key regulatory factor in...
The roles and molecular interactions of polyamines (PAs) in the nucleus are not fully understood. Here their effect on nucleosome stability, a key regulatory factor in eukaryotic gene control, is reported, as measured in agarose embedded nuclei of H2B-GFP expressor HeLa cells. Nucleosome stability was assessed by quantitative microscopy [1,2] in situ, in close to native state of chromatin, preserving the nucleosome constrained topology of the genomic DNA. A robust destabilizing effect was observed in the millimolar concentration range in the case of spermine, spermidine as well as putrescine, which was strongly pH and salt concentration-dependent, and remained significant also at neutral pH. The integrity of genomic DNA was not affected by PA treatment, excluding DNA break-elicited topological relaxation as a factor in destabilization. The binding of PAs to DNA was demonstrated by the displacement of ethidium bromide, both from deproteinized nuclear halos and from plasmid DNA. The possibility that DNA methylation patterns may be influenced by PA levels is contemplated in the context of gene expression and DNA methylation correlations identified in the NCI-60 panel-based CellMiner database: methylated loci in subsets of high-ODC1 cell lines and the dependence of PER3 DNA methylation on PA metabolism.
Topics: DNA; HeLa Cells; Humans; Nucleosomes; Polyamines; Putrescine; Spermidine
PubMed: 35395253
DOI: 10.1016/j.abb.2022.109184 -
Biomarkers : Biochemical Indicators of... Mar 2021The significant increase of periodontitis, chronic kidney disease (CKD), Alzheimer's disease and cancer can be attributed to an ageing population. Each disease produces... (Review)
Review
The significant increase of periodontitis, chronic kidney disease (CKD), Alzheimer's disease and cancer can be attributed to an ageing population. Each disease produces a range of biomarkers that can be indicative of disease onset and progression. Biomarkers are defined as cellular (intra/extracellular components and whole cells), biochemical (metabolites, ions and toxins) or molecular (nucleic acids, proteins and lipids) alterations which are measurable in biological media such as human tissues, cells or fluids. An interesting group of biomarkers that merit further investigation are the polyamines. Polyamines are a group of molecules consisting of cadaverine, putrescine, spermine and spermidine and have been implicated in the development of a range of systemic diseases, in part due to their production in periodontitis. Cadaverine and putrescine within the periodontal environment have demonstrated cell signalling interfering abilities, by way of leukocyte migration disruption. The polyamines spermine and spermidine in tumour cells have been shown to inhibit cellular apoptosis, effectively prolonging tumorigenesis and continuation of cancer within the host. Polyamine degradation products such as acrolein have been shown to exacerbate renal damage in CKD patients. Thus, the use of such molecules has merit to be utilized in the early indication of such diseases in patients.
Topics: Acrolein; Alzheimer Disease; Apoptosis; Biomarkers; Biotransformation; Cadaverine; Cell Movement; Humans; Leukocytes; Neoplasms; Periodontitis; Putrescine; Renal Insufficiency, Chronic; Spermidine; Spermine
PubMed: 33439737
DOI: 10.1080/1354750X.2021.1875506 -
European Journal of Pharmacology Nov 2021Spermine, spermidine and putrescine polyamines are naturally occurring ubiquitous positively charged amines and are essential metabolites for biological functions in our... (Review)
Review
Spermine, spermidine and putrescine polyamines are naturally occurring ubiquitous positively charged amines and are essential metabolites for biological functions in our life. These compounds play a crucial role in many cell processes, including cellular proliferation, growth, and differentiation. Intracellular levels of polyamines depend on their biosynthesis, transport and degradation. Polyamine levels are high in cancer cells, which leads to the promotion of tumor growth, invasion and metastasis. Targeting polyamine metabolism as an anticancer strategy is considerably rational. Due to compensatory mechanisms, a single strategy does not achieve satisfactory clinical effects when using a single agent. Combination regimens are more clinically promising for cancer chemoprevention because they work synergistically with causing little or no adverse effects due to each individual agent being used at lower doses. Moreover, bioactive substances have advantages over single chemical agents because they can affect multiple targets. In this review, we discuss anticancer strategies targeting polyamine metabolism and describe how combination treatments and effective natural active ingredients are promising therapies. The existing research suggests that polyamine metabolic enzymes are important therapeutic targets and that combination therapies can be more effective than monotherapies based on polyamine depletion.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Biological Products; Homeostasis; Humans; Neoplasms; Polyamines
PubMed: 34464603
DOI: 10.1016/j.ejphar.2021.174456 -
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 -
Advances in Medical Sciences Mar 2021Nitric oxide (NO) and polyamines: putrescine, spermidine and spermine, are key arginine metabolites in mammalian tissues that play critical roles i.a. in regulation of... (Review)
Review
Nitric oxide (NO) and polyamines: putrescine, spermidine and spermine, are key arginine metabolites in mammalian tissues that play critical roles i.a. in regulation of vascular tone (NO), and cell cycle regulation (polyamines). In the brain, both classes of molecules additionally have neuromodulatory and neuroprotective potential, and NO also a neurotoxic potential. Here we review evidence that brain tumors use the NO- and polyamine-synthesizing machineries to the benefit of their differentiation and growth from healthy glia and neurons. With a few exceptions, brain tumors show increased activities of one or all of the three arginine (Arg) to NO-converting nitric oxide synthase (NOS) isoforms (iNOS, eNOS, nNOS), but also elevated activities of polyamines-generating and modifying enzymes: arginase I/II, ornithine decarboxylase and spermidine/spermine N-acetyltransferase. The degree of stimulation of NO- and polyamine synthesis often correlates with brain tumor malignancy. Excess NO, but also spermine, spermidine and their N-acetylated forms, are tumor- and context-dependently involved in angiogenesis, tumor initiation and growth, and resistance to chemo- or radiotherapy. Hypothetically, increased demand for NO and/or polyamines is likely to contribute to Arg auxotrophy of malignant brain tumors, albeit the causal nexus awaits experimental verification.
Topics: Animals; Arginine; Brain Neoplasms; Humans; Nitric Oxide; Polyamines
PubMed: 33711670
DOI: 10.1016/j.advms.2021.02.006 -
Biomolecules Apr 2020As obligate intracellular parasites, viruses rely on host cells for the building blocks of progeny viruses. Metabolites such as amino acids, nucleotides, and lipids are... (Review)
Review
As obligate intracellular parasites, viruses rely on host cells for the building blocks of progeny viruses. Metabolites such as amino acids, nucleotides, and lipids are central to viral proteins, genomes, and envelopes, and the availability of these molecules can restrict or promote infection. Polyamines, comprised of putrescine, spermidine, and spermine in mammalian cells, are also critical for virus infection. Polyamines are small, positively charged molecules that function in transcription, translation, and cell cycling. Initial work on the function of polyamines in bacteriophage infection illuminated these molecules as critical to virus infection. In the decades since early virus-polyamine descriptions, work on diverse viruses continues to highlight a role for polyamines in viral processes, including genome packaging and viral enzymatic activity. On the host side, polyamines function in the response to virus infection. Thus, viruses and hosts compete for polyamines, which are a critical resource for both. Pharmacologically targeting polyamines, tipping the balance to favor the host and restrict virus replication, holds significant promise as a broad-spectrum antiviral strategy.
Topics: Animals; Bacteriophages; Humans; Mammals; Metabolic Networks and Pathways; Plant Viruses; Polyamines; Virus Diseases
PubMed: 32325677
DOI: 10.3390/biom10040628 -
Scientific Reports Mar 2022The purpose of this study is to provide an increased understanding of the molecular mechanisms responsible for mammalian polyamine transport, a process that has been a...
The purpose of this study is to provide an increased understanding of the molecular mechanisms responsible for mammalian polyamine transport, a process that has been a long-standing 'black box' for the polyamine field. Here, we describe how ATP13A3, a P-type ATPase, functions as a polyamine transporter in response to different polyamine stimuli and polyamine-targeted therapies in highly proliferating pancreatic cancer cells. We assessed the expression, cellular localization and the response of the human ATP13A3 protein to polyamine treatments in different pancreatic cancer cell lines using Western blot and immunofluorescence microscopy. Using CRISPR mutagenesis and radiolabeled polyamine uptake assays, we investigated the role of ATP13A3 protein in polyamine transport. Highly metastatic cancer cells with high polyamine import express higher levels of the full-length ATP13A3 compared to cells with slow proliferation and low import activity. Highlighting its role in polyamine trafficking, the localization of ATP13A3 is altered in the presence of polyamine stimuli and polyamine-targeted therapies in these cells. Using CRISPR mutagenesis, we demonstrate that the first membrane-associated domain of this protein is critical and indispensable for its function as a spermidine and spermine transporter in cells. Further analysis of existing databases revealed that pancreatic cancer patients with high expression of ATP13A3 have decreased overall survival consistent with the role of intracellular polyamines in supporting tumor growth. Our studies shed light on the mysterious polyamine transport process in human cells and clearly establishes ATP13A3 as an intrinsic component of the spermidine and spermine transport system in humans.
Topics: Adenosine Triphosphatases; Animals; Biological Transport; Humans; Mammals; Membrane Transport Proteins; Pancreatic Neoplasms; Polyamines; Spermidine; Spermine
PubMed: 35260637
DOI: 10.1038/s41598-022-07712-4 -
Amino Acids Feb 2020
Topics: Animals; Congresses as Topic; Humans; Polyamines
PubMed: 32072296
DOI: 10.1007/s00726-020-02821-8 -
International Journal of Molecular... Apr 2022The polyamines, spermine (Spm) and spermidine (Spd), are important for cell growth and function. Their homeostasis is strictly controlled, and a key downregulator of the...
The polyamines, spermine (Spm) and spermidine (Spd), are important for cell growth and function. Their homeostasis is strictly controlled, and a key downregulator of the polyamine pool is the polyamine-inducible protein, antizyme 1 (OAZ1). OAZ1 inhibits polyamine uptake and targets ornithine decarboxylase (ODC), the rate-limiting enzyme of polyamine biosynthesis, for proteasomal degradation. Here we report, for the first time, that polyamines induce dimerization of mouse recombinant full-length OAZ1, forming an (OAZ1)-Polyamine complex. Dimerization could be modulated by functionally active -methylated spermidine mimetics (MeSpds) by changing the position of the methyl group along the Spd backbone-2-MeSpd was a poor inducer as opposed to 1-MeSpd, 3-MeSpd, and Spd, which were good inducers. Importantly, the ability of compounds to inhibit polyamine uptake correlated with the efficiency of the (OAZ1)-Polyamine complex formation. Thus, the (OAZ1)-Polyamine complex may be needed to inhibit polyamine uptake. The efficiency of polyamine-induced ribosomal +1 frameshifting of OAZ1 mRNA could also be differentially modulated by MeSpds-2-MeSpd was a poor inducer of OAZ1 biosynthesis and hence a poor downregulator of ODC activity unlike the other MeSpds. These findings offer new insight into the OAZ1-mediated regulation of polyamine homeostasis and provide the chemical tools to study it.
Topics: Animals; Dimerization; Frameshifting, Ribosomal; Mice; Ornithine Decarboxylase; Polyamines; Proteins; Spermidine
PubMed: 35563006
DOI: 10.3390/ijms23094614