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International Journal of Molecular... Sep 2019Acute kidney injury (AKI) refers to an abrupt decrease in kidney function. It affects approximately 7% of all hospitalized patients and almost 35% of intensive care... (Review)
Review
Acute kidney injury (AKI) refers to an abrupt decrease in kidney function. It affects approximately 7% of all hospitalized patients and almost 35% of intensive care patients. Mortality from acute kidney injury remains high, particularly in critically ill patients, where it can be more than 50%. The primary causes of AKI include ischemia/reperfusion (I/R), sepsis, or nephrotoxicity; however, AKI patients may present with a complicated etiology where many of the aforementioned conditions co-exist. Multiple bio-markers associated with renal damage, as well as metabolic and signal transduction pathways that are involved in the mediation of renal dysfunction have been identified as a result of the examination of models, patient samples, and clinical data of AKI of disparate etiologies. These discoveries have enhanced our ability to diagnose AKIs and to begin to elucidate the mechanisms involved in their pathogenesis. Studies in our laboratory revealed that the expression and activity of spermine/spermidine N-acetyltransferase (SAT1), the rate-limiting enzyme in polyamine back conversion, were enhanced in kidneys of rats after I/R injury. Additional studies revealed that the expression of spermine oxidase (SMOX), another critical enzyme in polyamine catabolism, is also elevated in the kidney and other organs subjected to I/R, septic, toxic, and traumatic injuries. The maladaptive role of polyamine catabolism in the mediation of AKI and other injuries has been clearly demonstrated. This review will examine the biochemical and mechanistic basis of tissue damage brought about by enhanced polyamine degradation and discuss the potential of therapeutic interventions that target polyamine catabolic enzymes or their byproducts for the treatment of AKI.
Topics: Acetyltransferases; Acute Kidney Injury; Animals; Biomarkers; Gene Expression; Gene Expression Regulation, Enzymologic; Humans; Metabolic Networks and Pathways; Oxidoreductases Acting on CH-NH Group Donors; Polyamines; Polyamine Oxidase
PubMed: 31561575
DOI: 10.3390/ijms20194790 -
The Journal of Biological Chemistry Nov 2018Polyamines (PAs) are indispensable polycations ubiquitous to all living cells. Among their many critical functions, PAs contribute to the oxidative balance of the cell.... (Review)
Review
Polyamines (PAs) are indispensable polycations ubiquitous to all living cells. Among their many critical functions, PAs contribute to the oxidative balance of the cell. Beginning with studies by the Tabor laboratory in bacteria and yeast, the requirement for PAs as protectors against oxygen radical-mediated damage has been well established in many organisms, including mammals. However, PAs also serve as substrates for oxidation reactions that produce hydrogen peroxide (HO) both intra- and extracellularly. As intracellular concentrations of PAs can reach millimolar concentrations, the HO amounts produced through their catabolism, coupled with a reduction in protective PAs, are sufficient to cause the oxidative damage associated with many pathologies, including cancer. Thus, the maintenance of intracellular polyamine homeostasis may ultimately contribute to the maintenance of oxidative homeostasis. Again, pioneering studies by Tabor and colleagues led the way in first identifying spermine oxidase in They also first purified the extracellular bovine serum amine oxidase and elucidated the products of its oxidation of primary amine groups of PAs when included in culture medium. These investigations formed the foundation for many polyamine-related studies and experimental procedures still performed today. This Minireview will summarize key innovative studies regarding PAs and oxidative damage, starting with those from the Tabor laboratory and including the most recent advances, with a focus on mammalian systems.
Topics: Animals; Humans; Hydrogen Peroxide; Monoamine Oxidase; Oxidative Stress; Oxidoreductases Acting on CH-NH Group Donors; Polyamines; Polyamine Oxidase
PubMed: 30333229
DOI: 10.1074/jbc.TM118.003337 -
Nature Reviews. Cancer Nov 2018Advances in our understanding of the metabolism and molecular functions of polyamines and their alterations in cancer have led to resurgence in the interest of targeting... (Review)
Review
Advances in our understanding of the metabolism and molecular functions of polyamines and their alterations in cancer have led to resurgence in the interest of targeting polyamine metabolism as an anticancer strategy. Increasing knowledge of the interplay between polyamine metabolism and other cancer-driving pathways, including the PTEN-PI3K-mTOR complex 1 (mTORC1), WNT signalling and RAS pathways, suggests potential combination therapies that will have considerable clinical promise. Additionally, an expanding number of promising clinical trials with agents targeting polyamines for both therapy and prevention are ongoing. New insights into molecular mechanisms linking dysregulated polyamine catabolism and carcinogenesis suggest additional strategies that can be used for cancer prevention in at-risk individuals. In addition, polyamine blocking therapy, a strategy that combines the inhibition of polyamine biosynthesis with the simultaneous blockade of polyamine transport, can be more effective than therapies based on polyamine depletion alone and may involve an antitumour immune response. These findings open up new avenues of research into exploiting aberrant polyamine metabolism for anticancer therapy.
Topics: Biological Transport; Humans; Neoplasms; Polyamines; Signal Transduction
PubMed: 30181570
DOI: 10.1038/s41568-018-0050-3 -
Amino Acids Mar 2014Polyamines, including spermine, spermidine, and the precursor diamine, putrescine, are naturally occurring polycationic alkylamines that are required for eukaryotic cell... (Review)
Review
Polyamines, including spermine, spermidine, and the precursor diamine, putrescine, are naturally occurring polycationic alkylamines that are required for eukaryotic cell growth, differentiation, and survival. This absolute requirement for polyamines and the need to maintain intracellular levels within specific ranges require a highly regulated metabolic pathway primed for rapid changes in response to cellular growth signals, environmental changes, and stress. Although the polyamine metabolic pathway is strictly regulated in normal cells, dysregulation of polyamine metabolism is a frequent event in cancer. Recent studies suggest that the polyamine catabolic pathway may be involved in the etiology of some epithelial cancers. The catabolism of spermine to spermidine utilizes either the one-step enzymatic reaction of spermine oxidase (SMO) or the two-step process of spermidine/spermine N (1)-acetyltransferase (SSAT) coupled with the peroxisomal enzyme N (1)-acetylpolyamine oxidase. Both catabolic pathways produce hydrogen peroxide and a reactive aldehyde that are capable of damaging DNA and other critical cellular components. The catabolic pathway also depletes the intracellular concentrations of spermidine and spermine, which are free radical scavengers. Consequently, the polyamine catabolic pathway in general and specifically SMO and SSAT provide exciting new targets for chemoprevention and/or chemotherapy.
Topics: Aldehydes; Animals; Antineoplastic Combined Chemotherapy Protocols; Carcinogenesis; Humans; Hydrogen Peroxide; Neoplasms; Polyamines
PubMed: 23771789
DOI: 10.1007/s00726-013-1529-6 -
International Journal of Molecular... Aug 2023The aging of the global population has necessitated the identification of effective anti-aging technologies based on scientific evidence. Polyamines (putrescine,...
The aging of the global population has necessitated the identification of effective anti-aging technologies based on scientific evidence. Polyamines (putrescine, spermidine, and spermine) are essential for cell growth and function. Age-related reductions in polyamine levels have been shown to be associated with reduced cognitive and physical functions. We have previously found that the expression of spermine oxidase (SMOX) increases with age; however, the relationship between SMOX expression and cellular senescence remains unclear. Therefore, we investigated the relationship between increased SMOX expression and cellular senescence using human-liver-derived HepG2 cells. Intracellular spermine levels decreased and spermidine levels increased with the serial passaging of cells (aged cells), and aged cells showed increased expression of SMOX. The levels of acrolein-conjugated protein, which is produced during spermine degradation, also increases. Senescence-associated β-gal activity was increased in aged cells, and the increase was suppressed by MDL72527, an inhibitor of acetylpolyamine oxidase (AcPAO) and SMOX, both of which are enzymes that catalyze polyamine degradation. DNA damage accumulated in aged cells and MDL72527 reduced DNA damage. These results suggest that the SMOX-mediated degradation of spermine plays an important role in cellular senescence. Our results demonstrate that cellular senescence can be controlled by inhibiting spermine degradation using a polyamine-catabolizing enzyme inhibitor.
Topics: Humans; Spermidine; Spermine; Cellular Senescence; Aging; Polyamines
PubMed: 37686212
DOI: 10.3390/ijms241713397 -
Biochemical Society Transactions Apr 2007The induction of polyamine catabolism by specific anti-tumour polyamine analogues has increased interest in the roles polyamine catabolism play in cell growth, death and... (Review)
Review
The induction of polyamine catabolism by specific anti-tumour polyamine analogues has increased interest in the roles polyamine catabolism play in cell growth, death and response to various anti-tumour agents. The relatively recent finding of an inducible mammalian spermine oxidase (SMO/PAOh1), in addition to the two-step spermidine/spermine N(1)-acetyltransferanse (SSAT)/N(1)-acetylpolyamine oxidase (APAO) catabolic pathway, underscores the complexities of the regulation of polyamine catabolism by various stimuli. Furthermore, recent data indicate that infectious agents and mediators of inflammation can also up-regulate polyamine catabolism. Induction of SSAT by these agents can reduce intracellular polyamine concentrations and cell growth rate, thus providing a beneficial mechanism by which cells may adapt to inflammatory stress. However, increased polyamine catabolism can also result in substantial increases in intracellular reactive oxygen species (ROS) through the production of H(2)O(2) as a by-product of either APAO or SMO/PAOh1 activity. This increased generation of ROS can have different results, depending on the mechanism of induction and cell types involved. Targeted killing of tumour cells by agents that stimulate SSAT/APAO and/or SMO/PAOh1 is obviously a 'good' effect. However, induction of SMO/PAOh1 by inflammation or infectious agents has the potential to produce sufficient ROS in normal, non-tumour cells to lead to DNA damage, mutation and, potentially, carcinogenic transformation ('bad'). The variation in the induction of these polyamine catabolic enzymes, as well as the level and timing of this induction will dictate the cellular outcome in the presence of both desirable and undesirable effects ('ugly'). Here we discuss the relative role of each of the steps in polyamine catabolism in response to inflammatory stress.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Cell Transformation, Neoplastic; Homeostasis; Humans; Inflammation; Models, Biological; NF-kappa B; Neoplasms; Polyamines; Signal Transduction
PubMed: 17371265
DOI: 10.1042/BST0350300 -
Cellular and Molecular Life Sciences :... Jul 2003The polyamines spermidine and spermine along with the diamine putrescine are involved in many cellular processes, including chromatin condensation, maintenance of DNA... (Review)
Review
The polyamines spermidine and spermine along with the diamine putrescine are involved in many cellular processes, including chromatin condensation, maintenance of DNA structure, RNA processing, translation and protein activation. The polyamines influence the formation of compacted chromatin and have a well-established role in DNA aggregation. Polyamines are used in the posttranslational modification of eukaryotic initiation factor 5A, which regulates the transport and processing of specific RNA. The polyamines also participate in a novel RNA-decoding mechanism, a translational frame-shift, of at least two known genes, the TY1 transposon and mammalian antizyme. Polyamines are crucial for their own regulation and are involved in feedback mechanisms affecting both polyamine synthesis and catabolism. Recently, it has become apparent that the polyamines are able to influence the action of the protein kinase casein kinase 2. Here we address several roles of polyamines in gene expression.
Topics: Animals; Casein Kinase II; DNA; Gene Expression Regulation; Humans; Nucleic Acid Conformation; Protein Biosynthesis; Protein Processing, Post-Translational; Protein Serine-Threonine Kinases; Putrescine; Spermidine; Spermine; Transcription, Genetic
PubMed: 12943227
DOI: 10.1007/s00018-003-2332-4 -
Proceedings of the National Academy of... Mar 2024Polyamines are a class of small polycationic alkylamines that play essential roles in both normal and cancer cell growth. Polyamine metabolism is frequently dysregulated...
Polyamines are a class of small polycationic alkylamines that play essential roles in both normal and cancer cell growth. Polyamine metabolism is frequently dysregulated and considered a therapeutic target in cancer. However, targeting polyamine metabolism as monotherapy often exhibits limited efficacy, and the underlying mechanisms are incompletely understood. Here we report that activation of polyamine catabolism promotes glutamine metabolism, leading to a targetable vulnerability in lung cancer. Genetic and pharmacological activation of spermidine/spermine N1-acetyltransferase 1 (SAT1), the rate-limiting enzyme of polyamine catabolism, enhances the conversion of glutamine to glutamate and subsequent glutathione (GSH) synthesis. This metabolic rewiring ameliorates oxidative stress to support lung cancer cell proliferation and survival. Simultaneous glutamine limitation and SAT1 activation result in ROS accumulation, growth inhibition, and cell death. Importantly, pharmacological inhibition of either one of glutamine transport, glutaminase, or GSH biosynthesis in combination with activation of polyamine catabolism synergistically suppresses lung cancer cell growth and xenograft tumor formation. Together, this study unveils a previously unappreciated functional interconnection between polyamine catabolism and glutamine metabolism and establishes cotargeting strategies as potential therapeutics in lung cancer.
Topics: Humans; Lung Neoplasms; Glutamine; Polyamines; Lung; Cell Death; Acetyltransferases; Spermine
PubMed: 38513095
DOI: 10.1073/pnas.2319429121 -
Bioscience, Biotechnology, and... Jul 2022Polyamines (putrescine, spermidine, and spermine) are compounds with amino groups at both ends of a hydrocarbon. Polyamines produced by intestinal bacteria suppress... (Review)
Review
Polyamines (putrescine, spermidine, and spermine) are compounds with amino groups at both ends of a hydrocarbon. Polyamines produced by intestinal bacteria suppress chronic inflammation and enhance the intestinal barrier in the colon, and are also transferred into the blood via the colonic epithelium, resulting in significant improvement of host cognitive performance and life extension in mice. Upregulation of polyamine production by gut microbes can help compensate for the aging-associated decrease in polyamine content through the uptake of intestinal luminal polyamine, thereby extending the healthy life expectancy of the host. This review summarizes recent advances in the study of polyamine metabolism and transport in gut microbes, with particular reference to Escherichia coli and the most predominant species of the gut microbiota. Furthermore, we describe polyamine production by a novel hybrid system comprised of multiple gut microbes, as well as from high-polyamine-producing lactic acid bacteria derived from fermented foods.
Topics: Animals; Biological Transport; Escherichia coli; Gastrointestinal Microbiome; Mice; Polyamines; Putrescine; Spermidine; Spermine
PubMed: 35648468
DOI: 10.1093/bbb/zbac080 -
Methods in Molecular Biology (Clifton,... 2018Polyamines are small aliphatic amines that are found in both prokaryotic and eukaryotic organisms. These growth regulators have been implicated in abiotic and biotic... (Review)
Review
Polyamines are small aliphatic amines that are found in both prokaryotic and eukaryotic organisms. These growth regulators have been implicated in abiotic and biotic stresses as well as plant development and morphogenesis. Several studies have also suggested a key role of polyamines during fruit set and early development. Polyamines have also been linked to fruit ripening and in the regulation of fruit quality-related traits.Recent studies indicate that during ripening of both climacteric and non-climacteric fruits, a decline in total polyamine contents is observed together with an increased catabolism of these growth regulators.In this review, we explore the current knowledge on polyamine biosynthesis and catabolism during fruit set and ripening. The study of the role of polyamine metabolism in fruit ripening indicates the possible application of these natural polycations to control ripening and postharvest decay as well as to improve fruit quality traits.
Topics: Fruit; Gene Expression Regulation, Plant; Metabolic Networks and Pathways; Plant Development; Plant Growth Regulators; Plants; Polyamines
PubMed: 29080186
DOI: 10.1007/978-1-4939-7398-9_36