Polyamine Oxidase and Acrolein as Novel Biochemical Markers for Diagnosis of Cerebral Stroke

Tomitori, Hideyuki; Usui, Teruyoshi; Saeki, Naokatsu; Ueda, Shiro; Kase, Hiroshi; Nishimura, Kazuhiro; Kashiwagi, Keiko; Igarashi, Kazuei

doi:10.1161/01.str.0000190004.36793.2d

Cited by 159 publications

(116 citation statements)

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“…We recently found that increased levels of protein-conjugated acrolein (PC-Acro) and the enzymes responsible for its production, polyamine oxidases (spermine oxidase and acetylpolyamine oxidase), are good biomarkers for human stroke. 1 We also found that measurement of PC-Acro together with interleukin-6 and C-reactive protein makes it possible to identify small infarctions, that is, silent brain infarction, with high sensitivity (89%) and specificity (91%). 2 This tool for early identification of stroke may help in the application of suitable therapy to delay or reduce aggravation of stroke.…”

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Intense Correlation Between Brain Infarction and Protein-Conjugated Acrolein

Saiki

Nishimura

Ishii

et al. 2009

Stroke

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Background and Purpose-We recently found that increases in plasma levels of protein-conjugated acrolein and polyamine oxidases, enzymes that produce acrolein, are good markers for stroke. The aim of this study was to determine whether the level of protein-conjugated acrolein is increased and levels of spermine and spermidine, the substrates of acrolein production, are decreased at the locus of infarction. Methods-A unilateral infarction was induced in mouse brain by photoinduction after injection of Rose Bengal. The volume of the infarction was analyzed using the public domain National Institutes of Health image program. The level of protein-conjugated acrolein at the locus of infarction and in plasma was measured by Western blotting and enzyme-linked immunosorbent assay, respectively. The levels of polyamines at the locus of infarction and in plasma were measured by high-performance liquid chromatography. Results-The level of protein-conjugated acrolein was greatly increased, and levels of spermine and spermidine were decreased at the locus of infarction at 24 hours after the induction of stroke. The size of infarction was significantly decreased by N-acetylcysteine, a scavenger of acrolein. It was also found that the increases in the protein-conjugated acrolein, polyamines, and polyamine oxidases in plasma were observed after the induction of stroke. Key Words: acrolein Ⅲ brain infarction Ⅲ neuroprotective agents Ⅲ polyamines Ⅲ risk factors B rain stroke is a serious pathology. However, there is a lack of good biomarkers for the early phase of stroke. We recently found that increased levels of protein-conjugated acrolein (PC-Acro) and the enzymes responsible for its production, polyamine oxidases (spermine oxidase and acetylpolyamine oxidase), are good biomarkers for human stroke. 1 We also found that measurement of PC-Acro together with interleukin-6 and C-reactive protein makes it possible to identify small infarctions, that is, silent brain infarction, with high sensitivity (89%) and specificity (91%). 2 This tool for early identification of stroke may help in the application of suitable therapy to delay or reduce aggravation of stroke. Conclusions-The results indicate that the induction of infarction is well correlated with the increase in protein-It is thought that cell damage is mainly caused by reactive oxygen species (ROS) 3 such as superoxide anion radical (O 2 Ϫ⅐ ), hydrogen peroxide (H 2 O 2 ), and hydroxyl radical (⅐OH). However, when we compared the toxicity of acrolein (CH 2 ϭCHCHO) and ROS, we found that acrolein was more toxic than H 2 O 2 4 and slightly more toxic than ⅐OH 5 in cell culture systems. Furthermore, acrolein is thought to be produced by lipid peroxidation, 6 but we found that it was more effectively produced from 2 polyamines (spermine and spermidine), 1 which are abundant and essential for cell growth in eukaryotic cells. 7 Acrolein is spontaneously formed from 3-aminopropanal (NH 2 [CH 2 ] 2 CHO) produced from spermine by spermine oxidase (SMO) and less effectively from 3-acetam...

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“…Accordingly, severity of renal failure and cerebral stroke is correlated well with the level of protein-conjugated acrolein. 1,2,18,30 …”

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Intense Correlation Between Brain Infarction and Protein-Conjugated Acrolein

Saiki

Nishimura

Ishii

et al. 2009

Stroke

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“…In addition to H 2 O 2 , SMO produces 3-aminopropanal, a byproduct that contributes to the formation of acrolein, a highly reactive aldehyde. Acrolein associated with elevated polyamine catabolism has been strongly implicated in the etiology of diseases including ischemia-reperfusion injuries, renal failure, stroke, and silent brain infarction (39)(40)(41)(42)(43)(44). Further, elevated SMO expression has been observed in inflammation-associated human diseases including gastritis (22), ulcerative colitis (23), and prostatic intraepithelial neoplasia (24).…”

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Polyamine catabolism contributes to enterotoxigenic Bacteroides fragilis -induced colon tumorigenesis

Goodwin¹,

Shields²,

Wu³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

501

353

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It is estimated that the etiology of 20-30% of epithelial cancers is directly associated with inflammation, although the direct molecular events linking inflammation and carcinogenesis are poorly defined. In the context of gastrointestinal disease, the bacterium enterotoxigenic Bacteroides fragilis (ETBF) is a significant source of chronic inflammation and has been implicated as a risk factor for colorectal cancer. Spermine oxidase (SMO) is a polyamine catabolic enzyme that is highly inducible by inflammatory stimuli resulting in increased reactive oxygen species (ROS) and DNA damage. We now demonstrate that purified B. fragilis toxin (BFT) upregulates SMO in HT29/c1 and T84 colonic epithelial cells, resulting in SMO-dependent generation of ROS and induction of γ-H2A.x, a marker of DNA damage. Further, ETBF-induced colitis in C57BL/6 mice is associated with increased SMO expression and treatment of mice with an inhibitor of polyamine catabolism, N 1 ,N 4 -bis(2,3-butandienyl)-1,4-butanediamine (MDL 72527), significantly reduces ETBF-induced chronic inflammation and proliferation. Most importantly, in the multiple intestinal neoplasia (Min) mouse model, treatment with MDL 72527 reduces ETBF-induced colon tumorigenesis by 69% (P < 0.001). The results of these studies indicate that SMO is a source of bacteria-induced ROS directly associated with tumorigenesis and could serve as a unique target for chemoprevention.inflammatory bowel diseases | adenomatous polyposis coli I t is estimated that chronic inflammation associated with microbial infection directly contributes to the etiology of about 20% of epithelial cancers. The chronic inflammatory microenvironment is characterized by immune dysregulation and elevated levels of reactive oxygen species [ROS; including superoxide, hydrogen peroxide (H 2 O 2 ), and singlet oxygen]. These features result in activation of stress response pathways and oncogenes, down-regulation of tumor suppressor genes, cell and tissue damage, and contribute to tumor initiation, promotion, and progression. However, the precise molecular links between inflammation and carcinogenesis remain to be clarified (1, 2).In the colon, alterations in the physiological balance between the diverse and abundant microbiota (w10 12 organisms per gram feces) and the host are a common source of inflammation. Bacteroides spp comprise a significant proportion of colonic commensal bacteria and members of this group include symbionts and the leading human anaerobic pathogen, Bacteroides fragilis. Enterotoxigenic B. fragilis (ETBF) represent a molecular subtype characterized by a single unique virulence determinant, the production and secretion of a 20-kDa metalloprotease enterotoxin (B. fragilis toxin; BFT). ETBF have been epidemiologically associated with acute diarrheal diseases in humans and livestock, inflammatory bowel diseases (IBD), and colorectal cancer (reviewed in ref.3). Exposure of intestinal epithelial cell lines to BFT results in cleavage of the cell adhesion and tumor suppressor protein E-cadherin, ...

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“…Recently, elevated levels of an acrolein-protein conjugate ( N ⑀ -(3-formyl-3,4-dehydropiperidino)-lysine, FDP-lysine) 61 , 69 were demonstrated in plasma of stroke patients using ACR-Lysine Adduct ELISA System (NOF Corporation, Tokyo, Japan). 70 In addition to its formation as a lipid peroxidation byproduct, acrolein is a ubiquitous environmental contaminant that is present in automobile exhaust and formed by the burning of fats during cooking. 71 Acrolein, by far the strongest electrophile among all ␣ , ␤ -unsaturated aldehydes, reacts with DNA bases including guanine, adenine, cytosine, and thymidine to form cyclic adducts, the major exocyclic adduct being acrolein-deoxyguanosine.…”

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Lipids and lipidomics in brain injury and diseases

Adibhatla

Hatcher

Dempsey

2006

AAPS J

147

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Lipidomics is systems-level analysis and characterization of lipids and their interacting moieties. The amount of information in the genomic and proteomic fi elds is greater than that in the lipidomics fi eld, because of the complex nature of lipids and the limitations of tools for analysis. The main innovation during recent years that has spurred advances in lipid analysis has been the development of new mass spectroscopic techniques, particularly the " soft ionization " techniques electrospray ionization and matrix-assisted laser desorption/ionization. Lipid metabolism may be of particular importance for the central nervous system, as it has a high concentration of lipids. The crucial role of lipids in cell signaling and tissue physiology is demonstrated by the many neurological disorders, including bipolar disorders and schizophrenia, and neurodegenerative diseases such as Alzheimer ' s, Parkinson ' s, and Niemann-Pick diseases, that involve deregulated lipid metabolism. Altered lipid metabolism is also believed to contribute to cerebral ischemic (stroke) injury. Lipidomics will provide a molecular signature to a certain pathway or a disease condition. Lipidomic analyses (characterizing complex mixtures of lipids and identifying previously unknown changes in lipid metabolism) together with RNA silencing, using small interfering RNA (siRNA), may provide powerful tools to elucidate the specifi c roles of lipid intermediates in cell signaling and open new opportunities for drug development.K e yw o r ds: Acrolein , arachidonic acid , cerebral ischemia , cytidine-5 ′ -diphosphocholine , CDP-choline , citicoline , docosahexaenoic acid , 4-hydroxynonenal , lipidomics , lipid peroxidation , MALDI-TOF , ESI-MS-MS , neuroprotectin D1 , 10,17S-docosatriene , phospholipases , phospholipids , RNA silencing , small interfering RNA , siRNA , reactive oxygen species , stroke INTRODUCTIONPhospholipids are important components of all mammalian cells and have a variety of biological functions: (1) they form lipid bilayers that provide structural integrity necessary for protein function, (2) they function as an energy reservoir (eg, triglycerides), and (3) they serve as precursors for various second messengers such as arachidonic acid, docosahexaenoic acid, ceramide, 1,2-diacylglycerol, phosphatidic acid, and lyso-phosphatidic acid. A deeper knowledge of the complexity of phospholipid metabolism will elevate our understanding of the role of lipids in maintaining normal cell physiology and how alterations in lipid metabolism contribute to various disease states. DEFINING A LIPIDLipids comprise an enormous number of chemically distinct molecules arising from combinations of fatty acids with various backbone structures. Indeed, it is diffi cult to defi ne what lipids are. Defi ning lipids as a class of biological molecules that share a high degree of solubility in organic solvents is considered at once too broad and too narrow, encompassing structurally and functionally unrelated molecules and excluding lipids, such as ganglioside...

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Polyamine Oxidase and Acrolein as Novel Biochemical Markers for Diagnosis of Cerebral Stroke

Cited by 159 publications

References 19 publications

Intense Correlation Between Brain Infarction and Protein-Conjugated Acrolein

Intense Correlation Between Brain Infarction and Protein-Conjugated Acrolein

Polyamine catabolism contributes to enterotoxigenic Bacteroides fragilis -induced colon tumorigenesis

Lipids and lipidomics in brain injury and diseases

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