{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T05:20:02Z","timestamp":1790918402179,"version":"4.1.0"},"reference-count":45,"publisher":"Frontiers Media SA","issue":"4","license":[{"start":{"date-parts":[[2010,4,1]],"date-time":"2010-04-01T00:00:00Z","timestamp":1270080000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Exp Biol Med (Maywood)"],"published-print":{"date-parts":[[2010,4]]},"abstract":"<jats:p>\n                    The detrimental role of superoxide anion (O\n                    <jats:sub>2<\/jats:sub>\n                    <jats:sup>\u2212<\/jats:sup>\n                    ) has been well documented in the pathogenesis of ischemia\u2013reperfusion (I\/R) injury. Our and other studies suggested that one critical source of O\n                    <jats:sub>2<\/jats:sub>\n                    <jats:sup>\u2212<\/jats:sup>\n                    generation may be xanthine oxidase (XO). We thus hypothesized that I\/R injury could be protected by inhibiting XO activity, which would reduce the amount of O\n                    <jats:sub>2<\/jats:sub>\n                    <jats:sup>\u2212<\/jats:sup>\n                    and hence reduce pathogenic consequences. Among various XO inhibitors, we previously found 4-amino-6-hydroxypyrazolo[3,4- d]pyrimidine (AHPP) exhibited potent XO inhibitory activity. Here, we report that the covalent conjugate of AHPP with amphipathic styrene\u2013maleic acid copolymer (SMA-AHPP) showed protective effect against I\/R-induced injury in a rat hepatic I\/R model. Liver ischemia was induced by occluding both the portal vein and the hepatic artery for 30 min, and followed by reperfusion. SMA-AHPP was administered via the tail vein two hours before ischemia was initiated. A remarkable increase of liver enzymes in plasma (aspartate aminotransferase, AST; alanine aminotransferase, ALT and lactate dehydrogenase, LDH) was detected three hours after reperfusion, whereas prior injection of SMA-AHPP greatly suppressed this increase of AST, ALT and LDH. Moreover, induction of inflammatory cytokines, i.e. tumor necrosis factor-alpha (TNF- \u03b1), interleukin-12 (IL-12) and monocyte chemotactic protein-1 (MCP-1) by I\/R were significantly inhibited by SMA-AHPP treatment. Accordingly, cytotoxic effect or apoptosis in the liver caused by I\/R was clearly reduced by SMA-AHPP pretreatment. Furthermore, thiobarbituric acid-reactive substance assay showed a significant decrease of lipid peroxidation in rat liver after the administration of SMA-AHPP, which is parallel with the decreased XO activity after SMA-AHPP treatment, indicating the involvement of reactive oxygen species generated by XO. In addition, SMA-AHPP was found to bind to albumin, thus to exhibit prolonged in vivo (plasma) half-life. These results suggest that SMA-AHPP exerted a potent cytoprotective effect against I\/R injury in rat liver, by inhibiting XO activity and the subsequent generation of O\n                    <jats:sub>2<\/jats:sub>\n                    <jats:sup>\u2212<\/jats:sup>\n                    .\n                  <\/jats:p>","DOI":"10.1258\/ebm.2009.009304","type":"journal-article","created":{"date-parts":[[2010,5,28]],"date-time":"2010-05-28T12:59:36Z","timestamp":1275051576000},"page":"487-496","source":"Crossref","is-referenced-by-count":15,"title":["Tissue protective effect of xanthine oxidase inhibitor, polymer conjugate of (styrene\u2013maleic acid copolymer) and (4-amino-6-hydroxypyrazolo[3,4-\n                    <i>d<\/i>\n                    ]pyrimidine), on hepatic ischemia\u2013reperfusion injury"],"prefix":"10.3389","volume":"235","author":[{"given":"Jun","family":"Fang","sequence":"first","affiliation":[{"name":"Laboratory of Microbiology & Oncology, Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto 860-0082"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takahiro","family":"Seki","sequence":"additional","affiliation":[{"name":"Laboratory of Microbiology & Oncology, Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto 860-0082"},{"name":"Regional Cooperative Research Center, Kumamoto University, Kumamoto 861-2202, Japan"},{"name":"Current address:Department of Clinical Pharmacology, University of Oxford, Oxford, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haibo","family":"Qin","sequence":"additional","affiliation":[{"name":"Laboratory of Microbiology & Oncology, Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto 860-0082"},{"name":"Department of Applied Microbiology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gahininath Y","family":"Bharate","sequence":"additional","affiliation":[{"name":"Laboratory of Microbiology & Oncology, Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto 860-0082"},{"name":"Department of Applied Chemistry, Sojo University, Kumamoto 860-0082, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arun K","family":"Iyer","sequence":"additional","affiliation":[{"name":"Laboratory of Microbiology & Oncology, Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto 860-0082"},{"name":"Current address:Department of Radiology & Biomedical Imaging, University of California San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Maeda","sequence":"additional","affiliation":[{"name":"Laboratory of Microbiology & Oncology, Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto 860-0082"},{"name":"Regional Cooperative Research Center, Kumamoto University, Kumamoto 861-2202, Japan"},{"name":"Department of Applied Chemistry, Sojo University, Kumamoto 860-0082, 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