{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,12]],"date-time":"2025-11-12T14:16:42Z","timestamp":1762957002046,"version":"build-2065373602"},"reference-count":49,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2022,9,4]],"date-time":"2022-09-04T00:00:00Z","timestamp":1662249600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Natural Science Foundation of China","award":["21976120","81761138045","41675123"],"award-info":[{"award-number":["21976120","81761138045","41675123"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Bilirubin (BR) is a tetrapyrrolic compound stemming from heme catabolism with diverse physiological functions. It can be oxidized by H2O2 to form several degradation products, some of which have been detected in vivo and may contribute to the pathogenesis of certain diseases. However, the oxidative degradation of BR is complex and the conditions that BR degradation occurs pathophysiologically remain obscure. Neutrophils are known to generate large amounts of reactive oxygen species, including H2O2, upon activation and they are mobilized to inflammatory sites; therefore, we hypothesized that activated neutrophils could cause BR degradation, which could occur at inflammatory sites. In the present study, we investigated BR degradation by H2O2 and identified hematinic acid (BHP1) and a new product BHP2, whose structure was characterized as 2,5-diformyl-4-methyl-1H-pyrrole-3-propanoic acid. An LC-MS\/MS method for the quantitation of the two compounds was then established. Using the LC-MS\/MS method, we observed the concentration-dependent formation of BHP1 and BHP2 in mouse neutrophils incubated with 10 and 30 \u03bcM of BR with the yields being 16 \u00b1 3.2 and 31 \u00b1 5.9 pmol\/106 cells for BHP1, and 25 \u00b1 4.4 and 71 \u00b1 26 pmol\/106 cells for BHP2, respectively. After adding phorbol 12-myristate 13-acetate, a neutrophil agonist, to 30 \u03bcM of BR-treated cells, the BHP1 yield increased to 43 \u00b1 6.6 pmol\/106 cells, whereas the BHP2 one decreased to 47 \u00b1 9.2 pmol\/106 cells. The two products were also detected in hemorrhagic skins of mice with dermal inflammation and hemorrhage at levels of 4.5 \u00b1 1.9 and 0.18 \u00b1 0.10 nmol\/g tissue, respectively, which were significantly higher than those in the non-hemorrhagic skins. BHP2 was neurotoxic starting at 0.10 \u03bcM but BHP1 was not, as assessed using Caenorhabditis elegans as the animal model. Neutrophil-mediated BR degradation may be a universally pathophysiological process in inflammation and can be particularly important under pathological conditions concerning hemorrhage.<\/jats:p>","DOI":"10.3390\/biom12091237","type":"journal-article","created":{"date-parts":[[2022,9,5]],"date-time":"2022-09-05T20:48:25Z","timestamp":1662410905000},"page":"1237","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["A New Product of Bilirubin Degradation by H2O2 and Its Formation in Activated Neutrophils and in an Inflammatory Mouse Model"],"prefix":"10.3390","volume":"12","author":[{"given":"Fei-Fei","family":"Yu","sequence":"first","affiliation":[{"name":"Institute of Environmental Pollution and Health, School of Environmental and Chemical Engineering, Shanghai University, Shanghai 200444, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yao","family":"Yuan","sequence":"additional","affiliation":[{"name":"Shanghai Jiao Tong University-Hangzhou Future Sci-Tech City Joint Research Center for Tumor Immunotherapy, Hangzhou Innovation Institute for Systems Oncology, Hangzhou 311121, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan","family":"Ao","sequence":"additional","affiliation":[{"name":"Ministry of Education-Shanghai Key Laboratory of Children\u2019s Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6816-0786","authenticated-orcid":false,"given":"Li","family":"Hua","sequence":"additional","affiliation":[{"name":"School of Public Health, Hongqiao International Institute of Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wu","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Environmental Pollution and Health, School of Environmental and Chemical Engineering, Shanghai University, Shanghai 200444, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yiyi","family":"Cao","sequence":"additional","affiliation":[{"name":"School of Public Health, Hongqiao International Institute of Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jing","family":"Xi","sequence":"additional","affiliation":[{"name":"School of Public Health, Hongqiao International Institute of Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2211-7803","authenticated-orcid":false,"given":"Yang","family":"Luan","sequence":"additional","affiliation":[{"name":"School of Public Health, Hongqiao International Institute of Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shangwei","family":"Hou","sequence":"additional","affiliation":[{"name":"Shanghai Jiao Tong University-Hangzhou Future Sci-Tech City Joint Research Center for Tumor Immunotherapy, Hangzhou Innovation Institute for Systems Oncology, Hangzhou 311121, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3472-8393","authenticated-orcid":false,"given":"Xin-Yu","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Public Health, Hongqiao International Institute of Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1449","DOI":"10.1152\/physrev.00003.2016","article-title":"Heme oxygenases in cardiovascular health and disease","volume":"96","author":"Ayer","year":"2016","journal-title":"Physiol. 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