{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T14:09:11Z","timestamp":1791295751595,"version":"4.1.0"},"reference-count":42,"publisher":"National Academy of Sciences","issue":"19","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2001,9,11]]},"abstract":"<jats:p>\n                    Excessive nitric oxide (NO) production in cytokine-activated \u03b2 cells has been implicated in \u03b2 cell disruption in type 1 diabetes. \u03b2 cells are very vulnerable to NO-induced apoptosis. However, the mechanism underlying this phenomenon is unclear. Low concentrations of NO that lead to apoptosis apparently do not cause severe DNA damage in mouse MIN6 \u03b2 cells. CHOP, a C\/EBP homologous protein that is induced by endoplasmic reticulum (ER) stress and plays a role in growth arrest and cell death, was induced by a NO donor,\n                    <jats:italic>S<\/jats:italic>\n                    -nitroso-\n                    <jats:italic>N<\/jats:italic>\n                    -acetyl-\n                    <jats:sc>d,l<\/jats:sc>\n                    -penicillamine (SNAP). SNAP increased cytosolic Ca\n                    <jats:sup>2+<\/jats:sup>\n                    , and only agents depleting ER Ca\n                    <jats:sup>2+<\/jats:sup>\n                    induced CHOP expression and led to apoptosis, suggesting that NO depletes ER Ca\n                    <jats:sup>2+<\/jats:sup>\n                    . Overexpression of calreticulin increased the Ca\n                    <jats:sup>2+<\/jats:sup>\n                    content of ER and afforded protection to cells against NO-mediated apoptosis. Furthermore, pancreatic islets from CHOP knockout mice showed resistance to NO. We conclude that NO depletes ER Ca\n                    <jats:sup>2+<\/jats:sup>\n                    , causes ER stress, and leads to apoptosis. Thus, ER Ca\n                    <jats:sup>2+<\/jats:sup>\n                    stores are a new target of NO, and the ER stress pathway is a major mechanism of NO-mediated \u03b2 cell apoptosis.\n                  <\/jats:p>","DOI":"10.1073\/pnas.191207498","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T10:44:19Z","timestamp":1027680259000},"page":"10845-10850","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":518,"title":["Nitric oxide-induced apoptosis in pancreatic \u03b2 cells is mediated by the endoplasmic reticulum stress pathway"],"prefix":"10.1073","volume":"98","author":[{"given":"Seiichi","family":"Oyadomari","sequence":"first","affiliation":[{"name":"Departments of Molecular Genetics and Metabolic Medicine, Kumamoto University School of Medicine, Honjo 2-2-1, Kumamoto 860-0811, Japan; Department of Host Defense, Research Institute for Microbial Diseases, and Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Corporation, Osaka University Medical School, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan; Department of Biochemistry, Chiba University School of Medicine, Inohana 1-8-1, Chiba 260-8670, Japan; and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kiyoshi","family":"Takeda","sequence":"additional","affiliation":[{"name":"Departments of Molecular Genetics and Metabolic Medicine, Kumamoto University School of Medicine, Honjo 2-2-1, Kumamoto 860-0811, Japan; Department of Host Defense, Research Institute for Microbial Diseases, and Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Corporation, Osaka University Medical School, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan; Department of Biochemistry, Chiba University School of Medicine, Inohana 1-8-1, Chiba 260-8670, Japan; and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaki","family":"Takiguchi","sequence":"additional","affiliation":[{"name":"Departments of Molecular Genetics and Metabolic Medicine, Kumamoto University School of Medicine, Honjo 2-2-1, Kumamoto 860-0811, Japan; Department of Host Defense, Research Institute for Microbial Diseases, and Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Corporation, Osaka University Medical School, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan; Department of Biochemistry, Chiba University School of Medicine, Inohana 1-8-1, Chiba 260-8670, Japan; and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomomi","family":"Gotoh","sequence":"additional","affiliation":[{"name":"Departments of Molecular Genetics and Metabolic Medicine, Kumamoto University School of Medicine, Honjo 2-2-1, Kumamoto 860-0811, Japan; Department of Host Defense, Research Institute for Microbial Diseases, and Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Corporation, Osaka University Medical School, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan; Department of Biochemistry, Chiba University School of Medicine, Inohana 1-8-1, Chiba 260-8670, Japan; and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makoto","family":"Matsumoto","sequence":"additional","affiliation":[{"name":"Departments of Molecular Genetics and Metabolic Medicine, Kumamoto University School of Medicine, Honjo 2-2-1, Kumamoto 860-0811, Japan; Department of Host Defense, Research Institute for Microbial Diseases, and Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Corporation, Osaka University Medical School, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan; Department of Biochemistry, Chiba University School of Medicine, Inohana 1-8-1, Chiba 260-8670, Japan; and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ikuo","family":"Wada","sequence":"additional","affiliation":[{"name":"Departments of Molecular Genetics and Metabolic Medicine, Kumamoto University School of Medicine, Honjo 2-2-1, Kumamoto 860-0811, Japan; Department of Host Defense, Research Institute for Microbial Diseases, and Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Corporation, Osaka University Medical School, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan; Department of Biochemistry, Chiba University School of Medicine, Inohana 1-8-1, Chiba 260-8670, Japan; and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shizuo","family":"Akira","sequence":"additional","affiliation":[{"name":"Departments of Molecular Genetics and Metabolic Medicine, Kumamoto University School of Medicine, Honjo 2-2-1, Kumamoto 860-0811, Japan; Department of Host Defense, Research Institute for Microbial Diseases, and Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Corporation, Osaka University Medical School, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan; Department of Biochemistry, Chiba University School of Medicine, Inohana 1-8-1, Chiba 260-8670, Japan; and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eiichi","family":"Araki","sequence":"additional","affiliation":[{"name":"Departments of Molecular Genetics and Metabolic Medicine, Kumamoto University School of Medicine, Honjo 2-2-1, Kumamoto 860-0811, Japan; Department of Host Defense, Research Institute for Microbial Diseases, and Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Corporation, Osaka University Medical School, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan; Department of Biochemistry, Chiba University School of Medicine, Inohana 1-8-1, Chiba 260-8670, Japan; and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masataka","family":"Mori","sequence":"additional","affiliation":[{"name":"Departments of Molecular Genetics and Metabolic Medicine, Kumamoto University School of Medicine, Honjo 2-2-1, Kumamoto 860-0811, Japan; Department of Host Defense, Research Institute for Microbial Diseases, and Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Corporation, Osaka University Medical School, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan; Department of Biochemistry, Chiba University School of Medicine, Inohana 1-8-1, Chiba 260-8670, Japan; and..."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2001,8,28]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF00403906"},{"key":"e_1_3_3_2_2","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/B978-012370420-7\/50002-2","volume-title":"Nitric 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