PubMed:23582235 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PubMed/sourceid/23582235","sourcedb":"PubMed","sourceid":"23582235","source_url":"http://www.ncbi.nlm.nih.gov/pubmed/23582235","text":"Zinc promotes the death of hypoxic astrocytes by upregulating hypoxia-induced hypoxia-inducible factor-1alpha expression via poly(ADP-ribose) polymerase-1.\nAIM: Pathological release of excess zinc ions has been implicated in ischemic brain cell death. However, the underlying mechanisms remain to be elucidated. In stroke, ischemia-induced zinc release and hypoxia-inducible factor-1 (HIF-1) accumulation concurrently occur in the ischemic tissue. The present study tests the hypothesis that the presence of high intracellular zinc concentration is a major cause of modifications to PARP-1 and HIF-1α during hypoxia, which significantly contributes to cell death during ischemia.\nMETHODS: Primary cortical astrocytes and C8-D1A cells were exposed to different concentrations of zinc chloride. Cell death rate and protein expression of HIF-1 and Poly(ADP-ribose) polymerase (PARP)-1 were examined after 3-h hypoxic treatment.\nRESULTS: Although 3-h hypoxia or 100 μM of zinc alone did not induce noticeable cytotoxicity, their combination led to a dramatic increase in astrocytic cell death in a zinc-concentration-dependent manner. Exposure of astrocytes to hypoxia for 3 h remarkably increased the levels of intracellular zinc and HIF-1α protein, which was further augmented by added exogenous zinc. Notably, HIF-1α knockdown blocked zinc-induced astrocyte death. Moreover, knockdown of PARP-1, another important protein in the response of hypoxia, attenuated the overexpression of HIF-1α and reduced the cell death rate.\nCONCLUSIONS: Our studies show that zinc promotes hypoxic cell death through overexpression of the hypoxia response factor HIF-1α via the cell fate determine factor PARP-1 modification, which provides a novel mechanism for zinc-mediated ischemic brain injury.","tracks":[{"project":"Allie","denotations":[{"id":"SS1_23582235_4_0","span":{"begin":357,"end":383},"obj":"expanded"},{"id":"SS2_23582235_4_0","span":{"begin":385,"end":390},"obj":"abbr"},{"id":"SS1_23582235_8_0","span":{"begin":845,"end":872},"obj":"expanded"},{"id":"SS2_23582235_8_0","span":{"begin":874,"end":878},"obj":"abbr"}],"relations":[{"id":"AE1_23582235_4_0","pred":"abbreviatedTo","subj":"SS1_23582235_4_0","obj":"SS2_23582235_4_0"},{"id":"AE1_23582235_8_0","pred":"abbreviatedTo","subj":"SS1_23582235_8_0","obj":"SS2_23582235_8_0"}],"attributes":[{"subj":"SS1_23582235_4_0","pred":"source","obj":"Allie"},{"subj":"SS2_23582235_4_0","pred":"source","obj":"Allie"},{"subj":"SS1_23582235_8_0","pred":"source","obj":"Allie"},{"subj":"SS2_23582235_8_0","pred":"source","obj":"Allie"}]},{"project":"CHEMDNER-training-test","denotations":[{"id":"T1","span":{"begin":192,"end":196},"obj":"SYSTEMATIC"},{"id":"T2","span":{"begin":340,"end":344},"obj":"SYSTEMATIC"},{"id":"T3","span":{"begin":527,"end":531},"obj":"SYSTEMATIC"},{"id":"T4","span":{"begin":778,"end":791},"obj":"SYSTEMATIC"},{"id":"T5","span":{"begin":845,"end":861},"obj":"SYSTEMATIC"},{"id":"T6","span":{"begin":968,"end":972},"obj":"SYSTEMATIC"},{"id":"T7","span":{"begin":1094,"end":1098},"obj":"SYSTEMATIC"},{"id":"T8","span":{"begin":1222,"end":1226},"obj":"SYSTEMATIC"},{"id":"T9","span":{"begin":1294,"end":1298},"obj":"SYSTEMATIC"},{"id":"T10","span":{"begin":1334,"end":1338},"obj":"SYSTEMATIC"},{"id":"T11","span":{"begin":1557,"end":1561},"obj":"SYSTEMATIC"},{"id":"T12","span":{"begin":1744,"end":1748},"obj":"SYSTEMATIC"},{"id":"T1","span":{"begin":0,"end":4},"obj":"SYSTEMATIC"},{"id":"T2","span":{"begin":132,"end":861},"obj":"SYSTEMATIC"}],"attributes":[{"subj":"T1","pred":"source","obj":"CHEMDNER-training-test"},{"subj":"T2","pred":"source","obj":"CHEMDNER-training-test"},{"subj":"T3","pred":"source","obj":"CHEMDNER-training-test"},{"subj":"T4","pred":"source","obj":"CHEMDNER-training-test"},{"subj":"T5","pred":"source","obj":"CHEMDNER-training-test"},{"subj":"T6","pred":"source","obj":"CHEMDNER-training-test"},{"subj":"T7","pred":"source","obj":"CHEMDNER-training-test"},{"subj":"T8","pred":"source","obj":"CHEMDNER-training-test"},{"subj":"T9","pred":"source","obj":"CHEMDNER-training-test"},{"subj":"T10","pred":"source","obj":"CHEMDNER-training-test"},{"subj":"T11","pred":"source","obj":"CHEMDNER-training-test"},{"subj":"T12","pred":"source","obj":"CHEMDNER-training-test"},{"subj":"T1","pred":"source","obj":"CHEMDNER-training-test"},{"subj":"T2","pred":"source","obj":"CHEMDNER-training-test"}]},{"project":"PubmedHPO","denotations":[{"id":"T1","span":{"begin":315,"end":321},"obj":"HP_0001297"}],"attributes":[{"subj":"T1","pred":"source","obj":"PubmedHPO"}]},{"project":"PubMed_Structured_Abstracts","denotations":[{"id":"T1","span":{"begin":161,"end":679},"obj":"OBJECTIVE"},{"id":"T2","span":{"begin":689,"end":924},"obj":"METHODS"},{"id":"T3","span":{"begin":934,"end":1521},"obj":"RESULTS"},{"id":"T4","span":{"begin":1535,"end":1780},"obj":"CONCLUSIONS"}],"attributes":[{"subj":"T1","pred":"source","obj":"PubMed_Structured_Abstracts"},{"subj":"T2","pred":"source","obj":"PubMed_Structured_Abstracts"},{"subj":"T3","pred":"source","obj":"PubMed_Structured_Abstracts"},{"subj":"T4","pred":"source","obj":"PubMed_Structured_Abstracts"}]}],"config":{"attribute types":[{"pred":"source","value type":"selection","values":[{"id":"Allie","color":"#ec93e4","default":true},{"id":"CHEMDNER-training-test","color":"#93ecda"},{"id":"PubmedHPO","color":"#ecc093"},{"id":"PubMed_Structured_Abstracts","color":"#a693ec"}]}]}}