{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T14:32:14Z","timestamp":1787841134306,"version":"build-2784847793"},"reference-count":37,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","license":[{"start":{"date-parts":[[2025,7,2]],"date-time":"2025-07-02T00:00:00Z","timestamp":1751414400000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:title>Abstract:<\/jats:title>\n                  <jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Heme-regulated inhibitor (HRI\/EIF2AK1) is a protein kinase that initiates the integrated stress response (ISR) following mitochondrial damage and\/or oxidative stress. Dependent on a context, ISR may promote death or recovery of cells under stress. This study was initiated to determine HRI contributions to brain damage after experimental intracerebral hemorrhage (ICH) where oxidative toxicity of hemoglobin is a major trigger of neural cell loss.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>MATERIALS AND METHODS:<\/jats:title>\n                    <jats:p>\n                      Publicly available transcriptomic data from a mouse model of ICH were analyzed using standard bioinformatic tools.\n                      <jats:italic toggle=\"yes\">Hri\u2212\/\u2212 and<\/jats:italic>\n                      wild-type control mice were subjected to unilateral collagenase-induced ICH followed by evaluation of forelimb functional deficits (adhesive tape removal), brain histology (Fluoro-Jade B staining of degenerating neurons and immunofluorescence for GFAP and CD36), and extravasated brain hemoglobin assays. Tail bleeding time and platelet number were determined to assess hemostasis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      ISR transcripts were robustly overrepresented in the transcriptome of the peri-hematoma region of wild-type mice at 1-day post-ICH induction, suggesting acute ISR activation. After ICH,\n                      <jats:italic toggle=\"yes\">Hri\u2212\/\u2212<\/jats:italic>\n                      mice showed greater impairment of forelimb function and exacerbated brain damage as indicated by increases of (1) GFAP-negative lesion area, (2) number of degenerating neurons, and (3) signal area of the activated macrophage marker CD36. These effects correlated with acute increases of hemoglobin extravasation, lower platelet counts, and prolonged tail bleeding.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>\n                      While ISR is activated by ICH and may play a role in secondary injury, impaired hemostasis is a likely driver of enhanced ICH severity in\n                      <jats:italic toggle=\"yes\">Hri\u2212\/\u2212<\/jats:italic>\n                      mice.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.4103\/bc.bc_163_24","type":"journal-article","created":{"date-parts":[[2025,7,2]],"date-time":"2025-07-02T16:00:10Z","timestamp":1751472010000},"page":"133-143","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":0,"title":["Exacerbation of hemorrhagic stroke and impaired hemostasis in mice deficient of the integrated stress response kinase heme-regulated inhibitor"],"prefix":"10.4103","volume":"12","author":[{"given":"Lukasz P.","family":"Slomnicki","sequence":"first","affiliation":[{"name":"Kentucky Spinal Cord Injury Research Center, University of Louisville, Louisville, KY, USA"},{"name":"Department of Neurological Surgery, University of Louisville, Louisville, KY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel L.","family":"Owens","sequence":"additional","affiliation":[{"name":"Department of Neurological Surgery, University of Louisville, Louisville, KY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily R.","family":"Hodges","sequence":"additional","affiliation":[{"name":"Kentucky Spinal Cord Injury Research Center, University of Louisville, Louisville, KY, USA"},{"name":"Department of Neurological Surgery, University of Louisville, Louisville, KY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordan","family":"McNeely","sequence":"additional","affiliation":[{"name":"Kentucky Spinal Cord Injury Research Center, University of Louisville, Louisville, KY, USA"},{"name":"Department of Neurological Surgery, University of Louisville, Louisville, KY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darlene A.","family":"Burke","sequence":"additional","affiliation":[{"name":"Kentucky Spinal Cord Injury Research Center, University of Louisville, Louisville, KY, USA"},{"name":"Department of Neurological Surgery, University of Louisville, Louisville, KY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia H.","family":"Chariker","sequence":"additional","affiliation":[{"name":"Department of Neuroscience Training, University of Louisville, Louisville, KY, USA"},{"name":"Kentucky Biomedical Research Infrastructure Network Bioinformatics Core, University of Louisville, Louisville, KY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric Christian","family":"Rouchka","sequence":"additional","affiliation":[{"name":"Kentucky Biomedical Research Infrastructure Network Bioinformatics Core, University of Louisville, Louisville, KY, USA"},{"name":"Department of Biochemistry and Molecular Genetics, University of Louisville, Louisville, KY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sujata Saraswat","family":"Ohri","sequence":"additional","affiliation":[{"name":"Kentucky Spinal Cord Injury Research Center, University of Louisville, Louisville, KY, USA"},{"name":"Department of Neurological Surgery, University of Louisville, Louisville, KY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dale","family":"Ding","sequence":"additional","affiliation":[{"name":"Department of Neurological Surgery, University of Louisville, Louisville, KY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michal","family":"Hetman","sequence":"additional","affiliation":[{"name":"Kentucky Spinal Cord Injury Research Center, University of Louisville, Louisville, KY, USA"},{"name":"Department of Neurological Surgery, University of Louisville, Louisville, KY, USA"},{"name":"Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2025,7,2]]},"reference":[{"key":"R1-20260330","doi-asserted-by":"crossref","first-page":"1204","DOI":"10.1161\/CIRCRESAHA.121.319949","article-title":"Cerebral hemorrhage: Pathophysiology, treatment, and future directions","volume":"130","author":"Magid-Bernstein","year":"2022","journal-title":"Circ Res"},{"key":"R2-20260330","doi-asserted-by":"crossref","first-page":"eaat5314","DOI":"10.1126\/science.aat5314","article-title":"The integrated stress response:From 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