{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T15:37:45Z","timestamp":1770824265698,"version":"3.50.1"},"reference-count":42,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2022,9,6]],"date-time":"2022-09-06T00:00:00Z","timestamp":1662422400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81330029"],"award-info":[{"award-number":["81330029"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Aims: Annexin A5 (ANXA5) exhibited potent antithrombotic, antiapoptotic, and anti-inflammatory properties in a previous study. The role of ANXA5 in traumatic brain injury (TBI)-induced intestinal injury is not fully known. Main methods: Recombinant human ANXA5 (50 \u00b5g\/kg) or vehicle (PBS) was administered to mice via the tail vein 30 min after TBI. Mouse intestine tissue was gathered for hematoxylin and eosin staining 0.5 d, 1 d, 2 d, and 7 d after modeling. Intestinal Western blotting, immunofluorescence, TdT-mediated dUTP nick-end labeling staining, and enzyme-linked immunosorbent assays were performed 2 days after TBI. A series of kits were used to assess lipid peroxide indicators such as malonaldehyde, superoxide dismutase activity, and catalase activity. Key findings: ANXA5 treatment improved the TBI-induced intestinal mucosa injury at different timepoints and significantly increased the body weight. It significantly reduced apoptosis and matrix metalloproteinase-9 and inhibited the degradation of tight-junction-associated protein in the small intestine. ANXA5 treatment improved intestinal inflammation by regulating inflammation-associated factors. It also mitigated the lipid peroxidation products 4-HNE, 8-OHDG, and malonaldehyde, and enhanced the activity of the antioxidant enzymes, superoxide dismutase and catalase. Lastly, ANXA5 significantly enhanced nuclear factor E2-related factor 2 (Nrf2) and hemeoxygenase-1, and decreased high mobility group box 1 (HMGB1). Significance: Collectively, the results suggest that ANXA5 inhibits TBI-induced intestinal injury by restraining oxidative stress and inflammatory responses. The mechanisms involved sparking the Nrf2\/hemeoxygenase-1-induced antioxidant system and suppressing the HMGB1 pathway. ANXA5 may be an attractive therapeutic candidate for protecting against TBI-induced intestinal injury.<\/jats:p>","DOI":"10.3390\/molecules27185755","type":"journal-article","created":{"date-parts":[[2022,9,7]],"date-time":"2022-09-07T01:51:57Z","timestamp":1662515517000},"page":"5755","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Recombinant Human Annexin A5 Alleviated Traumatic-Brain-Injury Induced Intestinal Injury by Regulating the Nrf2\/HO-1\/HMGB1 Pathway"],"prefix":"10.3390","volume":"27","author":[{"given":"Hejun","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300000, China"},{"name":"Graduate School, Tianjin Medical University, Tianjin 300000, China"},{"name":"Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin 300000, China"},{"name":"Department of Neurosurgery, First Hospital of Qinhuangdao, Qinhuangdao 066000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yalong","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300000, China"},{"name":"Graduate School, Tianjin Medical University, Tianjin 300000, China"},{"name":"Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin 300000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tuo","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300000, China"},{"name":"Graduate School, Tianjin Medical University, Tianjin 300000, China"},{"name":"Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin 300000, China"},{"name":"Department of Neurosurgery, Yantai Yuhuangding Hospital, Yantai 264000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fanjian","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300000, China"},{"name":"Graduate School, Tianjin Medical University, Tianjin 300000, China"},{"name":"Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin 300000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruilong","family":"Peng","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300000, China"},{"name":"Graduate School, Tianjin Medical University, Tianjin 300000, China"},{"name":"Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin 300000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cong","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300000, China"},{"name":"Graduate School, Tianjin Medical University, Tianjin 300000, China"},{"name":"Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin 300000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300000, China"},{"name":"Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin 300000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianning","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300000, China"},{"name":"Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin 300000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1016\/S1474-4422(20)30182-4","article-title":"Clinical characteristics and outcomes in patients with traumatic brain injury in China: A prospective, multicentre, longitudinal, observational study","volume":"19","author":"Gao","year":"2020","journal-title":"Lancet Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.ijscr.2018.01.014","article-title":"A case series of closed head trauma with pituitary stalk disruption resulting in hypopituitarism","volume":"43","author":"Khan","year":"2018","journal-title":"Int. J. Surg. Case Rep."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1089\/neu.2020.7526","article-title":"Traumatic Brain Injury Induces Gastrointestinal Dysfunction and Dysbiosis of Gut Microbiota Accompanied by Alterations of Bile Acid Profile","volume":"39","author":"You","year":"2022","journal-title":"J. Neurotrauma."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.bbi.2017.06.018","article-title":"Bidirectional brain-gut interactions and chronic pathological changes after traumatic brain injury in mice","volume":"66","author":"Ma","year":"2017","journal-title":"Brain Behav. Immun."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1087","DOI":"10.1126\/science.abi6087","article-title":"Signaling inflammation across the gut-brain axis","volume":"374","author":"Agirman","year":"2021","journal-title":"Science"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2119","DOI":"10.1089\/neu.2016.4764","article-title":"Extracellular signal-regulated kinase\/nuclear factor-erythroid2-like2\/heme oxygenase-1 pathway-mediated mitophagy alleviates traumatic brain injury-induced intestinal mucosa damage and epithelial barrier dysfunction","volume":"34","author":"Liu","year":"2017","journal-title":"J. Neurotrauma."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1016\/j.neubiorev.2019.05.012","article-title":"Making sense of gut feelings in the traumatic brain injury pathogenesis","volume":"102","author":"Royes","year":"2019","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1472","DOI":"10.1111\/epi.16909","article-title":"Disruption of intestinal barrier and endotoxemia after traumatic brain injury: Implications for post-traumatic epilepsy","volume":"62","author":"Mazarati","year":"2021","journal-title":"Epilepsia"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"11632","DOI":"10.1016\/S0021-9258(18)99004-6","article-title":"The antioxidant responsive element. Activation by oxidative stress and identifi-cation of the DNA consensus sequence required for functional activity","volume":"266","author":"Rushmore","year":"1991","journal-title":"J. Biol. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1016\/j.bbadis.2016.11.005","article-title":"Nrf2 signaling pathway: Pivotal roles in inflammation","volume":"1863","author":"Ahmed","year":"2017","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Mansouri, A., Reiner, \u017d., Ruscica, M., Tedeschi-Reiner, E., Radbakhsh, S., Bagheri Ekta, M., and Sahebkar, A. (2022). Antioxidant effects of statins by modulating Nrf2 and Nrf2\/HO-1 signaling in different diseases. J. Clin. Med., 11.","DOI":"10.3390\/jcm11051313"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1016\/j.pharep.2016.12.011","article-title":"The Nrf2-ARE signaling pathway: An update on its regulation and possible role in cancer prevention and treatment","volume":"69","author":"Paluszczak","year":"2017","journal-title":"Pharmacol. Rep."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1080\/17435390.2021.1919330","article-title":"Stabilization of Nrf2 leading to HO-1 activation protects against zinc oxide nanoparticles-induced endothe-lial cell death","volume":"15","author":"Zhang","year":"2021","journal-title":"Nanotoxicology"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.freeradbiomed.2022.05.016","article-title":"Protective actions of nuclear factor erythroid 2-related factor 2 (NRF2) and downstream pathways against environmental stressors","volume":"187","author":"Jimenez","year":"2022","journal-title":"Free Radic. Biol. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.cyto.2008.07.005","article-title":"Increased intestinal inflammatory response and gut barrier dysfunction in Nrf2-deficient mice after traumatic brain injury","volume":"44","author":"Jin","year":"2008","journal-title":"Cytokine"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"953","DOI":"10.1016\/j.bbamcr.2008.01.030","article-title":"Extracellular annexin A5: Functions of phosphatidylserine-binding and two-dimensional crystallization","volume":"1783","author":"Kenis","year":"2008","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1002\/cbin.11239","article-title":"Loss of annexin A5 expression attenuates the lipopolysaccharide-induced inflammatory re-sponse of rat alveolar macrophages","volume":"44","author":"Zhang","year":"2020","journal-title":"Cell Biol. Int."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"844","DOI":"10.1016\/j.surg.2019.05.020","article-title":"Protective effect of phosphatidylserine blockade in sepsis induced organ dysfunction","volume":"166","author":"Beattie","year":"2019","journal-title":"Surgery"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1177\/1933719118773497","article-title":"Micromolar Zinc in Annexin A5 Anticoagulation as a Potential Remedy for RPRGL3- Associated Recurrent Pregnancy Loss","volume":"26","author":"Danisik","year":"2019","journal-title":"Reprod. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"424","DOI":"10.2119\/molmed.2016.00026","article-title":"Annexin A5 increases survival in murine sepsis model by inhibiting HMGB1-mediated pro-inflammation and coagulation","volume":"22","author":"Park","year":"2016","journal-title":"Mol. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"6753","DOI":"10.1038\/s41598-018-25143-y","article-title":"Annexin A5 reduces infarct size and improves cardiac function after myocardial ischemia-reperfusion injury by suppression of the cardiac inflammatory response","volume":"8","author":"Pluijmert","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"74263","DOI":"10.18632\/oncotarget.19392","article-title":"Annexin A5 suppresses cyclooxygenase-2 expression by downregulating the protein kinase C-zeta-nuclear factor-kappaB signaling pathway in prostate cancer cells","volume":"8","author":"Baek","year":"2017","journal-title":"Oncotarget"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1001\/archsurg.1970.01340280030009","article-title":"Intestinal Mucosal Lesion in Low-Flow States","volume":"101","author":"Chiu","year":"1970","journal-title":"Arch. Surg."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1177\/0271678X15625351","article-title":"Cerebroprotection by the neuronal PGE2 receptor EP2 after intracerebral hemorrhage in middle-aged mice","volume":"37","author":"Wu","year":"2017","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"282","DOI":"10.3389\/fncel.2016.00282","article-title":"The Expression of NP847 and Sox2 after TBI and Its Influence on NSCs","volume":"10","author":"Gu","year":"2016","journal-title":"Front. Cell. Neurosci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.bbi.2017.05.009","article-title":"The bidirectional gut-brain-microbiota axis as a potential nexus between traumatic brain injury, inflammation, and disease","volume":"66","author":"Sundman","year":"2017","journal-title":"Brain Behav. Immun."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2776","DOI":"10.3748\/wjg.v9.i12.2776","article-title":"Alterations of intestinal mucosa structure and barrier function following traumatic brain injury in rats","volume":"9","author":"Hang","year":"2003","journal-title":"World J. Gastroenterol."},{"key":"ref_28","first-page":"1059","article-title":"Stimulating the central nervous system to prevent intestinal dysfunction after traumatic brain injury","volume":"68","author":"Bansal","year":"2010","journal-title":"J. Trauma."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1042\/CS20180919","article-title":"Activation of G protein\u2013coupled estrogen receptor protects intestine from ischemia\/reperfusion injury in mice by protecting the crypt cell proliferation","volume":"133","author":"Chai","year":"2019","journal-title":"Clin. Sci."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Al-Sadi, R., Engers, J., Haque, M., King, S., Al-Omari, D., and Ma, T.Y. (2021). Matrix Metalloproteinase-9 (MMP-9) induced disruption of intestinal epithelial tight junction barrier is mediated by NF-kappaB activation. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0249544"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1016\/j.biopha.2017.08.038","article-title":"Quercetin attenuates the ischemia reperfusion induced COX-2 and MPO expression in the small intestine mucosa","volume":"95","author":"Maretta","year":"2017","journal-title":"Biomed. Pharmacother."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1038\/nri1594","article-title":"High-mobility group box 1 protein (HMGB1): Nuclear weapon in the immune arsenal","volume":"5","author":"Lotze","year":"2005","journal-title":"Nat. Rev. Immunol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"968","DOI":"10.4049\/jimmunol.2100593","article-title":"HMGB1-mediated neutrophil extracellular trap formation exacerbates intestinal ische-mia\/reperfusion-induced acute lung injury","volume":"208","author":"Zhan","year":"2022","journal-title":"J. Immunol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1186\/s12974-020-01863-9","article-title":"Aucubin alleviates oxidative stress and inflammation via Nrf2-mediated signaling activity in experimental traumatic brain injury","volume":"17","author":"Wang","year":"2020","journal-title":"J. Neuroinflammation"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"5816837","DOI":"10.1155\/2021\/5816837","article-title":"Fecal microbiota transplantation is a promising method to restore gut microbiota dysbiosis and relieve neu-rological deficits after traumatic brain injury","volume":"2021","author":"Du","year":"2021","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.freeradbiomed.2020.12.010","article-title":"STING-dependent induction of lipid peroxidation mediates intestinal ischemia-reperfusion injury","volume":"163","author":"Wu","year":"2021","journal-title":"Free Radic. Biol. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.ab.2016.10.021","article-title":"Assessment of lipid peroxidation by measuring malondialdehyde (MDA) and relatives in biological samples: Analytical and biological challenges","volume":"524","author":"Tsikas","year":"2017","journal-title":"Anal. Biochem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"118367","DOI":"10.1016\/j.lfs.2020.118367","article-title":"Maternal exposure to high-fat and high-cholesterol diet induces arterial hypertension and oxi-dative stress along the gut-kidney axis in rat offspring","volume":"261","author":"Neto","year":"2020","journal-title":"Life Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1002\/mc.20465","article-title":"Molecular mechanisms of Nrf2-mediated antioxidant response","volume":"48","author":"Li","year":"2009","journal-title":"Mol. Carcinog."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"103236","DOI":"10.1016\/j.etap.2019.103236","article-title":"The role of ANXA5 in DBP-induced oxidative stress through ERK\/Nrf2 pathway","volume":"72","author":"Zhang","year":"2019","journal-title":"Environ. Toxicol. Pharmacol."},{"key":"ref_41","first-page":"395","article-title":"Higenamine regulates Nrf2-HO-1-Hmgb1 axis and attenuates intestinal ischemia\u2013reperfusion injury in mice","volume":"64","author":"Liu","year":"2015","journal-title":"Agents Actions"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"6933","DOI":"10.4049\/jimmunol.180.10.6933","article-title":"Heme oxygenase-1 protects against neutrophil-mediated intestinal damage by down-regulation of neutrophil p47phox and p67phox activity and O2\u2212 production in a two-hit model of alcohol intoxication and burn injury","volume":"180","author":"Li","year":"2008","journal-title":"J. Immunol."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/18\/5755\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:24:21Z","timestamp":1760142261000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/18\/5755"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,6]]},"references-count":42,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2022,9]]}},"alternative-id":["molecules27185755"],"URL":"https:\/\/doi.org\/10.3390\/molecules27185755","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,6]]}}}