{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T02:50:25Z","timestamp":1788922225525,"version":"build-2803163510"},"reference-count":85,"publisher":"Wiley","issue":"22","license":[{"start":{"date-parts":[[2025,7,21]],"date-time":"2025-07-21T00:00:00Z","timestamp":1753056000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2025,7,21]],"date-time":"2025-07-21T00:00:00Z","timestamp":1753056000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2025,11]]},"abstract":"<jats:sec>\n                    <jats:title>Background and Purpose<\/jats:title>\n                    <jats:p>Lysosomal membrane permeabilization (LMP) is exacerbated following spinal cord injury (SCI), leading to increased neuronal cell death. Ubiquitination may affect LMP by regulating the stability and functionality of lysosomal membranes. Semax, a synthetic heptapeptide, comprising the ACTH (4\u20137) fragment and a C\u2010terminal Pro\u2013Gly\u2013Pro tripeptide, exhibits neuroprotective properties and improves cognitive function. Given the key roles of LMP and ubiquitination in SCI pathophysiology, this study investigated how Semax could modulate these pathways to affect functional recovery following SCI.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>An SCI mouse model was generated by impacting the spinal cord of female C57BL\/6 mice at T9\u2010T10. Functional recovery in SCI mice was evaluated using histochemical methods, along with footprint analysis, Basso scores and inclined plane tests. Marker levels and distributions in the SCI model and in the PC12 cell neuroinflammation model were analysed using immunofluorescence, Western blot, RT\u2010qPCR and transmission electron microscopy. RNA sequencing, network pharmacology and molecular docking were used to identify possible molecular targets of Semax.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>Semax improved SCI functional recovery and inhibited LMP\u2010related pyroptosis in SCI mice and neuroinflammation models, by decreasing oxidative stress. RNA\u2010seq and other analyses found that Semax regulated the ubiquitin specific protease USP18. USP18 knockdown confirmed Semax's role in SCI recovery. Network pharmacology and docking revealed the \u03bc\u2010opioid receptor as a Semax target.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion and Implications<\/jats:title>\n                    <jats:p>Semax promoted SCI functional recovery by targeting \u03bc\u2010opioid receptors, which regulated USP18 and, subsequently, deubiquitination of the fat mass and obesity\u2010associated protein (FTO), suggesting its potential for SCI treatment.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.70122","type":"journal-article","created":{"date-parts":[[2025,7,22]],"date-time":"2025-07-22T05:18:59Z","timestamp":1753161539000},"page":"5489-5516","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Semax peptide targets the \u03bc opioid receptor gene\n                    <i>Oprm1<\/i>\n                    to promote deubiquitination and functional recovery after spinal cord injury in female mice"],"prefix":"10.1111","volume":"182","author":[{"given":"Rongjie","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Orthopaedics The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University  Wenzhou China"},{"name":"Zhejiang Provincial Key Laboratory of Orthopaedics  Wenzhou China"},{"name":"The Second Clinical Medical College of Wenzhou Medical University  Wenzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yituo","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery Zhongshan Hospital, Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haosheng","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University  Wenzhou China"},{"name":"Zhejiang Provincial Key Laboratory of Orthopaedics  Wenzhou China"},{"name":"The Second Clinical Medical College of Wenzhou Medical University  Wenzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University  Wenzhou China"},{"name":"Zhejiang Provincial Key Laboratory of Orthopaedics  Wenzhou China"},{"name":"The Second Clinical Medical College of Wenzhou Medical University  Wenzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junlei","family":"Lv","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University  Wenzhou China"},{"name":"Zhejiang Provincial Key Laboratory of Orthopaedics  Wenzhou China"},{"name":"The Second Clinical Medical College of Wenzhou Medical University  Wenzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liting","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University  Wenzhou China"},{"name":"Zhejiang Provincial Key Laboratory of Orthopaedics  Wenzhou China"},{"name":"The Second Clinical Medical College of Wenzhou Medical University  Wenzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongyi","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University  Wenzhou China"},{"name":"Zhejiang Provincial Key Laboratory of Orthopaedics  Wenzhou China"},{"name":"The Second Clinical Medical College of Wenzhou Medical University  Wenzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenyu","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University  Wenzhou China"},{"name":"Zhejiang Provincial Key Laboratory of Orthopaedics  Wenzhou China"},{"name":"The Second Clinical Medical College of Wenzhou Medical University  Wenzhou China"},{"name":"School of Pharmaceutical Sciences Wenzhou Medical University  Wenzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weikai","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University  Wenzhou China"},{"name":"Zhejiang Provincial Key Laboratory of Orthopaedics  Wenzhou China"},{"name":"The Second Clinical Medical College of Wenzhou Medical University  Wenzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongwei","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University  Wenzhou China"},{"name":"Zhejiang Provincial Key Laboratory of Orthopaedics  Wenzhou China"},{"name":"The Second Clinical Medical College of Wenzhou Medical University  Wenzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhefan","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University  Wenzhou China"},{"name":"Zhejiang Provincial Key Laboratory of Orthopaedics  Wenzhou China"},{"name":"The Second Clinical Medical College of Wenzhou Medical University  Wenzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoxu","family":"Cai","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University  Wenzhou China"},{"name":"Zhejiang Provincial Key Laboratory of Orthopaedics  Wenzhou China"},{"name":"The Second Clinical Medical College of Wenzhou Medical University  Wenzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7374-6506","authenticated-orcid":false,"given":"Jian","family":"Xiao","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences Wenzhou Medical University  Wenzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lihui","family":"Yin","sequence":"additional","affiliation":[{"name":"Central Laboratory The First Affiliated Hospital of Wenzhou Medical University  Wenzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenfei","family":"Ni","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University  Wenzhou China"},{"name":"Zhejiang Provincial Key Laboratory of Orthopaedics  Wenzhou China"},{"name":"The Second Clinical Medical College of Wenzhou Medical University  Wenzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,7,21]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2017.18"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.183954"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jare.2020.08.004"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.16177"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.16181"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.16180"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.16176"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.14112"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21207533"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-019-0185-4"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1089\/neu.2006.23.635"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2019.08.004"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-020-00630-3"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.17333"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2019.00014"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15868"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10571-009-9432-0"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2006.07.108"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2006.03658.x"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.3390\/genes11060681"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2014.150"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2016.02.009"},{"key":"e_1_2_12_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2024.05.008"},{"key":"e_1_2_12_25_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40290-023-00499-3"},{"key":"e_1_2_12_26_1","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.45467"},{"key":"e_1_2_12_27_1","doi-asserted-by":"publisher","DOI":"10.5483\/BMBRep.2022.55.7.054"},{"key":"e_1_2_12_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/s12276-023-01087-w"},{"key":"e_1_2_12_29_1","doi-asserted-by":"publisher","DOI":"10.1111\/cns.14221"},{"key":"e_1_2_12_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbi.2012.08.010"},{"key":"e_1_2_12_31_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21186825"},{"key":"e_1_2_12_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/path.1885"},{"key":"e_1_2_12_33_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24043219"},{"key":"e_1_2_12_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2022.04.003"},{"key":"e_1_2_12_35_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M116.752113"},{"key":"e_1_2_12_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2017.05.005"},{"key":"e_1_2_12_37_1","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2009.3005"},{"key":"e_1_2_12_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-019-1764-1"},{"key":"e_1_2_12_39_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.24433"},{"key":"e_1_2_12_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioactmat.2022.04.029"},{"key":"e_1_2_12_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2020.113273"},{"key":"e_1_2_12_42_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15178"},{"key":"e_1_2_12_43_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12951-022-01273-4"},{"key":"e_1_2_12_44_1","doi-asserted-by":"publisher","DOI":"10.1002\/adhm.202300123"},{"key":"e_1_2_12_45_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41421-023-00622-3"},{"key":"e_1_2_12_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2021.11.029"},{"key":"e_1_2_12_47_1","doi-asserted-by":"publisher","DOI":"10.1111\/jpi.12769"},{"key":"e_1_2_12_48_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40824-023-00339-0"},{"key":"e_1_2_12_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ecoenv.2024.116195"},{"key":"e_1_2_12_50_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-021-03988-3"},{"key":"e_1_2_12_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2021.12.009"},{"key":"e_1_2_12_52_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2164-15-228"},{"key":"e_1_2_12_53_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jafc.2c07581"},{"key":"e_1_2_12_54_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gks1230"},{"key":"e_1_2_12_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tplants.2016.09.002"},{"key":"e_1_2_12_56_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.26287"},{"key":"e_1_2_12_57_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2017.09.005"},{"key":"e_1_2_12_58_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.3000410"},{"key":"e_1_2_12_59_1","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2024.2353548"},{"key":"e_1_2_12_60_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-46428-z"},{"key":"e_1_2_12_61_1","doi-asserted-by":"publisher","DOI":"10.7150\/thno.71086"},{"key":"e_1_2_12_62_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41418-021-00907-8"},{"key":"e_1_2_12_63_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules27103159"},{"key":"e_1_2_12_64_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2745"},{"key":"e_1_2_12_65_1","doi-asserted-by":"publisher","DOI":"10.1111\/cpr.12992"},{"key":"e_1_2_12_66_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2015.01.002"},{"key":"e_1_2_12_67_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2023.102938"},{"key":"e_1_2_12_68_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-024-04001-1"},{"key":"e_1_2_12_69_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mam.2018.07.002"},{"key":"e_1_2_12_70_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22126179"},{"key":"e_1_2_12_71_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-05164-4"},{"key":"e_1_2_12_72_1","doi-asserted-by":"publisher","DOI":"10.1186\/s11658-020-00245-6"},{"key":"e_1_2_12_73_1","doi-asserted-by":"publisher","DOI":"10.1002\/ejhf.1320"},{"key":"e_1_2_12_74_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2019.00392"},{"key":"e_1_2_12_75_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2010.06.044"},{"key":"e_1_2_12_76_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuint.2023.105554"},{"key":"e_1_2_12_77_1","doi-asserted-by":"publisher","DOI":"10.1111\/tra.12613"},{"key":"e_1_2_12_78_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-023-02848-0"},{"key":"e_1_2_12_79_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-024-04290-6"},{"key":"e_1_2_12_80_1","doi-asserted-by":"publisher","DOI":"10.1002\/ctm2.269"},{"key":"e_1_2_12_81_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules23112839"},{"key":"e_1_2_12_82_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb3358"},{"key":"e_1_2_12_83_1","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2022.949939"},{"key":"e_1_2_12_84_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1330678"},{"key":"e_1_2_12_85_1","doi-asserted-by":"publisher","DOI":"10.3892\/mmr.2021.12056"},{"key":"e_1_2_12_86_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12951-024-02610-5"}],"container-title":["British Journal of Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/bph.70122","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/bph.70122","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/bph.70122","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T06:31:18Z","timestamp":1775629878000},"score":1,"resource":{"primary":{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/10.1111\/bph.70122"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,21]]},"references-count":85,"journal-issue":{"issue":"22","published-print":{"date-parts":[[2025,11]]}},"alternative-id":["10.1111\/bph.70122"],"URL":"https:\/\/doi.org\/10.1111\/bph.70122","archive":["Portico"],"relation":{},"ISSN":["0007-1188","1476-5381"],"issn-type":[{"value":"0007-1188","type":"print"},{"value":"1476-5381","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,21]]},"assertion":[{"value":"2024-11-19","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-05-31","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-07-21","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}