{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T02:25:25Z","timestamp":1792031125579,"version":"4.4.0"},"reference-count":43,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Stroke"],"published-print":{"date-parts":[[2021,5]]},"abstract":"<jats:sec>\n                    <jats:title>Background and Purpose:<\/jats:title>\n                    <jats:p>\n                      CAPN1 (calpain1)\u2014an intracellular Ca\n                      <jats:sup>2+<\/jats:sup>\n                      -regulated cysteine protease\u2014can be activated under cerebral ischemia. However, the mechanisms by which CAPN1 activation promotes cerebral ischemic injury are not defined.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>In the present study, we used adeno-associated virus-mediated genetic knockdown and pharmacological blockade (MDL-28170) of CAPN1 to investigate the role of CAPN1 in the regulation of the autophagy-lysosomal pathway and neuronal damage in 2 models, rat permanent middle cerebral occlusion in vivo model and oxygen-glucose\u2013deprived primary neuron in vitro model.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>CAPN1 was activated in the cortex of permanent middle cerebral occlusion\u2013operated rats and oxygen-glucose deprivation\u2013exposed neurons. Genetic and pharmacological inhibition of CAPN1 significantly attenuated ischemia-induced lysosomal membrane permeabilization and subsequent accumulation of autophagic substrates in vivo and in vitro. Moreover, inhibition of CAPN1 increased autophagosome formation by decreasing the cleavage of the autophagy regulators BECN1 (Beclin1) and ATG (autophagy-related gene) 5. Importantly, the neuron-protective effect of MDL-28170 on ischemic insult was reversed by cotreatment with either class III-PI3K (phosphatidylinositol 3-kinase) inhibitor 3-methyladenine or lysosomal inhibitor chloroquine (chloroquine), suggesting that CAPN1 activation-mediated impairment of autophagic flux is crucial for cerebral ischemia-induced neuronal damage.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>The present study demonstrates for the first time that ischemia-induced CAPN1 activation impairs lysosomal function and suppresses autophagosome formation, which contribute to the accumulation of substrates and aggravate the ischemia-induced neuronal cell damage. Our work highlights the vital role of CAPN1 in the regulation of cerebral ischemia\u2013mediated autophagy-lysosomal pathway defects and neuronal damage.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/strokeaha.120.032749","type":"journal-article","created":{"date-parts":[[2021,4,20]],"date-time":"2021-04-20T05:09:45Z","timestamp":1618895385000},"page":"1809-1821","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":36,"title":["CAPN1 (Calpain1)-Mediated Impairment of Autophagic Flux Contributes to Cerebral Ischemia-Induced Neuronal Damage"],"prefix":"10.1161","volume":"52","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2622-9327","authenticated-orcid":true,"given":"Yueyang","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Physiology, Shenyang Medical College, China (Y.L., Y. Yao, Y. Yang, R.C., M.-S.Z.)."},{"name":"Department of Pharmacology, Shenyang Pharmaceutical University, China (Y.L., X.C., H.Z., X.F., X.Y., J.Y.)."},{"name":"Department of Cardiology, The Affiliated Ganzhou Hospital of Nanchang University, China (J.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8910-0205","authenticated-orcid":true,"given":"Xiaohang","family":"Che","sequence":"additional","affiliation":[{"name":"Department of Physiology, Shenyang Medical College, China (Y.L., Y. Yao, Y. Yang, R.C., M.-S.Z.)."},{"name":"Department of Pharmacology, Shenyang Pharmaceutical University, China (Y.L., X.C., H.Z., X.F., X.Y., J.Y.)."},{"name":"Department of Cardiology, The Affiliated Ganzhou Hospital of Nanchang University, China (J.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haotian","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Physiology, Shenyang Medical College, China (Y.L., Y. Yao, Y. Yang, R.C., M.-S.Z.)."},{"name":"Department of Pharmacology, Shenyang Pharmaceutical University, China (Y.L., X.C., H.Z., X.F., X.Y., J.Y.)."},{"name":"Department of Cardiology, The Affiliated Ganzhou Hospital of Nanchang University, China (J.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxiao","family":"Fu","sequence":"additional","affiliation":[{"name":"Department of Physiology, Shenyang Medical College, China (Y.L., Y. Yao, Y. Yang, R.C., M.-S.Z.)."},{"name":"Department of Pharmacology, Shenyang Pharmaceutical University, China (Y.L., X.C., H.Z., X.F., X.Y., J.Y.)."},{"name":"Department of Cardiology, The Affiliated Ganzhou Hospital of Nanchang University, China (J.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Yao","sequence":"additional","affiliation":[{"name":"Department of Physiology, Shenyang Medical College, China (Y.L., Y. Yao, Y. Yang, R.C., M.-S.Z.)."},{"name":"Department of Pharmacology, Shenyang Pharmaceutical University, China (Y.L., X.C., H.Z., X.F., X.Y., J.Y.)."},{"name":"Department of Cardiology, The Affiliated Ganzhou Hospital of Nanchang University, China (J.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Physiology, Shenyang Medical College, China (Y.L., Y. Yao, Y. Yang, R.C., M.-S.Z.)."},{"name":"Department of Pharmacology, Shenyang Pharmaceutical University, China (Y.L., X.C., H.Z., X.F., X.Y., J.Y.)."},{"name":"Department of Cardiology, The Affiliated Ganzhou Hospital of Nanchang University, China (J.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Physiology, Shenyang Medical College, China (Y.L., Y. Yao, Y. Yang, R.C., M.-S.Z.)."},{"name":"Department of Pharmacology, Shenyang Pharmaceutical University, China (Y.L., X.C., H.Z., X.F., X.Y., J.Y.)."},{"name":"Department of Cardiology, The Affiliated Ganzhou Hospital of Nanchang University, China (J.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruiping","family":"Cai","sequence":"additional","affiliation":[{"name":"Department of Physiology, Shenyang Medical College, China (Y.L., Y. Yao, Y. Yang, R.C., M.-S.Z.)."},{"name":"Department of Pharmacology, Shenyang Pharmaceutical University, China (Y.L., X.C., H.Z., X.F., X.Y., J.Y.)."},{"name":"Department of Cardiology, The Affiliated Ganzhou Hospital of Nanchang University, China (J.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangnan","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Physiology, Shenyang Medical College, China (Y.L., Y. Yao, Y. Yang, R.C., M.-S.Z.)."},{"name":"Department of Pharmacology, Shenyang Pharmaceutical University, China (Y.L., X.C., H.Z., X.F., X.Y., J.Y.)."},{"name":"Department of Cardiology, The Affiliated Ganzhou Hospital of Nanchang University, China (J.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2791-5281","authenticated-orcid":true,"given":"Jingyu","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Physiology, Shenyang Medical College, China (Y.L., Y. Yao, Y. Yang, R.C., M.-S.Z.)."},{"name":"Department of Pharmacology, Shenyang Pharmaceutical University, China (Y.L., X.C., H.Z., X.F., X.Y., J.Y.)."},{"name":"Department of Cardiology, The Affiliated Ganzhou Hospital of Nanchang University, China (J.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9075-345X","authenticated-orcid":true,"given":"Ming-Sheng","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Physiology, Shenyang Medical College, China (Y.L., Y. Yao, Y. Yang, R.C., M.-S.Z.)."},{"name":"Department of Pharmacology, Shenyang Pharmaceutical University, China (Y.L., X.C., H.Z., X.F., X.Y., J.Y.)."},{"name":"Department of Cardiology, The Affiliated Ganzhou Hospital of Nanchang University, China (J.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_5_2_2","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2015.1100356"},{"key":"e_1_3_5_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2008.07.022"},{"key":"e_1_3_5_4_2","doi-asserted-by":"publisher","DOI":"10.4161\/auto.6412"},{"key":"e_1_3_5_5_2","doi-asserted-by":"publisher","DOI":"10.1097\/NEN.0b013e31821352bd"},{"key":"e_1_3_5_6_2","doi-asserted-by":"publisher","DOI":"10.4161\/auto.8.2.18599"},{"key":"e_1_3_5_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2017.34"},{"key":"e_1_3_5_8_2","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2018.1531196"},{"key":"e_1_3_5_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceca.2004.03.001"},{"key":"e_1_3_5_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2016.05.008"},{"key":"e_1_3_5_11_2","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.300.3.717"},{"key":"e_1_3_5_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.jcbfm.9600595"},{"key":"e_1_3_5_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0024-3205(02)01506-0"},{"key":"e_1_3_5_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2010.02.087"},{"key":"e_1_3_5_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jstrokecerebrovasdis.2017.10.020"},{"key":"e_1_3_5_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.taap.2014.03.025"},{"key":"e_1_3_5_17_2","doi-asserted-by":"publisher","DOI":"10.1080\/01616412.2016.1250459"},{"key":"e_1_3_5_18_2","doi-asserted-by":"publisher","DOI":"10.1179\/016164101101198776"},{"key":"e_1_3_5_19_2","doi-asserted-by":"publisher","DOI":"10.1210\/endo.143.4.8752"},{"key":"e_1_3_5_20_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M501603200"},{"key":"e_1_3_5_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2013.05.019"},{"key":"e_1_3_5_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2017.299"},{"key":"e_1_3_5_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2012.46"},{"key":"e_1_3_5_24_2","doi-asserted-by":"publisher","DOI":"10.4161\/auto.6.8.13337"},{"key":"e_1_3_5_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1482"},{"key":"e_1_3_5_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2011.29"},{"key":"e_1_3_5_27_2","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.13-12951"},{"key":"e_1_3_5_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2014.203"},{"key":"e_1_3_5_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0166-2236(99)01479-4"},{"key":"e_1_3_5_30_2","doi-asserted-by":"publisher","DOI":"10.4103\/0366-6999.155109"},{"key":"e_1_3_5_31_2","doi-asserted-by":"publisher","DOI":"10.1186\/s40478-017-0431-y"},{"key":"e_1_3_5_32_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1142-17.2017"},{"key":"e_1_3_5_33_2","doi-asserted-by":"publisher","DOI":"10.1002\/hipo.10127"},{"key":"e_1_3_5_34_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-015-9275-2"},{"key":"e_1_3_5_35_2","doi-asserted-by":"publisher","DOI":"10.4161\/auto.5.4.7666"},{"key":"e_1_3_5_36_2","doi-asserted-by":"publisher","DOI":"10.4161\/auto.6.1.10326"},{"key":"e_1_3_5_37_2","doi-asserted-by":"publisher","DOI":"10.4161\/auto.25132"},{"key":"e_1_3_5_38_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.STR.0000227259.15506.24"},{"key":"e_1_3_5_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2008.09.007"},{"key":"e_1_3_5_40_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2013.02.072"},{"key":"e_1_3_5_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0301-0082(00)00006-x"},{"key":"e_1_3_5_42_2","doi-asserted-by":"publisher","DOI":"10.4161\/auto.8.1.18217"},{"key":"e_1_3_5_43_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2019.05.030"},{"key":"e_1_3_5_44_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.080796"}],"container-title":["Stroke"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/STROKEAHA.120.032749","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T12:21:59Z","timestamp":1785154919000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/STROKEAHA.120.032749"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5]]},"references-count":43,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2021,5]]}},"alternative-id":["10.1161\/STROKEAHA.120.032749"],"URL":"https:\/\/doi.org\/10.1161\/strokeaha.120.032749","relation":{},"ISSN":["0039-2499","1524-4628"],"issn-type":[{"value":"0039-2499","type":"print"},{"value":"1524-4628","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5]]},"assertion":[{"value":"2020-09-20","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-12-11","order":1,"name":"revised","label":"Revised","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-03-17","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-04-20","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}