{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T22:41:52Z","timestamp":1789512112535,"version":"build-2803163510"},"reference-count":30,"publisher":"Institute of Physiology of the Czech Academy of Sciences","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Physiol Res"],"published-print":{"date-parts":[[2024,8,31]]},"abstract":"<jats:p>While 3-N-butylphthalide (NBP) has demonstrated notable cardioprotective effects, its precise role in mitigating myocardial arrhythmia following ischemia\/reperfusion (IR) injury in diabetes remains unclear. This study aimed to explore the potential mechanisms through which NBP mitigates reperfusion-induced myocardial arrhythmia in diabetic rats, with a particular focus on mitochondrial function and biogenesis, endoplasmic reticulum (ER) stress, and oxidative\/inflammatory responses. Sixty Sprague-Dawley rats were divided into non-diabetic and diabetic groups, subjected to in-vivo myocardial IR injury, and treated with NBP (100 mg\/kg, intraperitoneally) through different modalities: preconditioning, postconditioning, or a combination of both.  Electrocardiography (ECG) was employed to assess the incidence and severity of arrhythmia. Fluorometric, Western blotting and ELISA analyses were utilized to measure the mitochondrial, ER stress, and cellular outcomes. Treatment of non-diabetic rats with NBP in preconditioned, postconditioned, and combined approaches significantly reduced cardiotroponin-I and the frequency and severity of arrhythmias induced by IR injury. However, only the combined preconditioning plus postconditioning approach of NBP had protective and antiarrhythmic effects in diabetic rats, in an additive manner. Moreover, the NBP combined approach improved mitochondrial function and upregulated the expression of PGC-1\u03b1, Sirt1, and glutathione while concurrently downregulating ER stress and oxidative and pro-inflammatory-related proteins in diabetic rats. In conclusion, the combined approach of NBP treatment was effective in mitigating myocardial arrhythmia in diabetic rats. This approach coordinates interactions within the mitochondria-endoplasmic reticulum network and inhibits oxidative and inflammatory mediators, offering a promising strategy for managing myocardial arrhythmia in diabetic patients.<\/jats:p>","DOI":"10.33549\/physiolres.935307","type":"journal-article","created":{"date-parts":[[2024,9,7]],"date-time":"2024-09-07T10:08:14Z","timestamp":1725703694000},"page":"529-541","source":"Crossref","is-referenced-by-count":3,"title":["3-N-Butylphthalide Confers Antiarrhythmic Features in Ischemia\/Reperfusion Injury of Diabetic Heart by Targeting Mitochondria-Endoplasmic Reticulum Network and Inhibiting Oxidative Stress and Inflammation"],"prefix":"10.33549","author":[{"given":"R","family":"Han","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B","family":"Duan","sequence":"additional","affiliation":[{"name":"Department of Cardiac Surgery, First Affiliated Hospital of Kunming Medical University, Kunming, China. pikachu615@sina.com"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"19169","reference":[{"key":"ref0","doi-asserted-by":"publisher","unstructured":"Hausenloy DJ, Yellon DM. Myocardial ischemia-reperfusion injury: a neglected therapeutic target. J Clin Invest. 2013;123(1):92-100. https:\/\/doi.org\/10.1172\/JCI62874","DOI":"10.1172\/jci62874"},{"key":"ref1","doi-asserted-by":"publisher","unstructured":"Ferdinandy P, Hausenloy DJ, Heusch G, Baxter GF, Schulz R. Interaction of risk factors, comorbidities, and comedications with ischemia\/reperfusion injury and cardioprotection by preconditioning, postconditioning, and remote conditioning. Pharmacol Rev. 2014;66(4):1142-1174. https:\/\/doi.org\/10.1124\/pr.113.008300","DOI":"10.1124\/pr.113.008300"},{"key":"ref2","doi-asserted-by":"publisher","unstructured":"Kalofoutis C, Piperi C, Kalofoutis A, Harris F, Phoenix D, Singh J. Type II diabetes mellitus and cardiovascular risk factors: Current therapeutic approaches. Exp Clin Cardiol. 2007;12(1):17-28.","DOI":"10.1196\/annals.1372.001"},{"key":"ref3","doi-asserted-by":"publisher","unstructured":"Penna C, Andreadou I, Aragno M, Beauloye C, Bertrand L, Lazou A, Falc\u00e3o-Pires I, Bell R, Zuurbier CJ, Pagliaro P, Hausenloy DJ. Effect of hyperglycaemia and diabetes on acute myocardial ischaemia-reperfusion injury and cardioprotection by ischaemic conditioning protocols. Br J Pharmacol. 2020;177(23):5312-5335. https:\/\/doi.org\/10.1111\/bph.14993","DOI":"10.1111\/bph.14993"},{"key":"ref4","doi-asserted-by":"publisher","unstructured":"Soares ROS, Losada DM, Jordani MC, \u00c9vora P, Castro-E-Silva O. Ischemia\/reperfusion injury revisited: an overview of the latest pharmacological strategies. Int J Mol Sci. 2019;20(20):5034. https:\/\/doi.org\/10.3390\/ijms20205034","DOI":"10.3390\/ijms20205034"},{"key":"ref5","doi-asserted-by":"publisher","unstructured":"Chen Y, Xin Y, Cheng Y, Liu X. Mitochondria-endoplasmic reticulum contacts: the promising regulators in diabetic cardiomyopathy. Oxid Med Cell Longev. 2022;2022:2531458. https:\/\/doi.org\/10.1155\/2022\/2531458","DOI":"10.1155\/2022\/2531458"},{"key":"ref6","doi-asserted-by":"publisher","unstructured":"Hamilton S, Terentyeva R, Clements RT, Belevych AE, Terentyev D. Sarcoplasmic reticulum-mitochondria communication; implications for cardiac arrhythmia. J Mol Cell Cardiol. 2021;156:105-113. https:\/\/doi.org\/10.1016\/j.yjmcc.2021.04.002","DOI":"10.1016\/j.yjmcc.2021.04.002"},{"key":"ref7","doi-asserted-by":"publisher","unstructured":"Lopez-Crisosto C, Pennanen C, Vasquez-Trincado C, Morales PE, Bravo-Sagua R, Quest AFG, Chiong M, Lavandero S. Sarcoplasmic reticulum-mitochondria communication in cardiovascular pathophysiology. Nat Rev Cardiol. 2017;14(6):342-360. https:\/\/doi.org\/10.1038\/nrcardio.2017.23","DOI":"10.1038\/nrcardio.2017.23"},{"key":"ref8","doi-asserted-by":"publisher","unstructured":"Li J, Zhang D, Brundel BJJM, Wiersma M. Imbalance of ER and mitochondria interactions: prelude to cardiac ageing and disease? Cells. 2019;8(12):1617.\u00a8https:\/\/doi.org\/10.3390\/cells8121617","DOI":"10.3390\/cells8121617"},{"key":"ref9","unstructured":"Yan RY, Wang SJ, Yao GT, Liu ZG, Xiao N. The protective effect and its mechanism of 3-n-butylphthalide pretreatment on cerebral ischemia reperfusion injury in rats. Eur Rev Med Pharmacol Sci. 2017;21(22):5275-5282."},{"key":"ref10","doi-asserted-by":"publisher","unstructured":"Wang S, Ma F, Huang L, Zhang Y, Peng Y, Xing C, Feng Y, Wang X, Peng Y. Dl-3-n-Butylphthalide (NBP): A Promising Therapeutic Agent for Ischemic Stroke. CNS Neurol Disord Drug Targets. 2018;17(5):338-347. https:\/\/doi.org\/10.2174\/1871527317666180612125843","DOI":"10.2174\/1871527317666180612125843"},{"key":"ref11","doi-asserted-by":"publisher","unstructured":"Zhang D, Zheng N, Fu X, Shi J, Zhang J. Dl-3-n-butylphthalide attenuates myocardial ischemia reperfusion injury by suppressing oxidative stress and regulating cardiac mitophagy via the PINK1\/Parkin pathway in rats. J Thorac Dis. 2022;14(5):1651-1662. https:\/\/doi.org\/10.21037\/jtd-22-585","DOI":"10.21037\/jtd-22-585"},{"key":"ref12","doi-asserted-by":"publisher","unstructured":"Tan SW, Xie T, Malik TH, Gao Y. Advances of neurovascular protective potential of 3-N-butylphthalide and its derivatives in diabetic related diseases. J Diabetes Complications. 2022;36(11):108335. https:\/\/doi.org\/10.1016\/j.jdiacomp.2022.108335","DOI":"10.1016\/j.jdiacomp.2022.108335"},{"key":"ref13","doi-asserted-by":"publisher","unstructured":"Grisanti LA. Diabetes and arrhythmias: pathophysiology, mechanisms and therapeutic outcomes. Front Physiol. 2018;9:1669. https:\/\/doi.org\/10.3389\/fphys.2018.01669","DOI":"10.3389\/fphys.2018.01669"},{"key":"ref14","doi-asserted-by":"publisher","unstructured":"Ferdinandy P, Andreadou I, Baxter GF, B\u00f8tker HE, Davidson SM, Dobrev D, Gersh BJ, Heusch G, Lecour S, Ruiz-Meana M, Zuurbier CJ, Hausenloy DJ, Schulz R. Interaction of cardiovascular nonmodifiable risk factors, comorbidities and comedications with ischemia\/reperfusion injury and cardioprotection by pharmacological treatments and ischemic conditioning. Pharmacol Rev. 2023;75(1):159-216. https:\/\/doi.org\/10.1124\/pharmrev.121.000348","DOI":"10.1124\/pharmrev.121.000348"},{"key":"ref15","doi-asserted-by":"publisher","unstructured":"Xia Z, Chen B, Zhou C, Wang Y, Ren J, Yao X, Yang Y, Wan Q, Lian Z. Protective effect of ischaemic postconditioning combined with nicorandil on myocardial ischaemia-reperfusion injury in diabetic rats. BMC Cardiovasc Disord. 2022;22(1):518. https:\/\/doi.org\/10.1186\/s12872-022-02967-1","DOI":"10.1186\/s12872-022-02967-1"},{"key":"ref16","doi-asserted-by":"publisher","unstructured":"Gao P, Yan Z, Zhu Z. Mitochondria-associated endoplasmic reticulum membranes in cardiovascular diseases. Front Cell Dev Biol. 2020;8:604240. https:\/\/doi.org\/10.3389\/fcell.2020.604240","DOI":"10.3389\/fcell.2020.604240"},{"key":"ref17","doi-asserted-by":"publisher","unstructured":"Burgos-Mor\u00f3n E, Abad-Jim\u00e9nez Z, Mara\u00f1\u00f3n AM, Iannantuoni F, Escribano-L\u00f3pez I, L\u00f3pez-Dom\u00e8nech S, Salom C, Jover A, Mora V, Roldan I, Sol\u00e1 E, Rocha M, V\u00edctor VM. Relationship between oxidative stress, er stress, and inflammation in Type 2 diabetes: the battle continues. J Clin Med. 2019;8(9):1385. https:\/\/doi.org\/10.3390\/jcm8091385","DOI":"10.3390\/jcm8091385"},{"key":"ref18","doi-asserted-by":"publisher","unstructured":"Li Y, Gao Y, Li G. Preclinical multi-target strategies for myocardial ischemia-reperfusion injury. Front Cardiovasc Med. 2022;9:967115. https:\/\/doi.org\/10.3389\/fcvm.2022.967115","DOI":"10.3389\/fcvm.2022.967115"},{"key":"ref19","doi-asserted-by":"publisher","unstructured":"Badalzadeh R, Mohammadi M, Najafi M, Ahmadiasl N, Farajnia S, Ebrahimi H. The additive effects of ischemic postconditioning and cyclosporine-A on nitric oxide activity and functions of diabetic myocardium injured by ischemia\/reperfusion. J Cardiovasc Pharmacol Ther. 2012;17(2):181-9. https:\/\/doi.org\/10.1177\/1074248411416118","DOI":"10.1177\/1074248411416118"},{"key":"ref20","doi-asserted-by":"publisher","unstructured":"Zhang F, Lin JJ, Tian HN, Wang J. Effect of exercise on improving myocardial mitochondrial function in decreasing diabetic cardiomyopathy. Exp Physiol. 2024;109(2):190-201. https:\/\/doi.org\/10.1113\/EP091309","DOI":"10.1113\/ep091309"},{"key":"ref21","doi-asserted-by":"publisher","unstructured":"Tian X, He W, Yang R, Liu Y. Dl-3-n-butylphthalide protects the heart against ischemic injury and H9c2 cardiomyoblasts against oxidative stress: involvement of mitochondrial function and biogenesis. J Biomed Sci. 2017;24(1):38. https:\/\/doi.org\/10.1186\/s12929-017-0345-9","DOI":"10.1186\/s12929-017-0345-9"},{"key":"ref22","doi-asserted-by":"publisher","unstructured":"San-Mill\u00e1n I. The key role of mitochondrial function in health and disease. Antioxidants (Basel). 2023;12(4):782. https:\/\/doi.org\/10.3390\/antiox12040782","DOI":"10.3390\/antiox12040782"},{"key":"ref23","doi-asserted-by":"publisher","unstructured":"van der Weg K, Prinzen FW, Gorgels AP. Editor's Choice- Reperfusion cardiac arrhythmias and their relation to reperfusion-induced cell death. Eur Heart J Acute Cardiovasc Care. 2019;8(2):142-152. https:\/\/doi.org\/10.1177\/2048872618812148","DOI":"10.1177\/2048872618812148"},{"key":"ref24","doi-asserted-by":"publisher","unstructured":"Wu MY, Yiang GT, Liao WT, Tsai AP, Cheng YL, Cheng PW, Li CY, Li CJ. Current mechanistic concepts in ischemia and reperfusion injury. Cell Physiol Biochem. 2018;46(4):1650-1667. https:\/\/doi.org\/10.1159\/000489241","DOI":"10.1159\/000489241"},{"key":"ref25","doi-asserted-by":"publisher","unstructured":"Yu Y, Zhu Y, Sun X, Li Y, Wang M, Dong B, Sun X, Hou W. DL-3-n-butylphthalide protects H9c2 cardiomyoblasts from ischemia\/reperfusion injury by regulating HSP70 expression via PI3K\/AKT pathway activation. Exp Ther Med. 2021;22(3):1008. https:\/\/doi.org\/10.3892\/etm.2021.10441","DOI":"10.3892\/etm.2021.10441"},{"key":"ref26","doi-asserted-by":"publisher","unstructured":"Li W, Wei D, Zhu Z, Xie X, Zhan S, Zhang R, Zhang G, Huang L. Dl-3-n-Butylphthalide Alleviates Hippocampal Neuron Damage in Chronic Cerebral Hypoperfusion via Regulation of the CNTF\/CNTFR\u03b1\/JAK2\/STAT3 Signaling Pathways. Front Aging Neurosci. 2021;12:587403. https:\/\/doi.org\/10.3389\/fnagi.2020.587403","DOI":"10.3389\/fnagi.2020.587403"},{"key":"ref27","doi-asserted-by":"publisher","unstructured":"Niu X, Li M, Gao Y, Xu G, Dong X, Chu B, Lv P. DL-3-n-butylphthalide suppressed autophagy and promoted angiogenesis in rats with vascular dementia by activating the Shh\/Ptch1 signaling pathway. Neurosci Lett. 2021;765:136266. https:\/\/doi.org\/10.1016\/j.neulet.2021.136266","DOI":"10.1016\/j.neulet.2021.136266"},{"key":"ref28","doi-asserted-by":"publisher","unstructured":"Acheampong A, M\u00e9lot C, Benjelloun M, Cheval M, Reye F, Delporte C, van Antwerpen P, Franck T, Mc Entee K, van de Borne P. Effects of hyperoxia and cardiovascular risk factors on myocardial ischaemia-reperfusion injury: a randomized, sham-controlled parallel study. Exp Physiol. 202;106(5):1249-1262. https:\/\/doi.org\/10.1113\/EP089320","DOI":"10.1113\/ep089320"},{"key":"ref29","doi-asserted-by":"publisher","unstructured":"Russell JS, Griffith TA, Helman T, Du Toit EF, Peart JN, Headrick JP. Chronic type 2 but not type 1 diabetes impairs myocardial ischaemic tolerance and preconditioning in C57Bl\/6 mice. Exp Physiol. 2019;104(12):1868-1880. https:\/\/doi.org\/10.1113\/EP088024","DOI":"10.1113\/ep088024"}],"container-title":["Physiological Research"],"original-title":[],"language":"en","deposited":{"date-parts":[[2024,9,7]],"date-time":"2024-09-07T10:08:26Z","timestamp":1725703706000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.biomed.cas.cz\/physiolres\/pdf\/2024\/73_529.pdf"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8,31]]},"references-count":30,"URL":"https:\/\/doi.org\/10.33549\/physiolres.935307","relation":{},"ISSN":["1802-9973","0862-8408"],"issn-type":[{"value":"1802-9973","type":"electronic"},{"value":"0862-8408","type":"print"}],"subject":[],"published":{"date-parts":[[2024,8,31]]}}}