Nobiletin alleviates myocardial ischemia-reperfusion injury via ferroptosis in rats with type-2 diabetes mellitus
Susceptibility to myocardial ischemia-reperfusion (IR) injury in type-2 diabetes (T2DM) remains disputed, although studies have reported that ferroptosis is associated with myocardial IR injury. Nobiletin, a flavonoid isolated from citrus peels, is an antioxidant that possesses anti-inflammatory and...
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| Veröffentlicht in: | Biomedicine & pharmacotherapy 2023-07, Vol.163, p.114795-114795, Article 114795 |
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| creator | Huang, Qin Tian, Liqun Zhang, Yi Qiu, Zhen Lei, Shaoqing Xia, Zhong-Yuan |
| description | Susceptibility to myocardial ischemia-reperfusion (IR) injury in type-2 diabetes (T2DM) remains disputed, although studies have reported that ferroptosis is associated with myocardial IR injury. Nobiletin, a flavonoid isolated from citrus peels, is an antioxidant that possesses anti-inflammatory and anti-diabetic activities. However, it remains unknown whether nobiletin has any protective effects on susceptibility to myocardial IR injury during T2DM in rats via ferroptosis. To investigate the effects and underlying mechanisms of nobiletin on myocardial IR injury during T2DM, we induced myocardial IR model in rats at T2DM onset vs mature disease. We also established a high-fat high-glucose (HFHG) and hypoxia-reoxygenation (H/R) model in H9c2 cells to imitate abnormal glycolipid metabolism during T2DM. Myocardial injury, oxidative stress and ferroptosis towards myocardial IR in rats with mature T2DM but not at T2DM onset were increased. These changes were restored under treatment with ferrostain-1 or nobiletin. Both ferrostain-1 and nobiletin decreased the expression of ferroptosis-related proteins including Acyl-CoA synthetase long chain family member 4 (ACSL4) and nuclear receptor coactivator 4 (NCOA4) but not glutathione peroxidase 4 (GPX4) in rats with mature T2DM and cells with HFHG and H/R injury. Nobiletin strengthened the effect of si-ACSL4 on inhibiting ACSL4 expression, and also inhibited the effect of Erastin or oe-ACSL4 on increasing ACSL4 expression. Taken together, our data indicates that ferroptosis involves in susceptibility to myocardial IR injury in rats during T2DM. Nobiletin has therapeutic potential for alleviating myocardial IR injury associated with ACSL4- and NCOA4-related ferroptosis.
[Display omitted]
•The mature but not onset of T2DM in rats have a higher susceptibility to myocardial IR injury, relating to ferroptosis.•Not all of ferroptosis-related proteins participates in myocardial IR injury in diabetic rats.•ACSL4- and NCOA4-related ferroptosis involves in the susceptibility to myocardial IR during T2DM in rats.•Nobiletin mitigates myocardial IR injuryin diabetic rats via inhibiting ACSL4- and NCOA4-related ferroptosis. |
| doi_str_mv | 10.1016/j.biopha.2023.114795 |
| format | Article |
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[Display omitted]
•The mature but not onset of T2DM in rats have a higher susceptibility to myocardial IR injury, relating to ferroptosis.•Not all of ferroptosis-related proteins participates in myocardial IR injury in diabetic rats.•ACSL4- and NCOA4-related ferroptosis involves in the susceptibility to myocardial IR during T2DM in rats.•Nobiletin mitigates myocardial IR injuryin diabetic rats via inhibiting ACSL4- and NCOA4-related ferroptosis.</description><identifier>ISSN: 0753-3322</identifier><identifier>EISSN: 1950-6007</identifier><identifier>DOI: 10.1016/j.biopha.2023.114795</identifier><identifier>PMID: 37146415</identifier><language>eng</language><publisher>France: Elsevier Masson SAS</publisher><subject>Animals ; Diabetes Mellitus, Type 2 - complications ; Diabetes Mellitus, Type 2 - drug therapy ; Ferroptosis ; Flavones - pharmacology ; Flavones - therapeutic use ; Myocardial Ischemia - drug therapy ; Myocardial ischemia-reperfusion injury ; Myocardial Reperfusion Injury - drug therapy ; Myocardial Reperfusion Injury - metabolism ; Nobiletin ; Rats ; Reperfusion Injury - metabolism ; Susceptibility ; Type-2 diabetes</subject><ispartof>Biomedicine & pharmacotherapy, 2023-07, Vol.163, p.114795-114795, Article 114795</ispartof><rights>2023 The Authors</rights><rights>Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c408t-530ff61e64a491dc2acd0992754a0152601390951ee168db9e1b3f7004f647d03</citedby><cites>FETCH-LOGICAL-c408t-530ff61e64a491dc2acd0992754a0152601390951ee168db9e1b3f7004f647d03</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S075333222300584X$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65534</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37146415$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Huang, Qin</creatorcontrib><creatorcontrib>Tian, Liqun</creatorcontrib><creatorcontrib>Zhang, Yi</creatorcontrib><creatorcontrib>Qiu, Zhen</creatorcontrib><creatorcontrib>Lei, Shaoqing</creatorcontrib><creatorcontrib>Xia, Zhong-Yuan</creatorcontrib><title>Nobiletin alleviates myocardial ischemia-reperfusion injury via ferroptosis in rats with type-2 diabetes mellitus</title><title>Biomedicine & pharmacotherapy</title><addtitle>Biomed Pharmacother</addtitle><description>Susceptibility to myocardial ischemia-reperfusion (IR) injury in type-2 diabetes (T2DM) remains disputed, although studies have reported that ferroptosis is associated with myocardial IR injury. Nobiletin, a flavonoid isolated from citrus peels, is an antioxidant that possesses anti-inflammatory and anti-diabetic activities. However, it remains unknown whether nobiletin has any protective effects on susceptibility to myocardial IR injury during T2DM in rats via ferroptosis. To investigate the effects and underlying mechanisms of nobiletin on myocardial IR injury during T2DM, we induced myocardial IR model in rats at T2DM onset vs mature disease. We also established a high-fat high-glucose (HFHG) and hypoxia-reoxygenation (H/R) model in H9c2 cells to imitate abnormal glycolipid metabolism during T2DM. Myocardial injury, oxidative stress and ferroptosis towards myocardial IR in rats with mature T2DM but not at T2DM onset were increased. These changes were restored under treatment with ferrostain-1 or nobiletin. Both ferrostain-1 and nobiletin decreased the expression of ferroptosis-related proteins including Acyl-CoA synthetase long chain family member 4 (ACSL4) and nuclear receptor coactivator 4 (NCOA4) but not glutathione peroxidase 4 (GPX4) in rats with mature T2DM and cells with HFHG and H/R injury. Nobiletin strengthened the effect of si-ACSL4 on inhibiting ACSL4 expression, and also inhibited the effect of Erastin or oe-ACSL4 on increasing ACSL4 expression. Taken together, our data indicates that ferroptosis involves in susceptibility to myocardial IR injury in rats during T2DM. Nobiletin has therapeutic potential for alleviating myocardial IR injury associated with ACSL4- and NCOA4-related ferroptosis.
[Display omitted]
•The mature but not onset of T2DM in rats have a higher susceptibility to myocardial IR injury, relating to ferroptosis.•Not all of ferroptosis-related proteins participates in myocardial IR injury in diabetic rats.•ACSL4- and NCOA4-related ferroptosis involves in the susceptibility to myocardial IR during T2DM in rats.•Nobiletin mitigates myocardial IR injuryin diabetic rats via inhibiting ACSL4- and NCOA4-related ferroptosis.</description><subject>Animals</subject><subject>Diabetes Mellitus, Type 2 - complications</subject><subject>Diabetes Mellitus, Type 2 - drug therapy</subject><subject>Ferroptosis</subject><subject>Flavones - pharmacology</subject><subject>Flavones - therapeutic use</subject><subject>Myocardial Ischemia - drug therapy</subject><subject>Myocardial ischemia-reperfusion injury</subject><subject>Myocardial Reperfusion Injury - drug therapy</subject><subject>Myocardial Reperfusion Injury - metabolism</subject><subject>Nobiletin</subject><subject>Rats</subject><subject>Reperfusion Injury - metabolism</subject><subject>Susceptibility</subject><subject>Type-2 diabetes</subject><issn>0753-3322</issn><issn>1950-6007</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kE1v1DAQhi0EokvhHyDkI5cs48_EFyRU8SVVcIGz5TgTrVdJnNpO0f57XFI4chpp9Mw7Mw8hrxkcGTD97nzsQ1xP7siBiyNjsjXqCTkwo6DRAO1TcoBWiUYIzq_Ii5zPAKC06J6TK9EyqSVTB3L3LfZhwhIW6qYJ74MrmOl8id6lIbiJhuxPOAfXJFwxjVsOcaFhOW_pQitNR0wpriXmkGubJlcy_RXKiZbLig2nNaTHP5k4TaFs-SV5Nrop46vHek1-fvr44-ZLc_v989ebD7eNl9CVRgkYR81QSycNGzx3fgBjeKukA6a4BiYMGMUQme6G3iDrxdgCyFHLdgBxTd7uuWuKdxvmYuf6Sz3CLRi3bHnHwDAtTFdRuaM-xZwTjnZNYXbpYhnYB9n2bHfZ9kG23WXXsTePG7Z-xuHf0F-7FXi_A1j_vA-YbPYBF49DSOiLHWL4_4bfFzmTVA</recordid><startdate>202307</startdate><enddate>202307</enddate><creator>Huang, Qin</creator><creator>Tian, Liqun</creator><creator>Zhang, Yi</creator><creator>Qiu, Zhen</creator><creator>Lei, Shaoqing</creator><creator>Xia, Zhong-Yuan</creator><general>Elsevier Masson SAS</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>202307</creationdate><title>Nobiletin alleviates myocardial ischemia-reperfusion injury via ferroptosis in rats with type-2 diabetes mellitus</title><author>Huang, Qin ; Tian, Liqun ; Zhang, Yi ; Qiu, Zhen ; Lei, Shaoqing ; Xia, Zhong-Yuan</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c408t-530ff61e64a491dc2acd0992754a0152601390951ee168db9e1b3f7004f647d03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Animals</topic><topic>Diabetes Mellitus, Type 2 - complications</topic><topic>Diabetes Mellitus, Type 2 - drug therapy</topic><topic>Ferroptosis</topic><topic>Flavones - pharmacology</topic><topic>Flavones - therapeutic use</topic><topic>Myocardial Ischemia - drug therapy</topic><topic>Myocardial ischemia-reperfusion injury</topic><topic>Myocardial Reperfusion Injury - drug therapy</topic><topic>Myocardial Reperfusion Injury - metabolism</topic><topic>Nobiletin</topic><topic>Rats</topic><topic>Reperfusion Injury - metabolism</topic><topic>Susceptibility</topic><topic>Type-2 diabetes</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Huang, Qin</creatorcontrib><creatorcontrib>Tian, Liqun</creatorcontrib><creatorcontrib>Zhang, Yi</creatorcontrib><creatorcontrib>Qiu, Zhen</creatorcontrib><creatorcontrib>Lei, Shaoqing</creatorcontrib><creatorcontrib>Xia, Zhong-Yuan</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Biomedicine & pharmacotherapy</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Huang, Qin</au><au>Tian, Liqun</au><au>Zhang, Yi</au><au>Qiu, Zhen</au><au>Lei, Shaoqing</au><au>Xia, Zhong-Yuan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Nobiletin alleviates myocardial ischemia-reperfusion injury via ferroptosis in rats with type-2 diabetes mellitus</atitle><jtitle>Biomedicine & pharmacotherapy</jtitle><addtitle>Biomed Pharmacother</addtitle><date>2023-07</date><risdate>2023</risdate><volume>163</volume><spage>114795</spage><epage>114795</epage><pages>114795-114795</pages><artnum>114795</artnum><issn>0753-3322</issn><eissn>1950-6007</eissn><abstract>Susceptibility to myocardial ischemia-reperfusion (IR) injury in type-2 diabetes (T2DM) remains disputed, although studies have reported that ferroptosis is associated with myocardial IR injury. Nobiletin, a flavonoid isolated from citrus peels, is an antioxidant that possesses anti-inflammatory and anti-diabetic activities. However, it remains unknown whether nobiletin has any protective effects on susceptibility to myocardial IR injury during T2DM in rats via ferroptosis. To investigate the effects and underlying mechanisms of nobiletin on myocardial IR injury during T2DM, we induced myocardial IR model in rats at T2DM onset vs mature disease. We also established a high-fat high-glucose (HFHG) and hypoxia-reoxygenation (H/R) model in H9c2 cells to imitate abnormal glycolipid metabolism during T2DM. Myocardial injury, oxidative stress and ferroptosis towards myocardial IR in rats with mature T2DM but not at T2DM onset were increased. These changes were restored under treatment with ferrostain-1 or nobiletin. Both ferrostain-1 and nobiletin decreased the expression of ferroptosis-related proteins including Acyl-CoA synthetase long chain family member 4 (ACSL4) and nuclear receptor coactivator 4 (NCOA4) but not glutathione peroxidase 4 (GPX4) in rats with mature T2DM and cells with HFHG and H/R injury. Nobiletin strengthened the effect of si-ACSL4 on inhibiting ACSL4 expression, and also inhibited the effect of Erastin or oe-ACSL4 on increasing ACSL4 expression. Taken together, our data indicates that ferroptosis involves in susceptibility to myocardial IR injury in rats during T2DM. Nobiletin has therapeutic potential for alleviating myocardial IR injury associated with ACSL4- and NCOA4-related ferroptosis.
[Display omitted]
•The mature but not onset of T2DM in rats have a higher susceptibility to myocardial IR injury, relating to ferroptosis.•Not all of ferroptosis-related proteins participates in myocardial IR injury in diabetic rats.•ACSL4- and NCOA4-related ferroptosis involves in the susceptibility to myocardial IR during T2DM in rats.•Nobiletin mitigates myocardial IR injuryin diabetic rats via inhibiting ACSL4- and NCOA4-related ferroptosis.</abstract><cop>France</cop><pub>Elsevier Masson SAS</pub><pmid>37146415</pmid><doi>10.1016/j.biopha.2023.114795</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Diabetes Mellitus, Type 2 - complications Diabetes Mellitus, Type 2 - drug therapy Ferroptosis Flavones - pharmacology Flavones - therapeutic use Myocardial Ischemia - drug therapy Myocardial ischemia-reperfusion injury Myocardial Reperfusion Injury - drug therapy Myocardial Reperfusion Injury - metabolism Nobiletin Rats Reperfusion Injury - metabolism Susceptibility Type-2 diabetes |
| title | Nobiletin alleviates myocardial ischemia-reperfusion injury via ferroptosis in rats with type-2 diabetes mellitus |
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