Naoxintong capsule accelerates mitophagy in cerebral ischemia-reperfusion injury via TP53/PINK1/PRKN pathway based on network pharmacology analysis and experimental validation
The incidence and mortality of cerebrovascular diseases are increasing year by year. Cerebral ischemia-reperfusion injury (CIRI) is common in patients with ischemic stroke. Naoxintong (NXT) is composed of a variety of Chinese medicines and has the ability to treat CIRI. The aim of this study is to i...
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| Veröffentlicht in: | Journal of ethnopharmacology 2025-01, Vol.336, p.118721, Article 118721 |
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| creator | Shang, Jinfeng Wen, Yinlian Zhang, Xiaolu Huang, Guijinfeng Chen, Wenbin Wang, Bohong Wu, Kai Xiang, Quan Liu, Xin |
| description | The incidence and mortality of cerebrovascular diseases are increasing year by year. Cerebral ischemia-reperfusion injury (CIRI) is common in patients with ischemic stroke. Naoxintong (NXT) is composed of a variety of Chinese medicines and has the ability to treat CIRI.
The aim of this study is to investigate whether NXT regulates mitophagy in CIRI based on network pharmacology analysis and experimental validation.
Oxygen and glucose deprivation/re-oxygenation (OGD/R, 2/22 h) model of PC12 cells and transient middle cerebral artery occlusion (tMCAO, 2/22 h) model of rats were established. Pharmacodynamic indicators include neurological deficit score, 2,3,5-triphenyte-trazoliumchloride (TTC) staining, hematoxylin-eosin (HE) staining and cell viability. Network pharmacology was used to predict pharmacological mechanisms. Pharmacological mechanism indexes include transmission electron microscopy (TEM), drug affinity responsive target stability (DARTS), cellular thermal shift assay (CETSA), immunohistochemistry (IHC), western blot (WB) and immunofluorescence (IF). Kevetrin (an agonists of p53) and pifithrin-α (an inhibitor of p53) used to detect the key role of p53 in mitophagy of NXT.
NXT (1% serum containing NXT and 110 mg/kg) improved the damage of OGD/R PC12 cells and tMCAO rats, and this protective effect was related to the anti-oxidation and ability to promote mitophagy of NXT. NXT and pifithrin-α increased the expression of promoting-mitophagy targets (PINK1, PRKN and LC3B) and inhibited the expression of inhibiting-mitophagy targets (p52) via restraining p53, and finally accelerated mitophagy caused by CIRI.
This study demonstrates that NXT promotes mitophagy in CIRI through restraining p53 and promoting PINK1/PRKN in vivo and in vitro.
[Display omitted]
•Regulating autophagy and mitophagy is a method to alleviate CIRI.•NXT alleviated damage caused by CIRI in vivo and in vitro.•NXT accelerates mitophagy in CIRI via TP53/PINK1/PRKN pathway. |
| doi_str_mv | 10.1016/j.jep.2024.118721 |
| format | Article |
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The aim of this study is to investigate whether NXT regulates mitophagy in CIRI based on network pharmacology analysis and experimental validation.
Oxygen and glucose deprivation/re-oxygenation (OGD/R, 2/22 h) model of PC12 cells and transient middle cerebral artery occlusion (tMCAO, 2/22 h) model of rats were established. Pharmacodynamic indicators include neurological deficit score, 2,3,5-triphenyte-trazoliumchloride (TTC) staining, hematoxylin-eosin (HE) staining and cell viability. Network pharmacology was used to predict pharmacological mechanisms. Pharmacological mechanism indexes include transmission electron microscopy (TEM), drug affinity responsive target stability (DARTS), cellular thermal shift assay (CETSA), immunohistochemistry (IHC), western blot (WB) and immunofluorescence (IF). Kevetrin (an agonists of p53) and pifithrin-α (an inhibitor of p53) used to detect the key role of p53 in mitophagy of NXT.
NXT (1% serum containing NXT and 110 mg/kg) improved the damage of OGD/R PC12 cells and tMCAO rats, and this protective effect was related to the anti-oxidation and ability to promote mitophagy of NXT. NXT and pifithrin-α increased the expression of promoting-mitophagy targets (PINK1, PRKN and LC3B) and inhibited the expression of inhibiting-mitophagy targets (p52) via restraining p53, and finally accelerated mitophagy caused by CIRI.
This study demonstrates that NXT promotes mitophagy in CIRI through restraining p53 and promoting PINK1/PRKN in vivo and in vitro.
[Display omitted]
•Regulating autophagy and mitophagy is a method to alleviate CIRI.•NXT alleviated damage caused by CIRI in vivo and in vitro.•NXT accelerates mitophagy in CIRI via TP53/PINK1/PRKN pathway.</description><identifier>ISSN: 0378-8741</identifier><identifier>ISSN: 1872-7573</identifier><identifier>EISSN: 1872-7573</identifier><identifier>DOI: 10.1016/j.jep.2024.118721</identifier><identifier>PMID: 39173723</identifier><language>eng</language><publisher>Ireland: Elsevier B.V</publisher><subject>Animals ; Brain Ischemia - drug therapy ; Cerebral ischemia-reperfusion injury ; Drugs, Chinese Herbal - pharmacology ; Infarction, Middle Cerebral Artery - drug therapy ; Infarction, Middle Cerebral Artery - pathology ; Male ; Mitophagy ; Mitophagy - drug effects ; Naoxintong capsule ; Network Pharmacology ; Neuroprotective Agents - pharmacology ; PC12 Cells ; Protein Kinases - metabolism ; Rats ; Rats, Sprague-Dawley ; Reperfusion Injury - drug therapy ; Reperfusion Injury - metabolism ; Signal Transduction - drug effects ; TP53/PINK1/PRKN pathway ; Tumor Suppressor Protein p53 - metabolism ; Ubiquitin-Protein Ligases</subject><ispartof>Journal of ethnopharmacology, 2025-01, Vol.336, p.118721, Article 118721</ispartof><rights>2024 Elsevier B.V.</rights><rights>Copyright © 2024 Elsevier B.V. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c235t-ec55cac1be485d5a689f13a6edf4303ab2b96af210124cde12e3993777ffd8c3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.jep.2024.118721$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,778,782,3539,27907,27908,45978</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39173723$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Shang, Jinfeng</creatorcontrib><creatorcontrib>Wen, Yinlian</creatorcontrib><creatorcontrib>Zhang, Xiaolu</creatorcontrib><creatorcontrib>Huang, Guijinfeng</creatorcontrib><creatorcontrib>Chen, Wenbin</creatorcontrib><creatorcontrib>Wang, Bohong</creatorcontrib><creatorcontrib>Wu, Kai</creatorcontrib><creatorcontrib>Xiang, Quan</creatorcontrib><creatorcontrib>Liu, Xin</creatorcontrib><title>Naoxintong capsule accelerates mitophagy in cerebral ischemia-reperfusion injury via TP53/PINK1/PRKN pathway based on network pharmacology analysis and experimental validation</title><title>Journal of ethnopharmacology</title><addtitle>J Ethnopharmacol</addtitle><description>The incidence and mortality of cerebrovascular diseases are increasing year by year. Cerebral ischemia-reperfusion injury (CIRI) is common in patients with ischemic stroke. Naoxintong (NXT) is composed of a variety of Chinese medicines and has the ability to treat CIRI.
The aim of this study is to investigate whether NXT regulates mitophagy in CIRI based on network pharmacology analysis and experimental validation.
Oxygen and glucose deprivation/re-oxygenation (OGD/R, 2/22 h) model of PC12 cells and transient middle cerebral artery occlusion (tMCAO, 2/22 h) model of rats were established. Pharmacodynamic indicators include neurological deficit score, 2,3,5-triphenyte-trazoliumchloride (TTC) staining, hematoxylin-eosin (HE) staining and cell viability. Network pharmacology was used to predict pharmacological mechanisms. Pharmacological mechanism indexes include transmission electron microscopy (TEM), drug affinity responsive target stability (DARTS), cellular thermal shift assay (CETSA), immunohistochemistry (IHC), western blot (WB) and immunofluorescence (IF). Kevetrin (an agonists of p53) and pifithrin-α (an inhibitor of p53) used to detect the key role of p53 in mitophagy of NXT.
NXT (1% serum containing NXT and 110 mg/kg) improved the damage of OGD/R PC12 cells and tMCAO rats, and this protective effect was related to the anti-oxidation and ability to promote mitophagy of NXT. NXT and pifithrin-α increased the expression of promoting-mitophagy targets (PINK1, PRKN and LC3B) and inhibited the expression of inhibiting-mitophagy targets (p52) via restraining p53, and finally accelerated mitophagy caused by CIRI.
This study demonstrates that NXT promotes mitophagy in CIRI through restraining p53 and promoting PINK1/PRKN in vivo and in vitro.
[Display omitted]
•Regulating autophagy and mitophagy is a method to alleviate CIRI.•NXT alleviated damage caused by CIRI in vivo and in vitro.•NXT accelerates mitophagy in CIRI via TP53/PINK1/PRKN pathway.</description><subject>Animals</subject><subject>Brain Ischemia - drug therapy</subject><subject>Cerebral ischemia-reperfusion injury</subject><subject>Drugs, Chinese Herbal - pharmacology</subject><subject>Infarction, Middle Cerebral Artery - drug therapy</subject><subject>Infarction, Middle Cerebral Artery - pathology</subject><subject>Male</subject><subject>Mitophagy</subject><subject>Mitophagy - drug effects</subject><subject>Naoxintong capsule</subject><subject>Network Pharmacology</subject><subject>Neuroprotective Agents - pharmacology</subject><subject>PC12 Cells</subject><subject>Protein Kinases - metabolism</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Reperfusion Injury - drug therapy</subject><subject>Reperfusion Injury - metabolism</subject><subject>Signal Transduction - drug effects</subject><subject>TP53/PINK1/PRKN pathway</subject><subject>Tumor Suppressor Protein p53 - metabolism</subject><subject>Ubiquitin-Protein Ligases</subject><issn>0378-8741</issn><issn>1872-7573</issn><issn>1872-7573</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2025</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kcFu1DAQhi0EotvCA3BBPnLJrh0ncSJOqCq0arWs0N6tiT3pOiRxsJNt81S8Il5t4chp5vDN_8_MT8gHztac8WLTrlsc1ylLszXnpUz5K7I61UTmUrwmKyZkmZQy4xfkMoSWMSZ5xt6SC1FxKWQqVuT3FtyzHSY3PFINY5g7pKA1duhhwkB7O7nxAI8LtQPV6LH20FEb9AF7C4nHEX0zB-uGCLSzX-jRAt3vcrHZ3W3v-Wb3435LR5gOT7DQGgIaGtkBpyfnf9Io7XvQrnPRAQbolmBDbAzF56hsexym6HeEzhqYoss78qaBLuD7l3pF9l9v9te3ycP3b3fXXx4SnYp8SlDnuQbNa8zK3ORQlFXDBRRomkwwAXVaVwU0aXxjmmmDPEVRVUJK2TSm1OKKfDrLjt79mjFMqo83Y9fBgG4OSrCqSGVZljKi_Ixq70Lw2Kgx7g1-UZypU0yqVTEmdYpJnWOKMx9f5Oe6R_Nv4m8uEfh8BjDeeLToVdAWB43GetSTMs7-R_4PTcmneg</recordid><startdate>20250110</startdate><enddate>20250110</enddate><creator>Shang, Jinfeng</creator><creator>Wen, Yinlian</creator><creator>Zhang, Xiaolu</creator><creator>Huang, Guijinfeng</creator><creator>Chen, Wenbin</creator><creator>Wang, Bohong</creator><creator>Wu, Kai</creator><creator>Xiang, Quan</creator><creator>Liu, Xin</creator><general>Elsevier B.V</general><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>20250110</creationdate><title>Naoxintong capsule accelerates mitophagy in cerebral ischemia-reperfusion injury via TP53/PINK1/PRKN pathway based on network pharmacology analysis and experimental validation</title><author>Shang, Jinfeng ; Wen, Yinlian ; Zhang, Xiaolu ; Huang, Guijinfeng ; Chen, Wenbin ; Wang, Bohong ; Wu, Kai ; Xiang, Quan ; Liu, Xin</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c235t-ec55cac1be485d5a689f13a6edf4303ab2b96af210124cde12e3993777ffd8c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2025</creationdate><topic>Animals</topic><topic>Brain Ischemia - drug therapy</topic><topic>Cerebral ischemia-reperfusion injury</topic><topic>Drugs, Chinese Herbal - pharmacology</topic><topic>Infarction, Middle Cerebral Artery - drug therapy</topic><topic>Infarction, Middle Cerebral Artery - pathology</topic><topic>Male</topic><topic>Mitophagy</topic><topic>Mitophagy - drug effects</topic><topic>Naoxintong capsule</topic><topic>Network Pharmacology</topic><topic>Neuroprotective Agents - pharmacology</topic><topic>PC12 Cells</topic><topic>Protein Kinases - metabolism</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Reperfusion Injury - drug therapy</topic><topic>Reperfusion Injury - metabolism</topic><topic>Signal Transduction - drug effects</topic><topic>TP53/PINK1/PRKN pathway</topic><topic>Tumor Suppressor Protein p53 - metabolism</topic><topic>Ubiquitin-Protein Ligases</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Shang, Jinfeng</creatorcontrib><creatorcontrib>Wen, Yinlian</creatorcontrib><creatorcontrib>Zhang, Xiaolu</creatorcontrib><creatorcontrib>Huang, Guijinfeng</creatorcontrib><creatorcontrib>Chen, Wenbin</creatorcontrib><creatorcontrib>Wang, Bohong</creatorcontrib><creatorcontrib>Wu, Kai</creatorcontrib><creatorcontrib>Xiang, Quan</creatorcontrib><creatorcontrib>Liu, Xin</creatorcontrib><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>Journal of ethnopharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Shang, Jinfeng</au><au>Wen, Yinlian</au><au>Zhang, Xiaolu</au><au>Huang, Guijinfeng</au><au>Chen, Wenbin</au><au>Wang, Bohong</au><au>Wu, Kai</au><au>Xiang, Quan</au><au>Liu, Xin</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Naoxintong capsule accelerates mitophagy in cerebral ischemia-reperfusion injury via TP53/PINK1/PRKN pathway based on network pharmacology analysis and experimental validation</atitle><jtitle>Journal of ethnopharmacology</jtitle><addtitle>J Ethnopharmacol</addtitle><date>2025-01-10</date><risdate>2025</risdate><volume>336</volume><spage>118721</spage><pages>118721-</pages><artnum>118721</artnum><issn>0378-8741</issn><issn>1872-7573</issn><eissn>1872-7573</eissn><abstract>The incidence and mortality of cerebrovascular diseases are increasing year by year. Cerebral ischemia-reperfusion injury (CIRI) is common in patients with ischemic stroke. Naoxintong (NXT) is composed of a variety of Chinese medicines and has the ability to treat CIRI.
The aim of this study is to investigate whether NXT regulates mitophagy in CIRI based on network pharmacology analysis and experimental validation.
Oxygen and glucose deprivation/re-oxygenation (OGD/R, 2/22 h) model of PC12 cells and transient middle cerebral artery occlusion (tMCAO, 2/22 h) model of rats were established. Pharmacodynamic indicators include neurological deficit score, 2,3,5-triphenyte-trazoliumchloride (TTC) staining, hematoxylin-eosin (HE) staining and cell viability. Network pharmacology was used to predict pharmacological mechanisms. Pharmacological mechanism indexes include transmission electron microscopy (TEM), drug affinity responsive target stability (DARTS), cellular thermal shift assay (CETSA), immunohistochemistry (IHC), western blot (WB) and immunofluorescence (IF). Kevetrin (an agonists of p53) and pifithrin-α (an inhibitor of p53) used to detect the key role of p53 in mitophagy of NXT.
NXT (1% serum containing NXT and 110 mg/kg) improved the damage of OGD/R PC12 cells and tMCAO rats, and this protective effect was related to the anti-oxidation and ability to promote mitophagy of NXT. NXT and pifithrin-α increased the expression of promoting-mitophagy targets (PINK1, PRKN and LC3B) and inhibited the expression of inhibiting-mitophagy targets (p52) via restraining p53, and finally accelerated mitophagy caused by CIRI.
This study demonstrates that NXT promotes mitophagy in CIRI through restraining p53 and promoting PINK1/PRKN in vivo and in vitro.
[Display omitted]
•Regulating autophagy and mitophagy is a method to alleviate CIRI.•NXT alleviated damage caused by CIRI in vivo and in vitro.•NXT accelerates mitophagy in CIRI via TP53/PINK1/PRKN pathway.</abstract><cop>Ireland</cop><pub>Elsevier B.V</pub><pmid>39173723</pmid><doi>10.1016/j.jep.2024.118721</doi></addata></record> |
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| subjects | Animals Brain Ischemia - drug therapy Cerebral ischemia-reperfusion injury Drugs, Chinese Herbal - pharmacology Infarction, Middle Cerebral Artery - drug therapy Infarction, Middle Cerebral Artery - pathology Male Mitophagy Mitophagy - drug effects Naoxintong capsule Network Pharmacology Neuroprotective Agents - pharmacology PC12 Cells Protein Kinases - metabolism Rats Rats, Sprague-Dawley Reperfusion Injury - drug therapy Reperfusion Injury - metabolism Signal Transduction - drug effects TP53/PINK1/PRKN pathway Tumor Suppressor Protein p53 - metabolism Ubiquitin-Protein Ligases |
| title | Naoxintong capsule accelerates mitophagy in cerebral ischemia-reperfusion injury via TP53/PINK1/PRKN pathway based on network pharmacology analysis and experimental validation |
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