Rutaecarpine alleviates hepatic ischemia‒reperfusion injury in liver transplantation by inhibiting inflammatory response and oxidative stress
BackgroundDonation after circulatory death (DCD) livers are limited by mandatory warm ischemia and are more susceptible to ischemia‒reperfusion injury (IRI). Inflammation and oxidative stress play key roles in the development of hepatic IRI, and Rutaecarpine (Rut) has anti-inflammatory and anti-oxid...
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Frontiers Media S.A.
2025-02-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2025.1539744/full |
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| author | Yan Liu Yan Liu Feng Qi Lun-Jian Xiang Zhu-Jun Yi Sheng-Wei Li |
| author_facet | Yan Liu Yan Liu Feng Qi Lun-Jian Xiang Zhu-Jun Yi Sheng-Wei Li |
| author_sort | Yan Liu |
| collection | DOAJ |
| description | BackgroundDonation after circulatory death (DCD) livers are limited by mandatory warm ischemia and are more susceptible to ischemia‒reperfusion injury (IRI). Inflammation and oxidative stress play key roles in the development of hepatic IRI, and Rutaecarpine (Rut) has anti-inflammatory and anti-oxidative stress effects. The aim of this study was to investigate whether Rut can alleviate hepatic IRI in liver transplantation (LT) and to explore the underlying mechanisms.MethodsRat DCD LT and oxygen-glucose deprivation/reoxygenation (OGD/R) cell models were established to clarify the effect of Rut on hepatic IRI. The key molecules involved in the hepatoprotective effects of Rut were identified through joint analysis of data from LT patients and drug targets. The target was further validated by in silico, in vivo and in vitro experiments.ResultsRut significantly alleviated liver dysfunction, pathological injury, and apoptosis and improved the survival rate of the rats subjected to LT. In addition, Rut significantly inhibited inflammatory response and oxidative stress. Rut also had similar effects on OGD/R-induced hepatocyte injury. Mechanistically, bioinformatics analysis and in vivo and in vitro experiments revealed that PDE4B may be a key target by which Rut exerts its protective effect, and molecular docking and cellular thermal shift assay confirmed this result. The function of PDE4B was studied via gene intervention technology, and the results showed that PDE4B can aggravate hepatic IRI. Furthermore, PDE4B overexpression abrogated the protective effect of Rut on the liver in LT.ConclusionRut alleviates hepatic IRI by targeting PDE4B to inhibit inflammation and oxidative stress. These findings highlight the potential of Rut as a drug candidate for the treatment of patients undergoing LT. |
| format | Article |
| id | doaj-art-7cde0b5be84f47709fd09207717c6691 |
| institution | Kabale University |
| issn | 1663-9812 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Pharmacology |
| spelling | doaj-art-7cde0b5be84f47709fd09207717c66912025-02-03T05:12:04ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122025-02-011610.3389/fphar.2025.15397441539744Rutaecarpine alleviates hepatic ischemia‒reperfusion injury in liver transplantation by inhibiting inflammatory response and oxidative stressYan Liu0Yan Liu1Feng Qi2Lun-Jian Xiang3Zhu-Jun Yi4Sheng-Wei Li5Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, ChinaDepartment of Hepatobiliary Surgery, Chongqing University Three Gorges Hospital, Chongqing, ChinaDepartment of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, ChinaDepartment of Hepatobiliary Surgery, Chongqing University Three Gorges Hospital, Chongqing, ChinaDepartment of Hepatobiliary Surgery, Chongqing University Three Gorges Hospital, Chongqing, ChinaDepartment of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, ChinaBackgroundDonation after circulatory death (DCD) livers are limited by mandatory warm ischemia and are more susceptible to ischemia‒reperfusion injury (IRI). Inflammation and oxidative stress play key roles in the development of hepatic IRI, and Rutaecarpine (Rut) has anti-inflammatory and anti-oxidative stress effects. The aim of this study was to investigate whether Rut can alleviate hepatic IRI in liver transplantation (LT) and to explore the underlying mechanisms.MethodsRat DCD LT and oxygen-glucose deprivation/reoxygenation (OGD/R) cell models were established to clarify the effect of Rut on hepatic IRI. The key molecules involved in the hepatoprotective effects of Rut were identified through joint analysis of data from LT patients and drug targets. The target was further validated by in silico, in vivo and in vitro experiments.ResultsRut significantly alleviated liver dysfunction, pathological injury, and apoptosis and improved the survival rate of the rats subjected to LT. In addition, Rut significantly inhibited inflammatory response and oxidative stress. Rut also had similar effects on OGD/R-induced hepatocyte injury. Mechanistically, bioinformatics analysis and in vivo and in vitro experiments revealed that PDE4B may be a key target by which Rut exerts its protective effect, and molecular docking and cellular thermal shift assay confirmed this result. The function of PDE4B was studied via gene intervention technology, and the results showed that PDE4B can aggravate hepatic IRI. Furthermore, PDE4B overexpression abrogated the protective effect of Rut on the liver in LT.ConclusionRut alleviates hepatic IRI by targeting PDE4B to inhibit inflammation and oxidative stress. These findings highlight the potential of Rut as a drug candidate for the treatment of patients undergoing LT.https://www.frontiersin.org/articles/10.3389/fphar.2025.1539744/fulldonation after circulatory deathliver transplantationrutaecarpineoxidative stressinflammatory response |
| spellingShingle | Yan Liu Yan Liu Feng Qi Lun-Jian Xiang Zhu-Jun Yi Sheng-Wei Li Rutaecarpine alleviates hepatic ischemia‒reperfusion injury in liver transplantation by inhibiting inflammatory response and oxidative stress Frontiers in Pharmacology donation after circulatory death liver transplantation rutaecarpine oxidative stress inflammatory response |
| title | Rutaecarpine alleviates hepatic ischemia‒reperfusion injury in liver transplantation by inhibiting inflammatory response and oxidative stress |
| title_full | Rutaecarpine alleviates hepatic ischemia‒reperfusion injury in liver transplantation by inhibiting inflammatory response and oxidative stress |
| title_fullStr | Rutaecarpine alleviates hepatic ischemia‒reperfusion injury in liver transplantation by inhibiting inflammatory response and oxidative stress |
| title_full_unstemmed | Rutaecarpine alleviates hepatic ischemia‒reperfusion injury in liver transplantation by inhibiting inflammatory response and oxidative stress |
| title_short | Rutaecarpine alleviates hepatic ischemia‒reperfusion injury in liver transplantation by inhibiting inflammatory response and oxidative stress |
| title_sort | rutaecarpine alleviates hepatic ischemia reperfusion injury in liver transplantation by inhibiting inflammatory response and oxidative stress |
| topic | donation after circulatory death liver transplantation rutaecarpine oxidative stress inflammatory response |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2025.1539744/full |
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