Dexmedetomidine protects against N-Nitrosodiethylamine induced acute hepatic damage by modulating autophagy and apoptosis through SIRT1
Abstract Purpose Dexmedetomidine (DEX) has been extensively studied for its protective effects on multiple organs, primarily attributed to its anti-inflammatory and anti-apoptotic properties. However, the molecular mechanisms underlying its effects in acute hepatic damage induced by N-Nitrosodiethyl...
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Springer
2025-07-01
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| Series: | Anesthesiology and Perioperative Science |
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| Online Access: | https://doi.org/10.1007/s44254-025-00113-6 |
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| author | Ruixin Wu Sailan Tang Aoxue Xu Qi Xue Shuwen He Qizhi Liao Chanjuan Chen Dachen Zhou Xianwen Hu Nianliang Zhang Gang Li Ye Zhang Chunxia Huang |
| author_facet | Ruixin Wu Sailan Tang Aoxue Xu Qi Xue Shuwen He Qizhi Liao Chanjuan Chen Dachen Zhou Xianwen Hu Nianliang Zhang Gang Li Ye Zhang Chunxia Huang |
| author_sort | Ruixin Wu |
| collection | DOAJ |
| description | Abstract Purpose Dexmedetomidine (DEX) has been extensively studied for its protective effects on multiple organs, primarily attributed to its anti-inflammatory and anti-apoptotic properties. However, the molecular mechanisms underlying its effects in acute hepatic damage induced by N-Nitrosodiethylamine (DEN) remain unclear. This study aims to investigate the role of DEX in mitigating DEN-induced acute hepatic damage and elucidate the involvement of the silent information regulator 1 (SIRT1)-autophagy axis in this process. Methods Acute hepatic damage was induced by a single intraperitoneal injection of 1% DEN (10 mg/kg). DEX (20, 40, or 80 μg/kg) was administered intraperitoneally 30 min prior to DEN exposure. Additionally, the SIRT1 inhibitor Selisistat (EX527) or the autophagy inhibitor 3-MA was administered intraperitoneally 30 min after DEN injection. Histopathological changes, inflammatory and oxidative responses were assessed 24 h post-DEN exposure. The roles of autophagy and SIRT1 were further examined using hepatocyte-specific SIRT1 knockout mice (SIRT1f/fALBcre+/−). Results A single injection of DEN significantly induced acute hepatic damage, characterized by marked elevations in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), hepatocyte necrosis, inflammatory cell infiltration, and increased oxidative stress burden. Dexmedetomidine pretreatment effectively attenuated hepatic damage, as evidenced by significant reductions in ALT, AST, and reactive oxygen species (ROS) accumulation. The expressions of LC3B and SIRT1 were upregulated following DEX pretreatment, with increased co-localization between the two proteins. However, the hepatoprotective effects of DEX were abolished when SIRT1 was inhibited by EX527 or genetically deleted in in SIRT1f/fALBcr e +/ – mice. Conclusions Dexmedetomidine significantly alleviates DEN-induced acute hepatic damage through a mechanism involving the upregulation of autophagy and SIRT1 activity. These findings suggest that DEX may be a promising therapeutic strategy for treating severe hepatic damage and other forms of acute organ injury. |
| format | Article |
| id | doaj-art-38db84303ea444959cdf24f668f1b312 |
| institution | Kabale University |
| issn | 2731-8389 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Springer |
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| series | Anesthesiology and Perioperative Science |
| spelling | doaj-art-38db84303ea444959cdf24f668f1b3122025-08-20T04:01:47ZengSpringerAnesthesiology and Perioperative Science2731-83892025-07-013311710.1007/s44254-025-00113-6Dexmedetomidine protects against N-Nitrosodiethylamine induced acute hepatic damage by modulating autophagy and apoptosis through SIRT1Ruixin Wu0Sailan Tang1Aoxue Xu2Qi Xue3Shuwen He4Qizhi Liao5Chanjuan Chen6Dachen Zhou7Xianwen Hu8Nianliang Zhang9Gang Li10Ye Zhang11Chunxia Huang12Department of Anesthesiology and Perioperative Medicine, the Second Affiliated Hospital of Anhui Medical UniversityDepartment of Anesthesiology and Perioperative Medicine, the Second Affiliated Hospital of Anhui Medical UniversityDepartment of Anesthesiology and Perioperative Medicine, the Second Affiliated Hospital of Anhui Medical UniversityDepartment of Anesthesiology and Perioperative Medicine, the Second Affiliated Hospital of Anhui Medical UniversityDepartment of Anesthesiology and Perioperative Medicine, the Second Affiliated Hospital of Anhui Medical UniversityDepartment of Anesthesiology and Perioperative Medicine, the Second Affiliated Hospital of Anhui Medical UniversityDepartment of Oncology, the Second Affiliated Hospital of Anhui Medical UniversityDepartment of Oncology, the Second Affiliated Hospital of Anhui Medical UniversityDepartment of Anesthesiology and Perioperative Medicine, the Second Affiliated Hospital of Anhui Medical UniversityDepartment of Anesthesiology and Perioperative Medicine, People’s Hospital of RizhaoDepartment of Anesthesiology and Perioperative Medicine, People’s Hospital of RizhaoDepartment of Anesthesiology and Perioperative Medicine, the Second Affiliated Hospital of Anhui Medical UniversityDepartment of Anesthesiology and Perioperative Medicine, the Second Affiliated Hospital of Anhui Medical UniversityAbstract Purpose Dexmedetomidine (DEX) has been extensively studied for its protective effects on multiple organs, primarily attributed to its anti-inflammatory and anti-apoptotic properties. However, the molecular mechanisms underlying its effects in acute hepatic damage induced by N-Nitrosodiethylamine (DEN) remain unclear. This study aims to investigate the role of DEX in mitigating DEN-induced acute hepatic damage and elucidate the involvement of the silent information regulator 1 (SIRT1)-autophagy axis in this process. Methods Acute hepatic damage was induced by a single intraperitoneal injection of 1% DEN (10 mg/kg). DEX (20, 40, or 80 μg/kg) was administered intraperitoneally 30 min prior to DEN exposure. Additionally, the SIRT1 inhibitor Selisistat (EX527) or the autophagy inhibitor 3-MA was administered intraperitoneally 30 min after DEN injection. Histopathological changes, inflammatory and oxidative responses were assessed 24 h post-DEN exposure. The roles of autophagy and SIRT1 were further examined using hepatocyte-specific SIRT1 knockout mice (SIRT1f/fALBcre+/−). Results A single injection of DEN significantly induced acute hepatic damage, characterized by marked elevations in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), hepatocyte necrosis, inflammatory cell infiltration, and increased oxidative stress burden. Dexmedetomidine pretreatment effectively attenuated hepatic damage, as evidenced by significant reductions in ALT, AST, and reactive oxygen species (ROS) accumulation. The expressions of LC3B and SIRT1 were upregulated following DEX pretreatment, with increased co-localization between the two proteins. However, the hepatoprotective effects of DEX were abolished when SIRT1 was inhibited by EX527 or genetically deleted in in SIRT1f/fALBcr e +/ – mice. Conclusions Dexmedetomidine significantly alleviates DEN-induced acute hepatic damage through a mechanism involving the upregulation of autophagy and SIRT1 activity. These findings suggest that DEX may be a promising therapeutic strategy for treating severe hepatic damage and other forms of acute organ injury.https://doi.org/10.1007/s44254-025-00113-6DexmedetomidineAcute hepatic damageSIRT1Autophagy |
| spellingShingle | Ruixin Wu Sailan Tang Aoxue Xu Qi Xue Shuwen He Qizhi Liao Chanjuan Chen Dachen Zhou Xianwen Hu Nianliang Zhang Gang Li Ye Zhang Chunxia Huang Dexmedetomidine protects against N-Nitrosodiethylamine induced acute hepatic damage by modulating autophagy and apoptosis through SIRT1 Anesthesiology and Perioperative Science Dexmedetomidine Acute hepatic damage SIRT1 Autophagy |
| title | Dexmedetomidine protects against N-Nitrosodiethylamine induced acute hepatic damage by modulating autophagy and apoptosis through SIRT1 |
| title_full | Dexmedetomidine protects against N-Nitrosodiethylamine induced acute hepatic damage by modulating autophagy and apoptosis through SIRT1 |
| title_fullStr | Dexmedetomidine protects against N-Nitrosodiethylamine induced acute hepatic damage by modulating autophagy and apoptosis through SIRT1 |
| title_full_unstemmed | Dexmedetomidine protects against N-Nitrosodiethylamine induced acute hepatic damage by modulating autophagy and apoptosis through SIRT1 |
| title_short | Dexmedetomidine protects against N-Nitrosodiethylamine induced acute hepatic damage by modulating autophagy and apoptosis through SIRT1 |
| title_sort | dexmedetomidine protects against n nitrosodiethylamine induced acute hepatic damage by modulating autophagy and apoptosis through sirt1 |
| topic | Dexmedetomidine Acute hepatic damage SIRT1 Autophagy |
| url | https://doi.org/10.1007/s44254-025-00113-6 |
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