Toxicological Research

Korean Society of Toxicology & Korea Environmental Mutagen Society (한국독성학회)
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Phloretin targets SIRT1 to alleviate oxidative stress, apoptosis, and inflammation in deep venous thrombosis

  • Xiaodong Wang (Department of Vascular Surgery, Zhejiang Academy of Traditional Chinese Medicine) ;
  • Jin Yan (Department of Vascular Surgery, Zhejiang Academy of Traditional Chinese Medicine) ;
  • Xiaolong Ni (Department of Vascular Surgery, Zhejiang Academy of Traditional Chinese Medicine) ;
  • Sipin Hu (Department of Vascular Surgery, Zhejiang Academy of Traditional Chinese Medicine) ;
  • Mingwan Zhang (Department of Pharmacy, Zhejiang Academy of Traditional Chinese Medicine) ;
  • Yin Ying (Department of Pharmacy, Zhejiang Academy of Traditional Chinese Medicine)
  • Received : 2023.02.28
  • Accepted : 2023.08.14
  • Published : 2024.01.15
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Abstract

Deep vein thrombosis (DVT) is a type of venous thromboembolism posing a serious threat to health on a global scale. Phloretin is a potential natural product that has a variety of pharmacological activities. Besides, some Chinese medicines reported that deacetylase sirtuin (SIRT)1 treats DVT by anti-inflammatory and anti-platelet production. However, the specific binding targets and binding modes have not been elaborated. The present study was to investigate whether phloretin attenuates DVT in model rats and oxidized low-density lipoprotein (ox-LDL) induced human umbilical vein endothelial cells (HUVECs), and to explore its potential target. The results revealed that the treatment of phloretin, especially pretreatment of it elevated tissue plasminogen activator (t-PA), superoxide dismutase (SOD), prothrombin time (PT), thrombin time (TT), activated partial thromboplastin time (APTT), and cell apoptosis proteins whereas it suppressed plasminogen activator inhibitor (PAI), malondialdehyde (MDA), reactive oxygen species (ROS), fibrinogen (FIB) in DVT rats and cells. Concurrently, phloretin inhibited collagen type I alpha 1 (COL1A1), transforming growth factor-β1 (TGF-β1), and inflammatory factors while it enhanced nuclear factor erythroid 2-related factor 2 (Nrf-2), heme oxygenase 1 (HO-1). In addition, 20 µM phloretin exerted powerful effective protection in HUVECs with DVT model. Later, the surface plasmon resonance (SPR) confirmed that phloretin has a high affinity with SIRT1. Furthermore, siRNA-SIRT1 transfection abolished the protective effect of phloretin against ox-LDL-induced DVT in HUVECs, indicating that phloretin targets SIRT1 to alleviate oxidative stress, cell apoptosis, and inflammation in DVT rats and HUVECs.

Keywords

Acknowledgement

This work was supported by Zhejiang Provincial Natural Science Foundation of China (No. LGF21H020002), Chinese Medical and Health Research Project of Zhejiang Province (2021ZA038) and Chinese Medical and Health Research Project of Zhejiang Province (2022ZA039).

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