Yichun Ji1, Wenwen Si2, Juan Zeng3, Liqiao Huang4, Zifeng Huang2, Lijun Zhao2, Jiahui Liu5, Meiling Zhu6, Weihong Kuang7. 1. Shenzhen Bao'an Traditional Chinese Medicine Hospital, Guangzhou University of Chinese Medicine, Shenzhen, 518133, China. Electronic address: 20182127172@stu.gzucm.edu.cn. 2. Shenzhou Hospital of Integrated Traditional Chinese and Western Medicine, Guangzhou University of Chinese Medicine, Shenzhen, 518104, China. 3. Department of Gastroenterology, The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China. 4. School of Pharmacy, Guangdong Medical University, Dongguan, 524023, China. 5. Department of Traditional Chinese Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510405, China. 6. Shenzhou Hospital of Integrated Traditional Chinese and Western Medicine, Guangzhou University of Chinese Medicine, Shenzhen, 518104, China. Electronic address: meilingzhubazyy@126.com. 7. School of Pharmacy, Guangdong Medical University, Dongguan, 524023, China. Electronic address: kuangwh@gdmu.edu.cn.
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE: Niujiaodihuang Detoxify Decoction (NDD) is an integrated traditional Chinese medicine prescription that has been used as a therapeutic agent for the treatment of acute liver failure (ALF). However, the mechanisms underlying its action remain unclear. AIM OF THE STUDY: To determine the protective effect of NDD on D-galactosamine/lipopolysaccharide (D-GalN/LPS)-induced ALF and explore the underlying mechanisms. MATERIALS AND METHODS: We characterized the NDD fingerprint by HPLC and established D-GalN/LPS-induced ALF models in Sprague-Dawley rats and LO2 cells. Next, we measured the protective and antiferroptotic effects of NDD in vivo and in vitro. To further investigate the molecular mechanisms underlying the effects of NDD, we performed metabolomic analysis of the liver tissue using LC-MS/MS. RESULTS: Results of serum biochemical analysis, liver histopathology, and cell viability showed that NDD effectively relieved the liver injury. It reduced the accumulation of labile iron and alleviated lipid peroxidation by enhancing GPX4 activity. The mitochondrial morphology indicated that NDD exerted its hepatoprotective effect through an antiferroptotic activity. Metabolomic analysis showed that NDD treatment increased the levels of cysteine, decreased those of glutamate, and ameliorated the D-GalN/LPS-induced reduction in the levels of glutathione (GSH). The results for intracellular levels of reduced (GSH) and oxidized (GSSG) glutathione were consistent with those of metabolomic analysis. CONCLUSION: Our findings indicate that NDD exerts hepatoprotective activity by evoking the reprogramming of GSH metabolism, and thereby, inhibiting ferroptosis.
ETHNOPHARMACOLOGICAL RELEVANCE: Niujiaodihuang Detoxify Decoction (NDD) is an integrated traditional Chinese medicine prescription that has been used as a therapeutic agent for the treatment of acute liver failure (ALF). However, the mechanisms underlying its action remain unclear. AIM OF THE STUDY: To determine the protective effect of NDD on D-galactosamine/lipopolysaccharide (D-GalN/LPS)-induced ALF and explore the underlying mechanisms. MATERIALS AND METHODS: We characterized the NDD fingerprint by HPLC and established D-GalN/LPS-induced ALF models in Sprague-Dawley rats and LO2 cells. Next, we measured the protective and antiferroptotic effects of NDD in vivo and in vitro. To further investigate the molecular mechanisms underlying the effects of NDD, we performed metabolomic analysis of the liver tissue using LC-MS/MS. RESULTS: Results of serum biochemical analysis, liver histopathology, and cell viability showed that NDD effectively relieved the liver injury. It reduced the accumulation of labile iron and alleviated lipid peroxidation by enhancing GPX4 activity. The mitochondrial morphology indicated that NDD exerted its hepatoprotective effect through an antiferroptotic activity. Metabolomic analysis showed that NDD treatment increased the levels of cysteine, decreased those of glutamate, and ameliorated the D-GalN/LPS-induced reduction in the levels of glutathione (GSH). The results for intracellular levels of reduced (GSH) and oxidized (GSSG) glutathione were consistent with those of metabolomic analysis. CONCLUSION: Our findings indicate that NDD exerts hepatoprotective activity by evoking the reprogramming of GSH metabolism, and thereby, inhibiting ferroptosis.
Authors: Adrian S Siregar; Marie Merci Nyiramana; Eun-Jin Kim; Soo Buem Cho; Min Seok Woo; Dong Kun Lee; Seong-Geun Hong; Jaehee Han; Sang Soo Kang; Deok Ryong Kim; Yeung Joon Choi; Dawon Kang Journal: Mar Drugs Date: 2021-10-28 Impact factor: 5.118