PMID- 36096356 OWN - NLM STAT- MEDLINE DCOM- 20221018 LR - 20221026 IS - 1873-4596 (Electronic) IS - 0891-5849 (Linking) VI - 192 DP - 2022 Nov 1 TI - Exosomes derived from human umbilical cord mesenchymal stem cells ameliorate experimental non-alcoholic steatohepatitis via Nrf2/NQO-1 pathway. PG - 25-36 LID - S0891-5849(22)00565-2 [pii] LID - 10.1016/j.freeradbiomed.2022.08.037 [doi] AB - BACKGROUND: No approved effective therapy for non-alcoholic steatohepatitis (NASH) is currently available. Exosomes derived from mesenchymal stem cells (MSCs) perform the functions such as inhibiting inflammation, anti-oxidative stress, regulating immunity, but it is not clear whether human umbilical cord mesenchymal stem cells (hUC-MSCs) exosomes protect against NASH through Nrf2/NQO-1 pathway. Therefore, this study was conducted to investigate the effects of hUC-MSCs exosomes on NASH through Nrf2/NQO-1 pathway in vivo and in vitro. METHODS: C57BL/6J male mice were fed with high fat and high cholesterol diet (HFHC) and methionine choline deficiency diet (MCD). Mice were treated with or without hUC-MSCs exosomes by tail intravenous injection. The liver histology, lipid metabolism and oxidative stress were evaluated. HepG2 and AML12 cells were incubated with palmitic acid (PA) and MCD conditioned medium, respectively. Then the therapeutic effect of hUC-MSCs exosomes in steatotic cells was evaluated. To elucidate the signaling pathways, the Nrf2-specific blocker ML385 was applied to intervene in vitro. RESULTS: In NASH models, hUC-MSCs exosomes attenuated steatosis in hepatocytes, altered the abnormal expression of lipid-related genes including SREBP-1c, PPAR-alpha, Fabp5, CPT1alpha, ACOX and FAS, suppressed the hepatic inflammatory responses by decreasing the expression of F4/80(+) macrophages, CD11c(+) macrophages as well as the content of TNF-alpha and IL-6. hUC-MSCs exosomes also inhibited oxidative stress by reducing the level of MDA, CYP2E1 and ROS, increasing the activity of SOD and GSH in hepatocytes. Notably, hUC-MSCs exosomes enhanced the protein ratio of p-Nrf2/Nrf2 and the protein expression of NQO-1. Moreover, in vitro, the therapeutic effects of hUC-MSCs exosomes on lipid deposition and ROS were reversed by ML385. Also, ML385 reduced the protein expression of p-Nrf2 and NQO-1 in vitro. CONCLUSION: Nrf2/NQO-1 antioxidant signaling pathway may play a key role in the treatment of NASH by hUC-MSCs exosomes. CI - Copyright (c) 2022 Elsevier Inc. All rights reserved. FAU - Kang, Yaxing AU - Kang Y AD - Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China; Department of Endocrinology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China. FAU - Song, Yiran AU - Song Y AD - Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China. FAU - Luo, Yuxin AU - Luo Y AD - Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China. FAU - Song, Jia AU - Song J AD - Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China. FAU - Li, Chenyang AU - Li C AD - Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China. FAU - Yang, Shuangshuang AU - Yang S AD - Shandong Qilu Cell Therapy Engineering Technology Co., Ltd, Jinan, Shandong, China. FAU - Guo, Jinbo AU - Guo J AD - Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China. FAU - Yu, Jun AU - Yu J AD - Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China. Electronic address: yujun86@hotmail.com. FAU - Zhang, Xiaolan AU - Zhang X AD - Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China. Electronic address: xiaolanzh@126.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20220910 PL - United States TA - Free Radic Biol Med JT - Free radical biology & medicine JID - 8709159 RN - 0 (Antioxidants) RN - 0 (Culture Media, Conditioned) RN - 0 (FABP5 protein, human) RN - 0 (Fatty Acid-Binding Proteins) RN - 0 (Interleukin-6) RN - 0 (NF-E2-Related Factor 2) RN - 0 (Peroxisome Proliferator-Activated Receptors) RN - 0 (Reactive Oxygen Species) RN - 0 (Sterol Regulatory Element Binding Protein 1) RN - 0 (Tumor Necrosis Factor-alpha) RN - 2V16EO95H1 (Palmitic Acid) RN - 97C5T2UQ7J (Cholesterol) RN - AE28F7PNPL (Methionine) RN - EC 1.14.13.- (Cytochrome P-450 CYP2E1) RN - EC 1.15.1.1 (Superoxide Dismutase) RN - EC 1.6.5.2 (NAD(P)H Dehydrogenase (Quinone)) RN - EC 1.6.5.2 (NQO1 protein, human) SB - IM MH - Animals MH - Antioxidants/metabolism MH - Cholesterol/metabolism MH - Culture Media, Conditioned MH - Cytochrome P-450 CYP2E1/metabolism MH - *Exosomes/metabolism MH - Fatty Acid-Binding Proteins/metabolism MH - Humans MH - Interleukin-6/metabolism MH - Male MH - *Mesenchymal Stem Cells/metabolism MH - Methionine/metabolism MH - Mice MH - Mice, Inbred C57BL MH - *NAD(P)H Dehydrogenase (Quinone)/genetics/metabolism MH - *NF-E2-Related Factor 2/genetics/metabolism MH - *Non-alcoholic Fatty Liver Disease/metabolism MH - Palmitic Acid MH - Peroxisome Proliferator-Activated Receptors/metabolism MH - Reactive Oxygen Species/metabolism MH - Sterol Regulatory Element Binding Protein 1/metabolism MH - Superoxide Dismutase/metabolism MH - Tumor Necrosis Factor-alpha/metabolism MH - Umbilical Cord/cytology OTO - NOTNLM OT - Exosomes OT - Mesenchymal stem cell OT - Non-alcoholic steatohepatitis OT - Nrf2 OT - Oxidative stress COIS- Declaration of competing interest The authors declare that there are no potential competing interests. EDAT- 2022/09/13 06:00 MHDA- 2022/10/19 06:00 CRDT- 2022/09/12 19:26 PHST- 2022/07/04 00:00 [received] PHST- 2022/08/17 00:00 [revised] PHST- 2022/08/29 00:00 [accepted] PHST- 2022/09/13 06:00 [pubmed] PHST- 2022/10/19 06:00 [medline] PHST- 2022/09/12 19:26 [entrez] AID - S0891-5849(22)00565-2 [pii] AID - 10.1016/j.freeradbiomed.2022.08.037 [doi] PST - ppublish SO - Free Radic Biol Med. 2022 Nov 1;192:25-36. doi: 10.1016/j.freeradbiomed.2022.08.037. Epub 2022 Sep 10.