PMID- 33113501 OWN - NLM STAT- MEDLINE DCOM- 20210115 LR - 20240226 IS - 1618-095X (Electronic) IS - 0944-7113 (Linking) VI - 80 DP - 2021 Jan TI - Modulation of IR as a therapeutic target to prevent NASH using NRF from Diceratella elliptica (DC.) jonsell. Strong Nrf2 and leptin inducer as well as NF-kB inhibitor. PG - 153388 LID - S0944-7113(20)30218-X [pii] LID - 10.1016/j.phymed.2020.153388 [doi] AB - BACKGROUND: Insulin resistance (IR) and lipotoxicity were evidenced as the major nonalcoholic steatohepatitis (NASH) initiators. However, absence of the effective treatment against NASH progression raised our aim to discover a new promising insulin modulator and NSH preventer. PURPOSE: Our study aimed to extract and prepare a nitriles rich fraction (NRF) from Diceratella elliptica (DC.) Jonsell, investigate its insulin-sensitizing & anti-NASH potentialities and address its molecular targets in IR-NASH pathogenesis. STUDY DESIGN: NRF was prepared using natural autolysis method and compounds were identified. Then, seventy male Wistar rats were feed high fat diet (HFD) or normal pellets for 35 days. In day 14th, HFD rats were injected by Streptozotocin (STZ) once and treatment was started in day 21st with either NRF (30, 60 and 120 mg/kg; orally) or pioglitazone (PioG) (10 mg/kg; i.p) beside HFD. While, NRF-alone rats were treated with NRF (120 mg/kg; orally) beside the normal pellets. Body weight, glucose homeostasis, hepatopathological examinations were performed. METHODS: Gas liquid chromatography-mass spectrophotometry (GLC/MS) was used for compounds' identification while spectrophotometer was used for total glucosinolates (GLS) quantification. Also, the biochemical and molecular investigations concerned with liver lipotoxicity, oxidative stress, inflammation and insulin signaling pathway were investigated and confirmed with the computational prediction of the major compounds' targets. RESULTS: Butenyl and benzyl GLS were the major along with other volatile compounds. NRF had significantly increased the insulin sensitivity and improved NASH-hisptopathology showing hepatoprotective effect. While, the fraction's anti-NASH potentiality was evidenced in the normalized hepatic steatosis markers, inflammation and oxidative stress key transcriptional factors resulting in induction of insulin receptor substrates (IRSs) phosphorylation and its downstream effectors. CONCLUSION: NRF has reversed IR, stimulated leptin secretion and prevented NASH initiation showing promising anti-NASH and anti-fibrotic effects. CI - Copyright (c) 2020 Elsevier GmbH. All rights reserved. FAU - Mohammed, Eman D AU - Mohammed ED AD - Department of Clinical Pharmacology, Nanjing Drum Tower Hospital, Pharmacy Collage of Nanjing Medical University, Nanjing 210000, China; Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210000, China; Natural Products Unit, Medicinal and Aromatic Plants Department, Desert Research Centre, Cairo, Egypt. FAU - Zhang, Zechuan AU - Zhang Z AD - Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210000, China. FAU - Tian, Wenfang AU - Tian W AD - Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210000, China. FAU - Gangarapu, Venkatanarayana AU - Gangarapu V AD - Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210000, China. FAU - Al-Gendy, A A AU - Al-Gendy AA AD - Department of Pharmacognosy, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt. FAU - Chen, Jun AU - Chen J AD - Department of Pathology, Nanjing Drum Tower Hospital of Nanjing University Medical School, Nanjing 210000, China. Electronic address: ichenjun@qq.com. FAU - Wei, Jifu AU - Wei J AD - Research Division of Clinical Pharmacology, The First Affiliated Hospital, Pharmacy College of Nanjing Medical University, Nanjing 210000, China. FAU - Sun, Beicheng AU - Sun B AD - Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210000, China; Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing 210000, China. Electronic address: sunbc@nju.edu.cn. LA - eng PT - Journal Article DEP - 20201016 PL - Germany TA - Phytomedicine JT - Phytomedicine : international journal of phytotherapy and phytopharmacology JID - 9438794 RN - 0 (Glucosinolates) RN - 0 (Leptin) RN - 0 (NF-E2-Related Factor 2) RN - 0 (NF-kappa B) RN - 0 (Nfe2l2 protein, rat) RN - 0 (Nitriles) RN - 0 (Plant Extracts) RN - X4OV71U42S (Pioglitazone) SB - IM MH - Animals MH - Brassicaceae/*chemistry MH - Diet, High-Fat/adverse effects MH - Glucosinolates/analysis MH - *Insulin Resistance MH - Leptin/metabolism MH - Liver/drug effects/metabolism/pathology MH - Male MH - NF-E2-Related Factor 2/metabolism MH - NF-kappa B/antagonists & inhibitors/metabolism MH - Nitriles/chemistry/pharmacology MH - Non-alcoholic Fatty Liver Disease/etiology/metabolism/*prevention & control MH - Oxidative Stress/drug effects MH - Pioglitazone/pharmacology MH - Plant Extracts/chemistry/*pharmacology MH - Rats, Wistar MH - Signal Transduction MH - Rats OTO - NOTNLM OT - Glucosinolate OT - Insulin resistance OT - Leptin stimulator OT - Nitrile OT - Nonalcoholic steatohepatitis OT - Nrf2 EDAT- 2020/10/29 06:00 MHDA- 2021/01/16 06:00 CRDT- 2020/10/28 20:07 PHST- 2019/10/03 00:00 [received] PHST- 2020/10/06 00:00 [revised] PHST- 2020/10/11 00:00 [accepted] PHST- 2020/10/29 06:00 [pubmed] PHST- 2021/01/16 06:00 [medline] PHST- 2020/10/28 20:07 [entrez] AID - S0944-7113(20)30218-X [pii] AID - 10.1016/j.phymed.2020.153388 [doi] PST - ppublish SO - Phytomedicine. 2021 Jan;80:153388. doi: 10.1016/j.phymed.2020.153388. Epub 2020 Oct 16.