利用 Diceratella elliptica（DC.）jonsell 中的 NRF 调节 IR 作为预防 NASH 的治疗靶点。强 Nrf2 和瘦素诱导剂以及 NF-κB 抑制剂。
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.
机构信息
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.
Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210000, China.
出版信息
Phytomedicine. 2021 Jan;80:153388. doi: 10.1016/j.phymed.2020.153388. Epub 2020 Oct 16.
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.
背景
胰岛素抵抗（IR）和脂毒性被认为是非酒精性脂肪性肝炎（NASH）的主要启动因素。然而，缺乏针对 NASH 进展的有效治疗方法促使我们寻找一种新的有前途的胰岛素调节剂和 NASH 预防剂。
目的
本研究旨在从 Diceratella elliptica（DC.）Jonsell 中提取并制备富含腈的馏分（NRF），研究其胰岛素增敏和抗 NASH 潜力，并探讨其在 IR-NASH 发病机制中的分子靶点。
研究设计
采用天然自溶法制备 NRF，鉴定化合物。然后，将 70 只雄性 Wistar 大鼠给予高脂肪饮食（HFD）或正常饲料 35 天。在第 14 天，HFD 大鼠一次性注射链脲佐菌素（STZ），并在第 21 天开始治疗，给予 NRF（30、60 和 120mg/kg；口服）或吡格列酮（PioG）（10mg/kg；ip），同时给予 HFD。而 NRF 单独治疗组则给予正常饲料的 NRF（120mg/kg；口服）。检测体重、葡萄糖稳态、肝组织病理学变化。
方法
气相色谱-质谱联用仪（GLC/MS）用于鉴定化合物，分光光度计用于定量总硫代葡萄糖苷（GLS）。此外，还对与肝脂毒性、氧化应激、炎症和胰岛素信号通路相关的生化和分子变化进行了研究，并通过计算预测主要化合物的靶点进行了验证。
结果
丁基和苄基 GLS 是主要的，还有其他挥发性化合物。NRF 显著提高了胰岛素敏感性，改善了 NASH 组织病理学，表现出肝保护作用。此外，该馏分的抗 NASH 潜力表现在肝脂肪变性标志物的正常化、炎症和氧化应激关键转录因子的诱导，导致胰岛素受体底物（IRSs）磷酸化及其下游效应物的诱导。
结论
NRF 逆转了 IR，刺激了瘦素的分泌，并预防了 NASH 的发生，显示出有希望的抗 NASH 和抗纤维化作用。
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