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 |
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| Affiliation: | 1. Department of Clinical Pharmacology, Nanjing Drum Tower Hospital, Pharmacy Collage of Nanjing Medical University, Nanjing 210000, China;2. Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210000, China;3. Natural Products Unit, Medicinal and Aromatic Plants Department, Desert Research Centre, Cairo, Egypt;4. Department of Pharmacognosy, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt;5. Department of Pathology, Nanjing Drum Tower Hospital of Nanjing University Medical School, Nanjing 210000, China;6. Research Division of Clinical Pharmacology, The First Affiliated Hospital, Pharmacy College of Nanjing Medical University, Nanjing 210000, China;7. Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing 210000, China;1. Laboratory of Immunopathology of Neglected Diseases and Cancer, State University of Londrina – UEL. Rodovia Celso Garcia Cid Campus Zip Code 86057-970, Post Box 10.011. Londrina, PR, Brazil;2. Graduate Program in Biosciences and Biotechnology, Carlos Chagas Institute (ICC), Fiocruz, Curitiba, Paraná, Brazil;3. Laboratory of Biotransformation and Phytochemistry, State University of Londrina, Paraná, Brazil;4. Laboratory of Research for Pain, Neuropathy and Inflammation, State University of Londrina, Paraná, Brazil;5. Laboratory of Tumor of Biology, State University of West Paraná, Francisco Beltrão, Paraná, Brazil;6. Laboratory of Toxicological Genetics, State University of Londrina, PR, Brazil;1. Department of Chinese Medicine, Taichung Hospital, Ministry of Health and Welfare, Taichung, Taiwan;2. Department of Anesthesiology, Taipei Medical University Hospital, Taipei, Taiwan Hospital, Taipei, Taiwan;3. Department of Anesthesiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan;4. Anesthesiology and Health Policy Research Center, Taipei Medical University Hospital, Taipei, Taiwan;5. Department of Anesthesiology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan;6. Department of Surgery, China Medical University Hospital, Taichung, Taiwan;7. Department of Surgery, University of Illinois, Chicago, IL, United States;8. Department of Neurology, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan;9. School of Chinese Medicine for Post-Baccalaureate, I-Shou University, Kaohsiung, Taiwan;10. Research Center of Big Data and Meta-Analysis, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan;11. School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan;12. Program for the Clinical Drug Discovery from Botanical Herbs, Taipei Medical University, Taipei, Taiwan;1. Laboratory of Inflammation and Molecular Pharmacology, School of Basic Medical Sciences & Biomedical Research Institute, Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, Shiyan 442000, China;2. State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China;3. Hubei Key Laboratory of Natural Products Research and Development, College of Biological and Pharmaceutical Sciences, China Three Gorges University, Yichang 443002, China;4. Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou 510405, China;1. Department of Pharmacy, University of Naples Federico II, via Domenico Montesano 49, 80131 Naples, Italy;2. Samnium Medical Soc. Cooperative, 82100 Benevento, Italy;3. Department of Internal Medicine, Hospital Cardarelli, Via Antonio Cardarelli, 80131 Naples, Italy;4. Department of Clinical Medicine and Surgery - Section of Infectious Diseases, University of Naples Federico II, via Sergio Pansini 5, 80131 Naples, Italy;5. Applied Statistic Unit, Department of Earth and Environmental Sciences, University of Pavia, viale Taramelli 24, 27100 Pavia, Italy;6. Department of Life Sciences, University of Modena and Reggio Emilia, Via Campi 213/D, 41121 Modena, Italy;7. B Natural R&D Unit, via Gran Sasso 33, 20011 Corbetta (MI), Italy;8. International Research Center for Food Nutrition and Safety, Jiangsu University, Zhenjiang 212013, China;1. College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China;2. Ocean College, Zhoushan Campus, Zhejiang University, Zhoushan 316021, China;3. Zhejiang Center for Medical Device Evaluation, Hangzhou 310009, China.;4. Department of Pharmacy, Zhejiang Cancer Hospital, Hangzhou 310022, China |
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| Abstract: | BackgroundInsulin 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.PurposeOur 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 designNRF 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.MethodsGas 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.ResultsButenyl 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.ConclusionNRF has reversed IR, stimulated leptin secretion and prevented NASH initiation showing promising anti-NASH and anti-fibrotic effects. |
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