Rosavin Ameliorates Hepatic Inflammation and Fibrosis in the NASH Rat Model via Targeting Hepatic Cell Death

Background: Non-alcoholic fatty liver disease (NAFLD) represents the most common form of chronic liver disease that urgently needs effective therapy. Rosavin, a major constituent of the Rhodiola Rosea plant of the family Crassulaceae, is believed to exhibit multiple pharmacological effects on diverse diseases. However, its effect on non-alcoholic steatohepatitis (NASH), the progressive form of NAFLD, and the underlying mechanisms are not fully illustrated. Aim: Investigate the pharmacological activity and potential mechanism of rosavin treatment on NASH management via targeting hepatic cell death-related (HSPD1/TNF/MMP14/ITGB1) mRNAs and their upstream noncoding RNA regulators (miRNA-6881-5P and lnc-SPARCL1-1:2) in NASH rats. Results: High sucrose high fat (HSHF) diet-induced NASH rats were treated with different concentrations of rosavin (10, 20, and 30 mg/kg/day) for the last four weeks of dietary manipulation. The data revealed that rosavin had the ability to modulate the expression of the hepatic cell death-related RNA panel through the upregulation of both (HSPD1/TNF/MMP14/ITGB1) mRNAs and their epigenetic regulators (miRNA-6881-5P and lnc-SPARCL1-1:2). Moreover, rosavin ameliorated the deterioration in both liver functions and lipid profile, and thereby improved the hepatic inflammation, fibrosis, and apoptosis, as evidenced by the decreased protein levels of IL6, TNF-α, and caspase-3 in liver sections of treated animals compared to the untreated NASH rats. Conclusion: Rosavin has demonstrated a potential ability to attenuate disease progression and inhibit hepatic cell death in the NASH animal model. The produced effect was correlated with upregulation of the hepatic cell death-related (HSPD1, TNF, MMP14, and ITGB1) mRNAs—(miRNA-6881-5P—(lnc-SPARCL1-1:2) RNA panel

A global action agenda for turning the tide on fatty liver disease

Funding Information: the Liver (CASL), Duke University, European Association for the Study of the Liver (EASL), Gastroenterology Updates, IBD, Liver Disease (GUILD), Houston Methodist, International Liver Transplantation Society (ILTS), Pakistan Society for the Study of Liver Disease (PSSLD), and University of Alabama, Birmingham (UAB). She received grants from Durect Corp, Genentech-Roche, Gilead, GlaxoSmithKline, Helio Health, and the National Institutes of Health. She has other interests with the American Association for the Study of Liver Diseases (AASLD), Clinical Care Options (CCO), the Hepatitis B Foundation, HBV Forum, Indian National Association for the Study of the Liver (INASL), and Simply Speaking. Emmanuel A. Tsochatzis consults, advises, and is on the speakers’ bureau for Novo Nordisk. He consults and advises Boehringer Ingelheim and Pfizer. He is on the speakers’ bureau for Dr Falk. He has other interests with EASL Governing Board. Luca Valenti consults, advises, is on the speakers’ bureau, and received grants from Gilead. He consults and advises Boehringer Ingelheim, Intercept, Pfizer, Novo Nordisk. He consults for Astra Zeneca and Diatech Pharmacogenetics. He is on the speakers’ board for AbbVie, Alfa-Sigma, MSD, and Viatris. He holds intellectual property rights with Takeda. Marcela Villota-Rivas consults for the European Association for the Study of The Liver (EASL). Shira Zelber-Sagi is on the speakers’ board for AbbVie. Jörn M. Schatten-berg consults, is on the speakers’ bureau, and is employed by Gilead. He consults, is on the speakers’ bureau, received grants from Boehringer Ingelheim. He consults and is on the speakers’ bureau for Madrigal and Novo Nordisk. He consults for Albireo Pharma, Apollo Endosurgery, Astra Zeneca, Bayer, Bristol Myers Squibb, GlaxoSmithKline, Intercept, Ipsen, Inventiva, MSD, Northsea Therapeutics, Novartis, Pfizer, Roche, Sanofi, and Siemens Healthineer. He is on the speakers’ bureau for Echosens, HistoIndex, and MedPublico GmbH. He received grants from, and Siemens Healthcare GmbH. He owns stock in AGED diagnostics and Hepta Bio. Vincent Wai-Sun Wong consults, is on the speakers’ bureau, received grants, and is employed by Gilead. He consults, is on the speakers’ bureau, and employed by AbbVie. He consults and is on the speakers’ bureau for Novo Nordisk. He consults for Boehringer Ingelheim, Echosens, Intercept, Inventiva, Pfizer, Sag-imet, and TARGET PharmaSolutions. He is on the speakers’ bureau for Abbott and Unilab. He owns stock in Illuminatio Medical Technology Limited. Zobair M. Younossi consults for Abbott, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Cymabay, Gilead, GlaxoSmithKline, Intercept, Madrigal, Merck, Novo Nordisk, Quest, and Siemens. The remaining authors have no conflicts to report. Funding Information: Ingelheim, Bristol Myers Squibb, Corcept, DSM, Galec-tin, Genentech, Genfit, Hepagene, Healio, Inventiva, Ionis, Merck, NGM, Noom, NorthSea, Poxel, and Viking. Quentin M. Anstee, on behalf of Newcastle University, consults and advises for Alimentiv, Akero, AstraZeneca, Axcella, 89Bio, Boehringer Ingelheim, Bristol Myers Squibb, Galmed, GENFIT, Genentech, Gilead, GlaxoS-mithKline, Hanmi, HistoIndex, Intercept, Inventiva, Ionis, IQVIA, Janssen, Madrigal, Medpace, Merck, NGM Bio, Novartis, Novo Nordisk, PathAI, Pfizer, Prosciento, Poxel, Resolution Therapeutics, Ridgeline Therapeutics, Roche, RTI, Shionogi, and Terns. He is on the speakers’ bureau for Fishawack, Integritas Communications, Kenes, Novo Nordisk, Madrigal, Medscape, and Springer Healthcare. He received grants from AstraZeneca, Boehringer Ingelheim, and Intercept. He holds intellectual property rights with Elsevier, Ltd. He serves as coordinator of the IMI2 LITMUS consortium. Ramon Bataller is on the speakers’ bureau for AbbVie. Thomas Berg consults, advises, is on the speakers’ bureau, received grants, and employed by AbbVie, Gilead, and Intercept. He consults, is on the speakers’ bureau, and is employed by Janssen. He consults, is on the speakers’ bureau, and received grants from MSD/Merck, Novartis, Orphalan, and Sequana Medical. He consults and is on the speakers’ bureau for Alexion, Bayer, Eisai, Ipsen, SIRTEX, and SOBI. He consults and received grants from Humedics. He consults for Enyo Pharma, Glax-oSmithKline, HepaRegeniX GmbH, Roche, and Shio-nogi. He is on the speakers’ bureau for Advance Pharma, Falk Foundation, and MedUpdate GmbH. He received grants from Bristol Myers Squibb, Merz, and Norgine. Paul N. Brennan consults for Resolution Therapeutics. He is on the speakers’ bureau for Takeda. Patrizia Burra advises and is on the speakers’ bureau for Chiesi Farmaceutici and Gilead. She advises Astellas, Biotest, Kedrion, Novartis, and Sandoz. She is employed by Alpha Wasserman. Helena Cortez-Pinto consults, advises, and is on the speakers’ bureau for EISAI and Roche Portugal. She consults for Novo Nordisk and Orphalan. Kenneth Cusi consults and received grants from Novo Nordisk. He consults for Aligos, Allergan, Altimmune, Arrowhead, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Coherus, Covance, Eli Lilly, Fractyl, Genentech, Gilead, Hanmi, Intercept, Janssen, Madrigal, Pfizer, Prosciento, Sagimet, and Siemens. He received grants from Cirius, Echosens, Inventiva, LabCorp, National Institute of Health, Nordic Bioscience, Novartis, Poxel, and Zydus. Nikos Dedes advises Gilead and GlaxoSmithKline. He has other interests with the Greek Patients Association and the Positive Voice (PLHIV Association). Ajay Duseja has other interests with the Indian National Association for the Study of the Liver (INASL). Sven M. Francque consults, is on the speakers’ bureau, and received grants from GENFIT, Gilead, Inventiva, and Merck Sharp & Dome. He consults and is on the speakers’ bureau for Publisher Copyright: Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.Background and Aims: Fatty liver disease is a major public health threat due to its very high prevalence and related morbidity and mortality. Focused and dedicated interventions are urgently needed to target disease prevention, treatment, and care. Approach and Results: We developed an aligned, prioritized action agenda for the global fatty liver disease community of practice. Following a Delphi methodology over 2 rounds, a large panel (R1 n = 344, R2 n = 288) reviewed the action priorities using Qualtrics XM, indicating agreement using a 4-point Likert-scale and providing written feedback. Priorities were revised between rounds, and in R2, panelists also ranked the priorities within 6 domains: epidemiology, treatment and care, models of care, education and awareness, patient and community perspectives, and leadership and public health policy. The consensus fatty liver disease action agenda encompasses 29 priorities. In R2, the mean percentage of “agree” responses was 82.4%, with all individual priorities having at least a super-majority of agreement (> 66.7% “agree”). The highest-ranked action priorities included collaboration between liver specialists and primary care doctors on early diagnosis, action to address the needs of people living with multiple morbidities, and the incorporation of fatty liver disease into relevant non-communicable disease strategies and guidance. Conclusions: This consensus-driven multidisciplinary fatty liver disease action agenda developed by care providers, clinical researchers, and public health and policy experts provides a path to reduce fatty liver disease prevalence and improve health outcomes. To implement this agenda, concerted efforts will be needed at the global, regional, and national levels.publishersversionepub_ahead_of_prin