1. A novel combination therapy targets sonic hedgehog signaling by the dual inhibition of HMG-CoA reductase and HSP90 in rats with non-alcoholic steatohepatitis.
- Author
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Mohammed OA, Youssef ME, Doghish AS, Hamad RS, Abdel-Reheim MA, Alghamdi M, Alamri MMS, Alfaifi J, Adam MIE, Alharthi MH, Alhalafi AH, Bahashwan E, Rezigalla AA, BinAfif DF, Abdel-Ghany S, Attia MA, Elmorsy EA, Al-Noshokaty TM, Fikry H, Saleh LA, and Saber S
- Subjects
- Animals, Male, Humans, Hep G2 Cells, Diet, High-Fat adverse effects, Liver drug effects, Liver metabolism, Drug Therapy, Combination, Rats, Rats, Sprague-Dawley, Cholesterol metabolism, Non-alcoholic Fatty Liver Disease drug therapy, Non-alcoholic Fatty Liver Disease metabolism, Hedgehog Proteins metabolism, Hedgehog Proteins antagonists & inhibitors, Signal Transduction drug effects, HSP90 Heat-Shock Proteins antagonists & inhibitors, HSP90 Heat-Shock Proteins metabolism, Hydroxymethylglutaryl-CoA Reductase Inhibitors pharmacology, Hydroxymethylglutaryl-CoA Reductase Inhibitors therapeutic use
- Abstract
Non-alcoholic steatohepatitis (NASH) is characterized by liver inflammation, fat accumulation, and collagen deposition. Due to the limited availability of effective treatments, there is a pressing need to develop innovative strategies. Given the complex nature of the disease, employing combination approaches is essential. Hedgehog signaling has been recognized as potentially promoting NASH, and cholesterol can influence this signaling by modifying the conformation of PTCH1 and SMO activity. HSP90 plays a role in the stability of SMO and GLI proteins. We revealed significant positive correlations between Hedgehog signaling proteins (Shh, SMO, GLI1, and GLI2) and both cholesterol and HSP90 levels. Herein, we investigated the novel combination of the cholesterol-lowering agent lovastatin and the HSP90 inhibitor PU-H71 in vitro and in vivo. The combination demonstrated a synergy score of 15.09 and an MSA score of 22.85, as estimated by the ZIP synergy model based on growth inhibition rates in HepG2 cells. In a NASH rat model induced by thioacetamide and a high-fat diet, this combination therapy extended survival, improved liver function and histology, and enhanced antioxidant defense. Additionally, the combination exhibited anti-inflammatory and anti-fibrotic potential by influencing the levels of TNF-α, TGF-β, TIMP-1, and PDGF-BB. This effect was evident in the suppression of the Col1a1 gene expression and the levels of hydroxyproline and α-SMA. These favorable outcomes may be attributed to the combination's potential to inhibit key Hedgehog signaling molecules. In conclusion, exploring the applicability of this combination contributes to a more comprehensive understanding and improved management of NASH and other fibrotic disorders., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)
- Published
- 2024
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