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A Bioinformatic and Mechanistic Study Elicits The Journal name: Drug Design, Development and Therapy Article Designation: Original Research Year: 2015 Volume: 9 Drug Design, Development and Therapy Dovepress Running head verso: He et al Running head recto: UA reverses liver fibrosis in rats open access to scientific and medical research DOI: http://dx.doi.org/10.2147/DDDT.S85426 Open Access Full Text Article ORIGINAL RESEARCH A bioinformatic and mechanistic study elicits the antifibrotic effect of ursolic acid through the attenuation of oxidative stress with the involvement of ERK, PI3K/Akt, and p38 MAPK signaling pathways in human hepatic stellate cells and rat liver Wenhua He1,* Abstract: NADPH oxidases (NOXs) are a predominant mediator of redox homeostasis in Feng Shi1,* hepatic stellate cells (HSCs), and oxidative stress plays an important role in the pathogenesis Zhi-Wei Zhou2,* of liver fibrosis. Ursolic acid (UA) is a pentacyclic triterpenoid with various pharmacological Bimin Li1 activities, but the molecular targets and underlying mechanisms for its antifibrotic effect in the Kunhe Zhang1 liver remain elusive. This study aimed to computationally predict the molecular interactome Xinhua Zhang1 and mechanistically investigate the antifibrotic effect of UA on oxidative stress, with a focus on NOX4 activity and cross-linked signaling pathways in human HSCs and rat liver. Drug–drug Canhui Ouyang1 interaction via chemical–protein interactome tool, a server that can predict drug–drug interac- Shu-Feng Zhou2 tion via chemical–protein interactome, was used to predict the molecular targets of UA, and 1 Xuan Zhu Database for Annotation, Visualization, and Integrated Discovery was employed to analyze 1Department of Gastroenterology, the the signaling pathways of the predicted targets of UA. The bioinformatic data showed that First Affiliated Hospital of Nanchang there were 611 molecular proteins possibly interacting with UA and that there were over 49 University, Nanchang, Jiangxi, People’s Republic of China; 2Department of functional clusters responding to UA. The subsequential benchmarking data showed that UA Pharmaceutical Sciences, College of significantly reduced the accumulation of type I collagen in HSCs in rat liver, increased the Pharmacy, University of South Florida, Tampa, FL, USA expression level of MMP-1, but decreased the expression level of TIMP-1 in HSC-T6 cells. UA also remarkably reduced the gene expression level of type I collagen in HSC-T6 cells. Fur- *These authors contributed equally to this work thermore, UA remarkably attenuated oxidative stress via negative regulation of NOX4 activity and expression in HSC-T6 cells. The employment of specific chemical inhibitors, SB203580, LY294002, PD98059, and AG490, demonstrated the involvement of ERK, PI3K/Akt, and p38 MAPK signaling pathways in the regulatory effect of UA on NOX4 activity and expression. Correspondence: Xuan Zhu Collectively, the antifibrotic effect of UA is partially due to the oxidative stress attenuating effect Department of Gastroenterology, the First through manipulating NOX4 activity and expression. The results suggest that UA may act as a Affiliated Hospital of Nanchang University, 17 Yongwai Main St, Nanchang 330006, promising antifibrotic agent. More studies are warranted to evaluate the safety and efficacy of Jiangxi, People's Republic of China UA in the treatment of liver fibrosis. Tel +86 791 8869 2505 Keywords: ursolic acid, liver fibrosis, NADPH oxidase, ROS, DDI-CPI, DAVID Fax +86 791 8862 3153 Email [email protected] Shu-Feng Zhou Introduction Department of Pharmaceutical Sciences, Liver fibrosis remains the major cause of morbidity and mortality worldwide. It causes College of Pharmacy, University of South several notorious complications, including ascites, portal hypertension, encephalopathy, Florida, 12901 Bruce B Downs Boulevard, MDC 30, Tampa, FL 33612, USA and liver failure, and it accelerates the risk of hepatocellular carcinoma, placing a sub- Tel +1 813 974 6276 stantial burden to individual, society, and health care system.1,2 The liver fibrosis-driven Fax +1 813 905 9885 Email [email protected] chronic liver disease and cirrhosis cause 36,427 deaths and with a ratio of 11.5/100,000 in submit your manuscript | www.dovepress.com Drug Design, Development and Therapy 2015:9 3989–4104 3989 Dovepress © 2015 He et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further http://dx.doi.org/10.2147/DDDT.S85426 permission from Dove Medical Press Limited, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Limited. Information on how to request permission may be found at: http://www.dovepress.com/permissions.php He et al Dovepress 2013 in USA.1 This is a complicated etiology of hepatic fibro- anti-inflammatory, and anticancer activities.14 UA exerts a sis. Viral infection is the most common contributing factor to protective effect against ethanol-induced toxicity in isolated liver fibrosis affecting 1%–2% of the US population,3 and liver rat hepatocytes and ethanol-mediated experimental liver fibrosis resultant cirrhosis is projected to reach 45% of those damage in rats.15,16 Our previous studies showed that UA infected with hepatitis C virus patients in 2030.4 Hepatitis significantly inhibited the proliferation of HSCs and induced B virus is the main type of hepatitis virus in the People’s apoptosis in vitro.17 Moreover, Steinkamp-Fenske et al18 Republic of China with a substantial contribution to the inci- showed that UA downregulated the expression level of NOX4 dence of liver fibrosis.5,6 Moreover, nonalcoholic fatty liver and suppressed ROS generation in human endothelial cells. disease and nonalcoholic steatohepatitis are also important However, there is a lack of study on the antifibrotic effect of causes of liver fibrosis, and over 20% of patients with non- UA, and the underlying mechanisms of the antifibrotic effect alcoholic steatohepatitis progress to cirrhosis worldwide.7 In of UA are largely unknown. addition, other etiologies of liver fibrosis and its late-stage Therefore, the present study aimed to evaluate the molec- liver injury include alcohol-induced disease, drug-induced ular targets of UA and analyze the molecular interactome toxicity, other liver infections (eg, schistosomiasis), immune- of UA using computational and bioinformatic approaches mediated liver diseases (eg, autoimmune hepatitis), metabolic and, subsequently, examine the antifibrotic effect of UA and disorders (eg, lipid, glycogen, or metal storage disorders), and delineate the underlying mechanisms in HSCs and Sprague cholestasis (eg, secondary biliary cirrhosis). Dawley rats. To date, the molecular mechanisms that underlie the development of liver fibrosis have been extensively inves- Materials and methods tigated, including epithelial to mesenchymal transition and Prediction of the interactome of UA and pathway inflammatory response.8–10 Notably, increasing evidence sug- analysis by molecular docking and bioinformatic gests that oxidative stress has been implicated in the patho- approach genesis of liver fibrosis, with the intracellular accumulation of The prediction of interactome of UA was performed using excessive reactive oxygen species (ROS), and the compelling the drug–drug interaction via chemical–protein interactome evidence shows the involvement of ROS in the development (DDI-CPI) tool (http://cpi.bio-x.cn/ddi/) as previously of liver fibrosis with a regulatory role in a variety of cellular described.19 DDI-CPI is a web-based server that can be processes.7,10–13 However, the specific targets and signaling used to predict DDI via CPI.20,21 In brief, protein targets pathways have not been fully mapped yet, and the sources were obtained from a third-party protein structure database of ROS have not yet been conclusively determined in the named PDBbind (http://sw16.im.med.umich.edu/databases/ pathogenesis of liver fibrosis. There are several enzymatic pdbbind/index.jsp), which was based on the contents of sources of ROS, including NADPH oxidase (NOX) family Protein Data Bank (PDB).22 There are a total of 1,780 PDB of oxidoreductases, nitric oxide synthases, xanthine oxidase, entries of human proteins available in PDBbind, and a total and cytochrome P450, of which NOX is the most important of 301 nonredundant PDBs corresponding to 353 ligand- ROS-generating enzyme in both plants and animals, espe- binding pockets were identified from it, with 86% of which cially in mammals. In the liver, NOX has been involved in have resolutions ,2.5 Å. The docking boxes for each of the fibrogenesis. In particular, NOX4 is one of seven NOX iso- pockets were defined by expanding the circumscribed cube of forms and is the most widely distributed isoform.11 It has been the pocket with a margin of 8 Å at six directions (up, down, reported that a functionally active form of NOX is expressed front, back, left, and right). For the preparation of the UA, in hepatic stellate cells (HSCs) and that NOX-generated ROS the 2D structure of the UA was downloaded from PubChem. serve as a second messenger for profibrogenic factor signal The hydrogen and Gasteiger charge were added, and the transduction in HSCs. However, regulation of NOX in HSCs PDB file was converted into mol2 format using VEGA ZZ.
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