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Phosphodiesterase (PDE) inhibitors have shown remarkable antioxidant and anti\u2010inflammatory potential in different disease sets including liver diseases. This study aimed to compare the ameliorative effect of different PDE inhibitors on a high\u2010fat diet (HFD)\u2010induced NAFLD. Male Wistar rats were fed a HFD for 16\u00a0weeks to induce NAFLD, and then, oral treatments of a vehicle or different PDE inhibitors (pentoxifylline (50\u00a0mg\/kg), cilostazol (20\u00a0mg\/kg), or sildenafil (5\u00a0mg\/kg)) were started in the last four weeks and given on a daily basis. Rats\u2019 body composition and liver indices were recorded. Serum levels of liver enzymes, glucose, insulin, bilirubin, total cholesterol, triglycerides, and nitric oxide were measured. Liver tissues were used for histopathological examination and detecting oxidative stress and inflammatory markers. Results showed that different PDE inhibitors exhibited different efficacy against liver injury and metabolic disorders associated with HFD\u2010induced NAFLD in rodents evident by different strength\u2010ameliorated effects on the aforementioned parameters. Compared to cilostazol and sildenafil, insulin resistance, hepatic oxidative stress, and inflammatory markers were significantly reduced by pentoxifylline treatment. Furthermore, pentoxifylline nearly completely reversed hepatocyte steatosis and exhibited superior rectifying effect on the rats\u2019 liver status compared with other PDE inhibitors. This investigation highlighted the potential role of PDE inhibitors in NAFLD treatment. Pentoxifylline had the most remarkable ameliorative effects against NAFLD, while sildenafil was the least effective.<\/jats:p>","DOI":"10.1111\/fcp.12530","type":"journal-article","created":{"date-parts":[[2019,12,30]],"date-time":"2019-12-30T05:59:25Z","timestamp":1577685565000},"page":"353-364","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Comparative effectiveness of phosphodiesterase 3, 4, and 5 inhibitors in amelioration of high\u2010fat diet\u2010induced nonalcoholic fatty liver in rats"],"prefix":"10.1111","volume":"34","author":[{"given":"Reham M.","family":"El\u2010Deen","sequence":"first","affiliation":[{"name":"Undersecretary Preventive Sector General Administration Viral Hepatitis Ministry of Health and Population Cairo 11516 Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6907-4441","authenticated-orcid":false,"given":"Gehan H.","family":"Heeba","sequence":"additional","affiliation":[{"name":"Department of Pharmacology &amp; Toxicology Faculty of Pharmacy Minia University El\u2010Minia 61511 Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3770-7128","authenticated-orcid":false,"given":"Rania G.","family":"Abdel\u2010latif","sequence":"additional","affiliation":[{"name":"Department of Pharmacology &amp; Toxicology Faculty of Pharmacy Minia University El\u2010Minia 61511 Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed M.A.","family":"Khalifa","sequence":"additional","affiliation":[{"name":"Department of Pharmacology &amp; Toxicology Faculty of Pharmacy Minia University El\u2010Minia 61511 Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,1,14]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0200656"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.24376"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tem.2008.08.005"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpg.2014.07.008"},{"key":"e_1_2_8_6_1","first-page":"10","article-title":"Non alcoholic fatty liver overview","volume":"3","author":"Debes M.S.","year":"2015","journal-title":"Pathology"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.3390\/nu9040387"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2018.06.005"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-0037-1615860"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tem.2013.10.004"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/mnfr.201500016"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.metabol.2018.09.001"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1155\/2016\/9185987"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1186\/1465-9921-5-4"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1124\/pr.58.3.5"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1515\/jbcpp-2017-0011"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.3923\/ijp.2015.814.820"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2018.09.061"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0735-1097(98)00656-1"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-0037-1615863"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1527-3466.2001.tb00076.x"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00210-012-0729-z"},{"key":"e_1_2_8_23_1","first-page":"21","article-title":"Ghrelin reduces TNF\u2010\u03b1\u2013induced human hepatocyte apoptosis, autophagy, and pyroptosis: role in obesity\u2010associated NAFLD","volume":"104","author":"Ezquerro S.","year":"2018","journal-title":"J. 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