الفهرس 
Introduction & Aim Of The WOnly 14 pages are availabe for public view
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Abstract
Non-alcoholic fatty liver disease (NAFLD) is a significant public health problem that is concomitantly increasing along with the high prevalence of obesity and diabetes. NAFLD represents the hepatic manifestation of metabolic syndrome and it ranges from simple steatosis to non-alcoholic steatohepatitis (NASH) and cirrhosis.
It is ambiguous to explain the exact pathogenesis of NAFLD; however, two-hit and multiple-hit hypotheses were suggested to describe the factors and mechanisms of hepatocellular damage associated with triglycerides accumulation in NAFLD. The first hit included is insulin resistance, which leads to hepatic lipid accumulation. Then, additional hits of oxidative stress and inflammatory cascades are thought to mediate disease progression and fibrosis. Since insulin resistance has a crucial role in NAFLD which made it highly prevalent in type 2 diabetic individuals, suggested therapy approaches including metformin are developed to manage NAFLD in diabetic patients via improving insulin resistance.
Another possible pathway for controlling NAFLD is via suppression of other pathological hits including oxidative stress and inflammation that stimulate signaling pathways of fibrosis and cellular injury.
Phosphodiesterase (PDE) inhibitors showed a remarkable potential in controlling inflammatory and oxidative stress in various diseases via maintaining cyclic adenosine monophosphate (cAMP)/cyclic guanosine monophosphate (cGMP) homeostasis. cAMP/cGMP are secondary messenger molecules which control multiple cellular process including cell differentiation, lipid metabolism and inflammation. Additionally, researches showed that potentiation of cAMP/cGMP signaling by different PDE inhibitors could counteract the oxidative stress and inflammation reported in NAFLD animal models. Due to its multiple pathological pathways, there is no single FDA approved drug for NAFLD treatment. Hence, we suppose that targeting different pathological hits by using combined therapies could bring additional benefits in NAFLD treatment over one drug usage.
In this setting, the present study aimed to recognize and compare the ameliorative effect of different PDE inhibitors (namely: pentoxiphylline, cilostazol or sildenafil) on a high-fat diet (HFD)-induced NAFLD. Also, another aim of this study is to investigate the possible protective effects of metformin alone and in combination with the three different PDE inhibitors. The benefits of these combinations and the possible mechanisms underlie their effects in NAFLD were also studied.
The animals used in this study were adult male Wistar albino rats (13-14 weeks old), weighing 200-250 g.
First part of the work: Rats were fed a high-fat diet (HFD) for 16 weeks to induce NAFLD and then, oral treatments of vehicle or different PDE inhibitors; pentoxiphylline (50 mg/kg/day), cilostazol (20 mg/kg/day) or sildenafil (5 mg/kg/day) were started in the last 4 weeks.
Second part of the work: Rats were fed a high-fat diet (HFD) for 16 weeks to induce NAFLD. Starting from week 12, rats received either metformin (200 mg/kg/day) alone or in combination with pentoxiphylline (50 mg/kg/day), cilostazol (20 mg/kg/day) or sildenafil (5 mg/kg/day).
During the study, rats had free access to food and water and all treatments were administered orally once in the morning. At the end of the study, rat’s body weight changes and indices of liver and body composition 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 including TNF-α, NF-кB, and iNOS.
The results of the present study revealed that:
- HFD administration resulted in hepatic steatosis and inflammation in rats. In addition, liver index, body composition index, activities of liver enzymes, and serum lipids deviated from normal. Further, a significant elevations were recorded compared to control in term of serum glucose, insulin and HOMA-IR, oxidative stress parameters, hepatic TNF-α and NF-кB gene expression and iNOS protein expression.
- Results, also, showed that different PDE inhibitors exhibited different efficacy against liver injury and metabolic disorders associated with HFD-induced NAFLD in rodents evident by different strength-ameliorated effects on the aforementioned parameters.
- Moreover, rats treated with metformin showed a significant improvement in the aforementioned parameters. However, addition of pentoxiphylline to metformin treatment synergized its action and produced fortified effect against HFD-induced NAFLD better than other PDE inhibitors.
In conclusion, the present study revealed the important role of PDE inhibitors in controlling NAFLD. The antioxidant and anti-inflammatory effects of pentoxiphylline were superior in improving liver status in rats with NAFLD. Even though cilostazol and sildenafil also showed a notable ameliorative effect against NAFLD, sildenafil was the less effective with reduced anti-inflammatory effect. Moreover, data from this study indicated that combined treatment of metformin and pentoxiphylline had the most remarkable ameliorated effects against HFD-induced NAFLD; further clinical investigations are in-need to approve PDE inhibitors for NAFLD treatment.