الفهرس 
Introduction and Aim of The WorkOnly 14 pages are availabe for public view
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Abstract
Cholestasis is defined as an interruption in the flow and secretion of bile, or at any rate a significant reduction in both. Cholestasis can result from a breakdown in bile acid synthesis, an issue with hepatocyte or ductular cell transporters, or an estimated blockage of the external bile ducts. The first is referred to as intrahepatic cholestasis, whereas the second is extrahepatic cholestasis. A useful model to study the molecular mechanisms of chemically induced cholestasis, with both acute and chronic damage, is ANIT-feeding. The reaction of cytotoxic and pro-inflammatory mediators has been emphasized in early investigations on the etiology of ANIT-induced cholestatic liver damage. In this model, exposure of the hepatic tissue to high concentrations of the hydrophobic bile acids during cholestasis generates a massive storm of ROS that activate inflammatory response to produce more ROS that produce sudden and sever liver injury. On the other hand, the growth of the biliary tree and the healing of damaged bile ducts help to facilitate bile outflow from the liver. The etiology of cholestasis was influenced by a mismatch between healing and destruction.
Consequently, the negative consequences of ANIT-induced hepatic injury could be reduced by the ability of these pharmacological agents to reduce inflammation and free radicals. Therefore, the purpose of the current study was to examine the hepatoprotective, anti-oxidant, anti-inflammatory and anti-pyroptotic effects of QU, Sild, PTX or their combinations against cholestasis caused by ANIT administration and their part in the modification of TLRP3/NF-kB and NLRP3/IL-1β signaling pathways as well as Nrf-2 expression.
To attain this objective, study has been designed as follows: seventy adult male albino rats were divided randomly into seven groups each of ten rats; group I: (sham control): received 0.5% carboxymethyl cellulose at a dose of (0.5 ml/100g) orally once daily for 10 days. group II: Rats received 0.5% carboxymethyl cellulose at a dose of (0.5 ml/100g) orally once daily for 10 days rats and then were challenged with ANIT as a single dose of 60 mg/kg; P.O. group III: rats were treated with quercetin (50 mg/kg) orally once daily for 7 consecutive days before ANIT-challenge (60 mg/kg; P.O) and continued for 2 days after ANIT. group IV: rats were treated with Sildenafil at a dose of 10 mg/kg, P.O. twice daily for 7 consecutive days before ANIT-challenge (60 mg/kg; P.O) and continued for 2 days after ANIT. group V: rats were administrated pentoxifylline at a dose of 50 mg/kg/day, P.O. for 7 consecutive days before ANIT-challenge (60 mg/kg; P.O) and continued for 2 days after ANIT. group VI: both quercetin and sildenafil are separately administered as the doses for 7 consecutive days before ANIT-challenge (60 mg/kg; P.O) and continued for 2 days after ANIT. group VII: both quercetin and pentoxifylline are separately administered as the doses for 7 consecutive days before ANIT-challenge (60 mg/kg; P.O) and continued for 2 days after ANIT.
Samples of blood were gained after twelve hours of administration of final dose, through optical mechanism and livers were separated. Both serum and tissue samples were gathered to look into biomarker (liver function enzymes, oxidative stress markers, and anti-pyroptotic markers), mRNA NF-κB-p65, Nrf-2, TLR-4 and NLRP-3 expression , protein expression of HO-1, Nrf2, PPAR-γ, NLRP-3, cleavedCaspase-1, NF-κβ-p65, IL-1β and IKK- β In addition, confirmation of these result by histological work.
The results revealed that, ANIT-induced cholestatic model causes a significant alteration in liver functions, and oxidative stress markers as compared to sham control. Furthermore, up-regulation of NF-κB-p65, NLRP3, TLR-4, cleavedCaspase-1, IL-1β and IKK- β concomitantly with down-regulation of Nrf-2, HO-1 and PPAR-γ were observed. Treatment with QU, Sild, PTX and their combinations significantly alleviated the disturbance induced by ANIT treatment. These findings were further supported by the improvement in histopathological features. Additionally, co-administration of QU and Sild or PTX was found to significantly improve hepatic dysfunction due to ANIT comparing to the individual therapies.
Finally, it could be concluded that
1.The hepatic dysfunction due to ANIT model is due to oxidative stress and inflammatory processes.
2.Parameters, that were measured in this study, provide a strong evidence for antioxidant, anti-inflammatory and anti-pyroptotic power of quercetin, sildenafil and pentoxifylline.
3.The protective mechanisms of these drugs are attributed to their anti-oxidant effects via reduction of modulation of Nrf-2 signaling, anti-inflammatory effects through modulation of TLRP3/NF-kβ and anti-pyroptotic activity through modulation of NLRP3/IL-1β
4.Combination of quercetin with either sildenafil or pentoxifylline is more effective than administration of each drug alone for protection against hepatic cholestasis.
5. The findings of the current investigation indicate the therapeutic potential of these drugs in treatment of hepatic cholestasis. However, further clinical trials are required to confirm that.