الفهرس 
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Abstract
In the present study, the effects of threeantioxidants namely hesperidin, thymoquinoneandquercitrin on several parameters related to cisplatin-induced nephrotoxicity and hepatotoxicity in rats were studied in comparison with silymarin. The antioxidant drugs were given for normal as well as cisplatin-treated rats. Drugs were givenfor 7 days starting one day before cisplatin injection. The effects of the test drugs were estimated on serum creatinine and BUN levels, serum ALT and AST activities and serum TG and TC levels. Furthermore, the effect of test drugs was studied onkidney and liver contents of MDA, GSH and NO. Histopathological examination of both kidney and liver tissues was done. In addition, western blot analysis was done to determine the effect of cisplatin and test drugs on NF-𝜅Band phosphorylated Akt expression levels in kidney and liver tissues. In addition, an invitroexperiment was done to detect the effect of test drugs on the anticancer activity of cisplatin when combined with it on two different cell lines namely human breast adenocarcinoma (MCF-7 and human hepatocellular carcinoma (HepG-2)using MTT assay.
The main findings of the present study can be summarized as follows:
Invivofindings:
1. Silymarin (100 mg/kg), hesperidin (200 mg/kg), thymoquinone (50 mg/kg) or quercitrin (20 mg/kg),as single treatments, did not significantly affect serum creatinine and BUN levels, serum ALT and AST activities and serum TG and TC levels in normal animals.
2. Cisplatin (7.5 mg/kg) significantly elevated serum creatinine and BUN levels, serum ALT and AST activities and significantly affect serum TG and TC levels.
3. Silymarin (100 mg/kg) significantly reduced cisplatin-induced elevation in serum creatinine and BUN levels, serum ALT and AST activities and serum TG and TC levels.
4. Hesperidin (100 mg/kg) significantly reduced cisplatin-induced elevations in serum creatinine and BUN levels, serum ALTand AST activities while it did not significantly affect cisplatin-induced increase in serum TG and TC levels.
5. Hesperidin (200 mg/kg)significantly reduced cisplatin-induced elevation in serum creatinine and BUN levels, serum ALT and AST activities and serum TG and TC levels.
6. Thymoquinone (20, 50 mg/kg), in a dose-dependent manner, significantly reduced cisplatin-induced increase in serum creatinine and BUN levels, serum ALT and AST activities and serum TG and TC levels.
7. Quercitrin (10 mg/kg) did not significantly affect cisplatin-induced elevation in serum creatinine and BUN levels, serum ALT and AST activities and serum TG and TC levels.
8. Quercitrin (20 mg/kg) significantly reduced cisplatin-induced increase in serum creatinine and BUN levels, serum ALT and AST activities and serum TG and TC levels.
9. Silymarin (100mg/kg), hesperidin (200 mg/kg), thymoquinone (50 mg/kg) or quercitrin (20 mg/kg),as a single treatments, did not significantly affect kidney and liver content of MDA, GSH and NO in normal animals.
10. Cisplatin (7.5 mg/kg) significantly elevated kidney and liver MDA and NO contents while significantly reduced kidney and liver GSH content.
11. Silymarin (100 mg/kg) significantly reduced cisplatin-induced increase in kidney and liver content of MDA and NO while it significantly increased cisplatin-induced decrease in kidney and liver content of GSH.
12. Hesperidin (100 mg/kg) significantly reduced cisplatin-induced increase in liver MDA and significantly elevated cisplatin-induced reduction in liver and kidney GSH contents while it did not significantly affect cisplatin-induced elevation in kidney MDA and liver and kidney NO contents.
13. Hesperidin (200 mg/kg) significantly reduced cisplatin-induced increase in in kidney and liver content of MDA and NO while it significantly increased cisplatin-induced decrease in kidney and liver content of GSH.
14. Thymoquinone (20, 50 mg/kg), in a dose-dependent manner,significantly reduced cisplatin-induced increase in kidney and liver content of MDA and NO while it significantly increased cisplatin-induced reduction in kidney and liver content of GSH.
15. Quercitrin (10 mg/kg) did not significantly affect cisplatin-induced increase in kidney and liver content of MDA and NO or cisplatin-induced decrease in kidney and liver content of GSH.
16. Quercitrin (20 mg/kg) significantly reduced cisplatin-induced increase in kidney and liver content of MDA and NO while it significantly increased cisplatin-induced reduction in kidney and liver content of GSH.
17. Histopathological examination of kidney and liver tissues of rats treated withsilymarin (100 mg/kg), hesperidin (200 mg/kg), thymoquinone (50 mg/kg) or quercitrin (20 mg/kg), as single treatments, did not show any significant disruption of the normal kidney and liver patterns.
18. Histopathological examination of groups treated with cisplatin (7.5 mg/kg) showed kidney damage manifested by coagulation necrosis in most of the tubules associated with congestion in the glomerular tuft and cystic dilatation as well as cast formation in the tubules.
19. Histopathological examination of groups treated withthe combination of silymarin (100 mg/kg), hesperidin (200 mg/kg), thymoquinone (50 mg/kg) or quercitrin (20 mg/kg) and cisplatinshowed very mild changes than those in cisplatin group indicating that they began to restore the normal appearance of kidney tissues.
20. Histopathological examination of groups treated with cisplatin (7.5 mg/kg) showed liver damage manifested by fatty degeneration of the hepatocytes and dilated congested portal vein with loss of normal hepatic architecture.
21. Histopathological examination of groups treated withthe combination of silymarin (100 mg/kg), hesperidin (200 mg/kg), thymoquinone (50 mg/kg) or quercitrin (20 mg/kg) and cisplatinshowed very mild changes compared to those in cisplatin group indicating that they began to restore the normal appearance of liver tissues.
22. Western blot analysis of kidney and liver tissues of rats treated with silymarin (100 mg/kg), hesperidin (200 mg/kg), thymoquinone (50 mg/kg) or quercitrin (20 mg/kg), as a single treatment, did not affect the expression level of NF-𝜅B and phosphorylated Akt protein as compared to normal group.
23. Cisplatin (7.5 mg/kg) increased the expression level of kidney and liver NF-𝜅B as compared to normal group.
24. Silymarin (100 mg/kg), hesperidin (200 mg/kg), thymoquinone (50 mg/kg) or quercitrin (20 mg/kg) decreased cisplatin-induced elevation in kidney and liver NF-𝜅B expression levels.
25. Cisplatin (7.5 mg/kg) decreased the expression level of kidney and liver phosphorylated Aktas compared to normal group.
26. Silymarin (100 mg/kg), hesperidin (200 mg/kg), thymoquinone (50 mg/kg) or quercitrin (20 mg/kg) elevated cisplatin-induced reduction in kidney and liver phosphorylated Aktexpression levels.
Invitrofindings:
27. Hesperidin, thymoquinone and quercitrin,as single treatments, produced a dose-dependent cytotoxic effect on both human breast adenocarcinoma (MCF-7) and human hepatocellular carcinoma (HepG-2) cells.
28. Combinations of hesperidin, thymoquinone or quercitrin with cisplatin did not alter the cytotoxic effect of cisplatinon both human breast adenocarcinoma (MCF-7) and human hepatocellular carcinoma (HepG-2) cells.
from the previous findings it could be concluded that:
1. Hesperidin, thymoquinone&quercitrinpossess no renotoxic or hepatotoxic effects on normal rats.
2. Cisplatin produces severe nephrotoxicity and hepatotoxicity in rats, where oxidative stress plays an important role as evidenced by increased kidney and liver contents of lipid peroxides, NO and depletion of GSH.
3. Cisplatin also induces inflammation and apoptosis as evidenced by increase in NF-𝜅B and decrease in phosphorylatedAktexpression levels.
4. Hesperidin, thymoquinone&quercitrin could be promising agentsfor clinical use as nephro&hepato protection against cisplatin-induced nephrotoxicity & hepatotoxicity. Their effects were similar to that of silymarin.
5. The most likely proposed mechanism for the renal and hepatic protection conferred by these drugs is related to their antioxidant properties
6. In addition, these drugs possess anti-inflamatory and anti-apoptic properties due their ability to inhibit cisplatin-induced increase in NF-𝜅B and decrease in phosphorylatedAktexpression levels.
7. Test drugs did not reduce the antitumor activity of cisplatin which is of value when combined together.
8. Consequently, test drugs can be used as protective agents against cisplatin-induced nephrotoxicity and hepatotoxicity without affecting its anticancer activity and this might have important applications for the use of cisplatin in cancer chemotherapy.
9. Further clinical studies are required to prove present findings.