الفهرس 
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Abstract
Our study estimated the therapeutic effect of MLT-NPs against hepatotoxicity and nephrotoxicity induced by 5-FU in rats. sixty male adult Sprague-Dawley rats were randomly divided into four groups. In 5-FU group, rats were received physiological saline for 14 days. On day 9, this group were received a 5-FU at a dose of 20 mg/kg b. wt. intraperitoneal for a further five days. In 5-FU + MLT-NPs, rats were received melatonin loaded nanoparticles (5 mg/kg. b. wt.) for 14 days intraperitoneally. This group were received 5-FU at a dose of 20 mg/kg intraperitoneally for a further five days. In MLT-NPs group, rats were received melatonin loaded nanoparticles (5 mg/kg. b. wt.) intraperitoneally for 14 days. Rats of Control group were received physiological saline intraperitoneally for 14 days.
Rats were sacrificed and blood samples were collected for biochemical analysis of liver function parameters (ALT and AST), kidney function parameters (urea and creatinine) in addition to oxidative stress indices (MDA and TAO). Specimens from liver and kidney were taken for histopathological examination.
Concerning the biochemical analysis of liver function test, the 5-FU administered group indicated a significant increase in the level of serum AST and ALT when compared with 5-FU + MLT-NPs group and the control group. 5-FU + MLT-NPs group was a significant decrease in serum AST and ALT in comparison with 5-FU administered group. Regarding the kidney function test, the 5-FU administered group showed a significant increase in the level of serum urea and creatinine when compared with 5-FU + MLT-NPs group and the control group. 5-FU + MLT-NPs group was a significant decrease in serum urea and creatinine in comparison with 5-FU administered group
The level of serum MDA presented a significant increase in 5-FU administered group when compared with 5-FU + MLT-NPs group and the control group. 5-FU + MLT-NPs group was significant decrease in serum MDA in comparison with 5-FU administered group. The serum level of TAO was significantly decreased in the 5-FU administered group when compared with 5-FU + MLT-NPs group and the control one. There was a significant increase in 5-FU and MLT group in comparison with 5-FU administered group.
Histopathological examination of HE stained tissue sections from the liver of the sacrified rats received 5-FU showed vascular changes and paranchymatous changes. Vascular changes including hyperemia of blood vessel, thrombosis endothelial inury and hemorrhage. Parenchymatous changes were in the form of apoptosis, vacuolar degeneration, kupffer cell proliferation, focal inflammatocy cell infiltration and hepatocellular necrois.
Examination of liver specimens from 5-FU + MLT-NPs group showed Mild Vascular changes including hyperemia of blood vessels,endothelial damage and Thrombosis. According to lesions score, the parenchymatous changes observed in 5FU+MLT-NPs group were less than those seen in 5-FU group. The lesions were less in number and severity. Examination of liver specimens from control group and MLT group exhibited normal architecture of hepatocyte .
Histopathological examination of kidney sections from rats received 5-FU showed mild vascular changes were in the form of congestion of blood vessels and hemorrhage. Vacuolation of the mesangial, endothelial and glomerular epithelial cells. Glomerular changes including thickening of glomerular basement membrane , necrosis of glomerular capillaries and mesangial cells, hyaline cast and atrophy of the glomerulus in which there was decrease in the size of glomerulus. The renal tubular changes were in the form of vacuolation of the renal tubular epithelium and focal interstitial infiltration of mononuclear inflammatory cells.
Examination of kidney specimens from rats in 5-FU + MLT-NPs group showed few vascular changes in the form of congestion of blood vessels and hemorrhage. According to lesions score, the glomerular and tublular changes observed in 5FU+MLT-NPs group were less than those seen in 5-FU group. The lesions were less in number and severity. The glomerular changes were in form of vacuolation of the mesangial, endothelial and glomerular epithelial cells and thickening of glomerular basment membrane. No hyaline cast or glomerular atrophy were observed. Examination of kidney specimens from MLT NPS group and control group demonstrated normal architecture with normal glomeruli and renal tubules.
Immunohistochemical examination of liver and kidneys of 5-FU group showed an apparent increase in caspase 3 expression. There was significant reduction in caspase 3 expression in 5-FU +MTL-NPs group.
from previous results, it was concluded that the administration of 5-FU induced serious histopathological lesions in liver and kidneys in rats. The lesions were associated with increase in oxidative stress and decrease in antioxidant enzymes. MLT-NPs administration ameliorated the hepatic and renal lesions induced by 5-FU administration in addition to improved liver and kidney function parameters and oxidative stress indices.