الفهرس 
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Abstract
This study aimed to explore the possible hepatorenal protective effects of QRC nanoparticles against CYP-induced hepatorenal damage. Sixty male albino rats weighting 180 ± 20 gm were divided into four equal groups. CYP treated group (group A): included 15 rats that were injected with a dose of CYP (200 mg/kg) intraperitoneally on days 10, 17, and 24 of experiment. QRC-NPs and CYP treated group (group. B): included 15 rats that were administrated QRC-NPs orally at a dosage of (50 mg/kg) daily until the end of the experiment, they were also given a dose of CYP i.p. on days 10, 17, and 24 of the experiment. Control group (group. C): included 15 rats that were given a dose of saline on days 10, 17, and 24 of experiment. QRC-NPs only treated group (group. D): included 15 rats that were given QRC-NPs orally at the dose of (50 mg/kg) during the experiment. Five rats from each group at days 11, 18 and 25 of experiment were sacrificed. Samples were collected 24 hours after CYP injection for biochemical, histopathological and ultrastructural examinations.
Biochemical analysis of liver and kidney function tests and oxidative stress indices in the serum of CYP treated group after a single CYP dose revealed oxidative stress and disturbances in the liver and kidney function that appeared as significant elevation of the BUN, AST, ALT and MDA levels and markedly decreased the TAOC when compared to control rats. While injection of two or - and three CYP doses (200 mg/kg) with one-week intervals, significantly boosted the creatinine, BUN, total protein, AST, ALT, and MDA levels and significantly lowered the TAOC.
Biochemical results of QRC-NPs and CYP treated group significantly diminished the elevated AST and MDA levels and significantly elevated the diminished TAOC after a single CYP dose. While QRC-NPs significantly decreased the raised levels of creatinine, BUN, ALT and total protein and increased the lowered TAOC after two CYP dose. Besides, it significantly lowered the elevated levels of creatinine, AST, ALT and MDA levels and significantly augmented the decreased TAOC after three CYP dose in comparison to the CYP treated group.
Histopathological examination of the hepatic tissue section of the CYP-treated group after single CYP dose showed vascular changes, including a severe degree of congestion and dilatation of the central vein, as well as a moderate degree of the following lesions: portal blood vessel congestion, early-stage perivascular fibrosis and injury to the endothelial cell lining of blood vessels. Furthermore, necrobiotic changes such as liver cell vacuolation and coagulative necrosis of hepatocytes were seen. Then the hepatic damage was confirmed by TEM revealing nuclear chromatin lysis, mitochondrial swelling, dilation and swelling of RER and glycogen depletion.
The histopathological results for liver tissue after administration of two CYP doses to the CYP treated group were congestion of hepatic blood vessels similar to that seen after a single CYP dose, as well as hepatic sinusoidal dilatation that progressed to severe grade and severe grade of necrobiotic changes. The liver tissue also showed oval cell proliferation in the portal area. While TEM showed a nucleus with peripheral condensation of chromatin, mitochondria appeared shrunken and pyknotic. In other hepatocytes appeared swollen and more translucent hepatocytes cytoplasm with loss of organelles and more glycogen depletion.
Rats in CYP treated group (24hrs post 3rd dose of CYP) showed liver lesions in the form of vascular and parenchymal changes. The vascular changes included congestion and dilatation of the portal and central vein and hepatic sinusoid. Focal area of hemorrhage with lytic necrosis of hepatocytes and portal and perivascular fibrosis as well as oval cell proliferation were observed. The necrobiotic changes of hepatocytes showed the same severity that was seen after two CYP dose. Examination by TEM showed abundant fat globules, karyorrhexis and increased severity of earlier lesions that were seen after single and two CYP dose.
Histopathological examination of H&E-stained sections of kidney tissue 24 hrs later single CYP dose showed a moderate degree of congestion of blood vessels, mild degree of hemorrhage, severe degree of glomerular swelling due to glomerular capillary congestion with dilatation of bowman’s space, moderate degree of glomerular swelling due to proliferation of mesangial cells, moderate degree of proteinaceous cast, mild degree of coagulative necrosis, moderate degree of diffuse hemorrhagic nephritis and neutrophil cells infiltration .
The renal tissue histopathological findings of the CYP-treated group following two CYP doses were particular microscopical findings that were not seen after a single CYP dose which are moderate grade of the following lesions: vasculitis, focal segmental glomerulosclerosis, perivascular and interstitial fibrosis and thickening of bowman’s capsule and glomerular basement membrane, mild grade atrophy of glomerular capillary tuft and severe grade vacuolar degeneration of renal tubules epithelium. The glomerular swelling due to capillary congestion that was seen after a single CYP dose, progressed to moderate grade, while glomerular swelling due to mesangial cell proliferation was also seen but in the same earlier grade. Furthermore, the renal tubules showed moderate grade blood vessel congestion and interstitial hemorrhage and coagulative necrosis with proteinaceous cast as described previously after a single CYP dose but progressed to severe grade.
Regarding, the histopathological examination of renal tissue sections of the CYP-treated group after three CYP doses, similar histopathological lesions to that seen after two CYP doses were observed. However, the severity of glomerular atrophy, glomerular swelling due to capillary congestion and blood vessel congestion were increased more after three CYP doses. Transmission electron microscopy revealed podocyte swelling and thickening of the glomerular basement membrane. Examination of renal tubular epithelium revealed dispersion of nuclear chromatin, numerous vacuoles in the cytoplasm, fat globules, and lysosome granules, the mitochondria appeared hyperplastic with variations of their size and many of them appeared pyknotic and the lumen of tubules showed occluded with proteinaceous casts.
Histopathological examination of hepatic tissue of the QRC-NPs and CYP group after a single, two, and three CYP dose revealed mild hepatic lesions with high protection after three CYP doses as compared to CYP treated group. The overall lesions included mild vascular changes such as congestion of portal blood vessels, dilatation of hepatic sinusoid, injury of endothelial cell lining. Besides, absence of inflammatory cell infiltration, lytic necrosis of hepatocytes, hemorrhage, and fibrosis. The necrobiotic changes such as vacuolar degeneration and coagulative necrosis of hepatocytes appeared in mild grade. By TEM, there were mild alterations were recognized including less translucent area, Kupffer cells hypertrophy, dilated hepatic sinusoids, and hepatocyte appeared with normal mitochondria. The hepatic tissues were seen as normal particularly after administration of QRC-NPs before and along three CYP doses injections.
Examination of the kidney of rats in QRC-NPs and CYP treated group (day 11) revealed ameliorative effects were expressed by presence of mild to moderate degree of glomerular swelling due to mesangial cells proliferation or congestion of glomerular capillary and mild degree of the following lesions: congestion of blood vessel, thickening of glomerular basement membrane, proteinaceous cast, vacuolar degeneration, coagulative necrosis of renal tubules and focal hemorrhagic nephritis.
Rats in the QRC-NPs and CYP treated group (day 18) the revealed absence of most vascular, glomerular, and tubular lesions that were previously seen in CYP treated group after injection of two CYP doses. Furthermore, the glomerular swelling due to mesangial cell proliferation, vacuolar degeneration, and proteinaceous cast of renal tubules were ameliorated.
Examination of the kidneys of rats of QRC-NPs and CYP treated group (day 25) revealed strong protection from oxidative damage and turned renal tissue to nearly normal status. However, there were very mild glomerular alterations such as glomerular swelling either due to congestion of the glomerular capillary or proliferation of mesangial cells and renal tubules showed a mild degree of vacuolar degeneration.
The control group and QRC-NPs only treated group revealed the normal histological structure of both the liver and kidney.