الفهرس 
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Abstract
The present study provides much evidence of the preventive effects of artichoke leaf and flower hydroethanolic extracts on DEN/2AAF-induced hepatocarcinogenicity, nephrotoxicity and lung-cancer in Wistar rats.
In this study, the adult Wistar rats were divided into four groups, six for each were designed as follow:
group I (Normal control group): Animals were given equivalent volume of saline (0.9% NaCl) intraperitoneally for 2 weeks (one time/week), in addition to equivalent volume of 1% carboxymethylcellulose (CMC) (1 % w/v) orally as vehicle every other day alternatively until the end of the experiment (17 weeks). Starting from the 3rd week, rats were given equivalent volume of 1% tween 80, orally four times per week for three weeks.
group II (DEN/2AAF-administered control group): The animals within this group received DEN (150 mg/kg b.w./week for two weeks) dissolved in 0.9% saline, intraperitoneally (Abdel-Moneim et al., 2017). Additionally, an equivalent volume of 1% carboxymethylcellulose (CMC) (1 % w/v) was administered by oral gavage. One week next the last injection of DEN, 2-AAF (20 mg/kg b.w) (de Lujan Alvarez et al., 2002) dissolved in 1 % tween 80 was given orally (4 times /week) for three weeks, then rats were sacrificed after 17 weeks from the beginning of the experiment.
group III (DEN/2AAF-administered group treated with Artichoke leaf extract (ALE): rats were given DEN/2AAF as in group II and was orally treated with artichoke leaf extract (ALE) at a dose of 100 mg/kg b.w. (Llorente et al., 2014) dissolved in 5 ml of 1% CMC (1 % w/v) for 17 weeks from the beginning of the experiment.
group IV (DEN/2AAF-administered group treated with artichoke flower extract (AFE): This group was given DEN/2AAF as group II and was treated orally with artichoke flower extract (AFE) at a dose of 100 mg/kg b.w. (Llorente et al., 2014) dissolved in 5 ml of 1% CMC (1 % w/v) for 17 weeks from the beginning of the experiment.
In the current study, the animals treated with DEN/2AAF showed hepatocellular carcinoma manifested by the increased serum ALT, AST, ALP and γGT activities and total bilirubin level besides lowering total protein and albumin levels. The treatment of DEN/2AAF-administered rats with artichoke leaf and flower hydroethanolic extracts led to marked amendment in these liver function parameters in serum.
The attained data also showed a significant increase of AFP and CEA levels in DEN/2AAF-administered rats. The treatment of DEN/2AAF-administered animals with artichoke leaf and flower hydroethanolic extracts provides significant improvement of these changes.
The administration of DEN and 2AAF increased the pro-inflammatory cytokines TNF-α and IL-1β but the treatments of DEN/2AAF-administered rats with artichoke leaf and flower hydroethanolic extracts improved these alterations. On the other hand, administration of DEN and 2AAF decreased the anti- inflammatory cytokines IL-4 and IL-10 but the treatments of DEN/2AAF-administered rats with artichoke leaf and flower hydroethanolic extracts also improved these alterations.
Concerning liver oxidative stress, the increase of LPO products were decreased in the DEN/2AAF-adminstered rats due artichoke leaf and flower hydroethanolic extracts treatment. Concerning antioxidant defense system, the depleted glutathione content as well as the decreased glutathione peroxidase, glutathione-S-transferase, glutathione reductase and superoxide dismutase activities of DEN/2AAF-administered rats were potentially increased as a result of artichoke leaf and flower hydroethanolic extracts administration.
The administration of DEN and 2AAF decreased mRNA gene expressions of hepatic tissue P53 and Bcl-2 while the treatment of these animals with artichoke leaf and flower hydroethanolic extracts increased its expression.
On the other hand, the liver of DEN/2AAF-administered rats led to histological change that show trabecular hepatocellular carcinoma, fibrolamellar hepatocellular carcinoma, clear-variant and sarcomatoid hepatocellular carcinoma, solid growth pattern HCC, biliary cirrhosis and well-differentiated HCC shows tumor cells with obvious resemblance to hepatocytes characterized by enlarged atypic nuclei with prominent nucleoli around normal hepatocytes. The treatment of these animals with artichoke leaf and flower hydroethanolic extracts successfully prevented most of these biochemical and histological alterations.
Nephrotoxicity-induced by DEN/2AAF was manifested by elevations in serum biochemical variables related to kidney dysfunction, creatinine, urea and uric acid concentrations, while the treatment of DEN/2AAF-administered rats with artichoke leaf and flower hydroethanolic extracts decreased the elevated levels of serum creatinine, urea and uric acid.
Regarding kidney oxidative stress the elevated kidney LPO products were potentially decreased in the DEN/2AAF-adminstered rats due to treatment with artichoke leaf and flower hydroethanolic extracts. Concerning antioxidant defense system, the depleted glutathione content as well as the decreased glutathione peroxidase, glutathione-S-transferase, glutathione reductase and superoxide dismutase activities of DEN/2AAF-administered rats were potentially increased as a result of artichoke leaf and flower hydroethanolic extracts treatment.
Regarding apoptosis, the current investigation showed a non-significant change of kidney the mRNA expression of p53, and a significant decrease in the mRNA expression of Bcl-2, in the kidney of DEN/2AAF-administered rats compared to the normal group. Otherwise, ALE and AFE produced non-significant change in p53. Bcl-2 mRNA expression level, on the other hand, significantly increased when compared to DEN/2AAFadministered control group reflecting the anti-apoptotic activities of both extracts.
Renal injury induced by DEN/2AAF-administration was confirmed by the histological changes including hyperplastic proliferation of the glomerulus, hyperemic medullary rays, sever congestion appear in the inter tubular blood vessels of renal cortex and medulla in addition to moderate vacular degeneration in the renal tubules.. The treatment of these animals with artichoke leaf and flower hydroethanolic extracts successfully improvement the histological alterations.
Lung cancer induced by DEN/2AAF was evidenced by changes in lung oxidative stress and antioxidant defense system. Regarding lung oxidative stress, the increase of LPO products were decreased in the DEN/2AAF-adminstered rats due artichoke leaf and flower hydroethanolic extracts treatment. Concerning antioxidant defense system, the depleted glutathione content as well as the decreased glutathione peroxidase, glutathione-S-transferase, glutathione reductase and superoxide dismutase activities of DEN/2AAF-administered rats were potentially increased as a result of artichoke leaf and flower hydroethanolic extracts administration.
The administration of DEN and 2AAF decreased mRNA gene expressions of pulmonary tissue P53 and Bcl-2 while the treatment of these animals with artichoke leaf and flower hydroethanolic extracts increased its expression.
On the other hand, the lung of DEN/2AAF-administered rats led to histological changes like peribronchial and perivascular aggregation of tumor cells. Lymph vessel occupied by numerous tumor cells, the neoplastic cells show polymorphism and mitotic figures but lung section of DEN/2AAF-administered rat treated with artichoke leaf and flower hydroethanolic extracts showed improvement in the histopathological deteriorated changes.
In conclusion, the possible preventive effects of artichoke leaf and flower hydroethanolic extracts on DEN/2AAF-induced hepatocarcinogenesity, nephrotoxicity and lung cancer may be explained on the basis of oxidant-antioxidant system management, regulation of the inflammatory status as well as modulation of the apoptotic pathway.