الفهرس 
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Abstract
The present study provides much evidence of the preventive effect of eugenol on DENA/AAF-induced hepatocarcinogenicity and pulmonary carcinoma in Wistar rats.
In this study, the adult Wistar rats were divided into three groups, ten for each were designed as follow:
• group I (This group was kept as a normal group): The included rats of this group received, by i.p. route, the equivalent volume of saline (0.9% NaCl) at the beginning of experiment for 2 weeks (one time/week). Starting from the 3rd week, the rats received the equivalent volume of 1% tween 80, by oral gavage, four times per week for three weeks. This group was also orally given the equivalent volume 1% carboxymethylcellulose (CMC) (1 % w/v) as vehicle every other day till the end of the experiment.
• group II (DENA/AAF-administered group was kept as control): The animals within this group were given i.p. injection of DENA (150 mg/kg b.w./week for two weeks) dissolved in 0.9% saline. One week after the last injection of DENA, AAF (20 mg/kg b.w.) (de Lujan Alvarez et al., 2002) in 1 % tween 80 was administrated orally by gavage four days per week for three weeks, then rats were sacrificed after 17 weeks from the beginning of the experiment.
• group III (DENA/AAF-administered group treated with eugenol): This group was given DENA/AAF as group II and was orally treated with eugenol at a do;se of 20 mg/kg b.w. (Ferland et al., 2012) dissolved in 5 ml of 1% CMC (1 % w/v) and was administered to rats by oral gavage every other day for 17 weeks from the beginning of the experiment.
In the present study, the animals treated with DENA/AAF showed a significant liver damage manifested by the increased serum ALT, AST and ALP activities and total bilirubin level as well as the lowered albumin level. The treatment of DENA/AAF-administered rats with eugenol led to marked improvements in these liver function parameters in serum.
The obtained data also revealed a significant increase of AFP, CEA and CA19.9 levels in DENA/AAF-administered rats. The treatment of DENA/AAF-administered animals with eugenol successfully ameliorated these changes.
Regarding liver oxidative stress, the increase of LPO products were decreased in the DENA/AAF-adminstered rats due to eugenol treatment. Regarding antioxidant defense system, the depleted glutathione content as well as the decreased glutathione peroxidase and superoxide dismutase activities of DENA/AAF-administered rats were potentially increased as a result of eugenol administration.
Concerning inflammation, DENA/AAF-administered rats showed increase in the hepatic pro-inflammatory cytokines TNF-α and IL-1β and anti-inflammatory cytokine NF-κB as well as decreased Nrf2. while the treatment of these animals with eugenol decreased its levels as well as increased Nrf2.
The administration of DENA and AAF increased hepatic tissue Bcl-2 expression level, moreover, decreased in p53 and Bax expression levels in rats administered DENA and AAF but Bcl-2 was decreased as well as increased P53 and Bax in the DENA/AAF-administered rats treated with eugenol.
The administration of DENA and AAF increased hepatic Ki-67 level but the treatment of DENA/AAF-administered rats with eugenol improved its alteration.
These biochemical changes are concomitant with the liver histological ones that include changes like hepatocellular carcinoma cells, tumor nests surrounded with fibrous tissue, congested blood vessels and also inflammatory cell infiltrations, as tumor cells appeared with peripheral condensed chromatin in the nucleus, some hepatocytes have dark shrunken nuclei, activated Kupffer cells, hepatocytes with binucleated cells and hepatocytes with multi nuclei cells. The treatment of these animals with eugenol successfully prevented most of these biochemical and histological alterations.
Lung cancer induced by DENA/AAF 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 DENA/AAF-administered rats due eugenol treatment. Concerning antioxidant defense system, the depleted glutathione content as well as the decreased glutathione peroxidase and superoxide dismutase activities of DENA/AAF-administered rats were potentially increased as a result of eugenol administration.
In case of inflammation, the administration of DENA/AAF revealed the increase of pulmonary tissue TNF-α, IL-1β and NF-κB as well as decreased Nrf2. while the treatment of DENA/AAF-administered rats with eugenol decreased the elevated levels TNF-α, IL-1β and NF-κB as well as increased Nrf2.
In case of lung apoptosis, the increase of pulmonary tissue Bcl-2 expression level, moreover, decreased in p53 and Bax expression levels in rats administered DENA/AAF. Otherwise, eugenol treatment decreased these markers as well as p53 increased when compared to DENA/AAF-administered control group.
DENA/AAF administration was evidenced by increased pulmonary Ki-67 level while eugenol treatment decreased its elevation.
On the other hand, the lung of DENA/AAF-administered rats led to histological changes like diffuse thickening in interstitial tissue, Sheets of tumor cells with abundant cytoplasm and mostly vesicular nuclei with several conspicuous nucleoli, severe degenerated blood vessel, sloughing of cells into alveoli, micropapillary adenocarcinoma consists of small papillary clusters of glandular cells growing within this airspace, mild fibrotic thickening of the alveolar walls and lepidic pneumocytes and club cells proliferate to line alveolar walls, but lung section of DENA/AAF-administered rat treated with eugenol showed improvement in the histopathological deteriorated changes.
In conclusion, the possible preventive effect of eugenol on DENA/AAF-induced carcinogenesis and hepato-pulmonary carcinoma may be explained on the basis of oxidant-antioxidant system management, suppression of cell proliferation, modulation of the inflammatory status as well as activation of the apoptotic pathway. However, clinical studies are required to assess the safety and the efficacy of this agent in human beings.