الفهرس 
LITERATURE REVIEWOnly 14 pages are availabe for public view
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Abstract
SUMMARY
Hepatocellular carcinoma (HCC), the most common neoplasm among primary liver malignancies, is the sixth most prevalent malignancy and the second-leading cause of cancer-related death worldwide. It is mostly associated with liver fibrosis or cirrhosis arising from persistent liver injuries. Disturbances in the hepatic antioxidant/oxidative stress and inflammatory systems have been implicated in the development and progression of cirrhosis to induce liver cancer. Additionally, overexpression of inflammatory cytokines linked to overproduction of reactive oxygen species (ROS) could inhibit apoptosis, presumably by activating the nuclear factor (NF)-κB-dependent pathway. Target-based therapy is widely regarded to represent the future treatment of cancer; and the stability of miRNAs in the circulation of both healthy and diseased tissue makes them ideal biomarkers for different diseases. Thus, successful miRNA-based therapy would certainly lead to improved efficacy.
Scientific interest in cancer management has been directed toward the utilization of natural products high in polyphenolic compounds due to their reported chemopreventive potential, and in an effort to prevent toxicities induced by carcinogenesis xenobiotics. The present study evaluated and compared the chemoprevention effects of pomegranate juice (PJ, 10 mL/ kg b.w) and punicalagin (PCG, 18.5 mg/ kg b.w) given orally and daily for 11 weeks on experimentally-induced hepatocellular carcinogenesis rat model by intraperitoneal injection of diethylnitrosamine (DENA, 50 mg / kg b.w, once weekly) for 9 consecutive weeks. Moreover, this study tested a potential signaling pathway by surveying oxidative stress, inflammation, and apoptosis with particular focus on miR-21 expression.
The results of the present study showed that the HCC (DENA-induced carcinogenesis) group had a significant decrease (P< 0.05–0.001, compared with the control group) in body weight, liver weight, serum total protein and IL-10 levels, and liver CAT and SOD activities. While, it showed a significant increase (P < 0.05–0.001, compared with the control group) in liver relative weight, serum ALAT activity, serum TNF-α levels, liver NF-κB-p65, MDA and NO levels and in the activity of liver GST. Additionally, HCC group showed a significant downregulation in hepatic caspase-3 and Bax mRNA expression (P < 0.05) accompanied by a significant upregulation in the Bcl-XL and Bcl-2 mRNA expression (P< 0.05 and P < 0.001, respectively). Also, the Bax/Bcl-2 ratio showed a significant decrease (P < 0.001) in the HCC group as compared to the control group. Moreover, HCC rats showed a significant upregulation in the expression of serum circulating miR-21 (P < 0.05) as compared to control rats.
On the other hand, oral treatment of the carcinogenesis rats with PJ significantly increased (P< 0.05-0.001, compared with the HCC group) body weight, serum total protein and IL-10 levels and significantly decreased (P < 0.05- 0.001, compared with the HCC group) the relative liver weight, serum ALAT, serum TNF-α and liver NF-κB-p65 levels. Additionally, oral treatment of the carcinogenesis rats with PJ led to a significant increase (P < 0.01–0.001) in the activity of liver CAT and SOD coupled with a significant decrease in the activity of GST (P < 0.05) and MDA and NO levels in liver as compared with the HCC group.
While, oral treatment of the carcinogenesis rats with PCG significantly increased (P < 0.01- 0.001) body weight and serum TNF-α level. Also, and PCG treatment increases IL-10 levels, however, the increase was statistically non-significant (P > 0.05) as compared with the HCC group. However, carcinogenesis rats that received PCG showed non-significant (P > 0.05) effect on the liver weight, the relative liver weight, serum total protein levels, serum ALAT activity or hepatic NF-κB-p65 level when compared with the HCC group. Additionally, oral treatment of the carcinogenesis rats with PCG led to a significant decrease in the hepatic activity of GST (P < 0.05), and a significant increase in liver SOD activity (P< 0.001) accompanied with a non-significant increase (P> 0.05) in liver CAT activity as compared with the HCC group. Also, treatment of the carcinogenesis group with PCG showed a significant decrease (P< 0.001, compared with the HCC group) in the elevations of liver MDA and NO levels that were reported in the HCC group.
Moreover, oral treatment of the carcinogenesis rats with either PJ or PCG improved the disturbances in apoptosis as shown by the significant upregulation (P < 0.001) in hepatic caspase-3 and Bax mRNA expression and the significant increased (P < 0.001) Bax/Bcl-2 ratio, coupled with a significant downregulation in hepatic Bcl-XL and Bcl-2 mRNA expression and serum circulating miR-21 (P < 0.001) as compared with HCC rats.
In conclusion, the present study revealed the chemopreventive role of PJ and PCG against hepatocarcinogenesis and elucidated their possible mechanisms of action. Both of PJ and PCG downregulated miR-21 expression and triggered apoptosis related genes expression. However; PJ was superior to pure PCG in improving the hepatic antioxidant defence state and the inflammatory status, which increases its’ chemoprevention effectiveness against DENA-induced hepatocellular carcinogenesis. So, further studies are required to provide the appropriate dose-response of PCG on HCC.