Hepatocellular carcinoma (HCC) accounting about 75% of hepatic neoplasia, making it the most common kind of liver cancer worldwide. So, this study was planned to evaluate the beneficial chemopreventive efficacy of hesperidin (Hes) in experimental model of Diethyl nitrosamine (DEN) / Carbon tetrachloride (CCl4) –induced HCC in rats. Thirty male rats were divided into 3 equal groups. Group 1 (normal control): rats didn't receive any treatment. Group 2 (HCC): HCC was induced in rats by injection of DEN (200mg/kg b.w/i.p), then 2 weeks later of DEN injection rats received 3 weekly successive doses of CCl4 (3ml/kg b.wt/ orally) at 1:1 dilution in corn oil as a promoter of carcinogenic effect. DEN and CCl4 administration were repeated once again after 5 weeks. Group 3 (HCC+ hesperidin): 15 weeks after HCC induction, rats treated with Hes (150 mg/kg b.wt), orally and continued for 6 weeks. A significant increase in serum ALT, AST and ALP activities were observed in HCC-induced rats.  However, significant downregulation of liver Nrf2, Caspase-3, Bcl-2 and MicroRNA-34a with upregulation of FGF-2 and MicroRNA-221 with Global DNA hyper-methylation were observed in HCC group. Hesperidin treatment exhibited downregulation of microRNA-221 and FGF-2 with upregulation of Nrf2, Bcl-2, caspase 3 gene and Global DNA hypo-methylation. Interestingly, improvement of liver histopathological alterations supported the chemopreventive activity of Hesperidin. Conclusively, Hesperidin ameliorates the progression of HCC and has promising chemopreventive, and antiangiogenic activity, inhibiting growth promoting oncogene and initiation of gene regulating apoptosis and protects the liver from oxidative damage and inflammation.

This study investigated epigenetic mechanisms by which DNA methylation affects the function of bovine adaptive immune system cells, particularly during the peripartum period, when shifts in type 1 and type 2 immune response (IR) biases are thought to occur. Stimulation of CD4+ T-lymphocytes isolated from 5 Holstein dairy cows before and after parturition with concanavalin A (ConA) and stimulation of CD4+ T-lymphocytes isolated from 3 Holstein dairy cows in mid-lactation with ConA alone or ConA plus dexamethasone (Dex) had significant effects on production of the cytokines interferon gamma (IFN-γ, type 1) and interleukin 4 (IL-4, type 2) that were consistent with DNA methylation profiles of the IFN-γ gene promoter region but not consistent for the IL-4 promoter region. ConA stimulation increased the production of both cytokines before and after parturition. It decreased DNA methylation in the IFN-γ promoter region but increased for IL-4 promoter region. Parturition was associated with an increase in IFN-γ production in ConA-stimulated cells that approached significance. Overall, DNA methylation in both promoter regions increased between the prepartum and postpartum periods, although this did not correlate with secreted cytokine concentrations. Dexamethasone treated cells acted in a manner consistent with the glucocorticoid’s immunosuppressive activity, which mimicked the change at the IFN-γ promoter region observed during parturition. These results support pregnancy as type 2 IR biased, with increases of IFN-γ occurring after parturition and an increase in IL-4 production before calving. It is likely that these changes may be epigenetically controlled.