Thus, the ratio of Bax/Bcl-2 determines, in part, the susceptibility of cells to death signals and might be a critical factor in a cell��s threshold for apoptosis. In this study, the expression of Bax and Bcl-2 proteins in zebularine-treated HepG2 cells was A 286982 examined by western blot assay. We found that although Bax protein levels were not affected, Bcl-2 protein level was downregulated with zebularine treatment, which led to a marked increase in the Bax/Bcl-2 ratio and then apoptosis. Initially identified as an antiviral protein, PKR is best known for triggering cell defense responses and initiating innate immune responses by arresting general protein synthesis and inducing apoptosis during virus infection. Activated PKR, known as a eukaryotic initiation factor 2-alpha kinase, induces the phosphorylation of eIF-2a, which inhibits the initiation of translation through the tRNA-40S ribosomal subunit. On the other hand, PKR is involved in controlling the transcription of Bcl-2 in HepG2 cells, mediated by the transcription factor NF-kB. In this study, we observed that zebularine can reduce the phosphorylation of PKR, which indicates the activated PKR. In addition, overexpression of PKR reduced zebularine-induced cell death. Thus, our results suggest that zebularine decreases the activity of PKR and results in apoptotic cell death via reduced NFkB activity and the downregulation of Bcl-2. The fact that zebularine inhibits the growth of bladder, breast, and cervical cancer cells and that PKR is ubiquitously AC 265347 expressed led us to hypothesize that zebularine induced the cell growth arrest via the downregulation of PKR in other cancer cells. When we examined the effect of zebularine on PKR expression in HeLa cells, we observed, however, that zebularine did not decrease the phosphorylation of PKR and the total PKR level. These results suggest that there are differences in the mechanism by which zebularine inhibits cell growth among the different types of carcinomas. The action and mechanisms of zebularine must therefore be further investigated in other cancer cells. In conclusion, our observation indicated that zebularine inhibited cell growth and induced apoptotic cell death, which contributed to its antiproliferation effects against hepatocellular carcinoma HepG2 cells. The most likely mechanism underlying the zebularine-induced growth arrest involves an initial induction of p44/42 phosphorylation and an increase in p21WAF/CIP1 expression, which leads to a reduction in G1-related CDKs such as CDK2 protein and p-Rb, and then ultimately arrests the HepG2 cell cycle. Furthermore, zebularine decreased the activity of PKR, and resulted in apoptotic cell death via the downregulation of Bcl- 2. IL-15 is a pleiotropic and pro-inflammatory cytokine, is produced by activated blood monocytes, macrophages, dendritic cells, and activated glial cells. In the Texas Alzheimer��s Research and Care Consortium cohort, serum levels of IL-15 were significantly and negatively related to total neuropsychiatric symptoms and symptom of hyperactivity in patients with AD. In a cohort of AD patients, IL-15 was significantly related to basic activities of daily living in AD patients in a gender dependent manner. Lower levels of IL-15 were related to greater functional dependence for males whereas increased levels of IL-15 were related to greater dependence for females. IL-15 binds to its unique receptor, IL-15R��, as well as two co-receptors Interleukin – 2R? and IL-2R�� common chain. In addition to promoting T cell proliferation and inducing cytolytic effector cells, including natural killer and cytotoxic cells, IL-15 also stimulates B-cells to proliferate and secrete immunoglobulins.