TY - JOUR TI - Anti-inflammatory, epigenetic regulatory role of phytochemicals and pkpd modeling of pharmacological effects DO - https://doi.org/doi:10.7282/T32N54FN PY - 2016 AB - Chronic inflammation is considered to play an important factor in neoplastic progression via the induction of reactive oxygen, reactive nitrogen species and induction of growth promoting cytokines. Thus, it is very important to develop new drugs that can inhibit inflammation and prevent cancer formation or progression. Dietary phytochemicals are derived from natural sources and are found commonly in the fruits and vegetables consumed regularly as part of the diet. Understanding the mechanism by which the natural compounds inhibit inflammation and prevent cancers is very important and could pave way to developing new targets and drugs for chemoprevention. During my dissertation, I have studied the anti-inflammatory properties of phytochemicals like Curcumin, Phenethylisothiocyanate (PEITC) and Ursolic acid (UA). The importance of Nrf2, a transcription factor in attenuating inflammation was studied using macrophages from Nrf2 (+/+) and Nrf2 (-/-) mice. The results showed that Nrf2 plays a major role in the anti-inflammatory effects of Curcumin and PEITC as seen from the differences between Nrf2 (+/+) and Nrf2 (-/-) mice macrophages. The anti-inflammatory effect of Curcumin was further evaluated iii in rats. The results showed that Curcumin suppressed lipopolysaccharide (LPS) induced inflammation as well as some epigenetic modifying genes like DNA methyltransferases and Histone deacetylases. The pharmacological response was modeled using an indirect response approach.The epigenetic modulatory role of PEITC was tested in LNCaP (androgne sensitive human prostate adenocarcinoma) cells, the results revealed that PEITC inhibits DNA methylation and increased transcription of RASSF1A, a tumor suppressor gene and in turn promotes apoptosis. Ursolic acid (UA), a pentacyclic triterpenoid was studied for its anti-inflammatory and epigeneitc modulatory role in PTEN-CaP2 cells (Prostate specific PTEN null epithelial cell line). UA suppressed LPS induced inflammatory cytokines as well as inhibited HDAC protein expression along with increasing the expression of Nrf2 a master regulator of anti-oxidate stress response pathway and NQO1. Collectively, the results demonstrated the anti-inflammatory and epigenetic modulatory potential of phytochemicals in vitro and in vivo. KW - Pharmaceutical Science KW - Phytochemicals KW - Inflammation LA - eng ER -