30^th Experts Meet On Cancer Therapy

Current data have shown that Punicalagin (PUN), an ellagitannin isolated from Pomegranate, possesses anti-inflammatory and anti-oxidant properties. However, its direct targets have not yet been reported. This is the first report that PTP1B serves as a direct target of PUN, with IC50 value of 1.04 μM. Results from NPOI further showed that the Kon and Koff of PUN-PTP1B complex were 3.38e2 M-1s-1 and 4.13e-3 s-1, respectively. Computation simulation by Autodock 4.0 predicted that PUN inhibited PTP1B via binding to Cys215, Arg221 and Arg24. Moreover, inhibition of PTP1B by PUN promoted an M2c macrophage polarization and enhanced anti-inflammatory expression, including IL-10 and M-CSF. Based on gene expression profile, we elucidated that PUN treatment significantly up-regulated 275 genes and down-regulated 1059 genes. M1 like macrophage marker genes, such as Tlr4, Irf1/2, Hmgb1 and Stat1 were down-regulated, while M2 marker genes, including Tmem171, Gpr35, Csf1, Il1rn, Cebpb, Fos, Vegfα, Slc11a1 and Bhlhe40 were up-regulated in PUN-treated macrophages. Hmox-1, a gene encoding HO-1 protein, was preferentially expressed with 16-fold change. Inhibition of HO-1 obviously restored PUN-induced M2 Polarization and IL-10 secretion. In addition, phosphorylation of both Akt and Stat3 contributed to PUN-induced HO-1 expression. This study provided new insights into the mechanisms of PUN-mediated Anti-Inflammatory and Anti-Oxidant activities and provided new therapeutic strategies for Inflammatory diseases.