Identification of pheophorbide a as an inhibitor of receptor for advanced glycation end products in Mallotus japonicus

Accumulation of advanced glycation end products (AGEs) plays an important role in diabetes, immunoinflammation, and cardiovascular and neurodegenerative diseases. Since AGEs mediate their pathological effects through interaction with receptor for AGEs (RAGE), RAGE antagonists would provide a useful therapeutic option for various health disorders. Therefore, in this study, we aimed to identify phytochemicals that would inhibit binding of AGEs to RAGE, which may help develop new drug leads and/or nutraceuticals for AGE-RAGE-related diseases. On screening ethanol extracts obtained from 700 plant Materials collected in Myanmar, we found that the ethanol extract from the leaves of Mallotus philippensis inhibited the binding of AGEs to RAGE. We also found that the leaves of M. japonicus, which belongs to the same genera and distributes abundantly in Japan, exhibited the inhibitory activity similar to M. philippensis. Activity-guided fractionation and LC/MS analysis of the ethanol extract of M. japonicus helped identify pheophorbide a (PPBa) as a major component in the active fraction, along with some other pheophorbide derivatives. PPBa exhibited potent inhibitory activity against AGE-RAGE binding, with an IC₅₀ value (0.102 μM) comparable to that of dalteparin (0.084 μM). PPBa may be a valuable natural product for use as a therapeutic agent and/or a nutraceutical against various health complications arising from activation of the AGE-RAGE axis.