Anti-Inflammatory Effects of Natural Triterpene QMs

FIGURE 8.1 Inhibition of the NF-kB signaling pathway with celastrol 76. 

The inhibition of the phosphorylation of IkBoc by celastrol in the NF-kB signaling pathway is not cell specific72-75 and thus significantly broadened the potential medicinal applications of natural triterpene QMs. Celastrol 76 has been evaluated in the treatment of Crohn s disease,76 which is a chronic relapsing inflammatory bowel disease. In the peripheral blood mononuclear cells, celastrol 76 reduced the levels of 

In the NF-kB pathway with celastrol 76, the inhibition of the iKBa degradation is due to the upstream blockage of the kinase activity and not by the direct inhibition of proteasome activity. On the contrary, direct inhibition of proteasome activity was observed with celastrol 76 and pristimerin 2 in prostate cancer cells.90-92 Both triterpene QMs directly inhibited the activity of the 20S subunits of proteasome at 2.5 iM and induced the accumulation of ubiquitinated proteins over time in cells, 

The structure-activity relation of triterpene QMs on the anti-inflammatory effect has been investigated with a series of analogues by comparing inhibition of the IL-1 (3 production in the LPS-induced monocytes.93-94 Clearly, the conjugated QM structure with alkenes is essential for the observed inhibition, and similar inhibitory effect was found with derivatives that are capable to form the conjugated QM through hydrolysis and/or oxidation.93-94 Also, the presence of the E ring in the triterpene QM structure is an additional contributor. 

---