p38 mitogen-activated protein kinase (MAPK) plays a key role in cellular response, proliferation, survival, cell cycle and cancer migration. Moreover, the p38 MAPK family includes p38α (MAPK14), p38β (MAPK11), p38γ (MAPK12), and p38δ (MAPK13). Besides, the four p38 MAPK family members have distinct tissue expression patterns, with p38α ubiquitously expressed at significant levels in most cell types. Among them, p38α consists of two domains, a 135-residue N-terminal domain mainly composed of β-sheets and a 225-residue C-terminal domain mainly composed of α-helices, with a catalytic site in between, namely ATP binding pocket. In addition, p38α is considered a potential target in a variety of diseases, including inflammatory diseases and cancer. p38α and p38β increase cell proliferation and invasion in the colon, follicular lymphoma, ovarian, and most recently pancreatic cancers.

Cyclocurcumin is a potent p38α inhibitor for rheumatoid arthritis research.

Cyclocurcumin is a potent p38α inhibitor. It shows antirheumatic, anti-vasoconstrictive, and antioxidant activities. In some in vitro studies, Cyclocurcumin (10-40 μM; 18 h) causes significant dose-dependent inhibition of TNF-α release in LPS-stimulated human macrophages. Firstly, it (5-25 μM) exhibits concentration-dependent (IC₅₀ = 14.9±1.0 μM) vasoconstriction induced by cyclophenylephrine in freshly isolated rat aorta. Secondly, Cyclocurcumin (5-25 μM; 30 min) inhibits intracellular calcium influx in a dose-dependent manner. In addition, it inhibits L-type calcium channel-mediated vasoconstriction in a concentration-dependent manner. Then, the anticontractile effect of Cyclocurcumin is reversible. Importantly, Cyclocurcumin has a strong activity of scavenging ˙OH and ˙OOH free radicals. Also, it’s 4′-OH phenolic free radicals preferentially scavenge ˙OH and ˙OOH free radicals through the atom transfer mechanism in water and the physiological environment.

In conclusion, Cyclocurcumin is a potent p38α inhibitor with antirheumatic, anti-vasoconstrictive, and antioxidant activities.

References:

[1] Min Fu, et al. Int J Mol Med. 2017 May;39(5):1164-1172. 

[2] Keunyoung Kim, et al. J Nat Prod. 2017 Jan 27;80(1):196-200.