Nrf2 is a transcription factor, that regulates the expression of antioxidant proteins. Besides, Nrf2 protects against oxidative damage triggered by injury and inflammation. Importantly, NRF2 appears to participate in a complex regulatory network and performs a pleiotropic role in the regulation of metabolism, inflammation, autophagy, proteostasis, mitochondrial physiology, and immune responses. Mainly, Nrf2 is accumulated in the cytoplasm at a low level caused by Kelch-like ECH-associated protein 1 (Keap1) to regulate proteasome-dependent degradation. So, It is feasible to produce a promising Nrf2 activator via the inhibition of Keap1.
Praelolide is a potent Nrf2 activator, suppresses osteoclastogenesis and ROS production.
From: Qi X, et al. Eur J Med Chem. 2022 Nov 24;246:114948.
Praelolide (10 µM) shows anti-osteoclastogenesis activities with an inhibitory ratio of 100% in bone marrow monocytes/macrophages (BMMs). Besides, Praelolide (1, 1.25, 5, 10 µM; 1-5 days) inhibits bone resorption of osteoclasts and actin ring formation in BMMs. Moreover, Praelolide (5, 10 µM) inhibits RANKL-induced mRNA levels of NFATc1, cathepsin K, MMP-9 and TRAP in BMMs. Moreover, Praelolide (5, 10 µM; 6 h) increases the protein expression of Nrf2, HO-1 and NQO1, enhancing the stability of the Nrf2 protein.
Praelolide (10 µM; 0-60 min) inhibits RANKL-induced NF-κB and MAPK signaling pathways and inhibits RANKL-induced phosphorylation of ERK, p38 MAPK, IKBα, and p65 NF-kB in pre-osteoclasts. Meanwhile, Praelolide (0, 20, 50, 100 µM; 24 h) interferes with the interaction between Keap1 and Nrf2 by binding to Keap1 protein in RAW264.7 cells. In addition, Praelolide (2, 5, 10 µM; co-treated for 6 days) remarkably increases the amount of bone mineralization in prednisolone-treated zebrafish larvae especially at the concentration of 5 μM which even excelled 10 μM Praelolide-treated group.
All in all, Praelolide is a potent Nrf2 activator and suppresses osteoclastogenesis and reactive oxygen species (ROS) production.