Azoramide, a powerful, orally bioavailable small molecule, functions as a modulator of the unfolded protein response (UPR). It enhances ER protein folding capabilities and increases the capacity of ER chaperones, providing protection against ER stress. Furthermore, azoramide mitigates ER stress induced by PLA2G6 mutations by adjusting the unfolded protein response, boosts CERB signaling to restore mitochondrial function, and prevents apoptosis in dopaminergic (DA) neurons. Its efficacy extends to anti-diabetic activities[1].[2].
体内研究
When administered orally at 150 mg/kg daily for seven days to Huh7 cells and ob/ob mice, azoramide significantly enhances glucose homeostasis in mice with genetic obesity. It also maintains beta-cell function and survival amidst metabolic ER stress[1].
体外研究
In Huh7 cells, azoramide, applied at concentrations ranging from 0.01 to 100 µM for durations of up to 24 hours, modulates ER folding and secretion capabilities without triggering ER stress[1].
At a concentration of 15 µM over 2 to 16 hours, it safeguards cells from ER stress induced experimentally. Azoramide effectively counteracts the secretion induced by Tunicamycin of ATF6LD-Cluc and reverses the Tm-caused reduction in ASGR-Cluc secretion. It also inhibits the Tm-induced expression of GRP78 and CHOP proteins[1].
In Hepa 1-6 cells treated with 15 µM azoramide for 2 to 16 hours, the drug modifies ER calcium homeostasis and retains a higher fraction of calcium within the ER[1].
In the context of neurodegeneration, azoramide, at concentrations up to 10 µM over five days, reduces the loss of PLA2G6D331Y/D331Y iPSC-derived midbrain DA neurons[2].
With a 10 µM dosage for five days, it lowers the rise in reactive oxygen species (ROS) and mitigates the decrease in mitochondrial membrane potential in these neurons. Additionally, the same concentration over a period of 0 to 30 days curbs mitochondrial fragmentation in PLA2G6D331Y/D331Y midbrain DA neurons[2].
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