The dual-targeting mechanism of an anti-inflammatory diarylheptanoid from Curcuma zedoaria (Christm.) Roscoe with the capacity for β2-adrenoreceptor agonism and NLRP3 inhibition

Chronic obstructive pulmonary disease (COPD) is a common respiratory disease characterized by symptoms of shortness of breath and chronic inflammation. Curcuma zedoaria (Christm.) Roscoe is a well-documented traditional medical herb that is frequently used in the treatment of COPD. Previously, we identified a diarylheptanoid compound (1-(4-hydroxy-5-methoxyphenyl)-7-(4,5-dihydroxyphenyl)-3,5-dihydroxyheptane; abbreviated as HMDD) from this herb that exhibited potent agonistic activity on β2-adrenergic receptors (β2 adrenoreceptor) that are present on airway smooth muscle cells. In this work, we used chemically synthesized HMDD compound, and confirmed its bioactivity on β2 adrenoreceptors. Then by a proteomics study and anti-inflammatory evaluation detections, we found that HMDD downregulated the nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) signaling pathway and suppressed the NLRP3 receptor expression in RAW264.7 macrophages and in a COPD model in A549 lung carcinoma cells. HMDD also decreased nitric oxide production levels, and impacted other interleukins and the phosphorylation of NF-κB and ERK pathways. We performed molecular docking of HMDD on β2 adrenoreceptor and NLRP3 protein models. This work reports the anti-inflammatory effects of HMDD and suggests a dual-targeting mechanism of β2-adrenoreceptor agonism and NLRP3 inhibition. Such a mechanism scientifically supports the clinical uses of Curcuma zedoaria (Christm.) Roscoe in treating COPD, as it can simultaneously relieve persistent breathlessness and inflammation. HMDD can be considered as a potential non-steroidal anti-inflammatory drug in novel therapy design for the treatment of COPD and other inflammatory diseases.