Inhibition of Human Group IIA‐Secreted Phospholipase A₂ and THP‐1 Monocyte Recruitment by Maslinic Acid

Abstract

Maslinic acid is a natural pentacyclic triterpenoid which has anti-inflammatory properties. A recent study showed that secretory phospholipase A2 (sPLA2) may be a potential binding target of maslinic acid. The human group IIA (hGIIA)-sPLA2 is found in human sera and their levels are correlated with severity of inflammation. This study aims to determine whether maslinic acid interacts with hGIIA-sPLA2 and inhibits inflammatory response induced by this enzyme. It is shown that maslinic acid enhanced intrinsic fluorescence of hGIIA-sPLA2 and inhibited its enzyme activity in a concentration-dependent manner. Molecular docking revealed that maslinic acid binds to calcium binding and interfacial phospholipid binding site, suggesting that it inhibit access of catalytic calcium ion for enzymatic reaction and block binding of the enzyme to membrane phospholipid. The hGIIA-sPLA2 enzyme is also responsible in mediating monocyte recruitment and differentiation. Results showed that maslinic acid inhibit hGIIA-sPLA2-induced THP-1 cell differentiation and migration, and the effect observed is specific to hGIIA-sPLA2 as cells treated with maslinic acid alone did not significantly affect the number of adherent and migrated cells. Considering that hGIIA-sPLA2 enzyme is known to hydrolyze glyceroacylphospholipids present in lipoproteins and cell membranes, maslinic acid may bind and inhibit hGIIA-sPLA2 enzymatic activity, thereby reduces the release of fatty acids and lysophospholipids which stimulates monocyte migration and differentiation. This study is the first to report on the molecular interaction between maslinic acid and inflammatory target hGIIA-sPLA2 as well as its effect towards hGIIA-sPLA2-induced THP-1 monocyte adhesive and migratory capabilities, an important immune-inflammation process in atherosclerosis.

Small-molecule inhibitors as potential therapeutics and as tools to understand the role of phospholipases A2

“…Maslinic acid, a natural pentacyclic triterpenoid, was proved to interact directly with human GIIA sPLA 2 and inhibit the enzyme activity in a concentration-dependent manner, by binding to the calcium binding and phospholipid interfacial site. Maslinic acid also inhibited human GIIA sPLA 2 -induced THP-1 cell differentiation and migration [100].…”

Maslinic acid alleviates ischemia/reperfusion-induced inflammation by downregulation of NFκB-mediated adhesion molecule expression

“…Of interest, Yap et al . 48 reported that MA suppresses sPLA2-IIA-mediated monocyte migration. Hence, we suggest that this may have additionally contributed to the herein observed inhibition of macrophage recruitment in the dorsal skinfold chamber tissue of MA-treated animals.…”

Phospholipase A2 Drives Tumorigenesis and Cancer Aggressiveness through Its Interaction with Annexin A1

“…Maslinic acid, a natural pentacyclic triterpenoid, was proved to inhibit the sPLA 2 enzyme activity in a concentration-dependent manner. In addition, maslinic acid inhibits the inflammation induced by sPLA 2 , including PGE2 production and differentiation and migration of inflammatory cells [185,186]. Indeed, maslinic acid induces different anticancer effects in multiple tumors like those affecting the breast, prostate, pancreas, kidneys, lungs, and gastro-intestinal tract [187,188].…”