Group IIA Secretory PLA2 Inhibition by Ursolic Acid: A Potent Anti-Inflammatory Molecule

Abstract

Ursolic acid (3beta-hydroxy-urs-12-en-28-oic acid) isolated from many medicinal plants has diverse pharmacologically important properties, including strong anti-inflammatory activity. However its interaction with pro-inflammatory PLA2 is not known. Ursolic acid inhibited secretory PLA2 (sPLA2) enzymes purified from Vipera russelli, Naja naja venom and human pleural fluid and synovial fluid. IC50 values determined for these enzymes ranged from 12 to 18 microM. Group II secretory PLA2 from both venoms & human inflammatory source were found to be sensitive to inhibition in comparison with group I cobra venom sPLA2. Variation in Ca2+ concentration from 2.5-15 mM did not alter the level of inhibition. Similarly sPLA2 inhibition by ursolic acid is independent of substrate concentration. Ursolic acid interacts with purified venom sPLA2 enzymes and enhances relative fluorescence intensity in a dose dependent manner. In the presence of ursolic acid apparent shift in the far UV-CD spectra of sPLA2 was observed, indicating a direct interaction with the enzyme and formation of enzyme-ursolic acid complex. This complex results in irreversible inhibition of sPLA2 as evident by dialysis study. Inhibition of sPLA2 induced mouse paw edema and indirect hemolytic activity confirmed its sPLA2 inhibitory activity in vivo and in situ respectively. These studies revealed that the strong anti-inflammatory activity of ursolic acid is by inhibiting sPLA2 enzymes.

Ursolic and oleanolic acids as antimicrobial and immunomodulatory compounds for tuberculosis treatment

“…Interestingly, UA and OA antagonize TGF-β1 activity by blocking the binding of its specific receptor [21,22], which is the same function as the soluble receptor type 3 or betaglycan. Moreover, UA and OA also suppress prostaglandin production by blocking the binding of c-Jun to the response element of the COX-2 promoter, thus preventing the transcription of this enzyme [54], or by irreversible inhibition of secretory phospholipase A2 [55,56]. Thus, the restoration of the protective cytokine pattern observed in animals treated with UA or OA could be attributable to the modulating effect that they have on TGF-β and COX-2 activity.…”

Genistein, a potent inhibitor of secretory phospholipase A2: a new insight in down regulation of inflammation

“…At the concentration of 18 lM, oedema ratio was decreased significantly compared to controlled oedematous leg (P \ 0.01) which is in accordance with the in vitro and in situ sPLA 2 inhibition. The effect of genistein is comparable with ursolic acid which decreased oedema ratio of VRV-PL-V significantly at 15 lM concentration (Nataraj et al 2007) To investigate the systemic effect of genistein in inhibiting the oedema inducing activity of VRV-PL V, the genistein (21 lM) was administered i.p. half an hour before the administration of VRV-PL-V. Genistein partially inhibited (25%) the oedema inducing activity of VRV-PL-V enzyme.…”

“…IC 50 concentration was calculated by Boltzmann concentration response analysis using origin 6.1 software. Ursolic acid is a known inhibitor of sPLA 2 enzyme (Nataraj et al 2007) and used as positive control. Control experiments were performed with DMSO and the highest concentration of DMSO in reaction mixture is 0.03%.…”

Biochemical and pharmacological characterization of Trimersurus malabaricus snake venom

“…7,[15][16][17] Among these enzymes, proteases and PLA 2 enzymes are known to induce diversified pathological symptoms and are responsible for local tissue damage. 6,7,[18][19][20][21][22][23] Henceforth, the present report provides the major manifestation of T. malabaricus venom and toxicities that have not been well studied.…”