Abstract
Carnosic acid (CA) and its semisynthetic derivatives display relevant gastroprotective effects on HCl/ethanol induced gastric lesions in mice. However, little is known on the mechanisms of action of the new compounds. The aim of the present work was to assess the gastroprotective action mechanisms of CA and its derivatives using human cell culture models. A human gastric adenocarcinoma cell line (AGS) and lung fibroblasts (MRC-5) were used to reveal the possible mechanisms involved. The ability of the compounds to protect cells against sodium taurocholate (NaT)-induced damage, and to increase the cellular reduced glutathione (GSH) and prostaglandin E2 (PGE2) content was determined using AGS cells. Stimulation of cell proliferation was studied employing MRC-5 fibroblasts. Carnosic acid and its derivatives 10–18 raised GSH levels in AGS cells. While CA did not increase the PGE2 content in AGS cells, all derivatives significantly stimulated PGE2 synthesis, the best effect being found for the 12-O-indolebutyrylmethylcarnosate 13. A significant increase in MRC-5 fibroblast proliferation was observed for the derivatives 7 and 16–18. The antioxidant effect of the compounds was assessed by the inhibition of lipid peroxidation in human erythrocyte membranes, scavenging of superoxide anion and DPPH discoloration assay. The new CA derivatives showed gastroprotective effects by different mechanisms, including protection against cell damage induced by NaT, increase in GSH content, stimulation of PGE2 synthesis and cell proliferation.
Highlights
Rosemary (Rosmarinus officinalis L.) is a shrub occurring in all countries of the Mediterranean basin and introduced into Latin America during the early Spanish conquest
Several reports suggest that the gastroprotective action mechanisms of terpenes are based mainly on the increase in the defensive factors of the gastric mucosa rather than on the inhibition of the gastric aggressive factors [3,11,19]
Studies carried out with terpenes include the works on the monoterpene limonene and the essential oil of Citrus aurantium [20], the diterpene solidagenone [11], as well as the triterpene oleanolic acid [12] and the diterpenes ferruginol [13], carnosic acid [3] as well as the Carnosic acid (CA) sources R. officinalis [2] and S. officinalis [5]
Summary
Rosemary (Rosmarinus officinalis L.) is a shrub occurring in all countries of the Mediterranean basin and introduced into Latin America during the early Spanish conquest. Some structure-activity relationships/trends of natural and semisynthetic diterpenes from the plant using the HCl/ethanol induced gastric ulcer lesions in mice have been published [3,4]. Carnosic acid (CA) is the main diterpene constituent of rosemary and it occurs in several Lamiaceae species, including Salvia officinalis [5]. Carnosic acid, belonging to the abietane skeleton, has been found to display several biological effects, including gastroprotective [2,4], chemopreventive, anti-inflammatory [6], antioxidant [6,7] and anti-adipogenic activity [8]. Most of the studies on the gastroprotective effect of abietane diterpenes were carried out using either the natural products or their semisynthetic derivatives. Carnosic acid and its semisynthetic derivatives display relevant gastroprotective effect on HCl/ethanol induced gastric lesions in mice [3,4]. Less is known on the action mechanisms involved in the gastroprotective effect of the products
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