Antiatherogenic effect of Pistacia lentiscus via GSH restoration and downregulation of CD36 mRNA expression


      Pistacia lentiscus var. Chia (Anacardiaceae) grows almost exclusively on Chios Island, Greece, and gives a resinous exudate resin used for culinary purposes by Mediterranean people. We investigated the molecular mechanisms through which total polar extract of the resin inhibits oxidized low-density lipoprotein (oxLDL) cytotoxic effect on peripheral blood mononuclear cell (PBMC). Cells exposed to oxLDL underwent apoptosis and necrosis, dependent on the duration of exposure. When culturing cells with oxLDL and the polar extract concurrently, we observed inhibition of both the phenomena. Because under oxidative stress the pro-oxidant systems outbalance the antioxidant, potentially producing oxidative damage and ultimately leading to cell death, we measured the levels of intracellular antioxidant glutathione (GSH). Additionally, we measured CD36 expression, a class B scavenger receptor, on CD14-positive cells, as CD36 has been identified as the oxLDL receptor in macrophages and may play a pivotal role in atherosclerotic foam cell formation. oxLDL decreased GSH levels and upregulated CD36 expression. P. lentiscus extract restored GSH levels and downregulated CD36 expression, even at the mRNA level. In order to find out the biologically drastic constituents of the resin’s polar extract, fractions derived from RP-HPLC analysis were examined for their antioxidant effect on oxidatively stressed PBMC. The triterpenoid fraction revealed remarkable increase in intracellular GSH. We suggest GSH restoration and downregulation of CD36 mRNA expression as the pathways via which P. lentiscus triterpenes exert antioxidant/antiatherogenic effect. Additionally, our results provide strong evidence of the resin’s antiatherogenic effect; therefore it is credited with beneficial health aspects.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Henriksen T.
        • Mahoney E.
        • Steinberg D.
        Enhanced macrophage degradation of low density lipoprotein previously incubated with cultured endothelial cells, recognition by receptors for acetylated low density lipoproteins.
        Proc. Natl. Acad. Sci. U.S.A. 1981; 78: 6499-6503
        • Steinberg D.
        • Parthasarathy S.
        • Carew T.E.
        • Khoo J.C.
        • Witztum J.L.
        Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenesity.
        N. Engl. J. Med. 1989; 320: 915-924
        • Fuhrman B.
        • Volkova N.
        • Aviram M.
        Oxidative stress increases the expression of the CD36 scavenger receptor and the cellular uptake of oxidized low-density lipoprotein in macrophages from atherosclerotic mice, protective role of antioxidants and of paraoxonase.
        Atherosclerosis. 2002; 161: 307-316
        • Steinbrecher U.P.
        Receptors for oxidized low density lipoprotein.
        Biochim. Biophys. Acta. 1999; 1436: 279-298
        • Silverstein R.
        • Febbraio L.M.
        CD36 and atherosclerosis.
        Curr. Opin. Lipidol. 2000; 11: 483-491
        • Yoshida H.
        • Quehenberger O.
        • Kondratenko N.
        • Green S.
        • Steinberg D.
        Minimally oxidized low-density lipoprotein increases expression of scavenger receptor A, CD36 and macrosialin in resident mouse peritoneal macrophages.
        Arterioscler Thromb. Vasc. Biol. 1998; 18: 794-802
        • Aviram M.
        Review on human studies on oxidative damage and antioxidant protection related to cardiovascular diseases.
        Free Radic. Res. 2000; 33: S85-S97
        • Deckert V.
        • Dersumaux C.
        • Athias A.
        • et al.
        Prevention of LDL α-tocopherol consumption, cholesterol oxidation, and vascular endothelium dysfanction by polyphenolic compounds from red wine.
        Atherosclerosis. 2002; 165: 41-50
        • Visioli F.
        • Poli A.
        • Galli C.
        Antioxidant and other biological activities of phenols from olives and olive oil.
        Med. Res. Rev. 2002; 22: 65-75
        • Andrikopoulos N.K.
        • Kaliora A.C.
        • Assimopoulou A.N.
        • Papageorgiou V.P.
        Inhibitory activity of minor polyphenolic and nonpolyphenolic constituents of olive oil against in vitro low-density lipoprotein oxidation.
        J. Med. Food. 2002; 5: 1-7
        • Andrikopoulos N.K.
        • Kaliora A.C.
        • Assimopoulou A.N.
        • Papageorgiou V.P.
        Biological activity of some naturally occurring resins, gums and pigments against the in vitro LDL oxidation.
        Phytother. Res. 2003; 17: 501-507
        • Al-Said M.S.
        • Aggel A.M.
        • Parmar N.
        • Tariq M.
        Evaluation of mastic, a crude drug obtained from Pistacia lentiscus for gastric and duodenal anti-ulcer activity.
        J. Ethnopharmacol. 1986; 15: 271-278
        • Huwez F.U.
        • Thirlwell D.
        • Al’Aldeen D.A.A.
        Mastic gum kills Helicobacter pylori.
        N Engl. J. Med. 1999; 339: 1946
        • Janakat S.
        • Al-Merie H.
        Evaluation of hepatoprotective effect of Pistacia lentiscus, Phillyrea latifolia and Nicotiana glauca.
        J. Ethnopharmacol. 2002; 83: 135-138
        • Janciauskiene S.
        • Moraga F.
        • Lindgren S.
        C-terminal fragment of alpha1-antitrypsin activates human monocytes to a pro-inflammatory state through interactions with the CD36 scavenger receptor and LDL receptor.
        Atherosclerosis. 2001; 158: 41-51
        • Fortun A.
        • Khalil A.
        • Gagne D.
        • et al.
        Monocytes influence the fate of T cells challenged with oxidised low density lipoproteins towards apoptosis or MHC-restricted proliferation.
        Atherosclerosis. 2001; 156: 11-21
        • Gutfinger T.
        Polyphenols in olive oil.
        J. Am. Oil Chem. Soc. 1981; 58: 966-968
        • Balla G.
        • Jacob H.S.
        • Eaton J.W.
        • Vercellotti G.M.
        Hemin. A possible physiological mediator of low density lipoprotein oxidation and endothelial Injury.
        Arterioscler. Thromb. 1991; 11: 1700-1711
        • Baxevanis C.N.
        • Reclos G.J.
        • Gritzapis A.D.
        • Dedoussis G.V.Z.
        • Missitzis I.
        • Papamichail M.
        Elevated prostaglandin E2 production by monocytes is responsible for the depressed levels of natural killer cell function in patients with breast cancer.
        Cancer. 1993; 72: 491-501
        • Dedoussis G.V.Z.
        • Mouzaki A.
        • Theodoropoulou M.
        • et al.
        Endogenous interleukin 6 conveys resistance to cis-diamminedichloroplatinum-mediated apoptosis of the K562 human leukemic cell line.
        Exp. Cell Res. 1999; 249: 269-278
        • Devaraj S.
        • Hugou I.
        • Jialal I.
        α-Tocopherol decreases CD36 expression in human monocyte-derived macrophages.
        J. Lipid Res. 2001; 42: 521-527
        • Andrikopoulos N.K.
        • Bruschweiler H.
        • Felber H.
        • Taeschler Ch.
        HPLC analysis of phenolic antioxidants, tocopherols and triglycerides.
        J. Am. Oil Chem. Soc. 1991; 68: 359-364
        • Kaliora A.C.
        • Mylona A.
        • Chiou A.
        • Petsios D.G.
        • Andrikopoulos N.K.
        Detection and identification of simple phenolics in Pistacia lentiscus resin, A.C.
        J. Liq. Chromatogr. Relat. Technol. 2004; 27: 289-300
        • Kerry N.
        • Abbey M.
        Red wine and fractionated phenolic compounds prepared from red wine inhibit low density lipoprotein oxidation in vitro.
        Atherosclerosis. 1999; 135: 93-102
        • Andrikopoulos N.K.
        • Kaliora A.C.
        • Assimopoulou A.N.
        • Papageorgiou V.P.
        Biological activity of saliva against in vitro LDL oxidation after chewing commercial chewing gums.
        Ital. J. Food Sci. 2002; 14: 279-289
        • Shen L.
        • Sevanian A.
        oxLDL induces macrophage α-GCS+HS protein expression: a role for oxLDL-associated lipid hydroperoxide in GSH synthesis.
        J. Lipid Res. 2001; 42: 813-823
        • Ghibelli L.
        • Fanelli C.
        • Rotilio G.
        • et al.
        Rescue of cells from apoptosis by inhibition of active GSH extrusion.
        FASEB J. 1998; 12: 479-486
        • Han C.Y.
        • Pak Y.K.
        Oxidation-dependent effects of oxidized LDL: proliferation or cell death.
        Exp. Mol. Med. 1999; 31: 165-173
        • Feng J.
        • Han J.
        • Pearce S.F.A.
        • et al.
        Induction of CD36 expression by oxidized LDL and IL-4 by a common signaling pathway dependent on protein kinase C and PPAR-α.
        J. Lipid Res. 2000; 41: 688-696
        • Papageorgiou V.P.
        • Bkolachristianopoulou M.N.
        • Apazidou K.K.
        • Psarros E.E.
        Gas chromatographic-mass spectroscopic analysis of the acidic triterpenic fraction of mastic gum.
        J. Chromatogr. A. 1997; 769: 263-273
        • Somova L.O.
        • Nadar A.
        • Rammanan P.
        • Shode F.O.
        Cardiovascular, antihyperlipidemic and antioxidant effects of oleanolic and ursolic acids in experimental hypertension.
        Phytomedicine. 2003; 10: 115-121
        • Somova L.I.
        • Shode F.O.
        • Ramnanan P.
        • Nadar A.
        Antihypertensive, antiatherosclerotic and antioxidant activity of triterpenoids isolated from Olea europaea, subspecies africana leaves.
        J. Ethnopharmacol. 2003; 84: 299-305
        • Ursini F.
        • Tubaro F.
        • Rong J.
        • Sevanian A.
        Optimization of nutrition: polyphenols and vascular protection.
        Nutr. Rev. 1999; 57: 241-249