Phytosterols and Triterpenoids for Prevention and Treatment of Metabolic-related Liver Diseases and Hepatocellular Carcinoma

Author(s): Isabel Sánchez-Crisóstomo, Eduardo Fernández-Martínez *, Raquel Cariño-Cortés , Gabriel Betanzos-Cabrera, Rosa A. Bobadilla-Lugo.

Journal Name: Current Pharmaceutical Biotechnology

Volume 20 , Issue 3 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Background: Liver ailments are among the leading causes of death; they originate from viral infections, chronic alcoholism, and autoimmune illnesses, which may chronically be precursors of cirrhosis; furthermore, metabolic syndrome may worsen those hepatopathies or cause Non-alcoholic Fatty Liver Disease (NAFLD) that may advance to non-alcoholic steatohepatitis (NASH). Cirrhosis is the late-stage liver disease and can proceed to hepatocellular carcinoma (HCC). Pharmacological treatment options for liver diseases, cirrhosis, and HCC, are limited, expensive, and not wholly effective. The use of medicinal herbs and functional foods is growing around the world as natural resources of bioactive compounds that would set the basis for the development of new drugs.

Review and Conclusion: Plant and food-derived sterols and triterpenoids (TTP) possess antioxidant, metabolic-regulating, immunomodulatory, and anti-inflammatory activities, as well as they are recognized as anticancer agents, suggesting their application strongly as an alternative therapy in some chronic diseases. Thus, it is interesting to review current reports about them as hepatoprotective agents, but also because they structurally resemble cholesterol, sexual hormones, corticosteroids and bile acids due to the presence of the steroid nucleus, so they all can share pharmacological properties through activating nuclear and membrane receptors. Therefore, sterols and TTP appear as a feasible option for the prevention and treatment of chronic metabolic-related liver diseases, cirrhosis, and HCC.

Keywords: Hepatocellular carcinoma, liver, metabolic syndrome, nuclear receptors, phytosterols, triterpenes.

[1]
Cowan, M.M. Plant products as antimicrobial agents. Clin. Microbiol. Rev., 1999, 12(4), 564-582.
[2]
Ganesan, K.; Jayachandran, M.; Xu, B. A critical review on hepatoprotective effects of bioactive food components. Crit. Rev. Food Sci. Nutr., 2017, 1-65.
[3]
Opara, E.C.; Rockway, S.W. Antioxidants and micronutrients. Dis. Mon., 2006, 52(4), 151-163.
[4]
Zaloga, G.P. Phytosterols, lipid administration, and liver disease during parenteral nutrition. J. Parenter. Enteral Nutr., 2015, 39(1S), 39S-60S.
[5]
Karin, M.; Dhar, D. Liver carcinogenesis: from naughty chemicals to soothing fat and the surprising role of NRF2. Carcinogenesis, 2016, 37(6), 541-546.
[6]
Ghany, M.; Hoofnagle, J.H. In Harrison’s Internal Medicine; Kasper, D.L., Ed.; McGraw-Hill: New York, 2004, Vol. 2, pp. 1808-1812.
[7]
Saleem, T.M.; Chetty, C.M.; Ramkanth, S.; Rajan, V.; Kumar, K.M.; Gauthaman, K. Hepatoprotective herbs-a review. Int. J. Pharm. Sci. Res., 2010, 1(1), 1-5.
[8]
Worman, H.J. The Liver Disorders Sourcebook, 1st ed; Lowell House: Chicago, 1999.
[9]
Vuda, M.; D’Souza, R.; Upadhya, S.; Kumar, V.; Rao, N.; Kumar, V.; Boillat, C.; Mungli, P. Hepatoprotective and antioxidant activity of aqueous extract of Hybanthus enneaspermus against CCl4-induced liver injury in rats. Exp. Toxicol. Pathol., 2012, 64(7-8), 855-859.
[10]
Michael, M.D.; Kulkarni, R.N.; Postic, C.; Previs, S.F.; Shulman, G.I.; Magnuson, M.A.; Kahn, C.R. Loss of insulin signaling in hepatocytes leads to severe insulin resistance and progressive hepatic dysfunction. Mol. Cell, 2000, 6(1), 87-97.
[11]
Adeva-Andany, M.M.; Pérez-Felpete, N.; Fernández-Fernández, C.; Donapetry-García, C.; Pazos-García, C. Liver glucose metabolism in humans. Biosci. Rep., 2016, 36(6), e00416.
[12]
Mato, J.M.; Martínez-Chantar, M.L.; Lu, S.C. S-adenosyl-methionine metabolism and liver disease. Ann. Hepatol., 2015, 12(2), 183-189.
[13]
Mittal, S.; El-Serag, H.B. Epidemiology of HCC: consider the population. J. Clin. Gastroenterol., 2013, 47, S2.
[14]
Yip, T.C.F.; Chan, H.L.Y.; Wong, V.W.S.; Tse, Y.K.; Lam, K.L.Y.; Wong, G.L.H. Impact of age and gender on risk of hepatocellular carcinoma after hepatitis B surface antigen seroclearance. J. Hepatol., 2017, 67(5), 902-908.
[15]
Recio-Boiles, A.; Babiker, H.M. Cancer, Liver 2017, 1st ed; StatPearls: Florida, 2017.
[16]
O’neill, S.; O’driscoll, L. Metabolic syndrome: A closer look at the growing epidemic and its associated pathologies. Obes. Rev., 2015, 16(1), 1-12.
[17]
Alberti, K.G.M.; Zimmet, P.; Shaw, J. The metabolic syndrome - a new worldwide definition. Lancet, 2005, 366(9491), 1059-1062.
[18]
Grundy, S.M. Metabolic syndrome pandemic. Arterioscler. Thromb. Vasc. Biol., 2008, 28(4), 629-636.
[19]
Wellen, K.E.; Hotamisligil, G.S. Inflammation, stress, and diabetes. J. Clin. Invest., 2005, 115(5), 1111-1119.
[20]
Stocker, R.; Keaney, J.F. Role of oxidative modifications in atherosclerosis. Physiol. Rev., 2004, 84(4), 1381-1478.
[21]
Bonomini, F.; Rodella, L.F.; Rezzani, R. Metabolic syndrome, aging and involvement of oxidative stress. Aging Dis., 2015, 6(2), 109.
[22]
Byrne, C.D. Dorothy Hodgkin Lecture 2012 Non‐alcoholic fatty liver disease, insulin resistance and ectopic fat: A new problem in diabetes management. Diabet. Med., 2012, 29(9), 1098-1107.
[23]
Kantartzis, K.; Machann, J.; Schick, F.; Fritsche, A.; Häring, H.U.; Stefan, N. The impact of liver fat vs. visceral fat in determining categories of prediabetes. Diabetologia, 2010, 53(5), 882-889.
[24]
Gao, Z.; Zhang, J.; Kheterpal, I.; Kennedy, N.; Davis, R.J.; Ye, J. Sirtuin 1 (SIRT1) protein degradation in response to persistent c-Jun N-terminal kinase 1 (JNK1) activation contributes to hepatic steatosis in obesity. J. Biol. Chem., 2011, 286(25), 22227-22234.
[25]
Samuel, V.T.; Liu, Z.X.; Qu, X.; Elder, B.D.; Bilz, S.; Befroy, D.; Romanelli, A.J.; Shulman, G.I. Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease. J. Biol. Chem., 2004, 279(31), 32345-32353.
[26]
Mehal, W.Z. The Gordian Knot of dysbiosis, obesity and NAFLD. Nat. Rev. Gastroenterol. Hepatol., 2013, 10(11), 637.
[27]
Byrne, C.D.; Targher, G. Ectopic fat, insulin resistance, and nonalcoholic fatty liver disease: Implications for cardiovascular disease. Arterioscler. Thromb. Vasc. Biol., 2014, 34(6), 1155-1161.
[28]
Li, X.; Gao, Y.; Xu, H.; Hou, J.; Gao, P. Diabetes mellitus is a significant risk factor for the development of liver cirrhosis in chronic hepatitis C patients. Sci. Rep., 2017, 7(1), 9087.
[29]
Donadon, V.; Balbi, M.; Casarin, P.; Vario, A.; Alberti, A. Association between hepatocellular carcinoma and type 2 diabetes mellitus in Italy: potential role of insulin. World J. Gastroenterol., 2008, 14(37), 5695.
[30]
Girish, C.; Pradhan, S.C. Indian herbal medicines in the treatment of liver diseases: problems and promises. Fundam. Clin. Pharmacol., 2012, 26(2), 180-189.
[31]
Hovenkamp, E.; Demonty, I.; Plat, J.; Lütjohann, D.; Mensink, R.P.; Trautwein, E.A. Biological effects of oxidized phytosterols: A review of the current knowledge. Prog. Lipid Res., 2008, 47(1), 37-49.
[32]
Guardiola, F.; Codony, R.; Addis, P.; Rafecas, M.; Boatella, J. Biological effects of oxysterols: Current status. Food Chem. Toxicol., 1996, 34(2), 193-211.
[33]
Sottero, B.; Gamba, P.; Gargiulo, S.; Leonarduzzi, G.; Poli, G. Cholesterol oxidation products and disease: An emerging topic of interest in medicinal chemistry. Curr. Med. Chem., 2009, 16(6), 685-705.
[34]
Piironen, V.; Lindsay, D.G.; Miettinen, T.A.; Toivo, J.; Lampi, A.M. Plant sterols: Biosynthesis, biological function and their importance to human nutrition. J. Sci. Food Agric., 2000, 80(7), 939-966.
[35]
Brufau, G.; Canela, M.A.; Rafecas, M. Phytosterols: physiologic and metabolic aspects related to cholesterol-lowering properties. Nutr. Res., 2008, 28(4), 217-225.
[36]
Demel, R.A.; De Kruyff, B. The function of sterols in membranes. Biochim. Biophys. Acta, 1976, 457(2), 109-132.
[37]
Schuler, I.; Milon, A.; Nakatani, Y.; Ourisson, G.; Albrecht, A.M.; Benveniste, P.; Hartman, M.A. Differential effects of plant sterols on water permeability and on acyl chain ordering of soybean phosphatidylcholine bilayers. Proc. Natl. Acad. Sci. USA, 1991, 88(16), 6926-6930.
[38]
Guy, R.K. Inhibition of sonic hedgehog autoprocessing in cultured mammalian cells by sterol deprivation. Proc. Natl. Acad. Sci. USA, 2000, 97(13), 7307-7312.
[39]
Karpen, H.E.; Bukowski, J.T.; Hughes, T.; Gratton, J.P.; Sessa, W.C.; Gailani, M.R. The sonic hedgehog receptor patched associates with caveolin-1 in cholesterol-rich microdomains of the plasma membrane. J. Biol. Chem., 2001, 276(22), 19503-19511.
[40]
Li, J.; Nagpal, P.; Vitart, V.; McMorris, T.C.; Chory, J. A role for brassinosteroids in light-dependent development of Arabidopsis. Science, 1996, 272(5260), 398-401.
[41]
Svoboda, J.A.; Weirich, G.F. Sterol metabolism in the tobacco hornworm, Manduca sexta-a review. Lipids, 1995, 30(3), 263-267.
[42]
Corio-Costet, M.; Chapuis, L.; Mouillet, J.; Delbecque, J. Sterol and ecdysteroid profiles of Serratula tinctoria (L.): Plant and cell cultures producing steroids. Insect Biochem. Mol. Biol., 1993, 23(1), 175-180.
[43]
Brunt, S.A.; Silver, J.C. Molecular cloning and characterization of two distinct hsp 85 sequences from the steroid responsive fungus Achlya ambisexualis. Curr. Genet., 1991, 19(5), 383-388.
[44]
Benveniste, P. Biosynthesis and accumulation of sterols. Annu. Rev. Plant Biol., 2004, 55, 429-457.
[45]
Raju, M.; Babu, D.; Kumar, B.; Rajashekar, C. The role of phytosterols enriched foods-a review. IOSR J. Environ. Sci. Toxicol. Food Technol., 2013, 7, 40-47.
[46]
Gylling, H.; Simonen, P. Phytosterols, phytostanols, and lipoprotein metabolism. Nutrients, 2015, 7(9), 7965-7977.
[47]
Valsta, L.; Lemström, A.; Ovaskainen, M.L.; Lampi, A.M.; Toivo, J.; Korhonen, T.; Piironen, V. Estimation of plant sterol and cholesterol intake in Finland: quality of new values and their effect on intake. Br. J. Nutr., 2004, 92(4), 671-678.
[48]
Klingberg, S.; Andersson, H.; Mulligan, A.; Bhaniani, A.; Welch, A.; Bingham, S.; Khaw, K.; Andersson, S.; Ellegård, L. Food sources of plant sterols in the EPIC Norfolk population. Eur. J. Clin. Nutr., 2008, 62(6), 695.
[49]
Bacchetti, T.; Masciangelo, S.; Bicchiega, V.; Bertoli, E.; Ferretti, G. Phytosterols, phytostanols and their esters: From natural to functional foods. Med. J. Nutrition Metab., 2011, 4(3), 165-172.
[50]
Moreau, R.A.; Whitaker, B.D.; Hicks, K.B. Phytosterols, phytostanols, and their conjugates in foods: Structural diversity, quantitative analysis, and health-promoting uses. Prog. Lipid Res., 2002, 41(6), 457-500.
[51]
Dufourc, E.J. Sterols and membrane dynamics. J. Chem. Biol., 2008, 1(1-4), 63-77.
[52]
Schaller, H. The role of sterols in plant growth and development. Prog. Lipid Res., 2003, 42(3), 163-175.
[53]
Kangsamaksin, T.; Chaithongyot, S.; Wootthichairangsan, C.; Hanchaina, R.; Tangshewinsirikul, C.; Svasti, J. Lupeol and stigmasterol suppress tumor angiogenesis and inhibit cholangiocarcinoma growth in mice via downregulation of tumor necrosis factor-α. PLoS One, 2017, 12(12), e0189628.
[54]
Smet, E.D.; Mensink, R.P.; Plat, J. Effects of plant sterols and stanols on intestinal cholesterol metabolism: Suggested mechanisms from past to present. Mol. Nutr. Food Res., 2012, 56(7), 1058-1072.
[55]
Amiot, M.J.; Knol, D.; Cardinault, N.; Nowicki, M.; Bott, R.; Antona, C.; Borel, P.; Bernard, J.P.; Duchateau, G.; Lairon, D. Phytosterol ester processing in the small intestine: Impact on cholesterol availability for absorption and chylomicron cholesterol incorporation in healthy humans. J. Lipid Res., 2011, 52(6), 1256-1264.
[56]
Halling, K.K.; Slotte, J.P. Membrane properties of plant sterols in phospholipid bilayers as determined by differential scanning calorimetry, resonance energy transfer and detergent-induced solubilization. Biochim. Biophys. Acta Biomembr., 2004, 1664(2), 161-171.
[57]
Awad, A.; Chen, Y.C.; Fink, C.; Hennessey, T. Beta-Sitosterol inhibits HT-29 human colon cancer cell growth and alters membrane lipids. Anticancer Res., 1996, 16(5A), 2797-2804.
[58]
Ratnayake, W.; Plouffe, L.; L’Abbé, M.; Trick, K.; Mueller, R.; Hayward, S. Comparative health effects of margarines fortified with plant sterols and stanols on a rat model for hemorrhagic stroke. Lipids, 2003, 38(12), 1237-1247.
[59]
Jones, P.J.; Raeini-Sarjaz, M.; Jenkins, D.J.; Kendall, C.W.; Vidgen, E.; Trautwein, E.A.; Lapsley, K.G.; Marchie, A.; Cunnane, S.C.; Connelly, P.W. Effects of a diet high in plant sterols, vegetable proteins, and viscous fibers (dietary portfolio) on circulating sterol levels and red cell fragility in hypercholesterolemic subjects. Lipids, 2005, 40(2), 169-174.
[60]
Awad, A.B.; Hartati, M.S.; Fink, C.S. Phytosterol feeding induces alteration in testosterone metabolism in rat tissues. J. Nutr. Biochem., 1998, 9(12), 712-717.
[61]
Hendriks, H.; Brink, E.; Meijer, G.; Princen, H.; Ntanios, F. Safety of long-term consumption of plant sterol esters-enriched spread. Eur. J. Clin. Pharmacol., 2003, 57(5), 681-692.
[62]
Hong, M.; Li, S.; Tan, H.Y.; Wang, N.; Tsao, S.W.; Feng, Y. Current status of herbal medicines in chronic liver disease therapy: The biological effects, molecular targets and future prospects. Int. J. Mol. Sci., 2015, 16(12), 28705-28745.
[63]
Siddique, H.R.; Saleem, M. Beneficial health effects of lupeol triterpene: A review of preclinical studies. Life Sci., 2011, 88(7-8), 285-293.
[64]
Baptissart, M.; Vega, A.; Maqdasy, S.; Caira, F.; Baron, S.; Lobaccaro, J.M.A.; Volle, D.H. Bile acids: From digestion to cancers. Biochimie, 2013, 95(3), 504-517.
[65]
Nagao, K.; Yanagita, T. Bioactive lipids in metabolic syndrome. Prog. Lipid Res., 2008, 47(2), 127-146.
[66]
Hiebl, V.; Ladurner, A.; Latkolik, S.; Dirsch, V.M. Natural products as modulators of the nuclear receptors and metabolic sensors LXR, FXR and RXR. Biotechnol. Adv., 2018, 36(6), 1657-1698.
[67]
Grover, J.; Vats, V. Shifting paradigm: From conventional to alternative medicines an introduction on traditional Indian medicines. Asia Pac. Biotech. News, 2001, 5(01), 28-32.
[68]
Awad, A.B.; Toczek, J.; Fink, C.S. Phytosterols decrease prostaglandin release in cultured P388D1/MAB macrophages. Prostaglandins Leukot. Essent. Fatty Acids, 2004, 70(6), 511-520.
[69]
Saleem, M. Lupeol, a novel anti-inflammatory and anti-cancer dietary triterpene. Cancer Lett., 2009, 285(2), 109-115.
[70]
Islam, M.S.; Yoshida, H.; Matsuki, N.; Ono, K.; Nagasaka, R.; Ushio, H.; Guo, Y.; Hiramatsu, T.; Hosoya, T.; Murata, T. Antioxidant, free radical-scavenging, and NF-κB–inhibitory activities of phytosteryl ferulates: Structure-activity studies. J. Pharmacol. Sci., 2009, 111(4), 328-337.
[71]
Aldini, R.; Micucci, M.; Cevenini, M.; Fato, R.; Bergamini, C.; Nanni, C.; Cont, M.; Camborata, C.; Spinozzi, S.; Montagnani, M. Antiinflammatory effect of phytosterols in experimental murine colitis model: Prevention, induction, remission study. PLoS Med., 2014, 9(9), e108112.
[72]
Craig, W.J. Health effects of vegan diets. Am. J. Clin. Nutr., 2009, 89(5), 1627S-1633S.
[73]
Fraser, G.E. Associations between diet and cancer, ischemic heart disease, and all-cause mortality in non-Hispanic white California Seventh-day Adventists. Am. J. Clin. Nutr., 1999, 70(3), 532s-538s.
[74]
Key, T.J.; Appleby, P.N.; Spencer, E.A.; Travis, R.C.; Roddam, A.W.; Allen, N.E. Mortality in British vegetarians: Results from the European prospective investigation into cancer and nutrition (EPIC-Oxford). Am. J. Clin. Nutr., 2009, 89(5), 1613S-1619S.
[75]
Dewell, A.; Weidner, G.; Sumner, M.D.; Chi, C.S.; Ornish, D. A very-low-fat vegan diet increases intake of protective dietary factors and decreases intake of pathogenic dietary factors. J. Am. Diet. Assoc., 2008, 108(2), 347-356.
[76]
Nair, P.P. Diet, nutrition intake and metabolism in populations at high and low risk for colon cancer. Am. J. Clin. Nutr., 1984, 40(4), 880-886.
[77]
Raicht, R.F.; Cohen, B.I.; Fazzini, E.P.; Sarwal, A.N.; Takahashi, M. Protective effect of plant sterols against chemically induced colon tumors in rats. Cancer Res., 1980, 40(2), 403-405.
[78]
Deschner, E.; Cohen, B.; Raicht, R. The kinetics of the protective effect of β-sitosterol against MNU-induced colonic neoplasia. J. Cancer Res. Clin. Oncol., 1982, 103(1), 49-54.
[79]
Awad, A.B.; Hernandez, A.Y.; Fink, C.S.; Mendel, S.L. Effect of dietary phytosterols on cell proliferation and protein kinase C activity in rat colonic mucosa. Nutr. Cancer, 1997, 27(2), 210-215.
[80]
Awad, A.B.; Fink, C.S. Phytosterols as anticancer dietary components: evidence and mechanism of action. J. Nutr., 2000, 130(9), 2127-2130.
[81]
Awad, A.B.; Fink, C.; Williams, H.; Kim, U. In vitro and in vivo (SCID mice) effects of phytosterols on the growth and dissemination of human prostate cancer PC-3 cells. Eur. J. Cancer Prev., 2001, 10(6), 507-513.
[82]
Koczurkiewicz, P.; Czyż, J.; Podolak, I.; Wójcik, K.; Galanty, A.; Janeczko, Z.; Michalik, M. Multidirectional effects of triterpene saponins on cancer cells-mini-review of in vitro studies. Acta Biochim. Pol., 2015, 62(3), 383-393.
[83]
Safe, S.H.; Prather, P.L.; Brents, L.K.; Chadalapaka, G.; Jutooru, I. Unifying mechanisms of action of the anticancer activities of triterpenoids and synthetic analogs. Anticancer. Agents Med. Chem., 2012, 12(10), 1211-1220.
[84]
Ramprasath, V.R.; Awad, A.B. Role of phytosterols in cancer prevention and treatment. J. AOAC Int., 2015, 98(3), 735-738.
[85]
Bradford, P.G.; Awad, A.B. Modulation of signal transduction in cancer cells by phytosterols. Biofactors, 2010, 36(4), 241-247.
[86]
Spector, A.A.; Yorek, M.A. Membrane lipid composition and cellular function. J. Lipid Res., 1985, 26(9), 1015-1035.
[87]
Leikin, A.I.; Brenner, R.R. Fatty acid desaturase activities are modulated by phytosterol incorporation in microsomes. Biochim. Biophys. Acta, 1989, 1005(2), 187-191.
[88]
Schweikert, H.; Tunn, U.; Habenicht, U.F.; Arnold, J.; Senge, T.; Schulze, H.; Schröder, F.; Blom, J.; Ennemoser, O.; Horniger, W. Effects of estrogen deprivation on human benign prostatic hyperplasia. J. Steroid Biochem. Mol. Biol., 1993, 44(4-6), 573-576.
[89]
Peterson, D. Effect of soybean sterols in the diet on plasma and liver cholesterol in chicks. Proc. Soc. Exp. Biol. Med., 1951, 78(1), 143-147.
[90]
Peterson, D.; Nichols, C.; Shneour, E.; Gaffey, H.; Robbins, R.; Peek, N. Some relationships among dietary sterols, plasma and liver cholesterol levels, and atherosclerosis in chicks: One figure. J. Nutr., 1952, 47(1), 57-65.
[91]
Kobayashi, M.; Hamada, T.; Goto, H.; Imaizumi, K.; Ikeda, I. Comparison of effects of dietary unesterified and esterified plant sterols on cholesterol absorption in rats. J. Nutr. Sci. Vitaminol., 2008, 54(3), 210-214.
[92]
Pollak, O. Successful prevention of experimental hypercholesteremia and cholesterol atherosclerosis in the rabbit. Circulation, 1953, 7(5), 696-701.
[93]
Lees, A.M.; Mok, H.Y.; Lees, R.S.; McCluskey, M.A.; Grundy, S.M. Plant sterols as cholesterol-lowering agents: Clinical trials in patients with hypercholesterolemia and studies of sterol balance. Atherosclerosis, 1977, 28(3), 325-338.
[94]
Heinemann, T.; Kullak-Ublick, G.A.; Pietruck, B.; Von Bergmann, K. Mechanisms of action of plant sterols on inhibition of cholesterol absorption. Eur. J. Clin. Pharmacol., 1991, 40(1), S59-S63.
[95]
Mattson, F.H.; Grundy, S.M.; Crouse, J.R. Optimizing the effect of plant sterols on cholesterol absorption in man. Am. J. Clin. Nutr., 1982, 35(4), 697-700.
[96]
Field, F.J.; Mathur, S.N. Beta-Sitosterol: Esterification by intestinal acyl-coenzyme A: cholesterol acyltransferase (ACAT) and its effect on cholesterol esterification. J. Lipid Res., 1983, 24(4), 409-417.
[97]
Spilburg, C.A.; Goldberg, A.C.; McGill, J.B.; Stenson, W.F.; Racette, S.B.; Bateman, J.; McPherson, T.B.; Ostlund, R.E. Fat-free foods supplemented with soy stanol-lecithin powder reduce cholesterol absorption and LDL cholesterol. J. Am. Diet. Assoc., 2003, 103(5), 577-581.
[98]
Doornbos, A.; Meynen, E.; Duchateau, G.; Van Der Knaap, H.; Trautwein, E. Intake occasion affects the serum cholesterol lowering of a plant sterol-enriched single-dose yoghurt drink in mildly hypercholesterolaemic subjects. Eur. J. Clin. Nutr., 2006, 60(3), 325-333.
[99]
Söderholm, P.; Alfthan, G.; Koskela, A.; Adlercreutz, H.; Tikkanen, M. The effect of high-fiber rye bread enriched with nonesterified plant sterols on major serum lipids and apolipoproteins in normocholesterolemic individuals. Nutr. Metab. Cardiovasc. Dis., 2012, 22(7), 575-582.
[100]
Jakulj, L.; Vissers, M.N.; Rodenburg, J.; Wiegman, A.; Trip, M.D.; Kastelein, J.J. Plant stanols do not restore endothelial function in pre-pubertal children with familial hypercholesterolemia despite reduction of low-density lipoprotein cholesterol levels. J. Pediatr., 2006, 148(4), 495-500.
[101]
De Jongh, S.; Vissers, M.; Rol, P.; Bakker, H.; Kastelein, J.; Stroes, E. Plant sterols lower LDL cholesterol without improving endothelial function in prepubertal children with familial hypercholesterolaemia. J. Inherit. Metab. Dis., 2003, 26(4), 343-352.
[102]
Hallikainen, M.; Lyyra-Laitinen, T.; Laitinen, T.; Ågren, J.J.; Pihlajamäki, J.; Rauramaa, R.; Miettinen, T.A.; Gylling, H. Endothelial function in hypercholesterolemic subjects: effects of plant stanol and sterol esters. Atherosclerosis, 2006, 188(2), 425-432.
[103]
Raitakari, O.T.; Salo, P.; Gylling, H.; Miettinen, T.A. Plant stanol ester consumption and arterial elasticity and endothelial function. Br. J. Nutr., 2008, 100(3), 603-608.
[104]
Ntanios, F.Y.; Jones, P.J.; Frohlich, J.J. Dietary sitostanol reduces plaque formation but not lecithin cholesterol acyl transferase activity in rabbits. Atherosclerosis, 1998, 138(1), 101-110.
[105]
Plat, J.; Beugels, I.; Gijbels, M.J.; de Winther, M.P.; Mensink, R.P. Plant sterol or stanol esters retard lesion formation in LDL receptor-deficient mice independent of changes in serum plant sterols. J. Lipid Res., 2006, 47(12), 2762-2771.
[106]
Weingärtner, O.; Lütjohann, D.; Ji, S.; Weisshoff, N.; List, F.; Sudhop, T.; von Bergmann, K.; Gertz, K.; König, J.; Schäfers, H.J. Vascular effects of diet supplementation with plant sterols. J. Am. Coll. Cardiol., 2008, 51(16), 1553-1561.
[107]
Preetha, S.; Kanniappan, M.; Selvakumar, E.; Nagaraj, M.; Varalakshmi, P. Lupeol ameliorates aflatoxin B1-induced peroxidative hepatic damage in rats. Comp. Biochem. Physiol. C Toxicol. Pharmacol., 2006, 143(3), 333-339.
[108]
Bhandari, P.; Patel, N.K.; Bhutani, K.K. Synthesis of new heterocyclic lupeol derivatives as nitric oxide and pro-inflammatory cytokine inhibitors. Bioorg. Med. Chem. Lett., 2014, 24(15), 3596-3599.
[109]
Ezzat, S.M.; Abdallah, H.M.; Fawzy, G.A.; El-Maraghy, S.A. Hepatoprotective constituents of Torilis radiata Moench (Apiaceae). Nat. Prod. Res., 2012, 26(3), 282-285.
[110]
Khan, M.F.; Maurya, C.K.; Dev, K.; Arha, D.; Rai, A.K.; Tamrakar, A.K.; Maurya, R. Design and synthesis of lupeol analogues and their glucose uptake stimulatory effect in L6 skeletal muscle cells. Bioorg. Med. Chem. Lett., 2014, 24(12), 2674-2679.
[111]
Lakshmi, V.; Mahdi, A.A.; Ahmad, M.K.; Agarwal, S.K.; Srivastava, A.K. Antidiabetic activity of lupeol and lupeol esters in streptozotocin-induced diabetic rats. Bangladesh Pharm. J., 2015, 17(2), 138-146.
[112]
Fukuda, Y.; Sakai, K.; Matsunaga, S.; Tokuda, H.; Tanaka, R. Cancer chemopreventive effect of orally administrated lupane-type triterpenoid on ultraviolet light B induced photocarcinogenesis of hairless mouse. Cancer Lett., 2006, 240(1), 94-101.
[113]
Hata, K.; Hori, K.; Takahashi, S. Differentiation-and apoptosis-inducing activities by pentacyclic triterpenes on a mouse melanoma cell line. J. Nat. Prod., 2002, 65(5), 645-648.
[114]
Mutai, C.; Abatis, D.; Vagias, C.; Moreau, D.; Roussakis, C.; Roussis, V. Cytotoxic lupane-type triterpenoids from Acacia mellifera. Phytochemistry, 2004, 65(8), 1159-1164.
[115]
Chaturvedi, P.K.; Bhui, K.; Shukla, Y. Lupeol: Connotations for chemoprevention. Cancer Lett., 2008, 263(1), 1-13.
[116]
Lee, T.K.; Poon, R.T.; Wo, J.Y.; Ma, S.; Guan, X.Y.; Myers, J.N.; Altevogt, P.; Yuen, A.P. Lupeol suppresses cisplatin-induced nuclear factor-κB activation in head and neck squamous cell carcinoma and inhibits local invasion and nodal metastasis in an orthotopic nude mouse model. Cancer Res., 2007, 67(18), 8800-8809.
[117]
Prasad, S.; Kalra, N.; Shukla, Y. Hepatoprotective effects of lupeol and mango pulp extract of carcinogen induced alteration in Swiss albino mice. Mol. Nutr. Food Res., 2007, 51(3), 352-359.
[118]
Kallubai, M.; Rachamallu, A.; Yeggoni, D.P.; Subramanyam, R. Comparative binding mechanism of lupeol compounds with plasma proteins and its pharmacological importance. Mol. Biosyst., 2015, 11(4), 1172-1183.
[119]
Salazar, J.R.; Martínez-Vazquez, M.; Cespedes, C.L.; Ramírez-Apan, T.; Nieto-Camacho, A.; Rodriguez-Silverio, J.; Flores-Murrieta, F. Anti-inflammatory and cytotoxic activities of chichipegenin, peniocerol, and macdougallin isolated from Myrtillocactus geometrizans (Mart. ex Pfeiff.) Con. Z. Naturforsch. C, 2011, 66(1-2), 24-30.
[120]
Bolaños-Carrillo, M.A.; Ventura-Gallegos, J.L.; Saldivar-Jiménez, A.D.; Zentella-Dehesa, A.; Martínez-Vázquez, M. Effect of sterols isolated from Myrtillocactus geometrizans on growth inhibition of colon and breast cancer cells. J. Evid. Based Complementary Altern. Med., 2015, 2015, 589350.
[121]
Choi, Y.H.; Kong, K.R.; Kim, Y.; Jung, K.O.; Kil, J.H.; Rhee, S.H.; Park, K.Y. Induction of Bax and activation of caspases during β-sitosterol-mediated apoptosis in human colon cancer cells. Int. J. Oncol., 2003, 23(6), 1657-1662.
[122]
Matsuda, H.; Akaki, J.; Nakamura, S.; Okazaki, Y.; Kojima, H.; Tamesada, M.; Yoshikawa, M. Apoptosis-inducing effects of sterols from the dried powder of cultured mycelium of Cordyceps sinensis. Chem. Pharm. Bull., 2009, 57(4), 411-414.
[123]
Kim, Y.S.; Li, X.F.; Kang, K.H.; Ryu, B.; Kim, S.K. Stigmasterol isolated from marine microalgae Navicula incerta induces apoptosis in human hepatoma HepG2 cells. BMB Rep., 2014, 47(8), 433.
[124]
Qi, W.Y.; Li, Y.; Hua, L.; Wang, K.; Gao, K. Cytotoxicity and structure activity relationships of phytosterol from Phyllanthus emblica. Fitoterapia, 2013, 84, 252-256.
[125]
Seo, D.Y.; Lee, S.R.; Heo, J.W.; No, M.H.; Rhee, B.D.; Ko, K.S.; Kwak, H.B.; Han, J. Ursolic acid in health and disease. Korean J. Physiol. Pharmacol., 2018, 22(3), 235-248.
[126]
Mettlin, C. Recent developments in the epidemiology of prostate cancer. Eur. J. Cancer, 1997, 33(3), 340-347.
[127]
Hirano, T.; Homma, M.; Oka, K. Effects of stinging nettle root extracts and their steroidal components on the Na+, K+-ATPase of the benign prostatic hyperplasia. Planta Med., 1994, 60(1), 30-33.
[128]
Nishizuka, Y. Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C. Science, 1992, 258(5082), 607-614.
[129]
Hannun, Y.A.; Linardic, C.M. Sphingolipid breakdown products: anti-proliferative and tumor-suppressor lipids. Biochim. Biophys. Acta. Biomembr., 1993, 1154(3-4), 223-236.
[130]
Key, T.J.; Allen, N.E.; Spencer, E.A.; Travis, R.C. The effect of diet on risk of cancer. Lancet, 2002, 360(9336), 861-868.
[131]
Awad, A.B.; Garcia, M.; Fink, C. Effect of dietary phytosterols on rat tissue lipids. Nutr. Cancer, 1997, 29(3), 212-216.
[132]
von Holtz, R.L.; Fink, C.S.; Awad, A.B. Beta‐Sitosterol activates the sphingomyelin cycle and induces apoptosis in LNCaP human prostate cancer cells. Nutr. Cancer, 1998, 32(1), 8-12.
[133]
Wolff, R.A.; Dobrowsky, R.T.; Bielawska, A.; Obeid, L.M.; Hannun, Y.A. Role of ceramide-activated protein phosphatase in ceramide-mediated signal transduction. J. Biol. Chem., 1994, 269(30), 19605-19609.
[134]
Awad, A.B.; Gan, Y.; Fink, C.S. Effect of beta-sitosterol, a plant sterol, on growth, protein phosphatase 2A, and phospholipase D in LNCaP cells. Nutr. Cancer, 2000, 36(1), 74-78.
[135]
Gómez-Muñoz, A. Ceramide‐1‐phosphate: A novel regulator of cell activation. FEBS Lett., 2004, 562(1-3), 5-10.
[136]
Andrieu-Abadie, N.; Levade, T. Sphingomyelin hydrolysis during apoptosis. Biochim. Biophys. Acta, 2002, 1585(2), 126-134.
[137]
Jayadev, S.; Liu, B.; Bielawska, A.E.; Lee, J.Y.; Nazaire, F.; Pushkareva, M.Y.; Obeid, L.M.; Hannun, Y.A. Role for ceramide in cell cycle arrest. J. Biol. Chem., 1995, 270(5), 2047-2052.
[138]
Kolesnick, R. The therapeutic potential of modulating the ceramide/sphingomyelin pathway. J. Clin. Invest., 2002, 110(1), 3-8.
[139]
Duan, R.D. Alkaline sphingomyelinase: An old enzyme with novel implications. Biochim. Biophys. Acta, 2006, 1761(3), 281-291.
[140]
Hertervig, E.; Nilsson, Å.; Nyberg, L.; Duan, R.D. Alkaline sphingomyelinase activity is decreased in human colorectal carcinoma. Cancer, 1997, 79(3), 448-453.
[141]
Wu, J.; Cheng, Y.; Nilsson, Å.; Duan, R.D. Identification of one exon deletion of intestinal alkaline sphingomyelinase in colon cancer HT-29 cells and a differentiation-related expression of the wild-type enzyme in Caco-2 cells. Carcinogenesis, 2004, 25(8), 1327-1333.
[142]
Vivancos, M.; Moreno, J.J. Beta-Sitosterol modulates antioxidant enzyme response in RAW 264.7 macrophages. Free Radic. Biol. Med., 2005, 39(1), 91-97.
[143]
Woyengo, T.; Ramprasath, V.; Jones, P. Anticancer effects of phytosterols. Eur. J. Clin. Nutr., 2009, 63(7), 813-820.
[144]
Shahzad, N.; Khan, W.; Shadab, M.; Ali, A.; Saluja, S.S.; Sharma, S.; Al-Allaf, F.A.; Abduljaleel, Z.; Ibrahim, I.A.A.; Abdel-Wahab, A.F. Phytosterols as a natural anticancer agent: Current status and future perspective. Biomed. Pharmacother., 2017, 88, 786-794.
[145]
Moon, D.O.; Lee, K.J.; Choi, Y.H.; Kim, G.Y. β-Sitosterol-induced-apoptosis is mediated by the activation of ERK and the downregulation of Akt in MCA-102 murine fibrosarcoma cells. Int. J. Immunopharmacol., 2007, 7(8), 1044-1053.
[146]
Park, C.; Moon, D.O.; Rhu, C.H.; Choi, B.T.; Lee, W.H.; Kim, G.Y.; Choi, Y.H. β-Sitosterol induces anti-proliferation and apoptosis in human leukemic U937 cells through activation of caspase-3 and induction of Bax/Bcl-2 ratio. Biol. Pharm. Bull., 2007, 30(7), 1317-1323.
[147]
Awad, A.B.; Chinnam, M.; Fink, C.; Bradford, P. β-Sitosterol activates Fas signaling in human breast cancer cells. Phytomedicine, 2007, 14(11), 747-754.
[148]
Markov, V.A.; Zenkova, A.M.; Logashenko, B.E. Modulation of tumour-related signaling pathways by natural pentacyclic triterpenoids and their semisynthetic derivatives. Curr. Med. Chem., 2017, 24(13), 1277-1320.
[149]
Rubis, B.; Paszel, A.; Kaczmarek, M.; Rudzinska, M.; Jelen, H.; Rybczynska, M. Beneficial or harmful influence of phytosterols on human cells? Br. J. Nutr., 2008, 100(6), 1183-1191.
[150]
Guseva, N.V.; Taghiyev, A.F.; Rokhlin, O.W.; Cohen, M.B. Contribution of death receptor and mitochondrial pathways to Fas‐mediated apoptosis in the prostatic carcinoma cell line PC3. Prostate, 2002, 51(4), 231-240.
[151]
Bouic, P.; Etsebeth, S.; Liebenberg, R.; Albrecht, C.; Pegel, K.; Van Jaarsveld, P. Beta-sitosterol and beta-sitosterol glucoside stimulate human peripheral blood lymphocyte proliferation: Implications for their use as an immunomodulatory vitamin combination. Int. J. Immunopharmacol., 1996, 18(12), 693-700.
[152]
Bouic, P.J. The role of phytosterols and phytosterolins in immune modulation: A review of the past 10 years. Curr. Opin. Clin. Nutr. Metab. Care, 2001, 4(6), 471-475.
[153]
Moreno, J.J. Effect of olive oil minor components on oxidative stress and arachidonic acid mobilization and metabolism by macrophages RAW 264.7. Free Radic. Biol. Med., 2003, 35(9), 1073-1081.
[154]
Wal, A.; Srivastava, R.; Wal, P.; Rai, A.; Sharma, S. Lupeol as a magical drug. Pharm. Biol. Eval., 2015, 2(5), 142-151.
[155]
Awad, A.B.; Williams, H.; Fink, C.S. Phytosterols reduce in vitro metastatic ability of MDA-MB-231 human breast cancer cells. Nutr. Cancer, 2001, 40(2), 157-164.
[156]
Ostlund, R.E. Phytosterols in human nutrition. Annu. Rev. Nutr., 2002, 22(1), 533-549.
[157]
Duboc, H.; Taché, Y.; Hofmann, A.F. The bile acid TGR5 membrane receptor: From basic research to clinical application. Dig. Liver Dis., 2014, 46(4), 302-312.
[158]
Chow, M.D.; Lee, Y.H.; Guo, G.L. The role of bile acids in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Mol. Aspects Med., 2017, 56, 34-44.
[159]
Li, T.; Chiang, J.Y. Nuclear receptors in bile acid metabolism. Drug Metab. Rev., 2013, 45(1), 145-155.
[160]
Santori, F.R. Nuclear hormone receptors put immunity on sterols. . Eur. J. Immunol., 2015, 45(10), 2730-2741.
[161]
Chiang, J.Y. Bile acid metabolism and signaling in liver disease and therapy. Liver Res., 2017, 1(1), 3-9.
[162]
Guthrie, G.; Tackett, B.; Stoll, B.; Martin, C.; Olutoye, O.; Burrin, D.G. Phytosterols synergize with endotoxin to augment inflammation in Kupffer cells but alone have limited direct effect on hepatocytes. J. Parenter. Enteral Nutr., 2018, 42(1), 37-48.
[163]
Zhu, C.; Fuchs, C.; Halilbasic, E.; Trauner, M. Bile acids in regulation of inflammation and immunity: Friend or foe. Clin. Exp. Rheumatol., 2016, 34(4)(Suppl. 98), 25-31.
[164]
Wang, B.; Tontonoz, P. Liver X receptors in lipid signalling and membrane homeostasis. Nat. Rev. Endocrinol., 2018, 14(8), 452-463.
[165]
Fessler, M.B. The challenges and promise of targeting the liver X receptors for treatment of inflammatory disease. Pharmacol. Ther., 2018, 181, 1-12.
[166]
Grattan, B.J. Plant sterols as anticancer nutrients: evidence for their role in breast cancer. Nutrients, 2013, 5(2), 359-387.
[167]
Carter, B.A.; Taylor, O.A.; Prendergast, D.R.; Zimmerman, T.L.; Von Furstenberg, R.; Moore, D.D.; Karpen, S.J. Stigmasterol, a soy lipid–derived phytosterol, is an antagonist of the bile acid nuclear receptor FXR. Pediatr. Res., 2007, 62(3), 301-306.
[168]
Marinozzi, M.; Castro Navas, F.F.; Maggioni, D.; Carosati, E.; Bocci, G.; Carloncelli, M.; Giorgi, G.; Cruciani, G.; Fontana, R.; Russo, V. Side-chain modified ergosterol and stigmasterol derivatives as liver X receptor agonists. J. Med. Chem., 2017, 60(15), 6548-6562.
[169]
Navas, F.F.C.; Giorgi, G.; Maggioni, D.; Pacciarini, M.; Russo, V.; Marinozzi, M. C24-hydroxylated stigmastane derivatives as liver X receptor agonists. Chem. Phys. Lipids, 2018, 212, 44-50.
[170]
El Kharrassi, Y.; Samadi, M.; Lopez, T.; Nury, T.; El Kebbaj, R.; Andreoletti, P.; El Hajj, H.I.; Vamecq, J.; Moustaid, K.; Latruffe, N. Biological activities of schottenol and spinasterol, two natural phytosterols present in argan oil and in cactus pear seed oil, on murine miroglial BV2 cells. Biochem. Biophys. Res. Commun., 2014, 446(3), 798-804.
[171]
Lottenberg, A.M.; Bombo, R.; Ilha, A.; Nunes, V.S.; Nakandakare, E.R.; Quintão, E.C. Do clinical and experimental investigations support an antiatherogenic role for dietary phytosterols/stanols? IUBMB Life, 2012, 64(4), 296-306.
[172]
Gylling, H.; Plat, J.; Turley, S.; Ginsberg, H.N.; Ellegård, L.; Jessup, W.; Jones, P.J.; Lütjohann, D.; Maerz, W.; Masana, L. Plant sterols and plant stanols in the management of dyslipidaemia and prevention of cardiovascular disease. Atherosclerosis, 2014, 232(2), 346-360.


Rights & PermissionsPrintExport Cite as


Article Details

VOLUME: 20
ISSUE: 3
Year: 2019
Page: [197 - 214]
Pages: 18
DOI: 10.2174/1389201020666190219122357
Price: $58

Article Metrics

PDF: 18
HTML: 6