Seeds, Leaves and Roots of Thapsia garganica as a Source of New Potent Lipases Inhibitors: In vitro and In silico Studies

Author(s): Halima Nebeg*, Khedidja Benarous, Talia Serseg, Asma Lazreg, Hafidha Hassani, Mohamed Yousfi

Journal Name: Endocrine, Metabolic & Immune Disorders - Drug Targets
Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders

Volume 19 , Issue 5 , 2019

Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


Background and Objective: Lipase inhibitors have gained great interest because they could help in the therapy of many diseases, however, unfortunately, only a few drugs are currently available on the market. Therefore, the aim of this work was to evaluate for the first time the lipase inhibition effect of Thapsia garganica extracts from seeds, leaves and roots.

Methods: Polyphenols and flavonoids contents were determined using spectrophotometric method. Inhibitory activity of ethyl acetate extracts from seeds, leaves and roots of T. garganica against Candida rugosa lipase was determined. To uncover the active constituents responsible for this anti-lipase activity, further investigations were performed by employing theoretical docking simulations, using AutoDock Vina program to discuss the nature of interactions and the inhibition mechanism by major bioactive compounds synthesized by this plant.

Results: Seeds, leaves and roots extracts of T. garganica showed appreciable contents of polyphenols and flavonoids which is most in seeds extract with 2.90±0.02mg GAE/gdw and 1.53±0.05mg QE/gdw, respectively. Hence, their inhibitory activities against Candida rugosa lipase were determined as IC50 of 1.19mg/ml, 1.96mg/ml and 1.87mg/ml, respectively. Docking simulations have shown that nortribolid and tribolid are best inhibitors for both lipases (Candida rugosa and human pancreatic lipases).

Conclusion: Testing the anti-lipase activity of the ethyl acetate extracts of T. garganica revealed a potent lipase inhibition activity, which suggests the use of these molecules as anti-obesity drugs.

Keywords: Candida rugosa lipase, human pancreatic lipase, inhibition, IC50, Thapsia garganica, polyphenols, flavonoids, molecular docking.

Bialecka, F.E.; Fabiszewska, A.U.; Krzyczkowska, J.; Kurylowicz, A. Synthetic and natural lipase inhibitors. Mini Rev. Med. Chem., 2018, 18(8), 672-683.
Winkler, F.K.; D’Arcy, A.; Hunziker, W. Structure of human pancreatic lipase. Nature, 1990, 343(6260), 771-774.
Stitziel, N.O. Human genetic insights into lipoproteins and risk of cardiometabolic disease. Curr. Opin. Lipidol., 2017, 28(2), 113-119.
Hauptman, J.B.; Jeunet, F.S.; Hartmann, D. Initial studies in humans with the novel gastrointestinal lipase inhibitor Ro 18-0647 (tetrahydrolipstatin). Am. J. Clin. Nutr., 1992, 55(1), 309S-313S.
Drent, M.L.; van der Veen, E.A. Lipase inhibition: A novel concept in the treatment of obesity. Int. J. Obes. Relat. Metab. Disord., 1993, 17(4), 241-244.
Grippa, E.; Valla, R.; Battinelli, L.; Mazzanti, G.; Saso, L.; Silvestrini, B. Inhibition of Candida rugosa lipase by berberine and structurally related alkaloids, evaluated by high-performance liquid chromatography. Biosci. Biotechnol. Biochem., 1999, 63(9), 1557-1562.
The Euro+Med Plantbase Project. (Accessed October 4, 2018).
Makunga, N.P.; Jäger, A.K.; van Staden, J. Micropropagation of Thapsia garganica a medicinal plant. Plant Cell Rep., 2003, 21(10), 967-973.
Casiglia, S.; Riccobono, L.; Bruno, M.; Rosselli, S.; Senatore, F. Chemical composition of the essential oil from Thapsia garganica L. (Apiaceae) grown wild in sicily and its antimicrobial activity. Nat. Prod. Res., 2016, 30(9), 1042-1052.
Boudghene, S.O.; Amrani, N. Un angioedème de topographie bilatérale suite au contact avec une plante (Thapsia garganica). Rev. Fr. Allergol., 2015, 55(3), 235.
Jager, A.; Schottlander, B.; Smitt, U.; Nyman, U. Somatic embryogenesis in cell cultures of Thapsia garganica. Plant Cell Rep., 1993, 12(9), 517-520.
Bouimeja, B.; El Hidan, M.A.; Touloun, O.; Ait Laaradia, M.; Ait Dra, L.; El Khoudri, N.; Chait, A.; Boumezzough, A. Anti-scorpion venom activity of Thapsia garganica methanolic extract: Histopathological and biochemical evidences. J. Ethnopharmacol., 2018, 211, 340-347.
Singleton, V.L.; Orthofer, R.; Lamuela-Raventós, R.M. Analysis of total phenols and other oxidation substrates and antioxidants by means of folin-ciocalteu reagent. Methods Enzymol., 1999, 299(1), 152-178.
Singleton, V.L.; Joseph, A.R. Colorimetry of total phenolics with phosphomolybdic-phosphotungstic acid reagent. Am. J. Enol. Vitic., 1965, 16(3), 144-158.
Blainski, A.; Lopes, G.C.; De Mello, J.C.P. Application and analysis of the folin ciocalteu method for the determination of the total phenolic content from limonium brasiliense L. Molecules, 2013, 18(6), 6852-6865.
Zhishen, J.; Mengcheng, T.; Jianming, W. The determination of flavonoid contents in mulberry and their scavenging effects on superoxide radicals. Food Chem., 1999, 64(4), 555-559.
Dewanto, V.; Wu, X.; Adom, K.K.; Liu, R.H. Thermal processing enhances the nutritional value of tomatoes by increasing total antioxidant activity. J. Agric. Food Chem., 2002, 50(10), 3010-3014.
Benarous, K.; Djeridane, A.; Kameli, A.; Yousfi, M. Inhibition of Candida rugosa lipase by secondary metabolites extracts of three algerian plants and their antioxydant activities. Curr. Enzym. Inhib., 2013, 9(1), 75-82.
Benarous, K.; Bombarda, I.; Iriepa, I.; Moraleda, I.; Gaetan, H.; Linani, A.; Yousfi, M. Harmaline and hispidin from Peganum harmala and Inonotus hispidus with binding affinity to Candida rugosa lipase: In silico and in vitro studies. Bioorg. Chem., 2015, 62, 1-7.
Yang, L.; Wen, K.S.; Ruan, X.; Zhao, Y.X.; Wei, F.; Wang, Q. Response of plant secondary metabolites to environmental factors. Molecules, 2018, 23(4), 762.
Yoshikawa, M.; Shimoda, H.; Nishida, N.; Takada, M.; Matsuda, H. Salacia reticulate and its polyphenolic constituents with lipase inhibitory and lipolytic activities have mild antiobesity effects in rats. J. Nutr., 2002, 132(7), 1819-1824.
Park, H.J.; Jung, U.J.; Lee, M.K.; Cho, S.J.; Jung, H.K.; Hong, J.H.; Park, Y.B.; Kim, S.R.; Shim, S.; Jung, J.; Choi, M.S. Modulation of lipid metabolism by polyphenol-rich grape skin extract improves liver steatosis and adiposity in high fat fed mice. Mol. Nutr. Food Res., 2012, 57(2), 360-364.
Sosnowska, D.; Podsędek, A.; Redzynia, M.; Kucharska, A.Z. Inhibitory effect of black chokeberry fruit polyphenols on pancreatic lipase-searching for most active inhibitors. J. Funct. Foods, 2018, 49, 196-204.
Les, F.; Arbonés-Mainar, J.M.; Valero, M.S.; López, V. Pomegranate polyphenols and urolithin A inhibit α-glucosidase, dipeptidyl peptidase-4, lipase, triglyceride accumulation and adipogenesis related genes in 3T3-L1 adipocyte-like cells. J. Ethnopharmacol., 2018, 220, 67-74.
Verma, M.; Rai, G.K.; Kaur, D. Effect of extraction solvents on phenolic content and antioxidant activities of Indian gooseberry and guava. Int. Food Res. J., 2018, 2, 762-768.
Sembiring, E.N.; Elya, B.; Sauriasari, R. Phytochemical screening, total flavonoid and total phenolic content and antioxidant activity of different parts of Caesalpinia bonduc (L.). Roxb. Pharmacogn. J., 2017, 10(1), 123-127.
Neffati, N.; Aloui, Z.; Karoui, H.; Guizani, I.; Boussaid, M.; Zaouali, Y. Phytochemical composition and antioxidant activity of medicinal plants collected from the Tunisian flora. Nat. Prod. Res., 2017, 31(13), 1583-1588.
Saleem, F.; Sarkar, D.; Ankolekar, C.; Shetty, K. Phenolic bioactives and associated antioxidant and anti-hyperglycemic functions of select species of Apiaceae family targeting for type 2 diabetes relevant nutraceuticals. Ind. Crops Prod., 2017, 107, 518-525.
Mekinić, I.G.; Šimat, V.; Ljubenkov, I.; Burčul, F.; Grga, M.; Mihajlovski, M.; Skroza, D. Influence of the vegetation period on sea fennel, Crithmum maritimum L. (Apiaceae), phenolic composition, antioxidant and anticholinesterase activities. Ind. Crops Prod., 2018, 124, 947-953.
Varga, E.; Schmidt, I.; Szövérfi, B.; Pop, M.D.; Kelemen, H. Phenolic content from medicinal plants and their products used in veterinary medicine. Acta Medica. Marisiensis, 2018, 2, 77-82.
Christova-Bagdassarian, V.L.; Bagdassarian, K.S.; Atanassova, M.S.; Ahmad, M.A. Comparative analysis of total phenolic and total flavonoid contents, rutin, tannins and antioxidant capacity in apiaceae and lamiaceae families. Indian J. Hortic., 2014, 4(3/4), 131-140.
Gebhardt, Y.; Witte, S.; Forkmann, G.; Lukačin, R.; Matern, U.; Martens, S. Molecular evolution of flavonoid dioxygenases in the family Apiaceae. Phytochemistry, 2005, 66(11), 1273-1284.
Belfeki, H.; Mejri, M.; Hassouna, M. Antioxidant and anti-lipases activities in vitro of Mentha viridis and Eucalyptus globulus extracts. Ind. Crops Prod., 2016, 89, 514-521.
Franco, R.R.; Justino, A.B.; Silva, H.C.G.; Peixoto, L.G.; Espindola, F.S. Antioxidant and anti-glycation capacities of some medicinal plants and their potential inhibitory against digestive enzymes related to type 2 diabetes mellitus. J. Ethnopharmacol., 2016, 215, 140-146.
Unuofin, J.O.; Otunola, G.A.; Afolayan, A.J. In vitro α-amylase, α-glucosidase, lipase inhibitory and cytotoxic activities of tuber extracts of Kedrostis africana (L.) Cogn. Heliyon, 2018, 4(9)e00810
Moon, S.H.; Kiim, M.Y. Phytochemical profile, antioxidant, antimicrobial and antipancreatic lipase activities of fermented Camellia japonica L leaf extracts. T.J.N.P.R. 2018, 17(5), 905-912.
Ercan, P.; El, S.N. Inhibitory effects of chickpea and Tribulus terrestris on lipase, -amylase and -glucosidase. Food Chem., 2016, 205, 163-169.
Pereira, M.N.; Justino, A.B.; Martins, M.M.; Peixoto, L.G.; Vilela, D.D.; Santos, P.S.; Espindola, F.S. Stephalagine, an alkaloid with pancreatic lipase inhibitory activity isolated from the fruit peel of Annona crassiflora Mart. Ind. Crops Pro., 2017, 97, 324-329.
Patil, S.G.; Patil, M.P.; Maheshwari, V.L.; Patil, R.H. In vitro lipase inhibitory effect and kinetic properties of di-terpenoid fraction from Calotropis procera (Aiton). Biocatal. Agric. Biotechnol., 2015, 4(4), 579-585.
Bustanji, Y.; Al-Masri, I.M.; Mohammad, M.; Hudaib, M.; Tawaha, K.; Tarazi, H. AlKhatib, H.S. Pancreatic lipase inhibition activity of trilactone terpenes of Ginkgo biloba. J. Enzyme Inhib. Med. Chem., 2011, 26(4), 453-459.
Drew, D.P.; Krichau, N.; Reichwald, K.; Simonsen, H.T. Guaianolides in apiaceae: Perspectives on pharmacology and biosynthesis. Phytochem. Rev., 2009, 8(3), 581-599.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Page: [683 - 696]
Pages: 14
DOI: 10.2174/1871530319666190128122211
Price: $65

Article Metrics

PDF: 21