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Anti-inflammatory and anti-colon cancer potential of yerba mate (Ilex paraguariensis St. Hilaire) bioactive constituents

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Title: Anti-inflammatory and anti-colon cancer potential of yerba mate (Ilex paraguariensis St. Hilaire) bioactive constituents
Author(s): Puangpraphant, Sirima
Director of Research: de Mejia, Elvira
Doctoral Committee Chair(s): Jeffery, Elizabeth H.
Doctoral Committee Member(s): de Mejia, Elvira; Chen, Hong; Seigler, David
Department / Program: Food Science & Human Nutrition
Discipline: Food Science & Human Nutrition
Degree Granting Institution: University of Illinois at Urbana-Champaign
Degree: Ph.D.
Genre: Dissertation
Subject(s): Yerba mate (Ilex paraguarienesis) anti-inflammation colon cancer
Abstract: Yerba mate (Ilex paraguariensis A.St.-Hil.) tea is growing in popularity around the world and contains several classes of constituents mainly caffeoyl derivatives, xanthines, flavonoids and triterpenoid saponins that have been associated with cancer prevention. However, which constituents of yerba mate are involved in the protective effects against colon carcinogenesis is not clearly understood. The objective of this study was to evaluate the dietary prevention of colon carcinogenesis by identifying novel constituents in yerba mate. The first aim was to investigate the potential anti-inflammatory effect of yerba mate tea (MT) extracts, its constituents and their interactions in LPS-induced RAW 264.7 macrophages. MT extract, decaffeinated MT extract, chlorogenic acid (CHA), caffeine from MT (matein), mate saponins, quercetin, ursolic and oleanolic acids were tested by measuring their ability to inhibit COX-2/PGE2 and iNOS/NO pathways. Quercetin was the most potent inhibitor of pro-inflammatory responses at a concentration 10 times lower than the concentrations used of other compounds (IC50 = 11.6 μM for NO, 7.9 μM for iNOS, and 6.5 μM for PGE2). Mate saponins (IC50 = 20 μM) and oleanolic acid (IC50 = 80 μM) significantly inhibited iNOS/NO pathways, whereas ursolic acid showed low or no inhibition at 100 μM. Combination of quercetin/ mate saponins (0.001:0.004, molar ratio) resulted in synergistic interaction inhibiting both NO and PGE2 production and suppressed IL-6 and IL-1β production, which resulted in inhibition of nuclear translocation of NF-κB. MT extract did not have a potent anti-inflammatory effect, perhaps due to the antagonistic effect of some of its components. However, whole MT consumption still has a promising anti-inflammatory outcome mainly through the PGE2/COX-2 pathway. The second aim was to quantify and purify constituents from yerba mate that are not commercially available and assess their anti-inflammatory and anti-colon cancer capabilities in vitro. Matesaponins were partially purified and quantified by preparative chromatography, HPLC and LC/ESI-MS-MS. Yerba mate contained 10–15 mg/g dry weight total saponins. Mate saponins significantly inhibited iNOS, PGE2 and COX-2 and reduced nuclear translocation of NF- κB subunits p50 (49.8%) and p65 (49.0%). Mate saponins inhibited cell proliferation of HT-29 (IC50 = 201.8 μM) and RKO (IC50 = 181.0 μM), arrested cells at G1 to S phase through upregulating p21 and p27 proteins, caused cells to undergo apoptosis through an increase of the ratio of Bax:Bcl-2 protein expression and activated caspase-3 activity. Mate saponins induced apoptosis and cytotoxicity in human colorectal cancer cells independent of p53 status due to the capability of induction of p53 in mutated p53 cells (HT-29). Mate saponins have potent chemopreventive properties and they specifically upregulated the p53 cascade. Dicaffeoylquinic acids (diCQAs) were purified from yerba mate using flash chromatography, resulting in two fractions one containing 3,4- and 3,5-diCQAs and the other 4,5-diCQA with NMR-confirmed structures. Both diCQA fractions inhibited LPS-induced RAW 264.7 macrophage inflammation by suppressing NO/iNOS and PGE2/COX-2 pathways through inhibiting nucleus translocation of NF-κB subunits, p50 and p65. The diCQA fractions inhibited RKO and HT-29 cell proliferation by inducing apoptosis in a time- and concentration-dependent manner, through increased the activation of caspase-8 leading to cleavage of caspase-3.The results suggest that diCQAs in yerba mate could be potential anti-cancer agents and could mitigate other diseases also associated with inflammation. The third aim was to assess the effect of yerba mate aqueous extract and mate saponins on the development of colon pre-neoplastic lesions, aberrant crypt foci (ACF), in the azoxymethane (AOM)-induced model using male F344 rats. The animals received a basal diet and a mate aqueous extract (2% w/v) as drinking fluid, or mate saponins (0.01%, w/w) mixed with the basal diet 2 weeks before AOM injection and throughout the experimental period 6 weeks after first AOM injection. The mate aqueous extract (2% w/v) significantly decreased the number of AOM-induced ACF when compared to the control (21.1% reduction, p < 0.05) by downregulating NF-κB p65 activity (88.8% inhibition), decreasing iNOS (54.5% inhibition) and COX-2 (56.6% inhibition) proinflammatory mediators and β-catenin pathways by increasing GSK-3β activity (41.1% induction) suggesting its potential preventive role. Mate saponins did not reduce the number of ACF (p > 0.05), but significantly suppressed iNOS and COX-2 expressions through inhibition of NF-κB p65 activation (81.7% inhibition). In conclusion, the results of this research demonstrate for the first time, the anti-inflammatory and anti-colon cancer potential of yerba mate and its isolated constituents and provide the foundation for future studies of the benefits of yerba mate and its potential role in preventing colon carcinogenesis.
Issue Date: 2012-02-01
URI: http://hdl.handle.net/2142/29589
Rights Information: Copyright 2011 Sirima Puangpraphant
Date Available in IDEALS: 2014-02-01
Date Deposited: 2011-12
 

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