Novel colon‐available triterpenoids identified in raspberry fruits exhibit antigenotoxic activities in vitro

SCOPE Ileostomy studies provide a unique insight into digestion of food, allowing identification of physiologically relevant dietary phytochemicals and their metabolites important to gut health. We previously reported the consistent increase of components in ileal fluids of ileostomates after consumption of raspberries with use of nontargeted LC-MSn techniques and data deconvolution software highlighting two major unknown components (m/z 355 and 679). METHODS AND RESULTS In-depth LC-MSn analyses suggested that the ileal m/z 355 components were p-coumaroyl glucarates. These compounds have not been identified previously and were confirmed in raspberry extracts after partial purification. The major ileal component with m/z 679 was a glycoside with an aglycone of m/z 517 and was present as two peaks in extracts of whole puree, unseeded puree, and isolated seeds. These components were purified using Sephadex LH20 and C18 SPE units and identified as major, novel raspberry triterpenoid glycosides. This triterpenoid-enriched fraction (100 nM) protected against H2 O2 -induced DNA damage in both colon cancer and normal cell lines and altered expression of cytoprotective genes. CONCLUSION The presence of these novel raspberry triterpenoid components in ileal fluids indicates that they would be colon-available in vivo, so confirmation of their anticancer bioactivities is of key physiological relevance.

[1]  M. Lean,et al.  New insights into the bioavailability of red raspberry anthocyanins and ellagitannins. , 2015, Free radical biology & medicine.

[2]  S. G. Monteiro,et al.  Antimutagenic action of the triterpene betulinic acid isolated from Scoparia dulcis (Scrophulariaceae). , 2015, Genetics and molecular research : GMR.

[3]  A. Crozier,et al.  Chronic administration of a microencapsulated probiotic enhances the bioavailability of orange juice flavanones in humans. , 2015, Free radical biology & medicine.

[4]  Ming Liu,et al.  Synergy between sulforaphane and selenium in protection against oxidative damage in colonic CCD841 cells. , 2015, Nutrition research.

[5]  S. N. El,et al.  Mind the gap—deficits in our knowledge of aspects impacting the bioavailability of phytochemicals and their metabolites—a position paper focusing on carotenoids and polyphenols , 2015, Molecular nutrition & food research.

[6]  E. Weiderpass,et al.  Consumption of berries, fruits and vegetables and mortality among 10,000 Norwegian men followed for four decades , 2015, European Journal of Nutrition.

[7]  F. Lombó,et al.  Bioavailability of Dietary Polyphenols and Gut Microbiota Metabolism: Antimicrobial Properties , 2015, BioMed research international.

[8]  S. Mayne,et al.  Dietary intake of flavonoids and oesophageal and gastric cancer: incidence and survival in the United States of America (USA) , 2015, British Journal of Cancer.

[9]  K. Gupta,et al.  Combinatorial chemopreventive effect of butyric acid, nicotinamide and calcium glucarate against the 7,12-dimethylbenz(a)anthracene induced mouse skin tumorigenesis attained by enhancing the induction of intrinsic apoptotic events. , 2015, Chemico-biological interactions.

[10]  J. Gaforio,et al.  The differential localization of a methyl group confers a different anti-breast cancer activity to two triterpenes present in olives. , 2015, Food & function.

[11]  Ji-Hyung Seo,et al.  Anti-inflammatory effect of a standardized triterpenoid-rich fraction isolated from Rubus coreanus on dextran sodium sulfate-induced acute colitis in mice and LPS-induced macrophages. , 2014, Journal of ethnopharmacology.

[12]  Hua-Bin Li,et al.  Resources and Biological Activities of Natural Polyphenols , 2014, Nutrients.

[13]  M. Lean,et al.  Orange juice (poly)phenols are highly bioavailable in humans. , 2014, The American journal of clinical nutrition.

[14]  P. V. van Leeuwen,et al.  Intravenous glutamine supplementation enhances renal de novo arginine synthesis in humans: a stable isotope study. , 2014, The American journal of clinical nutrition.

[15]  Dr David Vauzour,et al.  Bioavailability, bioactivity and impact on health of dietary flavonoids and related compounds: an update , 2014, Archives of Toxicology.

[16]  I. Rowland,et al.  Tracking (Poly)phenol components from raspberries in ileal fluid. , 2014, Journal of agricultural and food chemistry.

[17]  P. Kroon,et al.  The pharmacokinetics of anthocyanins and their metabolites in humans , 2014, British journal of pharmacology.

[18]  N. Seeram Berries and human health: research highlights from the Fifth Biennial Berry Health Benefits Symposium. , 2014, Journal of agricultural and food chemistry.

[19]  A. Rodriguez-Mateos,et al.  Berry (poly)phenols and cardiovascular health. , 2014, Journal of agricultural and food chemistry.

[20]  C. Mardones,et al.  Isolation and structural elucidation of anthocyanidin 3,7-β-O-diglucosides and caffeoyl-glucaric acids from calafate berries. , 2014, Journal of agricultural and food chemistry.

[21]  B. Burton-Freeman,et al.  Berries: anti-inflammatory effects in humans. , 2014, Journal of agricultural and food chemistry.

[22]  I. Rowland,et al.  In vitro and in vivo models of colorectal cancer: antigenotoxic activity of berries. , 2014, Journal of agricultural and food chemistry.

[23]  E. Riboli,et al.  Behavioral and dietary risk factors for noncommunicable diseases. , 2013, The New England journal of medicine.

[24]  F. Sun,et al.  Bioactivity-Guided Fractionation of Physical Fatigue-Attenuating Components from Rubus parvifolius L. , 2013, Molecules.

[25]  J. Holst,et al.  A single supplement of a standardised bilberry (Vaccinium myrtillus L.) extract (36 % wet weight anthocyanins) modifies glycaemic response in individuals with type 2 diabetes controlled by diet and lifestyle , 2013, Journal of Nutritional Science.

[26]  A. Clarke,et al.  Increased consumption of fruit and vegetables for the primary prevention of cardiovascular diseases. , 2013, The Cochrane database of systematic reviews.

[27]  A. Rodriguez-Mateos,et al.  Dietary (poly)phenolics in human health: structures, bioavailability, and evidence of protective effects against chronic diseases. , 2013, Antioxidants & redox signaling.

[28]  T. Preston,et al.  Human metabolism and elimination of the anthocyanin, cyanidin-3-glucoside: a (13)C-tracer study. , 2013, The American journal of clinical nutrition.

[29]  C. Cho,et al.  Antitumor effects of novel compound, guttiferone K, on colon cancer by p21Waf1/Cip1‐mediated G0/G1 cell cycle arrest and apoptosis , 2013, International journal of cancer.

[30]  I. Rowland,et al.  Persistence of Anticancer Activity in Berry Extracts after Simulated Gastrointestinal Digestion and Colonic Fermentation , 2012, PloS one.

[31]  D. Stewart,et al.  Berry Polyphenols Inhibit Digestive Enzymes: a Source of Potential Health Benefits? , 2012 .

[32]  R. Prior Anthocyanins: Understanding Their Absorption and Metabolism , 2012 .

[33]  M. Giusti,et al.  High-purity isolation of anthocyanins mixtures from fruits and vegetables--a novel solid-phase extraction method using mixed mode cation-exchange chromatography. , 2011, Journal of chromatography. A.

[34]  T. Slaga,et al.  Dietary D-glucarate effects on the biomarkers of inflammation during early post-initiation stages of benzo[a]pyrene-induced lung tumorigenesis in A/J mice. , 2010, Oncology letters.

[35]  A. Collins,et al.  Protective effects of ursolic acid and luteolin against oxidative DNA damage include enhancement of DNA repair in Caco-2 cells. , 2010, Mutation research.

[36]  B. Burton-Freeman Postprandial metabolic events and fruit-derived phenolics: a review of the science , 2010, British Journal of Nutrition.

[37]  Vincent Zoete,et al.  Potency ranking of triterpenoids as inducers of a cytoprotective enzyme and as inhibitors of a cellular inflammatory response via their electron affinity and their electrophilicity index. , 2010, Chemico-biological interactions.

[38]  M. Lean,et al.  Bioavailability of multiple components following acute ingestion of a polyphenol-rich juice drink. , 2010, Molecular nutrition & food research.

[39]  Alan Crozier,et al.  Bioavailability of anthocyanins and ellagitannins following consumption of raspberries by healthy humans and subjects with an ileostomy. , 2010, Journal of agricultural and food chemistry.

[40]  M. Soares,et al.  Mechanisms of cell protection by heme oxygenase-1. , 2010, Annual review of pharmacology and toxicology.

[41]  M. Nair,et al.  Ursolic acid analogues: non-phenolic functional food components in Jamaican raspberry fruits , 2009 .

[42]  L. Howard,et al.  Ellagitannin composition of blackberry as determined by HPLC-ESI-MS and MALDI-TOF-MS. , 2008, Journal of agricultural and food chemistry.

[43]  I. Rowland,et al.  Colon-available raspberry polyphenols exhibit anti-cancer effects on in vitro models of colon cancer , 2007, Journal of carcinogenesis.

[44]  E. Richling,et al.  Studies on apple and blueberry fruit constituents: do the polyphenols reach the colon after ingestion? , 2006, Molecular nutrition & food research.

[45]  M. Sporn,et al.  The synthetic triterpenoids, CDDO and CDDO-imidazolide, are potent inducers of heme oxygenase-1 and Nrf2/ARE signaling. , 2005, Cancer research.

[46]  L. Berliner,et al.  NAD(P)H:quinone oxidoreductase 1: role as a superoxide scavenger. , 2004, Molecular pharmacology.

[47]  M. Pfaffl,et al.  A new mathematical model for relative quantification in real-time RT-PCR. , 2001, Nucleic acids research.

[48]  G. W. Robertson,et al.  A comparison of the composition of epicuticular wax from red raspberry (Rubus idaeus L.) and hawthorn (Crataegus monogyna Jacq.) flowers. , 2000, Phytochemistry.

[49]  C. Finn,et al.  Antioxidant properties of domesticated and wild Rubus species , 2000 .

[50]  J. Wolfender,et al.  LC/ES-MS analysis of triterpene glycosides: rapid estimation of the saponin content of dried berries of Phytolacca dodecandra , 1999 .

[51]  H. Matsuda,et al.  Effects of oleanolic acid glycosides on gastrointestinal transit and ileus in mice. , 1999, Bioorganic & medicinal chemistry.

[52]  網本 佳容子,et al.  Triterpenoid Saponins of Aquifoliaceous Plants. XI.Ilexosides XLI-XLV from the Leaves of Ilex rotunda THUNB. , 1993 .

[53]  R. Kasai,et al.  Oleanane and ursane glucosides from Rubus species , 1992 .

[54]  M. Hansen,et al.  Re-examination and further development of a precise and rapid dye method for measuring cell growth/cell kill. , 1989, Journal of immunological methods.

[55]  I. Johnson,et al.  Influence of saponins on gut permeability and active nutrient transport in vitro. , 1986, The Journal of nutrition.

[56]  T. Mosmann Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. , 1983, Journal of immunological methods.

[57]  B. I. Diamondstone,et al.  Mechanisms of the Liebermann-Burchard and Zak color reactions for cholesterol. , 1974, Clinical chemistry.

[58]  A. Clarke,et al.  Increased consumption of fruit and vegetables for the primary prevention of cardiovascular diseases. , 2012, The Cochrane database of systematic reviews.

[59]  F. Stintzing,et al.  Investigations into the phenolic constituents of dog's mercury (Mercurialis perennis L.) by LC-MS/MS and GC-MS analyses. , 2012, Phytochemical analysis : PCA.

[60]  J. Szemraj,et al.  Metabolism, uptake, and excretion of a D-glucaric acid salt and its potential use in cancer prevention. , 1997, Cancer detection and prevention.

[61]  R. Kasai,et al.  A dimeric triterpene-glycoside fromRubus coreanus , 1990 .