Isolation and synergism of in vitro anti-inflammatory and quinone reductase (QR) inducing agents from the fruits of Morinda citrifolia (noni)

Abstract The tropical fruits and fruit products of Morinda citrifolia , commonly known as noni, are consumed as a food or dietary supplement with purported health benefits. The objective of this study was to investigate the potential anti-inflammatory and cancer preventive effects of noni fruit puree extracts. Bioassay-guided fractionation of an ethyl acetate (EtOAc) extract of noni, comprising ~ 2% noni puree solids, led to the isolation of scopoletin ( 1 ), rutin ( 2 ), and quercetin ( 3 ). Quantitative HPLC analysis of the EtOAc extract revealed levels (dry weight basis) of scopoletin at 0.62 μmol/g, quercetin at 0.26 μmol/g and rutin at 0.045 μmol/g. Scopoletin and quercetin inhibited the production of nitric oxide (NO) in a concentration-dependent manner in lipopolysaccharide (LPS)-induced RAW 264.7 macrophage cells and exhibited quinone reductase (QR) induction in cultured Hepa 1c1c7 cells. Increases in QR activity in induced cells were associated with increases in QR protein as confirmed by Western blots. Combinations of scopoletin and quercetin at a low ( in vitro anti-inflammatory and anti-cancer effects of noni fruits as functional foods and dietary supplements.

[1]  K. Parkin,et al.  [6]-Dehydroshogaol, a minor component in ginger rhizome, exhibits quinone reductase inducing and anti-inflammatory activities that rival those of curcumin , 2010 .

[2]  Y. Surh,et al.  NF-κB and Nrf2 as prime molecular targets for chemoprevention and cytoprotection with anti-inflammatory and antioxidant phytochemicals , 2008, Genes & Nutrition.

[3]  J. Pezzuto,et al.  Quinone reductase induction as a biomarker for cancer chemoprevention. , 2006, Journal of natural products.

[4]  J. Um,et al.  Use of scopoletin to inhibit the production of inflammatory cytokines through inhibition of the IκB/NF-κB signal cascade in the human mast cell line HMC-1 , 2007 .

[5]  A. Murakami,et al.  Synergistic suppression of superoxide and nitric oxide generation from inflammatory cells by combined food factors. , 2003, Mutation research.

[6]  Kazumi Matsumoto,et al.  Anti-inflammatory and potential cancer chemopreventive constituents of the fruits of Morinda citrifolia (Noni). , 2007, Journal of natural products.

[7]  B. West,et al.  Lipoxygenase inhibitory constituents of the fruits of noni (Morinda citrifolia) collected in Tahiti. , 2007, Journal of natural products.

[8]  Wan-Wan Lin,et al.  Inhibition of iNOS gene expression by quercetin is mediated by the inhibition of IkappaB kinase, nuclear factor-kappa B and STAT1, and depends on heme oxygenase-1 induction in mouse BV-2 microglia. , 2005, European journal of pharmacology.

[9]  Youn-Chul Kim,et al.  Scopoletin suppresses pro-inflammatory cytokines and PGE2 from LPS-stimulated cell line, RAW 264.7 cells. , 2004, Fitoterapia.

[10]  O. Potterat,et al.  Identification of TLC markers and quantification by HPLC-MS of various constituents in noni fruit powder and commercial noni-derived products. , 2007, Journal of agricultural and food chemistry.

[11]  G. Russo.  Ins and outs of dietary phytochemicals in cancer chemoprevention. , 2007, Biochemical pharmacology.

[12]  M. N. Lutfiyya,et al.  Morinda Citrifolia (Noni) Reduces Cancer Risk in Current Smokers by Decreasing Aromatic DNA Adducts , 2009, Nutrition and cancer.

[13]  E. Fialho,et al.  The antioxidant capacity and polyphenol content of organic and conventional retail vegetables after domestic cooking , 2009 .

[14]  A. Santamaria,et al.  Direct measurement of NAD(P)H:quinone reductase from cells cultured in microtiter wells: a screening assay for anticarcinogenic enzyme inducers. , 1988, Analytical biochemistry.

[15]  C. Jun,et al.  Scopoletin: An Inducible Nitric Oxide Synthesis Inhibitory Active Constituent from Artemisia feddei , 1999, Planta medica.

[16]  Mian-Ying Wang,et al.  Morinda citrifolia (Noni): a literature review and recent advances in Noni research. , 2002, Acta pharmacologica Sinica.

[17]  S. Begum,et al.  Isolation and structural elucidation of chemical constituents from the fruits ofMorinda citrifolia Linn , 2007 .

[18]  J. Fahey,et al.  Chemoprotection against cancer by phase 2 enzyme induction. , 1995, Toxicology letters.

[19]  A. Kong,et al.  Synergistic Effect of Combination of Phenethyl Isothiocyanate and Sulforaphane or Curcumin and Sulforaphane in the Inhibition of Inflammation , 2008, Pharmaceutical Research.

[20]  A. Kinghorn,et al.  Chemical constituents of the fruits of Morinda citrifolia (Noni) and their antioxidant activity. , 2005, Journal of natural products.

[21]  M. Heinonen,et al.  Anti-Inflammatory Effects of Flavonoids: Genistein, Kaempferol, Quercetin, and Daidzein Inhibit STAT-1 and NF-κB Activations, Whereas Flavone, Isorhamnetin, Naringenin, and Pelargonidin Inhibit only NF-κB Activation along with Their Inhibitory Effect on iNOS Expression and NO Production in Activated , 2007, Mediators of inflammation.

[22]  A. Kong,et al.  Dietary cancer-chemopreventive compounds: from signaling and gene expression to pharmacological effects. , 2005, Trends in pharmacological sciences.

[23]  A. Murakami,et al.  Combinatorial Effects of Nonsteroidal Anti-inflammatory Drugs and Food Constituents on Production of Prostaglandin E2 and Tumor Necrosis Factor-α in RAW264.7 Murine Macrophages , 2003, Bioscience, biotechnology, and biochemistry.

[24]  A. Kinghorn,et al.  An anthraquinone with potent quinone reductase-inducing activity and other constituents of the fruits of Morinda citrifolia (noni). , 2005, Journal of natural products.

[25]  F. Denizot,et al.  Rapid colorimetric assay for cell growth and survival. Modifications to the tetrazolium dye procedure giving improved sensitivity and reliability. , 1986, Journal of immunological methods.

[26]  A. Murakami,et al.  Cancer prevention with food factors: alone and in combination. , 2004, BioFactors.

[27]  Kyung-Tae Lee,et al.  Preventive effect of Ginkgo biloba extract (GBB) on the lipopolysaccharide-induced expressions of inducible nitric oxide synthase and cyclooxygenase-2 via suppression of nuclear factor-kappaB in RAW 264.7 cells. , 2006, Biological & pharmaceutical bulletin.

[28]  S. Abramson,et al.  Nitric Oxide: A Novel Mediator of Inflammation , 1995, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[29]  C. Paraskeva,et al.  A cyclooxygenase-2 (COX-2) selective non-steroidal anti-inflammatory drug enhances the growth inhibitory effect of butyrate in colorectal carcinoma cells expressing COX-2 protein: regulation of COX-2 by butyrate. , 2000, Carcinogenesis.

[30]  M. M. Mu,et al.  The inhibitory action of quercetin on lipopolysaccharide-induced nitric oxide production in RAW 264.7 macrophage cells , 2001, Journal of endotoxin research.

[31]  B. Timmermann,et al.  The effect of extracts from ginger rhizome on inflammatory mediator production. , 2007, Phytomedicine : international journal of phytotherapy and phytopharmacology.

[32]  A. Dinkova-Kostova,et al.  Coordinate regulation of enzyme markers for inflammation and for protection against oxidants and electrophiles , 2008, Proceedings of the National Academy of Sciences.

[33]  Nong-xue Qiu,et al.  Polyphenols contents and antioxidant capacity of 68 Chinese herbals suitable for medical or food uses , 2008 .

[34]  M. Peyrat-Maillard,et al.  Antioxidant activity of phenolic compounds in 2,2′-azobis (2-amidinopropane) dihydrochloride (AAPH)-induced oxidation: Synergistic and antagonistic effects , 2003 .

[35]  K. Lee,et al.  Efficient 1H nuclear magnetic resonance method for improved quality control analyses of Ginkgo constituents. , 2004, Journal of agricultural and food chemistry.

[36]  Giovanni Pennisi,et al.  Cellular Stress Response: A Novel Target for Chemoprevention and Nutritional Neuroprotection in Aging, Neurodegenerative Disorders and Longevity , 2008, Neurochemical Research.

[37]  B. West,et al.  Development and validation of an RP-HPLC method for the analysis of anthraquinones in noni fruits and leaves. , 2009 .

[38]  E. Taskin,et al.  Apoptosis‐inducing effects of Morinda citrifolia L. and doxorubicin on the Ehrlich ascites tumor in Balb‐c mice , 2009, Cell biochemistry and function.

[39]  W. Cao,et al.  Protective effects of ethanolic extracts of buckwheat groats on DNA damage caused by hydroxyl radicals , 2008 .

[40]  F. Cianchi,et al.  iNOS/COX-2 Pathway Interaction: A Good Molecular Target for Cancer Treatment , 2005 .

[41]  J. Pezzuto,et al.  Cancer chemopreventive activity mediated by 4'-bromoflavone, a potent inducer of phase II detoxification enzymes. , 1999, Cancer research.

[42]  R. T. Rosen,et al.  Novel trisaccharide fatty acid ester identified from the fruits of Morinda citrifolia (Noni). , 1999, Journal of agricultural and food chemistry.

[43]  A. Mesecar,et al.  Molecular mechanisms of natural products in chemoprevention: induction of cytoprotective enzymes by Nrf2. , 2008, Molecular nutrition & food research.

[44]  A. Kong,et al.  Activation of Nrf2-antioxidant signaling attenuates NFkappaB-inflammatory response and elicits apoptosis. , 2008, Biochemical pharmacology.

[45]  J. Pezzuto,et al.  Compounds obtained fromSida acuta with the potential to induce quinone reductase and to inhibit 7,12-dimethylbenz-[a]anthracene-induced preneoplastic lesions in a mouse mammary organ culture model , 2003, Archives of pharmacal research.

[46]  D. Hou,et al.  Action of Nrf2 and Keap1 in ARE-mediated NQO1 expression by quercetin. , 2007, Free radical biology & medicine.