SUCO NONI!! DO TAITI... alguem sabe sobre ele?

[Visitante jotaneves]

Agora sim a discussão tomou um rumo legal... dava até pra abrir um novo tópico... pessoal, já ouvi estórias de que se pegarmos plantas ou qq outro item natura da Amazônia para criarmos um produto temos que pagar royalties a empresas americanas e japonesas, pq eles já patentearam quase tudo ! É mole ???

Amigos.

Vou deixar aqui a minha contribuição em defesa da fruta Noni e do Suco Tahitian Noni.

Antes de tudo, gostaria de esclarecer que o suco não é remédio, não cura AIDS, Câncer ou qualquer outra doença, não é milagroso e nem espanta mau olhado!

Algumas pessoas inescrupulosas tem se aproveitado de doentes com câncer ou aids ou osteoporose e outras mais para vender o produto com o discurso de que cura tudo. É mentira!

O Noni age no nosso organismo fortalecendo nosso sistema imunológico. Ele é rico em nutrientes e principalmente em XERONINA, um alcalóide de importância fundamental em nosso organismo.

O Suco de Noni em questão, nada mais é do que um suplemento alimentar.

Existem algumas centenas de trabalhos científicos à respeito do fruto (nome científico: Morinda Citrifolia). Vocês mesmos podem fazer uma busca em um site de publicação científica: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?CMD=Display&DB=pubmed ou então no altavista, google ou outro qualquer, ou ainda entrar em sites de universidades sérias do Hawaí, EUA ou da Europa. No Brasil não existem pesquisas à respeito (a fruta é nativa da Polinésia)

Abaixo deixo alguns trabalhos publicados com suas devidas referências bibliográficas.

Espero ter contribuído para desmistificar algumas crenças e conceitos errados sobre o fruto e o suco de noni, do qual sou um distribuidor.

Conheço muitas pessoas sérias que fazem o mesmo que eu. Falam a verdade sobre o Noni.

Muito obrigado pela atenção.

Abraços,

Jota Neves

Segue publicações científicas:

1: Langford J, Doughty A, Wang M, Clayton L, Babich M.

Effects of Morinda citrifolia on quality of life and auditory function in

postmenopausal women.

J Altern Complement Med. 2004 Oct;10(5):737-9. No abstract available.

PMID: 15650461 [PubMed - indexed for MEDLINE]

2: Shotipruk A, Kiatsongserm J, Pavasant P, Goto M, Sasaki M.

Pressurized hot water extraction of anthraquinones from the roots of Morinda

citrifolia.

Biotechnol Prog. 2004 Nov-Dec;20(6):1872-5.

PMID: 15575725 [PubMed - in process]

3: Hounzangbe-Adote MS, Paolini V, Fouraste I, Moutairou K, Hoste H.

In vitro effects of four tropical plants on three life-cycle stages of the

parasitic nematode, Haemonchus contortus.

Res Vet Sci. 2005 Apr;78(2):155-60.

PMID: 15563923 [PubMed - in process]

4: Bhuyan R, Saikia CN.

Isolation of colour components from native dye-bearing plants in northeastern

India.

Bioresour Technol. 2005 Feb;96(3):363-72.

PMID: 15474939 [PubMed - in process]

5: Jagetia GC, Baliga MS.

The evaluation of nitric oxide scavenging activity of certain Indian medicinal

plants in vitro: a preliminary study.

J Med Food. 2004 Fall;7(3):343-8.

PMID: 15383230 [PubMed - in process]

6: Kamiya K, Tanaka Y, Endang H, Umar M, Satake T.

Chemical constituents of Morinda citrifolia fruits inhibit copper-induced

low-density lipoprotein oxidation.

J Agric Food Chem. 2004 Sep 22;52(19):5843-8.

PMID: 15366830 [PubMed - indexed for MEDLINE]

7: Carr ME, Klotz J, Bergeron M.

Coumadin resistance and the vitamin supplement "Noni".

Am J Hematol. 2004 Sep;77(1):103. No abstract available.

PMID: 15307118 [PubMed - indexed for MEDLINE]

8: Wong DK.

Are immune responses pivotal to cancer patient's long term survival? Two

clinical case-study reports on the effects of Morinda citrifolia (Noni).

Hawaii Med J. 2004 Jun;63(6):182-4.

PMID: 15298088 [PubMed - indexed for MEDLINE]

9: Komaraiah P, Navratil M, Carlsson M, Jeffers P, Brodelius M, Brodelius PE,

Kieran PM, Mandenius CF.

Growth behavior in plant cell cultures based on emissions detected by a

multisensor array.

Biotechnol Prog. 2004 Jul-Aug;20(4):1245-50.

PMID: 15296455 [PubMed - indexed for MEDLINE]

10: Li YF, Liu YQ, Yang M, Wang HL, Huang WC, Zhao YM, Luo ZP.

The cytoprotective effect of inulin-type hexasaccharide extracted from Morinda

officinalis on PC12 cells against the lesion induced by corticosterone.

Life Sci. 2004 Aug 13;75(13):1531-8.

PMID: 15261759 [PubMed - indexed for MEDLINE]

11: Yao H, Wu H, Feng CH, Zhao S, Liang SJ.

[Relation between root structure and accumulation of anthraquinones of Morinda

officinalis]

Shi Yan Sheng Wu Xue Bao. 2004 Apr;37(2):96-102. Chinese.

PMID: 15259981 [PubMed - indexed for MEDLINE]

12: Ettarh RR, Emeka P.

Morinda lucida extract induces endothelium-dependent and -independent

relaxation of rat aorta.

Fitoterapia. 2004 Jun;75(3-4):332-6.

PMID: 15158991 [PubMed - indexed for MEDLINE]

13: Lachaise D, Silvain JF.

How two Afrotropical endemics made two cosmopolitan human commensals: the

Drosophila melanogaster-D. simulans palaeogeographic riddle.

Genetica. 2004 Mar;120(1-3):17-39. Review.

PMID: 15088644 [PubMed - indexed for MEDLINE]

14: Chong TM, Abdullah MA, Fadzillah NM, Lai OM, Lajis NH.

Anthraquinones production, hydrogen peroxide level and antioxidant vitamins in

Morinda elliptica cell suspension cultures from intermediary and production

medium strategies.

Plant Cell Rep. 2004 Jul;22(12):951-8. Epub 2004 Apr 06.

PMID: 15067428 [PubMed - indexed for MEDLINE]

15: Hornick CA, Myers A, Sadowska-Krowicka H, Anthony CT, Woltering EA.

Inhibition of angiogenic initiation and disruption of newly established human

vascular networks by juice from Morinda citrifolia (noni).

Angiogenesis. 2003;6(2):143-9.

PMID: 14739620 [PubMed - indexed for MEDLINE]

16: Jeffers P, Raposo S, Lima-Costa ME, Connolly P, Glennon B, Kieran PM.

Focussed beam reflectance measurement (FBRM) monitoring of particle size and

morphology in suspension cultures of Morinda citrifolia and Centaurea

calcitrapa.

Biotechnol Lett. 2003 Dec;25(23):2023-8.

PMID: 14719817 [PubMed - indexed for MEDLINE]

17: Furusawa E, Hirazumi A, Story S, Jensen J.

Antitumour potential of a polysaccharide-rich substance from the fruit juice of

Morinda citrifolia (Noni) on sarcoma 180 ascites tumour in mice.

Phytother Res. 2003 Dec;17(10):1158-64.

PMID: 14669249 [PubMed - indexed for MEDLINE]

18: McClatchey W.

From Polynesian healers to health food stores: changing perspectives of Morinda

citrifolia (Rubiaceae).

Integr Cancer Ther. 2002 Jun;1(2):110-20; discussion 120. Review.

PMID: 14664736 [PubMed - indexed for MEDLINE]

19: Block KI.

Editorial: On psycho-oncology, lycopene and the Noni fruit.

Integr Cancer Ther. 2002 Jun;1(2):107-9. No abstract available.

PMID: 14664735 [PubMed - indexed for MEDLINE]

20: Siddiqui BS, Ismail FA, Gulzar T, Begum S.

Isolation and structure determination of a benzofuran and a bis-nor-isoprenoid

from Aspergillus niger grown on the water soluble fraction of Morinda citrifolia

Linn. leaves.

Nat Prod Res. 2003 Oct;17(5):355-60.

PMID: 14526916 [PubMed - indexed for MEDLINE]

21: Stalman M, Koskamp AM, Luderer R, Vernooy JH, Wind JC, Wullems GJ, Croes

AF.

Regulation of anthraquinone biosynthesis in cell cultures of Morinda

citrifolia.

J Plant Physiol. 2003 Jun;160(6):607-14.

PMID: 12872482 [PubMed - indexed for MEDLINE]

22: He H, Xu HH.

[in vitro culture and the Agrobacterium-mediated genetic transformation of

Morinda officinalis]

Zhongguo Zhong Yao Za Zhi. 2002 Oct;27(10):733-5. Chinese.

PMID: 12776548 [PubMed - indexed for MEDLINE]

23: Sang S, Liu G, He K, Zhu N, Dong Z, Zheng Q, Rosen RT, Ho CT.

New unusual iridoids from the leaves of noni (Morinda citrifolia L.) show

inhibitory effect on ultraviolet B-induced transcriptional activator protein-1

(AP-1) activity.

Bioorg Med Chem. 2003 Jun 12;11(12):2499-502.

PMID: 12757717 [PubMed - indexed for MEDLINE]

24: Allen DD, Lockman PR, Roder KE, Dwoskin LP, Crooks PA.

Active transport of high-affinity choline and nicotine analogs into the central

nervous system by the blood-brain barrier choline transporter.

J Pharmacol Exp Ther. 2003 Mar;304(3):1268-74.

PMID: 12604705 [PubMed - indexed for MEDLINE]

25: Pan C, Huang H, Zhan R, Xu H, Liao G.

[Diagnosis and integrative evaluation on soil fertility of three Chinese

medicinal materials in GAP plots]

Zhong Yao Cai. 2002 Mar;25(3):157-9. Chinese.

PMID: 12583155 [PubMed - indexed for MEDLINE]

26: Cimanga K, Hermans N, Apers S, Van Miert S, Van den Heuvel H, Claeys M,

Pieters L, Vlietinck A.

Complement-inhibiting iridoids from Morinda morindoides.

J Nat Prod. 2003 Jan;66(1):97-102.

PMID: 12542353 [PubMed - indexed for MEDLINE]

27: Li YF, Gong ZH, Yang M, Zhao YM, Luo ZP.

Inhibition of the oligosaccharides extracted from Morinda officinalis, a

Chinese traditional herbal medicine, on the corticosterone induced apoptosis in

PC12 cells.

Life Sci. 2003 Jan 10;72(:933-42.

PMID: 12493574 [PubMed - indexed for MEDLINE]

28: Slovick J.

Manufacturer agrees to cease unproved claims about Noni juice.

Posit Living. 1999 May;8(4):10. No abstract available.

PMID: 12492064 [PubMed - indexed for MEDLINE]

29: Wilkins LH Jr, Grinevich VP, Ayers JT, Crooks PA, Dwoskin LP.

N-n-alkylnicotinium analogs, a novel class of nicotinic receptor antagonists:

interaction with alpha4beta2* and alpha7* neuronal nicotinic receptors.

J Pharmacol Exp Ther. 2003 Jan;304(1):400-10.

PMID: 12490617 [PubMed - indexed for MEDLINE]

30: Wang MY, West BJ, Jensen CJ, Nowicki D, Su C, Palu AK, Anderson G.

Morinda citrifolia (Noni): a literature review and recent advances in Noni

research.

Acta Pharmacol Sin. 2002 Dec;23(12):1127-41. Review.

PMID: 12466051 [PubMed - indexed for MEDLINE]

31: McKoy ML, Thomas EA, Simon OR.

Preliminary investigation of the anti-inflammatory properties of an aqueous

extract from Morinda citrifolia (noni).

Proc West Pharmacol Soc. 2002;45:76-8. No abstract available.

PMID: 12434536 [PubMed - indexed for MEDLINE]

32: Saludes JP, Garson MJ, Franzblau SG, Aguinaldo AM.

Antitubercular constituents from the hexane fraction of Morinda citrifolia

Linn. (Rubiaceae).

Phytother Res. 2002 Nov;16(7):683-5.

PMID: 12410555 [PubMed - indexed for MEDLINE]

33: Hagendoorn M, Wagner AM, Segers G, Van Der Plas L, Oostdam A, Van Walraven

HS.

Cytoplasmic Acidification and Secondary Metabolite Production in Different

Plant Cell Suspensions (A Comparative Study).

Plant Physiol. 1994 Oct;106(2):723-730.

PMID: 12232364 [PubMed - as supplied by publisher]

34: Iturriza Gomara M, Wong C, Blome S, Desselberger U, Gray J.

Rotavirus subgroup characterisation by restriction endonuclease digestion of a

cDNA fragment of the VP6 gene.

J Virol Methods. 2002 Aug;105(1):99-103.

PMID: 12176146 [PubMed - indexed for MEDLINE]

35: Salleh MN, Runnie I, Roach PD, Mohamed S, Abeywardena MY.

Inhibition of low-density lipoprotein oxidation and up-regulation of

low-density lipoprotein receptor in HepG2 cells by tropical plant extracts.

J Agric Food Chem. 2002 Jun 19;50(13):3693-7.

PMID: 12059144 [PubMed - indexed for MEDLINE]

36: MacDonald N.

Profile: Dr. Noni MacDonald. Interview by Cynthia Martin.

Hosp Q. 2002 Spring;5(3):80-2, 84. No abstract available.

PMID: 12055872 [PubMed - indexed for MEDLINE]

37: Wilkins LH Jr, Haubner A, Ayers JT, Crooks PA, Dwoskin LP.

N-n-alkylnicotinium analogs, a novel class of nicotinic receptor antagonist:

inhibition of S(-)-nicotine-evoked [(3)H]dopamine overflow from superfused rat

striatal slices.

J Pharmacol Exp Ther. 2002 Jun;301(3):1088-96.

PMID: 12023541 [PubMed - indexed for MEDLINE]

38: Protano G, Riccobono F.

High contents of rare earth elements (REEs) in stream waters of a Cu-Pb-Zn

mining area.

Environ Pollut. 2002;117(3):499-514.

PMID: 11911532 [PubMed - indexed for MEDLINE]

39: Zhang ZQ, Yuan L, Yang M, Luo ZP, Zhao YM.

The effect of Morinda officinalis How, a Chinese traditional medicinal plant,

on the DRL 72-s schedule in rats and the forced swimming test in mice.

Pharmacol Biochem Behav. 2002 May;72(1-2):39-43.

PMID: 11900767 [PubMed - indexed for MEDLINE]

40: Wang MY, Su C.

Cancer preventive effect of Morinda citrifolia (Noni).

Ann N Y Acad Sci. 2001 Dec;952:161-8.

PMID: 11795436 [PubMed - indexed for MEDLINE]

41: Li YF, Yuan L, Xu YK, Yang M, Zhao YM, Luo ZP.

Antistress effect of oligosaccharides extracted from Morinda officinalis in

mice and rats.

Acta Pharmacol Sin. 2001 Dec;22(12):1084-8.

PMID: 11749804 [PubMed - indexed for MEDLINE]

42: Truong A, Xing X, Forsayeth JR, Dwoskin LP, Crooks PA, Cohen BN.

Pharmacological differences between immunoisolated native brain and

heterologously expressed rat alpha4beta2 nicotinic receptors.

Brain Res Mol Brain Res. 2001 Nov 30;96(1-2):68-76.

PMID: 11731010 [PubMed - indexed for MEDLINE]

43: Szabadvary F, Vamos E.

[Lecturers in chemistry at the Medical Faculty of the University of

Nagyszombat]

Orvostort Kozl. 1994;40(3-4):45-54. Hungarian.

PMID: 11639449 [PubMed - indexed for MEDLINE]

44: Liu G, Bode A, Ma WY, Sang S, Ho CT, Dong Z.

Two novel glycosides from the fruits of Morinda citrifolia (noni) inhibit AP-1

transactivation and cell transformation in the mouse epidermal JB6 cell line.

Cancer Res. 2001 Aug 1;61(15):5749-56.

PMID: 11479211 [PubMed - indexed for MEDLINE]

45: [No authors listed]

Noni plant may help TB.

AIDS Patient Care STDS. 2001 Mar;15(3):175. No abstract available.

PMID: 11332409 [PubMed - indexed for MEDLINE]

46: Suarez-Almazor ME, Kendall CJ, Dorgan M.

Surfing the Net--information on the World Wide Web for persons with arthritis:

patient empowerment or patient deceit?

J Rheumatol. 2001 Jan;28(1):185-91.

PMID: 11196523 [PubMed - indexed for MEDLINE]

47: Wang M, Kikuzaki H, Jin Y, Nakatani N, Zhu N, Csiszar K, Boyd C, Rosen RT,

Ghai G, Ho CT.

Novel glycosides from noni (Morinda citrifolia).

J Nat Prod. 2000 Aug;63(:1182-3.

PMID: 10978225 [PubMed - indexed for MEDLINE]

48: Mueller BA, Scott MK, Sowinski KM, Prag KA.

Noni juice (Morinda citrifolia): hidden potential for hyperkalemia?

Am J Kidney Dis. 2000 Feb;35(2):310-2.

PMID: 10676732 [PubMed - indexed for MEDLINE]

49: Wang M, Kikuzaki H, Csiszar K, Boyd CD, Maunakea A, Fong SF, Ghai G, Rosen

RT, Nakatani N, Ho CT.

Novel trisaccharide fatty acid ester identified from the fruits of Morinda

citrifolia (Noni).

J Agric Food Chem. 1999 Dec;47(12):4880-2.

PMID: 10606546 [PubMed - indexed for MEDLINE]

50: Hirazumi A, Furusawa E.

An immunomodulatory polysaccharide-rich substance from the fruit juice of

Morinda citrifolia (noni) with antitumour activity.

Phytother Res. 1999 Aug;13(5):380-7.

PMID: 10441776 [PubMed - indexed for MEDLINE]

51: MacLoughlin PF, Malone DM, Murtagh JT, Kieran PM.

The effects of turbulent jet flows on plant cell suspension cultures

Biotechnol Bioeng. 1998 Jun 20;58(6):595-604.

PMID: 10099297 [PubMed - as supplied by publisher]

52: Hirazumi A, Furusawa E, Chou SC, Hokama Y.

Immunomodulation contributes to the anticancer activity of morinda citrifolia

(noni) fruit juice.

Proc West Pharmacol Soc. 1996;39:7-9. No abstract available.

PMID: 8895953 [PubMed - indexed for MEDLINE]

53: Hirazumi A, Furusawa E, Chou SC, Hokama Y.

Anticancer activity of Morinda citrifolia (noni) on intraperitoneally implanted

Lewis lung carcinoma in syngeneic mice.

Proc West Pharmacol Soc. 1994;37:145-6. No abstract available.

PMID: 7984648 [PubMed - indexed for MEDLINE]

54: Wechsler TD, Brunisholz RA, Frank G, Zuber H.

Isolation and protein chemical characterization of the B806-866 antenna complex

of the green thermophilic bacterium Chloroflexus aurantiacus.

J Photochem Photobiol B. 1991 Jan;8(2):189-97.

PMID: 1904920 [PubMed - indexed for MEDLINE]

55: LA BARRE J, HANS M, HANS MJ.

[Apropos of the hypotensive, diuretic and tranquilizing properties of purified

extracts of Morinda.]

Bull Acad R Med Belg. 1961;1:567-81. French. No abstract available.

PMID: 13757907 [PubMed - OLDMEDLINE for Pre1966]

56: YOUNGKEN HW Sr, JENKINS HJ, BUTLER CL.

Studies on Morinda citrifolia L. II.

J Am Pharm Assoc Am Pharm Assoc. 1960 May;49:271-3. No abstract available.

PMID: 13855457 [PubMed - OLDMEDLINE for Pre1966]

57: YOUNGKEN HW Sr.

A study of the root of Morinda citrifolia Linne. I.

J Am Pharm Assoc Am Pharm Assoc (Baltim). 1958 Mar;47(3, Part 1):162-5. No

abstract available.

PMID: 13525210 [PubMed - OLDMEDLINE for Pre1966]

58: DANG-VAN-HO.

[Treatment and prevention of hypertension and its cerebral complications by

total root extracts of Morinda citrifolia.]

Presse Med. 1955 Nov 2;63(72):1478. French. No abstract available.

PMID: 13280670 [PubMed - OLDMEDLINE for Pre1966]

59: PARIS R, NGUYEN-BA-TUOC.

[A Rubiaceae containing anthracene derivatives: Morinda persicaefolia;

structure of morindine (morindoside).]

Ann Pharm Fr. 1954 Dec;12(12):794-9. French. No abstract available.

PMID: 14362136 [PubMed - OLDMEDLINE for Pre1966]

60: DANG-VAN-HO.

[A basic treatment for arterial hypertension with extracts of the roots of

Morinda citrifilia (Cay-Nhau).]

Presse Med. 1954 Jul 3;62(48):1020-1. French. No abstract available.

PMID: 13194596 [PubMed - OLDMEDLINE for Pre1966]

[Visitante jotaneves]

http://cancerres.aacrjournals.org/cgi/content/full/61/15/5749#SEC2

Carcinogenesis

Two Novel Glycosides from the Fruits of Morinda Citrifolia (Noni) Inhibit AP-1 Transactivation and Cell Transformation in the Mouse Epidermal JB6 Cell Line1

Guangming Liu, Ann Bode, Wei-Ya Ma, Shengmin Sang, Chi-Tang Ho and Zigang Dong2

The Hormel Institute, University of Minnesota, Austin, Minnesota 55912 [G. L., A. B., W-Y. M., Z. D.], and The Department of Food Science and Center for Advanced Food Technology, Rutgers University, New Brunswick, New Jersey 08901-8520 [s. S., C-T. H.]

ABSTRACT

The fruit juice of Morinda citrifolia (noni), a plant originally grown in the Hawaiian and Tahitian islands, has long been used by islanders to treat diseases, including cancer. Two novel glycosides, 6-O-(ß-D-glucopyranosyl)-1-O-octanoyl-ß-D-glucopyranose and asperulosidic acid, extracted from the juice of noni fruits, were used to examine their effects on 12-O-tedtradecanoylphorbol-13-acetate (TPA)- and epidermal growth factor (EGF)-induced AP-1 transactivation and cell transformation in mouse epidermal JB6 cells. The results indicated that both compounds were effective in suppressing TPA- or EGF-induced cell transformation and associated AP-1 activity. TPA- or EGF-induced phosphorylation of c-Jun, but not extracellular signal-regulated kinases or p38 kinases, was also blocked by the compounds, indicating that c-Jun N-terminal kinases were critical in mediating TPA- or EGF-induced AP-1 activity and subsequent cell transformation in JB6 cells.

INTRODUCTION

Morinda citrifolia (Rubiaceae), known as "noni" locally, is a plant grown in the Hawaiian and Tahitian islands. The stem, bark, root, leaf, and fruits of the plant have been used traditionally by islanders as medicines to treat a broad range of diseases, including diabetes, hypertension, and cancer (1 , 2) . The fruit juice of Morinda citrifolia or noni contains a polysaccharide-rich substance called noni-ppt that has been reported to have antitumor activity in the Lewis lung peritoneal carcinoma model (3) . Noni-ppt administration significantly prolonged the survival duration of inbred Lewis lung tumor-bearing mice (1) . Noni-ppt was suggested to suppress tumor growth through its regulation of the host immune system (4) . It was reported to stimulate the release of several potential mediators, including TNF-,3 IL-1ß, IL-10, IL-12 p70, IFN-, and nitric oxide (4) . Some individual compounds from noni juice were reported to function as ras inhibitors and thus suppressed ras-expressing tumors (2) . Improved survival time and curative effects occurred when noni-ppt was combined with suboptimal doses of standard chemotherapeutic agents, which suggests important clinical applications of noni-ppt as a supplemental agent in cancer treatment (4) .

To elucidate the mechanism of the antitumorigenic effects of noni-ppt, we studied the effects of compounds isolated from noni-ppt on AP-1 activity and cellular transformation in mouse epidermal JB6 cells. AP-1 is an inducible eukaryotic transcription factor containing products of the jun and fos oncogene families (5, 6, 7) . The inducible AP-1 complexes are composed of Jun-Jun or Jun-Fos dimers. When stimulated, AP-1 binds to transactivation promoter region TREs (TPA response elements) and induces transcription of several genes involved in cell proliferation, metastasis, and metabolism ( . Many stimuli are able to induce AP-1 activity (5) , including the phorbol ester TPA, and EGF. These are the two most commonly used experimental stimuli used to activate AP-1 and induce cellular transformation in many different cell types and animal models (9) . Increased AP-1 activity is associated with malignant transformation and cancer promoting agents, such as UV radiation (10) , growth factors (11) , phorbol esters (12 , 13) , and transforming oncogenes (11) . In JB6 mouse epidermal cell lines, TPA and EGF were shown to induce AP-1 transcriptional activity in promotion-sensitive (P+), but not in promotion-resistant (P-), cellular phenotypes (12) . When AP-1 induction was blocked, P+ cells reverted to the P- phenotype, indicating that AP-1 activity is required for TPA- or EGF-induced cell transformation (12) . On the other hand, inhibition of AP-1 activity has been shown to lead to suppression of cell transformation (14) . Some chemopreventive agents, including aspirin, sodium salicylate, tea polyphenols, perillyl alcohol, and retinoic acid, have been reported to inhibit cell transformation and tumor promotion and were also found to suppress AP-1 transactivation (14, 15, 16, 17, 18, 19, 20) . All of these results strongly indicate that the inhibition of AP-1 activity leads to the suppression of tumor promotion.

Reports focusing on chemopreventive effects of the fruits of noni are limited. Here we used two novel compounds, NB10 (Fig. 1A) and NB11 (Fig. 1B) , isolated from the juice of noni fruits to examine their effects on AP-1 transactivation and subsequent cell transformation in mouse epidermal JB6 cells. Because AP-1 has an important role in tumorigenesis, the results of this investigation may provide new insights into the mechanism of noni juice in tumor suppression and the possibility for its application in tumor prevention and treatment.

Fig. 2. NB10 or NB11 suppress both TPA- and EGF-induced AP-1 activity. Stably transfected JB6 P+1–1 AP-1 luciferase reporter cells were cultured as described in "Materials and Methods." The cells were starved in 0.5% FBS/MEM and treated with different concentrations of NB10 or NB11 as indicated. After a 30-min treatment of the cells with NB10 or NB11, 20 ng/ml of TPA or EGF were or were not added, and the cells were cultured for another 24 h before harvest. AP-1 activity is expressed as a fold increase of relative luciferase units as assessed by luminometer. In A, TPA or EGF treatment induced a 3.3- or 3.6-fold increase in AP-1 activity, respectively, and NB10 (150 µM) significantly inhibited AP-1 activity [47%; *, a significant (P < 0.01) inhibition compared with TPA or EGF treatment with no inhibitor present; bars, SD of triplicate experiments, four wells each]. NB10 alone had no effect (P > 0.05; bars, SD of triplicate experiments, four wells each) on basal AP-1 activity. In B, NB11 (150 µM) significantly inhibited TPA- or EGF-induced AP-1 activity [53 or 49%, respectively; *, a significant (P < 0.01) inhibition compared with EGF treatment with no inhibitor present; bars, SD of triplicate experiments, four wells each]. NB11 alone caused a slight but insignificant (P > 0.05; bars, SD of triplicate experiments, four wells each) reduction of basal AP-1 activity.

MATERIALS AND METHODS

Cell Culture and Reagents.

AP-1 luciferase reporter plasmid stably transfected mouse epidermal JB6 P+ 1–1 and the JB6 P+ mouse epidermal cell line, Cl 41, were cultured in monolayers at 37°C, 5% CO2 using Eagle’s MEM containing 5% FBS, 2 mM L-glutamine, and 25 µg of gentamicin/ml. FBS and MEM were from Bio Whittaker, Inc. (Walkersville, MD); PD169316, TPA, aprotinin, and leupeptin were from Sigma Chemical Co. (St. Louis, MO); EGF was from Clonetics (San Diego, CA); NB10 and NB11 were extracted, and the structures were determined as described previously (2 , 21) ; the luciferase assay substrate was from Promega (Madison, WI); and antibodies against ERKs or p38 kinase, specific antibodies against phosphorylated sites of ERKs, p38 kinase, and the JNK assay kit were from New England Biolabs, Inc. (Beverly, MA).

Luciferase Assay for AP-1 Transactivation.

Confluent monolayers of JB6 P+ 1–1 cells were trypsinized, and 8000 viable cells suspended in 100 µl of 5% FBS MEM were added to each well of a 96-well plate. Plates were incubated at 37°C in a humidified atmosphere of 5% CO2. When cells reached 80–90% confluence, they were starved by culturing them in 0.1% FBS MEM for another 24 h. The cells were then treated for 30 min with different concentrations of NB10 or NB11 as indicated and then exposed to TPA (20 ng/ml) or EGF (20 ng/ml) for 24 h. After treatment, cells were extracted with 100 µl of lysis buffer [0.1 M potassium phosphate buffer (pH 7.; 1% Triton X-100; 1 mM DTT; 2 mM EDTA], and luciferase activity was measured using a luminometer (Monolight 2010). The results are expressed as relative AP-1 activity (22) .

Anchorage-independent Transformation Assay.

The effect of NB10 or NB11 on TPA- or EGF-induced cell transformation was investigated in JB6 C1 41 cells. Cells (8 x 103/ml) were exposed to TPA or EGF with or without NB10, NB11 (10–150 µM), or PD169316 (0.05–0.2 µM) in 1 ml of 0.33% Basale Medium Eagle agar containing 10% FBS >3.5 ml of 0.5% Basale Medium Eagle agar medium containing 10% FBS. The cultures were maintained in a 37°C, 5% CO2 incubator for 4 weeks, and the cell colonies were scored as described by Colburn et al. (23) . The effects of the compounds on cell transformation of JB6 C1 41 cells are presented as a percentage inhibition of cell transformation compared with TPA- or EGF-stimulated cells in soft agar.

AP-1 DNA Binding Studies.

EMSA was performed essentially as described (24) . Nuclear protein extracts were prepared from JB6 C1 41 cells by the modified method of Monick et al. (25) . Briefly, JB6 C1 41 cells were cultured in 10-cm dishes and starved in 0.1% FBS MEM at 37°C in a 5% CO2 incubator as described earlier. After a 24 h starvation, the cells were treated for 30 min with different concentrations of NB10, NB11, or PD169316 as indicated and then exposed to TPA (20 ng/ml) or EGF (20 ng/ml) for another 12 h. Then the cells were harvested and disrupted in 500 µl of lysis buffer A [25 mM HEPES (pH 7., 50 mM KCl, 0.5% NP-40, 100 µM DTT, 10 µg/ml leupeptin, 25 µg/ml aprotinin, and 1 mM PMSF]. After a 1-min centrifugation (16,000 x g, 4°C), the pellet containing the nuclei was washed once with 500 µl of buffer B (buffer A without NP-40). The pellet containing the nuclei was resuspended in 150 µl of extraction buffer (buffer B but with 500 mM KCl and 10% glycerol) and shaken at 4°C for 30 min. The nuclear extracts were stored at -70°C until analysis. The DNA binding reaction (for EMSA) was carried out at room temperature for 30 min in a mixture containing 4 µg of nuclear protein, 1 µg of poly (dI-dC), and 15,000 cpm of 32P-labeled double-stranded AP-1 oligonucleotide (5'-CGCTTGATGAGTCAGCCGGAA-3'). The samples were fractionated through a 5% polyacrylamide gel. Gels were dried and analyzed using the Storm 840 Phospho-Image System (Molecular Dynamics).

JNK Assay.

JB6 Cl 41 cells were cultured and starved in 0.1% FBS MEM at 37°C in a 5% CO2 incubator as described earlier. The cells were treated for 30 min with different concentrations of NB10 or NB11 and then exposed to TPA (20 ng/ml) or EGF (20 ng/ml) followed by culturing for another 30 min. The JNK assay was carried out according to the protocol of New England Biolabs, Inc. In brief, the cells were washed once with ice-cold PBS and disrupted in 300 µl of lysis buffer [20 mM Tris (pH 7.4), 150 mM NaCl, 1 mM EDTA, 1 mM EGTA, 1% Triton, 2.5 mM Na PPi, 1 mM ß-glycerophosphate, 1 mM Na3VO4, 1 mg/ml leupeptin, and 1 mM PMSF] per sample. The lysates were sonicated and centrifuged, and 250 µl of the supernatant fraction were incubated with 2 µg of the N-terminal c-Jun (1–89) fusion protein bound to glutathione-Sepharose beads. The mixed samples were gently rocked overnight at 4°C. The beads were then washed twice with 500 µl of lysis buffer with PMSF and twice with 500 µl of the kinase buffer [25 mM Tris (pH 7.5), 5 mM ß-glycerophosphate, 2 mM DTT, 0.1 mM Na3VO4, and 10 mM MgCl2]. The kinase reactions were carried out at 30°C for 30 min in the presence of 100 µM ATP. c-Jun phosphorylation was selectively measured by Western immunoblotting using a chemiluminescent detection system (enhanced chemiluminescence) and a specific c-Jun antibody against phosphorylation of c-Jun at Ser63.

Immunoblotting for Phosphorylated JNKs, ERKs, and p38 Kinase.

Immunoblotting for the phosphorylated proteins of JNKs, ERKs, and p38 kinase was carried out using specific MAPK antibodies against phosphorylated sites of JNKs, ERKs, or p38 kinase (14) , according to the manufacturer’s recommendations. Antibody-bound proteins were detected by chemiluminescence (enhanced chemiluminescence; New England Biolabs, Inc.) and analyzed using the Storm 840 Phosphor-Image System (Molecular Dynamics). JNKs, ERKs, and p38 kinase were detected by specific MAPK antibodies against JNKs, ERKs, and p38 as inner controls.

Statistical Analysis.

Significant differences in AP-1 activity were determined using the Student t test. The results are expressed as means ± SD.

RESULTS

NB10 and NB11 Suppress AP-1 Activity in JB6 Cells.

The AP-1 complex not only mediates cell transformation and tumorigenesis, but it also appears to be involved in a broad range of physiological functions, including cell proliferation, survival, and apoptosis (26) . To examine if NB10 or NB11 influences AP-1 activity and to exclude the possibility that either compound alone may affect the induction of AP-1, we investigated the effect of NB10 or NB11 on AP-1 activity in AP-1 luciferase reporter plasmid stably transfected mouse epidermal JB6 P+ 1–1 cells. We observed a slight but insignificant (P > 0.05) inhibition of basal AP-1 activity by NB11 compared with untreated cells (Fig. 2) . When JB6 cells were pretreated 30 min with NB10 or NB11 at the concentration indicated, both TPA- (Fig. 3A) and EGF-induced AP-1 activity were significantly inhibited by 150 µM NB10 (Fig. 2A) or NB11 (Fig. 2B ; P < 0.01). DMSO used to dissolve the compounds had no effect on stimulated AP-1 activity (data not shown), and NB10 or NB11 caused no significant growth inhibition in the range of concentrations used in these experiments (Fig. 3A) . Moreover, neither NB10 nor NB11 caused a reduction of [3H]dThd incorporation in TPA-treated cells (Fig. 3B) .

Fig. 3. The effects of NB10 or NB11 with or without TPA on JB6 cell proliferation. JB6 P+1–1 cells (5 x 103) were seeded in 96-well plates. After culturing overnight, the cells were treated with the concentration of NB10 or NB11 indicated for 1 h, and then 20 ng/ml of TPA were or were not added. After culturing another 24 h in a 37°C, 5% CO2 incubator, [3H]dThd (0.5 µCi/well, 1 µCi = 37 GBq) was added to each well. The cells were harvested 12 h later, and incorporation of [3H]dThd was measured by liquid scintillation counting. The results are presented as cpm. In A, no significant difference in [3H]dThd incorporation could be detected at any concentration of NB10 or NB11 compared with control medium (P > 0.05; bars, SD of six wells). In B, NB10 or NB11 also did not cause a reduction of [3H]dThd incorporation in TPA-treated cells.

NB10 and NB11 Suppress Anchorage-independent Cell Transformation.

Both TPA- and EGF-induced cell transformation on soft agar were significantly suppressed by NB10 or NB11 (Fig. 4, A and . NB10 appeared to be more effective at the concentrations of 10, 50, and 100 µM (Fig. 4A , P < 0.01, indicated by *) than NB11 (Fig. 4B) in suppressing TPA-induced cell transformations on soft agar. NB10 and NB11 inhibited EGF-induced cell transformations only at the highest concentration (150 µM, Fig. 4B ). The inhibitory effects of both compounds on AP-1 activity agree with their inhibitory effects on cell transformation. Therefore, these results suggest that the inhibition of cell transformation by the compounds is through their suppression of AP-1 activity.

Fig. 4. NB10 or NB11 suppresses both TPA- and EGF-stimulated cell transformation on soft agar. JB6 Cl 41 cells seeded in triplicate wells were exposed to 20 ng/ml of TPA or EGF with or without NB10 or NB11 at the concentrations indicated and as described in "Materials and Methods." Cell colonies were scored after 4 weeks of incubation in a 37°C, 5% CO2 atmosphere. In A, NB10 or NB11 effectively inhibited TPA-induced cell transformation on soft agar in a dose-dependent manner [*, a significant (P < 0.01) inhibition compared with TPA treatment with no inhibitor present; bars, SD of three wells each concentration]. In B, both compounds inhibited EGF-induced cell transformation but only at the highest concentration tested [150 µM; *, a significant (P < 0.01) inhibition compared with EGF treatment with no inhibitor present; bars, SD of three wells each concentration].

NB10 and NB11 Repress AP-1 DNA Binding.

In its function as a transcription factor, AP-1 mediates gene expression induced by TPA, growth factors, cytokines, and other stimuli (27) . AP-1 DNA binding activity was assessed by EMSA (27) , and results indicated that TPA (20 ng/ml; Fig. 5, A and B ) or EGF (20 ng/ml; Fig. 5D ) induced a significant increase in AP-1 DNA binding. The DNA binding was specific for AP-1 because a 10-fold excess of unlabeled AP-1 probe successfully competed with the labeled probe (Fig. 5A , Lane 1). NB10 or NB11 (100 µM) alone had little effect on AP-1 binding (Fig. 5A , Lanes 3 and 4, respectively). Both NB10 and NB11 successfully blocked TPA- or EGF-induced AP-1 DNA binding activity (Fig. 5, B and D , Lanes 3–6). A compound concentration of 100 µM was much more effective than 50 µM in blocking TPA- or EGF-induced AP-1 DNA-binding activity. Although these results somewhat reflected the inhibitory effects of NB10 and NB11 on AP-1 transactivation and cell transformation, they were not in total agreement. This was not surprising because AP-1 transactivation and DNA binding activity do not always mirror one another in their ability to activate transcription of target genes (27) . Still, the reduced AP-1 DNA binding activity induced by higher concentrations of NB10 or NB11 may have a role in the mechanism leading to inhibition of AP-1 transactivation.

Fig. 5. NB10 and NB11 block TPA- or EGF-induced AP-1 DNA binding. JB6 Cl 41 cells were treated, nuclear proteins were extracted, and EMSA were carried out as described in "Materials and Methods." In A, TPA strongly induces AP-1 DNA binding (Lane 5), and the binding is specific as indicated by the effective competition of a 10-fold excess of the unlabeled AP-1 probe (Lane 1). NB10 or NB11 alone have little effect on AP-1 DNA binding (Lanes 3 and 4 compared with Lane 2). In B, a 100 µM concentration of NB10 or NB11 effectively blocks TPA-induced AP-1 DNA binding (Lanes 4 and 6 compared with Lane 2). C, quantitation analysis of Fig. 5B from performances of EMSA using nuclear extracts from different cell preparations. In D, EGF induces AP-1 binding (Lane 2), and 100 µM NB10 or NB11 decreases EGF-induced AP-1 binding (Lanes 4 and 6). E, quantitation analysis of Fig. 5D from performances of EMSA using nuclear extracts from different cell preparations.

TPA- or EGF-induced Phosphorylation of ERKs and p38 Kinases Was Not Inhibited by NB10 or NB11.

ERKs have been suggested to be most efficiently stimulated by growth factors and phorbol esters, whereas p38 kinase was shown to be induced by growth factors but not phorbol esters (27) . In the current experiment, both TPA and EGF induced a strong phosphorylation of ERKs and p38 kinases (Fig. 6, A and . However, NB10 or NB11 had no effect on the phosphorylation of either ERKs or p38 kinases (Fig. 6, A and , indicating that ERKs and p38 kinases are not the targets of these compounds that lead to suppression of AP-1 activity in JB6 cells.

Fig. 6. Neither NB10 nor NB11 have an effect on TPA- or EGF-induced phosphorylation of ERKs or p38 kinase. JB6 Cl 41 cells were treated, and Western blot analysis was carried out as described in "Materials and Methods." Treatment with either TPA (A) or EGF ( induces phosphorylation of ERKs or p38 kinase, and treatment with NB10 or NB11 had no effect on that phosphorylation (A and .

NB10 and NB11 Suppress TPA- or EGF-induced Phosphorylation of c-Jun.

MAPKs contribute to the induction of AP-1 activity in response to a broad range of extracellular stimuli (27) . Among the three types of MAPKs, JNKs are suggested to mediate the effects of UV irradiation or TNF (27) . In the present experiment, we did not observe phosphorylation of JNKs induced by TPA or EGF (data not shown). However, both TPA and EGF induced an increase in JNKs activity that was measured by the phosphorylation of c-Jun, a direct substrate of JNKs (Fig. 7, A and . NB10 or NB11 (50–100 µM) diminished TPA- or EGF-stimulated phosphorylation of c-Jun (Fig. 7, A and . Because this method is more sensitive and more accurate in reflecting JNK activity in vivo (28 , 29) , the results suggested that the inhibition of c-Jun phosphorylation is one of the mechanisms contributing to the suppression of AP-1 activity and subsequent cell transformation by NB10 and NB11.

Fig. 7. NB10 and NB11 block TPA- or EGF-induced JNK activity. JB6 Cl 41 cells were treated with NB10 or NB11 and exposed to TPA or EGF as described in "Materials and Methods." JNK activity was determined by using the N-terminal c-Jun (1–89) fusion protein bound to glutathione-Sepharose beads to selectively "pull down" the JNK protein from cell lysates. The kinase reaction was carried out in the presence of 100 µM ATP, and phosphorylation of c-Jun, a direct substrate of JNK, was determined by Western immunoblotting using a specific antibody against phosphorylation of c-Jun at Ser63. Both TPA (A) and EGF ( induce phosphorylation of c-Jun at Ser63, and both NB10 and NB11 markedly block the TPA- or EGF-induced phosphorylation. JNK by Western immunoblotting was applied as controls for the same volume of proteins in cell lysates when pulled down together with c-Jun (1–89) fusion protein bound to glutathione-Sepharose beads.

PD169316 Suppresses AP-1 DNA Binding and Anchorage-independent Cell Transformation.

PD169316 is a specific inhibitor of MAPK p38. However, the compound is also known to inhibit phosphorylation of JNKs (Fig. 8 ; Refs. 30 and 31 ). To further determine whether JNK is important in mediating AP-1 activity and cell transformation, we used PD169316 to block AP-1 DNA binding and cell transformation induced by TPA or EGF in JB6 cells. The compound effectively blocked TPA- or EGF-induced AP-1 DNA binding and anchorage-independent cell transformation at the same concentrations in which it blocked JNK phosphorylation (Figs. 9 and 10 ).

Fig. 8. PD169316 blocks UVB-induced phosphorylation of p38 or JNK kinase. JB6 Cl 41 cells were treated, and Western blot analysis was carried out as described in "Materials and Methods." Treatment with UVB (4 kJ/m2) induces phosphorylation of p38 or JNK, and 0.05 µM or 0.1 µM PD169316 effectively blocks UVB-induced phosphorylation of p38 or JNK, respectively.

Fig. 9. PD169316 blocks TPA- or EGF-induced AP-1 DNA binding. JB6 Cl 41 cells were treated, nuclear proteins were extracted, and EMSA was carried out as described in "Materials and Methods." In A, PD169316 in the concentration indicated effectively blocks TPA-induced AP-1 DNA binding (Lanes 3–5 compared with Lane 2). B, quantitation analysis of Fig. 9A from three performances of EMSA using nuclear extracts from different cell preparations. In C, PD169316 in the concentration indicated effectively blocks EGF-induced AP-1 DNA binding (Lanes 3–5 compared with Lane 2). D, quantitation analysis of Fig. 9C from three performances of EMSA using nuclear extracts from different cell preparations.

Fig. 10. PD169316 suppresses both TPA- and EGF-stimulated cell transformation on soft agar. JB6 Cl 41 cells seeded in triplicate wells were exposed to 20 ng/ml TPA or EGF with or without PD169316 at the concentrations indicated and as described in "Materials and Methods." Cell colonies were scored after 4 weeks of incubation in a 37°C, 5% CO2 atmosphere. In A, PD169316 effectively inhibited TPA-induced cell transformation on soft agar [*, a significant (P < 0.01) inhibition compared with TPA treatment with no inhibitor present; bars, SD of three wells each concentration]. In B, PD169316 inhibited EGF-induced cell transformation on soft agar [*, a significant (P < 0.01) inhibition compared with EGF treatment with no inhibitor present; bars, SD of three wells each concentration].

DISCUSSION

Morinda Citrifolia (noni) is one of a variety of plants that have been used locally in the Hawaiian and Tahitian islands to treat a variety of diseases, including cancer, for hundreds or thousands of years (1, 2, 3, 4) . Two glycosides, one novel and one known, NB10 and NB11 respectively, were recently isolated from the fruits of noni (2 , 21) . NB10 was obtained as a white powder (21) , and its structure is shown in Fig. 1A . NB11 (Fig. 1B) was isolated as a colorless oil (2) , which has been found earlier in many other plants (32) . Pharmacological studies revealed that NB11 has an antimutagenic function (33) . In the current study, we investigated the effects of these two noni glycosides on AP-1 transactivation and subsequent cell transformation in the mouse epidermal JB6 cell line. The JB6 cell line is a well-established system used extensively as an in vitro model for the study of tumor promotion and antitumor promotion (12, 13, 14 , 34) . Our results indicated that both compounds blocked TPA- or EGF-induced JNK activity, which most likely explains their inhibitory effect on AP-1 transactivation and the subsequent reduction in cell transformation induced by TPA or EGF.

As a sequence-specific transcriptional activator, AP-1 mediates a broad range of external stimuli that lead to gene transcription. Many stimuli, including TPA, growth factors, and UV radiation that induce AP-1, are associated with tumorigenesis (5 , 6) . Neoplastic transformation is often associated with a dramatic increase in AP-1 activity (35) , and this transient induction of AP-1 has been shown to be involved in the promotion of epidermal tumors (17 , 36, 37, 38) . Constitutive AP-1 activity has been associated with the malignant conversion of papillomas to carcinomas (39) as well. Chemopreventive agents or modification of AP-1 proteins that inhibit AP-1 activation are effective in preventing cell transformation or tumorigenesis (18 , 35 , 40 , 41) . Both TPA and EGF are tumor promoters that stimulate malignant transformation. In our experiments, both NB10 and NB11 suppressed TPA- or EGF-stimulated JB6 cell transformation on soft agar. A corresponding inhibition of TPA- or EGF-induced AP-1 activity was also found, suggesting that the inhibition of tumorigenesis by these compounds is through the inhibition of AP-1 activity.

Many mechanisms are involved in the up- and down-regulation of AP-1 activity (5) . MAPKs are the most common pathways known to mediate AP-1 function (27) , and in the current experiment, TPA or EGF activated all three members of the MAPK family: JNKs, ERKs, and p38 kinases. However, NB10 and NB11 were only able to block TPA- or EGF-stimulated JNK activity and not ERK or p38 kinase activities. Although both JNKs and ERKs of the MAPK family have been reported to be able to induce AP-1 activity (27) , each of the kinases may activate different AP-1 components resulting in the transcription of different genes (27) . Many reports indicated that JNKs are critical in mediating AP-1 transactivation and malignant transformation (19 , 42, 43, 44, 45) . For instance, we have reported that TNF--induced cell transformation requires activation of JNKs (46) . We also reported recently that TPA-induced skin tumorigenesis was strikingly suppressed in JNK-2-deficient mice (47) . In the human lung carcinoma A549 cell line, when EGF-induced JNK activity was blocked, the EGF-stimulated proliferation effect, but not the basal proliferation rate, was completely blocked (42) . Moreover, PD98059, a specific MAP/ERK inhibitor (48) , completely blocked ERK activation by EGF and basal cell growth, but not EGF-stimulated growth, indicating that JNKs may be a preferential effector pathway for the growth-inducing properties of EGF (42) . In our experiments, the inhibition of TPA- or EGF-induced JNK activity by NB10 or NB11 agreed well with the inhibitory effects of the compounds on TPA- or EGF-induced AP-1 activity, AP-1 DNA binding, and cell transformation. Furthermore, PD169316, a specific inhibitor of both MAPK p38 and JNKs (30 , 31) , also suppressed TPA- or EGF-induced AP-1 DNA binding and cell transformation. Considering the fact that MAPK families JNKs and ERKs, but not p38, are mainly involved in activating AP-1 (27) , it was more likely that PD169316 suppressed AP-1 via its blocking of JNKs. These results indicated that the inhibition of JNKs was critical in diminishing TPA- or EGF-induced AP-1 activity and subsequent cell transformation.

The two glycosides, the novel NB10 and the known NB11 from Morinda Citrifolia (noni), were effective in inhibiting cell transformation induced by TPA or EGF in the mouse epidermal JB6 cell line. The inhibition was found to be associated with the inhibitory effects of these compounds on AP-1 activity. The compounds also blocked phosphorylation of c-Jun, a substrate of JNKs, suggesting that JNKs are a critical target for the compounds in mediating AP-1 activity and cell transformation.

FOOTNOTES

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 Supported by The Hormel Foundation, NIH Grants CA81064, CA74916, and CA77646, and American Institute for Cancer Research Grant 99A062.

2 To whom requests for reprints should be addressed, at The Hormel Institute, University of Minnesota, 801 16th Avenue NE, Austin, MN 55912. Phone: (507) 437-9640; Fax: (507) 437-9606; E-mail: zgdong@smig.net.

3 The abbreviations used are: TNF, tumor necrosis factor; NB10, 6-O-(ß-D-glucopyranosyl)-1-O-octanoyl-ß-D-glucopyranose; NB11, asperulosidic acid; AP-1, transcription activator protein 1; TPA, 12-O-tetradecanoylphorbol-13-acetate; EGF, epidermal growth factor; ERK, extracellular signal regulated kinase; JNK, c-Jun N-terminal kinase; IL, interleukin; FBS, fetal bovine serum; EMSA, electrophoretic mobility shift assays; PMSF, phenylmethylsulfonyl fluoride; dThd, thymidine; MAPK, mitogen-activated protein kinase.

Received 1/ 9/01; accepted 5/10/01.

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[Visitante rafinha]

Daqui a pouco vai virar moda suplementar com Pfaffia Paniculata e suco de Noni.

Já tou vendo o forum cheio dos tópicos:

-Maximize resultados com Noni

-Pfaffia no pós-treino

-Pfaffia + Noni + Carbo.... está certo?

heauheaheauhaeuheuhaeuheua, suco de nni eh o meu 0

[wendelm]

Acesse: http://200.162.73.34/marcelo/index.htm

e acredite se quiser.