The oxidative modification of low-density lipoprotein (LDL) plays an important role in the genesis of arteriosclerosis. The present study focused on the effects of the fruits of Morinda citrifolia on preventing arteriosclerosis. The MeOH extract and CHCl(3)-, EtOAc-, n-BuOH-, and H(2)O-soluble phases derived from the fruits of M. citrifolia were evaluated for their inhibitory activity on copper-induced LDL oxidation by the thiobarbituric acid-reactive substances (TBARS) method. The MeOH extract and EtOAc-soluble phase showed 88 and 96% inhibition, respectively. Six lignans were isolated by repeated column chromatography from the EtOAc-soluble phase. These compounds were determined by spectroscopic analysis to be 3,3'-bisdemethylpinoresinol (1), americanol A (2), americanin A (3), americanoic acid A (4), morindolin (5), and isoprincepin (6), of which 4 and 5 are novel compounds. These compounds inhibited copper-induced LDL oxidation in a dose-dependent manner. 1, 2, 5, and 6 exhibited remarkably strong activities, which were the same or better than that of the known antioxidant 2,6-di-tert-butyl-p-cresol. The IC(50) values for 1, 2, 5, and 6 were 1.057, 2.447, 2.020, and 1.362 microM, respectively. The activity of these compounds is mainly due to their number of phenolic hydroxyl groups.

Morinda citrifolia L. (Rubiaceae), known as "noni", is a small tree that grows widely across Polynesia. The roots, barks, stems, leaves and fruits have been used traditionally as a folk medicine for the treatment of many diseases 1) including diabetes, hypertension 2) and cancer.3) Furthermore, today "noni juice", which is made from the fruits of this plant, is widely drunk for the purported prevention of lifestyle-related diseases such as diabetes, hypertension, cardiopathy and cerebral apoplexy caused by arteriosclerosis. In our previous study of the bioactive constituents of M. citrifolia fruits for the prevention of arteriosclerosis, six lignans were isolated as active components.4) The rubiaceous plant is well-known for its anthraquinone and iridoid constituents. In earlier studies of anthraquinones from M. citrifolia, morenone-1, morenone-2, nordamnacanthal, morindone, rubiadin, rubiadin-1-methyl ether and 7-hydroxy-8-methoxy-2-methylanthraquinone were identified in the root. 9) In studies of iridoids from M. citrifolia, asperuloside, 10) asperulosidic acid, 11) 6a-hydroxyadoxoside, 12) 6b,7b-epoxy-8-episplendoside, 12) borreriagenin, 12) citrifolinin B, 12) deacetylasperuloside 12) and dehydromethoxygaertneroside 12) were all isolated from the fruits, while citrifolinin A and citrifolinoside were isolated from the leaves. 13,14) The present paper describes the isolation and characterization of one new anthraquinone, 5,15-dimethylmorindol (1), together with five known anthraquinones, alizarin-1-methylether (2), 15) anthragallol-1,3-dimethylether (3), 16) anthragallol-2-methylether (4), 17) 6-hydroxy-anthragallol-1,3-dimethylether (5) 18) and morindone-5-methylether (6), 19) and one new iridoid, morindacin (7), together with two known iridoids, asuperlosidic acid (8) 20) and deacetylasperulosidic acid (9). (Fig. 2). From the above results, compound 1 was characterized as 1,6-dihydroxy-5-methoxy-2-methoxymethylanthraquinone. This compound was named as 5,15-O-dimethylmorindol, as it is the 5,15-dimethylether of morindone 15-alcohol.Compound 7, a colorless syrup, gave a molecular formula of C 10 H 14 O 5 by HR-FAB-MS. The IR spectrum of 7 indicated absorption bands due to hydroxyl and lactone functions at 3400 cm Ϫ1 and 1743 cm .27 (C-6)]. The connectivities of the quaternary carbons (C-3, C-8) were deduced by a HMBC experiment (Fig. 3). In the HMBC spectrum, one quaternary carbon signal at H COSY spectra, the planar structure was established. Furthermore, the relative stereostructure of 7 was characterized on the basis of a NOESY From the fruits of Morinda citrifolia L., one new anthraquinone, 5,15-O-dimethylmorindol, together with five known anthraquinones and one new iridoid, morindacin, together with two known iridoids, were isolated. Their structures were elucidated by analysis of spectroscopic data.

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Objective: Stressful exercise reduces the plasma pro-inflammatory cytokine concentration in response to lipopolysaccharide (LPS). The aim of this study was to clarify the mechanism of exhaustive exercise-induced suppression of the plasma tumor necrosis factor (TNF)-α concentration in response to LPS. Methods: Male C3H/HeN mice (n = 66) were randomized to treadmill running to exhaustion (Ex) or a sedentary (Non-Ex) condition. Monocytes and splenic macrophages were collected from some animals, and other animals were injected with LPS (1 mg/kg) immediately after the exercise. The liver, lung and spleen tissues in the mice were removed 30 min after the LPS injection for determination of TNF-α mRNA expression. Blood and tissue samples were collected for determination of TNF-α and TNF receptors (TNFR) 1 h after the LPS injection. Results: Although there was a significant suppression in LPS-induced plasma TNF-α in the Ex mice when compared to the Non-Ex mice (p < 0.01), soluble TNFR in plasma was not affected by the exercise. There was no change in cell-surface expression of Toll-like receptor 4 (TLR4) and in LPS-induced TNF-α mRNA expression and TNFR content in tissues between the Ex and Non-Ex groups. Interestingly, TNF-α contents in the liver, lung and spleen of the Ex mice were significantly lower than those of the Non-Ex group (p < 0.01, p < 0.01 and p < 0.05, respectively). Conclusion: These data suggest that exhaustive exercise-induced suppression of the plasma TNF-α concentration despite LPS stimulation might depend on translation of TNF-α in tissues.

URL: http://www.clinicaltrials.gov. Unique identifier: NCT01994720.

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