The antinociceptive and anti-inflammatory action of the CHCl3-soluble phase and its main active component, damnacanthal, isolated from the root of Morinda citrifolia.

Morinda citrifolia (Rubiaceae, Noni) is a traditional medicine with various pharmacological activities. We investigated if the MeOH-, CHCl(3)- and BuOH-soluble phase and its main active component, damnacanthal, isolated from the Noni root, have antinociceptive and anti-inflammatory actions in mice. The CHCl(3)-soluble phase (3 g/kg, per os (p.o.)) significantly reduced pain-related behavior observed in the formalin test. These effects were not suppressed by pretreatment with naloxone (1 mg/kg, intraperitoneally (i.p.)), an opioid receptor antagonist. The CHCl(3)-soluble phase (3 g/kg, p.o.) significantly reduced histamine-induced paw edema. The MeOH- and BuOH-soluble phase had no effect in either test. Furthermore, damnacanthal (10-100 mg/kg, p.o.) exerted an antinociceptive effect on chemical nociceptive stimuli, and decreased histamine-induced paw edema. Damnacanthal was weakly bound to the histamine H(1) receptor. These data suggest that the CHCl(3)-soluble phase of the Noni root has antinociceptive and anti-inflammatory effects. Furthermore, these effects of damnacanthal isolated from the Noni root is mediated in part by the histamine H(1) receptor.

Morinda citrifolia fruit juice prevents ischemic neuronal damage through suppression of the development of post-ischemic glucose intolerance.

Fruit juice of Morinda citrifolia (Noni juice) is a well-known health drink and has various pharmacological properties including antioxidant and anti-inflammatory effects. We have hitherto found the protective effect of Noni juice on brain damage caused by ischemic stress in mice. In addition, we also recently reported that regulation of post-ischemic glucose intolerance might be important for good prognosis. Here, we focused on the effect of Noni juice on the development of the post-ischemic glucose intolerance as a cerebral protective mechanism. Noni juice was obtained from the mature fruit grown in Okinawa (about 1.5 L/4 kg of fruit; 100% ONJ). Male ddY mice were given 10% ONJ in drinking water for 7 days. Then, mice were subjected to 2 h of middle cerebral artery occlusion (MCAO). Ingestion of 10% ONJ suppressed the development of neuronal damage after MCAO. Interestingly, glucose intolerance observed on the 1st day after MCAO completely disappeared after 10% ONJ administration. Furthermore, ONJ treatment significantly increased serum insulin levels much further than the control group on the 1st day, while serum adiponectin levels were not affected at all. These results suggest that ONJ could facilitate insulin secretion after ischemic stress and may attenuate the development of glucose intolerance. These mechanisms may contribute to the neuronal protective effect of ONJ against ischemic stress.

[Involvement of glycemic control in the inhibiting effect of Morinda citrifolia on cerebral ischemia-induced neuronal damage].

Fruit juice of Morinda citrifolia (Rubiaceae, Noni juice) is a well-known healthy drink and has various pharmacological properties including antioxidant and anti-inflammatory effects. We have hitherto found the protective effect of Noni juice on neuronal damage caused by ischemic stress in mice. In addition, we have also recently reported that suppression of post-ischemic glucose intolerance might be important for good prognosis. Here, we focused on the effect of Noni juice on the development of the post-ischemic glucose intolerance as a cerebral protective mechanism. Noni juice was obtained from the mature fruit grown in Okinawa (ONJ). Male ddY mice were given 10% ONJ in drinking water for 7 d. Then, mice were subjected to 2 h of middle cerebral artery occlusion (MCAO). We found that 10% ONJ treatment suppressed the development of neuronal damage after MCAO. Interestingly, glucose intolerance observed on 1 d after MCAO completely disappeared by 10% ONJ. Furthermore, 10% ONJ treatment significantly increased serum insulin levels much further than the control group on 1 d, while serum adiponectin levels were not affected at all. These results suggest that ONJ could facilitate insulin secretion and may attenuate the development of glucose intolerance under ischemic stress. These functions may contribute to the neuronal protective effect of ONJ against ischemic stress.

Chemical constituents of Baeckea frutescens leaves inhibit copper-induced low-density lipoprotein oxidation.

Oxidative modification of LDL plays an important role in the genesis of arteriosclerosis. This study focused on the effects of the leaves of Baeckea frutescens in the prevention of arteriosclerosis. The leaves of B. frutescens have afforded, besides known flavonoid and chromone glycosides, a novel biflavonoid glycoside, characterized as 3-O-alpha-L-rhamnopyranosylmyricetinyl-(I-2'',II-2'')-3-O-alpha-L-rhamnopyranosylmyricetin on the basis of chemical and spectral evidence. This compound exhibited marked inhibition of copper-induced LDL oxidation.

Preventive effect of Morinda citrifolia fruit juice on neuronal damage induced by focal ischemia.

It is known that the fruit juice of Morinda citrifolia (M. citrifolia, Noni, Rubiaceae) has various pharmacological effects such as antioxidant or anti-inflammatory activities, which may help the inhibition of ischemic neuronal damage. Here, we examined the effect of the fruit juice of M. citrifolia (Noni juice) on the brain damage caused by ischemic stress in mice. Noni juice was obtained from the mature fruit grown in Okinawa (about 1.5 l/4 kg of fruit; 100% Okinawa Noni juice (ONJ). Male ddY mice were supplied with 3% or 10% juice in the drinking water for 7 d, and compared to the control group. On the 7th day, mice were subjected to 2 h of middle cerebral artery occlusion (MCAO). Interestingly, the intake of juice reduced the infarct volume as analyzed by 2,3,5-triphenyltetrazolium chloride (TTC) staining on the 3rd day of MCAO when compared to the control group. Furthermore, we found that the neurological deficit scores (NDS) were decreased after the reperfusion in the juice-supplied mice. On the other hand, the intake of juice did not affect the expression levels of antioxidant such as Cu/Zn superoxide dismutase. The present study suggests that Noni juice may have a preventive effect against cerebral ischemic stress, while further studies are needed to explain the detailed mechanism.

New anthraquinone glycosides from the roots of Morinda citrifolia.

Six new anthraquinone glycosides: digiferruginol-1-methylether-11-O-beta-gentiobioside (1); digiferruginol-11-O-beta-primeveroside (2); damnacanthol-11-O-beta-primeveroside (3); 1-methoxy-2-primeverosyloxymethyl-anthraquinone-3-olate (4); 1-hydroxy-2-primeverosyloxymethyl-anthraquinone-3-olate (5); and 1-hydroxy-5,6-dimethoxy-2-methyl-7-primeverosyloxyanthraquinone (6) were isolated from Morinda citrifolia (Rubiaceae) roots together with four known anthraquinone glycosides. The structures of the new compounds were established using spectral methods. For five of the new compounds, the sugar is attached via the hydroxymethyl group of the anthraquinone C-2 carbon. This type of bond is rarely found for anthraquinone glycosides isolated from natural sources.

[Protective effect of Morinda citrifolia on the ischemic neuronal damage].

The fruits juice of Morinda citrifolia (Noni juice) is a well known healthy drink and has various pharmacological effects such as antioxidant. Here, we focused on the protective effect of Okinawa Noni juice (ONJ) against ischemic stress using cerebral ischemia-reperfusion model mice. We found that free intake of 10% ONJ for 7 days showed the protective effect on neuronal damage after ischemic stress, while 3% ONJ did not show such effects. It has recently reported that glucose intolerance might be induced by ischemic stress and controlling of the blood glucose levels in the early phase of ischemic stress seems to be important for good prognosis. Interestingly, we have found the glucose intolerance was developed on 1st day after ischemic stress, while it disappeared on 3rd day. On the other hand, neuronal damage gradually developed from 1st to 5th day after ischemic stress. These results indicate that development of glucose intolerance might be one of the exacerbating factors of neuronal damage after ischemic stress. Noteworthy, the development of glucose intolerance on 1st day after ischemic stress significantly suppressed by ONJ in a dose-dependent manner. These results suggest that protective effect of ONJ might be mediated by suppression of ischemic stress-induced glucose intolerance.

Chemical constituents of Morinda citrifolia roots exhibit hypoglycemic effects in streptozotocin-induced diabetic mice.

The hypoglycemic effects of the chemical constituents of Morinda citrifolia roots was evaluated in streptozotocin (STZ)-induced diabetic mice. The CHCl3, EtOAc, n-BuOH and H2O soluble phases of the MeOH extract of M. citrifolia roots were administrated orally to STZ-induced diabetic mice. Only the n-BuOH soluble phase showed a significant reduction of the blood glucose levels. From the biologically active n-BuOH soluble phase, two iridoids and three anthraquinones were isolated as main constituents. These compounds were identified by spectroscopic analysis to be deacetylasperulosidic acid (1), asperulosidic acid (2), damnacanthol-3-O-beta-D-primeveroside (3), lucidin 3-O-beta-D-primeveroside (4) and morindone-6-O-beta-D-primeveroside (5). 3 and 4 exhibited the hypoglycemic effects, which were anthraquinones with no substituents in one aromatic ring.

The anti-thrombotic active constituents from Centella asiatica.

The in vitro effects of a methanol extract from the aerial parts of Centella asiatica on shear-induced platelet activation and coagulation were assessed after oral administration to rats, by subjecting non-anticoagulated blood to haemostatometry. 3,5-Di-O-caffeoyl quinic acid, 1,5-di-O-caffeoyl quinic acid, 3,4-di-O-caffeoyl quinic acid, 4,5-di-O-caffeoyl quinic acid, and chlorogenic acid, together with asiaticoside, kaempferol, quercetine, kaempferol-3-O-beta-D-glucoside and quercetin-3-O-beta-D-glucoside were all isolated from the methanol extract. Amongst these, only 3,5-di-O-caffeoylquinic acid showed significant inhibition of shear-induced platelet activation and dynamic coagulation. The reactive curve of the inhibitory effect on the platelet reaction and the dynamic coagulation showed a bell-shape.

Beta-sitosterol-3-O-beta-D-glucopyranoside: a eukaryotic DNA polymerase lambda inhibitor.

Beta-sitosterol-3-O-beta-D-glucopyranoside (compound 1), a steroidal glycoside isolated from onion (Allium cepa L.) selectively inhibited the activity of mammalian DNA polymerase lambda (pol lambda) in vitro. The compound did not influence the activities of replicative DNA polymerases such as alpha, delta and epsilon, but also showed no effect even on the activity of pol beta which is thought to have a very similar three-dimensional structure to the pol beta-like region of pol lambda. Since parts of compound 1 such as beta-sitosterol (compound 2) and D-glucose (compound 3) did not influence the activities of any enzymes tested, the converted structure of compounds 2 and 3 might be important for pol lambda inhibition. The inhibitory effect of compound 1 on both intact pol lambda (i.e. residues 1-575) and a truncated pol lambda lacking the N-terminal BRCA1 C-terminus (BRCT) domain (133-575, del-1 pol lambda) was dose-dependent, and 50% inhibition was observed at a concentration of 9.1 and 5.4 microM, respectively. The compound 1-induced inhibition of del-1 pol lambda activity was non-competitive with respect to both the DNA template-primer and the dNTP substrate. On the basis of these results, the pol lambda inhibitory mechanism of compound 1 is discussed.

New anthraquinone and iridoid from the fruits of Morinda citrifolia.

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.

Chemical constituents of Morinda citrifolia fruits inhibit copper-induced low-density lipoprotein oxidation.

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.

Inhibition of DNA polymerases and DNA topoisomerase II by triterpenes produced by plant callus.

We found that some triterpene compounds could not only selectively inhibit the activities of mammalian DNA polymerase alpha (pol alpha) and beta (pol beta), but could also potently inhibit DNA topoisomerase II (topo II) [Biochem. J. 350 (2000) 757]. Here, we report that natural triterpenes produced by callus from an ancient Chinese medicinal plant were also inhibitors of the enzymes, and some were more selective than others. The natural triterpenes with a carboxyl group equally inhibited the activities of pol alpha, pol beta, and topo II, while the olide-type triterpenes with a ketone group suppressed the activities of pol beta and topo II, but not pol alpha. The other triterpenes from the callus hardly influenced these enzyme activities. As also described previously [J. Biochem. 130 (2001) 657], pol beta and topo II have a three-dimensionally similar triterpene-binding region, which is a pocket in which specific compounds can insert. The newly found triterpene inhibitors might structure-dependently insert into the pocket, and the pocket structure of each enzyme might, three-dimensionally but slightly, differ among them. The triterpene frames could be used for screening new inhibitors of the enzymes, and computer-simulated drug design using the frame and pocket structure may in theory be a possible approach to develop new inhibitors.