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1.  Morinda citrifolia (Noni) Juice Augments Mammary Gland Differentiation and Reduces Mammary Tumor Growth in Mice Expressing the Unactivated c-erbB2 Transgene 
Morinda citrifolia (noni) is reported to have many beneficial properties, including on immune, inflammatory, quality of life, and cancer endpoints, but little is known about its ability to prevent or treat breast cancer. To test its anticancer potential, the effects of Tahitian Noni Juice (TNJ) on mammary carcinogenesis were examined in MMTV-neu transgenic mice. Mammary tumor latency, incidence, multiplicity, and metastatic incidence were unaffected by TNJ treatment, which suggests that it would not increase or decrease breast cancer risk in women taking TNJ for its other benefits. However, noni may be useful to enhance treatment responses in women with existing HER2/neu breast cancer since TNJ resulted in significant reductions in tumor weight and volume and in longer tumor doubling times in mice. Remarkably, its ability to inhibit the growth of this aggressive form of cancer occurred with the mouse equivalent of a recommended dose for humans (<3 oz/day). A 30-day treatment with TNJ also induced significant changes in mammary secondary ductule branching and lobuloalveolar development, serum progesterone levels, and estrous cycling. Additional studies investigating TNJ-induced tumor growth suppression and modified reproductive responses are needed to characterize its potential as a CAM therapy for women with and without HER2+ breast cancer.
PMCID: PMC3351229  PMID: 22619689
2.  Antioxidant activity of noni juice in heavy smokers 
Noni (Morinda citrifolia) juice has demonstrated antioxidant activity in vitro and in vivo. To evaluate this activity in humans, noni juice from Tahiti (TNJ) was evaluated in a 30 day, double-blind, and placebo controlled clinical trial with 285 current heavy smokers. Research participants were randomly assigned to three daily treatment groups: 118 mL placebo, 29.5 mL TNJ, and 118 mL TNJ. Plasma superoxide anion radicals (SAR) and lipid hydroperoxide (LOOH) levels were measured pre and post-intervention.
After 30 days, mean SAR decreased from 0.26 ± 0.14 to 0.19 ± 0.10 μmol/mL in the 29.5 mL dose group (P < 0.01) and from 0.26 ± 0.22 to 0.18 ± 0.11 μmol/mL in the 118 mL dose group (P < 0.001). LOOH levels decreased from 0.53 ± 0.19 to 0.40 ± 0.10 μmol/mL in the 29.5 mL dose group (P < 0.001) and from 0.55 ± 0.21 to 0.40 ± 0.14 μmol/mL in the 118 mL dose group (P < 0.001). No significant reductions in SAR or LOOH levels were observed in the placebo group.
The results suggest an antioxidant activity from noni juice in humans exposed to tobacco smoke, thereby replicating the results found previous chemical and in vivo tests.
PMCID: PMC2765950  PMID: 19807926
3.  Noni Juice Improves Serum Lipid Profiles and Other Risk Markers in Cigarette Smokers 
The Scientific World Journal  2012;2012:594657.
Cigarette smoke-induced oxidative stress leads to dyslipidemia and systemic inflammation. Morinda citrifolia (noni) fruit juice has been found previously to have a significant antioxidant activity. One hundred thirty-two adult heavy smokers completed a randomized, double blind, placebo-controlled clinical trial designed to investigate the effect of noni juice on serum cholesterol, triglyceride, low density lipoprotein cholesterol (LDL), high density lipoprotein cholesterol (HDL), high-sensitivity C-reactive protein (hs-CRP), and homocysteine. Volunteers drank noni juice or a fruit juice placebo daily for one month. Drinking 29.5 mL to 188 mL of noni juice per day significantly reduced cholesterol levels, triglycerides, and hs-CRP. Decreases in LDL and homocysteine, as well increases in HDL, were also observed among noni juice drinkers. The placebo, which was devoid of iridoid glycosides, did not significantly influence blood lipid profiles or hs-CRP. Noni juice was able to mitigate cigarette smoke-induced dyslipidemia, an activity associated with the presence of iridoids.
PMCID: PMC3477557  PMID: 23097636
4.  In Vivo Antioxidant Activity of Deacetylasperulosidic Acid in Noni 
Deacetylasperulosidic acid (DAA) is a major phytochemical constituent of Morinda citrifolia (noni) fruit. Noni juice has demonstrated antioxidant activity in vivo and in human trials. To evaluate the role of DAA in this antioxidant activity, Wistar rats were fed 0 (control group), 15, 30, or 60 mg/kg body weight per day for 7 days. Afterwards, serum malondialdehyde concentration and superoxide dismutase and glutathione peroxidase activities were measured and compared among groups. A dose-dependent reduction in malondialdehyde was evident as well as a dose-dependent increase in superoxide dismutase activity. DAA ingestion did not influence serum glutathione peroxidase activity. These results suggest that DAA contributes to the antioxidant activity of noni juice by increasing superoxide dismutase activity. The fact that malondialdehyde concentrations declined with increased DAA dose, despite the lack of glutathione peroxidase-inducing activity, suggests that DAA may also increase catalase activity. It has been previously reported that noni juice increases catalase activity in vivo but additional research is required to confirm the effect of DAA on catalase. Even so, the current findings do explain a possible mechanism of action for the antioxidant properties of noni juice that have been observed in human clinical trials.
PMCID: PMC3859119  PMID: 24371540
5.  Evaluation of the Wound-healing Activity of Ethanolic Extract of Morinda citrifolia L. Leaf 
Morinda citrifolia L. (noni) is one of the most important traditional Polynesian medicinal plants. The primary indigenous use of this plant appears to be of the leaves, as a topical treatment for wound healing. The ethanol extract of noni leaves (150 mg kg−1 day−1) was used to evaluate the wound-healing activity on rats, using excision and dead space wound models. Animals were randomly divided into two groups of six for each model. Test group animals in each model were treated with the ethanol extract of noni orally by mixing in drinking water and the control group animals were maintained with plain drinking water. Healing was assessed by the rate of wound contraction, time until complete epithelialization, granulation tissue weight and hydoxyproline content. On day 11, the extract-treated animals exhibited 71% reduction in the wound area when compared with controls which exhibited 57%. The granulation tissue weight and hydroxyproline content in the dead space wounds were also increased significantly in noni-treated animals compared with controls (P < 0.002). Enhanced wound contraction, decreased epithelialization time, increased hydroxyproline content and histological characteristics suggest that noni leaf extract may have therapeutic benefits in wound healing.
PMCID: PMC2722214  PMID: 18955257
excision and dead space wound; hydroxyproline; Morinda citrifolia; wound healing
6.  Noni juice is not hepatotoxic 
Noni juice (Morinda citrifolia) has been approved for use as a safe food within the European Union, following a review of safety. Since approval, three cases of acute hepatitis in Austrian noni juice consumers have been published, where a causal link is suggested between the liver dysfunction and ingestion of anthraquinones from the plant. Measurements of liver function in a human clinical safety study of TAHITIAN NONI® Juice, as well as subacute and subchronic animal toxicity tests revealed no evidence of adverse liver effects at doses many times higher than those reported in the case studies. Additionally, M. citrifolia anthraquinones occur in the fruit in quantities too small to be of any toxicological significance. Further, these do not have chemical structures capable of being reduced to reactive anthrone radicals, which were implicated in previous cases of herbal hepototoxicity. The available data reveals no evidence of liver toxicity.
PMCID: PMC4087581  PMID: 16773722
Noni juice; Morinda citrifolia; Novel food; Human clinical safety study
7.  Anti-allergic activity of the Morinda citrifolia extract and its constituents 
Pharmacognosy Research  2014;6(3):260-265.
Morinda citrifolia (Rubiaceae), commonly known as noni is distributed throughout tropical and sub-tropical regions of the world. Anti-allergic effects of noni have not been reported despite the clinical usage as an anti-allergic agent.
Materials and Methods:
To investigate the anti-allergic effects of the 50% ethanolic extract of M. citrifolia fruits and leaves (MCF-ext and MCL-ext), dinitrofluorobenzene (DNFB)-induced triphasic cutaneous reaction and picryl chloride-induced contact dermatitis (PC-CD) tests were performed.
In DNFB-induced triphasic cutaneous reaction, oral administration of MCF-ext and MCL-ext exhibited dose-dependent inhibition of cutaneous reaction at 1 h (immediate phase response) after the DNFB challenge. MCF-ext also inhibited ear swelling at 24 h (late phase response) and 8 days (very late phase response) after the DNFB challenge. The effect of MCL-ext on the immediate phase response was attributed to the anti-degranulation from RBL-2H3 cells, while MCF-ext had no significant effect on degranulation. The active components of anti-degranulation activity in MCL-ext were determined to be ursolic acid, rutin and kaempferol-3-O-α-L-rhamnopyranosyl-(1→6)-β-D-glucopyranoside. In the PC-CD test, both MCF-ext and MCL-ext showed an anti-swelling effect but the potency of MCF-ext was stronger than MCL-ext.
These data suggest that noni fruits and leaves can be a daily consumable material for the prevention of allergic symptoms.
PMCID: PMC4080509  PMID: 25002809
Allergy; contact dermatitis; degranulation; IgE-mediated triphasic cutaneous reaction; Morinda citrifolia
8.  Anxiolytic, sedative, and hypnotic activities of aqueous extract of Morinda citrifolia fruit 
Morinda citrifolia (Indian mulberry or noni) fruit has been long used as a folk medicine for a wide range of health purposes as it is claimed to have analgesic, antiinflammatory, antioxidant, detoxifier, and cell-rejuvenator properties. A recent study has revealed central nervous system suppressant nature of its extract. Hence, the present study has evaluated the anxiolytic, sedative, and hypnotic effects of the aqueous extracts of Morinda citrifolia in rodents in comparison to diazepam. Anxiety was assessed by ‘Isolation-induced aggression’ model, sedation by ‘Spontaneous locomotor activity using actophotometer’ and hypnotic activity by ‘Prolongation of ketamine-induced sleeping time’. Six male mice were used for each of the groups and postdose, all the six that received diazepam had shown an inhibition of aggression, whereas in the test group, five of six mice and none in the control group had shown an inhibition of aggression (P = 0.0007). Similarly, for the sedative activity, the total number of spontaneous locomotor activity at 30 min following drug administration was found to be 364.67 ± 10.74, 123.16 ± 8.33, and 196.67 ± 3.7, while at 60 min it was found to be 209 ± 12.98, 49 ± 5.78, and 92 ± 2.5 (mean ± SD) for the control, standard, and test groups of mice respectively (P < 0.001). Hypnotic activity was measured by prolongation of ketamine-induced sleeping time wherein the onset and duration of loss of righting reflex were compared among each group of mice. The time in minutes for the onset in control, standard, and test groups was 4.01 ± 0.22, 1.23 ± 0.05, and 2.23 ± 0.07, respectively. The duration of loss of righting reflex was 44.23 ± 0.59, 56.03 ± 1.34, and 50.57 ± 0.36, respectively. Both these were statistically significant (P < 0.001). However, more clinical studies are needed to assess the long-term effects of the extract in humans.
PMCID: PMC4061592  PMID: 24948855
Herb; noni; sleep
9.  Morinda citrifolia L. (noni) and memantine attenuate periventricular tissue injury of the fourth ventricle in hydrocephalic rabbits☆ 
Neural Regeneration Research  2013;8(9):773-782.
This study was designed to evaluate the neuroprotective effects of Morinda citrifolia L. (Rubiaceae), commonly known as noni, and memantine (a N-methy-D-aspartate receptor inhibitor) on hydrocephalus-induced neurodegenerative disorders. Kaolin was injected into the cistern magna of male adult New Zealand rabbits to establish a hydrocephalus animal model. Memantine (20 mg/kg, intraperitoneally; memantine-treated group) or noni (5 mL/kg, intragastrically; noni-treated group) was administered daily for 2 weeks. Microtubule-associated protein-2 and caspase-3 immunohistochemistry were performed to detect neuronal degeneration and apoptosis in the periventricular tissue of the fourth ventricle of rabbits. Microtubule-associated protein-2 staining density was significantly decreased in the hydrocephalic group, while the staining density was significantly increased in the memantine- and noni-treated groups, especially in the noni-treated group. Noni treatment decreased the number of caspase-3-positive cells in rabbits with hydrocephalus, while memantine had no effect. These findings suggest that noni exhibits more obvious inhibitory effects on hydrocephalus-induced neurodegenerative disorders than memantine in periventricular tissue of the fourth ventricle.
PMCID: PMC4146082  PMID: 25206724
neural regeneration; neurodegenerative disease; traditional Chinese medicine; hydrocephalus; Morinda citrifolia L. (noni); memantine; fourth ventricle; periventricular tissue; microtubule-associated protein-2; caspase-3; apoptosis; grants-supported paper; photographs-containing paper; neuroregeneration
10.  Odorant-Binding Proteins OBP57d and OBP57e Affect Taste Perception and Host-Plant Preference in Drosophila sechellia  
PLoS Biology  2007;5(5):e118.
Despite its morphological similarity to the other species in the Drosophila melanogaster species complex, D. sechellia has evolved distinct physiological and behavioral adaptations to its host plant Morinda citrifolia, commonly known as Tahitian Noni. The odor of the ripe fruit of M. citrifolia originates from hexanoic and octanoic acid. D. sechellia is attracted to these two fatty acids, whereas the other species in the complex are repelled. Here, using interspecies hybrids between D. melanogaster deficiency mutants and D. sechellia, we showed that the Odorant-binding protein 57e (Obp57e) gene is involved in the behavioral difference between the species. D. melanogaster knock-out flies for Obp57e and Obp57d showed altered behavioral responses to hexanoic acid and octanoic acid. Furthermore, the introduction of Obp57d and Obp57e from D. simulans and D. sechellia shifted the oviposition site preference of D. melanogaster Obp57d/eKO flies to that of the original species, confirming the contribution of these genes to D. sechellia's specialization to M. citrifolia. Our finding of the genes involved in host-plant determination may lead to further understanding of mechanisms underlying taste perception, evolution of plant–herbivore interactions, and speciation.
Author Summary
Most herbivorous insects specialize on one or a few host plants; understanding the processes and genetics underlying this specialization has broad implications across biology. Drosophila sechellia, a fruit fly endemic to the Seychelles, feeds exclusively on the ripe fruit of Morinda citrifolia, a tropical plant commonly known as Tahitian Noni. Although other fruit flies never approach this fruit because of its toxins, D. sechellia is resistant and is actually attracted by the same toxins. D. sechellia is a close relative of D. melanogaster, an established model species of genetics. By comparing D. melanogaster and D. sechellia, we revealed that two genes encoding odorant-binding proteins, Obp57d and Obp57e, are not only involved in the fruit fly's taste perception, but can also change the behavioral response of the flies to the toxins contained in the fruit. By knowing how an insect's food preference is determined by its genes, we can gain insight into how insect lifestyles evolve and investigate whether such changes can lead to the formation of new species. We can also begin to understand how to manipulate insects' behavior by changing their preference for particular substances.
Hybrids ofDrosophila melanogaster mutants andD. sechellia reveal genes involved in the behavioral difference that makessechellia specialized to its host plant, with implications for understanding plant-herbivore interactions and speciation
PMCID: PMC1854911  PMID: 17456006
11.  Ethnoveterinary Application of Morinda Citrifolia Fruit Puree on a Commercial Heifer Rearing Facility with Endemic Salmonellosis 
We have previously reported that Morinda citrifolia (noni) puree modulates neonatal calves developmental maturation of the innate and adaptive immune system. In this study, the effect of noni puree on respiratory and gastrointestinal (GI), health in preweaned dairy calves on a farm with endemic salmonellosis was examined. Two clinical trials were conducted whereby each trial evaluated one processing technique of noni puree. Trials 1 and 2 tested noni versions A and B, respectively. Puree analysis and trial methods were identical to each other, with the calf as the experimental unit. Calves were designated to 1 of 3 treatment groups in each trial and received either: 0, 15 or 30 mL every 12 hr of noni supplement for the first 3 weeks of life. Health scores, weaning age, weight gain from admission to weaning, and weaned by 6 weeks, were used as clinical endpoints for statistical analysis. In trial 1, calves supplemented with 15 mL noni puree of version A every 12 hr had a higher probability of being weaned by 6 weeks of age than control calves (P = 0.04). In trial 2, calves receiving 30 mL of version B every 12 hr had a 54.5% reduction in total medical treatments by 42 days of age when compared to controls (P = 0.02). There was a trend in reduced respiratory (61%), and GI (52%) medical treatments per calf when compared to controls (P = 0.06 and 0.08, respectively). There were no differences in weight gain or mortality for any treatment group in either trial.
PMCID: PMC3746350  PMID: 24082318
Morinda citrifolia; natural products; neonatal calf; noni; dairy
12.  Liver Protective Effects of Morinda citrifolia (Noni) 
This study evaluated the protective effects of Noni fruit juice on acute liver injury induced by carbon tetrachloride (CCl4) in female Sprague-Dawley (SD) rats. Liver damage (micro-centrilobular necrosis) was observed in animals pretreated with 20% placebo (drinking water) + CCl4. However, pretreatment with 20% Noni juice in drinking water + CCl4 resulted in markedly decreased hepatotoxic lesions. Furthermore, serum alanine aminotransferase and aspartate aminotransferase levels were significantly lower in the Noni group than the placebo group. In a correlative time-dependent study, one dose of CCl4 (0.25 mL/kg in corn oil, p.o.) in female SD rats, pretreated with 10% placebo for 12 days, caused sequential progressive hepatotoxic lesions over a 24 h period, while a protective effect from 10% Noni juice pretreatment was observed. These results suggest that Noni juice is effective in protecting the liver from extrinsic toxin exposure.
PMCID: PMC2413119  PMID: 18317933
Morinda citrifolia; Noni; Liver protection; Carbon tetrachloride
13.  Effect of Noni (Morinda citrifolia Linn.) Fruit and Its Bioactive Principles Scopoletin and Rutin on Rat Vas Deferens Contractility: An Ex Vivo Study 
The Scientific World Journal  2014;2014:909586.
This study examined the effect of methanolic extract of Morinda citrifolia Linn. (MMC) and its bioactive principles, scopoletin and rutin, on dopamine- and noradrenaline-evoked contractility in isolated rat vas deferens preparations. MMC (1–40 mg/mL), scopoletin (1–200 μg/mL), and rutin hydrate (0.6–312.6 μg/mL) dose-dependently inhibited the contractility evoked by submaximal concentrations of both dopamine and noradrenaline, respectively. Haloperidol and prazosin, reference dopamine D2, and α1-adrenoceptors antagonists significantly reversed the dopamine- and noradrenaline-induced contractions, respectively, in a dose-dependent manner. Interestingly, MMC per se at higher doses (60–100 mg/mL) showed dose-dependent contractile response in rat vas deferens which was partially inhibited by high doses of haloperidol but not by prazosin. These results demonstrated the biphasic effects of MMC on dopaminergic system; that is, antidopaminergic effect at lower concentrations (<40 mg/mL) and dopaminergic agonistic effect at higher concentrations (>60 mg/mL). However, similar contractile response at high doses of scopoletin (0.5–5 mg/mL) and rutin hydrate (0.5–5 mg/mL) per se was not observed. Therefore, it can be concluded that the bioactive principles of MMC, scopoletin, and rutin might be responsible for the antidopaminergic and antiadrenergic activities of MMC.
PMCID: PMC4090441  PMID: 25045753
14.  Morinda citrifolia (Noni) as an Anti-Inflammatory Treatment in Women with Primary Dysmenorrhoea: A Randomised Double-Blind Placebo-Controlled Trial 
Introduction. Noni (Morinda citrifolia) has been used for many years as an anti-inflammatory agent. We tested the efficacy of Noni in women with dysmenorrhea. Method. We did a prospective randomized double-blind placebo-controlled trial in 100 university students of 18 years and older over three menstrual cycles. Patients were invited to participate and randomly assigned to receive 400 mg Noni capsules or placebo. They were assessed for baseline demographic variables such as age, parity, and BMI. They were also assessed before and after treatment, for pain, menstrual blood loss, and laboratory variables: ESR, hemoglobin, and packed cell volume. Results. Of the 1027 women screened, 100 eligible women were randomized. Of the women completing the study, 42 women were randomized to Noni and 38 to placebo. There were no significant differences in any of the variables at randomization. There were also no significant differences in mean bleeding score or pain score at randomization. Both bleeding and pain scores gradually improved in both groups as the women were observed over three menstrual cycles; however, the improvement was not significantly different in the Noni group when compared to the controls. Conclusion. Noni did not show a reduction in menstrual pain or bleeding when compared to placebo.
PMCID: PMC3569913  PMID: 23431314
15.  Antidiabetic Effect of Morinda citrifolia (Noni) Fermented by Cheonggukjang in KK-Ay Diabetic Mice 
Antidiabetic effects of Morinda citrifolia (aka Noni) fermented by Cheonggukjang (fast-fermented soybean paste) were evaluated using a T2DM (type 2 diabetes mellitus) murine model. Six-week-old KK-Ay/TaJcl mice were randomly divided into four groups: (1) the diabetic control (DC) group, provided with a normal mouse diet; (2) the positive control (PC) group, provided with a functional health food diet; (3) the M. citrifolia (MC) group, provided with an MC-based diet; (4) the fermented M. citrifolia (FMC) group, provided with an FMC-based diet. Over a testing period of 90 days, food and water intake decreased significantly in the FMC and PC groups compared with the DC group. Blood glucose levels in the FMC group were 211.60–252.20 mg/dL after 90 days, while those in the control group were over 400 mg/dL after 20 days. In addition, FMC supplementation reduced glycosylated hemoglobin (HbA1c) levels, enhanced insulin sensitivity, and significantly decreased serum triglycerides and low-density lipoprotein (LDL) cholesterol. Furthermore, a fermented M. citrifolia 70% ethanolic extract (FMCE) activated peroxisome proliferator-activated receptor-(PPAR-) γ and stimulated glucose uptake via stimulation of AMP-activated protein kinase (AMPK) in cultured C2C12 cells. These results suggest that FMC can be employed as a functional health food for T2DM management.
PMCID: PMC3434424  PMID: 22969823
16.  Docking studies of Vitamin C, Vitamin E, Damnacanthal and Scopoletin with human lens gamma D-crystalline 
Bioinformation  2013;9(14):721-724.
Vitamin C, Vitamin E, scopoletin and damnacanthal are the major constituents of Noni (Morinda citrifolia). These compounds are known to have good medicinal properties and they are known to act as antioxidants. Loss of vision in elderly is due to opaqueness of the lens proteins such as gamma-D-crystallin during oxidative stress conditions. Therefore, it is of importance to find the potential interaction of Vitamin C, Vitamin E, Scopoletin and Damnacanthal with the lens protein gamma-D-crystallin. Hence, their physical binding to gamma-D crystallin (PDB ID: 2G98) was evaluated using molecular and structural docking procedures. Results show the potential binding of all the above anti-oxidants to gamma-D-crystalline with equal affinity. Thus, the role of cumulative anti-oxidant effect in Noni fruit juice through their potential yet predicted interaction with the lens protein gamma-D-crystallin is implied for cataract treatment.
PMCID: PMC3746095  PMID: 23976828
Cataract formation; Oxidative stress; gamma-D-crystallin; Anti-oxidants; Docking scores
17.  Damnacanthal is a potent inducer of apoptosis with anticancer activity by stimulating p53 and p21 genes in MCF-7 breast cancer cells 
Oncology Letters  2014;7(5):1479-1484.
Damnacanthal, an anthraquinone compound, is isolated from the roots of Morinda citrifolia L. (noni), which has been used for traditional therapy in several chronic diseases, including cancer. Although noni has long been consumed in Asian and Polynesian countries, the molecular mechanisms by which it exerts several benefits are starting to emerge. In the present study, the effect of damnacanthal on MCF-7 cell growth regulation was investigated. Treatment of MCF-7 cells with damnacanthal for 72 h indicated an antiproliferative activity. The MTT method confirmed that damnacanthal inhibited the growth of MCF-7 cells at the concentration of 8.2 μg/ml for 72 h. In addition, the drug was found to induce cell cycle arrest at the G1 checkpoint in MCF-7 cells by cell cycle analysis. Damnacanthal induced apoptosis, determined by Annexin V-fluorescein isothiocyanate/propidium iodide (PI) dual-labeling, acridine-orange/PI dyeing and caspase-7 expression. Furthermore, damnacanthal-mediated apoptosis involves the sustained activation of p21, leading to the transcription of p53 and the Bax gene. Overall, the present study provided significant evidence demonstrating that p53-mediated damnacanthal induced apoptosis through the activation of p21 and caspase-7.
PMCID: PMC3997671  PMID: 24765160
damnacanthal; MCF-7; anticancer; caspase; p53; p21; apoptosis
18.  Damnacanthal, a Noni component, exhibits anti-tumorigenic activity in human colorectal cancer cells 
Damnacanthal, an anthraquinone compound, is isolated from the roots of Morinda citrifolia L. (noni), which has been used for traditional therapy in several chronic diseases including cancer. Although noni has been consumed for a long time in Asian and Polynesian countries, the molecular mechanisms by which it exerts several benefits are starting to emerge. In this report, we examined systematic approaches on the cancer suppressing capability of damnacanthal in colorectal tumorigenesis. Damnacanthal exhibits cell growth arrest as well as caspase activity induction in colorectal cancer cells. We also examined several potential target proteins and found that the pro-apoptotic protein Nonsteroidal anti-inflammatory activated gene-1 (NAG-1) is highly induced. Subsequently, we have found that damnacanthal also enhances transcription factor C/EBPβ, which controls NAG-1 transcriptional activity. Blocking of C/EBPβ by shRNA results in the reduction of NAG-1 expression as well as caspase activity in the presence of damnacanthal. Taken together, these results indicate that damnacanthal increases anti-tumorigenic activity in human colorectal cancer cells, and C/EBPβ plays a role in damnacanthal-induced NAG-1 expression.
PMCID: PMC3222750  PMID: 21852088
Damnacanthal; Noni; NAG-1; GDF15; C/EBPβ; Colorectal cancer
19.  Dopamine drives Drosophila sechellia adaptation to its toxic host 
eLife  null;3:e03785.
Many insect species are host-obligate specialists. The evolutionary mechanism driving the adaptation of a species to a toxic host is, however, intriguing. We analyzed the tight association of Drosophila sechellia to its sole host, the fruit of Morinda citrifolia, which is toxic to other members of the melanogaster species group. Molecular polymorphisms in the dopamine regulatory protein Catsup cause infertility in D. sechellia due to maternal arrest of oogenesis. In its natural host, the fruit compensates for the impaired maternal dopamine metabolism with the precursor l-DOPA, resuming oogenesis and stimulating egg production. l-DOPA present in morinda additionally increases the size of D. sechellia eggs, what in turn enhances early fitness. We argue that the need of l-DOPA for successful reproduction has driven D. sechellia to become an M. citrifolia obligate specialist. This study illustrates how an insect's dopaminergic system can sustain ecological adaptations by modulating ontogenesis and development.
eLife digest
Many insect species rely on another animal or plant species for their own reproduction. For example, a fruit fly called Drosophila sechellia—which is found in the Seychelles—will only feed and lay its eggs on the fruit of a species of tree called Morinda citrifolia. This pairing is particularly unusual because these fruits, commonly called morinda, are toxic to all other Drosophila species.
Female Drosophila sechellia flies produce fewer eggs than other Drosophila species, which makes it difficult to raise this species in the laboratory. However providing these flies with morinda fruit, or chemicals from this fruit, was known to increase the expression of many genes involved in egg production and stimulate the flies to lay more eggs. Nevertheless, the reasons why this species of fruit fly depends on the toxic morinda fruit were unclear.
Now Lavista-Llanos et al. have confirmed that feeding Drosophila sechellia flies a diet of morinda fruit—instead of a typical laboratory diet—causes these flies to produce six-times as many eggs. Furthermore, this morinda diet had effects that went beyond the previously reported stimulatory effects of acidic chemicals in the fruits triggering the flies to lay more eggs.
Egg production in flies is controlled by dopamine, and a lack of this hormone is known to reduce the size of other fruit flies' ovaries and the number of eggs that they produce. Lavista-Llanos et al. went on to feed female Drosophila sechellia flies the chemical building blocks that make up the dopamine hormone, and one such chemical (called l-DOPA) caused the flies to produce more eggs. This did not occur when the flies were fed dopamine itself.
Lavista-Llanos et al. discovered that Drosophila sechellia flies have very high levels of dopamine but much lower levels of l-DOPA than other Drosophila fly species; and revealed that this was because a gene called Catsup is mutated in Drosophila sechellia. When Lavista-Llanos et al. mutated the same gene in another Drosophila species, the mutant flies produced fewer eggs and abnormally accumulated an enzyme (which makes l-DOPA) inside their developing eggs—just like Drosophila sechellia.
The presence of l-DOPA in morinda fruit partly compensates for the reduced fertility of Drosophila sechellia and the other flies with mutations in the Catsup gene. Lavista-Llanos et al. discovered that removing or replacing l-DOPA in the morinda fruit caused the flies to produce fewer eggs. Furthermore, the l-DOPA present in morinda increases the size of Drosophila sechellia eggs, which in turn helps them to survive their toxic environment.
Lavista-Llanos et al. also discovered that feeding dopamine to vulnerable Drosophila species helps them to cope with the toxic effects of a morinda diet. One of the next challenges will be to uncover how chemicals from the morinda fruit affect the dopamine system of the flies. It is also unknown if the dopamine hormone also influences the strong attraction that Drosophila sechellia feels towards its only host, the morinda fruit.
PMCID: PMC4270095  PMID: 25487989
Drosophila sechellia; Morinda citrifolia; dopamine; oogenesis; evolution; tyrosine hydroxilase; D. melanogaster; other
20.  Antispasmodic and vasodilator activities of Morinda citrifolia root extract are mediated through blockade of voltage dependent calcium channels 
Morinda citrifolia (Noni) is an edible plant with wide range of medicinal uses. It occurs exclusively in tropical climate zone from India through Southeast Asia and Australia to Eastern Polynesia and Hawaii. The objective of this study was to explore the possible mode(s) of action for its antispasmodic, vasodilator and cardio-suppressant effects to rationalize its medicinal use in gut and cardiovascular disorders.
Isolated tissue preparations such as, rabbit jejunum, rat and rabbit aorta and guinea pig atria were used to test the antispasmodic and cardiovascular relaxant effects and the possible mode of action(s) of the 70% aqueous-ethanolic extract of Morinda citrifolia roots (Mc.Cr).
The Mc.Cr produced a concentration-dependent relaxation of spontaneous and high K+ induced contractions in isolated rabbit jejunum preparations. It also caused right ward shift in the concentration response curves of Ca++, similar to that of verapamil. In guinea-pig right atria, Mc.Cr caused inhibition of both atrial force and rate of spontaneous contractions. In rabbit thoracic aortic preparations, Mc.Cr also suppressed contractions induced by phenylephrine (1.0 μM) in normal- Ca++ and Ca++-free Kerb's solutions and by high K+, similar to that of verapamil. In rat thoracic aortic preparations, Mc.Cr also relaxed the phenylephrine (1.0 μM)-induced contractions. The vasodilatory responses were not altered in the presence of L-NAME (0.1 mM) or atropine (1.0 μM) and removal of endothelium.
These results suggest that the spasmolytic and vasodilator effects of Mc.Cr root extract are mediated possibly through blockade of voltage-dependent calcium channels and release of intracellular calcium, which may explain the medicinal use of Morinda citrifolia in diarrhea and hypertension. However, more detailed studies are required to assess the safety and efficacy of this plant.
PMCID: PMC2829485  PMID: 20070879
21.  Ethanol-induced hyperactivity is associated with hypodopaminergia in the 22-TNJ ENU-mutated mouse 
Alcohol (Fayetteville, N.Y.)  2009;43(6):421-431.
Characterization of neurochemical and behavioral responses to ethanol in phenotypically distinct mouse strains can provide insight into the mechanisms of ethanol stimulant actions. Increases in striatal dopamine (DA) levels have often been linked to ethanol-induced hyperactivity. We examined the functional status of the DA system and behavioral responsiveness to ethanol, cocaine and a DA receptor agonist in an N-ethyl-N-nitrosourea (ENU)-mutagenized mouse strain, 22-TNJ, generated by the Integrative Neuroscience Initiative on Alcoholism Consortium. The 22-TNJ mouse strain exhibited greater locomotor responses to 2.25 g/kg ethanol and 10 mg/kg cocaine, compared to control mice. In vivo microdialysis showed low baseline DA levels and a larger DA increase with both 2.25 g/kg ethanol and 10 mg/kg cocaine. In in vitro voltammetry studies, the 22-TNJ mice displayed increased Vmax rates for DA uptake, possibly contributing to the low baseline DA levels found with microdialysis. Finally, 22-TNJ mice showed enhanced in vitro autoreceptor sensitivity to the D2/D3 agonist, quinpirole, and greater locomotor responses to both autoreceptor-selective and postsynaptic receptor-selective doses of apomorphine, compared to controls. Taken together, these results indicate that the dopaminergic system of the 22-TNJ mouse is low-functioning compared to control, with consequent receptor supersensitivity, such that mutant animals exhibit enhanced behavioral responses to DA-activating drugs such as ethanol. Thus, the 22-TNJ mouse represents a model for a relatively hypodopaminergic system, and could provide important insights into the mechanisms of hyperresponsiveness to ethanol’s stimulant actions.
PMCID: PMC2782517  PMID: 19801272
Dopamine D2 receptor; N-ethyl-N-nitrosurea; ethanol; cyclic voltammetry and microdialysis
22.  Noni juice reduces lipid peroxidation–derived DNA adducts in heavy smokers 
Food Science & Nutrition  2013;1(2):141-149.
Food plants provide important phytochemicals which help improve or maintain health through various biological activities, including antioxidant effects. Cigarette smoke–induced oxidative stress leads to the formation of lipid hydroperoxides (LOOHs) and their decomposition product malondialdehyde (MDA), both of which cause oxidative damage to DNA. Two hundred forty-five heavy cigarette smokers completed a randomized, double-blind, placebo-controlled clinical trial designed to investigate the effect of noni juice on LOOH- and MDA-DNA adducts in peripheral blood lymphocytes (PBLs). Volunteers drank noni juice or a fruit juice placebo every day for 1 month. DNA adducts were measured by 32P postlabeling analysis. Drinking 29.5–118 mL of noni juice significantly reduced adducts by 44.6–57.4%. The placebo, which was devoid of iridoid glycosides, did not significantly influence LOOH- and MDA-DNA adduct levels in current smokers. Noni juice was able to mitigate oxidative damage of DNA in current heavy smokers, an activity associated with the presence of iridoids.
PMCID: PMC3967752  PMID: 24804023
Antioxidant; DNA adducts; Morinda citrifolia; noni
23.  YKP1447, A Novel Potential Atypical Antipsychotic Agent 
(S)-Carbamic acid 2-[4-(4-fluoro-benzoyl)-piperidin-1-yl]-1-phenyl-ethyl ester hydrochloride (YKP1447) is a novel "atypical" antipsychotic drug which selectively binds to serotonin (5-HT2A, Ki=0.61 nM, 5-HT2C, Ki=20.7 nM) and dopamine (D2, Ki=45.9 nM, D3, Ki=42.1 nM) receptors with over 10~100-fold selectivity over the various receptors which exist in the brain. In the behavioral studies using mice, YKP1447 antagonized the apomorphine-induced cage climbing (ED50=0.93 mg/kg) and DOI-induced head twitch (ED50=0.18 mg/kg) behavior. In the dextroamphetamine-induced hyperactivity and conditioned avoidance response (CAR) paradigm in rats, YKP1447 inhibited the hyperactivity induced by amphetamine (ED50=0.54 mg/kg) and the avoidance response (ED50=0.48 mg/kg); however, unlike other antipsychotic drugs, catalepsy was observed only at much higher dose (ED50=68.6 mg/kg). Based on the CAR and catalepsy results, the therapeutic index (TI) value for YKP1447 is over 100 (i.p.). These results indicate that YKP1447 has an atypical profile and less undesirable side effects than currently available drugs.
PMCID: PMC2766698  PMID: 19885000
YKP1447; Serotonin and dopamine receptors; Schizophrenia; Atypical antipsychotics; CAR; Catalepsy
24.  Drug-Induced Liver Injury Associated with Noni (Morinda citrifolia) Juice and Phenobarbital 
Noni (Morinda citrifolia) juice is a popular herbal dietary supplement globally used for preventive or therapeutic purposes in a variety of ailments, claiming to exhibit hepatoprotective properties as well. Herein we present the case of a 38-year-old woman who developed acute liver injury associated with noni juice consumption on a long-term (9 months) anticonvulsant therapy. Clinical presentation and liver biopsy were consistent with severe, predominantly hepatocellular type of injury. Both agents were stopped and corticosteroids were initiated. Five months later the patient had fully recovered. Although in the literature the hepatotoxicity of noni juice remains speculative, sporadic but emerging cases of noni juice-associated liver injury address the need to clarify and investigate potential harmful effects associated with this supplement.
PMCID: PMC3573787  PMID: 23467452
Drug-induced liver injury; Herb-induced liver injury; Noni juice; Phenobarbital
25.  Evaluation of the behavioral and pharmacokinetic profile of SYA013, a homopiperazine analogue of haloperidol in rats 
SYA013, a homopiperazine analogue of haloperidol, was further evaluated for antipsychotic potential using additional animal models. Previously, SYA013 was tested in mice with an antipsychotic screening model in which it inhibited apomorphine induced climbing behavior, indicating antagonism of the dopaminergic system and the potential for use in the treatment of schizophrenia. In this study, SYA013 was shown to inhibit both d-amphetamine-induced locomotor activity in rats and conditioned avoidance response (CAR) in rats in a dose dependent manner and in the case of CAR, without producing any escape failure responses (EFR), two tests predictive of antipsychotic action. The selective 5HT1A antagonist WAY100,635 was used to determine if binding of SYA013 to the 5HT1A receptor contributed to suppression of CAR. The results indicated that 0.63 mg/kg WAY100,635 did not have a significant effect on the inhibition of CAR by SYA013. Pharmacokinetic parameters in brain and plasma were determined for SYA013. A log brain/plasma concentration ratio at tmax of 1.48 suggests that SYA013 readily crosses the blood brain barrier (BBB).
The hypothesis that binding of SYA013 to the 5HT1A receptor contributed to the lack of significant catalepsy was investigated using the 5HT1A antagonist WAY100,635. The results of acute and semi-chronic tests suggest that binding to the 5HT1A receptor alone did not significantly account for the lack of catalepsy. Lack of catalepsy was preserved after the semi-chronic challenge with SYA013. These tests further indicate that SYA013 has a pharmacological profile with the potential for use in the treatment of neuropsychiatric diseases. In addition, the 5HT1A receptor does not appear to play a significant role in the pharmacological profile of SYA013.
PMCID: PMC3383382  PMID: 22588199
5HT1A receptor; Catalepsy test chamber instrument; Conditioned avoidance response; Locomotor activity; Antipsychotic profile; SYA013

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