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Resveratrol, a phytoalexin present in grapes and other edible foods, has been reported to have beneficial effects against various diseases including cancer. We previously reported that resveratrol and its derivative, caffeic acid-adducted resveratrol, selectively inhibit the three-dimensional (3D) proliferation of a human colorectal cancer cell line, HCT116 with activating KRAS mutation. Herein, we demonstrated that a novel compound, ferulic acid-bound resveratrol, also represses the 3D proliferation of HCT116 cells. We observed that resveratrol conjugated to two ferulic acids represses the 3D proliferation of HCT116 cells more strongly than resveratrol and resveratrol conjugated to one ferulic acid. Resveratrol conjugated to two ferulic acids also inhibited the 3D proliferation of MCF7 human breast cancer cells. We further uncovered that the resveratrol derivative increases the mRNA level of the tumor suppressor p15, a CDK inhibitor that functions as a brake of cell proliferation in HCT116 cells. These results imply that the resveratrol derivative represses 3D proliferation via increasing p15 expression in HCT116 cells.

This article describes the biological activities of heartwood extracts from Yakushima native cedar (Cryptomeria japonica) and identifies their main active compounds. Black heartwood and red heartwo...

One of the conventional strategies for treating osteoporosis is to eliminate the multinucleated osteoclasts that are responsible for bone resorption. Our previous study revealed that ursolic acid, isolated from leaves of loquat that is used as tasty tea in Japan, suppressed osteoclastogenesis. We confirmed that ursolic acid exhibited osteoclast differentiation inhibitory activity with an 50% inhibitory concentration (IC50) value of 5.4 ± 0.96 μM. To disclose its mechanism of action, this study first uses polymer-coated magnetic nanobeads to identify potential target proteins. As a result, we identified a nuclear exporter protein named exportin 5 (XPO5). Further studies demonstrated that knockdown of XPO5 significantly blocks osteoclast differentiation ( P < 0.01). Expression profiling of mature microRNAs in the cells revealed that downregulation of XPO5 by small interfering RNA or by ursolic acid could downregulate the expression of mature microRNA let-7g-5p during osteoclast differentiation ( P < 0.01). Collectively, our findings suggest that ursolic acid inhibits osteoclast differentiation through targeting XPO5, which provides further evidence for the healthy function of the tea. This study also provides new insights into the role of XPO5 and its mediated microRNAs in treatment for bone resorption diseases.

Ganoderma lingzhi is a traditional medicinal mushroom, and its extract contains many bioactive compounds. Triterpenoids and polysaccharides are the primary bioactive components that contribute to its medicinal properties. In this study, we quantified 18 triterpenoids, total triterpenoid content and total polysaccharide content in the ethanol and water extracts of G. lingzhi at different growth stages. Triterpenoids were quantified by liquid chromatograph-tandem mass spectrometry in the multiple-reaction-monitoring mode. Total triterpenoid and total polysaccharide content were determined by colorimetric analysis. The results indicated that the fruit bodies at an early growth stage had a higher content of ganoderic acid A, C2, I and LM2, as well as of ganoderenic acid C and D, than those at a later growth stage. In contrast, ganoderic acid K, TN and T-Q contents were higher in mature fruit bodies (maturation stage). The highest total triterpenoid and total polysaccharide contents were found in fruit bodies before maturity (stipe elongation stage or early stage of pileus formation). Our results provide information which will contribute to the establishment of an efficient cultivation system for G. lingzhi with a higher content of triterpenoids.

Resveratrol is a polyphenolic compound in many edible foods including grapes, peanuts, and berries. Several studies have revealed the beneficial effects of resveratrol against various diseases such as heart disease, diabetes, obesity, neurological disorders, and cancer. A recent study showed that resveratrol inhibits the proliferation of HCT116 human colorectal cancer cells in three-dimensional culture (3DC) via induction of luminal apoptosis in HCT116 cell spheroids. In this study, we showed that a novel compound, caffeic acid-adducted resveratrol, has a stronger inhibitory effect on the growth of HCT116 cell spheroids in 3DC than resveratrol. It showed almost the same inhibitory efficacy as 5-fluorouracil, a conventional anticancer drug. We further showed that the resveratrol derivative did not affect the growth of HKe3 cell spheroids derived from HCT116 cells by disruption of the activating mutant KRAS gene. These results suggest that the resveratrol derivative inhibits the growth of HCT116 cell spheroids via inhibition of an oncogenic KRAS-mediated signaling pathway.

Hericium erinaceus (H. erinaceus) improves the symptoms of menopause. In this study, using ovariectomized mice as a model of menopause, we investigated the anti-obesity effect of this mushroom in menopause. Mice fed diets containing H. erinaceus powder showed significant decreases in the amounts of fat tissue, plasma levels of total cholesterol, and leptin. To determine the mechanism, groups of mice were respectively fed a diet containing H. erinaceus powder, a diet containing ethanol extract of H. erinaceus, and a diet containing a residue of the extract. As a result, H. erinaceus powder was found to increase fecal lipid levels in excreted matter. Further in vitro investigation showed that ethanol extract inhibited the activity of lipase, and four lipase-inhibitory compounds were isolated from the extract: hericenone C, hericenone D, hericenone F, and hericenone G. In short, we suggest that H. erinaceus has an anti-obesity effect during menopause because it decreases the ability to absorb lipids.

The quantitative analysis of organosulfur compounds is important for the quality control of various garlic products along with studying their molecular functionality and nutraceutical properties. In this study, a liquid chromatography-tandem mass spectrometry-selected reaction monitoring (LC-MS/MS-SRM) method with electrospray ionization detection was developed and validated for the rapid, simultaneous quantification of four representative organosulfur compounds in garlic: alliin, S-allyl-L-cysteine, γ-glutamyl-S-allyl-L-cysteine, and allicin. Stable SRM transitions were achieved for these compounds under optimized conditions, and the linear range extended from 1 to 2000 ng/mL. The limits of detection and quantification ranged from 0.003 to 0.058 ng/mL and from 0.01 to 0.19 ng/mL, respectively. Excellent recovery and reproducibility at different spiking levels were achieved. The method was successfully applied to the simultaneous quantification of organosulfur compounds in fresh garlic samples. This highly selective and sensitive LC-MS/MS-SRM method is expected to be a useful tool for studying molecular functionality and the quality control of garlic products.

An aliphatic ester of hydroxysalicylic acid (6), reported for the first time from a natural source in addition to five known compounds were isolated from the fermented Carica papaya L. preparation, a commercialized functional food. The known compounds were identified as 5-hydroxymethylfurfuraldehyde (1), trans-caffeic acid (2), butyl 4-hydroxybenzoate (butylparaben) (3), lycopene (4), benzyl isothiocyanate (5). Compounds 1 and 3 were reported for the first time from Papaya fruits through this study. The new compound showed a moderate antioxidant activity and a potent hair growth stimulating activity in vitro.

This article presents multiple potential uses of the Yakushima native cedar (Cryptomeria japonica), known in Japan as the Yaku-sugi tree. The Yaku-sugi was divided into four parts: leaves, branches with leaves, branches, and stems. We obtained the essential oil, hydrosol, distillation residue, and distillation wastewater from the trees. Essential oil and hydrosol were determined to be volatile organic compounds. All samples were screened for the following bioactivities: antioxidative, antibacterial, and anti-melanogenesis activities. Freeze-dried distillation residue was tested to assess whether it had a deodorizing effect. The main component of the leaf essential oil was found to be monoterpenes. In contrast, the stem essential oil mainly contained sesquiterpenes. In terms of bioactivities, the leaf essential oil showed antibacterial activity and the stem essential oil showed anti-melanogenesis activity. Distillation residue and wastewater showed many activities, including antioxidant, antibacterial, and...

The in vitro antioxidant, anti-obesity, anti-allergy and skin-lightening effects of extracts from strawberry fruits (ripe and unripe) and nine other plant parts of Amaou strawberry ( Fragaria × ananassa var. Amaou ) were comparatively investigated by using the antioxidant assay and inhibition assays of lipase, adipocyte differentiation, β-hexosaminidase release, melanogenesis and tyrosinase. Their total phenolic content and the main phenolic compounds were also determined. The ripe strawberry fruits were found to possess potential anti-obesity and skin-lightening effects. The ethanol extracts from unripe strawberry fruits and several other parts like the crown, stolon leaf and flower showed more strong activities in the bioactivity assays conducted. The phytochemical profile varied among extracts from various parts of the plant. Ellagic acid was found in every part of the strawberry plant except the root. Our study provides valuable evidence that strawberry fruit is a food with potential anti-obesity and skin-lightening functions. The findings also support that several inedible parts of the strawberry plant have great potential to be used as the ingredients of functional food products.

This study investigated in vitro the α-glucosidase inhibitory activity of resin from the Sakhalin fir tree ( Abies sachalinensis). The resin showed extremely high activity (IC50 of 17.3 µg/mL). We isolated 8 compounds from the resin and identified them. All of the compounds isolated from A. sachalinensis resin are reported for the first time in the present study. In an α-glucosidase inhibitory assay, 6 compounds—(holophyllane C (1), (−) -(24 E)-23-oxo-3,4- seco-9β H-lanosta-4(28),6,8(14),24-tetraen-3,26-dioic acid (2), abiesonic acid (3), (−) -(24 E)-23-oxo-3,4- seco-9β H-lanosta-4(28),7,24-triene-3,26-dioic acid (4), 3,4- seco-4(28),6,8(14),22Z,24-mariesapentaen-26,23-olide-3-oic acid (5), and (−) -abiesonic acid 3-methyl ester (6))—showed high activity (their IC50 values were 25.1, 20.9, 82.4, 20.5, 27.3, and 20.5 µg/mL, respectively). These compounds should contribute to the resin’s α-glucosidase inhibitory activity. From an industrial point of view, these findings provide new data to support that the resin of A. sachalinensis is a rich source of α-glucosidase inhibitors, which are highly valuable for their potential to be developed as functional health foods.

The loquat, Eriobotrya japonica Lindl. (Rosaceae), is a small tree native to Japan and China that is widely cultivated for its succulent fruit. Its leaves are used as an ingredient of a tasty tea called "Biwa cha" in Japanese. The anti-osteoporosis effects of the leaves of loquat in vitro and in vivo have been investigated. After 15 days of feeding normal diet or diet supplemented with 5% loquat leaves, the body weight, viscera weights, and bone mineral density (BMD) of both groups of eight ovariectomized (OVX) mice were compared. The result showed that the loss of BMD in loquat-fed mice was significantly prevented in three parts of the body, especially in the trabecular bone of the head (P < 0.05), abdomen (P < 0.01), and lumbar (P < 0.05) compared to the control group. No hypertrophy in the uterus by the loquat leaves diet was observed. The effect of the extract (447.25 g) prepared from the dried leaves of loquat (2.36 kg) was further studied on RANKL-induced osteoclast differentiation and cell viability. The extract suppressed the differentiation of osteoclasts under 50, 125, 250, and 500 μg/mL. Through bioactivity-guided fractionation, ursolic acid (1) was isolated and inhibited osteoclast differentiation under 4 and 10 μg/mL. It was concluded that loquat leaves possess the potential to suppress ovariectomy-induced bone mineral density deterioration.

The present study examined the effects of enzymatically hydrolyzed collagen peptides on the level of hippocampal neurogenesis and emotional behavior in adult mice. For this purpose, two kinds of enzymatically hydrolyzed collagen peptides, the lower or higher molecular weight peptides (LP: below 2,000, HP: about 30,000) were administered orally to C57BL/6 mice for 4 weeks. As a result, the density of proliferating cells in subgranular zone of hippocampus showed a 1.2-fold increase in LP mice as compared with HP mice. Additionally, LP mice spent less time in closed arms than HP mice in elevated plus maze test to examine anxiety-related behavior. These results suggest that oral administration of the lower molecular weight peptides derived from collagen enhanced the hippocampal neurogenesis and exerted emotional behavior in adult mice.

Volatile constituents from natural plants have sometimes been used for the treatment of mental disorders, but the efficacy of many plants has not been determined. Here, we investigated the effects of the essential oil of the Siberian fir tree, Abies sibirica (Pinaceae), on individuals during and after performance of a sustained task on a visual display terminal (VDT). Participants who breathed air containing the essential oil showed prolonged heartbeat intervals and increased theta activity as measured by electroencephalography in the recovery period after the VDT task, but not during the task. The volatile constituents emitted from the essential oil of A. sibirica through the odorant delivery system for 40 min were a-pinene (80.4 μg), santene (3.1 μg), tricyclene (2.4 μg), camphene (24.2 μg), β-pinene (2.6 μg), myrcene (1.0 μg), 6-3-carene (14.4 μg), limonene (3.8 μg), and bornyl acetate (1.0 μg). These results show that the essential oil of A. sibirica reduced arousal levels after the VDT task, and might be useful for the prevention of VDT-related mental health disturbance.

Capsinoids are nonpungent compounds that are found in almost all pungent peppers and are abundant in the sweet pepper cultivar CH-19 Sweet. Since the discovery of capsinoids 13 years ago, various physiological effects of these compounds - especially reduction of visceral fat - have been observed both in rodents and humans. Recently, capsules containing capsinoids have become commercially available and comprehensive studies have been performed on the metabolism and toxicity of capsinoids.This article reviews all the literature from 1998 to date providing details on the nature and physiological effects of capsinoids. In addition to this, the article also looks at their metabolism as well as their acute and chronic toxicity including their genotoxicity and teratology.Capsinoids are the most promising compounds among all known transient receptor potential vanilloid 1 agonists. The physiological activities of capsinoids are similar to those of capsaicin, the most pungent food component of red pepper, but appear to be much safer to use as a therapeutic compound. That said, there is still a need for further research into the capsinoid mechanism of action before it can be 'green-lighted' for therapeutic use.

We investigated the changes in autonomic nervous activity, body temperature, blood pressure (BP), and heart rate (HR) after intake of the non-pungent pepper CH-19 Sweet and of hot red pepper in humans to elucidate the mechanisms of diet-induced thermogenesis (DIT) due to CH-19 Sweet. We found that CH-19 Sweet activates the sympathetic nervous system (SNS) and enhances thermogenesis as effectively as hot red pepper, ant that the heat loss effect due to CH-19 Sweet is weaker than that due to hot red pepper. Furthermore, we found that intake of CH-19 Sweet does not affect systolic BP or HR, while hot red pepper transiently elevates them. These results indicate that DIT due to CH-19 Sweet can be induced via the activation of SNS as well as hot red pepper, but that the changes in BP, HR, and heat loss effect are different between these peppers.

We investigated the effect of capsiate, a nonpungent natural capsaicin analog, on the swimming capacity of mice in an adjustable-current water pool. Male BALB/c mice orally given capsiate (10 mg/kg) were able to keep swimming longer before exhaustion than the control mice. After 30 min of swimming, the residual glycogen in the gastrocnemius muscle was higher, the serum free fatty acid concentration tended to be higher, and the serum lactic acid concentration was significantly lower in the capsiate-administered mice. The value for the respiratory exchange ratio of the capsiate group was significantly lower during both resting and treadmill running. These physiological differences were abolished by administering the vanilloid receptor antagonist, capsazepin (0.17 mmol/kg, i.p.). The mice were not averse to the capsiate solution during a 4-h two-bottle choice test. These results suggest that the oral administration of capsiate enhanced fat oxidation and spared carbohydrate utilization, and consequently increased the endurance swimming capacity of the mice via stimulation of their vanilloid receptors. Practical application of capsiate is expected.

Capsiate is a nonpungent capsaicin analog, a recently identified principle of the nonpungent red pepper cultivar CH-19 Sweet. In the present study, we report that 2-wk treatment of capsiate increased metabolic rate and promoted fat oxidation at rest, suggesting that capsiate may prevent obesity. To explain these effects, at least in part, we examined uncoupling proteins (UCPs) and thyroid hormones. UCPs and thyroid hormones play important roles in energy expenditure, the maintenance of body weight, and thermoregulation. Two-week treatment of capsiate increased the levels of UCP1 protein and mRNA in brown adipose tissue and UCP2 mRNA in white adipose tissue. This dose of capsiate did not change serum triiodothyronine or thyroxine levels. A single dose of capsiate temporarily raised both UCP1 mRNA in brown adipose tissue and UCP3 mRNA in skeletal muscle. These results suggest that UCP1 and UCP2 may contribute to the promotion of energy metabolism by capsiate, but that thyroid hormones do not.

We investigated the effect of a single oral administration of conjugated linoleic acid (CLA) on energy metabolism in mice. Male Std ddY mice were orally administered CLA (5 mL/kg weight) or linoleic acid (5 mL/kg weight) (both solutions at concentrations of 73.5%) as a control. Oxygen consumption was significantly greater in the CLA-administered mice than in the control mice. Respiratory quotient was slightly lower in the CLA-adminis-tered mice than in the control mice. We calculated fat and carbohydrate oxidation from oxygen consumption and respiratory quotient. Fat oxidation in the CLA-administered mice was significantly higher than in the control mice, and there was no difference in carbohydrate oxidation. Serum concentrations of noradrenalin and adrenalin in the CLA administered mice were significantly higher than in the control mice. These results suggested that CLA enhanced sympathetic nervous activity and energy metabolism.

We investigated the dose-effect of the long-term intake of conjugated linoleic acid (CLA) on the energy metabolism and fat accumulation in mice. Five-week-old male Std ddY mice were fed on a diet containing none (control), 0.25%, 0.5% or 1.0% CLA for 4 or 8 weeks. The body weight was lower in the CLA groups than in the control group, and significant differences were detected between the 1.0% CLA group and the control group at both 4 and 8 weeks. The epididymal and perirenal adipose tissue weights were significantly lower in the CLA groups than in the control group. The liver weight and hepatic triglyceride values were higher in the 1.0% CLA group than in the other groups. The metabolic rate was measured after 8 weeks by using a gas analyzer. The oxygen consumption of the mice in the CLA groups was significantly higher than that of the control mice. Since there was a significant effect on the mice supplemented with 0.25% CLA, low concentration of CLA is suggested to suppress the body fat accumulation and increase the energy metabolism.

We assessed the sympatho-vagal activities of the heart after administration of capsaicin by measuring the power spectral analysis in rats. There were major two frequency components of heart rate variability, which we defined as high (1.0 Hz

We investigated the effect of CH-19 Sweet, a nonpungent cultivar of red pepper, and capsiate, a nonpungent capsaicin analog found in CH-19 Sweet on body temperature in mice. The body temperature was recorded from conscious and unrestrained mice by use of a telemetry system. The body temperature in the mice administered CH-19 Sweet was higher than in the mice administered California-Wandar, which contains no capsiate or capsaicin. The body temperature in the mice administered capsiate was higher than in the mice administered the vehicle. Furthermore, we injected capsazepine, a specific antagonist of vanilloid receptors, into the peritoneal cavity and orally administered capsiate via a stomach tube to mice. The body temperature in the mice pretreated with capsazepine was lower than in the mice injected with the vehicle. This result suggested that capsazepine suppressed the rise in body temperature induced by capsiate administration. In conclusion, CH-19 Sweet increased body temperature, and this effect may be induced by the vanilloid receptors' stimulation of capsiate.

Enhancement of energy expenditure and reducing energy intake are crucial for weight control. Capsiate, a non-pungent capsaicin analog, is known to suppress body fat accumulation and reduce body weight by enhancing of energy expenditure in both mice and humans. However, it is poorly understood whether suppressing body fat accumulation by capsiate administration is equal to exercise or not. The aim of this study is to compare the effects of repeated administration of capsiate and exercise and to investigate the weight rebound after repeated capsiate administration and/or exercise. In the present study, we report that 2 weeks treatment of capsiate and exercise increased energy metabolism and suppressed body fat accumulation during 4 more weeks of ad libitum feeding. The body weight in capsiate and exercise groups was significantly lower than that of control group. The oxygen consumption was significanlty increased in capsiate and exercise groups than in the vehicle administered mice. In addition, the abdominal adipose tissue weight in capsiate and exercise groups was significantly lower than that of control group. These results indicate that suppressing body fat accumulation by capsiate intake is beneficial for maintaining an ideal body weight as exercise.

(-)-Bornyl acetate is the main volatile constituent in numerous conifer oils and has a camphoraceous, pine-needle-like odor. It is frequently used as the conifer needle composition in soap, bath products, room sprays, and pharmaceutical products. However, the psychophysiological effects of (-)-bornyl acetate remained unclear. We investigated the effects of breathing air mixed with (-)-bornyl acetate at different doses (low-dose and high-dose conditions) on the individuals during and after VDT (visual display terminal) work using a visual discrimination task. The amounts of (-)-bornyl acetate through our odorant delivery system for 40 min were 279.4 µg in the low-dose and 716.3 µg in the high-dose (-)-bornyl acetate condition. (-)-Bornyl acetate induced changes of autonomic nervous system for relaxation and reduced arousal level after VDT work without any influences of task performance in low-dose condition, but not in high-dose condition.

Enhancing energy expenditure and reducing energy intake are both crucial for weight control. Capsinoids, which are non-pungent capsaicin analogs, are known to suppress body fat accumulation and reduce body weight by enhancing energy expenditure in both mice and humans. However, it is poorly understood whether the suppression of body fat accumulation by capsinoids has an advantage over dietary restriction. This study shows that the oxygen consumption was increased in mice administered with capsinoids but not in dietary-restricted mice, although there was a similar suppression of body fat accumulation in both groups. The weight rebound was more notable in the dietary-restricted mice than in the mice administered with capsinoids. These results indicate that suppressing body fat accumulation by capsinoids was more beneficial than a restricted diet for maintaining body weight.

Vascular endothelial growth factor (VEGF) is implicated as a molecular mediator for adult neurogenesis and behavioral effects of antidepressant drugs. However, these potential roles of VEGF in the CNS have not been clarified in model animals. Here we have created transgenic mice overexpressing a short active variant of VEGF-A (VEGF120) in forebrain. Expression of VEGF120 significantly enhanced cell proliferation and angiogenesis, as exemplified by the formation of an enlarged reddish brain. Adult neurogenesis in hippocampus was markedly stimulated without affecting cell differentiation of neural progenitor cells. Hippocampal neurogenesis was particularly robust in young adult animals, but it declined with age and reduced to control levels by 20 weeks under continuous expression of VEGF120. Thus, VEGF alone is not sufficient to support the long-term enhancement of adult neurogenesis, and VEGF-induced vascularization per se does not necessarily predict increased neurogenesis. In transgenic mice, we observed significant changes in affective behaviors. VEGF was found to have not only antidepressant effects but also anxiolytic effects. In addition, we found that VEGF significantly reduced fear and aggression. In contrast, basal activities under natural conditions were not affected much. Unexpectedly, these characteristic behaviors were maintained in older transgenic mice undergoing a reduced level of cell proliferation in hippocampus, suggesting that there is potential dissociation between adult neurogenesis and mood regulation. Our data indicate that VEGF exerts strong neurogenic and angiogenic effects in postnatal brain and influences different forms of affective behaviors.

This study examined the effects of odors on sustained attention during a vigilance task. Two essential oils (lavender and eucalyptus) and two materials (l-menthol and linalyl acetate) were compared with a control. The increase in reaction time was significantly lower with lavender than with the control. The results suggest that the administration of lavender helped to maintain sustained attention during the long-term task.

We investigated the effects of a single oral administration of capsiate, which is found in the fruits of a non-pungent cultivar of pepper, CH-19 Sweet, and has the same structure as capsaicin except for replacement of NH by O in the alkyl chain, on the thermogenesis and fat accumulation in mice. The oxygen consumption and serum adrenalin concentration were higher in both the capsaicin (10 mg/kg-body weight) and capsiate (10 mg/kg-body weight) groups than those in the control group. We also examined the effects of 2 weeks of administration of capsaicin and capsiate on body fat accumulation. Eevery day for 2 weeks administration of capsiate (10, 50 mg/kg-body weight/day) markedly suppressed body fat accumulation as well as capsaicin (10 mg/kg-body weight/day). These results suggest that capsiate promotes energy metabolism and suppresses body fat accumulation as does capsaicin.

We investigated the effect of CH-19 Sweet, a non-pungent cultivar of red pepper, on body temperature and oxygen consumption in humans. CH-19 Sweet was given to 11 healthy volunteers, and core body temperature, body surface temperature and oxygen consumption were measured. The control group ingested California-Wandar, which contained neither capsaicin nor capsiate. The core body temperature in the CH-19 Sweet group was significantly higher than that in the control group (P