Randomised, double-blind, parallel group comparison of Ashitaba (Angelica Keiskei) chalcone effects on visceral fat areas and waist circumference of overweight persons.

This randomised, placebo-controlled, double-blind, parallel-group study aimed to determine whether encapsulated Ashitaba chalcone (16 mg comprising 10.1 mg 4-hydroxyderricin and 5.9 mg xanthoangelol) could reduce obesity in 17 men and 25 women with a body mass index (BMI) of 25 to < 30. Participants ingested capsules containing either the chalcone or a placebo daily for 12 weeks. The primary endpoint was changes in visceral fat areas determined by computed tomography (CT) at baseline, and at 8 and 12 weeks later. The primary endpoint, abdominal visceral fat area, was significantly reduced in the chalcone, compared with a placebo group 12 weeks after screening (p < 0.05). The secondary endpoint, waist circumference, was significantly decreased in the chalcone, compared with the placebo group at weeks 8 and 12 (p < 0.05 at week 8; p < 0.01 at week 12). Therefore, Ashitaba chalcone has anti-obesity benefits for overweight men and women.

Xanthoangelol promotes early embryonic development of porcine embryos by relieving endoplasmic reticulum stress and enhancing mitochondrial function.

RESEARCH QUESTION: Does the addition of an antioxidant agent, xanthoangelol (XAG), to the culture medium improve in-vitro development of porcine embryos? DESIGN: Early porcine embryos were incubated in the presence of 0.5 µmol/l XAG in in-vitro culture (IVC) media and analysed using various techniques, including immunofluorescence staining, reactive oxygen species (ROS) detection, TdT-mediated dUTP nick-end labelling (TUNEL), and reverse transcription followed by quantitative polymerase chain reaction (RT-qPCR). RESULTS: The addition of 0.5 µmol/l XAG to IVC media increased the rate of blastocyst formation, total cell number, glutathione concentrations and proliferative capacity, while reducing reactive oxygen species concentrations, apoptosis and autophagy. In addition, upon XAG treatment, the abundance of mitochondria and mitochondrial membrane potential significantly increased (both P < 0.001), and the genes related to mitochondrial biogenesis (TFAM, NRF1 and NRF2) were significantly up-regulated (all P < 0.001). XAG treatment also significantly increased the endoplasmic reticulum abundance (P < 0.001) and reduced the concentrations of endoplasmic reticulum stress (ERS) marker GRP78 (P = 0.003) and expression of the ERS-related genes EIF2α, GRP78, CHOP, ATF6, ATF4, uXBP1 and sXBP 1 (all P < 0.001). CONCLUSION: XAG promotes early embryonic development in porcine embryos in vitro by reducing oxidative stress, enhancing mitochondrial function and relieving ERS.

EPRS/GluRS promotes gastric cancer development via WNT/GSK-3ß/ß-catenin signaling pathway.

BACKGROUND: Glutamyl-prolyl-tRNA synthetase (EPRS/GluRS) is primarily part of the multi-synthetase complex that may play a key role in cancer development. However, the biological function, molecular mechanism, and inhibitor of EPRS have not been investigated in gastric cancer (GC). METHODS: Immunohistochemistry was performed to detect the expression of EPRS in human gastric tumor tissues. Knocking down of EPRS, cell-derived xenograft mouse model, and patient-derived xenograft mouse model was used to identify the biological function of EPRS. Immunoprecipitation was applied to elucidate the interaction between EPRS and SCYL2. Computer docking model and multiple in vitro and in vivo experiments were conducted to discover EPRS inhibitors. RESULTS: Here, we report that EPRS is frequently overexpressed in GC tissues compared to that adjacent controls and its overexpression predicts poor prognosis in GC patients. Functionally, high expression of EPRS positively co-relates with GC development both in vitro and in vivo. Mechanistically, EPRS directly binds with SCYL2 to enhance the activation of WNT/GSK-3ß/ß-catenin signaling pathway and the accumulation of ß-catenin in the nuclear, leading to GC cell proliferation and tumor growth. Moreover, we identified that xanthoangelol (XA) and 4-hydroxyderricin (4-HD) can directly bind to EPRS to block WNT/GSK-3ß/ß-catenin signaling pathway. More importantly, XA and 4-HD restrain gastric cancer patient-derived xenograft tumor growth and Helicobacter pylori combined with alcohol-induced atrophic gastritis and gastric tumorigenesis. CONCLUSION: These findings unveil a promising strategy for GC prevention and therapy by targeting EPRS-mediated WNT/GSK-3ß/ß-catenin cascades. Moreover, XA and 4-HD may be effective reagents used for GC prevention and therapy.

The plant-derived chalcone Xanthoangelol targets the membrane of Gram-positive bacteria.

Xanthoangelol is a geranylated chalcone isolated from fruits of Amorpha fructicosa that exhibits antibacterial effects at low micromolar concentration against Gram-positive bacterial pathogens such as methicillin-resistant Staphylococcus aureus (MRSA), Enterococcus faecium and Enterococcus faecalis. We demonstrate that Xanthoangelol treatment of Gram-positive bacteria affects bacterial membrane integrity and leads to a leakage of intracellular metabolites. This correlates with a rapid collapse of the membrane potential and results in a fast and strong bactericidal effect. Proteomic profiling of Xanthoangelol-treated cells revealed signatures of cell wall and/or membrane damage and oxidative stress. Xanthoangelol specifically disturbs the membrane of Gram-positive bacteria potentially by forming pores resulting in cell lysis. In contrast, Xanthoangelol treatment of human cells showed only mildly hemolytic and cytotoxic effects at higher concentrations. Therefore, geranylated chalcones such as Xanthoangelol are promising lead structures for new antimicrobials against drug-resistant gram-positive pathogens.

Autophagy induction by xanthoangelol exhibits anti-metastatic activities in hepatocellular carcinoma.

Xanthoangelol (XAG), a prenylated chalcone isolated from the Japanese herb Angelica keiskei Koidzumi, has been reported to exhibit antineoplastic properties. However, the specific anti-tumor activity of XAG in human hepatocellular carcinoma (HCC), and the relevant mechanisms are not known. Herein, we evaluated the effect of XAG against HCC in vitro and in vivo. Although XAG treatment did not significantly reduce the viability of the Hep3B and Huh7 cell lines, it suppressed cell migration, invasion, and EMT. This anti-metastatic effect of XAG was due to induction of autophagy, because treatment with the autophagy inhibitor 3-methyadenine (3-MA) or knockdown of the pro-autophagy Beclin-1 effectively abrogated the XAG-induced suppression of metastasis. Mechanistically, XAG induced autophagy via activation of the AMPK/mTOR signaling pathway, and XAG treatment dramatically increased the expression of p-AMPK while decreasing p-mTOR expression. In addition, blocking AMPK/mTOR axis with compound C abrogated the autophagy-mediated inhibition of metastasis. The murine model of HCC metastasis also showed that XAG effectively reduced the number of metastatic pulmonary nodules. Taken together, our results revealed that autophagy via the activation of AMPK/mTOR pathway is essential for the anti-metastatic effect of XAG against HCC. These findings not only contribute to our understanding of the anti-tumor activity of XAG but also provide a basis for its clinical application in HCC. Before this study, evidence of XAG on HCC was purely anecdotal; present study provides the first comprehensive assessments of XAG on HCC metastasis and investigates its underlying mechanism. Results suggest that XAG exerts anti-metastatic properties against HCC through inducing autophagy which is mediated by the activation of AMPK/mTOR signaling pathway. This research extends our knowledge about the antineoplastic properties of XAG and suggests that induction autophagy may represent future treatment strategies for metastatic HCC.

The pharmacology activities of Angelica keiskei Koidzumi and its efficacy and safety in humans.

Chronic exposure to elevated levels of pro-oxidant factors may cause structural failings at the mitochondrial DNA level and alteration of antioxidant enzymes (glutathione peroxidase, catalase, and superoxide dismutase). Oxidative stress is an imbalance between the capacity of endogenous non-enzymatic antioxidants (glutathione, alpha-lipoic acid, uric acid, ferritin, metallothionein, melatonin, and bilirubin) and the occurrence of pro-oxidant factors which may lead to the pathogenesis of various diseases that affects the kidneys, pancreas, central nervous system, and cardiovascular system. Therefore, the utilization of medicinal plants with antioxidant activity, e.g., Angelica keiskei Koidzumi which contains chalcones, is interesting to be explored. Chalcones exhibit direct and indirect antioxidant activity and prevent oxidative stress by decreasing ROS, RNS, and superoxide production. In this review, we discuss the pharmacology activities of A. keiskei Koidzumi and its efficacy in humans. The articles were explored on PubMed and Google Scholar databases and based on the titles and abstracts related to the topic of interest, and 55 articles were selected. Two main chalcones of this plant, 4-hydroxyderricin and xanthoangelol, have been reported for their various pharmacology activities. The efficacy of A. keiskei was confirmed in anti-obesity, hepatoprotective, anti-diabetes mellitus, and increasing plasma antioxidants in patients with metabolic syndrome. A keiskei is safe as proven by only mild or no adverse events reported, thus it is prospective to be further developed as an antioxidant nutraceutical.

Two Prenylated Chalcones, 4-Hydroxyderricin, and Xanthoangelol Prevent Postprandial Hyperglycemia by Promoting GLUT4 Translocation via the LKB1/AMPK Signaling Pathway in Skeletal Muscle Cells.

SCOPE: Stimulation of glucose uptake in the skeletal muscle is crucial for the prevention of postprandial hyperglycemia. Insulin and certain polyphenols enhance glucose uptake through the translocation of glucose transporter 4 (GLUT4) in the skeletal muscle. The previous study reports that prenylated chalcones, 4-hydroxyderricin (4-HD), and xanthoangelol (XAG) promote glucose uptake and GLUT4 translocation in L6 myotubes, but their underlying molecular mechanism remains unclear. This study investigates the mechanism in L6 myotubes and confirms antihyperglycemia by 4-HD and XAG. METHODS AND RESULTS: In L6 myotubes, 4-HD and XAG promote glucose uptake and GLUT4 translocation through the activation of adenosine monophosphate-activated protein kinase (AMPK) and liver kinase B1 (LKB1) signaling pathway without activating phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) and Janus kinases (JAKs)/signal transducers and activators of transcriptions (STATs) pathways. Moreover, Compound C, an AMPK-specific inhibitor, as well as siRNA targeting AMPK and LKB1 completely canceled 4-HD and XAG-increased glucose uptake. Consistently, oral administration of 4-HD and XAG to male ICR mice suppresses acute hyperglycemia in an oral glucose tolerance test. CONCLUSION: In conclusion, LKB1/AMPK pathway and subsequent GLUT4 translocation in skeletal muscle cells are involved in Ashitaba chalcone-suppressed acute hyperglycemia.

Supplementation with Ashitaba (Angelica keiskei) Yellow Stem Exudate Prevents Aging-Induced Thrombotic Tendencies and Systemic Inflammation Without Affecting Body Weight Gain in Mice.

Angelica keiskei Koidzumi (Ashitaba) is a traditional folk medicine and health supplement in Japan. Ashitaba yellow stem exudate (AYE) contains abundant chalcones and thus has the potential to treat and prevent many pathological states such as cancer, inflammation, obesity, diabetics, thrombosis, and hypertension. Levels of plasminogen activator inhibitor 1 (PAI-1), a key regulator of the fibrinolytic system, increase with age in mouse plasma. Therefore, we aimed to determine the effects of AYE on plasma thrombotic parameters in aging mice. Long-term (52 weeks) AYE supplementation significantly decreased age-induced increases of PAI-1 in mouse plasma. Supplementation with AYE decreased levels of the acute-phase and fibrinolytic protein plasma plasminogen, and significantly decreased those of tumor necrosis factor α. These results suggested that continuous intake of AYE throughout life decreases age-induced systemic inflammation and prevents thrombotic tendencies without affecting body weight gain in aged mice. Our findings showed that supplementing diets with AYE might help to prevent thrombotic diseases in elderly individuals.

Bioherbicides for sustainable barnyard grass management in paddy field: an in-silico perspective.

Paddy (Oryza sativa) yield is greatly influenced by the insidious presence of rice-mimicking weed, widely known as barnyard grass. This study explores the promising natural ACCase inhibitors that could enhance paddy yield by controlling weeds. A total of 2828 natural compounds were examined using diverse computational techniques. The results of this study depict that CNP0390839 (xanthoangelol) exhibited a better XP Gscore (-7.328 kcal/mol) and MM/GBSA score (-84.24 kcal/mol) than other investigated compounds. Importantly, ACCase-xanthoangelol complexes was thermodynamically stable with an RMSD value of ∼1.2 nm. Of note, 72% xanthoangelol resides in the Angelica keiskei plant root which exhibits 55% weed-inhibitory action. The A. keiskei plant mainly inhibits the hypocotyl (71.8 ± 5.4%) and root region (55.3 ± 4.7%) of weeds. Moreover, the existence of dihydroxyphenyl scaffold in xanthoangelol was also witnessed in literatures for weed inhibitory action. Overall, xanthoangelol might prove to be an effective ACCase herbicide in paddy weed management.

Inhibitory activity of xanthoangelol isolated from Ashitaba (Angelica keiskei Koidzumi) towards α-glucosidase and dipeptidyl peptidase-IV: in silico and in vitro studies.

In Indonesia, the sap of Angelica keiskei Koidzumi has been utilized traditionally as a blood-sugar reducer, nonetheless, its molecular mechanism still needs to be studied. This study aimed to isolate xanthoangelol (XA) from the yellow sap of A. keiskei planted in Mount Rinjani, Indonesia, and to investigate its mechanism by in silico and in vitro methods towards α-glucosidase and dipeptidyl peptidase-IV (DPP-IV). The dried yellow sap was macerated using ethanol, subjected to liquid-liquid extraction using a different polarity of solvents, further gradient-eluted with column chromatography. The isolated compound, formed as yellow crystals, melting point 114-114.4 °C, λmax 368 nm, m/z 393.20 [M + H]+, was confirmed as XA. Acarbose, an α-glucosidase inhibitor, and sitagliptin, a DPP-IV inhibitor, respectively, were employed as the reference drugs for both the in silico and in vitro studies. XA interacts with essential amino acid residues 232-237 in the N-terminal N-loop of α-glucosidase by forming a hydrogen bond with Ala234, a salt-bridge with Asp232, and 9 hydrophobic interactions (binding energy -7.81 kcal/mol; Ki = 1.99 µM). These binding modes resemble those of acarbose. Moreover, XA forms hydrogen bonds with Glu205 and Glu206 in the subsite S2 and π-π interaction with Phe357 in the extensive subsite S2 of DPP-IV (binding energy -8.34 kcal/mol; Ki = 0.873 µM), which are similar to those of sitagliptin. XA inhibits both α-glucosidase (IC50 XA = 14.45 µM; IC50 acarbose = 207 µM) and DPP-IV (IC50 XA = 10.49 µM; IC50 sitagliptin = 0.87 µM). Taken together, XA isolated from the yellow sap of A. keiskei Koidzumi might possess the potential to be further developed as an inhibitor of α-glucosidase and DPP-IV.

Pharmacological mechanism of xanthoangelol underlying Nrf-2/TRPV1 and anti-apoptotic pathway against scopolamine-induced amnesia in mice.

Alzheimer's disease (AD) is a well-known type of age-related dementia. The present study was conducted to investigate the effect of xanthoangelol against memory deficit and neurodegeneration associated with AD. Preliminarily, xanthoangelol produced neuroprotective effect against H2O2-induced HT-22 cells. Furthermore, effect of xanthoangelol against scopolamine-induced amnesia in mice was determined by intraperitoneally (i.p.) administering xanthoangelol (1, 10 and 20 mg/kg), 30 min prior to induction. Mice were administered scopolamine at a concentration of 1 mg/kg; i.p. for the induction of amnesia associated with AD. Xanthoangelol dose dependently reduced the symptoms of Alzheimer's disease as observed by the results obtained from the behavioral analysis performed using Morris water maze and Y-maze test. The immunohistochemical analysis suggested that xanthoangelol significantly improved Keap-1/Nrf-2 signaling pathway. It greatly reduced the effects of oxidative stress and showed improvement in the anti-oxidant enzyme such as GSH, GST, SOD and catalase. Additionally, xanthoangelol decreased the expression of transient receptor potential vanilloid 1 (TRPV-1), a nonselective cation channel, involved in synaptic plasticity and memory. It activated the anti-oxidants and attenuated the apoptotic (Bax/Bcl-2) pathway. Xanthoangelol also significantly attenuated the scopolamine-induced neuroinflammation by the inhibition of interleukin-1 beta (IL-1ß), and tumor necrosis factor-α (TNF-α) levels. The histological analysis, showed a significant reduction in amyloid plaques by xanthoangelol. Therefore, the present study indicated that xanthoangelol has the ability to ameliorate the AD symptoms by attenuating neuroinflammation and neurodegeneration induced by scopolamine.

Effects of Microbial Transformation on the Biological Activities of Prenylated Chalcones from Angelica keiskei.

Microbial transformation is an alternative method for structural modification. The current study aimed at application of microbial transformation for discovering new derivatives and investigating the structure-activity relationship of isobavachalcone (1), 4-hydroxyderricin (2), and xanthoangelol (3) isolated from the herb Angelica keiskei. In the initial screening process, 1-3 were incubated with microbes using a two-stage fermentation method and analyzed through TLC monitoring. The screening results showed that Rhizopus oryzae and Mucor hiemalis were able to transform 1 and 2, respectively. Additionally, M. hiemalis and Mortierella ramanniana var. angulispora were able to transform 3. Following scale-up fermentation, four new (4, 5, 7, and 10) and five known (6, 8, 9, 11, and 12) metabolites were produced. Cytotoxicity of all the compounds (1-12) was investigated using three human cancer cell lines including A375P, HT-29, and MCF-7 by MTT method. Meanwhile, the tyrosinase inhibitory activity of 1-12 was evaluated using l-tyrosine as a substrate. Overall, 1 and 3 displayed the highest cytotoxicity, and 5 and 7 exhibited the most potent tyrosinase inhibitory activity with relatively low cytotoxicity. This allowed us to postulate that the introduction of 4'-O-glucopyranosyl group led to the reduction in cytotoxicity and improvement in tyrosinase inhibitory activity.

Xanthoangelol alleviates cerebral ischemia reperfusion injury in rats.

Ischemia/reperfusion (I/R) injury accounts to be a prime cause of neurological deficit following stroke. This study aimed to explore the neuro-protective effects of Xanthoangelol (XAG) on I/R-induced injury in both in vivo and in vitro models. Our data demonstrated that XAG can shrink infarct size and brain edema in middle cerebral artery occlusion (MCAO) model. In addition, XAG was capable of alleviating the neurological deficit in rats that have undergone MCAO procedure. Meanwhile, antiapoptotic activities of XAG against I/R-induced neuronal injury were evidenced and further illustrated that XAG elicits antiapoptotic activities by suppressing excessive oxidative stress via nuclear factor erythroid-2-related factor 2 activation. Overall, our study revealed that XAG displayed the potential to be utilized as a neuroprotective agent against I/R-induced neurological injury.

Activation of Nrf2/HO-1 signaling: An important molecular mechanism of herbal medicine in the treatment of atherosclerosis via the protection of vascular endothelial cells from oxidative stress.

Introduction: Recently, Nrf2/HO-1 has received extensive attention as the main regulatory pathway of intracellular defense against oxidative stress and is considered an ideal target for alleviating endothelial cell (EC) injury. Objectives: This paper aimed to summarized the natural monomers/extracts that potentially exert protective effects against oxidative stress in ECs. Methods: A literature search was carried out regarding our topic with the keywords of "atherosclerosis" or "Nrf2/HO-1" or "vascular endothelial cells" or "oxidative stress" or "Herbal medicine" or "natural products" or "natural extracts" or "natural compounds" or "traditional Chinese medicines" based on classic books of herbal medicine and scientific databases including Pubmed, SciFinder, Scopus, the Web of Science, GoogleScholar, BaiduScholar, and others. Then, we analyzed the possible molecular mechanisms for different types of natural compounds in the treatment of atherosclerosis via the protection of vascular endothelial cells from oxidative stress. In addition, perspectives for possible future studies are discussed. Results: These agents with protective effects against oxidative stress in ECs mainly include phenylpropanoids, flavonoids, terpenoids, and alkaloids. Most of these agents alleviate cell apoptosis in ECs due to oxidative stress, and the mechanisms are related to Nrf2/HO-1 signaling activation. However, despite continued progress in research on various aspects of natural agents exerting protective effects against EC injury by activating Nrf2/HO-1 signaling, the development of new drugs for the treatment of atherosclerosis (AS) and other CVDs based on these agents will require more detailed preclinical and clinical studies. Conclusion: Our present paper provides updated information of natural agents with protective activities on ECs against oxidative stress by activating Nrf2/HO-1. We hope this review will provide some directions for the further development of novel candidate drugs from natural agents for the treatment of AS and other CVDs.

Toxicological assessment of Ashitaba Chalcone.

The plant Angelica keiskei contains two main physiologically active flavonoid chalcones, 4-hydroxyderricin and xanthoangelol. Known as ashitaba in Japan, powder from the sap is widely consumed for its medicinal properties in Asia as a dietary supplement. Limited previously reported mammalian studies were without evidence of toxicity. GLP studies reported here, including a bacterial reverse mutation assay, a chromosome aberration assay, and an in vivo micronucleus assay are negative for genotoxicity. A GLP- compliant 90-day repeated oral gavage study of ashitaba yellow sap powder containing 8.45% chalcones in Sprague Dawley rats resulted in expected known physiological effects on coagulation parameters and plasma lipids at 300 and 1000 mg/kg/day. Ashitaba-related pathology included a dose-related male rat-specific alpha 2-urinary globulin nephropathy at 100, 300, and 1000 mg/kg/day and jejunal lymphangiectasia in both sexes at 1000 mg/kg/day. All other study parameters and histopathological changes were incidental or not of toxicological concern. Based on these studies ashitaba chalcone powder is not genotoxic with a NOAEL of 300 mg/kg in male and female rats.

Two chalcones, 4-hydroxyderricin and xanthoangelol, stimulate GLUT4-dependent glucose uptake through the LKB1/AMP-activated protein kinase signaling pathway in 3T3-L1 adipocytes.

4-Hydroxyderricin (4HD) and xanthoangelol (XAG) are major components of n-hexane/ethyl acetate (5:1) extract of the yellow-colored stem juice of Angelica keiskei. 4-Hydroxyderricin and XAG have been reported to increase glucose transporter 4 (GLUT4)-dependent glucose uptake in 3T3-L1 adipocytes, but the detailed mechanism of this phenomenon remains unknown. This present study was aimed at clarifying the detailed mechanism by which 4HD and XAG increase GLUT4-dependent glucose uptake in 3T3-L1 adipocytes. Both 4HD and XAG increased glucose uptake and GLUT4 translocation to the plasma membrane. 4-Hydroxyderricin and XAG also stimulated the phosphorylation of 5' adenosine monophosphate-activated protein kinase (AMPK) and its downstream target acetyl-CoA carboxylase. In addition, phosphorylation of liver kinase B1 (LKB1), which acts upstream of AMPK, was also increased by 4HD and XAG treatment. Small interfering RNA knockdown of LKB1 attenuated 4HD- and XAG-stimulated AMPK phosphorylation and suppressed glucose uptake. These findings demonstrate that 4HD and XAG can increase GLUT4-dependent glucose uptake through the LKB1/AMPK signaling pathway in 3T3-L1 adipocytes.

Bioassay-guided isolation and identification of anti-platelet-active compounds from the root of Ashitaba (Angelica keiskei Koidz.).

Platelet aggregation is fundamental to a wide range of physiological and pathological processes, including the induction of thrombosis and arteriosclerosis. Anti-platelet activity of a crude methanol extract and solvent fractions of Ashitaba roots (Angelica keiskei Koidz.) was evaluated using a turbidimetric method using washed rabbit platelets. We identified the anti-platelet activities of two chalcones, 4-hydroxyderricin and xanthoangelol, isolated from the ethyl acetate-soluble fraction of Ashitaba roots by using a bioassay-guided isolation method. 4-Hydroxyderricin and xanthoangelol effectively inhibited platelet aggregation induced by collagen (IC50 of 41.9 and 35.9 µM, respectively), platelet-activating factor (IC50 of 46.1 and 42.3 µM, respectively) and phorbol 12-myristate 13-acetate (IC50 of 16.5 and 45.9 µM, respectively). These compounds did not inhibit thrombin-induced platelet aggregation (IC50 of>80 µM). The results suggest that the chalcones 4-hydroxyderricin and xanthoangelol may be potent anti-thrombotic components of A. keiskei Koidz.

Inhibitory effects of 4-hydroxyderricin and xanthoangelol on lipopolysaccharide-induced inflammatory responses in RAW264 macrophages.

The Japanese herb, Ashitaba (Angelica keiskei Koidzumi), contains two prenylated chalcones, 4-hydroxyderricin and xanthoangelol, which are considered to be the major active compounds of Ashitaba. However, their effects on inflammatory responses are poorly understood. In the present study, we investigated the effects and underlying molecular mechanisms of 4-hydroxyderricin and xanthoangelol on lipopolysaccharide (LPS)-induced inflammatory responses in RAW264 mouse macrophages. LPS-mediated production of nitric oxide (NO) was markedly reduced by 4-hydroxyderricin (10 µM) and xanthoangelol (5 µM) compared with their parent compound, chalcone (25 µM). They also inhibited LPS-induced secretion of tumor necrosis factor-alpha (TNF-α) and expression of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2). Although chalcone decreased the DNA-binding activity of both activator protein-1 (AP-1) and nuclear factor-kappa B (NF-κB), 4-hydroxyderricin and xanthoangelol suppressed only AP-1 and had no effect on NF-κB. On the other hand, all of the tested chalcones reduced the phosphorylation (at serine 536) level of the p65 subunit of NF-κB. 4-Hydroxyderricin and xanthoangelol may be promising for the prevention of inflammatory diseases.

Xanthoangelol and 4-Hydroxyderricin Are the Major Active Principles of the Inhibitory Activities against Monoamine Oxidases on Angelica keiskei K.

Monoamine oxidase inhibitors (MAOI) have been widely used as antidepressants. Recently, there has been renewed interest in MAO inhibitors. The activity-guided fractionation of extracts from Angelica keiskei Koidzumi (A. keiskei K.) led to the isolation of two prenylated chalcones, xanthoangelol and 4-hydroxyderricin and a flavonoid, cynaroside. These three isolated compounds are the major active ingredients of A. keiskei K. to inhibit the MAOs and DBH activities. Xanthoangelol is a nonselective MAO inhibitor, and a potent dopamine ß-hydroxylase (DBH) inhibitor. IC50 values of xanthoangelol to MAO-A and MAO-B were calculated to be 43.4 µM, and 43.9 µM. These values were very similar to iproniazid, which is a nonselective MAO inhibitor used as a drug against depression. The IC50 values of iproniazid were 37 µM, and 42.5 µM in our parallel examination. Moreover, IC50 value of xanthoangelol to DBH was calculated 0.52 µM. 4-Hydroxyderricin is a potent selective MAO-B inhibitor and also mildly inhibits DBH activity. The IC50 value of 4-hydroxyderricin to MAO-B was calculated to be 3.43 µM and this value was higher than that of deprenyl (0.046 µM) used as a positive control for selective MAO-B inhibitor in our test. Cynaroside is a most potent DBH inhibitor. The IC50 value of cynaroside to DBH was calculated at 0.0410 µM. Results of this study suggest that the two prenylated chalcones, xanthoangelol and 4-hydroxyderricin isolated from A. keiskei K., are expected for potent candidates for development of combined antidepressant drug. A. keiskei K. will be an excellent new bio-functional food material that has the combined antidepressant effect.