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Anti-diabetic Activities of Chalcones Derived from Ashitaba
Abstract
Ashitaba, (Angelica keiskei), is a perennial belonging to Umbelliferae and has been taken as a healthpromoting vegetable around the Hachijo Island area. Ashitaba has been known to contain about 20 kinds of chalcones, and two major chalcones such as xanthoangelol (XA) and 4-hydroxyderricin (4HD) are more abundantly included than other chalcones. We previously found that these two chalcones have insulin-like activities such as the induction of adipocyte differentiation and the enhancement of glucose uptake. Moreover, 4HD especially showed stronger promoting activity of glucose uptake and preventive effect on the progression of diabetes in genetically diabetic mice than the XA. In this report, we tested whether 4HD can reduce the blood glucose levels of mice which developed hyperglycemia associated with insulin resistance, and the structure-activity relationships of chalcones on glucose uptake using other Ashitaba chalcones and synthetic chalcones. As a result, 4HD showed a lowering effect of blood glucose levels of diabetic mice, probably due to the enhancement of glucose uptake. Thus, it is suggested that 4HD exert a hypoglycemic action via an insulin-independent pathway. In the structure-activity relationship, both 4'methoxy group and 3'-large substituted group, such as prenyl, geranyl, farnesyl and benzyl of A ring were considered to be essential for glucose uptake promoting activity.
... Koidz. lowered blood sugar by demonstrating insulin-like activity with preventive effects of (4HD) on the development of diabetes in genetically diabetic KK-A y mice (Enoki et al., 2007;Enoki et al., 2010). ...
... In vivo Chalcone 4HD: ↓blood sugar level No effects on secretion of insulin diet containing 0.15% chalcone 4HD (Enoki et al., 2010) Five derivatives from isoliquiritigenin (ISL)/natural from Glycyrrhiza glabra L ...
... Koidz. lowered blood sugar by demonstrating insulin-like activity with preventive effects of (4HD) on the development of diabetes in genetically diabetic KK-A y mice (Enoki et al., 2007;Enoki et al., 2010). ...
... In vivo Chalcone 4HD: ↓blood sugar level No effects on secretion of insulin diet containing 0.15% chalcone 4HD (Enoki et al., 2010) Five derivatives from isoliquiritigenin (ISL)/natural from Glycyrrhiza glabra L ...
... Koidz. lowered blood sugar by demonstrating insulin-like activity with preventive effects of (4HD) on the development of diabetes in genetically diabetic KK-A y mice (Enoki et al., 2007;Enoki et al., 2010). ...
... In vivo Chalcone 4HD: ↓blood sugar level No effects on secretion of insulin diet containing 0.15% chalcone 4HD (Enoki et al., 2010) Five derivatives from isoliquiritigenin (ISL)/natural from Glycyrrhiza glabra L ...
Chalcones are amongst the leading bioactive flavonoids with a therapeutic potential implicated to an array of bioactivities investigated by a series of preclinical and clinical studies. In this article, different scientific databases were searched to retrieve studies depicting the biological activities of chalcones and their derivatives. This review comprehensively describes preclinical studies on chalcones and their derivatives describing their immense significance as antidiabetic, anticancer, anti-inflammatory, antimicrobial, antioxidant, antiparasitic, psychoactive and neuroprotective agents. Besides, clinical trials revealed their use in the treatment of chronic venous insufficiency, skin conditions and cancer. Bioavailability studies on chalcones and derivatives indicate possible hindrance and improvement in relation to its nutraceutical and pharmaceutical applications. Multifaceted and complex underlying mechanisms of chalcone actions demonstrated their ability to modulate a number of cancer cell lines, to inhibit a number of pathological microorganisms and parasites and to control a number of signaling molecules and cascades related to disease modification. Clinical studies on chalcones revealed general absence of adverse effects besides reducing the clinical signs and symptoms with decent bioavailability. Further studies are needed to elucidate their structure-activity, toxicity concerns, cellular basis of mode of action and interactions with other molecules.
Angelica keiskei (Ashitaba in Japanese), a traditional herb in Japan, contains abundant prenylated chalcones. It has been reported that the chalcones from A. keiskei showed such bioactivities as anti-bacterial, anti-cancer and anti-diabetic effects. Xanthoangelol, 4-hydroxyderricin and six new chalcones were isolated in this study from an ethanol extract of A. keiskei by octadecyl silyl (ODS) and silica gel chromatography, and identified by 1D- and 2D-nuclear magnetic resonance (NMR) and high-resolution mass spectrometric analyses. The chalcones from A. keiskei markedly increased the expression of the adiponectin gene and the production of adiponectin in 3T3-L1 adipocytes. These results suggest that the chalcones from A. keiskei might be useful for preventing the metabolic syndrome.
Angelica keiskei is a traditional herb peculiar to Japan and abundantly contains vitamins, dietary fiber and such polyphenols as chalcone. We investigated in the present study the effect of A. keiskei on insulin resistance and hypertriglyceridemia in fructose-drinking rats as a model for the metabolic syndrome. Male Wistar rats were given a 15% fructose solution as drinking water for 11 weeks. Fructose significantly increased the levels of serum insulin and triglyceride (TG) compared with the control level. Treatment with an ethanol extract of A. keiskei (AE) significantly reduced the levels of blood glucose (-16.5%), serum insulin (-47.3%), HOMA-R (-56.4%) and TG (-24.2%). A hepatic gene analysis showed that fructose reduced the expression of the genes related to fatty acid β-oxidation and high-density lipoprotein (HDL) production. Treatment with AE enhanced the expression of the acyl-CoA oxidase 1 (ACO1), medium-chain acyl-CoA dehydrogenase (MCAD), ATP-binding membrane cassette transporter A1 (ABCA1) and apolipoprotein A1 (Apo-A1) genes. These results suggest that AE improved the insulin resistance and hypertriglyceridemia of the fructose-drinking rats.
Changes in human behaviour and lifestyle over the last century have resulted in a dramatic increase in the incidence of diabetes worldwide. The epidemic is chiefly of type 2 diabetes and also the associated conditions known as 'diabesity' and 'metabolic syndrome'. In conjunction with genetic susceptibility, particularly in certain ethnic groups, type 2 diabetes is brought on by environmental and behavioural factors such as a sedentary lifestyle, overly rich nutrition and obesity. The prevention of diabetes and control of its micro- and macrovascular complications will require an integrated, international approach if we are to see significant reduction in the huge premature morbidity and mortality it causes.
Adiponectin is an adipokine that is specifically and abundantly expressed in adipose tissue and directly sensitizes the body to insulin. Hypoadiponectinemia, caused by interactions of genetic factors such as SNPs in the Adiponectin gene and environmental factors causing obesity, appears to play an important causal role in insulin resistance, type 2 diabetes, and the metabolic syndrome, which are linked to obesity. The adiponectin receptors, AdipoR1 and AdipoR2, which mediate the antidiabetic metabolic actions of adiponectin, have been cloned and are downregulated in obesity-linked insulin resistance. Upregulation of adiponectin is a partial cause of the insulin-sensitizing and antidiabetic actions of thiazolidinediones. Therefore, adiponectin and adiponectin receptors represent potential versatile therapeutic targets to combat obesity-linked diseases characterized by insulin resistance. This Review describes the pathophysiology of adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome.
A new chalcone, xanthoangelol was isolated from the roots of Angelica keiskei KOIDZUMI (Umbelliferae), and was elucidated as 2', 4', 4-trihydroxy-3'-[(E)-3, 7-dimethyl-2, 6-octadienyl] chalcone.
Two chalcone derivatives, xanthoangelol (1) and 4-hydroxyderricin (II) isolated from Angelica keiskei Koidzumi, inhibited pig gastric H+, K(+)-ATPase with IC50 values of 1.8 and 3.3 microM, respectively. The inhibition by I or II was competitive with respect to ATP and was non-competitive with respect to K+ I and II also inhibited K+, stimulated p-nitrophenyl phosphatase, with IC50 values of 1.3 and 3.5 microM, respectively. Proton transport in-vitro was inhibited by I or II, in a dose-dependent manner, 1 at 100 mg kg-1, i.p. significantly inhibited acid secretion and the formation of stress-induced gastric lesions. These results suggest that the antisecretory effect of 1 is due to the inhibition of gastric H+, K(+)-ATPase.
The inhibitory activity of angiotensin I-converting enzyme (ACE) was extracted with 80% ethanol from the leaves of Ashitaba (Angelica keiskei). The present ACE inhibitor was fractionated and separated with various chromatographies. The antihypertensive effects of the sample (G fraction) from Ashitaba on spontaneously hypertensive rats (SHR) were observed by long-term administration for 10 wk. Another sample (S fraction) from Ashitaba also had antihypertensive effects after a single intravenous administration to SHR. The sample was further purified by using several chromatographies. The ACE inhibitor fraction was characterized as follows: no significant absorbance, a zwitterion, a water-soluble substance and a positive ninhydrin reaction. According to a mass spectrum analysis, the molecular weight of the ACE inhibitor was determined to be 303 and Na-salt ions of carboxyl groups were detected. The ACE inhibitor from Ashitaba contained in the anti-hypertensive fraction was speculated to be very similar to authentic nicotianamine based on a comparative study of inhibitory activity, mass spectrum analysis and thin-layer chromatographies.
The epidemic of type 2 diabetes and impaired glucose tolerance is one of the main causes of morbidity and mortality worldwide. In both disorders, tissues such as muscle, fat and liver become less responsive or resistant to insulin. This state is also linked to other common health problems, such as obesity, polycystic ovarian disease, hyperlipidaemia, hypertension and atherosclerosis. The pathophysiology of insulin resistance involves a complex network of signalling pathways, activated by the insulin receptor, which regulates intermediary metabolism and its organization in cells. But recent studies have shown that numerous other hormones and signalling events attenuate insulin action, and are important in type 2 diabetes.
The roots of Angelica keiskei Koizumi have traditionally been used as a health food, with diuretic, laxative, analeptic and galactagogic effects. It has been thought that the roots and leaves of A. keiskei have preventive effects against coronary heart disease, hypertension and cancer. In the present study, we examined the antitumor and antimetastatic activities of various fractions isolated from a 50% ethanol extract of A. keiskei roots. The ethyl acetate-soluble fraction of the 50% ethanol extract inhibited tumor growth in LLC-bearing mice at a daily dose of 100 mg/kg prolonged survival time and inhibited metastasis to the lung after surgical removal of primary tumors. Two active substances were isolated from fractions 1 and 2: compound 1 was identified as xanthoangelol based on the data of the (1)H- and (13)C-NMR spectra. Xanthoangelol inhibited tumor growth in LLC-bearing mice as well as lung metastasis and prolonged survival time in carcinectomized mice at a daily dose of 50 mg per kg. Furthermore, xanthoangelol (50 or 100 mg per kg daily) inhibited liver metastasis and the growth of metastasized tumor cells in the livers of mice with intrasplenically implanted LLC. Xanthoangelol inhibited DNA synthesis in LLC cells at concentrations of 10 and 100 microM, but it had no effect on DNA synthesis in HUVECs or on the adherence of LLC cells to HUVECs. Xanthoangelol inhibited tumor-induced neovascularization (in vivo) at doses of 10 and 20 mg per kg, and it inhibited the Matrigel-induced formation of capillary-like tubes by HUVECs at concentrations of 1-100 microM. Furthermore, xanthoangelol inhibited the binding of VEGF to HUVECs at concentrations of 1-100 microM. These results indicate that the antitumor and/or antimetastatic activities of xanthoangelol may be due to inhibition of DNA synthesis in LLC cells and of tumor-induced neovascularization through inhibition of the formation of capillary-like tubes by vascular endothelial cells and inhibition of the binding of VEGF to vascular endothelial cells.
From an ethyl acetate-soluble fraction of the exudate obtained from the stems of Angelica keiskei (Umbelliferae), 17 compounds, viz. five chalcones (1-5), seven coumarins (6-12), three flavanones (13-15), one diacetylene (16), and one 5-alkylresorcinol (17), were isolated. These compounds were evaluated with respect to their inhibitory effects on the induction of Epstein-Barr virus early antigen (EBV-EA) by 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells, which is known to be a primary screening test for antitumor-promoters. With the exception of three compounds (10, 16, and 17), all other compounds tested showed potent inhibitory effects on EBV-EA induction (92-100% inhibition at 1x10(3)mol ratio/TPA). In addition, upon evaluation of these compounds for the inhibitory effects against activation of (+/-)-(E)-methyl-2-[(E)-hydroxy-imino]-5-nitro-6-methoxy-3-hexemide (NOR 1), a nitric oxide (NO) donor, as a primary screening test for antitumor-initiators, two chalcones (2 and 3) and six coumarins (6-11) exhibited potent inhibitory effects.
The roots of Angelica keiskei Koizumi (Umbelliferae) have traditionally been used as a health food considered to have diuretic, laxative, analeptic and lactagogue effects. Recently, it has been thought that the roots and herbs of A. keiskei have preventive effects against coronary heart disease, hypertension and cancer. It has been reported that chalcone derivatives, such as xanthoangelol and 4-hydroxyderricin, are isolated as main components from this root. Recently, we reported that the 50 % ethanol extract, the ethyl acetate-soluble fraction and the isolated xanthoangelol, inhibited tumor growth and metastasis to the lung in Lewis lung carcinoma (LLC)-bearing mice. In the present study, we examined the effects of 4-hydroxyderricin on tumor growth and metastasis to the lung or liver in subcutaneous or intrasplenic LLC-implanted C57BL/6J female mice. 4-Hydroxyderricin at a dose of 50 mg/kg x 2/day orally inhibited the tumor growth in subcutaneous LLC-implanted mice and inhibited the lung metastasis and prolonged the survival time in mice after the removal of subcutaneous tumors by surgical operation. Doxorubicin (5 mg/kg x 2/week, i. p.) inhibited the tumor growth and metastasis to the lung, but it shortened the survival time and reduced the survival rate compared to those in 4-hydroxyderricin-treated mice. 4-Hydroxyderricin inhibited DNA synthesis in LLC cells at a concentration of 100 microM, but it had no effect on the DNA synthesis in human umbilical vein endothelial cells (HUVECs) or on the adherence of LLC cells to HUVECs. 4-Hydroxyderricin inhibited Matrigel-induced formation of capillary-like tubes by HUVECs at concentrations of 10 to 100 microM. The weights of the spleen and thymus in mice with subcutaneously implanted LLC were maintained close to those of normal mice by orally administered 4-hydroxyderricin. In addition, 4-hydroxyderricin (50 mg/kg x 2/day) inhibited the reduction of the numbers of lymphocytes, CD4+, CD8+ and natural killer (NK)-T cells in the spleen of tumor-removed mice. Doxorubicin reduced the numbers of lymphocytes, CD4+, CD8+ and NK cells compared to those in LLC-removed mice. These results suggest that the antitumor and antimetastatic activities of 4-hydroxyderricin may be modulated by the immune system and the inhibition of angiogenesis.
1. Previously, we found that Angelica keiskei extract (ethyl acetate extract from the yellow liquid of stems) elevated serum high-density lipoprotein (HDL) levels and reduced liver triglyceride content in stroke-prone spontaneously hypertensive rats (SHRSP). To identify the active substance in A. keiskei extract, we examined the effect of 4-hydroxyderricin, a characteristic chalcone isolated from the yellow liquid of stems, on blood pressure and lipid metabolism in SHRSP.
2. Six-week-old male SHRSP were fed diets containing 0.07% 4-hydroxyderricin for 7 weeks with free access to the diet and water. Elevation of systolic blood pressure was significantly suppressed after 7 weeks treatment. Serum very low-density lipoprotein (VLDL) levels were significantly reduced, without any effect on HDL levels, and were associated with a significant decrease in the serum concentration of free fatty acids.
3. In the liver, significant decreases in relative liver weight and triglyceride content were found after treatment with 4-hydroxyderricin for 7 weeks.
4. An investigation of hepatic mRNA expression of proteins involved in lipid metabolism indicated that a significant decrease in microsomal triglyceride transferprotein may be responsible for the decrease in serum VLDL levels and that significant decreases in adipocyte determination and differentiation factor 1 and fatty acid synthase may be responsible for the decrease in hepatic triglyceride content.
5. In conclusion, dietary 4-hydroxyderricin produces suppression of the elevation of systolic blood pressure, reduction of serum VLDL levels and a decrease in hepatic triglyceride content in SHRSP.
Diabetes mellitus is a chronic disease that is characterized by hyperglycemia caused by insufficient insulin action. We have explored the edible ingredients from folk medicines in Japan that contain substances complementing insulin action, such as the induction of adipocyte differentiation and the enhancement of glucose uptake. We eventually found that the ethanol extract from a Japanese herb "Ashitaba", Angelica keiskei, contained two major chalcones of 4-hydroxyderricin (4-HD) and xanthoangelol that showed strong insulin-like activities via a pathway independent of the peroxisome proliferator-activated receptor-gamma activation. The 4-HD especially showed the preventive effects on the progression of diabetes in genetically diabetic KK-Ay mice.