Johji Yamahara

Salacinol, potent antidiabetic principle with unique thiosugar sulfonium sulfate structure from the ayurvedic traditional medicine Salacia reticulata in Sri Lanka and India

A most potent natural α-glucosidase inhibitor named salacinol has been isolated from an antidiabetic Ayurvedic traditional medicine, Salacia reticulatawight, through bioassay-guided separation. The stereostructure of salacinol was determined on the basis of chemical and physicochemical evidence, which included the X-ray crystallographic analysis, and the molecular conformation showed the unique spiro-like configuration of the inner salt comprised of 1-deoxy-4-thioarabinofuranosyl cation and 1′-deoxyerythrosyl-3′-sulfate anion.

The inhibitory effects of mangiferin, a naturally occurring glucosylxanthone, in bowel carcinogenesis of male F344 rats

Mangiferin, 1,3,6,7-tetrahydroxyxanthone-C2-beta-D-glucoside, is one of xanthone derivatives and C-glucosylxanthones, is widely distributed in higher plants and is one of constituents of folk medicines. Recent studies showed that mangiferin has a potential as an anti-oxidant and an anti-viral agent. In this study, we examined the effects of mangiferin in rat colon carcinogenesis induced by chemical carcinogen, azoxymethane (AOM). We performed two experiments: a short-term assay to investigate the effects of mangiferin on the development of preneoplastic lesions by AOM, aberrant crypt foci (ACF), and the following long-term assay for the influence of mangiferin on tumorigenesis induced by AOM. In the short-term assay, 0.1% mangiferin in a diet significantly inhibited the ACF development in rats treated with AOM compared to rats treated with AOM alone (64.6+/-22.0 vs. 108.3+/-43.0). In the long-term assay, the group treated with 0.1% mangiferin in initiation phase of the experimental protocol had significantly lower incidence and multiplicity of intestinal neoplasms induced by AOM (47.3 and 41.8% reductions of the group treated with AOM alone for incidence and multiplicity, respectively). In addition, the cell proliferation in colonic mucosa was reduced in rats treated with mangiferin (65-85% reductions of the group treated with AOM alone). These results suggest that mangiferin has potential as a naturally-occurring chemopreventive agent.

Inhibitory effects of plumbagin and juglone on azoxymethane-induced intestinal carcinogenesis in rats

The effects of two naphthoquinones, juglone and plumbagin, and an isocoumarin, hydrangenol, on intestinal carcinogenesis in rats were examined by dietary exposure during the initiation phase. Starting at 5 weeks of age, male F344 rats were fed the diets containing either of the test chemicals at a concentration of 200 ppm or the control diet without the compounds. At 6 weeks of age, all animals were treated with s.c. injections of azoxymethane (AOM) (15 mg/kg body weight, once weekly for 3 weeks) or saline alone. Animals fed experimental diets were changed to the control diet 1 week after the last carcinogen treatment. Animals given plumbagin together with the carcinogen had a lower incidence (41%) and smaller multiplicity (0.48 +/- 0.62) of tumors in the entire intestine compared with those exposed to carcinogen alone (68% and 1.04 +/- 0.62) (P < 0.05 and < 0.01, respectively). The incidence and multiplicity of tumors in the small intestine (7% and 0.07 +/- 0.25) and the multiplicity of tumors in the entire intestine (0.60 +/- 0.76) of animals treated with juglone and the carcinogen were significantly less than those of animals treated with carcinogen alone (P < 0.05 in each). Hydrangenol tended to decrease the incidence and the multiplicity of tumors in the entire intestine induced by AOM, but the effect was not statistically significant. The present data suggest that the naphthoquinones, juglone and plumbagin, could be promising chemopreventive agents for human intestinal neoplasia.

Pomegranate flower improves cardiac lipid metabolism in a diabetic rat model: role of lowering circulating lipids.

1 Excess triglyceride (TG) accumulation and increased fatty acid (FA) oxidation in the diabetic heart contribute to cardiac dysfunction. Punica granatum flower (PGF) is a traditional antidiabetic medicine. Here, we investigated the effects and mechanisms of action of PGF extract on abnormal cardiac lipid metabolism both in vivo and in vitro. 2 Long‐term oral administration of PGF extract (500 mg kg−1) reduced cardiac TG content, accompanied by a decrease in plasma levels of TG and total cholesterol in Zucker diabetic fatty (ZDF) rats, indicating improvement by PGF extract of abnormal cardiac TG accumulation and hyperlipidemia in this diabetic model. 3 Treatment of ZDF rats with PGF extract lowered plasma FA levels. Furthermore, the treatment suppressed cardiac overexpression of mRNAs encoding for FA transport protein, peroxisome proliferator‐activated receptor (PPAR)‐α, carnitine palmitoyltransferase‐1, acyl‐CoA oxidase and 5′‐AMP‐activated protein kinase α2, and restored downregulated cardiac acetyl‐CoA carboxylase mRNA expression in ZDF rats, whereas it showed little effect in Zucker lean rats. The results suggest that PGF extract inhibits increased cardiac FA uptake and oxidation in the diabetic condition. 4 PGF extract and its component oleanolic acid enhanced PPAR‐α luciferase reporter gene activity in human embryonic kidney 293 cells, and this effect was completely suppressed by a selective PPAR‐α antagonist MK‐886, consistent with the presence of PPAR‐α activator activity in the extract and this component. 5 Our findings suggest that PGF extract improves abnormal cardiac lipid metabolism in ZDF rats by activating PPAR‐α and thereby lowering circulating lipid and inhibiting its cardiac uptake.

The anti-ulcer effect in rats of ginger constituents

The effects of ginger, a pungent stomachic natural medicine, on HCl/ethanol-induced gastric lesions in rats, were examined. The orally administered acetone extract at 1000 mg/kg and zingiberene, the main terpenoid from acetone extract, at 100 mg/kg significantly inhibited gastric lesions by 97.5 and 53.6%, respectively. 6-Gingerol, the pungent principle, at 100 mg/kg significantly inhibited gastric lesions by 54.5%. These results suggest that zingiberene, the terpenoid and 6-gingerol are important constituents in stomachic medications containing ginger.

Pomegranate flower: a unique traditional antidiabetic medicine with dual PPAR-α/-γ activator properties

PPARs are transcription factors belonging to the superfamily of nuclear receptors. PPAR‐α is involved in the regulation of fatty acid (FA) uptake and oxidation, inflammation and vascular function, while PPAR‐γ participates in FA uptake and storage, glucose homeostasis and inflammation. The PPARs are thus major regulators of lipid and glucose metabolism. Synthetic PPAR‐α or PPAR‐γ agonists have been widely used in the treatment of dyslipidaemia, hyperglycaemia and their complications. However, they are associated with an incidence of adverse events. Given the favourable metabolic effects of both PPAR‐α and PPAR‐γ activators, as well as their potential to modulate vascular disease, combined PPAR‐α/‐γ activation has recently emerged as a promising concept, leading to the development of mixed PPAR‐α/‐γ activators. However, some major side effects associated with the synthetic dual activators have been reported. It is unclear whether this is a specific effect of the particular synthetic compounds or a class effect. To date, a medication that may combine the beneficial metabolic effects of PPAR‐α and PPAR‐γ activation with fewer undesirable side effects has not been successfully developed. Pomegranate plant parts are used traditionally for the treatment of various disorders. However, only pomegranate flower has been prescribed in Unani and Ayurvedic medicines for the treatment of diabetes. This review provides a new understanding of the dual PPAR‐α/‐γ activator properties of pomegranate flower in the potential treatment of diabetes and its associated complications.

Salacia root, a unique Ayurvedic medicine, meets multiple targets in diabetes and obesity.

In many traditional schools of medicine it is claimed that a balanced modulation of several targets can provide a superior therapeutic effect and decrease in side effect profile compared to a single action from a single selective ligand, especially in the treatment of certain chronic and complex diseases, such as diabetes and obesity. Diabetes and obesity have a multi-factorial basis involving both genetic and environmental risk factors. A wide array of medicinal plants and their active constituents play a role in the prevention and treatment of diabetes. Salacia roots have been used in Ayurvedic medicine for diabetes and obesity since antiquity, and have been extensively consumed in Japan, the United States and other countries as a food supplement for the prevention of obesity and diabetes. Recent pharmacological studies have demonstrated that Salacia roots modulate multiple targets: peroxisome proliferator-activated receptor-alpha-mediated lipogenic gene transcription, angiotensin II/angiotensin II type 1 receptor, alpha-glucosidase, aldose reductase and pancreatic lipase. These multi-target actions may mainly contribute to Salacia root-induced improvement of type 2 diabetes and obesity-associated hyperglycemia, dyslipidemia and related cardiovascular complications seen in humans and rodents. The results of bioassay-guided identification indicate that mangiferin, salacinol, kotalanol and kotalagenin 16-acetate are at least in part responsible for these multi-target regulatory activities of Salacia roots. The evidence suggests that this unique traditional medicine fulfills a multiple-target strategy in the prevention and treatment of diabetes and obesity. Although toxicological studies have suggested minimal adverse effects of the herbal medicine in rodents, a clinical trial is crucial to further confirm the safety of Salacia roots. In addition, further mechanistic studies are necessary in order to allow a better understanding of how use of Salacia root may interact with other therapeutic interventions.

Pomegranate flower extract diminishes cardiac fibrosis in zucker diabetic fatty rats : Modulation of cardiac endothelin-1 and nuclear factor-kappaB pathways

The diabetic heart shows increased fibrosis, which impairs cardiac function. Endothelin (ET)-1 and nuclear factor-kappaB (NF-κB) interactively regulate fibroblast growth. We have recently demonstrated that Punica granatum flower (PGF), a Unani anti-diabetic medicine, is a dual activator of peroxisome proliferator-activated receptor (PPAR)-α and -γ, and improves hyperglycemia, hyperlipidemia, and fatty heart in Zucker diabetic fatty (ZDF) rat, a genetic animal model of type 2 diabetes and obesity. Here, we demonstrated that six-week treatment with PGF extract (500 mg/kg, p.o.) in Zucker diabetic fatty rats reduced the ratios of van Gieson-stained interstitial collagen deposit area to total left ventricular area and perivascular collagen deposit areas to coronary artery media area in the heart. This was accompanied by suppression of overexpressed cardiac fibronectin and collagen I and III mRNAs. Punica granatum flower extract reduced the up-regulated cardiac mRNA expression of ET-1, ETA, inhibitor-κBβ and c-jun, and normalized the down-regulated mRNA expression of inhibitor-κBα in Zucker diabetic fatty rats. In vitro, Punica granatum flower extract and its components oleanolic acid, ursolic acid, and gallic acid inhibited lipopolysaccharide-induced NF-κB activation in macrophages. Our findings indicate that Punica granatum flower extract diminishes cardiac fibrosis in Zucker diabetic fatty rats, at least in part, by modulating cardiac ET-1 and NF-κB signaling.

Pomegranate flower ameliorates fatty liver in an animal model of type 2 diabetes and obesity

AIMS OF THE STUDY Fatty liver is the most common cause of abnormal liver function tests. We investigated the effect and its underlying mechanism of pomegranate flower (PGF), a traditional antidiabetic medicine, on fatty liver. MATERIALS AND METHODS At the endpoint of treatment of male Zucker diabetic fatty (ZDF) rats with PGF extract (500 mg/kg, p.o. x 6 weeks), liver weight index, hepatic lipid contents (enzymatic colorimetric methods) and droplet accumulation (Oil Red O staining) were determined. Gene profiles (RT-PCR) were analyzed in the liver of ZDF rats and in human liver-derived HepG2 cell line. RESULTS PGF-treated ZDF rats showed reduced ratio of liver weight to tibia length, hepatic triglyceride contents and lipid droplets. These effects were accompanied by enhanced hepatic gene expression of peroxisome proliferator-activated receptor (PPAR)-alpha, carnitine palmitoyltransferase-1 and acyl-CoA oxidase (ACO), and reduced stearoyl-CoA desaturase-1. In contrast, PGF showed minimal effects on expression of genes responsible for synthesis, hydrolysis or uptake of fatty acid and triglycerides. PGF treatment also increased PPAR-alpha and ACO mRNA levels in HepG2 cells. CONCLUSION Our findings suggest that this Unani medicine ameliorates diabetes and obesity-associated fatty liver, at least in part, by activating hepatic expression of genes responsible for fatty acid oxidation.

Inhibitory Effects of Dietary Protocatechuic Acid and Costunolide on 7,12-Dimethylbenz[a ]anthracene-induced Hamster Cheek Pouch Carcinogenesis

The modifying effects of dietary exposure to two natural products, protocatechuic acid (PCA) and Costunolide during the development of neoplasms in oral carcinogenesis initiated with 7,12‐dimethyl‐benz[a]anthracene (DMBA) were investigated in male Syrian golden hamsters. All hamsters except those in the test chemical alone and control groups received DMBA (0.5%) in mineral oil to the right buccal pouch 3 times per week for 4 or 6 weeks. At 13 weeks of age, the groups exposed to DMBA were fed diet containing PCA or Costunolide at a dose of 0.2 g/kg diet (200 ppm) for 17 weeks. The other groups consisted of hamsters given mineral oil alone for 6 weeks, or given 200 ppm PCA or Costunolide alone, or untreated. All animals were necropsied at the termination of the experiment (week 24). PCA or costunolide significantly decreased the tumor burden (P<0.001‐P<0.05) and the extent of dysplastic areas (%) (P<0.001‐P<0.05). PCA significantly decreased the mean number of AgNORs/nucleus (P<0.05). The BrdUrd‐labeling index was reduced by dietary administration of test compounds, though not significantly. These results suggest that PCA and costunolide inhibited hamster buccal pouch carcinogenesis and such inhibition may be related to suppression of cell proliferation in the buccal mucosa. It was also found that telomerase activity expressed in neoplastic and preneoplastic lesions of hamster buccal pouch epithelium after DMBA treatment correlated with the histopathological degree of malignancy.