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.

Potential applications of Chinese herbal medicines with hemostatic properties.

Various herbal medicines with hemostatic properties have been applied for centuries to accelerate hemostasis and control bleeding. However, the mechanisms of action and active constituents remain unknown. This report provides an overview of current clinical hemostatic agents and their disadvantages, then focuses on the clinical value of Chinese herbal medicines with unique hemostatic features that modern medicines lack. A comprehensive review of hemostatic agents derived from Chinese herbal medicines and their potential medical applications is also presented.

Ashitaba (Angelica Keiskei) Exudate Prevents Increases in Plasminogen Activator Inhibitor-1 Induced by Obesity in Tsumura Suzuki Obese Diabetic Mice.

Angelica keiskei koidzumi (ashitaba) is consumed as a traditional folk medicine and health food in Japan. Ashitaba extract contains abundant flavonoids containing chalcones. Plasminogen activator inhibitor-1 (PAI-1) is the primary physiological inhibitor of tissue plasminogen activator. Excessive amounts of PAI-1 in plasma disrupt the fibrinolytic balance and promote a prothrombotic state with which thrombosis and cardiovascular diseases are associated. In the present study, we investigated the effects of ashitaba yellow exudate (AE) on enhanced PAI-1 levels in Tsumura Suzuki obese diabetic (TSOD) mice. AE significantly decreased food efficiency and plasma PAI-1 in TSOD mice but did not affect lean control Tsumura Suzuki nonobese (TSNO) mice. AE also decreased some parameters in the plasma, such as glucose, insulin, tumor necrosis factor alpha (TNF-α) and gains in body weight, subcutaneous, mesenteric fat weight in TSOD mice but had little effect on these parameters in TSNO mice. Levels of adipose PAI-1 were significantly higher in TSOD than in TSNO mice. Major sources of plasma PAI-1 are thought to be adipose tissue and liver. AE significantly suppressed PAI-1 protein levels in the livers of both TSOD and TSNO mice. These results suggest that AE decreased plasma PAI-1 levels by suppressing both the adipose tissue retention of PAI-1 protein and liver PAI-1 production in TSOD mice. Supplementing the diet with AE might help to prevent thrombotic diseases or alleviate the risk of thrombotic diseases as well as to suppress metabolic state in obese individuals.

Positions of Hydroxyl Groups in Chrysin are Critical for Inhibiting Plasminogen Activator Inhibitor-1 Release from Human Umbilical Vein Endothelial Cells.

Chrysin suppresses the TNFα-induced increase in the secretion of plasma plasminogen activator inhibitor 1 (PAl-1), a risk factor for thrombotic diseases, from human umbilical vein endothelial cells (HUVECs). The present study aimed to determine the association between the location of the hydroxyl groups in chrysin.to levels of-PAI-1. in the medium of HUVEC stimulated with TNFα. We cultured HUVEC for 3 h in medium containing chrysin or various flavonoids and then stimulated them with TNFα (10 ng/mL) for 12 h. Levels of PAI-1 antigen measured using ELISA showed that chrysin significantly inhibited the PAl- I increase with an IC50 of 15.6 µM. The flavones, galangin, baicalein, 5-hydroxyflavone, 6-hydroxyflavone, 7-hydroxyflavone and quercetin did not significantly inhibit the PAI- increase. Apigenin and luteolin were cytotoxic and thus their ability to inhibit PAI production could not be evaluated. Chrysin also inhibited PAI- mRNA expression whereas the other compounds did not. Hydroxyl groups located in the A-5 and A-7 positions were essential for the inhibitoryactivity, which along with cytotoxicity, was significantly influenced by adding a third hydroxyl group.

Screening for hemostatic activities of popular Chinese medicinal herbs in vitro.

AIMS: This study aimed to identify new hemostyptics by assessing the coagulation enhancing activity of 114 Chinese herbal extracts in vitro. METHODS: Herbs were boiled in water for 30 min, filtered and then lyophilized filtrates (10 mg/mL) were dissolved in water. Coagulation was assayed as prothrombin time (PT). Plasma diluted in saline was incubated with each extract for 5 min and then PT reagent was added, followed by CaCl2 solution and the time taken to form clots was measured. Extracts that decreased coagulation time were regarded as containing active compounds. The abilities of extracts to activate Factor XII were assessed and the activated form of factor XII (XIIa) was resolved by SDS-PAGE and visualized by silver staining. RESULTS: Coagulation time was obviously shortened by extracts of Alpinia Rhizome, Areca, Artemisia Leaf, Cassia Bark, Danshen Root, Ephedra Herb, Epimedium Herb, Forsythia Fruit, Great Burdock Achene, Moutan Bark, Perilla Herb, Red Paeony Root, Schizonepeta Spike, Senticosus Rhizome, Sweet Annie, Uncaria Thorn and Zanthoxylum Peel. Factor XII was obviously activated by extracts of Artemisia Leaf and Great Burdock Achene, and slightly by Perilla herb. CONCLUSION: Some popular Chinese medicinal herbs have potential as hemostatic agents and could thus be develope as new strategies for the treatment and prevention of bleeding.

Xanthoangelols isolated from Angelica keiskei inhibit inflammatory-induced plasminogen activator inhibitor 1 (PAI-1) production.

The folk medicine Angelica keiskei (Ashitaba) exhibits antitumor, antioxidant and antidiabetic activities and it has recently attracted attention as a health food. Ashitaba is thought to have antithrombotic properties, but this has not yet been scientifically proven. The elevation of plasma plasminogen activator inhibitor 1 (PAI-1), an inhibitor of fibrinolysis results in a predisposition to the risk of thrombosis. The present study showed that Ashitaba exudates injected intraperitoneally and orally administered over long-term suppressed the lipopolysaccharide (LPS) induced PAI-1 increase in mouse plasma. We also found that xanthoangelol, xanthoangelols B and D, the components of Ashitaba exudates, significantly inhibited TNFα-induced PAI-1 production from human umbilical vein endothelial cells (HUVECs). These findings suggest that Ashitaba can decrease elevated PAI-1 production, and that daily consumption of Ashitaba product might maintain anticoagulant status by inhibiting elevations in PAI-1 under inflammatory conditions.

Experimental study on the hemostatc activity of Pollen Typhae: a traditional folk medicine used by external and oral application.

Pollen Typhae is the traditional Chinese herbal medicine widely used to treat the hemorrhagic diseases both by external and oral application. The present study examines the hemostatic properties and its components of Pollen Typhae. Pollen extract significantly reduced prothrombin time (PT), activated partial prothrombin time (APTT) and recalcification time. Pollen extract directly activated factor XII in the coagulation cascade. Acidic polysaccharide in the pollen that adsorbed to the diethylaminoethyl (DEAE) column was the causative agent of factor XII activation. These results suggested that an electronegative charge attributed to an acidic polysaccharide in the pollen extract contributed to the hemostatic activity. We then examined the hemostatic activity of administered pollen extract in the mouse tail bleeding model. Tail bleeding was significantly decreased after oral administration of the pollen extract, whereas the acidic polysaccharide fraction did not affect the duration of tail bleeding. These results suggest that the oral anticoagulant effect of Pollen Typhae is attributed to compounds other than acidic polysaccharides. We concluded that the activation of the intrinsic coagulation pathway by the acidic polysaccharide contributes to the external hemostatic property of Pollen Typhae, and the action of components such as flavonoids that possess anticoagulant activity are causative agent when orally administered.

CLOCK regulates the circadian rhythm of kaolin-induced writhing behavior in mice.

Kaolin-induced writhing reaction is a simple and convenient model of bradykinin-induced pain for assessment of analgesic actions. In this study, we demonstrated that the number of kaolin-induced writhing reaction was fluctuated in a circadian manner that peaked at the end of the resting period (dusk) and reduced during the active (dark) period in mice. Circadian rhythm of the writhing intensity was completely phase-shifted by a time-imposed restricted feeding. On the other hand, 24 h of food deprivation did not affect the writhing intensity, suggesting that the endogenous clock that can be entrained to the scheduled feeding is responsible to the circadian intensity of the writhing reaction. Day/night fluctuation of the writhing intensity was completely abolished and the writhing reaction was significantly reduced in the circadian clock deficient Clock-mutant mice, although the kaolin-induced bradykinin production and blood pressure suppression were not affected in these mutant mice. Our present study suggested that the circadian variation of the pain sensitivity is governed by the food-entrainable endogenous clock and by the circadian clock molecules in mammals.