Beneficial effects of oral supplementation with ferulic acid, a plant phenolic compound, on the human skin barrier in healthy men.

Ferulic acid (FA) is a phytochemical compound with various physiologic functions. To clarify the effect of FA intake on skin barrier function (SBF), we conducted a placebo-controlled double-blind pilot trial. Sixteen healthy subjects were divided into 2 groups (n = 8) and ingested capsules containing either FA (200 mg) or placebo daily for 2 weeks. Two measures of SBF, transepidermal water loss and stratum corneum hydration, were assessed before and 2 weeks after the start of the study. Autonomic nervous activity, which is suggested to be related to SBF, was also measured. Compared with the values obtained before the start of the study, FA intake significantly reduced transepidermal water loss (from 6.1 ± 1.1 to 4.8 ± 1.0 g/m2/h, p = 0.005) and increased stratum corneum hydration (from 30.1 ± 7.6 to 32.3 ± 8.1 a.u., p = 0.027) after 2 weeks. In addition, the amount change in sympathetic nervous activity was significantly reduced after ingesting the FA capsules compared with the placebo capsules (-0.7 ± 1.6 vs. 1.1 ± 1.4, p = 0.035). These findings suggest that FA supplementation decreases sympathetic nervous activity and strengthens SBF in healthy men.

Chlorogenic acid-enriched green coffee bean extract affects arterial stiffness assessed by the cardio-ankle vascular index in healthy men: a pilot study.

The effect of chlorogenic acid-enriched green coffee bean extract (cGCE) intake on arterial stiffness was investigated using the cardio-ankle vascular index (CAVI) as a novel surrogate marker for predicting arteriosclerosis. A placebo-controlled double-blind pilot study was conducted with 16 healthy Japanese men. Subjects were divided into two groups and consumed beverages containing either cGCE or placebo daily for 2 weeks. The CAVI, the primary endpoint of the study, was evaluated at the beginning of the study and 2 weeks later. Endothelium-dependent flow-mediated dilation (FMD) and sympathetic nervous activity (SNA), which are thought to be related to the CAVI, were also measured. The CAVI change was significantly greater in the cGCE group than in the placebo group. In addition, FMD increased and SNA decreased in the cGCE group. These findings suggest that 2-week ingestion of cGCE may improve arterial stiffness as assessed by the CAVI.

Rice bran triterpenoids improve postprandial hyperglycemia in healthy male adults: a randomized, double-blind, placebo-controlled study.

BACKGROUND: Compared to white rice, brown rice induces a lower glycemic response in healthy and diabetic humans. This effect is partly attributed to the higher amounts of water- or oil-soluble bran components and dietary fiber in brown rice. We hypothesized that dietary supplementation with oil-soluble rice bran triterpenoids (RBTs; triterpene alcohol and sterol prepared from rice bran) might reduce the incidence of postprandial hyperglycemia in healthy humans. OBJECTIVE: We examined the acute effects of a single RBT-supplemented meal on the postprandial blood glucose responses of healthy male adults in a double-blind, randomized, placebo-controlled, crossover trial. DESIGN: Nineteen subjects consumed a test meal containing either placebo- or RBT-supplemented olive oil. Blood biomarkers were evaluated in a fasting state and up to 240 min postprandially. RESULTS: Compared to the placebo-supplemented meal, the RBT-supplemented meal significantly suppressed the increase in postprandial blood glucose level. A subclass analysis revealed that RBT-supplemented oil significantly reduced blood glucose increases in subjects with higher postprandial blood glucose elevations. Postprandial increases in blood insulin, glucose-dependent insulinotropic peptide (GIP), and glucagon-like peptide-1 (GLP-1) levels did not differ between the groups. CONCLUSION: These results suggest that RBT consumption improves postprandial hyperglycemia in healthy humans, especially those with higher postprandial glucose increases.

Coffee polyphenol consumption improves postprandial hyperglycemia associated with impaired vascular endothelial function in healthy male adults.

Epidemiological studies indicate that habitual coffee consumption lowers the risk of diabetes and cardiovascular diseases. Postprandial hyperglycemia is a direct and independent risk factor for cardiovascular diseases. We previously demonstrated that coffee polyphenol ingestion increased secretion of Glucagon-like peptide 1 (GLP-1), which has been shown to exhibit anti-diabetic and cardiovascular effects. We hypothesized coffee polyphenol consumption may improve postprandial hyperglycemia and vascular endothelial function by increasing GLP-1 release and/or reducing oxidative stress. To examine this hypothesis, we conducted a randomized, acute, crossover, intervention study in healthy male adults, measuring blood parameters and flow-mediated dilation (FMD) after ingestion of a meal with or without coffee polyphenol extract (CPE). Nineteen subjects consumed a test meal with either a placebo- or CPE-containing beverage. Blood biomarkers and FMD were measured at fasting and up to 180 minutes postprandially. The CPE beverage led to a significantly lower peak postprandial increase in blood glucose and diacron-reactive oxygen metabolite, and significantly higher postprandial FMD than the placebo beverage. Postprandial blood GLP-1 increase tended to be higher after ingestion of the CPE beverage, compared with placebo. Subclass analysis revealed that the CPE beverage significantly improved postprandial blood GLP-1 response and reduced blood glucose increase in the subjects with a lower insulinogenic index. Correlation analysis showed postprandial FMD was negatively associated with blood glucose increase after ingestion of the CPE beverage. In conclusion, these results suggest that coffee polyphenol consumption improves postprandial hyperglycemia and vascular endothelial function, which is associated with increased GLP-1 secretion and decreased oxidative stress in healthy humans.

Hesperidin metabolite hesperetin-7-O-glucuronide, but not hesperetin-3'-O-glucuronide, exerts hypotensive, vasodilatory, and anti-inflammatory activities.

Orally ingested hesperidin (HES) is hydrolyzed into hesperetin in the gastrointestinal tract and conjugated during absorption. Hesperetin conjugates are the main circulating metabolites in human and rat plasma. We previously reported that glucosyl hesperidin (GHES), a water-soluble HES derivative, prevents hypertension via improvement of endothelial dysfunction in spontaneously hypertensive rats (SHRs). Although these hesperetin conjugates seem to be responsible for hypotensive and endothelium-dependent vasodilatory activities of dietary GHES, little is known about the mechanisms of action of these conjugated metabolites. Therefore, the aim of the present study was to investigate the effects of hesperetin-7-O-ß-d-glucuronide (HPT7G) and hesperetin-3'-O-ß-d-glucuronide (HPT3'G), which are the predominant HES metabolites in rat plasma, on blood pressure and endothelial function. Intravenous administration of HPT7G (5 mg kg(-1)) decreased blood pressure in anesthetized SHRs. HPT7G enhanced endothelium-dependent vasodilation in response to acetylcholine, but had no effect on endothelium-independent vasodilation in response to sodium nitroprusside (SNP) in aortas isolated from SHRs. HPT7G decreased hydrogen peroxide-induced intracellular adhesion molecule-1 and monocyte chemoattractant protein-1 mRNA expression in rat aortic endothelial cells. In contrast, HPT3'G had little effect on these parameters. In conclusion, HPT7G exerted hypotensive, vasodilatory and anti-inflammatory activities, similar to hesperetin and these effects are associated, in part, with the activity of GHES and HES to improve hypertension and endothelial dysfunction.

Effects of continuous ingestion of hesperidin and glucosyl hesperidin on vascular gene expression in spontaneously hypertensive rats.

Hesperidin (HES) and glucosyl hesperidin (GHES) have antihypertensive effects. In the present study, to clarify the antihypertensive mechanisms, we compared the effects of continuous ingestion of HES and GHES in spontaneously hypertensive rats (SHRs). HES and GHES ingestion for 8 wk significantly prevented hypertension and suppressed the mRNA expression of NADPH oxidase subunits and thromboxane A2 synthase in SHR aortas. Further, hesperetin, a common metabolite of HES and GHES, reduced thromboxane B2 release from SHR aortas. These findings indicate that continuous ingestion of HES and GHES prevents hypertension via regulating the gene expression related to the modulation of vascular tone.

Glucosyl hesperidin prevents endothelial dysfunction and oxidative stress in spontaneously hypertensive rats.

OBJECTIVE: Glucosyl hesperidin (G-hesperidin), a water-soluble hesperidin derivative, has antihypertensive effects. A detailed understanding of the mechanism of the blood pressure-lowering effect, however, remains obscure. The aim of this work was to investigate the underlying mechanisms involved in the hypotensive effect of G-hesperidin in spontaneously hypertensive rats (SHRs) and normotensive Wistar-Kyoto rats (WKYs). METHODS: Fourteen-week-old SHRs and WKYs were fed a control or G-hesperidin (50 mg/kg) diet for 8 wk. Blood pressure was recorded weekly. After 8 wk, the vasodilatory responses of isolated aortas to acetylcholine and sodium nitroprusside were assessed. Expression of mRNAs related to regulation of blood pressure and vascular tone in the aorta also was investigated. Urinary 8-hydroxy-2'-deoxyguanosine, an oxidative stress marker, was measured. Cardiac and vascular hypertrophies were observed. RESULTS: In SHRs, the ingestion of G-hesperidin inhibited the development of hypertension. G-hesperidin enhanced endothelium-dependent vasodilation in response to acetylcholine, but had no effect on endothelium-independent vasodilation in response to sodium nitroprusside. G-hesperidin decreased mRNA expression of nicotinamide adenine dinucleotide phosphate oxidase subunits in aorta, which are the main source of superoxide anion in the vasculature; endothelial nitric oxide synthase expression was unchanged. Urinary 8-hydroxy-2'-deoxyguanosine was reduced significantly by G-hesperidin treatment. G-hesperidin suppressed cardiac and vascular hypertrophies. In contrast, G-hesperidin had no effects in WKYs. CONCLUSION: Continuous ingestion of G-hesperidin reduces oxidative stress by inhibiting nicotinamide adenine dinucleotide phosphate oxidase expression in the vasculature, thereby ameliorating endothelial dysfunction and hypertension in SHRs.

Hydroxyhydroquinone interferes with the chlorogenic acid-induced restoration of endothelial function in spontaneously hypertensive rats.

BACKGROUND: Coffee is a rich source of antioxidative polyphenols, but epidemiological studies and interventional trials have failed to demonstrate any clear beneficial effects of coffee consumption on hypertension. The interaction between hydroxyhydroquinone (HHQ) and 5-caffeoylquinic acid (CQA) was examined, in an attempt to understand the controversial effects of coffee on hypertension. METHODS: Male Wistar Kyoto (WKY) rats or spontaneously hypertensive rats (SHRs, 14 weeks old) were divided into the following four groups; those on a control diet, 0.005% HHQ diet, 0.5% CQA diet, and HHQ plus CQA diet. The rats were fed the above diets for 8 weeks, and the tail arterial blood pressure was monitored in conscious rats at 2-week intervals. Urinary nitric oxide (NO) metabolites and hydrogen peroxide (H(2)O(2)) excretion were measured 8 weeks after the start of the experiment. Endothelium-dependent and -independent vasorelaxant responses and immunohistochemical staining for nitrotyrosine were examined in aortas. RESULTS: HHQ inhibited the CQA-induced improvement in hypertension, urinary NO metabolites or H(2)O(2) excretion, endothelial dysfunction, and nitrotyrosine deposits in aortas in SHR. However, the administration of HHQ alone had little effect on either strain. CONCLUSIONS: Based on the content ratio of HHQ and chlorogenic acids in coffee, HHQ interfered with the CQA-induced improvement in blood pressure and endothelial function in SHR. The results explain, at least in part, the conflicting action of coffee drinking on hypertension and vascular reactivity.

Ferulic acid restores endothelium-dependent vasodilation in aortas of spontaneously hypertensive rats.

BACKGROUND: Ferulic acid (FA), a phytochemical constituent, has antihypertensive effects, but a detailed understanding of its effects on vascular function remains unclear. The vasoreactivity of FA was assessed using aortic rings isolated from normotensive Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR). METHODS: The effects of FA (10(-5) to 10(-3) mol/L) on vasodilatory responses were evaluated based on contractile responses induced by phenylephrine (10(-6) mol/L) in thoracic aortic rings from male WKY rats and SHR. Basal nitric oxide (NO) bioavailability in the aorta was determined from the contractile response induced by the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME, 10(-4) mol/L). The effects of FA on the production of NADPH-dependent superoxide anion were examined in SHR aortas. The impact of hydroxyhydroquinone, a generator of superoxide anions, on the FA-induced enhancement in acetylcholine-stimulated vasodilation was also investigated. RESULTS: The FA (10(-3) mol/L)-induced relaxation was partially blocked by removal of the endothelium or by pretreating SHR aortas with L-NAME. FA increased NO bioavailability, and decreased NADPH-dependent superoxide anion levels in SHR aortas. Ferulic acid improved acetylcholine-induced endothelium-dependent vasodilation in SHR, but not in WKY. Furthermore, the simultaneous addition of hydroxyhydroquinone significantly inhibited the increase in acetylcholine-induced vasodilation by FA. CONCLUSIONS: Ferulic acid restores endothelial function through enhancing the bioavailability of basal and stimulated NO in SHR aortas. The results explain, in part, the mechanisms underlying the effects of FA on blood pressure (BP) in SHR.

Chlorogenic acid attenuates hypertension and improves endothelial function in spontaneously hypertensive rats.

BACKGROUND AND OBJECTIVES: Epidemiologic studies indicate that ingestion of vegetables and fruit inhibits the development of cardiovascular disease. Chlorogenic acids are abundant phenolic compounds contained in vegetables and fruits, but the impact of dietary chlorogenic acids on vascular function in hypertension is not known. We therefore examined the effects of 5-caffeoylquinic acid (CQA), a representative chlorogenic acid, on blood pressure and vascular function in age-matched normotensive Wistar-Kyoto rats and spontaneously hypertensive rats. METHODS AND RESULTS: A single ingestion of CQA (30-600 mg/kg) reduced blood pressure in spontaneously hypertensive rats, an effect that was blocked by administration of a nitric oxide synthase inhibitor, N(G)-nitro-L-arginine methyl ester. When spontaneously hypertensive rats were fed diets containing 0.5% CQA for 8 weeks (approximately 300 mg/kg per day), the development of hypertension was inhibited compared with the control diet group. CQA ingestion increased urinary excretion of nitric oxide metabolites and decreased urinary excretion of hydrogen peroxide; decreased NADPH-dependent superoxide anion production in the aorta, suggesting that dietary CQA inhibited vascular NADPH oxidase activity; significantly improved acetylcholine-induced endothelium-dependent vasodilation in the aorta; and markedly reduced the degree of immunohistochemical staining for nitrotyrosine and media hypertrophy in aorta sections. In contrast, CQA had no effects in Wistar-Kyoto rats. CONCLUSIONS: Dietary CQA reduces oxidative stress and improves nitric oxide bioavailability by inhibiting excessive production of reactive oxygen species in the vasculature, and leads to the attenuation of endothelial dysfunction, vascular hypertrophy, and hypertension in spontaneously hypertensive rats.

Green coffee bean extract improves human vasoreactivity.

Our previous study revealed the antihypertensive effects of green coffee bean extract (GCE) ingestion in spontaneously hypertensive rats. We suggested that this antihypertensive action was due to the fact that GCE contains chlorogenic acid (CQA) as a major phenolic compound, and CQA in turn contains ferulic acid as a metabolic component that acts on nitric oxide (NO) derived from the vascular endothelium. In this study, the effects of GCE on blood vessels were evaluated in healthy males. The subjects were 20 healthy males with reduced vasodilation responses measured by strain gauge plethysmograms (SPG) to ischemic reactive hyperemia. Of the 20 subjects, 10 (mean age, 37.2 years) ingested a test drink containing GCE (CQA: 140 mg/day), and the other 10 (mean age, 34.8 years) ingested a placebo drink for 4 months. During the ingestion period, SPG, pulse wave velocity (PWV), and serum biochemical parameters were measured, and acceleration plethysmograms (APG) were taken. The reactive hyperemia ratio (RHR) in the test drink group began to increase after ingestion for 1 month and was significantly higher (p <0.05) than that in the placebo group after ingestion for 3 months and 4 months. In addition, after ingestion for 4 months, the test drink group showed a significant decrease (p <0.01) in the plasma total homocysteine level compared with the pre-ingestion level. However, there were no significant differences in PWV or APG between the test drink group and the placebo drink group. The improvement in RHR after ingestion of a drink containing GCE suggested an improvement in vasoreactivity by this component.

The sedative effects and mechanism of action of cedrol inhalation with behavioral pharmacological evaluation.

It has been reported that cedarwood oil has sedative effects when inhaled. In this study, we evaluated sedative effects of inhaled cedrol, which is a major component of cedarwood oil. Accumulative spontaneous motor activity was significantly decreased in the cedrol-exposed Wistar rats. Similar results were confirmed in caffeine-treated Wistar rats, spontaneously hypertensive rats (SHR), and ddY mice. In addition, exposure to cedrol prolonged pentobarbital-induced sleeping time in Wistar rats. To investigate whether cedrol, which has a very faint aroma, affects the olfactory system, the nasal cavities of Wistar rats were treated with zinc sulfate to reduce olfactory function. Two days later, the pentobarbital-induced sleep time was measured as described above. Compared to intact rats, the sleep prolongation effect was decreased in a lavender-roman chamomile mixed oil exposure positive control group, indicating that olfactory function was impaired. In contrast, prolongation of the sleeping time did not change in the cedrol exposure group. The above findings indicate that cedrol inhalation had marked sedative effects regardless of the animal species or the functional state of the autonomic nerves, suggesting that the mechanism of action is via a pathway other than the olfactory system.