Hesperetin is an aglycone of citrus flavonoids and is expected to exert a vasodilatation effect in vivo. We developed water-dispersible hesperetin by the process of micronization to enhance the bioavailability of hesperetin. This study aimed to assess the effect of this process on the bioavailability of hesperetin and to estimate its efficiency on vasodilatation-related functions using endothelial cells in vitro and a human volunteer study at a single dose in vivo. We found that water-dispersible hesperetin was absorbed rapidly, with its maximum plasma concentration (C(max)) being 10.2 ± 1.2 μM, and that the time to reach C(max), which is within 1 h if 150 mg of this preparation was orally administered in humans. LC-MS analyses of the plasma at C(max) demonstrated that hesperetin accumulated in the plasma as hesperetin 7-O-β-D-glucuronide (Hp7GA), hesperetin 3'-O-β-D-glucuronide (Hp3'GA) and hesperetin sulfate exclusively. Similar to hesperetin, Hp7GA enhanced nitric oxide (NO) release by inhibiting nicotinamide adenine dinucleotide phosphate-oxidase (NADPH oxidase) activity in a human umbilical vein endothelial cell culture system, indicating that plasma hesperetin metabolites can improve vasodilatation in the vascular system. A volunteer study using women with cold sensitivity showed that a single dose of water-dispersible hesperetin was effective on peripheral vasodilatation.These results strongly suggest that rapid accumulation with higher plasma concentration enables hesperetin to exert a potential vasodilatation effect by the endothelial action of its plasma metabolites. Water-dispersible hesperetin may be useful to improve the health effect of dietary hesperetin.
We studied the psychological stress-reducing effect of chocolate enriched with gamma-aminobutyric acid (GABA), on stress induced by an arithmetic task using changes of heart rate variability (HRV) and salivary chromogranin A (CgA). Subjects ingested 10 g chocolate enriched with 28 mg GABA (GABA chocolate); 15 min after the ingestion, subjects were assigned an arithmetic task for 15 min. After the task, an electrocardiogram was recorded and saliva samples were collected. HRV was determined from the electrocardiogram, and the activity of the autonomic nervous system was estimated through HRV. The CgA concentration of all saliva samples, an index for acute psychological stress, was measured. From HRV, those taking GABA chocolate made a quick recovery to the normal state from the stressful state. The CgA value after the task in those taking GABA chocolate did not increased in comparison with that before ingestion. From these results, GABA chocolate was considered to have a psychological stress-reducing effect.
Infections of human papillomavirus (HPV) induce a variety of benign tumors, such as warts and condylomas. During the process of aberrant cell proliferation, genetic mutations are accumulated in the cells, from which malignant tumor cells arise. The viral oncoproteins E6 and E7 are known to help disrupt the cell cycle checkpoint machinery and accelerate chromosomal instability, events which are critical in malignant conversion. However, the mechanisms involved in the hyperplasia caused by HPV infection have remained unknown. We analysed the effects of regulatory genes of HPV18, a typical high-risk-type HPV, on the formation of the epithelial organ by using an organotypic culture system, and found that E7 had potent activity to induce hyperplasia, to which the disruption of the pRb pathway was well correlated. However, analysis with the E7 variants indicated that other pocket proteins are also involved in the activity.
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