Arctigenin Prevents Retinal Edema in a Murine Retinal Vein Occlusion Model.

Macular edema causes vision loss in patients with retinal vein occlusion (RVO) and diabetic macular edema (DME). The intravitreal injection of anti-vascular endothelial growth factor (VEGF) agents is used for treatment; however, this therapy is invasive, and recurrence occurs in some cases. The establishment of a non-invasive treatment would help to solve these problems. Here, we focused on arctigenin, a lignan polyphenol found in burdock sprout, and has effects on inflammatory and microcirculatory when taken orally. We hypothesized that oral intake of arctigenin could be effective against retinal edema in RVO and DME. In this study, the degree of retinal edema by measuring the total retinal thickness using optical coherence tomography (OCT) and the thickness of the inner nuclear layer (INL) by hematoxylin-eosin (H&E) staining were investigated. Oral administration of arctigenin ameliorated retinal edema in an RVO murine model by inhibiting the decrease in occludin and vascular endothelial (VE)-cadherin. Moreover, in retinas with edema, arctigenin suppressed the induction of VEGF, tumor necrosis factor α (TNFα), and matrix metallopeptidase 9 (MMP9). Next, the effects of arctigenin on barrier function were assessed in human retinal microvascular endothelial cells (HRMECs) by measuring the trans-endothelial electrical resistance (TEER) and conducting fluorescein isothiocyanate (FITC)-dextran permeability assays. Arctigenin showed a protective effect against VEGF-induced barrier dysfunction. In addition, arctigenin inhibited the TNFα-mediated activation of the nuclear factor-kappaB (NF-κB)/p38 mitogen-activated protein kinase (MAPK) pathway. These results suggested that oral administration of arctigenin has beneficial effects on retinal edema by inhibiting vascular hyperpermeability in endothelial cells.

Change in plasma lactate concentration during arctigenin administration in a phase I clinical trial in patients with gemcitabine-refractory pancreatic cancer.

Arctigenin is evaluated for antitumor efficacy in patients with pancreatic cancer. It has an inhibitory activity on mitochondrial complex I.Therefore, plasma lactate level of patients after arctigenin administration was evaluated for biomarker of clinical response and/or adverse effect. Plasma lactate level in 15 patients enrolled in a Phase I clinical trial of GBS-01 rich in arctigenin was analyzed by colorimetric assay. Statistical analyses for association of plasma lactate and clinical responses, pharmacokinetics of arctigenin, and background factors of each patient by multivariate and univariate analyses.In about half of the patients, transient increase of lactate was observed. Correlation between plasma lactate level and pharmacokinetic parameters of arctigenin and its glucuronide conjugate, and clinical outcome was not detected. Regarding to the determinant of lactate level, only slight association with liver function test was detected. Plasma lactate level is primary determined by reutilization rather than production for antitumor effect and dose not serve as a biomarker. Arctigenin, inhibition of mitochondrial complex I, plasma lactate concentration, phase I clinical trial of GBS-01, Cori cycle.

Phase I trial of GBS-01 for advanced pancreatic cancer refractory to gemcitabine.

GBS-01, an extract from the fruit of Arctium lappa L. is an orally administered drug rich in arctigenin, which has been reported to exert antitumor activity by attenuating the tolerance of cancer cells to glucose deprivation. We investigated the maximum tolerated dose of GBS-01 based on the frequency of the dose-limiting toxicities (DLTs) and pharmacokinetics in patients with advanced pancreatic cancer refractory to gemcitabine. GBS-01 was given orally at escalating doses from 3.0 g (containing 1.0 g burdock fruit extract) to 12.0 g q.d. A DLT was defined as a grade 4 hematological toxicity and grade 3 or 4 non-hematological toxicity appearing during the first 28 days of treatment. Fifteen patients (GBS-01 dose level 1 [3.0 g], three patients; dose level 2 [7.5 g], three patients; and dose level 3 [12.0 g], nine patients) were enrolled. None of the patients at any of the three dose levels showed any sign of DLTs. The main adverse events were increased serum γ-glutamyl transpeptidase, hyperglycemia, and increased serum total bilirubin; however, all the toxicities were mild. Of the 15 patients, 1 showed confirmed partial response and 4 patients had stable disease. The median progression-free and overall survival of the patients were 1.1 and 5.7 months, respectively. The pharmacokinetic study revealed a high bioavailability of arctigenin and rapid conjugation of the drug with glucuronic acid. The recommended dose of GBS-01 was 12.0 g q.d, and favorable clinical responses were obtained. This trial was registered at UMIN-CTR (http://www.umin.ac.jp/ctr/index-j.htm), identification number UMIN000005787.

Anti-austeric activity of phenolic constituents of seeds of Arctium lappa.

From seeds of Arctium lappa L. (Asteraceae) we obtained arctigenin (1), arctiin (2), chlorogenic acid (3), 4,5-dicaffeoylquinic acid (4), 3,5-dicaffeoylquinic acid (5), 3,4-dicaffeoylquinic acid (6), matairesinol (11), isolappaol A (12), lappaol F (14), and lappaol B (15), together with 1:1 mixtures of isolappaol C (7) and lappaol C (8), arctignan E (9) and arctignan D (10), and 12 and lappaol A (13), while 3,3',4'-tri-O-demethylarctigenin (16), 3,3'-di-O-demethyl-4'-dehydroxyarctigenin (17), and 3-O-demethylarctigenin (18) were obtained by anaerobic microbiological metabolism of 1. Then, we evaluated the in vitro preferential cytotoxic activity of these pure compounds and 1:1 mixtures, together with enterodiol (19) and enterolactone (20), against human pancreatic cancer PANC-1 cells in nutrient-deprived medium (NDM). Among them, 1 and 18 showed potent activity, with PC50 values of 1.75 and 4.38 microM, respectively, while 11, 15, and 17 showed mild activity with PC50 values of 31.1, 30.9, and 38.7 microM, respectively. By comparing their structures and PC50 values, the following structural moieties could be concluded to be important for the preferential cytotoxicity of 1: 1) the 3-hydroxy-4-methoxyphenyl group at the 2-position on the gamma-butyrolactone ring, 2) the less polar substituent at the 3-position on the gamma-butyrolactone ring, and 3) the gamma-butyrolactone ring.

Relationships among skin conditions, mood, and polyunsaturated fatty acids of RBCs in healthy women.

Little is known about nonpathological facial skin problems at present. The aim of the present study was to investigate the relationships among facial skin conditions, mood, and the fatty acid composition of red blood cells (RBCs) in women. One hundred and thirty-two apparently healthy Japanese women aged between 20 and 60 years were recruited. Facial skin conditions were analyzed using a Robo Skin Analyzer, and the RBC fatty acid composition was also determined. Questionnaires concerning mood were administered. Forehead pigmentation was more mood-dependent (in 20s group) and less arachidonic acid (AA)-dependent (in all participants) than that in other areas of the face. Actually there was no correlation in pigmentation between the forehead and other areas of the face when adjusted for age, smoking, and drinking. Skin conditions were adversely correlated with a negative mood. α-Linolenic acid concentrations were negatively correlated with negative mood scores. Pigmentation characteristics in the forehead were independent from other areas of the face. Negative mood and AA were adversely correlated with skin conditions.

Effects of keishibukuryoganryokayokuinin (gui-zhi-fu-ling-wanliao-jia-yiyiren) on the epidermal pigment cells from DBA/2 mice exposed to ultraviolet B (UVB) and/or progesterone.

The production of melanin is not only activated by external factors such as sunlight or UV-exposure, but is also considered to be triggered by hormonal factors, particularly sex hormones such as ovarian hormones. Previously, keishibukuryoganryokayokuinin (KBY) was reported to increase the pigmentation and moisture content of dermis in women during the luteal phase of the menstrual cycle, thus suggesting that progesterone could play a critical role in the development of skin pigmentation. In the present study, female DBA/2 mice, a dilute brown strain, were used to examine the effects of KBY on the increase in epidermal pigment cells in mice exposed to ultraviolet B (UVB) radiation or progesterone in an attempt to elucidate its mechanism. An increase in epidermal pigment cells was observed in mice exposed to progesterone. To the best of our knowledge, this is the first study to demonstrate that progesterone causes pigmentation in vivo. Furthermore, administration of KBY to progesterone-exposed mice significantly reduced the number of epidermal pigment cells. However, KBY had no such effects on UVB-induced pigmentation. Another important finding was the gain in body weight in progesterone-exposed mice, while body weight gain was reduced by KBY. The body weight gain was believed to be due to sodium and fluid retention, a kind of adverse effect of progesterone, which may further affect the intracellular pH of melanosomes, which synthesize melanin, in turn, leading to melanin production because tyrosinase activity is linked to the intracellular pH environment. This may help explain the mechanism of the role of KBY in pigmentation.

Polyunsaturated fatty acids and blood circulation in the forebrain during a mental arithmetic task.

The effects of polyunsaturated fatty acids on human cerebral blood oxygenation have yet to be extensively investigated. In this study, healthy participants (14 men, 40 women) aged between 20 and 49 years were recruited. All female participants entered the trial at the start of their menstrual cycle. Blood was sampled before measuring cerebral blood oxygenation in the prefrontal cortex (PFC) and prior to administering two kinds of questionnaires, the Profile of Mood States (POMS) and a questionnaire regarding participants' arousal level. Blood oxygenation in the PFC was continuously monitored immediately before and during the Uchida-Kraepelin Performance (UKP) test as a mental arithmetic task. Changes in the tissue oxygenation index (the ratio of oxyhemoglobin to oxyhemoglobin+deoxyhemoglobin; TOI, a simplified index for cerebral blood circulation) were measured by near-infrared spectroscopy. Multiple regression analysis was performed with sex, age, smoking and drinking as confounding factors. Eicosapentaenoic acid (EPA) was positively associated with TOI, which was positively associated with arousal level and inversely associated with negative mood (POMS). EPA and docosahexaenoic acid were inversely associated with depression-dejection (POMS) and positively associated with arousal level and overall performance in the UKP test. We suggest that EPA might increase the oxygenation level in the PFC, in turn improving various psychological parameters and performance.

Evaluation of estrogen receptor Beta binding of pruni cortex and its constituents.

The bark of Prunus jamasakura Siebold (Pruni Cortex) has long been used in Japan as a folk remedy and is one of ingredients of the Kampo formula, Jumi-haidoku-to (JHT). JHT is used for treatment of skin diseases such as acne (acne vulgaris). According to Kampo medicinal sources, Quercus Cortex can be used in place of Pruni Cortex. In this study, we found that water extracts of Pruni Cortex, not Quercus Cortex showed a binding effect on estrogen receptor beta (ERbeta). Thus, their chemical analysis was carried out by GC-MS and found that five unique constituents (i.e., sakuranetin, naringenin, genistein, genkwanin and arctigenin) were detected in Pruni Cortex. The ERbeta binding capacity of these constituents was examined using 70 ng/ml 17beta-estradiol, as the positive control with 100% ERbeta binding. Among them, genistein (60% at 10 ng/ml) showed the strongest binding capacity than naringenin (60% at 1000 ng/ml) and sakuranetin (40% at 1000 ng/ml). These results suggested that Pruni Cortex in JHT could play an important role in treatment of acne. In addition, those of Pruni Cortex from different harvest places were also examined in their chemical contents and ERbeta binding capacity. The extracts of Pruni Cortex from Kyushu in Japan and Anhui Province in China showed higher contents of genistein and stronger ERbeta binding capacity than that of Pruni Cortex from Tokushima Prefecture in Japan.