Different effects of high-fat and high-sucrose diets on the physiology of perivascular adipose tissues of the thoracic and abdominal aorta.

Vascular diseases such as atherosclerosis and aneurysms are associated with diet. Perivascular adipose tissue (PVAT) was reportedly involved in the regulation of vascular functions. It is suggested that imbalanced diets can cause PVAT inflammation and dysfunction as well as impaired vascular function. However, the association between diets and PVAT are not clearly understood. Here, we showed that a high-fat and a high-sucrose diet affected PVAT at different sites. A high-fat diet induced increased number of large-sized lipid droplets and increased CD (Cluster of differentiation) 68+ macrophage- and monocyte chemotactic protein (MCP)-1-positive areas in the abdominal aortic PVAT (aPVAT). In addition, a high-fat diet caused decreased collagen fibre-positive area and increased CD68+ macrophage- and MCP-1-positive areas in the abdominal aorta. In contrast, a high-sucrose diet induced increased number of large-sized lipid droplets, increased CD68+ macrophage- and MCP-1-positive areas, and decreased UCP-1 positive area in the thoracic aortic PVAT (tPVAT). A high-sucrose diet caused decreased collagen fibre-positive area and increased CD68+ macrophage- and MCP-1-positive areas in the thoracic aorta. These results could be attributed to the different adipocyte populations in the tPVAT and aPVAT. Our results provide pathological evidence to improve our understanding of the relationship between diet and vascular diseases.

Mixing Ginkgo biloba Extract with Sesame Extract and Turmeric Oil Increases Bioavailability of Ginkgolide A in Mice Brain.

Ginkgo biloba extract (GBE) is widely used as herbal medicine. Preventive effect of GBE against dementia, including Alzheimer's disease, has been reported. The bioactive compounds in GBE that impart these beneficial effects, flavonoids and terpene lactones, have poor bioavailability. Our previous study found distribution of bioactive compounds of sesame extract in mice brain after mixing it with turmeric oil. Here, we evaluate the distribution of bioactive compounds of GBE by combining it with the mixture of sesame extract and turmeric oil (MST). The content of terpene lactones in mice serum was significantly increased in a dose-dependent manner after administration of GBE. However, the contents of terpene lactones in mice brain were not significantly changed. Concentration of ginkgolide A in mice brain increased significantly when GBE was co-administrated with MST than when GBE was administered alone. These results suggest that MST may be effective in enhancing the bioavailability of ginkgolide A in GBE.

[Assessing the Effects of Prescription Adjustment and Medication Non-adherence Associated with Medication Efficacy Classifications from Leftover Drugs through the SETSUYAKU-BAG Campaign].

　The increase in medical expenditure has been worsening and poses a serious social problem. Commonly, leftover drugs are retained by patients. We estimated the possible reduction in prescription rates by appropriately reusing leftover drugs, and investigated the medication efficacy classifications that render leftover drugs due to the medication non-adherence. A retrospective cross-sectional survey of prescription data was performed at community pharmacies engaged in the appropriate reuse of leftover drugs through the SETSUYAKU-BAG campaign. We evaluated the drug costs and number of drugs originally prescribed, the reduction in expenditure and numbers after the use of leftover drugs, and then calculated the prescription reduction ratio (PRR) based on the number of drugs. Factors contributing to non-adherence were analyzed by the PRR. After reviewing the prescription information of 1792 patients, the reduction rate in drug expenditure was found to be 20.1%. Purgatives, Chinese medicines, and agents for peptic ulcer had higher PRRs and belonged to the top ten medications according to the prescription efficacy classifications. Non-adherence associated with the medication efficacy classifications was assessed by analyzing 5466 formulations. Thirty percent of formulations were found to be non-adherent. According to the medication efficacy classifications, six medications including agents for hyperlipidemias, peptic ulcer, psychotropics agents, and others, were less adherent than antihypertensives. These results suggest that adjusting prescriptions by appropriately reusing leftover drugs in community pharmacies could reduce medical costs. Further considerations are necessary for improving medication adherence in Japan. Healthcare providers should monitor medication adherence more carefully, with the results identified in this study.

Effects of ginsenosides on the expression of cytochrome P450s and transporters involved in cholesterol metabolism.

An extract from red ginseng (steamed and dried roots of Panax ginseng C.A. Meyer; RGE) has been shown to promote cholesterol metabolism in the liver. We have reported that RGE induced the hepatic expression of cytochrome P450 (CYP)7A1, involved in cholesterol metabolism. Other cholesterol metabolism-related proteins, such as CYP8B1, CYP27A1, multidrug resistance-associated protein (MRP)2, MRP3, and Na(+) taurocholate cotransporting polypeptide (NTCP), are involved in cholesterol metabolism. The purpose of this study was to clarify whether RGE affected mRNA expression of cholesterol metabolism-related CYPs and transporters in the liver of hypercholesterolemic rats and rat primary hepatocytes. In-vivo studies showed little differences in CYP8B1, CYP27A1, MRP2, MRP3, and NTCP mRNA expression levels between hypercholesterolemic rats with or without RGE treatments. However, the disruption of the membrane localization of MRP2 was suppressed by RGE treatments in hypercholesterolemic rats. In-vitro studies using rat primary hepatocytes showed upregulation of CYP8B1 and MRP2 mRNA by the addition of RGE (100 and 500 µg/mL). We further examined which ginsenosides contributed to the upregulation of CYP8B1 and MRP2 mRNA levels. Ginsenoside Re enhanced the mRNA level of CYP8B1, whereas ginsenosides Rb2 and Rg2 enhanced MRP2 mRNA levels. These results suggest that the in-vitro exposure of hepatocytes to RGE or some ginsenosides could lead to upregulation of CYP8B1 and MRP2, resulting in the alteration of biosynthesis and disposition of bile acids.

Increased effects of ginsenosides on the expression of cholesterol 7α-hydroxylase but not the bile salt export pump are involved in cholesterol metabolism.

An extract from red ginseng [steamed and dried roots of Panax ginseng C.A. Meyer (RGE)] has been shown to have various actions on physiological functions. The mechanisms by which RGE promotes cholesterol metabolism in the liver are unclear, but RGE decreases the plasma levels of cholesterol. We investigated whether RGE affected the mRNA expression of cholesterol metabolism-related proteins such as cytochrome P450 (CYP)7A1 and bile salt export pump (BSEP) in the liver in hypercholesterolemic rats and rat primary hepatocytes. In-vivo studies showed the upregulation of CYP7A1 mRNA in hypercholesterolemic rats treated with RGE. Treatment with RGE exhibited decreased ratios of low-density lipoprotein-cholesterol to high-density lipoprotein-cholesterol compared with hypercholesterolemia without RGE. In-vitro studies also showed the upregulation of CYP7A1 mRNA and protein levels by the addition of RGE to rat primary hepatocytes. The mRNA levels of BSEP exhibited few changes. The sustained levels of the liver X receptor (LXR) in vivo and the increased levels of LXR in vitro on RGE treatment could be involved in the upregulation of CYP7A1. To clarify the effects of 11 ginsenosides including RGE on the mRNA levels of CYP7A1 and BSEP, we performed in-vitro experiments using rat primary hepatocytes. The ginsenosides Ro, Rg3, Re, Rg1, and Rg2 exhibited increased mRNA levels of CYP7A1. These results suggest that several ginsenosides including RGE promoted cholesterol metabolism due to upregulation of CYP7A1.

Effects of ginseng rhizome and ginsenoside Ro on testosterone 5α-reductase and hair re-growth in testosterone-treated mice.

This research program on the novel functions of Panax ginseng C. A. Meyer focused on the effects of ginseng rhizome on hair re-growth in androgenetic alopecia. Extracts of red ginseng rhizome showed greater dose-dependent inhibitory effects against testosterone 5α-reductase (5αR) when compared with extracts of the main root. Ginsenoside Ro, the predominant ginsenoside in the rhizome, and ginsenoside Rg(3), a unique ginsenoside in red ginseng, showed inhibitory activity against 5αR with IC(50) values of 259.4 and 86.1 µm, respectively. The rhizome of P. japonicus, which contains larger amounts of ginsenoside Ro, also inhibited 5αR. Topical administration of extracts of red ginseng rhizomes (2 mg/mouse) and ginsenoside Ro (0.2 mg/mouse) to shaved skin inhibited hair re-growth suppression after shaving in the testosterone-treated C57BL/6 mice. These results suggest that red ginseng rhizomes containing both oleanane- and dammarane-type ginsenosides are a promising raw material for cosmetic use. This is the first report that ginsenoside Ro enhances in vivo hair re-growth based on their inhibitory activity against 5αR in the androgenetic alopecia model.

[Medicinal history and ginsenosides composition of Panax ginseng rhizome, "Rozu"].

Ginseng is prepared from Panax ginseng C.A. Meyer root. The root of wild P. ginseng has long tortuous rhizome called traditionally "Rozu" in Japanese. In the present historical studies on ginseng, it has been proven that ginseng has sometimes been used after removing "Rozu" due to its emetic effects. However, ginseng with "Rozu" is prescribed in almost all the present Kampo formulations used clinically in China and Japan. Possible reasons for this are (1) some formulations including "Rozu" have been used for vomiting resulting from the retention of fluid in the intestine and stomach, "tan-in" in Japanese, and (2) the present cultivated ginseng has shorter "Rozu" than wild ginseng. Furthermore, it is proved that "Rozu", rich in ginsenoside Ro with oleanane-type aglycone, is distinguished from ginseng roots rich in ginsenosides Rb1 and Rg1 with dammarane-type aglycone. This is the first report to declare the distribution of ginsenosides in underground parts of wild P. ginseng. Ginsenoside Ro is a minor ginsenoside in ginseng whereas it is the major ginsenoside in P. japonicus rhizome (chikusetsu-ninjin in Japanese). Ginsenoside Ro is characterized by antiinflammatory effects which differ from ginsenosides Rb1 and Rg1 responsible for adaptogenic effects of ginseng. These results suggest that "Rozu" containing both oleanane- and dammarane-type ginsenosides might be a promising raw material distinct from ginseng root or P. japonicus rhizome.