Visceral fat accumulation induces insulin resistance, abnormal glucose metabolism, abnormal lipid metabolism and hypertension. Furthermore, even when these individual diseases are present in only a mild form, if more than one of these diseases is present, this may induce development of arteriosclerosis or ischemic cardiovascular diseases.1,2) For these reasons, it is important that some form of medical therapy including exercise and diet therapy be devised to prevent the development of obesity and various metabolic disorders.Bofutsushosan, a traditional Japanese herbal medicine comprising 18 crude drugs (Table 1), has been an effective treatment for obesity, constipation and hypertension. Bofutsushosan was shown to reduce body weight and improve impaired glucose tolerance in a clinical trial.3) In addition, several pharmacological studies have reported on its ability to counter obesity, [4][5][6][7][8] fatty liver, 9,10) and arteriosclerotic diseases. 11)In the present study, we investigated the preventive effects of Bofutsushosan on various disease states (diabetes, hyperlipidemia, hypertension and diabetic peripheral neuropathy) that accompany metabolic disorders, focusing on visceral fat accumulation using a model animal, TSOD (Tsumura, Suzuki, Obese, Diabetes) mice, which are known to develop disease states similar to human metabolic disorders including glucose intolerance, hyperlipidemia, hypertension, hyperinsulinemia and peripheral neuropathy. [12][13][14] MATERIALS AND METHODS Experimental AnimalsWe used male TSOD mice aged 3 weeks. As a control animal, male TSNO (Tsumura, Suzuki, Non-Obesity) mice 12) aged 3 weeks were used as these animals do not develop obesity and various metabolic disorders. All mice were obtained from the Institute for Animal Reproduction (Ibaragi Prefecture). The animals were housed in an animal room under the following conditions: room temperature of 23Ϯ2°C, relative humidity of 55Ϯ10% and 12 h of light per day. In the 1-week acclimation period, the animals were given ad libitum powder feed MF (Oriental Yeast Co., Ltd.) and water. Following this period, the powder feed was switched to the study feed containing the test drug, and the animals were kept for further 8 weeks. We certify that all ap- Clinical and Biomedical Sciences, Showa Pharmaceutical University; 3-3165 Higashi-tamagawagakuen, Machida, Tokyo 142-8501, Japan. Received January 23, 2008; accepted May 7, 2008; published online May 8, 2008 Visceral fat accumulation has been reported as the most important risk factor for the development of various metabolic disorders. In this study, the preventive effects of Bofutsushosan, a Japanese Kampo preparation, on obesity and various metabolic disorders were investigated focusing on visceral fat accumulation using Tsumura, Suzuki, Obese, Diabetes (TSOD) mice, which showed significant accumulation of visceral fat, and developed metabolic disorders including glucose intolerance, hyperlipidemia, hypertension and hyperinsulinemia. At 2 months after initiation of the study, the c...
In human, aquaporins (AQPs) are expressed in a variety of tissues, and there are currently 13 known types of AQPs: AQP0 through AQP12.1) Several members of the AQP family are expressed in the intestinal tract, and at least 8 types are known to exist there: AQP1, AQP2, AQP3, AQP4, AQP7, AQP8, AQP9, and AQP10. 2-4)The main types expressed in mucosal epithelial cells in the colon are AQP3, AQP4 and AQP8.5) It has been reported that vasoactive intestinal polypeptide (VIP), a gastrointestinal hormone, is the causative agent in Verner-Morrison syndrome, a disease associated with diarrhoea 6) ; that intravenous administration of VIP in healthy adults causes diarrhoea 7) ; that serum VIP concentrations are elevated in rats with colitis 8) ; and that VIP increases mRNA and protein expression levels of AQP3 in HT-29 cells, which are human colonic epithelial cells.9) It has also been reported that following resection of the small bowel in rats, there is an increase in the mRNA expression of AQP3 in the colon as diarrhoea occurs.9) Based on these findings, AQP3 appears to play a particularly important role in water transport in the colon. Despite suggestions of an apparent relationship between the occurrence of diarrhoea and AQP3 expression levels, the manner in which variations in AQP3 expression are related to the mechanism of action of laxatives has yet to be elucidated.It is believed that commonly used osmotic laxatives, such as magnesium sulphate (MgSO 4 ) and magnesium oxide (MgO), induce diarrhoea by causing an increase in the osmotic pressure in the intestinal tract, 10) but no details are known about the relationship between these osmotic laxatives and water transport. In the present study, we investigated the role of AQP3 in the colon on the laxative effect of MgSO 4 , a widely used osmotic laxative. First, rats were administered MgSO 4 , and faecal water content was measured over time as an indicator of diarrhoea. Then, by analyzing the expression level of genes that sharply increase as a result of increased osmotic pressure, we investigated the relationship between diarrhoea and osmotic pressure. Next, protein expression levels of AQP3, AQP4, and AQP8 in the rat colon were analyzed by immunostaining in order to investigate the distribution and intensity of AQP expression. By analyzing the expression of AQP3 in the colons of rats administered MgSO 4 , the relationship between the expression level and the laxative effects of MgSO 4 was then investigated. MATERIALS AND METHODS AnimalsMale Wistar rats (10 weeks old) were purchased from Sankyo Labo Service Corp., Inc. (Tokyo, Japan). Each rat was caged separately and kept at room temperature (24Ϯ1°C) and 55Ϯ5% humidity with 12 h of light (artificial illumination; 08:00-20:00). The present study was conducted in accordance with the Guiding Principles for the Care and Use of Laboratory Animals, as adopted by the Committee on Animal Research at Hoshi University.Treatment Rats were fasted for 18 h before MgSO 4 administration (water provided ad libitum). An aqueous solut...
Ciprofloxacin (CPX), a new quinolone antibiotic, is reported to reduce CYP3A expression in the liver when administered to rats. The present study investigates whether the reduction in intestinal flora is involved in this reduction of CYP3A. While hepatic Cyp3a11 expression and triazolam metabolic activity were significantly reduced by CPX treatment of SPF mice, no significant changes were seen by CPX treatment of germ-free (GF) mice. Lithocholic acid (LCA)-producing bacteria in the feces as well as hepatic level of taurine conjugate of LCA were significantly reduced in CPX-treated SPF mice. Cyp3a11 expression in GF mice was significantly elevated when treated with LCA, known as an activator of fernesoid X receptor and pregnane X receptor. These results indicate that antibiotics such as CPX, having antimicrobial spectrums against LCA-producing bacteria, possibly cause decrease in LCA in the liver, resulting in lower CYP3A expression. The intestinal flora is reported to be altered also by stress, disease and age etc. The findings of the present study suggest that these changes in intestinal flora may modify CYP expression and contribute to individual differences in pharmacokinetics.
The plasma concentration of repaglinide is reported to increase greatly when given after repeated oral administration of itraconazole and gemfibrozil. The present study analyzed this interaction based on a physiologically based pharmacokinetic (PBPK) model incorporating inhibition of the hepatic uptake transporter and metabolic enzymes involved in repaglinide disposition. Firstly, the plasma concentration profiles of inhibitors (itraconazole, gemfibrozil, and gemfibrozil glucuronide) were reproduced by a PBPK model to obtain their pharmacokinetic parameters. The plasma concentration profiles of repaglinide were then analyzed by a PBPK model, together with those of the inhibitors, assuming a competitive inhibition of CYP3A4 by itraconazole, mechanism-based inhibition of CYP2C8 by gemfibrozil glucuronide, and inhibition of organic anion transporting polypeptide (OATP) 1B1 by gemfibrozil and its glucuronide. The plasma concentration profiles of repaglinide were well reproduced by the PBPK model based on the above assumptions, and the optimized values for the inhibition constants (0.0676 nM for itraconazole against CYP3A4; 14.2 mM for gemfibrozil against OATP1B1; and 5.48 mM for gemfibrozil glucuronide against OATP1B1) and the fraction of repaglinide metabolized by CYP2C8 (0.801) were consistent with the reported values. The validity of the obtained parameters was further confirmed by sensitivity analyses and by reproducing the repaglinide concentration increase produced by concomitant gemfibrozil administration at various timings/doses. The present findings suggested that the reported concentration increase of repaglinide, suggestive of synergistic effects of the coadministered inhibitors, can be quantitatively explained by the simultaneous inhibition of the multiple clearance pathways of repaglinide.
To investigate the pharmacokinetic characteristics in TSOD (Tsumura, Suzuki, obese, diabetes) mice, a model of type 2 diabetes and obesity, the expressions of major hepatic CYP enzymes in TSOD and TSNO (Tsumura, Suzuki, non-obesity; control) mice were compared. The 7-month-old TSOD mice, which represented severe obesity/diabetes-related pathophysiology, showed higher expressions of Cyp2c and Cyp3a compared with TSNO mice, while those of Cyp1a and Cyp2e were lower. Cyp3a metabolic activity was also higher in TSOD mice. In the 7-month-old liver, pregnane X receptor (PXR) (nuclear receptor) and peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) (cofactor) mRNA expression were higher in TSOD mice, possibly playing a role in the altered expression of Cyp3a. This specifically altered CYP expression in TSOD mice suggests that the biotransformation of drugs metabolized by these CYP enzymes differs from that in normal animals. Based on these findings, further investigation on the relationship between altered CYP expression and pathophysiology may be useful in elucidating changes in pharmacokinetics in obese/diabetic patients.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.