Orange Juice and Its Component, Hesperidin, Decrease the Expression of Multidrug Resistance-Associated Protein 2 in Rat Small Intestine and Liver

We investigated the effects of orange juice (OJ) or hesperidin, a component of OJ, on the pharmacokinetics of pravastatin (PRV) and the expression of both protein and mRNA of multidrug resistance-associated protein 2 (Mrp2) in the rat small intestine and liver. Eight-week-old male Sprague-Dawley rats were used in this study. OJ or a 0.079% hesperidin suspension was administered orally for 2 days. Tap water was given as a control. A single dose of PRV at 100 mg/kg p.o. was administered after 2 days of OJ, hesperidin, or tap water ingestion. The AUC, Cmax, and t1/2 values of PRV were significantly increased in OJ group. Mrp2 protein and mRNA levels in the small intestine and liver, respectively, were significantly decreased after the ingestion of OJ. The same results were obtained with hesperidin. These results suggest that the changes in PRV pharmacokinetic parameters and the decrease in Mrp2 expression caused by OJ are due to hesperidin in the juice

Role of Gremlins in the Aortic Arch of Spontaneously Hypertensive and Hyperlipidemic Rats

Atherosclerosis is a lifestyle-related disease that plays a major role in cardiovascular disease. Recently, we found that gene expression of Gremlin 2, an antagonist of bone morphogenetic protein (BMP), was significantly increased in the aorta of spontaneously hypertensive and hyperlipidemic rats (SHHRs) fed a high-fat, 30% sucrose solution diet (HFDS). However, the role of Gremlin 1 (Grem1) and Gremlin 2 (Grem2) in the aortic arch of rats under hypertensive, hyperlipidemic, and hyperglycemic conditions remains unclear. Therefore, in the present study we investigated the molecular role of Gremlins in the aorta of SHHRs. Four-month-old male Sprague-Dawley rats and SHHRs were fed a normal diet or the HFDS ad libitum for 4 months. Then, gene and protein expression was analyzed using quantitative polymerase chain reaction and western blotting, respectively. Grem1 and Grem2 protein expression was increased, whereas phosphorylated Smad1/5 protein expression was low, in the aorta of SHHRs fed the HFDS. In addition, the expression of the downstream gene targets of BMP, namely inhibitor of DNA binding 1 (Id1) and atonal homolog 8 (Atoh8), was decreased in aortas of SHHRs fed the HFDS. Furthermore, mRNA expression of Snail, α-smooth muscle actin (αSMA), and Fibronectin was increased in SHHRs fed the HFDS. These findings suggest that upregulation of Gremlins attenuates the activation of BMP signaling, which contributes to fibrogenesis of the aorta

Vildagliptin Improves Glucose Tolerance and Decreases Plasma Triglycerides in Sprague-Dawley Rats

The number of patients with lifestyle-related diseases, including type 2 diabetes, is increasing. The onset of type 2 diabetes can be prevented by dietary and exercise interventions, as well as drug therapy. Dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists have attracted attention recently as treatments for diabetes, and incretin hormones have been reported to have a protective effect on pancreatic β-cells. It is not clear whether vildagliptin (VIL) can prevent the progression of lifestyle-related disease. Thus, in the present study, Sprague-Dawley rats were fed a high-fat diet with sucrose water (HFDS) to determine whether VIL could inhibit deterioration in glucose tolerance and improve other biomarkers of lipid disorder. Four-month-old male Sprague-Dawley rats were divided into three groups (n = 7 in each group); one group was fed a normal diet for 4 months, whereas the remaining two groups were fed the HFDS, with or without VIL for 4 months. When rats were 7 months of age, they were subjected to an intraperitoneal glucose tolerance test (IPGTT); biomarkers of lipid disorder were measured in 8-month-old rats. There was a decrease in the glucose spike in the IPGTT 10min after loading in the HFDS + VIL group and plasma triglyceride (TG) levels were significantly lower in these rats compared with the HFDS group. The decreased TG levels in HFDS + VIL rats were accompanied by decreases in plasma chylomicron levels. These results suggest that VIL can prophylactically inhibit decreases in pancreatic β-cell function in type 2 diabetes and reduce the risk of cardiovascular disease due to high TG levels. Thus, VIL administration may contribute to the prevention of lifestyle-related disease

Increase in Matrix Metalloproteinase-2 and 9 in the Liver of Nonalcoholic Steatohepatitis (NASH) Model Rats

Nonalcoholic steatohepatitis (NASH) is regarded as a hepatic manifestation of the metabolic syndrome which can progress to hepatic cirrhosis and hepatocellular carcinoma. It is thought that matrix metalloproteinases (MMPs) play an important role in hepatic fibrosis and we previously reported a correlation between oxidative stress and MMP-9 expression. However, the expression of MMPs and tissue inhibitors of metalloproteinases (TIMPs) in the progression of NASH is unclear. In this study we used spontaneously hypertensive and hyperlipidemic rats (SHHR) fed a high-fat diet and 30% sucrose solution (HFDS) as a model for NASH, in order to clarify the relationships between oxidative stress, liver weight (LW), MMPs and TIMPs at various time-points in the progression of NASH. Male SHHR and Sprague-Dawley (SD) rats were divided into four groups: SHHR-normal diet (ND), SHHR-HFDS, SD-ND and SD-HFDS. Hepatic fibrosis was clearly increased at 13 months in SHHR-HFDS, resembpling NASH. LW and oxidative stress markers in plasma were increased in SHHR-HFDS compared to the other groups. Oxidative stress was correlated with LW in all rats. Expression of MMP-2, MMP-9, TIMP-1 and TIMP-2 mRNA, measured by real-time polymerase chain reaction, was increased in the liver of SHHR-HFDS at 13 months. This study suggests that oxidative stress, MMPs and TIMPs may play an important role in the progression of NASH

Visceral Fat Accumulation is Associated with Oxidative Stress and Increased Matrix Metalloproteinase-9 Expression in Atherogenic Factor-overlapped Model Rats

Visceral fat accumulation in lifestyle-related diseases increases the risk of atherosclerosis. Matrix metalloproteinases (MMPs) play an important role in the progression of atherosclerosis. We examined atherogenic factor-overlapped model rats to clarify the relationships among visceral fat, oxidative stress, and MMPs. We used four groups of male, 11-month-old, spontaneously hypertensive hyperlipidemic rats (SHHRs) or Sprague-Dawley (SD) rats. Animals were fed either a diet of high fat and 30% sucrose solution (HFDS) or a normal diet (ND) ad libitum for 6 months. The visceral fat weight increased by approximately three fold in SHHR-HFDS compared to SHHR-ND. The oxidative stress marker in plasma and MMP-9 mRNA expression in white blood cells increased in SHHR-HFDS compared to the other groups. A correlation was determined between oxidative stress and visceral fat or MMP-9 mRNA in all rats. Lipid deposition and immunostaining of CD68 and MMP-9 were observed mainly in the intima of aorta in SHHR-HFDS, while tissue inhibitor of metalloproteinase-1 mRNA expression decreased in both SHHR groups. The findings suggested that increased oxidative stress due to the visceral fat accumulation induced MMP-9 expression and macrophage accumulation in the intima of aorta in lifestyle-related disease model rats

Disease-Association Analysis of an Inflammation-Related Feedback Loop

SummaryThe IL-6-triggered positive feedback loop for NFκB signaling (or the IL-6 amplifier/Inflammation amplifier) was originally discovered as a synergistic-activation signal that follows IL-17/IL-6 stimulation in nonimmune cells. Subsequent results from animal models have shown that the amplifier is activated by stimulation of NFκB and STAT3 and induces chemokines and inflammation via an NFκB loop. However, its role in human diseases is unclear. Here, we combined two genome-wide mouse screens with SNP-based disease association studies, revealing 1,700 genes related to the IL-6 amplifier, 202 of which showed 492 indications of association with ailments beyond autoimmune diseases. We followed up on ErbB1 from our list. Blocking ErbB1 signaling suppressed the IL-6 amplifier, whereas the expression of epiregulin, an ErbB1 ligand, was higher in patients with inflammatory diseases. These results indicate that the IL-6 amplifier is indeed associated with human diseases and disorders and that the identified genes may make for potential therapeutic targets