Dual induction of caspase 3- and transglutaminase-dependent apoptosis by acyclic retinoid in hepatocellular carcinoma cells

<p>Abstract</p> <p>Background</p> <p>Hepatocellular carcinoma has a high mortality rate due to its rate of recurrence. Acyclic retinoid prevents recurrence of hepatocellular carcinoma in patients after surgical removal of their primary tumors by inducing apoptosis in hepatocellular carcinoma cells, although the molecular mechanisms of action are not understood.</p> <p>Methods</p> <p>Human hepatocellular carcinoma cells in culture, as well as nude mice transplanted with hepatocellular carcinoma cells and rats given with <it>N</it>-diethylnitrosamine were treated with acyclic retinoid. Changes in activated caspase 3 and transglutaminase 2 (TG2) levels, Sp1 cross-linking and its activities, expression of epidermal growth factor receptor, and apoptotic levels were measured.</p> <p>Results</p> <p>Acyclic retinoid simultaneously stimulated the activation of caspase 3, and the expression, nuclear localization and crosslinking activity of TG2, resulting in crosslinking and inactivation of the transcription factor, Sp1, thereby reducing expression of epidermal growth factor receptor and cell death in three hepatocellular carcinoma cell lines. These effects were partially restored by a caspase inhibitor, transfection of antisense TG2, restoration of functional Sp1, or an excess of epidermal growth factor. Nuclear expression of TG2 and crosslinked Sp1, as also activated caspase 3 were found in both hepatocellular carcinoma cells transplanted into nude mice and cancerous regions within the liver in <it>N</it>-diethylnitrosamine-induced hepatocarcinogenesis model in rats, following treatment of animals with acyclic retinoid.</p> <p>Conclusions</p> <p>Treatment with acyclic retinoid produces a dual activation of caspase 3 and TG2 induced apoptosis of hepatocellular carcinoma cells via modification and inactivation of Sp1, resulting in reduced expression of epidermal growth factor receptor.</p

Effects of xylitol on metabolic parameters and visceral fat accumulation

Xylitol is widely used as a sweetener in foods and medications. Xylitol ingestion causes a small blood glucose rise, and it is commonly used as an alternative to high-energy supplements in diabetics. In previous studies, a xylitol metabolite, xylulose-5-phosphate, was shown to activate carbohydrate response element binding protein, and to promote lipogenic enzyme gene transcription in vitro; however, the effects of xylitol in vivo are not understood. Here we investigated the effects of dietary xylitol on lipid metabolism and visceral fat accumulation in rats fed a high-fat diet. Sprague-Dawley rats were fed a high-fat diet containing 0 g (control), 1.0 g/100 kcal (X1) or 2.0 g/100 kcal (X2) of xylitol. After the 8-week feeding period, visceral fat mass and plasma insulin and lipid concentrations were significantly lower in xylitol-fed rats than those in high-fat diet rats. Gene expression levels of ChREBP and lipogenic enzymes were higher, whereas the expression of sterol regulatory-element binding protein 1c was lower and fatty acid oxidation-related genes were significantly higher in the liver of xylitol-fed rats as compared with high-fat diet rats. In conclusion, intake of xylitol may be beneficial in preventing the development of obesity and metabolic abnormalities in rats with diet-induced obesity

Improvement of Glucose Metabolism in Patients with Impaired Glucose Tolerance or Diabetes by Long-Term Administration of a Palatinose-Based Liquid Formula as a Part of Breakfast

A palatinose-based liquid formula (palatinose-formula), suppresses postprandial plasma glucose and insulin levels in healthy men. The objective of this study was to investigate the effects of long-term palatinose-formula ingestion on glucose metabolism in patients with impaired glucose tolerance (IGT) or type 2 diabetes. Two patients with IGT and 7 patients with type 2 diabetes participated in the palatinose-formula and dextrin-based liquid formula (dextrin-formula) loading test and long-term palatinose-formula administration study. After a 3-month control period, palatinose-formula (1046 kJ) was ingested daily by patients as a part of breakfast for 5 months. In the loading test, palatinose-formula suppressed postprandial plasma glucose and insulin levels and areas under the curve compared with those after dextrin-formula ingestion. In the long-term study, glycated hemoglobin levels (after 3 months and 5 months of treatment) and serum 8-hydroxydeoxyguanosine levels (after 5 months of treatment) were markedly decreased comparing with those at baseline. Intake of 1046 kJ palatinose-formula as a part of breakfast over a long-term period may be effective for improvement of glucose metabolism in patients with IGT or type 2 diabetes

The Anti-Obesity Effect of the Palatinose-Based Formula Inslow is Likely due to an Increase in the Hepatic PPAR-α and Adipocyte PPAR-γ Gene Expressions

Abdominal obesity is a principal risk factor in the development of metabolic syndrome. Previously, we showed that a palatinose-based liquid formula, Inslow/MHN-01, suppressed postprandial plasma glucose level and reduced visceral fat accumulation better than the standard formula (SF). To elucidate the mechanism of Inslow-mediated anti-obesity effect, expression levels of genes involved in the glucose and lipid metabolism were compared in Inslow- and SF-fed rats. Both fasting plasma insulin level and average islet sizes were reduced in the Inslow group. We also found less abdominal fat accumulation and reduced hepatic triacylglycerol content in the Inslow group. Expression of the β-oxidation enzymes and uncoupling potein-2 (UCP-2) mRNAs in the liver of the Inslow group were higher than the SF group, which was due to a concomitant higher expression of the peroxisome proliferator-activated receptor (PPAR)-α mRNA in the former. Furthermore, expression of the UCP-2 and adiponectin mRNAs in the epididymal fat were higher in the Inslow group than the SF group, and were stimulated by a concomitant increase of the PPAR-γ gene expression in the former. These results strongly suggested that the anti-obesity effect of Inslow was due to an increase in the hepatic PPAR-α and adipocyte PPAR-γ gene expressions

Palatinose and oleic acid act together to prevent pancreatic islet disruption in nondiabetic obese Zucker rats

We showed previously that 8-wk consumption of a diet containing palatinose (P, a slowly-absorbed sucrose analogue) and oleic acid (O) ameliorates but a diet containing sucrose (S) and linoleic acid (L) aggravates metabolic abnormalities in Zucker fatty (fa/fa) rats. In this study, we aimed to identify early changes in metabolism in rats induced by certain combinations of carbohydrates and fatty acids. Specifically, male Zucker fatty rats were fed an isocaloric diet containing various combinations of carbohydrates (P S) and fatty acids (O L). After 4 wk, no significant differences in bodyweight, visceral fat mass, plasma parameters (glucose, insulin, lipids, and adipokines), hepatic adiposity and gene expression, and adipose inflammation were observed between dietary groups. In contrast, pancreatic islets of palatinose-fed (PO and PL) rats were smaller and less fibrotic than sucrose-fed (SO and SL) rats. The abnormal_-cell distribution and sporadic staining of active caspase-3 common to islets of linoleic-acid-fed rats were not observed in oleic-acid-fed (PO and SO) rats. Accordingly, progressive_-cell loss was seen in SL rats, but not in PO rats. These findings suggest that pancreatic islets may be initial sites that translate the effects of different combinations of dietary carbohydrates and fats into metabolic changes

Increasing early insulin secretion compensate adequately for hepatic insulin resistance in CCl4-induced cirrhosis rats

A number of recent publications have reported an increased frequency prevalence of glucose intolerance with hyperinsulinemia in liver cirrhosis. The aim of this work was to detect, in CCl4-induced liver cirrhosis rat, the presence and starting point of muscle and liver insulin resistance. Eighteen rats received intraperitoneal injection of 2 ml of soybean oil containing of CCl4 twice a week for 20 weeks. We executed standard oral glucose tolerance and clamp study to evaluate systemic insulin resistance. Hepatic glucose uptake was much lower in CCl4 group than that in control group, but peripheral glucose uptake was not decreased in this study. In contrast, early-phase insulin secretion was enhanced in CCl4 rat using oral glucose load during clamp methods. These data suggested that increased early insulin secretion compensate adequately for hepatic insulin resistance in rats. However there was a report that peripheral glucose uptake was decreased in the case of human liver cirrhosis, which was formed in the course of time. In a chronic condition, this may be associated with reduced insulin content and developed systemic insulin resistance in liver cirrhosis. Then a long term observation study will be required to examine the presence of muscle insulin resistance in liver cirrhosis

横断的・総合的な幼稚園教育教員養成プログラムの構築研究

本研究では，別冊『－平成30年度広島大学大学院教育学研究科共同研究プロジェクト－横断的・総合的な幼稚園教育教員養成プログラムの構築研究論文集』を作成し，紙幅の都合で本報告書に掲載できなかった調査・研究の成果を掲載した

iNOS Promotes Proteasome-Dependent Degradation of IRS-2 and Suppresses PDX-1 Expression by Activating GSK-3β in Pancreatic β-Cells

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