Synthesis of Novel Temperature-responsive Polymer Gel of Poly(aspartic acid)s

Recently, thermo-responsive polymer gels have been studied in various research fields such as drug delivery system. One of represetative thermo-responsive polymer gels is poly(N-isopropylacrylamide) gel (PNIPAAm) that has a rapid and reversible volume phase transition. However, PNIPAAm is not biodegradable, resulting in limitation of its use in medical fields. Novel thermo-responsive polymer gel was prepared by closslinking of isopropylamine modified poly(succinimide) (IPA-PSI) (Poly[α,β -(DL-aspartate isopropyl amide)-co-(succinimide)]) with hexamethylenediamine. Because of peptide bonds in backbone, therefore, it is expected to possess biodegradability and biocompatibility. These gels changed their volume in response to change of environment such as temperature, pH and concentration of salt in water. Crosslinkage density and substitution degree of IPA-PSI affected volume phase transition bahavior of the gel

Hyperuricemia in type 2 diabetic model KK-Ay/Ta mice: a potent animal model with positive correlation between insulin resistance and plasma high uric acid levels

Abstract Objective Hyperuricemia is recognized as a main cause of gout. Accumulating clinical evidence suggests that hyperuricemia is strongly associated with insulin resistance and abnormal glucose metabolism. However, there seem no proper animal models for investigating such associations. Ideal animal model is considered to be hyperuricemic as well as diabetic. Selecting the KK-Ay/Ta mouse model, the relationship between hyperuricemia and insulin resistance has been studied to characterize such an animal model. Results Male type 2 diabetic KK-Ay/Ta and age-matched normal C57BL/6J mice were maintained on a basal 20% casein diet for 35 days. Food intake, body weight gain, levels of plasma uric acid, glucose, insulin, homeostasis model assessment of insulin resistance (HOMA-IR), and triglyceride in KK-Ay/Ta mice were significantly higher than those in normal mice. Plasma uric acid levels showed significant positive correlations with plasma glucose, insulin, HOMA-IR and triglyceride levels. These results suggest that the KK-Ay/Ta mouse strain is useful for studies on correlation between hyperuricemia and insulin resistance, and for those on effects of foods and their components on the relations

Antidiabetic Effect of Urolithin A in Cultured L6 Myotubes and Type 2 Diabetic Model KK-A^y/Ta Mice with Glucose Intolerance

Diabetes is caused by abnormal glucose metabolism, and muscle, the largest tissue in the human body, is largely involved. Urolithin A (UroA) is a major intestinal and microbial metabolite of ellagic acid and ellagitannins and is found in fruits such as strawberry and pomegranate. In this present study, we investigated the antidiabetic effects of UroA in L6 myotubes and in KK-Ay/Ta, a mouse model of type 2 diabetes (T2D). UroA treatment elevated the glucose uptake (GU) of L6 myotubes in the absence of insulin. This elevation in GU by UroA treatment was partially inhibited by the concurrent addition of LY294002, an inhibitor of phosphatidylinositol 3-kinase (PI3K) which activates Akt (PKB: protein kinase B) or Compound C, an inhibitor of 5′-adenosine monophosphate-activated protein kinase (AMPK). Moreover, UroA was found to activate both pathways of Akt and AMPK, and then to promote translocation of glucose transporter 4 (GLUT4) from the cytosol to the plasma membrane in L6 myotubes. Based on these in vitro findings, an intraperitoneal glucose tolerance test (IPGTT) was performed after the oral administration of UroA for 3 weeks to KK-Ay/Ta mice with glucose intolerance. UroA was demonstrated to alleviate glucose intolerance. These results suggest that UroA is a biofactor with antihyperglycemic effects in the T2D state

Dopamine Release in the Ventromedial Hypothalamus of Growing Chickens Decreases when They are Fed a Lysine Devoid Diet

Deficiencies of single essential amino acids decreases food intake and this is likely to be involved in the central nervous system. Central mechanism underlying the decreased food intake induced by amino acid deficiency in chickens remains to be elucidated. We determined the hypothalamic interstitial monoamines (dopamine, norepinephrine and serotonin) with brain microdialysis technique to investigate whether hypothalamic monoaminergic system is associated with the reduction of food intake in growing chickens on a lysine devoid (LD) diet (a purified diet with a crystalline amino acid mixture not containing lysine as a sole source of nitrogen). Microdialysis probes had been inserted at the ventromedial (VMH) and lateral hypothalamus (LH) before presenting the diets. Perfusate was collected every 30min from two hours before feeding the LD diet to five hours later. Monoamines in the perfusate were determined using a high performance liquid chromatography. Chickens on the LD diets ate as much as the control chickens for early three hours, but the former ate less amount of food than the control one four and five hours after presenting the diet. Out of the ventromedial hypothalamic monoamines, dopamine level of the LD group started to decrease from the basal line one hour later and was lower than that of the control group 3.5 hours and afterward. Compared with the control group norepinephrine level of the LD group showed no change. Serotonin level was lower in the LD than control groups at one and four hours. The level of monoamines in the lateral hypothalamus did not differ between the dietary treatments. In conclusion, the present results demonstrate that feeding the lysine devoid diet decreased DA release in the VMH not in the LH before food intake started to decrease

Quercetin enhances fatty acid β-oxidation by inducing lipophagy in AML12 hepatocytes

Recent evidence demonstrated that chronic intake of quercetin attenuated hepatic fat accumulation in various animal models of obesity and diabetes. However, whether quercetin has the ability to enhance energy metabolism in hepatocytes and its exact mechanisms have yet to be identified. In the present study, we investigated whether quercetin directly enhanced the energy metabolism of cultured hepatocytes by focusing on lipophagy, involving selective autophagic degradation of lipid droplets. As an indicator of mitochondrial respiration, oxygen consumption was measured following 12-h treatment with quercetin or its related flavonoids, isorhamnetin and rutin (10 μM) using an extracellular flux analyzer. Treatment of alpha mouse liver 12 (AML12) hepatocytes with quercetin enhanced mitochondrial respiration, but isorhamnetin and rutin did not. Results of a palmitate-bovine serum albumin fatty acid oxidation assay showed that quercetin significantly increased the oxygen consumption of AML12 hepatocytes, suggesting enhanced fatty acid β-oxidation. However, as expression levels of mitochondrial oxidative phosphorylation proteins were unaltered by quercetin, we explored whether lipophagy contributed to enhanced fatty acid β-oxidation. Increased colocalization of lipid droplets and lysosomes confirmed that quercetin promoted lipophagy in AML12 hepatocytes. Furthermore, pharmacological inhibition of the autophagy–lysosomal pathway abolished the enhancement of fatty acid β-oxidation induced by quercetin in AML12 hepatocytes, suggesting that the enhancement of lipophagy by quercetin contributed to increased fatty acid β-oxidation. Finally, we showed that quercetin could activate AMPK signaling, which regulates autophagy even under nutrient-sufficient conditions. Our findings indicate that quercetin enhanced energy metabolism by a potentially novel mechanism involving promotion of lipophagy to produce the substrate for fatty acid β-oxidation in mitochondria through activation of AMPK signaling. Our results suggest the possibility that nutrient-induced lipophagy might contributes to the reduction of fat in hepatocytes