Diet modification and its influence on metabolic and related pathological alterations in the SHR/NDmcr-cp rat,an animal model of the metabolic syndrome

SHR/NDmcr-cp (SHR/NDcp) rats, which carry a nonsense mutation of the leptin receptor gene, are known to spontaneously develop hypertension, obesity and hyperlipidemia, and have therefore found use as an animal model of the metabolic syndrome and type 2 diabetes. However, some recent studies on SHR/NDcp rats revealed only mild elevation of blood glucose levels. To investigate whether metabolic factors including blood glucose and histopathological alterations of SHR/NDcp rats deteriorate with a diabetogenic diet, biochemical and histopathological examinations were conducted with animals fed normal or diabetogenic diets for 20 weeks. SHR/NDcp rats receiving the normal diet displayed obesity, hypertension, hyperlipidemia, and mild elevation of blood glucose and HbA1c levels. Urinary glucose excretion was noted in only 1 out of 6 animals. Histologically, macro- and micro-vesicular steatosis in the liver, glomerular and tubular damages in the kidney and islet hyperplasia mainly of beta cells in the pancreas were characteristically noted. In SHR/NDcp rats fed the diabetogenic diet, obesity was more severe, with higher blood glucose and HbA1c levels, increased numbers of animals with urinary glucose excretion, and more pronounced hepatic steatosis and renal tubular changes. However, elevation of blood glucose levels and urinary glucose excretion proved transient. These observations indicate that the diabetic state and associated histopathological alterations in SHR/NDcp rats are exacerbated by feeding a diabetogenic diet, but the effects are limited. Elevated islet function with compensative insulin secretion might be related to amelioration of the hyperglycemic state. Further diet modification could be needed to induce a more prominent and persistent diabetic state in SHR/NDcp rats.     

AU-1 from Agavaceae plants causes transient increase in p21/Cip1 expression in renal adenocarcinoma ACHN cells in an miR-34-dependent manner

Here, we show that AU-1, spirostanol saponin isolated from Agavaceae plants, causes a transient increase in cyclin-dependent kinase inhibitor (CDKI) p21/Cip1 through the upregulation of miRNAs, miR-34 and miR-21. AU-1 stimulated p21/Cip1 expression without exerting cytotoxicity against different types of carcinoma cell lines. In renal adenocarcinoma ACHN cells, AU-1 transiently elevated the expression level of p21/Cip1 protein without marked increases in p21/Cip1 mRNA levels. Rapid and transient increases in miR-34 and miR-21, both of which are known to upregulate p21/Cip1, were observed in AU-1-treated cells. Inhibitor for miR-34 and for miR-21 significantly blocked the AU-1-caused increase in p21/Cip1, indicating that elevation of p21/Cip1 protein by AU-1 is dependent on these microRNAs. We further clarified that NAD-dependent deacetylase SIRT1, a direct target of miR-34, is decreased by the treatment with AU-1. Furthermore, we found that SIRT1-knockdown increases p21/Cip1 protein levels in an miR-21-dependent manner. On the other hand, ectopic expression of p21/Cip1 resulted in the lowered expression of miR-34 and miR-21, suggesting that reciprocal regulation exists between p21/Cip1 and these miRNAs. We propose that the following feedback network composed of miR-34/SIRT1/miR-21/p21 is triggered by the treatment with AU-1: in cells treated with AU-1, transient elevation of miR-34 leads to the downregulation of SIRT1, thereby miR-21 is freed from SIRT1-dependent suppression. Then, elevated miR-21 upregulates p21/Cip1 protein, followed by the suppression of miR-34 expression.     

Lifestyle intervention might easily improve blood pressure in hypertensive men with the C genotype of angiotensin II type 2 receptor gene

BACKGROUND/OBJECTIVESRecent studies have reported an association of the angiotensin II type 2 receptor (AT2R) 3123Cytosine/Adenine (3123C/A) polymorphism with essential hypertension and cardiovascular diseases. The purpose of the study was to investigate whether the AT2R 3123C/A polymorphism affects blood pressure for free-living hypertensive men during a 5-month intervention period.SUBJECTS/METHODSThe subjects were free-living hypertensive Japanese men aged 40 to 75 years who agreed to intervention in the period from 2004 to 2011. Detection of the AT2R 3123C/A polymorphism was determined by polymerase chain reaction. The dietary intervention was designed to decrease salt level and to increase potassium level through cooking instructions and self-monitoring of the diet. The exercise session consisted of activities such as stretching, resistance training, and walking. Blood pressure, urinary sodium and potassium excretion, dietary and lifestyle data, and non-fasting venous blood sample were collected at baseline and after the intervention period.RESULTSThirty nine subjects were eligible for participation and the follow-up rate was 97.4%. The C allele proportion was 57.9%. AT2R 3123C/A polymorphism was X-chromosome-linked, therefore we analyzed the C and A genotypes. At baseline, no significant differences were observed between the genotype groups. After the intervention, there were no significant differences in lifestyle habit between the groups. Nevertheless, the estimated salt excretion (g/day) was significantly decreased only in the C genotype (13.0-10.3, P = 0.031). No significant change was observed in systolic blood pressure (SBP) (mmHg) in the A genotype, but a significant decrease was observed in the C genotype (150.0-141.5, P = 0.024).CONCLUSTIONSIn the C genotype, it might be easy to improve SBP through lifestyle intervention in free-living hypertensive Japanese men, however generalization could not be achieved by the small sample size.     

Neurocognitive and psychiatric disorders-related axonal degeneration in Parkinson's disease

Neurocognitive and psychiatric disorders have significant consequences for quality of life in patients with Parkinson's disease (PD). In the current study, we evaluated microstructural white matter (WM) alterations associated with neurocognitive and psychiatric disorders in PD using neurite orientation dispersion and density imaging (NODDI) and linked independent component analysis (LICA). The indices of NODDI were compared between 20 and 19 patients with PD with and without neurocognitive and psychiatric disorders, respectively, and 25 healthy controls using tract-based spatial statistics and tract-of-interest analyses. LICA was applied to model inter-subject variability across measures. A widespread reduction in axonal density (indexed by intracellular volume fraction [ICVF]) was demonstrated in PD patients with and without neurocognitive and psychiatric disorders, as compared with healthy controls. Compared with patients without neurocognitive and psychiatric disorders, patients with neurocognitive and psychiatric disorders exhibited more extensive (posterior predominant) decreases in axonal density. Using LICA, ICVF demonstrated the highest contribution (59% weight) to the main effects of diagnosis that reflected widespread decreases in axonal density. These findings suggest that axonal loss is a major factor underlying WM pathology related to neurocognitive and psychiatric disorders in PD, whereas patients with neurocognitive and psychiatric disorders had broader axonal pathology, as compared with those without. LICA suggested that the ICVF can be used as a useful biomarker of microstructural changes in the WM related to neurocognitive and psychiatric disorders in PD.     

Photorefractive Composite Based on a Monolithic Polymer

A new class of photorefractive (PR) composite based on a fully functionalized polymer with high phase‐stability is reported. The polymer containing non‐linear optical (NLO) chromophores and charge‐transporting carbazole moieties is synthesized by a polymer‐analogous reaction. The polymer is doped with plasticizer, NLO dye, and sensitizer to fabricate the PR composite. The NLO dye is the same as the NLO chromophore moiety in the polymer side chain. The PR performance of the composite is evaluated by degenerated four‐wave mixing and two‐beam coupling measurements. A diffraction efficiency of 30% at a relatively low applied electric field of 45 V μm^?1 is achieved. Despite a high concentration of NLO dye, the composites show good stability for a long period without phase separation.