Peroxisome proliferator-activated receptor delta (PPARdelta), a novel target site for drug discovery in metabolic syndrome.

The development of new treatments for metabolic syndrome is urgent project for decreasing the prevalence of coronary heart disease and diabetes mellitus in the advanced countries. Peroxisome proliferator-activated receptor (PPAR)alpha and gamma agonists have shed light on the treatment of hypertriglyceridemia and type 2 diabetes mellitus, respectively. Among PPARs, analysis of the PPARdelta functions is lagging behind because specific PPARdelta agonists have not been developed. The appearance of new PPARdelta agonists is brightening the prospects for elucidating the physiological role of PPARdelta. PPARdelta is a new target for the treatment of metabolic syndrome. In particular, the fact that fatty acid oxidation and energy dissipation in skeletal muscle and adipose tissue by PPARdelta agonists lead to improved lipid profile, reduced adiposity and insulin sensitivity is a breakthrough. It seems that treatment of PPARdelta agonists operate similarly to the caloric restriction and prolonged exercise. We suggest that the physiological role of PPARdelta may be an indicator for switching from glucose metabolism to fatty acid metabolism. To receive new benefits of PPARdelta agonists against metabolic syndrome by increasing fatty acid consumption in skeletal muscle and adipose tissue, we need to unveil more details on the functions of PPARdelta itself and its agonists in the future.     

Variants of calpain-10 gene and its association with type 2 diabetes mellitus in a Chinese population

Variants of calpain-10 gene (CAPN 10) have recently been reported to be associated with type 2 diabetes (T2DM). Haplotype combination 112/121 defined by three single nucleotide polymorphisms (SNPs) (UCSNP-43, -19 and -63) of CAPN 10 conferred the highest risk for T2DM in Mexican-Americans. In this study, we aim to examine whether these genetic variants contribute to the susceptibility for T2DM in a Chinese population. The frequencies of these three SNPs were determined in 168 patients with T2DM and 104 controls. Distribution of alleles, genotypes and haplotypes at three loci were not significantly different between the two groups. No difference was observed in the 112/121 haplotype combination distribution. However, haplotype combination 112/221 was more prevalent in the control group than in T2DM group (16.35% versus 7.14%, p = 0.025). Control subjects with haplotype combination 112/121 had higher serum cholesterol level than others without haplotype combination 112/121 (5.7 +/- 1.4 versus 5.2 +/- 0.7, p = 0.011). Our results suggest that haplotype combination 112/221 associated with reduced risk for T2DM and haplotype combination 112/121 might be a risk factor for increased serum cholesterol in Chinese population.     

Evaluation of esophageal function in patients with gastroesophageal reflux disease using transnasal endoscopy

Background and Aims:  To investigate the utility of a new method of carrying out esophageal manometry using a narrow gauge manometry catheter via a transnasal endoscope.
Methods:  The Frequency Scale for the Symptoms of gastroesophageal reflux disease (GERD) (FSSG), a GERD-specific questionnaire, was given to 45 subjects. Subjects 
underwent transnasal endoscopy with three dry and three wet (3 mL water) swallows. Direct observations of the primary peristaltic wave and peristaltic pressure measurement were conducted simultaneously.
Results:  Endoscopic observation of lower esophageal motility associated with swallowing revealed dilatation of the esophageal lumen after swallowing, followed by contraction in association with the primary peristaltic wave. The peristaltic pressure was significantly lower with increased FSSG scores for dry swallows ( r  = −0.347, P  = 0.0212), but no significant correlation was seen for wet swallows.
Conclusions:  The significant negative correlation between reflux symptoms and peristaltic pressure in dry swallows was thought to be that reduced pressure immediately rostral to the lower esophageal sphincter leads to decreased clearance following gastric acid reflux, playing a large part in the onset of symptoms.     

Peroxisome proliferator-activated receptor δ (PPARδ), a novel target site for drug discovery in metabolic syndrome

The development of new treatments for metabolic syndrome is urgent project for decreasing the prevalence of coronary heart disease and diabetes mellitus in the advanced countries. Peroxisome proliferator-activated receptor (PPAR)α and γ agonists have shed light on the treatment of hypertriglyceridemia and type 2 diabetes mellitus, respectively. Among PPARs, analysis of the PPARδ functions is lagging behind because specific PPARδ agonists have not been developed. The appearance of new PPARδ agonists is brightening the prospects for elucidating the physiological role of PPARδ. PPARδ is a new target for the treatment of metabolic syndrome. In particular, the fact that fatty acid oxidation and energy dissipation in skeletal muscle and adipose tissue by PPARδ agonists lead to improved lipid profile, reduced adiposity and insulin sensitivity is a breakthrough. It seems that treatment of PPARδ agonists operate similarly to the caloric restriction and prolonged exercise. We suggest that the physiological role of PPARδ may be an indicator for switching from glucose metabolism to fatty acid metabolism. To receive new benefits of PPARδ agonists against metabolic syndrome by increasing fatty acid consumption in skeletal muscle and adipose tissue, we need to unveil more details on the functions of PPARδ itself and its agonists in the future.     

Clinical application of experimental cortical dysplasia in rats

This report details clinical and experimental studies of focal cortical dysplasia. The first part deals with 14 surgical cases of children with intractable epilepsy. At surgery, intraoperative electrocorticography was performed to localize the epileptic foci under neuroleptanalgesia. Thirteen patients showed epileptiform discharges on this preresection electrocorticography. All foci in noneloquent areas were resected. Patients who had undergone total lesionectomy with complete focus resection showed the most favorable postoperative results. However, the positive correlation between the intraoperative electrocorticographic findings and the pathologic classification of cortical dysplasia was not found in the present study. Nine patients have been seizure free with reduced medication and two patients have achieved worthwhile improvement. We conclude that intraoperative electrocorticography can improve the surgical outcome for intractable epilepsy by localizing epileptic foci for resection. The second part describes a kainic acid-induced experimental model of focal cortical dysplasia, which demonstrated not only the epileptic properties of the dysplasia but also the perilesional epileptogenicity. The findings supported the surgical results for the patients with focal cortical dysplasia.     

Expression of liver X receptor α and lipid metabolism in granulocyte–macrophage colony-stimulating factor-induced human monocyte-derived macrophage

Liver X receptor (LXR) is a nuclear receptor that acts as a sterol sensor and metabolic regulator of cholesterol and lipid homeostasis. The foam cell transformation of macrophages (Mφ) is considered a critical process in atherosclerotic lesions. The relationship, however, of the foam cell transformation of Mφ and LXR is not fully understood. The purpose of the present study was to examine the expression of LXRα, retinoid X receptor (RXR)α, ATP-binding cassette transporter (ABCA1), and macrophage scavenger receptor A (MSR-A), and lipid accumulation in human monocyte-derived Mφ. The expression of LXRα, ABCA1, MSR-A in 7 day cultured granulocyte–macrophage colony-stimulating factor (GM-CSF)-induced Mφ (GM-Mφ) was significantly higher than that in 7 day cultured M-CSF-induced Mφ (M-Mφ). The expression levels of LXRα, ABCA1 and MSR-A protein decreased from 48 h to 5 days after the addition of lipopolysaccharide (LPS) in GM-Mφ, but only MSR-A protein decreased at 5 days after the addition of LPS in M-Mφ. Intracellular lipid accumulation was clearly observed when GM-Mφ was pre-stimulated with LPS for 48 h and incubated with oxidized LDL for an additional 5 days. These findings suggest that the inhibitory activity of LXRα, ABCA1 and MSR-A by LPS may be related to the transformation of Mφs, especially GM-Mφ into foam cells.     

Regional differences in the functional and biochemical properties of endothelin receptor subtypes in the rabbit prostatic urethra

OBJECTIVE: To examine the regional differences in the functional (pharmacological) and biochemical properties of endothelin (ET) receptors in the rabbit prostatic urethra. MATERIALS AND METHODS: The properties of ET receptors in 6-month-old male rabbit prostatic urethras were examined using isolated muscle-bath and radioligand receptor-binding techniques. Using plasma membrane suspensions, saturation and inhibition experiments with [(125)I]ET-1 and unlabelled agonists and antagonists (ET(A)-selective antagonist BQ123, and ET(B)-selective agonist sarafotoxin 6c, STX6c) were done to determine the ET receptor densities and their subtype specificities in the different regions of the urethra. RESULTS: The ETs (ET-1 and ET-3) produced significant concentration-dependent contractile responses in the smooth muscle strips from the different regions of the urethra. Although the maximum contractile responses induced by ET-1 were similar in the different regions, the maximum contractile responses induced by ET-3 were greater in the distal region than in the proximal or middle regions, suggesting that the contractile response to ET-1 is more potent than that to ET-3 in all regions, and that there are region-specific differences in the responses to ET-3 but not ET-1. Moreover, the ET-3-induced contractile response was suppressed by BQ788 (a selective antagonist of the ET(B) receptor) suggesting that the ET(B) receptor subtype contributes to the contractile responses mediated by ET-3. The ET receptors were expressed in higher concentrations in the distal than in the proximal or middle regions. BQ123 and STX6c inhibited [(125)I]ET-1 binding in all regions with high and low affinity constants, indicating the presence of both ET(A) and ET(B) receptor subtypes. The proportions of high-affinity binding sites for BQ123, representing ET(A) receptors, were approximately 68%, 63% and 42% in the proximal, middle and distal regions, respectively. By contrast, the proportions of high-affinity binding sites for STX6c, representing ET(B) receptors, were approximately 27%, 35% and 52% in the proximal, middle, and distal regions, respectively. These data indicate the presence of regional differences in the densities and subtype specificities of ET receptor subtypes, and the existence of regional differences in the rabbit prostatic urethra. CONCLUSION: The results suggest regional differences in ET(B) receptor subtypes that mediate contractile responses to ET-3, reflecting differences in the densities and specificities of the ET receptor subtypes in the rabbit prostatic urethra.     

Longitudinal study of procedural memory in patients with Alzheimer-type dementia]

We never forget how to ride a bicycle, and it is thought that procedural memories are retained for a long time. Recently, it was reported that patients with dementia of the Alzheimer type(DAT) could not only acquire, but also retain, long-lasting procedural memories. Previous group studies had shown procedural memory retention times of only 1 month in DAT patients, while amnesic patients and healthy people could retain such memories for 12 months. The relationship between the ability to retain procedural memory and the stage of the disease is not clear, as to date there has been no longitudinal study of procedural memory retention in DAT patients. Thus, we examined DAT patients' ability to retain long-term procedural memories (after 1, 5 and 20 months), and analyzed the relationship between procedural memory ability and the progress of disease. Motor-type procedural memory was examined using the mirror tracing task and the bi-manual coordinated tracing task. All three of the DAT patients showed improvement in their performance. The time required for the tracing was reduced between trials, and the improvement did not disappear between sessions, or rather, their times further decreased in subsequent sessions. Even the most severe DAT patient (Mini Mental State Examination(MMSE) score of 4) was able to acquire the procedural memory and retain it for at least 3 months. Furthermore, one of the subjects showed retention of the procedural memory at 20 months. Our results suggest that DAT patients can retain procedural memories for extended periods, with no relationship between retention ability and disease progression. It is possible for even severely demented patients to acquire and retain motor-type procedural memories. Cognitive rehabilitation in DAT appears to be effective, and it is possible for DAT patients to learn new things. It may be that DAT patients can ameliorate their quality of life by using retained procedural memory.