The ameliorative effects of exercise on cognitive impairment and white matter injury from blood-brain barrier disruption induced by chronic cerebral hypoperfusion in adolescent rats.

Vascular dementia is the progressive change in blood vessels that leads to neuronal injuries in vulnerable areas induced by chronic cerebral hypoperfusion (CCH). CCH induces disruption of blood-brain barrier (BBB), and this BBB disruption can initiate the cognitive impairment and white matter injury. In the present study, we evaluated the effect of treadmill exercise on the cognitive impairment, white matter injury, and BBB disruption induced by CCH. Vascular dementia was induced by permanent bilateral common carotid arteries occlusion (BCCAO) in rats. The rats in the exercise group were made to run on a treadmill for 30min once a day for 14 weeks, starting 4 weeks after birth. Our results revealed that treadmill exercise group was alleviated the cognitive impairment and myelin degradation induced by CCH. The disruption of BBB after CCH indicates degradation of occludin, zonula occluden-1 (ZO-1), and up-regulation of matrix metalloproteinases (MMPs). Treadmill exercise may provide protective effects on BBB disruption from degradation of occludin, ZO-1, and overexpression of MMP-9 after CCH. These findings suggest that treadmill exercise ameliorates cognitive impairment and white matter injury from BBB disruption induced by CCH in rats. The present study will be valuable for means of prophylactic and therapeutic intervention for patients with CCH.

Leuconostoc citreum HJ-P4 (KACC 91035) regulates immunoglobulin E in an ovalbumin-induced allergy model and induces interleukin-12 through nuclear factor-kappa B and p38/c-Jun N-terminal kinases signaling in macrophages.

Leuconostoc citreum (L. citreum) HJ-P4 (KACC 91035) is one of the major predominant species in kimchi fermentation in Korea. The purpose of the present study was to test the immunomodulatory capacity of L. citreum to modulate the IgE-mediated allergic response and to examine the involvement of NF-kappaB and MAPK in IL-12 production in macrophages. Balb/c mice were sensitized with OVA/alum and oral administration of L. citreum to the mice began before or after the OVA sensitization. Protein and mRNA expression of Th1 cytokines in splenocytes by L. citreum in vitro was measured. The role of NF-kappaB and MAPK such as p38, ERK1/2 and JNK in L. citreum-induced IL-12 was investigated in peritoneal macrophages and RAW264.7 cell lines. L. citreum inhibited the serum levels of total IgE, IgG1 and IgG2a altogether and increased OVA-specific IFN-gamma production in splenocytes from pre- and post-sensitized animals. However, the downregulation of IL-4 and IL-5 production was observed only in the pre-sensitization group. The ability of L. citreum to stimulate IFN-gamma was dependent on its induction of IL-12. NF-kappaB, p38 and JNK were mainly involved in L. citreum-induced IL-12 production. In conclusion, the current study demonstrated that L. citreum is able to regulate serum IgE generation at the induction and effector phases of allergic response through overall control over antibody production and that its involvement of IL-12 production was mediated through NF-kappaB and p38/JNK. Taken together, the use of L. citreum can be useful in preventing the development and progression of IgE production.

Serum obestatin/ghrelin ratio is altered in patients after distal gastrectomy.

BACKGROUND/AIMS: Ghrelin is a peptide hormone produced mainly in the stomach, and obestatin is derived by proteolytic cleavage of the ghrelin prepro-hormone. The aim of this study was to determine the postoperative serial changes in these hormones and whether hyperplasia of ghrelin-expressing cells occurs in the remnant stomach. METHODS: We prospectively analyzed serial serum samples of 45 early gastric cancer patients and remnant stomach samples of 24 patients. RESULT: The serum obestatin level on day 2 was lower than that on day 0, and it subsequently returned to the level observed on day 0. In contrast, the serum ghrelin level was lower on days 120 and 210 than on day 0. Eventually, the obestatin/ghrelin ratio was significantly high on day 210 (p = 0.0003). Moreover, we did not observe an increase in the number of ghrelin-expressing cells. The number of ghrelin-expressing cells correlated with the serum ghrelin level. CONCLUSION: The serum level of obestatin and ghrelin exhibits a different time course in patients who have undergone gastrectomy, and there was no ghrelin-expressing cell hyperplasia in the remnant stomach despite the decrease in serum ghrelin.

Immunomodulatory effect of Schizonepeta tenuifolia water extract on mouse Th1/Th2 cytokine production in-vivo and in-vitro.

Schizonepeta tenuifolia (ST) is a major herbal constituent included in treatments for the common cold with fever, ostitis media and other skin inflammations. The present study investigated the effect of ST water extract on the pattern of cytokine production from activated T cells in-vivo and in-vitro. When ST (200 mgkg(-1)) was given orally to mice for 7 days before i.v. injection of anti-CD3 antibody, it significantly decreased mRNA levels of interleukin (IL)-4, interferon (IFN)-gamma and T-bet. Our flow cytometric analysis showed that ST administration significantly increased CD69 expression but showed little effect on the subsets of T cells. When we cultured mouse CD4 T cells under Th1/Th2 differentiation in the presence of ST, the suppressive activity of ST on IFN-gamma involved T-bet, but the downregulation of IL-4 occurred independently of the Th2 transcription factors GATA binding protein 3 (GATA-3) and c-Maf. However, it increased IL-2 secretion during Th1/Th2 differentiation. Our study demonstrates that ST regulates inflammatory responses by reducing the release of Th1 and Th2 cytokines from T cells and prevents unprimed CD4 T cells from differentiating into Th1 and Th2 cells.

Peptide YY, cholecystokinin, insulin and ghrelin response to meal did not change, but mean serum levels of insulin is reduced in children with Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is a contiguous gene syndrome characterized by uncontrollable eating or hyperphagia. Several studies have confirmed that plasma ghrelin levels are markedly elevated in PWS adults and children. The study of anorexigenic hormones is of interest because of their regulation of appetite by negative signals. To study the pattern and response of the anorexigenic hormones such as cholecystokinin (CCK) and peptide YY (PYY) to a meal in PWS, we measured the plasma CCK, PYY, ghrelin and serum insulin levels in PWS patients (n=4) and in controls (n=4) hourly for a day, and analyzed hormone levels and hormonal responses to meals. Repeated measures of ANOVA of hormone levels demonstrated that only insulin levels decreased (p=0.013) and CCK (p=0.005) and ghrelin (p=0.0007) increased in PWS over 24 hr. However, no significant group x time interactions (ghrelin: p=0.89, CCK: p=0.93, PYY: p=0.68 and insulin: p=0.85) were observed; in addition, there were no differences in an assessment of a three-hour area under the curve after breakfast. These results suggest that the response pattern of hormones to meals in PWS patients parallels that of normal controls. In addition, the decrease of insulin levels over 24 hr, in spite of obesity and elevated ghrelin levels, suggests that the baseline insulin level, not the insulin response to meals, may be abnormal in patients with PWS.

Marked suppression of ghrelin concentration by insulin in Prader-willi syndrome.

The plasma ghrelin has been reported to be elevated in Prader-Willi syndrome (PWS) and modulated by insulin. It was hypothesized that insulin might have a more pronounced effect on reducing plasma ghrelin in PWS patients, which would influence appetite. This study investigated the degree of ghrelin suppression using an euglycemic hyperinsulinemic clamp in children with PWS (n=6) and normal children (n=6). After a 90-min infusion of insulin, the plasma ghrelin level decreased from a basal value of 0.86+/-0.15 to 0.58+/-0.12 ng/mL in the controls, and from 2.38+/-0.76 to 1.12+/-0.29 ng/mL in children with PWS (p=0.011). The area under the curve below the baseline level over the 90 min insulin infusion was larger in children with PWS than in controls (-92.82+/-44.4 vs. -10.41+/-2.87 ng/mL/90 min) (p=0.011). The insulin sensitivity measured as the glucose infusion rate at steady state was similar in the two groups (p=0.088). The decrease in the ghrelin levels in response to insulin was more pronounced in the children with PWS than in the controls. However, the level of ghrelin was always higher in the children with PWS during the clamp study. This suggests that even though insulin sensitivity to ghrelin is well maintained, an increase in the baseline ghrelin levels is characteristic of PWS.

Obestatin is not elevated or correlated with insulin in children with Prader-Willi syndrome.

CONTEXT: Obestatin is a peptide hormone derived from the proteolytic cleavage of ghrelin preprohormone. In Prader-Willi syndrome (PWS), the levels of total ghrelin (TG) and acylated ghrelin (AG) are increased, and these hormones are regulated by insulin. OBJECTIVE: Our objective was to analyze the changes in the obestatin levels after glucose loading and to characterize the correlations of obestatin with TG, AG, and insulin. DESIGN: Plasma obestatin, TG, AG, and insulin levels were measured in PWS children (n = 15) and controls (n = 18) during an oral glucose tolerance test. SETTING: All subjects were admitted to the Samsung Medical Center. INTERVENTIONS: An oral glucose tolerance test was performed after an overnight fast. MAIN OUTCOME MEASURES: The plasma levels of obestatin, TG, AG, and serum insulin were measured at 0, 30, 60, 90, and 120 min after glucose challenge, and areas under the curves (AUCs) were calculated. RESULTS: No significant difference in AUC of the plasma obestatin was found between the PWS children and normal obese controls (P = 0.885), although AUC of AG (P = 0.002) and TG (P = 0.003) were increased in the PWS children. Moreover, There was a negative correlation between the AUC of AG and AUC of insulin both in PWS (r = -0.432; P = 0.049) and in controls (r = -0.507; P = 0.016). However, AUC of obestatin was not significantly correlated with AUC of insulin (in PWS, r = 0.168 and P = 0.275; in controls, r = -0.331 and P = 0.09). CONCLUSIONS: Our results indicate that plasma obestatin is not elevated in PWS children and is not regulated by insulin both in PWS children and in obese controls.

Regional cerebral glucose metabolic abnormality in Prader-Willi syndrome: A 18F-FDG PET study under sedation.

UNLABELLED: Prader-Willi syndrome (PWS) is a genetic disorder caused by the nonexpression of paternal genes in the PWS region of chromosome 15q11-13 and is the most common cause of human syndromic obesity. METHODS: We investigated regional brain metabolic impairment in children with PWS by 18F-FDG PET. Sixteen children with PWS (9 males, 7 females; mean age +/- SD, 4.2 +/- 1.1 y) and 7 healthy children (4 males, 3 females; mean age +/- SD, 4.0 +/- 1.7 y) underwent brain 18F-FDG PET in the resting state. The images of PWS children were compared using statistical parametric mapping analysis with those of healthy children in a voxelwise manner. RESULTS: Group comparison showed that children with PWS had decreased glucose metabolism in the right superior temporal gyrus and left cerebellar vermis, regions that are associated with taste perception/food reward and cognitive and emotional function, respectively. Metabolism was increased in the right orbitofrontal, bilateral middle frontal, right inferior frontal, left superior frontal, and bilateral anterior cingulate gyri, right temporal pole, and left uncus, regions that are involved in cognitive functions related to eating or obsessive-compulsive behavior. Interestingly, no significant metabolic abnormality was found in the hypothalamus, the brain region believed to be most involved in energy intake and expenditure. CONCLUSION: This study describes the neural substrate underlying the abnormal eating behavior and psychobehavioral problems of PWS.

Suppression of acylated ghrelin during oral glucose tolerance test is correlated with whole-body insulin sensitivity in children with Prader-Willi syndrome.

CONTEXT: Decreased fasting ghrelin levels and decreased ghrelin suppression in overweight children have been reported to be associated with insulin resistance. However, Prader-Willi syndrome (PWS) is associated with increased total ghrelin levels and relative hypoinsulinemia. OBJECTIVE: The objective of the study was to analyze changes in acylated ghrelin (AG) and des-acylated ghrelin (DAG) levels after glucose loading and characterize correlations between insulin sensitivity and ghrelin suppression. DESIGN: Plasma glucose, insulin, AG, and DAG levels were measured in PWS children (n = 11) and normal obese controls (n = 10) during oral glucose tolerance testing. SETTING: All subjects were admitted to the Samsung Medical Center. INTERVENTIONS: Oral glucose tolerance testing was performed in all subjects after an overnight fast. MAIN OUTCOME MEASURES: Plasma levels of the hormones AG, DAG, and insulin, and those of glucose at 0, 30, 60, 90, and 120 min after glucose challenge were measured, and whole-body insulin sensitivity index (WBISI) values were calculated. RESULTS: AG levels fell markedly more from fasting levels in PWS children than normal healthy obese controls at 30, 60, and 90 min after glucose challenge, but no significant differences in DAG levels were observed at any time between PWS patients and controls. Fasting AG and DAG levels were found to correlate with WBISI in PWS, and absolute suppressions (Delta from baseline) in AG at 30 min after glucose challenge (nadir) were also correlated with WBISI in PWS (r = 0.64, P = 0.035). CONCLUSIONS: Our results suggest that AG is sensitively suppressed by insulin and that this suppression correlated with insulin sensitivity in PWS children.

Increased density of ghrelin-expressing cells in the gastric fundus and body in Prader-Willi syndrome.

CONTEXT: The levels of ghrelin, an orexigenic hormone secreted by oxyntic cells in the digestive tract, are elevated in Prader-Willi syndrome (PWS) and GH deficiency (GHD) patients. In this study, we hypothesized that the hyperghrelinemia observed in PWS is related to IGF-I or GH/IGF axis deficiency. DESIGN: We investigated the densities of ghrelin-expressing cells (GECs), the amounts of ghrelin in gastric tissues, and ghrelin levels in plasma in 16 PWS patients and compared these results with those of 13 GHD patients and comparison groups (19 normal lean and 10 normal obese subjects). RESULTS: In the gastric body and fundus, 2- to 3-fold increases in the numbers of GECs (P < 0.001) and in the amounts of ghrelin (P < 0.018) were noted in PWS patients vs. comparison groups, whereas GEC numbers in GHD patients were similar to those of the comparison group despite elevated fasting plasma ghrelin levels. In addition, IGF-I sd scores in PWS were not found to be correlated with GEC densities, the amounts of ghrelin expressed in gastric tissues, or plasma ghrelin levels. CONCLUSIONS: Our results suggest that IGF-I or GH/IGF axis deficiency appears to be unrelated to observed GEC increases in the stomach of patients with PWS.

Hyperghrelinemia does not accelerate gastric emptying in Prader-Willi syndrome patients.

Prader-Willi syndrome (PWS) is the most common form of syndromic obesity associated with hyperphagia. Because ghrelin stimulates gastric motility in rodents, and PWS patients have 3- to 4-fold higher fasting plasma ghrelin concentrations than normal subjects, we hypothesized that hyperphagia associated with PWS may be partly explained by rapid gastric emptying due to the increased gastric motility caused by ghrelin. We determined gastric emptying times (GETs) and measured ghrelin levels in 11 PWS children and 11 age-, sex-, and body mass index-matched controls using a standard meal containing [(99m)Tc]diaminetriaminepentacetate. Median plasma ghrelin levels before (precibum) and after the GET study were higher in PWS patients than in controls (P = 0.004 and P = 0.001, respectively). Median percent gastric retentions at 90 min after the standard meal were 57.1% (range, 34.0-83.2%) in PWS patients and 40.2% (range, 27.2-60.2%) in controls (P = 0.03). In particular, precibum ghrelin concentrations were not significantly correlated with the rate of gastric emptying in PWS patients (P = 0.153; r = 0.461) or controls (P = 0.911; r = 0.048). Our results show that gastric emptying in PWS is reduced despite higher ghrelin levels, and that the voracious appetite associated with PWS is related to another mechanism.

Correlation between fasting plasma ghrelin levels and age, body mass index (BMI), BMI percentiles, and 24-hour plasma ghrelin profiles in Prader-Willi syndrome.

Ghrelin is a GH-releasing acylated peptide found in the stomach and a centrally acting food intake stimulator. Prader-Willi syndrome (PWS) is a genetic disorder characterized by a voracious appetite and increased fasting ghrelin levels. In this report we describe 24-h ghrelin profiles in PWS children (n = 5) and compare these with age, sex, and body mass index (BMI)-matched controls (n = 5). A 3- to 4-fold increase in ghrelin levels was found in PWS over a 24-h period, compared with controls (P < 0.001). Interestingly, there was a greater tendency for the up-regulation of ghrelin level in lean PWS than in obese PWS. To confirm this finding, we measured fasting ghrelin levels in 39 patients with PWS. Inverse correlations were found between plasma ghrelin levels and the following: age (r = -0.408, P = 0.005), BMI (r = -0.341, P = 0.017), percentage of the ideal weight for age (r = -0.382, P = 0.008), and BMI percentile (r = -0.311, P = 0.027). Our data show that there may be a suppressive (or up-regulating) controlling mechanism of ghrelin secretion in obese (or lean) PWS children. We hope that our data may further explain the mechanisms underlying the insatiable appetite and obesity characteristic of PWS.

Polymorphism of the Helicobacter pylori feoB gene in Korea: a possible relation with iron-deficiency anemia?

BACKGROUND: Helicobacter pylori is a causative agent of gastritis, and H. pylori infection is thought to be correlated with iron-deficiency anemia (IDA) at puberty. The H. pylori feoB gene product, a high-affinity ferrous iron transporter, plays a central role in iron acquisition and virulence. This study was undertaken to analyze H. pylori feoB status according to clinical data, including antral gastritis with or without IDA. METHODS: Fourteen H. pylori-positive patients aged from 10 to 18 years were categorized into subgroups based on the presence or absence of IDA. Eight patients were diagnosed as having IDA; the other six showed normal hematological findings. Genomic DNA was isolated from H. pylori cultured from each gastric biopsy specimen. Five sets of primers were used for the PCR amplification of the feoB gene. Linking and sequencing of PCR products generated the feoB region, which was 1.93 kb in size. The feoB gene sequences of H. pylori J99 and 26695 were compared with the clinical strains, and the sequences of feoB regions in the IDA (+) and (-) groups were compared. RESULTS: Sequence analysis of the complete coding region of the feoB gene revealed 16 sites of polymorphism or mutation. Among these, three polymorphisms (E/T254A, I263V, and K511Q) were indigenous to the Korean clinical strains. Although statistically significant differences were observed at four sites (K127T, A273S/P, I438V and I441T) between IDA (+) and (-), the number of specimens was too low to assess the significance of the differences. CONCLUSION: The four polymorphisms of the feoB gene observed appear to be related to the clinical phenotype of IDA, but the relation is unclear because of the small number of strains studied. Further studies are required to confirm a correlation between IDA and H. pylori infection.

Genotypes of the Helicobacter pylori vacA signal sequence differ with age in Korea.

BACKGROUND: Studies on Helicobacter pylori genotypes have focused on adults in developed countries, and data on the genotypes of Helicobacter pylori recovered from the children are rare. MATERIALS AND METHODS: One hundred and twenty-eight biopsy samples from patients with H. pylori infection were studied. The patients' ages ranged from 9 to 83 years. PCR analysis for vacA genotypes was performed using DNA extracted from biopsy specimens. RESULTS: Genotyping of the s-region showed s1a in 33 (25.8%) samples and s1c in 82 (64.1%) samples. When the specimens were grouped by age, the distribution of s-region genotype was found to be significantly different between groups (p = .002). The prevalence of s1a was 45.2% in patients < 20 years old, but 14.9% in patients > or = 50 years old. On the other hand, the prevalence of s1c or recombinant s1a-s1c was higher in those > or = 50 years old. The distribution of the m-region did not differ significantly with age (p = .110). CONCLUSIONS: Strain populations infecting Korean adults and children differ.

Lactoferrin sequestration and its contribution to iron-deficiency anemia in Helicobacter pylori-infected gastric mucosa.

BACKGROUND AND AIM: It is known that lactoferrin serves as a source of iron for Helicobacter pylori in gastric mucosa. The present study was undertaken to investigate the relationship between lactoferrin and H. pylori infection coexistent with iron-deficiency anemia by determining the lactoferrin levels in gastric biopsy specimens, and by locating the major sites of lactoferrin expression, according to the presence or absence of iron-deficiency anemia. METHODS: One hundred and one adolescents who underwent gastroduodenoscopy were divided into four groups: controls without H. pylori infection (NL; n =43); patients with H. pylori infection (HP; n = 26); patients with iron-deficiency anemia (IDA; n = 6); and patients with H. pylori gastritis and coexisting iron-deficiency anemia (HPIDA; n = 26). The gastric mucosal levels of lactoferrin were measured by immunoassay. Immunohistochemical technique was used to allow identification of the location and quantification of the lactoferrin expression. RESULTS: The mucosal level of lactoferrin was highest (3.93 +/- 2.73 ng/microg protein) in HPIDA, followed by 2.67 +/- 1.79 ng/microg protein in HP, 0.59 +/- 0.57 ng/microg protein in NL and 0.14 +/- 0.10 ng/microg protein in IDA. Their multiple comparisons were statistically significant at the 0.05 level. After the eradication of H. pylori in 12 HPIDA patients who underwent follow-up endoscopy, the mean mucosal level of lactoferrin decreased significantly, while the blood hemoglobin level correspondingly increased. The major sites of lactoferrin expression by immunohistochemistry were in glands and neutrophils within epithelium. Lactoferrin was stained weakly in NL and IDA, and strongly in HP and HPIDA. CONCLUSION: The lactoferrin sequestration in the gastric mucosa of HPIDA was remarkable, and this finding seems to give a clue that leads to the clarification of the mechanism by which H. pylori infection contributes to iron-deficiency anemia.