The Association of Serum Total Peptide YY (PYY) with Obesity and Body Fat Measures in the CODING Study.

PubMed

Cahill, Farrell; Ji, Yunqi; Wadden, Danny; Amini, Peyvand; Randell, Edward; Vasdev, Sudesh; Gulliver, Wayne; Sun, Guang

2014-01-01

PYY is an appetite suppressing hormone. Low circulating PYY has been linked to greater BMI. However data is controversial and this association has not been verified in large human populations. The purpose of this study was to investigate if fasting serum total PYY is associated with obesity status and/or adiposity at the population level. A total of 2094 subjects (Male-523, Female-1571) participated in this investigation. Total PYY was measured in fasting serum by enzyme-linked immunosorbent assay. Obesity status (NW-normal-weight, OW-overweight and OB-obese) was determined by the Bray Criteria according to body fat percentage measured by dual-energy x-ray absorptiometry and the WHO criteria according to BMI. One-way ANOVA and multiple regression was used to assess the adiposity-specific association between PYY and the following; weight, BMI, waist-circumference, hip-circumference, waist-hip ratio, percent body fat (%BF), trunk fat (%TF), android fat (%AF) and gynoid fat (%GF). PYY was not significantly different among NW, OW and OB groups defined by neither %BF nor BMI for both men and women. However among women, fasting PYY was positively associated with adiposity measures. Women with the highest (Top 33%) waist-circumference, %BF and %TF had significantly higher PYY (10.5%, 8.3% and 9.2% respectively) than women with the lowest (Bottom 33%). Age, smoking, medication use and menopause were all positively associated with PYY levels in women but not in men. To our knowledge this is the largest population based study, with the most comprehensive analysis and measures of confounding factors, to explore the relationship of circulating PYY with obesity. Contrary to initial findings in the literature we discovered that PYY was positively associated with body fat measures (waist-circumference, %BF and %TF) in women. Although the effect size of the positive association of PYY with obesity in women is small, and potentially negligible, it may in fact represent a protective

Adiponectin and peptide YY in the fasting blue fox (Alopex lagopus).

PubMed

Mustonen, Anne-Mari; Pyykönen, Teija; Nieminen, Petteri

2005-02-01

Adiponectin (Acrp30) and peptide YY (PYY) are weight-regulatory hormones participating in the control of energy homeostasis. This study investigated the effects of long-term wintertime fasting on plasma Acrp30 and PYY levels in the carnivorous blue fox, a farm-bred variant of the arctic fox (Alopex lagopus). Plasma Acrp30 and PYY concentrations were determined with radioimmunoassays during a 22-day period of fasting, which led to a 20.3% reduction in body mass of the animals (n=32). Sixteen fed blue foxes served as the control group. Acrp30 and PYY were present in blue fox plasma at similar or lower levels as reported previously for other mammals. Fasting had no acute effects on Acrp30 or PYY concentrations of the blue foxes. However, the Acrp30 levels of the fasted blue foxes were 24%-48% higher than in the fed animals between days 8-22 of fasting. Fasted blue foxes also had 6.2-fold higher plasma PYY concentrations after 15 days of fasting. Acrp30 and PYY seem to play roles in the body weight-regulation of the blue fox during long-term fasting, but their specific functions and physiological significance remain to be determined.

Changes in circulating peptide YY and ghrelin are associated with early smoking relapse.

PubMed

Lemieux, Andrine M; al'Absi, Mustafa

2018-01-01

Ghrelin and peptide YY (PYY) during ad libitum smoking have been associated with decreased reported craving (ghrelin) and increased positive affect (PYY), and higher baseline ghrelin levels predicted subsequent increased risk of smoking relapse. The current study assessed PYY and ghrelin during ad libitum smoking and again after the initial 48h of a smoking cessation attempt. The data compared smokers who abstained for 28days (n=37), smokers who relapsed (n=54), and nonsmokers (n=37). Plasma samples and subjective measures assessing craving and mood were collected at the beginning of each session. Results showed that relapsers experienced greater levels of distress (ps <0.01). While nonsmokers and abstainers showed no change in ghrelin across the initial 48h, relapsers declined (p <0.01). With PYY, relapsers increased (p <0.05) across the early abstinent phase. PYY and ghrelin may be useful predictors of relapse, specifically in reference to early withdrawal. Copyright © 2017. Published by Elsevier B.V.

Peptide YY induces characteristic meal patterns of aged mice.

PubMed

Mogami, Sachiko; Yamada, Chihiro; Fujitsuka, Naoki; Hattori, Tomohisa

2017-11-01

Changes in eating behavior occur in the elderly due to oral and swallowing dysfunctions. We aimed to clarify the difference between basal meal patterns of young and aged mice in relation to appetite regulating hormones. Thirty two of young (7-week-old) and aged (23-25-month-old) C57BL/6 male mice were acclimated to a single housing and then transferred to a highly sensitive automated feeding monitoring device. Feeding behavior was monitored from the onset of the dark phase after habituation to the device. Plasma peptide YY (PYY) levels were assessed under the several feeding status or after treatment of PYY. PYY and its receptor (NPY Y2 receptor, Y2R) antagonist were intraperitoneally administered 30min before the monitoring. Although the basal 24-h meal amounts did not differ by age, the total meal time and frequency of minimum feeding activity (bout) were significantly increased and the average bout size and time per bout were significantly decreased in aged mice. PYY dynamics were abnormal and the temporal reduction in food intake by exogenous PYY was more prominent in aged mice than in young mice. PYY administration to young mice induced aged-like meal patterns, and Y2R antagonist administration to aged mice induced young-like meal patterns. Aged mice exhibited characteristic meal patterns probably due to PYY metabolism dysfunction and/or enhanced PYY-Y2R signaling, suggesting a novel method for assessing eating difficulties in aged animals and a potential target for the remedy. Copyright © 2017 Elsevier Inc. All rights reserved.

Neuropeptide Y and peptide YY: important regulators of energy metabolism.

PubMed

Nguyen, Amy D; Herzog, Herbert; Sainsbury, Amanda

2011-02-01

An overview of recent developments documenting the neuropeptide Y (NPY) family's role in energy metabolism. Specifically focusing on site-specific functions of NPY and increasing evidence of peptide YY (PYY) as a weight loss therapeutic. Studying the NPY family in hypothalamic nuclei, other than the arcuate and paraventricular nuclei, is a recent shift in metabolic research. NPY overexpression in the dorsomedial hypothalamus increases food intake whereas its ablation in this area reduces hyperphagia and obesity. Similarly, NPY exerts orexigenic effects in the ventromedial nucleus. However, specific arcuate Y2 receptor ablation leads to positive energy balance, suggesting the NPY family demonstrates location-specific functions. Peripherally, dual blockade of cannabinoid and NPY pathways has synergistic effects on weight loss, as does combined administration of PYY3-36 and oxyntomodulin in reducing food intake, perhaps due to the recently discovered role of PYY in mediating intestinal Gpr119 activity and controlling glucose tolerance. Conditional Y receptor knockout models have provided deeper insights on NPY's functions according to location. Further study of PYY appears vital, due to recent evidence of its role in intestinal motility, with exercise positively influencing PYY levels.

Coffee, hunger, and peptide YY.

PubMed

Greenberg, James A; Geliebter, Allan

2012-06-01

There is evidence from several empirical studies suggesting that coffee may help people control body weight. Our objective was to assess the effects of caffeine, caffeinated coffee, and decaffeinated coffee, both alone and in combination with 75 g of glucose, on perceived hunger and satiety and related peptides. We conducted a placebo-controlled single-blinded randomized 4-way crossover trial. Eleven healthy male volunteers (mean age, 23.5 ± 5.7 years; mean BMI, 23.6 ± 4.2 kg/m(2)) ingested 1 of 3 test beverages (caffeine in water, caffeinated coffee, or decaffeinated coffee) or placebo (water), and 60 minutes later they ingested the glucose. Eight times during each laboratory visit, hunger and satiety were assessed by visual analog scales, and blood samples were drawn to measure 3 endogenous peptides associated with hunger and satiety: ghrelin, peptide YY (PYY), and leptin. Compared to placebo, decaffeinated coffee yielded significantly lower hunger during the whole 180-minute study period and higher plasma PYY for the first 90 minutes (p < 0.05). Caffeine in water had no effects on hunger or PYY. Caffeinated coffee showed a pattern between that of decaffeinated coffee and caffeine in water. These findings suggest that one or more noncaffeine ingredients in coffee may have the potential to decrease body weight. Glucose ingestion did not change the effects of the beverages. Our randomized human trial showed that decaffeinated coffee can acutely decrease hunger and increase the satiety hormone PYY.

Elevated plasma peptide YY in human neonates and infants.

PubMed

Adrian, T E; Smith, H A; Calvert, S A; Aynsley-Green, A; Bloom, S R

1986-12-01

Plasma concentrations of peptide YY (PYY) were measured in cord blood and at 6, 12, and 18 days of postnatal life in 24 healthy preterm neonates, from cord blood of eight full-term neonates, and from peripheral blood of 13 infants 9 months old. Concentrations were high in cord blood (73 +/- 9 pmol/liter versus adult fasting 10.4 +/- 1.3, p less than 0.001) and rose postnatally in the premature infants to 399 +/- 48 pmol/liter at 6 days, 489 +/- 42 at 12 days, and fell to 414 +/- 43 at 18 days. Plasma PYY concentrations were much lower in infants 9 months old (32 +/- 3 pmol/liter), suggesting that the postnatal surge of plasma PYY is a feature of early adaptation to extrauterine life. Gel permeation chromatograms revealed that the major circulating form of PYY in the neonate eluted in a position identical to that of the pure 36 amino acid peptide. There was, however, evidence of two larger molecular forms that may be precursor molecules. Because PYY is a peptide that exhibits potent effects on gastrointestinal secretion and motility in humans, these observations suggest that this candidate gut hormone may be important in the adaptation to enteral nutrition in the neonate.

Impact of restraint and disinhibition on PYY plasma levels and subjective feelings of appetite.

PubMed

Martins, C; Robertson, M D; Morgan, L M

2010-10-01

The impact of eating behaviours on circulating levels of appetite-regulating hormones remains largely unknown. The aims of this study were to assess the role of restraint and disinhibition on fasting/postprandial peptide YY (PYY) plasma levels and subjective feelings of appetite in normal-weight individuals and to determine whether the effect was energy load dependent. 33 participants (12 men) were classified as restrained/unrestrained and low/high in disinhibition based on Three Factor Eating Questionnaire-18R and Dutch Eating Behaviour Questionnaire. The impact of restraint/disinhibition on PYY plasma levels and feelings of appetite was measured, after a 500kcal and 1000kcal breakfast, using a randomised crossover design. Restraint did not impact on either fasting or postprandial PYY plasma levels, but participants with high disinhibition had a tendency towards a blunted postprandial PYY response. Moreover, restrained eaters reported lower ratings of prospective food consumption postprandially, and a tendency towards higher fullness/lower hunger. In conclusion, circulating PYY is unaffected by restrained eating behaviour, despite being associated with increased fullness and reduced hunger in the fed state. High levels of disinhibition tend to be associated with a blunted PYY response and this may contribute towards the susceptibility to overconsumption and increased risk of weight gain characteristic of this trait.

Molecular cloning, expression analysis, and potential food intake attenuation effect of peptide YY in grass carp (Ctenopharyngodon idellus).

PubMed

Chen, Yong; Shen, Yubang; Pandit, Narayan Prasad; Fu, Jianjun; Li, Da; Li, Jiale

2013-06-15

The peptide YY (PYY) is a 36 amino acid peptide involved in the food intake control in vertebrates. We have cloned and characterized a PYY gene from grass carp Ctenopharyngodon idellus. The full-length cDNA encodes a precursor protein of grass carp PYY (gcPYY) that consists of a putative 28-amino acid signal peptide, a 36-amino acid mature peptide, an amidation-proteolytic site, and a 30-amino acid carboxy-terminal extension. The gcPYY gene is comprised of 4 exons interspaced by 3 introns as seen in PYYs from other species. Amino acid alignment and gene structure comparison indicate that the structure of PYY is well preserved throughout vertebrate phylogeny. The tissue distribution and postprandial changes in gcPYY mRNA expression were evaluated by real-time PCR, which showed that the gcPYY is expressed abundantly in the central nervous system, with significantly increased expression following a single meal. During embryogenesis, the presence of gcPYY mRNA was detected in early developing embryos, and high expression levels were observed when most larvae completed their switch from endogenous nourishment to exogenous feeding. Reduced food intake by juveniles during a single meal after giving perpheral injection of gcPYY1-36 suggests a potentially important role of PYY in the food intake attenuation in grass carp. Copyright © 2013 Elsevier Inc. All rights reserved.

PYY[3-36] administration decreases the respiratory quotient and reduces adiposity in diet-induced obese mice.

PubMed

Adams, Sean H; Lei, Chunli; Jodka, Carolyn M; Nikoulina, Svetlana E; Hoyt, Julie A; Gedulin, Bronislava; Mack, Christine M; Kendall, Eric S

2006-01-01

In rodents, weight reduction after peptide YY[3-36] (PYY[3-36]) administration may be due largely to decreased food consumption. Effects on other processes affecting energy balance (energy expenditure, fuel partitioning, gut nutrient uptake) remain poorly understood. We examined whether s.c. infusion of 1 mg/(kg x d) PYY[3-36] (for up to 7 d) increased metabolic rate, fat combustion, and/or fecal energy loss in obese mice fed a high-fat diet. PYY[3-36] transiently reduced food intake (e.g., 25-43% lower at d 2 relative to pretreatment baseline) and decreased body weight (e.g., 9-10% reduction at d 2 vs. baseline) in 3 separate studies. Mass-specific metabolic rate in kJ/(kg x h) in PYY[3-36]-treated mice did not differ from controls. The dark cycle respiratory quotient (RQ) was transiently decreased. On d 2, it was 0.747 +/- 0.008 compared with 0.786 +/- 0.004 for controls (P < 0.001); light cycle RQ was reduced throughout the study in PYY[3-36]-treated mice (0.730 +/- 0.006) compared with controls (0.750 +/- 0.009; P < 0.001). Epididymal fat pad weight in PYY[3-36]-treated mice was approximately 50% lower than in controls (P < 0.01). Fat pad lipolysis ex vivo was not stimulated by PYY[3-36]. PYY[3-36] decreased basal gallbladder emptying in nonobese mice. Fecal energy loss was negligible ( approximately 2% of ingested energy) and did not differ between PYY[3-36]-treated mice and controls. Thus, negative energy balance after PYY[3-36] administration in diet-induced obese mice results from reduced food intake with a relative maintenance of mass-specific energy expenditure. Fat loss and reduced RQ highlight the potential for PYY[3-36] to drive increased mobilization of fat stores to help meet energy requirements in this model.

Changes of intestinal mucosal and plasma PYY in a diarrhea model rat and influence of loperamide as the treatment agent for diarrhea.

PubMed

Hirotani, Yoshihiko; Mikajiri, Kyoko; Ikeda, Kenji; Myotoku, Michiaki; Kurokawa, Nobuo

2008-09-01

Peptide YY (PYY) is produced by endocrine cells in the lower gastrointestinal tract. The main functions of PYY are antisecretory effects in the colon and inhibition of gastrointestinal motility. We chose PYY as an index of the intrinsic factor in diarrhea and examined the influence of changes induced in a diarrhea rat model by administration of 4 types of laxative and loperamide hydrochloride (loperamide) as an agent for the treatment of diarrhea. A specific radioimmunoassay was performed to determine plasma and intestinal mucosal PYY concentrations. PYY in the rat intestinal tissue extract was distributed at a high density in the lower intestinal mucosa. In the diarrhea rat model, multiple changes in PYY concentrations in the intestinal mucosa and plasma were observed. In rats administered castor oil and sodium picosulfate, the intestinal mucosal PYY levels significantly decreased in a dose-dependent manner. Plasma PYY levels significantly decreased only in rats administered magnesium citrate. Next, we examined the influence of loperamide administration on the intestinal mucosa and plasma PYY concentrations in these rats. Loperamide administration resulted in multiple changes in plasma and intestinal mucosa PYY concentrations, along with an improvement in the diarrhea. Our research showed that the endocrine hormone PYY is involved in the onset of diarrhea, the course of the condition, and the manifestation of medicinal effects in the lower intestine.

PYY3–36 and Oxyntomodulin Can Be Additive in Their Effect on Food Intake in Overweight and Obese Humans

PubMed Central

Field, Benjamin C.T.; Wren, Alison M.; Peters, Veronique; Baynes, Kevin C.R.; Martin, Niamh M.; Patterson, Michael; Alsaraf, Sara; Amber, Vian; Wynne, Katie; Ghatei, Mohammad A.; Bloom, Stephen R.

2010-01-01

OBJECTIVE Peptide YY3–36 (PYY3–36), a Y2 receptor agonist, and oxyntomodulin, a glucagon-like peptide 1 (GLP-1) receptor agonist, are cosecreted by intestinal L-cells after each meal. Separately each hormone acts as an endogenous satiety signal and reduces appetite in humans when infused intravenously. The aim of the current study was to investigate whether the anorectic effects of PYY3–36 and oxyntomodulin can be additive. RESEARCH DESIGN AND METHODS Twelve overweight or obese human volunteers underwent a randomized, double-blinded, placebo-controlled study. An ad libitum test meal was used to measure energy intake during intravenous infusions of either PYY3–36 or oxyntomodulin or combined PYY3–36/oxyntomodulin. RESULTS Energy intake during coadministration of PYY3–36 and oxyntomodulin was reduced by 42.7% in comparison with the saline control and was significantly lower than that during infusions of either hormone alone. CONCLUSIONS The anorectic effects of PYY3–36 and oxyntomodulin can be additive in overweight and obese humans. Coadministration of Y2 receptor agonists and GLP-1 receptor agonists may be a useful treatment strategy for obesity. PMID:20357366

Changes of the peptide YY levels in the intestinal tissue of rats with experimental colitis following oral administration of mesalazine and prednisolone.

PubMed

Hirotani, Yoshihiko; Mikajiri, Kyoko; Ikeda, Kenji; Myotoku, Michiaki; Kurokawa, Nobuo

2008-09-01

Few studies have reported the changes in the peptide YY (PYY) levels in the intestinal tissue of rats with ulcerative colitis (UC) following oral administration of mesalazine and prednisolone. We investigated the effects of these drugs on the intestinal mucosal PYY levels in a rat model of UC. We confirmed that the PYY levels in the rat intestinal mucosal tissue were high in the lower intestinal tract. The leukocyte count and hemoglobin levels approached the normal values after administering mesalazine or prednisolone to rats treated with 3% dextran sulfate sodium (DSS). The PYY levels in the caecum and colon decreased significantly after administering DSS but increased when mesalazine was administered in a tissue-specific manner. Unlike mesalazine, the PYY levels increased in the ileum in addition to the colon and rectum after administering prednisolone. However, neither of the drugs induced any changes in the plasma PYY levels. These findings indicate that changes in the intestinal tissue PYY levels may be partially involved in the improvement of DSS-induced UC in rats following the administration of these drugs.

Peptide YY in diabetics treated chronically with an intestinal glucosidase inhibitor.

PubMed

Füessl, H S; Adrian, T E; Uttenthal, L O; Bloom, S R

1988-10-03

Peptide YY (PYY) is a recently discovered peptide found in the distal ileum and colon. It circulates in plasma and concentrations rise in malabsorptive conditions. The potential of PYY as an indicator of impaired carbohydrate digestion was studied in a pharmacological model of intestinal glucosidase inhibition. Thirteen type-2 diabetics on long-term treatment with the alpha-glucosidase inhibitor acarbose (3 x 100 mg per day) had test meals with and without acarbose 100 mg before and after the treatment period (mean 46 weeks), a test meal with acarbose after 20 weeks of continuous treatment and a final test meal without acarbose 6 weeks after cessation of treatment. Without acarbose mean plasma PYY concentrations rose from a mean basal value of 11.5 +/- 2.9 pmol/l to 19.5 +/- 3.9 pmol/l 120 min postprandially (P less than 0.01). Acarbose treatment did not effect basal plasma PYY concentrations but significantly enhanced food stimulated PYY concentrations acutely, at 20 weeks and at the final treatment test meal. Mean incremental integrated plasma responses (area under curve) rose by 183%, 184% and 169%, respectively (P less than 0.05). After cessation of treatment postprandial responses returned to pretreatment values within 6 weeks. Conversely, the integrated incremetal postprandial plasma responses of glucose and insulin were reversibly reduced by acarbose to 58% +/- 9% and 60% +/- 10% of controls, respectively. Self-assesed side effects of flatulence and more frequent bowel action showed no regular relationship to the PYY response. PYY seems to act as an indicator of the increased carbohydrate load to the distal intestine even in the absence of clinical symptoms. It may contribute to the hypoglycaemic effect of alpha-glucosidase inhibitors by slowing down intestinal transit.

Dietary resistant starch upregulates total GLP-1 and PYY in a sustained day-long manner through fermentation in rodents.

PubMed

Zhou, June; Martin, Roy J; Tulley, Richard T; Raggio, Anne M; McCutcheon, Kathleen L; Shen, Li; Danna, Samuel Colby; Tripathy, Sasmita; Hegsted, Maren; Keenan, Michael J

2008-11-01

Glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) are anti-diabetes/obesity hormones secreted from the gut after meal ingestion. We have shown that dietary-resistant starch (RS) increased GLP-1 and PYY secretion, but the mechanism remains unknown. RS is a fermentable fiber that lowers the glycemic index of the diet and liberates short-chain fatty acids (SCFAs) through fermentation in the gut. This study investigates the two possible mechanisms by which RS stimulates GLP-1 and PYY secretion: the effect of a meal or glycemic index, and the effect of fermentation. Because GLP-1 and PYY secretions are stimulated by nutrient availability in the gut, the timing of blood sample collections could influence the outcome when two diets with different glycemic indexes are compared. Thus we examined GLP-1 and PYY plasma levels at various time points over a 24-h period in RS-fed rats. In addition, we tested proglucagon (a precursor to GLP-1) and PYY gene expression patterns in specific areas of the gut of RS-fed rats and in an enteroendocrine cell line following exposure to SCFAs in vitro. Our findings are as follows. 1) RS stimulates GLP-1 and PYY secretion in a substantial day-long manner, independent of meal effect or changes in dietary glycemia. 2) Fermentation and the liberation of SCFAs in the lower gut are associated with increased proglucagon and PYY gene expression. 3) Glucose tolerance, an indicator of increased active forms of GLP-1 and PYY, was improved in RS-fed diabetic mice. We conclude that fermentation of RS is most likely the primary mechanism for increased endogenous secretions of total GLP-1 and PYY in rodents. Thus any factor that affects fermentation should be considered when dietary fermentable fiber is used to stimulate GLP-1 and PYY secretion.

Macronutrient Regulation of Ghrelin and Peptide YY in Pediatric Obesity and Prader-Willi Syndrome.

PubMed

Gumus Balikcioglu, Pinar; Balikcioglu, Metin; Muehlbauer, Michael J; Purnell, Jonathan Q; Broadhurst, David; Freemark, Michael; Haqq, Andrea M

2015-10-01

The roles of macronutrients and GH in the regulation of food intake in pediatric obesity and Prader-Willi Syndrome (PWS) are poorly understood. We compared effects of high-carbohydrate (HC) and high-fat (HF) meals and GH therapy on ghrelin, insulin, peptide YY (PYY), and insulin sensitivity in children with PWS and body mass index (BMI) -matched obese controls (OCs). In a randomized, crossover study, 14 PWS (median, 11.35 y; BMI z score [BMI-z], 2.15) and 14 OCs (median, 11.97 y; BMI-z, 2.35) received isocaloric breakfast meals (HC or HF) on separate days. Blood samples were drawn at baseline and every 30 minutes for 4 hours. Mixed linear models were adjusted for age, sex, and BMI-z. Relative to OCs, children with PWS had lower fasting insulin and higher fasting ghrelin and ghrelin/PYY. Ghrelin levels were higher in PWS across all postprandial time points (P < .0001). Carbohydrate was more potent than fat in suppressing ghrelin levels in PWS (P = .028); HC and HF were equipotent in OCs but less potent than in PWS (P = .011). The increase in PYY following HF was attenuated in PWS (P = .037); thus, postprandial ghrelin/PYY remained higher throughout. A lesser increase in insulin and lesser decrease in ghrelin were observed in GH-treated PWS patients than in untreated patients; PYY responses were comparable. Children with PWS have fasting and postprandial hyperghrelinemia and an attenuated PYY response to fat, yielding a high ghrelin/PYY ratio. GH therapy in PWS is associated with increased insulin sensitivity and lesser postprandial suppression of ghrelin. The ratio Ghrelin/PYY may be a novel marker of orexigenic drive.

Effect of weight loss by a low-fat diet and a low-carbohydrate diet on peptide YY levels.

PubMed

Essah, P A; Levy, J R; Sistrun, S N; Kelly, S M; Nestler, J E

2010-08-01

To compare the effects of weight loss by an energy-restricted low-fat diet vs low-carbohydrate diet on serum peptide YY (PYY) levels. 8-Week prospective study of 30 obese adults (mean age: 42.8+/-2.0 years, mean body mass index 35.5+/-0.6 kg m(-2)). After 8 weeks, subjects on the low-carbohydrate diet lost substantially more weight than those on the low-fat diet (5.8 vs 0.99 kg, P<0.001). Weight loss by either diet resulted in a 9% reduction in both mean fasting serum PYY levels (baseline: 103.5+/-8.8 pg ml(-1), after weight loss: 94.1+/-6.5 pg ml(-1), P<0.01) and postprandial area under the curve (AUC) PYY (baseline: (20.5+/-1.5) x 10(3) pg h(-1) ml(-1), after weight loss: mean AUC PYY (18.8+/-1.4) x 10(3) pg h(-1) ml(-1), P<0.001). There was a trend towards lower levels of PYY with greater degrees of weight loss. Reduced PYY levels after weight loss by an energy-restricted low-fat or low-carbohydrate diet likely represents a compensatory response to maintain energy homeostasis and contributes to difficulty in weight loss during energy-restricted diets.

Effect of weight loss by a low-fat diet and a low-carbohydrate diet on peptide YY levels

PubMed Central

Essah, P. A.; Levy, J. R.; Sistrun, S. N.; Kelly, S. M.; Nestler, J. E.

2010-01-01

Objective To compare the effects of weight loss by an energy-restricted low-fat diet versus low-carbohydrate diet on serum peptide YY (PYY) levels. Design 8-week prospective study of 30 obese adults (mean age: 42.8 ± 2.0 years, mean BMI 35.5 ± 0.6 kg/m2). Results After 8 weeks, subjects on the low-carbohydrate diet lost substantially more weight than those on the low-fat diet (5.8 kg vs. 0.99 kg, p<0.001). Weight loss by either diet resulted in a 9% reduction in both mean fasting serum PYY levels (baseline: 103.5 ± 8.8 pg/ml, after weight loss: 94.1 ± 6.5 pg/ml, p<0.01) and postprandial AUC PYY (baseline: (20.5 ± 1.5) × 103 pg·hr−1ml−1, after weight loss: mean AUC PYY (18.8 ± 1.4) × 103 pg·hr−1ml−1 p<0.001). There was a trend towards lower levels of PYY with greater degrees of weight loss. Conclusions Reduced PYY levels after weight loss by an energy-restricted low-fat or low-carbohydrate diet likely represents a compensatory response to maintain energy homeostasis and contributes to difficulty in weight loss during energy-restricted diets. PMID:20351741

High serum fasting peptide YY (3-36) is associated with obesity-associated insulin resistance and type 2 diabetes.

PubMed

Ukkola, Olavi H; Puurunen, Veli-Pekka; Piira, Olli-Pekka; Niva, Jarkko T; Lepojärvi, E Samuli; Tulppo, Mikko P; Huikuri, Heikki V

2011-10-10

We studied whether serum fasting levels of active form of peptide YY (PYY), PYY(3-36), are associated with obesity and related phenotypes. The study population consisted of 428 patients with coronary artery disease and diagnosed type 2 diabetes and 440 patients with coronary artery disease but without evidence of diabetes from the ARTEMIS study. The patients were recruited from the consecutive series of patients undergoing coronary angiography in the Oulu University Hospital. The patients without diabetes underwent a 2-hour oral glucose tolerance test. PYY(3-36) levels were analyzed by human PYY(3-36) specific radioimmunoassay. Result suggested that when PYY(3-36) tertiles were considered, high serum fasting PYY(3-36) concentration was associated with high body mass index, waist circumference, hemoglobin A1c, fasting blood glucose, leptin, triglyceride (p for all p ≤ 0.001), serum insulin (p=0.013) and with a low high-density lipoprotein cholesterol (p=0.004) concentrations in the analyses adjusted for age, sex and study group. The link high PYY(3-36)-high insulin level was evident in subjects with normal glucose tolerance (p<0.05). The prevalence of diabetes was 72%, 46% and 30% in the highest, medium and lowest PYY(3-36) tertile (p<0.001). The PYY(3-36) concentrations (after adjustment for age, sex and body mass index) were higher in type 2 diabetics compared to subjects with impaired fasting glucose, impaired glucose tolerance and normal glucose tolerance (p<0.001 for trend). In conclusion, fasting PYY(3-36) concentrations in type 2 diabetic subjects are high. Although high PYY(3-36) is strongly linked to obesity and associated insulin resistance, the relation between PYY(3-36) and type 2 diabetes is independent of body fatness. Copyright © 2011 Elsevier B.V. All rights reserved.

Macronutrient Regulation of Ghrelin and Peptide YY in Pediatric Obesity and Prader-Willi Syndrome

PubMed Central

Balikcioglu, Metin; Muehlbauer, Michael J.; Purnell, Jonathan Q.; Broadhurst, David; Freemark, Michael; Haqq, Andrea M.

2015-01-01

Background: The roles of macronutrients and GH in the regulation of food intake in pediatric obesity and Prader-Willi Syndrome (PWS) are poorly understood. Objective: We compared effects of high-carbohydrate (HC) and high-fat (HF) meals and GH therapy on ghrelin, insulin, peptide YY (PYY), and insulin sensitivity in children with PWS and body mass index (BMI) –matched obese controls (OCs). Methods: In a randomized, crossover study, 14 PWS (median, 11.35 y; BMI z score [BMI-z], 2.15) and 14 OCs (median, 11.97 y; BMI-z, 2.35) received isocaloric breakfast meals (HC or HF) on separate days. Blood samples were drawn at baseline and every 30 minutes for 4 hours. Mixed linear models were adjusted for age, sex, and BMI-z. Results: Relative to OCs, children with PWS had lower fasting insulin and higher fasting ghrelin and ghrelin/PYY. Ghrelin levels were higher in PWS across all postprandial time points (P < .0001). Carbohydrate was more potent than fat in suppressing ghrelin levels in PWS (P = .028); HC and HF were equipotent in OCs but less potent than in PWS (P = .011). The increase in PYY following HF was attenuated in PWS (P = .037); thus, postprandial ghrelin/PYY remained higher throughout. A lesser increase in insulin and lesser decrease in ghrelin were observed in GH-treated PWS patients than in untreated patients; PYY responses were comparable. Conclusion: Children with PWS have fasting and postprandial hyperghrelinemia and an attenuated PYY response to fat, yielding a high ghrelin/PYY ratio. GH therapy in PWS is associated with increased insulin sensitivity and lesser postprandial suppression of ghrelin. The ratio Ghrelin/PYY may be a novel marker of orexigenic drive. PMID:26259133

Peptide YY, neuropeptide Y and corticotrophin-releasing factor modulate gastrointestinal motility and food intake during acute stress.

PubMed

Forbes, Sarah C; Cox, Helen M

2014-11-01

Peripheral neuropeptide Y (NPY) provides protection against the endocrine, feeding and gastrointestinal (GI) responses to stress; however, it is not yet established how it interacts with corticotrophin-releasing factor (CRF) to mediate these effects. Peptide YY (PYY) also has significant roles in GI motility and food intake but little is known about its role in stress responses. Upper GI transit, fecal pellet output (FPO) and feeding responses, and the role of CRF1 receptors, during restraint or a novel environment stress, were ascertained in PYY-/-, NPY-/- and wild type (WT) mice, with CRF and the CRF1 antagonist, antalarmin, injected intraperitoneally. Upper GI transit and FPO were significantly increased in PYY-/- mice during restraint stress. Exogenous CRF increased defecation during placement in a novel environment in WT mice through CRF1 , while CRF1 blockade reduced defecation in WT and NPY-/- mice but had no effect in PYY-/- mice. In addition, CRF1 blockade had no effect on upper GI transit in WT mice, or on food intake in PYY-/- or NPY-/- mice, but it significantly increased food intake in WT mice. Endogenous NPY appears to inhibit the colonic motor response induced by CRF1 activation, unlike PYY, while both peptides are required for CRF1 modulation of feeding behavior during stress. Overall, these results provide new insights into the mechanism by which PYY and NPY affect stress responses. © 2014 John Wiley & Sons Ltd.

Ghrelin and PYY levels in adolescents with severe obesity: effects of weight loss induced by long-term exercise training and modified food habits.

PubMed

Gueugnon, Carine; Mougin, Fabienne; Nguyen, Nhu Uyen; Bouhaddi, Malika; Nicolet-Guénat, Marie; Dumoulin, Gilles

2012-05-01

This study investigated (a) changes in ghrelin and peptide YY (PYY) concentrations during a weight reduction programme and (b) baseline ghrelin and PYY levels as predictors of weight loss in 32 severely obese adolescents (BMI z score = 4.1). Subjects spent an academic year in an institution for childhood obesity. Fasting ghrelin and PYY, leptin, insulin levels and insulin resistance were measured at baseline (month 0) and during the programme (months 3, 6, 9). In addition, 15 normal-weight teenagers served as reference for the baseline assessments. At baseline, obese teenagers had lower ghrelin and PYY concentrations than normal-weight adolescents (P < 0.05). Moreover, they showed significantly higher leptin, insulin levels and homeostasis model assessment (HOMA) (P < 0.0001). During the lifestyle modification, there was a significant decrease in body weight among obese teenagers, associated with an increase in ghrelin (apparent from month 6; P < 0.05), a decrease in leptin (from month 3; P < 0.05) and a decrease in insulin and HOMA (from month 3; P < 0.0001), without any significant change in PYY. Anthropometrical changes were correlated neither with baseline ghrelin levels nor with changes in ghrelin and PYY after the lifestyle modification. However, higher baseline PYY tended to correlate with greater anthropometrical changes (P < 0.1). In adolescents with severe obesity, a long-term combination of supervised aerobic exercises and a balanced diet led to weight reduction and increased ghrelin concentrations, without any change in PYY concentrations. Moreover, baseline PYY concentrations might be considered as predictors of weight loss.

Presence and dynamics of leptin, GLP-1, and PYY in human breast milk at early postpartum.

PubMed

Schueler, Jessica; Alexander, Brenda; Hart, Ann Marie; Austin, Kathleen; Larson-Meyer, D Enette

2013-07-01

The presence of appetite hormones, namely glucagon-like peptide-1 (GLP-1), peptide YY (PYY), and leptin in breast milk may be important in infant feeding regulation and infant growth. This study evaluated whether concentrations of GLP-1, PYY, and leptin change across a single feeding (from fore- to hindmilk), and are associated with maternal and infant anthropometrics. Thirteen postpartum women (mean ± SD: 25.6 ± 4.5 years, 72.0 ± 11.9 kg) provided fore- and hindmilk samples 4-5 weeks after delivery and underwent measurements of body weight and composition by Dual X-ray Absorptiometry. GLP-1, PYY, and leptin concentrations were measured using radioimmunoassay, and milk fat content was determined by creamatocrit. Concentration of GLP-1 and content of milk fat was higher in hindmilk than foremilk (P ≤ 0.05). PYY and leptin concentrations did not change between fore- and hindmilk. Both leptin concentration and milk fat content were correlated with indices of maternal adiposity, including body mass index (r = 0.65-0.85, P < 0.02), and fat mass (r = 0.65-0.84, P < 0.02). Hindmilk GLP-1 was correlated with infant weight gain from birth to 6 months (r = -0.67, P = 0.034). The presence of appetite hormones in breast milk may be important in infant appetite and growth regulation. Copyright © 2013 The Obesity Society.

Appetite-related peptides in childhood and adolescence: role of ghrelin, PYY, and GLP-1.

PubMed

Horner, Katy; Lee, SoJung

2015-11-01

During childhood and adolescence, a number of factors, including age, puberty, sex, race, and body composition, may contribute to differences in satiety, food intake, and appetite-related peptides. These peptides include the orexigenic peptide ghrelin and anorexigenic gut peptides peptide YY (PYY) and glucagon-like peptide-1 (GLP-1). For example, lower fasting ghrelin levels, lower postprandial ghrelin suppression, and blunted PYY and GLP-1 responses to food intake could contribute to a dysregulation of appetite in already obese children and adolescents. Whereas, changes in these peptides observed during puberty could facilitate growth. A greater understanding of the major moderating factors of appetite-related peptides in the pediatric population is essential to improve interpretation of study findings and for effective tailoring of strategies targeting appetite control to individuals. While more studies are needed, there is some evidence to suggest that exercise-based lifestyle interventions could be a potential therapeutic strategy to improve appetite-peptide profiles in overweight and obese children and adolescents. The aim of this review is (i) to discuss the potential moderating factors of ghrelin, PYY, and GLP-1, including age and puberty, sex, race and body composition; and (ii) to examine the effects of exercise interventions on these appetite-related gut peptides in children and adolescents.

Hedonic eating in Prader–Willi syndrome is associated with blunted PYY secretion

PubMed Central

Rigamonti, A. E.; Bini, S.; Piscitelli, F.; Lauritano, A.; Di Marzo, V.; Vanetti, C.; Agosti, F.; De Col, A.; Lucchetti, E.; Grugni, G.; Sartorio, A.

2017-01-01

ABSTRACT Hedonic and homeostatic hunger represent two different forms of eating: just for pleasure or following energy deprivation, respectively. Consumption of food for pleasure was reported to be associated with increased circulating levels of both the orexigenic peptide ghrelin and some specific endocannabinoids in normal-weight subjects and patients with morbid obesity. To date, the effects of palatable food on these mediators in Prader–Willi syndrome (PWS) are still unknown. To explore the role of some gastrointestinal orexigenic and anorexigenic peptides and endocannabinoids (and some related congeners) in chocolate consumption, we measured changes in circulating levels of ghrelin, cholecystokinin (CCK), peptide YY (PYY), anandamide (AEA), 2-arachidonoyl-glycerol (2-AG), palmitoylethanolamide (PEA) and oleoylethanolamide (OEA) in eight satiated adult PWS patients after consumption of chocolate and, on a separate day, of a non-palatable isocaloric food with the same macronutrient composition. Evaluation of hunger and satiety was also performed by visual analogic scale. The anticipatory phase and the consumption of food for pleasure were associated with decreased circulating levels of PYY. An increase in PEA levels was also observed. By contrast, circulating levels of ghrelin, CCK, AEA, 2-AG and OEA did not differ before and after the exposure/ingestion of either chocolate or non-palatable foods. Hunger and satiety were similar in the hedonic and non-palatable sessions. In conclusion, when motivation to eat is promoted by highly palatable foods, a depressed post-prandial PYY secretion is observed in PWS. Although preliminary, these findings seem to hypothesize a possible role of PYY agonists in the management of PWS patients. Abbreviations: AEA, Anandamide; 2-AG, 2-arachidonoyl-glycerol; CB1, cannabinoid receptor type 1; OEA, oleoylethanolamide; PEA, palmitoylethanolamide; PWS: Prader-Willi syndrome; VAS, visual analog scales PMID:28659728

Anorexia Induction by the Trichothecene Deoxynivalenol (Vomitoxin) Is Mediated by the Release of the Gut Satiety Hormone Peptide YY

PubMed Central

Pestka, James J.

2012-01-01

Consumption of deoxynivalenol (DON), a trichothecene mycotoxin known to commonly contaminate grain-based foods, suppresses growth of experimental animals, thus raising concerns over its potential to adversely affect young children. Although this growth impairment is believed to result from anorexia, the initiating mechanisms for appetite suppression remain unknown. Here, we tested the hypothesis that DON induces the release of satiety hormones and that this response corresponds to the toxin’s anorectic action. Acute ip exposure to DON had no effect on plasma glucagon-like peptide-1, leptin, amylin, pancreatic polypeptide, gastric inhibitory peptide, or ghrelin; however, the toxin was found to robustly elevate peptide YY (PYY) and cholecystokinin (CCK). Specifically, ip exposure to DON at 1 and 5mg/kg bw induced PYY by up to 2.5-fold and CCK by up to 4.1-fold. These responses peaked within 15–120min and lasted up to 120min (CCK) and 240min (PPY), corresponding with depressed rates of food intake. Direct administration of exogenous PYY or CCK similarly caused reduced food intake. Food intake experiments using the NPY2 receptor antagonist BIIE0246 and the CCK1A receptor antagonist devazepide, individually, suggested that PYY mediated DON-induced anorexia but CCK did not. Orolingual exposure to DON induced plasma PYY and CCK elevation and anorexia comparable with that observed for ip exposure. Taken together, these findings suggest that PYY might be one critical mediator of DON-induced anorexia and, ultimately, growth suppression. PMID:22903826

Anorexia induction by the trichothecene deoxynivalenol (vomitoxin) is mediated by the release of the gut satiety hormone peptide YY.

PubMed

Flannery, Brenna M; Clark, Erica S; Pestka, James J

2012-12-01

Consumption of deoxynivalenol (DON), a trichothecene mycotoxin known to commonly contaminate grain-based foods, suppresses growth of experimental animals, thus raising concerns over its potential to adversely affect young children. Although this growth impairment is believed to result from anorexia, the initiating mechanisms for appetite suppression remain unknown. Here, we tested the hypothesis that DON induces the release of satiety hormones and that this response corresponds to the toxin's anorectic action. Acute ip exposure to DON had no effect on plasma glucagon-like peptide-1, leptin, amylin, pancreatic polypeptide, gastric inhibitory peptide, or ghrelin; however, the toxin was found to robustly elevate peptide YY (PYY) and cholecystokinin (CCK). Specifically, ip exposure to DON at 1 and 5mg/kg bw induced PYY by up to 2.5-fold and CCK by up to 4.1-fold. These responses peaked within 15-120 min and lasted up to 120 min (CCK) and 240 min (PPY), corresponding with depressed rates of food intake. Direct administration of exogenous PYY or CCK similarly caused reduced food intake. Food intake experiments using the NPY2 receptor antagonist BIIE0246 and the CCK1A receptor antagonist devazepide, individually, suggested that PYY mediated DON-induced anorexia but CCK did not. Orolingual exposure to DON induced plasma PYY and CCK elevation and anorexia comparable with that observed for ip exposure. Taken together, these findings suggest that PYY might be one critical mediator of DON-induced anorexia and, ultimately, growth suppression.

Increased plasma PYY levels following supplementation with the functional fiber PolyGlycopleX in healthy adults.

PubMed

Reimer, R A; Pelletier, X; Carabin, I G; Lyon, M; Gahler, R; Parnell, J A; Wood, S

2010-10-01

A variety of dietary fibers have been shown to alter satiety hormone gene expression and secretion. The objective of this study was to examine plasma satiety hormone concentrations in healthy subjects consuming either PolyGlycopleX (PGX) or control (skim milk powder) for 21 days. A randomized, double-blind, placebo-controlled clinical study was conducted in 54 healthy male and female adults. Participants consumed 5 g per day of PGX or control for 1 week followed by 2 additional weeks of 10 g per day of assigned product (n=27 per group). Primary outcomes measured at three visits (V1, V2 and V3) were plasma active glucagon-like peptide-1 (GLP-1) total ghrelin, peptide YY (PYY) and insulin. There was a significant effect of visit for fasting PYY with control participants experiencing decreased PYY levels over time while PGX prevented this decline. When stratified by body mass index (BMI), PGX increased fasting PYY levels from week 1 to week 3 compared with control in participants with BMI <23 kg/m(2). There was a significant effect of visit for fasting ghrelin with levels decreasing in both PGX and control groups over time. No differences were detected in fasting GLP-1 levels. Although there was a 14% reduction in fasting insulin between V1 and V3 with PGX this was not significantly different from control. PGX is a highly viscous, functional fiber that modifies satiety hormone secretion in healthy adults. Its' potential to act similarly in overweight adults warrants investigation.

Basal and meal-stimulated ghrelin, PYY, CCK levels and satiety in lean women with polycystic ovary syndrome: effect of low-dose oral contraceptive.

PubMed

Arusoglu, Gulcan; Koksal, Gulden; Cinar, Nese; Tapan, Serkan; Aksoy, Duygu Yazgan; Yildiz, Bulent O

2013-11-01

Ghrelin is an orexigenic peptide that stimulates food intake, whereas peptide YY (PYY) and cholecystokinin (CCK) are anorexigenic gut hormones. Patients with polycystic ovary syndrome (PCOS) appear to have alterations in appetite regulation. We aimed to determine whether fasting or meal-stimulated ghrelin, PYY, CCK, and satiety responses are different between lean PCOS patients and healthy women. We also aimed to assess the potential effect of oral contraceptive use on these hormones and satiety response. We conducted a prospective observational study in a university practice. Eighteen lean PCOS patients and 18 healthy control women matched for age and body mass index underwent measurements of circulating ghrelin, PYY, CCK, and satiety index (SI) before and after a standardized mixed meal at 0, 15, 30, 45, 60, 90, 120, and 180 minutes. For PCOS patients who were treated with ethinyl estradiol 30 μg/drospirenone 3 mg for 3 months, measurements were repeated. We measured ghrelin, PYY, and CCK levels and SI. At baseline, fasting ghrelin, PYY, CCK, and SI values in PCOS patients were not different from controls. Meal-stimulated PYY, CCK, and SI were also not different between the groups, whereas PCOS patients had significantly lower meal-stimulated ghrelin levels compared to controls (P = .04). Ghrelin, PYY, CCK, and SI did not show a significant change after treatment with ethinyl estradiol/drospirenone for 3 months. Basal and stimulated hunger and satiety hormones in lean PCOS patients are not different from lean healthy women, except for a lower meal-stimulated ghrelin response. Short-term use of a low-dose oral contraceptive does not have an effect on appetite regulation of PCOS.

Estrogen and peptide YY are associated with bone mineral density in premenopausal exercising women.

PubMed

Scheid, J L; Toombs, R J; Ducher, G; Gibbs, J C; Williams, N I; De Souza, M J

2011-08-01

In women with anorexia nervosa, elevated fasting peptide YY (PYY) is associated with decreased bone mineral density (BMD). Prior research from our lab has demonstrated that fasting total PYY concentrations are elevated in exercising women with amenorrhea compared to ovulatory exercising women. The purpose of this study was to assess the association between fasting total PYY, average monthly estrogen exposure and BMD in non-obese premenopausal exercising women. Daily urine samples were collected and assessed for metabolites of estrone 1-glucuronide (E1G) and pregnandiol glucuronide (PdG) for at least one menstrual cycle if ovulatory or a 28-day monitoring period if amenorrheic. Fasting serum samples were pooled over the measurement period and analyzed for total PYY and leptin. BMD and body composition were assessed by dual-energy X-ray absorptiometry. Multiple regression analyses were performed to determine whether measures of body composition, estrogen status, exercise minutes, leptin and PYY explained a significant amount of the variance in BMD at multiple sites. Premenopausal exercising women aged 23.8±0.9years with a mean BMI of 21.2±0.4kg/m(2) exercised 346±48min/week and had a peak oxygen uptake of 49.1±1.8mL/kg/min. Thirty-nine percent (17/44) of the women had amenorrhea. Fasting total PYY concentrations were negatively associated with total body BMD (p=0.033) and total hip BMD (p=0.043). Mean E1G concentrations were positively associated with total body BMD (p=0.033) and lumbar spine (L2-L4) BMD (p=0.047). The proportion of variance in lumbar spine (L2-L4) BMD explained by body weight and E1G cycle mean was 16.4% (R(2)=0.204, p=0.012). The proportion of variance in hip BMD explained by PYY cycle mean was 8.6% (R(2)=0.109, p=0.033). The proportion of variance in total body BMD explained by body weight and E1G cycle mean was 21.9% (R(2)=0.257, p=0.003). PYY, mean E1G and body weight are associated with BMD in premenopausal exercising women. Thus, elevated

Elevated PYY is associated with energy deficiency and indices of subclinical disordered eating in exercising women with hypothalamic amenorrhea.

PubMed

Scheid, Jennifer L; Williams, Nancy I; West, Sarah L; VanHeest, Jaci L; De Souza, Mary Jane

2009-02-01

The purpose of this study was twofold: (1) to determine if gastrointestinal hormones, associated with energy intake and energy balance, are altered in exercising women with hypothalamic amenorrhea and (2) to assess the association between gastrointestinal hormones and behavioural indicators of subclinical disordered eating in exercising women with hypothalamic amenorrhea. This cross-sectional study analyzed serum ghrelin, peptide YY (PYY), glucagon-like peptide-1 (GLP-1), menstrual status (by E1G and PdG), resting energy expenditure (REE), and subclinical eating behaviours in sedentary ovulatory (SedOv), exercising ovulatory (ExOv), and exercising amenorrheic (ExAmen) women. Groups were similar with respect to age (23.8+/-0.6 years) and BMI (21.4+/-0.3 kg/m(2)). The ratio of REE to predicted REE (REE:predicted REE) was 0.94+/-0.02, 0.94+/-0.02, and 0.88+/-0.02 in the SedOv, ExOv, and ExAmen groups, respectively. The REE:predicted REE in the ExAmen group was consistent with an energy deficiency. LogPYY, ghrelin, dietary cognitive restraint, and drive for thinness were elevated in the ExAmen group compared to other groups. GLP-1 concentrations were similar among groups. LogPYY correlated with drive for thinness and REE/FFM. In conclusion, fasting PYY and ghrelin concentrations are elevated in exercising women with FHA and both gastrointestinal peptides may serve as a proxy indicator of energy deficiency in this population.

Combination of Peptide YY3–36 with GLP-17–36 amide Causes an Increase in First-Phase Insulin Secretion after IV Glucose

PubMed Central

Tan, Tricia M.; Salem, Victoria; Troke, Rachel C.; Alsafi, Ali; Field, Benjamin C. T.; De Silva, Akila; Misra, Shivani; Baynes, Kevin C. R.; Donaldson, Mandy; Minnion, James; Ghatei, Mohammad A.; Godsland, Ian F.

2014-01-01

Context: The combination of peptide YY (PYY) and glucagon-like peptide-1 (GLP-1) has been proposed as a potential treatment for diabetes and obesity. However, the combined effects of these hormones, PYY3–36 and GLP-17–36 amide, on glucose homeostasis are unknown. Objective: This study sought to investigate the acute effects of PYY3–36 and GLP-17–36 amide, individually and in combination, on insulin secretion and sensitivity. Setting and Design: Using a frequently sampled iv glucose tolerance test (FSIVGTT) and minimal modeling, this study measured the effects of PYY3–36 alone, GLP-17–36 amide alone, and a combination of PYY3–36 and GLP-17–36 amide on acute insulin response to glucose (AIRg) and insulin sensitivity index (SI) in 14 overweight human volunteers, studied in a clinical research facility. Results: PYY3–36 alone caused a small but nonsignificant increase in AIRg. GLP-17–36 amide alone and the combination of PYY3–36 and GLP-17–36 amide did increase AIRg significantly. No significant differences in SI were observed with any intervention. Conclusions: PYY3–36 lacks any significant acute effects on first-phase insulin secretion or SI when tested using an FSIVGTT. Both GLP-17–36 amide alone and the combination of PYY3–36 and GLP-17–36 amide increase first-phase insulin secretion. There does not seem to be any additive or synergistic effect between PYY3–36 and GLP-17–36 amide on first-phase insulin secretion. Neither hormone alone nor the combination had any significant effects on SI. PMID:25144632

Correlations of circulating peptide YY and ghrelin with body weight, rate of weight gain, and time required to achieve the recommended daily intake in preterm infants.

PubMed

Chen, XiaFang; Du, XueLiang; Zhu, JianXing; Xie, LiJuan; Zhang, YongJun; He, ZhenJuan

2012-07-01

The objective was to elucidate the relationships between serum concentrations of the gut hormone peptide YY (PYY) and ghrelin and growth development in infants for potential application to the clinical observation index. Serum concentrations of PYY and ghrelin were measured using radioimmunoassay from samples collected at the clinic. For each patient, gestational age, birth weight, time required to return to birth weight, rate of weight gain, time required to achieve recommended daily intake (RDI) standards, time required for full-gastric feeding, duration of hospitalization, and time of administration of total parenteral nutrition were recorded. Serum PYY and ghrelin concentrations were significantly higher in the preterm group (N = 20) than in the full-term group (N = 20; P < 0.01). Within the preterm infant group, the serum concentrations of PYY and ghrelin on postnatal day (PND) 7 (ghrelin = 1485.38 ± 409.24; PYY = 812.37 ± 153.77 ng/L) were significantly higher than on PND 1 (ghrelin = 956.85 ± 223.09; PYY = 545.27 ± 204.51 ng/L) or PND 3 (ghrelin = 1108.44 ± 351.36; PYY = 628.96 ± 235.63 ng/L; P < 0.01). Both serum PYY and ghrelin concentrations were negatively correlated with body weight, and the degree of correlation varied with age. Serum ghrelin concentration correlated negatively with birth weight and positively with the time required to achieve RDI (P < 0.05). In conclusion, serum PYY and ghrelin concentrations reflect a negative energy balance, predict postnatal growth, and enable compensation. Further studies are required to elucidate the precise concentration and roles of PYY and ghrelin in newborns and to determine the usefulness of measuring these hormones in clinical practice.

Genome-wide analysis of YY2 versus YY1 target genes

PubMed Central

Chen, Li; Shioda, Toshi; Coser, Kathryn R.; Lynch, Mary C.; Yang, Chuanwei; Schmidt, Emmett V.

2010-01-01

Yin Yang 1 (YY1) is a critical transcription factor controlling cell proliferation, development and DNA damage responses. Retrotranspositions have independently generated additional YY family members in multiple species. Although Drosophila YY1 [pleiohomeotic (Pho)] and its homolog [pleiohomeotic-like (Phol)] redundantly control homeotic gene expression, the regulatory contributions of YY1-homologs have not yet been examined in other species. Indeed, targets for the mammalian YY1 homolog YY2 are completely unknown. Using gene set enrichment analysis, we found that lentiviral constructs containing short hairpin loop inhibitory RNAs for human YY1 (shYY1) and its homolog YY2 (shYY2) caused significant changes in both shared and distinguishable gene sets in human cells. Ribosomal protein genes were the most significant gene set upregulated by both shYY1 and shYY2, although combined shYY1/2 knock downs were not additive. In contrast, shYY2 reversed the anti-proliferative effects of shYY1, and shYY2 particularly altered UV damage response, platelet-specific and mitochondrial function genes. We found that decreases in YY1 or YY2 caused inverse changes in UV sensitivity, and that their combined loss reversed their respective individual effects. Our studies show that human YY2 is not redundant to YY1, and YY2 is a significant regulator of genes previously identified as uniquely responding to YY1. PMID:20215434

NPY1–36 and PYY1–36 activate cardiac fibroblasts: an effect enhanced by genetic hypertension and inhibition of dipeptidyl peptidase 4

PubMed Central

Zhu, Xiao; Gillespie, Delbert G.

2015-01-01

Cardiac sympathetic nerves release neuropeptide Y (NPY)1–36, and peptide YY (PYY)1–36 is a circulating peptide; therefore, these PP-fold peptides could affect cardiac fibroblasts (CFs). We examined the effects of NPY1–36 and PYY1–36 on the proliferation of and collagen production ([3H]proline incorporation) by CFs isolated from Wistar-Kyoto (WKY) normotensive rats and spontaneously hypertensive rats (SHRs). Experiments were performed with and without sitagliptin, an inhibitor of dipeptidyl peptidase 4 [DPP4; an ectoenzyme that metabolizes NPY1–36 and PYY1–36 (Y1 receptor agonists) to NPY3–36 and PYY3–36 (inactive at Y1 receptors), respectively]. NPY1–36 and PYY1–36, but not NPY3–36 or PYY3–36, stimulated proliferation of CFs, and these effects were more potent than ANG II, enhanced by sitagliptin, blocked by BIBP3226 (Y1 receptor antagonist), and greater in SHR CFs. SHR CF membranes expressed more receptor for activated C kinase (RACK)1 [which scaffolds the Gi/phospholipase C (PLC)/PKC pathway] compared with WKY CF membranes. RACK1 knockdown (short hairpin RNA) and inhibition of Gi (pertussis toxin), PLC (U73122), and PKC (GF109203X) blocked the proliferative effects of NPY1–36. NPY1–36 and PYY1–36 stimulated collagen production more potently than did ANG II, and this was enhanced by sitagliptin and greater in SHR CFs. In conclusion, 1) NPY1–36 and PYY1–36, via the Y1 receptor/Gi/PLC/PKC pathway, activate CFs, and this pathway is enhanced in SHR CFs due to increased localization of RACK1 in membranes; and 2) DPP4 inhibition enhances the effects of NPY1–36 and PYY1–36 on CFs, likely by inhibiting the metabolism of NPY1–36 and PYY1–36. The implications are that endogenous NPY1–36 and PYY1–36 could adversely affect cardiac structure/function by activating CFs, and this may be exacerbated in genetic hypertension and by DPP4 inhibitors. PMID:26371160

Peptide YY3–36 and 5-Hydroxytryptamine Mediate Emesis Induction by Trichothecene Deoxynivalenol (Vomitoxin)

PubMed Central

Pestka, James J.

2013-01-01

Deoxynivalenol (DON, vomitoxin), a trichothecene mycotoxin produced by Fusarium sp. that frequently occurs in cereal grains, has been associated with human and animal food poisoning. Although a common hallmark of DON-induced toxicity is the rapid onset of emesis, the mechanisms for this adverse effect are not fully understood. Recently, our laboratory has demonstrated that the mink (Neovison vison) is a suitable small animal model for investigating trichothecene-induced emesis. The goal of this study was to use this model to determine the roles of two gut satiety hormones, peptide YY3–36 (PYY3–36) and cholecystokinin (CCK), and the neurotransmitter 5-hydroxytryptamine (5-HT) in DON-induced emesis. Following ip exposure to DON at 0.1 and 0.25mg/kg bw, emesis induction ensued within 15–30min and then persisted up to 120min. Plasma DON measurement revealed that this emesis period correlated with the rapid distribution and clearance of the toxin. Significant elevations in both plasma PYY3–36 (30–60min) and 5-HT (60min) but not CCK were observed during emesis. Pretreatment with the neuropeptide Y2 receptor antagonist JNJ-31020028 attenuated DON- and PYY-induced emesis, whereas the CCK1 receptor antagonist devezapide did not alter DON’s emetic effects. The 5-HT3 receptor antagonist granisetron completely suppressed induction of vomiting by DON and the 5-HT inducer cisplatin. Granisetron pretreatment also partially blocked PYY3–36-induced emesis, suggesting a potential upstream role for this gut satiety hormone in 5-HT release. Taken together, the results suggest that both PYY3–36 and 5-HT play contributory roles in DON-induced emesis. PMID:23457120

Effects of miglitol, vildagliptin, or their combination on serum insulin and peptide YY levels and plasma glucose, cholecystokinin, ghrelin, and obestatin levels.

PubMed

Aoki, Kazutaka; Kamiyama, Hiroshi; Masuda, Kiyomi; Kamiko, Kazunari; Noguchi, Yoshihiko; Tajima, Kazuki; Terauchi, Yasuo

2014-01-01

We previously reported that combination therapy with an α-glucosidase inhibitor (αGI) and a dipeptidyl peptidase-4 (DPP-4) inhibitor increased active glucagon-like peptide-1 (GLP-1) levels and decreased total glucose-dependent insulinotropic polypeptide (GIP) levels, compared with monotherapy, in non-diabetic men. However, the peptide YY (PYY), cholecystokinin (CCK), ghrelin, and obestatin levels in patients receiving a combination of αGIs and DPP-4 inhibitors have not been previously reported. We evaluated the effect of miglitol, vildagliptin, or their combination on these parameters. Miglitol and/or vildagliptin were administered according to four different intake schedules in eleven non-diabetic men (C: no drug, M: miglitol; V: vildagliptin, M+V: miglitol+vildagliptin). Blood samples were collected at 0, 30, 60, and 120 min after the start of breakfast. The plasma glucose, serum insulin, serum total PYY (PYY1-36 and PYY3-36), plasma CCK, plasma active ghrelin, and plasma obestatin levels were measured. The area under the curve (AUC) of the serum total PYY level in the M group was significantly greater than that in the C group, and the AUC of the serum total PYY level in the M+V group was significantly lower than that in the M group. The combination therapy did not change the AUC of the plasma CCK, plasma active ghrelin, plasma obestatin, and ghrelin/obestatin levels, compared with the control. The results of our study suggested that combination therapy with miglitol and vildagliptin had no effect on appetite regulation hormones, such as total PYY, CCK, active ghrelin, and obestatin, compared with the levels in the control group.

Elucidation of the Binding Mode of the Carboxyterminal Region of Peptide YY to the Human Y2 Receptor.

PubMed

Xu, Bo; Vasile, Silvana; Østergaard, Søren; Paulsson, Johan F; Pruner, Jasna; Åqvist, Johan; Wulff, Birgitte S; Gutiérrez-de-Terán, Hugo; Larhammar, Dan

2018-04-01

Understanding the agonist-receptor interactions in the neuropeptide Y (NPY)/peptide YY (PYY) signaling system is fundamental for the design of novel modulators of appetite regulation. We report here the results of a multidisciplinary approach to elucidate the binding mode of the native peptide agonist PYY to the human Y 2 receptor, based on computational modeling, peptide chemistry and in vitro pharmacological analyses. The preserved binding orientation proposed for full-length PYY and five analogs, truncated at the amino terminus, explains our pharmacological results where truncations of the N-terminal proline helix showed little effect on peptide affinity. This was followed by receptor mutagenesis to investigate the roles of several receptor positions suggested by the modeling. As a complement, PYY-(3-36) analogs were synthesized with modifications at different positions in the common PYY/NPY C-terminal fragment ( 32 TRQRY 36 -amide). The results were assessed and interpreted by molecular dynamics and Free Energy Perturbation (FEP) simulations of selected mutants, providing a detailed map of the interactions of the PYY/NPY C-terminal fragment with the transmembrane cavity of the Y 2 receptor. The amidated C-terminus would be stabilized by polar interactions with Gln288 6.55 and Tyr219 5.39 , while Gln130 3.32 contributes to interactions with Q 34 in the peptide and T 32 is close to the tip of TM7 in the receptor. This leaves the core, α -helix of the peptide exposed to make potential interactions with the extracellular loops. This model agrees with most experimental data available for the Y 2 system and can be used as a basis for optimization of Y 2 receptor agonists. Copyright © 2018 by The Author(s).

Correlations of circulating peptide YY and ghrelin with body weight, rate of weight gain, and time required to achieve the recommended daily intake in preterm infants

PubMed Central

Chen, XiaFang; Du, Xueliang; Zhu, JianXing; Xie, LiJuan; Zhang, YongJun; He, ZhenJuan

2012-01-01

The objective was to elucidate the relationships between serum concentrations of the gut hormone peptide YY (PYY) and ghrelin and growth development in infants for potential application to the clinical observation index. Serum concentrations of PYY and ghrelin were measured using radioimmunoassay from samples collected at the clinic. For each patient, gestational age, birth weight, time required to return to birth weight, rate of weight gain, time required to achieve recommended daily intake (RDI) standards, time required for full-gastric feeding, duration of hospitalization, and time of administration of total parenteral nutrition were recorded. Serum PYY and ghrelin concentrations were significantly higher in the preterm group (N = 20) than in the full-term group (N = 20; P < 0.01). Within the preterm infant group, the serum concentrations of PYY and ghrelin on postnatal day (PND) 7 (ghrelin = 1485.38 ± 409.24; PYY = 812.37 ± 153.77 ng/L) were significantly higher than on PND 1 (ghrelin = 956.85 ± 223.09; PYY = 545.27 ± 204.51 ng/L) or PND 3 (ghrelin = 1108.44 ± 351.36; PYY = 628.96 ± 235.63 ng/L; P < 0.01). Both serum PYY and ghrelin concentrations were negatively correlated with body weight, and the degree of correlation varied with age. Serum ghrelin concentration correlated negatively with birth weight and positively with the time required to achieve RDI (P < 0.05). In conclusion, serum PYY and ghrelin concentrations reflect a negative energy balance, predict postnatal growth, and enable compensation. Further studies are required to elucidate the precise concentration and roles of PYY and ghrelin in newborns and to determine the usefulness of measuring these hormones in clinical practice. PMID:22527125

Antral G-cell in gastrin and gastrin-cholecystokinin knockout animals.

PubMed

Friis-Hansen, Lennart; Wierup, Nils; Rehfeld, Jens F; Sundler, Frank

2005-07-01

The antral hormone gastrin is the key regulator of gastric acid secretion, mucosal growth and differentiation. Gastrin is synthesized in the endocrine G-cells in the antroduodenal mucosa. We have now examined the way in which the loss of gastrin alone or gastrin plus cholecystokinin (CCK) affects the antral G-cell. Immunohistochemistry, radioimmunoassay and quantitative real-time polymerase chain reaction techniques were employed to examine the expression of genes belonging to the G-cell secretory pathway in gastrin and gastrin-CCK knockout mice. Transmission electron microscopy was used to examine the ultrastructure of the G-cells. The number of G-cells increased but the secretory granules were few and abnormally small in the G-cells of both mouse models compared with wildtypes. Thus, gastrin is not necessary for the formation of G-cells as such but the lack of gastrin reduces the number and size of their secretory granules suggesting that gastrin is vital for the formation and/or maintenance of secretory granules in G-cells.

Gastrin blood test

MedlinePlus

Peptic ulcer - gastrin blood test ... to an abnormal amount of gastrin. This includes peptic ulcer disease . ... Too much gastrin can causes severe peptic ulcer disease. A higher ... kidney disease Long-term gastritis Over-activity of the gastrin- ...

The impact of weight loss on the 24-h profile of circulating peptide YY and its association with 24-h ghrelin in normal weight premenopausal women.

PubMed

Hill, Brenna R; De Souza, Mary Jane; Wagstaff, David A; Williams, Nancy I

2013-11-01

Peptide YY (PYY) and ghrelin exhibit a reciprocal association and antagonistic physiological effects in the peripheral circulation. Research has yet to clarify the effect of weight loss on the 24h profile of PYY or its association to 24h ghrelin. We sought to determine if diet- and exercise-induced weight loss affects the 24h profile of PYY and its association with 24h ghrelin in normal weight, premenopausal women. Participants (n = 13) were assessed at baseline (BL) and after a 3-month diet and exercise intervention (post). Blood samples obtained q10 min for 24h were assayed for total PYY and total ghrelin q60 min from 0800 to 1000 h and 2000 to 0800 h and q20 min from 1000 to 2000 h. The ghrelin/PYY ratio was used as an index of hormonal exposure. Statistical analyses included paired t-tests and linear mixed effects modeling. Body weight (-1.85 ± 0.67 kg; p = 0.02), and body fat (-2.53 ± 0.83%; p = 0.01) decreased from BL to post. Ghrelin AUC (5252 ± 2177 pg/ml/24h; p=0.03), 24h mean (216 ± 90 pg/ml; p = 0.03) and peak (300 ± 134 pg/ml; p = 0.047) increased from BL to post. No change occurred in PYY AUC (88.2 ± 163.7 pg/ml; p = 0.60), 24h mean (4.8 ± 6.9 pg/ml; p = 0.50) or peak (3.6 ± 6.4 pg/ml; p = 0.58). The 24h association between PYY and ghrelin at baseline (p = 0.04) was weakened at post (p = 0.14); however, the ghrelin/PYY lunch ratio increased (p = 0.01) indicating the potential for ghrelin predominance over PYY in the circulation. PYY and ghrelin are reciprocally associated during a period of weight stability, but not following weight loss. An "uncoupling" may have occurred, particularly at lunch, due to factors that modulate ghrelin in response to weight loss. Copyright © 2013 Elsevier Inc. All rights reserved.

Ghrelin and peptide YY increase with weight loss during a 12-month intervention to reduce dietary energy density in obese women

PubMed Central

Hill, Brenna R.; Rolls, Barbara J.; Roe, Liane S.; De Souza, Mary Jane; Williams, Nancy I.

2013-01-01

Reducing dietary energy density (ED) promotes weight loss; however, underlying mechanisms are not well understood. The purpose of this study was to determine if low-ED diets facilitate weight loss through actions on ghrelin and peptide YY (PYY), independent of influences of psychosocial measures. Seventy-one obese women (BMI 30–40kg/m2) ages 22–60y received counseling to reduce ED. Fasting blood samples were analyzed for total ghrelin and total PYY by radioimmunoassay at mo 0, 3, 6, and 12. Restraint, disinhibition, and hunger were assessed by the Eating Inventory. Body weight (−7.8 ± 0.5kg), BMI (−2.9 ± 0.2kg/m2), body fat (−3.0 ± 0.3%), and ED (−0.47 ± 0.05kcal/g or −1.97 ± 0.21kJ/g) decreased from mo 0 to 6 (p<0.05) after which no change occurred from mo 6 to 12. Ghrelin increased in a curvilinear fashion (mo 0: 973 ± 39, mo 3: 1024 ± 37, mo 6: 1109 ± 44, and mo 12: 1063 ± 45pg/ml, p<0.001) and PYY increased linearly (mo 0: 74.2 ± 3.1, mo 3: 76.4 ± 3.2, mo 6: 77.2 ± 3.0, mo 12: 82.8 ± 3.2pg/ml, p<0.001). ED, body weight, and hunger predicted ghrelin, with ED being the strongest predictor (ghrelin = 2674.8 + 291.6 × ED − 19.2 × BW − 15 × H; p<0.05). There was a trend toward a significant association between ED and PYY (PYY = 115.0 − 43.1 × ED; p=0.05). Reductions in ED may promote weight loss and weight loss maintenance by opposing increases in ghrelin and promoting increases in PYY. PMID:24076434

Neuropeptide Y and peptide YY inhibit excitatory synaptic transmission in the rat dorsal motor nucleus of the vagus

PubMed Central

Browning, Kirsteen N; Travagli, R Alberto

2003-01-01

Pancreatic polypeptides (PPs) such as neuropeptide Y (NPY) and peptide YY (PYY) exert profound, vagally mediated effects on gastrointestinal (GI) motility and secretion. Whole-cell patch clamp recordings were made from brainstem slices containing identified GI-projecting rat dorsal motor nucleus of the vagus (DMV) neurons to determine the mechanism of action of PPs. Electrical stimulation of nucleus tractus solitarii (NTS) induced excitatory postsynaptic currents (EPSCs) that were reduced in a concentration-dependent manner by NPY and PYY (both at 0.1–300 nm) in 65 % of the neurons. An increase in the paired-pulse ratio without changes in the postsynaptic membrane input resistance or EPSC rise and decay time suggested that the effects of PPs on EPSCs were due to actions at presynaptic receptors. The Y1 and Y2 receptor selective agonists [Leu31,Pro34]NPY and NPY(3–36) (both at 100 nm) mimicked the inhibition of NPY and PYY on the EPSC amplitude. The effects of 100 nm NPY, but not PYY, were antagonized partially by the Y1 receptor selective antagonist BIBP3226 (0.1 μm). In addition, the inhibition of the EPSC amplitude induced by NPY, but not PYY, was attenuated partially by pretreatment with the α2 adrenoceptor antagonist yohimbine (10 μm), and occluded partially by the α2 adrenoceptor agonist UK14,304 (10 μm) as well as by pretreatment with reserpine. Pretreatment with a combination of BIBP3226 and yohimbine almost completely antagonized the NPY-mediated effects on EPSCs. Contrary to the inhibition of EPSCs, perfusion with PPs had no effect on the amplitude of inhibitory postsynaptic currents (IPSCs) and a minimal effect on a minority of DMV neurons. Differences in the receptor subtypes utilized and in the mechanism of action of NPY and PYY may indicate functional differences in their roles within the circuitry of the dorsal vagal complex (DVC). PMID:12730340

Lactation and appetite-regulating hormones: increased maternal plasma peptide YY concentrations 3-6 months postpartum.

PubMed

Vila, Greisa; Hopfgartner, Judith; Grimm, Gabriele; Baumgartner-Parzer, Sabina M; Kautzky-Willer, Alexandra; Clodi, Martin; Luger, Anton

2015-10-28

Breast-feeding is associated with maternal hormonal and metabolic changes ensuring adequate milk production. In this study, we investigate the impact of breast-feeding on the profile of changes in maternal appetite-regulating hormones 3-6 months postpartum. Study participants were age- and BMI-matched lactating mothers (n 10), non-lactating mothers (n 9) and women without any history of pregnancy or breast-feeding in the previous 12 months (control group, n 10). During study sessions, young mothers breast-fed or bottle-fed their babies, and maternal blood samples were collected at five time points during 90 min: before, during and after feeding the babies. Outcome parameters were plasma concentrations of ghrelin, peptide YY (PYY), leptin, adiponectin, prolactin, cortisol, insulin, glucose and lipid values. At baseline, circulating PYY concentrations were significantly increased in lactating mothers (100·3 (se 6·7) pg/ml) v. non-lactating mothers (73·6 (se 4·9) pg/ml, P=0·008) and v. the control group (70·2 (se 9) pg/ml, P=0·021). We found no differences in ghrelin, leptin and adiponectin values. Baseline prolactin concentrations were over 4-fold higher in lactating mothers (P<0·001). Lactating women had reduced TAG levels and LDL-cholesterol:HDL-cholesterol ratio, but increased waist circumference, when compared with non-lactating women. Breast-feeding sessions further elevated circulating prolactin (P<0·001), but induced no acute effects on appetite-regulating hormones. In summary, one single breast-feeding session did not acutely modulate circulating appetite-regulating hormones, but increased baseline PYY concentrations are associated with prolonged lactation. PYY might play a role in the coordination of energy balance during lactation, increasing fat mobilisation from maternal depots and ensuring adequate milk production for the demands of the growing infant.

Comparison of postprandial profiles of ghrelin, active GLP-1, and total PYY to meals varying in fat and carbohydrate and their association with hunger and the phases of satiety.

PubMed

Gibbons, Catherine; Caudwell, Phillipa; Finlayson, Graham; Webb, Dominic-Luc; Hellström, Per M; Näslund, Erik; Blundell, John E

2013-05-01

The relationship between postprandial peptides at circulating physiological levels and short-term appetite control is not well understood. The purpose of this study was first to compare the postprandial profiles of ghrelin, glucagon-like peptide 1 (GLP-1), and peptide YY (PYY) after isoenergetic meals differing in fat and carbohydrate content and second to examine the relationships between ghrelin, GLP-1, and PYY with hunger, fullness, and energy intake. Plasma was collected before and periodically after the meals for 180 minutes, after which time ad libitum food was provided. Simultaneous ratings of hunger and fullness were tracked for 180 minutes through phases identified as early (0-60 minutes) and late (60-180 minutes) satiety. This study was conducted at the Psychobiology and Energy Balance Research Unit, University of Leeds. The participants were 16 healthy overweight/obese adults. Changes in hunger and fullness and metabolic markers were indicators of the impact of the meals on satiety. Ghrelin was influenced similarly by the 2 meals [F(1, 12) = 0.658, P = .433] and was significantly associated with changes in hunger (P < .05), which in turn correlated with food intake (P < .05). GLP-1 and PYY increased more by the high-fat meal [F(1, 15) = 5.099 and F(1, 14) = 5.226, P < .05]. GLP-1 was negatively associated with hunger in the late satiety phase and with energy intake (P < .05), but the PYY profile was not associated with hunger or fullness, nor was PYY associated with food intake. The results demonstrate that under these conditions, these peptides respond differently to ingested nutrients. Ghrelin and GLP-1, but not PYY, were associated with short-term control of appetite over the measurement period.

Role of Peptide YY3-36 and Glucose-Dependent Insulinotropic Polypeptide in Anorexia Induction by Trichothecences T-2 Toxin, HT-2 Toxin, Diacetoxyscirpenol, and Neosolaniol.

PubMed

Zhang, Jie; Jia, Hui; Wang, Qingqing; Zhang, Yajie; Wu, Wenda; Zhang, Haibin

2017-09-01

Trichothecences, secondary metabolites produced by Fusarium, are serious health risks to humans and animals worldwide. Although type A trichothecence-induced food refusal has been observed, the mechanism underlying the anorexia caused by these compounds is not fully understood. In this study, we hypothesized that anorexia induced by type A trichothecenes, including T-2 toxin (T-2), HT-2 toxin (HT-2), diacetoxyscirpenol (DAS), and neosolaniol (NEO), in mice corresponds to the changes in the gut satiety hormones peptide YY3-36 (PYY3-36) and glucose-dependent insulinotropic polypeptide (GIP) in plasma. A well-characterized mouse food refusal model was used in this assay. Oral exposure to or intraperitoneal (ip) injection of 1 mg/kg bw T-2, HT-2, DAS, or NEO resulted in dramatically decreased food intake, and PYY3-36 and GIP concentrations were elevated accordingly. Specifically, the PYY3-36 and GIP concentrations peaked at 2 h following oral exposure to these 4 toxins individually, although the durations were not identical. After ip administration of T-2 or HT-2, PYY3-36 significantly increased within 6 h. However, no significant difference was found in the DAS and NEO groups. The GIP levels peaked within 2, 2, 0.5, and 0.5 h, respectively, and remained increased up to 6, 6, 2, and 6 h, respectively, following T-2, HT-2, DAS, or NEO ip exposure. The increase in GIP was greater than that of PYY3-36 after exposure to the 4 toxins using 2 administration routes. Together, these findings suggest that PYY3-36 and GIP play a role in T-2-, HT-2-, DAS-, and NEO-induced anorexia. © The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Canine bombesin-like gastrin releasing peptides stimulate gastrin release and acid secretion in the dog.

PubMed Central

Bunnett, N W; Clark, B; Debas, H T; Del Milton, R C; Kovacs, T O; Orloff, M S; Pappas, T N; Reeve, J R; Rivier, J E; Walsh, J H

1985-01-01

The synthetic mammalian bombesin-like peptides, canine gastrin releasing peptide 27, 23 and 10, and porcine gastrin releasing peptide 27 were compared with amphibian bombesin 14 and 10 during intravenous infusions into six conscious dogs with chronic gastric cannulae. Gastrin and gastrin releasing peptide were measured in peripherally sampled venous blood by radioimmunoassay and gastric acid secretions were collected. All forms of gastrin releasing peptide stimulated gastrin release and gastric acid secretion in a dose-dependent manner. The larger canine and porcine peptides were more potent than the decapeptide. Bombesin 14 was more potent than bombesin 10. A rise in the venous concentration of immunoreactive gastrin releasing peptide of only 20 fmol ml-1 stimulated gastrin release to about 50% of maximal. Gastrin releasing peptide 10 was cleared from the circulation three times faster than the larger forms and this may account for the apparent differences in potency. PMID:3839849

A case of severe anorexia, excessive weight loss and high peptide YY levels after sleeve gastrectomy.

PubMed

Pucci, Andrea; Cheung, Wui Hang; Jones, Jenny; Manning, Sean; Kingett, Helen; Adamo, Marco; Elkalaawy, Mohamed; Jenkinson, Andrew; Finer, Nicholas; Doyle, Jacqueline; Hashemi, Majid; Batterham, Rachel L

2015-01-01

Sleeve gastrectomy (SG) is the second most commonly performed bariatric procedure worldwide. Altered circulating gut hormones have been suggested to contribute post-operatively to appetite suppression, decreased caloric intake and weight reduction. In the present study, we report a 22-year-old woman who underwent laparoscopic SG for obesity (BMI 46 kg/m(2)). Post-operatively, she reported marked appetite reduction, which resulted in excessive weight loss (1-year post-SG: BMI 22 kg/m(2), weight loss 52%, >99th centile of 1-year percentage of weight loss from 453 SG patients). Gastrointestinal (GI) imaging, GI physiology/motility studies and endoscopy revealed no anatomical cause for her symptoms, and psychological assessments excluded an eating disorder. Despite nutritional supplements and anti-emetics, her weight loss continued (BMI 19 kg/m(2)), and she required nasogastric feeding. A random gut hormone assessment revealed high plasma peptide YY (PYY) levels. She underwent a 3 h meal study following an overnight fast to assess her subjective appetite and circulating gut hormone levels. Her fasted nausea scores were high, with low hunger, and these worsened with nutrient ingestion. Compared to ten other post-SG female patients, her fasted circulating PYY and nutrient-stimulated PYY and active glucagon-like peptide 1 (GLP1) levels were markedly elevated. Octreotide treatment was associated with suppressed circulating PYY and GLP1 levels, increased appetite, increased caloric intake and weight gain (BMI 22 kg/m(2) after 6 months). The present case highlights the value of measuring gut hormones in patients following bariatric surgery who present with anorexia and excessive weight loss and suggests that octreotide treatment can produce symptomatic relief and weight regain in this setting. Roux-en-Y gastric bypass and SG produce marked sustained weight reduction. However, there is a marked individual variability in this reduction, and post-operative weight loss

Immunohistochemical study on the ontogenetic development of the regional distribution of peptide YY, pancreatic polypeptide, and glucagon-like peptide 1 endocrine cells in bovine gastrointestinal tract.

PubMed

Pyarokhil, Asadullah Hamid; Ishihara, Miyuki; Sasaki, Motoki; Kitamura, Nobuo

2012-04-10

The regional distribution and relative frequency of peptide YY (PYY)-, pancreatic polypeptide (PP)-, and glucagon-like peptide 1 (GLP-1)-immunoreactive (IR) cells were determined immunohistochemically in the gastrointestinal tract at seven ontogenetic stages in pre- and postnatal cattle. Different frequencies of PYY-, PP-, and GLP-1-IR cells were found in the intestines at all stages; they were not found in the esophagus and stomach. The frequencies varied depending on the intestinal segment and the developmental stage. The frequencies of PYY- and PP-IR cells were lower in the small intestine and increased from ileum to rectum, whereas GLP-1-IR cells were more numerous in duodenum and jejunum, decreased in ileum and cecum, and increased again in colon and rectum. The frequencies also varied according to pre- and postnatal stages. All three cell types were most numerous in fetus, and decreased in calf and adult groups, indicating that the frequencies of these three types of endocrine cells decrease with postnatal development. The results suggest that these changes vary depending on feeding habits and adaptation of growth, secretion, and motility of intestine at different ontogenetic stages of cattle. Copyright © 2011 Elsevier B.V. All rights reserved.

Short communication: expression of peptide YY, proglucagon, neuropeptide Y receptor Y2, and glucagon-like peptide-1 receptor in bovine peripheral tissues.

PubMed

Pezeshki, A; Muench, G P; Chelikani, P K

2012-09-01

The role of distal gut signals in control of feed intake and metabolism in cattle has received scant attention. Peptide YY (PYY) and glucagon-like peptide-1, which are secreted from enteroendocrine cells of the distal gut in monogastrics have several functions, including regulation of energy balance. However, little is known of the tissue expression of these peptides and their receptors in cattle. The aim of the current study was to characterize the tissue distribution of PYY, neuropeptide Y receptor Y2 (Y2), proglucagon (GCG), and glucagon-like peptide-1 receptor (GLP1R) in various peripheral tissues of cattle. Four male 7-wk-old dairy calves were euthanized and 16 peripheral tissues were collected. Conventional PCR and quantitative real-time PCR were performed to confirm tissue expression and quantify the transcript abundance in various tissues. The results of conventional PCR revealed that mRNA for both PYY and Y2 was detectable in the rumen, abomasum, duodenum, jejunum, ileum, and colon but not in other tissues. Quantitative real-time PCR data demonstrated that PYY mRNA was 2- to 3-fold greater in the pancreas, kidney, and heart relative to the liver. By conventional PCR, GCG mRNA was detected in the abomasum, duodenum, jejunum, ileum, and colon and GLP1R mRNA was expressed in all gut segments, pancreas, spleen, and kidney. Quantitative real-time PCR data demonstrated that, relative to transcript abundance in the liver, GCG mRNA was 4- to 40-fold higher from abomasum to colon, and GLP1R mRNA was 50- to 300-fold higher from the rumen to colon, 14-fold greater in the pancreas, 18-fold higher in the spleen, and 166-fold greater in the kidney. The tissue distribution of PYY, GCG, and their receptors observed in the current study is, in general, consistent with expression patterns in monogastrics. The predominant expression of PYY, Y2, and GCG in the gut, and the presence of GLP1R in multiple peripheral tissues suggest a role for PYY in controlling gut functions and

Effects of an elemental diet, inert bulk and different types of dietary fibre on the response of the intestinal epithelium to refeeding in the rat and relationship to plasma gastrin, enteroglucagon, and PYY concentrations.

PubMed Central

Goodlad, R A; Lenton, W; Ghatei, M A; Adrian, T E; Bloom, S R; Wright, N A

1987-01-01

Refeeding starved rats with an elemental diet resulted in a marked increase in crypt cell production rate (CCPR) in the proximal small intestine but not in the distal regions of the gut. Little effect on CCPR was noted when inert bulk (kaolin) was added to the elemental diet. Addition of a poorly fermentable dietary fibre (purified wood cellulose) had little effect on intestinal epithelial cell proliferation except in the distal colon where it significantly increased CCPR. A more readily fermentable fibre (purified wheat bran) caused a large proliferative response in the proximal, mid, and distal colon and in the distal small intestine. A gel forming fibre only significantly stimulated proliferation in the distal colon; the rats in this group, however, did not eat all the food given. There was no significant correlation between CCPR and plasma gastrin concentrations, but plasma enteroglucagon concentrations were significantly correlated with CCPR in almost all the sites studied. Plasma PYY concentrations also showed some correlation with CCPR, especially in the colon. Thus while inert bulk cannot stimulate colonic epithelial cell proliferation fermentable fibre is capable of stimulating proliferation in the colon, and especially in the distal colon: it can also stimulate proliferation in the distal small intestine and it is likely that plasma enteroglucagon may have a role to play in this process. Images Fig. 1 PMID:3030902

The Effect of a Subcutaneous Infusion of GLP-1, OXM, and PYY on Energy Intake and Expenditure in Obese Volunteers

PubMed Central

Tan, Tricia; Behary, Preeshila; Tharakan, George; Minnion, James; Al-Najim, Werd; Albrechtsen, Nicolai J. Wewer; Holst, Jens J.

2017-01-01

Background: Roux-en-Y gastric bypass (RYGB) surgery is currently the most effective treatment of obesity, although limited by availability and operative risk. The gut hormones Glucagon-like peptide-1 (GLP-1), Peptide YY (PYY), and Oxyntomodulin (OXM) are elevated postprandially after RYGB, which has been postulated to contribute to its metabolic benefits. Objective: We hypothesized that infusion of the three gut hormones to achieve levels similar to those encountered postprandially in RYGB patients might be effective in suppressing appetite. The aim of this study was to investigate the effect of a continuous infusion of GLP-1, OXM, and PYY (GOP) on energy intake and expenditure in obese volunteers. Methods: Obese volunteers were randomized to receive an infusion of GOP or placebo in a single-blinded, randomized, placebo-controlled crossover study for 10.5 hours a day. This was delivered subcutaneously using a pump device, allowing volunteers to remain ambulatory. Ad libitum food intake studies were performed during the infusion, and energy expenditure was measured using a ventilated hood calorimeter. Results: Postprandial levels of GLP-1, OXM, and PYY seen post RYGB were successfully matched using 4 pmol/kg/min, 4 pmol/kg/min, and 0.4 pmol/kg/min, respectively. This dose led to a mean reduction of 32% in food intake. No significant effects on resting energy expenditure were observed. Conclusion: This is, to our knowledge, the first time that an acute continuous subcutaneous infusion of GOP, replicating the postprandial levels observed after RYGB, is shown to be safe and effective in reducing food intake. This data suggests that triple hormone therapy might be a useful tool against obesity. PMID:28379519

Endogenous peptide YY and neuropeptide Y inhibit colonic ion transport, contractility and transit differentially via Y1 and Y2 receptors

PubMed Central

Tough, IR; Forbes, S; Tolhurst, R; Ellis, M; Herzog, H; Bornstein, JC; Cox, HM

2011-01-01

BACKGROUND AND PURPOSE Peptide YY (PYY) and neuropeptide Y (NPY) activate Y receptors, targets under consideration as treatments for diarrhoea and other intestinal disorders. We investigated the gastrointestinal consequences of selective PYY or NPY ablation on mucosal ion transport, smooth muscle activity and transit using wild-type, single and double peptide knockout mice, comparing mucosal responses with those from human colon. EXPERIMENTAL APPROACH Mucosae were pretreated with a Y1 (BIBO3304) or Y2 (BIIE0246) receptor antagonist and changes in short-circuit current recorded. Colonic transit and colonic migrating motor complexes (CMMCs) were assessed in vitro and upper gastrointestinal and colonic transit measured in vivo. KEY RESULTS Y receptor antagonists revealed tonic Y1 and Y2 receptor-mediated antisecretory effects in human and wild-type mouse colon mucosae. In both, Y1 tone was epithelial while Y2 tone was neuronal. Y1 tone was reduced 90% in PYY−/− mucosa but unchanged in NPY−/− tissue. Y2 tone was partially reduced in NPY−/− or PYY−/− mucosae and abolished in tetrodotoxin-pretreated PYY−/− tissue. Y1 and Y2 tone were absent in NPYPYY−/− tissue. Colonic transit was inhibited by Y1 blockade and increased by Y2 antagonism indicating tonic Y1 excitation and Y2 inhibition respectively. Upper GI transit was increased in PYY−/− mice only. Y2 blockade reduced CMMC frequency in isolated mouse colon. CONCLUSIONS AND IMPLICATIONS Endogenous PYY and NPY induced significant mucosal antisecretory tone mediated by Y1 and Y2 receptors, via similar mechanisms in human and mouse colon mucosa. Both peptides contributed to tonic Y2-receptor-mediated inhibition of colonic transit in vitro but only PYY attenuated upper GI transit. PMID:21457230

Connective tissue growth factor is activated by gastrin and involved in gastrin-induced migration and invasion.

PubMed

Bhandari, Sabin; Bakke, Ingunn; Kumar, J; Beisvag, Vidar; Sandvik, Arne K; Thommesen, Liv; Varro, Andrea; Nørsett, Kristin G

2016-06-17

Connective tissue growth factor (CTGF) has been reported in gastric adenocarcinoma and in carcinoid tumors. The aim of this study was to explore a possible link between CTGF and gastrin in gastric epithelial cells and to study the role of CTGF in gastrin induced migration and invasion of AGS-GR cells. The effects of gastrin were studied using RT-qPCR, Western blot and assays for migration and invasion. We report an association between serum gastrin concentrations and CTGF abundancy in the gastric corpus mucosa of hypergastrinemic subjects and mice. We found a higher expression of CTGF in gastric mucosa tissue adjacent to tumor compared to normal control tissue. We showed that gastrin induced expression of CTGF in gastric epithelial AGS-GR cells via MEK, PKC and PKB/AKT pathways. CTGF inhibited gastrin induced migration and invasion of AGS-GR cells. We conclude that CTGF expression is stimulated by gastrin and involved in remodeling of the gastric epithelium. Copyright © 2016 Elsevier Inc. All rights reserved.

Impaired postprandial releases/syntheses of ghrelin and PYY(3-36) and blunted responses to exogenous ghrelin and PYY(3-36) in a rodent model of diet-induced obesity.

PubMed

Xu, Junying; McNearney, Terry A; Chen, J D Z

2011-04-01

This study investigated the effects of peripheral administration of ghrelin and PYY(3-36) on food intake and plasma and tissue fasting and postprandial ghrelin and PYY(3-36) levels in normal-weight (NW) and diet-induced-obese (DIO) rats. In experiment one, NW and DIO rats received a single intraperitoneal injection of saline, PYY(3-36) or ghrelin; food intake was measured for 4 h. In experiment two, total plasma ghrelin and PYY(3-36), gastric fundus ghrelin, and ascending colon PYY(3-36) were measured either after a 20-h fast or 2 h after refeeding in NW and DIO rats by radioimmunoassay. Compared to the NW rats, findings in the DIO rats revealed: (i) a reduced sensitivity to both the anorectic effect of exogenous PYY(3-36) and the orexigenic effect of exogenous ghrelin; (ii) the postprandial plasma ghrelin levels were significantly higher; and (iii) refeeding decreased endogenous plasma ghrelin levels by 53% in the NW rats and 39% in DIO rats. Refeeding increased the plasma PYY(3-36) level by 58% in the NW rats versus 9% in the DIO rats (P=0.003). Compared with regular rats, DIO rats exhibit blunted responses in food intake to exogenous ghrelin and PYY(3-36). Although endogenous ghrelin and PYY(3-36) in DIO rats are not altered in the fasting state, their responses to food ingestion are blunted in comparison with regular rats. © 2011 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.

Peptide YY: a potential therapy for obesity.

PubMed

Renshaw, D; Batterham, R L

2005-03-01

Obesity now represents a modern epidemic in western society with major health and economic consequences. Unfortunately, previous pharmacological approaches to the treatment of obesity have been associated with life-threatening side effects and limited efficacy. Over recent years there has been a marked increase in our understanding of the physiological mechanisms that regulate body weight and how these are perturbed in obesity. One therapeutic strategy is to develop drugs which both mimic and enhance the body's own satiety signals. The gut hormone peptide tyrosine tyrosine (PYY), which is released postprandially from the gastrointestinal tract, has recently been shown to be a physiological regulator of food intake. Peripheral administration of PYY reduces feeding in rodents via a mechanism which requires the Y2 receptor and is thought to primarily involve modulation of the hypothalamic arcuate nucleus (ARC) circuitry. In humans a single 90-minute infusion of PYY has been shown to markedly reduce subsequent 24-hour caloric intake in lean, normal-weight and obese subjects. Moreover, obese subjects have been found to have low levels of fasting and postprandial PYY suggesting a role for this hormone in the pathogenesis of obesity. Although studies examining the effects of chronic peripheral administration of PYY to humans are awaited, the results from continuous infusion studies in a number of obese rodent models are encouraging with reductions in food intake, body weight and adiposity observed. Potential therapeutic manipulations based on the PYY system include development of Y2 agonists, exogenously administration of PYY or increased endogenous release from the gastrointestinal tract.

A high carbohydrate, but not fat or protein meal attenuates postprandial ghrelin, PYY and GLP-1 responses in Chinese men

PubMed Central

Parvaresh Rizi, Ehsan; Loh, Tze Ping; Baig, Sonia; Chhay, Vanna; Huang, Shiqi; Caleb Quek, Jonathan; Tai, E. Shyong; Toh, Sue-Anne

2018-01-01

It is known that the macronutrient content of a meal has different impacts on the postprandial satiety and appetite hormonal responses. Whether obesity interacts with such nutrient-dependent responses is not well characterized. We examined the postprandial appetite and satiety hormonal responses after a high-protein (HP), high-carbohydrate (HC), or high-fat (HF) mixed meal. This was a randomized cross-over study of 9 lean insulin-sensitive (mean±SEM HOMA-IR 0.83±0.10) and 9 obese insulin-resistant (HOMA-IR 4.34±0.41) young (age 21–40 years), normoglycaemic Chinese men. We measured fasting and postprandial plasma concentration of glucose, insulin, active glucagon-like peptide-1 (GLP-1), total peptide-YY (PYY), and acyl-ghrelin in response to HP, HF, or HC meals. Overall postprandial plasma insulin response was more robust in the lean compared to obese subjects. The postprandial GLP-1 response after HF or HP meal was higher than HC meal in both lean and obese subjects. In obese subjects, HF meal induced higher response in postprandial PYY compared to HC meal. HP and HF meals also suppressed ghrelin greater compared to HC meal in the obese than lean subjects. In conclusion, a high-protein or high-fat meal induces a more favorable postprandial satiety and appetite hormonal response than a high-carbohydrate meal in obese insulin-resistant subjects. PMID:29385178

YY Sex: a Polar Candidate

NASA Astrophysics Data System (ADS)

Gabdeev, M. M.; Shimanskiy, V. V.; Borisov, N. V.; Tazieva, Z. R.

2017-06-01

We present spectroscopic investigations of a cataclysmic variable star, YY Sex. There are some uncertainties in the classification of this object. We calculate Doppler maps for Hβ and HeII λ4686Å and show that there is no sign of disk accretion in YY Sex. Consequently, we conclude that YY Sex is a polar.

Radioimmunoassay of gastrin

DOE Office of Scientific and Technical Information (OSTI.GOV)

McGuigan, J.E.

1976-01-26

The use of gastrin radioimmunoassay for differentiating between the Zollinger--Ellison syndrome and common peptic ulcer is discussed. This technique makes it possible to detect the syndrome with greater certainty than measurement of gastric acid secretion. Other clinical disorders in which increased serum gastrin levels occur are pernicious anemia, chronic gastritis, achlorhydria, renal failure, and intestinal resection. (HLW)

Relation of gastric acid and pepsin secretion to serum gastrin levels in dogs given bombesin and gastrin-17.

PubMed

Hirschowitz, B I; Molina, E

1983-05-01

To quantitate bombesin stimulation of gastric acid and pepsin via release of gastrin, five gastric fistula dogs were given graded doses (60-1,250 pmol X kg-1 X h-1) of bombesin tetradecapeptide and 40-2,000 pmol X kg-1 X h-1 of synthetic gastrin-17 (G-17). Acid and pepsin output and serum gastrin were proportional to the dose of stimulant. The half-maximal dose of bombesin for gastrin release was 200 pmol X kg-1 X h-1. Bombesin-stimulated acid secretion related to serum gastrin concentrations was congruent with the G-17 curve, but with a maximum of only 62% of the G-17 maximum before declining by 27% despite higher serum gastrin levels. This suggested that bombesin stimulates acid secretion only via gastrin release and inhibits at higher doses by releasing another inhibitory peptide, most likely somatostatin, which is also released by bombesin. The same mechanism could apply to supramaximal inhibition of acid and pepsin seen with high doses of G-17. Because the pepsin curve related to serum gastrin was to the left of the G-17 curve, we concluded that another secretagogue released by bombesin acts synergistically with gastrin on pepsin secretion. Therefore, bombesin stimulates gastric secretion through gastrin release, but its effects are modified by peptides coreleased to a) increase pepsin output at low doses and b) limit the output of acid and pepsin to 50-60% of the G-17 maximum.

The Role of YY1 in Prostate Cancer

DTIC Science & Technology

2010-03-01

Inhibiting YY1 translation [57] DETANONOate (nitric oxide donor) Inhibiting YY1 mRNA synthesis and YY1-DNA association [109,110...overexpression increases tumor cell sensitivity to TRAIL via blocking YY1 expression. YY1 expression can also be inhibited by DETANONOate (a nitric

Serum Gastrin in Chronic Gastritis

PubMed Central

Korman, M. G.; Strickland, R. G.; Hansky, J.

1971-01-01

Fasting gastrin levels in serum were measured in 49 patients with different types of chronic gastritis and in matched controls. In 15 patients with established pernicious anaemia the mean (± S.E. of mean) level of gastrin was greatly raised (699 ± 99 pg/ml). In 17 patients with chronic atrophic gastritis, seropositive for parietal cell antibody but with adequate vitamin-B12 absorption, the level was also raised (476 ± 74 pg/ml). By contrast, in “simple” atrophic gastritis seronegative for parietal cell antibody the gastrin levels were significantly lower for both diffuse atrophic gastritis (129 ± 31 pg/ml) and multifocal gastritis (14 ± 4 pg/ml). These levels were similar to those in the controls (46 ± 7 pg/ml). The mechanism of the raised gastrin levels remains uncertain, but neither achlorhydria nor in vivo action of the parietal cell antibody wholly accounted for the hypergastrinaemia. We conclude that hypergastrinaemia is characteristic of gastritis associated with autoimmune reactions to gastric antigens and pernicious anaemia and that a raised serum gastrin is a useful marker of the type of gastritis that tends to progress to the gastric lesion of pernicious anaemia. The findings suggest that this type of gastritis is an essentially different disease from “simple” atrophic gastritis, and the differences in gastrin levels may be due to sparing of the antral mucosa in the autoimmune type but not in “simple” gastritis. PMID:5550864

Regulation of hindbrain Pyy expression by acute food deprivation, prolonged caloric restriction, and weight loss surgery in mice

PubMed Central

Gelegen, C.; Chandarana, K.; Choudhury, A. I.; Al-Qassab, H.; Evans, I. M.; Irvine, E. E.; Hyde, C. B.; Claret, M.; Andreelli, F.; Sloan, S. E.; Leiter, A. B.; Withers, D. J.

2012-01-01

PYY is a gut-derived putative satiety signal released in response to nutrient ingestion and is implicated in the regulation of energy homeostasis. Pyy-expressing neurons have been identified in the hindbrain of river lamprey, rodents, and primates. Despite this high evolutionary conservation, little is known about central PYY neurons. Using in situ hybridization, PYY-Cre;ROSA-EYFP mice, and immunohistochemistry, we identified PYY cell bodies in the gigantocellular reticular nucleus region of the hindbrain. PYY projections were present in the dorsal vagal complex and hypoglossal nucleus. In the hindbrain, Pyy mRNA was present at E9.5, and expression peaked at P2 and then decreased significantly by 70% at adulthood. We found that, in contrast to the circulation, PYY-(1–36) is the predominant isoform in mouse brainstem extracts in the ad libitum-fed state. However, following a 24-h fast, the relative amounts of PYY-(1–36) and PYY-(3–36) isoforms were similar. Interestingly, central Pyy expression showed nutritional regulation and decreased significantly by acute starvation, prolonged caloric restriction, and bariatric surgery (enterogastroanastomosis). Central Pyy expression correlated with body weight loss and circulating leptin and PYY concentrations. Central regulation of energy metabolism is not limited to the hypothalamus but also includes the midbrain and the brainstem. Our findings suggest a role for hindbrain PYY in the regulation of energy homeostasis and provide a starting point for further research on gigantocellular reticular nucleus PYY neurons, which will increase our understanding of the brain stem pathways in the integrated control of appetite and energy metabolism. PMID:22761162

Role of gastrin-peptides in Barrett's and colorectal carcinogenesis

PubMed Central

Chueca, Eduardo; Lanas, Angel; Piazuelo, Elena

2012-01-01

Gastrin is the main hormone responsible for the stimulation of gastric acid secretion; in addition, gastrin and its derivatives exert proliferative and antiapoptotic effects on several cell types. Gastrin synthesis and secretion are increased in certain situations, for example, when proton pump inhibitors are used. The impact of sustained hypergastrinemia is currently being investigated. In vitro experiments and animal models have shown that prolonged hypergastrinemia may be related with higher cancer rates; although, this relationship is less clear in human beings. Higher gastrin levels have been shown to cause hyperplasia of several cell types; yet, the risk for developing cancer seems to be the same in normo- and hypergastrinemic patients. Some tumors also produce their own gastrin, which can act in an autocrine manner promoting tumor growth. Certain cancers are extremely dependent on gastrin to proliferate. Initial research focused only on the effects of amidated gastrins, but there has been an interest in intermediates of gastrin in the last few decades. These intermediates aren’t biologically inactive; in fact, they may exert greater effects on proliferation and apoptosis than the completely processed forms. In certain gastrin overproduction states, they are the most abundant gastrin peptides secreted. The purpose of this review is to examine the gastrin biosynthesis process and to summarize the results from different studies evaluating the production, levels, and effects of the main forms of gastrin in different overexpression states and their possible relationship with Barrett’s and colorectal carcinogenesis. PMID:23236230

Acute effects of intravenous cocaine administration on serum concentrations of ghrelin, amylin, glucagon-like peptide-1, insulin, leptin and peptide YY and relationships with cardiorespiratory and subjective responses.

PubMed

Bouhlal, Sofia; Ellefsen, Kayla N; Sheskier, Mikela B; Singley, Erick; Pirard, Sandrine; Gorelick, David A; Huestis, Marilyn A; Leggio, Lorenzo

2017-11-01

Food intake and use of drugs of abuse like cocaine share common central and peripheral physiological pathways. Appetitive hormones play a major role in regulating food intake; however, little is known about the effects of acute cocaine administration on the blood concentrations of these hormones in cocaine users. We evaluated serum concentrations of six appetitive hormones: ghrelin (total and acyl-ghrelin), amylin, glucagon-like peptide-1 (GLP-1), insulin, leptin and peptide YY (PYY), as well as acute cardiorespiratory and subjective responses of 8 experienced cocaine users who received 25mg intravenous (IV) cocaine. Serum concentrations of GLP-1 (p=0.014) and PYY (p=0.036) were significantly decreased one hour following IV cocaine administration; there was a trend towards a decrease for insulin (p=0.055) and amylin (p=0.063) concentrations, while no significant IV cocaine effect was observed for ghrelin (total or acyl-ghrelin) or leptin concentrations (p's≫>0.5). We also observed associations between hormone concentrations acutely affected by IV cocaine (GLP-1, PYY, insulin, amylin) and some cocaine-related cardiorespiratory and subjective responses (e.g., increased heart and respiratory rates; feeling high and anxious). These findings show a significant effect of acute IV cocaine administration on some appetitive hormones and suggest potential associations between these hormones and cocaine-related cardiorespiratory and subjective responses. Additional research is needed to further investigate the potential mechanisms underlining these associations. Published by Elsevier B.V.

Role of gastrin-releasing peptides in breast cancer metastasis.

PubMed

Ni, Chunsheng; Zhao, Xiulan; Sun, Tao; Liu, Yanrong; Gu, Qiang; Sun, Baocun

2012-12-01

The gastrin-releasing peptide, which is an unfolded protein response regulator and functions as a Ca(2+)-binding molecular chaperone in the endoplasmic reticulum, is a regulatory human peptide that elicits gastrin release and regulates gastric acid secretion and enteric motor function. It has been shown to exhibit mitogenic activity in small cell lung cancer and plays a role in a lot of other human cancers including tumors in colon, stomach, pancreas, breast, and prostate. This study investigated the gastrin-releasing peptide expression in breast cancer to demonstrate the role of this biomarker in breast cancer metastasis. Gastrin-releasing peptide was analyzed in breast cancer tissue microarray specimens, including 200 primary breast cancer specimens and the corresponding lymph nodes from the same patients, through immunohistochemistry. The effect of gastrin-releasing peptide on the invasion ability of MCF-7 cells was evaluated using transwell assays. Gastrin-releasing peptide was highly expressed in breast cancer patients with lymph node metastasis. Besides, among the patients with lymph node metastasis, the ones with higher expression of gastrin-releasing peptide had shorter survival time. Overexpression of gastrin-releasing peptide significantly enhanced cell invasiveness. Conversely, a knockdown of gastrin-releasing peptide through the short hairpin RNA approach remarkably reduced MCF-7 cell invasion. Gastrin-releasing peptide expression may be associated with lymph node metastasis and may be used as an indicator of undesirable prognosis in patients with breast cancer. Copyright © 2012 Elsevier Inc. All rights reserved.

Gastrin Receptor-Avid Peptide Conjugates

DOEpatents

Hoffman, Timothy J.; Volkert, Wynn A.; Li, Ning; Sieckman, Gary; Higginbotham, Chrys-Ann

2005-07-26

A compound for use as a therapeutic or diagnostic radiopharmaceutical includes a group capable of complexing a medically useful metal attached to a moiety which is capable of binding to a gastrin releasing peptide receptor. A method for treating a subject having a neoplastic disease includes administering to the subject an effective amount of a radiopharmaceutical having a metal chelated with a chelating group attached to a moiety capable of binding to a gastrin releasing peptide receptor expressed on tumor cells with subsequent internalization inside of the cell. A method of forming a therapeutic or diagnostic compound includes reacting a metal synthon with a chelating group covalently linked with a moiety capable of binding a gastrin releasing peptide receptor.

Gastrin receptor-avid peptide conjugates

DOEpatents

Hoffman, Timothy J.; Volkert, Wynn A.; Li, Ning; Sieckman, Gary; Higginbotham, C. A.

2001-01-01

A compound for use as a therapeutic or diagnostic radiopharmaceutical includes a group capable of complexing a medically useful metal attached to a moiety which is capable of binding to a gastrin releasing peptide receptor. A method for treating a subject having a neoplastic disease includes administering to the subject an effective amount of a radiopharmaceutical having a metal chelated with a chelating group attached to a moiety capable of binding to a gastrin releasing peptide receptor expressed on tumor cells with subsequent internalization inside of the cell. A method of forming a therapeutic or diagnostic compound includes reacting a metal synthon with a chelating group covalently linked with a moiety capable of binding a gastrin releasing peptide receptor.

Gastrin receptor-avid peptide conjugates

DOEpatents

Hoffman, Timothy J.; Volkert, Wynn A.; Sieckman, Gary; Smith, Charles J.; Gali, Hariprasad

2006-06-13

A compound for use as a therapeutic or diagnostic radiopharmaceutical includes a group capable of complexing a medically useful metal attached to a moiety which is capable of binding to a gastrin releasing peptide receptor. A method for treating a subject having a neoplastic disease includes administering to the subject an effective amount of a radiopharmaceutical having a metal chelated with a chelating group attached to a-moiety capable of binding to a gastrin releasing peptide receptor expressed on tumor cells with subsequent internalization inside of the cell. A method of forming a therapeutic or diagnostic compound includes reacting a metal synthon with a chelating group covalently linked with a moiety capable of binding a gastrin releasing peptide receptor.

Gastrin receptor-avid peptide conjugates

DOEpatents

Hoffman, Timothy J.; Volkert, Wynn A.; Li, Ning; Sieckman, Gary; Higginbotham, Chrys-Ann

2006-12-12

A compound for use as a therapeutic or diagnostic radiopharmaceutical includes a group capable of complexing a medically useful metal attached to a moiety which is capable of binding to a gastrin releasing peptide receptor. A method for treating a subject having a neoplastic disease includes administering to the subject an effective amount of a radiopharmaceutical having a metal chelated with a chelating group attached to a moiety capable of binding to a gastrin releasing peptide receptor expressed on tumor cells with subsequent internalization inside of the cell. A method of forming a therapeutic or diagnostic compound includes reacting a metal synthon with a chelating group covalently linked with a moiety capable of binding a gastrin releasing peptide receptor.

LX4211 increases serum glucagon-like peptide 1 and peptide YY levels by reducing sodium/glucose cotransporter 1 (SGLT1)-mediated absorption of intestinal glucose.

PubMed

Powell, David R; Smith, Melinda; Greer, Jennifer; Harris, Angela; Zhao, Sharon; DaCosta, Christopher; Mseeh, Faika; Shadoan, Melanie K; Sands, Arthur; Zambrowicz, Brian; Ding, Zhi-Ming

2013-05-01

LX4211 [(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol], a dual sodium/glucose cotransporter 1 (SGLT1) and SGLT2 inhibitor, is thought to decrease both renal glucose reabsorption by inhibiting SGLT2 and intestinal glucose absorption by inhibiting SGLT1. In clinical trials in patients with type 2 diabetes mellitus (T2DM), LX4211 treatment improved glycemic control while increasing circulating levels of glucagon-like peptide 1 (GLP-1) and peptide YY (PYY). To better understand how LX4211 increases GLP-1 and PYY levels, we challenged SGLT1 knockout (-/-) mice, SGLT2-/- mice, and LX4211-treated mice with oral glucose. LX4211-treated mice and SGLT1-/- mice had increased levels of plasma GLP-1, plasma PYY, and intestinal glucose during the 6 hours after a glucose-containing meal, as reflected by area under the curve (AUC) values, whereas SGLT2-/- mice showed no response. LX4211-treated mice and SGLT1-/- mice also had increased GLP-1 AUC values, decreased glucose-dependent insulinotropic polypeptide (GIP) AUC values, and decreased blood glucose excursions during the 6 hours after a challenge with oral glucose alone. However, GLP-1 and GIP levels were not increased in LX4211-treated mice and were decreased in SGLT1-/- mice, 5 minutes after oral glucose, consistent with studies linking decreased intestinal SGLT1 activity with reduced GLP-1 and GIP levels 5 minutes after oral glucose. These data suggest that LX4211 reduces intestinal glucose absorption by inhibiting SGLT1, resulting in net increases in GLP-1 and PYY release and decreases in GIP release and blood glucose excursions. The ability to inhibit both intestinal SGLT1 and renal SGLT2 provides LX4211 with a novel dual mechanism of action for improving glycemic control in patients with T2DM.

Serum gastrin concentrations in dogs with liver disorders.

PubMed

Mazaki-Tovi, M; Segev, G; Yas-Natan, E; Lavy, E

2012-07-07

Dogs with liver disorders often display gastrointestinal signs that may be triggered by ulceration. The liver is important for inactivation of some forms of gastrin. Therefore, hypergastrinaemia has been implicated in the pathogenesis of gastrointestinal ulcerations related to liver dysfunction. The aim of this study was to determine serum gastrin concentrations in dogs with liver disease. Fasted blood samples were collected from 15 dogs with newly diagnosed liver disease and 18 healthy dogs. Gastrin concentrations were significantly lower in dogs with congenital portosystemic shunt compared with healthy dogs (P=0.003). No significant difference (P=0.6) in gastrin concentration was revealed between dogs with hepatocellular disease and healthy dogs. Serum gastrin concentrations were not significantly associated with the occurrence of vomiting, anorexia, diarrhoea, or melaena in dogs with liver disorders. These findings did not provide support for the role of hypergastrinaemia in the development of gastrointestinal signs associated with liver disease in dogs. Decreased serum concentrations of gastrin in a dog with liver disease may suggest the presence of portosystemic shunt. Further investigation is warranted to determine the importance of hyopogastrinaemia in congenital postosystemic shunts in dogs and to evaluate potential alterations in serum gastrin concentrations in specific hepatocellular diseases.

Paradoxical effects of gastrin releasing peptide on gastrin release and gastric secretion in the rat.

PubMed

Takagi, A; Moriga, M; Narusawa, H; Uchino, H; Aono, M

1986-12-01

The effects of gastrin releasing peptide (GRP) on gastrin release and gastric secretion were studied in anesthetized rats. Intravenous infusion of GRP (1-16 micrograms/kg/hr) caused a dose-dependent increase in serum gastrin level, however, it had no effect on basal gastric secretion in the lumen-perfused stomach preparation. Furthermore, GRP inhibited gastric secretion stimulated by pentagastrin or histamine dose-dependently, but not by carbachol. Simultaneous infusion of GRP and a beta adrenergic blocking agent, propranolol, an inhibitor of somatostatin release, did not alter the inhibitory effect of GRP on pentagastrin-stimulated gastric secretion. These results suggest that the inhibitory effect of GRP on gastric secretion in a stimulated condition is mediated via peptide hormones coreleased by GRP, and not via beta-adrenergic pathways.

YY1 Control of AID-Dependent Lymphomagenesis

DTIC Science & Technology

2015-07-01

lymphomagenesis by conditional deletion of the yy1 gene in germinal center B cells using γ1-CRE mice. 2. KEYWORDS Yin-Yang 1 (YY1), B Cell Lymphoma, Activation...AWARD NUMBER: W81XWH-14- 1 -0171 TITLE: YY1 Control of AID-Dependent Lymphomagenesis PRINCIPAL INVESTIGATOR: Michael Atchison, Ph.D CONTRACTING...reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions

Gastrin and the growth of the gastrointestinal tract.

PubMed Central

Ekundayo, A A; Lee, C Y; Goodlad, R A

1995-01-01

While the proliferative effects of gastrin in the gastric fundus are well established, there is a considerable degree of confusion regarding the role of gastrin on the growth of the small intestine and colon. The hypothesis that gastrin is trophic throughout the gut was tested by giving three doses of pentagastrin and one of gastrin 17 to rats maintained by total parenteral nutrition (TPN). The rats were fed intravenously for one week, with the various peptides added to the TPN diet. The number of vincristine arrested metaphases per gland or crypt was then scored to determine the proliferative state. Both gastrin 17 and pentagastrin were found to be trophic in the gastric fundus, but not to the gastric antrum. A proliferative response was also seen in the duodenum, but with little evidence of a dose response element. No effect on small bowel weight was seen, and no proliferative effect was noted in the mid small bowel, thus the duodenal effect could be attributed to a local action of increased acid output on the duodenum, not a general role throughout the small intestine. No proliferative effects of pentagastrin or gastrin were seen in the colon. It is therefore concluded that the trophic role of gastrin is restricted to the gastric fundus and the proximal duodenum. PMID:7883218

Function of YY1 in Long-Distance DNA Interactions

PubMed Central

Atchison, Michael L.

2014-01-01

During B cell development, long-distance DNA interactions are needed for V(D)J somatic rearrangement of the immunoglobulin (Ig) loci to produce functional Ig genes, and for class switch recombination (CSR) needed for antibody maturation. The tissue-specificity and developmental timing of these mechanisms is a subject of active investigation. A small number of factors are implicated in controlling Ig locus long-distance interactions including Pax5, Yin Yang 1 (YY1), EZH2, IKAROS, CTCF, cohesin, and condensin proteins. Here we will focus on the role of YY1 in controlling these mechanisms. YY1 is a multifunctional transcription factor involved in transcriptional activation and repression, X chromosome inactivation, Polycomb Group (PcG) protein DNA recruitment, and recruitment of proteins required for epigenetic modifications (acetylation, deacetylation, methylation, ubiquitination, sumoylation, etc.). YY1 conditional knock-out indicated that YY1 is required for B cell development, at least in part, by controlling long-distance DNA interactions at the immunoglobulin heavy chain and Igκ loci. Our recent data show that YY1 is also required for CSR. The mechanisms implicated in YY1 control of long-distance DNA interactions include controlling non-coding antisense RNA transcripts, recruitment of PcG proteins to DNA, and interaction with complexes involved in long-distance DNA interactions including the cohesin and condensin complexes. Though common rearrangement mechanisms operate at all Ig loci, their distinct temporal activation along with the ubiquitous nature of YY1 poses challenges for determining the specific mechanisms of YY1 function in these processes, and their regulation at the tissue-specific and B cell stage-specific level. The large numbers of post-translational modifications that control YY1 functions are possible candidates for regulation. PMID:24575094

Transfection of embryonated Muscovy duck eggs with a recombinant plasmid is suitable for rescue of infectious Muscovy duck parvovirus.

PubMed

Wang, Jianye; Huang, Yu; Ling, Jueyi; Wang, Zhixiang; Zhu, Guoqiang

2017-12-01

For members of the family Parvoviridae, rescue of infectious virus from recombinant plasmid is usually done in cultured cells. In this study, the whole genome of the pathogenic Muscovy duck parvovirus (MDPV) strain YY was cloned into the pBluescript II (SK) vector, generating recombinant plasmid pYY. With the aid of a transfection reagent, pYY plasmid was inoculated into 11-day-old embryonated Muscovy duck eggs via the chorioallantoic membrane route, resulting in the successful rescue of infectious virus and death of the embryos. The rescued virus exhibited pathogenicity in Muscovy ducklings similar to that of its parental strain, as evaluated based on the mortality rate. The results demonstrate that plasmid transfection in embryonated Muscovy duck eggs is a convenient and efficacious method for rescue of infectious MDPV in comparison to transfection of primary cells, which is somewhat time-consuming and laborious.

YY1 positively regulates human UBIAD1 expression

DOE Office of Scientific and Technical Information (OSTI.GOV)

Funahashi, Nobuaki, E-mail: nfunahashi@ri.ncgm.go.jp; Department of Metabolic Disorder, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, Tokyo; Hirota, Yoshihisa

Vitamin K is involved in bone formation and blood coagulation. Natural vitamin K compounds are composed of the plant form phylloquinone (vitamin K{sub 1}) and a series of bacterial menaquionones (MK-n; vitamin K{sub 2}). Menadione (vitamin K{sub 3}) is an artificial vitamin K compound. MK-4 contains 4-isoprenyl as a side group in the 2-methyl-1,4-naphthoquinone common structure and has various bioactivities. UbiA prenyltransferase domain containing 1 (UBIAD1 or TERE1) is the menaquinone-4 biosynthetic enzyme. UBIAD1 transcript expression significantly decreases in patients with prostate carcinoma and overexpressing UBIAD1 inhibits proliferation of a tumour cell line. UBIAD1 mRNA expression is ubiquitous in mousemore » tissues, and higher UBIAD1 mRNA expression levels are detected in the brain, heart, kidneys and pancreas. Several functions of UBIAD1 have been reported; however, regulation of the human UBIAD1 gene has not been elucidated. Here we report cloning and characterisation of the human UBIAD1 promoter. A 5′ rapid amplification of cDNA ends analysis revealed that the main transcriptional start site was 306 nucleotides upstream of the translation initiation codon. Deletion and mutation analyses revealed the functional importance of the YY1 consensus motif. Electrophoretic gel mobility shift and chromatin immunoprecipitation assays demonstrated that YY1 binds the UBIAD1 promoter in vitro and in vivo. In addition, YY1 small interfering RNA decreased endogenous UBIAD1 mRNA expression and UBIAD1 conversion activity. These results suggest that YY1 up-regulates UBIAD1 expression and UBIAD1 conversion activity through the UBIAD1 promoter. - Highlights: • We cloned the human UBIAD1 promoter. • The functional importance of the YY1 motif was identified in the UBIAD1 promoter. • YY1 binds the UBIAD1 promoter in vitro and in vivo. • Knockdown of YY1 significantly decreased UBIAD1 expression. • YY1 up-regulates UBIAD1 conversion activity through the

The Studies on the Gastrin Levels in the Patients with Renal Failure

PubMed Central

Kim, Myung Hwan; Kim, Han Su; Rim, Kyu Sung; Bang, Ik Soo; Kim, Myung Jae; Chang, Rin; Min, Young II

1986-01-01

Fasting and postprandial gastrin levels were measured by radioimmunoassay in serum from 15 patients with renal failure and compared with those in 15 healthy controls. Pre- and posthemodialysis gastrin levels were also measured. The fasting serum gastrin levels and serum gastrin response to a standard meal in the patients with renal failure were significantly higher than those in normal controls. Fasting and meal stimulated gastrin levels were not significantly different in renal failure patients with peptic ulcer when compared with those in renal failure patients without peptic ulcer. There were no statistically significant differences in the serum gastrin levels before and after hemodialysis in patients with renal failure. PMID:15759375

A Novel YY1-miR-1 Regulatory Circuit in Skeletal Myogenesis Revealed by Genome-Wide Prediction of YY1-miRNA Network

PubMed Central

Lu, Leina; Zhou, Liang; Chen, Eric Z.; Sun, Kun; Jiang, Peiyong; Wang, Lijun; Su, Xiaoxi; Sun, Hao; Wang, Huating

2012-01-01

microRNAs (miRNAs) are non-coding RNAs that regulate gene expression post-transcriptionally, and mounting evidence supports the prevalence and functional significance of their interplay with transcription factors (TFs). Here we describe the identification of a regulatory circuit between muscle miRNAs (miR-1, miR-133 and miR-206) and Yin Yang 1 (YY1), an epigenetic repressor of skeletal myogenesis in mouse. Genome-wide identification of potential down-stream targets of YY1 by combining computational prediction with expression profiling data reveals a large number of putative miRNA targets of YY1 during skeletal myoblasts differentiation into myotubes with muscle miRs ranking on top of the list. The subsequent experimental results demonstrate that YY1 indeed represses muscle miRs expression in myoblasts and the repression is mediated through multiple enhancers and recruitment of Polycomb complex to several YY1 binding sites. YY1 regulating miR-1 is functionally important for both C2C12 myogenic differentiation and injury-induced muscle regeneration. Furthermore, we demonstrate that miR-1 in turn targets YY1, thus forming a negative feedback loop. Together, these results identify a novel regulatory circuit required for skeletal myogenesis and reinforce the idea that regulatory circuitries involving miRNAs and TFs are prevalent mechanisms. PMID:22319554

A PYY Q62P variant linked to human obesity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ahituv, Nadav; Kavaslar, Nihan; Schackwitz, Wendy

2005-06-27

Members of the pancreatic polypeptide family and the irreceptors have been implicated in the control of food intake in rodents and humans. To investigate whether nucleotide changes in these candidate genes result in abnormal weight in humans, we sequenced the coding exons and splice sites of seven family members (NPY, PYY, PPY, NPY1R, NPY2R, NPY4R, and NPY5R) in a large cohort of extremely obese (n=379) and lean (n=378) individuals. In total we found eleven rare non-synonymous variants, four of which exhibited familial segregation, NPY1R L53P and PPY P63L with leanness and NPY2R D42G and PYY Q62P with obesity. Functional analysismore » of the obese variants revealed NPY2R D42G to have reduced cell surface expression, while previous cell culture based studies indicated variant PYY Q62P to have altered receptor binding selectivity and we show that it fails to reduce food intake through mouse peptide injection experiments. These results support that rare non-synonymous variants within these genes can alter susceptibility to human body mass index extremes.« less

GROWTH OF HUMAN PANCREATIC CANCER IS INHIBITED BY DOWN-REGULATION OF GASTRIN GENE EXPRESSION

PubMed Central

Matters, Gail L.; Harms, John F.; McGovern, Christopher O.; Jayakumar, Calpurnia; Crepin, Keisha; Smith, Zachary P.; Nelson, Melissa C.; Stock, Heather; Fenn, Craig W.; Kaiser, James; Kester, Mark; Smith, Jill P.

2009-01-01

Objectives This study evaluated the effects of gastrin mRNA down-regulation on growth of human pancreatic cancer. Methods Gastrin expression was examined in human pancreatic cancer cell lines by RT-PCR and peptide expression was assessed by immunocytochemistry. Gastrin was down-regulated using either stable transfection of an antisense gastrin cDNA or one of three shRNA (short hairpin RNA) constructs. Tumor formation was evaluated following either subcutaneous or orthotopic injections into nude mice. The effect of nanoliposomes loaded with gastrin siRNA was tested in mice bearing pancreatic tumors. Results Stable transfection of gastrin antisense or shRNAs into BxPC-3 cells resulted in clones with >90% reduction in gastrin mRNA. Tumor growth rate and incidence of metastases in both wild type and transfected pancreatic cancer cells was directly proportional to the degrees of gastrin mRNA expression. Immunofluoresence analysis confirmed that gastrin peptide levels were decreased in antisense and shRNA tumors. Gastrin knockdown clones had lower Ki-67 and increased cleaved caspase-3 staining, consistent with known effects of gastrin on proliferation and apoptosis. Tumors in mice treated with gastrin siRNA were smaller than controls. Conclusions These results suggest that RNAi targeting of gastrin could serve as an effective treatment for pancreatic cancer. PMID:19465883

Postprandial PYY increase by resistant starch supplementation is independent of net portal appearance of short-chain fatty acids in pigs.

PubMed

Ingerslev, Anne Krog; Mutt, Shivaprakash Jagalur; Lærke, Helle Nygaard; Hedemann, Mette Skou; Theil, Peter Kappel; Nielsen, Kirstine Lykke; Jørgensen, Henry; Herzig, Karl-Heinz; Bach Knudsen, Knud Erik

2017-01-01

Increased dietary fiber (DF) fermentation and short-chain fatty acid (SCFA) production may stimulate peptide tyrosine-tyrosine (PYY) secretion. In this study, the effects of hindgut SCFA production on postprandial PYY plasma levels were assessed using different experimental diets in a porto-arterial catheterized pig model. The pigs were fed experimental diets varying in source and levels of DF for one week in 3×3 Latin square designs. The DF sources were whole-wheat grain, wheat aleurone, rye aleurone-rich flour, rye flakes, and resistant starch. Postprandial blood samples were collected from the catheters and analyzed for PYY levels and net portal appearance (NPA) of PYY was correlated to NPA of SCFA. No significant effects of diets on NPA of PYY were observed (P > 0.05), however, resistant starch supplementation increased postprandial NPA of PYY levels by 37 to 54% compared with rye-based and Western-style control diets (P = 0.19). This increase was caused by higher mesenteric artery and portal vein PYY plasma levels (P < 0.001) and was independent of SCFA absorption (P > 0.05). The PYY levels were higher in response to the second daily meal compared with the first daily meal (P < 0.001), but similar among diets (P > 0.10). In conclusion, the increased postprandial PYY responses in pigs fed with different levels and sources of DF are not caused by an increased SCFA absorption and suggest that other mechanisms such as neural reflexes and possibly an increased flow of digesta in the small intestine may be involved. The content of DF and SCFA production did not affect PYY levels.

Cytoplasmic YY1 Is Associated with Increased Smooth Muscle-Specific Gene Expression

PubMed Central

Favot, Laure; Hall, Susan M.; Haworth, Sheila G.; Kemp, Paul R.

2005-01-01

Immediately after birth the adluminal vascular SMCs of the pulmonary elastic arteries undergo transient actin cytoskeletal remodeling as well as cellular de-differentiation and proliferation. Vascular smooth muscle phenotype is regulated by serum response factor, which is itself regulated in part by the negative regulator YY1. We therefore studied the subcellular localization of YY1 in arteries of normal newborn piglets and piglets affected by neonatal pulmonary hypertension. We found that YY1 localization changed during development and that expression of γ-smooth muscle actin correlated with expression of cytoplasmic rather than nuclear YY1. Analysis of the regulation of YY1 localization in vitro demonstrated that polymerized γ-actin sequestered EGFP-YY1 in the cytoplasm and that YY1 activation of c-myc promoter activity was inhibited by LIM kinase, which increases actin polymerization. Consistent with these data siRNA-mediated down-regulation of YY1 in C2C12 cells increased SM22-α expression and inhibited cell proliferation. Thus, actin polymerization controls subcellular YY1 localization, which contributes to vascular SMC proliferation and differentiation in normal pulmonary artery development. In the absence of actin depolymerization, YY1 does not relocate to the nucleus, and this lack of relocation may contribute to the pathobiology of pulmonary hypertension. PMID:16314465

The RAPID method for blood processing yields new insight in plasma concentrations and molecular forms of circulating gut peptides.

PubMed

Stengel, Andreas; Keire, David; Goebel, Miriam; Evilevitch, Lena; Wiggins, Brian; Taché, Yvette; Reeve, Joseph R

2009-11-01

The correct identification of circulating molecular forms and measurement of peptide levels in blood entails that the endocrine peptide being studied is stable and recovered in good yields during blood processing. However, it is not clear whether this is achieved in studies using standard blood processing. Therefore, we compared peptide concentration and form of 12 (125)I-labeled peptides using the standard procedure (EDTA-blood on ice) and a new method employing Reduced temperatures, Acidification, Protease inhibition, Isotopic exogenous controls, and Dilution (RAPID). During standard processing there was at least 80% loss for calcitonin-gene-related peptide and cholecystokinin-58 (CCK-58) and more than 35% loss for amylin, insulin, peptide YY forms (PYY((1-36)) and PYY((3-36))), and somatostatin-28. In contrast, the RAPID method significantly improved the recovery for 11 of 12 peptides (P < 0.05) and eliminated the breakdown of endocrine peptides occurring after standard processing as reflected in radically changed molecular forms for CCK-58, gastrin-releasing peptide, somatostatin-28, and ghrelin. For endogenous ghrelin, this led to an acyl/total ghrelin ratio of 1:5 instead of 1:19 by the standard method. These results show that the RAPID method enables accurate assessment of circulating gut peptide concentrations and forms such as CCK-58, acylated ghrelin, and somatostatin-28. Therefore, the RAPID method represents an efficacious means to detect circulating variations in peptide concentrations and form relevant to the understanding of physiological function of endocrine peptides.

Is raised plasma peptide YY after intestinal resection in the rat responsible for the trophic response?

PubMed Central

Savage, A P; Gornacz, G E; Adrian, T E; Ghatei, M A; Goodlad, R A; Wright, N A; Bloom, S R

1985-01-01

The relationship between the adaptive response and plasma PYY concentrations after small bowel resection has been investigated. Seventy five per cent proximal small bowel resection resulted in a rise in plasma PYY at six days from 28 +/- 3.1 to 85 +/- 12.3 pmol/l (p less than 0.001) and this difference was maintained to 48 days. Plasma PYY correlates both with crypt cell production rate (CCPR) in the ileum and with plasma enteroglucagon levels. In a second study, PYY or saline was infused over a 12 day period. There were no significant changes in intestinal wet weight or CCPR in any part of the bowel studied. This indicates that it is unlikely that PYY exerts a major trophic effect on the gastrointestinal tract. PMID:3841330

Is raised plasma peptide YY after intestinal resection in the rat responsible for the trophic response?

PubMed

Savage, A P; Gornacz, G E; Adrian, T E; Ghatei, M A; Goodlad, R A; Wright, N A; Bloom, S R

1985-12-01

The relationship between the adaptive response and plasma PYY concentrations after small bowel resection has been investigated. Seventy five per cent proximal small bowel resection resulted in a rise in plasma PYY at six days from 28 +/- 3.1 to 85 +/- 12.3 pmol/l (p less than 0.001) and this difference was maintained to 48 days. Plasma PYY correlates both with crypt cell production rate (CCPR) in the ileum and with plasma enteroglucagon levels. In a second study, PYY or saline was infused over a 12 day period. There were no significant changes in intestinal wet weight or CCPR in any part of the bowel studied. This indicates that it is unlikely that PYY exerts a major trophic effect on the gastrointestinal tract.

YY1 Protects Cardiac Myocytes from Pathologic Hypertrophy by Interacting with HDAC5

PubMed Central

Dockstader, Karen; McKinsey, Timothy A.

2008-01-01

YY1 is a transcription factor that can repress or activate the transcription of a variety of genes. Here, we show that the function of YY1 as a repressor in cardiac myocytes is tightly dependent on its ability to interact with histone deacetylase 5 (HDAC5). YY1 interacts with HDAC5, and overexpression of YY1 prevents HDAC5 nuclear export in response to hypertrophic stimuli and the increase in cell size and re-expression of fetal genes that accompany pathological cardiac hypertrophy. Knockdown of YY1 results in up-regulation of all genes present during fetal development and increases the cell size of neonatal cardiac myocytes. Moreover, overexpression of a YY1 deletion construct that does not interact with HDAC5 results in transcription activation, suggesting that HDAC5 is necessary for YY1 function as a transcription repressor. In support of this relationship, we show that knockdown of HDAC5 results in transcription activation by YY1. Finally, we show that YY1 interaction with HDAC5 is dependent on the HDAC5 phosphorylation domain and that overexpression of YY1 reduces HDAC5 phosphorylation in response to hypertrophic stimuli. Our results strongly suggest that YY1 functions as an antihypertrophic factor by preventing HDAC5 nuclear export and that up-regulation of YY1 in human heart failure may be a protective mechanism against pathological hypertrophy. PMID:18632988

YY1 Haploinsufficiency Causes an Intellectual Disability Syndrome Featuring Transcriptional and Chromatin Dysfunction.

PubMed

Gabriele, Michele; Vulto-van Silfhout, Anneke T; Germain, Pierre-Luc; Vitriolo, Alessandro; Kumar, Raman; Douglas, Evelyn; Haan, Eric; Kosaki, Kenjiro; Takenouchi, Toshiki; Rauch, Anita; Steindl, Katharina; Frengen, Eirik; Misceo, Doriana; Pedurupillay, Christeen Ramane J; Stromme, Petter; Rosenfeld, Jill A; Shao, Yunru; Craigen, William J; Schaaf, Christian P; Rodriguez-Buritica, David; Farach, Laura; Friedman, Jennifer; Thulin, Perla; McLean, Scott D; Nugent, Kimberly M; Morton, Jenny; Nicholl, Jillian; Andrieux, Joris; Stray-Pedersen, Asbjørg; Chambon, Pascal; Patrier, Sophie; Lynch, Sally A; Kjaergaard, Susanne; Tørring, Pernille M; Brasch-Andersen, Charlotte; Ronan, Anne; van Haeringen, Arie; Anderson, Peter J; Powis, Zöe; Brunner, Han G; Pfundt, Rolph; Schuurs-Hoeijmakers, Janneke H M; van Bon, Bregje W M; Lelieveld, Stefan; Gilissen, Christian; Nillesen, Willy M; Vissers, Lisenka E L M; Gecz, Jozef; Koolen, David A; Testa, Giuseppe; de Vries, Bert B A

2017-06-01

Yin and yang 1 (YY1) is a well-known zinc-finger transcription factor with crucial roles in normal development and malignancy. YY1 acts both as a repressor and as an activator of gene expression. We have identified 23 individuals with de novo mutations or deletions of YY1 and phenotypic features that define a syndrome of cognitive impairment, behavioral alterations, intrauterine growth restriction, feeding problems, and various congenital malformations. Our combined clinical and molecular data define "YY1 syndrome" as a haploinsufficiency syndrome. Through immunoprecipitation of YY1-bound chromatin from affected individuals' cells with antibodies recognizing both ends of the protein, we show that YY1 deletions and missense mutations lead to a global loss of YY1 binding with a preferential retention at high-occupancy sites. Finally, we uncover a widespread loss of H3K27 acetylation in particular on the YY1-bound enhancers, underscoring a crucial role for YY1 in enhancer regulation. Collectively, these results define a clinical syndrome caused by haploinsufficiency of YY1 through dysregulation of key transcriptional regulators. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

YY1 Regulates Melanocyte Development and Function by Cooperating with MITF

PubMed Central

Bell, Robert J. A.; Tran, Thanh-Nga T.; Haq, Rizwan; Liu, Huifei; Love, Kevin T.; Langer, Robert; Anderson, Daniel G.; Larue, Lionel; Fisher, David E.

2012-01-01

Studies of coat color mutants have greatly contributed to the discovery of genes that regulate melanocyte development and function. Here, we generated Yy1 conditional knockout mice in the melanocyte-lineage and observed profound melanocyte deficiency and premature gray hair, similar to the loss of melanocytes in human piebaldism and Waardenburg syndrome. Although YY1 is a ubiquitous transcription factor, YY1 interacts with M-MITF, the Waardenburg Syndrome IIA gene and a master transcriptional regulator of melanocytes. YY1 cooperates with M-MITF in regulating the expression of piebaldism gene KIT and multiple additional pigmentation genes. Moreover, ChIP–seq identified genome-wide YY1 targets in the melanocyte lineage. These studies mechanistically link genes implicated in human conditions of melanocyte deficiency and reveal how a ubiquitous factor (YY1) gains lineage-specific functions by co-regulating gene expression with a lineage-restricted factor (M-MITF)—a general mechanism which may confer tissue-specific gene expression in multiple lineages. PMID:22570637

Methylation of transcription factor YY2 regulates its transcriptional activity and cell proliferation

PubMed Central

Wu, Xiao-nan; Shi, Tao-tao; He, Yao-hui; Wang, Fei-fei; Sang, Rui; Ding, Jian-cheng; Zhang, Wen-juan; Shu, Xing-yi; Shen, Hai-feng; Yi, Jia; Gao, Xiang; Liu, Wen

2017-01-01

Yin Yang 1 (YY1) is a multifunctional DNA-binding transcription factor shown to be critical in a variety of biological processes, and its activity and function have been shown to be regulated by multitude of mechanisms, which include but are not limited to post-translational modifications (PTMs), its associated proteins and cellular localization. YY2, the paralog of YY1 in mouse and human, has been proposed to function redundantly or oppositely in a context-specific manner compared with YY1. Despite its functional importance, how YY2’s DNA-binding activity and function are regulated, particularly by PTMs, remains completely unknown. Here we report the first PTM with functional characterization on YY2, namely lysine 247 monomethylation (K247me1), which was found to be dynamically regulated by SET7/9 and LSD1 both in vitro and in cultured cells. Functional study revealed that SET7/9-mediated YY2 methylation regulated its DNA-binding activity in vitro and in association with chromatin examined by chromatin immunoprecipitation coupled with sequencing (ChIP-seq) in cultured cells. Knockout of YY2, SET7/9 or LSD1 by CRISPR (clustered, regularly interspaced, short palindromic repeats)/Cas9-mediated gene editing followed by RNA sequencing (RNA-seq) revealed that a subset of genes was positively regulated by YY2 and SET7/9, but negatively regulated by LSD1, which were enriched with genes involved in cell proliferation regulation. Importantly, YY2-regulated gene transcription, cell proliferation and tumor growth were dependent, at least partially, on YY2 K247 methylation. Finally, somatic mutations on YY2 found in cancer, which are in close proximity to K247, altered its methylation, DNA-binding activity and gene transcription it controls. Our findings revealed the first PTM with functional implications imposed on YY2 protein, and linked YY2 methylation with its biological functions. PMID:29098080

Effects of differently composed feeds and physical stress on plasma gastrin concentration in horses.

PubMed

Sandin, A; Girma, K; Sjöholm, B; Lindholm, A; Nilsson, G

1998-01-01

Plasma gastrin concentrations were determined in 6 Standardbreds (4 geldings and 2 mares) after 3 different meals consisting of unlimited amounts of hay (8-9 kg per horse), a restricted amount of hay (0.6 kg/100 kg body-weight) and grain (0.2 kg/100 kg body-weight) in combination or of grain alone (0.2 kg/100 kg body-weight). In another series of experiments the possible role of gastrin as a stress hormone was investigated. Plasma gastrin and cortisol concentrations were determined during fasting and compared with concentrations during hay feeding. In addition, gastrin and cortisol concentrations were determined before, during and after 2 kinds of physical exercise on a treadmill. Meal stimulation significantly increased the plasma gastrin concentration, irrespective of the meal composition. An immediate and large increase in plasma gastrin concentration was found when voluminous meals were given, whereas a small meal evoked a later onset of gastrin release, suggesting that gastric distention plays an important role in inducing gastrin release during a meal. Meals consisting of grain seem to evoke a slower onset and then a more prolonged gastrin response than a hay meal, possibly due to different emptying rates of the stomach. Nervous excitation may play a minor role in the activation of gastrin release in horses. No experimental support was obtained for the idea that gastrin acts as a stress hormone in the horse.

Transcription factor YY1 can control AID-mediated mutagenesis in mice.

PubMed

Zaprazna, Kristina; Basu, Arindam; Tom, Nikola; Jha, Vibha; Hodawadekar, Suchita; Radova, Lenka; Malcikova, Jitka; Tichy, Boris; Pospisilova, Sarka; Atchison, Michael L

2018-02-01

Activation-induced cytidine deminase (AID) is crucial for controlling the immunoglobulin (Ig) diversification processes of somatic hypermutation (SHM) and class switch recombination (CSR). AID initiates these processes by deamination of cytosine, ultimately resulting in mutations or double strand DNA breaks needed for SHM and CSR. Levels of AID control mutation rates, and off-target non-Ig gene mutations can contribute to lymphomagenesis. Therefore, factors that control AID levels in the nucleus can regulate SHM and CSR, and may contribute to disease. We previously showed that transcription factor YY1 can regulate the level of AID in the nucleus and Ig CSR. Therefore, we hypothesized that conditional knock-out of YY1 would lead to reduction in AID localization at the Ig locus, and reduced AID-mediated mutations. Using mice that overexpress AID (IgκAID yy1 f/f ) or that express normal AID levels (yy1 f/f ), we found that conditional knock-out of YY1 results in reduced AID nuclear levels, reduced localization of AID to the Sμ switch region, and reduced AID-mediated mutations. We find that the mechanism of YY1 control of AID nuclear accumulation is likely due to YY1-AID physical interaction which blocks AID ubiquitination. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

High Affinity Binding of Indium and Ruthenium Ions by Gastrins

PubMed Central

Baldwin, Graham S.; George, Graham N.; Pushie, M. Jake

2015-01-01

The peptide hormone gastrin binds two ferric ions with high affinity, and iron binding is essential for the biological activity of non-amidated forms of the hormone. Since gastrins act as growth factors in gastrointestinal cancers, and as peptides labelled with Ga and In isotopes are increasingly used for cancer diagnosis, the ability of gastrins to bind other metal ions was investigated systematically by absorption spectroscopy. The coordination structures of the complexes were characterized by extended X-ray absorption fine structure (EXAFS) spectroscopy. Changes in the absorption of gastrin in the presence of increasing concentrations of Ga3+ were fitted by a 2 site model with dissociation constants (Kd) of 3.3 x 10−7 and 1.1 x 10−6 M. Although the absorption of gastrin did not change upon the addition of In3+ ions, the changes in absorbance on Fe3+ ion binding in the presence of indium ions were fitted by a 2 site model with Kd values for In3+ of 6.5 x 10−15 and 1.7 x 10−7 M. Similar results were obtained with Ru3+ ions, although the Kd values for Ru3+ of 2.6 x 10−13 and 1.2 x 10−5 M were slightly larger than observed for In3+. The structures determined by EXAFS all had metal:gastrin stoichiometries of 2:1 but, while the metal ions in the Fe, Ga and In complexes were bridged by a carboxylate and an oxygen with a metal-metal separation of 3.0–3.3 Å, the Ru complex clearly demonstrated a short range Ru—Ru separation, which was significantly shorter, at 2.4 Å, indicative of a metal-metal bond. We conclude that gastrin selectively binds two In3+ or Ru3+ ions, and that the affinity of the first site for In3+ or Ru3+ ions is higher than for ferric ions. Some of the metal ion-gastrin complexes may be useful for cancer diagnosis and therapy. PMID:26457677

The Yin and Yang of YY1 in the nervous system

PubMed Central

He, Ye; Casaccia-Bonnefil, Patrizia

2008-01-01

The transcription factor Yin Yang 1 (YY1) is a multifunctional protein that can activate or repress gene expression depending on the cellular context. YY1 is ubiquitously expressed and highly conserved between species. However its role varies in diverse cell types and includes proliferation, differentiation and apoptosis. This review will focus on the function of YY1 in the nervous system including its role in neural development, neuronal function, developmental myelination and neurological disease. The multiple functions of YY1 in distinct cell types are reviewed and the possible mechanisms underlying the cell specificity for these functions are discussed. PMID:18485096

Fats infused intraduodenally affect the postprandial secretion of the exocrine pancreas and the plasma concentration of cholecystokinin but not of peptide YY in growing pigs.

PubMed

Jakob, S; Mosenthin, R; Zabielski, R; Rippe, C; Winzell, M S; Gacsalyi, U; Laubitz, D; Grzesiuk, E; Pierzynowski, S G

2000-10-01

In pigs, the spontaneous secretion of the exocrine pancreas and the release of cholecystokinin (CCK) and peptide YY (PYY) after intraduodenal infusion of fully saturated synthetic fats differing in chain length was studied. Growing pigs (n = 6) were prepared with pancreatic duct catheters, duodenal T-cannulas and catheters placed in the jugular vein. The pigs were fed 2 g/100 g body twice daily. Beginning with the morning feeding, a medium-chain triglyceride (MCT: glycerol tricaprylate), a long-chain triglyceride (LCT: glycerol tristearate) or saline was infused at a rate of 0.1 g/100 g body. Pancreatic juice was collected, beginning 1 h preprandially until 3 h postprandially. Blood samples were obtained 15 min preprandially and 15, 45, 90 and 150 min postprandially. The infusion of MCT evoked a change in the trend of the curve for the volume of secretion of pancreatic juice, lipase and colipase concentrations and outputs. The trend of the curve did not change over time for CCK and PYY. Differences between the trends of the curves for the saline and MCT treatment were observed for volume of secretion, protein output, lipase content and output, trypsin and colipase output. Differences in the trends of the curves between MCT and LCT were obtained for the outputs of protein, lipase and colipase. Plasma CCK levels were lower as a result of the MCT treatment compared with the saline and LCT treatments. The results suggest an immediate, distinguished response of the porcine exocrine pancreas to fats differing in chain length.

An integral projection model with YY-males and application to evaluating grass carp control

USGS Publications Warehouse

Erickson, Richard A.; Eager, Eric A.; Brey, Marybeth; Hansen, Michael J.; Kocovsky, Patrick

2017-01-01

Invasive fish species disrupt ecosystems and cause economic damage. Several methods have been discussed to control populations of invasive fish including the release of YY-males. YY-males are fish that have 2 male chromosomes compared to a XY-male. When YY-males mate, they only produce male (XY) offspring. This decreases the female proportion of the population and can, in theory, eradicate local populations by biasing the sex-ratio. YY-males have been used as a population control tool for brook trout in montane streams and lakes in Idaho, USA. The YY-male control method has been discussed for grass carp in Lake Erie, North America. We developed and presented an integral projection model for grass carp to model the use of YY-males as a control method for populations in this lake. Using only the YY-male control method, we found that high levels of YY-males would need to be release annually to control the species. Specifically, these levels were the same order of magnitude as the baseline adult population (e.g., 1000 YY-males needed to be released annual for 20 years to control a baseline adult population of 2500 grass carp). These levels may not be reasonable or obtainable for fisheries managers given the impacts of YY-males on aquatic vegetation and other constraints of natural resource management.

The nuclear matrix protein NMP-1 is the transcription factor YY1.

PubMed Central

Guo, B; Odgren, P R; van Wijnen, A J; Last, T J; Nickerson, J; Penman, S; Lian, J B; Stein, J L; Stein, G S

1995-01-01

NMP-1 was initially identified as a nuclear matrix-associated DNA-binding factor that exhibits sequence-specific recognition for the site IV regulatory element of a histone H4 gene. This distal promoter domain is a nuclear matrix interaction site. In the present study, we show that NMP-1 is the multifunctional transcription factor YY1. Gel-shift and Western blot analyses demonstrate that NMP-1 is immunoreactive with YY1 antibody. Furthermore, purified YY1 protein specifically recognizes site IV and reconstitutes the NMP-1 complex. Western blot and gel-shift analyses indicate that YY1 is present within the nuclear matrix. In situ immunofluorescence studies show that a significant fraction of YY1 is localized in the nuclear matrix, principally but not exclusively associated with residual nucleoli. Our results confirm that NMP-1/YY1 is a ubiquitous protein that is present in both human cells and in rat osteosarcoma ROS 17/2.8 cells. The finding that NMP-1 is identical to YY1 suggests that this transcriptional regulator may mediate gene-matrix interactions. Our results are consistent with the concept that the nuclear matrix may functionally compartmentalize the eukaryotic nucleus to support regulation of gene expression. Images Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 PMID:7479833

Pancreatic β-Cells Express the Fetal Islet Hormone Gastrin in Rodent and Human Diabetes.

PubMed

Dahan, Tehila; Ziv, Oren; Horwitz, Elad; Zemmour, Hai; Lavi, Judith; Swisa, Avital; Leibowitz, Gil; Ashcroft, Frances M; In't Veld, Peter; Glaser, Benjamin; Dor, Yuval

2017-02-01

β-Cell failure in type 2 diabetes (T2D) was recently proposed to involve dedifferentiation of β-cells and ectopic expression of other islet hormones, including somatostatin and glucagon. Here we show that gastrin, a stomach hormone typically expressed in the pancreas only during embryogenesis, is expressed in islets of diabetic rodents and humans with T2D. Although gastrin in mice is expressed in insulin + cells, gastrin expression in humans with T2D occurs in both insulin + and somatostatin + cells. Genetic lineage tracing in mice indicates that gastrin expression is turned on in a subset of differentiated β-cells after exposure to severe hyperglycemia. Gastrin expression in adult β-cells does not involve the endocrine progenitor cell regulator neurogenin3 but requires membrane depolarization, calcium influx, and calcineurin signaling. In vivo and in vitro experiments show that gastrin expression is rapidly eliminated upon exposure of β-cells to normal glucose levels. These results reveal the fetal hormone gastrin as a novel marker for reversible human β-cell reprogramming in diabetes. © 2017 by the American Diabetes Association.

Pancreatic β-Cells Express the Fetal Islet Hormone Gastrin in Rodent and Human Diabetes

PubMed Central

Dahan, Tehila; Ziv, Oren; Horwitz, Elad; Zemmour, Hai; Lavi, Judith; Swisa, Avital; Leibowitz, Gil; Ashcroft, Frances M.; In’t Veld, Peter

2017-01-01

β-Cell failure in type 2 diabetes (T2D) was recently proposed to involve dedifferentiation of β-cells and ectopic expression of other islet hormones, including somatostatin and glucagon. Here we show that gastrin, a stomach hormone typically expressed in the pancreas only during embryogenesis, is expressed in islets of diabetic rodents and humans with T2D. Although gastrin in mice is expressed in insulin+ cells, gastrin expression in humans with T2D occurs in both insulin+ and somatostatin+ cells. Genetic lineage tracing in mice indicates that gastrin expression is turned on in a subset of differentiated β-cells after exposure to severe hyperglycemia. Gastrin expression in adult β-cells does not involve the endocrine progenitor cell regulator neurogenin3 but requires membrane depolarization, calcium influx, and calcineurin signaling. In vivo and in vitro experiments show that gastrin expression is rapidly eliminated upon exposure of β-cells to normal glucose levels. These results reveal the fetal hormone gastrin as a novel marker for reversible human β-cell reprogramming in diabetes. PMID:27864307

Subjective satiety and plasma PYY concentration after wholemeal pasta.

PubMed

Costabile, Giuseppina; Griffo, Ettore; Cipriano, Paola; Vetrani, Claudia; Vitale, Marilena; Mamone, Gianfranco; Rivellese, Angela A; Riccardi, Gabriele; Giacco, Rosalba

2018-06-01

Dietary fiber and whole grain foods may contribute to the regulation of appetite; however, evidence has produced inconclusive findings. The objective was to evaluate the effects of an experimental wholemeal pasta on appetite ratings, plasma concentrations of gastrointestinal hormones involved in appetite control, and postprandial glucose/insulin responses in healthy adults. Fourteen healthy adults (7M/7F), mean age 30±2 yrs (mean±SEM), participated in a randomized, controlled, crossover trial. Participants consumed on two different days, at one week interval, 117g of wholemeal pasta or 100g of refined wheat pasta (control pasta), similar in energy and macronutrient composition except for fiber amount, which was higher in wholemeal pasta (11 vs 3 g). Appetite ratings, glucose/insulin/lipid and gastrointestinal hormone responses were measured at fasting and for 4-h after the ingestion of the pasta tests, after which self-reported energy intake for 8-h was evaluated. After the wholemeal pasta, the desire to eat and the sensation of hunger were lower (-16%, p=0.04 and -23%, p=0.004, respectively) and satiety was higher (+13%; p=0.08) compared with the control pasta; no effect on self-reported energy intake at subsequent meal was observed. After wholemeal pasta, glucose, triglyceride increased and GLP-1 responses were not different compared to control pasta but insulin response at 30 min (p<0.05) and ghrelin at 60 min (p=0.03) were lower and PYY levels higher (AUC=+44%, p=0.001). The appetite rating changes correlated with PYY plasma levels (p<0.03). In conclusion, consumption of whole grain instead of refined wheat pasta contributed to appetite control but did not seem to influence acute energy balance. Appetite ratings were associated with modifications in PYY hormone concentrations. Copyright © 2018 Elsevier Ltd. All rights reserved.

Elevated serum gastrin is associated with a history of advanced neoplasia in Barrett's esophagus.

PubMed

Wang, Judy S; Varro, Andrea; Lightdale, Charles J; Lertkowit, Nantaporn; Slack, Kristen N; Fingerhood, Michael L; Tsai, Wei Yann; Wang, Timothy C; Abrams, Julian A

2010-05-01

Proton pump inhibitors (PPIs) are frequently prescribed to patients with Barrett's esophagus (BE), but in a subset, they can induce significant hypergastrinemia. Elevated levels of gastrin have been associated with tumorigenic effects in a number of gastrointestinal cancers. We decided to investigate the association between serum gastrin levels and dysplasia in BE. We performed a cross-sectional study and enrolled patients with BE without dysplasia, low-grade dysplasia (LGD), high-grade dysplasia (HGD), or adenocarcinoma (AC), as well as gastroesophageal reflux disease controls, all chronically taking PPIs. Fasting serum gastrin was measured, and data were collected on patient characteristics, medication use, and the highest degree of BE neoplasia. A total of 95 patients were enrolled. The mean age was 64.7 (+/-10.0) years, and 70.5% were male. The median serum gastrin level was 40 pM. There was no significant difference in gastrin levels with increased degrees of BE neoplasia (overall P=0.68). In multivariable analysis, the highest quartile of gastrin was associated with significantly increased odds of advanced neoplasia (HGD or AC) (odds ratio (OR): 5.46, 95% confidence interval (CI): 1.20-24.8). In BE patients taking PPIs, an elevated serum gastrin is associated with a history of HGD or AC. Prospective studies are needed to determine whether patients with nondysplastic BE and elevated serum gastrin are at increased risk for neoplastic progression.

Binding and degradation of 125I-gastrin by plasma membranes from homogenized rat gastric mucosa.

PubMed

Kleveland, P M; Waldum, H L

1986-06-01

Binding of 125I-gastrin to the 270-30,000 g fraction from homogenized rat oxyntic mucosa was studied. 'Specific' binding was calculated by subtracting the binding at excess cold gastrin from the binding with labelled gastrin (250 pM) only. At 30 degrees C specific binding rose rapidly to a short-lived maximum before falling gradually, whereas at 15 degrees C and 0 degree C specific binding rose gradually to a higher plateau level. The reduced binding at 30 degrees C could be caused by degradation of either the tracer or the binding site or by a combination of these two events. Degradation of 125I-gastrin was evaluated by trichloroacetic acid (TCA) precipitation, fast protein liquid chromatography, and binding to a gastrin antibody (immunoreactivity). The effect of incubation on the binding site was evaluated by preincubation of the homogenate fraction before adding gastrin. In separate studies, the proteolytic activity of the homogenate fraction was studied by TCA precipitation of radioactive casein. Different enzyme inhibitors tested were virtually ineffective in preventing gastrin and casein degradation. Only lowering the incubation temperature to 15 degrees C or lower could prevent this degradation. The reduced and transient binding of 125I-gastrin at 30 degrees C most probably reflects tracer degradation. Accordingly, the gastrin binding experiments were performed at 15 degrees C. Only homogenates from the oxyntic area of the stomach bound 125I-gastrin specifically and with a Kd of 0.8 nM (Scatchard analysis). However, micromolar concentrations of unlabelled gastrin were required to inhibit half maximal binding of the tracer. The tracer binding was unaffected by secretin, slightly reduced by a CCK-9 analogue, and more markedly reduced by pentagastrin.

Investigation of 5-HT3 receptor-triggered serotonin release from guinea-pig isolated colonic mucosa: a role of PYY-containing endocrine cell.

PubMed

Kojima, Shu-Ichi; Kojima, Ken; Fujita, Tomoe

2017-03-15

The effect of a 5-HT 3 receptor-selective agonist SR57227A was investigated on the outflow of 5-hydroxytryptamine (5-HT) from isolated muscle layer-free mucosal preparations of guinea-pig colon. The mucosal preparations were incubated in vitro and the outflow of 5-HT from these preparations was determined by high-performance liquid chromatography with electrochemical detection. SR57227A (100μM) produced a tetrodotoxin-resistant and sustained increase in the outflow of 5-HT from the mucosal preparations. The SR57227A-evoked sustained 5-HT outflow was completely inhibited by the 5-HT 3 receptor antagonist ramosetron (1μM). The neuropeptide Y 1 receptor antagonist BIBO3304 (100nM) partially inhibited the SR57227A-evoked sustained 5-HT outflow, but the Y 2 receptor antagonist BIIE0246 (1μM) or the glucagon-like peptide-1 (GLP-1) receptor antagonist exendin-(9-39) (1μM), showed a minimal effect on the SR57227A-evoked sustained 5-HT outflow. In the presence of BIBO3304 (100nM) and exendin-(9-39) (1μM), SR57227A (100μM) failed to produce a sustained increase in the outflow of 5-HT. The Y 1 receptor agonist [Leu 31 , Pro 34 ]-neuropeptide Y (10nM), but not GLP-1-(7-36) amide (100nM), produced a sustained increase in the outflow of 5-HT. We found that 5-HT 3 receptor-triggered 5-HT release from guinea-pig colonic mucosa is mediated by the activation of 5-HT 3 receptors located at endocrine cells (enterochromaffin cells and peptide YY (PYY)-containing endocrine cells). The activation of both Y 1 and GLP-1 receptors appears to be required for the maintenance of 5-HT 3 receptor-triggered 5-HT release. It is therefore considered that 5-HT 3 receptors located at colonic mucosa play a crucial role in paracrine signaling between enterochromaffin cells and PYY-containing endocrine cells. Copyright © 2017 Elsevier B.V. All rights reserved.

Retro-inverso forms of gastrin5-12 are as biologically active as glycine-extended gastrin in vitro but not in vivo.

PubMed

Marshall, Kathryn M; Laval, Marie; Sims, Ioulia; Shulkes, Arthur; Baldwin, Graham S

2015-12-01

Non-amidated gastrin peptides such as glycine-extended gastrin (Ggly) are biologically active in vitro and in vivo and have been implicated in the development of gastric and colonic cancers. Previous studies have shown that the truncated form of Ggly, the octapeptide LE5AY, was still biologically active in vitro, and that activity was dependent on ferric ion binding but independent of binding to the cholecystokinin 2 (CCK2) receptor. The present work was aimed at creating more stable gastrin-derived 'super agonists' using retro-inverso technology. The truncated LE5AY peptide was synthesized using end protecting groups in three forms with l-amino acids (GL), d-amino acids (GD) or retro-inverso (reverse order with d-amino acids; GRI). All of these peptides bound ferric ions with a 2:1 (Fe: peptide) ratio. As predicted, Ggly, GL and GRI were biologically active in vitro and increased cell proliferation in mouse gastric epithelial (IMGE-5) and human colorectal cancer (DLD-1) cell lines, and increased cell migration in DLD-1 cells. These activities were likely via the same mechanism as Ggly since no CCK1 or CCK2 binding was identified, and GD remained inactive in all assays. Surprisingly, unlike Ggly, GL and GRI were not active in vivo. While Ggly stimulated colonic crypt height and proliferation rates in gastrin knockout mice, GL and GRI did not. The apparent lack of activity may be due to rapid clearance of these smaller peptides. Nevertheless further work designing and testing retro-inverso gastrins is warranted, as it may lead to the generation of super agonists that could potentially be used to treat patients with gastrointestinal disorders with reduced mucosal function. Copyright © 2015 Elsevier Inc. All rights reserved.

Associations of serum leptin, ghrelin and peptide YY levels with physical activity and cardiorespiratory fitness in adolescent boys with different BMI values

PubMed Central

Tillmann, Vallo; Purge, Priit; Lätt, Evelin; Jürimäe, Jaak

2017-01-01

The aim of this study was to investigate the differences in associations of serum acylated and des-acylated ghrelin, peptide YY (PYY) and leptin levels with physical activity (PA) and cardiorespiratory fitness (CReF) in adolescent boys (mean age of 14.0 years) with overweight (OWB; n=55) and with normal weight (NWB; n=154). Methods: Total PA was measured by 7-day accelerometry (counts/min) and CReF by peak oxygen consumption (VO2peak/kg). Results: No differences were found in serum PYY, acylated ghrelin or des-acyl ghrelin levels, whereas mean leptin (11.6±10.6 vs. 2.0±2.7 ng/ml; p<0.05) and insulin (18.1±8.7 vs. 11.0±6.2 mU/l; p<0.05) levels were significantly higher in OWB compared to NWB. Mean CReF was significantly lower in OWB compared to NWB (39.7±8.7 vs. 50.5±6.8 ml/min/kg; p<0.05). Leptin was negatively correlated with CReF in both groups (r=-0.43; p<0.05), des-acylated ghrelin with CReF only in OWB (r =-0.36; p<0.05). In OWB leptin was negatively correlated with total PA (r=-0.32; p<0.05) and positively with sedentary time of PA (r=0.35; p<0.05). In NWB 28.1% of the variability of CReF was determined by leptin and insulin resistance index (HOMA-IR), whereas in OWB 71.9% was determined by trunk FM and BMI. Conclusions: Leptin concentration was inversely associated with CReF in adolescent boys independently of BMI in both groups, while des-acylated ghrelin was associated with CReF only in OWB. Low PA in OWB was associated with high serum leptin level. PMID:29472737

Role of gastrin-releasing peptide in pepsinogen secretion from the isolated perfused rat stomach.

PubMed

Skak-Nielsen, T; Holst, J J; Christensen, J D; Fjalland, B

1988-10-01

We studied the effects of the neuropeptide gastrin-releasing peptide on pepsinogen secretion using an isolated perfused rat stomach with intact vagal innervation. Following electrical stimulation of the vagus nerves, the pepsin output to the luminal effluent increased from 94 +/- 7 to 182 +/- 24 units pepsin/min and the release of immunoreactive gastrin-releasing peptide to the venous effluent increased from 0.059 +/- 0.014 to 0.138 +/- 0.028 pmol/min. Infusion of gastrin-releasing peptide at 10(-8) M significantly increased pepsin output (from 87 +/- 17 to 129 +/- 22 units pepsin/min) and simultaneous infusion of gastrin-releasing peptide and carbachol at 10(-8) and 10(-6) M, respectively, resulted in an increase to almost 4 times the basal values. Atropine reduced but did not abolish the pepsin response to vagal stimulation and to infusion of gastrin-releasing peptide. Our results suggest that gastrin-releasing peptide participates in the vagal control of pepsinogen secretion.

Essential and Unexpected Role of YY1 to Promote Mesodermal Cardiac Differentiation

PubMed Central

Gregoire, Serge; Karra, Ravi; Passer, Derek; Deutsch, Marcus-Andre; Krane, Markus; Feistritzer, Rebecca; Sturzu, Anthony; Domian, Ibrahim; Saga, Yumiko; Wu, Sean M.

2013-01-01

Rational Cardiogenesis is regulated by a complex interplay between transcription factors. However, little is known about how these interactions regulate the transition from mesodermal precursors to cardiac progenitor cells (CPCs). Objective To identify novel regulators of mesodermal cardiac lineage commitment. Methods and Results We performed a bioinformatic-based transcription factor binding site analysis on upstream promoter regions of genes that are enriched in embryonic stem cell (ESC)-derived CPCs. From 32 candidate transcription factors screened, we found that YY1, a repressor of sarcomeric gene expression, is present in CPCs in vivo. Interestingly, we uncovered the ability of YY1 to transcriptionally activate Nkx2.5, a key marker of early cardiogenic commitment. YY1 regulates Nkx2.5 expression via a 2.1 kb cardiac-specific enhancer as demonstrated by in vitro luciferase-based assays and in vivo chromatin immunoprecipitation (ChIP) and genome-wide sequencing analysis. Furthermore, the ability of YY1 to activate Nkx2.5 expression depends on its cooperative interaction with Gata4 at a nearby chromatin. Cardiac mesoderm-specific loss-of-function of YY1 resulted in early embryonic lethality. This was corroborated in vitro by ESC-based assays where we show that the overexpression of YY1 enhanced the cardiogenic differentiation of ESCs into CPCs. Conclusion These results demonstrate an essential and unexpected role for YY1 to promote cardiogenesis as a transcriptional activator of Nkx2.5 and other CPC-enriched genes. PMID:23307821

Expression of metastasis suppressor gene AES driven by a Yin Yang (YY) element in a CpG island promoter and transcription factor YY2.

PubMed

Kakizaki, Fumihiko; Sonoshita, Masahiro; Miyoshi, Hiroyuki; Itatani, Yoshiro; Ito, Shinji; Kawada, Kenji; Sakai, Yoshiharu; Taketo, M Mark

2016-11-01

We recently found that the product of the AES gene functions as a metastasis suppressor of colorectal cancer (CRC) in both humans and mice. Expression of amino-terminal enhancer of split (AES) protein is significantly decreased in liver metastatic lesions compared with primary colon tumors. To investigate its downregulation mechanism in metastases, we searched for transcriptional regulators of AES in human CRC and found that its expression is reduced mainly by transcriptional dysregulation and, in some cases, by additional haploidization of its coding gene. The AES promoter-enhancer is in a typical CpG island, and contains a Yin-Yang transcription factor recognition sequence (YY element). In human epithelial cells of normal colon and primary tumors, transcription factor YY2, a member of the YY family, binds directly to the YY element, and stimulates expression of AES. In a transplantation mouse model of liver metastases, however, expression of Yy2 (and therefore of Aes) is downregulated. In human CRC metastases to the liver, the levels of AES protein are correlated with those of YY2. In addition, we noticed copy-number reduction for the AES coding gene in chromosome 19p13.3 in 12% (5/42) of human CRC cell lines. We excluded other mechanisms such as point or indel mutations in the coding or regulatory regions of the AES gene, CpG methylation in the AES promoter enhancer, expression of microRNAs, and chromatin histone modifications. These results indicate that Aes may belong to a novel family of metastasis suppressors with a CpG-island promoter enhancer, and it is regulated transcriptionally. © 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Islet Cells Serve as Cells of Origin of Pancreatic Gastrin-Positive Endocrine Tumors.

PubMed

Bonnavion, Rémy; Teinturier, Romain; Jaafar, Rami; Ripoche, Doriane; Leteurtre, Emmanuelle; Chen, Yuan-Jia; Rehfeld, Jens F; Lepinasse, Florian; Hervieu, Valérie; Pattou, François; Vantyghem, Marie-Christine; Scoazec, Jean-Yves; Bertolino, Philippe; Zhang, Chang Xian

2015-10-01

The cells of origin of pancreatic gastrinomas remain an enigma, since no gastrin-expressing cells are found in the normal adult pancreas. It was proposed that the cellular origin of pancreatic gastrinomas may come from either the pancreatic cells themselves or gastrin-expressing cells which have migrated from the duodenum. In the current study, we further characterized previously described transient pancreatic gastrin-expressing cells using cell lineage tracing in a pan-pancreatic progenitor and a pancreatic endocrine progenitor model. We provide evidence showing that pancreatic gastrin-expressing cells, found from embryonic day 12.5 until postnatal day 7, are derived from pancreatic Ptf1a(+) and neurogenin 3-expressing (Ngn3(+)) progenitors. Importantly, the majority of them coexpress glucagon, with 4% coexpressing insulin, indicating that they are a temporary subpopulation of both alpha and beta cells. Interestingly, Men1 disruption in both Ngn3 progenitors and beta and alpha cells resulted in the development of pancreatic gastrin-expressing tumors, suggesting that the latter developed from islet cells. Finally, we detected gastrin expression using three human cohorts with pancreatic endocrine tumors (pNETs) that have not been diagnosed as gastrinomas (in 9/34 pNETs from 6/14 patients with multiple endocrine neoplasia type 1, in 5/35 sporadic nonfunctioning pNETs, and in 2/20 sporadic insulinomas), consistent with observations made in mouse models. Our work provides insight into the histogenesis of pancreatic gastrin-expressing tumors. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Islet Cells Serve as Cells of Origin of Pancreatic Gastrin-Positive Endocrine Tumors

PubMed Central

Bonnavion, Rémy; Teinturier, Romain; Jaafar, Rami; Ripoche, Doriane; Leteurtre, Emmanuelle; Chen, Yuan-Jia; Rehfeld, Jens F.; Lepinasse, Florian; Hervieu, Valérie; Pattou, François; Vantyghem, Marie-Christine; Scoazec, Jean-Yves; Bertolino, Philippe

2015-01-01

The cells of origin of pancreatic gastrinomas remain an enigma, since no gastrin-expressing cells are found in the normal adult pancreas. It was proposed that the cellular origin of pancreatic gastrinomas may come from either the pancreatic cells themselves or gastrin-expressing cells which have migrated from the duodenum. In the current study, we further characterized previously described transient pancreatic gastrin-expressing cells using cell lineage tracing in a pan-pancreatic progenitor and a pancreatic endocrine progenitor model. We provide evidence showing that pancreatic gastrin-expressing cells, found from embryonic day 12.5 until postnatal day 7, are derived from pancreatic Ptf1a+ and neurogenin 3-expressing (Ngn3+) progenitors. Importantly, the majority of them coexpress glucagon, with 4% coexpressing insulin, indicating that they are a temporary subpopulation of both alpha and beta cells. Interestingly, Men1 disruption in both Ngn3 progenitors and beta and alpha cells resulted in the development of pancreatic gastrin-expressing tumors, suggesting that the latter developed from islet cells. Finally, we detected gastrin expression using three human cohorts with pancreatic endocrine tumors (pNETs) that have not been diagnosed as gastrinomas (in 9/34 pNETs from 6/14 patients with multiple endocrine neoplasia type 1, in 5/35 sporadic nonfunctioning pNETs, and in 2/20 sporadic insulinomas), consistent with observations made in mouse models. Our work provides insight into the histogenesis of pancreatic gastrin-expressing tumors. PMID:26169832

Radiolabeled gastrin/CCK analogs in tumor diagnosis: towards higher stability and improved tumor targeting.

PubMed

Kaloudi, A; Nock, B A; Krenning, E P; Maina, T; De Jong, M

2015-09-01

Cholecystokinin subtype 2 receptors (CCK2R) are overexpressed in several human cancers, including medullary thyroid carcinoma. Gastrin and cholecystokinin (CCK) peptides that bind with high affinity and specificity to CCK2R can be used as carriers of radioactivity to CCK2R-expressing tumor sites. Several gastrin and CCK related peptides have been proposed for diagnostic imaging and radionuclide therapy of primary and metastatic CCK2R-positive human tumors. Their clinical application has been restricted to a great extent by their fast in vivo degradation that eventually compromises tumor uptake. This problem has been addressed by structural modifications of gastrin and CCK motifs, which, however, often lead to suboptimal pharmacokinetic profiles. A major enzyme implicated in the catabolism of gastrin and CCK based peptides is neutral endopeptidase (NEP), which is widely distributed in the body. Coinjection of the NEP inhibitor phosphoramidon (PA) with radiolabeled gastrin and other peptide analogs has been recently proposed as a new promising strategy to increase bioavailability and tumor-localization of radiopeptides in tumor sites. Specifically, co-administration of PA with the truncated gastrin analog [(111)In-DOTA]MG11 ([((111)In-DOTA)DGlu(10)]gastrin(10-17)) impressively enhanced the levels of intact radiopeptide in mouse circulation and has led to an 8-fold increase of CCK2R-positive tumor uptake in SCID mice. This increased tumor uptake, visualized also by SPECT/CT imaging, is expected to eventually translate into higher diagnostic sensitivity and improved therapeutic efficacy of radiolabeled gastrin analogs in CCK2R-expressing cancer patients.

Nuclear Factor YY1 Inhibits Transforming Growth Factor β- and Bone Morphogenetic Protein-Induced Cell Differentiation

PubMed Central

Kurisaki, Keiko; Kurisaki, Akira; Valcourt, Ulrich; Terentiev, Alexei A.; Pardali, Katerina; ten Dijke, Peter; Heldin, Carl-Henrik; Ericsson, Johan; Moustakas, Aristidis

2003-01-01

Smad proteins transduce transforming growth factor β (TGF-β) and bone morphogenetic protein (BMP) signals that regulate cell growth and differentiation. We have identified YY1, a transcription factor that positively or negatively regulates transcription of many genes, as a novel Smad-interacting protein. YY1 represses the induction of immediate-early genes to TGF-β and BMP, such as the plasminogen activator inhibitor 1 gene (PAI-1) and the inhibitor of differentiation/inhibitor of DNA binding 1 gene (Id-1). YY1 inhibits binding of Smads to their cognate DNA elements in vitro and blocks Smad recruitment to the Smad-binding element-rich region of the PAI-1 promoter in vivo. YY1 interacts with the conserved N-terminal Mad homology 1 domain of Smad4 and to a lesser extent with Smad1, Smad2, and Smad3. The YY1 zinc finger domain mediates the association with Smads and is necessary for the repressive effect of YY1 on Smad transcriptional activity. Moreover, downregulation of endogenous YY1 by antisense and small interfering RNA strategies results in enhanced transcriptional responses to TGF-β or BMP. Ectopic expression of YY1 inhibits, while knockdown of endogenous YY1 enhances, TGF-β- and BMP-induced cell differentiation. In contrast, overexpression or knockdown of YY1 does not affect growth inhibition induced by TGF-β or BMP. Accordingly, YY1 does not interfere with the regulation of immediate-early genes involved in the TGF-β growth-inhibitory response, the cell cycle inhibitors p15 and p21, and the proto-oncogene c-myc. In conclusion, YY1 represses Smad transcriptional activities in a gene-specific manner and thus regulates cell differentiation induced by TGF-β superfamily pathways. PMID:12808092

Transgenic over-expression of YY1 induces pathologic cardiac hypertrophy in a sex-specific manner

PubMed Central

Stauffer, Brian L.; Dockstader, Karen; Russell, Gloria; Hijmans, Jamie; Walker, Lisa; Cecil, Mackenzie; Demos-Davies, Kimberly; Medway, Allen; McKinsey, Timothy A.; Sucharov, Carmen C.

2015-01-01

YY1 can activate or repress transcription of various genes. In cardiac myocytes in culture YY1 has been shown to regulate expression of several genes involved in myocyte pathology. YY1 can also acutely protect the heart against detrimental changes in gene expression. In this study we show that cardiac over-expression of YY1 induces pathologic cardiac hypertrophy in male mice, measured by changes in gene expression and lower ejection fraction/fractional shortening. In contrast, female animals are protected against pathologic gene expression changes and cardiac dysfunction. Furthermore, we show that YY1 regulates, in a sex-specific manner, the expression of mammalian enable (Mena), a factor that regulates cytoskeletal actin dynamics and whose expression is increased in several models of cardiac pathology, and that Mena expression in humans with heart failure is sex-dependent. Finally, we show that sex differences in YY1 expression are also observed in human heart failure. In summary, this is the first work to show that YY1 has a sex-specific effect in the regulation of cardiac pathology. PMID:25935483

Absorption and fluorescence emission spectroscopic characters of naphtho-homologated yy-DNA bases and effect of methanol solution and base pairing.

PubMed

Zhang, Laibin; Li, Huifang; Li, Jilai; Chen, Xiaohua; Bu, Yuxiang

2010-03-01

A comprehensive theoretical study of electronic transitions of naphtho-homologated base analogs, namely, yy-T, yy-C, yy-A, and yy-G, was performed. The nature of the low-lying excited states is discussed, and the results are compared with those from experiment and also with those of y-bases. Geometrical characteristics of the lowest excited singlet pipi* and npi* states were explored using the CIS method, and the effects of methanol solution and paring with their complementary natural bases on the relevant absorption and emission spectra of these modified bases were examined. The calculated excitation and emission energies agree well with the measured data, where experimental results are available. In methanol solution, the fluorescence from yy-A and yy-G would be expected to occur around 539 and 562 nm, respectively, suggesting that yy-A is a green-colored fluorophore, whereas yy-G is a yellow-colored fluorophore. The methanol solution was found to red-shift both the absorption and emission maxima of yy-A, yy-T, and yy-C, but blue-shift those for yy-G. Generally, though base pairing has no significant effects on the absorption and fluorescence maxima of yy-A, yy-C, and yy-T, it blue-shifts those for yy-G. (c) 2009 Wiley Periodicals, Inc.

G cells and gastrin in chronic alcohol-treated rats.

PubMed

Todorović, Vera; Koko, Vesna; Budec, Mirela; Mićić, Mileva; Micev, Marjan; Pavlović, Mirjana; Vignjević, Sanja; Drndarević, Neda; Mitrović, Olivera

2008-02-01

Numerous reports have described gastric mucosal injury in rats treated with high ethanol concentrations. However, to the best of our knowledge, ultrastructural characteristics of G cells and antral gastrin levels have not been previously reported, either in rats that chronically consumed alcohol or in human alcoholics. The goal of this study was to examine the effect of ethanol consumption (8.5 g/kg) over a 4-month period, under controlled nutritional conditions, on antral and plasma levels of gastrin, ultrastructure of G cells, morphometric characteristics of G cells by stereological methods, and analysis of endocrine cells in the gastric mucosa by immunohistochemistry. The chronic alcohol consumption resulted in a nonsignificant decrease in gastrin plasma levels and unchanged antral gastrin concentrations. A slightly damaged glandular portion of the gastric mucosa and dilatation of small blood vessels detected by histological analysis, suggests that ethanol has a toxic effect on the mucosal surface. Chronic alcohol treatment significantly decreased the number of antral G cells per unit area, and increased their cellular, nuclear, and cytoplasmatic profile areas. In addition, the volume density and diameter of G-cell granules, predominantly the pale and lucent types, were increased, indicating inhibition of gastrin release. Ethanol treatment also decreased the number of gastric somatostatin-, serotonin-, and histamine-immunoreactive cells, except the somatostatin cells in the pyloric mucosa, as well as both G: D: enterochromaffin cells (EC) cell ratios in the antrum and D: ECL cell ratios in the fundus. These results indicate that the change of morphometric parameters in G cells may be related to cellular dysfunction. Our findings also suggest that regulation of G-cell secretion was not mediated by locally produced somatostatin in ethanol-consuming rats, but may involve gastric luminal content and/or neurotransmitters of gastric nerve fibers.

A role for hippocampal gastrin-releasing peptide receptors in extinction of aversive memory.

PubMed

Luft, Tatiana; Flores, Debora G; Vianna, Monica R M; Schwartsmann, Gilberto; Roesler, Rafael; Izquierdo, Ivan

2006-06-26

Although the gastrin-releasing peptide receptor has been implicated in memory consolidation, previous studies have not examined whether it is involved in extinction. Here we show that gastrin-releasing peptide receptor blockade in the hippocampus disrupts extinction of aversive memory. Male rats were trained in inhibitory avoidance conditioning and then returned repeatedly to the training context without shock on a daily basis for 3 days. Infusion of a gastrin-releasing peptide receptor antagonist or the protein synthesis inhibitor anisomycin into the dorsal hippocampus immediately after the first extinction session blocked extinction. These drugs did not affect performance in subsequent sessions when the first extinction session (1 day after training) was omitted. The results indicate that hippocampal gastrin-releasing peptide receptors are involved in memory extinction.

Elevated Serum Gastrin Is Associated With a History of Advanced Neoplasia in Barrett’s Esophagus

PubMed Central

Wang, Judy S.; Varro, Andrea; Lightdale, Charles J.; Lertkowit, Nantaporn; Slack, Kristen N.; Fingerhood, Michael L.; Tsai, Wei Yann; Wang, Timothy C.; Abrams, Julian A.

2011-01-01

OBJECTIVES Proton pump inhibitors (PPIs) are frequently prescribed to patients with Barrett’ s esophagus (BE), but in a subset, they can induce significant hypergastrinemia. Elevated levels of gastrin have been associated with tumorigenic effects in a number of gastrointestinal cancers. We decided to investigate the association between serum gastrin levels and dysplasia in BE. METHODS We performed a cross-sectional study and enrolled patients with BE without dysplasia, low-grade dysplasia (LGD), high-grade dysplasia (HGD), or adenocarcinoma (AC), as well as gastroesophageal reflux disease controls, all chronically taking PPIs. Fasting serum gastrin was measured, and data were collected on patient characteristics, medication use, and the highest degree of BE neoplasia. RESULTS A total of 95 patients were enrolled. The mean age was 64.7 (±10.0) years, and 70.5 % were male. The median serum gastrin level was 40 pM. There was no significant difference in gastrin levels with increased degrees of BE neoplasia (overall P = 0.68). In multivariable analysis, the highest quartile of gastrin was associated with significantly increased odds of advanced neoplasia (HGD or AC) (odds ratio (OR): 5.46, 95 % confidence interval (CI): 1.20–24.8). CONCLUSIONS In BE patients taking PPIs, an elevated serum gastrin is associated with a history of HGD or AC. Prospective studies are needed to determine whether patients with nondysplastic BE and elevated serum gastrin are at increased risk for neoplastic progression. PMID:19904251

YY1 Controls Immunoglobulin Class Switch Recombination and Nuclear Activation-Induced Deaminase Levels

PubMed Central

Zaprazna, Kristina

2012-01-01

Activation-induced deaminase (AID) is an enzyme required for class switch recombination (CSR) and somatic hypermutation (SHM), processes that ensure antibody maturation and expression of different immunoglobulin isotypes. AID function is tightly regulated by tissue- and stage-specific expression, nuclear localization, and protein stability. Transcription factor YY1 is crucial for early B cell development, but its function at late B cell stages is unknown. Here, we show that YY1 conditional knockout in activated splenic B cells interferes with CSR. Knockout of YY1 did not affect B cell proliferation, transcription of the AID and IgM genes, or levels of various switch region germ line transcripts. However, we show that YY1 physically interacts with AID and controls the accumulation of nuclear AID, at least in part, by increasing nuclear AID stability. We show for the first time that YY1 plays a novel role in CSR and controls nuclear AID protein levels. PMID:22290437

Low gastric acid and high plasma gastrin in high-anxiety Wistar Kyoto rats.

PubMed

Florentzson, Malin; Svensson, Karin; Astin-Nielsen, Maria; Andersson, Kjell; Håkanson, Rolf; Lindstrom, Erik

2009-01-01

Wistar Kyoto (WKY) rats are more susceptible to stress-evoked ulcerations than Sprague-Dawley (SPD) rats. We have already demonstrated that gastrin cells are more active and ghrelin cells less active in WKY rats than in SPD rats. The purpose of this study was to compare endocrine cell activity and gastric acid output in WKY and SPD rats. Gastric acid output was determined in conscious rats with gastric fistula. Plasma gastrin and ghrelin levels were measured after an overnight fast. Acid secretagogues (gastrin, histamine and carbachol) were given by continuous subcutaneous infusion. The volume of gastric juice, and the acidity and acid output were all significantly lower (p <0.05) in fasted WKY rats than in fasted SPD rats. Gastrin evoked a 4-fold (p <0.01) and 3-fold (p <0.05) increase in gastric acid output in SPD rats and WKY rats, respectively. Histamine raised the acid output 1.6-fold in SPD rats (p=0.06) and 3-fold in WKY rats (p <0.05), while carbachol failed to affect the acid output (weak increase, p >0.05). Fasting plasma ghrelin levels were 2-fold higher in SPD rats than in WKY rats (p <0.01) while fasting gastrin levels were 10-fold higher in WKY rats than in SPD rats (p <0.05). Neither the parietal-cell density nor the oxyntic mucosal thickness differed between the two strains. The results of the present study suggest that a high gastrin cell activity in WKY rats is secondary to a low gastric acidity. Whether the high gastrin cell activity is linked to susceptibility to stress ulcer in WKY rats warrants further investigation.

Analysis of gastrin-releasing peptide gene and gastrin-releasing peptide receptor gene in patients with agoraphobia.

PubMed

Zimmermann, Katrin; Görgens, Heike; Bräuer, David; Einsle, Franziska; Noack, Barbara; von Kannen, Stephanie; Grossmann, Maria; Hoyer, Jürgen; Strobel, Alexander; Köllner, Volker; Weidner, Kerstin; Ziegler, Andreas; Hemmelmann, Claudia; Schackert, Hans K

2014-10-01

A gastrin-releasing peptide receptor (GRPR) knock-out mouse model provided evidence that the gastrin-releasing peptide (GRP) and its neural circuitry operate as a negative feedback-loop regulating fear, suggesting a novel candidate mechanism contributing to individual differences in fear-conditioning and associated psychiatric disorders such as agoraphobia with/without panic disorder. Studies in humans, however, provided inconclusive evidence on the association of GRP and GRPR variations in agoraphobia with/without panic disorder. Based on these findings, we investigated whether GRP and GRPR variants are associated with agoraphobia. Mental disorders were assessed via the Munich-Composite International Diagnostic Interview (M-CIDI) in 95 patients with agoraphobia with/without panic disorder and 119 controls without any mental disorders. A complete sequence analysis of GRP and GRPR was performed in all participants. We found no association of 16 GRP and 7 GRPR variants with agoraphobia with/without panic disorder.

Nicotine Suppressed Fetal Adrenal StAR Expression via YY1 Mediated-Histone Deacetylation Modification Mechanism.

PubMed

Liu, Lian; Wang, Jian-Fei; Fan, Jie; Rao, Yi-Song; Liu, Fang; Yan, You-E; Wang, Hui

2016-09-03

Steroidogenic acute regulatory (StAR) protein plays a pivotal role in steroidogenesis. Previously, we have demonstrated that prenatal nicotine exposure suppressed fetal adrenal steroidogenesis via steroidogenic factor 1 deacetylation. This study further explored the potential role of the transcriptional repressor Yin Yang 1 (YY1) in nicotine-mediated StAR inhibition. Nicotine was subcutaneously administered (1.0 mg/kg) to pregnant rats twice per day and NCI-H295A cells were treated with nicotine. StAR and YY1 expression were analyzed by real-time PCR, immunohistochemistry, and Western blotting. Histone modifications and the interactions between the YY1 and StAR promoter were assessed using chromatin immunoprecipitation (ChIP). Prenatal nicotine exposure increased YY1 expression and suppressed StAR expression. ChIP assay showed that there was a decreasing trend for histone acetylation at the StAR promoter in fetal adrenal glands, whereas H3 acetyl-K14 at the YY1 promoter presented an increasing trend following nicotine exposure. Furthermore, in nicotine-treated NCI-H295A cells, nicotine enhanced YY1 expression and inhibited StAR expression. ChIP assay showed that histone acetylation decreased at the StAR promoter in NCI-H295A cells and that the interaction between the YY1 and StAR promoter increased. These data indicated that YY1-medicated histone deacetylation modification in StAR promoters might play an important role in the inhibitory effect of nicotine on StAR expression.

Nicotine Suppressed Fetal Adrenal StAR Expression via YY1 Mediated-Histone Deacetylation Modification Mechanism

PubMed Central

Liu, Lian; Wang, Jian-Fei; Fan, Jie; Rao, Yi-Song; Liu, Fang; Yan, You-E; Wang, Hui

2016-01-01

Steroidogenic acute regulatory (StAR) protein plays a pivotal role in steroidogenesis. Previously, we have demonstrated that prenatal nicotine exposure suppressed fetal adrenal steroidogenesis via steroidogenic factor 1 deacetylation. This study further explored the potential role of the transcriptional repressor Yin Yang 1 (YY1) in nicotine-mediated StAR inhibition. Nicotine was subcutaneously administered (1.0 mg/kg) to pregnant rats twice per day and NCI-H295A cells were treated with nicotine. StAR and YY1 expression were analyzed by real-time PCR, immunohistochemistry, and Western blotting. Histone modifications and the interactions between the YY1 and StAR promoter were assessed using chromatin immunoprecipitation (ChIP). Prenatal nicotine exposure increased YY1 expression and suppressed StAR expression. ChIP assay showed that there was a decreasing trend for histone acetylation at the StAR promoter in fetal adrenal glands, whereas H3 acetyl-K14 at the YY1 promoter presented an increasing trend following nicotine exposure. Furthermore, in nicotine-treated NCI-H295A cells, nicotine enhanced YY1 expression and inhibited StAR expression. ChIP assay showed that histone acetylation decreased at the StAR promoter in NCI-H295A cells and that the interaction between the YY1 and StAR promoter increased. These data indicated that YY1-medicated histone deacetylation modification in StAR promoters might play an important role in the inhibitory effect of nicotine on StAR expression. PMID:27598153

Regulatory effect and mechanism of gastrin and its antagonists on colorectal carcinoma

PubMed Central

He, Shuang-Wu; Shen, Kang-Qiang; He, Yu-Jun; Xie, Bin; Zhao, Yan-Ming

1999-01-01

AIM: To explore the effect and mechanism of gastrin and its an tagonists proglumide and somatostatin on colorectal carcinoma and their clinical significance. METHODS: A model of transplanted human colonic carcinoma was established from SW480 cell line in gymnomouse body. The volume and weight of transplanted carcinoma was observed under the effect of pentagatrin (PG), proglumide (PGL) and octapeptide somotostatin (SMS201-995, SMS). The cAMP content of carcinoma cell was determined by radioimmunoassay and the DNA, protein content and cell cycle were determined by flow-cytometry. The amount of viable cells was determined by MTT colorimetric analysis, IP3 content was determined by radioimmuno assay, Ca2+ concentration in cell by fluorometry and PKC activity by isotopic enzymolysis. The expression of gastrin, c-myc, c-fos and rasP21 in 48 case s of colorectal carcinoma tissue was detected by the immuno-cytochemistry SP method. Argyrophilia nucleolar organizer regions was determined with argyrophilia stain. RESULTS: The volume, weight, cAMP, DNA and protein content in carcinoma cell, cell amount and proliferation index of S and G2M phase in PG group were all significantly higher than those of control group. When PG was at the concentration of 25 mg/L, the amount of viable cells, IP3 content and Ca2+ concentration in cell and membrane PKC activity in PG group were significantly higher than those in control group; when PGL was at a concentration of 32 mg/L, they dropped to the lowest level in PG (25 mg/L) + PGL group, but without significant difference from the control group. The positive expression rate of gastrin, c-myc, c-fos and rasP21 in carcinoma tissue was 39.6%, 54.2%, 47.9% and 54.2% respectively and significantly higher than that in mucosa 3 cm and 6 cm adjacent to carcinoma tissue and normal colorectal mucosa. The positive expression rate of gastrin of highly-differentiated adenocarcinoma group was significantly higher than that of poorly-differentiated and

NF-κB–YY1–miR-29 Regulatory Circuitry in Skeletal Myogenesis and Rhabdomyosarcoma

PubMed Central

Wang, Huating; Garzon, Ramiro; Sun, Hao; Ladner, Katherine J.; Singh, Ravi; Dahlman, Jason; Cheng, Alfred; Hall, Brett M.; Qualman, Stephen J.; Chandler, Dawn S.; Croce, Carlo M.; Guttridge, Denis C.

2008-01-01

SUMMARY Studies support the importance of microRNAs in physiological and pathological processes. Here we describe the regulation and function of miR-29 in myogenesis and Rhabdomyosarcoma (RMS). Results demonstrate that in myoblasts miR-29 is repressed by NF-κB acting through YY1 and the Polycomb. During myogenesis, NF-κB and YY1 downregulation causes derepression of miR-29, which in turn accelerates differentiation by targeting its repressor YY1. However, in RMS cells and primary tumors that possess impaired differentiation, miR-29 is epigenetically silenced by an activated NF-κB-YY1 pathway. Reconstitution of miR-29 in RMS in mice inhibits tumor growth and stimulates differentiation, suggesting that miR-29 acts as a tumor suppressor through its pro-myogenic function. Together, results identify a NF-κB–YY1–miR-29 regulatory circuit whose disruption may contribute to RMS. SIGNIFICANCE MicroRNAs regulate skeletal myogenesis, but their impact in muscle diseases is not well understood. Here we describe miR-29 as an enhancer of myogenic differentiation and a suppressor of RMS. We find that miR-29 exists in a regulatory circuit involving NF-κB and YY1. In myoblasts NF-B acts through YY1 to epigenetically suppress miR-29, while during differentiation miR-29 is induced to facilitate myogenesis by a negative feedback on YY1. Significantly, RMS tumors lose miR-29 due to an elevation in NF-B and YY1, and readjustment of miR-29 levels in RMS stimulates differentiation. Thus, myogenesis is dependent on NF-κB–YY1–miR-29 circuitry whose dysfunction may contribute to RMS pathogenesis. Such findings offer potential avenues for the diagnosis and treatment of muscle relevant cancers. PMID:18977326

Gastrin Induces Nuclear Export and Proteasome Degradation of Menin in Enteric Glial Cells.

PubMed

Sundaresan, Sinju; Meininger, Cameron A; Kang, Anthony J; Photenhauer, Amanda L; Hayes, Michael M; Sahoo, Nirakar; Grembecka, Jolanta; Cierpicki, Tomasz; Ding, Lin; Giordano, Thomas J; Else, Tobias; Madrigal, David J; Low, Malcolm J; Campbell, Fiona; Baker, Ann-Marie; Xu, Haoxing; Wright, Nicholas A; Merchant, Juanita L

2017-12-01

The multiple endocrine neoplasia, type 1 (MEN1) locus encodes the nuclear protein and tumor suppressor menin. MEN1 mutations frequently cause neuroendocrine tumors such as gastrinomas, characterized by their predominant duodenal location and local metastasis at time of diagnosis. Diffuse gastrin cell hyperplasia precedes the appearance of MEN1 gastrinomas, which develop within submucosal Brunner's glands. We investigated how menin regulates expression of the gastrin gene and induces generation of submucosal gastrin-expressing cell hyperplasia. Primary enteric glial cultures were generated from the VillinCre:Men1 FL/FL :Sst -/- mice or C57BL/6 mice (controls), with or without inhibition of gastric acid by omeprazole. Primary enteric glial cells from C57BL/6 mice were incubated with gastrin and separated into nuclear and cytoplasmic fractions. Cells were incubated with forskolin and H89 to activate or inhibit protein kinase A (a family of enzymes whose activity depends on cellular levels of cyclic AMP). Gastrin was measured in blood, tissue, and cell cultures using an ELISA. Immunoprecipitation with menin or ubiquitin was used to demonstrate post-translational modification of menin. Primary glial cells were incubated with leptomycin b and MG132 to block nuclear export and proteasome activity, respectively. We obtained human duodenal, lymph node, and pancreatic gastrinoma samples, collected from patients who underwent surgery from 1996 through 2007 in the United States or the United Kingdom. Enteric glial cells that stained positive for glial fibrillary acidic protein (GFAP+) expressed gastrin de novo through a mechanism that required PKA. Gastrin-induced nuclear export of menin via cholecystokinin B receptor (CCKBR)-mediated activation of PKA. Once exported from the nucleus, menin was ubiquitinated and degraded by the proteasome. GFAP and other markers of enteric glial cells (eg, p75 and S100B), colocalized with gastrin in human duodenal gastrinomas. MEN1-associated

Eradication of Helicobacter pylori restores the inhibitory effect of cholecystokinin on postprandial gastrin release in duodenal ulcer patients.

PubMed Central

Konturek, J W; Gillessen, A; Konturek, S J; Domschke, W

1995-01-01

Helicobacter pylori infection may be associated with duodenal ulcer (DU) and accompanied by enhanced gastrin release but the mechanism of this H pylori related hypergastrinaemia in DU patients is unclear. Cholecystokinin (CCK) has been implicated in the feedback control of gastrin release and gastric acid secretion in healthy subjects. This study therefore investigated if CCK participates in the impairment of postprandial gastrin release and gastric secretion in six DU patients. Tests were undertaken with and without elimination of endogenous CCK by loxiglumide, a selective CCK-A receptors antagonist, before and after eradication of H pylori with triple therapy (omeprazole, amoxicyllin, bismuth). In H pylori positive DU patients, the post-prandial decline in pH (with median pH 3.5) was accompanied by a pronounced increment in plasma gastrin but the administration of loxiglumide did not affect significantly this postprandial rise in plasma gastrin and gastric pH profile. After eradication of H pylori, the plasma gastrin concentration was reduced while the median postprandial pH was significantly increased (median pH 4.3). The administration of loxiglumide resulted in significantly greater increase in postprandial plasma gastrin and greater decrease in pH (median pH 3.1) in these patients. This study shows that (a) infection with H pylori is accompanied by an enhanced gastrin release and gastric acidity in DU patients, (b) the failure of loxiglumide to affect plasma gastrin or gastric acid secretion in H pylori infected DU patients could be attributed, at least in part, to the failure of endogenous CCK to control gastrin release and gastric secretion by releasing somatostatin, and (c) the test with loxiglumide may be useful in the identification of patients with impaired feedback control of gastrin release and gastric secretion resulting from infection with H pylori. PMID:7489932

The zinc fingers of YY1 bind single-stranded RNA with low sequence specificity.

PubMed

Wai, Dorothy C C; Shihab, Manar; Low, Jason K K; Mackay, Joel P

2016-11-02

Classical zinc fingers (ZFs) are traditionally considered to act as sequence-specific DNA-binding domains. More recently, classical ZFs have been recognised as potential RNA-binding modules, raising the intriguing possibility that classical-ZF transcription factors are involved in post-transcriptional gene regulation via direct RNA binding. To date, however, only one classical ZF-RNA complex, that involving TFIIIA, has been structurally characterised. Yin Yang-1 (YY1) is a multi-functional transcription factor involved in many regulatory processes, and binds DNA via four classical ZFs. Recent evidence suggests that YY1 also interacts with RNA, but the molecular nature of the interaction remains unknown. In the present work, we directly assess the ability of YY1 to bind RNA using in vitro assays. Systematic Evolution of Ligands by EXponential enrichment (SELEX) was used to identify preferred RNA sequences bound by the YY1 ZFs from a randomised library over multiple rounds of selection. However, a strong motif was not consistently recovered, suggesting that the RNA sequence selectivity of these domains is modest. YY1 ZF residues involved in binding to single-stranded RNA were identified by NMR spectroscopy and found to be largely distinct from the set of residues involved in DNA binding, suggesting that interactions between YY1 and ssRNA constitute a separate mode of nucleic acid binding. Our data are consistent with recent reports that YY1 can bind to RNA in a low-specificity, yet physiologically relevant manner. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

Eradicating Helicobacter pylori infection lowers gastrin mediated acid secretion by two thirds in patients with duodenal ulcer.

PubMed

el-Omar, E; Penman, I; Dorrian, C A; Ardill, J E; McColl, K E

1993-08-01

Helicobacter pylori (H pylori) raises serum gastrin but it is unclear whether this stimulates increased acid secretion. Gastrin mediated acid secretion and plasma gastrin after the intravenous infusion of gastrin releasing peptide was studied in nine H pylori negative and nine H pylori positive healthy volunteers, and in 11 duodenal ulcer patients. Nine of the last group were re-examined one month after eradication of H pylori. The median acid output (mmol/h) to gastrin releasing peptide (40 pmol/kg/h) in the H pylori positive healthy volunteers was 15.1 (range 3.3-38.3), which was three times that of the H pylori negative healthy volunteers (median = 5.5, range 1.0-9.0) (p < 0.02). The median acid output in the duodenal ulcer patients with H pylori was 37 (range 8.5-57), which was > six times that of the H pylori negative healthy volunteers. Eradication of H pylori in the duodenal ulcer patients lowered their acid secretion by a median of 66% (range 30%-80%) (p < 0.01) and to values equivalent to the H pylori positive healthy volunteers. The pepsin output in response to gastrin releasing peptide followed the same pattern as the acid output. The median plasma gastrin concentrations during gastrin releasing peptide were similar in the H pylori positive duodenal ulcer patients (150 ng/l, range 95-400) and H pylori positive healthy volunteers (129 ng/l, range 23-420) and both were appreciably higher than H pylori negative healthy volunteers (60 ng/l, range 28-135) (p < 0.005 for each). Eradication of H pylori lowered the plasma gastrin in the duodenal ulcer patients to values equivalent to the H pylori negative healthy volunteers. These findings show a threefold increase in acid secretion in H pylori positive healthy volunteers that is explained by H pylori induced hypergastrinaemia and a sixfold increase in acid secretion in the duodenal ulcer patients that is explained by the combination of H pylori induced hypergastrinaemia and an exaggerated acid response to

Eradicating Helicobacter pylori infection lowers gastrin mediated acid secretion by two thirds in patients with duodenal ulcer.

PubMed Central

el-Omar, E; Penman, I; Dorrian, C A; Ardill, J E; McColl, K E

1993-01-01

Helicobacter pylori (H pylori) raises serum gastrin but it is unclear whether this stimulates increased acid secretion. Gastrin mediated acid secretion and plasma gastrin after the intravenous infusion of gastrin releasing peptide was studied in nine H pylori negative and nine H pylori positive healthy volunteers, and in 11 duodenal ulcer patients. Nine of the last group were re-examined one month after eradication of H pylori. The median acid output (mmol/h) to gastrin releasing peptide (40 pmol/kg/h) in the H pylori positive healthy volunteers was 15.1 (range 3.3-38.3), which was three times that of the H pylori negative healthy volunteers (median = 5.5, range 1.0-9.0) (p < 0.02). The median acid output in the duodenal ulcer patients with H pylori was 37 (range 8.5-57), which was > six times that of the H pylori negative healthy volunteers. Eradication of H pylori in the duodenal ulcer patients lowered their acid secretion by a median of 66% (range 30%-80%) (p < 0.01) and to values equivalent to the H pylori positive healthy volunteers. The pepsin output in response to gastrin releasing peptide followed the same pattern as the acid output. The median plasma gastrin concentrations during gastrin releasing peptide were similar in the H pylori positive duodenal ulcer patients (150 ng/l, range 95-400) and H pylori positive healthy volunteers (129 ng/l, range 23-420) and both were appreciably higher than H pylori negative healthy volunteers (60 ng/l, range 28-135) (p < 0.005 for each). Eradication of H pylori lowered the plasma gastrin in the duodenal ulcer patients to values equivalent to the H pylori negative healthy volunteers. These findings show a threefold increase in acid secretion in H pylori positive healthy volunteers that is explained by H pylori induced hypergastrinaemia and a sixfold increase in acid secretion in the duodenal ulcer patients that is explained by the combination of H pylori induced hypergastrinaemia and an exaggerated acid response to

Postprandial response of ghrelin and PYY and indices of low-grade chronic inflammation in lean young women with polycystic ovary syndrome.

PubMed

Zwirska-Korczala, K; Sodowski, K; Konturek, S J; Kuka, D; Kukla, M; Brzozowski, T; Cnota, W; Woźniak-Grygiel, E; Jaworek, J; Bułdak, R; Rybus-Kalinowska, B; Fryczowski, M

2008-08-01

The aim of the study were to answer the question 1.) Whether circulating pro-inflammatory markers of endothelial dysfunction and due to chronic low-grade inflammation of obesity, are altered in untreated lean, young relatively healthy polycystic ovary syndrome (PCOS) patients in comparison with healthy controls; 2.) Whether postprandial plasma concentration pattern of ghrelin and PYY can be predictable as risk factors for atherosclerosis and depend of obesity. Forty young women with PCOS were divided in two groups: 19 lean and 21 obese. The control group included 20 lean, healthy volunteers. Plasma total and active ghrelin, total PYY and PYY(3-36), serum adiponectin and insulin were measured using RIA technique, serum sCD40L, visfatin, sP-, sE-selectins, resistin by EIA. Composition of test meal was: 527 kcal total and consisted of 24.1% fat, 54.4% carbohydrate and 21.5% protein. Total and active ghrelin and total PYY were significantly lower in obese PCOS women, whereas active ghrelin was also significantly lower in lean PCOS women compared to controls. Postprandial plasma total ghrelin levels decrease were blunted in lean and obese compared to controls (12.8 % and 18.2% vs 28.2 %). Postprandial plasma active ghrelin decreased in lean and obese PCOS groups (49.9 % and 44.1 %) and controls (63.8 %). PCOS subjects exhibited smaller rises in postprandial levels of total PYY. Postprandial plasma PYY(3-36) levels increased in obese PCOS women (30.9 %) and controls (41%), whereas lean PCOS women exhibited blunted increase (11.5%). sCD40L levels increased, whereas adiponectin decreased in PCOS groups independently, whereas rise in visfatin, sE- and sP-selectin and the fall in adiponectin was associated with obesity. sP- and sE -selectins correlated positively with obesity. In summary, our study provides the first evidence that lean untreated young PCOS women contribute to the so called "pancreatic islet adaptation to insulin resistance" because of ghrelin and PYY

Role of Indigenous Lactobacilli in Gastrin-Mediated Acid Production in the Mouse Stomach ▿

PubMed Central

Takahashi, Hidenori; Nakano, Yasuhiro; Matsuoka, Takashi; Kumaki, Nobue; Asami, Yukio; Koga, Yasuhiro

2011-01-01

It is known that the stomach is colonized by indigenous lactobacilli in mice. The aim of this study was to examine the role of such lactobacilli in the development of the stomach. For a DNA microarray analysis, germ-free BALB/c mice were orally inoculated with 109 CFU lactobacilli, and their stomachs were excised after 10 days to extract RNA. As a result, lactobacillus-associated gnotobiotic mice showed dramatically decreased expression of the gastrin gene in comparison to germ-free mice. The mean of the log2 fold change in the gastrin gene was −4.3. Immunohistochemistry also demonstrated the number of gastrin-positive (gastrin+) cells to be significantly lower in the lactobacillus-associated gnotobiotic mice than in the germ-free mice. However, there was no significant difference in the number of somatostatin+ cells in these groups of mice. Consequently, gastric acid secretion also decreased in the mice colonized by lactobacilli. In addition, an increase in the expression of the genes related to muscle system development, such as nebulin and troponin genes, was observed in lactobacillus-associated mice. Moreover, infection of germ-free mice with Helicobacter pylori also showed the down- and upregulation of gastrin and muscle genes, respectively, in the stomach. These results thus suggested that indigenous lactobacilli in the stomach significantly affect the regulation of gastrin-mediated gastric acid secretion without affecting somatostatin secretion in mice, while H. pylori also exerts such an effect on the stomach. PMID:21803885

Peptide YY: a gut hormone associated with anorexia during infectious diarrhea in children.

PubMed

Beck, Amy L; Cabrera, Lilia; Pan, William K Y; Cama, Vitaliano; Friedland, Jon S; Ghatei, Mohammad A; Bloom, Stephen R; Lewis, Judy; Gilman, Robert H

2008-11-01

To evaluate the effects of diarrhea on appetite among Peruvian children age 12 to 71 months and to assess whether elevated plasma levels of peptide YY, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-1beta contribute to anorexia in this population. A total of 46 Peruvian children with diarrhea and 46 healthy controls underwent an observed feeding trial that was repeated when cases were healthy. Blood samples were obtained from 30 cases and 30 controls at the first trial and from 30 cases at the second trial and assayed for peptide YY, TNF-alpha, and IL-1beta. In the cases, mean consumption was less when sick than when healthy. The mean plasma level of peptide YY was higher for cases than controls and higher for cases when sick than when healthy. TNF-alpha levels were higher in cases than controls at visit 1 and also higher in cases when sick than when healthy. There were no differences in IL-1beta levels between cases and controls or between cases when sick and healthy. Peptide YY levels in children with diarrhea correlated with the likelihood of them eating less when sick than when healthy. Elevated serum peptide YY may be a mechanism for anorexia in children with diarrhea.

Genome-wide survey by ChIP-seq reveals YY1 regulation of lincRNAs in skeletal myogenesis

PubMed Central

Lu, Leina; Sun, Kun; Chen, Xiaona; Zhao, Yu; Wang, Lijun; Zhou, Liang; Sun, Hao; Wang, Huating

2013-01-01

Skeletal muscle differentiation is orchestrated by a network of transcription factors, epigenetic regulators, and non-coding RNAs. The transcription factor Yin Yang 1 (YY1) silences multiple target genes in myoblasts (MBs) by recruiting Ezh2 (Enhancer of Zeste Homologue2). To elucidate genome-wide YY1 binding in MBs, we performed chromatin immunoprecipitation (ChIP)-seq and found 1820 specific binding sites in MBs with a large portion residing in intergenic regions. Detailed analysis demonstrated that YY1 acts as an activator for many loci in addition to its known repressor function. No significant co-occupancy was found between YY1 and Ezh2, suggesting an additional Ezh2-independent function for YY1 in MBs. Further analysis of intergenic binding sites showed that YY1 potentially regulates dozens of large intergenic non-coding RNAs (lincRNAs), whose function in myogenesis is underexplored. We characterized a novel muscle-associated lincRNA (Yam-1) that is positively regulated by YY1. Yam-1 is downregulated upon differentiation and acts as an inhibitor of myogenesis. We demonstrated that Yam-1 functions through in cis regulation of miR-715, which in turn targets Wnt7b. Our findings not only provide the first genome-wide picture of YY1 association in muscle cells, but also uncover the functional role of lincRNA Yam-1. PMID:23942234

Interrelation between ghrelin and gastrin in patients with combination of chronic gastritis and type 2 diabetes mellitus.

PubMed

Sirchak, Elizaveta S; Patskun, Silviya V

2018-01-01

Introduction: Ghrelin is 28-amino-acid peptide that is produced by X/A-like cells present in the stomach. Gastrin is a hormone that stimulates gastric acid secretion and mucosal cell growth. The aim: to study the interrelation between ghrelin and gastrin levels in patients with combination of chronic gastritis and type 2 diabetes mellitus. Materials and methods: 60 Helicobacter pylori positive patients with a combination of chronic gastritis and type 2 diabetes mellitus were examined. The diagnosis of type 2 diabetes mellitus is based on the recommendations of the International Diabetes Federation (IDF, 2005). Gastric acid secretion function was studied by intra-stomach express-pH-metry (method of prof. V.N. Chernobrov). Serum gastrin was determined using ELISA using Gastrin-EIA test kit Cat. No. CS 001 030. Serum ghrelin was determined by immunoassay analysis using the Human Ghrelin ELISA Kit from RayBiotech No. 1.03930005306. Results: The obtained data testify to the existence of a feedback between the level of ghrelin and gastrin in the blood of patients with chronic gastritis and type 2 diabetes mellitus. That is, with increasing levels of gastrin in the blood, the level of ghrelin in the blood decreases and vice versa with a decrease in the level of gastrin in the blood, the level of ghrelin - increases. Conclusions: A significantly higher level of ghrelin was found in patients with type 2 diabetes mellitus and chronic gastritis compared with control group. The reverse association between gastrin and ghrelin levels in patients with combination of chronic gastritis and type 2 diabetes mellitus has been obtained.

Characterization of an amidated form of pancreatic polypeptide from the daddy sculpin (Cottus scorpius).

PubMed

Conlon, J M; Schmidt, W E; Gallwitz, B; Falkmer, S; Thim, L

1986-12-30

The primary structure of pancreatic polypeptide from the teleostean fish, Cottus scorpius (daddy sculpin) was established as: YPPQPESPGGNASPEDWAKYHAAVRHYVNLITRQRYNH2 The presence of a COOH-terminally alpha-amidated amino acid was established using an HPLC method of general applicability. Although the peptide shows strong homology towards anglerfish pancreatic polypeptide (86%), homology towards porcine peptide YY (PYY) (61%) and porcine neuropeptide Y (NPY) (61%) was greater than towards porcine pancreatic polypeptide (PP) (47%). This result supports suggestions that the gene duplication events which led to PP, NPY and PYY formation took place after the time of divergence of fish and mammals.

A gastrin releasing peptide from the porcine nonantral gastric tissue.

PubMed

McDonald, T J; Nilsson, G; Vagne, M; Ghatei, M; Bloom, S R; Mutt, V

1978-09-01

This paper presents evidence for the existence in extracts from porcine non-antral gastric tissue of a peptide capable of causing substantial rises of plasma immunoreactive gastrin levels in a dose dependent manner and of stimulation of gastric acid and pepsin secretion. Obtained data show that the peptide is basic and that its gastrin releasing properties are at least partially resistant to atropinisation and beta-receptor blockade. Antrectomy almost eliminates the rise in plasma IRGa when the peptide is administered. The possible relationship of this peptide to amphibian bombesin is discussed.

A gastrin releasing peptide from the porcine nonantral gastric tissue.

PubMed Central

McDonald, T J; Nilsson, G; Vagne, M; Ghatei, M; Bloom, S R; Mutt, V

1978-01-01

This paper presents evidence for the existence in extracts from porcine non-antral gastric tissue of a peptide capable of causing substantial rises of plasma immunoreactive gastrin levels in a dose dependent manner and of stimulation of gastric acid and pepsin secretion. Obtained data show that the peptide is basic and that its gastrin releasing properties are at least partially resistant to atropinisation and beta-receptor blockade. Antrectomy almost eliminates the rise in plasma IRGa when the peptide is administered. The possible relationship of this peptide to amphibian bombesin is discussed. PMID:361511

Suppression of gastrin release and gastric secretion by gastric inhibitory polypeptide (GIP) and vasoactive intestinal polypeptide (VIP).

PubMed Central

Villar, H V; Fender, H R; Rayford, P L; Bloom, S R; Ramus, N I; Thompson, J C

1976-01-01

Five dogs prepared with Heidenhain pouches received infusions of saline, GIP and VIP before and after a standard meat meal. Blood samples were obtained under basal conditions and at subsequent intervals for measurement of gastrin, insulin, GIP and VIP by radioimmunoassay. GIP and VIP infusions had no effect on basal levels of gastrin. GIP and VIP (in common with secretin and glucagon) were found to suppress food-stimulated release of gastrin and gastrin-stimulated acid secretion from the Heidenhain pouch. Insulin levels were significantly elevated during GIP and VIP infusions. Food released GIP (and perhaps VIP. PMID:938120

The hot corona of YY Mensae

NASA Technical Reports Server (NTRS)

Guedel, M.; Guinan, E. F.; Skinner, S. L.; Linsky, J. L.

1996-01-01

The results of a long time series of Rosat position sensitive proportional counter (PSPC) pointings are reported on together with the first Advanced Satellite for Cosmology and Astrophysics (ASCA) observation of the FK Comae-type star YY Mensae. This star reveals a hot dominant plasma of up to 3 keV, with less material at 0.7 keV.

Gastrin stimulates renal dopamine production by increasing the renal tubular uptake of l-DOPA.

PubMed

Jiang, Xiaoliang; Zhang, Yanrong; Yang, Yu; Yang, Jian; Asico, Laureano D; Chen, Wei; Felder, Robin A; Armando, Ines; Jose, Pedro A; Yang, Zhiwei

2017-01-01

Gastrin is a peptide hormone that is involved in the regulation of sodium balance and blood pressure. Dopamine, which is also involved in the regulation of sodium balance and blood pressure, directly or indirectly interacts with other blood pressure-regulating hormones, including gastrin. This study aimed to determine the mechanisms of the interaction between gastrin and dopamine and tested the hypothesis that gastrin produced in the kidney increases renal dopamine production to keep blood pressure within the normal range. We show that in human and mouse renal proximal tubule cells (hRPTCs and mRPTCs, respectively), gastrin stimulates renal dopamine production by increasing the cellular uptake of l-DOPA via the l-type amino acid transporter (LAT) at the plasma membrane. The uptake of l-DOPA in RPTCs from C57Bl/6J mice is lower than in RPTCs from normotensive humans. l-DOPA uptake in renal cortical slices is also lower in salt-sensitive C57Bl/6J than in salt-resistant BALB/c mice. The deficient renal cortical uptake of l-DOPA in C57Bl/6J mice may be due to decreased LAT-1 activity that is related to its decreased expression at the plasma membrane, relative to BALB/c mice. We also show that renal-selective silencing of Gast by the renal subcapsular injection of Gast siRNA in BALB/c mice decreases renal dopamine production and increases blood pressure. These results highlight the importance of renal gastrin in stimulating renal dopamine production, which may give a new perspective in the prevention and treatment of hypertension. Copyright © 2017 the American Physiological Society.

Gastrin regulates ABCG2 to promote the migration, invasion and side populations in pancreatic cancer cells via activation of NF-κB signaling

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Juan; Xin, Beibei; Wang, Hui

Gastrin is absent in most normal adult pancreatic tissues but is highly expressed in pancreatic cancer tissues. Although Gastrin expression was reported to be associated with tumor proliferation in human pancreatic cancer, studies on the relationship between Gastrin and tumor metastasis in pancreatic cancer are rare. In this study, we performed an analysis to determine the effects of Gastrin on modulating the side populations, cell proportion and tumor cell metastatic potential and invasion activity and explored its mechanisms in pancreatic cancer. We indicated that Gastrin and ABCG2 were widely expressed in pancreatic cancer cell lines and overexpressed in cancer tissues.more » Gastrin induced ABCG2 expression, and this effect was mediated by NF-κB activation. Gastrin regulated the SP proportion of BxPC-3 cells via modulating ABCG2 expression. Through the regulation of the functions of NF-κB/ABCG2, Gastrin functionally promoted the migration and invasion in pancreatic cancer cell. The present study indicated that Gastrin induced ABCG2 expression by activating NF-κB and thereby modulated the SP proportion, tumor cell metastatic potential and invasion activity in pancreatic cancer. Gastrin could serve as an effective therapeutic target for the metastasis of pancreatic cancer. - Highlights: • Gastrin induces ABCG2 expression mediated by NF-κB activation. • Gastrin regulates NF-κB's function that binds to the ABCG2 promoter in BxPC-3 cells. • Gastrin promotes the SP proportion in BxPC-3 cells by modulating ABCG2 expression via activation of NF-κB molecule. • Gastrin induces an increase in migration and invasion potential in pancreatic cancer cell by regulating NF-κB/ABCG2 signaling.« less

Gut Hormones, Appetite Suppression and Cachexia in Patients with Pulmonary TB

PubMed Central

Chang, Suzanne W.; Pan, William S.; Lozano Beltran, Daniel; Oleyda Baldelomar, Lizet; Solano, Marco Antonio; Tuero, Iskra; Friedland, Jon S.; Torrico, Faustino; Gilman, Robert H.

2013-01-01

Background Cachexia is a hallmark of pulmonary tuberculosis and is associated with poor prognosis. A better understanding of the mechanisms behind such weight loss could reveal targets for therapeutic intervention. The role of appetite-regulatory hormones in tuberculosis is unknown. Methods and Findings 41 subjects with newly-diagnosed pulmonary TB (cases) were compared to 82 healthy controls. We measured appetite, body mass index (BMI), % body fat (BF), plasma peptide YY (PYY), leptin, ghrelin, and resistin for all subjects. Measurements were taken at baseline for controls and at treatment days 0, 30, and 60 for cases. Baseline appetite, BMI, and BF were lower in cases than in controls and improved during treatment. PYY, ghrelin, and resistin were significantly elevated in cases and fell during treatment. Leptin was lower in cases and rose with treatment. Appetite was inversely related to PYY in cases. High pre-treatment PYY predicted reduced gains in appetite and BF. PYY was the strongest independent predictor of appetite in cases across all time points. Conclusions Appetite-regulatory hormones are altered in TB patients. As hormones normalize during treatment, appetite is restored and nutritional status improves. High baseline PYY is an indicator of poor prognosis for improvement in appetite and nutrition during treatment. Wasting in TB patients may partly be mediated by upregulation of PYY with resulting appetite suppression. PMID:23358528

CCKB/gastrin receptors mediate changes in sodium and potassium absorption in the isolated perfused rat kidney.

PubMed

von Schrenck, T; Ahrens, M; de Weerth, A; Bobrowski, C; Wolf, G; Jonas, L; Jocks, T; Schulz, M; Bläker, M; Neumaier, M; Stahl, R A

2000-09-01

To evaluate the function of cholecystokinin B (CCKB)/gastrin receptors in the rat kidney, we identified the receptors by Northern blot and localized the receptors by immunohistochemistry. The functional effects of gastrin were studied under standardized in vitro conditions using the isolated perfused kidney. Rat kidneys were mounted in an organ bath by attaching the renal artery to a perfusion system. A catheter was inserted into the renal vein and the ureter to collect samples that were analyzed for the concentrations of electrolytes. After a preperfusion period, gastrin-17-I was given via the renal artery (10-8 to 10-6 mol/L). Subsequently, hemodynamic parameters (for example, perfusate flow) and changes in sodium and potassium absorption were determined. All data were subjected to a nonparametric analysis of variance and, in case of significant results, to subsequent paired comparisons by the a posteriori Wilcoxon test. Northern blot analysis detected CCKB receptor transcripts in total RNA isolated from kidneys. Immunohistochemistry localized CCKB receptors on tubules and collecting duct cells. Compared with controls, gastrin (10-6 mol/L) caused a decrease in the fractional sodium reabsorption (basal 80%, 10 minutes after application of gastrin 71%, after 20 minutes 62%, P < 0.05). This effect was inhibited by the CCKB receptor antagonist L-365,260. Gastrin decreased urinary potassium excretion at 10-8 and 10-6 mol/L [maximal decrease at 10-6 mol/L from baseline values (100%) to 49% after 10 minutes and to 69% after 20 minutes, P < 0.05, N = 6]. This effect was also abolished by the CCKB receptor antagonist L-365,260. Gastrin (10-6 mol/L) reduced perfusate flow by 31% (P < 0.05). CCKB receptors are expressed in the rat kidney on tubules and collecting ducts. These receptors mediate changes in renal potassium and sodium absorption. In addition, gastrin causes a decrease in perfusate flow, indicating that CCKB receptors might also modulate vascular resistance in

ENDOTHELIN-STIMULATED HUMAN B-TYPE NATRIURETIC PEPTIDE GENE EXPRESSION IS MEDIATED BY YY1 IN ASSOCIATION WITH HDAC2

PubMed Central

Glenn, Denis J.; Wang, Feng; Chen, Songcang; Nishimoto, Minobu; Gardner, David G.

2009-01-01

Increased B-type natriuretic peptide (BNP) gene expression is regarded as one of the hallmarks of cardiac myocyte hypertrophy. Here we demonstrate that both basal and endothelin-1 (ET-1) -dependent stimulation of human (h) BNP gene transcription requires the presence of an intact Yin Yang 1 (YY1) binding site positioned at -62 bp relative to the transcription start site. Mutation of this site reduced both basal and stimulated hBNP promoter activity. This site was shown to bind YY1 both in vitro and within the context of the intact cell. The latter interaction increased following ET-1 treatment. Exposure to ET-1 also resulted in increased nuclear localization of YY1 and a reduction in acetylation of the YY1 protein. Overexpression of wild type YY1 increased both basal and endothelin-stimulated hBNP promoter activity, while a carboxy terminal deletion mutant of YY1 was devoid of activity. Treatment with the histone deacetylase inhibitor trichostatin A (TSA) resulted in decreased hBNP reporter activity. YY1 was shown to associate with histone deacetylase 2 (HDAC2), and HDAC2 was shown to associate directly with the hBNP promoter in the intact cell. Collectively these findings demonstrate that YY1 plays an important role in regulating the transcriptional activity of the hBNP gene promoter. These data suggest a model in which YY1 activates hBNP transcription through interaction with HDAC2. PMID:19139378

21 CFR 862.1325 - Gastrin test system.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Gastrin test system. 862.1325 Section 862.1325 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test Systems § 862...

21 CFR 862.1325 - Gastrin test system.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Gastrin test system. 862.1325 Section 862.1325 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test Systems § 862...

Yeast two-hybrid cloning of a novel zinc finger protein that interacts with the multifunctional transcription factor YY1.

PubMed Central

Kalenik, J L; Chen, D; Bradley, M E; Chen, S J; Lee, T C

1997-01-01

Muscle-restricted transcription of sarcomeric actin genes is negatively controlled by the zinc finger protein YY1, which is down-regulated at the protein level during myogenic differentiation. To identify cellular proteins that might mediate the function/stability of YY1 in muscle cells, we screened an adult human muscle cDNA library using the yeast two-hybrid cloning system. We report the isolation and characterization of a novel protein termed YAF2 (YY1- associated factor 2) that interacts with YY1. The YAF2 cDNA encodes a 180 amino acid basic protein (pI 10.5) containing a single N-terminal C2-X10-C2 zinc finger. Lysine clusters are present that may function as a nuclear localization signal. Domain mapping analysis shows that the first and second zinc fingers of YY1 are targeted for YAF2 protein interaction. In contrast to the down-regulation of YY1, YAF2 message levels increase during in vitro differentiation of both rat skeletal and cardiac muscle cells. YAF2 appears to have a promyogenic regulatory role, since overexpression of YAF2 in C2 myoblasts stimulates myogenic promoter activity normally restricted by YY1. Co-transfection of YY1 reverses the stimulatory effect of YAF2. YAF2 also greatly potentiates proteolytic cleavage of YY1 by the calcium- activated protease m-calpain. The isolation of YAF2 may help in understanding the mechanisms through which inhibitors of myogenic transcription may be antagonized or eliminated by proteolysis during muscle development. PMID:9016636

Improvement of autism spectrum disorder symptoms in three children by using gastrin-releasing peptide.

PubMed

Becker, Michele Michelin; Bosa, Cleonice; Oliveira-Freitas, Vera Lorentz; Goldim, José Roberto; Ohlweiler, Lygia; Roesler, Rafael; Schwartsmann, Gilberto; Riesgo, Rudimar Dos Santos

2016-01-01

To evaluate the safety, tolerability and potential therapeutic effects of gastrin-releasing peptide in three children with autistic spectrum disorder. Case series study with the intravenous administration of gastrin-releasing peptide in the dose of 160pmol/kg for four consecutive days. To evaluate the results, parental impressions the Childhood Autism Rating Scale (CARS) and the Clinical Global Impression (CGI) Scale. Each child underwent a new peptide cycle after two weeks. The children were followed for four weeks after the end of the infusions. The gastrin-releasing peptide was well tolerated and no child had adverse effects. Two children had improved social interaction, with a slight improvement in joint attention and the interaction initiatives. Two showed reduction of stereotypes and improvement in verbal language. One child lost his compulsion to bathe, an effect that lasted two weeks after each infusion cycle. Average reduction in CARS score was 2.8 points. CGI was "minimally better" in two children and "much better" in one. This study suggests that the gastrin-releasing peptide is safe and may be effective in improving key symptoms of autism spectrum disorder, but its results should be interpreted with caution. Controlled clinical trials-randomized, double-blinded, and with more children-are needed to better evaluate the possible therapeutic effects of gastrin-releasing peptide in autism. Copyright © 2016 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.

In adults with Prader-Willi syndrome, elevated ghrelin levels are more consistent with hyperphagia than high PYY and GLP-1 levels.

PubMed

Purtell, Louise; Sze, Lisa; Loughnan, Georgina; Smith, Ellie; Herzog, Herbert; Sainsbury, Amanda; Steinbeck, Katharine; Campbell, Lesley V; Viardot, Alexander

2011-08-01

Prader-Willi syndrome (PWS) is a leading genetic cause of obesity, characterized by hyperphagia, endocrine and developmental disorders. It is suggested that the intense hyperphagia could stem, in part, from impaired gut hormone signaling. Previous studies produced conflicting results, being confounded by differences in body composition between PWS and control subjects. Fasting and postprandial gut hormone responses were investigated in a cross-sectional cohort study including 10 adult PWS, 12 obese subjects matched for percentage body fat and central abdominal fat, and 10 healthy normal weight subjects. PYY[total], PYY[3-36], GLP-1[active] and ghrelin[total] were measured by ELISA or radioimmunoassay. Body composition was assessed by dual energy X-ray absorptiometry. Visual analog scales were used to assess hunger and satiety. In contrast to lean subjects (p<0.05), PWS and obese subjects were similarly insulin resistant and had similar insulin levels. Ghrelin[total] levels were significantly higher in PWS compared to obese subjects before and during the meal (p<0.05). PYY[3-36] meal responses were higher in PWS than in lean subjects (p=0.01), but not significantly different to obese (p=0.08), with an additional non-significant trend in PYY[total] levels. There were no significant differences in self-reported satiety between groups, however PWS subjects reported more hunger throughout (p=0.003), and exhibited a markedly reduced meal-induced suppression of hunger (p=0.01) compared to lean or obese subjects. Compared to adiposity-matched control subjects, hyperphagia in PWS is not related to a lower postprandial GLP-1 or PYY response. Elevated ghrelin levels in PWS are consistent with increased hunger and are unrelated to insulin levels. Copyright © 2011 Elsevier Ltd. All rights reserved.

Upregulation of miR-146a by YY1 depletion correlates with delayed progression of prostate cancer

PubMed Central

Huang, Yeqing; Tao, Tao; Liu, Chunhui; Guan, Han; Zhang, Guangyuan; Ling, Zhixin; Zhang, Lei; Lu, Kai; Chen, Shuqiu; Xu, Bin; Chen, Ming

2017-01-01

Previously published studies explained that the excessive expression of miR-146a influences the prostate cancer (PCa) cells in terms of apoptosis, progression, and viability. Although miR-146a acts as a tumor suppressor, current knowledge on the molecular mechanisms that controls its expression in PCa is limited. In this study, gene set enrichment analysis (GSEA) showed negatively enriched expression of miR-146a target gene sets and positively enriched expression of gene sets suppressed by the enhancer of zeste homolog 2 (EZH2) after YY1 depletion in PCa cells. The current results demonstrated that the miR-146a levels in PCa tissues with high Gleason scores (>7) are significantly lower than those in PCa tissues with low Gleason scores (≤7), which were initially observed in the clinical specimens. An inverse relationship between YY1 and miR-146a expression was also observed. Experiments indicated the decrease in cell viability, proliferation, and promoting apoptosis after YY1 depletion, while through inhibiting miR-146a could alleviate the negative effect brought by YY1 depletion. We detected the reversed adjustment of YY1 to accommodate miR-146a transcriptions. On the basis of YY1 depletion, we determined that the expression of miR-146a increased after EZH2 knockdown. We validated the combination of YY1 and its interaction with EZH2 at the miR-146a promoter binding site, thereby prohibiting the transcriptional activity of miR-146a in PCa cells. Our results suggested that YY1 depletion repressed PCa cell viability and proliferation and induced apoptosis at least in a miR-146a-assisted manner. PMID:28101571

Contribution of either YY1 or BclXL-induced inhibition by the NO-donor DETANONOate in the reversal of drug resistance, both in vitro and in vivo. YY1 and BclXL are overexpressed in prostate cancer.

PubMed

Huerta-Yepez, Sara; Baritaki, Stavroula; Baay-Guzman, Guillermina; Hernandez-Luna, Marco A; Hernandez-Cueto, Angeles; Vega, Mario I; Bonavida, Benjamin

2013-02-28

Nitric oxide (NO) donors have been shown to activate or inhibit constitutively-activated survival/anti-apoptotic pathways, such as NF-κB, in cancer cells. We report here that treatment of drug-resistant human prostate carcinoma cell lines with high levels (500-1000 μM) of the NO-donor DETANONOate sensitized the resistant tumor cells to apoptosis by CDDP and the combination was synergistic. We hypothesized that DETANONOate inhibits previously identified NF-κB-regulated resistant factors such as Yin Yang 1 (YY1) and Bcl-2/BclXL. Lysates from tumor cells treated with DETANONOate showed inhibition of YY1 and BclXL expressions. Transfection with either YY1 or BclXL siRNA resulted in the inhibition of both YY1 and BclXL expressions and sensitized the cells to CDDP apoptosis. Mice bearing PC-3 tumor xenografts and treated with the combination of DETANONOate and CDDP resulted in significant inhibition of tumor growth; treatment with single agent alone did not have any effect on tumor growth. Analysis of patients TMA tissues with prostatic cancer revealed higher expression of both YY1 and BclXL as a function of tumor grades and their levels were directly correlated. Thus, both YY1 and BclXL are potential prognostic biomarkers. Overall, the above findings suggest that one mechanism of DETANONOate-induced sensitization of resistant tumor cells to CDDP correlated with the inhibition of NF-κB and its targets YY1 and BclXL. The examination of the combination of NO donors and cytotoxic therapy in the treatment of resistant prostate cancer may be warranted. Published by Elsevier Inc.

Chronic proton pump inhibition therapy in the diagnostic accuracy of serum pepsinogen I and gastrin concentrations to identify pernicious anaemia.

PubMed

Martín-Alcolea, Mariam; Rodríguez-Hernández, Inés; Aldea, Marta; Rosas, Irene; Juncà, Jordi; Granada, Maria Luisa

2017-06-01

Chronic use of proton pump inhibitors (PPIs) leads to increases in gastrin and pepsinogen-I serum concentrations. To asses if chronic treatment with PPIs has an effect on serum gastrin and pepsinogen-I concentrations for the diagnosis of pernicious anaemia (PA). Serum gastrin and pepsinogen-I were measured in 38 patients with PA and 74 without PA (controls); 17/38 PA patients and 36/74 controls were treated with PPIs. Receiver Operating Curves (ROC) were used to compare diagnostic accuracy of gastrin and pepsinogen-I for PA in patients under chronic treatment with PPIs and in untreated patients. PPI treatment increased pepsinogen-I in patients and in controls, while gastrin increased only in controls. In untreated patients, a pepsinogen-I <8.3ng/mL had 95.2% sensitivity and 100% specificity, whereas a gastrin >115pg/mL had 100% sensitivity and 92.11% specificity for PA diagnosis. In PPI-treated patients, a pepsinogen I<24.1ng/mL had a lower sensitivity (82.4%) but retained 100% specificity, however the best cut-off point for gastrin, 610pg/mL, had a very low sensitivity (58%). PPI chronic treatment decreased the diagnostic accuracy for the studied biomarkers, particularly of gastrin. In PPI-treated patients, serum pepsinogen-I concentrations >24.1ng/mL allowed rejecting a PA diagnosis with 100% specificity. Copyright © 2017 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

YY1 as a controlling factor for the Peg3 and Gnas imprinted domains

PubMed Central

Kim, Jeong Do; Hinz, Angela K.; Choo, Jung Ha; Stubbs, Lisa; Kim, Joomyeong

2007-01-01

Imprinting Control Regions (ICRs) often harbor tandem arrays of transcription factor binding sites, as demonstrated by the identification of multiple YY1 binding sites within the ICRs of Peg3, Nespas, and Xist/Tsix domains. In the current study, we have sought to characterize possible roles of YY1 in transcriptional control and epigenetic modification of these imprinted domains. RNA interference-based knockdown experiments in Neuro2A cells resulted in overall transcriptional up-regulation of most of the imprinted genes within the Peg3 domain and also, concomitantly, caused significant loss in the DNA methylation of Peg3-DMR (Differentially Methylated Regions). A similar overall and coordinated expression change was also observed for the imprinted genes of the Gnas domain: up-regulation of Nespas and down-regulation of Nesp and Gnasxl. YY1 knockdown also resulted in changes in the expression levels of Xist and Snrpn. These results support the idea that YY1 plays a major role, as a trans factor, for the control of these imprinted domains. PMID:17067777

Effect of nephrectomy on the rate and pattern of the disappearance of exogenous gastrin in dogs

PubMed Central

Clendinnen, B. Guy; Reeder, David D.; Brandt, E. N.; Thompson, James C.

1973-01-01

Studies of gastrin metabolism were performed in four dogs before and after nephrectomy. Synthetic human gastrin I was infused for two hours and serum samples were obtained at various times during and after infusion. Serum concentrations of gastrin were measured by radioimmunoassay. A two-compartment model was employed to calculate half-lives under each of four experimental conditions, low and high infusion rates, used both before and after nephrectomy. The model half-life was greatly prolonged after nephrectomy at both infusion rates (from 2·54 min to 5·15 min at the low rate, and from 2·85 min to 7·88 min at the high rate). The metabolic clearance rate, an expression of the rate of catabolism during infusion, decreased significantly after nephrectomy at both infusion rates. These observations indicate that the kidney is an important organ for the catabolism of exogenous gastrin. PMID:4719213

Positive correlation between symptoms and circulating motilin, pancreatic polypeptide and gastrin concentrations in functional bowel disorders.

PubMed Central

Preston, D M; Adrian, T E; Christofides, N D; Lennard-Jones, J E; Bloom, S R

1985-01-01

Motilin, pancreatic polypeptide and gastrin blood concentrations in response to drinking water have been studied in 40 patients with functional bowel disease and compared with results in two groups of healthy control subjects. Patients with slow transit constipation and idiopathic megacolon showed impaired motilin release. Pancreatic polypeptide release was reduced in patients with slow transit constipation, but increased in those with functional diarrhoea. Gastrin release was impaired in all groups complaining of chronic constipation. Circulating motilin, pancreatic polypeptide and gastrin concentrations appear to bear some relationship to intestinal transit time in patients with functional bowel disorders. PMID:4054704

Positive correlation between symptoms and circulating motilin, pancreatic polypeptide and gastrin concentrations in functional bowel disorders.

PubMed

Preston, D M; Adrian, T E; Christofides, N D; Lennard-Jones, J E; Bloom, S R

1985-10-01

Motilin, pancreatic polypeptide and gastrin blood concentrations in response to drinking water have been studied in 40 patients with functional bowel disease and compared with results in two groups of healthy control subjects. Patients with slow transit constipation and idiopathic megacolon showed impaired motilin release. Pancreatic polypeptide release was reduced in patients with slow transit constipation, but increased in those with functional diarrhoea. Gastrin release was impaired in all groups complaining of chronic constipation. Circulating motilin, pancreatic polypeptide and gastrin concentrations appear to bear some relationship to intestinal transit time in patients with functional bowel disorders.

Effects of resistant starch, a non-digestible fermentable fiber, on reducing body fat.

PubMed

Keenan, Michael J; Zhou, Jun; McCutcheon, Kathleen L; Raggio, Anne M; Bateman, H Gale; Todd, Emily; Jones, Christina K; Tulley, Richard T; Melton, Sheri; Martin, Roy J; Hegsted, Maren

2006-09-01

To assess the effects of energy dilution with non-fermentable and fermentable fibers on abdominal fat and gut peptide YY (PYY) and glucagon-like peptide (GLP)-1 expressions, three rat studies were conducted to: determine the effects of energy dilution with a non-fermentable fiber, compare similar fiber levels of fermentable and non-fermentable fibers, and compare similar metabolizable energy dilutions with fermentable and non-fermentable fibers. In Study 1, rats were fed one of three diets with different metabolizable energy densities. In Study 2, rats were fed diets with similar fiber levels using high amylose-resistant cornstarch (RS) or methylcellulose. In Study 3, rats were fed diets with a similar dilution of metabolizable energy using cellulose or RS. Measurements included food intake, body weight, abdominal fat, plasma PYY and GLP-1, gastrointestinal tract weights, and gene transcription of PYY and proglucagon. Energy dilution resulted in decreased abdominal fat in all studies. In Study 2, rats fed fermentable RS had increased cecal weights and plasma PYY and GLP-1, and increased gene transcription of PYY and proglucagon. In Study 3, RS-fed rats had increased short-chain fatty acids in cecal contents, plasma PYY (GLP-1 not measured), and gene transcription for PYY and proglucagon. Inclusion of RS in the diet may affect energy balance through its effect as a fiber or a stimulator of PYY and GLP-1 expression. Increasing gut hormone signaling with a bioactive functional food such as RS may be an effective natural approach to the treatment of obesity.

Comparative effects of intraduodenal protein and lipid on ghrelin, peptide YY, and leptin release in healthy men.

PubMed

Ullrich, Sina S; Otto, Bärbel; Hutchison, Amy T; Luscombe-Marsh, Natalie D; Horowitz, Michael; Feinle-Bisset, Christine

2015-02-15

Intraduodenal infusion of lipid or protein potently reduces subsequent energy intake. There is evidence that the underlying mechanisms differ significantly between the two nutrients. While intraduodenal lipid stimulates glucagon-like peptide-1 and CCK much more than protein, the release of insulin and glucagon is substantially greater in response to protein. Ghrelin and PYY are both involved in short-term regulation, while leptin is a long-term regulator, of energy balance; the acute effects of nutrients on leptin release are unclear. We investigated the comparative effects of intraduodenal lipid and protein on plasma ghrelin, PYY, and leptin concentrations. Thirteen lean, young men received 90-min intraduodenal infusions of protein (whey hydrolysate) or lipid (long-chain triglyceride emulsion) at a rate of 3 kcal/min, or saline control, on three separate days. Blood samples were collected at baseline and regularly during infusions. Both lipid and protein potently suppressed plasma ghrelin compared with control (both P < 0.001), with no difference between them. While both lipid and protein stimulated plasma PYY (P < 0.001), the effect of lipid was substantially greater than that of protein (P < 0.001). Neither intraduodenal lipid nor protein affected plasma leptin. In conclusion, intraduodenal lipid and protein have discrepant effects on the release of PYY, but not ghrelin. When considered with our previous findings, it appears that, with the exception of ghrelin, the energy intake-suppressant effects of lipid and protein are mediated by different mechanisms. Copyright © 2015 the American Physiological Society.

NF-κB Regulation of YY1 Inhibits Skeletal Myogenesis through Transcriptional Silencing of Myofibrillar Genes▿ †

PubMed Central

Wang, Huating; Hertlein, Erin; Bakkar, Nadine; Sun, Hao; Acharyya, Swarnali; Wang, Jingxin; Carathers, Micheal; Davuluri, Ramana; Guttridge, Denis C.

2007-01-01

NF-κB signaling is implicated as an important regulator of skeletal muscle homeostasis, but the mechanisms by which this transcription factor contributes to muscle maturation and turnover remain unclear. To gain insight into these mechanisms, gene expression profiling was examined in C2C12 myoblasts devoid of NF-κB activity. Interestingly, even in proliferating myoblasts, the absence of NF-κB caused the pronounced induction of several myofibrillar genes, suggesting that NF-κB functions as a negative regulator of late-stage muscle differentiation. Although several myofibrillar promoters contain predicted NF-κB binding sites, functional analysis using the troponin-I2 gene as a model revealed that NF-κB-mediated repression does not occur through direct DNA binding. In the search for an indirect mediator, the transcriptional repressor YinYang1 (YY1) was identified. While inducers of NF-κB stimulated YY1 expression in multiple cell types, genetic ablation of the RelA/p65 subunit of NF-κB in both cultured cells and adult skeletal muscle correlated with reduced YY1 transcripts and protein. NF-κB regulation of YY1 occurred at the transcriptional level, mediated by direct binding of the p50/p65 heterodimer complex to the YY1 promoter. Furthermore, YY1 was found associated with multiple myofibrillar promoters in C2C12 myoblasts containing NF-κB activity. Based on these results, we propose that NF-κB regulation of YY1 and transcriptional silencing of myofibrillar genes represent a new mechanism by which NF-κB functions in myoblasts to modulate skeletal muscle differentiation. PMID:17438126

Plant-rich mixed meals based on Palaeolithic diet principles have a dramatic impact on incretin, peptide YY and satiety response, but show little effect on glucose and insulin homeostasis: an acute-effects randomised study.

PubMed

Bligh, H Frances J; Godsland, Ian F; Frost, Gary; Hunter, Karl J; Murray, Peter; MacAulay, Katrina; Hyliands, Della; Talbot, Duncan C S; Casey, John; Mulder, Theo P J; Berry, Mark J

2015-02-28

There is evidence for health benefits from 'Palaeolithic' diets; however, there are a few data on the acute effects of rationally designed Palaeolithic-type meals. In the present study, we used Palaeolithic diet principles to construct meals comprising readily available ingredients: fish and a variety of plants, selected to be rich in fibre and phyto-nutrients. We investigated the acute effects of two Palaeolithic-type meals (PAL 1 and PAL 2) and a reference meal based on WHO guidelines (REF), on blood glucose control, gut hormone responses and appetite regulation. Using a randomised cross-over trial design, healthy subjects were given three meals on separate occasions. PAL2 and REF were matched for energy, protein, fat and carbohydrates; PAL1 contained more protein and energy. Plasma glucose, insulin, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP) and peptide YY (PYY) concentrations were measured over a period of 180 min. Satiation was assessed using electronic visual analogue scale (EVAS) scores. GLP-1 and PYY concentrations were significantly increased across 180 min for both PAL1 (P= 0·001 and P< 0·001) and PAL2 (P= 0·011 and P= 0·003) compared with the REF. Concomitant EVAS scores showed increased satiety. By contrast, GIP concentration was significantly suppressed. Positive incremental AUC over 120 min for glucose and insulin did not differ between the meals. Consumption of meals based on Palaeolithic diet principles resulted in significant increases in incretin and anorectic gut hormones and increased perceived satiety. Surprisingly, this was independent of the energy or protein content of the meal and therefore suggests potential benefits for reduced risk of obesity.

Effect of increasing Helicobacter pylori ammonia production by urea infusion on plasma gastrin concentrations.

PubMed Central

Chittajallu, R S; Neithercut, W D; Macdonald, A M; McColl, K E

1991-01-01

It has been proposed that the hypergastrinaemia in subjects with Helicobacter pylori infection is caused by the action of the ammonia produced by the organism's urease activity on the antral G cells. To investigate this hypothesis we examined the effect on plasma gastrin of increasing the bacterium's ammonia production by infusing urea intragastrically to eight H pylori positive duodenal ulcer patients. After a 60 minute control intragastric infusion of dextrose solution at 2 ml/minute, a similar infusion containing urea (50 mmol/l) was continued for four hours. During the urea infusion, the median gastric juice urea concentration rose from 1.1 mmol/l (range 0.3-1.6) to 15.5 mmol/l (range 7.9-21.3) and this resulted in an increase in the ammonium concentration from 2.3 mmol/l (range 1.3-5.9) to 6.1 mmol/l (range 4.2-11.9) (p less than 0.01). This appreciable rise in ammonia production did not result in any change in the plasma gastrin concentration. The experiment was repeated one month after eradication of H pylori, at which time the median basal gastrin was 20 ng/l (range 15-25), significantly less than the value before eradication (30 ng/l range 15-60) (p less than 0.05). On this occasion, the gastric juice ammonium concentration was considerably reduced at 0.4 mmol/l (range 0.1-0.9) and the urea infusion did not raise the ammonium concentration or change the plasma gastrin concentration. In conclusion, augmenting H pylori ammonia production does not cause any early change in plasma gastrin. PMID:1991633

Stimulation of gastrin release and gastric secretion: effect of bombesin and a nonapeptide in fistula dogs with and without fundic vagotomy.

PubMed

Hirschowitz, B I; Gibson, R G

1978-01-01

Bombesin and a synthetic bombesin nonapeptide were studied by intravenous infusion at a dose of 0.5 microgram.kg-1.h-1 for 4 h in 7 dogs with esophagostomy and gastric fistula. In 3 of the dogs who had highly selective (fundic) vagotomy, mean integrated gastrin output over 4 h was double that in the 4 dogs with vagi intact during both nonapeptide (1,554 vs. 700 pg.ml-1.4 h-1) and bombesin infusion (2,442 vs. 1,440 pg.ml-1.4 h-1). Peak concentrations of serum gastrin reached during bombesin (490 +/- 100 vs. 320 +/- 90) were higher than those during nonapeptide infusion (270 +/- 40 vs. 160 +/- 28 pg/ml) in the vagotomized and intact dogs, respectively. The difference between vagotomized and vagally intact dogs suggests that the fundic vagotomy removed an inhibitor of gastrin release from the innervated antrum. Despite these differences in gastrin release, gastric acid output with the two peptides was the same (49--52 mEq/4 h) whether the fundus was denervated or innervated. This suggests that bombesin may stimulate gastric acid secretion by the release of an additional secretagogue which is not measured by the gastrin assay. Neither of the two inhibitors of gastrin release--antral acidification to pH 1.4 or less or atropine (100 microgram/kg)-- inhibited gastrin release by bombesin, even though the atropine reduced acid output by 80%. Bombesin is a potent gastric stimulus whose action is only partly explained by the measured gastrin release.

Increased Expression of PcG Protein YY1 Negatively Regulates B Cell Development while Allowing Accumulation of Myeloid Cells and LT-HSC Cells

PubMed Central

Pan, Xuan; Jones, Morgan; Jiang, Jie; Zaprazna, Kristina; Yu, Duonan; Pear, Warren; Maillard, Ivan; Atchison, Michael L.

2012-01-01

Ying Yang 1 (YY1) is a multifunctional Polycomb Group (PcG) transcription factor that binds to multiple enhancer binding sites in the immunoglobulin (Ig) loci and plays vital roles in early B cell development. PcG proteins have important functions in hematopoietic stem cell renewal and YY1 is the only mammalian PcG protein with DNA binding specificity. Conditional knock-out of YY1 in the mouse B cell lineage results in arrest at the pro-B cell stage, and dosage effects have been observed at various YY1 expression levels. To investigate the impact of elevated YY1 expression on hematopoetic development, we utilized a mouse in vivo bone marrow reconstitution system. We found that mouse bone marrow cells expressing elevated levels of YY1 exhibited a selective disadvantage as they progressed from hematopoietic stem/progenitor cells to pro-B, pre-B, immature B and re-circulating B cell stages, but no disadvantage of YY1 over-expression was observed in myeloid lineage cells. Furthermore, mouse bone marrow cells expressing elevated levels of YY1 displayed enrichment for cells with surface markers characteristic of long-term hematopoietic stem cells (HSC). YY1 expression induced apoptosis in mouse B cell lines in vitro, and resulted in down-regulated expression of anti-apoptotic genes Bcl-xl and NFκB2, while no impact was observed in a mouse myeloid line. B cell apoptosis and LT-HSC enrichment induced by YY1 suggest that novel strategies to induce YY1 expression could have beneficial effects in the treatment of B lineage malignancies while preserving normal HSCs. PMID:22292011

Preclinical Evaluation of 68Ga-DOTA-Minigastrin for the Detection of Cholecystokinin-2/Gastrin Receptor–Positive Tumors

PubMed Central

Brom, Maarten; Joosten, Lieke; Laverman, Peter; Oyen, Wim J.G.; Béhé, Martin; Gotthardt, Martin; Boerman, Otto C.

2011-01-01

In comparison to somatostatin receptor scintigraphy, gastrin receptor scintigraphy using 111In-DTPA-minigastrin (MG0) showed added value in diagnosing neuroendocrine tumors. We investigated whether the 68Ga-labeled gastrin analogue DOTA-MG0 is suited for positron emission tomography (PET), which could improve image quality. Targeting of cholecystokinin-2 (CCK2)/gastrin receptor–positive tumor cells with DOTA-MG0 labeled with either 111In or 68Ga in vitro was investigated using the AR42J rat tumor cell line. Biodistribution was examined in BALB/c nude mice with a subcutaneous AR42J tumor. In vivo PET imaging was performed using a preclinical PET–computed tomographic scanner. DOTA-MG0 showed high receptor affinity in vitro. Biodistribution studies revealed high tumor uptake of 68Ga-DOTA-MG0: 4.4 ± 1.3 %ID/g at 1 hour postinjection. Coadministration of an excess unlabeled peptide blocked the tumor uptake (0.7 ± 0.1 %ID/g), indicating CCK2/gastrin receptor–mediated uptake (p = .0005). The biodistribution of 68Ga-DOTA-MG0 was similar to that of 111In-DOTA-MG0. Subcutaneous and intraperitoneal tumors were clearly visualized by small-animal PET imaging with 5 MBq 68Ga-DOTA-MG0. 111In- and 68Ga-labeled DOTA-MG0 specifically accumulate in CCK2/gastrin receptor–positive AR42J tumors with similar biodistribution apart from the kidneys. AR42J tumors were clearly visualized by microPET. Therefore, 68Ga-DOTA-MG0 is a promising tracer for PET imaging of CCK2/gastrin receptor–positive tumors in humans. PMID:21439259

Preclinical evaluation of 68Ga-DOTA-minigastrin for the detection of cholecystokinin-2/gastrin receptor-positive tumors.

PubMed

Brom, Maarten; Joosten, Lieke; Laverman, Peter; Oyen, Wim J G; Béhé, Martin; Gotthardt, Martin; Boerman, Otto C

2011-04-01

In comparison to somatostatin receptor scintigraphy, gastrin receptor scintigraphy using 111In-DTPA-minigastrin (MG0) showed added value in diagnosing neuroendocrine tumors. We investigated whether the 68Ga-labeled gastrin analogue DOTA-MG0 is suited for positron emission tomography (PET), which could improve image quality. Targeting of cholecystokinin-2 (CCK2)/gastrin receptor-positive tumor cells with DOTA-MG0 labeled with either 111In or 68Ga in vitro was investigated using the AR42J rat tumor cell line. Biodistribution was examined in BALB/c nude mice with a subcutaneous AR42J tumor. In vivo PET imaging was performed using a preclinical PET-computed tomographic scanner. DOTA-MG0 showed high receptor affinity in vitro. Biodistribution studies revealed high tumor uptake of 68Ga-DOTA-MG0: 4.4 ± 1.3 %ID/g at 1 hour postinjection. Coadministration of an excess unlabeled peptide blocked the tumor uptake (0.7 ± 0.1 %ID/g), indicating CCK2/gastrin receptor-mediated uptake (p  =  .0005). The biodistribution of 68Ga-DOTA-MG0 was similar to that of 111In-DOTA-MG0. Subcutaneous and intraperitoneal tumors were clearly visualized by small-animal PET imaging with 5 MBq 68Ga-DOTA-MG0. 111In- and 68Ga-labeled DOTA-MG0 specifically accumulate in CCK2/gastrin receptor-positive AR42J tumors with similar biodistribution apart from the kidneys. AR42J tumors were clearly visualized by microPET. Therefore, 68Ga-DOTA-MG0 is a promising tracer for PET imaging of CCK2/gastrin receptor-positive tumors in humans.

The Effect of Exercise Intensity on Total PYY and GLP-1 in Healthy Females: A Pilot Study.

PubMed

Hallworth, Jillian R; Copeland, Jennifer L; Doan, Jon; Hazell, Tom J

2017-01-01

We compared the acute response of anorexigenic signals (total PYY and GLP-1) in response to submaximal and supramaximal exercise. Nine females completed three sessions: (1) moderate-intensity continuous training (MICT; 30 min; 65%  VO 2max ); (2) sprint interval training (SIT; 6 × 30 sec "all-out" cycling sprints with 4 min recovery); or (3) control (CTRL; no exercise). PYY and GLP-1 were measured via blood samples drawn before, immediately after, and 90 min after exercise. Perceptions of hunger were rated using a visual analogue scale at all blood sampling time points. There was a session × time interaction for GLP-1 ( p = 0.004) where SIT and MICT ( p < 0.015 and p < 0.001) were higher compared to CTRL both immediately and 90 min after exercise. There was a main effect of time for PYY where 90 min after exercise it was decreased versus before and immediately after exercise. There was a session × time interaction for hunger with lower ratings following SIT versus MICT ( p = 0.027) and CTRL ( p = 0.031) 90 min after exercise. These results suggest that though GLP-1 is elevated after exercise in women, it is not affected by exercise intensity though hunger was lower 90 min after exercise with SIT. As the sample size is small further study is needed to confirm these findings.

Appetite, Glycemia, and Entero-Insular Hormone Responses Differ Between Oral, Gastric-Remnant, and Duodenal Administration of a Mixed-Meal Test After Roux-en-Y Gastric Bypass.

PubMed

Gero, Daniel; Steinert, Robert E; Hosa, Hanna; Cummings, David E; Bueter, Marco

2018-06-01

To examine the effect of different feeding routes on appetite and metabolic responses after Roux-en-Y gastric bypass (RYGB). A standard liquid meal was administered either orally, into the gastric remnant, or intraduodenally 6 months after RYGB. Changes in plasma glucose, insulin, glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), peptide YY (PYY), and appetite were measured pre- and postprandially. Postprandial GLP-1 and PYY responses were similar, whereas glucose, insulin, and GIP levels differed markedly after oral versus intraduodenal feeding. Intraduodenal feeding prompted an intermediate appetite response (i.e., between oral and intragastric). For postprandial glucose, insulin, and GIP levels, the intraduodenal route was more similar to the intragastric than the oral route. Intragastric administration did not evoke changes in appetite, glucose, or insulin; however, it slightly increased GLP-1 and PYY and moderately increased GIP. Appetite and metabolic responses after RYGB depend on the route by which nutrients enter the gastrointestinal tract. © 2018 by the American Diabetes Association.

The Effect of Salt Intake and Potassium Supplementation on Serum Gastrin Levels in Chinese Adults: A Randomized Trial

PubMed Central

Wang, Yuan-Yuan; He, Wen-Wen; Liu, Yan-Chun; Lin, Yi-Feng; Hong, Lu-Fei

2017-01-01

Excess dietary salt is strongly correlated with cardiovascular disease, morbidity, and mortality. Conversely, potassium likely elicits favorable effects against cardiovascular disorders. Gastrin, which is produced by the G-cells of the stomach and duodenum, can increase renal sodium excretion and regulate blood pressure by acting on the cholecystokinin B receptor. The aim of our study was to assess the effects of altered salt and potassium supplementation on serum gastrin levels in humans. A total of 44 subjects (38–65 years old) were selected from a rural community in northern China. All subjects were sequentially maintained on a relatively low-salt diet for 7 days (3.0 g/day of NaCl), a high-salt diet for 7 days (18.0 g/day of NaCl), and then a high-salt diet supplemented with potassium for another 7 days (18.0 g/day of NaCl + 4.5 g/day of KCl). The high-salt intake significantly increased serum gastrin levels (15.3 ± 0.3 vs. 17.6 ± 0.3 pmol/L). This phenomenon was alleviated through potassium supplementation (17.6 ± 0.3 vs. 16.5 ± 0.4 pmol/L). Further analyses revealed that serum gastrin was positively correlated with 24 h urinary sodium excretion (r = 0.476, p < 0.001). By contrast, gastrin level was negatively correlated with blood pressure in all dietary interventions (r = −0.188, p = 0.031). The present study indicated that variations in dietary salt and potassium supplementation affected the serum gastrin concentrations in the Chinese subjects. PMID:28420122

CCK receptors-related signaling involved in nitric oxide production caused by gastrin 17 in porcine coronary endothelial cells.

PubMed

Grossini, Elena; Caimmi, Philippe; Molinari, Claudio; Uberti, Francesca; Mary, David; Vacca, Giovanni

2012-03-05

In anesthetized pigs gastrin-17 increased coronary blood flow through CCK1/CCK2 receptors and β(2)-adrenoceptors-related nitric oxide (NO) release. Since the intracellular pathway has not been investigated the purpose of this study was to examine in coronary endothelial cells the CCK1/CCK2 receptors-related signaling involved in the effects of gastrin-17 on NO release. Gastrin-17 caused a concentration-dependent increase of NO production (17.3-62.6%; p<0.05), which was augmented by CCK1/CCK2 receptors agonists (p<0.05). The effect of gastrin-17 was amplified by the adenylyl-cyclase activator and β(2)-adrenoceptors agonist (p<0.05), abolished by cAMP/PKA and β(2)-adrenoceptors and CCK1/CCK2 receptors blockers, and reduced by PLC/PKC inhibitor. Finally, Western-blot revealed the preferential involvement of PKA vs. PKC as downstream effectors of CCK1/CCK2 receptors activation leading to Akt, ERK, p38 and endothelial NOS (eNOS) phosphorylation. In conclusion, in coronary endothelial cells, gastrin-17 induced eNOS-dependent NO production through CCK1/CCK2 receptors- and β(2)-adrenoceptors-related pathway. The intracellular signaling involved a preferential PKA pathway over PKC. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

ACE-like hydrolysis of gastrin analogs and CCK-8 by fundic mucosal cells of different species with release of the amidated C-terminal dipeptide.

PubMed

Dubreuil, P; Fulcrand, P; Rodriguez, M; Laur, J; Bali, J P; Martinez, J

1990-06-19

Various gastrin analogues and CCK-8 (Asp-Tyr(SO3H)-Met-Gly-Trp-Met-Asp-Phe-NH2) are hydrolyzed in vitro by angiotensin-converting enzyme (ACE), the main and initial cleavage occurring at the Met-Asp (or Leu-Asp) bond, releasing the C-terminal dipeptide amide Asp-Phe-NH2. Tetragastrin analogues (e.g., Boc-Trp-Leu-Asp-Phe-NH2) are degraded by a vesicular membrane fraction from rat gastric mucosa, yielding the C-terminal dipeptide Asp-Phe-NH2. We report here on the degradation of gastrin analogues and CCK-8 by a gastric mucosal cell preparation containing specific gastrin receptors. We have shown that gastrin analogues were specifically degraded by gastric mucosal cells from different species (e.g., rabbit and dog) at 37 degrees C (pH 7.4), releasing the C-terminal dipeptide Asp-Phe-NH2, similarly to ACE. This cleavage was found to be temperature and pH sensitive, and was inhibited by metalloproteinase inhibitors and by captopril, strongly suggesting that this enzymatic system closely resembles ACE. We have also demonstrated that a close correlation seems to exist between the apparent affinity of the gastrin analogues for gastrin receptors on gastric mucosal cells, and their ability of being hydrolyzed by this cell preparation. Moreover, all gastrin analogues which have been demonstrated to act as gastrin antagonists remained unaffected in the incubation conditions.

Subject standardization, acclimatization, and sample processing affect gut hormone levels and appetite in humans.

PubMed

Chandarana, Keval; Drew, Megan E; Emmanuel, Julian; Karra, Efthimia; Gelegen, Cigdem; Chan, Philip; Cron, Nicholas J; Batterham, Rachel L

2009-06-01

Gut hormones represent attractive therapeutic targets for the treatment of obesity and type 2 diabetes. However, controversy surrounds the effects that adiposity, dietary manipulations, and bariatric surgery have on their circulating concentrations. We sought to determine whether these discrepancies are due to methodologic differences. Ten normal-weight males participated in a 4-way crossover study investigating whether fasting appetite scores, plasma acyl-ghrelin, active glucagon-like peptide-1 (GLP-1), and peptide YY3-36 (PYY3-36) levels are altered by study-induced stress, prior food consumption, and sample processing. Study visit order affected anxiety, plasma cortisol, and temporal profiles of appetite and plasma PYY3-36, with increased anxiety and cortisol concentrations on the first study day. Plasma cortisol area under the curve (AUC) correlated positively with plasma PYY3-36 AUC. Despite a 14-hour fast, baseline hunger, PYY3-36 concentrations, temporal appetite profiles, PYY3-36 AUC, and active GLP-1 were affected by the previous evening's meal. Sample processing studies revealed that sample acidification and esterase inhibition are required when measuring acyl-ghrelin and dipeptidyl-peptidase IV inhibitor addition for active GLP-1. However, plasma PYY3-36 concentrations were unaffected by addition of dipeptidyl-peptidase IV. Accurate assessment of appetite, feeding behavior, and gut hormone concentrations requires standardization of prior food consumption and subject acclimatization to the study protocol. Moreover, because of the labile nature of acyl-ghrelin and active GLP-1, specialized sample processing needs to be undertaken.

No association of peptide tyrosine-tyrosine (PYY) gene R72T variant with obesity in the Kampar Health Clinic cohort, Malaysia.

PubMed

Chan, P M; Fan, S H; Say, Y H

2011-08-01

Peptide Tyrosine-Tyrosine (PYY) is a 36-amino acid peptide hormone released post-prandially from the endocrine cells in the intestinal tract to suppress pancreatic secretions and eventually reduce appetite. The R72T variant in the PYY gene (rs1058046) has been associated with increased susceptibility to obesity. Therefore, the objective of this study was to investigate the association of this variant with obesity and its related anthropometric measurements among the Kampar Health Clinic cohort, Malaysia. A total of 197 (78 males, 119 females; 98 non-obese, 99 obese) subjects were recruited by convenience sampling and anthropometric measurements were taken. Genotyping was performed using StuI Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP), revealing 61 RR, 94 RT and 42 TT subjects. Most of the obese subjects had the RT genotype (50.5%), while only 18.2% were TT. PYY R72T genotypes and alleles had no association with obesity (p = 0.535; 0.074, respectively), gender (p = 0.767; p = 0.100, respectively) but were associated with ethnicity (p = 0.003; p = 0.002, respectively). Among the 13 anthropometric measurements taken, significant difference was only found in Waist Circumference (WC) and Visceral Fat Level (VFL) among the alleles, suggesting that subjects with T allele will have an increment of 1.82 cm in WC and 1.32% in VFL. The R72T variant in PYY gene was not associated with obesity and most of its related anthropometric measurements. This suggests that other genes and/or environmental factors like dietary habits and lifestyle factors may be the contributors of obesity.

Effect of Roux-en-Y gastric bypass on the distribution and hormone expression of small-intestinal enteroendocrine cells in obese patients with type 2 diabetes.

PubMed

Rhee, Nicolai A; Wahlgren, Camilla D; Pedersen, Jens; Mortensen, Brynjulf; Langholz, Ebbe; Wandall, Erik P; Friis, Steffen U; Vilmann, Peter; Paulsen, Sarah J; Kristiansen, Viggo B; Jelsing, Jacob; Dalbøge, Louise S; Poulsen, Steen S; Holst, Jens J; Vilsbøll, Tina; Knop, Filip K

2015-10-01

We studied the impact of Roux-en-Y gastric bypass (RYGB) on the density and hormonal gene expression of small-intestinal enteroendocrine cells in obese patients with type 2 diabetes. Twelve patients with diabetes and 11 age- and BMI-matched controls underwent RYGB followed by enteroscopy ~10 months later. Mucosal biopsies taken during surgery and enteroscopy were immunohistochemically stained for glucagon-like peptide-1 (GLP-1), peptide YY (PYY), cholecystokinin (CCK), glucose-dependent insulinotropic polypeptide (GIP) and prohormone convertase 2 (PC2) and the expression of GCG (encoding preproglucagon), PYY, CCK, GIP, GHRL (encoding ghrelin), SCT (encoding secretin), NTS (encoding neurotensin) and NR1H4 (encoding farnesoid X receptor) was evaluated. The density of cells immunoreactive for GLP-1, CCK and GIP increased in patients after RYGB and the density of those immunoreactive for GLP-1, PYY, CCK and PC2 increased in controls. In both groups, GHRL, SCT and GIP mRNA was reduced after RYGB while PYY, CCK, NTS and NR1H4 gene expression was unaltered. GCG mRNA was upregulated in both groups. Numerous alterations in the distribution of enteroendocrine cells and their expression of hormonal genes are seen after RYGB and include increased density of GLP-1-, PYY-, CCK-, GIP- and PC2-positive cells, reduced gene expression of GHRL, SCT and GIP and increased expression of GCG.

Effects of prepartum fat supplementation on plasma concentrations of glucagon-like peptide-1, peptide YY, adropin, insulin, and leptin in periparturient dairy cows.

PubMed

Zapata, Rizaldy C; Salehi, Reza; Ambrose, Divakar J; Chelikani, Prasanth K

2015-10-01

Dietary fat supplementation during the periparturient period is one strategy to increase energy intake and attenuate the degree of negative energy balance during early lactation; however, little is known of the underlying hormonal and metabolic adaptations. We evaluated the effects of prepartum fat supplementation on energy-balance parameters and plasma concentrations of glucagon-like peptide-1, peptide tyrosine-tyrosine (PYY), adropin, insulin, leptin, glucose, nonesterified fatty acid, and β-hydroxybutyric acid in dairy cows. Twenty-four pregnant dairy cows were randomized to diets containing either rolled canola or sunflower seed at 8% of dry matter, or no oilseed supplementation, during the last 5 wk of gestation and then assigned to a common lactation diet postpartum. Blood samples were collected at -2, +2, and +14 h relative to feeding, at 2 wk after the initiation of the diets, and at 2 wk postpartum. Dietary canola and sunflower supplementation alone did not affect energy balance, body weight, and plasma concentrations of glucagon-like peptide-1, PYY, adropin, insulin, leptin, nonesterified fatty acid, and β-hydroxybutyric acid; however, canola decreased and sunflower tended to decrease dry matter intake. We also observed that the physiological stage had a significant, but divergent, effect on circulating hormones and metabolite concentrations. Plasma glucagon-like peptide-1, PYY, adropin, nonesterified fatty acid, and β-hydroxybutyric acid concentrations were greater postpartum than prepartum, whereas glucose, insulin, leptin, body weight, and energy balance were greater prepartum than postpartum. Furthermore, the interaction of treatment and stage was significant for leptin and adropin, and tended toward significance for PYY and insulin; only insulin exhibited an apparent postprandial increase. Postpartum PYY concentrations exhibited a strong negative correlation with body weight, suggesting that PYY may be associated with body weight regulation during

Helicobacter pylori potentiates epithelial:mesenchymal transition in gastric cancer: links to soluble HB-EGF, gastrin and matrix metalloproteinase-7

PubMed Central

Yin, Yinfei; Grabowska, Anna M; Clarke, Philip A; Whelband, Elisabeth; Robinson, Karen; Argent, Richard H; Tobias, Amanda; Kumari, Rajendra; Atherton, John C

2010-01-01

Background and aims Helicobacter pylori (H pylori) infection is a major risk factor in the development of distal gastric adenocarcinoma. Development of the invasive phenotype is associated with the phenomenon of epithelial:mesenchymal transition (EMT). Soluble heparin-binding epidermal growth factor (HB-EGF) has been implicated in this process. A study was undertaken to investigate the possibility that matrix metalloproteinase (MMP)-7 is upregulated in H pylori infection as a result of hypergastrinaemia, which may enhance shedding of HB-EGF and contribute towards EMT in gastric adenocarcinoma cell lines. Methods Three gastric epithelial cell lines (AGS, MGLVA1 and ST16) were co-cultured with the pathogenic H pylori strain 60190 and non-pathogenic strain Tx30a in an in vitro infection model. Gene expression was quantified by real-time PCR, HB-EGF shedding by ELISA and protein expression by immunofluorescence or immunohistochemistry. The INS-GAS mouse, a transgenic mouse model of gastric carcinogenesis which overexpresses amidated gastrin, was used to investigate the in vivo relationship between HB-EGF, MMP-7, gastrin and EMT. Results The pathogenic strain of H pylori significantly upregulated EMT-associated genes Snail, Slug and vimentin in all three gastric cell lines to a greater degree than the non-pathogenic strain. Pathogenic H pylori also upregulated HB-EGF shedding, a factor implicated in EMT, which was partially dependent on both gastrin and MMP-7 expression. Gastrin and MMP-7 siRNAs and MMP-7 neutralising antibody significantly reduced upregulation of HB-EGF shedding in H pylori infected gastric cell lines and reduced EMT gene expression. The effect of H pylori on EMT was also reversed by gastrin siRNA. Neutralisation of gastrin in the INS-GAS mouse model reduced expression of MMP-7, HB-EGF and key EMT proteins. Conclusion The upregulation of MMP-7 by pathogenic H pylori is partially dependent on gastrin and may have a role in the development of gastric

Gastric sensorimotor functions and hormone profile in normal weight, overweight, and obese people.

PubMed

Vazquez Roque, Maria I; Camilleri, Michael; Stephens, Debra A; Jensen, Michael D; Burton, Duane D; Baxter, Kari L; Zinsmeister, Alan R

2006-12-01

Peptide YY (PYY) levels are reported to be decreased in obesity. The relation between gastric functions, satiation, and gut hormones in obesity is incompletely understood. The aim of this study was to compare gastric volumes, emptying, maximum tolerated volumes, postchallenge symptoms, and selected gut hormones in normal, overweight, or obese healthy volunteers. In 73 nonbulimic normal, overweight, or obese participants weighing less than 137 kg, we measured gastric emptying of solids and liquids by scintigraphy (gastric emptying half-time [GE t(1/2)]); gastric volumes by single-photon emission computed tomography; maximum tolerated volumes and symptoms by satiation test; and plasma leptin, ghrelin, insulin, glucagon-like peptide 1, and PYY levels. Groups were compared using 1-way analysis of covariance adjusted for sex. Univariate associations among measured responses were assessed using Spearman correlations. Multiple linear regression models, adjusting for weight and sex, assessed the independent ability of gastric functions and hormones to predict satiation volume. Obese and overweight subjects had significantly lower postprandial gastric volumes, higher fasting and postprandial insulin and leptin levels, and lower fasting ghrelin and lower postprandial reduction in ghrelin levels. PYY levels were not different in obese or overweight subjects compared with controls. The GE t(1/2) was correlated inversely with postprandial PYY; increased body weight was associated with faster GE t(1/2) of solids (r(s) = 0.33, P = .005) and liquids (r(s) = 0.24, P = .04). Postprandial changes in gastric volume and PYY were independent predictors of satiation (both P = .01). Overweight or obesity are associated with lower postprandial gastric volumes and normal PYY levels. Gastric emptying influences postprandial PYY levels. Postprandial PYY and gastric volume independently predict satiation volume in nonbulimic people across a wide body mass index range.

Ulex europaeus agglutinin-I binds to developing gastrin cells.

PubMed

Ge, Z H; Blom, J; Larsson, L I

1998-03-01

We have previously reported that antropyloric gastrin (G) and somatostatin (D) cells derive from precursor (G/D) cells that coexpress both hormones. We have now analyzed this endocrine cell pedigree for binding of Ulex europaeus agglutinin-I (UEA-I), which previously has been reported to represent a useful marker for cell differentiation. Subpopulations of G/D, D, and G cells were all found to express UEA-I binding. Labelling with bromodeoxyuridine showed that UEA-I positive G cells possessed a higher labelling index than UEA-I negative G cells. These data suggest that the UEA-I positive G cells represent maturing cells still involved in DNA synthesis and cell division. Electron microscopically, specific UEA-I binding sites were localized to the secretory granules and the apical cell membrane of G cells. We conclude that UEA-I represents a differentiation marker for G cells. Moreover, the presence of UEA-I binding sites in these cells may be relevant for Helicobacter pylori-mediated disturbances of gastric acid secretion and gastrin hypersecretion.

Human gastrin-releasing peptide gene is located on chromosome 18.

PubMed

Naylor, S L; Sakaguchi, A Y; Spindel, E; Chin, W W

1987-01-01

Gastrin-releasing peptide (GRP), a bombesin-like peptide, increases plasma levels of gastrin, pancreatic polypeptide, glucagon, gastric inhibitory peptide, and insulin. GRP is produced in large quantities by small-cell lung cancer and acts as a growth factor for these cells. To determine if chromosomal changes in small-cell lung cancer are related to the expression of GRP, we chromosomally mapped the gene using human-mouse somatic cell hybrids. Twenty hybrids, characterized for human chromosomes, were analyzed by Southern filter hybridization of DNA digested with EcoRI. Human DNA cut with EcoRI yields a major band of 6.8 kb and a minor band of 11.3 kb. The 6.8 kb band segregated concordantly with chromosome 18 and the marker peptidase A. The chromosome 3 abnormalities seen in small-cell lung cancer do not correlate with the chromosomal location of GRP, suggesting that the elevated expression of this gene may be due to mechanisms other than chromosomal rearrangement.

Influence of Helicobacter pylori, sex, and age on serum gastrin and pepsinogen concentrations in subjects without symptoms and patients with duodenal ulcers.

PubMed Central

Mossi, S; Meyer-Wyss, B; Renner, E L; Merki, H S; Gamboni, G; Beglinger, C

1993-01-01

The relation between Helicobacter pylori (H pylori) infection and fasting gastrin and pepsinogen-I and -II concentrations was evaluated in 278 volunteers without symptoms and the results were compared with the values obtained in 35 patients with duodenal ulcers. H pylori infection was determined with the 13C-urea breath test in subjects without symptoms and with endoscopy, biopsy (histology and culture), and quick urease test (CLO-test) in patients with duodenal ulcers. Gastrin and pepsinogen-I and -II concentrations were assayed with specific radioimmunoassay systems. The results clearly indicate that fasting gastrin and pepsinogen-I and -II concentrations were significantly higher in H pylori positive compared with H pylori negative subjects. Neither age nor sex affected basal gastrin and pepsinogen concentrations in H pylori negative subjects. Fasting gastrin, pepsinogen-I and -II concentrations in serum samples were similar in H pylori positive persons with no symptoms and those with duodenal ulcers suggesting that similar mechanisms are involved in increasing plasma concentrations of these variables in both populations. Hypergastrinaemia and hyperpepsinogenaemia are therefore probably secondary to active H pylori infection. PMID:8314506

The gastrin/cholecystokinin-B receptor on prostate cells--a novel target for bifunctional prostate cancer imaging.

PubMed

Sturzu, Alexander; Klose, Uwe; Sheikh, Sumbla; Echner, Hartmut; Kalbacher, Hubert; Deeg, Martin; Nägele, Thomas; Schwentner, Christian; Ernemann, Ulrike; Heckl, Stefan

2014-02-14

The means of identifying prostate carcinoma and its metastases are limited. The contrast agents used in magnetic resonance imaging clinical diagnostics are not taken up into the tumor cells, but only accumulate in the interstitial space of the highly vasculated tumor. We examined the gastrin/cholecystokinin-B receptor as a possible target for prostate-specific detection using the C-terminal seven amino acid sequence of the gastrin peptide hormone. The correct sequence and a scrambled control sequence were coupled to the fluorescent dye rhodamine and the magnetic resonance imaging contrast agent gadolinium (Gd)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA). Expression analysis of the gastrin receptor mRNA was performed by reverse transcriptase polymerase chain reaction on PC3 prostate carcinoma cells, U373 glioma, U2OS osteosarcoma and Colo205 colon carcinoma cells. After having confirmed elevated expression of gastrin receptor in PC3 cells and very low expression of the receptor in Colo205 cells, these two cell lines were used to create tumor xenografts on nude mice for in vivo experiments. Confocal lasers scanning microscopy and magnetic resonance imaging showed a high specificity of the correct conjugate for the PC3 xenografts. Staining of the PC3 xenografts was much weaker with the scrambled conjugate while the Colo205 xenografts showed no marked staining with any of the conjugates. In vitro experiments comparing the correct and scrambled conjugates on PC3 cells by magnetic resonance relaxometry and fluorescence-activated cell sorting confirmed markedly higher specificity of the correct conjugate. The investigations show that the gastrin receptor is a promising tumor cell surface target for future prostate-cancer-specific imaging applications. Copyright © 2013 Elsevier B.V. All rights reserved.

Interaction of the Transcription Start Site Core Region and Transcription Factor YY1 Determine Ascorbate Transporter SVCT2 Exon 1a Promoter Activity

PubMed Central

Qiao, Huan; May, James M.

2012-01-01

Transcription of the ascorbate transporter, SVCT2, is driven by two distinct promoters in exon 1 of the transporter sequence. The exon 1a promoter lacks a classical transcription start site and little is known about regulation of promoter activity in the transcription start site core (TSSC) region. Here we present evidence that the TSSC binds the multifunctional initiator-binding protein YY1. Electrophoresis shift assays using YY1 antibody showed that YY1 is present as one of two major complexes that specifically bind to the TSSC. The other complex contains the transcription factor NF-Y. Mutations in the TSSC that decreased YY1 binding also impaired the exon 1a promoter activity despite the presence of an upstream activating NF-Y/USF complex, suggesting that YY1 is involved in the regulation of the exon 1a transcription. Furthermore, YY1 interaction with NF-Y and/or USF synergistically enhanced the exon 1a promoter activity in transient transfections and co-activator p300 enhanced their synergistic activation. We propose that the TSSC plays a vital role in the exon 1a transcription and that this function is partially carried out by the transcription factor YY1. Moreover, co-activator p300 might be able to synergistically enhance the TSSC function via a “bridge” mechanism with upstream sequences. PMID:22532872

Trophic effect of bombesin on the rat pancreas: is it mediated by the release of gastrin or cholecystokinin?

PubMed

Lhoste, E; Aprahamian, M; Pousse, A; Hoeltzel, A; Stock-Damge, C

1985-01-01

This work investigates the effect, on the rat pancreas, of a chronic administration of bombesin in function of the dose and duration of treatment and examines whether this effect may be mediated by the release of endogenous gastrin or cholecystokinin. Bombesin, administered three times daily for 5 or 15 days, induced a marked increase in pancreatic weight, its protein, RNA and enzyme contents with the dose of 10 micrograms/kg body weight; the ratios of pancreatic weight, protein and RNA contents to DNA contents increased significantly after a 5 day treatment, suggesting cellular hypertrophy. Pancreatic DNA content was markedly enhanced after a 15 day treatment, suggesting cellular hyperplasia. Antrectomy decreased plasma gastrin levels, but did not alter the pancreatico-trophic action of a 10 micrograms/kg bombesin treatment for 5 days. Proglumide, an inhibitor of cholecystokinin and gastrin in the pancreas, did not affect the growth of the pancreas induced by a 10 micrograms/kg bombesin treatment for 5 days. It is concluded that chronic bombesin induces, in the rat pancreas, cellular hypertrophy or hyperplasia depending on the duration of treatment. Pancreatic hypertrophy is not mediated by the release of endogenous gastrin or cholecystokinin.

Rho GTPases and p21-activated kinase in the regulation of proliferation and apoptosis by gastrins.

PubMed

He, Hong; Baldwin, Graham S

2008-01-01

Gastrins, including amidated gastrin (Gamide) and glycine-extended gastrin (Ggly), accelerate the growth of gastrointestinal cancer cells by stimulation of proliferation and inhibition of apoptosis. Gamide and Ggly activate different G proteins of the Rho family of small GTPases. For example, Gamide signals Rac/Cdc42 to activate p21-activated kinase 1 while Ggly signals Rho to activate Rho-activated kinase. p21-activated kinase 1 and Rho-activated kinase induce changes in phosphorylation or expression, respectively, of proteins of the Bcl-2 family, which then affect the caspase cascade with consequent inhibition of apoptosis. In addition, interaction of p21-activated kinase 1 with beta-catenin results in phosphorylation of beta-catenin, which enhances its translocation in to the nucleus, activation of TCF4-dependent transcription, and proliferation and migration. The central role of the beta-catenin pathway in carcinogenesis suggests that specific inhibitors of p21-activated kinase 1 may in the future provide novel therapies for gastrointestinal malignancies.

Cholecystokinin in the control of gastric acid and plasma gastrin and somatostatin secretion in healthy subjects and duodenal ulcer patients before and after eradication of Helicobacter pylori.

PubMed

Konturek, J W

1994-12-01

Exogenous cholecystokinin (CCK) is known to effect gastric secretory and motor functions but its physiological role in the control of these functions in healthy subjects and duodenal ulcer (DU) patients is unknown. In this study involving four series of young healthy normal and DU subjects, the gastric secretory tests were performed under basal conditions and following stimulation by modified sham-feeding (MSF), i.v. infusion of caerulein, gastrin releasing peptide (GRP) or pentagastrin (p-gastrin) (series A), after 500 ml of standard meal without or with addition of 15% soybean oil (series B) or acidification of meal to pH 2.5 (series C), and finally after eradication of Helicobacter pylori (HP) (series D). Studies were carried out without or with the pretreatment with placebo or loxiglumide, a specific antagonist of type A CCK receptors. In series A, the gastric secretion obtained by aspiration technique was measured after secretagogues (MSF, caerulein, GRP or p-gastrin), whereas in series B, C, and D intragastric pH was measured before and after test meal and plasma gastrin, CCK and somatostatin were assayed by specific radioimmunoassays. In healthy subjects, MSF increased gastric acid outputs to about 36% of p-gastrin maximum and treatment with loxiglumide failed to affect this secretion. Standard meal enhanced acid output to about 50% of p-gastrin maximum and raised plasma levels of gastrin, CCK but not somatostatin. The pretreatment with loxiglumide resulted in further increase both in gastric acid secretion and plasma gastrin and CCK, while somatostatin level was significantly reduced. Infusion of graded doses of caerulein or GRP resulted in dose-dependent stimulation of gastric acid secretion reaching, respectively, 35% and 25% of p-gastrin maximum. When loxiglumide was added, the acid responses to caerulein and GRP were further increased by 2-3 folds, attaining a peak similar to the p-gastrin maximum. Administration of loxiglumide resulted in a significant

Preoperative assessment of gut hormones does not correlate to weight loss after Roux-en-Y gastric bypass surgery.

PubMed

Werling, Malin; Fändriks, Lars; Vincent, Royce P; Royce, Vincent P; Cross, Gemma F; le Roux, Carel W; Olbers, Torsten

2014-01-01

Roux-en-Y gastric bypass (RYGB) surgery is an effective and frequently used surgical treatment for severe obesity. Postoperative weight loss varies markedly, but biomarkers to predict weight loss outcomes remain elusive. Levels of the satiety gut hormones glucagon like peptide-1 (GLP-1) and peptide YY (PYY) are attenuated in obese patients but elevated after RYGB surgery. We aimed to evaluate the preoperative responses of GLP-1 and PYY to a standard meal as a predictor of weight loss after RYGB surgery. We hypothesized that weak satiety gut hormone responses preoperatively, would predict poor weight loss after RYGB surgery. Preoperatively 43 patients (F = 25/M = 18) had GLP-1 and PYY measured in the fasting state and at 30-minute intervals over 180 minutes after a standard 400 kcal mixed meal. Weight loss was assessed at weight stability after surgery (mean 16.2 mo [CI 15.516.9]). Body mass index decreased from 44.0 kg/m(2) (CI 42.2-45.7) before surgery to 30.3 kg/m(2) (CI 28.4-32.2) after surgery (P<.001). Preoperative GLP-1 and PYY responses to food intake; as delta value between fasting and maximum as well as total responses during 180 minutes did not correlate to total weight loss (GLP-1; rho = .060 and rho = -.089, PYY; rho = -.03 and rho = -.022, respectively) or to excess weight loss % (GLP-1; rho = .051 and rho = -.064, PYY; rho = -.1 and rho = -.088, respectively). Preoperative responses of GLP-1 and PYY to a 400 kcal mixed meal do not correlate to postoperative weight loss after RYGB surgery for morbid obesity. Copyright © 2014 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.

Novel activity of angiotensin-converting enzyme. Hydrolysis of cholecystokinin and gastrin analogues with release of the amidated C-terminal dipeptide.

PubMed Central

Dubreuil, P; Fulcrand, P; Rodriguez, M; Fulcrand, H; Laur, J; Martinez, J

1989-01-01

ACE (angiotensin-converting enzyme; peptidyl dipeptidase A; EC 3.4.15.1), cleaves C-terminal dipeptides from active peptides containing a free C-terminus. We investigated the hydrolysis of cholecystokinin-8 [CCK-8; Asp-Tyr(SO3H)-Met-Gly-Trp-Met-Asp-Phe-NH2] and of various gastrin analogues by purified rabbit lung ACE. Although these peptides are amidated at their C-terminal end, they were metabolized by ACE to several peptide fragments. These fragments were analysed by h.p.l.c., isolated and identified by comparison with synthetic fragments, and by amino acid analysis. The initial and major site of hydrolysis was the penultimate peptide bond, which generated a major product, the C-terminal amidated dipeptide Asp-Phe-NH2. As a secondary cleavage, ACE subsequently released di- or tri-peptides from the C-terminal end of the remaining N-terminal fragments. The cleavage of CCK-8 and gastrin analogues was inhibited by ACE inhibitors (Captopril and EDTA), but not by other enzyme inhibitors (phosphoramidon, thiorphan, bestatin etc.). Hydrolysis of [Leu15]gastrin-(14-17)-peptide [Boc (t-butoxycarbonyl)-Trp-Leu-Asp-Phe-NH2] in the presence of ACE was found to be dependent on the chloride-ion concentration. Km values for the hydrolysis of CCK-8, [Leu15]gastrin-(11-17)-peptide and Boc-[Leu15]gastrin-(14-17)-peptide at an NaCl concentration of 300 mM were respectively 115, 420 and 3280 microM, and the catalytic constants were about 33, 115 and 885 min-1. The kcat/Km for the reactions at 37 degrees C was approx. 0.28 microM-1.min-1, which is approx. 35 times less than that reported for the cleavage of angiotensin I. These results suggest that ACE might be involved in the metabolism in vivo of CCK and gastrin short fragments. PMID:2554881

Expression of cholecystokinin2-receptor in rat and human L cells and the stimulation of glucagon-like peptide-1 secretion by gastrin treatment.

PubMed

Cao, Yang; Cao, Xun; Liu, Xiao-Min

2015-03-01

Gastrin is a gastrointestinal hormone secreted by G cells. Hypergastrinemia can improve blood glucose and glycosylated hemoglobin levels. These positive effects are primarily due to the trophic effects of gastrin on β-cells. In recent years, many receptors that regulate secretion of glucagon-like peptide 1 (GLP-1) have been identified in enteroendocrine L cell lines. This led us to hypothesize that, in addition to the trophic effects of gastrin on β-cells, L cells also express cholecystokinin2-receptor (CCK2R), which may regulate GLP-1 secretion and have synergistic effects on glucose homeostasis. Our research provides a preliminary analysis of CCK2R expression and the stimulating effect of gastrin treatment on GLP-1 secretion in a human endocrine L cell line, using RT-PCR, Western blot, immunocytochemistry, and ELISA analyses. The expression of proglucagon and prohormone convertase 3, which regulate GLP-1 biosynthesis, were also analyzed by real-time PCR. Double immunofluorescence labeling was utilized to assess the intracellular localization of CCK2R and GLP-1 in L cells harvested from rat colon tissue. Our results showed that CCK2R was expressed in both the human L cell line and the rat L cells. We also showed that treatment with gastrin, a CCK2R agonist, stimulated the secretion of GLP-1, and that this effect was likely due to increased expression of proglucagon and PCSK1 (also known as prohormone convertase 3 (PC3 gene)). These results not only provide a basis for the role gastrin may play in intestinal L cells, and may also provide the basis for the development of a method of gastrin-mediated glycemic regulation. Copyright © 2014 Elsevier GmbH. All rights reserved.

From YY Boo (eclipsing binary) via J1407 (ringed companion) to WD 1145+017 (white dwarf with debris disk) (Abstract)

NASA Astrophysics Data System (ADS)

Hambsch, F.-J.

2018-06-01

(Abstract only) Several years ago by accident I observed YY Boo outside of an eclipse and was very surprised to see a short term periodic variation of about 0.1 mag. That was completely unexpected and it initiated an international campaign by amateurs to identify the cause of these variations. It turned out that YY Boo showed a pulsation period of about 88 min in addition to being an Algol type eclipsing binary. Hence it turned out that YY Boo has become a new member of a class of pulsating eclipsing binary systems with, at that time, the second largest amplitude after BO Her.

Timosaponin derivative YY-23 acts as a non-competitive NMDA receptor antagonist and exerts a rapid antidepressant-like effect in mice.

PubMed

Zhang, Qi; Guo, Fei; Fu, Zhi-wen; Zhang, Bing; Huang, Cheng-gang; Li, Yang

2016-02-01

N-methyl-D-aspartic acid (NMDA) receptor modulators have shown promising results as potential antidepressant agents, whereas timosaponins extracted from the Chinese herb Rhizoma Anemarrhenae exhibit antidepressant activities. In the present study we examined whether YY-23, a modified metabolite of timosaponin B-III, could affect NMDA receptors in rat hippocampal neurons in vitro, and evaluated its antidepressant-like effects in stressed mice. NMDA-induced currents were recorded in acutely dissociated rat hippocampal CA1 neurons using a whole-cell recording technique. C57BL/6 mice were exposed to a 6-week chronic mild stress (CMS) or a 10-d chronic social defeat stress (CSDS). The stressed mice were treated with YY-23 (20 mg·kg(-1)·d(-1)) or a positive-control drug, fluoxetine (10 mg·kg(-1)·d(-1)) for 3 weeks. Behavioral assessments were carried out every week. In acutely dissociated rat hippocampal CA1 neurons, YY-23 selectively and reversibly inhibited NMDA-induced currents with an EC50 value of 2.8 μmol/L. This inhibition of NMDA-induced currents by YY-23 was non-competitive, and had no features of voltage-dependency or use-dependency. Treatment of the stressed mice with YY-23 not only reversed CMS-induced deficiency of sucrose preference and immobility time, and CSDS-induced reduction of social interaction, but also had faster onset as compared to fluoxetine. YY-23 is a novel non-competitive antagonist of NMDA receptors with promising rapid antidepressant-like effects in mouse models of CMS and CSDS depression.

Brown Adipose YY1 Deficiency Activates Expression of Secreted Proteins Linked to Energy Expenditure and Prevents Diet-Induced Obesity

PubMed Central

Verdeguer, Francisco; Soustek, Meghan S.; Hatting, Maximilian; Blättler, Sharon M.; McDonald, Devin; Barrow, Joeva J.

2015-01-01

Mitochondrial oxidative and thermogenic functions in brown and beige adipose tissues modulate rates of energy expenditure. It is unclear, however, how beige or white adipose tissue contributes to brown fat thermogenic function or compensates for partial deficiencies in this tissue and protects against obesity. Here, we show that the transcription factor Yin Yang 1 (YY1) in brown adipose tissue activates the canonical thermogenic and uncoupling gene expression program. In contrast, YY1 represses a series of secreted proteins, including fibroblast growth factor 21 (FGF21), bone morphogenetic protein 8b (BMP8b), growth differentiation factor 15 (GDF15), angiopoietin-like 6 (Angptl6), neuromedin B, and nesfatin, linked to energy expenditure. Despite substantial decreases in mitochondrial thermogenic proteins in brown fat, mice lacking YY1 in this tissue are strongly protected against diet-induced obesity and exhibit increased energy expenditure and oxygen consumption in beige and white fat depots. The increased expression of secreted proteins correlates with elevation of energy expenditure and promotion of beige and white fat activation. These results indicate that YY1 in brown adipose tissue controls antagonistic gene expression programs associated with energy balance and maintenance of body weight. PMID:26503783

Gastrin producing G-cells after chronic ethanol and low protein nutrition.

PubMed

Koko, V; Todorović, V; Varagić, J; Micev, M; Korać, A; Bajcetić, M; Cakić-Milosević, M; Nedeljković, M; Drndarević, N

1998-11-01

Male Wistar rats, (2 months old), randomly divided according to the diet offered to four groups (C-control; A- alcoholized, PD-protein-deprived, A-PD- alcoholized protein-deprived). In group A and A-PD rats, the number of gastrin producing G-cells was significantly lower. The volume density of G-cells was significantly decreased in alcoholic rats. Fasting serum gastrin level (FSGL) significantly raised due to combined effect of alcohol consumption and protein malnutrition. In group A rats, the profile area of G-cells and their nuclei increased. In PD rats, the profile area of G cells also increased. There were no differences in nucleus/cell ratio due to alcohol ingestion alone, but it decreased significantly in PD and A-PD rats. Pale and lucent types of granules were predominantly seen in G-cells of animals of group A and A-PD. Mean diameter of granules increased in A, PD and A-PD rats. Other endocrine cells (ECL, D, EC) also decreased in number in A rats. Somatostatin producing D-cells decreased significantly in A-PD rats, both in fundic and pyloric mucosa.

Analysis of the genome sequence of the pathogenic Muscovy duck parvovirus strain YY reveals a 14-nucleotide-pair deletion in the inverted terminal repeats.

PubMed

Wang, Jianye; Huang, Yu; Zhou, Mingxu; Zhu, Guoqiang

2016-09-01

Genomic information about Muscovy duck parvovirus is still limited. In this study, the genome of the pathogenic MDPV strain YY was sequenced. The full-length genome of YY is 5075 nucleotides (nt) long, 57 nt shorter than that of strain FM. Sequence alignment indicates that the 5' and 3' inverted terminal repeats (ITR) of strain YY contain a 14-nucleotide-pair deletion in the stem of the palindromic hairpin structure in comparison to strain FM and FZ91-30. The deleted region contains one "E-box" site and one repeated motif with the sequence "TTCCGGT" or "ACCGGAA". Phylogenetic trees constructed based the protein coding genes concordantly showed that YY, together with nine other MDPV isolates from various places, clustered in a separate branch, distinct from the branch formed by goose parvovirus (GPV) strains. These results demonstrate that, despite the distinctive deletion, the YY strain still belongs to the classical MDPV group. Moreover, the deletion of ITR may contribute to the genome evolution of MDPV under immunization pressure.

Effects of targeted delivery of propionate to the human colon on appetite regulation, body weight maintenance and adiposity in overweight adults

PubMed Central

Chambers, Edward S; Viardot, Alexander; Psichas, Arianna; Morrison, Douglas J; Murphy, Kevin G; Zac-Varghese, Sagen E K; MacDougall, Kenneth; Preston, Tom; Tedford, Catriona; Finlayson, Graham S; Blundell, John E; Bell, Jimmy D; Thomas, E Louise; Mt-Isa, Shahrul; Ashby, Deborah; Gibson, Glen R; Kolida, Sofia; Dhillo, Waljit S; Bloom, Stephen R; Morley, Wayne; Clegg, Stuart; Frost, Gary

2015-01-01

Objective The colonic microbiota ferment dietary fibres, producing short chain fatty acids. Recent evidence suggests that the short chain fatty acid propionate may play an important role in appetite regulation. We hypothesised that colonic delivery of propionate would increase peptide YY (PYY) and glucagon like peptide-1 (GLP-1) secretion in humans, and reduce energy intake and weight gain in overweight adults. Design To investigate whether propionate promotes PYY and GLP-1 secretion, a primary cultured human colonic cell model was developed. To deliver propionate specifically to the colon, we developed a novel inulin-propionate ester. An acute randomised, controlled cross-over study was used to assess the effects of this inulin-propionate ester on energy intake and plasma PYY and GLP-1 concentrations. The long-term effects of inulin-propionate ester on weight gain were subsequently assessed in a randomised, controlled 24-week study involving 60 overweight adults. Results Propionate significantly stimulated the release of PYY and GLP-1 from human colonic cells. Acute ingestion of 10 g inulin-propionate ester significantly increased postprandial plasma PYY and GLP-1 and reduced energy intake. Over 24 weeks, 10 g/day inulin-propionate ester supplementation significantly reduced weight gain, intra-abdominal adipose tissue distribution, intrahepatocellular lipid content and prevented the deterioration in insulin sensitivity observed in the inulin-control group. Conclusions These data demonstrate for the first time that increasing colonic propionate prevents weight gain in overweight adult humans. Trial registration number NCT00750438. PMID:25500202

Disturbance of gut satiety peptide in purging disorder.

PubMed

Keel, Pamela K; Eckel, Lisa A; Hildebrandt, Britny A; Haedt-Matt, Alissa A; Appelbaum, Jonathan; Jimerson, David C

2018-01-01

Little is known about biological factors that contribute to purging after normal amounts of food-the central feature of purging disorder (PD). This study comes from a series of nested studies examining ingestive behaviors in bulimic syndromes and specifically evaluated the satiety peptide YY (PYY) and the hunger peptide ghrelin in women with PD (n = 25), bulimia nervosa-purging (BNp) (n = 26), and controls (n = 26). Based on distinct subjective responses to a fixed meal in PD (Keel, Wolfe, Liddle, DeYoung, & Jimerson, ), we tested whether postprandial PYY response was significantly greater and ghrelin levels significantly lower in women with PD compared to controls and women with BNp. Participants completed structured clinical interviews, self-report questionnaires, and laboratory assessments of gut peptide and subjective responses to a fixed meal. Women with PD demonstrated a significantly greater postprandial PYY response compared to women with BNp and controls, who did not differ significantly. PD women also endorsed significantly greater gastrointestinal distress, and PYY predicted gastrointestinal intestinal distress. Ghrelin levels were significantly greater in PD and BNp compared to controls, but did not differ significantly between eating disorders. Women with BNp endorsed significantly greater postprandial hunger, and ghrelin predicted hunger. PD is associated with a unique disturbance in PYY response. Findings contribute to growing evidence of physiological distinctions between PD and BNp. Future research should examine whether these distinctions account for differences in clinical presentation as this could inform the development of specific interventions for patients with PD. © 2017 Wiley Periodicals, Inc.

[Serological tests of functional activity of the digestive system (gastrin, pepsinogen-I, trypsin), general IgE and serum cortisol levels in children with hepatitis A and B].

PubMed

Kalagina, L S; Pavlov, Ch S; Fomin, Iu A

2013-01-01

The mild form of hepatitis A and B with children is attended by a functional activity of pancreatic gland (tripsin), mucous coats of stomach and duodenum (gastrin) which permits to consider them as a factor of the risk of digestive organs combined pathology starting with the disease acuity. Differences in gastrin levels with children depending on hepatitis etiology were specified. Highest levels of gastrin were observed with persons suffering from hepatitis B.

Bombesin-induced gastrin release from canine G cells is stimulated by Ca2+ but not by protein kinase C, and is enhanced by disruption of rho/cytoskeletal pathways.

PubMed Central

Seensalu, R; Avedian, D; Barbuti, R; Song, M; Slice, L; Walsh, J H

1997-01-01

Isolated canine G cells in primary culture have been used to study calcium, protein kinase C (PKC), and rho/cytoskeletal-dependent intracellular pathways involved in bombesin- stimulated gastrin release. A method to obtain highly purified G cells by culture (64% G cells) after flow cytometry on elutriated fractions of cells from digested canine gastric antral mucosa has been developed. Pretreatment of G cells with thapsigargin (10(-8)-10(-6) M) and release experiments in Ca2+-containing or -depleted media showed that influx of Ca2+ into the cells and not acute release from intracellular stores plays an important role in bombesin-stimulated gastrin release. Inhibition of PKC by the specific inhibitor GF 109 203X did not affect bombesin-stimulated release. Rho, a small GTP-binding protein that regulates the actin cytoskeleton, is specifically antagonized by Clostridium botulinum C3 exoenzyme. C3 (10 microg/ml) enhanced basal and bombesin-stimulated gastrin release by 315 and 266%, respectively. The importance of the cytoskeleton for regulation of gastrin release was emphasized by a more pronounced release of gastrin when the organization of the actin cytoskeleton was disrupted by cytochalasin D (5 x 10(-)7 and 10(-)6 M). Wortmannin, a potent inhibitor of phosphoinositide-3-kinase, did not alter bombesin-stimulated gastrin release. Thus, it is concluded that bombesin-induced gastrin release from canine G cells is stimulated by Ca2+ but not by PKC, and is enhanced by disruption of rho/cytoskeletal pathways. PMID:9276720

Bombesin-induced gastrin release from canine G cells is stimulated by Ca2+ but not by protein kinase C, and is enhanced by disruption of rho/cytoskeletal pathways.

PubMed

Seensalu, R; Avedian, D; Barbuti, R; Song, M; Slice, L; Walsh, J H

1997-09-01

Isolated canine G cells in primary culture have been used to study calcium, protein kinase C (PKC), and rho/cytoskeletal-dependent intracellular pathways involved in bombesin- stimulated gastrin release. A method to obtain highly purified G cells by culture (64% G cells) after flow cytometry on elutriated fractions of cells from digested canine gastric antral mucosa has been developed. Pretreatment of G cells with thapsigargin (10(-8)-10(-6) M) and release experiments in Ca2+-containing or -depleted media showed that influx of Ca2+ into the cells and not acute release from intracellular stores plays an important role in bombesin-stimulated gastrin release. Inhibition of PKC by the specific inhibitor GF 109 203X did not affect bombesin-stimulated release. Rho, a small GTP-binding protein that regulates the actin cytoskeleton, is specifically antagonized by Clostridium botulinum C3 exoenzyme. C3 (10 microg/ml) enhanced basal and bombesin-stimulated gastrin release by 315 and 266%, respectively. The importance of the cytoskeleton for regulation of gastrin release was emphasized by a more pronounced release of gastrin when the organization of the actin cytoskeleton was disrupted by cytochalasin D (5 x 10(-)7 and 10(-)6 M). Wortmannin, a potent inhibitor of phosphoinositide-3-kinase, did not alter bombesin-stimulated gastrin release. Thus, it is concluded that bombesin-induced gastrin release from canine G cells is stimulated by Ca2+ but not by PKC, and is enhanced by disruption of rho/cytoskeletal pathways.

Correlation of the expression of YY1 and Fas cell surface death receptor with apoptosis of peripheral blood mononuclear cells, and the development of multiple organ dysfunction in children with sepsis.

PubMed

Reséndiz-Martínez, Judith; Asbun-Bojalil, Juan; Huerta-Yepez, Sara; Vega, Mario

2017-05-01

Multiple organ dysfunction (MOD) is a lethal complication in children with sepsis. Apoptosis of several cell types is involved in this process, and it is associated with increased Fas cell surface death receptor (Fas) expression. As YY1 transcription factor (YY1) negatively regulates the expression of Fas in cancer models, and is associated with the clinical outcome, it may be important in MOD. The present study aimed to determine the association between the expression of Fas, YY1 and apoptosis in children with sepsis, and its association with MOD, these factors were analyzed in 30 pediatric patients that had been diagnosed with sepsis. Peripheral blood mononuclear cells were purified from patients, and YY1 and Fas protein expression was assessed by immunocytochemistry. Apoptosis was determined by terminal deoxynucleotidyl transferase dUTP nick‑end labeling. Sepsis was monitored using clinical parameters, pediatric logistic organ dysfunction (PELOD) score and the pediatric mortality index. The results demonstrated that Fas expression was directly correlated with apoptosis levels and the expression of YY1 was inversely correlated with apoptosis levels. Patients with high levels of apoptosis exhibited increased disease severity and poor clinical outcome. Notably, the findings of the present study demonstrated that there were higher survival rates in patients with high YY1 expression, compared with those with low YY1 expression. Additionally, patients with MOD exhibited lower proportions of apoptotic cells compared with sepsis patients without MOD. Furthermore, the PELOD score was positively correlated with Fas and inversely correlated with YY1 expression. Finally, high apoptosis and low YY1 expression were prognostic factors associated with poor survival rates. These data suggested that YY1 may be important for apoptosis induction via the regulation of Fas during sepsis. Therefore, Fas may be a potential therapeutic target to prevent MOD through regulation of YY1

Correlation of the expression of YY1 and Fas cell surface death receptor with apoptosis of peripheral blood mononuclear cells, and the development of multiple organ dysfunction in children with sepsis

PubMed Central

Reséndiz-Martínez, Judith; Asbun-Bojalil, Juan; Huerta-Yepez, Sara; Vega, Mario

2017-01-01

Multiple organ dysfunction (MOD) is a lethal complication in children with sepsis. Apoptosis of several cell types is involved in this process, and it is associated with increased Fas cell surface death receptor (Fas) expression. As YY1 transcription factor (YY1) negatively regulates the expression of Fas in cancer models, and is associated with the clinical outcome, it may be important in MOD. The present study aimed to determine the association between the expression of Fas, YY1 and apoptosis in children with sepsis, and its association with MOD, these factors were analyzed in 30 pediatric patients that had been diagnosed with sepsis. Peripheral blood mononuclear cells were purified from patients, and YY1 and Fas protein expression was assessed by immunocytochemistry. Apoptosis was determined by terminal deoxynucleotidyl transferase dUTP nick-end labeling. Sepsis was monitored using clinical parameters, pediatric logistic organ dysfunction (PELOD) score and the pediatric mortality index. The results demonstrated that Fas expression was directly correlated with apoptosis levels and the expression of YY1 was inversely correlated with apoptosis levels. Patients with high levels of apoptosis exhibited increased disease severity and poor clinical outcome. Notably, the findings of the present study demonstrated that there were higher survival rates in patients with high YY1 expression, compared with those with low YY1 expression. Additionally, patients with MOD exhibited lower proportions of apoptotic cells compared with sepsis patients without MOD. Furthermore, the PELOD score was positively correlated with Fas and inversely correlated with YY1 expression. Finally, high apoptosis and low YY1 expression were prognostic factors associated with poor survival rates. These data suggested that YY1 may be important for apoptosis induction via the regulation of Fas during sepsis. Therefore, Fas may be a potential therapeutic target to prevent MOD through regulation of YY1

YY1 binding association with sex-biased transcription revealed through X-linked transcript levels and allelic binding analyses.

PubMed

Chen, Chih-Yu; Shi, Wenqiang; Balaton, Bradley P; Matthews, Allison M; Li, Yifeng; Arenillas, David J; Mathelier, Anthony; Itoh, Masayoshi; Kawaji, Hideya; Lassmann, Timo; Hayashizaki, Yoshihide; Carninci, Piero; Forrest, Alistair R R; Brown, Carolyn J; Wasserman, Wyeth W

2016-11-18

Sex differences in susceptibility and progression have been reported in numerous diseases. Female cells have two copies of the X chromosome with X-chromosome inactivation imparting mono-allelic gene silencing for dosage compensation. However, a subset of genes, named escapees, escape silencing and are transcribed bi-allelically resulting in sexual dimorphism. Here we conducted in silico analyses of the sexes using human datasets to gain perspectives into such regulation. We identified transcription start sites of escapees (escTSSs) based on higher transcription levels in female cells using FANTOM5 CAGE data. Significant over-representations of YY1 transcription factor binding motif and ChIP-seq peaks around escTSSs highlighted its positive association with escapees. Furthermore, YY1 occupancy is significantly biased towards the inactive X (Xi) at long non-coding RNA loci that are frequent contacts of Xi-specific superloops. Our study suggests a role for YY1 in transcriptional activity on Xi in general through sequence-specific binding, and its involvement at superloop anchors.

Analysis of the 2-deoxy-D-glucose-induced vagal stimulation of gastric secretion and gastrin release in dogs using methionine-enkephalin, morphine and naloxone.

PubMed

Anderson, W; Molina, E; Rentz, J; Hirschowitz, B I

1982-09-01

Gastric acid and pepsin secreted in 3 hr and antral gastrin released in response to vagal excitation induced by 2-deoxy-D-glucose (2DG), 625 mumol/kg i.v., were studied in six conscious trained gastric fistula dogs. During a 2-hr infusion, Met-enkephalin (96 nmol/kg/hr; delta receptor) reduced the 2DG response by 50%; when the enkephalin was stopped there was a rapid rebound to peak values. Met-enkephalin also blocked the release of gastrin in the first 15 min. By itself, Met-enkephalin did not stimulate secretion and slightly depressed gastrin. By contrast, morphine (96 nmol/kg/hr; mu receptor) augmented and sustained the 2DG gastric acid secretory response. This effect was blocked by naloxone. Morphine alone caused a small rise in serum gastrin after 90 min, followed by a delayed gastric acid secretion of about 30% of the peak 2DG response. Naloxone, a mu opiate antagonist (mu/delta, 27:1), also inhibited the 2DG gastric secretory response by about 50% and augmented the Met-enkephalin inhibition of secretion without blocking either the secretory rebound or the effect on gastrin release. None of the three opiates changed the direct cholinergic gastric secretory or gastrin-releasing effects of bethanechol. Thus, vagal stimulation of the stomach involves pathways which can be influenced by both mu and delta opiates, with apparently opposite effects, proximal to the level of acetylcholine action on the gastric mucosa. The central and peripheral control points in the activation of the stomach via the vagus which are sensitive to opiates have yet to be located and explained.

Metabolism and inactivation of gastrin releasing peptide by endopeptidase-24.11 in the dog.

PubMed

Bunnett, N W; Turner, A J; Debas, H T

1989-09-01

The purpose of this investigation was to examine the metabolism and inactivation of gastrin releasing peptide 10 (GRP10) by endopeptidase-24.11 prepared from the stomach wall. GRP10 was metabolized in vitro by gastric endopeptidase-24.11. The metabolites were purified by high-pressure liquid chromatography and identified as (1-8) GRP10 and (9-10) GRP10 by amino acid analysis, indicating hydrolysis of the His8-Leu9 bond. The intravenous administration of GRP10 to conscious dogs stimulated gastrin release, gastric acid secretion, pancreatic protein secretion and pancreatic bicarbonate secretion. Incubation of GRP10 with endopeptidase-24.11 significantly diminished the biological activity of the digests compared to control digests containing heat-inactivated enzyme. This effect was abolished by the enzyme inhibitor phosphoramidon. It is concluded that endopeptidase-24.11 from the stomach metabolizes and inactivates GRP10.

Unexpectedly increased anorexigenic postprandial responses of PYY and GLP-1 to fast ice cream consumption in adult patients with Prader-Willi syndrome.

PubMed

Rigamonti, A E; Bini, S; Grugni, G; Agosti, F; De Col, A; Mallone, M; Cella, S G; Sartorio, A

2014-10-01

The effect of eating rate on the release of anorexigenic gut peptides in Prader-Willi syndrome (PWS), a neurogenetic disorder clinically characterized by hyperphagia and excessive obesity, has not been investigated so far. Postprandial PYY and GLP-1 levels to fast (5 min) and slow (30 min) ice cream consumption were measured in PWS adult patients and age-matched patients with simple obesity and normal-weighted subjects. Visual analog scales (VASs) were used to evaluate the subjective feelings of hunger and satiety. Fast ice cream consumption stimulated GLP-1 release in normal subjects, a greater increase being observed with slow feeding. Fast or slow feeding did not change circulating levels of GLP-1 in obese patients, while, unexpectedly, fast feeding (but not slow feeding) stimulated GLP-1 release in PWS patients. Plasma PYY concentrations increased in all groups, irrespective of the eating rate. Slow feeding was more effective in stimulating PYY release in normal subjects, while fast feeding was more effective in PWS patients. Slow feeding evoked a lower hunger and higher satiety compared with fast feeding in normal subjects, this finding being not evident in obese patients. Unexpectedly, fast feeding evoked a lower hunger and higher satiety in PWS patients in comparison with slow feeding. Fast feeding leads to higher concentrations of anorexigenic gut peptides and favours satiety in PWS adult patients, this pattern being not evident in age-matched patients with simple obesity, thus suggesting the existence of a different pathophysiological substrate in these two clinical conditions. © 2013 John Wiley & Sons Ltd.

Cloning and characterization of cDNAs encoding human gastrin-releasing peptide.

PubMed Central

Spindel, E R; Chin, W W; Price, J; Rees, L H; Besser, G M; Habener, J F

1984-01-01

We have prepared and cloned cDNAs derived from poly(A)+ RNA from a human pulmonary carcinoid tumor rich in immunoreactivity to gastrin-releasing peptide, a peptide closely related in structure to amphibian bombesin. Mixtures of synthetic oligodeoxyribonucleotides corresponding to amphibian bombesin were used as hybridization probes to screen a cDNA library prepared from the tumor RNA. Sequencing of the recombinant plasmids shows that human gastrin-releasing peptide (hGRP) mRNA encodes a precursor of 148 amino acids containing a typical signal sequence, hGRP consisting of 27 or 28 amino acids, and a carboxyl-terminal extension peptide. hGRP is flanked at its carboxyl terminus by two basic amino acids, following a glycine used for amidation of the carboxyl-terminal methionine. RNA blot analyses of tumor RNA show a major mRNA of 900 bases and a minor mRNA of 850 bases. Blot hybridization analyses using human genomic DNA are consistent with a single hGRP-encoding gene. The presence of two mRNAs encoding the hGRP precursor protein in the face of a single hGRP gene raises the possibility of alternative processing of the single RNA transcript. Images PMID:6207529

Evaluation of Gastric pH and Serum Gastrin Concentrations in Cats with Chronic Kidney Disease.

PubMed

Tolbert, M K; Olin, S; MacLane, S; Gould, E; Steiner, J M; Vaden, S; Price, J

2017-09-01

Chronic kidney disease (CKD) is a highly prevalent condition in cats. Advanced CKD is associated with hyporexia and vomiting, which typically are attributed to uremic toxins and gastric hyperacidity. However, gastric pH studies have not been performed in cats with CKD. To determine if cats with CKD have decreased gastric pH compared to age-matched, healthy cats. Based on previous work demonstrating an association of hypergastrinemia and CKD, we hypothesized that cats with CKD would have decreased gastric pH compared to healthy, age-matched control cats. 10 CKD cats; 9 healthy control cats. All cats with concurrent disease were excluded on the basis of history, physical examination, CBC, plasma biochemistry profile, urinalysis, urine culture, serum total thyroxine concentration, and serum symmetric dimethylarginine concentration (controls only) obtained within 24 hours of pH monitoring and assessment of serum gastrin concentrations. Serum for gastrin determination was collected, and 12-hour continuous gastric pH monitoring was performed in all cats. Serum gastrin concentration, mean pH, and percentage time that gastric pH was strongly acidic (pH <1 and <2) were compared between groups. No significant differences in serum gastrin concentrations were observed between groups (medians [range]: CKD, 18.7 ng/dL [<10-659.0]; healthy, 54.6 ng/dL [<10-98.0]; P-value = 0.713) or of any pH parameters including mean ± SD gastric pH (CKD, 1.8 ± 0.5; healthy, 1.6 ± 0.3; P-value = 0.23). These findings suggest that cats with CKD may not have gastric hyperacidity compared to healthy cats and, therefore, may not need acid suppression. Thus, further studies to determine if there is a benefit to acid suppression in cats with CKD are warranted. Copyright © 2017 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.

CacyBP/SIP nuclear translocation induced by gastrin promotes gastric cancer cell proliferation

PubMed Central

Zhai, Hui-Hong; Meng, Juan; Wang, Jing-Bo; Liu, Zhen-Xiong; Li, Yuan-Fei; Feng, Shan-Shan

2014-01-01

AIM: To investigate the role of nuclear translocation of calcyclin binding protein, also called Siah-1 interacting protein (CacyBP/SIP), in gastric carcinogenesis. METHODS: The expression of CacyBP/SIP protein in gastric cancer cell lines was detected by Western blot. Immunofluorescence experiments were performed on gastric cancer cell lines that had been either unstimulated or stimulated with gastrin. To confirm the immunofluorescence findings, the relative abundance of CacyBP/SIP in nuclear and cytoplasmic compartments was assessed by Western blot. The effect of nuclear translocation of CacyBP/SIP on cell proliferation was examined using MTT assay. The colony formation assay was used to measure clonogenic cell survival. The effect of CacyBP/SIP nuclear translocation on cell cycle progression was investigated. Two CacyBP/SIP-specific siRNA vectors were designed and constructed to inhibit CacyBP/SIP expression in order to reduce the nuclear translocation of CacyBP/SIP, and the expression of CacyBP/SIP in stably transfected cells was determined by Western blot. The effect of inhibiting CacyBP/SIP nuclear translocation on cell proliferation was then assessed. RESULTS: CacyBP/SIP protein was present in most of gastric cancer cell lines. In unstimulated cells, CacyBP/SIP was distributed throughout the cytoplasm; while in stimulated cells, CacyBP/SIP was found mainly in the perinuclear region. CacyBP/SIP nuclear translocation generated a growth-stimulatory effect on cells. The number of colonies in the CacyBP/SIP nuclear translocation group was significantly higher than that in the control group. The percentage of stimulated cells in G1 phase was significantly lower than that of control cells (69.70% ± 0.46% and 65.80% ± 0.60%, control cells and gastrin-treated SGC7901 cells, P = 0.008; 72.99% ± 0.46% and 69.36% ± 0.51%, control cells and gastrin-treated MKN45 cells, P = 0.022). CacyBP/SIPsi1 effectively down-regulated the expression of CacyBP/SIP, and cells stably

CacyBP/SIP nuclear translocation induced by gastrin promotes gastric cancer cell proliferation.

PubMed

Zhai, Hui-Hong; Meng, Juan; Wang, Jing-Bo; Liu, Zhen-Xiong; Li, Yuan-Fei; Feng, Shan-Shan

2014-08-07

To investigate the role of nuclear translocation of calcyclin binding protein, also called Siah-1 interacting protein (CacyBP/SIP), in gastric carcinogenesis. The expression of CacyBP/SIP protein in gastric cancer cell lines was detected by Western blot. Immunofluorescence experiments were performed on gastric cancer cell lines that had been either unstimulated or stimulated with gastrin. To confirm the immunofluorescence findings, the relative abundance of CacyBP/SIP in nuclear and cytoplasmic compartments was assessed by Western blot. The effect of nuclear translocation of CacyBP/SIP on cell proliferation was examined using MTT assay. The colony formation assay was used to measure clonogenic cell survival. The effect of CacyBP/SIP nuclear translocation on cell cycle progression was investigated. Two CacyBP/SIP-specific siRNA vectors were designed and constructed to inhibit CacyBP/SIP expression in order to reduce the nuclear translocation of CacyBP/SIP, and the expression of CacyBP/SIP in stably transfected cells was determined by Western blot. The effect of inhibiting CacyBP/SIP nuclear translocation on cell proliferation was then assessed. CacyBP/SIP protein was present in most of gastric cancer cell lines. In unstimulated cells, CacyBP/SIP was distributed throughout the cytoplasm; while in stimulated cells, CacyBP/SIP was found mainly in the perinuclear region. CacyBP/SIP nuclear translocation generated a growth-stimulatory effect on cells. The number of colonies in the CacyBP/SIP nuclear translocation group was significantly higher than that in the control group. The percentage of stimulated cells in G1 phase was significantly lower than that of control cells (69.70% ± 0.46% and 65.80% ± 0.60%, control cells and gastrin-treated SGC7901 cells, P = 0.008; 72.99% ± 0.46% and 69.36% ± 0.51%, control cells and gastrin-treated MKN45 cells, P = 0.022). CacyBP/SIPsi1 effectively down-regulated the expression of CacyBP/SIP, and cells stably transfected by Cacy

YY v TURKEY: INFERTILITY AS A PRE-CONDITION FOR GENDER CONFIRMATION SURGERY.

PubMed

Dunne, Peter

2015-01-01

In YY v Turkey, the Second Chamber of the European Court of Human Rights (ECtHR) held that Turkey's refusal, over a period of many years, to authorise gender confirmation surgery because the applicant remained capable of procreating was a violation of the right to private life under Art. 8 of the European Convention on Human Rights. The Second Chamber's judgment acknowledges, and gives practical effect to, the 'physical and moral security' of transgender persons. YY has the potential to revolutionise gender confirming health care in Europe and will hopefully ensure that, where individuals do seek to medically transition, they need only access to treatments that are both necessary and desired. The ECtHR's decision may also impact upon the legal recognition of transgender identities. While not the direct focus of the Second Chamber's assessment, legal gender recognition is a constant theme throughout the judgment, and many of the Court's arguments are equally applicable to legal schemes for acknowledging preferred gender. © The Author 2015. Published by Oxford University Press; all rights reserved. For Permissions, please email: journals.permissions@oup.com.

YY1 binding association with sex-biased transcription revealed through X-linked transcript levels and allelic binding analyses

PubMed Central

Chen, Chih-yu; Shi, Wenqiang; Balaton, Bradley P.; Matthews, Allison M.; Li, Yifeng; Arenillas, David J.; Mathelier, Anthony; Itoh, Masayoshi; Kawaji, Hideya; Lassmann, Timo; Hayashizaki, Yoshihide; Carninci, Piero; Forrest, Alistair R. R.; Brown, Carolyn J.; Wasserman, Wyeth W.

2016-01-01

Sex differences in susceptibility and progression have been reported in numerous diseases. Female cells have two copies of the X chromosome with X-chromosome inactivation imparting mono-allelic gene silencing for dosage compensation. However, a subset of genes, named escapees, escape silencing and are transcribed bi-allelically resulting in sexual dimorphism. Here we conducted in silico analyses of the sexes using human datasets to gain perspectives into such regulation. We identified transcription start sites of escapees (escTSSs) based on higher transcription levels in female cells using FANTOM5 CAGE data. Significant over-representations of YY1 transcription factor binding motif and ChIP-seq peaks around escTSSs highlighted its positive association with escapees. Furthermore, YY1 occupancy is significantly biased towards the inactive X (Xi) at long non-coding RNA loci that are frequent contacts of Xi-specific superloops. Our study suggests a role for YY1 in transcriptional activity on Xi in general through sequence-specific binding, and its involvement at superloop anchors. PMID:27857184

DNA breathing dynamics distinguish binding from nonbinding consensus sites for transcription factor YY1 in cells.

PubMed

Alexandrov, Boian S; Fukuyo, Yayoi; Lange, Martin; Horikoshi, Nobuo; Gelev, Vladimir; Rasmussen, Kim Ø; Bishop, Alan R; Usheva, Anny

2012-11-01

The genome-wide mapping of the major gene expression regulators, the transcription factors (TFs) and their DNA binding sites, is of great importance for describing cellular behavior and phenotypic diversity. Presently, the methods for prediction of genomic TF binding produce a large number of false positives, most likely due to insufficient description of the physiochemical mechanisms of protein-DNA binding. Growing evidence suggests that, in the cell, the double-stranded DNA (dsDNA) is subject to local transient strands separations (breathing) that contribute to genomic functions. By using site-specific chromatin immunopecipitations, gel shifts, BIOBASE data, and our model that accurately describes the melting behavior and breathing dynamics of dsDNA we report a specific DNA breathing profile found at YY1 binding sites in cells. We find that the genomic flanking sequence variations and SNPs, may exert long-range effects on DNA dynamics and predetermine YY1 binding. The ubiquitous TF YY1 has a fundamental role in essential biological processes by activating, initiating or repressing transcription depending upon the sequence context it binds. We anticipate that consensus binding sequences together with the related DNA dynamics profile may significantly improve the accuracy of genomic TF binding sites and TF binding-related functional SNPs.

Selective targeting of the repressive transcription factors YY1 and cMyc to disrupt quiescent human immunodeficiency viruses.

PubMed

Barton, Kirston; Margolis, David

2013-02-01

Quiescent HIV-1 infection of resting CD4(+) T cells is an obstacle to eradication of HIV-1 infection. These reservoirs are maintained, in part, by repressive complexes that bind to the HIV-1 long terminal repeat (LTR) and recruit histone deacetylases (HDACs). cMyc and YY1 are two transcription factors that are recruited as part of well-described, distinct complexes to the HIV-1 LTR and in turn recruit HDACs. In prior studies, depletion of single factors that recruit HDAC1 in various cell lines was sufficient to upregulate LTR activity. We used short hairpin RNAs (shRNAs) to test the effect of targeted disruption of a single transcription factor on quiescent proviruses in T cell lines. In this study, we found that depletion of YY1 significantly increases mRNA and protein expression from the HIV-1 promoter in some contexts, but does not affect HDAC1, HDAC2, HDAC3, or acetylated histone 3 occupancy of the HIV-1 LTR. Conversely, depletion of cMyc or cMyc and YY1 does not significantly alter the level of transcription from the LTR or affect recruitment of HDACs to the HIV-1 LTR. Furthermore, global inhibition of HDACs with the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) enhanced the increase in LTR transcription in cells that were depleted of YY1.These findings show that despite prior isolated findings, redundancy in repressors of HIV-1 LTR expression will require selective targeting of multiple restrictive mechanisms to comprehensively induce the escape of quiescent proviruses from latency.

The effect of the mammalian neuropeptide, gastrin-releasing peptide (GRP), on gastrointestinal and pancreatic hormone secretion in man.

PubMed

Wood, S M; Jung, R T; Webster, J D; Ghatei, M A; Adrian, T E; Yanaihara, N; Yanaihara, C; Bloom, S R

1983-10-01

Gastrin-releasing peptide, a newly isolated mammalian peptide similar in its structure and actions to the amphibian peptide, bombesin, has recently been localized to nerves in the brain, gut and pancreas. The present study investigates its effects on gut and pancreatic peptides in man. Intravenous infusion of 0.7 and 2.9 pmol min-1 kg-1 produced significant elevation of plasma gastrin, cholecystokinin-like immunoreactivity and neurotensin. It was found also to potentiate glucose-dependent insulin secretion. Its specific location in nerve fibres in the proximal gut and pancreas and its selective effect on gastroenteropancreatic peptides may favour its role as a physiological regulatory neuropeptide.

Fasting lowers gastrin-releasing peptide and Fsh mRNA in the ovine anterior pituitary gland

USDA-ARS?s Scientific Manuscript database

Estrogen receptor beta (ER-ß), LH, and FSH are important mediators of reproduction. FSH stimulates follicle recruitment and development. During anorexia, serum concentrations of FSH and LH decrease. Gastrin-releasing peptide (GRP), neuromedin B (NMB), peroxisome proliferator-activated receptor-gamma...

Fasting lowers gastrin-releasing peptide and FSH mRNA in the ovine anterior pituitary gland

USDA-ARS?s Scientific Manuscript database

Estrogen receptor beta (ER-ß), LH, and FSH are important mediators of reproduction. FSH stimulates follicle recruitment and development. During anorexia, serum concentrations of FSH and LH decrease. Gastrin-releasing peptide (GRP), neuromedin B (NMB), peroxisome proliferator-activated receptor-gamma...

Diacylglycerol Acyltransferase-1 (DGAT1) Inhibition Perturbs Postprandial Gut Hormone Release

PubMed Central

Lin, Hua V.; Chen, Dunlu; Shen, Zhu; Zhu, Lei; Ouyang, Xuesong; Vongs, Aurawan; Kan, Yanqing; Levorse, John M.; Kowalik, Edward J.; Szeto, Daphne M.; Yao, Xiaorui; Xiao, Jianying; Chen, Shirley; Liu, Jinqi; Garcia-Calvo, Marga; Shin, Myung K.; Pinto, Shirly

2013-01-01

Diacylglycerol acyltransferase-1 (DGAT1) is a potential therapeutic target for treatment of obesity and related metabolic diseases. However, the degree of DGAT1 inhibition required for metabolic benefits is unclear. Here we show that partial DGAT1 deficiency in mice suppressed postprandial triglyceridemia, led to elevations in glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) only following meals with very high lipid content, and did not protect from diet-induced obesity. Maximal DGAT1 inhibition led to enhanced GLP-1 and PYY secretion following meals with physiologically relevant lipid content. Finally, combination of DGAT1 inhibition with dipeptidyl-peptidase-4 (DPP-4) inhibition led to further enhancements in active GLP-1 in mice and dogs. The current study suggests that targeting DGAT1 to enhance postprandial gut hormone secretion requires maximal inhibition, and suggests combination with DPP-4i as a potential strategy to develop DGAT1 inhibitors for treatment of metabolic diseases. PMID:23336002

Effects of gonadotropin-releasing hormone (GnRH) on gastric secretion and gastrin release in the dog.

PubMed

Soldani, G; Del Tacca, M; Bambini, G; Polloni, A; Bernardini, C; Martinotti, E; Martino, E

1982-01-01

The effects of GnRH on gastric secretion and gastrin release from dogs provided with gastric fistulae and Heidenhain pouches have been investigated. A transient yet significant inhibition of pentagastrin-stimulated secretion from gastric fistulae was observed, while secretion from Heidenhain pouches was unchanged. The maximal inhibitory effect of GnRH on both acid and pepsin secretion stimulated by 2-deoxy-D-glucose was obtained from gastric fistulae. On the contrary, GnRH failed to affect either acid secretion stimulated by bethanechol or acid secretion and gastrin release induced by bombesin. The present results indicate that GnRH possesses an inhibitory action on gastric secretion from the vagally innervated stomach of the dog. The most likely inhibitory mechanism seems to be represented by a decrease of the vagal activity.

Rituximab-induced inhibition of YY1 and Bcl-xL expression in Ramos non-Hodgkin's lymphoma cell line via inhibition of NF-kappa B activity: role of YY1 and Bcl-xL in Fas resistance and chemoresistance, respectively.

PubMed

Vega, Mario I; Jazirehi, Ali R; Huerta-Yepez, Sara; Bonavida, Benjamin

2005-08-15

Rituximab treatment of B non-Hodgkin's lymphoma (NHL) cell lines inhibits the constitutive NF-kappaB activity and results in the sensitization of tumor cells to both chemotherapy and Fas-induced apoptosis. Cells expressing dominant active IkappaB or treated with NF-kappaB-specific inhibitors were sensitive to both drugs and Fas agonist mAb (CH-11)-induced apoptosis. Down-regulation of Bcl-xL expression via inhibition of NF-kappaB activity correlated with chemosensitivity. The direct role of Bcl-xL in chemoresistance was demonstrated by the use of Bcl-xL-overexpressing Ramos cells, Ramos hemagglutinin (HA)-Bcl-x, which were not sensitized by rituximab to drug-induced apoptosis. However, inhibition of Bcl-xL in Ramos HA-Bcl-x resulted in sensitization to drug-induced apoptosis. The role of Bcl-xL expression in the regulation of Fas resistance was not apparent; Ramos HA-Bcl-x cells were as sensitive as the wild type to CH-11-induced apoptosis. Several lines of evidence support the direct role of the transcription repressor yin-yang 1 (YY1) in the regulation of resistance to CH-11-induced apoptosis. Inhibition of YY1 activity by either rituximab or the NO donor DETANONOate or after transfection with YY1 small interfering RNA resulted in up-regulation of Fas expression and sensitization to CH-11-induced apoptosis. These findings suggest two mechanisms underlying the chemosensitization and immunosensitization of B-NHL cells by rituximab via inhibition of NF-kappaB. The regulation of chemoresistance by NF-kappaB is mediated via Bcl-xL expression, whereas the regulation of Fas resistance by NF-kappaB is mediated via YY1 expression and activity. The potential clinical significance of these findings is discussed.

Impact of Exercise and Dietary Fatty Acid Composition from a High-fat Diet on Markers of Hunger and Satiety

PubMed Central

Cooper, JA; Watras, AC; Paton, CM; Wegner, FH; Adams, AK; Schoeller, DA

2014-01-01

Objective To compare the effects of both dietary fatty acid composition and exercise vs. sedentary conditions on circulating levels of hunger and satiety hormones. Eight healthy males were randomized in a 2×2 crossover design. The four treatments were 3 days of HF diets (50% of energy) containing high saturated fat (22% of energy) with exercise (SE) or sedentary (SS) conditions, and high monounsaturated fat (30% of energy) with exercise (UE) or sedentary (US) conditions. Cycling exercise was completed at 45% of VO2max for 2h daily. On the third HF day, 20 blood specimens were drawn over a 24h period for each hormone (leptin, insulin, ghrelin, and peptide YY (PYY)). A visual analog scale (VAS) was completed hourly between 0800 and 2200. Average 24h leptin and insulin levels were lower while 24h PYY was higher during exercise vs sedentary conditions. FA composition did not differentially affect 24h hormone values. VAS scores for hunger and fullness did not differ between any treatment but did correlate with ghrelin, leptin, and insulin. High saturated or unsaturated fat diets did not differ with respect to markers of hunger or satiety. Exercise decreased 24h leptin and insulin while increasing PYY regardless of FA composition. PMID:21035513

Metabolic profiling in Prader-Willi syndrome and nonsyndromic obesity: sex differences and the role of growth hormone.

PubMed

Irizarry, Krystal A; Bain, James; Butler, Merlin G; Ilkayeva, Olga; Muehlbauer, Michael; Haqq, Andrea M; Freemark, Michael

2015-12-01

To identify metabolic factors controlling appetite and insulin sensitivity in PWS and assess effects of GH treatment. We compared amino acids, fatty acids and acylcarnitines in GH-treated and untreated PWS children and obese and lean controls to identify biomarkers associated with ghrelin, peptide YY and markers of insulin sensitivity (adiponectin and HOMA-IR). Compared with obese controls (OC), children with PWS had fasting hyperghrelinaemia, hyperadiponectinaemia, hypoinsulinaemia and increased ghrelin/PYY. Hyperghrelinaemia, hyperadiponectinaemia and hypoinsulinaemia were more striking in PWS females than males, and decreases in BCAA were detected only in PWS females. GH-treated PWS subjects had lower leptin and higher IGF-1 and adiponectin than untreated subjects; fasting ghrelin, PYY and insulin levels were comparable. Ghrelin correlated inversely with BCAA in PWS but not OC. Adiponectin correlated negatively with BMIz and HOMA-IR in PWS; in contrast, adiponectin correlated more strongly with BCAA than BMIz or HOMA-IR in OC. BCAA levels were lower in PWS females than OC females and correlated inversely with ghrelin. Low BCAA in PWS females may promote hyperghrelinaemia and hyperphagia, while hyperadiponectinaemia may maintain insulin sensitivity despite excess weight gain. GH treatment may reduce leptin and increase adiponectin, but does not affect fasting ghrelin or PYY. © 2015 John Wiley & Sons Ltd.

Metabolic profiling in Prader-Willi syndrome and non-syndromic obesity: sex differences and the role of growth hormone

PubMed Central

Irizarry, Krystal A.; Bain, James; Butler, Merlin G.; Ilkayeva, Olga; Muehlbauer, Michael; Haqq, Andrea M.; Freemark, Michael

2015-01-01

Objectives To identify metabolic factors controlling appetite and insulin sensitivity in PWS and assess effects of GH treatment. Methods We compared amino acids, fatty acids, and acylcarnitines in GH-treated and untreated PWS children and obese and lean controls to identify biomarkers associated with ghrelin, peptide YY, and markers of insulin sensitivity (adiponectin and HOMA-IR). Results Compared with obese controls (OC), children with PWS had hyperghrelinemia, hyperadiponectinemia, hypoinsulinemia, and increased ghrelin/PYY. Hyperghrelinemia, hyperadiponectinemia, and hypoinsulinemia were more striking in PWS females than males and decreases in BCAA were detected only in PWS females. GH-treated PWS subjects had lower leptin and higher IGF-1 and adiponectin than untreated subjects; ghrelin, PYY, and insulin levels were comparable. Ghrelin correlated inversely with BCAA in PWS but not OC. Adiponectin correlated negatively with BMIz and HOMA-IR in PWS; in contrast, adiponectin correlated more strongly with BCAA than BMIz or HOMA-IR in OC. Conclusions BCAA levels were lower in PWS females than OC females and correlated inversely with ghrelin. Low BCAA in PWS females may promote hyperghrelinemia and hyperphagia, while hyperadiponectinemia may maintain insulin sensitivity despite excess weight gain. GH treatment may reduce leptin and increase adiponectin, but does not affect ghrelin or PYY. PMID:25736874

Ghrelin, CCK, GLP-1, and PYY(3-36): Secretory Controls and Physiological Roles in Eating and Glycemia in Health, Obesity, and After RYGB.

PubMed

Steinert, Robert E; Feinle-Bisset, Christine; Asarian, Lori; Horowitz, Michael; Beglinger, Christoph; Geary, Nori

2017-01-01

The efficacy of Roux-en-Y gastric-bypass (RYGB) and other bariatric surgeries in the management of obesity and type 2 diabetes mellitus and novel developments in gastrointestinal (GI) endocrinology have renewed interest in the roles of GI hormones in the control of eating, meal-related glycemia, and obesity. Here we review the nutrient-sensing mechanisms that control the secretion of four of these hormones, ghrelin, cholecystokinin (CCK), glucagon-like peptide-1 (GLP-1), and peptide tyrosine tyrosine [PYY(3-36)], and their contributions to the controls of GI motor function, food intake, and meal-related increases in glycemia in healthy-weight and obese persons, as well as in RYGB patients. Their physiological roles as classical endocrine and as locally acting signals are discussed. Gastric emptying, the detection of specific digestive products by small intestinal enteroendocrine cells, and synergistic interactions among different GI loci all contribute to the secretion of ghrelin, CCK, GLP-1, and PYY(3-36). While CCK has been fully established as an endogenous endocrine control of eating in healthy-weight persons, the roles of all four hormones in eating in obese persons and following RYGB are uncertain. Similarly, only GLP-1 clearly contributes to the endocrine control of meal-related glycemia. It is likely that local signaling is involved in these hormones' actions, but methods to determine the physiological status of local signaling effects are lacking. Further research and fresh approaches are required to better understand ghrelin, CCK, GLP-1, and PYY(3-36) physiology; their roles in obesity and bariatric surgery; and their therapeutic potentials. Copyright © 2017 the American Physiological Society.

Acute increases in serum colonic short-chain fatty acids elicited by inulin do not increase GLP-1 or PYY responses but may reduce ghrelin in lean and overweight humans.

PubMed

Rahat-Rozenbloom, S; Fernandes, J; Cheng, J; Wolever, T M S

2017-08-01

Colonic fermentation of dietary fibre to short-chain fatty acids (SCFA) influences appetite hormone secretion in animals, but SCFA production is excessive in obese animals. This suggests there may be resistance to the effect of SCFA on appetite hormones in obesity. To determine the effects of inulin (IN) and resistant starch (RS) on postprandial SCFA, and gut hormone (glucagon-like peptide (GLP-1), peptide-tyrosine-tyrosine (PYY) and ghrelin) responses in healthy overweight/obese (OWO) vs lean (LN) humans. Overnight-fasted participants (13 OWO and 12 LN) consumed 300 ml water containing 75 g glucose (GLU) as control or 75 g GLU plus 24 g IN, or 28.2 g RS using a randomised, single-blind, cross-over design. Blood for appetite hormones and SCFA was collected at intervals over 6 h. A standard lunch was served 4 h after the test drink. Relative to GLU, IN, but not RS, significantly increased SCFA areas under the curve (AUC) from 4-6 h (AUC 4-6 ). Neither IN nor RS affected GLP-1 or PYY-AUC 4-6 . Although neither IN nor RS reduced ghrelin-AUC 4-6 compared with GLU, ghrelin at 6 h after IN was significantly lower than that after GLU (P<0.05). After IN, relative to GLU, the changes in SCFA-AUC 4-6 were negatively related to the changes in ghrelin-AUC 4-6 (P=0.017). SCFA and hormone responses did not differ significantly between LN and OWO. Acute increases in colonic SCFA do not affect GLP-1 or PYY responses in LN or OWO subjects, but may reduce ghrelin. The results do not support the hypothesis that SCFA acutely stimulate PYY and GLP-1 secretion; however, a longer adaptation to increased colonic fermentation or a larger sample size may yield different results.

[Effect of sibutramine (meridia) on body composition, peptide YY3-36 and serotonin levels in patients with exogenous constitutional obesity].

PubMed

Vlasova, Iu Iu; Ametov, A S

2010-01-01

To evaluate the impact of gradual weight loss and the positive effect of sibutramine on metabolic parameters and the levels of serotonin and neuropeptide YY3-36 levels in patients with exogenous constitutional obesity (ECO). The study included 36 patients (24 women and 12 men; mean age 37.56 +/- 0.9 years) with a verified diagnosis of ECO. The height, body weight, waist and hip circumference (WC and HC), and body mass index (BMI) were determined. Adipose tissue content was estimated by a bioimpedance method using an adipose mass analyzer. Serum peptide YY3-36 levels were measured by enzyme immunoassay and blood serotonin concentrations were estimated by high performance liquid chromatography with an electrochemical method. 12-week sibutramine therapy caused a significant reduction in body weight, WC, HC, and BMI (p < 0.05) in all the patients. At the same time they were found to have a considerable body composition change (total body and visceral fat was decreased, total body water increased, and systemic metabolism was lowered). The mean peptide YY3-36 level was significantly decreased. Sibutramine did not affect the serum content of total serotonin in the sera of patients. Sibutramine used in the combined therapy in patients with ECO contributes to an effective and steady-state weight loss. Sibutramine treatment causes a reduction in total neuropeptide YY3-36, systemic metabolism, and adipose tissue at the expense of the visceral depot.

The Ku Protein Complex Interacts with YY1, Is Up-Regulated in Human Heart Failure, and Represses α Myosin Heavy-Chain Gene Expression

PubMed Central

Sucharov, Carmen C.; Helmke, Steve M.; Langer, Stephen J.; Perryman, M. Benjamin; Bristow, Michael; Leinwand, Leslie

2004-01-01

Human heart failure is accompanied by repression of genes such as α myosin heavy chain (αMyHC) and SERCA2A and the induction of fetal genes such as βMyHC and atrial natriuretic factor. It seems likely that changes in MyHC isoforms contribute to the poor contractility seen in heart failure, because small changes in isoform composition can have a major effect on the contractility of cardiac myocytes and the heart. Our laboratory has recently shown that YY1 protein levels are increased in human heart failure and that YY1 represses the activity of the human αMyHC promoter. We have now identified a region of the αMyHC promoter that binds a factor whose expression is increased sixfold in failing human hearts. Through peptide mass spectrometry, we identified this binding activity to be a heterodimer of Ku70 and Ku80. Expression of Ku represses the human αMyHC promoter in neonatal rat ventricular myocytes. Moreover, overexpression of Ku70/80 decreases αMyHC mRNA expression and increases skeletal α-actin. Interestingly, YY1 interacts with Ku70 and Ku80 in HeLa cells. Together, YY1, Ku70, and Ku80 repress the αMyHC promoter to an extent that is greater than that with YY1 or Ku70/80 alone. Our results suggest that Ku is an important factor in the repression of the human αMyHC promoter during heart failure. PMID:15367688

Repression of PDGF-R-α after cellular injury involves TNF-α, formation of a c-Fos-YY1 complex, and negative regulation by HDAC.

PubMed

Zhang, Ning; Chan, Cecilia W S; Sanchez-Guerrero, Estella; Khachigian, Levon M

2012-06-01

Wound healing is a complex dynamic process involving a variety of cell types, including fibroblasts that express and respond to cytokines and growth factors in the local microenvironment. The mechanisms controlling gene expression after injury at a transcriptional level are poorly understood. Here we show that decreased expression of a key receptor, PDGF-receptor (R)-α, after fibroblast injury is due to the release and paracrine activity of TNF-α. TNF-α inhibits PDGF-R-α expression and this involves formation of a c-Fos-Yin Yang 1 (YY1) complex and histone deacetylase (HDAC) activity. c-Fos, induced by TNF-α, negatively regulates PDGF-R-α transcription. Small interfering RNA (siRNA) targeting c-Fos or the zinc finger transcription factor YY1 inhibits TNF-α suppression of PDGF-R-α expression. Coimmunoprecipitation studies show that TNF-α stimulates the formation of a complex between c-Fos with YY1. Furthermore, chromatin immunoprecipitation (ChIP) analysis reveals the enrichment of c-Fos, YY1, and HDAC-1 at the PDGF-R-α promoter in cells exposed to TNF-α. With suberoylanilide hydroxamic acid (SAHA) and HDAC-1 siRNA, we demonstrate that HDAC mediates TNF-α repression of PDGF-R-α. These findings demonstrate that transcriptional repression of PDGF-R-α after fibroblast injury involves paracrine activity of endogenous TNF-α, the formation of a c-Fos-YY1 complex, and negative regulatory activity by HDAC.

(99m)Tc-labeled gastrins of varying peptide chain length: Distinct impact of NEP/ACE-inhibition on stability and tumor uptake in mice.

PubMed

Kaloudi, Aikaterini; Nock, Berthold A; Lymperis, Emmanouil; Krenning, Eric P; de Jong, Marion; Maina, Theodosia

2016-06-01

In situ inhibition of neutral endopeptidase (NEP) has been recently shown to impressively increase the bioavailability and tumor uptake of biodegradable gastrin radioligands. Furthermore, angiotensin converting enzyme (ACE) has been previously shown to cleave gastrin analogs in vitro. In the present study, we have assessed the effects induced by single or dual NEP/ACE-inhibition on the pharmacokinetic profile of three (99m)Tc-labeled gastrins of varying peptide chain length: [(99m)Tc]SG6 ([(99m)Tc-N4-Gln(1)]gastrin(1-17)), [(99m)Tc]DG2 ([(99m)Tc-N4-Gly(4),DGlu(5)]gastrin(4-17)) and [(99m)Tc]DG4 ([(99m)Tc-N4-DGlu(10)]gastrin(10-17)). Mouse blood samples were collected 5min after injection of each of [(99m)Tc]SG6/DG2/DG4 together with: a) vehicle, b) the NEP-inhibitor phosphoramidon (PA), c) the ACE-inhibitor lisinopril (Lis), or d) PA plus Lis and were analyzed by RP-HPLC for radiometabolite detection. Biodistribution was studied in SCID mice bearing A431-CCK2R(+/-) xenografts at 4h postinjection (pi). [(99m)Tc]SG6 or [(99m)Tc]DG4 was coinjected with either vehicle or the above described NEP/ACE-inhibitor regimens; for [(99m)Tc]DG2 control and PA animal groups were only included. Treatment of mice with PA induced significant stabilization of (99m)Tc-radiotracers in peripheral blood, while treatment with Lis or Lis+PA affected the stability of des(Glu)5 [(99m)Tc]DG4 only. In line with these findings, PA coinjection led to notable amplification of tumor uptake of radiopeptides compared to controls (P<0.01). Only [(99m)Tc]DG4 profited by single Lis (2.06±0.39%ID/g vs 0.99±0.13%ID/g in controls) or combined Lis+PA coinjection (8.91±1.61%ID/g vs 4.89±1.33%ID/g in PA-group). Furthermore, kidney uptake remained favourably low and unaffected by PA and/or Lis coinjection only in the case of [(99m)Tc]DG4 (<1.9%ID/g) resulting in the most optimal tumor-to-kidney ratios. In situ NEP/ACE-inhibition diversely affected the in vivo profile of (99m)Tc-radioligands based on

Changes in Gastrointestinal Hormones and Leptin After Roux-en-Y Gastric Bypass Surgery

PubMed Central

Beckman, Lauren M.; Beckman, Tiffany R.; Sibley, Shalamar D.; Thomas, William; Ikramuddin, Sayeed; Kellogg, Todd A.; Ghatei, Mohammad A.; Bloom, Stephen R.; le Roux, Carel W.; Earthman, Carrie P.

2014-01-01

Background Roux-en-Y gastric bypass (RYGB) imparts long-term weight loss, the mechanisms for which are not well understood. Changes in leptin and gastrointestinal (GI) hormones, including glucagon-like peptide 1 (GLP-1), peptide YY (PYY), and ghrelin, may contribute to the relative success of RYGB compared with conventional weight loss methods. This study evaluated changes in GI hormones and leptin post-RYGB. The study also evaluated whether GI hormones differed after a short-term dose of protein or fat. Methods GLP-1, PYY, ghrelin, and leptin were assessed in 16 women before RYGB and up to 1 year after RYGB. Plasma was collected before and at several times after a short-term equicaloric dose of protein or fat. Results GLP-1 area under the curve (AUC) increased at week 6 and 1 year in the fat beverage (FAT-BEV) group compared with baseline. PYY AUC remained elevated at 1 year in the FAT-BEV group. Ghrelin AUC decreased at week 2, week 6, and 1 year in the protein beverage (PRO-BEV) group compared with baseline. Ghrelin AUC was lower in the PRO-BEV group compared with the FAT-BEV group at week 6. Fasted leptin decreased at all visits in both groups and was lower in the FAT-BEV group compared with the PRO-BEV group at 1 year. Conclusions Changes from baseline were evident for all GI hormones and leptin; some differences were evident soon after surgery (ghrelin, leptin), whereas others were maintained long term (GLP-1, PYY, ghrelin, leptin). In response to a short-term stimulus, protein suppressed ghrelin and fat potently stimulated GLP-1 and PYY. Future work in this area is warranted. PMID:21378246

Appetite Regulatory Hormones in Women With Anorexia Nervosa: Binge-Eating/Purging Versus Restricting Type

PubMed Central

Eddy, Kamryn T.; Lawson, Elizabeth A.; Meade, Christina; Meenaghan, Erinne; Horton, Sarah E.; Misra, Madhusmita; Klibanski, Anne; Miller, Karen K.

2015-01-01

Objective Anorexia nervosa is a psychiatric illness characterized by low weight, disordered eating, and hallmark neuroendocrine dysfunction. Behavioral phenotypes are defined by predominant restriction or bingeing/purging; binge-eating/purging type anorexia nervosa is associated with poorer outcome. The pathophysiology underlying anorexia nervosa types is unknown, but altered hormones, known to be involved in eating behaviors, may play a role. Method To examine the role of anorexigenic hormones in anorexia nervosa subtypes, we examined serum levels of peptide YY (PYY; total and active [3-36] forms), brain-derived neurotrophic factor (BDNF), and leptin as primary outcomes in women with OSM-5 restricting type anorexia nervosa (n=50), binge-eating/purging type anorexia nervosa (n = 22), and healthy controls (n = 22).1n addition, women completed validated secondary outcome measures of eating disorder psychopathology (Eating Disorder Examination-Questionnaire) and depression and anxiety symptoms (Hamilton Rating Scales for Depression [HDRS] and Anxiety [HARS]). The study samples were collected from May 22, 2004, to February 7, 2012. Results Mean PYY 3-36 and leptin levels were lower and BDNF levels higher in binge-eating/purging type anorexia nervosa than in restricting type anorexia nervosa (all Pvalues <.05). After controlling for body mass index, differences in PYY and PYY 3-36 between anorexia nervosa types were significant (P<.05) and differences in BDNF were at the trend level (P < .10). PYY 3-36 was positively (r=0.27, P=.02) and leptin was negatively (r=−0.51, P< .0001) associated with dietary restraint; BDNF was positively associated with frequency of purging (r=0.21, P=.04); and leptin was negatively associated with frequency of bingeing (r=−0.29, P=.007) and purging (r=−0.31, P=.004). Conclusions Among women with anorexia nervosa, the anorexigenic hormones PYY, BDNF, and leptin are differentially regulated between the restricting and binge/purge types

H. pylori modifies methylation of global genomic DNA and the gastrin gene promoter in gastric mucosal cells and gastric cancer cells.

PubMed

Xie, Yuan; Zhou, Jian Jiang; Zhao, Yan; Zhang, Ting; Mei, Liu Zheng

2017-07-01

The aim of this study was to evaluate the correlation between H. pylori infection and global DNA methylation, as well as the methylation levels of the gastrin promoters. We constructed a eukaryotic expression vector, pcDNA3.1::cagA, and transfected it into GES-1 gastric mucosal cells and SGC-7901 gastric cancer cells. Both cell lines were infected with the H. pylori/CagA + strain NCTC11637. Then, we detected global DNA methylation by capture and detection antibodies, followed by colorimetric quantification. The methylation levels of the gastrin promoter were evaluated by base-specific cleavage and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. In H. pylori/CagA + -infected GES-1 and SGC-7901 cells, the methylation levels of genomic DNA decreased by 49.4% and 18.8%, and in GES-1 and SGC-7901 cells transfected with pcDNA3.1::cagA, the methylation levels of genomic DNA decreased by 17.05% and 25.6%, respectively. Among 24 methylation sites detected in the gastrin promoter region, the methylation levels of 9 CpG sites were significantly decreased in H. pylori/CagA+-infected and pcDNA3.1:: cagA-transfected cells in comparison to corresponding control cells. These results indicate that H. pylori/CagA + decreases the methylation of the genome and the gastrin promoter at some CpG sites in gastric mucosal and gastric cancer cells. Copyright © 2017. Published by Elsevier Ltd.

Effect of porcine gastrin releasing peptide on gastric secretion and motility and the release of hormonal peptides in conscious cats.

PubMed

Vagne, M; Collinet, M; Cuber, J C; Bernard, C; Chayvialle, J A; McDonald, T J; Mutt, V

1987-01-01

The effect of porcine gastrin releasing peptide (GRP) was compared to those of bombesin (BBS) and pentagastrin (PG) in conscious cats. GRP and BBS augmented acid and pepsin secretions, as well as antral motility with an early effect comparable to that produced by pentagastrin with an elevation of low amplitude contractions and a diminution of high amplitude contractions. BBS and GRP increased plasma gastrin and pancreatic polypeptide (PP) levels and decreased motilin levels measured by a C terminus-directed antiserum. In all cases, BBS and GRP displayed parallel dose-response curves. PG showed slight differences in the slopes of the dose-response curves slopes of the dose-response curves except for acid secretion stimulation where no difference was noted (PG was the most effective) and for pepsin stimulation where the difference was large (PG was much less effective). According to the different targets studied, BBS was 4 to 9 times more potent than GRP, 6 to 200 times more than PG. Gastrin release, elicited by the lowest ED50 of both BBS and GRP, should be considered as their primary effect in the cat.

Long term omeprazole therapy for reflux esophagitis: Follow-up in serum gastrin levels, EC cell hyperplasia and neoplasia

PubMed Central

Singh, Pankaj; Indaram, Anant; Greenberg, Ronald; Visvalingam, Vernu; Bank, Simmy

2000-01-01

AIM: To evaluate the long-term safety of omeprazole in patients of gastroesophageal reflux disease resistant to treatment with H2 receptor antagonist. METHODS: We prospectively followed 33 patients on omeprazole therapy for severe erosive esophagitis for 5-8 years, with periodic gastrin levels, H. pylori infection, gastric biopsies for incidence of ECL cell hyperplasia, carcinoids, gastric atrophy and neoplasia. A total 185 patient follow-up years and 137 gastric biopsies were done. RESULTS: Among the 33 patients, 36% reached their peak gastrin levels in an average of 8 mo to one year, then drifted Down slowly over 1-2 year period to just above their baseline level, 24% of the patients had a peak gastrin level above 400 ng·L-1 and one patient had a peak level above 1000 ng·L-1. One patient had a mild ECL cell hyperplasia which was self-limiting and did not show any dysplastic changes. Eighteen percent of patients were positive for H. pylori infection. The gastric biopsies did not show gastric atrophy, intestinal metaplasia or neoplastic changes. CONCLUSION: In a series of 33 patients followed for 5-8 years on omeprazole therapy for severe reflux esophagitis, we did not observe any evidence of significant ECL cell hyperplasia, gastric atrophy, intestinal metaplasia, dysplasia or neoplastic changes. PMID:11819697

Phage display selection of fully human antibody fragments to inhibit growth-promoting effects of glycine-extended gastrin 17 on human colorectal cancer cells.

PubMed

Khajeh, Shirin; Tohidkia, Mohammad Reza; Aghanejad, Ayuob; Mehdipour, Tayebeh; Fathi, Farzaneh; Omidi, Yadollah

2018-06-09

Glycine-extended gastrin 17 (G17-Gly), a dominant processing intermediate of gastrin gene, has been implicated in the development or maintenance of colorectal cancers (CRCs). Hence, neutralizing G17-Gly activity by antibody entities can provide a potential therapeutic strategy in the patients with CRCs. To this end, we isolated fully human antibody fragments from a phage antibody library through biopanning against different epitopes of G17-Gly in order to obtain the highest possible antibody diversity. ELISA screening and sequence analysis identified 2 scFvs and 4 V L antibody fragments. Kinetic analysis of the antibody fragments by SPR revealed K D values to be in the nanomolar range (87.9-334 nM). The selected anti-G17-Gly antibody fragments were analyzed for growth inhibition and apoptotic assays in a CRC cell line, HCT-116, which is well-characterized for expressing gastrin intermediate species but not amidated gastrin. The antibody fragments exhibited significant inhibition of HCT-116 cells proliferation ranging from 36.5 to 73% of controls. Further, Annexin V/PI staining indicated that apoptosis rates of scFv H8 and V L G8 treated cells were 45.8 and 63%, respectively. Based on these results, we for the first time, demonstrated the isolation of anti-G17-Gly human scFv and V L antibodies with potential therapeutic applications in G17-Gly-responsive tumors.

Comparison of effect of an increased dosage of vonoprazan versus vonoprazan plus lafutidine on gastric acid inhibition and serum gastrin.

PubMed

Suzuki, Takahiro; Kagami, Takuma; Uotani, Takahiro; Yamade, Mihoko; Hamaya, Yasushi; Iwaizumi, Moriya; Osawa, Satoshi; Sugimoto, Ken; Miyajima, Hiroaki; Furuta, Takahisa

2018-01-01

Vonoprazan, a novel potassium-competitive acid blocker, elicits potent acid inhibition and hypergastrinemia at a dose of 20 mg. Its recommended maintenance dose for gastro-esophageal reflux disease is 10 mg, which is sometimes insufficient for preventing nocturnal acid breakthrough (NAB). Concomitant use of a histamine 2 receptor antagonist (H 2 RA) is effective for NAB. However, further acid inhibition by addition of H2RA has concern of hypergastrinemia again. Lafutidine (H2RA) is known to stimulate somatostatin release. The aim of this study is to compare the levels of acid inhibition and serum gastrin attained by addition of lafutidine to vonoprazan 10 mg with levels after a dose increase of vonoprazan from 10 to 20 mg. Thirteen healthy volunteers underwent 24-h intragastric pH monitoring and serum gastrin measurements on day 7 of three different regimens: vonoprazan 10 mg, vonoprazan 10 mg plus lafutidine 10 mg, and vonoprazan 20 mg. Median pH 4 holding time ratios (range) by vonoprazan 10 mg, vonoprazan 10 mg plus lafutidine 10 mg, and vonoprazan 20 mg were 82% (47-88%), 88% (76-93%), and 99% (95-100%) while those at nighttime from 10 p.m. to 8 a.m. were 94% (29-100%), 100% (95-100%), and 100%, respectively. The incidences of NAB with vonoprazan 10 mg, vonoprazan plus lafutidine, and vonoprazan 20 mg were 38, 8, and 0%, respectively. Respective serum gastrin levels were 420 (173-508), 323 (196-521), and 504 (400-812) pg/ml. Addition of lafutidine 10 mg to vonoprazan 10 mg achieved sufficient acid inhibition, especially at nighttime, without further increase of serum gastrin levels.

Transcription factors YY1, Sp1 and Sp3 modulate dystrophin Dp71 gene expression in hepatic cells.

PubMed

Peñuelas-Urquides, Katia; Becerril-Esquivel, Carolina; Mendoza-de-León, Laura C; Silva-Ramírez, Beatriz; Dávila-Velderrain, José; Cisneros, Bulmaro; de León, Mario Bermúdez

2016-07-01

Dystrophin Dp71, the smallest product encoded by the Duchenne muscular dystrophy gene, is ubiquitously expressed in all non-muscle cells. Although Dp71 is involved in various cellular processes, the mechanisms underlying its expression have been little studied. In hepatic cells, Dp71 expression is down-regulated by the xenobiotic β-naphthoflavone. However, the effectors of this regulation remain unknown. In the present study we aimed at identifying DNA elements and transcription factors involved in Dp71 expression in hepatic cells. Relevant DNA elements on the Dp71 promoter were identified by comparing Dp71 5'-end flanking regions between species. The functionality of these elements was demonstrated by site-directed mutagenesis. Using EMSAs and ChIP, we showed that the Sp1 (specificity protein 1), Sp3 (specificity protein 3) and YY1 (Yin and Yang 1) transcription factors bind to the Dp71 promoter region. Knockdown of Sp1, Sp3 and YY1 in hepatic cells increased endogenous Dp71 expression, but reduced Dp71 promoter activity. In summary, Dp71 expression in hepatic cells is carried out, in part, by YY1-, Sp1- and Sp3-mediated transcription from the Dp71 promoter. © 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.

The Effect of a 20 km Run on Appetite Regulation in Long Distance Runners

PubMed Central

Kojima, Chihiro; Ishibashi, Aya; Ebi, Kumiko; Goto, Kazushige

2016-01-01

The purpose of the present study was to investigate appetite-related hormonal responses and energy intake after a 20 km run in trained long distance runners. Twenty-three male long-distance runners completed two trials: either an exercise trial consisting of a 20 km outdoor run (EX) or a control trial with an identical period of rest (CON). Blood samples were collected to determine plasma acylated ghrelin, peptide YY3-36 (PYY3-36) and other hormonal and metabolite concentrations. Energy intake during a buffet test meal was also measured 30 min after the exercise or rest periods. Although plasma acylated ghrelin concentrations were significantly decreased after the 20 km run (p < 0.05), plasma PYY3-36 did not change significantly following exercise. Absolute energy intake during the buffet test meal in EX (1325 ± 55 kcal) was significantly lower than that in CON (1529 ± 55 kcal), and there was a relatively large degree of individual variability for exercise-induced changes in energy intake (−40.2% to 12.8%). However, exercise-induced changes in energy intake were not associated with plasma acylated ghrelin or PYY3-36 responses. The results demonstrated that a 20 km run significantly decreased plasma acylated ghrelin concentrations and absolute energy intake among well-trained long distance runners. PMID:27792164

Effect of aerobic exercise on hunger feelings and satiety regulating hormones in obese teenage girls.

PubMed

Prado, Wagner L; Balagopal, P Babu; Lofrano-Prado, Mara C; Oyama, Lila M; Tenório, Thiago Ricardo; Botero, João Paulo; Hill, James O

2014-11-01

Exercise is implicated in modifying subsequent energy intake (EI) through alterations in hunger and/or satiety hormones. Our aim was to examine the effects of aerobic exercise on hunger, satiety regulatory peptides, and EI in obese adolescents. Nine obese girls (age: 13-18 years old, BMI: 33.74 ± 4.04 kg/m2) participated in this randomized controlled crossover study. Each participant randomly underwent 2 experimental protocols: control (seated for 150 min) and exercise (exercised for 30 min on a treadmill performed at ventilatory threshold [VT] intensity and then remained seated for 120 min). Leptin, peptide YY(3-36) (PYY(3-36)), and subjective hunger were measured at baseline as well as 30 min and 150 min, followed by 24-hr EI measurement. Exercise session resulted in an acute increase in PYY(3-36) (p < .01) without changes in leptin and/or hunger scores. The control session increased hunger scores (p < .01) and decreased circulating leptin levels (p = .03). There was a strong effect size for carbohydrate intake (d = 2.14) and a modest effect size for protein intake (d = 0.61) after the exercise compared with the control session. Exercise performed at VT intensity in this study appears to provoke a state of transient anorexia in obese girls. These changes may be linked to an increase in circulating PYY3-36 and maintenance of leptin levels.

Effects of different modes of exercise on appetite and appetite-regulating hormones.

PubMed

Kawano, Hiroshi; Mineta, Mayuko; Asaka, Meiko; Miyashita, Masashi; Numao, Shigeharu; Gando, Yuko; Ando, Takafumi; Sakamoto, Shizuo; Higuchi, Mitsuru

2013-07-01

The present study determined the changes in appetite and appetite-regulating gut hormones during and following bouts of both rope skipping exercise (weight-bearing) and bicycle ergometer exercise (non-weight-bearing). After a 12-h fast, 15 young men (mean ± SD, age 24.4 ± 1.7 yrs, maximal oxygen uptake 47.0 ± 6.5 mL/kg/min) participated in three 160 min trials: (1) rope skipping exercise (295 ± 40 kcal, 3 sets × 10 min with 5-min interval, then rested for 120 min); (2) bicycle ergometer exercise (288 ± 36 kcal, 3 sets × 10 min with 5-min interval, then rested for 120 min); (3) control (rested for 160 min). Ratings of perceived hunger and acylated ghrelin were suppressed and total peptide YY (PYY) were increased during and immediately after exercise in both exercise trials, but glucagon liked peptide-1 was not changed. Furthermore, suppressed hunger during rope skipping exercise was greater than that during bicycle ergometer exercise, but there were no differences in acylated ghrelin and total PYY. These results indicate that weight-bearing exercise has a greater exercise-induced appetite suppressive effect compared with non-weight-bearing exercise, and both forms of exercise lowered acylated ghrelin and increased total PYY, but the changes did not differ significantly between exercise modes. Copyright © 2013 Elsevier Ltd. All rights reserved.

Changes in gut hormone levels and negative energy balance during aerobic exercise in obese young males.

PubMed

Ueda, Shin-ya; Yoshikawa, Takahiro; Katsura, Yoshihiro; Usui, Tatsuya; Nakao, Hayato; Fujimoto, Shigeo

2009-04-01

We examined whether changes in gut hormone levels due to a single bout of aerobic exercise differ between obese young males and normal controls, and attempted to determine the involvement of hormonal changes during exercise in the regulation of energy balance (EB) in these obese subjects. Seven obese and seven age-matched subjects of normal weight participated in exercise and rest sessions. Subjects consumed a standardized breakfast that was followed by constant cycling exercise at 50% VO(2max) or rest for 60 min. At lunch, a test meal was presented, and energy intake (EI) and relative energy intake (REI) were calculated. Blood samples were obtained at 30 min intervals during both sessions for measurement of glucose, insulin, glucagon, ghrelin, peptide YY (PYY), and glucagon-like peptide-1 (GLP-1). Plasma levels of PYY and GLP-1 were increased by exercise, whereas plasma ghrelin levels were unaffected by exercise. The areas under the curve (AUC) of the time courses of PYY and GLP-1 levels did not significantly differ between the two groups. In contrast, EI and REI were decreased by exercise in both groups, and energy deficit was significantly larger in obese subjects than in normal controls. The present findings suggest that short-term EB during a single exercise session might be regulated not by increased amounts of these gut hormones per se.

CRHR2/Ucn2 signaling is a novel regulator of miR-7/YY1/Fas circuitry contributing to reversal of colorectal cancer cell resistance to Fas-mediated apoptosis.

PubMed

Pothoulakis, Charalabos; Torre-Rojas, Monica; Duran-Padilla, Marco A; Gevorkian, Jonathan; Zoras, Odysseas; Chrysos, Emmanuel; Chalkiadakis, George; Baritaki, Stavroula

2018-01-15

Colorectal cancer (CRC) responds poorly to immuno-mediated cytotoxicity. Underexpression of corticotropin-releasing-hormone-receptor-2 (CRHR2) in CRC, promotes tumor survival, growth and Epithelial to Mesenchymal Transition (EMT), in vitro and in vivo. We explored the role of CRHR2 downregulation in CRC cell resistance to Fas/FasL-mediated apoptosis and the underlying molecular mechanism. CRC cell sensitivity to CH11-induced apoptosis was compared between Urocortin-2 (Ucn2)-stimulated parental and CRHR2-overexpressing CRC cell lines and targets of CRHR2/Ucn2 signaling were identified through in vitro and ex vivo analyses. Induced CRHR2/Ucn2 signaling in SW620 and DLD1 cells increased specifically their sensitivity to CH11-mediated apoptosis, via Fas mRNA and protein upregulation. CRC compared to control tissues had reduced Fas expression that was associated with lost CRHR2 mRNA, poor tumor differentiation and high risk for distant metastasis. YY1 silencing increased Fas promoter activity in SW620 and re-sensitized them to CH11-apoptosis, thus suggesting YY1 as a putative transcriptional repressor of Fas in CRC. An inverse correlation between Fas and YY1 expression was confirmed in CRC tissue arrays, while elevated YY1 mRNA was clinically relevant with advanced CRC grade and higher risk for distant metastasis. CRHR2/Ucn2 signaling downregulated specifically YY1 expression through miR-7 elevation, while miR-7 modulation in miR-7 high SW620-CRHR2+ and miR-7 low HCT116 cells, had opposite effects on YY1 and Fas expressions and cell sensitivity to CH11-killing. CRHR2/Ucn2 signaling is a negative regulator of CRC cell resistance to Fas/FasL-apoptosis via targeting the miR-7/YY1/Fas circuitry. CRHR2 restoration might prove effective in managing CRC response to immune-mediated apoptotic stimuli. © 2017 UICC.

Sperm quality analysis in XX, XY and YY males of the Nile tilapia (Oreochromis niloticus).

PubMed

Gennotte, V; François, E; Rougeot, C; Ponthier, J; Deleuze, S; Mélard, C

2012-07-01

In Nile tilapia (Oreochromis niloticus), individuals with atypical sexual genotype are commonly used in farming (use of YY males to produce all-male offspring), but they also constitute major tools to study sex determinism mechanisms. In other species, sexual genotype and sex reversal procedures affect different aspects of biology, such as growth, behavior and reproductive success. The aim of this study was to assess the influence of sexual genotype on sperm quality in Nile tilapia. Milt characteristics were compared in XX (sex-reversed), XY and YY males in terms of gonadosomatic index, sperm count, sperm motility and duration of sperm motility. Sperm motility was measured by computer-assisted sperm analysis (CASA) quantifying several parameters: total motility, progressive motility, curvilinear velocity, straight line velocity, average path velocity and linearity. None of the sperm traits measured significantly differed between the three genotypes. Mean values of gonadosomatic index, sperm concentration and sperm motility duration of XX, XY and YY males, respectively ranged from 0.92 to 1.33%, from 1.69 to 2.22 ×10(9) cells mL(-1) and from 18'04″ to 27'32″. Mean values of total motility and curvilinear velocity 1 min after sperm activation, respectively ranged from 53 to 58% and from 71 to 76 μm s(-1) for the three genotypes. After 3 min of activity, all the sperm motility and velocity parameters dropped by half and continued to slowly decrease thereafter. Seven min after activation, only 9 to 13% of spermatozoa were still progressive. Our results prove that neither sexual genotype nor hormonal sex reversal treatments affect sperm quality in male Nile tilapias with atypical sexual genotype. Copyright © 2012 Elsevier Inc. All rights reserved.

An EUV Study of the Eclipsing M-Dwarf Binary System YY GEM

NASA Technical Reports Server (NTRS)

Drake, Jeremy

2000-01-01

EUVE, SW, MW and LW spectra have been reduced and line fluxes measured. The Deep Survey data has been analyzed and light curves have been derived. The spectra around the HE II 304 region show some evidence of emission from the bright A companion star, Castor. Preliminary results for the metallicity of the corona of YY Gem were derived from the EUVE spectra and photometry and were presented at the AAS HEAD meeting; results are being finalized for publication in a referred journal.

Theranostic Prospects of Gastrin-Releasing Peptide Receptor-Radioantagonists in Oncology.

PubMed

Maina, Theodosia; Nock, Berthold A; Kulkarni, Harshad; Singh, Aviral; Baum, Richard P

2017-07-01

Gastrin-releasing peptide receptors (GRPRs) represent attractive targets for cancer diagnosis and therapy owing to their overexpression in widespread human tumors. Bombesin (BBN) analogues coupled to suitable chelators for stable radiometal binding have been proposed for diagnostic imaging and radionuclide therapy (theranostics) of GRPR-positive tumors. Recently, interest has shifted from BBN-like receptor agonists to GRPR-radioantagonists, because radioantagonists do not induce adverse effects after injection to patients and display superior pharmacokinetic in vivo profiles. Thus, they seem more advantageous for clinical use compared to agonists. Newer developments highlighting the theranostic potential of GRPR-radioantagonists in cancer patient management are presented herein. Copyright © 2017 Elsevier Inc. All rights reserved.

Acute Exercise and Appetite-Regulating Hormones in Overweight and Obese Individuals: A Meta-Analysis

PubMed Central

Deighton, Kevin; Atkinson, Jan Maria; Sari-Sarraf, Vahid; Atkinson, Greg

2016-01-01

In lean individuals, acute aerobic exercise is reported to transiently suppress sensations of appetite, suppress blood concentrations of acylated ghrelin (AG), and increase glucagon-like peptide-1 (GLP-1) and peptide-YY (PYY). Findings in overweight/obese individuals have yet to be synthesised. In this systematic review and meta-analysis, we quantified the effects that acute exercise has on AG and total PYY and GLP-1 in overweight/obese individuals. The potential for body mass index (BMI) to act as a moderator for AG was also explored. Six published studies (73 participants, 78% male, mean BMI: 30.6 kg·m−2) met the inclusion criteria. Standardised mean differences (SMDs) and standard errors were extracted for AG and total PYY and GLP-1 concentrations in control and exercise trials and synthesised using a random effects meta-analysis model. BMI was the predictor in metaregression for AG. Exercise moderately suppressed AG area-under-the-curve concentrations (pooled SMD: −0.34, 95% CI: −0.53 to −0.15). The magnitude of this reduction was greater for higher mean BMIs (pooled metaregression slope: −0.04 SMD/kg·m−2 (95% CI: −0.07 to 0.00)). Trivial SMDs were obtained for total PYY (0.10, 95% CI: −0.13 to 0.31) and GLP-1 (−0.03, 95% CI: −0.18 to 0.13). This indicates that exercise in overweight/obese individuals moderately alters AG in a direction that could be associated with decreased hunger and energy intake. This trial is registered with PROSPERO: CRD42014006265. PMID:28116150

Gastroenteric hormone responses to hedonic eating in healthy humans.

PubMed

Monteleone, Palmiero; Scognamiglio, Pasquale; Monteleone, Alessio Maria; Perillo, Donato; Canestrelli, Benedetta; Maj, Mario

2013-08-01

Hedonic eating differentiates from homeostatic eating on two main aspects: the first one is that eating occurs when there is no need for calorie ingestion and the second one is that the food is consumed exclusively for its gustatory and rewarding properties. Gastroeneteric hormones such as ghrelin, colecystokinin-33 (CCK) and peptide YY3-36 (PYY3-36) are known to play a pivotal role in the homeostatic control of food intake. To the contrary, their role in hedonic eating has been never investigated. Here we report peripheral responses of CCK, PYY3-36 and ghrelin to the consumption of food for pleasure in well-nourished satiated healthy subjects. Plasma levels of CCK, PYY3-36 and ghrelin were measured in 7 satiated healthy subjects before and after ad libitum consumption of both a highly pleasurable food (hedonic eating) and an isoenergetic non-pleasurable food (non-hedonic eating). The consumption of food for pleasure was associated to a significantly increased production of the hunger hormone ghrelin and a significantly decreased secretion of the satiety hormone CCK. No significant changes in plasma PYY3-36 levels occurred in the two eating conditions. These preliminary data demonstrate that in hedonic eating the peripheral hunger signal represented by ghrelin secretion is enhanced while the satiety signal of CCK production is decreased. This could be responsible for the persistence of peripheral cues allowing a continued eating as well as for the activation of endogenous reward mechanisms, which can drive food consumption in spite of no energy need, only for reward. Copyright © 2012 Elsevier Ltd. All rights reserved.

Loss of Xist RNA from the inactive X during B cell development is restored in a dynamic YY1-dependent two-step process in activated B cells

PubMed Central

Syrett, Camille M.; Sindhava, Vishal; Hodawadekar, Suchita; Myles, Arpita; Liang, Guanxiang; Zhang, Yue; Nandi, Satabdi; Cancro, Michael; Atchison, Michael

2017-01-01

X-chromosome inactivation (XCI) in female lymphocytes is uniquely regulated, as the inactive X (Xi) chromosome lacks localized Xist RNA and heterochromatin modifications. Epigenetic profiling reveals that Xist RNA is lost from the Xi at the pro-B cell stage and that additional heterochromatic modifications are gradually lost during B cell development. Activation of mature B cells restores Xist RNA and heterochromatin to the Xi in a dynamic two-step process that differs in timing and pattern, depending on the method of B cell stimulation. Finally, we find that DNA binding domain of YY1 is necessary for XCI in activated B cells, as ex-vivo YY1 deletion results in loss of Xi heterochromatin marks and up-regulation of X-linked genes. Ectopic expression of the YY1 zinc finger domain is sufficient to restore Xist RNA localization during B cell activation. Together, our results indicate that Xist RNA localization is critical for maintaining XCI in female lymphocytes, and that chromatin changes on the Xi during B cell development and the dynamic nature of YY1-dependent XCI maintenance in mature B cells predisposes X-linked immunity genes to reactivation. PMID:28991910

High penetrance of pheochromocytoma associated with the novel C634Y/Y791F double germline mutation in the RET protooncogene.

PubMed

Toledo, Rodrigo A; Wagner, Simona M; Coutinho, Flavia L; Lourenço, Delmar M; Azevedo, Juliana A; Longuini, Viviane C; Reis, Mariana T A; Siqueira, Sheila A C; Lucon, Antonio M; Tavares, Marcos R; Fragoso, Maria C B V; Pereira, Adelaide A; Dahia, Patricia L M; Mulligan, Lois M; Toledo, Sergio P A

2010-03-01

Previous studies have shown that double RET mutations may be associated with unusual multiple endocrine neoplasia type 2 (MEN 2) phenotypes. Our objective was to report the clinical features of patients harboring a previously unreported double mutation of the RET gene and to characterize this mutation in vitro. Sixteen patients from four unrelated families and harboring the C634Y/Y791F double RET germline mutation were included in the study. Large pheochromocytomas measuring 6.0-14 cm and weighing up to 640 g were identified in the four index cases. Three of the four tumors were bilateral. High penetrance of pheochromocytoma was also seen in the C634Y/Y791F-mutation-positive relatives (seven of nine, 77.7%). Of these, two cases had bilateral tumors, one presented with multifocal tumors, two cases had large tumors (>5 cm), and one case, which was diagnosed with a large (5.5 x 4.5 x 4.0 cm) pheochromocytoma, reported early onset of symptoms of the disease (14 yr old). The overall penetrance of pheochromocytoma was 84.6% (11 of 13). Development of medullary thyroid carcinoma in our patients seemed similar to that observed in patients with codon 634 mutations. Haplotype analysis demonstrated that the mutation did not arise from a common ancestor. In vitro studies showed the double C634Y/Y791F RET receptor was significantly more phosphorylated than either activated wild-type receptor or single C634Y and Y791F RET mutants. Our data suggest that the natural history of the novel C634Y/Y791F double mutation carries a codon 634-like pattern of medullary thyroid carcinoma development, is associated with increased susceptibility to unusually large bilateral pheochromocytomas, and is likely more biologically active than each individual mutation.

The effect of guar gum on carbohydrate-, fat- and protein-stimulated gut hormone secretion: modification of postprandial gastric inhibitory polypeptide and gastrin responses.

PubMed

Morgan, L M; Tredger, J A; Madden, A; Kwasowski, P; Marks, V

1985-05-01

The effect of incorporating guar gum into predominantly single-component meals of carbohydrate, fat or protein on liquid gastric emptying and on the secretion of gastric inhibitory polypeptide (GIP), gastrin and motilin, was studied in healthy human volunteers. Volunteers were given either 80 ml Hycal (carbohydrate meal), 150 g cooked lean minced beef (protein meal) or 200 ml double cream (fat meal) either with or without 5 or 6 g guar gum. Liquid gastric emptying was monitored in the fat and protein meals by taking 1.5 g paracetamol, consumed in water, with the meals and monitoring its appearance in circulation. Postprandial insulin and GIP levels were both significantly reduced by addition of guar gum to the carbohydrate meal. Postprandial GIP secretion was also reduced by addition of guar gum to the protein meal, but protein-stimulated gastrin secretion was enhanced by guar gum. There was a significant negative correlation between peak circulating gastrin levels and the corresponding GIP levels. Postprandial GIP secretion and plasma motilin levels were unaffected by addition of guar gum to the fat meal. 5 and 10 g guar gum/l solutions in water possessed buffering capacities between pH 2.75 and 5.5. Guar gum at 5 g/l caused no detectable change in liquid gastric-emptying time. The observed augmentation of gastrin secretion by guar gum following a protein meal could be due either to the buffering capacity of guar gum or to the attenuation of GIP secretion. It is possible that the chronic use of guar gum could be associated with changes in gastric acid secretion.

A Common Variant at the 14q32 Endometrial Cancer Risk Locus Activates AKT1 through YY1 Binding.

PubMed

Painter, Jodie N; Kaufmann, Susanne; O'Mara, Tracy A; Hillman, Kristine M; Sivakumaran, Haran; Darabi, Hatef; Cheng, Timothy H T; Pearson, John; Kazakoff, Stephen; Waddell, Nicola; Hoivik, Erling A; Goode, Ellen L; Scott, Rodney J; Tomlinson, Ian; Dunning, Alison M; Easton, Douglas F; French, Juliet D; Salvesen, Helga B; Pollock, Pamela M; Thompson, Deborah J; Spurdle, Amanda B; Edwards, Stacey L

2016-06-02

A recent meta-analysis of multiple genome-wide association and follow-up endometrial cancer case-control datasets identified a novel genetic risk locus for this disease at chromosome 14q32.33. To prioritize the functional SNP(s) and target gene(s) at this locus, we employed an in silico fine-mapping approach using genotyped and imputed SNP data for 6,608 endometrial cancer cases and 37,925 controls of European ancestry. Association and functional analyses provide evidence that the best candidate causal SNP is rs2494737. Multiple experimental analyses show that SNP rs2494737 maps to a silencer element located within AKT1, a member of the PI3K/AKT/MTOR intracellular signaling pathway activated in endometrial tumors. The rs2494737 risk A allele creates a YY1 transcription factor-binding site and abrogates the silencer activity in luciferase assays, an effect mimicked by transfection of YY1 siRNA. Our findings suggest YY1 is a positive regulator of AKT1, mediating the stimulatory effects of rs2494737 increasing endometrial cancer risk. Identification of an endometrial cancer risk allele within a member of the PI3K/AKT signaling pathway, more commonly activated in tumors by somatic alterations, raises the possibility that well tolerated inhibitors targeting this pathway could be candidates for evaluation as chemopreventive agents in individuals at high risk of developing endometrial cancer. Copyright © 2016 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Gastrin-releasing peptide in human nasal mucosa.

PubMed

Baraniuk, J N; Lundgren, J D; Goff, J; Peden, D; Merida, M; Shelhamer, J; Kaliner, M

1990-04-01

Gastrin-releasing peptide (GRP), the 27 amino acid mammalian form of bombesin, was studied in human inferior turbinate nasal mucosa. The GRP content of the mucosa measured by radioimmunoassay was 0.60 +/- 0.25 pmol/g tissue (n = 9 patients; mean +/- SEM). GRP-immunoreactive nerves detected by the immunogold method of indirect immunohistochemistry were found predominantly in small muscular arteries, arterioles, venous sinusoids, and between submucosal gland acini. 125I-GRP binding sites determined by autoradiography were exclusively and specifically localized to nasal epithelium and submucosal glands. There was no binding to vessels. The effects of GRP on submucosal gland product release were studied in short-term explant culture. GRP (10 microM) significantly stimulated the release of the serous cell-specific product lactoferrin, and [3H]glucosamine-labeled glycoconjugates which are products of epithelial goblet cells and submucosal gland cells. These observations indicate that GRP released from nerve fibers probably acts on glandular GRP receptors to induce glycoconjugate release from submucosal glands and epithelium and lactoferrin release from serous cells, but that GRP would probably not affect vascular permeability.

Co-delivery of a hydrophobic small molecule and a hydrophilic peptide by porous silicon nanoparticles.

PubMed

Liu, Dongfei; Bimbo, Luis M; Mäkilä, Ermei; Villanova, Francesca; Kaasalainen, Martti; Herranz-Blanco, Barbara; Caramella, Carla M; Lehto, Vesa-Pekka; Salonen, Jarno; Herzig, Karl-Heinz; Hirvonen, Jouni; Santos, Hélder A

2013-09-10

Nanoparticulate drug delivery systems offer remarkable opportunities for clinical treatment. However, there are several challenges when they are employed to deliver multiple cargos/payloads, particularly concerning the synchronous delivery of small molecular weight drugs and relatively larger peptides. Since porous silicon (PSi) nanoparticles (NPs) can easily contain high payloads of drugs with various properties, we evaluated their carrier potential in multi-drug delivery for co-loading of the hydrophobic drug indomethacin and the hydrophilic human peptide YY3-36 (PYY3-36). Sequential loading of these two drugs into the PSi NPs enhanced the drug release rate of each drug and also their amount permeated across Caco-2 and Caco-2/HT29 cell monolayers. Regardless of the loading approach used, dual or single, the drug permeation profiles were in good correlation with their drug release behaviour. Furthermore, the permeation studies indicated the critical role of the mucus intestinal layer and the paracellular resistance in the permeation of the therapeutic compounds across the intestinal wall. Loading with PYY3-36 also greatly improved the cytocompatibility of the PSi NPs. Conformational analysis indicated that the PYY3-36 could still display biological activity after release from the PSi NPs and permeation across the intestinal cell monolayers. These results are the first demonstration of the promising potential of PSi NPs for simultaneous multi-drug delivery of both hydrophobic and hydrophilic compounds. Copyright © 2013 Elsevier B.V. All rights reserved.

Early Serum Gut Hormone Concentrations Associated with Time to Full Enteral Feedings in Preterm Infants.

PubMed

Shanahan, Kristen H; Yu, Xinting; Miller, Laura G; Freedman, Steven D; Martin, Camilia R

2018-04-03

The primary objective of this study was to evaluate early postnatal serum gut hormone concentrations in preterm infants as predictors of time to full enteral feedings. The secondary objective was to identify infant characteristics and nutritional factors that modulate serum gut hormone concentrations and time to full enteral feedings. Sixty-four preterm infants less than 30 weeks of gestation were included in this retrospective cohort study. Serum gut hormone concentrations at postnatal days 0 and 7 were measured using enzyme-linked immunosorbent assays. Linear regression and mediation analyses were performed. Median (IQR) serum concentrations of glucose-dependent insulinotropic peptide (GIP) and peptide YY (PYY) on postnatal day 7 were 31.3 pg/mL (18.2, 52.3) and 1181.7 pg/mL (859.0, 1650.2), respectively. GIP and PYY concentrations on day 7 were associated with days to full enteral feedings after adjustment for confounders (β = -1.1, p = 0.03; and β = -0.002, p = 0.02, respectively). Nutritional intake was correlated with serum concentrations of GIP and PYY on postnatal day 7 and time to full enteral feedings. Mediation analysis revealed that the effect of serum gut hormone concentrations on time to full enteral feedings was not fully explained by nutritional intake. Intrauterine growth restriction (IUGR), mechanical ventilation on postnatal day 7, and patent ductus arteriosus (PDA) treated with indomethacin were associated with longer time to full enteral feedings. Serum concentrations of GIP and PYY on postnatal 7 are independently associated with time to full enteral feedings. The link between serum gut hormone concentrations and time to full enteral feedings is not fully mediated by nutritional factors, suggesting an independent mechanism underlying the influence of gut hormones on feeding tolerance and time to full enteral feedings.

SNP analyses of postprandial responses in (an)orexigenic hormones and feelings of hunger reveal long-term physiological adaptations to facilitate homeostasis.

PubMed

den Hoed, M; Smeets, A J P G; Veldhorst, M A B; Nieuwenhuizen, A G; Bouwman, F G; Heidema, A G; Mariman, E C M; Westerterp-Plantenga, M S; Westerterp, K R

2008-12-01

The postprandial responses in (an)orexigenic hormones and feelings of hunger are characterized by large inter-individual differences. Food intake regulation was shown earlier to be partly under genetic control. This study aimed to determine whether the postprandial responses in (an)orexigenic hormones and parameters of food intake regulation are associated with single nucleotide polymorphisms (SNPs) in genes encoding for satiety hormones and their receptors. Peptide YY (PYY), glucagon-like peptide 1 and ghrelin levels, as well as feelings of hunger and satiety, were determined pre- and postprandially in 62 women and 41 men (age 31+/-14 years; body mass index 25.0+/-3.1 kg/m(2)). Dietary restraint, disinhibition and perceived hunger were determined using the three-factor eating questionnaire. SNPs were determined in the GHRL, GHSR, LEP, LEPR, PYY, NPY, NPY2R and CART genes. The postprandial response in plasma ghrelin levels was associated with SNPs in PYY (215G>C, P<0.01) and LEPR (326A>G and 688A>G, P<0.01), and in plasma PYY levels with SNPs in GHRL (-501A>C, P<0.05) and GHSR (477G>A, P<0.05). The postprandial response in feelings of hunger was characterized by an SNP-SNP interaction involving SNPs in LEPR and NPY2R (668A>G and 585T>C, P<0.05). Dietary restraint and disinhibition were associated with an SNP in GHSR (477G>A, P<0.05), and perceived hunger with SNPs in GHSR and NPY (477G>A and 204T>C, P<0.05). Part of the inter-individual variability in postprandial responses in (an)orexigenic hormones can be explained by genetic variation. These postprandial responses represent either long-term physiological adaptations to facilitate homeostasis or reinforce direct genetic effects.

Role of Cholecystokinin in Anorexia Induction Following Oral Exposure to the 8-Ketotrichothecenes Deoxynivalenol, 15-Acetyldeoxynivalenol, 3-Acetyldeoxynivalenol, Fusarenon X, and Nivalenol

PubMed Central

Wu, Wenda; Zhou, Hui-Ren; He, Kaiyu; Pan, Xiao; Sugita-Konishi, Yoshiko; Watanabe, Maiko; Zhang, Haibin; Pestka, James J.

2014-01-01

Cereal grain contamination by trichothecene mycotoxins is known to negatively impact human and animal health with adverse effects on food intake and growth being of particular concern. The head blight fungus Fusarium graminearum elaborates five closely related 8-ketotrichothecene congeners: (1) deoxynivalenol (DON), (2) 3-acetyldeoxynivalenol (3-ADON), (3) 15-acetyldeoxynivalenol (15-ADON), (4) fusarenon X (FX), and (5) nivalenol (NIV). While anorexia induction in mice exposed intraperitoneally to DON has been linked to plasma elevation of the satiety hormones cholecystokinin (CCK) and peptide YY3–36 (PYY3–36), the effects of oral gavage of DON or of other 8-keotrichothecenes on release of these gut peptides have not been established. The purpose of this study was to (1) compare the anorectic responses to the aforementioned 8-ketotrichothecenes following oral gavage at a common dose (2.5 mg/kg bw) and (2) relate these effects to changes plasma CCK and PYY3–36 concentrations. Elevation of plasma CCK markedly corresponded to anorexia induction by DON and all other 8-ketotrichothecenes tested. Furthermore, the CCK1 receptor antagonist SR 27897 and the CCK2 receptor antagonist L-365,260 dose-dependently attenuated both CCK- and DON-induced anorexia, which was consistent with this gut satiety hormone being an important mediator of 8-ketotrichothecene-induced food refusal. In contrast to CCK, PYY3–36 was moderately elevated by oral gavage with DON and NIV but not by 3-ADON, 15-ADON, or FX. Taken together, the results suggest that CCK plays a major role in anorexia induction following oral exposure to 8-ketotrichothecenes, whereas PYY3–36 might play a lesser, congener-dependent role in this response. PMID:24385417

Effect of honey versus sucrose on appetite, appetite-regulating hormones, and postmeal thermogenesis.

PubMed

Larson-Meyer, D Enette; Willis, Kentz S; Willis, Lindsey M; Austin, Kathleen J; Hart, Ann Marie; Breton, Ashley B; Alexander, Brenda M

2010-10-01

Increased per capita consumption of sweeteners may be responsible in part for the rising prevalence of obesity in the United States. Recent studies suggest that consumption of honey is not associated with this same obesogenic effect and may have beneficial effects neuro on body weight. The purpose of this study was to evaluate whether the meal-induced responses of ghrelin and peptide YY(3-36) (PYY(3-36)) and/or meal-induced thermogenesis differ following a honey- versus a sucrose-containing meal. In a double-blind randomly assigned study, appetite hormones (ghrelin, PYY(3-36), leptin) and glycemic and thermic responses were evaluated following isoglucidic ∼450 kcal honey- or sucrose-containing breakfasts in 14 healthy, nonobese women (22 ± 3 y). Blood samples and hunger ratings were obtained at baseline and every 30 minutes for 240 minutes following the meal. Meal-induced thermogenesis was measured by indirect calorimetry. Ad libitum food intake was evaluated from a free-choice meal following the test meal. Honey consumption delayed the postprandial ghrelin response (p = 0.037), enhanced the total PYY (p = 0.007) response, and blunted the glucose response (p = 0.039) compared with consumption of the sucrose-containing meal. Meal-induced insulin response, hunger ratings, thermogenesis, and subsequent ad libitum food intake, however, did not differ (p > 0.10) between diet treatments. Alterations in meal-induced responses of ghrelin and PYY(3-36) but not meal-induced thermogenesis may be responsible in part for the potential "obesity protective" effect(s) of honey consumption. A blunted glycemic response may be beneficial for reducing glucose intolerance. Further research is required to determine if these findings hold true for obese individuals, for males, or with habitual consumption.

Individually timing high-protein preloads has no effect on daily energy intake, peptide YY and glucagon-like peptide-1.

PubMed

Willbond, S M; Doucet, É

2011-01-01

Gut hormones have been shown to influence energy intake (EI). To our knowledge, no study has investigated the effects of dietary patterns aimed at optimizing fullness on EI, appetite and gut hormones. To determine whether individually timing high-protein preloads would impact EI, appetite, and peptide YY and glucagon-like peptide-1 (GLP-1) levels. Ten men (body mass index = 25.5 ± 2.6 kg/m(2)) participated in a randomized crossover trial. The three conditions consisted of the self-selection of snacks (condition 1), or the consumption of a preload (300 kcal: 40% protein, 40% carbohydrates and 20% fat) at either 15 min (condition 2) or ∼ 50 min (individually set) (condition 3) before lunch and dinner. During each condition, a standardized breakfast was served, whereas lunch and dinner were self-selected from a five-item menu, and eaten ad libitum. Mealtime and daily EI were measured. Appetite, peptide YY and GLP-1 were sampled over 9 h. No differences in daily EI were noted across conditions (1 = 3078 ± 720 kcal; 2 = 2929 ± 264 kcal; 3 = 2998 ± 437 kcal; not significant). For the most part, daily profiles as well as premeal levels of peptide YY and GLP-1 were not different between conditions. Desire to eat, hunger and prospective food consumption were found to be lowest during condition 1 (P < 0.05). According to these results, it would seem that individually timing high-protein preloads does not reduce daily EI in healthy human subjects.

Plasma motilin, gastrin, and enteroglucagon and feeding in the human newborn.

PubMed Central

Lucas, A; Adrian, T E; Christofides, N; Bloom, S R; Aynsley-Green, A

1980-01-01

Plasma concentrations of motilin, gastrin, and enteroglucagon were measured in cord blood and during the first 24 days of life before feeding in 45 term and 63 preterm, healthy infants. Levels of these hormones rose steeply after birth, reaching concentrations that were much higher than those in fasting adults. These increases in hormone concentration were not present in a group of 10 preterm infants who had received only intravaenous dextrose from birth because of hyaline membrane disease. Our findings suggest that early enteral feeding may trigger the postnatal increase in plasma concentrations of gut hormones and that this could play an important role in the physiologaical adaptations to extrauterine nutrition. PMID:7436530

Motilin and gastrin secretion and lipid profile in preterm neonates following prebiotics supplementation: a double-blind randomized controlled study.

PubMed

Dasopoulou, Maria; Briana, Despina D; Boutsikou, Theodora; Karakasidou, Eirini; Roma, Eleftheria; Costalos, Christos; Malamitsi-Puchner, Ariadne

2015-03-01

Gut hormones play an important role in the adaptation of the immature neonatal gut, and their secretion may be modulated by prebiotics. Furthermore, prebiotics are well known for their hypolipidemic potentials. We tested the hypothesis that prebiotics could alter motilin and gastrin secretion and reduce lipids in healthy preterms. A total of 167 newborns were randomized to either a prebiotics enriched formula containing dietary oligosaccharides (short-chain galacto-oligo-saccharides/long-chain fructo-oligo-saccharides [scGOS/lcFOS]), at a concentration of 0.8 g/100 ml, or a common preterm formula. Day 1 and 16 basal motilin, gastrin concentrations, and lipids were evaluated together with growth parameters, gastric residue, bowel habits, and feeding tolerance. Adverse events including necrotizing enterocolitis (NEC) and septicemia were also recorded. Mean motilin increase and day 16 mean values were greater for the intervention, compared with the control group (P = .001, P = .005, respectively), while gastrin remained high in both groups. Mean cholesterol and low density lipoprotein (LDL) increase were significantly greater in the control, compared with the intervention (P = .037, and P = .001) group. Day 16 LDL levels were significantly higher in the control group. Mean weight was increased in the control group, while gastric residue was less and stool frequency was increased in the intervention group. NEC and septicemia were not statistically different between groups. A prebiotics enriched formula resulted in significant surge of motilin relating to reduced gastric residue, compared with a common preterm formula. Mean cholesterol change was lower, while LDL was not increased in the prebiotics group, compared with the control group. © 2013 American Society for Parenteral and Enteral Nutrition.

Influence of Running and Walking on Hormonal Regulators of Appetite in Women

PubMed Central

Larson-Meyer, D. Enette; Palm, Sonnie; Bansal, Aasthaa; Austin, Kathleen J.; Hart, Ann Marie; Alexander, Brenda M.

2012-01-01

Nine female runners and ten walkers completed a 60 min moderate-intensity (70% VO2max) run or walk, or 60 min rest in counterbalanced order. Plasma concentrations of the orexogenic peptide ghrelin, anorexogenic peptides peptide YY (PYY), glucagon-like peptide-1 (GLP-1), and appetite ratings were measured at 30 min interval for 120 min, followed by a free-choice meal. Both orexogenic and anorexogenic peptides were elevated after running, but no changes were observed after walking. Relative energy intake (adjusted for cost of exercise/rest) was negative in the meal following running (−194 ± 206 kcal) versus walking (41 ± 196 kcal) (P = 0.015), although both were suppressed (P < 0.05) compared to rest (299 ± 308 and 284 ± 121 kcal, resp.). The average rate of change in PYY and GLP-1 over time predicted appetite in runners, but only the change in GLP-1 predicted hunger (P = 0.05) in walkers. Results provide evidence that exercise-induced alterations in appetite are likely driven by complex changes in appetite-regulating hormones rather than change in a single gut peptide. PMID:22619704

What Does f[subscript xx]f[subscript yy] - f[superscript 2][subscript xy] Greater than 0 "Really" Mean?

ERIC Educational Resources Information Center

McCartin, Brian J.

2008-01-01

This note presents geometric and physical interpretations of the sufficient condition for a critical point to be a strict relative extremum: f[subscript xx]f[subscript yy] - f[superscript 2][subscript xy] greater than 0. The role of the double derivative f[subscript xy] in this inequality will be highlighted in these interpretations. (Contains 14…

Differences in the Postprandial Release of Appetite-Related Hormones Between Active and Inactive Men.

PubMed

Bøhler, Linn; Coutinho, Sílvia Ribeiro; Rehfeld, Jens F; Morgan, Linda; Martins, Catia

2018-02-12

Active, as opposed to inactive, individuals are able to adjust their energy intake after preloads of different energy content. The mechanisms responsible for this remain unknown. This study examined differences in plasma concentration of appetite-related hormones in response to breakfasts of different energy content, between active and inactive men. 16 healthy non-obese (BMI 18.5-27 kg/m 2 ) adult males (9 active, 7 inactive), participated in the study. Participants were given a high- (HE, 570 kcal) or a low-energy (LE, 205 kcal) breakfast in random order. Subjective feelings of appetite and plasma concentrations of active ghrelin (AG), active glucagon-like peptide 1 (GLP-1), total peptide YY (PYY), cholecystokinin (CCK) and insulin were measured in fasting and every 30 minutes up to 2.5 hours, in response to both breakfasts. Mixed ANOVA (fat mass (%) as a covariate) revealed a higher concentration of AG and lower concentration of GLP-1 and CCK after the LE breakfast (p<0.001 for all). Postprandial concentration of PYY was greater after the HE compared with the LE, but for inactive participants only (p=0.014). Active participants had lower postprandial concentrations of insulin than inactive participants (p<0.001). Differences in postprandial insulin between breakfasts were significantly lower in active compared with inactive participants (p<0.001). PA seems to modulate the postprandial plasma concentration of insulin and PYY after the intake of breakfasts of different energy content and that may contribute, at least partially, to the differences in short-term appetite control between active and inactive individuals.

Changes in Metabolic Hormones in Malaysian Young Adults following Helicobacter pylori Eradication

PubMed Central

Yap, Theresa Wan-Chen; Leow, Alex Hwong-Ruey; Azmi, Ahmad Najib; Francois, Fritz; Perez-Perez, Guillermo I; Blaser, Martin J.; Poh, Bee-Hoon; Loke, Mun-Fai; Goh, Khean-Lee; Vadivelu, Jamuna

2015-01-01

Background More than half of the world’s adults carry Helicobacter pylori. The eradication of H. pylori may affect the regulation of human metabolic hormones. The aim of this study was to evaluate the effect of H. pylori eradication on meal-associated changes in appetite-controlled insulinotropic and digestive hormones, and to assess post-eradication changes in body mass index as part of a currently on-going multicentre ESSAY (Eradication Study in Stable Adults/Youths) study. Methods We enrolled 29 H. pylori-positive young adult (18–30 year-old) volunteer subjects to evaluate the effect of H. pylori eradication on meal-associated changes on eight gastrointestinal hormones, using a multiplex bead assay. Changes in body mass index and anthropometric measurements were recorded, pre- and post-eradication therapy. Results Pre-prandial active amylin, total peptide YY (PYY) and pancreatic polypeptide (PP) levels were significantly elevated 12 months post-eradication compared with baseline (n = 18; Wilcoxon's signed rank test, p<0.05). Four of the post-prandial gut metabolic hormones levels (GLP-1, total PYY, active amylin, PP) were significantly higher 12 months post-eradication compared to baseline (n = 18; p<0.05). Following H. pylori eradication, the BMI and anthropometric values did not significantly change. Conclusions Our study indicates that H. pylori eradication was associated with long-term disturbance in three hormones (active amylin, PP and total PYY) both pre- and post-prandially and one hormone (GLP-1) post-prandially. Longer post-eradication monitoring is needed to investigate the long-term impact of the observed hormonal changes on metabolic homeostasis. PMID:26291794

78 FR 59779 - Regulations Y and YY: Application of the Revised Capital Framework to the Capital Plan and Stress...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-09-30

... and YY: Application of the Revised Capital Framework to the Capital Plan and Stress Test Rules AGENCY... stress test rules to require a bank holding company with total consolidated assets of $50 billion or more... advanced approaches for a given capital plan and stress test cycle and makes minor, technical changes to...

Orbital Solutions and Absolute Elements of the Eclipsing Binary YY Ceti

NASA Astrophysics Data System (ADS)

Williamon, Richard M.; Sowell, James R.

2012-05-01

YY Cet is a 10.5 mag semidetached variable with a 19 hr orbital period. The Wilson-Devinney program is used to simultaneously solve two new sets of UBV light curves together with preexisting photometry and single-line radial velocity measurements . The system has the lower-mass component completely filling its Roche lobe. The resulting masses are M1 = 1.78 ± 0.19 M⊙ and M2 = 0.92 ± 0.10 M⊙, and the radii are R1 = 2.08 ± 0.08 R⊙ and R2 = 1.62 ± 0.06 R⊙. Its computed distance is 534 ± 28 pc. Light- and velocity-curve parameters, orbital elements, and absolute dimensions are presented. A study of published TOM observations indicates that the period changed around 1999.

A Prospective, Placebo-Controlled Pilot Evaluation of the Effect of Omeprazole on Serum Calcium, Magnesium, Cobalamin, Gastrin Concentrations, and Bone in Cats.

PubMed

Gould, E; Clements, C; Reed, A; Giori, L; Steiner, J M; Lidbury, J A; Suchodolski, J S; Brand, M; Moyers, T; Emery, L; Tolbert, M K

2016-05-01

Chronic proton pump inhibitor administration has been associated with electrolyte and cobalamin deficiency, disrupted bone homeostasis, hypergastrinemia, and rebound acid hypersecretion in humans. It is unknown if this occurs in cats. Prolonged oral omeprazole results in altered bone mineral density or content, serum calcium, magnesium, cobalamin, and gastrin concentrations in healthy cats. Six healthy adult DSH cats. In a within subjects, before and after design, cats received placebo followed by omeprazole (0.83-1.6 mg/kg PO q12h) for 60 days each. Analysis of serum calcium, magnesium, cobalamin, and gastrin concentrations was performed on days 0, 30, and 60. Bone density and content were evaluated on days 0 and 60 of each intervention. Continuous data were analyzed using a two-way ANOVA (α = 0.006). On day 60 of omeprazole administration, continuous intragastric pH monitoring was performed in 2 cats to evaluate the effects of abrupt withdrawal of omeprazole. No significant changes were detected between treatments for any variables, except serum gastrin, which was significantly higher during omeprazole treatment in comparison to placebo (P = 0.002). Evidence of gastric hyperacidity was seen in both cats in which intragastric pH monitoring was performed following cessation of omeprazole. Although further studies with larger populations of cats will be needed to draw any definitive conclusions, these preliminary results suggest that prolonged PPI treatment results in hypergastrinemia and abrupt PPI withdrawal might result in RAH in cats. Copyright © 2016 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.

Application of 2-chlorotrityl resin in solid phase synthesis of (Leu15)-gastrin I and unsulfated cholecystokinin octapeptide. Selective O-deprotection of tyrosine.

PubMed

Barlos, K; Gatos, D; Kapolos, S; Poulos, C; Schäfer, W; Yao, W Q

1991-12-01

The carboxyl terminal dipeptide amide, Fmoc-Asp-Phe-NH2, of gastrin and cholecystokinin (CCK) has been attached in high yield through its free side chain carboxyl group to the acid labile 2-chlorotrityl resin. The obtained peptide resin ester has been applied in the solid phase synthesis of partially protected (Leu15)-gastrin I utilising Fmoc-amino acids. Quantitative cleavage of this peptide from resin, with the t-butyl type side chain protection intact is achieved using mixtures of acetic acid/trifluoroethanol/dichloromethane. Under the same conditions complete detritylation of the tyrosine phenoxy function occurs simultaneously. Thus, the solid-phase synthesis of peptides selectively deprotected at the side chain of tyrosine is rendered possible by the use of 2-chlorotrityl resin and Fmoc-Tyr(Trt)-OH. The efficiency of this approach has been proved by the subsequent high-yield synthesis of three model peptides and the CCK-octapeptide.

Inhibition by somatostatin (growth-hormone release-inhibiting hormone, GH-RIH) of gastric acid and pepsin and G-cell release of gastrin.

PubMed Central

Barros D'sa, A A; Bloom, S R; Baron, J H

1978-01-01

Somatostatin (cyclic growth-hormone release-inhibiting hormone--GH-RIH) was infused into dogs with gastric fistulae. Somatostatin inhibited gastric acid response to four gastric stimulants--insulin, food, histamine, and pentagastrin. Histamine- and pentagastrin-stimulated pepsins were inhibited similarly to inhibition of acid. Somatostatin inhibited the gastrin response to insulin and food. PMID:348581

A model describing the effect of sex-reversed YY fish in an established wild population: The use of a Trojan Y chromosome to cause extinction of an introduced exotic species.

PubMed

Gutierrez, Juan B; Teem, John L

2006-07-21

A novel means of inducing extinction of an exotic fish population is proposed using a genetic approach to shift the ratio of male to females within a population. In the proposed strategy, sex-reversed fish containing two Y chromosomes are introduced into a normal fish population. These YY fish result in the production of a disproportionate number of male fish in subsequent generations. Mathematical modeling of the system following introduction of YY fish at a constant rate reveals that female fish decline in numbers over time, leading to eventual extinction of the population.

Gastrin-releasing peptide stimulates glycoconjugate release from feline trachea

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lundgren, J.D.; Baraniuk, J.N.; Ostrowski, N.L.

1990-02-01

The effect of gastrin-releasing peptide (GRP) on respiratory glycoconjugate (RGC) secretion was investigated in a feline tracheal organ culture model. RGC secretion was stimulated by GRP in a dose-dependent fashion at concentrations from 10(-8) to 10(-5) M (range 15-38% increase above control) with a peak effect within 0.5-1 h of incubation. GRP-(14-27), the receptor binding portion of GRP, and the related molecule, bombesin, also stimulated RGC secretion by approximately 20% above control. Acetyl-GRP-(20-27) stimulated RGC release by 10%, whereas GRP-(1-16) was inactive. Autoradiographic studies with 125I-GRP revealed that specific binding was restricted to the submucosal glands and the surface epithelium.more » A specific radioimmunoassay showed the content of GRP in feline trachea after extraction with ethanol-acetic acid to be 156 +/- 91 fmol/g wet wt. Indirect immunohistochemistry indicated that ganglion cells located just outside the cartilage contained GRP-immunoreactive materials. GRP is a novel mucus secretagogue that may participate in regulating airway mucosal gland secretion.« less

Y2 receptor gene variants reduce the risk of hypertension in obese children and adolescents.

PubMed

Santoro, Nicola; Del Giudice, Emanuele Miraglia; Grandone, Anna; Marzuillo, Pierluigi; Cozzolino, Domenico; Di Salvo, Giovanni; Pacileo, Giuseppe; Calabrò, Raffaele; Perrone, Laura

2008-08-01

To verify whether peptide YY (PYY) and its Y2 receptor (Y2R) gene variants can be associated with obesity or hypertension or both in a cohort of obese children and adolescents. Two hundred and twenty-nine obese children (105 girls, mean z-score BMI 5.1 +/- 2.4; mean age 10.5 +/- 2.9 years) and 250 age and sex-matched lean controls (130 women, mean z-score BMI 0.5 +/- 1.1; mean age 10.3 +/- 2.8) were enrolled in the study. Height, weight, BMI, waist circumference and 24-h systolic and diastolic blood pressure were measured. Night-time, day-time and 24-h systolic and diastolic blood pressures were evaluated by 24 h ambulatory blood pressure measurement, and appropriate standard deviation scores according to sex, age and height were calculated. Molecular screening of the PYY and Y2R genes was performed. No new mutations were found. We observed three previously described polymorphisms: G767C on PYY and T585C and T936C on Y2R. An association study was carried out in obese patients. No associations were found between the PYY genotypes and the studied phenotypes. The Y2R gene variants, T585C and T936C, which are in almost complete linkage disequilibrium, were found to be associated with night-time, day-time and 24-h systolic and diastolic blood pressures. In particular, subject homozygotes for the T allele showed lower systolic and diastolic blood pressure values compared with the other genotypes. Moreover, obese children homozygous for the T585 allele showed a lower risk of developing hypertension than patients carrying the CC and CT genotypes (chi 6.9; df = 1, P = 0.03; odds ratio = 0.5, 95% confidence interval: 0.27-0.88). Our results suggest that Y2R gene variants are involved in blood pressure regulation in obese children and adolescents.

Changes in appetite related gut hormones in intensive care unit patients: a pilot cohort study

PubMed Central

Nematy, Mohsen; O'Flynn, Jacqui E; Wandrag, Liesl; Brynes, Audrey E; Brett, Stephen J; Patterson, Michael; Ghatei, Mohammad A; Bloom, Stephen R; Frost, Gary S

2006-01-01

Introduction The nutritional status of patients in the intensive care unit (ICU) appears to decline not only during their stay in the ICU but also after discharge from the ICU. Recent evidence suggests that gut released peptides, such as ghrelin and peptide YY (PYY) regulate the initiation and termination of meals and could play a role in the altered eating behaviour of sick patients. The aim of this study was to assess the patterns of ghrelin and PYY levels during the stay of ICU patients in hospital. Methods Sixteen ICU patients (60 ± 4.7 years, body mass index (BMI) 28.1 ± 1.7 kg/m2 (mean ± standard error of the mean)) underwent fasting blood sample collections on days 1, 3, 5, 14, 21 and 28 of their stay at Hammersmith and Charing Cross Hospitals. Changes in appetite and biochemical and anthropometric markers of nutritional status were recorded. A comparison was made to a group of 36 healthy volunteers matched for age and BMI (54.3 ± 2.9 years, p = 0.3; BMI 25.8 ± 0.8 kg/m2 p = 0.2). Results Compared to healthy subjects, ICU patients exhibited a significantly lower level of ghrelin (day one 297.8 ± 76.3 versus 827.2 ± 78.7 pmol/l, p < 0.001) during their stay in the ICU. This tended to rise to the normal level during the last three weeks of hospital stay. Conversely, ICU patients showed a significantly higher level of PYY (day one 31.5 ± 9.6 versus 11.3 ± 1.0 pmol/l, p < 0.05) throughout their stay in the ICU and on the ward, with a downward trend to the normal level during the last three weeks of stay. Conclusions Results from our study show high levels of PYY and low levels of ghrelin in ICU patients compared to healthy controls. There appears to be a relationship between the level of these gut hormones and nutritional intake. PMID:16420657

Eclipsing cataclysmic variables. Deep eclipses in H0928+501. YY Draconis, the whirling dervish. New x ray pulsar candidates from HEAO-1

NASA Technical Reports Server (NTRS)

Patterson, Joseph

1993-01-01

The status report covering the period from 1 June 1992 to 31 May 1993 is included. Areas of research include: (1) eclipsing cataclysmic variables; (2) deep eclipses in H0928+501; (3) YY Draconis, the Whirling Dervish; and (4) new x ray pulsar candidates from HEAO-1.

Critical evaluation of the expression of gastrin-releasing peptide in dorsal root ganglia and spinal cord

PubMed Central

Barry, Devin M; Li, Hui; Liu, Xian-Yu; Shen, Kai-Feng; Liu, Xue-Ting; Wu, Zhen-Yu; Munanairi, Admire; Chen, Xiao-Jun; Yin, Jun; Sun, Yan-Gang; Li, Yun-Qing

2016-01-01

There are substantial disagreements about the expression of gastrin-releasing peptide (GRP) in sensory neurons and whether GRP antibody cross-reacts with substance P (SP). These concerns necessitate a critical revaluation of GRP expression using additional approaches. Here, we show that a widely used GRP antibody specifically recognizes GRP but not SP. In the spinal cord of mice lacking SP (Tac1 KO), the expression of not only GRP but also other peptides, notably neuropeptide Y (NPY), is significantly diminished. We detected Grp mRNA in dorsal root ganglias using reverse transcription polymerase chain reaction, in situ hybridization and RNA-seq. We demonstrated that Grp mRNA and protein are upregulated in dorsal root ganglias, but not in the spinal cord, of mice with chronic itch. Few GRP+ immunostaining signals were detected in spinal sections following dorsal rhizotomy and GRP+ cell bodies were not detected in dissociated dorsal horn neurons. Ultrastructural analysis further shows that substantially more GRPergic fibers form synaptic contacts with gastrin releasing peptide receptor-positive (GRPR+) neurons than SPergic fibers. Our comprehensive study demonstrates that a majority of GRPergic fibers are of primary afferent origin. A number of factors such as low copy number of Grp transcripts, small percentage of cells expressing Grp, and the use of an eGFP GENSAT transgenic as a surrogate for GRP protein have contributed to the controversy. Optimization of experimental procedures facilitates the specific detection of GRP expression in dorsal root ganglia neurons. PMID:27068287

Differential Secretion of Satiety Hormones With Progression of Obesity in JCR: LA-corpulent Rats

PubMed Central

Parnell, Jill A.; Reimer, Raylene A.

2013-01-01

Objective To characterize the gastrointestinal tract at the onset and in well-established obesity. Methods and Procedures Lean (+/?) and obese (cp/cp) male JCR:LA-cp rats lacking a functional leptin receptor were killed at 3.5 weeks and 9 months of age and plasma concentrations of satiety hormones determined. The small intestine, colon, and stomach were measured, weighed, and mRNA levels of satiety genes quantified. Results At the onset of obesity, obese rats had greater intestine, colon, and liver mass when adjusted for body weight compared to lean rats. Conversely, adult rats with established obesity had lower intestine and colon mass and length after adjustment for body weight. Early changes in gene expression included decreased ghrelin mRNA levels in stomach and increased peptide YY (PYY) mRNA levels in duodenum of young obese rats. After massive accumulation of adipose tissue had occurred, adult obese rats had increased proglucagon and ghrelin mRNA expression in the proximal intestine. In the distal small intestine, obese rats had lower proglucagon, ghrelin, and PYY mRNA levels. Finally, at the onset and in well-established obesity, obese rats had higher plasma insulin, amylin, glucagon like peptide-1 (GLP-1), and PYY, a finding, with the exception of insulin, unique to this model. Plasma total ghrelin levels were significantly lower at the onset of obesity and established obesity compared to the lean rats. Discussion Several defects are manifested in the obese gut early on in the disease before the accumulation of large excesses of body fat and represent potential targets for early intervention in obesity. PMID:18239578

The receptive function of hypothalamic and brainstem centres to hormonal and nutrient signals affecting energy balance.

PubMed

Riediger, Thomas

2012-11-01

The hypothalamic arcuate nucleus (ARC) and the area postrema (AP) represent targets for hormonal and metabolic signals involved in energy homoeostasis, e.g. glucose, amylin, insulin, leptin, peptide YY (PYY), glucagon-like peptide 1 (GLP-1) and ghrelin. Orexigenic neuropeptide Y expressing ARC neurons are activated by food deprivation and inhibited by feeding in a nutrient-dependent manner. PYY and leptin also reverse or prevent fasting-induced activation of the ARC. Interestingly, hypothalamic responses to fasting are blunted in different models of obesity (e.g. diet-induced obesity (DIO) or late-onset obesity). The AP also responds to feeding-related signals. The pancreatic hormone amylin acts via the AP to control energy intake. Amylin-sensitive AP neurons are also glucose-responsive. Furthermore, diet-derived protein attenuates amylin responsiveness suggesting a modulation of AP sensitivity by macronutrient supply. This review gives an overview of the receptive function of the ARC and the AP to hormonal and nutritional stimuli involved in the control of energy balance and the possible implications in the context of obesity. Collectively, there is consistency between the neurophysiological actions of these stimuli and their effects on energy homoeostasis under experimental conditions. However, surprisingly little progress has been made in the development of effective pharmacological approaches against obesity. A promising way to improve effectiveness involves combination treatments (e.g. amylin/leptin agonists). Hormonal alterations (e.g. GLP-1 and PYY) are also considered to mediate body weight loss observed in obese patients receiving bariatric surgery. The effects of hormonal and nutritional signals and their interactions might hold the potential to develop poly-mechanistic therapeutic strategies against obesity.

The Role of Episodic Postprandial Peptides in Exercise-Induced Compensatory Eating.

PubMed

Gibbons, Catherine; Blundell, John E; Caudwell, Phillipa; Webb, Dominic-Luc; Hellström, Per M; Näslund, Erik; Finlayson, Graham

2017-11-01

Prolonged physical activity gives rise to variable degrees of body weight and fat loss, and is associated with variability in appetite control. Whether these effects are modulated by postprandial, peptides is unclear. We examined the role of postprandial peptide response in compensatory eating during 12 weeks of aerobic exercise and in response to high-fat, low-carbohydrate (HFLC) and low-fat, high-carbohydrate (LFHC) meals. Of the 32 overweight/obese individuals, 16 completed 12 weeks of aerobic exercise and 16 nonexercising control subjects were matched for age and body mass index. Exercisers were classified as responders or nonresponders depending on net energy balance from observed compared with expected body composition changes from measured energy expenditure. Plasma samples were collected before and after meals to compare profiles of total and acylated ghrelin, insulin, cholecystokinin, glucagon-like peptide 1 (GLP-1), and total peptide YY (PYY) between HFLC and LFHC meals, pre- and postexercise, and between groups. No differences between pre- and postintervention peptide release. Responders had greater suppression of acylated ghrelin (P < 0.05) than nonresponders, as well as higher postprandial levels of GLP-1 (P < 0.001) and total PYY (P < 0.001) compared with nonresponders and control subjects. No impact on postprandial peptide release was found after 12 weeks of aerobic exercise. Responders to exercise-induced weight loss showed greater suppression of acylated ghrelin and greater release of GLP-1 and total PYY at baseline. Therefore, episodic postprandial peptide profiles appear to form part of the pre-existing physiology of exercise responders and suggest differences in satiety potential may underlie exercise-induced compensatory eating. Copyright © 2017 Endocrine Society

The effect of a long-acting somatostatin analogue (SMS 201-995) on intermediary metabolism and gut hormones after a test meal in normal subjects.

PubMed

Fuessl, H S; Burrin, J M; Williams, G; Adrian, T E; Bloom, S R

1987-08-01

SMS 201-995 is an octapeptide analogue of somatostatin. The effect of a single subcutaneous (s.c.) injection of 50 micrograms SMS 201-995 on post-prandial intermediary metabolism was investigated in normal subjects. In spite of a long-lasting post-prandial suppression of insulin secretion, there were no significant changes in the plasma concentration of alanine, glycerol, 3-OH-butyrate or lactate. However, SMS 201-995 impairs carbohydrate tolerance, probably due to inhibition of insulin secretion. Basal and post-prandial plasma concentrations of the gut regulatory peptides pancreatic glucagon, motilin, pancreatic polypeptide, gastric inhibitory polypeptide, enteroglucagon, gastrin and peptide YY were suppressed up to 5 hours after subcutaneous administration of a single dose of SMS 201-995.

Effect of a herbal extract powder (YY-312) from Imperata cylindrica Beauvois, Citrus unshiu Markovich, and Evodia officinalis Dode on body fat mass in overweight adults: a 12-week, randomized, double-blind, placebo-controlled, parallel-group clinical trial.

PubMed

Cho, Young-Gyu; Jung, Ji-Hye; Kang, Jae-Heon; Kwon, Jin Soo; Yu, Seung Pil; Baik, Tae Gon

2017-07-28

YY-312 is a herbal extract powder from Imperata cylindrica Beauvois, Citrus unshiu Markovich, and Evodia officinalis Dode, which have health promoting effects, including body fat reduction. We aimed to evaluate the efficacy and safety of YY-312 for body fat reduction in overweight adults. This was a 12-week, randomized, double-blind, placebo-controlled, parallel-group clinical trial performed in overweight Korean adults aged 19-60 years with a body mass index of 25.0-29.9 kg/m 2 . The daily dose of YY-312 was 2400 mg (containing 1800 mg of active herbal extract and 600 mg of cyclodextrin). Primary outcomes were reductions in body fat mass (BFM) and body fat percentage (BF%) after 12 weeks. Secondary outcomes included reductions in body weight and waist circumference (WC) after 12 weeks. After 12 weeks, BFM (1.6 kg vs. 0.1 kg; P = 0.023) and BF% (1.5% vs. -0.2%; P = 0.018) decreased significantly more in the YY-312 group than in the placebo group, as did body weight (2.7 kg vs. 1.0 kg; P = 0.014) and WC (2.2 cm vs. 0.8 cm; P = 0.049). All safety parameters were within normal limits; no serious adverse events occurred in either group. In a 12-week clinical trial in overweight adults, YY-312 resulted in significantly greater reduction in body fat vs. placebo, while being safe and well tolerated. cris.nih.go.kr: ( KCT0001225 ).

Y2-receptor-mediated selective inhibition of slow, inhibitory postsynaptic potential in submucous neurones of guinea-pig caecum.

PubMed Central

Cunningham, S M; Mihara, S; Lees, G M

1994-01-01

1. The subtype of neuropeptide Y receptor mediating the selective inhibition of the slow inhibitory postsynaptic potential (i.p.s.p.) of submucous neurones in guinea-pig caecum was investigated by use of conventional intracellular electrophysiological recording techniques. 2. Neuropeptide Y (NPY) (1-300 nM) was found to depress or abolish reversibly the slow i.p.s.p. evoked by focal stimulation of internodal fibre tracts. At low concentrations (1-30 nM), a reduction in the duration of the slow i.p.s.p. was often apparent before any inhibition of the amplitude of this synaptic potential. 3. These inhibitory effects of NPY were mimicked by peptide YY (PYY; 0.3-100 nM), NPY13-36 (1-300 nM) and NPY22-36 (10-100 nM); [Leu31,Pro34]NPY ([Pro34]NPY) and bovine pancreatic polypeptide (bPP) were without pre- or postsynaptic effects at concentrations of up to 300 nM. The IC50 +/- s.e. mean values for PYY, NPY, and NPY13-36 were 2.7 +/- 0.3, 7.8 +/- 2.1 and 30 +/- 4.8 nM, respectively, and were significantly different from each other. Thus, the apparent rank order of potency was PYY > NPY > NPY13-36 >> [Pro34]NPY and bPP. 4. In concentrations of up to 300 nM, NPY and its analogues had no depressant effects on the active and passive properties of the impaled neurone and did not affect the amplitude or duration of either cholinergic fast synaptic potentials or non-cholinergic, slow excitatory postsynaptic potentials (e.p.s.ps). Furthermore, none of these peptides altered the amplitude or time-course of changes in membrane potential induced by focal application of acetylcholine or noradrenaline.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7858881

Impact of medium and long chain triglycerides consumption on appetite and food intake in overweight men.

PubMed

St-Onge, M-P; Mayrsohn, B; O'Keeffe, M; Kissileff, H R; Choudhury, A R; Laferrère, B

2014-10-01

Medium chain triglycerides (MCT) enhance thermogenesis and may reduce food intake relative to long chain triglycerides (LCT). The goal of this study was to establish the effects of MCT on appetite and food intake and determine whether differences were due to differences in hormone concentrations. Two randomized, crossover studies were conducted in which overweight men consumed 20 g of MCT or corn oil (LCT) at breakfast. Blood samples were obtained over 3 h. In Study 1 (n=10), an ad lib lunch was served after 3 h. In Study 2 (n=7), a preload containing 10 g of test oil was given at 3 h and lunch was served 1 h later. Linear mixed model analyses were performed to determine the effects of MCT and LCT oil on change in hormones and metabolites from fasting, adjusting for body weight. Correlations were computed between differences in hormones just before the test meals and differences in intakes after the two oils for Study 1 only. Food intake at the lunch test meal after the MCT preload (Study 2) was (mean±s.e.m.) 532±389 kcal vs 804±486 kcal after LCT (P<0.05). MCT consumption resulted in a lower rise in triglycerides (P=0.014) and glucose (P=0.066) and a higher rise in peptide YY (PYY, P=0.017) and leptin (P=0.036) compared with LCT (combined data). Correlations between differences in hormone levels (glucagon-like peptide (GLP-1), PYY) and differences in food intake were in the opposite direction to expectations. MCT consumption reduced food intake acutely but this does not seem to be mediated by changes in GLP-1, PYY and insulin.

Effects of exercise intensity on plasma concentrations of appetite-regulating hormones: Potential mechanisms.

PubMed

Hazell, Tom J; Islam, Hashim; Townsend, Logan K; Schmale, Matt S; Copeland, Jennifer L

2016-03-01

The physiological control of appetite regulation involves circulating hormones with orexigenic (appetite-stimulating) and anorexigenic (appetite-inhibiting) properties that induce alterations in energy intake via perceptions of hunger and satiety. As the effectiveness of exercise to induce weight loss is a controversial topic, there is considerable interest in the effect of exercise on the appetite-regulating hormones such as acylated ghrelin, peptide YY (PYY), glucagon-like peptide-1 (GLP-1), and pancreatic polypeptide (PP). Research to date suggests short-term appetite regulation following a single exercise session is likely affected by decreases in acylated ghrelin and increases in PYY, GLP-1, and PP. Further, this exercise-induced response may be intensity-dependent. In an effort to guide future research, it is important to consider how exercise alters the circulating concentrations of these appetite-regulating hormones. Potential mechanisms include blood redistribution, sympathetic nervous system activity, gastrointestinal motility, cytokine release, free fatty acid concentrations, lactate production, and changes in plasma glucose and insulin concentrations. This review of relevant research suggests blood redistribution during exercise may be important for suppressing ghrelin, while other mechanisms involving cytokine release, changes in plasma glucose and insulin concentrations, SNS activity, and muscle metabolism likely mediate changes in the anorexigenic signals PYY and GLP-1. Overall, changes in appetite-regulating hormones following acute exercise appear to be intensity-dependent, with increasing intensity leading to a greater suppression of orexigenic signals and greater stimulation of anorexigenic signals. However, there is less research on how exercise-induced responses in appetite-regulating hormones differ between sexes or different age groups. A better understanding of how exercise intensity and workload affect appetite across the sexes and life

Suggestion of new possibilities in approaching individual variability in appetite through constitutional typology: a pilot study

PubMed Central

2012-01-01

Background Appetite is intricately connected to eating behaviors and shows a high individual variability. In an attempt to approach the problem of gut hormone profiles, appetite, and eating behaviors at the individual level, we have adopted a constitutional typing system widely used in traditional East-Asian medicine, the Sasang constitutional typology, in order to determine the individual variations in appetite, eating behavior, and weight change. Methods This pilot study was designed to investigate the variability of appetite among individuals by tracking the gut hormone patterns across different constitutional types. Pre- and post-prandial concentrations of anorectic (peptide YY (PYY), glucagon-like peptide 1 (GLP-1)) and orexigenic (active ghrelin) gut hormones were measured in healthy, normal-weight (18.5 kg/m2 ≤BMI <23 kg/m2) male subjects aged 20–35 (Soyang (SY) (n = 9), Taeeum (TE) (n = 9), and Soeum (SE) (n = 10) constitutional types). Results Significant differences were found only in the PYY concentrations across the three groups (p = 0.031). The PYY concentration peaked at 30-min post-prandial in the SE group and was significantly higher compared to the other two groups (p = 0.004). The GLP-1 concentration peaked at 15-min post-prandial in the SE group (not significant). The ghrelin levels at 30-min pre-prandial were relatively lower in the TE group compared to the other groups (not significant). Conclusions In conclusion, although with weak statistical power, meaningful gut hormone patterns specific to each constitutional type were discovered in this pilot study, which could offer a new method of approaching the problem of appetite and eating behavior from the angle of individual variability in appetite. PMID:22889232

Interactions of the hormones leptin, ghrelin, adiponectin, resistin, and PYY3-36 with the reproductive system.

PubMed

Budak, Erdal; Fernández Sánchez, Manuel; Bellver, José; Cerveró, Ana; Simón, Carlos; Pellicer, Antonio

2006-06-01

To summarize the effects of novel hormones (leptin, ghrelin, adiponectin, resistin, and PYY3-36) secreted from adipose tissue and the gastrointestinal tract that have been discovered to exert different effects on several reproductive functions, such as the hypothalamic-pituitary-gonadal axis, embryo development, implantation physiology, and clinically relevant conditions. A MEDLINE computer search was performed to identify relevant articles. Leptin and ghrelin exert important roles on body weight regulation, eating behavior, and reproduction, acting on the central nervous system and target reproductive organs. As a marker of adequate nutritional stores, these hormones may act on the central nervous system to initiate the complex process of puberty and maintain normal reproductive function. In addition, leptin and ghrelin and their receptors are involved in reproductive events such as gonadal function, embryo development, and embryo-endometrial interaction. Leptin and ghrelin and other adipose tissue-secreted hormones have significant effects on reproduction. Acting through the brain, these hormones may serve as links between adipose tissue and the reproductive system to supply and regulate energy needs for normal reproduction and pregnancy. Future studies are needed to further clarify the role of these hormones in reproductive events and other related gynecological conditions.

Effect of Sipjeondaebo-Tang on Cancer-Induced Anorexia and Cachexia in CT-26 Tumor-Bearing Mice

PubMed Central

Jung, Ki Yong; Woo, Sang-Mi; Jun, Chan-Yong; Park, Jong Hyeong; Shin, Yong Cheol; Ko, Seong-Gyu

2014-01-01

Cancer-associated anorexia and cachexia are a multifactorial condition described by a loss of body weight and muscle with anorexia, asthenia, and anemia. Moreover, they correlate with a high mortality rate, poor response to chemotherapy, poor performance status, and poor quality of life. Cancer cachexia is regulated by proinflammatory cytokines such as interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor-α (TNF-α). In addition, glucagon like peptide-1 (GIP-1), peptide YY (PYY), ghrelin, and leptin plays a crucial role in food intake. In this study, we investigated the therapeutic effects of one of the traditional herbal medicines, Sipjeondaebo-tang (Juzen-taiho-to in Japanese; SJDBT), on cancer anorexia and cachexia in a fundamental mouse cancer anorexia/cachexia model, CT-26 tumor-bearing mice. SJDBT was more significantly effective in a treatment model where it was treated after anorexia and cachexia than in a prevention model where it was treated before anorexia and cachexia on the basis of parameters such as weights of muscles and whole body and food intakes. Moreover, SJDBT inhibited a production of IL-6, MCP-1, PYY, and GLP-1 and ameliorated cancer-induced anemia. Therefore, our in vivo studies provide evidence on the role of SJDBT in cancer-associated anorexia and cachexia, thereby suggesting that SJDBT may be useful for treating cancer-associated anorexia and cachexia. PMID:24963216

Effect of Sipjeondaebo-tang on cancer-induced anorexia and cachexia in CT-26 tumor-bearing mice.

PubMed

Choi, Youn Kyung; Jung, Ki Yong; Woo, Sang-Mi; Yun, Yee Jin; Jun, Chan-Yong; Park, Jong Hyeong; Shin, Yong Cheol; Cho, Sung-Gook; Ko, Seong-Gyu

2014-01-01

Cancer-associated anorexia and cachexia are a multifactorial condition described by a loss of body weight and muscle with anorexia, asthenia, and anemia. Moreover, they correlate with a high mortality rate, poor response to chemotherapy, poor performance status, and poor quality of life. Cancer cachexia is regulated by proinflammatory cytokines such as interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor- α (TNF- α). In addition, glucagon like peptide-1 (GIP-1), peptide YY (PYY), ghrelin, and leptin plays a crucial role in food intake. In this study, we investigated the therapeutic effects of one of the traditional herbal medicines, Sipjeondaebo-tang (Juzen-taiho-to in Japanese; SJDBT), on cancer anorexia and cachexia in a fundamental mouse cancer anorexia/cachexia model, CT-26 tumor-bearing mice. SJDBT was more significantly effective in a treatment model where it was treated after anorexia and cachexia than in a prevention model where it was treated before anorexia and cachexia on the basis of parameters such as weights of muscles and whole body and food intakes. Moreover, SJDBT inhibited a production of IL-6, MCP-1, PYY, and GLP-1 and ameliorated cancer-induced anemia. Therefore, our in vivo studies provide evidence on the role of SJDBT in cancer-associated anorexia and cachexia, thereby suggesting that SJDBT may be useful for treating cancer-associated anorexia and cachexia.

Facile solid-phase synthesis of sulfated tyrosine-containing peptides: total synthesis of human big gastrin-II and cholecystokinin (CCK)-39.

PubMed

Kitagawa, K; Aida, C; Fujiwara, H; Yagami, T; Futaki, S; Kogire, M; Ida, J; Inoue, K

2001-01-12

Chemical synthesis of tyrosine O-sulfated peptides is still a laborious task for peptide chemists because of the intrinsic acid-lability of the sulfate moiety. An efficient cleavage/deprotection procedure without loss of the sulfate is the critical difficulty remaining to be solved for fluoren-9-ylmethoxycarbonyl (Fmoc)-based solid-phase synthesis of sulfated peptides. To overcome the difficulty, TFA-mediated solvolysis rates of a tyrosine O-sulfate [Tyr(SO3H)] residue and two protecting groups, tBu for the hydroxyl group of Ser and 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl (Pbf) for the guanidino group of Arg, were examined in detail. The desulfation obeyed first-order kinetics with a large entropy (59.6 J.K-1.mol-1) and enthalpy (110.5 kJ.mol-1) of activation. These values substantiated that the desulfation rate of the rigidly solvated Tyr(SO3H) residue was strongly temperature-dependent. By contrast, the SN1-type deprotections were less temperature-dependent and proceeded smoothly in TFA of a high ionizing power. Based on the large rate difference between the desulfation and the SN1-type deprotections in cold TFA, an efficient deprotection protocol for the sulfated peptides was developed. Our synthetic strategy for Tyr(SO3H)-containing peptides with this effective deprotection protocol is as follows: (i) a sulfated peptide chain is directly constructed on 2-chlorotrityl resin with Fmoc-based solid-phase chemistry using Fmoc-Tyr(SO3Na)-OH as a building block; (ii) the protected peptide-resin is treated with 90% aqueous TFA at 0 degree C for an appropriate period of time for the cleavage and deprotection. Human cholecystokinin (CCK)-12, mini gastrin-II (14 residues), and little gastrin-II (17 residues) were synthesized with this method in 26-38% yields without any difficulties. This method was further applied to the stepwise synthesis of human big gastrin-II (34 residues), CCK-33 and -39. Despite the prolonged acid treatment (15-18 h at 0 degree C), the

Ghrelin, the proglucagon-derived peptides and peptide YY in nutrient homeostasis.

PubMed

Dong, Charlotte X; Brubaker, Patricia L

2012-12-01

Dysregulation of nutrient homeostasis is implicated in the current epidemics of obesity and type 2 diabetes mellitus. The maintenance of homeostasis in the setting of repeated cycles of feeding and fasting occurs through complex interactions between metabolic, hormonal and neural factors. Although pancreatic islets, the liver, muscle, adipocytes and the central nervous system are all key players in this network, the gastrointestinal tract is the first tissue exposed to ingested nutrients and thus has an important role. This Review focuses on several of the endocrine hormones released by the gastrointestinal tract prior to or during nutrient ingestion that have key roles in maintaining energy balance. These hormones include the gastric orexigenic hormone, ghrelin, and the distal L cell anorexigenic and metabolic hormones, glucagon-like peptide (GLP)-1, GLP-2, oxyntomodulin and peptide YY. Each of these hormones exerts a distinct set of biological actions to maintain nutrient homeostasis, the properties of which are currently, or might soon be, exploited in the clinic for the treatment of obesity and type 2 diabetes mellitus.

Effects of bolus doses of fat on small intestinal structure and on release of gastrin, cholecystokinin, peptide tyrosine-tyrosine, and enteroglucagon.

PubMed Central

Jenkins, A P; Ghatei, M A; Bloom, S R; Thompson, R P

1992-01-01

To investigate the enterotrophic effects of bolus doses of long chain triglycerides, two groups of eight female Wistar rats were fed identical diets with 48.2% total calories as the essential fatty acid rich oil Efamol. To one group the oil was given in twice daily bolus doses by gavage, while for the other group the oil was mixed with the remainder of the feed and thus consumed over 24 hours. The animals were killed after 20 to 22 days. Bolus dosing significantly increased parameters of mucosal mass along the length of the small intestine in association with an increase in two hour accumulation of vincristine arrested metaphases in small intestinal crypts. In a second experiment, four replicate studies were carried out, each involving two groups of 12 rats respectively fed as described above. After 21 days one animal from each group was killed every two hours, providing regular plasma samples over 24 hours for measurement of gastrin, cholecystokinin, peptide tyrosine-tyrosine and enteroglucagon. Bolus dosing markedly enhanced release of peptide tyrosine-tyrosine and enteroglucagon, but not of gastrin or cholecystokinin. Thus, the enhanced enterotrophic effects of bolus doses of long chain triglycerides could be mediated by release of a distally located gut peptide, perhaps enteroglucagon. PMID:1541417

Essential Roles of Raf/Extracellular Signal-regulated Kinase/Mitogen-activated Protein Kinase Pathway, YY1, and Ca2+ Influx in Growth Arrest of Human Vascular Smooth Muscle Cells by Bilirubin*

PubMed Central

Stoeckius, Marlon; Erat, Anna; Fujikawa, Tatsuya; Hiromura, Makoto; Koulova, Anna; Otterbein, Leo; Bianchi, Cesario; Tobiasch, Edda; Dagon, Yossi; Sellke, Frank W.; Usheva, Anny

2012-01-01

The biological effects of bilirubin, still poorly understood, are concentration-dependent ranging from cell protection to toxicity. Here we present data that at high nontoxic physiological concentrations, bilirubin inhibits growth of proliferating human coronary artery smooth muscle cells by three events. It impairs the activation of Raf/ERK/MAPK pathway and the cellular Raf and cyclin D1 content that results in retinoblastoma protein hypophosphorylation on amino acids S608 and S780. These events impede the release of YY1 to the nuclei and its availability to regulate the expression of genes and to support cellular proliferation. Moreover, altered calcium influx and calpain II protease activation leads to proteolytical degradation of transcription factor YY1. We conclude that in the serum-stimulated human vascular smooth muscle primary cell cultures, bilirubin favors growth arrest, and we propose that this activity is regulated by its interaction with the Raf/ERK/MAPK pathway, effect on cyclin D1 and Raf content, altered retinoblastoma protein profile of hypophosphorylation, calcium influx, and YY1 proteolysis. We propose that these activities together culminate in diminished 5 S and 45 S ribosomal RNA synthesis and cell growth arrest. The observations provide important mechanistic insight into the molecular mechanisms underlying the transition of human vascular smooth muscle cells from proliferative to contractile phenotype and the role of bilirubin in this transition. PMID:22262839

Systematic review with meta-analysis: diagnostic performance of the combination of pepsinogen, gastrin-17 and anti-Helicobacter pylori antibodies serum assays for the diagnosis of atrophic gastritis.

PubMed

Zagari, R M; Rabitti, S; Greenwood, D C; Eusebi, L H; Vestito, A; Bazzoli, F

2017-10-01

The combination of pepsinogen, gastrin-17 and anti-H. pylori antibodies serological assays (panel test) is a non-invasive tool for the diagnosis of atrophic gastritis. However, the diagnostic reliability of this test is still uncertain. To assess the diagnostic performance of the serum panel test for the diagnosis of atrophic gastritis. Medline via PubMed, Embase, Scopus, Cochrane Library databases and abstracts of international conferences proceedings were searched from January 1995 to December 2016 using the primary keywords "pepsinogens," "gastrin," "atrophic gastritis," "gastric precancerous lesions." Studies were included if they assessed the accuracy of the serum panel test for the diagnosis of atrophic gastritis using histology according to the updated Sydney System as reference standard. Twenty studies with a total of 4241 subjects assessed the performance of serum panel test for the diagnosis of atrophic gastritis regardless of the site in the stomach. The summary sensitivity was 74.7% (95% confidence interval (CI), 62.0-84.3) and the specificity was 95.6% (95%CI, 92.6-97.4). With a prevalence of atrophic gastritis of 27% (median prevalence across the studies), the negative predictive value was 91%. Few studies with small sample size assessed the performance of the test in detecting the site of atrophic gastritis. The combination of pepsinogen, gastrin-17 and anti-H. pylori antibodies serological assays appears to be a reliable tool for the diagnosis of atrophic gastritis. This test may be used for screening subjects or populations at high risk of gastric cancer for atrophic gastritis; however, a cost-effectiveness analysis is needed. © 2017 John Wiley & Sons Ltd.

The Diagnostic Value of Gastrin-17 Detection in Atrophic Gastritis

PubMed Central

Wang, Xu; Ling, Li; Li, Shanshan; Qin, Guiping; Cui, Wei; Li, Xiang; Ni, Hong

2016-01-01

Abstract A meta-analysis was performed to assess the diagnostic value of gastrin-17 (G-17) for the early detection of chronic atrophic gastritis (CAG). An extensive literature search was performed, with the aim of selecting publications that reported the accuracy of G-17 in predicting CAG, in the following databases: PubMed, Science Direct, Web of Science, Chinese Biological Medicine, Chinese National Knowledge Infrastructure, Wanfang, and VIP. To assess the diagnostic value of G-17, the following statistics were estimated and described: sensitivity, specificity, diagnostic odds ratios (DOR), summary receiver operating characteristic curves, area under the curve (AUC), and 95% confidence intervals (CIs). Thirteen studies that met the inclusion criteria were included in this meta-analysis, comprising 894 patients and 1950 controls. The pooled sensitivity and specificity of these studies were 0.48 (95% CI: 0.45–0.51) and 0.79 (95% CI: 0.77–0.81), respectively. The DOR was 5.93 (95% CI: 2.93–11.99), and the AUC was 0.82. G-17 may have potential diagnostic value because it has good specificity and a moderate DOR and AUC for CAG. However, more studies are needed to improve the sensitivity of this diagnostic tool in the future. PMID:27149493

Single oral doses of netazepide (YF476), a gastrin receptor antagonist, cause dose-dependent, sustained increases in gastric pH compared with placebo and ranitidine in healthy subjects.

PubMed

Boyce, M; David, O; Darwin, K; Mitchell, T; Johnston, A; Warrington, S

2012-07-01

Nonclinical studies have shown netazepide (YF476) to be a potent, selective, competitive and orally active gastrin receptor antagonist. To administer to humans for the first time single oral doses of netazepide, to assess their tolerability, safety, pharmacokinetics and effect on 24-h gastric pH. We did two randomised double-blind single-dose studies in healthy subjects. The first (n = 12) was a six-way incomplete crossover pilot study of rising doses of netazepide (range 0.5-100 mg) and placebo. The second (n = 20) was a five-way complete crossover study of netazepide 5, 25 and 100 mg, ranitidine 150 mg and placebo. In both trials we collected frequent blood samples, measured plasma netazepide and calculated pharmacokinetic parameters. In the comparative trial we measured gastric pH continuously for 24 h and compared treatments by percentage time gastric pH ≥4. Netazepide was well tolerated. Median t (max) and t (½) for the 100 mg dose were about 1 and 7 h, respectively, and the pharmacokinetics were dose-proportional. Netazepide and ranitidine each increased gastric pH. Onset of activity was similarly rapid for both. All netazepide doses were more effective than placebo (P ≤ 0.023). Compared with ranitidine, netazepide 5 mg was as effective, and netazepide 25 and 100 mg were much more effective (P ≤ 0.010), over the 24 h after dosing. Activity of ranitidine lasted about 12 h, whereas that of netazepide exceeded 24 h. In human: netazepide is an orally active gastrin antagonist, and gastrin has a major role in controlling gastric acidity. Repeated-dose studies are justified. NCT01538784 and NCT01538797. © 2012 Blackwell Publishing Ltd.

Early-effect of bariatric surgery (Scopinaro method) on intestinal hormones and adipokines in insulin resistant Wistar rat.

PubMed

Dib, N; Kiciak, A; Pietrzak, P; Ferenc, K; Jaworski, P; Kapica, M; Tarnowski, W; Zabielski, R

2013-10-01

Bariatric surgery consists in duodenal exclusion from the food passage in obese patients with coexistent type 2 diabetes. Nowadays bariatric surgery is considered the most effective method of glycemic index normalization and insulin resistance reduction. Recent results on obese and non-obese rats showed remission of type 2 diabetes symptoms within few days after the surgery. The aim of the present work was to analyze the mechanisms of neuro-hormonal regulation responsible for early normalization of metabolic syndrome after bariatric surgery. In present study the concentration of selected intestinal hormones and adipokines in blood plasma and gastrointestinal tissues were analyzed. Study was conducted on Wistar rats. Animals were divided into three groups (each n=6): control (SH) shame-operated rats; animals in which visceral fat tissue was extracted (LP); and rats in which Scopinaro bariatric surgery was performed (BPD). Immunochemistry analysis of blood plasma showed decrease of insulin concentration in BPD and LP and increase of polypeptide YY (PYY) in BPD group as compared to the control. In duodenal mucosa homogenates the tendency to reduce insulin in LP and BPD group, and increase PYY and visfatin in BPD group was observed. Histometry analysis showed reduction of mucosa thickness in excluded segments of gastrointestinal tract in BPD group as compared to the SH and LP. Concluding, model studies on rats allowed better understanding of mechanisms important for early normalization of glycemic index and insulin resistance reduction in rats.

Topical application of benzalkonium chloride to the stomach serosa increases gastric emptying time, acid secretion, serum gastrin and size of the mucosa.

PubMed

Zucoloto, S; Romanello, L M F; Garcia, S B; Sobreira, L F R; Barbosa, A J A; Troncon, L E A

2002-11-01

In the present study we evaluated the effects of gastric myenteric denervation using benzalkonium chloride (BAC) on the time for gastric emptying, as well as gastric secretion, and mucosal epithelial cell size and population in rats. Wistar rats were treated with topical serosal application of BAC to the stomach. Control animals received saline. Ninety days after surgery, gastric emptying time, gastric acid secretion and serum gastrin levels were studied. Next, the animals were sacrificed and the stomachs were removed, fixed in formalin and histologically processed for histomorphometry of the height, area and volume of the glandular portion, and volume and population of mucous, chief, parietal, G- and labelled cells. BAC animals showed a significant delay in gastric emptying and an increase in gastric acid secretion and serum gastrin levels. These animals also presented a significant reduction of myenteric neuron number, hypertrophy of parietal and chief cells, hyperplasia of G cells and an increase in the gastric mucosa area. The absence of the myenteric plexus seems to protect the stomach from the hyperplastic effects of hypergastrinemia. Gastric food stasis may act as a factor triggering morphological and functional alterations of the gastric epithelium. Although gastric food stasis is a common finding in medical practice, its physiopathological consequences are poorly understood and have not been frequently discussed in the literature.

Development of novel ligands for peptide GPCRs.

PubMed

Moran, Brian M; McKillop, Aine M; O'Harte, Finbarr Pm

2016-12-01

Incretin based glucagon-like peptide-1 receptor (GLP-1R) agonists which target a G-protein coupled receptor (GPCR) are currently used in the treatment of type 2 diabetes. This review focuses on GPCRs from pancreatic β-cells, including GLP-1, glucose-dependent insulinotropic polypeptide (GIP), glucagon, somatostatin, pancreatic polypeptide (PP), cholecystokinin (CCK), peptide YY (PYY), oxyntomodulin (OXM) and ghrelin receptors. In addition, fatty acids GPCRs are thought to have an increasing role in regulating peptide secretions namely short fatty acids GPCR (GPR41, GPR43), medium chain fatty acid GPCR (GPR84), long chain fatty acid GPCR (GPR40, GPR120) and cannabinoid-like GPCR (GPR55, GPR119). Several pre-clinical and clinical trials are currently ongoing in peptide GPCR based therapies, including dual and triple agonist peptides which activate two or more GPCRs simultaneously. Copyright © 2016 Elsevier Ltd. All rights reserved.

Effects of rabeprazole, 20 mg, or esomeprazole, 20 mg, on 24-h intragastric pH and serum gastrin in healthy subjects.

PubMed

Warrington, S; Baisley, K; Boyce, M; Tejura, B; Morocutti, A; Miller, N

2002-07-01

To compare the antisecretory effects of rabeprazole and esomeprazole in an open, randomized, two-way crossover, clinical pharmacology study. Twenty-four healthy subjects (14 men, 10 women; mean age 26.8 years) received rabeprazole 20 mg or esomeprazole 20 mg daily on days 1-5, with a 14-day 'wash-out'. Intragastric pH was recorded continuously, and serum gastrin measured, on days 0, 1 and 5. On day 0, mean intragastric pH AUC was significantly higher before the esomeprazole than before the rabeprazole treatment in four of the five time intervals analysed. On days 1 and 5, mean intragastric pH AUC was higher after rabeprazole than esomeprazole during 5-11, 14-24 and 0-24 h after dosing. Mean pH AUC in the first 5 h after dosing on day 5 was higher after esomeprazole than rabeprazole (P=0.012). On day 1, mean per cent times pH > 3 and > 4 were significantly greater after rabeprazole than esomeprazole during 0-14, 14-24 and 0-24 h. On day 5, mean serum gastrin AUC0-4 was higher (P = 0.017) after rabeprazole than esomeprazole (335 vs. 316 pg/mL.h). In this clinical pharmacology study, rabeprazole 20 mg daily was more effective than esomeprazole 20 mg daily in increasing intragastric pH and maintaining pH > 3 and > 4. On day 5, mean pH AUC was higher after esomeprazole than rabeprazole.

Intraduodenal infusion of a combination of tastants decreases food intake in humans.

PubMed

van Avesaat, Mark; Troost, Freddy J; Ripken, Dina; Peters, Jelmer; Hendriks, Henk Fj; Masclee, Ad Am

2015-10-01

Taste receptors are expressed not only in taste buds but also in the gastrointestinal tract. It has been hypothesized that these receptors may play a role in satiety and food intake. This study investigated the effect of intraduodenal tastant infusions (bitter, sweet, and umami) on food intake, hunger and fullness, gastrointestinal symptoms, and gastrointestinal peptide release. Fifteen healthy volunteers [6 male; mean ± SEM age: 23.9 ± 2.0 y; mean ± SEM body mass index (in kg/m(2)): 22.4 ± 0.3] received 5 treatments in a double-blind, randomized, placebo-controlled crossover design. Test days started with the insertion of a nasoduodenal catheter followed by a standardized liquid breakfast. Participants received an intraduodenal infusion 150 min after breakfast, containing quinine (bitter), rebaudioside A (sweet), monosodium glutamate (umami), a combination of the 3 tastants, or placebo (tap water) over a period of 60 min. Food intake was measured during an ad libitum meal, and visual analog scales were used to monitor gastrointestinal complaints and hunger and fullness scores. Blood samples were drawn at regular intervals for cholecystokinin, glucagon-like peptide 1 (GLP-1), and peptide YY (PYY) analysis. Infusion of the combination of tastants substantially decreased food intake (422 ± 97 compared with 486 ± 104 kcal for placebo, P < 0.05), whereas both a combination of tastants and umami decreased hunger scores compared with placebo. No change in cholecystokinin, GLP-1, or PYY concentrations was observed during the infusions. Intraduodenal infusions of the tastants did not result in gastrointestinal symptoms. Intraduodenal infusion of umami and a combination of tastants inhibits feelings of hunger, but only the latter also reduces food intake. However, these alterations were not accompanied by changes in the plasma concentrations of the gut-derived peptides cholecystokinin, GLP-1, or PYY. This trial was registered at clinicaltrials.gov as NCT01956838. �

Timeline of changes in appetite during weight loss with a ketogenic diet.

PubMed

Nymo, S; Coutinho, S R; Jørgensen, J; Rehfeld, J F; Truby, H; Kulseng, B; Martins, C

2017-08-01

Diet-induced weight loss (WL) leads to increased hunger and reduced fullness feelings, increased ghrelin and reduced satiety peptides concentration (glucagon-like peptide-1 (GLP-1), cholecystokinin (CCK) and peptide YY (PYY)). Ketogenic diets seem to minimise or supress some of these responses. The aim of this study was to determine the timeline over which changes in appetite occur during progressive WL with a ketogenic very-low-energy diet (VLED). Thirty-one sedentary adults (18 men), with obesity (body mass index: 37±4.5 kg m -2 ) underwent 8 weeks (wks) of a VLED followed by 4 wks of weight maintenance. Body weight and composition, subjective feelings of appetite and appetite-related hormones (insulin, active ghrelin (AG), active GLP-1, total PYY and CCK) were measured in fasting and postprandially, at baseline, on day 3 of the diet, 5 and 10% WL, and at wks 9 and 13. Data are shown as mean±s.d. A significant increase in fasting hunger was observed by day 3 (2±1% WL), (P<0.01), 5% WL (12±8 days) (P<0.05) and wk 13 (17±2% WL) (P<0.05). Increased desire to eat was observed by day 3 (P<0.01) and 5% WL (P<0.05). Postprandial prospective food consumption was significantly reduced at wk 9 (16±2% WL) (P<0.01). Basal total PYY was significantly reduced at 10% WL (32±8 days) (P<0.05). Postprandial active GLP-1 was increased at 5% WL (P<0.01) and CCK reduced at 5 and 10% WL (P<0.01, for both) and wk 9 (P<0.001). Basal and postprandial AG were significantly increased at wk 13 (P<0.001, both). WL with a ketogenic VLED transiently increases the drive to eat up to 3 weeks (5% WL). After that, and while participants are ketotic, a 10-17% WL is not associated with increased appetite. However, hunger feelings and AG concentrations increase significantly from baseline, once refeeding occurs.

l-phenylalanine modulates gut hormone release and glucose tolerance, and suppresses food intake through the calcium-sensing receptor in rodents.

PubMed

Alamshah, A; Spreckley, E; Norton, M; Kinsey-Jones, J S; Amin, A; Ramgulam, A; Cao, Y; Johnson, R; Saleh, K; Akalestou, E; Malik, Z; Gonzalez-Abuin, N; Jomard, A; Amarsi, R; Moolla, A; Sargent, P R; Gray, G W; Bloom, S R; Murphy, K G

2017-11-01

High-protein diets (HPDs) are associated with greater satiety and weight loss than diets rich in other macronutrients. The exact mechanisms by which HPDs exert their effects are unclear. However, evidence suggests that the sensing of amino acids produced as a result of protein digestion may have a role in appetite regulation and satiety. We investigated the effects of l-phenylalanine (L-Phe) on food intake and glucose homeostasis in rodents. We investigated the effects of the aromatic amino-acid and calcium-sensing receptor (CaSR) agonist l-phenylalanine (L-Phe) on food intake and the release of the gastrointestinal (GI) hormones peptide YY (PYY), glucagon-like peptide-1 (GLP-1) and ghrelin in rodents, and the role of the CaSR in mediating these effects in vitro and in vivo. We also examined the effect of oral l-Phe administration on glucose tolerance in rats. Oral administration of l-Phe acutely reduced food intake in rats and mice, and chronically reduced food intake and body weight in diet-induced obese mice. Ileal l-Phe also reduced food intake in rats. l-Phe stimulated GLP-1 and PYY release, and reduced plasma ghrelin, and also stimulated insulin release and improved glucose tolerance in rats. Pharmacological blockade of the CaSR attenuated the anorectic effect of intra-ileal l-Phe in rats, and l-Phe-induced GLP-1 release from STC-1 and primary L cells was attenuated by CaSR blockade. l-Phe reduced food intake, stimulated GLP-1 and PYY release, and reduced plasma ghrelin in rodents. Our data provide evidence that the anorectic effects of l-Phe are mediated via the CaSR, and suggest that l-Phe and the CaSR system in the GI tract may have therapeutic utility in the treatment of obesity and diabetes. Further work is required to determine the physiological role of the CaSR in protein sensing in the gut, and the role of this system in humans.

Single nucleotide polymorphisms in the neuropeptide Y2 receptor (NPY2R) gene and association with severe obesity in French white subjects.

PubMed

Siddiq, A; Gueorguiev, M; Samson, C; Hercberg, S; Heude, B; Levy-Marchal, C; Jouret, B; Weill, J; Meyre, D; Walley, A; Froguel, P

2007-03-01

Genetic variants of genes for peptide YY (PYY), neuropeptide Y2 receptor (NPY2R) and pancreatic polypeptide (PPY) were investigated for association with severe obesity. The initial screening of the genes for variants was performed by sequencing in a group of severely obese subjects (n=161). Case-control analysis of the common variants was then carried out in 557 severely obese adults, 515 severely obese children and 1,163 non-obese/non-diabetic control subjects. Rare variants were genotyped in 700 obese children and the non-obese/non-diabetic control subjects (n=1,163). Significant association was found for a 5' variant (rs6857715) in the NPY2R gene with both severe adult obesity (p=0.002) and childhood obesity (p=0.02). This significant association was further supported by a pooled allelic analysis of all obese cases (adults and children, n=928) vs the control subjects (n=938) (p=0.0004, odds ratio=1.3, 95% CI 1.1-1.5). Quantitative trait analysis of BMI and WHR was performed and significant association was observed for SNP rs1047214 in NPY2R with an increase in WHR in the severely obese children (co-dominant model p=0.005, recessive model p=0.001). Association was also observed for an intron 3 variant (rs162430) in the PYY gene with childhood obesity (p=0.04). No significant associations were observed for PPY variants. Only one rare variant in the NPY2R gene (C-5641T) was not found in lean individuals and this was found to co-segregate with obesity in one family. These results provide evidence of association for NPY2R and PYY gene variants with obesity and none for PPY variants. A rare variant of the NPY2R gene showed evidence of co-segregation with obesity and its contribution to obesity should be investigated further.

The Dynamics of Gastric Emptying and Self-Reported Feelings of Satiation Are Better Predictors Than Gastrointestinal Hormones of the Effects of Lipid Emulsion Structure on Fat Digestion in Healthy Adults-A Bayesian Inference Approach.

PubMed

Steingoetter, Andreas; Buetikofer, Simon; Curcic, Jelena; Menne, Dieter; Rehfeld, Jens F; Fried, Michael; Schwizer, Werner; Wooster, Tim J

2017-04-01

Background: Limited information exists on the relation between fat emulsion structure and its effect on the release of gastrointestinal hormones and feelings of satiation. Objective: We investigated the impact of fat emulsion droplet size, gravitational and acid stability, and redispersibility on gastrointestinal responses and sought to deduce the relative importance of the hormones ghrelin, cholecystokinin, glucagon-like peptide-1, and peptide YY (PYY) in controlling fat emptying and related satiation. Methods: Within a randomized, double-blind, 4-armed crossover study, an extensive data set was generated by MRI of gastric function, analysis of hormone profiles, and ratings of satiation in healthy participants [10 women and 7 men with a mean ± SD age of 25 ± 7 y and body mass index (in kg/m 2 ) of 22 ± 1] after intake of 4 different fat emulsions. Iterative Bayesian model averaging variable selection was used to investigate the influence of hormone profiles in controlling fat emulsion emptying and satiation. Results: The emulsion structure had a distinct effect on the gastric emptying (primary outcome), gastrointestinal hormone profiles, and ratings of satiation (secondary outcomes). Gravitational and acid stability were stronger modulators of fat emptying and hormone profiles than were emulsion droplet size or redispersibility. Cholecystokinin and PYY were most strongly affected by fat emulsion instability and droplet size. Although both hormones were relevant predictors of gastric emptying, only PYY was identified as a relevant predictor of satiation. Conclusions: This work indicates that evenly dispersed, stable, small-emulsion droplets within the stomach lead to prolonged gastric distension, longer ghrelin suppression, and accelerated fat sensing (cholecystokinin and PPY), triggering prolonged feelings of satiation. It suggests that the effects of emulsion instability and droplet size on energy consumption are best studied by assessing changes in gastric

Gastrin levels in mothers and neonates at delivery in various perinatal conditions.

PubMed

Morán, C; Carranza-Lira, S; Ochoa, R; Martínez, J C; Herrera, M; Fonseca, E; Zárate, A

1996-08-01

This study was designed to assess the variations of gastrin (Ga) serum levels in mothers and newborns at birth in some perinatal disorders. Ga levels were measured by RIA in maternal serum, amniotic fluid and cord sera of newborns in 55 cases with the following conditions: normal pregnancy and eutocic vaginal delivery (n = 8), repeat cesarean section (n = 10), and cardiotogographic register suggestive of fetal compromise (n = 15), cephalopelvic disproportion (n = 8), preeclampsia (n = 7) and postdate pregnancy (n = 7). Statistical analysis was performed by Mann-Whitney U test. Ga levels in cord sera of newborn and amniotic fluid in normal pregnancy and eutocic delivery were significantly higher (p < 0.02 and p < 0.01, respectively) than those found in patients with repeat cesarean operation. Serum Ga concentrations in women with postterm pregnancy were significantly higher (p < 0.02) than in women with prior cesarean section. Ga levels in amniotic fluid samples in the presence of suspected fetal compromise and postdate pregnancy were significantly higher (p < 0.001) than those observed in women who had repeat cesarean operation. Vaginal delivery and perinatal pathology may induce hypergastrinemia in both mother and neonate at birth.

Resistant starch lowers postprandial glucose and leptin in overweight adults consuming a moderate-to-high-fat diet: a randomized-controlled trial.

PubMed

Maziarz, Mindy Patterson; Preisendanz, Sara; Juma, Shanil; Imrhan, Victorine; Prasad, Chandan; Vijayagopal, Parakat

2017-02-21

High-amylose maize resistant starch type 2 (HAM-RS2) stimulates gut-derived satiety peptides and reduces adiposity in animals. Human studies have not supported these findings despite improvements in glucose homeostasis and insulin sensitivity after HAM-RS2 intake which can lower adiposity-related disease risk. The primary objective of this study was to evaluate the impact of HAM-RS2 consumption on blood glucose homeostasis in overweight, healthy adults. We also examined changes in biomarkers of satiety (glucagon-like peptide-1 [GLP-1], peptide YY [PYY], and leptin) and body composition determined by anthropometrics and dual-energy x-ray absorptiometry, dietary intake, and subjective satiety measured by a visual analogue scale following HAM-RS2 consumption. Using a randomized-controlled, parallel-arm, double-blind design, 18 overweight, healthy adults consumed either muffins enriched with 30 g HAM-RS2 (n = 11) or 0 g HAM-RS2 (control; n = 7) daily for 6 weeks. The HAM-RS2 and control muffins were similar in total calories and available carbohydrate. At baseline, total PYY concentrations were significantly higher 120 min following the consumption of study muffins in the HAM-RS2 group than control group (P = 0.043). Within the HAM-RS2 group, the area under the curve (AUC) glucose (P = 0.028), AUC leptin (P = 0.022), and postprandial 120-min leptin (P = 0.028) decreased independent of changes in body composition or overall energy intake at the end of 6 weeks. Fasting total PYY increased (P = 0.033) in the HAM-RS2 group, but changes in insulin or total GLP-1 were not observed. Mean overall change in subjective satiety score did not correlate with mean AUC biomarker changes suggesting the satiety peptides did not elicit a satiation response or change in overall total caloric intake. The metabolic response from HAM-RS2 occurred despite the habitual intake of a moderate-to-high-fat diet (mean range 34.5% to 39.4% of total calories). Consuming 30�

Stability of pro-gastrin-releasing peptide in serum versus plasma.

PubMed

Yoshimura, Toru; Fujita, Kenju; Kawakami, Satoshi; Takeda, Katsumichi; Chan, Sabrina; Beligere, Gangamani; Dowell, Barry

2008-01-01

Although serum assays for pro-gastrin-releasing peptide (ProGRP) assays have been commercially available in Japan for several years, the stability of ProGRP in serum and plasma has not been well documented. We investigated the stability of ProGRP in serum and plasma with fresh and stored (frozen) specimens, as well as the cause of the observed instability in serum. ProGRP concentrations in fresh serum were decreased by 6-28% after room temperature storage for 2 h and by 8-32% after 2-8 degrees C storage for 24 h. The average change in ProGRP concentrations in fresh plasma was within +/-10% of baseline for more than 4 h at room temperature and for more than 24 h at 2-8 degrees C. The incubation of a serine protease, thrombin (activated blood coagulation factor II), in a buffer solution containing ProGRP caused decreases in ProGRP concentrations. Following the addition of phenylmethylsulfonyl fluoride, a serine protease inhibitor, to serum, the serum stability for ProGRP was similar to that in plasma. ProGRP is significantly more stable in plasma than in serum. We speculate that thrombin in serum is one of the factors that inactivate ProGRP in serum by proteolysis of the ProGRP antigen. The use of plasma samples for ProGRP may improve the clinical reliability of this marker by minimizing preanalytical changes in ProGRP concentrations. (c) 2008 S. Karger AG, Basel.

The gut hormone response following Roux-en-Y gastric bypass: cross-sectional and prospective study.

PubMed

Pournaras, Dimitrios J; Osborne, Alan; Hawkins, Simon C; Mahon, David; Ghatei, Mohammad A; Bloom, Steve R; Welbourn, Richard; le Roux, Carel W

2010-01-01

Bariatric surgery is the most effective treatment option for obesity, and gut hormones are implicated in the reduction of appetite and weight after Roux-en-Y gastric bypass. Although there is increasing interest in the gut hormone changes after gastric bypass, the long-term changes have not been fully elucidated. Thirty-four participants were studied cross-sectionally at four different time points, pre-operatively (n = 17) and 12 (n = 6), 18 (n = 5) and 24 months (n = 6) after laparoscopic Roux-en-Y gastric bypass. Another group of patients (n = 6) were studied prospectively (18-24 months). All participants were given a standard 400 kcal meal after a 12-h fast, and plasma levels of peptide YY (PYY) and glucagon-like peptide-1 (GLP-1) were correlated with changes in appetite over 3 h using visual analogue scores. The post-operative groups at 12, 18 and 24 months had a higher post-prandial PYY response compared to pre-operative (p < 0.05). This finding was confirmed in the prospective study at 18 and 24 months. There was a trend for increasing GLP-1 response at 18 and 24 months, but this did not reach statistical significance (p = 0.189) in the prospective study. Satiety was significantly reduced in the post-operative groups at 12, 18 and 24 months compared to pre-operative levels (p < 0.05). Roux-en-Y gastric bypass causes an enhanced gut hormone response and increased satiety following a meal. This response is sustained over a 24-month period and may partly explain why weight loss is maintained.

Serum pro-gastrin-releasing peptide (31-98) in benign prostatic hyperplasia and prostatic carcinoma.

PubMed

Nagakawa, Osamu; Furuya, Yuzo; Fujiuchi, Yasuyoshi; Fuse, Hideki

2002-09-01

To clarify whether serum levels of pro-gastrin-releasing peptide (ProGRP) (31-98) could be a useful marker in patients with prostatic carcinoma. GRP is produced and secreted by prostatic neuroendocrine cells. Serum levels of ProGRP(31-98) were measured by enzyme-linked immunosorbent assay in 20 patients with benign prostatic hyperplasia and 107 patients with prostatic carcinoma. The mean serum levels of ProGRP(31-98) in patients with distant metastasis and hormone-resistant prostate cancer were significantly elevated compared with those in patients with organ-confined disease. Significantly elevated levels of ProGRP(31-98) were detected in 9 patients with prostatic carcinoma before any treatment. During hormone-resistant prostate cancer progression, ProGRP(31-98) levels were elevated in 9 patients (23%). Of the 9 patients with Stage D3 and elevated serum ProGRP, 4 had a normal serum prostate-specific antigen level. ProGRP may be a potential tumor marker for prostate cancer. Additional studies in large groups of patients are needed to define the clinical value of ProGRP.

A novel NF-κB/YY1/microRNA-10a regulatory circuit in fibroblast-like synoviocytes regulates inflammation in rheumatoid arthritis

PubMed Central

Mu, Nan; Gu, Jintao; Huang, Tonglie; Zhang, Cun; Shu, Zhen; Li, Meng; Hao, Qiang; Li, Weina; Zhang, Wangqian; Zhao, Jinkang; Zhang, Yong; Huang, Luyu; Wang, Shuning; Jin, Xiaohang; Xue, Xiaochang; Zhang, Wei; Zhang, Yingqi

2016-01-01

The main etiopathogenesis of rheumatoid arthritis (RA) is overexpressed inflammatory cytokines and tissue injury mediated by persistent NF-κB activation. MicroRNAs widely participate in the regulation of target gene expression and play important roles in various diseases. Here, we explored the mechanisms of microRNAs in RA. We found that microRNA (miR)-10a was downregulated in the fibroblast-like synoviocytes (FLSs) of RA patients compared with osteoarthritis (OA) controls, and this downregulation could be triggered by TNF-α and IL-1β in an NF-κB-dependent manner through promoting the expression of the YingYang 1 (YY1) transcription factor. Downregulated miR-10a could accelerate IκB degradation and NF-κB activation by targeting IRAK4, TAK1 and BTRC. This miR-10a-mediated NF-κB activation then significantly promoted the production of various inflammatory cytokines, including TNF-α, IL-1β, IL-6, IL-8, and MCP-1, and matrix metalloproteinase (MMP)-1 and MMP-13. In addition, transfection of a miR-10a inhibitor accelerated the proliferation and migration of FLSs. Collectively, our data demonstrates the existence of a novel NF-κB/YY1/miR-10a/NF-κB regulatory circuit that promotes the excessive secretion of NF-κB-mediated inflammatory cytokines and the proliferation and migration of RA FLSs. Thus, miR-10a acts as a switch to control this regulatory circuit and may serve as a diagnostic and therapeutic target for RA treatment. PMID:26821827

YY1 and HDAC9c transcriptionally regulate p38-mediated mesenchymal stem cell differentiation into osteoblasts

PubMed Central

Chen, Ya-Huey; Chung, Chiao-Chen; Liu, Yu-Chia; Lai, Wei-Chen; Lin, Zong-Shin; Chen, Tsung-Ming; Li, Long-Yuan; Hung, Mien-Chie

2018-01-01

Mesenchymal stem cells (MSCs) have a high self-renewal potential and can differentiate into various types of cells, including adipocytes, osteoblasts, and chondrocytes. Previously, we reported that the enhancer of zeste homolog 2 (EZH2), the catalytic component of the Polycomb-repressive complex 2, and HDAC9c mediate the osteogenesis and adipogenesis of MSCs. In the current study, we identify the role of p38 in osteogenic differentiation from a MAPK antibody array screen and investigate the mechanisms underlying its transcriptional regulation. Our data show that YY1, a ubiquitously expressed transcription factor, and HDAC9c coordinate p38 transcriptional activity to promote its expression to facilitate the osteogenic potential of MSCs. Our results show that p38 mediates osteogenic differentiation, and this has significant implications in bone-related diseases, bone tissue engineering, and regenerative medicine. PMID:29637005

Alterations in circadian and meal-induced gut peptide levels in lean and obese rats.

PubMed

Moghadam, Alexander A; Moran, Timothy H; Dailey, Megan J

2017-12-01

Alterations in gut hormone signaling are a likely contributing factor to the metabolic disturbances associated with overweight/obesity as they coordinate the timing of feeding behavior, absorption, and utilization of nutrients. These hormones are released in response to food intake, or follow a circadian or anticipatory pattern of secretion that is independent of nutrient stimulation. The aim of this study was to identify the degree to which high-fat diet-induced obesity would alter the daily rhythm of gut peptide plasma levels (glucagon-like peptide-1 [GLP-1], peptide YY [PYY], insulin or amylin [AMY]) or meal-induced levels in the middle of the light or dark cycle. Male Sprague-Dawley rats were fed a high-fat diet (OBESE) or chow (LEAN), implanted with jugular catheters, and blood samples were taken every 2 h throughout the light/dark cycle while freely feeding or after an Ensure liquid meal. We found that even when OBESE and LEAN animals ate the same kcals and have a similar pattern of food intake, there is a difference in both the levels and rhythm of plasma gut peptides. GLP-1 and PYY are higher during the light cycle in LEAN animals and AMY is higher in the OBESE group throughout the light/dark cycle. There was also a differential response of plasma gut signals after the Ensure meal, even though the composition and amount of intake of the meal were the same in both groups. These changes occur prior to the high-fat diet induced loss of glycemic control and may be a target for early intervention. Impact statement The aim of this study was to test if obesity would alter the daily rhythm of gut peptides or meal-induced levels in the middle of the light or dark cycle. We found that even when animals are eating the same amount (in kcal) of food that the obese animals have altered daily rhythms and meal-induced gut peptide levels. In particular, we are the first to show that obesity induces increases in peptide YY levels during the light cycle and amylin remains

Pro-Gastrin Releasing Peptide: A New Serum Marker for Endometrioid Adenocarcinoma.

PubMed

Kiseli, Mine; Caglar, Gamze Sinem; Yarci Gursoy, Asli; Tasci, Tolga; Candar, Tuba; Akincioglu, Egemen; Pabuccu, Emre Goksan; Boran, Nurettin; Tulunay, Gokhan; Umudum, Haldun

2018-06-13

Gastrin-releasing peptide (GRP) is thought to play a role in the metastatic process of various malignancies. The more stable precursor of GRP, pro-GRP (ProGRP), has been shown to be secreted by neuroendocrine tumors. This study was designed to assess the validity of ProGRP as a diagnostic marker in endometrioid adenocarcinomas (EAs) of the endometrium. Thirty-seven patients with a diagnosis of EA, 23 patients with endometrial hyperplasia, and 32 age-matched controls with normal endometrial histology were recruited for this study. Serum ProGRP and cancer antigen 125 (CA125) values were compared between groups. Median serum ProGRP levels were significantly higher in the cancer group compared to corresponding levels in both the hyperplasia and control groups (p = 0.008 and p < 0.001 respectively; endometrial cancer: 27.5 pg/mL; hyperplasia: 16.1 pg/mL; controls: 12.9 pg/mL). Age and endometrial thickness were positively correlated with ProGRP levels (r = 0.322, p = 0.006 and r = 0.269, p = 0.023, respectively). Receiver Operating Characteristic curve analyses for EA revealed a threshold of 20.81 pg/mL, with a sensitivity of 60.7% and specificity of 81.4%, positive predictive value of 68% and negative predictive value of 76.1%. Significantly higher ProGRP levels were observed in patients with EA than in controls. Serum ProGRP has good diagnostic sensitivity and specificity for EA. © 2018 S. Karger AG, Basel.

Roux-en-Y gastric bypass augments the feeding responses evoked by gastrin releasing peptides

PubMed Central

Washington, Martha C.; Mhalhal, Thaer R.; Berger, Tanisha Johnson-Rouse Jose; Heath, John; Seeley, Randy; Sayegh, Ayman I.

2016-01-01

Background Roux-en-Y gastric bypass (RYGB) is the most effective method for the treatment of obesity and metabolic disease Roux-en-Y gastric bypass (RYGB) may reduce body weight by altering the feeding responses evoked by the short term satiety peptides. Materials and Methods Here, we measured meal size (MS, chow), intermeal interval (IMI) length and satiety ratio (SR, IMI/MS; food consumed per a unit of time) by the small and the large forms of gastrin releasing peptide (GRP) in rats, GRP-10 and GRP-29 (0, 0.1, 0.5 nmol/kg) infused in the celiac artery (CA, supplies stomach and upper duodenum) and the cranial mesenteric artery (CMA, supplies small and large intestine) in a RYGB rat model. Results GRP-10 reduced MS, prolonged the IMI and increased the SR only in the RYGB group, whereas GRP-29 evoked these responses by both routes and in both groups. Conclusion The RYGB procedure augments the feeding responses evoked by exogenous GRP, possibly by decreasing total food intake, increasing latency to the first meal, decreasing number of meals or altering the sites of action regulating MS and IMI length by the two peptides. PMID:27884350

Gastrin-releasing peptide induces monocyte adhesion to vascular endothelium by upregulating endothelial adhesion molecules

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kim, Mi-Kyoung; Park, Hyun-Joo; Department of Dental Pharmacology, BK21 PLUS Project, School of Dentistry, Pusan National University, Yangsan 626-870

Gastrin-releasing peptide (GRP) is a neuropeptide that plays roles in various pathophysiological conditions including inflammatory diseases in peripheral tissues; however, little is known about whether GRP can directly regulate endothelial inflammatory processes. In this study, we showed that GRP promotes the adhesion of leukocytes to human umbilical vein endothelial cells (HUVECs) and the aortic endothelium. GRP increased the expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) by activating nuclear factor-κB (NF-κB) in endothelial cells. In addition, GRP activated extracellular signal-regulated kinase 1/2 (ERK1/2), p38MAPK, and AKT, and the inhibition of these signaling pathways significantly reduced GRP-inducedmore » monocyte adhesion to the endothelium. Overall, our results suggested that GRP may cause endothelial dysfunction, which could be of particular relevance in the development of vascular inflammatory disorders. - Highlights: • GRP induces adhesion of monocytes to vascular endothelium. • GRP increases the expression of endothelial adhesion molecules through the activation of NF-κB. • ERK1/2, p38MAPK, and Akt pathways are involved in the GRP-induced leukocyte adhesiveness to endothelium.« less

Catabolism of gastrin releasing peptide and substance P by gastric membrane-bound peptidases.

PubMed

Bunnett, N W; Kobayashi, R; Orloff, M S; Reeve, J R; Turner, A J; Walsh, J H

1985-01-01

The catabolism of two gastric neuropeptides, the C-terminal decapeptide of gastrin releasing peptide-27 (GRP10) and substance P (SP), by membrane-bound peptidases of the porcine gastric corpus and by porcine endopeptidase-24.11 ("enkephalinase") has been investigated. GRP10 was catabolized by gastric muscle peptidases (specific activity 1.8 nmol min-1 mg-1 protein) by hydrolysis of the His8-Leu9 bond and catabolism was inhibited by phosphoramidon (I50 approx. 10(-8) M), a specific inhibitor of endopeptidase-24.11. The same bond in GRP10 was cleaved by purified endopeptidase-24.11, and hydrolysis was equally sensitive to inhibition by phosphoramidon. SP was catabolized by gastric muscle peptidases (specific activity 1.7 nmol min-1 mg-1 protein) by hydrolysis of the Gln6-Phe7, Phe7-Phe8 and Gly9-Leu10 bonds, which is identical to the cleavage of SP by purified endopeptidase-24.11. The C-terminal cleavage of GRP10 and SP would inactivate the peptides. It is concluded that a membrane-bound peptidase in the stomach wall catabolizes and inactivates GRP10 and SP and that, in its specificity and sensitivity to phosphoramidon, this peptidase resembles endopeptidase-24.11.

Targeting gastrin-releasing peptide as a new approach to treat aggressive refractory neuroblastomas.

PubMed

Paul, Pritha; Gillory, Lauren A; Kang, JungHee; Qiao, Jingbo; Chung, Dai H

2011-03-01

The overall survival for neuroblastoma remains dismal, in part due to the emergence of resistance to chemotherapeutic drugs. We have demonstrated that gastrin-releasing peptide (GRP), a gut peptide secreted by neuroblastoma, acts as an autocrine growth factor. We hypothesized that knockdown of GRP will induce apoptosis in neuroblastoma cells and potentiate the cytotoxic effects of chemotherapeutic agents. The human neuroblastoma cell lines (JF, SK-N-SH) were transfected with small interfering (si) RNA targeted at GRP. Apoptosis was assessed by DNA fragmentation assay. Immunoblotting was used to confirm molecular markers of apoptosis, and flow cytometry was performed to determine cell cycle arrest after GRP knockdown. siGRP resulted in an increase in apoptosis in the absence of chemotherapeutic interventions. A combination of GRP silencing and chemotherapeutic drugs resulted in enhanced apoptosis when compared to either of the treatments alone. GRP silencing led to increased expression of proapoptotic proteins, p53 and p21. Silencing of GRP induces apoptosis in neuroblastoma cells; it acts synergistically with chemotherapeutic effects of etoposide and vincristine. GRP knockdown-mediated apoptosis appears to be associated with upregulation of p53 in neuroblastoma cells. Targeting GRP may be postulated as a potential novel agent for combinational treatment to treat aggressive neuroblastomas. Copyright © 2011 Mosby, Inc. All rights reserved.

The human gastrin precursor. Characterization of phosphorylated forms and fragments.

PubMed Central

Varro, A; Desmond, H; Pauwels, S; Gregory, H; Young, J; Dockray, G J

1988-01-01

There is a potential phosphorylation site in the C-terminal region of the precursor for the acid-stimulating hormone gastrin, which is immediately adjacent to an important cleavage point. In the present study we have sought to identify, separate, quantify and characterize phosphorylated and unphosphorylated forms of human progastrin and its fragments. Identification was made by two radioimmunoassays: (a) a novel assay employing an antibody raised to intact human progastrin; and (b) an assay using antibody reacting with the C-terminal tryptic fragment of human progastrin, as well as progastrin itself. Two forms of human progastrin isolated from a gastrinoma were separated by ion-exchange h.p.l.c., and had similar elution positions on reverse-phase h.p.l.c. and on gel filtration. The more acidic peptide contained close to equimolar amounts of phosphate. On trypsinization, peptides were released that co-eluted on ion-exchange h.p.l.c. with, and had the immunochemical properties of, naturally occurring C-terminal fragments of progastrin. One of the latter was isolated and shown by Edman degradation after derivatization with ethanethiol to have the sequence Ser (P)-Ala-Glu-Asp-Glu-Asn. Similar peptides occur in antral mucosa resected from ulcer patients. The unphosphorylated forms of progastrin predominated, whereas the phosphorylated forms of the C-terminal fragments were predominant. This distribution could be explained by preferential cleavage of phosphorylated progastrin. We conclude that in human progastrin, Ser-96 can occur in the phosphorylated form; this residue immediately follows a pair of basic residues (Arg-Arg) that are cleaved during synthesis of the biologically active product. PMID:3223964

The effect of meal frequency in a reduced-energy regimen on the gastrointestinal and appetite hormones in patients with type 2 diabetes: A randomised crossover study

PubMed Central

Belinova, Lenka; Kahleova, Hana; Oliyarnyk, Olena; Kazdova, Ludmila; Hill, Martin; Pelikanova, Terezie

2017-01-01

Background Appetite and gastrointestinal hormones (GIHs) participate in energy homeostasis, feeding behavior and regulation of body weight. We demonstrated previously the superior effect of a hypocaloric diet regimen with lower meal frequency (B2) on body weight, hepatic fat content, insulin sensitivity and feelings of hunger compared to the same diet divided into six smaller meals a day (A6). Studies with isoenergetic diet regimens indicate that lower meal frequency should also have an effect on fasting and postprandial responses of GIHs. The aim of this secondary analysis was to explore the effect of two hypocaloric diet regimens on fasting levels of appetite and GIHs and on their postprandial responses after a standard meal. It was hypothesized that lower meal frequency in a reduced-energy regimen leading to greater body weight reduction and reduced hunger would be associated with decreased plasma concentrations of GIHs: gastric inhibitory peptide (GIP), glucagon-like peptide-1(GLP-1), peptide YY(PYY), pancreatic polypeptide (PP) and leptin and increased plasma concentration of ghrelin. The postprandial response of satiety hormones (GLP-1, PYY and PP) and postprandial suppression of ghrelin will be improved. Methods In a randomized crossover study, 54 patients suffering from type 2 diabetes (T2D) underwent both regimens. The concentrations of GLP-1, GIP, PP, PYY, amylin, leptin and ghrelin were determined using multiplex immunoanalyses. Results Fasting leptin and GIP decreased in response to both regimens with no difference between the treatments (p = 0.37 and p = 0.83, respectively). Fasting ghrelin decreased in A6 and increased in B2 (with difference between regimens p = 0.023). Fasting PP increased in B2with no significant difference between regimens (p = 0.17). Neither GLP-1 nor PYY did change in either regimen. The decrease in body weight correlated negatively with changes in fasting ghrelin (r = -0.4, p<0.043) and the postprandial reduction of ghrelin

Dual role of NO donors in the reversal of tumor cell resistance and EMT: Downregulation of the NF-κB/Snail/YY1/RKIP circuitry.

PubMed

Bonavida, Benjamin; Baritaki, Stavroula

2011-01-01

Several studies have implicated the role of Nitric Oxide (NO) in the regulation of tumor cell behavior and have shown that NO either promotes or inhibits tumorigenesis. These conflicting findings have been resolved, in part, by the levels of NO used such that low levels promote tumor growth and high levels inhibit tumor growth. Our studies have focused on the use of high levels of NO provided primarily by the NO donor, DETANONOate. We have shown that treatment of resistant tumor cells with DETANONOate sensitizes them to apoptosis by both chemotherapeutic drugs and cytotoxic immunotherapeutic ligands. The underlying mechanisms by which NO sensitizes tumor cells to apoptosis were shown to be regulated, in part, by NO-mediated inhibition of the NF-κB survival/anti-apoptotic pathways and downstream of NF-κB by inhibition of the transcription factor Yin Yang 1 (YY1). In addition to NO-induced sensitization to apoptosis, we have also shown that NO induced the expression of the metastasis-suppressor/immunosurveillance cancer gene product, Raf-1 kinase inhibitor protein (RKIP). Overexpression of RKIP mimics NO in tumor cells-induced sensitization to apoptosis. The induction of RKIP by NO was the result of the inhibition of the RKIP repressor, Snail, downstream of NF-κB. These findings established the presence of a dysregulated NF-κB/Snail/YY1/ RKIP circuitry in resistance and that treatment with NO modifies this loop in tumor cells in favor of the inhibition of tumor cell survival and the response to cytotoxic drugs. Noteworthy, the NF-κB/Snail/YY1/RKIP loop consists of gene products that regulate the epithelial to mesenchymal transition (EMT) and, thus, tumor metastasis. Hence, we have found that treatment of metastatic cancer cell lines with DETANONOate inhibited the EMT phenotype, through both the inhibition of the metastasis-inducers, NF-κB and Snail and the induction of the metastasis-suppressor, RKIP. Altogether, the above findings establish, for the first time

A Hamster Model of Diet-Induced Obesity for Preclinical Evaluation of Anti-Obesity, Anti-Diabetic and Lipid Modulating Agents

PubMed Central

Hansen, Gitte; Fabricius, Katrine; Hansen, Henrik B.; Jelsing, Jacob; Vrang, Niels

2015-01-01

Aim Unlike rats and mice, hamsters develop hypercholesterolemia, and hypertriglyceridemia when fed a cholesterol-rich diet. Because hyperlipidemia is a hallmark of human obesity, we aimed to develop and characterize a novel diet-induced obesity (DIO) and hypercholesterolemia Golden Syrian hamster model. Methods and Results Hamsters fed a highly palatable fat- and sugar-rich diet (HPFS) for 12 weeks showed significant body weight gain, body fat accumulation and impaired glucose tolerance. Cholesterol supplementation to the diet evoked additional hypercholesterolemia. Chronic treatment with the GLP-1 analogue, liraglutide (0.2 mg/kg, SC, BID, 27 days), normalized body weight and glucose tolerance, and lowered blood lipids in the DIO-hamster. The dipeptidyl peptidase-4 (DPP-4) inhibitor, linagliptin (3.0 mg/kg, PO, QD) also improved glucose tolerance. Treatment with peptide YY3-36 (PYY3-36, 1.0 mg/kg/day) or neuromedin U (NMU, 1.5 mg/kg/day), continuously infused via a subcutaneous osmotic minipump for 14 days, reduced body weight and energy intake and changed food preference from HPFS diet towards chow. Co-treatment with liraglutide and PYY3-36 evoked a pronounced synergistic decrease in body weight and food intake with no lower plateau established. Treatment with the cholesterol uptake inhibitor ezetimibe (10 mg/kg, PO, QD) for 14 days lowered plasma total cholesterol with a more marked reduction of LDL levels, as compared to HDL, indicating additional sensitivity to cholesterol modulating drugs in the hyperlipidemic DIO-hamster. In conclusion, the features of combined obesity, impaired glucose tolerance and hypercholesterolemia in the DIO-hamster make this animal model useful for preclinical evaluation of novel anti-obesity, anti-diabetic and lipid modulating agents. PMID:26266945

Anticipatory and consummatory effects of (hedonic) chocolate intake are associated with increased circulating levels of the orexigenic peptide ghrelin and endocannabinoids in obese adults.

PubMed

Rigamonti, Antonello E; Piscitelli, Fabiana; Aveta, Teresa; Agosti, Fiorenza; De Col, Alessandra; Bini, Silvia; Cella, Silvano G; Di Marzo, Vincenzo; Sartorio, Alessandro

2015-01-01

Hedonic hunger refers to consumption of food just for pleasure and not to maintain energy homeostasis. Recently, consumption of food for pleasure was reported to be associated with increased circulating levels of both the orexigenic peptide ghrelin and the endocannabinoid 2-arachidonoyl-glycerol (2-AG) in normal-weight subjects. To date, the effects of hedonic hunger, and in particular of chocolate craving, on these mediators in obese subjects are still unknown. To explore the role of some gastrointestinal orexigenic and anorexigenic peptides and endocannabinoids (and some related congeners) in chocolate consumption, we measured changes in circulating levels of ghrelin, glucagon-like peptide 1 (GLP-1), peptide YY (PYY), anandamide (AEA), 2-AG, palmitoylethanolamide (PEA), and oleoylethanolamide (OEA) in 10 satiated severely obese subjects after consumption of chocolate and, on a separate day, of a non-palatable isocaloric food with the same bromatologic composition. Evaluation of hunger and satiety was also performed by visual analogic scale. The anticipatory phase and the consumption of food for pleasure were associated with increased circulating levels of ghrelin, AEA, 2-AG, and OEA. In contrast, the levels of GLP-1, PYY, and PEA did not differ before and after the exposure/ingestion of either chocolate or non-palatable foods. Hunger and satiety were higher and lower, respectively, in the hedonic session than in the non-palatable one. When motivation to eat is generated by exposure to, and consumption of, chocolate a peripheral activation of specific endogenous rewarding chemical signals, including ghrelin, AEA, and 2-AG, is observed in obese subjects. Although preliminary, these findings predict the effectiveness of ghrelin and endocannabinoid antagonists in the treatment of obesity.

Anticipatory and consummatory effects of (hedonic) chocolate intake are associated with increased circulating levels of the orexigenic peptide ghrelin and endocannabinoids in obese adults

PubMed Central

Rigamonti, Antonello E.; Piscitelli, Fabiana; Aveta, Teresa; Agosti, Fiorenza; De Col, Alessandra; Bini, Silvia; Cella, Silvano G.; Di Marzo, Vincenzo; Sartorio, Alessandro

2015-01-01

Background Hedonic hunger refers to consumption of food just for pleasure and not to maintain energy homeostasis. Recently, consumption of food for pleasure was reported to be associated with increased circulating levels of both the orexigenic peptide ghrelin and the endocannabinoid 2-arachidonoyl-glycerol (2-AG) in normal-weight subjects. To date, the effects of hedonic hunger, and in particular of chocolate craving, on these mediators in obese subjects are still unknown. Methods To explore the role of some gastrointestinal orexigenic and anorexigenic peptides and endocannabinoids (and some related congeners) in chocolate consumption, we measured changes in circulating levels of ghrelin, glucagon-like peptide 1 (GLP-1), peptide YY (PYY), anandamide (AEA), 2-AG, palmitoylethanolamide (PEA), and oleoylethanolamide (OEA) in 10 satiated severely obese subjects after consumption of chocolate and, on a separate day, of a non-palatable isocaloric food with the same bromatologic composition. Evaluation of hunger and satiety was also performed by visual analogic scale. Results The anticipatory phase and the consumption of food for pleasure were associated with increased circulating levels of ghrelin, AEA, 2-AG, and OEA. In contrast, the levels of GLP-1, PYY, and PEA did not differ before and after the exposure/ingestion of either chocolate or non-palatable foods. Hunger and satiety were higher and lower, respectively, in the hedonic session than in the non-palatable one. Conclusions When motivation to eat is generated by exposure to, and consumption of, chocolate a peripheral activation of specific endogenous rewarding chemical signals, including ghrelin, AEA, and 2-AG, is observed in obese subjects. Although preliminary, these findings predict the effectiveness of ghrelin and endocannabinoid antagonists in the treatment of obesity. PMID:26546790

Changes in levels of peripheral hormones controlling appetite are inconsistent with hyperphagia in leptin-deficient subjects.

PubMed

Saeed, Sadia; Bech, Paul R; Hafeez, Tayyaba; Alam, Rabail; Falchi, Mario; Ghatei, Mohammad A; Bloom, Stephen R; Arslan, Muhammad; Froguel, Philippe

2014-04-01

Congenital leptin deficiency, a rare genetic disorder due to a homozygous mutation in the leptin gene (LEP), is accompanied by extreme obesity and hyperphagia. A number of gastrointestinal hormones have been shown to critically regulate food intake but their physiological role in hyperphagic response in congenital leptin deficiency has not been elucidated. This study is the first to evaluate the fasting and postprandial profiles of gut-derived hormones in homozygous and heterozygous carriers of LEP mutation. The study subjects from two consanguineous families consisted of five homozygous and eight heterozygous carriers of LEP mutation, c.398delG. Ten wild-type normal-weight subjects served as controls. Fasting and 1-h postprandial plasma ghrelin, glucagon-like peptide (GLP) 1, peptide YY (PYY), leptin and insulin levels were measured by immunoassays. Fasting plasma ghrelin levels in homozygotes remained remarkably unchanged following food consumption (P = 0.33) in contrast to a significant decline in heterozygous (P < 0.03) and normal (P < 0.02) subjects. A significant postprandial increase in PYY was observed in heterozygous (P < 0.02) and control subjects (P < 0.01), but not in the homozygous group (P = 0.22). A postprandial rise in GLP-1 levels was significant (P < 0.02) in all groups. Interestingly, fasting leptin levels in heterozygotes were not significantly different from controls and did not change significantly following meal. Our results demonstrate that gut hormones play little or no physiological role in driving the hyperphagic response of leptin-deficient subjects. In contrast, fasting and postprandial levels of gut hormones in heterozygous mutation carriers were comparable to those of normal-weight controls.

Interindividual Responses of Appetite to Acute Exercise: A Replicated Crossover Study.

PubMed

Goltz, Fernanda R; Thackray, Alice E; King, James A; Dorling, James L; Atkinson, Greg; Stensel, David J

2018-04-01

Acute exercise transiently suppresses appetite, which coincides with alterations in appetite-regulatory hormone concentrations. Individual variability in these responses is suspected, but replicated trials are needed to quantify them robustly. We examined the reproducibility of appetite and appetite-regulatory hormone responses to acute exercise and quantified the individual differences in responses. Fifteen healthy, recreationally active men completed two control (60-min resting) and two exercise (60-min fasted treadmill running at 70% peak oxygen uptake) conditions in randomized sequences. Perceived appetite and circulating concentrations of acylated ghrelin and total peptide YY (PYY) were measured immediately before and after the interventions. Interindividual differences were explored by correlating the two sets of response differences between exercise and control conditions. Within-participant covariate-adjusted linear mixed models were used to quantify participant-condition interactions. Compared with control, exercise suppressed mean acylated ghrelin concentrations and appetite perceptions (all ES = 0.62-1.47, P < 0.001) and elevated total PYY concentrations (ES = 1.49, P < 0.001). For all variables, the standard deviation of the change scores was substantially greater in the exercise versus control conditions. Moderate-to-large positive correlations were observed between the two sets of control-adjusted exercise responses for all variables (r = 0.54-0.82, P ≤ 0.036). After adjusting for baseline measurements, participant-condition interactions were present for all variables (P ≤ 0.053). Our replicated crossover study allowed, for the first time, the interaction between participant and acute exercise response in appetite parameters to be quantified. Even after adjustment for individual baseline measurements, participants demonstrated individual differences in perceived appetite and hormone responses to acute exercise bouts beyond any random within

Influences of Dietary Added Sugar Consumption on Striatal Food-Cue Reactivity and Postprandial GLP-1 Response

PubMed Central

Dorton, Hilary M.; Luo, Shan; Monterosso, John R.; Page, Kathleen A.

2018-01-01

Sugar consumption in the United States exceeds recommendations from the American Heart Association. Overconsumption of sugar is linked to risk for obesity and metabolic disease. Animal studies suggest that high-sugar diets alter functions in brain regions associated with reward processing, including the dorsal and ventral striatum. Human neuroimaging studies have shown that these regions are responsive to food cues, and that the gut-derived satiety hormones, glucagon-like peptide-1 (GLP-1), and peptide YY (PYY), suppress striatal food-cue responsivity. We aimed to determine the associations between dietary added sugar intake, striatal responsivity to food cues, and postprandial GLP-1 and PYY levels. Twenty-two lean volunteers underwent a functional magnetic resonance imaging (fMRI) scan during which they viewed pictures of food and non-food items after a 12-h fast. Before scanning, participants consumed a glucose drink. A subset of 19 participants underwent an additional fMRI session in which they consumed water as a control condition. Blood was sampled for GLP-1, and PYY levels and hunger ratings were assessed before and ~75 min after drink consumption. In-person 24-h dietary recalls were collected from each participant on three to six separate occasions over a 2-month period. Average percent calories from added sugar were calculated using information from 24-h dietary recalls. A region-of-interest analysis was performed to compare the blood oxygen level-dependent (BOLD) response to food vs. non-food cues in the bilateral dorsal striatum (caudate/putamen) and ventral striatum (nucleus accumbens). The relationships between added sugar, striatal responses, and hormone changes after drink consumption were assessed using Spearman’s correlations. We observed a positive correlation between added sugar intake and BOLD response to food cues in the dorsal striatum and a similar trend in the nucleus accumbens after glucose, but not water, consumption. Added sugar intake

Influences of Dietary Added Sugar Consumption on Striatal Food-Cue Reactivity and Postprandial GLP-1 Response.

PubMed

Dorton, Hilary M; Luo, Shan; Monterosso, John R; Page, Kathleen A

2017-01-01

Sugar consumption in the United States exceeds recommendations from the American Heart Association. Overconsumption of sugar is linked to risk for obesity and metabolic disease. Animal studies suggest that high-sugar diets alter functions in brain regions associated with reward processing, including the dorsal and ventral striatum. Human neuroimaging studies have shown that these regions are responsive to food cues, and that the gut-derived satiety hormones, glucagon-like peptide-1 (GLP-1), and peptide YY (PYY), suppress striatal food-cue responsivity. We aimed to determine the associations between dietary added sugar intake, striatal responsivity to food cues, and postprandial GLP-1 and PYY levels. Twenty-two lean volunteers underwent a functional magnetic resonance imaging (fMRI) scan during which they viewed pictures of food and non-food items after a 12-h fast. Before scanning, participants consumed a glucose drink. A subset of 19 participants underwent an additional fMRI session in which they consumed water as a control condition. Blood was sampled for GLP-1, and PYY levels and hunger ratings were assessed before and ~75 min after drink consumption. In-person 24-h dietary recalls were collected from each participant on three to six separate occasions over a 2-month period. Average percent calories from added sugar were calculated using information from 24-h dietary recalls. A region-of-interest analysis was performed to compare the blood oxygen level-dependent (BOLD) response to food vs. non-food cues in the bilateral dorsal striatum (caudate/putamen) and ventral striatum (nucleus accumbens). The relationships between added sugar, striatal responses, and hormone changes after drink consumption were assessed using Spearman's correlations. We observed a positive correlation between added sugar intake and BOLD response to food cues in the dorsal striatum and a similar trend in the nucleus accumbens after glucose, but not water, consumption. Added sugar intake

Irregular meal-pattern effects on energy expenditure, metabolism, and appetite regulation: a randomized controlled trial in healthy normal-weight women.

PubMed

Alhussain, Maha H; Macdonald, Ian A; Taylor, Moira A

2016-07-01

Obesity is increasing in parallel with greater all-day food availability. The latter may promote meal irregularity, dysregulation of the energy balance, and poor metabolic health. We investigated the effect of meal irregularity on the thermic effect of food (TEF), lipid concentrations, carbohydrate metabolism, subjective appetite, and gut hormones in healthy women. Eleven normal-weight women (18-40 y of age) were recruited in a randomized crossover trial with two 14-d isoenergetic diet periods (identical foods provided and free living) that were separated by a 14-d habitual diet washout period. In period 1, participants followed a regular meal pattern (6 meals/d) or an irregular meal pattern (3-9 meals/d), and in period 2, the alternative meal pattern was followed. Before and after each period, when participants were fasting and for 3 h after intake of a test drink, measurements were taken of energy expenditure, circulating glucose, lipids (fasting only), insulin, glucagon-like peptide 1 (GLP-1), peptide YY (PYY), and ghrelin. An ad libitum test meal was offered. Subjective appetite ratings were assessed while fasting, after the test drink, after the ad libitum meal, and during the intervention. Continuous interstitial glucose monitoring was undertaken for 3 consecutive days during each intervention, and the ambulatory activity pattern was recorded (ambulatory energy expenditure estimation). Regularity was associated with a greater TEF (P < 0.05) and a lower incremental area under the curve (iAUC) for glucose after intake of the test drink (over 3 h) and, for some identical meals, during the 2 interventions (over 90 min) (day 7: after breakfast; day 9: after lunch and dinner). There was no difference between treatments for the test-drink gut hormone response. A time effect was noted for fasting GLP-1, fasting PYY, PYY responses, and hunger-rating responses to the test drink (P < 0.05). Lower hunger and higher fullness ratings were seen premeal and postmeal during

Associations of Circulating Gut Hormone and Adipocytokine Levels with the Spectrum of Gastroesophageal Reflux Disease

PubMed Central

Tseng, Ping-Huei; Yang, Wei-Shiung; Liou, Jyh-Ming; Lee, Yi-Chia; Wang, Hsiu-Po; Lin, Jaw-Town; Wu, Ming-Shiang

2015-01-01

Objective The pathogenesis of gastroesophageal reflux disease (GERD) is complex and poorly understood. We aim to investigate the association of various circulating peptide hormones with heterogenous manifestations of GERD. Methods One hundred and four patients that had experienced typical GERD symptoms (heartburn and/or acid regurgitation) for at least 3 episodes per week in the past 3 months were enrolled. All patients received a baseline assessment of symptom severity and frequency with the Reflux Disease Questionnaire and an upper endoscopy to classify GERD into erosive esophagitis (EE, n = 67), non-erosive esophagitis (NE, n = 37), and Barrett’s esophagus (BE, n = 8). Fifty asymptomatic subjects with an endoscopically normal esophagus were recruited as the control group. Complete anthropometric measures and blood biochemistry were obtained and fasting serum levels of adipocytokines (adiponectin and leptin) and gut hormones (ghrelin and peptide YY (PYY)) were determined by enzyme-linked immunosorbent assay in all subjects. Results All circulating peptide hormone levels were not statistically different between the GERD and control groups. However, GERD patients appeared to have lower PYY levels [median (25th-75th percentile), 80.1 (49.8–108.3) vs. 99.4 (65.8–131.9) pg/ml, p = 0.057] compared with control subjects. Among the GERD patients, ghrelin levels were inversely associated with the frequency and severity of acid regurgitation. In male GERD patients, EE was associated with significantly higher PYY levels [107.0 (55.0–120.8) vs. 32.8 (28.7–84.5) pg/ml, p = 0.026] but lower adiponectin levels [6.7 (5.6–9.3) vs. 9.9 (9.6–10.6) μg/ml, p = 0.034] than NE. Patients with BE had significantly lower adiponectin levels [6.0 (5.1–9.2) vs. 9.2 (7.1–11.2) μg/ml, p = 0.026] than those without BE. Conclusions Humoral derangement of circulating peptide hormones might participate in inflammation and symptom perception in patients suffering from GERD

Timeline of changes in appetite during weight loss with a ketogenic diet

PubMed Central

Nymo, S; Coutinho, S R; Jørgensen, J; Rehfeld, J F; Truby, H; Kulseng, B; Martins, C

2017-01-01

Background/objective: Diet-induced weight loss (WL) leads to increased hunger and reduced fullness feelings, increased ghrelin and reduced satiety peptides concentration (glucagon-like peptide-1 (GLP-1), cholecystokinin (CCK) and peptide YY (PYY)). Ketogenic diets seem to minimise or supress some of these responses. The aim of this study was to determine the timeline over which changes in appetite occur during progressive WL with a ketogenic very-low-energy diet (VLED). Subjects/methods: Thirty-one sedentary adults (18 men), with obesity (body mass index: 37±4.5 kg m−2) underwent 8 weeks (wks) of a VLED followed by 4 wks of weight maintenance. Body weight and composition, subjective feelings of appetite and appetite-related hormones (insulin, active ghrelin (AG), active GLP-1, total PYY and CCK) were measured in fasting and postprandially, at baseline, on day 3 of the diet, 5 and 10% WL, and at wks 9 and 13. Data are shown as mean±s.d. Results: A significant increase in fasting hunger was observed by day 3 (2±1% WL), (P<0.01), 5% WL (12±8 days) (P<0.05) and wk 13 (17±2% WL) (P<0.05). Increased desire to eat was observed by day 3 (P<0.01) and 5% WL (P<0.05). Postprandial prospective food consumption was significantly reduced at wk 9 (16±2% WL) (P<0.01). Basal total PYY was significantly reduced at 10% WL (32±8 days) (P<0.05). Postprandial active GLP-1 was increased at 5% WL (P<0.01) and CCK reduced at 5 and 10% WL (P<0.01, for both) and wk 9 (P<0.001). Basal and postprandial AG were significantly increased at wk 13 (P<0.001, both). Conclusions: WL with a ketogenic VLED transiently increases the drive to eat up to 3 weeks (5% WL). After that, and while participants are ketotic, a 10–17% WL is not associated with increased appetite. However, hunger feelings and AG concentrations increase significantly from baseline, once refeeding occurs. PMID:28439092

Comparative effect of chronic bombesin, gastrin-releasing peptide and caerulein on the rat pancreas.

PubMed

Damgé, C; Hajri, A; Lhoste, E; Aprahamian, M

1988-02-01

This study was designed to compare, on a molar basis, the effect of chronic bombesin, gastrin-releasing peptide (GRP) and caerulein on pancreatic growth in the rat. These 3 peptides were administered s.c. 3 times daily for 4 days at the following concentrations: 0.036, 0.36, 3.6 and 7.2 nmol/kg of body weight. Bombesin and GRP induced pancreatic growth in a dose-dependent manner from 3.6 nmol/kg. This growth was characterized by an increase in pancreatic weight, its protein and RNA contents but not in DNA content suggesting cellular hypertrophy. Caerulein exerted a biphasic effect on pancreatic growth, inducing cellular hypertrophy at low doses since 0.36 nmol/kg and atrophy with the highest dose (7.2 nmol/kg). Bombesin and caerulein (until 3.6 nmol/kg) increased the pancreatic content in chymotrypsin more than in amylase. The 7.2 nmol/kg caerulein treatment depressed all enzyme activities while the same dose of GRP increased pancreatic lipase content. It is concluded that (1) bombesin and GRP are equipotent trophic factors for the pancreas; (2) caerulein is the most potent factor and exerts a biphasic effect on pancreatic growth; (3) pancreatic growth and synthesis and/or secretion of enzymes are not regulated through the same mechanism.

Once-daily delayed-release metformin lowers plasma glucose and enhances fasting and postprandial GLP-1 and PYY: results from two randomised trials.

PubMed

DeFronzo, Ralph A; Buse, John B; Kim, Terri; Burns, Colleen; Skare, Sharon; Baron, Alain; Fineman, Mark

2016-08-01

Delayed-release metformin (Metformin DR) was developed to maximise gut-based mechanisms of metformin action by targeting the drug to the ileum. Metformin DR was evaluated in two studies. Study 1 compared the bioavailability and effects on circulating glucose and gut hormones (glucagon-like peptide-1, peptide YY) of Metformin DR dosed twice-daily to twice-daily immediate-release metformin (Metformin IR). Study 2 compared the bioavailability and glycaemic effects of Metformin DR dosages of 1,000 mg once-daily in the morning, 1,000 mg once-daily in the evening, and 500 mg twice-daily. Study 1 was a blinded, randomised, crossover study (three × 5 day treatment periods) of twice-daily 500 mg or 1,000 mg Metformin DR vs twice-daily 1,000 mg Metformin IR in 24 participants with type 2 diabetes conducted at two study sites (Celerion Inc.; Tempe, AZ, and Lincoln, NE, USA). Plasma glucose and gut hormones were assessed over 10.25 h at the start and end of each treatment period; plasma metformin was measured over 11 h at the end of each treatment period. Study 2 was a non-blinded, randomised, crossover study (three × 7 day treatment periods) of 1,000 mg Metformin DR once-daily in the morning, 1,000 mg Metformin DR once-daily in the evening, or 500 mg Metformin DR twice-daily in 26 participants with type 2 diabetes performed at a single study site (Celerion, Tempe, AZ). Plasma glucose was assessed over 24 h at the start and end of each treatment period, and plasma metformin was measured over 30 h at the end of each treatment period. Both studies implemented centrally generated computer-based randomisation using a 1:1:1 allocation ratio. A total of 24 randomised participants were included in study 1; of these, 19 completed the study and were included in the evaluable population. In the evaluable population, all treatments produced similar significant reductions in fasting glucose (median reduction range, -0.67 to -0.81 mmol/l across treatments) and

Production and evaluation of YY-male Brook Trout to eradicate nonnative wild brook trout populations

USGS Publications Warehouse

Kennedy, Patrick; Schill, Daniel J.; Meyer, Kevin A.; Campbell, Matthew R.; Vu, Ninh V.; Hansen, Michael J.

2017-01-01

Nonnative Brook Trout Salvelinus fontinalis were introduced throughout western North America in the early 1900s, resulting in widespread self-sustaining populations that are difficult to eradicate and often threaten native salmonid populations. A novel approach for their eradication involves use of YY male (MYY) Brook Trout (created in the hatchery by feminizing XY males and crossing them with normal XY males). If MYY Brook Trout survive after stocking, and reproduce successfully with wild females, in theory this could eventually drive the sex ratio of the wild population to 100% males, at which point the population would not be able to reproduce and would be eradicated. This study represents the first successful development of a FYY and MYY salmonid broodstock, which was produced in four years at relatively low cost. Field trials demonstrated that stocked hatchery MYY Brook Trout survived and produced viable MYY offspring in streams, although reproductive fitness appeared to have been lower than their wild conspecifics. Even if reduced fitness is the norm in both streams and alpine lakes, our population simulations suggest that eradication can be achieved in reasonable time periods under some MYY stocking scenarios, especially when wild Brook Trout are simultaneously suppressed in the population.

Resistant starch and protein intake enhances fat oxidation and feelings of fullness in lean and overweight/obese women.

PubMed

Gentile, Christopher L; Ward, Emery; Holst, Jens Juul; Astrup, Arne; Ormsbee, Michael J; Connelly, Scott; Arciero, Paul J

2015-10-29

Diets high in either resistant starch or protein have been shown to aid in weight management. We examined the effects of meals high in non-resistant or resistant starch with and without elevated protein intake on substrate utilization, energy expenditure, and satiety in lean and overweight/obese women. Women of varying levels of adiposity consumed one of four pancake test meals in a single-blind, randomized crossover design: 1) waxy maize (control) starch (WMS); 2) waxy maize starch and whey protein (WMS+WP); 3) resistant starch (RS); or 4) RS and whey protein (RS+WP). Total post-prandial energy expenditure did not differ following any of the four test meals (WMS = 197.9 ± 8.9; WMS+WP = 188 ± 8.1; RS = 191.9 ± 8.9; RS+WP = 195.8 ± 8.7, kcals/180 min), although the combination of RS+WP, but not either intervention alone, significantly increased (P <0.01) fat oxidation (WMS = 89.5 ± 5.4; WMS+WP = 84.5 ± 7.2; RS = 97.4 ± 5.4; RS+WP = 107.8 ± 5.4, kcals/180 min). Measures of fullness increased (125% vs. 45%) and hunger decreased (55% vs. 16%) following WP supplemented versus non-whey conditions (WMS+WP, RS+WP vs. WMS, RS), whereas circulating hunger and satiety factors were not different among any of the test meals. However, peptide YY (PYY) was significantly elevated at 180 min following RS+WP meal. The combined consumption of dietary resistant starch and protein increases fat oxidation, PYY, and enhances feelings of satiety and fullness to levels that may be clinically relevant if maintained under chronic conditions. This trial was registered at clinicaltrials.gov as NCT02418429.

Enteroendocrine K and L cells in healthy and type 2 diabetic individuals.

PubMed

Jorsal, Tina; Rhee, Nicolai A; Pedersen, Jens; Wahlgren, Camilla D; Mortensen, Brynjulf; Jepsen, Sara L; Jelsing, Jacob; Dalbøge, Louise S; Vilmann, Peter; Hassan, Hazem; Hendel, Jakob W; Poulsen, Steen S; Holst, Jens J; Vilsbøll, Tina; Knop, Filip K

2018-02-01

Enteroendocrine K and L cells are pivotal in regulating appetite and glucose homeostasis. Knowledge of their distribution in humans is sparse and it is unknown whether alterations occur in type 2 diabetes. We aimed to evaluate the distribution of enteroendocrine K and L cells and relevant prohormone-processing enzymes (using immunohistochemical staining), and to evaluate the mRNA expression of the corresponding genes along the entire intestinal tract in individuals with type 2 diabetes and healthy participants. In this cross-sectional study, 12 individuals with type 2 diabetes and 12 age- and BMI-matched healthy individuals underwent upper and lower double-balloon enteroscopy with mucosal biopsy retrieval from approximately every 30 cm of the small intestine and from seven specific anatomical locations in the large intestine. Significantly different densities for cells positive for chromogranin A (CgA), glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide, peptide YY, prohormone convertase (PC) 1/3 and PC2 were observed along the intestinal tract. The expression of CHGA did not vary along the intestinal tract, but the mRNA expression of GCG, GIP, PYY, PCSK1 and PCSK2 differed along the intestinal tract. Lower counts of CgA-positive and PC1/3-positive cells, respectively, were observed in the small intestine of individuals with type 2 diabetes compared with healthy participants. In individuals with type 2 diabetes compared with healthy participants, the expression of GCG and PYY was greater in the colon, while the expression of GIP and PCSK1 was greater in the small intestine and colon, and the expression of PCSK2 was greater in the small intestine. Our findings provide a detailed description of the distribution of enteroendocrine K and L cells and the expression of their products in the human intestinal tract and demonstrate significant differences between individuals with type 2 diabetes and healthy participants. NCT03044860.

NUTRALYS® pea protein: characterization of in vitro gastric digestion and in vivo gastrointestinal peptide responses relevant to satiety

PubMed Central

Overduin, Joost; Guérin-Deremaux, Laetitia; Wils, Daniel; Lambers, Tim T.

2015-01-01

Background Pea protein (from Pisum sativum) is under consideration as a sustainable, satiety-inducing food ingredient. Objective In the current study, pea-protein-induced physiological signals relevant to satiety were characterized in vitro via gastric digestion kinetics and in vivo by monitoring post-meal gastrointestinal hormonal responses in rats. Design Under in vitro simulated gastric conditions, the digestion of NUTRALYS® pea protein was compared to that of two dairy proteins, slow-digestible casein and fast-digestible whey. In vivo, blood glucose and gastrointestinal hormonal (insulin, ghrelin, cholecystokinin [CCK], glucagon-like peptide 1 [GLP-1], and peptide YY [PYY]) responses were monitored in nine male Wistar rats following isocaloric (11 kcal) meals containing 35 energy% of either NUTRALYS® pea protein, whey protein, or carbohydrate (non-protein). Results In vitro, pea protein transiently aggregated into particles, whereas casein formed a more enduring protein network and whey protein remained dissolved. Pea-protein particle size ranged from 50 to 500 µm, well below the 2 mm threshold for gastric retention in humans. In vivo, pea-protein and whey-protein meals induced comparable responses for CCK, GLP-1, and PYY, that is, the anorexigenic hormones. Pea protein induced weaker initial, but equal 3-h integrated ghrelin and insulin responses than whey protein, possibly due to the slower gastric breakdown of pea protein observed in vitro. Two hours after meals, CCK levels were more elevated in the case of protein meals compared to that of non-protein meals. Conclusions These results indicate that 1) pea protein transiently aggregates in the stomach and has an intermediately fast intestinal bioavailability in between that of whey and casein; 2) pea-protein- and dairy-protein-containing meals were comparably efficacious in triggering gastrointestinal satiety signals. PMID:25882536

Impact of medium and long chain triglycerides consumption on appetite and food intake in overweight men

PubMed Central

St-Onge, Marie-Pierre; Mayrsohn, Brian; O’Keeffe, Majella; Kissileff, Harry R.; Choudhury, Arindam Roy; Laferrère, Blandine

2014-01-01

Background Medium chain triglycerides (MCT) enhance thermogenesis and may reduce food intake relative to long chain triglycerides (LCT). The goal of this study was to establish the effects of MCT on appetite and food intake and determine whether differences were due to differences in hormone concentrations. Methods Two randomized, crossover studies were conducted in which overweight men consumed 20 g of MCT or corn oil (LCT) at breakfast. Blood samples were obtained over 3 h. In Study 1 (n=10), an ad lib lunch was served after 3 h. In Study 2 (n=7), a pre-load containing 10 g of test oil was given at 3 h and lunch was served 1 h later. Linear mixed model analyses were performed to determine the effects of MCT and LCT oil on change in hormones and metabolites from fasting, adjusting for body weight. Correlations were computed between differences in hormones just before the test meals and differences in intakes after the two oils for Study 1 only. Results Food intake at the lunch test meal after the MCT pre-load (Study 2) was (mean ± SEM) 532 ± 389 kcal vs. 804 ± 486 kcal after LCT (P < 0.05). MCT consumption resulted in a lower rise in triglycerides (P = 0.014) and glucose (P = 0.066) and a higher rise in peptide YY (P = 0.017) and leptin (P = 0.036) compared to LCT (combined data). Correlations between differences in hormone levels (GLP-1, PYY) and differences in food intake were in the opposite direction to expectations. Conclusions MCT consumption reduced food intake acutely but this does not seem to be mediated by changes in GLP-1, PYY, and insulin. PMID:25074387

Acute and second-meal effects of peanuts on glycaemic response and appetite in obese women with high type 2 diabetes risk: a randomised cross-over clinical trial.

PubMed

Reis, Caio E G; Ribeiro, Daniela N; Costa, Neuza M B; Bressan, Josefina; Alfenas, Rita C G; Mattes, Richard D

2013-06-01

Nut consumption is associated with a reduced risk of type 2 diabetes mellitus (T2DM). The aim of the present study was to assess the effects of adding peanuts (whole or peanut butter) on first (0-240 min)- and second (240-490 min)-meal glucose metabolism and selected gut satiety hormone responses, appetite ratings and food intake in obese women with high T2DM risk. A group of fifteen women participated in a randomised cross-over clinical trial in which 42·5 g of whole peanuts without skins (WP), peanut butter (PB) or no peanuts (control) were added to a 75 g available carbohydrate-matched breakfast meal. Postprandial concentrations (0-490 min) of glucose, insulin, NEFA, glucagon-like peptide-1 (GLP-1), peptide YY (PYY), cholecystokinin (CCK), appetitive sensations and food intake were assessed after breakfast treatments and a standard lunch. Postprandial NEFA incremental AUC (IAUC) (0-240 min) and glucose IAUC (240-490 min) responses were lower for the PB breakfast compared with the control breakfast. Insulin concentrations were higher at 120 and 370 min after the PB consumption than after the control consumption. Desire-to-eat ratings were lower, while PYY, GLP-1 and CCK concentrations were higher after the PB intake compared with the control intake. WP led to similar but non-significant effects. The addition of PB to breakfast moderated postprandial glucose and NEFA concentrations, enhanced gut satiety hormone secretion and reduced the desire to eat. The greater bioaccessibility of the lipid component in PB is probably responsible for the observed incremental post-ingestive responses between the nut forms. Inclusion of PB, and probably WP, to breakfast may help to moderate glucose concentrations and appetite in obese women.

Increased colonic propionate reduces anticipatory reward responses in the human striatum to high-energy foods.

PubMed

Byrne, Claire S; Chambers, Edward S; Alhabeeb, Habeeb; Chhina, Navpreet; Morrison, Douglas J; Preston, Tom; Tedford, Catriona; Fitzpatrick, Julie; Irani, Cherag; Busza, Albert; Garcia-Perez, Isabel; Fountana, Sofia; Holmes, Elaine; Goldstone, Anthony P; Frost, Gary S

2016-07-01

Short-chain fatty acids (SCFAs), metabolites produced through the microbial fermentation of nondigestible dietary components, have key roles in energy homeostasis. Animal research suggests that colon-derived SCFAs modulate feeding behavior via central mechanisms. In humans, increased colonic production of the SCFA propionate acutely reduces energy intake. However, evidence of an effect of colonic propionate on the human brain or reward-based eating behavior is currently unavailable. We investigated the effect of increased colonic propionate production on brain anticipatory reward responses during food picture evaluation. We hypothesized that elevated colonic propionate would reduce both reward responses and ad libitum energy intake via stimulation of anorexigenic gut hormone secretion. In a randomized crossover design, 20 healthy nonobese men completed a functional magnetic resonance imaging (fMRI) food picture evaluation task after consumption of control inulin or inulin-propionate ester, a unique dietary compound that selectively augments colonic propionate production. The blood oxygen level-dependent (BOLD) signal was measured in a priori brain regions involved in reward processing, including the caudate, nucleus accumbens, amygdala, anterior insula, and orbitofrontal cortex (n = 18 had analyzable fMRI data). Increasing colonic propionate production reduced BOLD signal during food picture evaluation in the caudate and nucleus accumbens. In the caudate, the reduction in BOLD signal was driven specifically by a lowering of the response to high-energy food. These central effects were partnered with a decrease in subjective appeal of high-energy food pictures and reduced energy intake during an ad libitum meal. These observations were not related to changes in blood peptide YY (PYY), glucagon-like peptide 1 (GLP-1), glucose, or insulin concentrations. Our results suggest that colonic propionate production may play an important role in attenuating reward-based eating

Slowly and rapidly digested fat emulsions are equally satiating but their triglycerides are differentially absorbed and metabolized in humans.

PubMed

Keogh, Jennifer B; Wooster, Tim J; Golding, Matthew; Day, Li; Otto, Bärbel; Clifton, Peter M

2011-05-01

Little is known about the effect of dietary fat emulsion microstructure on plasma TG concentrations, satiety hormones, and food intake. The aim of this study was to structure dietary fat to slow digestion and flatten postprandial plasma TG concentrations but not increase food intake. Emulsions were stabilized by egg lecithin (control), sodium sterol lactylate, or sodium caseinate/monoglyceride (CasMag) with either liquid oil or a liquid oil/solid fat mixture. In a randomized, double-blind, crossover design, 4 emulsions containing 30 g of fat in a 350-mL preload were consumed by 10 men and 10 women (BMI = 25.1 ± 2.8 kg/m(2); age = 58.8 ± 4.8 y). Pre- and postprandial plasma TG, cholecystokinin (CCK), glucagon-like peptide-1 (GLP-1), and peptide YY (PYY) concentrations and food intake were measured. In a second experiment in a subset of the participants (n = 8, 4 men and 4 women), (13)C-labeled mixed TG was incorporated into 2 different emulsions and breath (13)C was measured over 6 h. In the first experiment, the postprandial rise in plasma TG concentrations following the CasMag-stabilized emulsion containing 30% solid fat was lower than all other emulsions at 90 and 120 min (P < 0.05). Plasma CCK (P < 0.0001), GLP-1 (P < 0.01), and PYY (P < 0.001) concentrations were also reduced following this emulsion compared with control. Food intake at a test meal, eaten 3 h after the preload, did not differ among the emulsions. In the second experiment, when measured by the (13)C breath test, 25% of the TG in the CasMag emulsion was absorbed and metabolized compared with control. In conclusion, fat can be structured to decrease its effect on plasma TG concentrations without increasing food intake.

Phosphorylation of TNF-alpha converting enzyme by gastrin-releasing peptide induces amphiregulin release and EGF receptor activation.

PubMed

Zhang, Qing; Thomas, Sufi M; Lui, Vivian Wai Yan; Xi, Sichuan; Siegfried, Jill M; Fan, Huizhou; Smithgall, Thomas E; Mills, Gordon B; Grandis, Jennifer Rubin

2006-05-02

G protein-coupled receptors induce EGF receptor (EGFR) signaling, leading to the proliferation and invasion of cancer cells. Elucidation of the mechanism of EGFR activation by G protein-coupled receptors may identify new signaling paradigms. A gastrin-releasing peptide (GRP)/GRP receptor-mediated autocrine pathway was previously described in squamous cell carcinoma of head and neck. In the present study, we demonstrate that TNF-alpha converting enzyme (TACE), a disintegrin and metalloproteinse-17, undergoes a Src-dependent phosphorylation that regulates release of the EGFR ligand amphiregulin upon GRP treatment. Further investigation reveals the phosphatidylinositol 3-kinase (PI3-K) as the intermediate of c-Src and TACE, contributing to their association and TACE phosphorylation. Phosphoinositide-dependent kinase 1 (PDK1), a downstream target of PI3-K, has been identified as the previously undescribed kinase to directly phosphorylate TACE upon GRP treatment. These findings suggest a signaling cascade of GRP-Src-PI3-K-PDK1-TACE-amphiregulin-EGFR with multiple points of interaction, translocation, and phosphorylation. Furthermore, knockdown of PDK1 augmented the antitumor effects of the EGFR inhibitor erlotinib, indicating PDK1 as a therapeutic target to improve the clinical response to EGFR inhibitors.

Infusion of exogenous cholecystokinin-8, gastrin releasing peptide-29 and their combination reduce body weight in diet-induced obese male rats.

PubMed

Mhalhal, Thaer R; Washington, Martha C; Newman, Kayla; Heath, John C; Sayegh, Ayman I

2017-02-01

We hypothesized that exogenous gastrin releasing peptide-29 (GRP-29), cholecystokinin-8 (CCK-8) and their combination reduce body weight (BW). To test this hypothesis, BW was measured in four groups of diet-induced obese (DIO) male rats infused in the aorta (close to the junctions of the celiac and cranial mesenteric arteries) with saline, CCK-8 (0.5 nmol/kg), GRP-29 (0.5 nmol/kg) and CCK-8+GRP-29 (0.5 nmol/kg each) once daily for a total of 23 days. We found that CCK-8, GRP-29 and CCK-8+GRP-29 reduce BW relative to saline control. In conclusion, CCK-8, GRP-29 and their combination reduce BW in the DIO rat model. If infused near their gastrointestinal sites of action CCK-8, GRP-29 and their combination may have a role in regulating BW. Published by Elsevier Ltd.

Consuming Lower-Protein Nutrition Bars with Added Leucine Elicits Postprandial Changes in Appetite Sensations in Healthy Women.

PubMed

Bolster, Douglas R; Rahn, Maike; Kamil, Alison G; Bristol, Lindsey T; Goltz, Shellen R; Leidy, Heather J; Blaze Mt, Melvin; Nunez, Michael A; Guo, Elizabeth; Wang, Jianquan; Harkness, Laura S

2018-04-20

Higher-protein meals (>25 g protein/meal) have been associated with enhanced satiety but the role of amino acids is unclear. Leucine has been proposed to stimulate satiety in rodents but has not been assessed in humans. We assessed the acute effects of lower-protein nutrition bars, enhanced with a leucine peptide (LP), on postprandial appetite sensations in combination with plasma leucine and peptide YY (PYY) in healthy women. Utilizing a double-blind randomized crossover design, 40 healthy women [28 ± 7.5 y; body mass index (BMI, in kg/m2): 23.5 ± 2.4] consumed the following isocaloric (180 kcal) pre-loads on 3 separate visits: control bar [9 g protein with 0 g added LP (0-g LP)] or treatment bars [11 g protein with 2 g added LP (2-g LP) or 13 g protein with 3 g added LP (3-g LP)]. Pre- and postprandial hunger, desire to eat, prospective food consumption (PFC), fullness, and plasma leucine were assessed every 30 min for 240 min. Plasma PYY was assessed hourly for 240 min (n = 24). Main effects of time (P < 0.0001) and treatment (P < 0.03) were detected for postprandial hunger, desire to eat, PFC, and fullness. Post hoc analyses revealed that the 2-g and 3-g LP bars elicited greater increases in fullness and greater decreases in PFC compared with 0-g LP (all, P < 0.05) with no differences between the 2-g and 3-g LP bars. The 2-g bar elicited greater decreases in hunger and desire to eat compared with the 0-g LP bar (both, P ≤ 0.01), whereas 3-g LP did not. Appetite incremental areas under the curves (iAUCs) and PYY outcomes were not different between bars. A treatment × time interaction was detected for plasma leucine with increases occurring in a leucine-dose-dependent manner (P < 0.0001). Despite the dose-dependent increases in plasma leucine following the consumption of lower-protein bars enhanced with LP, only the 2-g LP bar elicited consistent postprandial changes in select appetite sensations compared with the 0-g LP bar. This study was

Diagnosis of Zollinger–Ellison syndrome in the era of PPIs, faulty gastrin assays, sensitive imaging and limited access to acid secretory testing

PubMed Central

Metz, David C.; Cadiot, Guillaume; Poitras, Pierre; Ito, Tetsuhide; Jensen, Robert T.

2017-01-01

In recent years the diagnosis of Zollinger-Ellison syndrome (ZES) has become increasingly controversial with several new approaches and criteria proposed, differing from the classical biochemical criterion of inappropriate hypergastrinemia (i.e., hypergastrinemia in the presence of hyperchlorhydria) (Table 1). These changes have come about because of the difficulty and potential dangers of stopping proton pump inhibitors (PPIs) for gastric acid analysis; the recognition than many of the current assays used to assess gastrin concentrations are unreliable; the development of sensitive imaging modalities that detect neuroendocrine tumors (NETs) including an increasing number of the primary gastrinomas; the increased use of percutaneous or endoscopic ultrasound (EUS)-directed biopsies/cytology and the general lack of availability of acid secretory testing. In this article we will discuss the basis for these controversies, review the proposed changes in diagnostic approaches and make recommendations for supporting the diagnosis of ZES in the modern era. PMID:29326808

Circulating levels of cholecystokinin and gastrin-releasing peptide in rainbow trout fed different diets.

PubMed

Jönsson, Elisabeth; Forsman, Antti; Einarsdottir, Ingibjörg E; Egnér, Barbro; Ruohonen, Kari; Björnsson, Björn Thrandur

2006-09-01

Cholecystokinin (CCK) and gastrin-releasing peptide (GRP) are gastrointestinal peptides thought to be important regulators of intake and digestion of food in vertebrates. In this study, pre- and postprandial plasma levels of CCK and GRP were measured in rainbow trout (Oncorhynchus mykiss) by the establishment of homologous radioimmunoassays, and the hormonal levels assessed in relation to dietary lipid:protein ratio and food intake. Fish were acclimated to either a high protein/low lipid diet (HP/LL diet; 14.1% lipids) or a normal protein/high lipid diet (NP/HL diet; 31.4% lipids). On three consecutive sampling days, radio-dense lead-glass beads were included in the diets for assessment of feed intake. Fish were terminally sampled for blood and stomach contents prior to feeding at time 0, and at 0.3, 1, 2, 4, 6, and 24 h after feeding. There was a postprandial elevation of plasma CCK levels, which was most evident after 4 and 6 h. Fish fed the NP/HL diet had higher plasma CCK levels compared with those fed the HP/LL diet. Plasma CCK levels were not affected by the amount of food ingested. GRP levels in plasma were not influenced by sampling time, diet, or feed intake. The results indicate that the endocrine release of gastrointestinal CCK is increased during feeding and may be further influenced by the dietary lipid:protein ratio in rainbow trout. Plasma GRP levels, on the other hand, appear not to be influenced by feeding or diet composition.

Immunopathological and Modulatory Effects of Cag A+ Genotype on Gastric Mucosa, Inflammatory Response, Pepsinogens, and Gastrin-17 Secretion in Iraqi Patients infected with H. pylori.

PubMed

Al-Ezzy, Ali Ibrahim Ali

2018-05-20

To determine the immunopathological correlation between Cag A+ H. pylori -specific IgG; pepsinogen I&II (PI&PII); gastrin-17 (G-17); status of gastric and duodenal mucosa and inflammatory activities on different gastroduodenal disorders. Eighty gastroduodenal biopsies were taken from patients with gastroduodenal disorders for histopathological evaluation and H. pylori diagnosis. Serum samples were used for evaluation of gastric hormones and detection of H. pylori -specific IgG antibodies. The tissue expression of H. pylori Cag A gene was detected by in situ hybridisation. H. pylori IgG antibodies were detected in (88.8%) of enrolled patients. According to Cag A gene expression, Significant difference (P value ˂ 0.05) was detected in levels of PG I; PGII, PG I/PG II among patients with gastric disorders. Serum G-17 level was negatively correlated with Cag A gene expression (P-value = 0.04). There was a significant correlation between H. pylori IgG and PG I; PG II; G-17. The current study revealed that corpus atrophic gastritis was diagnosed histologically with (5%) gastric ulcer cases; (3.75%) of duodenal ulcer cases; (3.75%) of duodenitis cases; (1.25%) of gastropathy cases and (8.75%) of gastritis cases. At the same time H. pylori gastritis diagnosed concurrently with (8.75%) of gastric ulcer cases; (11.25%) of duodenal ulcer cases; (17.5%) of gastropathy cases; (3.75%) of duodenitis cases and (2.5%) of prepyloric ulcer cases. A significant correlation was reported between the Immunopathological status of gastric mucosa and endoscopic mucosal finding among duodenal ulcer cases and gastritis cases only. A positive correlation was reported between serum levels of PGI; PGII; PGI/PGII; G-17; PMNs grade and Immunopathological status of the gastroduodenal mucosa of H. pylori Infected patients. A significant difference was reported in lymphocyte grades among gastric disorders without correlation with immunohistopathological changes in the mucosa (P-value = 0.002). A

Are the Yo-Yo intermittent recovery test levels 1 and 2 both useful? Reliability, responsiveness and interchangeability in young soccer players.

PubMed

Fanchini, Maurizio; Castagna, Carlo; Coutts, Aaron J; Schena, Federico; McCall, Alan; Impellizzeri, Franco M

2014-12-01

Abstract The aim of this study was to compare the reliability, internal responsiveness and interchangeability of the Yo-Yo intermittent recovery test level 1 (YY1), level 2 (YY2) and submaximal YY1 (YY1-sub). Twenty-four young soccer players (age 17 ± 1 years; height 177 ± 7 cm; body mass 68 ± 6 kg) completed each test five times within pre- and in-season; distances covered and heart rates (HRs) were measured. Reliability was expressed as typical error of measurement (TEM) and intraclass correlation coefficient (ICC). Internal responsiveness was determined as effect size (ES) and signal-to-noise ratio (ES TEM ). Interchangeability was determined with correlation between training-induced changes. The TEM and ICC for distances in the YY1 and YY2 and for HR in YY1-sub were 7.3% and 0.78, 7.1% and 0.93 and 2.2% and 0.78, respectively. The ESs and ES TEMs were 0.9 and 1.9 for YY1, 0.4 and 1.2 for YY2 and -0.3 and -0.3 for YY1-sub. Correlations between YY1 vs. YY2 and YY1-sub were 0.56 to 0.84 and -0.36 to -0.81, respectively. Correlations between change scores in YY1 vs. YY2 were 0.29 and -0.21 vs. YY1-sub. Peak HR was higher in YY1 vs. YY2. The YY1 and YY2 showed similar reliability; however, they were not interchangeable. The YY1 was more responsive to training compared to YY2 and YY1-sub.

Somatostatin, prostaglandin E2 and atropine inhibition of the gastric actions of bombesin in the dog.

PubMed

Hirschowitz, B I; Molina, E

1984-01-01

Bombesin, acetylcholine, prostaglandins and somatostatin are all thought to be involved in the regulation of gastrin release and gastric secretion. We have studied the effects of low doses of atropine, 16-16(Me)2-prostaglandin E2 (PGE2) and somatostatin-14 on bombesin-stimulated gastrin release and gastric acid and pepsin secretion in conscious fistula dogs. For reference, synthetic gastrin G-17 was studied with and without somatostatin. Bombesin, in a dose-related manner, increased serum gastrin, which in turn stimulated gastric acid and pepsin secretion in a serum gastrin, concentration-dependent manner. Somatostatin inhibited gastrin release by bombesin as well as the secretory stimulation by G-17; the combination of sequential effects resulted in a marked inhibition of bombesin-stimulated gastric acid and pepsin secretion. PGE2 also strongly inhibited gastrin release and acid and pepsin secretion. Atropine had no significant effect on gastrin release, but greatly inhibited gastric secretion. Thus somatostatin and PGE2 inhibited at two sites, gastrin release and gastrin effects, while atropine affected only the latter.

In vitro evaluation of (99m)Tc-EDDA/tricine-HYNIC-Q-Litorin in gastrin-releasing peptide receptor positive tumor cell lines.

PubMed

Yurt Lambrecht, Fatma; Durkan, Kübra; Ozgür, Aykut; Gündüz, Cumhur; Avcı, Cığır Biray; Susluer, Sunde Yılmaz

2013-05-01

Bombesin and its derivatives exhibit a high affinity for gastrin-releasing peptide receptor (GRPr), which is over-expressed in a variety of human cancers (prostate, pancreatic, lung, etc.). The aim of this study was to investigate the in vitro potential of the hydrazinonicotinamide (HYNIC)-Q-Litorin. (99m)Tc labeling was performed by using different co-ligands: tricine and ethylenediamine diacetic acid (EDDA). The radiochemical stability of radiolabeled peptide conjugates was checked at room temperature and in cysteine solution up to 24 h. The in vitro cell uptake of (99m)Tc-EDDA-HYNIC-Q-Litorin and (99m)Tc-tricine-HYNIC-Q-Litorin were evaluated on pancreatic tumor and control cell lines. Optimum specific activity and incubation time were determined for all the cell lines. The results showed that the cell uptake of the radiolabeled peptide conjugates in tumor cell lines were higher than in the control cell line. The findings of this study indicated the need for further development of in vivo study as a radiopharmaceutical for pancreatic tumor imaging.

Gastrin-Releasing Peptide (GRP) in the Ovine Uterus: Regulation by Interferon Tau and Progesterone1

PubMed Central

Song, Gwonhwa; Satterfield, M. Carey; Kim, Jinyoung; Bazer, Fuller W.; Spencer, Thomas E.

2008-01-01

Gastrin-releasing peptide (GRP) is abundantly expressed by endometrial glands of the ovine uterus and processed into different bioactive peptides, including GRP1-27, GRP18-27, and a C-terminus, that affect cell proliferation and migration. However, little information is available concerning the hormonal regulation of endometrial GRP and expression of GRP receptors in the ovine endometrium and conceptus. These studies determined the effects of pregnancy, progesterone (P4), interferon tau (IFNT), placental lactogen (CSH1), and growth hormone (GH) on expression of GRP in the endometrium and GRP receptors (GRPR, NMBR, BRS3) in the endometrium, conceptus, and placenta. In pregnant ewes, GRP mRNA and protein were first detected predominantly in endometrial glands after Day 10 and were abundant from Days 18 through 120 of gestation. Treatment with IFNT and progesterone but not CSH1 or GH stimulated GRP expression in the endometrial glands. Western blot analyses identified proGRP in uterine luminal fluid and allantoic fluid from Day 80 unilateral pregnant ewes but not in uterine luminal fluid of either cyclic or early pregnant ewes. GRPR mRNA was very low in the Day 18 conceptus and undetectable in the endometrium and placenta; NMBR and BRS3 mRNAs were undetectable in ovine uteroplacental tissues. Collectively, the present studies validate GRP as a novel IFNT-stimulated gene in the glands of the ovine uterus, revealed that IFNT induction of GRP is dependent on P4, and found that exposure of the ovine uterus to P4 for 20 days induces GRP expression in endometrial glands. PMID:18448839

Function of non-visual arrestins in signaling and endocytosis of the gastrin-releasing peptide receptor (GRP receptor).

PubMed

Schumann, Michael; Nakagawa, Tomoo; Mantey, Samuel A; Howell, Brian; Jensen, Robert T

2008-03-01

Little is known about the role of arrestins in gastrointestinal hormone/neurotransmitter receptor endocytosis. With other G protein-coupled receptors, arrestins induce G protein-uncoupling and receptor endocytosis. In this study, we used arrestin wild-type and dominant-negative mutant constructs to analyze the arrestin dependence of endocytosis and desensitization of the gastrin-releasing peptide receptor (GRP-R). Co-expression of the GRP-R with wild-type arrestin2 and arrestin3 increased not only GRP-R endocytosis but also GRP-R desensitization in arrestin-overexpressing cells. Co-expression of the dominant-negative mutants V53D-arrestin2 or V54D-arrestin3 reduced GRP-R endocytosis. Notably, different trafficking routes for agonist-activated GRP-R-arrestin2 and GRP-R-arrestin3 complexes were found. Arrestin3 internalizes with GRP-R to intracellular vesicles, arrestin2 splits from the GRP-R and localizes to the cell membrane. Also, the recycling pathway of the GRP-R was different if co-expressed with arrestin2 or arrestin3. Using different GRP-R mutants, the C-terminus and the 2nd intracellular loop of the GRP-R were found to be important for the GRP-R-arrestin interaction and for the difference in GRP receptor trafficking with the two arrestin subtypes. Our results show that both non-visual arrestins play an important role in GRP-R internalization and desensitization.

In Vivo Chromatin Targets of the Transcription Factor Yin Yang 2 in Trophoblast Stem Cells

PubMed Central

Pérez-Palacios, Raquel; Macías-Redondo, Sofía; Climent, María; Contreras-Moreira, Bruno; Muniesa, Pedro; Schoorlemmer, Jon

2016-01-01

Background Yin Yang 2 (YY2) is a zinc finger protein closely related to the well-characterized Yin Yang 1 (YY1). YY1 is a DNA-binding transcription factor, with defined functions in multiple developmental processes, such as implantation, cell differentiation, X inactivation, imprinting and organogenesis. Yy2 has been treated as a largely immaterial duplication of Yy1, as they share high homology in the Zinc Finger-region and similar if not identical in vitro binding sites. In contrast to these similarities, gene expression alterations in HeLa cells with attenuated levels of either Yy1 or Yy2 were to some extent gene-specific. Moreover, the chromatin binding sites for YY2, except for its association with transposable retroviral elements (RE) and Endogenous Retroviral Elements (ERVs), remain to be identified. As a first step towards defining potential Yy2 functions matching or complementary to Yy1, we considered in vivo DNA binding sites of YY2 in trophoblast stem (TS) cells. Results We report the presence of YY2 protein in mouse-derived embryonic stem (ES) and TS cell lines. Following up on our previous report on ERV binding by YY2 in TS cells, we investigated the tissue-specificity of REX1 and YY2 binding and confirm binding to RE/ERV targets in both ES cells and TS cells. Because of the higher levels of expression, we chose TS cells to understand the role of Yy2 in gene and chromatin regulation. We used in vivo YY2 association as a measure to identify potential target genes. Sequencing of chromatin obtained in chromatin-immunoprecipitation (ChIP) assays carried out with αYY2 serum allowed us to identify a limited number of chromatin targets for YY2. Some putative binding sites were validated in regular ChIP assays and gene expression of genes nearby was altered in the absence of Yy2. Conclusions YY2 binding to ERVs is not confined to TS cells. In vivo binding sites share the presence of a consensus binding motif. Selected sites were uniquely bound by YY2 as

New Gastrin Releasing Peptide Receptor-Directed [99mTc]Demobesin 1 Mimics: Synthesis and Comparative Evaluation.

PubMed

Nock, Berthold A; Charalambidis, David; Sallegger, Werner; Waser, Beatrice; Mansi, Rosalba; Nicolas, Guillaume P; Ketani, Eleni; Nikolopoulou, Anastasia; Fani, Melpomeni; Reubi, Jean-Claude; Maina, Theodosia

2018-04-12

We have previously reported on the gastrin releasing peptide receptor (GRPR) antagonist [ 99m Tc]1, ([ 99m Tc]demobesin 1, 99m Tc-[N 4 '-diglycolate-dPhe 6 ,Leu-NHEt 13 ]BBN(6-13)). [ 99m Tc]1 has shown superior biological profile compared to analogous agonist-based 99m Tc-radioligands. We herein present a small library of [ 99m Tc]1 mimics generated after structural modifications in (a) the linker ([ 99m Tc]2, [ 99m Tc]3, [ 99m Tc]4), (b) the peptide chain ([ 99m Tc]5, [ 99m Tc]6), and (c) the C-terminus ([ 99m Tc]7 or [ 99m Tc]8). The effects of above modifications on the biological properties of analogs were studied in PC-3 cells and tumor-bearing SCID mice. All analogs showed subnanomolar affinity for the human GRPR, while most receptor-affine 4 and 8 behaved as potent GRPR antagonists in a functional internalization assay. In mice bearing PC-3 tumors, [ 99m Tc]1-[ 99m Tc]6 exhibited GRPR-specific tumor uptake, rapidly clearing from normal tissues. [ 99m Tc]4 displayed the highest tumor uptake (28.8 ± 4.1%ID/g at 1 h pi), which remained high even after 24 h pi (16.3 ± 1.8%ID/g), well surpassing that of [ 99m Tc]1 (5.4 ± 0.7%ID/g at 24 h pi).

Liquid meal composition, postprandial satiety hormones, and perceived appetite and satiety in obese women during acute caloric restriction.

PubMed

Heden, Timothy D; Liu, Ying; Sims, Lauren; Kearney, Monica L; Whaley-Connell, Adam T; Chockalingam, Anand; Dellsperger, Kevin C; Fairchild, Timothy J; Kanaley, Jill A

2013-04-01

The purpose of this study was to compare postprandial satiety regulating hormone responses (pancreatic polypeptide (PP) and peptide tyrosine tyrosine (PYY)) and visual analog scale- (VAS) assessed perceived appetite and satiety between liquid high-protein (HP) and high-carbohydrate (HC) meals in obese women during acute (24-h) caloric restriction. Eleven obese premenopausal women completed two conditions in random order in which they consumed 1500 calories as six 250-calorie HP meals or six 250-calorie HC meals over a 12-h period. Blood samples were taken at baseline and every 20 min thereafter and analyzed for PP and PYY concentrations. At these same points, perceived hunger and fullness were assessed with a VAS. The incremental area under the curve (iAUC) was used to compare postprandial responses. The 12-h PP and PYY iAUC were greater (P≤0.05) during the HP condition (PP: 4727±1306 pg/ml×12 h, PYY: 1373±357 pg/ml×12 h) compared with the HC condition (PP: 2300±528 pg/ml×12 h, PYY: 754±246 pg/ml×12 h). Perceived hunger and fullness were not different between conditions (P>0.05). The greatest changes in PYY and perceived fullness occurred after the morning meals during both conditions. These data suggest that in obese women during acute caloric restriction before weight loss, i) liquid HP meals, compared with HC meals, result in greater postprandial PP and PYY concentrations, an effect not associated with differential appetite or satiety responses, and ii) meal-induced changes in PYY and satiety are greatest during the morning period, regardless of dietary macronutrient composition.

Hunger and satiety responses to high-fat meals after a high-polyunsaturated fat diet: A randomized trial.

PubMed

Stevenson, Jada L; Paton, Chad M; Cooper, Jamie A

2017-09-01

Previous studies have shown that polyunsaturated fats (PUFAs) elicit a greater response in satiety after a single-meal challenge compared with other types of fats. The long-term effects of PUFAs on satiety, however, remain unknown. The aim of this study was to determine subjective and physiological hunger and satiety responses to high-fat (HF) meals before and after a 7-d PUFA-rich diet. Twenty-six, healthy weight (body mass index 18-24.9 kg/m 2 ), sedentary adults were randomly assigned to either a 7-d PUFA-rich diet (n = 8 men and n = 8 women) or a 7-d control diet (n = 5 men and n = 5 women). After a 3-d lead-in diet, participants reported for the baseline visit where anthropometrics, fasting visual analog scale (VAS) measurements, and a fasting blood sample were collected. Then, two HF meals (breakfast and lunch) were consumed. Postprandial blood draws and VAS measures were collected approximately every 30 min for 4 h after each meal, for a total of 8 h. From pre- to post-PUFA-rich diet, there was a decrease in fasting ghrelin (P < 0.05) and an increase in fasting peptide YY (PYY; P < 0.05); however, there were no changes in fasting insulin or leptin concentrations. The postprandial response for PYY was higher after the PUFA-rich diet visit compared to baseline (P < 0.01). However, there were no differences in the postprandial response for ghrelin, insulin, leptin, or VAS measures from pre- to post-diet in either the PUFA-rich diet or control (ns). A PUFA-rich diet consumed for 7 d favorably altered fasting and postprandial physiological markers of hunger and satiety; yet, did not alter subjective ratings of hunger or fullness. Copyright © 2017 Elsevier Inc. All rights reserved.

Appetite and gut hormone responses to moderate-intensity continuous exercise versus high-intensity interval exercise, in normoxic and hypoxic conditions.

PubMed

Bailey, Daniel P; Smith, Lindsey R; Chrismas, Bryna C; Taylor, Lee; Stensel, David J; Deighton, Kevin; Douglas, Jessica A; Kerr, Catherine J

2015-06-01

This study investigated the effects of continuous moderate-intensity exercise (MIE) and high-intensity interval exercise (HIIE) in combination with short exposure to hypoxia on appetite and plasma concentrations of acylated ghrelin, peptide YY (PYY), and glucagon-like peptide-1 (GLP-1). Twelve healthy males completed four, 2.6 h trials in a random order: (1) MIE-normoxia, (2) MIE-hypoxia, (3) HIIE-normoxia, and (4) HIIE-hypoxia. Exercise took place in an environmental chamber. During MIE, participants ran for 50 min at 70% of altitude-specific maximal oxygen uptake (V˙O2max) and during HIIE performed 6 × 3 min running at 90% V˙O2max interspersed with 6 × 3 min active recovery at 50% V˙O2max with a 7 min warm-up and cool-down at 70% V˙O2max (50 min total). In hypoxic trials, exercise was performed at a simulated altitude of 2980 m (14.5% O2). Exercise was completed after a standardised breakfast. A second meal standardised to 30% of participants' daily energy requirements was provided 45 min after exercise. Appetite was suppressed more in hypoxia than normoxia during exercise, post-exercise, and for the full 2.6 h trial period (linear mixed modelling, p <0.05). Plasma acylated ghrelin concentrations were lower in hypoxia than normoxia post-exercise and for the full 2.6 h trial period (p <0.05). PYY concentrations were higher in HIIE than MIE under hypoxic conditions during exercise (p = 0.042). No differences in GLP-1 were observed between conditions (p > 0.05). These findings demonstrate that short exposure to hypoxia causes suppressions in appetite and plasma acylated ghrelin concentrations. Furthermore, appetite responses to exercise do not appear to be influenced by exercise modality. Copyright © 2015 Elsevier Ltd. All rights reserved.

The effect of Korean pine nut oil on in vitro CCK release, on appetite sensations and on gut hormones in post-menopausal overweight women.

PubMed

Pasman, Wilrike J; Heimerikx, Jos; Rubingh, Carina M; van den Berg, Robin; O'Shea, Marianne; Gambelli, Luisa; Hendriks, Henk F J; Einerhand, Alexandra W C; Scott, Corey; Keizer, Hiskias G; Mennen, Louise I

2008-03-20

Appetite suppressants may be one strategy in the fight against obesity. This study evaluated whether Korean pine nut free fatty acids (FFA) and triglycerides (TG) work as an appetite suppressant. Korean pine nut FFA were evaluated in STC-1 cell culture for their ability to increase cholecystokinin (CCK-8) secretion vs. several other dietary fatty acids from Italian stone pine nut fatty acids, oleic acid, linoleic acid, alpha-linolenic acid, and capric acid used as a control. At 50 muM concentration, Korean pine nut FFA produced the greatest amount of CCK-8 release (493 pg/ml) relative to the other fatty acids and control (46 pg/ml). A randomized, placebo-controlled, double-blind cross-over trial including 18 overweight post-menopausal women was performed. Subjects received capsules with 3 g Korean pine (Pinus koraiensis) nut FFA, 3 g pine nut TG or 3 g placebo (olive oil) in combination with a light breakfast. At 0, 30, 60, 90, 120, 180 and 240 minutes the gut hormones cholecystokinin (CCK-8), glucagon like peptide-1 (GLP-1), peptide YY (PYY) and ghrelin, and appetite sensations were measured. A wash-out period of one week separated each intervention day.CCK-8 was higher 30 min after pine nut FFA and 60 min after pine nut TG when compared to placebo (p < 0.01). GLP-1 was higher 60 min after pine nut FFA compared to placebo (p < 0.01). Over a period of 4 hours the total amount of plasma CCK-8 was 60% higher after pine nut FFA and 22% higher after pine nut TG than after placebo (p < 0.01). For GLP-1 this difference was 25% after pine nut FFA (P < 0.05). Ghrelin and PYY levels were not different between groups. The appetite sensation "prospective food intake" was 36% lower after pine nut FFA relative to placebo (P < 0.05). This study suggests that Korean pine nut may work as an appetite suppressant through an increasing effect on satiety hormones and a reduced prospective food intake.

Apelin-13 increased food intake with serum ghrelin and leptin levels in male rats.

PubMed

Saral, S; Alkanat, M; Sumer, A; Canpolat, S

2018-01-01

In this study, we aimed to explain the role of apelin-13 on body weight, food and water intake with serum leptin, ghrelin, neuropeptid Y (NPY) and peptid YY (PYY) levels in male rat. Thirty-two Sprague-Dawley male rats were used for the study. The rats were injected SP (0.9 %) intraperitoneally (i.p) in the control group and 30 (AP30), 100 (AP100) and 300 (AP300) µg/kg apelin-13 in the study groups, respectively, 10 min before the transition to dark period, for 10 days. During the experimental period, with light and dark periods of food and water intake, body weights were recorded in rats. Rats were euthanized and serum samples were obtained. In serum samples leptin, ghrelin, NPY and PYY levels were measured with specific ELISA kit. Apelin-13 was increased body weights in all three (AP30, AP100 and AP300) groups compared with the control group. AP100 and AP300 groups had increased food intake in the dark and the cumulative period, but in the light period food intake values were not significantly increased (p > 0.05). As for the value of water intake, compared with the control group, all dose of apelin-13 increased water intake during the dark and the cumulative period. There was no significant change in water intake in the light period. On the other hand, compared with the control group, serum leptin levels were found to increase in the groups administered 100 and 300 µg/kg of apelin-13 (p < 0.05). Ghrelin levels were found high in all groups treated with apelin-13. Serum levels of NPY decreased only in the 300 µg/kg apelin-13 treated group (p 0.05). Apelin-13 increases body weight in rats as well as food and water intake (dark and cumulative period). Additionally, ghrelin can mediate the orexigenic effect of apelin-13 in the regulation of food intake (Fig. 4, Ref. 37).

Effect of Roux-en-Y Gastric Bypass Surgery on Bile Acid Metabolism in Normal and Obese Diabetic Rats

PubMed Central

Bhutta, Hina Y; Rajpal, Neetu; White, Wendy; Freudenberg, Johannes M.; Liu, Yaping; Way, James; Rajpal, Deepak; Cooper, David C.; Young, Andrew; Tavakkoli, Ali; Chen, Lihong

2015-01-01

In addition to classic functions of facilitating hepatobiliary secretion and intestinal absorption of lipophilic nutrients, bile acids (BA) are also endocrine factors and regulate glucose and lipid metabolism. Recent data indicate that antiobesity bariatric procedures e.g. Roux-en-Y gastric bypass surgery (RYGB), which also remit diabetes, increase plasma BAs in humans, leading to the hypothesis that BAs may play a role in diabetes resolution following surgery. To investigate the effect of RYGB on BA physiology and its relationship with glucose homeostasis, we undertook RYGB and SHAM surgery in Zucker diabetic fatty (ZDF) and normoglycemic Sprague Dawley (SD) rats and measured plasma and fecal BA levels, as well as plasma glucose, insulin, Glucagon like peptide 1 (GLP-1) and Peptide YY (PYY), 2 days before and 3, 7, 14 and 28 days after surgery. RYGB decreased body weight and increased plasma GLP-1 in both SD and ZDF rats while decreasing plasma insulin and glucose in ZDF rats starting from the first week. Compared to SHAM groups, both SD-RYGB and ZDF-RYGB groups started to have increases in plasma total BAs in the second week, which might not contribute to early post-surgery metabolic changes. While there was no significant difference in fecal BA excretion between SD-RYGB and SD-SHAM groups, the ZDF-RYGB group had a transient 4.2-fold increase (P<0.001) in 24-hour fecal BA excretion on post-operative day 3 compared to ZDF-SHAM, which paralleled a significant increase in plasma PYY. Ratios of plasma and fecal cholic acid/chenodeoxycholic acid derived BAs were decreased in RYGB groups. In addition, tissue mRNA expression analysis suggested early intestinal BA reabsorption and potentially reduced hepatic cholic acid production in RYGB groups. In summary, we present novel data on RYGB-mediated changes in BA metabolism to further understand the role of BAs in RYGB-induced metabolic effects in humans. PMID:25798945

Semaglutide improves postprandial glucose and lipid metabolism, and delays first-hour gastric emptying in subjects with obesity.

PubMed

Hjerpsted, Julie B; Flint, Anne; Brooks, Ashley; Axelsen, Mads B; Kvist, Trine; Blundell, John

2018-03-01

To investigate the effects of semaglutide on fasting and postprandial glucose and lipid responses, and on gastric emptying. This was a randomized, double-blind, placebo-controlled, 2-period, crossover trial. Subjects with obesity (N = 30) received once-weekly subcutaneous semaglutide, dose-escalated to 1.0 mg, or placebo. After each 12-week treatment period, glucose and lipid metabolism were assessed before and after standardized meals. Gastric emptying (paracetamol absorption test) and peptide YY (PYY) response were also assessed. Semaglutide treatment significantly lowered fasting concentrations of glucose and glucagon, and increased insulin vs placebo (estimated treatment ratio: 0.95 [95% confidence interval: 0.91, 0.98]; 0.86 [0.75, 0.98]; 1.45 [1.20, 1.75], respectively). Postprandial glucose metabolism significantly improved with semaglutide vs placebo (incremental area under the curve 0 to 5 hours [iAUC 0-5h ]; estimated treatment difference: glucose -1.34 mmol h/L [-2.42, -0.27]; insulin -921 pmol h/L [-1461, -381]; C-peptide -1.42 nmol h/L [-2.33, -0.51]). Fasting and postprandial lipid metabolism improved with semaglutide vs placebo. First-hour gastric emptying after the meal was delayed with semaglutide vs placebo (AUC 0-1h ; estimated treatment ratio: 0.73 [0.61, 0.87]); this may have contributed to the lower postprandial glucose increase in semaglutide-treated subjects. Overall gastric emptying (AUC 0-5h ) was not statistically different between treatments. Fasting and postprandial PYY responses were significantly lower with semaglutide vs placebo (P = .0397 and P = .0097, respectively). Semaglutide improved fasting and postprandial glucose and lipid metabolism. Overall gastric emptying was similar to that with placebo; however, the observed first-hour delay with semaglutide may contribute to a slower entry of glucose into the circulation. © 2017 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

The stimulatory G protein Gsα is required in melanocortin 4 receptor-expressing cells for normal energy balance, thermogenesis and glucose metabolism.

PubMed

Podyma, Brandon; Sun, Hui; Wilson, Eric A; Carlson, Bradley; Pritikin, Ethan; Gavrilova, Oksana; Weinstein, Lee S; Chen, Min

2018-05-24

Central melanocortin 4 receptors (MC4Rs) stimulate energy expenditure and inhibit food intake. MC4Rs activate the G protein G s α, but whether G s α mediates all MC4R actions has not been established. Individuals with Albright hereditary osteodystrophy (AHO), who have heterozygous G s α-inactivating mutations, only develop obesity when the G s α mutation is present on the maternal allele because of tissue-specific genomic imprinting. Furthermore, evidence in mice implicates G s α imprinting within the central nervous system (CNS) in this disorder. In this study we examined the effects of G s α in MC4R-expressing cells on metabolic regulation. Mice with homozygous G s α deficiency in MC4R-expressing cells (MC4RGsKO) developed significant obesity with increased food intake and decreased energy expenditure, along with impaired insulin sensitivity and cold-induced thermogenesis. Moreover, the ability of the MC4R agonist melanotan-II (MTII) to stimulate energy expenditure and to inhibit food intake was impaired in MC4RGsKO mice. MTII failed to stimulate the secretion of the anorexigenic hormone peptide YY (PYY) from enteroendocrine L cells, a physiological response mediated by MC4R-G s α signaling, even though baseline PYY levels were elevated in these mice. In G s α heterozygotes, mild obesity and reduced energy expenditure were present only in mice with a G s α deletion on the maternal allele in MC4R-expressing cells, while food intake was unaffected. These results demonstrate that G s α signaling in MC4R-expressing cells is required for controlling energy balance, thermogenesis, and peripheral glucose metabolism. They further indicate that G s α imprinting in MC4R-expressing cells contributes to obesity in G s α KO mice and likely in individuals with AHO as well. Published under license by The American Society for Biochemistry and Molecular Biology, Inc.

Modulation of postprandial lipaemia by a single meal containing a commonly consumed interesterified palmitic acid-rich fat blend compared to a non-interesterified equivalent.

PubMed

Hall, Wendy L; Iqbal, Sara; Li, Helen; Gray, Robert; Berry, Sarah E E

2017-12-01

Interesterification of palm stearin and palm kernal (PSt/PK) is widely used by the food industry to create fats with desirable functional characteristics for applications in spreads and bakery products, negating the need for trans fatty acids. Previous studies have reported reduced postprandial lipaemia, an independent risk factor for CVD, following interesterified (IE) palmitic and stearic acid-rich fats that are not currently widely used by the food industry. The current study investigates the effect of the most commonly consumed PSt/PK IE blend on postprandial lipaemia. A randomised, controlled, crossover (1 week washout) double-blind design study (n = 12 healthy males, 18-45 years), compared the postprandial (0-4 h) effects of meals containing 50 g fat [PSt/PK (80:20); IE vs. non-IE] on changes in plasma triacylglycerol (TAG), glucose, glucose-dependent insulinotropic polypeptide (GIP), peptide YY (PYY), insulin, gastric emptying (paracetamol concentrations) and satiety (visual analogue scales). The postprandial increase in plasma TAG was higher following the IE PSt/PK versus the non-IE PSt/PK, with a 51 % greater incremental area under the curve [mean difference with 95 % CI 41 (23, 58) mmol/L min P = 0.001]. The pattern of lipaemia was different between meals; at 4-h plasma TAG concentrations declined following the IE fat but continued to rise following the non-IE fat. Insulin, glucose, paracetamol, PYY and GIP concentrations increased significantly after the test meals (time effect; P < 0.001 for all), but did not differ between test meals. Feelings of fullness were higher following the non-IE PSt/PK meal (diet effect; P = 0.034). No other significant differences were noted. Interesterification of PSt/PK increases early phase postprandial lipaemia (0-4 h); however, further investigation during the late postprandial phase (4-8 h) is warranted to determine the rate of return to baseline values. Clinicaltrials.gov as NCT02365987.

Alterations of sucrose preference after Roux-en-Y gastric bypass.

PubMed

Bueter, M; Miras, A D; Chichger, H; Fenske, W; Ghatei, M A; Bloom, S R; Unwin, R J; Lutz, T A; Spector, A C; le Roux, C W

2011-10-24

Roux-en-Y gastric bypass (gastric bypass) patients reportedly have changes in perception and consumption of sweet-tasting foods. This study aimed to further investigate alterations in sweet food intake in rats and sucrose detection in humans after gastric bypass. Wistar rats were randomized to gastric bypass or sham-operations and preference for sucrose (sweet), sodium chloride (salty), citric acid (sour) and quinine hydrochloride (bitter) was assessed with standard two-bottle intake tests (vs. water). Intestinal T1R2 and T1R3 expression and plasma levels of glucagon-like-peptide 1 (GLP-1) and peptide YY (PYY) were measured. Furthermore, obese patients and normal weight controls were tested for sucrose taste detection thresholds pre- and postoperatively. Visual analogue scales measuring hedonic perception were used to determine the sucrose concentration considered by patients and controls as "just about right" pre- and postoperatively. Gastric bypass reduced the sucrose intake relative to water in rats (p<0.001). Preoperative sucrose exposure reduced this effect. Preference or aversion for compounds representative of other taste qualities in naïve rats remained unaffected. Intestinal T1R2 and T1R3 expression was significantly decreased in the alimentary limb while plasma levels of GLP-1 and PYY were elevated after bypass in rats (p=0.01). Bypass patients showed increased taste sensitivity to low sucrose concentrations compared with controls (p<0.05), but both groups considered the same sucrose concentration as "just about right" postoperatively. In conclusion, gastric bypass reduces sucrose intake relative to water in sucrose-naïve rats, but preoperative sucrose experience attenuates this effect. Changes in sucrose taste detection do not predict hedonic taste ratings of sucrose in bypass patients which remain unchanged. Thus, factors other than the unconditional affective value of the taste may also play a role in determining food preferences after gastric bypass

Appetite hormones and the transition to hyperphagia in children with Prader-Willi syndrome.

PubMed

Goldstone, A P; Holland, A J; Butler, J V; Whittington, J E

2012-12-01

Prader-Willi syndrome (PWS) is a genetic neurodevelopmental disorder with several nutritional phases during childhood proceeding from poor feeding, through normal eating without and with obesity, to hyperphagia and life-threatening obesity, with variable ages of onset. We investigated whether differences in appetite hormones may explain the development of abnormal eating behaviour in young children with PWS. In this cross-sectional study, children with PWS (n=42) and controls (n=9) aged 7 months-5 years were recruited. Mothers were interviewed regarding eating behaviour, and body mass index (BMI) was calculated. Fasting plasma samples were assayed for insulin, leptin, glucose, peptide YY (PYY), ghrelin and pancreatic polypeptide (PP). There was no significant relationship between eating behaviour in PWS subjects and the levels of any hormones or insulin resistance, independent of age. Fasting plasma leptin levels were significantly higher (mean ± s.d.: 22.6 ± 12.5 vs 1.97 ± 0.79 ng ml(-1), P=0.005), and PP levels were significantly lower (22.6 ± 12.5 vs 69.8 ± 43.8 pmol l(-1), P<0.001) in the PWS group compared with the controls, and this was independent of age, BMI, insulin resistance or IGF-1 levels. However, there was no significant difference in plasma insulin, insulin resistance or ghrelin levels between groups, though PYY declined more rapidly with age but not BMI in PWS subjects. Even under the age of 5 years, PWS is associated with low levels of anorexigenic PP, as in older children and adults. Hyperghrelinaemia or hypoinsulinaemia was not seen in these young children with PWS. Change in these appetite hormones was not associated with the timing of the transition to the characteristic hyperphagic phase. However, abnormal and/or delayed development or sensitivity of the effector pathways of these appetitive hormones (for example, parasympathetic and central nervous system) may interact with low PP levels, and later hyperghrelinaemia or hypoinsulinaemia

Cholecystokinin type B receptor antagonist PD-136,450 is a partial secretory agonist in the stomach and a full agonist in the pancreas of the rat.

PubMed Central

Schmassmann, A; Garner, A; Flogerzi, B; Hasan, M Y; Sanner, M; Varga, L; Halter, F

1994-01-01

Gastrin (cholecystokinin type B (CCK-B)) receptor antagonists may help to elucidate the physiological role of gastrin, have therapeutic potential as acid antisecretory drugs, and may be of use as adjuvant therapy for gastrin sensitive tumours. In binding studies, the gastrin receptor antagonist PD-136,450 had at least 1000 fold greater affinity for gastrin (CCK-B) than CCK-A receptors. In this study the biological activity of PD-136,450 was evaluated in conscious and anaesthetised rats. PD-136,450 antagonised gastrin stimulated acid secretion after subcutaneous (IC50: 0.28 mumol/kg; conscious rats) and intravenous (IC50: 0.17 mumol/kg; anaesthetised rats) administration. In basal secreting fistula animals, the compound stimulated acid output to 30 (5)% of the maximal response to gastrin. Stimulant activity was not caused by gastrin release. As an agonist PD-136,450 was about 350 times less potent than gastrin-17 on a molar basis. In addition, PD-136,450 was a powerful agonist of pancreatic secretion in anaesthetised rats. The specific gastrin antagonist L-365,260 inhibited the (partial) agonist activity of PD-136,450 in the stomach and the specific CCK-A receptor antagonist L-364,718 inhibited the agonist activity of PD-136,450 in the pancreas. It is concluded that the agonist effect of PD-136,450 is mediated via interaction with the gastrin (CCK-B) receptor in the stomach and the CCK-A receptor in the pancreas. PMID:8307482

Neuropeptide Y, B-type natriuretic peptide, substance P and peptide YY are novel substrates of fibroblast activation protein-α.

PubMed

Keane, Fiona M; Nadvi, Naveed A; Yao, Tsun-Wen; Gorrell, Mark D

2011-04-01

Fibroblast activation protein-α (FAP) is a cell surface-expressed and soluble enzyme of the prolyl oligopeptidase family, which includes dipeptidyl peptidase 4 (DPP4). FAP is not generally expressed in normal adult tissues, but is found at high levels in activated myofibroblasts and hepatic stellate cells in fibrosis and in stromal fibroblasts of epithelial tumours. FAP possesses a rare catalytic activity, hydrolysis of the post-proline bond two or more residues from the N-terminus of target substrates. α(2)-antiplasmin is an important physiological substrate of FAP endopeptidase activity. This study reports the first natural substrates of FAP dipeptidyl peptidase activity. Neuropeptide Y, B-type natriuretic peptide, substance P and peptide YY were the most efficiently hydrolysed substrates and the first hormone substrates of FAP to be identified. In addition, FAP slowly hydrolysed other hormone peptides, such as the incretins glucagon-like peptide-1 and glucose-dependent insulinotropic peptide, which are efficient DPP4 substrates. FAP showed negligible or no hydrolysis of eight chemokines that are readily hydrolysed by DPP4. This novel identification of FAP substrates furthers our understanding of this unique protease by indicating potential roles in cardiac function and neurobiology. © 2011 The Authors Journal compilation © 2011 FEBS.

Expression of gastrin-releasing peptide by excitatory interneurons in the mouse superficial dorsal horn.

PubMed

Gutierrez-Mecinas, Maria; Watanabe, Masahiko; Todd, Andrew J

2014-12-11

Gastrin-releasing peptide (GRP) and its receptor have been shown to play an important role in the sensation of itch. However, although GRP immunoreactivity has been detected in the spinal dorsal horn, there is debate about whether this originates from primary afferents or local excitatory interneurons. We therefore examined the relation of GRP immunoreactivity to that seen with antibodies that label primary afferent or excitatory interneuron terminals. We tested the specificity of the GRP antibody by preincubating with peptides with which it could potentially cross-react. We also examined tissue from a mouse line in which enhanced green fluorescent protein (EGFP) is expressed under control of the GRP promoter. GRP immunoreactivity was seen in both primary afferent and non-primary glutamatergic axon terminals in the superficial dorsal horn. However, immunostaining was blocked by pre-incubation of the antibody with substance P, which is present at high levels in many nociceptive primary afferents. EGFP+ cells in the GRP-EGFP mouse did not express Pax2, and their axons contained the vesicular glutamate transporter 2 (VGLUT2), indicating that they are excitatory interneurons. In most cases, their axons were also GRP-immunoreactive. Multiple-labelling immunocytochemical studies indicated that these cells did not express either of the preprotachykinin peptides, and that they generally lacked protein kinase Cγ, which is expressed by a subset of the excitatory interneurons in this region. These results show that GRP is expressed by a distinct population of excitatory interneurons in laminae I-II that are likely to be involved in the itch pathway. They also suggest that the GRP immunoreactivity seen in primary afferents in previous studies may have resulted from cross-reaction of the GRP antibody with substance P or the closely related peptide neurokinin A.

Gastrin-releasing peptide receptor (GRPr) promotes EMT, growth, and invasion in canine prostate cancer.

PubMed

Elshafae, Said M; Hassan, Bardes B; Supsavhad, Wachiraphan; Dirksen, Wessel P; Camiener, Rachael Y; Ding, Haiming; Tweedle, Michael F; Rosol, Thomas J

2016-06-01

The gastrin-releasing peptide receptor (GRPr) is upregulated in early and late-stage human prostate cancer (PCa) and other solid tumors of the mammary gland, lung, head and neck, colon, uterus, ovary, and kidney. However, little is known about its role in prostate cancer. This study examined the effects of a heterologous GRPr agonist, bombesin (BBN), on growth, motility, morphology, gene expression, and tumor phenotype of an osteoblastic canine prostate cancer cell line (Ace-1) in vitro and in vivo. The Ace-1 cells were stably transfected with the human GRPr and tumor cells were grown in vitro and as subcutaneous and intratibial tumors in nude mice. The effect of BBN was measured on cell proliferation, cell migration, tumor growth (using bioluminescence), tumor cell morphology, bone tumor phenotype, and epithelial-mesenchymal transition (EMT) and metastasis gene expression (quantitative RT-PCR). GRPr mRNA expression was measured in primary canine prostate cancers and normal prostate glands. Bombesin (BBN) increased tumor cell proliferation and migration in vitro and tumor growth and invasion in vivo. BBN upregulated epithelial-to-mesenchymal transition (EMT) markers (TWIST, SNAIL, and SLUG mRNA) and downregulated epithelial markers (E-cadherin and β-catenin mRNA), and modified tumor cell morphology to a spindle cell phenotype. Blockade of GRPr upregulated E-cadherin and downregulated VIMENTIN and SNAIL mRNA. BBN altered the in vivo tumor phenotype in bone from an osteoblastic to osteolytic phenotype. Primary canine prostate cancers had increased GRPr mRNA expression compared to normal prostates. These data demonstrated that the GRPr is important in prostate cancer growth and progression and targeting GRPr may be a promising strategy for treatment of prostate cancer. Prostate 76:796-809, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Expression of matrix metalloproteinase-9 and bombesin/gastrin-releasing peptide in human prostate cancers and their lymph node metastases.

PubMed

Ishimaru, Hisashi; Kageyama, Yukio; Hayashi, Tetsuo; Nemoto, Tetsuo; Eishi, Yoshinobu; Kihara, Kazunori

2002-01-01

Neuroendocrine differentiation and subsequent excretion of neuropeptides have been demonstrated to be associated with progression of human prostate cancer. Among neuropeptides found to exist in the prostate, bombesin/gastrin-releasing peptide has been shown to upregulate matrix metalloproteinase-9 (MMP-9) in human prostate cancer cell lines. Expression levels of bombesin, MMP-9, and neuron-specific enolase were examined by immunohistochemistry in 41 cases of clinically organ-confined prostate cancers including 9 with microscopic lymph node metastases. Twenty-seven (64%) of the 41 radical prostatectomy specimens were positive for both MMP-9 and bombesin. Expression of these molecules was observed in almost the same population of the cancer cells. The remaining 14 cases were negative for both MMP-9 and bombesin. High-grade tumors (Gleason sum > or = 7) were more likely to express MMP-9 and bombesin (21/24:88%) than low-grade tumors (Gleason sum > or = 6) (7/17:41%). In eight of the nine cases with pathological lymph node metastases, expression of MMP-9 and bombesin was also noted in metastatic sites. Neuron-specific enolase was positive in 16 cases (39%) and not always associated with the expression of bombesin. Expression of bombesin and expression of MMP-9 are common in human prostate cancers and may be related to an aggressive phenotype.

Histone deacetylase inhibition prevents the impairing effects of hippocampal gastrin-releasing peptide receptor antagonism on memory consolidation and extinction.

PubMed

Petry, Fernanda S; Dornelles, Arethuza S; Lichtenfels, Martina; Valiati, Fernanda E; de Farias, Caroline Brunetto; Schwartsmann, Gilberto; Parent, Marise B; Roesler, Rafael

2016-07-01

Hippocampal gastrin-releasing peptide receptors (GRPR) regulate memory formation and extinction, and disturbances in GRPR signaling may contribute to cognitive impairment associated with neurodevelopmental disorders. Histone acetylation is an important epigenetic mechanism that regulates gene expression involved in memory formation, and histone deacetylase inhibitors (HDACis) rescue memory deficits in several models. The present study determined whether inhibiting histone deacetylation would prevent memory impairments produced by GRPR blockade in the hippocampus. Male Wistar rats were given an intrahippocampal infusion of saline (SAL) or the HDACi sodium butyrate (NaB) shortly before inhibitory avoidance (IA) training, followed by an infusion of either SAL or the selective GRPR antagonist RC-3095 immediately after training. In a second experiment, the infusions were administered before and after a retention test trial that served as extinction training. As expected, RC-3095 significantly impaired consolidation and extinction of IA memory. More importantly, pretraining administration of NaB, at a dose that had no effect when given alone, prevented the effects of RC-3095. In addition, the combination of NaB and RC-3095 increased hippocampal levels of the brain-derived neurotrophic factor (BDNF). These findings indicate that HDAC inhibition can protect against memory impairment caused by GRPR blockade. Copyright © 2016 Elsevier B.V. All rights reserved.

The role of "mixed" orexigenic and anorexigenic signals and autoantibodies reacting with appetite-regulating neuropeptides and peptides of the adipose tissue-gut-brain axis: relevance to food intake and nutritional status in patients with anorexia nervosa and bulimia nervosa.

PubMed

Smitka, Kvido; Papezova, Hana; Vondra, Karel; Hill, Martin; Hainer, Vojtech; Nedvidkova, Jara

2013-01-01

Eating disorders such as anorexia (AN) and bulimia nervosa (BN) are characterized by abnormal eating behavior. The essential aspect of AN is that the individual refuses to maintain a minimal normal body weight. The main features of BN are binge eating and inappropriate compensatory methods to prevent weight gain. The gut-brain-adipose tissue (AT) peptides and neutralizing autoantibodies play an important role in the regulation of eating behavior and growth hormone release. The mechanisms for controlling food intake involve an interplay between gut, brain, and AT. Parasympathetic, sympathetic, and serotoninergic systems are required for communication between brain satiety centre, gut, and AT. These neuronal circuits include neuropeptides ghrelin, neuropeptide Y (NPY), peptide YY (PYY), cholecystokinin (CCK), leptin, putative anorexigen obestatin, monoamines dopamine, norepinephrine (NE), serotonin, and neutralizing autoantibodies. This extensive and detailed report reviews data that demonstrate that hunger-satiety signals play an important role in the pathogenesis of eating disorders. Neuroendocrine dysregulations of the AT-gut-brain axis peptides and neutralizing autoantibodies may result in AN and BN. The circulating autoantibodies can be purified and used as pharmacological tools in AN and BN. Further research is required to investigate the orexigenic/anorexigenic synthetic analogs and monoclonal antibodies for potential treatment of eating disorders in clinical practice.

Impact of yogurt on appetite control, energy balance, and body composition.

PubMed

Tremblay, Angelo; Doyon, Caroline; Sanchez, Marina

2015-08-01

Recent data support the idea that regular yogurt consumption promotes body weight stability. The simplest explanation is that regular consumption of healthful foods such as yogurt results in decreased intake of less healthful foods containing high amounts of fat and/or sugar. There is also evidence to suggest that the high calcium and protein contents of yogurt and other dairy foods influence appetite and energy intake. The existence of a calcium-specific appetite control mechanism has been proposed. Milk proteins differ in terms of absorption rate and post-absorptive responses, which can influence their satiating properties. Studies in humans have shown that consumption of milk and yogurt increases the circulating concentration of the anorectic peptides glucagon-like peptide (GLP)-1 and peptide YY (PYY). The food matrix can also affect appetite and satiety. Yogurt is a fermented milk that contains bacteria that enrich the microbiota of the host. It appears that lean vs obese humans differ in the composition of their gut microbiota. The available relevant literature suggests that yogurt is a food that facilitates the regulation of energy balance. © The Author(s) 2015. Published by Oxford University Press on behalf of the International Life Sciences Institute. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

The Role of “Mixed” Orexigenic and Anorexigenic Signals and Autoantibodies Reacting with Appetite-Regulating Neuropeptides and Peptides of the Adipose Tissue-Gut-Brain Axis: Relevance to Food Intake and Nutritional Status in Patients with Anorexia Nervosa and Bulimia Nervosa

PubMed Central

Papezova, Hana; Vondra, Karel; Hill, Martin; Hainer, Vojtech; Nedvidkova, Jara

2013-01-01

Eating disorders such as anorexia (AN) and bulimia nervosa (BN) are characterized by abnormal eating behavior. The essential aspect of AN is that the individual refuses to maintain a minimal normal body weight. The main features of BN are binge eating and inappropriate compensatory methods to prevent weight gain. The gut-brain-adipose tissue (AT) peptides and neutralizing autoantibodies play an important role in the regulation of eating behavior and growth hormone release. The mechanisms for controlling food intake involve an interplay between gut, brain, and AT. Parasympathetic, sympathetic, and serotoninergic systems are required for communication between brain satiety centre, gut, and AT. These neuronal circuits include neuropeptides ghrelin, neuropeptide Y (NPY), peptide YY (PYY), cholecystokinin (CCK), leptin, putative anorexigen obestatin, monoamines dopamine, norepinephrine (NE), serotonin, and neutralizing autoantibodies. This extensive and detailed report reviews data that demonstrate that hunger-satiety signals play an important role in the pathogenesis of eating disorders. Neuroendocrine dysregulations of the AT-gut-brain axis peptides and neutralizing autoantibodies may result in AN and BN. The circulating autoantibodies can be purified and used as pharmacological tools in AN and BN. Further research is required to investigate the orexigenic/anorexigenic synthetic analogs and monoclonal antibodies for potential treatment of eating disorders in clinical practice. PMID:24106499

Co-occurring Conditions Toolkit: Mild Traumatic Brain Injury and Psychological Health

DTIC Science & Technology

2009-01-01

in OD yy Contraindi- cated with MAOIs within past 14 days of therapy yy Bupropion, Haloperidol and SSRIs may increase the TCA’s level which... Haloperidol (Haldol) yy Initial PTSD dose = 0.5mg TID or 1mg BID yy Max PTSD = 5mg QID yy Used in PTSD but therapeu- tic doses not established...yy The Opioid side effect of delirium may be treated with Haloperi- dol if phar- macologic treatment is deemed necessary yy Haloperidol may

Bombesin and G-17 dose responses in duodenal ulcer and controls.

PubMed

Hirschowitz, B I; Tim, L O; Helman, C A; Molina, E

1985-11-01

Gastric acid and pepsin secretion and serum gastrin concentrations were measured in nine patients with uncomplicated duodenal ulcer (DU) and 10 normal controls in the fasting state and in response to graded doses of bombesin, a tetradecapeptide gastrin releaser, and, for reference, synthetic gastrin G-17. Serum gastrin with bombesin stimulation was significantly greater in duodenal ulcer (maximum 467 pg/ml) than in controls (153 pg/ml), while in seven of the DU group tested gastrin levels after a meal were not different from that seen in five of the normal controls. Gastric acid concentrations and outputs were greater in duodenal ulcer with both stimuli. Secretory responses were then related to serum gastrin levels; despite increasing gastrin levels with bombesin stimulation, peak outputs achieved with bombesin were only 50% of G-17 maximum in normals and up to 90% of maximum in duodenal ulcer. Up to the point of peak response to bombesin, acid and pepsin outputs were the same with exogenous and endogenous gastrin, ie, bombesin acted only via G-17. Furthermore, in direct comparison of duodenal ulcer and normals with G-17 infusion, acid and pepsin outputs related to serum gastrin were congruent up to 75% of duodenal ulcer maximum, at which point normals reached their maximum level. These data have shown that duodenal ulcer patients are not more sensitive to either exogenous or endogenous gastrin; we have also shown regulatory defects in duodenal ulcer patients not previously described: an exaggerated release of gastrin with bombesin stimulation, and a defective inhibition of acid and pepsin secretion with higher doses of bombesin.

Epitope mapping of the gastrin-releasing peptide/anti-bombesin monoclonal antibody complex by proteolysis followed by matrix-assisted laser desorption ionization mass spectrometry.

PubMed

Papac, D I; Hoyes, J; Tomer, K B

1994-09-01

We have developed a method to rapidly identify the antigenic determinant for an antibody using in situ proteolysis of an immobilized antigen-antibody complex followed by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI/TOF). A mouse anti-bombesin monoclonal antibody was immobilized to agarose beads and then the antigen, gastrin-releasing peptide (GRP), was allowed to bind. Direct analysis of the immobilized antigen-antibody complex by MALDI/TOF is demonstrated and allows identification of ca. 1 pmol of the bound GRP. To identify the epitope, the immobilized antigen-antibody complex was subjected to proteolysis with trypsin, chymotrypsin, thermolysin, and aminopeptidase M. Following proteolysis, the part of the antigen in contact with the antibody and protected from proteolysis was identified directly by MALDI/TOF. Subsequently, the epitope was eluted from the immobilized antibody with 0.1 M glycine buffer (pH 2.3), separated by reversed-phase HPLC, and its identity confirmed by MALDI/TOF. Using this approach, the epitope for the anti-bombesin monoclonal antibody was shown to comprise the last 7-8 residues (HWAVGHLM-NH2) of GRP.

Essential Dosage-Dependent Functions of the Transcription Factor Yin Yang 1 in Late Embryonic Development and Cell Cycle Progression†

PubMed Central

Affar, El Bachir; Gay, Frédérique; Shi, Yujiang; Liu, Huifei; Huarte, Maite; Wu, Su; Collins, Tucker; Li, En; Shi, Yang

2006-01-01

Constitutive ablation of the Yin Yang 1 (YY1) transcription factor in mice results in peri-implantation lethality. In this study, we used homologous recombination to generate knockout mice carrying yy1 alleles expressing various amounts of YY1. Phenotypic analysis of yy1 mutant embryos expressing ∼75%, ∼50%, and ∼25% of the normal complement of YY1 identified a dosage-dependent requirement for YY1 during late embryogenesis. Indeed, reduction of YY1 levels impairs embryonic growth and viability in a dose-dependent manner. Analysis of the corresponding mouse embryonic fibroblast cells also revealed a tight correlation between YY1 dosage and cell proliferation, with a complete ablation of YY1 inducing cytokinesis failure and cell cycle arrest. Consistently, RNA interference-mediated inhibition of YY1 in HeLa cells prevents cytokinesis, causes proliferative arrest, and increases cellular sensitivity to various apoptotic agents. Genome-wide expression profiling identified a plethora of YY1 target genes that have been implicated in cell growth, proliferation, cytokinesis, apoptosis, development, and differentiation, suggesting that YY1 coordinates multiple essential biological processes through a complex transcriptional network. These data not only shed new light on the molecular basis for YY1 developmental roles and cellular functions, but also provide insight into the general mechanisms controlling eukaryotic cell proliferation, apoptosis, and differentiation. PMID:16611997

Yin yang 1 is a novel regulator of pulmonary fibrosis.

PubMed

Lin, Xin; Sime, Patricia J; Xu, Haodong; Williams, Marc A; LaRussa, Larry; Georas, Steve N; Guo, Jia

2011-06-15

The differentiation of fibroblasts into myofibroblasts is a cardinal feature of idiopathic pulmonary fibrosis (IPF). The transcription factor Yin Yang 1 (YY1) plays a role in the proliferation and differentiation of diverse cell types, but its role in fibrotic lung diseases is not known. To elucidate the mechanism by which YY1 regulates fibroblast differentiation and lung fibrosis. Lung fibroblasts were cultured with transforming growth factor (TGF)-β or tumor necrosis factor-α. Nuclear factor (NF)-κB, YY1, and α-smooth muscle actin (SMA) were determined in protein, mRNA, and promoter reporter level. Lung fibroblasts and lung fibrosis were assessed in a partial YY1-deficient mouse and a YY1(f/f) conditional knockout mouse after being exposed to silica or bleomycin. TGF-β and tumor necrosis factor-α up-regulated YY1 expression in lung fibroblasts. TGF-β-induced YY1 expression was dramatically decreased by an inhibitor of NF-κB, which blocked I-κB degradation. YY1 is significantly overexpressed in both human IPF and murine models of lung fibrosis, including in the aggregated pulmonary fibroblasts of fibrotic foci. Furthermore, the mechanism of fibrogenesis is that YY1 can up-regulate α-SMA expression in pulmonary fibroblasts. YY1-deficient (YY1(+/-)) mice were significantly protected from lung fibrosis, which was associated with attenuated α-SMA and collagen expression. Finally, decreasing YY1 expression through instilled adenovirus-cre in floxed-YY1(f/f) mice reduced lung fibrosis. YY1 is overexpressed in fibroblasts in both human IPF and murine models in a NF-κB-dependent manner, and YY1 regulates fibrogenesis at least in part by increasing α-SMA and collagen expression. Decreasing YY1 expression may provide a new therapeutic strategy for pulmonary fibrosis.

Targeted Disruption of Mouse Yin Yang 1 Transcription Factor Results in Peri-Implantation Lethality

PubMed Central

Donohoe, Mary E.; Zhang, Xiaolin; McGinnis, Lynda; Biggers, John; Li, En; Shi, Yang

1999-01-01

Yin Yang 1 (YY1) is a zinc finger-containing transcription factor and a target of viral oncoproteins. To determine the biological role of YY1 in mammalian development, we generated mice deficient for YY1 by gene targeting. Homozygosity for the mutated YY1 allele results in embryonic lethality in the mouse. YY1 mutants undergo implantation and induce uterine decidualization but rapidly degenerate around the time of implantation. A subset of YY1 heterozygote embryos are developmentally retarded and exhibit neurulation defects, suggesting that YY1 may have additional roles during later stages of mouse embryogenesis. Our studies demonstrate an essential function for YY1 in the development of the mouse embryo. PMID:10490658

Enhanced Ghrelin Levels and Hypothalamic Orexigenic AgRP and NPY Neuropeptide Expression in Models of Jejuno-Colonic Short Bowel Syndrome

PubMed Central

Gillard, Laura; Billiauws, Lore; Stan-Iuga, Bogdan; Ribeiro-Parenti, Lara; Jarry, Anne-Charlotte; Cavin, Jean-Baptiste; Cluzeaud, Françoise; Mayeur, Camille; Thomas, Muriel; Freund, Jean-Noël; Lacorte, Jean-Marc; Le Gall, Maude; Bado, André; Joly, Francisca; Le Beyec, Johanne

2016-01-01

Short bowel syndrome (SBS) patients developing hyperphagia have a better outcome. Gastrointestinal endocrine adaptations help to improve intestinal functions and food behaviour. We investigated neuroendocrine adaptations in SBS patients and rat models with jejuno-ileal (IR-JI) or jejuno-colonic (IR-JC) anastomosis with and without parenteral nutrition. Circulating levels of ghrelin, PYY, GLP-1, and GLP-2 were determined in SBS rat models and patients. Levels of mRNA for proglucagon, PYY and for hypothalamic neuropeptides were quantified by qRT-PCR in SBS rat models. Histology and immunostaining for Ki67, GLP-1 and PYY were performed in SBS rats. IR-JC rats, but not IR-JI, exhibited significantly higher crypt depths and number of Ki67-positive cells than sham. Fasting and/or postprandial plasma ghrelin and PYY concentrations were higher, or tend to be higher, in IR-JC rats and SBS-JC patients than in controls. Proglucagon and Pyy mRNA levels were significantly enhanced in IR-JC rats. Levels of mRNA coding hypothalamic orexigenic NPY and AgRP peptides were significantly higher in IR-JC than in sham rats. We demonstrate an increase of plasma ghrelin concentrations, major changes in hypothalamic neuropeptides levels and greater induction of PYY in SBS-JC rats and patients suggesting that jejuno-colonic continuity creates a peculiar environment promoting further gut-brain adaptations. PMID:27323884

Enhanced Ghrelin Levels and Hypothalamic Orexigenic AgRP and NPY Neuropeptide Expression in Models of Jejuno-Colonic Short Bowel Syndrome.

PubMed

Gillard, Laura; Billiauws, Lore; Stan-Iuga, Bogdan; Ribeiro-Parenti, Lara; Jarry, Anne-Charlotte; Cavin, Jean-Baptiste; Cluzeaud, Françoise; Mayeur, Camille; Thomas, Muriel; Freund, Jean-Noël; Lacorte, Jean-Marc; Le Gall, Maude; Bado, André; Joly, Francisca; Le Beyec, Johanne

2016-06-21

Short bowel syndrome (SBS) patients developing hyperphagia have a better outcome. Gastrointestinal endocrine adaptations help to improve intestinal functions and food behaviour. We investigated neuroendocrine adaptations in SBS patients and rat models with jejuno-ileal (IR-JI) or jejuno-colonic (IR-JC) anastomosis with and without parenteral nutrition. Circulating levels of ghrelin, PYY, GLP-1, and GLP-2 were determined in SBS rat models and patients. Levels of mRNA for proglucagon, PYY and for hypothalamic neuropeptides were quantified by qRT-PCR in SBS rat models. Histology and immunostaining for Ki67, GLP-1 and PYY were performed in SBS rats. IR-JC rats, but not IR-JI, exhibited significantly higher crypt depths and number of Ki67-positive cells than sham. Fasting and/or postprandial plasma ghrelin and PYY concentrations were higher, or tend to be higher, in IR-JC rats and SBS-JC patients than in controls. Proglucagon and Pyy mRNA levels were significantly enhanced in IR-JC rats. Levels of mRNA coding hypothalamic orexigenic NPY and AgRP peptides were significantly higher in IR-JC than in sham rats. We demonstrate an increase of plasma ghrelin concentrations, major changes in hypothalamic neuropeptides levels and greater induction of PYY in SBS-JC rats and patients suggesting that jejuno-colonic continuity creates a peculiar environment promoting further gut-brain adaptations.

Positron emission tomography (PET) imaging of prostate cancer with a gastrin releasing peptide receptor antagonist--from mice to men.

PubMed

Wieser, Gesche; Mansi, Rosalba; Grosu, Anca L; Schultze-Seemann, Wolfgang; Dumont-Walter, Rebecca A; Meyer, Philipp T; Maecke, Helmut R; Reubi, Jean Claude; Weber, Wolfgang A

2014-01-01

Ex vivo studies have shown that the gastrin releasing peptide receptor (GRPr) is overexpressed on almost all primary prostate cancers, making it a promising target for prostate cancer imaging and targeted radiotherapy. Biodistribution, dosimetry and tumor uptake of the GRPr antagonist ⁶⁴Cu-CB-TE2A-AR06 [(⁶⁴Cu-4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo(6.6.2)hexadecane)-PEG₄-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-LeuNH₂] were studied by PET/CT in four patients with newly diagnosed prostate cancer (T1c-T2b, Gleason 6-7). No adverse events were observed after injection of ⁶⁴Cu-CB-TE2A-AR06. Three of four tumors were visualized with high contrast [tumor-to-prostate ratio > 4 at 4 hours (h) post injection (p.i.)], one small tumor (T1c, < 5% tumor on biopsy specimens) showed moderate contrast (tumor-to-prostate ratio at 4 h: 1.9). Radioactivity was cleared by the kidneys and only the pancreas demonstrated significant accumulation of radioactivity, which rapidly decreased over time. ⁶⁴Cu-CB-TE2A-AR06 shows very favorable characteristics for imaging prostate cancer. Future studies evaluating ⁶⁴Cu-CB-TE2A-AR06 PET/CT for prostate cancer detection, staging, active surveillance, and radiation treatment planning are necessary.

Pathobiology and management of hypergastrinemia and the Zollinger-Ellison syndrome.

PubMed

Hirschowitz, B I

1992-01-01

Gastrin is both stimulatory and trophic to the cells of the gastric fundus--parietal and peptic cells, and enterochromaffin-like (ECL) cells which are major intermediaries of the gastrin effect. Gastrin (from the antrum) and acid (from the fundus) represent the interactive positive and negative limbs of a feedback loop. The nature and extent of sub-loops, perhaps involving the vagus, acetylcholine, histamine, and other peptides and cell products are at present unclear or unknown. Loss of either gastrin or acid has predictable consequences. Absent acid, as in pernicious anemia or as a result of omeprazole, leads to hypergastrinemia. In rats, such hypergastrinemia (gastrin > 1,000 pg/ml) causes fundic ECL hyperplasia and, eventually, carcinoids; in humans with pernicious anemia, hypergastrinemia causes ECL-cell hyperplasia, which may progress to carcinoids that are reversible upon withdrawal of gastrin, illustrated by three cases described here. Loss of gastrin by antrectomy for duodenal ulcer leads to fundic involution and marked reduction in basal acid output, maximal acid output, and fundic histamine. An uncontrolled excess of gastrin, as from a gastrinoma outside the negative feedback loop, causes acid and pepsin hypersecretion with upper GI mucosal damage, the Zollinger-Ellison syndrome. This paper summarizes the abnormal regulation of gastrin and the biology, natural history, diagnosis, and management of ZE syndrome by medical and surgical means.

Conserved RNA binding activity of a Yin-Yang 1 homologue in the ova of the purple sea urchin Strongylocentrotus purpuratus.

PubMed

Belak, Zachery R; Ovsenek, Nicholas; Eskiw, Christopher H

2018-05-23

Yin-Yang 1 (YY1) is a highly conserved transcription factor possessing RNA-binding activity. A putative YY1 homologue was previously identified in the developmental model organism Strongylocentrotus purpuratus (the purple sea urchin) by genomic sequencing. We identified a high degree of sequence similarity with YY1 homologues of vertebrate origin which shared 100% protein sequence identity over the DNA- and RNA-binding zinc-finger region with high similarity in the N-terminal transcriptional activation domain. SpYY1 demonstrated identical DNA- and RNA-binding characteristics between Xenopus laevis and S. purpuratus indicating that it maintains similar functional and biochemical properties across widely divergent deuterostome species. SpYY1 binds to the consensus YY1 DNA element, and also to U-rich RNA sequences. Although we detected SpYY1 RNA-binding activity in ova lysates and observed cytoplasmic localization, SpYY1 was not associated with maternal mRNA in ova. SpYY1 expressed in Xenopus oocytes was excluded from the nucleus and associated with maternally expressed cytoplasmic mRNA molecules. These data demonstrate the existence of an YY1 homologue in S. purpuratus with similar structural and biochemical features to those of the well-studied vertebrate YY1; however, the data reveal major differences in the biological role of YY1 in the regulation of maternally expressed mRNA in the two species.

RING1 and YY1 binding protein suppresses breast cancer growth and metastasis.

PubMed

Zhou, Hongyan; Li, Jie; Zhang, Zhanqiang; Ye, Runyi; Shao, Nan; Cheang, Tuckyun; Wang, Shenming

2016-12-01

Evidence suggests that RING1 and YY1 binding protein (RYBP) functions as a tumor suppressor. However, its role in breast cancer remains unclear. In the present study, the expression of RYBP was assessed in breast cancer patients and cell lines. Disease-free survival durations of breast cancer patients with high RYBP expression were determined based on the ATCG dataset. The effects of RYBP overexpression on cell growth, migration and invasive potency were also assessed. Nude mouse xenograft and lung metastasis models were also used to confirm the role of RYBP. The involvement of SRRM3 in RYBP-mediated breast cancer suppression was explored using SRRM3 siRNA. The potential relationship between RYBP, SRRM3, and REST-003 was examined by qPCR. The results showed that RYBP was downregulated in breast cancer patients and in several breast cancer cell lines. Breast cancer patients with high expression levels of RYBP displayed better disease-free survival. Overexpression of RYBP in MDA-MB-231 and SK-BR-3 cells significantly decreased cell proliferation, migration, and invasion ability, and increased the proportion of cells arrested in S-phase compared with the negative control cells. Additionally, upregulation of proliferation-related cell cycle proteins (cyclin A and cyclin B1) and E-cadherin, and downregulation of snail were observed in RYBP-overexpressing cells. Overexpression of RYBP reduced tumor volume and weight as well as metastatic foci in the lungs of nude mice. SRRM3 knockdown by siRNA, which is downregulated after RYBP overexpression, suppressed cell growth and metastasis in MDA-MB-231 and SK-BR-3 cells. Furthermore, qPCR analysis revealed that REST-003 ncRNA was downregulated in cells overexpressing RYBP and in SRRM3-inhibited cells. Moreover, cell invasion ability and growth were increased after SRRM3 upregulation in RYBP-overexpressing cells, but they were decreased following si-REST-003 transfection. In conclusion, overexpression of RYBP suppresses breast

Cloning of cDNAs encoding amphibian bombesin: evidence for the relationship between bombesin and gastrin-releasing peptide.

PubMed Central

Spindel, E R; Gibson, B W; Reeve, J R; Kelly, M

1990-01-01

Bombesin is a tetradecapeptide originally isolated from frog skin; its mammalian homologue is the 27-amino acid peptide gastrin-releasing peptide (GRP). cDNAs encoding GRP have been cloned from diverse species, but little is yet known about the amphibian bombesin precursor. Mass spectrometry of HPLC-separated skin exudate from Bombina orientalis was performed to demonstrate the existence of authentic bombesin in the skin of this frog. A cDNA library was prepared from the skin of B. orientalis and mixed oligonucleotide probes were used to isolate cDNAs encoding amphibian bombesin. Sequence analysis revealed that bombesin is encoded in a 119-amino acid prohormone. The carboxyl terminus of bombesin is flanked by two basic amino acids; the amino terminus is not flanked by basic amino acids but is flanked by a chymotryptic-like cleavage site. Northern blot analysis demonstrated similarly sized bombesin mRNAs in frog skin, brain, and stomach. Polymerase chain reaction was used to show that the skin and gut bombesin mRNAs encoded the identical prohormones. Prohormone processing, however, differed between skin and gut. Chromatography showed the presence of only authentic bombesin in skin whereas gut extracts contained two peaks of bombesin immunoreactivity, one consistent in size with bombesin and one closer in size to mammalian GRP. Thus the same bombesin prohormone is processed solely to bombesin in skin but is processed to a peptide similar in size to bombesin and to a peptide similar in size to mammalian GRP in stomach. Images PMID:2263631

Betulinic Acid Targets YY1 and ErbB2 through Cannabinoid Receptor-Dependent Disruption of MicroRNA-27a:ZBTB10 in Breast Cancer

PubMed Central

Liu, Xinyi; Jutooru, Indira; Lei, Ping; Kim, KyoungHyun; Lee, Syng-ook; Brents, Lisa K.; Prather, Paul L.; Safe, Stephen

2016-01-01

Treatment of ErbB2-overexpressing BT474 and MDA-MB-453 breast cancer cells with 1 to 10 μmol/L betulinic acid inhibited cell growth, induced apoptosis, downregulated specificity protein (Sp) transcription factors Sp1, Sp3, and Sp4, and decreased expression of ErbB2. Individual or combined knockdown of Sp1, Sp3, Sp4 by RNA interference also decreased expression of ErbB2 and this response was because of repression of YY1, an Sp-regulated gene. Betulinic acid–dependent repression of Sp1, Sp3, Sp4, and Sp-regulated genes was due, in part, to induction of the Sp repressor ZBTB10 and downregulation of microRNA-27a (miR-27a), which constitutively inhibits ZBTB10 expression, and we show for the first time that the effects of betulinic acid on the miR-27a:ZBTB10-Sp transcription factor axis were cannabinoid 1 (CB1) and CB2 receptor–dependent, thus identifying a new cellular target for this anticancer agent. PMID:22553354

A novel role of Yin-Yang-1 in pulmonary tuberculosis through the regulation of the chemokine CCL4.

PubMed

Rangel-Santiago, Jesus F; Baay-Guzman, Guillermina J; Duran-Padilla, Marco A; Lopez-Bochm, Karla A; Garcia-Romero, Beatriz L; Hernandez-Cueto, Daniel D; Pantoja-Escobar, Gerardo; Vega, Mario I; Hernandez-Pando, Rogelio; Huerta-Yepez, Sara

2016-01-01

Mycobacterium tuberculosis (M. tb) is the etiological agent of pulmonary tuberculosis (TB); this disease remains a worldwide health problem. Yin-Yang-1 (YY1) plays a major role in the maintenance and progression of some pulmonary diseases, including pulmonary fibrosis. However, the role of YY1 in TB remains unknown. The aim of this study was to elucidate the role of YY1 in the regulation of CCL4 and its implication in TB. We determined whether YY1 regulates CCL4 using reporter plasmids, ChIP and siRNA assays. Immunohistochemistry and digital pathology were used to measure the expression of YY1 and CCL4 in a mouse model of TB. A retrospective comparison of patients with TB and control subjects was used to measure the expression of YY1 and CCL4 using tissue microarrays. Our results showed that YY1 regulates the transcription of CCL4; moreover, YY1, CCL4 and TGF-β were overexpressed in the lung tissues of mice with TB during the late stages of the disease and the tissues of TB patients. The expression of CCL4 and TGF-β correlated with YY1 expression. In conclusion, YY1 regulates CCL4 transcription; moreover, YY1 is overexpressed in experimental and human TB and is positively correlated with CCL4 and TGF-β expression. Therefore, treatments that decrease YY1 expression may be a new therapeutic strategy against TB. Copyright © 2015 Elsevier Ltd. All rights reserved.

Pro-gastrin-releasing peptide (ProGRP) as a biomarker in small-cell lung cancer diagnosis, monitoring and evaluation of treatment response.

PubMed

Wojcik, Ewa; Kulpa, Jan Kanty

2017-01-01

Lung cancer belongs to malignant tumors that possess the highest rates of morbidity and mortality in the world. A number of morphological, biological and clinical features justify the distinction of small-cell carcinoma with respect to the other histological types of lung cancer. The predominant neuroendocrine phenotype is critical for the selection of biomarkers used in diagnostics, monitoring and evaluation of treatment response; early onset relapses in patients with small-cell lung cancer (SCLC) and the evaluation of their prognosis. Although for a long time the neuron-specific enolase (NSE) was considered to be the marker of choice for this tumor, it is now increasingly important to pay attention to concentrations of pro-gastrin-releasing peptide (ProGRP). The results of this marker have been implicated in the differential diagnosis of non-small lung cancer and SCLC, chemotherapy and radiotherapy monitoring as well as evaluation of treatment response. The subject of this series of studies is to determine the usefulness of ProGRP in the evaluation of patients' prognosis and its predictive value. The current aim for the optimization of the effectiveness of biochemical diagnostics of SCLC is recommended by complementary ProGRP and NSE studies. The present work is a summary of the latest reports regarding diagnostic utility of these markers in SCLC.

Omeprazole and PGC-formulated heparin binding epidermal growth factor normalizes fasting blood glucose and suppresses insulitis in multiple low dose streptozotocin diabetes model.

PubMed

Castillo, Gerardo M; Nishimoto-Ashfield, Akiko; Banerjee, Aryamitra A; Landolfi, Jennifer A; Lyubimov, Alexander V; Bolotin, Elijah M

2013-11-01

Our objective was to develop novel nanocarriers (protected graft copolymer, PGC) that improve the stability of heparin binding EGF (HBEGF) and gastrin and then to use PGC-formulated HBEGF (PGC-HBEGF) and Omeprazole (+/- PGC-gastrin) for normalizing fasting blood glucose (FBG) and improving islet function in diabetic mice. HBEGF, PGC-HBEGF, Omeprazole, Omeprazole + PGC-HBEGF, Omeprazole + PGC-gastrin + PGC-HBEGF and epidermal growth factor (EGF) + gastrin were tested in multiple low dose streptozotocin diabetic mice. Omeprazole + PGC-HBEGF normalized FBG and is better than EGF + gastrin at improving islet function and decreasing insulitis. Groups treated with Omeprazole, Omeprazole + PGC-HBEGF, or EGF + gastrin have significantly improved islet function versus saline control. All animals that received PGC-HBEGF had significantly reduced islet insulitis versus saline control. Non-FBG was lower for Omeprazole + PGC-gastrin + PGC-HBEGF but Omeprazole + PGC-HBEGF alone showed better FBG and glucose tolerance. Omeprazole + PGC-HBEGF provides a sustained exposure to both EGFRA and gastrin, improves islet function, and decreases insulitis in multiple low dose streptozotocin diabetic mice. Although HBEGF or EGF elevates non-FBG, it facilitates a reduction of insulitis and, in the presence of Omeprazole, provides normalization of FBG at the end of treatment. The study demonstrates Omeprazole and PGC-HBEGF is a viable treatment for diabetes.

Effect of the ingestion of the palm oil and glutamine in serum levels of GLP-1, PYY and glycemia in diabetes mellitus type 2 patients submitted to metabolic surgery.

PubMed

Takeuti, Tharsus Dias; Terra, Guilherme Azevedo; da Silva, Alex Augusto; Terra, Júverson Alves; da Silva, Luci Mara; Crema, Eduardo

2014-01-01

Incretins are hormones produced by the intestine and can stimulate the secretion of insulin, helping to diminish the post-prandial glycemia. The administration of an emulsion of palm oil can help in the maintenance of the weight, and can increase circulating incretins levels. Glutamine increases the concentration of incretins in diabetic people. Both can help in metabolic syndrome. To analyze the effects of ingestion of palm oil and glutamine in glycemia and in incretins in patients with diabetes submitted to surgical duodenojejunal exclusion with ileal interposition without gastrectomy. Eleven diabetic type 2 patients were included and were operated. They were called to laboratory follow-up without eating anything between eight and 12 hours. They had there blood collected after the stimulus of the palm oil and glutamine taken in different days. For the hormonal doses were used ELISA kits. The glycemia showed a meaningful fall between the fast and two hours after the stimulus of the palm oil (p=0,018). With the glutamine the GLP-1 showed an increase between the fast and one hour (p=0,32), the PYY showed an important increase between the fast and one hour after the stimulus (p=0,06), the glycemia showed a meaningful fall after two hours of the administration of the stimulus (p=0,03). Palm oil and glutamine can influence intestinal peptides and glucose.

Epitope mapping of the gastrin-releasing peptide/anti-bombesin monoclonal antibody complex by proteolysis followed by matrix-assisted laser desorption ionization mass spectrometry.

PubMed Central

Papac, D. I.; Hoyes, J.; Tomer, K. B.

1994-01-01

We have developed a method to rapidly identify the antigenic determinant for an antibody using in situ proteolysis of an immobilized antigen-antibody complex followed by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI/TOF). A mouse anti-bombesin monoclonal antibody was immobilized to agarose beads and then the antigen, gastrin-releasing peptide (GRP), was allowed to bind. Direct analysis of the immobilized antigen-antibody complex by MALDI/TOF is demonstrated and allows identification of ca. 1 pmol of the bound GRP. To identify the epitope, the immobilized antigen-antibody complex was subjected to proteolysis with trypsin, chymotrypsin, thermolysin, and aminopeptidase M. Following proteolysis, the part of the antigen in contact with the antibody and protected from proteolysis was identified directly by MALDI/TOF. Subsequently, the epitope was eluted from the immobilized antibody with 0.1 M glycine buffer (pH 2.3), separated by reversed-phase HPLC, and its identity confirmed by MALDI/TOF. Using this approach, the epitope for the anti-bombesin monoclonal antibody was shown to comprise the last 7-8 residues (HWAVGHLM-NH2) of GRP. PMID:7530543

Single crystal growth and structural evolution across the 1st order valence transition in (Pr1-yYy)1-xCaxCoO3-δ

NASA Astrophysics Data System (ADS)

Schreiber, N. J.; Zhang, Junjie; Zheng, Hong; Freeland, J. W.; Chen, Yu-Sheng; Mitchell, J. F.; Phelan, D.

2017-10-01

Praseodymium-containing cobalt perovskites, such as (Pr1-yYy)1-xCaxCoO3-δ, have been argued to undergo a first-order charge shift between Pr and hybridized Co-O orbitals that leads to a metal-insulator transition at a temperature, TVT. Magnetization and x-ray absorption spectroscopy measurements on single crystals of (Pr0.85Y0.15)0.7Ca0.3CoO3-δ grown in an IR image furnace under 40-60 bar of oxygen confirm the presence of this valence transition. Single crystal x-ray synchrotron diffraction measurements are consistent with an isomorphic phase transition at TVT. No evidence of charge ordering was revealed by the single crystal diffraction. Dissimilar to analytical transmission electron microscopy measurements performed on a grain from a polycrystalline sample that revealed an oxygen vacancy order-disorder transition at TVT, the present single-crystal measurements did not evidence such a transition, likely reflecting a lower density of oxygen vacancies in the high-pO2 grown single crystals.

Impact of concomitant Y and Mn substitution on superconductivity in La1 -yYyFe1 -xMnxAsO0.89F0.11

NASA Astrophysics Data System (ADS)

Kappenberger, Rhea; Hammerath, Franziska; Rousse, Pierre; Afrassa, Mesfin Asfaw; Haghighi, M. Hossein; Kamusella, Sirko; Prando, Giacomo; Lamura, Gianrico; Wolter, Anja U. B.; Moroni, Matteo; Sanna, Samuele; Carretta, Pietro; Hess, Christian; Grafe, Hans-Joachim; Klauss, Hans-Henning; Wurmehl, Sabine; Büchner, Bernd

2018-02-01

We discuss the impact of concomitant substitution of Fe by Mn and La by Y in optimally F-doped LaFeAsO0.89F0.11 . Mn has a known poisoning effect on superconductivity which is particularly strong in the La1111 system, where 0.2% of Mn were reported to completely suppress superconductivity. Through isovalent substitution of La by the much smaller Y we are able to inflict chemical pressure on the structure, which we show is stabilizing the superconducting state, resulting in a drastically larger amount of Mn needed to completely quench superconductivity. Interestingly, we find that the lattice parameter c changes significantly even for small amounts of Mn substitution within a series, which is unexpected taking only the differences between ionic radii into account. We discuss our findings in the light of electron localization caused by small amounts of paramagnetic Mn impurities in La1 -yYyFe1 -xMnxAsO0.89F0.11 also indicated by resistivity and Mößbauer measurements.

Omeprazole and PGC-formulated heparin binding epidermal growth factor normalizes fasting blood glucose and suppresses insulitis in multiple low dose streptozotocin diabetes model

PubMed Central

Castillo, Gerardo M.; Nishimoto-Ashfield, Akiko; Banerjee, Aryamitra A.; Landolfi, Jennifer A.; Lyubimov, Alexander V.; Bolotin, Elijah M.

2013-01-01

Purpose Our objective was to develop novel nanocarriers (protected graft copolymer, PGC) that improve the stability of heparin binding EGF (HBEGF) and gastrin and then to use PGC-formulated HBEGF (PGC-HBEGF) and Omeprazole (+/− PGC-gastrin) for normalizing fasting blood glucose (FBG) and improving islet function in diabetic mice. Method HBEGF, PGC-HBEGF, Omeprazole, Omeprazole+PGC-HBEGF, Omeprazole+PGC-gastrin+PGC-HBEGF and epidermal growth factor (EGF)+gastrin were tested in multiple low dose streptozotocin diabetic mice. Results Omeprazole+PGC-HBEGF normalized FBG and is better than EGF+gastrin at improving islet function and decreasing insulitis. Groups treated with Omeprazole, Omeprazole+PGC-HBEGF, or EGF+gastrin have significantly improved islet function versus saline control. All animals that received PGC-HBEGF had significantly reduced islet insulitis versus saline control. Non-FBG was lower for Omeprazole+PGC-gastrin+PGC-HBEGF but Omeprazole+PGC-HBEGF alone showed better FBG and glucose tolerance. Conclusions Omeprazole+PGC-HBEGF provides a sustained exposure to both EGFRA and gastrin, improves islet function, and decreases insulitis in multiple low dose streptozotocin diabetic mice. Although HBEGF or EGF elevates non-FBG, it facilitates a reduction of insulitis and, in the presence of Omeprazole, provides normalization of FBG at the end of treatment. The study demonstrates Omeprazole and PGC-HBEGF is a viable treatment for diabetes. PMID:23793991

Short-term ingestion of deoxynivalenol in naturally contaminated feed alters piglet performance and gut hormone secretion.

PubMed

Li, Ruonan; Li, Yansen; Su, Yongteng; Shen, Dan; Dai, Pengyuan; Li, Chunmei

2018-05-28

The mycotoxin deoxynivalenol (DON) generally exists in cereals and affects human and animal health. The aim of this study is to analyze the impacts of DON in naturally contaminated feed on piglet growth performance and intestinal hormone secretion in the short term. We randomly divided 5-week-old piglets into four groups: Control, DON 1,000, DON 2,000 and DON 3,000 groups. Piglets received a feed naturally contaminated with DON (approximately 400, 1,000, 2,000 or 3,000 μg/kg) for 21 days. Body weight showed no significant difference following exposure to DON. The balance of anti-oxidation and oxidation was disrupted by DON after 21 days. The concentration of tumor necrosis factor-alpha (TNF-α) and cyclooxgenase-2 (COX-2) significantly increased (p < .001) in all DON-treated groups. Gut anorexigenic hormone secretion of peptide YY (PYY) and cholecystokinin (CCK) had a time- and dose-dependent relationship with DON exposure; however, there was no effect on orexigenic hormone ghrelin secretion. Changes of histomorphology in the jejunum were observed in DON-treated groups, including villi flattening and fusion, and apical necrosis of villi. These results indicated that DON could suppress piglet growth performance and alter gut hormone secretion in the short term. © 2018 Japanese Society of Animal Science.

The Oncogenic Role of Yin Yang 1

PubMed Central

Zhang, Qiang; Stovall, Daniel B.; Inoue, Kazushi; Sui, Guangchao

2012-01-01

Yin Yang 1 (YY1) is a transcription factor with diverse and complex biological functions. YY1 either activates or represses gene transcription, depending on the stimuli received by the cells and its association with other cellular factors. Since its discovery, a biological role for YY1 in tumor development and progression has been suggested because of its regulatory activities toward multiple cancer-related proteins and signaling pathways and its overexpression in most cancers. In this review, we primarily focus on YY1 studies in cancer research, including the regulation of YY1 as a transcription factor, its activities independent of its DNA binding ability, the functions of its associated proteins, and mechanisms regulating YY1 expression and activities. We also discuss the correlation of YY1 expression with clinical outcomes of cancer patients and its target potential in cancer therapy. Although there is not a complete consensus about the role of YY1 in cancers based on its activities of regulating oncogene and tumor suppressor expression, most of the currently available evidence supports a proliferative or oncogenic role of YY1 in tumorigenesis. PMID:22248053

Duodenal and ileal glucose infusions differentially alter gastrointestinal peptides, appetite response, and food intake: a tube feeding study.

PubMed

Poppitt, Sally D; Shin, Hyun Sang; McGill, Anne-Thea; Budgett, Stephanie C; Lo, Kim; Pahl, Malcolm; Duxfield, Janice; Lane, Mark; Ingram, John R

2017-09-01

Background: Activation of the ileal brake through the delivery of nutrients into the distal small intestine to promote satiety and suppress food intake provides a new target for weight loss. Evidence is limited, with support from naso-ileal lipid infusion studies. Objective: The objective of the study was to investigate whether glucose infused into the duodenum and ileum differentially alters appetite response, food intake, and secretion of satiety-related gastrointestinal peptides. Design: Fourteen healthy male participants were randomly assigned to a blinded 4-treatment crossover, with each treatment of single-day duration. On the day before the intervention (day 0), a 380-cm multilumen tube (1.75-mm diameter) with independent port access to the duodenum and ileum was inserted, and position was confirmed by X-ray. Subsequently (days 1-4), a standardized breakfast meal was followed midmorning by a 90-min infusion of isotonic glucose (15 g, 235 kJ) or saline to the duodenum or ileum. Appetite ratings were assessed with the use of visual analog scales (VASs), blood samples collected, and ad libitum energy intake (EI) measured at lunch, afternoon snack, and dinner. Results: Thirteen participants completed the 4 infusion days. There was a significant effect of nutrient infused and site (treatment × time, P < 0.05) such that glucose-to-ileum altered VAS-rated fullness, satisfaction, and thoughts of food compared with saline-to-ileum (Tukey's post hoc, P < 0.05); decreased ad libitum EI at lunch compared with glucose-to-duodenum [-22%, -988 ± 379 kJ (mean ± SEM), Tukey's post hoc, P < 0.05]; and increased glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) compared with all other treatments (Tukey's post hoc, P < 0.05). Conclusions: Macronutrient delivery to the proximal and distal small intestine elicits different outcomes. Glucose infusion to the ileum increased GLP-1 and PYY secretion, suppressed aspects of VAS-rated appetite, and decreased ad libitum EI at a

Reducing dietary fat from a meal increases the bioavailability of exogenous carbohydrate without altering plasma glucose concentration.

PubMed

Knuth, Nicolas D; Shrivastava, Cara R; Horowitz, Jeffrey F

2009-01-01

The primary goal of this study was to determine the acute glycemic and endocrine responses to the reduction of fat content from a meal. On three separate occasions, nine overweight subjects (body mass index = 30 +/- 1 kg/m(2); 5 men, 4 women) consumed 1) a control meal ( approximately 800 kcal; 100 g of carbohydrate, 31 g of fat, and 30 g of protein), 2) a low-fat meal ( approximately 530 kcal; 100 g of carbohydrate, 1 g of fat, and 30 g of protein), or 3) a low-fat meal plus lipid infusion [same meal as low-fat meal, but the total energy provided was the same as control (800 kcal), with the "missing" fat ( approximately 30 g) provided via an intravenous lipid infusion]. All three meals contained [(13)C]glucose (3 mg/kg body wt) to assess the bioavailability of ingested glucose. During the 5-h period after each meal, we measured the recovery of [(13)C]glucose in plasma, plasma glucose, and insulin concentrations. We also measured plasma concentration of the gastrointestinal peptides: glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and peptide YY(3-36) (PYY(3-36)). The recovery of the ingested [(13)C]glucose in the hour after ingestion was greater (P < 0.05) after the low-fat than after the control meal [area under the curve (AUC): 1,206 +/- 252 and 687 +/- 161 microM.h, respectively]. However, removing dietary fat from the meal did not affect the plasma concentration of glucose or insulin. Importantly, [(13)C]glucose recovery was not different during the low-fat and lipid infusion trials (AUC: 1,206 +/- 252 and 1,134 +/- 247 microM.h, respectively), indicating that the accelerated delivery of exogenous glucose found after removing fat from the meal is due exclusively to the reduction of fat in the gastrointestinal tract. In parallel with these findings, the reduction in fat calories from the meal reduced plasma concentration of GIP, GLP-1, and PYY(3-36). In summary, these data suggest that removing fat from the diet expedited

Do Lactation-Induced Changes in Ghrelin, Glucagon-Like Peptide-1, and Peptide YY Influence Appetite and Body Weight Regulation during the First Postpartum Year?

PubMed Central

Larson-Meyer, D. Enette; Schueler, Jessica; Kyle, Erin; Austin, Kathleen J.; Hart, Ann Marie; Alexander, Brenda M.

2016-01-01

To determine whether fasting and meal-induced appetite-regulating hormones are altered during lactation and associated with body weight retention after childbearing, we studied 24 exclusively breastfeeding women (BMI = 25.2 ± 3.6 kg/m2) at 4-5 weeks postpartum and 20 never-pregnant controls (BMI = 24.0 ± 3.1 kg/m2). Ghrelin, PYY, GLP-1, and appetite ratings were measured before/and 150 minutes after a standardized breakfast and 60 minutes after an ad libitum lunch. Body weight/composition were measured at 6 and 12 months. Fasting and area under-the-curve responses for appetite-regulating hormones did not differ between lactating and control groups; ghrelinacyl, however, tended to track higher after the standardized breakfast in lactating women and was higher (p < 0.05) after the ad libitum lunch despite a 24% higher energy intake (p < 0.05). By 12 months, lactating women lost 5.3 ± 2.2 kg (n = 18), whereas control women (n = 15) remained weight stable (p = 0.019); fifteen of the lactating women returned to within ±2.0 kg of prepregnancy weight but three retained >6.0 kg. The retainers had greater (p < 0.05) postmeal ghrelin rebound responses following breakfast. Overall these studies do not support the hypothesis that appetite-regulating hormones are altered during lactation and associated with postpartum weight retention. Altered ghrelin responses, however, deserve further exploration. PMID:27313876

Distinct functions of opioid-related peptides and gastrin-releasing peptide in regulating itch and pain in the spinal cord of primates.

PubMed

Lee, Heeseung; Ko, Mei-Chuan

2015-06-29

How neuropeptides in the primate spinal cord regulate itch and pain is largely unknown. Here we elucidate the sensory functions of spinal opioid-related peptides and gastrin-releasing peptide (GRP) in awake, behaving monkeys. Following intrathecal administration, β-endorphin (10-100 nmol) and GRP (1-10 nmol) dose-dependently elicit the same degree of robust itch scratching, which can be inhibited by mu-opioid peptide (MOP) receptor and GRP receptor (BB2) antagonists, respectively. Unlike β-endorphin, which produces itch and attenuates inflammatory pain, GRP only elicits itch without affecting pain. In contrast, enkephalins (100-1000 nmol) and nociceptin-orphanin FQ (3-30 nmol) only inhibit pain without eliciting itch. More intriguingly, dynorphin A(1-17) (10-100 nmol) dose-dependently attenuates both β-endorphin- and GRP-elicited robust scratching without affecting pain processing. The anti-itch effects of dynorphin A can be reversed by a kappa-opioid peptide (KOP) receptor antagonist nor-binaltorphimine. These nonhuman primate behavioral models with spinal delivery of ligands advance our understanding of distinct functions of neuropeptides for modulating itch and pain. In particular, we demonstrate causal links for itch-eliciting effects by β-endorphin-MOP receptor and GRP-BB2 receptor systems and itch-inhibiting effects by the dynorphin A-KOP receptor system. These studies will facilitate transforming discoveries of novel ligand-receptor systems into future therapies as antipruritics and/or analgesics in humans.

How gastrin-releasing peptide receptor (GRPR) and αvβ3 integrin expression reflect reorganization features of tumors after hyperthermia treatments.

PubMed

Hallasch, Sandra; Frick, Sindy; Jung, Maximilian; Hilger, Ingrid

2017-07-31

The outcome of tumor treatment via hyperthermia in the clinic has been reported to be heterogeneous. Here, we assessed how the presence of gastrin-releasing peptide receptor (GRPR) and α v β 3 integrin together with the morphology of the vascularization reflects the growth behavior of tumors after hyperthermia treatment. MDA-MB-231 tumor bearing mice were treated either with high (46 °C) or low dose (42 °C) water hyperthermia for 60 min. Changes of GRPR and α v β 3 integrin expression were assessed via multiplexed optical imaging. Vascularization was reconstructed and quantified by µCT imaging after contrast agent injection. We found that high dose hyperthermia is capable of increasing the expression of GRPR, α v β 3 integrin, CD31, and Ki67 in tumors. Also the morphology of tumor vasculature changed (increased relative blood volume and small-diameter vessel density, decreased expression of α-SMA). Low dose hyperthermia induced comparatively moderate effects on the investigated protein expression pattern and vascular remodeling. We conclude that under defined circumstances, specific temperature doses affect the reorganization of tumor regrowth, which is triggered by residual "dormant" cells even though tumor volumes are transiently decreasing. Further on, GRPR, α v β 3 integrin expression are versatile tools to surveil potential tumor regrow during therapy, beyond the conventional determination of tumor volumes.

Nitric oxide sensitizes tumor cells to TRAIL-induced apoptosis via inhibition of the DR5 transcription repressor Yin Yang 1.

PubMed

Huerta-Yepez, Sara; Vega, Mario; Escoto-Chavez, Saul E; Murdock, Benjamin; Sakai, Toshiyuki; Baritaki, Stavroula; Bonavida, Benjamin

2009-02-01

Treatment of TRAIL-resistant tumor cells with the nitric oxide donor DETANONOate sensitizes the tumor cells to TRAIL-induced apoptosis concomitantly with DR5 upregulation. The mechanism of sensitization was examined based on the hypothesis that DETANONOate inhibits a transcription repressor Yin Yang 1 (YY1) that negatively regulates DR5 transcription. Treatment of the prostate carcinoma cell lines with DETANONOate inhibited both NF-kappaB and YY1 DNA-binding activities concomitantly with upregulation of DR5 expression. The direct role of YY1 in the regulation of TRAIL resistance was demonstrated in cells treated with YY1 siRNA resulting in TRAIL-induced apoptosis. The role of YY1 in the transcriptional regulation of DR5 was examined in cells treated with a DR5 luciferase reporter system (pDR5) and two constructs, namely, the pDR5/-605 construct with a deletion of the putative YY1 DNA-binding region (-1224 to -605) and a construct pDR5-YY1 with a mutation of the YY1 DNA-binding site. A significant (3-fold) augmentation of luciferase activity over baseline transfection with pDR5 was observed in cells transfected with the modified constructs. ChIP analysis corroborated the YY1 binding to the DR5 promoter. In vivo, tissues from nude mice bearing the PC-3 xenograft and treated with DETANONOate showed inhibition of YY1 and upregulation of DR5. The present findings demonstrate that YY1 negatively regulates DR5 transcription and expression and these correlated with resistance to TRAIL-induced apoptosis. DETANONOate inhibits both NF-kappaB and YY1 and in combination with TRAIL reverses tumor cell resistance to TRAIL apoptosis.

A combinatorial approach for the design of complementarity-determining region-derived peptidomimetics with in vitro anti-tumoral activity.

PubMed

Timmerman, Peter; Barderas, Rodrigo; Desmet, Johan; Altschuh, Danièle; Shochat, Susana; Hollestelle, Martine J; Höppener, Jo W M; Monasterio, Alberto; Casal, J Ignacio; Meloen, Rob H

2009-12-04

The great success of therapeutic monoclonal antibodies has fueled research toward mimicry of their binding sites and the development of new strategies for peptide-based mimetics production. Here, we describe a new combinatorial approach for the production of peptidomimetics using the complementarity-determining regions (CDRs) from gastrin17 (pyroEGPWLEEEEEAYGWMDF-NH(2)) antibodies as starting material for cyclic peptide synthesis in a microarray format. Gastrin17 is a trophic factor in gastrointestinal tumors, including pancreatic cancer, which makes it an interesting target for development of therapeutic antibodies. Screening of microarrays containing bicyclic peptidomimetics identified a high number of gastrin binders. A strong correlation was observed between gastrin binding and overall charge of the peptidomimetic. Most of the best gastrin binders proceeded from CDRs containing charged residues. In contrast, CDRs from high affinity antibodies containing mostly neutral residues failed to yield good binders. Our experiments revealed essential differences in the mode of antigen binding between CDR-derived peptidomimetics (K(d) values in micromolar range) and the parental monoclonal antibodies (K(d) values in nanomolar range). However, chemically derived peptidomimetics from gastrin binders were very effective in gastrin neutralization studies using cell-based assays, yielding a neutralizing activity in pancreatic tumoral cell lines comparable with that of gastrin-specific monoclonal antibodies. These data support the use of combinatorial CDR-peptide microarrays as a tool for the development of a new generation of chemically synthesized cyclic peptidomimetics with functional activity.

A Combinatorial Approach for the Design of Complementarity-determining Region-derived Peptidomimetics with in Vitro Anti-tumoral Activity*

PubMed Central

Timmerman, Peter; Barderas, Rodrigo; Desmet, Johan; Altschuh, Danièle; Shochat, Susana; Hollestelle, Martine J.; Höppener, Jo W. M.; Monasterio, Alberto; Casal, J. Ignacio; Meloen, Rob H.

2009-01-01

The great success of therapeutic monoclonal antibodies has fueled research toward mimicry of their binding sites and the development of new strategies for peptide-based mimetics production. Here, we describe a new combinatorial approach for the production of peptidomimetics using the complementarity-determining regions (CDRs) from gastrin17 (pyroEGPWLEEEEEAYGWMDF-NH2) antibodies as starting material for cyclic peptide synthesis in a microarray format. Gastrin17 is a trophic factor in gastrointestinal tumors, including pancreatic cancer, which makes it an interesting target for development of therapeutic antibodies. Screening of microarrays containing bicyclic peptidomimetics identified a high number of gastrin binders. A strong correlation was observed between gastrin binding and overall charge of the peptidomimetic. Most of the best gastrin binders proceeded from CDRs containing charged residues. In contrast, CDRs from high affinity antibodies containing mostly neutral residues failed to yield good binders. Our experiments revealed essential differences in the mode of antigen binding between CDR-derived peptidomimetics (Kd values in micromolar range) and the parental monoclonal antibodies (Kd values in nanomolar range). However, chemically derived peptidomimetics from gastrin binders were very effective in gastrin neutralization studies using cell-based assays, yielding a neutralizing activity in pancreatic tumoral cell lines comparable with that of gastrin-specific monoclonal antibodies. These data support the use of combinatorial CDR-peptide microarrays as a tool for the development of a new generation of chemically synthesized cyclic peptidomimetics with functional activity. PMID:19808684

Isolation of endopeptidase-24.11 (EC 3.4.24.11, "enkephalinase") from the pig stomach. Hydrolysis of substance P, gastrin-releasing peptide 10, [Leu5] enkephalin, and [Met5] enkephalin.

PubMed

Bunnett, N W; Turner, A J; Hryszko, J; Kobayashi, R; Walsh, J H

1988-10-01

The purpose of this investigation was to isolate the cell-surface enzyme endopeptidase-24.11 from the stomach wall of the pig and to examine the hydrolysis of the gastric neuropeptides. Endopeptidase-24.11 was isolated from gastric membranes by immunoadsorbent chromatography using a monoclonal antibody to porcine kidney endopeptidase-24.11. The enzyme was purified with a yield of 1.2 micrograms/g wet wt of fundic muscle. A single polypeptide chain of apparent subunit molecular weight of 90,000 was identified by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Gastric endopeptidase-24.11 hydrolyzed substance P, gastrin-releasing peptide 10, [Leu5] enkephalin, and [Met5] enkephalin by cleavage of peptide bonds on the N-terminal side of hydrophobic amino acids. The enzymatic activity was inhibited completely by phosphoramidon (10(-6) M) and strongly by 1,10-phenanthroline (10(-3) M), but was unaffected by captopril (10(-5) M).

Yin Yang-1 suppresses invasion and metastasis of pancreatic ductal adenocarcinoma by downregulating MMP10 in a MUC4/ErbB2/p38/MEF2C-dependent mechanism.

PubMed

Zhang, Jing-Jing; Zhu, Yi; Xie, Kun-Ling; Peng, Yun-Peng; Tao, Jin-Qiu; Tang, Jie; Li, Zheng; Xu, Ze-Kuan; Dai, Cun-Cai; Qian, Zhu-Yin; Jiang, Kui-Rong; Wu, Jun-Li; Gao, Wen-Tao; Du, Qing; Miao, Yi

2014-05-29

Increasing evidence indicates an important role of transcription factor Yin Yang-1 (YY1) in human tumorigenesis. However, its function in cancer remains controversial and the relevance of YY1 to pancreatic ductal adenocarcinoma (PDAC) remains to be clarified. In this study, we detected YY1 expression in clinical PDAC tissue samples and cell lines using quantitative RT-PCR, immunohistochemistry and western blotting. We also detected MUC4 and MMP10 mRNA levels in 108 PDAC samples using qRT-PCR and analyzed the correlations between YY1 and MUC4 or MMP10 expression. The role of YY1 in the proliferation, invasion and metastatic abilities of PDAC cells in vitro was studied by CCK-8 assay, cell migration and invasion assays. In vivo pancreatic tumor growth and metastasis was studied by a xenogenous subcutaneously implant model and a tail vein metastasis model. The potential mechanisms underlying YY1 mediated tumor progression in PDAC were explored by digital gene expression (DGE) sequencing, signal transduction pathways blockage experiments and luciferase assays. Statistical analysis was performed using the SPSS 15.0 software. We found that the expression of YY1 in PDACs was higher compared with their adjacent non-tumorous tissues and normal pancreas tissues. However, PDAC patients with high level overexpression of YY1 had better outcome than those with low level overexpression. YY1 expression levels were statistically negatively correlated with MMP10 expression levels, but not correlated with MUC4 expression levels. YY1 overexpression suppressed, whereas YY1 knockdown enhanced, the proliferation, invasion and metastatic properties of BXPC-3 cells, both in vitro and in vivo. YY1 suppresses invasion and metastasis of pancreatic cancer cells by downregulating MMP10 in a MUC4/ErbB2/p38/MEF2C-dependent mechanism. The present study suggested that YY1 plays a negative role, i.e. is a tumor suppressor, in PDAC, and may become a valuable diagnostic and prognostic marker of PDAC.

c-Abl phosphorylation of Yin Yang 1's conserved tyrosine 254 in the spacer region modulates its transcriptional activity.

PubMed

Daraiseh, Susan I; Kassardjian, Ari; Alexander, Karen E; Rizkallah, Raed; Hurt, Myra M

2018-05-25

Yin Yang 1 (YY1) is a multifunctional transcription factor that can activate or repress transcription depending on the promotor and/or the co-factors recruited. YY1 is phosphorylated in various signaling pathways and is critical for different biological functions including embryogenesis, apoptosis, proliferation, cell-cycle regulation and tumorigenesis. Here we report that YY1 is a substrate for c-Abl kinase phosphorylation at conserved residue Y254 in the spacer region. Pharmacological inhibition of c-Abl kinase by imatinib, nilotinib and GZD824, knock-down of c-Abl using siRNA, and the use of c-Abl kinase-dead drastically reduces tyrosine phosphorylation of YY1. Both radioactive and non-radioactive in vitro kinase assays, as well as co-immunoprecipitation in different cell lines, show that the target of c-Abl phosphorylation is tyrosine residue 254. c-Abl phosphorylation has little effect on YY1 DNA binding ability or cellular localization in asynchronous cells. However, functional studies reveal that c-Abl mediated phosphorylation of YY1 regulates YY1's transcriptional ability in vivo. In conclusion, we demonstrate the novel role of c-Abl kinase in regulation of YY1's transcriptional activity, linking YY1 regulation with c-Abl tyrosine kinase signaling pathways. Copyright © 2018. Published by Elsevier B.V.

EFFECT OF THE INGESTION OF THE PALM OIL AND GLUTAMINE IN SERUM LEVELS OF GLP-1, PYY AND GLYCEMIA IN DIABETES MELLITUS TYPE 2 PATIENTS SUBMITTED TO METABOLIC SURGERY

PubMed Central

TAKEUTI, Tharsus Dias; TERRA, Guilherme Azevedo; da SILVA, Alex Augusto; TERRA-JÚNIOR, Júverson Alves; da SILVA, Luci Mara; CREMA, Eduardo

2014-01-01

Background Incretins are hormones produced by the intestine and can stimulate the secretion of insulin, helping to diminish the post-prandial glycemia. The administration of an emulsion of palm oil can help in the maintenance of the weight, and can increase circulating incretins levels. Glutamine increases the concentration of incretins in diabetic people. Both can help in metabolic syndrome. Aim To analyze the effects of ingestion of palm oil and glutamine in glycemia and in incretins in patients with diabetes submitted to surgical duodenojejunal exclusion with ileal interposition without gastrectomy. Methods Eleven diabetic type 2 patients were included and were operated. They were called to laboratory follow-up without eating anything between eight and 12 hours. They had there blood collected after the stimulus of the palm oil and glutamine taken in different days. For the hormonal doses were used ELISA kits. Results The glycemia showed a meaningful fall between the fast and two hours after the stimulus of the palm oil (p=0,018). With the glutamine the GLP-1 showed an increase between the fast and one hour (p=0,32), the PYY showed an important increase between the fast and one hour after the stimulus (p=0,06), the glycemia showed a meaningful fall after two hours of the administration of the stimulus (p=0,03). Conclusion Palm oil and glutamine can influence intestinal peptides and glucose PMID:25409967

Variation of the H-Beta Emission Lines of Yy-Geminorum - Part Two - Change of Sectorial Structures of Active Regions

NASA Astrophysics Data System (ADS)

Kodaira, K.; Ichimura, K.

Sixty-three image-tube spectrograms of YY Gem (4 Å mm-1, λλ4820-4900 Å) are analyzed to yield the radial-velocity curves and the variations in the intensities and the widths of Hβ emission lines during the quiescent phase at epochs 1980 February 11-16, 1981 January 14-15, and 1981 March 11. The emission-line intensity of component A varied in a single-wave mode over an orbital period, with an apparent phase drift, -0.006019 fraction of the period per day from one epoch to another. The pattern of the intensity variation of component B changed within a few years. The ratio of the amplitudes of radial-velocity curves (KA/KB) of Hβ emission was found to be 0.91 in February 1980 but 1.01 in January 1981. This modulation in the ratio is interpreted as the results of the varying inhomogeneous distributions of emission intensities over the stellar surfaces which are inferred from the observed intensity variations under the assumption of synchronous rotation. A ratio KA/KB = 1.00±001 is proposed as the actual value which would be observed if the effects of inhomogeneities were negligible. The double-wave mode of the line-width variation over a period, which was found by Kodaira and Ichimura (1980), persisted for component A but changed into a single-wave mode for component B. No appreciable changes were detected in the average levels of both the intensity and width of Hβ emission lines within the last few years.

Gastrin-releasing peptide and its receptor increase arthritis fibroblast-like synoviocytes invasiveness through activating the PI3K/AKT pathway.

PubMed

Clarimundo, Vanessa Schuck; Farinon, Mirian; Pedó, Renata Ternus; Teixeira, Vivian Oliveira Nunes; Nör, Carolina; Gulko, Percio S; Xavier, Ricardo Machado; de Oliveira, Patricia Gnieslaw

2017-09-01

Rheumatoid arthritis (RA) is an autoimmune disease that leads to joint destruction. The fibroblast-like synoviocytes (FLS) has a central role on the disease pathophysiology. The present study aimed to examine the role of gastrin-releasing peptide (GRP) and its receptor (GRPR) on invasive behavior of mice fibroblast-like synoviocytes (FLS), as well as to evaluate GRP-induced signaling on PI3K/AKT pathway. The expression of GRPR in FLS was investigated by immunocytochemistry, western blot (WB) and qRT-PCR. The proliferation and invasion were assessed by SRB and matrigel-transwell assay after treatment with GRP and/or RC-3095 (GRPR antagonist), and/or Ly294002 (inhibitor of PI3K/AKT pathway). Finally, AKT phosphorylation was assessed by WB. GRPR protein was detected in FLS and the exposure to GRP increased FLS invasion by nearly two-fold, compared with untreated cells (p<0.05), while RC-3095 reversed that effect (p<0.001). GRP also increased phosphorylated AKT expression in FLS. When Ly294002 was added with GRP, it prevented the GRP-induced increased cell invasiveness (p<0.001). These data suggest that GRPR expression in FLS and that exogenous GRP are able to activate FLS invasion. This effect occurs at least in part through the AKT activation. Therefore, understanding of the GRP/GRPR pathway could be relevant in the development of FLS-targeted therapy for RA. Copyright © 2017 Elsevier Inc. All rights reserved.

Overexpression of pro-gastrin releasing peptide promotes the cell proliferation and progression in small cell lung cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gong, Zhiyun; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032; Lu, Renquan

Pro-gastrin releasing peptide (ProGRP) plays the role of oncogene in small cell lung cancer (SCLC). In this study, we aim to explore the biological function of ProGRP in SCLC cells and its potential mechanism. Expression of ProGRP in SCLC tissues and cell lines were detected by immunohistochemistry and western blot analysis, respectively. The transduced cell lines with ProGRP down-regulation were established using RNA interference technology. Cell viability, cologenic, apoptosis-associated assay and the biomarker levels determination for cell supernatant were performed in the transduced cells to elucidate the biological functions and mechanisms of ProGRP in SCLC cells. Our data showed thatmore » ProGRP protein was demonstrated a higher level in SCLC tissues and cells compared with the control, and its diagnostic efficiency was better than NSE, further, the higher levels of ProGRP were detected in the patients with extensive disease stage (P < 0.05), were also the unfavorable factor to the prognosis of SCLC patients. Additionally, the concentration of serum ProGRP is a useful biomarker in disease-monitoring of the patients with SCLC. Down-regulation of ProGRP significantly reduced SCLC cell growth, repressed colony formation, but increased cancer cell apoptosis. Additionally, repression of ProGRP also induced change in the cell cycle and output of NSE. Our data indicated that ProGRP serve as the useful biomarker in the management of SCLC and might be a potential therapeutic target. - Highlights: • ProGRP is overexpressed in the tissues and sera of the patients with SCLC. • Down-regulation of ProGRP inhibited cell proliferation. • Inhibition of ProGRP altered cell cycle distribution and triggers the apoptosis of lung cancer cells.« less

A functional SNP in the promoter region of TCOF1 is associated with reduced gene expression and YY1 DNA-protein interaction.

PubMed

Masotti, Cibele; Armelin-Correa, Lucia M; Splendore, Alessandra; Lin, Chin J; Barbosa, Angela; Sogayar, Mari C; Passos-Bueno, Maria Rita

2005-10-10

Treacher Collins syndrome (TCS) is an autosomal dominant craniofacial malformation caused by null mutations in the TCOF1 gene. High inter and intra familial clinical variability, ranging from mild malar hypoplasia to perinatal death due to airway collapse is observed, but, to date, no genotype-phenotype correlation has been reported. Considering haploinsufficiency as the molecular mechanism underlying the disease, we have hypothesized that mutations in the promoter region of the gene, which has never been previously characterized, in trans with a pathogenic mutation, could modulate the phenotype. Therefore, the aims of the present study were to determine the TCOF1 gene's core promoter and to identify mutations in this region that could contribute to the phenotypic variation observed in this syndrome. We have delimitated the minimal promoter to a region of less than 150 bp, with 63% of identity among 5 different species. We screened 1.2 kbp of the TCOF1 5' flanking sequence in the DNA obtained from 21 patients and 51 controls and identified four new single nucleotide polymorphisms (SNPs), one of which (-346C>T), was proved to be functional, as it decreased the promoter activity by 38%. Electrophoretic mobility shift assay (EMSA) analysis demonstrated that the -346T allele impairs DNA-binding to the YY1 transcription factor. This promoter variant represents a candidate allele to explain the clinical variability in patients bearing TCS.

Bombesin-like peptides stimulate growth hormone secretion mediated by the gastrin-releasing peptide receptor in cattle.

PubMed

Zhao, Hongqiong; Matsuda, Seinosuke; Thanthan, Sint; Yannaing, Swe; Kuwayama, Hideto

2012-10-01

This study was designed to determine the effects of bombesin-like peptides (BLPs) on the secretion of growth hormone (GH) and to characterize the receptor subtypes mediating these effects in cattle. Four experiments were conducted: (1) six steers were randomly assigned to receive intravenous (IV) bolus injections of 0, 0.2, 1.0, 12.5 and 50.0 μg/kg neuromedin C (NMC); (2) seven pre-weaned calves were IV injected with 1.0 μg/kg NMC; (3) six steers were IV injected with 2.5μg/kg bovine gastrin-releasing peptide (GRP), 1.0 μg/kg NMC combined with 20.0 μg/kg [d-Lys(3)]-GHRP-6 (an antagonist for the GH secretagogue receptor type 1a [GHS-R1a]), 1.0 μg/kg NMC combined with 20.0 μg/kg N-acetyl-GRP(20-26)-OCH(2)CH(3) (N-GRP-EE, an antagonist for the GRP receptor), 20.0 μg/kg N-GRP-EE alone, 1.0 μg/kg neuromedin B (NMB); and (4) four rats were IV injected 1.0 μg/kg NMC. A serial blood sample was collected before and after injection. Plasma GH levels dose-dependently increased at 5 min after NMC injection and the minimal effective dose was 1.0 μg/kg. Plasma GH level was elevated by GRP, but not by NMB. The NMC-induced elevation of GH was completely blocked by N-GRP-EE. The administration of NMC elevated GH level in pre-weaned calves but not in rats. Ghrelin level was unaffected by any treatments; and [d-Lys(3)]-GHRP-6 did not block the NMC-induced elevation of GH. The results indicate BLP-induced elevation of GH levels is mediated by the GRP receptor but not through a ghrelin/GHS-R1a pathway in cattle. Copyright © 2012 Elsevier Inc. All rights reserved.

Role of Endogenous Cholecystokinin on Growth of Human Pancreatic Cancer

PubMed Central

Matters, Gail L.; McGovern, Christopher; Harms, John F.; Markovic, Kevin; Anson, Krystal; Jayakumar, Calpurnia; Martenis, Melissa; Awad, Christina; Smith, Jill P.

2012-01-01

Cholecystokinin (CCK) and gastrin stimulate growth of pancreatic cancer. Although down regulation of gastrin inhibits growth of pancreatic cancer, the contribution of endogenous CCK to tumor growth is unknown. The purpose of this study was to evaluate the role of endogenous CCK on autocrine growth of pancreatic cancer. Pancreatic cancer cell lines were analyzed for CCK mRNA and peptide expression by real time RT-PCR and radioimmunoassay, respectively. The effect of endogenous CCK on growth was evaluated by treating cancer cells with CCK neutralizing antibodies and by down regulating CCK mRNA by RNAi. Wild type pancreatic cancer cells expressed significantly lower CCK mRNA and peptide levels than gastrin. Neither treatment of pancreatic cancer cells with CCK antibodies nor the down regulation of CCK mRNA and peptide by shRNAs altered growth in vitro or in vivo. Conversely, when gastrin mRNA expression was down regulated, the same cells failed to produce tumors in spite of having sustained levels of endogenous CCK. Pancreatic cancer cells produce CCK and gastrin; however, the autocrine production of gastrin is more important for stimulating tumor growth. PMID:21186400

Yin Yang 1 Promotes Hepatic Gluconeogenesis Through Upregulation of Glucocorticoid Receptor

PubMed Central

Lu, Yan; Xiong, Xuelian; Wang, Xiaolin; Zhang, Zhijian; Li, Jin; Shi, Guojun; Yang, Jian; Zhang, Huijie; Ning, Guang; Li, Xiaoying

2013-01-01

Gluconeogenesis is critical in maintaining blood glucose levels in a normal range during fasting. In this study, we investigated the role of Yin Yang 1 (YY1), a key transcription factor involved in cell proliferation and differentiation, in the regulation of hepatic gluconeogenesis. Our data showed that hepatic YY1 expression levels were induced in mice during fasting conditions and in a state of insulin resistance. Overexpression of YY1 in livers augmented gluconeogenesis, raising fasting blood glucose levels in C57BL/6 mice, whereas liver-specific ablation of YY1 using adenoviral shRNA ameliorated hyperglycemia in wild-type and diabetic db/db mice. At the molecular level, we further demonstrated that the major mechanism of YY1 in the regulation of hepatic glucose production is to modulate the expression of glucocorticoid receptor. Therefore, our study uncovered for the first time that YY1 participates in the regulation of hepatic gluconeogenesis, which implies that YY1 might serve as a potential therapeutic target for hyperglycemia in diabetes. PMID:23193188

Effects of intranasal and peripheral oxytocin or gastrin-releasing peptide administration on social interaction and corticosterone levels in rats.

PubMed

Kent, Pamela; Awadia, Alisha; Zhao, Leah; Ensan, Donna; Silva, Dinuka; Cayer, Christian; James, Jonathan S; Anisman, Hymie; Merali, Zul

2016-02-01

The intranasal route of drug administration has gained increased popularity as it is thought to allow large molecules, such as peptide hormones, more direct access to the brain, while limiting systemic exposure. Several studies have investigated the effects of intranasal oxytocin administration in humans as this peptide is associated with prosocial behavior. There are, however, few preclinical studies investigating the effects of intranasal oxytocin administration in rodents. Oxytocin modulates hypothalamic-pituitary-adrenal (HPA) axis functioning and it has been suggested that oxytocin's ability to increase sociability may occur through a reduction in stress reactivity. Another peptide that appears to influence both social behavior and HPA axis activity is gastrin-releasing peptide (GRP), but it is not known if these GRP-induced effects are related. With this in mind, in the present study, we assessed the effects of intranasal and intraperitoneal oxytocin and GRP administration on social interaction and release of corticosterone in rats. Intranasal and intraperitoneal administration of 20, but not 5 μg, of oxytocin significantly increased social interaction, whereas intranasal and peripheral administration of GRP (20 but not 5 μg) significantly decreased levels of social interaction. In addition, while intranasal oxytocin (20 μg) had no effect on blood corticosterone levels, a marked increase in blood corticosterone levels was observed following intraperitoneal oxytocin administration. With GRP, intranasal (20 μg) but not peripheral administration increased corticosterone levels. These findings provide further evidence that intranasal peptide delivery can induce behavioral alterations in rodents which is consistent with findings from human studies. In addition, the peptide-induced changes in social interaction were not linked to fluctuations in corticosterone levels. Copyright © 2015 Elsevier Ltd. All rights reserved.

Reduction in total plasma ghrelin levels following catecholamine depletion: relation to bulimic and depressive symptoms.

PubMed

Homan, Philipp; Grob, Simona; Milos, Gabriella; Schnyder, Ulrich; Hasler, Gregor

2013-09-01

There is increasing preclinical and clinical evidence of the important role played by the gastric peptide hormone ghrelin in the pathogenesis of symptoms of depression and eating disorders. To investigate the role of ghrelin and its considered counterpart, peptide tyrosine tyrosine (PYY), in the development of bulimic and depressive symptoms induced by catecholamine depletion, we administered the tyrosine hydroxylase inhibitor alpha-methyl-paratyrosine (AMPT) in a randomized, double-blind, placebo-controlled crossover, single-site experimental trial to 29 healthy controls and 20 subjects with fully recovered bulimia nervosa (rBN). We found a decrease between preprandial and postprandial plasma ghrelin levels (p<0.0001) and a postprandial rise in plasma PYY levels (p<0.0001) in both conditions in the entire study population. Plasma ghrelin levels decreased in the entire study population after treatment with AMPT compared to placebo (p<0.006). AMPT-induced changes in plasma ghrelin levels were negatively correlated with AMPT-induced depressive symptoms (p<0.004). Plasma ghrelin and plasma PYY levels were also negatively correlated (p<0.05). We did not observe a difference in ghrelin or PYY response to catecholamine depletion between rBN subjects and healthy controls, and there was no correlation between plasma ghrelin and PYY levels and bulimic symptoms induced by catecholamine depletion. These findings suggest a relationship between catecholamines and ghrelin with depressive symptoms. Copyright © 2013 Elsevier Ltd. All rights reserved.

Hypochlorhydria and hypergastrinaemia in rheumatoid arthritis.

PubMed Central

de Witte, T J; Geerdink, P J; Lamers, C B; Boerbooms, A M; van der Korst, J K

1979-01-01

In order to evaluate the incidence and aetiology of hypergastrinaemia 53 patients with seropositive rheumatoid arthritis were examined for gastric acid secretion, fasting serum gastrin concentration, circulating parietal cell antibodies, and some parameters of the activity of inflammation of rheumatoid arthritis. The basal and maximum acid output was found to be subnormal in this group (P less than 0.01), and in 11 of these patients (23%) the fasting serum gastrin levels were raised (P less than 0.05). This hypergastrinaemia correlated strongly with maximum acid output. Only in cases of achlorhydria or hypochlorhydria (maximum acid output less than 2 mmol/l) was the serum gastrin level markedly raised. Two out of 5 patients with achlorhydria were found to have circulating parietal cell antibodies, and 1 had decreased absorption of vitamin B12. No relationship was found between serum gastrin and duration or activity of rheumatoid arthritis; nor was there a relationship between basal serum gastrin and the various antirheumatic drugs administered. PMID:434940

Effects of Two Dietary Fibers as Part of Ready-to-Eat Cereal (RTEC) Breakfasts on Perceived Appetite and Gut Hormones in Overweight Women

PubMed Central

Lafond, David W.; Greaves, Kathryn A.; Maki, Kevin C.; Leidy, Heather J.; Romsos, Dale R.

2015-01-01

The effects of an enzyme-hydrolyzed arabinoxylan from wheat (AXOS) versus an intact arabinoxylan from flax (FLAX) added to a ready-to-eat cereal (RTEC) on the postprandial appetitive, hormonal, and metabolic responses in overweight women (BMI 25.0–29.9 kg/m2) were evaluated. Subsequent meal energy intake was also assessed. Two randomized, double-blind, crossover design studies were completed. For trial 1, the participants consumed the following RTEC breakfast, matched for total weight and varied in energy content: low-fiber (LF, 4 g); high-fiber (HF, 15 g) as either AXOS or FLAX. For trial 2, the participants consumed LF, HF-AXOS, and HF-FLAX RTECs but also consumed another LF breakfast that was isocaloric (LF-iso) to that of the HF breakfasts. Perceived appetite and blood samples (trial 2 only) were assessed before and after breakfast. An ad libitum lunch was offered 4 h post-breakfast. No differences in postprandial appetite responses were observed among any breakfasts in either trial. The HF-AXOS and HF-FLAX led to increased postprandial GLP-1 and peptide YY (PYY) concentrations vs. LF-iso. No differences were observed in lunch meal energy intake among breakfast meals in either trial. Collectively, these data suggest that 15 g of low molecular weight fiber added to RTECs did not affect perceived appetite or subsequent energy intake despite differences in satiety hormone signaling in overweight females. PMID:25689743

Gastrin-releasing peptide-induced down-regulation of tumor suppressor protein PTEN (phosphatase and tensin homolog deleted on chromosome ten) in neuroblastomas.

PubMed

Qiao, Jingbo; Kang, Junghee; Cree, Jeremy; Evers, B Mark; Chung, Dai H

2005-05-01

To evaluate whether aggressive, undifferentiated neuroblastomas express tumor suppressor protein PTEN (phosphatase and tensin homolog deleted on chromosome ten) and to examine the effects of gastrin-releasing peptide (GRP) on PTEN gene and protein expression. We have previously shown that neuroblastomas secrete GRP, which binds to its cell surface receptor (GRP-R) to stimulate cell growth in an autocrine fashion. However, the effects of GRP on expression of the tumor suppressor gene PTEN have not been elucidated in neuroblastomas. Paraffin-embedded sections from human neuroblastomas were analyzed for PTEN and phospho-Akt protein expression by immunohistochemistry. Human neuroblastoma cell lines (SK-N-SH and SH-SY5Y) were stably transfected with the plasmid pEGFP-GRP-R to establish GRP-R overexpression cell lines, and the effects of GRP on PTEN gene and protein expression were determined. A decrease in the ratio of PTEN to phospho-Akt protein expression was identified in poorly differentiated neuroblastomas. An increase in GRP binding capacity was confirmed in GRP-R overexpressing cells, which demonstrated an accelerated constitutive cell growth rate. PTEN gene and protein expression was significantly decreased in GRP-R overexpressing cells when compared with controls. Our findings demonstrate decreased expression of the tumor suppressor protein PTEN in more aggressive undifferentiated neuroblastomas. An increase in GRP binding capacity, as a result of GRP-R overexpression, down-regulates PTEN expression. These findings suggest that an inhibition of the tumor suppressor gene PTEN may be an important regulatory mechanism involved in GRP-induced cell proliferation in neuroblastomas.

Powerful inhibition of in-vivo growth of experimental hepatic cancers by bombesin/gastrin-releasing peptide antagonist RC-3940-II.

PubMed

Szepeshazi, Karoly; Schally, Andrew V; Rick, Ferenc G; Block, Norman L; Vidaurre, Irving; Halmos, Gabor; Szalontay, Luca

2012-10-01

Hepatic carcinoma is a major health problem worldwide. Its incidence is increasing in Western countries and there is currently no effective systemic therapy against it. Targeted treatment modalities developed in the past few years have provided very limited success. Development of new treatment strategies is therefore essential. We investigated the effects of bombesin/gastrin-releasing peptide (BN/GRP) antagonist RC-3940-II on experimental human liver cancers in nude mice. SK-Hep-1 and Hep-G2 cancers transplanted subcutaneously into nude mice were treated daily with 10 or 20 µg of RC-3940-II. Tumor growth was monitored for 50-184 days in five experiments. Tumor gene expression was analyzed with PCR array and protein expression by immunoblotting. Characteristics of BN/GRP receptors in the tumors were analyzed by binding assays. Effects of RC-3940-II on cell proliferation were investigated in vitro. RC-3940-II inhibited the growth of SK-Hep-1 cancers in nude mice by 65-98%, with total regression in 9 of 36 tumors in three experiments. The BN/GRP antagonist inhibited the growth of Hep-G2 cancers as well by 73-82% in two experiments, being effective even on originally large tumors. Gene expression analysis showed an increase in several angiogenesis inhibitors and decrease in proangiogenic genes after RC-3940-II treatment. Receptor assays demonstrated high-affinity binding sites for BN/GRP in both tumor lines. BN/GRP antagonist RC-3940-II powerfully inhibits growth of SK-Hep-1 and Hep-G2 cancers in nude mice. Its effect may be linked to changes in expression of those cancer genes important in angiogenesis, invasion, and metastasis. RC-3940-II may be considered for further investigations in treatment of liver cancers.

Gastrointestinal hormone secretion in women with polycystic ovary syndrome: an observational study.

PubMed

Lin, Tzuchun; Li, Shengxian; Xu, Hua; Zhou, Huan; Feng, Rilu; Liu, Wei; Sun, Yun; Ma, Jing

2015-11-01

Is the secretion of gastrointestinal hormones impaired in patients with polycystic ovary syndrome (PCOS)? Gastrointestinal hormone levels were abnormal in patients with PCOS. The hormones glucagon-like peptide-1 (GLP-1) and peptide tyrosine-tyrosine (PYY) are both involved in signaling satiety. Secretion of GLP-1 and PYY in response to nutrients in the small intestine plays an important role in energy metabolism. Most PCOS patients are overweight or obese, which suggests dysregulation of appetite. In order to evaluate levels of gastrointestinal hormones in PCOS, a cohort study was undertaken, involving 30 PCOS patients and 29 BMI-matched healthy women recruited from Shanghai Renji Hospital between 1 March 2013 and 30 May 2014. After an overnight fast, all participants underwent an oral glucose tolerance test. Blood was sampled frequently for measurement of blood glucose and plasma insulin, total GLP-1 and PYY concentrations. Fasting and postprandial insulin levels were significantly higher in patients with PCOS compared with the healthy controls (P < 0.05). Fasting and postprandial GLP-1 (t = 0 and 30 min; mean ± SEM) were also higher in PCOS group (17.5 ± 1.07 pM versus 14.1 ± 1.16 pM, P < 0.05; 29.7 ± 2.39 pM versus 22.8 ± 2.09 pM, P < 0.05). However, there were no differences in plasma PYY between patients with PCOS and healthy controls either fasting or postprandially. PYY levels were lower in obese PCOS patients than in lean PCOS patients (P < 0.05). The study involved a small number of subjects with PCOS, and examined hormone responses to oral glucose rather than a physiological meal. Deficient secretion of GLP-1 and PYY does not contribute to excessive food intake in the pathophysiology of PCOS. © The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Ab initio Study of Naptho-Homologated DNA Bases

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sumpter, Bobby G; Vazquez-Mayagoitia, Alvaro; Huertas, Oscar

2008-01-01

Naptho-homologated DNA bases have been recently used to build a new type of size expanded DNA known as yyDNA. We have used theoretical techniques to investigate the structure, tautomeric preferences, base-pairing ability, stacking interactions, and HOMO-LUMO gaps of the naptho-bases. The structure of these bases is found to be similar to that of the benzo-fused predecessors (y-bases) with respect to the planarity of the aromatic rings and amino groups. Tautomeric studies reveal that the canonical-like form of naptho-thymine (yyT) and naptho-adenine (yyA) are the most stable tautomers, leading to hydrogen-bonded dimers with the corresponding natural nucleobases that mimic the Watson-Crickmore » pairing. However, the canonical-like species of naptho-guanine (yyG) and naptho-cytosine (yyC) are not the most stable tautomers, and the most favorable hydrogen-bonded dimers involve wobble-like pairings. The expanded size of the naphto-bases leads to stacking interactions notably larger than those found for the natural bases, and they should presumably play a dominant contribution in modulating the structure of yyDNA duplexes. Finally, the HOMO-LUMO gap of the naptho-bases is smaller than that of their benzo-base counterparts, indicating that size-expansion of DNA bases is an efficient way of reducing their HOMO-LUMO gap. These results are examined in light of the available experimental evidence reported for yyT and yyC.« less

Ab initio study of naphtho-homologated DNA bases.

PubMed

Vazquez-Mayagoita, Alvaro; Huertas, Oscar; Fuentes-Cabrera, Miguel; Sumpter, Bobby G; Orozco, Modesto; Luque, F Javier

2008-02-21

Naphtho-homologated DNA bases have been recently used to build a new type of size-expanded DNA known as yyDNA. We have used theoretical techniques to investigate the structure, tautomeric preferences, base-pairing ability, stacking interactions, and HOMO-LUMO gaps of the naphtho-bases. The structure of these bases is found to be similar to that of the benzo-fused predecessors (y-bases) with respect to the planarity of the aromatic rings and amino groups. Tautomeric studies reveal that the canonical-like forms of naphtho-thymine (yyT) and naphtho-adenine (yyA) are the most stable tautomers, leading to hydrogen-bonded dimers with the corresponding natural nucleobases that mimic the Watson-Crick pairing. However, the canonical-like species of naphtho-guanine (yyG) and naphtho-cytosine (yyC) are not the most stable tautomers, and the most favorable hydrogen-bonded dimers involve wobble-like pairings. The expanded size of the naphtho-bases leads to stacking interactions notably larger than those found for the natural bases, and they should presumably play a dominant contribution in modulating the structure of yyDNA duplexes. Finally, the HOMO-LUMO gap of the naphtho-bases is smaller than that of their benzo-base counterparts, indicating that size-expansion of DNA bases is an efficient way of reducing their HOMO-LUMO gap. These results are examined in light of the available experimental evidence reported for yyT and yyC.

Expression and processing of human preprogastrin in murine medullary thyroid carcinoma cells.

PubMed

Daugherty, D F; Dickinson, C J; Takeuchi, T; Bachwich, D; Yamada, T

1991-05-01

Gastrin, the primary hormonal mediator of postprandial gastric acid secretion, is produced from its precursor progastrin by a series of posttranslational processing reactions including dibasic residue cleavage and carboxyl-terminal alpha-amidation. Progastrin contains three dibasic cleavage signals, Arg57Arg58, Lys74Lys75, and Arg94Arg95, that appear to be cleaved differently in different tissues. Differential processing is a potential means by which the production of biologically active peptides may be regulated in a tissue-specific manner. To study these reactions further, we used the pZipNeo SV(X) retroviral vector to express human gastrin cDNA in a heterologous cell line (MTC 6-23) known to be capable of processing other peptide precursors. The psi 2 packaging cell line transfected with the gastrin cDNA-retroviral construct (pSVXgas) produced progastrin, but no substantial amounts of processed amidated gastrin were detected. amounts of processed amidated gastrin were detected. In contrast, MTC 6-23 cells infected with the viral stock obtained from the supernatant of pSVXgas-transfected psi 2 cells produced carboxyl-terminally amidated gastrin in all of its standard molecular forms, including sulfated and nonsulfated forms of tetratriacontagastrin (G-34), heptadecagastrin (G-17), and tetradecagastrin (G-14). These studies indicate that heterologous endocrine cell lines infected with a retroviral-peptide cDNA construct can serve as useful models for peptide hormone posttranslational processing.

Divergent effects of bombesin and bethanechol on stimulated gastric secretion in duodenal ulcer and in normal men.

PubMed

Helman, C A; Hirschowitz, B I

1987-06-01

To further investigate differences in the responses of normals and patients with duodenal ulcer with respect to gastrin release and acid and pepsin secretion, we infused bombesin (1 microgram/kg X h) or bethanechol (40 micrograms/kg X h) during the middle hour of a 3-h infusion of pentagastrin and compared the results with a pentagastrin infusion without added drug. Pentagastrin dosage (0.1 microgram/kg X h) was set to give about half-maximal response, to detect either inhibition or further stimulation of gastric secretion, whereas the dose of bombesin was chosen to give maximal gastrin but less than maximal acid secretion. Serum gastrin and somatostatin were also measured. In all subjects tested, bethanechol produced no effects on acid, gastrin, or somatostatin release but increased pepsin output. By contrast, bombesin inhibited pentagastrin-stimulated acid output in all 6 normal men by an average of 55%, whereas it inhibited acid output in only 2 of the 9 men with duodenal ulcer. Serum gastrin increases after bombesin in duodenal ulcer were three to four times greater than in normals. Although bombesin stimulates acid only by releasing gastrin, we postulate that bombesin may also simultaneously limit acid and pepsin secretion and speculate that this effect could be mediated by bombesin-induced somatostatin release. The cause for differences between duodenal ulcer and normal remain speculative.

Effects of prolonged hypoxia and bed rest on appetite and appetite-related hormones.

PubMed

Debevec, Tadej; Simpson, Elizabeth J; Mekjavic, Igor B; Eiken, Ola; Macdonald, Ian A

2016-12-01

Environmental hypoxia and inactivity have both been shown to modulate appetite. To elucidate the independent and combined effects of hypoxia and bed rest-induced inactivity on appetite-related hormones and subjective appetite, eleven healthy, non-obese males underwent three experimental interventions in a cross-over and randomized fashion: 1) Hypoxic confinement combined with daily moderate-intensity exercise (HAMB, F i O 2  = 0.141 ± 0.004; P i O 2  = 90.0 ± 0.4 mmHg) 2) Bed rest in normoxia (NBR, F i O 2  = 0.209; P i O 2  = 133.1 ± 0.3 mmHg) and 3) Bed rest in hypoxia (HBR, F i O 2  = 0.141 ± 0.004; P i O 2  = 90.0 ± 0.4 mmHg). A mixed-meal tolerance test (MTT), followed by an ad libitum meal were performed before (Pre) and after 16-days (Post) of each intervention. Composite satiety scores (CSS) during the MTT were calculated from visual analogue scores, while fasting and postprandial concentrations of total ghrelin, peptide YY (PYY), glucagon-like peptide-1 (GLP-1) and leptin were quantified from arterialized-venous samples. Postprandial CSS were significantly lower at Post compared to Pre in NBR only (P < 0.05) with no differences observed in ad libitum meal intakes. Postprandial concentrations and incremental area under the curve (AUC) for total ghrelin and PYY were unchanged following all interventions. Postprandial GLP-1 concentrations were only reduced at Post following HBR (P < 0.05) with resulting AUC changes being significantly lower compared to HAMB (P < 0.01). Fasting leptin was reduced following HAMB (P < 0.05) with no changes observed following NBR and HBR. These findings suggest that independently, 16-day of simulated altitude exposure (∼4000 m) and bed rest-induced inactivity do not significantly alter subjective appetite or ad libitum intakes. The measured appetite-related hormones following both HAMB and HBR point to a situation of hypoxia-induced appetite stimulation, although this did not reflect in

Appetite and gut peptide responses to exercise and calorie restriction. The effect of modest energy deficits.

PubMed

Deighton, Kevin; Batterham, Rachel L; Stensel, David J

2014-10-01

Weight loss is the result of a sustained negative energy balance, which is typically achieved by decreasing food intake and/or increasing physical activity. Current evidence suggests that acute energy deficits of ~4820 kJ elicit contrasting homeostatic responses when induced by exercise and food restriction but the response to government-recommended energy deficits is unknown. Twelve healthy men (mean(SD): age 24(5) years, body mass index 23.8(2.7) kg⋅m(-2), maximum oxygen uptake 55.4(9.1) mL⋅kg(-1)⋅min(-1)) completed three 8 h trials (control (Con), exercise-induced energy deficit (Ex-Def) and food restriction (Food-Def)) separated by 1 week. Thirty minutes of cycling at 64.5(3.2)% of maximum oxygen uptake was performed in Ex-Def from 0 to 0.5 h, which induced an energy deficit of 1469(256) kJ. An equivalent energy deficit was induced in Food-Def (1478(275) kJ) by reducing the energy content of standardised test meals at 1 h and 4 h. Appetite ratings, acylated ghrelin and peptide YY3-36 concentrations were measured throughout each trial. An ad libitum meal was provided at 7 h. Appetite was higher in Food-Def than Ex-Def from 4 to 8 h (P = 0.033) and tended to be higher across the entire 8 h trial (P = 0.059). However, energy intake at the ad libitum meal did not differ between trials (P = 0.634; Con 4376 (1634); Food-Def 4481 (1846); Ex-Def 4217 (1850) kJ). Acylated ghrelin was not related to changes in appetite but plasma PYY3-36 concentrations were higher in Ex-Def than Food-Def (P < 0.05) and negatively correlated with changes in appetite across the entire 8 h trial (P = 0.037). An energy deficit of ~1475 kJ stimulated compensatory increases in appetite when induced via calorie restriction but not when achieved by an acute bout of exercise. Appetite responses were associated with changes in plasma PYY3-36 but not acylated ghrelin concentrations and did not influence subsequent energy intake. Copyright

The 2-monoacylglycerol moiety of dietary fat appears to be responsible for the fat-induced release of GLP-1 in humans.

PubMed

Mandøe, Mette J; Hansen, Katrine B; Hartmann, Bolette; Rehfeld, Jens F; Holst, Jens J; Hansen, Harald S

2015-09-01

Dietary triglycerides can, after digestion, stimulate the intestinal release of incretin hormones through activation of G protein-coupled receptor (GPR) 119 by 2-monoacylglycerol and by the activation of fatty acid receptors for long- and short-chain fatty acids. Medium-chain fatty acids do not stimulate the release of intestinal hormones. To dissect the mechanism of fat-induced glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) release in humans, we compared the effects of tributyrin (containing short-chain fatty acids; i.e., butyric acid), olive oil [containing long-chain fatty acids; e.g., oleic acid plus 2-oleoyl glycerol (2-OG)], and 1,3-dioctanoyl-2-oleoyl glycerol (C8-dietary oil), which is digested to form medium-chain fatty acids : i.e., octanoic acid : and 2-OG. In a randomized, single-blinded crossover study, 12 healthy white men [mean age: 24 y; BMI (in kg/m(2)): 22] were given the following 4 meals on 4 different days: 200 g carrots + 6.53 g tributyrin, 200 g carrots + 13.15 g C8-dietary oil, 200 g carrots + 19 g olive oil, or 200 g carrots. All of the lipids totaled 0.0216 mol. Main outcome measures were incremental areas under the curve for total GLP-1, GIP, and cholecystokinin (CCK) in plasma. C8-dietary oil and olive oil showed the same GLP-1 response [583 ± 101 and 538 ± 71 (pmol/L) × 120 min; P = 0.733], whereas the GIP response was higher for olive oil than for C8-dietary oil [3293 ± 404 and 1674 ± 270 (pmol/L) × 120 min; P = 0.002]. Tributyrin and carrots alone resulted in no increase in any of the measured hormones. Peptide YY (PYY) and neurotensin responses resembled those of GLP-1. Only olive oil stimulated CCK release. Under our study conditions, 2-OG and GPR119 activation can fully explain the olive oil-induced secretion of GLP-1, PYY, and neurotensin. In contrast, both oleic acid and 2-OG contributed to the GIP response. Dietary butyrate did not stimulate gut hormone secretion. Olive oil

Long-term proton pump induced hypergastrinaemia does induce lineage-specific restitution but not clonal expansion in benign Barrett's oesophagus in vivo.

PubMed

Obszynska, Jolanta A; Atherfold, Paul A; Nanji, Manoj; Glancy, Deborah; Santander, Sonia; Graham, Trevor A; Otto, William R; West, Kevin; Harrison, Rebecca F; Jankowski, Janusz A Z

2010-02-01

Barrett's oesophagus is a common premalignant lesion caused partly by acid reflux. Although the requisite therapy, proton pump inhibitors (PPIs), have been implicated in the progression of Barrett's oesophagus in animal models, harmful effects of prolonged PPI therapy in Barrett's oesophagus is both inconclusive and controversial. We therefore aimed to test the role of PPI-induced hypergastrinaemia in vitro and see whether any biological parameters were useful surrogates of long-term therapy in man. We undertook detailed serological and tissue assessment of gastrin and CCK(2) receptors in 90 patients randomised to different doses of PPI therapy during a detailed 2-year follow-up. We also undertook a comprehensive study of cell models to study the consequential biological effects of gastrin on the mucosa. Gastrin and its cognate receptor CCK(2)R were expressed highest in the stomach, then less in Barrett's oesophagus and least in squamous oesophagus (SqE) (n=20 paired t-test, p<0.01). Analysis of the change in Barrett's oesophagus segment length change in 70 patients who were randomised to high or low PPI dose showed no difference over 2 years (n=70 t-test, p=0.8). Prolonged PPI use did, however, increase the serum gastrin, (36 pg/ml+/-57 pg/ml to 103 pg/ml+/-94 pg/ml (paired t test, p<0.05)). In vitro gastrin also induced changes in OE33(E)(cckr) Barrett's oesophagus cells, but not OE21(E)(cckr) squamous cells, transfected with CCK(2)R; migration was induced by 1 ng/ml of gastrin but proliferation only increased with 100 ng/ml (paired t-test, p<0.01) and both were abolished by antagonists. While the short-term effects of gastrin enhance epithelial restitution in Barrett's oesophagus (but not squamous mucosa) there is no clinical evidence that Barrett's oesophagus length expands over time. This study, which is the largest and longest term randomised controlled trial of gastrin biology in Barrett's oesophagus, is further proof of the clinical safety of PPI therapy.

Immunocytochemical demonstration of neuropeptides in the fish-gill parasite, Diclidophora merlangi (Monogenoidea).

PubMed

Maule, A G; Halton, D W; Johnston, C F; Fairweather, I; Shaw, C

1989-05-01

Using the indirect immunofluorescence technique, immunoreactivity (IR) to three mammalian and one invertebrate regulatory peptide has been demonstrated in the nervous system of the monogenean gill parasite Diclidophora merlangi. IR to pancreatic polypeptide (PP), peptide tyrosine tyrosine (PYY) and FMRFamide was evident throughout central and peripheral nervous tissues, whereas vasoactive intestinal polypeptide (VIP)-IR was confined to a portion of the longitudinal ventral nerve cords. Staining patterns revealed the orthogonal arrangement of the nervous system consisting of paired cerebral ganglia, connecting post-pharyngeal commissure, three pairs of longitudinal nerve cords and associated neurones. PP-IR, PYY-IR and FMRFamide-IR were intense throughout the central nervous system of the worm. A small plexus of nerve fibres and somata in each peduncle was immunoreactive for FMRFamide and provided innervation to each of the eight posterior clamps. In the peripheral nervous system, PP-IR, PYY-IR and FMRFamide-IR occurred in an extensive nerve-net with fine, possibly sensory nerve endings in the tegument. PP-IR was also present in nerve fibres in the walls of the ootype, seminal vesicle and uterus. PYY- and FMRFamide-IRs, while evident in nerve fibres of the ootype wall, were also present in a distinct population of cells that encircles the ootype, and which are linked to it by fine cytoplasmic connectives. The majority of these somata were bipolar or multipolar. PYY-IR and FMRFamide-IR were also associated with nerve fibres and bipolar cells in the wall of the vitelline reservoir. Regulatory peptides would appear to play an integral role in neuronal functioning and egg development in D. merlangi.

Pathogenesis of tropical sprue: A pilot study of antroduodenal manometry, duodenocaecal transit time & fat-induced ileal brake

PubMed Central

Ghoshal, Uday C.; Kumar, Sunil; Misra, Asha; Choudhuri, Gourdas

2013-01-01

Background & objectives: Small intestinal bacterial overgrowth (SIBO) due to ileal brake-induced hypomotility may cause tropical sprue (TS). We evaluated effect of infusion of fat or placebo in duodenum randomly in patients with TS and healthy controls on antroduodenal manometry (ADM) and mediators of ileal brake, and duodenocaecal transit time (DCTT). Methods: ADM and DCTT (lactulose hydrogen breath test, HBT) were evaluated with placebo and fat in eight controls and 13 patients with TS (diagnostic criteria: tests showing malabsorption of two unrelated substances, abnormal duodenal histology, absence of other causes, response to antibiotics and folate). Results: Patients with TS (6 had SIBO by glucose HBT) were similar in age and gender with controls. After fat infusion, proximal gut motility index (MI) was reduced compared to fasting state in TS, and DCTT was longer in TS than controls (200 min, 120-380 vs. 130, 70-160, P=0.001), though comparable after placebo (70 min, 30-140 vs. 60, 40-90). TS patients had higher PYY and neurotensin than controls after fat infusion. DCTT after fat infusion correlated with plasma level of PYY in TS but not in controls. Post-fat PYY and neurotensin levels were higher in TS with lower BMI (<16 kg/m2) than those with higher BMI. Parameters of ileal brake (post-fat DCTT, PYY and neurotensin) were higher in patients with than without SIBO. Interpretation & conclusions: Fat infusion reduced proximal gut MI, increased DCTT, PYY, and neurotensin among patients with TS. Malabsorbed fat might cause exaggerated ileal brake reducing gut motility, promoting SIBO and bacterial colonization and malabsorption in TS. PMID:23481053

GPR41/FFAR3 and GPR43/FFAR2 as cosensors for short-chain fatty acids in enteroendocrine cells vs FFAR3 in enteric neurons and FFAR2 in enteric leukocytes.

PubMed

Nøhr, Mark K; Pedersen, Maria H; Gille, Andreas; Egerod, Kristoffer L; Engelstoft, Maja S; Husted, Anna Sofie; Sichlau, Rasmus M; Grunddal, Kaare V; Poulsen, Steen Seier; Han, Sangdon; Jones, Robert M; Offermanns, Stefan; Schwartz, Thue W

2013-10-01

The expression of short-chain fatty acid receptors GPR41/FFAR3 and GPR43/ free fatty acid receptor 2 (FFAR2) was studied in the gastrointestinal tract of transgenic monomeric red fluorescent protein (mRFP) reporter mice. In the stomach free fatty acid receptor 3 (FFAR3)-mRFP was expressed in a subpopulation of ghrelin and gastrin cells. In contrast, strong expression of FFAR3-mRFP was observed in all cholecystokinin, glucose-dependent insulinotropic peptide (GIP), and secretin cells of the proximal small intestine and in all glucagon-like peptide-1 (GLP-1), peptide YY, and neurotensin cells of the distal small intestine. Throughout the colon and rectum, FFAR3-mRFP was strongly expressed in the large population of peptide YY and GLP-1 cells and in the neurotensin cells of the proximal colon. A gradient of expression of FFAR3-mRFP was observed in the somatostatin cells from less than 5% in the stomach to more than 95% in the rectum. Substance P-containing enterochromaffin cells displayed a similar gradient of FFAR3-mRFP expression throughout the small intestine. Surprisingly, FFAR3-mRFP was also expressed in the neuronal cells of the submucosal and myenteric ganglia. Quantitative PCR analysis of fluorescence-activated cell sorting (FACS) purified FFAR3-mRFP positive cells confirmed the coexpression with the various peptide hormones as well as key neuronal marker proteins. The FFAR2-mRFP reporter was strongly expressed in a large population of leukocytes in the lamina propria of in particular the small intestine but surprisingly only weakly in a subpopulation of enteroendocrine cells. Nevertheless, synthetic ligands specific for either FFAR3 or FFAR2 each released GLP-1 from colonic crypt cultures and the FFAR2 agonist mobilized intracellular Ca²⁺ in FFAR2 positive enteroendocrine cells. It is concluded that FFAR3-mRFP serves as a useful marker for the majority of enteroendocrine cells of the small and large intestine and that FFAR3 and FFAR2 both act as sensors

Alterations in receptor expression or agonist concentration change the pathways gastrin-releasing peptide receptor uses to regulate extracellular signal-regulated kinase.

PubMed

Chen, Pei-Wen; Kroog, Glenn S

2004-12-01

G protein-coupled receptors activate extracellular signal-regulated kinases (ERKs) via different pathways in different cell types. In this study, we demonstrate that gastrin-releasing peptide receptor (GRPr) regulates ERK through multiple pathways in a single cell type depending upon receptor expression and agonist concentration. We examined stably transfected BALB/c 3T3 fibroblasts expressing GRPr constructs at different levels and treated the cells with several concentrations of bombesin (BN, a GRPr agonist) to activate a variable number of GRPr per cell. GRPr induced two waves of ERK activation and one wave of ERK inhibition. One wave of activation required an intact GRPr carboxyl-terminal domain (CTD). It peaked 6 min after addition of high BN concentration ([BN]) in cells with high GRPr expression. Another wave of activation was CTD-independent. It peaked 2 to 4 min after BN addition in cells when [BN] and/or GRPr expression were lower. The early wave of ERK activation was more sensitive than the later one to pretreatment with Bisindolylmaleimide I (GF 109203X) (a protein kinase C inhibitor) or hypertonic sucrose. Because these two waves of activation differ in time course, dose-response curve, requirement for GRPr CTD, and sensitivity to inhibitors, they result from different signaling pathways. A third pathway in these cells inhibited ERK phosphorylation 2 min after addition of high [BN] in cells with high GRPr expression. Furthermore, a GRPr-expressing human duodenal cancer cell line showed differential sensitivity to GF 109203X throughout BN-induced ERK activation, indicating that GRPr may activate ERK via multiple pathways in cells expressing endogenous GRPr.

Preparation and evaluation of 99mTc-EDDA/HYNIC-[Lys 3]-bombesin for imaging gastrin-releasing peptide receptor-positive tumours.

PubMed

Ferro-Flores, Guillermina; Arteaga de Murphy, Consuelo; Rodriguez-Cortés, Jeanette; Pedraza-López, Martha; Ramírez-Iglesias, María Teresa

2006-04-01

Bombesin is a peptide that was initially isolated from frog skin and which belongs to a large group of neuropeptides with many biological functions. The human equivalent is gastrin-releasing peptide (GRP), whose receptors are over-expressed in a variety of malignant tumours. To prepare a HYNIC-[Lys 3]-bombesin analogue that could be easily labelled with 99mTc from lyophilized kit formulations and to evaluate its potential as an imaging agent for GRP receptor-positive tumours. HYNIC was conjugated to the epsilon-amino group of Lys 3 residue at the N-terminal region of bombesin via succinimidyl-N-Boc-HYNIC at pH 9.0. 99mTc labelling was performed by addition of sodium pertechnetate solution and 0.2 M phosphate buffer pH 7.0 to a lyophilized formulation. Stability studies were carried out by reversed phase HPLC and ITLC-SG analyses in serum and cysteine solutions. In-vitro internalization was tested using human prostate cancer PC-3 cells with blocked and non-blocked receptors. Biodistribution and tumour uptake were determined in PC-3 tumour-bearing nude mice. 99mTc-EDDA/HYNIC-[Lys 3]-bombesin was obtained with radiochemical purities >93% and high specific activity ( approximately 0.1 GBq.nmol). Results of in-vitro studies demonstrated a high stability in serum and cysteine solutions, specific cell receptor binding and rapid internalization. Biodistribution data showed a rapid blood clearance, with predominantly renal excretion and specific binding towards GRP receptor-positive tissues such as pancreas and PC-3 tumours. 99mTc-EDDA/HYNIC-[Lys 3]-bombesin obtained from lyophilized kit formulations has promising characteristics for the diagnosis of malignant tumours that over-express the GRP receptor.

Effect of single dose of omeprazole on the gastrointestinal peptide response to food.

PubMed

Allen, J M; Adrian, T E; Webster, J; Howe, A; Bloom, S R

1984-02-01

The gastrointestinal peptide response to food was assessed in 6 healthy subjects following oral administration of 40 mg omeprazole. There was a small but statistically significant increase in basal plasma gastrin six hours after the dose of omeprazole, but the post-prandial plasma gastrin was not significantly increased. There was no significant effect on basal or post-prandial levels of somatostatin, insulin, pancreatic glucagon, enteroglucagon, gastric inhibitory polypeptide, pancreatic polypeptide, motilin, neurotensin, cholecystokinin, secretin, vasoactive intestinal peptide and gastrin-releasing peptide or blood glucose concentration.

Nuclear Receptor SHP Activates miR-206 Expression via a Cascade Dual Inhibitory Mechanism

PubMed Central

Song, Guisheng; Wang, Li

2009-01-01

MicroRNAs play a critical role in many essential cellular functions in the mammalian species. However, limited information is available regarding the regulation of miRNAs gene transcription. Microarray profiling and real-time PCR analysis revealed a marked down-regulation of miR-206 in nuclear receptor SHP−/− mice. To understand the regulatory function of SHP with regard to miR-206 gene expression, we determined the putative transcriptional initiation site of miR-206 and also its full length primary transcript using a database mining approach and RACE. We identified the transcription factor AP1 binding sites on the miR-206 promoter and further showed that AP1 (c-Jun and c-Fos) induced miR-206 promoter transactivity and expression which was repressed by YY1. ChIP analysis confirmed the physical association of AP1 (c-Jun) and YY1 with the endogenous miR-206 promoter. In addition, we also identified nuclear receptor ERRγ (NR3B3) binding site on the YY1 promoter and showed that YY1 promoter was transactivated by ERRγ, which was inhibited by SHP (NROB2). ChIP analysis confirmed the ERRγ binding to the YY1 promoter. Forced expression of SHP and AP1 induced miR-206 expression while overexpression of ERRγ and YY1 reduced its expression. The effects of AP1, ERRγ, and YY1 on miR-206 expression were reversed by siRNA knockdown of each gene, respectively. Thus, we propose a novel cascade “dual inhibitory” mechanism governing miR-206 gene transcription by SHP: SHP inhibition of ERRγ led to decreased YY1 expression and the de-repression of YY1 on AP1 activity, ultimately leading to the activation of miR-206. This is the first report to elucidate a cascade regulatory mechanism governing miRNAs gene transcription. PMID:19721712

Gastrin-releasing peptide receptor-induced internalization, down-regulation, desensitization, and growth: possible role for cyclic AMP.

PubMed

Benya, R V; Fathi, Z; Kusui, T; Pradhan, T; Battey, J F; Jensen, R T

1994-08-01

Stimulation of the gastrin-releasing peptide receptor (GRP-R) in Swiss 3T3 cells resembles that of a number of other recently described G protein-coupled receptors, insofar as both the phospholipase C and adenylyl cyclase signal transduction pathways are activated. GRP-R activation induces numerous alterations in both the cell and the receptor, but because two signal transduction pathways are activated it is difficult to determine the specific contributions of either pathway. We have found that BALB/3T3 fibroblasts transfected with the coding sequence for the GRP-R are pharmacologically indistinguishable from native receptor-expressing cells and activate phospholipase C in a manner similar to that of the native receptor but fail to increase cAMP in response to bombesin; thus, they may be useful cells to explore the role of activation of each pathway in altering cell and receptor function. Swiss 3T3 cells and GRP-R-transfected BALB/3T3 cells expressed identically glycosylated receptors that bound various agonists and antagonists similarly. G protein activation, as determined by evaluation of agonist-induced activation of phospholipase C and by analysis of the effect of guanosine-5'-(beta,gamma-imido)triphosphate on GRP-R binding affinity, was indistinguishable. Agonist stimulation of GRP-R caused similar receptor changes (internalization and down-regulation) and homologous desensitization in both cell types. Bombesin stimulation of Swiss 3T3 cells that had been preincubated with forskolin increased cAMP levels 9-fold, but no bombesin-specific increase in cAMP levels was detected in transfected cells, even though forskolin and cholera toxin increased cAMP levels in these cells. Quiescent Swiss 3T3 cells treated with bombesin rapidly increased c-fos mRNA levels and [3H]thymidine incorporation, whereas both effects were potentiated by forskolin. The specific protein kinase A inhibitor H-89 blocked increases in c-fos levels and [3H]thymidine incorporation induced by low

Mild cold induced thermogenesis: are BAT and skeletal muscle synergistic partners?

PubMed

Bal, Naresh C; Maurya, Santosh K; Pani, Sunil; Sethy, Chinmayee; Banerjee, Ananya; Das, Sarita; Patnaik, Srinivas; Kundu, Chanakya N

2017-10-31

There are two well-described thermogenic sites; brown adipose tissue (BAT) and skeletal muscle, which utilize distinct mechanisms of heat production. In BAT, mitochondrial metabolism is the molecular basis of heat generation, while it serves only a secondary role in supplying energy for thermogenesis in muscle. Here, we wanted to document changes in mitochondrial ultrastructure in these two tissue types based upon adaptation to mild (16°C) and severe (4°C) cold in mice. When reared at thermoneutrality (29°C), mitochondria in both tissues were loosely packed with irregular cristae. Interestingly, adaptation to even mild cold initiated ultrastructural remodeling of mitochondria including acquisition of more elaborate cristae structure in both thermogenic sites. The shape of mitochondria in the BAT remained mostly circular, whereas the intermyofibrilar mitochondria in the skeletal muscle became more elongated and tubular. The most dramatic remodeling of mitochondrial architecture was observed upon adaptation to severe cold. In addition, we report cold-induced alteration in levels of humoral factors: fibroblast growth factor 21 (FGF21), IL1α, peptide YY (PYY), tumor necrosis factor α (TNFα), and interleukin 6 (IL6) were all induced whereas both insulin and leptin were down-regulated. In summary, adaptation to cold leads to enhanced cristae formation in mitochondria in skeletal muscle as well as the BAT. Further, the present study indicates that circulating cytokines might play an important role in the synergistic recruitment of the thermogenic program including cross-talk between muscle and BAT. © 2017 The Author(s).

Carboxypeptidase E modulates intestinal immune homeostasis and protects against experimental colitis in mice.

PubMed

Bär, Florian; Föh, Bandik; Pagel, René; Schröder, Torsten; Schlichting, Heidi; Hirose, Misa; Lemcke, Susanne; Klinger, Antje; König, Peter; Karsten, Christian M; Büning, Jürgen; Lehnert, Hendrik; Fellermann, Klaus; Ibrahim, Saleh M; Sina, Christian

2014-01-01

Enteroendocrine cells (EEC) produce neuropeptides, which are crucially involved in the maintenance of the intestinal barrier. Hence, EEC dysfunction is suggested to be involved in the complex pathophysiology of inflammatory bowel disease (IBD), which is characterized by decreased intestinal barrier function. However, the underlying mechanisms for EEC dysfunction are not clear and suitable models for a better understanding are lacking. Here, we demonstrate that Carboxypeptidase E (CPE) is specifically expressed in EEC of the murine colon and ileum and that its deficiency is associated with reduced intestinal levels of Neuropeptide Y (NPY) and Peptide YY (PYY), which are both produced by EEC. Moreover, cpe-/- mice exhibit an aggravated course of DSS-induced chronic colitis compared to wildtype littermates. In addition, we observed elevated mucosal IL-6 and KC transcript levels already at baseline conditions in cpe-/- mice. Moreover, supernatants obtained from isolated intestinal crypts of cpe-/- mice lead to increased IL-6 and KC expression in MODE-K cells in the presence of LPS. This effect was reversible by co-administration of recombinant NPY, suggesting a CPE mediated immunosuppressive effect in the intestines by influencing the processing of specific neuropeptides. In this context, the chemotaxis of bone marrow derived macrophages towards respective supernatants was enhanced. In conclusion, our data point to an anti-inflammatory role of CPE in the intestine by influencing local cytokine levels and thus regulating the migration of myeloid immune cells into the mucosa. These findings highlight the importance of EEC for intestinal homeostasis and propose EEC as potential therapeutic targets in IBD.

Carboxypeptidase E Modulates Intestinal Immune Homeostasis and Protects against Experimental Colitis in Mice

PubMed Central

Pagel, René; Schröder, Torsten; Schlichting, Heidi; Hirose, Misa; Lemcke, Susanne; Klinger, Antje; König, Peter; Karsten, Christian M.; Büning, Jürgen; Lehnert, Hendrik; Fellermann, Klaus; Ibrahim, Saleh M.; Sina, Christian

2014-01-01

Enteroendocrine cells (EEC) produce neuropeptides, which are crucially involved in the maintenance of the intestinal barrier. Hence, EEC dysfunction is suggested to be involved in the complex pathophysiology of inflammatory bowel disease (IBD), which is characterized by decreased intestinal barrier function. However, the underlying mechanisms for EEC dysfunction are not clear and suitable models for a better understanding are lacking. Here, we demonstrate that Carboxypeptidase E (CPE) is specifically expressed in EEC of the murine colon and ileum and that its deficiency is associated with reduced intestinal levels of Neuropeptide Y (NPY) and Peptide YY (PYY), which are both produced by EEC. Moreover, cpe−/− mice exhibit an aggravated course of DSS-induced chronic colitis compared to wildtype littermates. In addition, we observed elevated mucosal IL-6 and KC transcript levels already at baseline conditions in cpe−/− mice. Moreover, supernatants obtained from isolated intestinal crypts of cpe−/− mice lead to increased IL-6 and KC expression in MODE-K cells in the presence of LPS. This effect was reversible by co-administration of recombinant NPY, suggesting a CPE mediated immunosuppressive effect in the intestines by influencing the processing of specific neuropeptides. In this context, the chemotaxis of bone marrow derived macrophages towards respective supernatants was enhanced. In conclusion, our data point to an anti-inflammatory role of CPE in the intestine by influencing local cytokine levels and thus regulating the migration of myeloid immune cells into the mucosa. These findings highlight the importance of EEC for intestinal homeostasis and propose EEC as potential therapeutic targets in IBD. PMID:25051500

Increased postprandial energy expenditure may explain superior long term weight loss after Roux-en-Y gastric bypass compared to vertical banded gastroplasty.

PubMed

Werling, Malin; Olbers, Torsten; Fändriks, Lars; Bueter, Marco; Lönroth, Hans; Stenlöf, Kaj; le Roux, Carel W

2013-01-01

Gastric bypass results in greater weight loss than Vertical banded gastroplasty (VBG), but the underlying mechanisms remain unclear. In addition to effects on energy intake the two bariatric techniques may differentially influence energy expenditure (EE). Gastric bypass in rats increases postprandial EE enough to result in elevated EE over 24 hours. This study aimed to investigate alterations in postprandial EE after gastric bypass and VBG in humans. Fourteen women from a randomized clinical trial between gastric bypass (n = 7) and VBG (n = 7) were included. Nine years postoperatively and at weight stability patients were assessed for body composition and calorie intake. EE was measured using indirect calorimetry in a respiratory chamber over 24 hours and focused on the periods surrounding meals and sleep. Blood samples were analysed for postprandial gut hormone responses. Groups did not differ regarding body composition or food intake either preoperatively or at study visit. Gastric bypass patients had higher EE postprandially (p = 0.018) and over 24 hours (p = 0.048) compared to VBG patients. Postprandial peptide YY (PYY) and glucagon like peptide 1 (GLP-1) levels were higher after gastric bypass (both p<0.001). Gastric bypass patients have greater meal induced EE and total 24 hours EE compared to VBG patients when assessed 9 years postoperatively. Postprandial satiety gut hormone responses were exaggerated after gastric bypass compared to VBG. Long-term weight loss maintenance may require significant changes in several physiological mechanisms which will be important to understand if non-surgical approaches are to mimic the effects of bariatric surgery.

Relationship between expression of gastrin, somatostatin, Fas/FasL and caspases in large intestinal carcinoma.

PubMed

Mao, Jia-Ding; Wu, Pei; Yang, Ying-Lin; Wu, Jian; Huang, He

2008-05-14

To explore the correlation between the mRNAs and protein expression of gastrin (GAS), somatostatin (SS) and apoptosis index (AI), apoptosis regulation gene Fas/FasL and caspases in large intestinal carcinoma (LIC). Expression of GAS and SS mRNAs were detected by nested RT-PCR in 79 cases of LIC. Cell apoptosis was detected by molecular biology in situ apoptosis detecting methods (TUNEL). Immunohistochemical staining for GAS, SS, Fas/FasL, caspase-3 and caspase-8 was performed according to the standard streptavidin-biotin-peroxidase (S-P) method. There was a significant positive correlation between mRNA and protein expression of GAS and SS (GASrs = 0.99, P < 0.01; SSrs = 0.98, P < 0.01). There was significant difference in positive expression rates of GAS, SS mRNAs and protein among different histological differentiation, histological types and Dukes' stage of LIC. The AI in GAS high and moderate expression groups was significantly lower than that in low expression groups (3.75 +/- 2.38 vs 7.82 +/- 2.38, P < 0.01; 5.51 +/- 2.66 vs 7.82 +/- 2.38, P < 0.01), and the AI in SS high and moderate expression groups was significantly higher than that in low expression groups (9.03 +/- 1.76 vs 5.35 +/- 3.00, P < 0.01; 7.44 +/- 2.67 vs 5.35 +/- 3.00, P < 0.01). There was a significant negative correlation between the integral ratio of GAS to SS and the AI (r(s) = -0.41, P < 0.01). The positive expression rate of FasL in GAS high and moderate expression groups was higher than that in low expression group (90.9% and 81.0% vs 53.2%, P < 0.05). The positive expression rates of Fas, caspase-8 and caspase-3 in SS high (90.0%, 90.0% and 100%) and moderate (80.0%, 70.0%, 75.0%) expression groups were higher than that in low expression group (53.1%, 42.9%, 49.0%) (90.0% and 80.0% vs 53.1%, P < 0.05; 90.0% and 70.0% vs 42.9%, P < 0.05; 100.0% and 75.0% vs 49.0%, P < 0.05). There was a significant positive correlation between the integral ratio of GAS to SS and the semiquantitative

Characterization of ligand binding and processing by gastrin-releasing peptide receptors in a small-cell lung cancer cell line.

PubMed Central

Cardona, C; Bleehen, N M; Reeve, J G

1992-01-01

The ligand-binding properties of the gastrin-releasing peptide (GRP) receptor and the cellular processing of GRP have been studied in the small-cell lung cancer (SCLC) cell line COR-L42. Scatchard analysis of GRP receptor expression indicated a single class of high-affinity receptors (Kd 1.5 nM) and approx. 6700 receptors/cell. GRP bound to its receptor with a Ki of 2.4 nM. The bombesin-related peptides neuromedin B (NMB) and phyllolitorin also bound to GRP receptors with Ki values of 22.7 and 59.1 nM respectively. Binding of 125I-GRP to COR-L42 cells increased rapidly at 37 degrees, achieved a maximum at 10 min and declined rapidly thereafter. At 4 degrees C, maximum binding was achieved at 30 min and the subsequent decline in cell-associated radioactivity was slower than that seen at 37 degrees C. Acid/salt extraction, to separate surface-bound ligand from internalized GRP, indicated that after receptor binding 125I-GRP was rapidly internalized. To determine the pathway of 125I-GRP degradation, binding studies were carried out with the lysosomotropic agent chloroquine (5 mM), and with phosphoramidon (10 microM), an inhibitor of the membrane-bound enzyme (EC 3.4.24.11). Both agents markedly inhibited the degradation of GRP, indicating that this process involves a lysosomal pathway and a phosphoramidon-sensitive pathway, possibly involving the EC 3.4.24.11 enzyme. GRP receptor down-regulation was observed following a 10 min exposure to 100 nM-GRP. With longer pretreatment times the number of binding sites recovered to 80% of control values. Treatment with 5 mM-chloroquine plus GRP or cycloheximide (10 micrograms/ml) plus GRP demonstrated that the majority of GRP receptors are recycled. NMB and phyllolitorin pretreatment did not influence the subsequent binding of 125I-GRP, suggesting that these peptides do not down-regulate GRP receptors. PMID:1310003

Sweet taste of saccharin induces weight gain without increasing caloric intake, not related to insulin-resistance in Wistar rats.

PubMed

Foletto, Kelly Carraro; Melo Batista, Bruna Aparecida; Neves, Alice Magagnin; de Matos Feijó, Fernanda; Ballard, Cíntia Reis; Marques Ribeiro, Maria Flávia; Bertoluci, Marcello Casaccia

2016-01-01

In a previous study, we showed that saccharin can induce weight gain when compared with sucrose in Wistar rats despite similar total caloric intake. We now question whether it could be due to the sweet taste of saccharin per se. We also aimed to address if this weight gain is associated with insulin-resistance and to increases in gut peptides such as leptin and PYY in the fasting state. In a 14 week experiment, 16 male Wistar rats received either saccharin-sweetened yogurt or non-sweetened yogurt daily in addition to chow and water ad lib. We measured daily food intake and weight gain weekly. At the end of the experiment, we evaluated fasting leptin, glucose, insulin, PYY and determined insulin resistance through HOMA-IR. Cumulative weight gain and food intake were evaluated through linear mixed models. Results showed that saccharin induced greater weight gain when compared with non-sweetened control (p = 0.027) despite a similar total caloric intake. There were no differences in HOMA-IR, fasting leptin or PYY levels between groups. We conclude that saccharin sweet taste can induce mild weight gain in Wistar rats without increasing total caloric intake. This weight gain was not related with insulin-resistance nor changes in fasting leptin or PYY in Wistar rats. Copyright © 2015 Elsevier Ltd. All rights reserved.

Anti-ulcerogenic mechanisms of the sesquiterpene lactone onopordopicrin-enriched fraction from Arctium lappa L. (Asteraceae): role of somatostatin, gastrin, and endogenous sulfhydryls and nitric oxide.

PubMed

de Almeida, Ana Beatriz Albino; Luiz-Ferreira, Anderson; Cola, Maíra; Di Pietro Magri, Luciana; Batista, Leonia Maria; de Paiva, Joseilson Alves; Trigo, José Roberto; Souza-Brito, Alba R M

2012-04-01

Arctium lappa L. has been used in folk medicine as a diuretic, depurative, and digestive stimulant and in dermatological conditions. The mechanisms involved in the anti-ulcerogenic activity of the sesquiterpene onopordopicrin (ONP)-enriched fraction (termed the ONP fraction), obtained from A. lappa leaves, were studied. The gastroprotective mechanism of the ONP fraction was evaluated in experimental in vivo models in rodents, mimicking this disease in humans. ONP fraction (50 mg/kg, p.o.) significantly inhibited the mucosal injury induced by ethanol/HCl solution (75%), indomethacin/bethanecol (68.9%), and stress (58.3%). When the ONP fraction was investigated in pylorus ligature, it did not induce alteration in the gastric volume but did modify the pH and total acid concentration of gastric juice. ONP fraction significantly increased serum somatostatin levels (82.1±4.1 vs. control group 12.7±4 pmol/L) and decreased serum gastrin levels (62.6±6.04 vs. control group 361.5±8.2 μU/mL). Mucus production was not significantly altered by the ONP fraction. Gastroprotection by the ONP fraction was completely inhibited by N-ethylmaleimide treatment and did not modify the effect in the animals pretreated with l-N(G)-nitroarginine methyl ester. These results suggest an antisecretory mechanism involved with the antiulcerogenic effect of the ONP fraction. However, only endogenous sulfhydryls play an important role in gastroprotection of the ONP fraction.

Decreased Genetic Dosage of Hepatic Yin Yang 1 Causes Diabetic-Like Symptoms

PubMed Central

Verdeguer, Francisco; Blättler, Sharon M.; Cunningham, John T.; Hall, Jessica A.; Chim, Helen

2014-01-01

Insulin sensitivity in liver is characterized by the ability of insulin to efficiently inhibit glucose production and fatty acid oxidation as well as promote de novo lipid biosynthesis. Specific dysregulation of glucose and lipid metabolism in liver is sufficient to cause insulin resistance and type 2 diabetes; this is seen by a selective inability of insulin to suppress glucose production while remaining insulin-sensitive to de novo lipid biosynthesis. We have previously shown that the transcription factor Yin Yang 1 (YY1) controls diabetic-linked glucose and lipid metabolism gene sets in skeletal muscle, but whether liver YY1-targeted metabolic genes impact a diabetic phenotype is unknown. Here we show that decreased genetic dosage of YY1 in liver causes insulin resistance, hepatic lipid accumulation, and dyslipidemia. Indeed, YY1 liver-specific heterozygous mice exhibit blunted activation of hepatic insulin signaling in response to insulin. Mechanistically, YY1, through direct recruitment to promoters, functions as a suppressor of genes encoding for metabolic enzymes of the gluconeogenic and lipogenic pathways and as an activator of genes linked to fatty acid oxidation. These counterregulatory transcriptional activities make targeting hepatic YY1 an attractive approach for treating insulin-resistant diabetes. PMID:24467246

Computing Critical Properties with Yang-Yang Anomalies

NASA Astrophysics Data System (ADS)

Orkoulas, Gerassimos; Cerdeirina, Claudio; Fisher, Michael

2017-01-01

Computation of the thermodynamics of fluids in the critical region is a challenging task owing to divergence of the correlation length and lack of particle-hole symmetries found in Ising or lattice-gas models. In addition, analysis of experiments and simulations reveals a Yang-Yang (YY) anomaly which entails sharing of the specific heat singularity between the pressure and the chemical potential. The size of the YY anomaly is measured by the YY ratio Rμ =C μ /CV of the amplitudes of C μ = - T d2 μ /dT2 and of the total specific heat CV. A ``complete scaling'' theory, in which the pressure mixes into the scaling fields, accounts for the YY anomaly. In Phys. Rev. Lett. 116, 040601 (2016), compressible cell gas (CCG) models which exhibit YY and singular diameter anomalies, have been advanced for near-critical fluids. In such models, the individual cell volumes are allowed to fluctuate. The thermodynamics of CCGs can be computed through mapping onto the Ising model via the seldom-used great grand canonical ensemble. The computations indicate that local free volume fluctuations are the origins of the YY effects. Furthermore, local energy-volume coupling (to model water) is another crucial factor underlying the phenomena.

Mixed endocrine gastric tumors associated with hypergastrinemia of antral origin.

PubMed Central

Larsson, L. I.; Rehfeld, J. F.; Stockbrügger, R.; Blohme, G.; Schöön, I. M.; Lundqvist, G.; Kindblom, L. G.; Säve-Söderberg, J.; Grimelius, L.; Olbe, L.

1978-01-01

A patient with atrophic gastritis and excessively raised serum gastrin concentrations (4000 to 5000 pg/ml) was found to have multiple polypous tumors of the gastric corpus mucosa. Following gastrectomy, serum gastrin concentrations decreased to undetectable levels. The tumors consisted of a mixed population of endocrine cells. The majority of tumor cells were of the ECL type, but, in addition, enterochromaffin cells of various subtypes as well as agranular cells were found. The tumors were locally invasive and invaded the walls of submucosal blood vessels. The surrounding mucosa showed a severe atrophic gastritis with intestinalization and contained numerous goblet cells, enterochromaffin cells, and cholecystokinin cells. Cholecystokinin cells do not occur in the normal oxyntic mucosa. Hence, the observation of this cell type in intestinalized gastric epithelium suggests that "intestinalization also is associated with changes in endocrine cell populations. Gastrin has been shown to affect the function of the ECL cells. Indications for a trophic action of gastrin on these cells have been obtained. It is discussed whether greatly raised serum gastrin levels in patients with atrophic gastritis may be associated with increased risks for the development of certain types of gastric tumors. Images Figure 4 Figure 5 Figure 6 Figure 7 Figure 1 Figure 2 Figure 3 PMID:696807

Further characterisation of the 'ileal brake' reflex in man--effect of ileal infusion of partial digests of fat, protein, and starch on jejunal motility and release of neurotensin, enteroglucagon, and peptide YY.

PubMed Central

Spiller, R C; Trotman, I F; Adrian, T E; Bloom, S R; Misiewicz, J J; Silk, D B

1988-01-01

Previous studies have shown that ileal infusion of partially digested triglyceride inhibits jejunal motility. The partial digest used in those studies contained a mixture of glycerol, free fatty acid, mono-, di-, and triglycerides. In Part I of the present study we have separately infused emulsions containing either glycerol 3.1 g (n = 6), oleic acid 9.6 g (n = 6), triolein 10 g (n = 12), or medium chain triglycerides 10 g (n = 6) into the ileum and have recorded the effect this has on jejunal motility. Five further subjects received infusions of partial hydrolysates of corn starch 10 g and lactalbumin 7 g. Marked inhibition of jejunal pressure wave activity was seen after all three lipid infusions, per cent activity falling from a control of 37.7 (7.7) to 6.2 (2.1) and 22.4 (8.2)% 30 min after completing the oleic acid and triolein infusions respectively, and from a control value of 39.5 (4.1) to 17.7 (4.7) after MCTs (all p less than 0.05). No significant fall occurred after infusion of glycerol, protein or carbohydrate. All three lipid infusions raised plasma concentrations of neurotensin, enteroglucagon and peptide YY equally effectively, although only the rise in peptide YY correlated significantly with the inhibition of jejunal pressure wave activity (r = 0.80, n = 6, p less than 0.05). In Part II of this study six subjects received a 3 ml/min jejunal infusion of an isotonic carbohydrate saline solution followed after three hours by a similar infusion of a partial digest of lipid. During each infusion flow and transit time was measured by marker and dye dilution. Jejunal infusion of the carbohydrate-saline solution was associated with low jejunal flow, 4.7 (1.0) ml/min and a mean transit time through the 50 cm study segment of 36.5 (7.1) min. By contrast jejunal infusion of partially digested triglyceride was associated with a markedly increased flow, 9.0 (1.2) ml/min, a fall in mean transit time to 20.3 (2.6) min and significant rises in pancreaticobiliary

A highly acid-resistant novel strain of Lactobacillus johnsonii No. 1088 has antibacterial activity, including that against Helicobacter pylori, and inhibits gastrin-mediated acid production in mice

PubMed Central

Aiba, Yuji; Nakano, Yasuhiro; Koga, Yasuhiro; Takahashi, Kenji; Komatsu, Yasuhiko

2015-01-01

A novel strain of Lactobacillus johnsonii No. 1088 was isolated from the gastric juice of a healthy Japanese male volunteer, and characterized for its effectiveness in the stomach environment. Lactobacillus johnsonii No. 1088 was found to have the strongest acid resistance among several lactobacilli examined (>10% of cells survived at pH 1.0 after 2 h), and such a high acid resistance property was a specific characteristic of this strain of L. johnsonii. When cultured with various virulent bacteria, L. johnsonii No. 1088 inhibited the growth of Helicobacter pylori,Escherichia coli O-157, Salmonella Typhimurium, and Clostridium difficile, in which case its effectiveness was more potent than that of a type strain of L. johnsonii,JCM2012. In addition to its effect in vitro, L. johnsonii No. 1088 inhibited the growth of H. pylori in human intestinal microbiota-associated mice in both its live and lyophilized forms. Moreover, L. johnsonii No. 1088 suppressed gastric acid secretion in mice via decreasing the number of gastrin-positive cells in the stomach. These results taken together suggest that L. johnsonii No. 1088 is a unique lactobacillus having properties beneficial for supporting H. pylori eradication by triple therapy including the use of a proton pump inhibitor (PPI) and also for prophylaxis of gastroesophageal reflux disease possibly caused after H. pylori eradication as a side effect of PPI. PMID:25771812

Radiometal-Dependent Biological Profile of the Radiolabeled Gastrin-Releasing Peptide Receptor Antagonist SB3 in Cancer Theranostics: Metabolic and Biodistribution Patterns Defined by Neprilysin.

PubMed

Lymperis, Emmanouil; Kaloudi, Aikaterini; Sallegger, Werner; Bakker, Ingrid L; Krenning, Eric P; de Jong, Marion; Maina, Theodosia; Nock, Berthold A

2018-05-16

Recent advances in oncology involve the use of diagnostic/therapeutic radionuclide-carrier pairs that target cancer cells, offering exciting opportunities for personalized patient treatment. Theranostic gastrin-releasing peptide receptor (GRPR)-directed radiopeptides have been proposed for the management of GRPR-expressing prostate and breast cancers. We have recently introduced the PET tracer 68 Ga-SB3 (SB3, DOTA- p-aminomethylaniline-diglycolic acid-DPhe-Gln-Trp-Ala-Val-Gly-His-Leu-NHEt), a receptor-radioantagonist that enables the visualization of GRPR-positive lesions in humans. Aiming to fully assess the theranostic potential of SB3, we herein report on the impact of switching 68 Ga to 111 In/ 177 Lu-label on the biological properties of resulting radiopeptides. Notably, the bioavailability of 111 In/ 177 Lu-SB3 in mice drastically deteriorated compared with metabolically robust 68 Ga-SB3, and as a result led to poorer 111 In/ 177 Lu-SB3 uptake in GRPR-positive PC-3 xenografts. The peptide cleavage sites were identified by chromatographic comparison of blood samples from mice intravenously receiving 111 In/ 177 Lu-SB3 with each of newly synthesized 111 In/ 177 Lu-SB3-fragments. Coinjection of the radioconjugates with the neprilysin (NEP)-inhibitor phosphoramidon led to full stabilization of 111 In/ 177 Lu-SB3 in peripheral mouse blood and resulted in markedly enhanced radiolabel uptake in the PC-3 tumors. In conclusion, in situ NEP-inhibition led to indistinguishable 68 Ga/ 111 In/ 177 Lu-SB3 profiles in mice emphasizing the theranostic prospects of SB3 for clinical use.

Cloning of an ets-Related Transcription Factor Involved in a Novel Epigenetic Mechanism of Mammary Carcinogenesis

DTIC Science & Technology

2001-05-01

dystrophin gene promoter is regulated by YY1 and DPBF (33). Other studies showed that serum response factor (SRF) is required for muscle-specific...transcriptional activation through CArG boxes (68) and that SRF competes with YY1 for binding to wild-type CArG elements (51). CBF-A has significant...between SRF and YY1 proteins at CArG elements has been described in chicken skeletal muscle cells(36). Our previous study in a rat mammary carcinoma cell

Chromogranin A as a useful neuroendocrine marker in patients with autoimmune Addison's disease.

PubMed

El Ali, Z; Fichna, M; Piniewska, J; Kosowicz, J; Grzymisławski, M

2010-03-01

Antiparietal cells antibodies (APC-Ab) are commonly found in patients with autoimmune Addison's disease (AAD), usually pointing to autoimmune atrophic gastritis and pernicious anemia. The autoaggression to the gastric proton pumpmay result in a long-term hypergastrinemia, which predisposes to enterochromaffin-like cell hyper/dysplasia and gastric carcinoids. We evaluated the clinical utility of assessing serum chromogranin A levels in patients with AAD. Serum chromogranin A, gastrin, and gastric APC-Ab levels were determined in 40 patients with AAD using commercially available kits. Serum chromogranin A and gastrin levels were found to be elevated in 27.5 and 22.5% of patients with AAD, respectively. The Addison's patients with elevated APC-Ab had significantly higher chromogranin A and gastrin levels, as compared to individuals with normal APC-Ab (chromogranin A: 128.00+/-123.08 vs 57.68+/-36.50 ng/ml, p=0.0036; gastrin: 141.38+/-191.43 vs 49.50+/-75.36 muU/ml, p=0.003). Additionally, the patients with AAD and coexisting elevated serum APC-Ab, contrary to those with normal levels, showed a significant correlation between the chromogranin A and gastrin concentrations (r=0.52, p=0.0092 vs r=0.211, p=0.43). Serum chromogranin A appeared also significantly correlated with APC-Ab levels (r=0.431, p=0.005). In patients with autoimmune Addison's disease hyperchromograninemia and hypergastrinemia occur with a prevalence of 27.5 and 22.5%, respectively. Addison's patients with coexisting elevated gastric APC-Ab, particularly with elevated gastrin levels, are at risk of enterochromaffin-like cells hyper/dysplasia. Serum chromogranin A assessment may complement histology for the early diagnosis of gastric carcinoid in these patients.

Comparison of winter wheat yield sensitivity to climate variables under irrigated and rain-fed conditions

NASA Astrophysics Data System (ADS)

Xiao, Dengpan; Shen, Yanjun; Zhang, He; Moiwo, Juana P.; Qi, Yongqing; Wang, Rende; Pei, Hongwei; Zhang, Yucui; Shen, Huitao

2016-09-01

Crop simulation models provide alternative, less time-consuming, and cost-effective means of determining the sensitivity of crop yield to climate change. In this study, two dynamic mechanistic models, CERES (Crop Environment Resource Synthesis) and APSIM (Agricultural Production Systems Simulator), were used to simulate the yield of wheat ( Triticum aestivum L.) under well irrigated (CFG) and rain-fed (YY) conditions in relation to different climate variables in the North China Plain (NCP). The study tested winter wheat yield sensitivity to different levels of temperature, radiation, precipitation, and atmospheric carbon dioxide (CO2) concentration under CFG and YY conditions at Luancheng Agro-ecosystem Experimental Stations in the NCP. The results from the CERES and APSIM wheat crop models were largely consistent and suggested that changes in climate variables influenced wheat grain yield in the NCP. There was also significant variation in the sensitivity of winter wheat yield to climate variables under different water (CFG and YY) conditions. While a temperature increase of 2°C was the threshold beyond which temperature negatively influenced wheat yield under CFG, a temperature rise exceeding 1°C decreased winter wheat grain yield under YY. A decrease in solar radiation decreased wheat grain yield under both CFG and YY conditions. Although the sensitivity of winter wheat yield to precipitation was small under the CFG, yield decreased significantly with decreasing precipitation under the rainfed YY treatment. The results also suggest that wheat yield under CFG linearly increased by ≈3.5% per 60 ppm (parts per million) increase in CO2 concentration from 380 to 560 ppm, and yield under YY increased linearly by ≈7.0% for the same increase in CO2 concentration.

Relationship between expression of gastrin, somatostatin, Fas/FasL and caspases in large intestinal carcinoma

PubMed Central

Mao, Jia-Ding; Wu, Pei; Yang, Ying-Lin; Wu, Jian; Huang, He

2008-01-01

AIM: To explore the correlation between the mRNAs and protein expression of gastrin (GAS), somatostatin (SS) and apoptosis index (AI), apoptosis regulation gene Fas/FasL and caspases in large intestinal carcinoma (LIC). METHODS: Expression of GAS and SS mRNAs were detected by nested RT-PCR in 79 cases of LIC. Cell apoptosis was detected by molecular biology in situ apoptosis detecting methods (TUNEL). Immunohistochemical staining for GAS, SS, Fas/FasL, caspase-3 and caspase-8 was performed according to the standard streptavidin-biotin-peroxidase (S-P) method. RESULTS: There was a significant positive correlation between mRNA and protein expression of GAS and SS (GASrs=0.99, P < 0.01; SSrs = 0.98, P < 0.01). There was significant difference in positive expression rates of GAS, SS mRNAs and protein among different histological differentiation, histological types and Dukes’ stage of LIC. The AI in GAS high and moderate expression groups was significantly lower than that in low expression groups (3.75 ± 2.38 vs 7.82 ± 2.38, P < 0.01; 5.51 ± 2.66 vs 7.82 ± 2.38, P < 0.01), and the AI in SS high and moderate expression groups was significantly higher than that in low expression groups (9.03 ± 1.76 vs 5.35 ± 3.00, P < 0.01; 7.44 ± 2.67 vs 5.35 ± 3.00, P < 0.01). There was a significant negative correlation between the integral ratio of GAS to SS and the AI (rs = -0.41, P < 0.01). The positive expression rate of FasL in GAS high and moderate expression groups was higher than that in low expression group (90.9% and 81.0% vs 53.2%, P < 0.05). The positive expression rates of Fas, caspase-8 and caspase-3 in SS high (90.0%, 90.0% and 100%) and moderate (80.0%, 70.0%, 75.0%) expression groups were higher than that in low expression group (53.1%, 42.9%, 49.0%) (90.0% and 80.0% vs 53.1%, P < 0.05; 90.0% and 70.0% vs 42.9%, P < 0.05; 100.0% and 75.0% vs 49.0%, P < 0.05). There was a significant positive correlation between the integral ratio of GAS to SS and the

Regulation and signaling of human bombesin receptors and their biological effects.

PubMed

Weber, H Christian

2009-02-01

This review will highlight recent advances in the understanding of molecular mechanisms by which mammalian bombesin receptors are regulated and which intracellular signaling pathways have been characterized to mediate agonist-dependent receptor biological effects. Mammalian bombesin receptors have been demonstrated to be involved in a larger array of physiological and pathophysiological conditions than previously reported. Pharmacological experiments in vitro and in vivo as well as utilization of animals genetically deficient of the gastrin-releasing peptide receptor demonstrated roles in memory and fear behavior, lung development and injury, small intestinal cell repair, autocrine tumor growth, and mediating signals for pruritus and penile reflexes. Intracellular signaling studies predominantly of the gastrin-releasing peptide receptor owing to its frequent overexpression in some human malignancies showed that PI3 kinase activation is an important mechanism of cell proliferation. Tumor cell treatment including gastrin-releasing peptide receptor antagonists combined with inhibition of epidermal growth factor receptor resulted in an additive effect on blocking cell proliferation. Novel molecular mechanisms of the orphan bombesin receptor subtype-3 and gastrin-releasing peptide receptor gene regulation have been elucidated. Inhibition of gastrin-releasing peptide receptor signaling in human malignancies represents an attractive target for pharmacological treatment. Novel functions of bombesin related peptides have been identified including processes in the central nervous system, lung and intestinal tract.

X2Y2 isomers: tuning structure and relative stability through electronegativity differences (X = H, Li, Na, F, Cl, Br, I; Y = O, S, Se, Te).

PubMed

El-Hamdi, Majid; Poater, Jordi; Bickelhaupt, F Matthias; Solà, Miquel

2013-03-04

We have studied the XYYX and X2YY isomers of the X2Y2 species (X = H, Li, Na, F, Cl, Br, I; Y = O, S, Se, Te) using density functional theory at the ZORA-BP86/QZ4P level. Our computations show that, over the entire range of our model systems, the XYYX isomers are more stable than the X2YY forms except for X = F and Y = S and Te, for which the F2SS and F2TeTe isomers are slightly more stable. Our results also point out that the Y-Y bond length can be tuned quite generally through the X-Y electronegativity difference. The mechanism behind this electronic tuning is the population or depopulation of the π* in the YY fragment.