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Sample records for peptide yy levels

  1. Effects of exercise on the levels of peptide YY and ghrelin.

    PubMed

    Li, J-B; Asakawa, A; Li, Y; Cheng, K; Inui, A

    2011-03-01

    Ghrelin and peptide YY (PYY) are brain-gut peptides that have a variety of physiological functions and are involved in energy regulation. Thus far, abnormalities in the expression and secretion of ghrelin and PYY are known to occur in lifestyle-related diseases, including obesity, and the improvement of these abnormalities has become an important challenge. Exercise has recently been reported to influence ghrelin and PYY concentrations. Exercise increases the PYY secretion. The effects of exercise on ghrelin levels vary with the study subject, timing of exercise, and duration of exercise. Here, we review the findings of recent studies on the association of PYY and ghrelin with obesity, particularly, on the influence of exercise on PYY and ghrelin levels. © J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York.

  2. Peptide-YY levels after a fat load in black and white women.

    PubMed

    Davis, Julianne; Hickner, Robert C; Tanenberg, Robert J; Barakat, Hisham

    2005-12-01

    To determine whether basal plasma peptide-YY (PYY) levels in overweight, middle-aged black women are different from those of white women of similar BMI and age and ascertain whether there is a difference between the two groups in plasma PYY levels in response to a liquid high fat load. Using a commercial radioimmunoassay kit, the concentration of PYY was measured at baseline and at 2, 4, 6, and 8 hours after ingesting a fatty liquid meal (86.5% of the calories from fat) in 12 black and 12 white women who were matched for age and BMI. PYY levels (picograms per milliliter) at baseline and at every other time-point of the test meal were significantly lower in the black than in the white group. In addition, the change in PYY concentration from baseline was lower in the black than in the white group only at 8 hours after the meal. The lower baseline level and the blunted PYY response of the black women to the fat load indicated that this signal for appetite suppression was reduced, which, in turn, might contribute to the enhanced obesity of the black women.

  3. Peptide YY Levels across Pubertal Stages and Associations with Growth Hormone

    PubMed Central

    Lloyd, Benjamin; Ravi, Praful; Mendes, Nara; Klibanski, Anne; Misra, Madhusmita

    2010-01-01

    Context: Changes in appetite-regulating peptides may impact food intake during puberty and facilitate the pubertal growth spurt. Peptide YY (PYY) is an anorexigenic hormone that is high in anorexia nervosa and low in obesity, inhibits GnRH secretion, and is suppressed by GH administration. The relationship between PYY and GH has not been examined across puberty. Objectives: We hypothesized that PYY would be inversely associated with GH in adolescents and would be lowest when GH is highest. Design and Setting: We conducted a cross-sectional study at a Clinical Research Center. Subjects: We studied 87 children, 46 boys and 41 girls ages 9–17 yr at Tanner stages 1–5 of puberty (10th–90th percentiles for body mass index). Outcome Measures: We measured fasting PYY and nadir GH levels after administration of an oral glucose load. Leptin levels were also measured. Results: Fasting PYY was lowest and nadir GH highest in boys in Tanner stages 3–4 (P = 0.02) and in girls in Tanner stages 2–3 (P = 0.02). Leptin levels were highest in early pubertal boys and late pubertal girls. For the group as a whole and within genders, even after controlling for body mass index, log nadir GH correlated inversely with log PYY (P = 0.003, 0.07, and 0.02). PYY levels did not correlate with leptin levels. Conclusions: During mid-puberty, at a time when GH levels are the highest, PYY is at a nadir, and these low PYY levels may facilitate pubertal progression and growth. PMID:20375207

  4. Peptide YY receptors in the brain

    SciTech Connect

    Inui, A.; Oya, M.; Okita, M.; Inoue, T.; Sakatani, N.; Morioka, H.; Shii, K.; Yokono, K.; Mizuno, N.; Baba, S.

    1988-01-15

    Radiolabelled ligand binding studies demonstrated that specific receptors for peptide YY are present in the porcine as well as the canine brains. Peptide YY was bound to brain tissue membranes via high-affinity (dissociation constant, 1.39 X 10(-10)M) and low-affinity (dissociation constant, 3.72 X 10(-8)M) components. The binding sites showed a high specificity for peptide YY and neuropeptide Y, but not for pancreatic polypeptide or structurally unrelated peptides. The specific activity of peptide YY binding was highest in the hippocampus, followed by the pituitary gland, the hypothalamus, and the amygdala of the porcine brain, this pattern being similarly observed in the canine brain. The results suggest that peptide YY and neuropeptide Y may regulate the function of these regions of the brain through interaction with a common receptor site.

  5. Relationships Between Fasting Serum Amylase and Ghrelin or Peptide YY3-36 Levels in Healthy Men.

    PubMed

    Tak, Young Jin; Yi, Yu Hyeon; Lee, Sang Yeoup; Kim, Yun Jin; Lee, Jeong Gyu; Cho, Young Hye

    2016-03-01

    Appetite and carbohydrate metabolism are important contributors to the development of obesity. Recently, low serum amylase was shown to be associated with obesity and metabolic disorder. We investigated the relationship between amylase and ghrelin or peptide YY (PYY) levels in healthy men. Twenty-one men were enrolled in this cross-sectional study; all subjects were asymptomatic with no medical history. Fasting serum amylase, ghrelin, PYY3-36, anthropometry, and nutritional intake were measured. Linear regression analyses were performed to examine associations between amylase and ghrelin or PYY3-36. The mean (SD) age and waist circumference of the subjects were 51.5 (10.9) years and 87.0 (4.4) cm, respectively. Amylase was found to be correlated with waist circumference (r = -0.438, P = 0.054), ghrelin (r = 0.533, P = 0.015), and PYY3-36 (r = -0.511, P = 0.021). Multivariate linear regression analysis revealed a negative association between amylase and PYY3-36 (β = -0.428, P = 0.045) but a nonsignificantly positive association between amylase and ghrelin (β = 0.260, P = 0.146). Amylase levels were found to be associated with ghrelin and PYY3-36 in healthy men. Amylase, ghrelin, and PYY3-36 may play a role in obesity; further research is required to identify the underlying mechanism.

  6. Influence of resistance and aerobic exercise on hunger, circulating levels of acylated ghrelin, and peptide YY in healthy males.

    PubMed

    Broom, David R; Batterham, Rachel L; King, James A; Stensel, David J

    2009-01-01

    Resistance (muscle strengthening) exercise is a key component of exercise recommendations for weight control, yet very little is known about the effects of resistance exercise on appetite. We investigated the effects of resistance and aerobic exercise on hunger and circulating levels of the gut hormones acylated ghrelin and peptide YY (PYY). Eleven healthy male students: age 21.1 +/- 0.3 yr, body mass index 23.1 +/- 0.4 kg/m(2), maximum oxygen uptake 62.1 +/- 1.8 ml.kg(-1).min(-1) (means +/- SE) undertook three, 8-h trials, 1) resistance exercise: a 90-min free weight lifting session followed by a 6.5-h rest period, 2) aerobic exercise: a 60-min run followed by a 7-h rest period, 3) control: an 8-h rest, in a randomized crossover design. Meals were provided 2 and 5 h into each trial. Hunger ratings and plasma concentrations of acylated ghrelin and PYY were measured throughout. Two-way ANOVA revealed significant (P < 0.05) interaction effects for hunger, acylated ghrelin, and PYY, indicating suppressed hunger and acylated ghrelin during aerobic and resistance exercise and increased PYY during aerobic exercise. A significant trial effect was observed for PYY, indicating higher concentrations on the aerobic exercise trial than the other trials (8 h area under the curve: control 1,411 +/- 110, resistance 1,381 +/- 97, aerobic 1,750 +/- 170 pg/ml 8 h). These findings suggest ghrelin and PYY may regulate appetite during and after exercise, but further research is required to establish whether exercise-induced changes in ghrelin and PYY influence subsequent food intake.

  7. Effect of Weight Loss by Diet or Gastric Bypass Surgery on Peptide YY3–36 Levels

    PubMed Central

    Oliván, Blanca; Teixeira, Julio; Bose, Mousumi; Bawa, Baani; Chang, Tangel; Summe, Heather; Lee, Hongchan; Laferrère, Blandine

    2010-01-01

    Objective To examine the effect of an equivalent weight loss, by gastric bypass surgery (GBP) or by diet, on peptide YY3–36 (PYY3–36), ghrelin, and leptin levels and to determine the effect of diabetes status on PYY3–36 levels. Summary Background Data The increased PYY3–36 levels after GBP may be involved in the magnitude and the sustainability of weight loss after surgery. Methods Of the 30 morbidly obese women who participated in the study, 21 had type 2 diabetes mellitus, and were studied before and after equivalent weight loss of 10 kg by either GBP (n = 11) or by diet (n = 10). Results PYY3–36 levels were higher in obese diabetic as compared with nondiabetic individuals (64.1 ± 34.4 pg/mL vs. 39.9 ± 21.1 pg/mL; P < 0.05). PYY3–36 levels increased markedly in response to oral glucose after GBP (peak: 72.3 ± 20.5 pg/mL–132.7 ± 49.7 pg/mL; P < 0.001; AUC0–180: 51.5 ± 23.3 pg/mL.min−1–91.1 ± 32.2 pg/mL.min−1 P < 0.001), but not after diet (peak: 85.5 ± 51.9 pg/mL–84.8 ± 41.13 pg/mL; P = NS; AUC0–180: 68.3 ± 38.5 pg/mL.min−1–61.1 ± 42.2 pg/mL.min−1 P = NS). Fasting ghrelin levels increased after diet (425 ± 91 pg/mL–519 ± 105 pg/mL; P < 0.05), but did not change after GBP (506 ± 121 pg/mL–482 ± 196 pg/mL; P = NS). Conclusions Diabetes status seems to be a determinant of PYY3–36 levels. GBP, but not diet-induced weight loss, resulted in markedly increased glucose-stimulated PYY3–36 levels. The increase in stimulated PYY3–36 levels after GBP is likely a result of the surgery rather than a secondary outcome of weight loss. Changes in PYY3–36 levels and ghrelin could contribute to the success of GBP in sustaining weight loss. PMID:19474685

  8. Effect of weight loss by diet or gastric bypass surgery on peptide YY3-36 levels.

    PubMed

    Oliván, Blanca; Teixeira, Julio; Bose, Mousumi; Bawa, Baani; Chang, Tangel; Summe, Heather; Lee, Hongchan; Laferrère, Blandine

    2009-06-01

    To examine the effect of an equivalent weight loss, by gastric bypass surgery (GBP) or by diet, on peptide YY3-36 (PYY3-36), ghrelin, and leptin levels and to determine the effect of diabetes status on PYY3-36 levels. The increased PYY3-36 levels after GBP may be involved in the magnitude and the sustainability of weight loss after surgery. Of the 30 morbidly obese women who participated in the study, 21 had type 2 diabetes mellitus, and were studied before and after equivalent weight loss of 10 kg by either GBP (n = 11) or by diet (n = 10). : PYY3-36 levels were higher in obese diabetic as compared with nondiabetic individuals (64.1 +/- 34.4 pg/mL vs. 39.9 +/- 21.1 pg/mL; P < 0.05). PYY3-36 levels increased markedly in response to oral glucose after GBP (peak: 72.3 +/- 20.5 pg/mL-132.7 +/- 49.7 pg/mL; P < 0.001; AUC0-180: 51.5 +/- 23.3 pg/mL x min-91.1 +/- 32.2 pg/mL x min P < 0.001), but not after diet (peak: 85.5 +/- 51.9 pg/mL-84.8 +/- 41.13 pg/mL; P = NS; AUC0-180: 68.3 +/- 38.5 pg/mL x min-61.1 +/- 42.2 pg/mL.min P = NS). Fasting ghrelin levels increased after diet (425 +/- 91 pg/mL-519 +/- 105 pg/mL; P < 0.05), but did not change after GBP (506 +/- 121 pg/mL-482 +/- 196 pg/mL; P = NS). Diabetes status seems to be a determinant of PYY3-36 levels. GBP, but not diet-induced weight loss, resulted in markedly increased glucose-stimulated PYY3-36 levels. The increase in stimulated PYY3-36 levels after GBP is likely a result of the surgery rather than a secondary outcome of weight loss. Changes in PYY3-36 levels and ghrelin could contribute to the success of GBP in sustaining weight loss.

  9. 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.

  10. Effects of peptide YY on gallbladder motility

    SciTech Connect

    Conter, R.L.; Roslyn, J.J.; Taylor, I.L.

    1987-06-01

    The effects of peptide YY (PYY) on cholecystokinin-stimulated gallbladder contraction were investigated in the prairie dog model. Twelve animals underwent laparotomy with catheter placement into the gallbladder and common bile duct (vent). The gallbladder was continuously perfused with (/sup 14/C)polyethylene glycol-labeled lactated Ringer at 0.03 ml/min, and vent effluent was collected at 2.5-min intervals. All animals received 20 min of intravenous infusion of cholecystokinin octapeptide (CCK-OP), 2.5 ng x kg/sup -1/ x min/sup -1/, immediately followed by 60-min infusions of either lactated Ringer (LR) or synthetic PYY, 10 or 50 ng x kg/sup -1/ x min/sup -1/. When LR was infused after CCK-OP, gallbladder filling increased by 15.4 +/- 10.5% with minimal changes in gallbladder pressure. Infusion of PYY/sub 10/ resulted in a significant increase in gallbladder volume and filling with a significant decrease in intragallbladder pressure. Similar findings were noted with PYY/sub 50/. These data indicate that synthetic PYY significantly augments gallbladder filling after CCK-OP-stimulated gallbladder contraction. These finding, coupled with the observation that PYY inhibits pancreatic secretion, suggest that this peptide may be the anti-CCK hormone and may have an important role in regulating biliary activity postprandially.

  11. Fasting and post-prandial peptide YY levels in obese patients before and after mini versus Roux-en-Y gastric bypass.

    PubMed

    Dardzińska, Jolanta A; Kaska, Łukasz; Wiśniewski, Piotr; Aleksandrowicz-Wrona, Ewa; Małgorzewicz, Sylwia

    2017-02-01

    BACKGROUNDː The mechanisms underlying the metabolic effect of surgical treatment for morbid obesity are still unclear. Furthermore, the hormonal and metabolic response to the promising and less-invasive version of Roux-en-Y gastric bypass (RYGB), i.e. mini gastric bypass (MGB), is poorly known. The aim of this study was to evaluate pre- and postprandial changes in peptide YY (PYY) and metabolic parameters in obese patients without diabetes and cardiovascular complications treated by both versions of gastric bypass. METHODSː Venous blood for PYY and other assays was collected three months before and six months after bariatric operation (MGB and RYGB), in the fasting state and two hours after the consumption of a standard 300-kcal mixed meal (Nutridrink Standard, Nutricia Advanced Medical Nutrition, part of the Danone company, Schiphol, The Netherlands). RESULTSː In the MGB group, elevated concentrations of the PYY has been detected both fasting and postprandially. The effect of the MGB on the PYY levels did not differ from the RYGB group outcomes. CONCLUSIONSː The results of our study suggest similar endocrine and metabolic effects of MGB and RYGB procedures. Long-term efficacy and metabolic benefits of MGB require further research.

  12. Effects of peptide YY[3-36] on short-term food intake in mice are not affected by prevailing plasma ghrelin levels.

    PubMed

    Adams, Sean H; Won, Wesley B; Schonhoff, Susan E; Leiter, Andrew B; Paterniti, James R

    2004-11-01

    The gut-derived hormones peptide YY[3-36] (PYY[3-36]) and ghrelin are believed to influence similar hypothalamic circuits, albeit with opposing actions on energy balance. Thus, we carried out a series of studies to evaluate the interaction of these hormones on short-term food intake responses in mice. Intraperitoneal PYY[3-36] injection reduced short-term food intake by up to 50% in overnight-fasted mice and in postabsorptive animals during the early and late light cycle. This effect was not sensitive to the prevailing endogenous plasma acyl-ghrelin concentrations, which ranged from high physiological (overnight-fasted, 1252 +/- 108 pg/ml) to low levels (late light cycle, 402 +/- 33 pg/ml). PYY[3-36] administration did not reduce plasma total or acyl-ghrelin concentration in conjunction with its anorexigenic actions. Ghrelin increased short-term food intake by up to 1.8-fold in mice treated ip in the early light cycle, but was ineffective in animals treated after an overnight fast or during the late light cycle. Ghrelin did not increase food intake or GH secretion unless plasma levels were increased above high physiological fasting values. The anorexigenic effect of PYY[3-36] over a range of doses was not compromised by coinjection of ghrelin, and PYY[3-36] reduced food intake in agouti mice, which lack fully functional melanocortin signaling. These results in mice support a model in which 1) PYY[3-36] diminishes short-term food intake at least in part through mechanisms distinct from the neuropeptide Y/proopiomelanocortin neural circuits engaged by ghrelin; and 2) a reduction in circulating ghrelin is not requisite for the anorexigenic effects of PYY[3-36].

  13. Modulation of taste responsiveness by the satiation hormone peptide YY

    PubMed Central

    La Sala, Michael S.; Hurtado, Maria D.; Brown, Alicia R.; Bohórquez, Diego V.; Liddle, Rodger A.; Herzog, Herbert; Zolotukhin, Sergei; Dotson, Cedrick D.

    2013-01-01

    It has been hypothesized that the peripheral taste system may be modulated in the context of an animal's metabolic state. One purported mechanism for this phenomenon is that circulating gastrointestinal peptides modulate the functioning of the peripheral gustatory system. Recent evidence suggests endocrine signaling in the oral cavity can influence food intake (FI) and satiety. We hypothesized that these hormones may be affecting FI by influencing taste perception. We used immunohistochemistry along with genetic knockout models and the specific reconstitution of peptide YY (PYY) in saliva using gene therapy protocols to identify a role for PYY signaling in taste. We show that PYY is expressed in subsets of taste cells in murine taste buds. We also show, using brief-access testing with PYY knockouts, that PYY signaling modulates responsiveness to bitter-tasting stimuli, as well as to lipid emulsions. We show that salivary PYY augmentation, via viral vector therapy, rescues behavioral responsiveness to a lipid emulsion but not to bitter stimuli and that this response is likely mediated via activation of Y2 receptors localized apically in taste cells. Our findings suggest distinct functions for PYY produced locally in taste cells vs. that circulating systemically.—La Sala, M. S., Hurtado, M. D., Brown, A. R., Bohórquez, D. V., Liddle, R. A., Herzog, H., Zolotukhin, S., Dotson, C. D. Modulation of taste responsiveness by the satiation hormone peptide YY. PMID:24043261

  14. The role of peptide YY in appetite regulation and obesity

    PubMed Central

    Karra, Efthimia; Chandarana, Keval; Batterham, Rachel L

    2009-01-01

    The last decade has witnessed a marked increase in our understanding of the importance of gut hormones in the regulation of energy homeostasis. In particular, the discovery that the gut hormone peptide YY 3–36 (PYY3–36) reduced feeding in obese rodents and humans fuelled interest in the role of PYY3–36 in body weight regulation. Pharmacological and genetic approaches have revealed that the Y2-receptor mediates the anorectic effects of PYY3–36 whilst mechanistic studies in rodents identified the hypothalamus, vagus and brainstem regions as potential sites of action. More recently, using functional brain imaging techniques in humans, PYY3–36 was found to modulate neuronal activity within hypothalamic and brainstem, and brain regions involved in reward processing. Several lines of evidence suggest that low circulating PYY concentrations predispose towards the development and or maintenance of obesity. Subjects with reduced postprandial PYY release exhibit lower satiety and circulating PYY levels that correlate negatively with markers of adiposity. In addition, mice lacking PYY are hyperphagic and become obese. Conversely, chronic PYY3–36 administration to obese rodents reduces adiposity, and transgenic mice with increased circulating PYY are resistant to diet-induced obesity. Moreover, there is emerging evidence that PYY3–36 may partly mediate the reduced appetite and weight loss benefits observed post-gastric bypass surgery. Taken together these findings, coupled with the retained responsiveness of obese subjects to the effects of PYY3–36, suggest that targeting the PYY system may offer a therapeutic strategy to help treat obesity. PMID:19064614

  15. Peptide YY producing strumal carcinoid tumor of the ovary.

    PubMed

    Matsunami, K; Takagi, H; Ichigo, S; Murase, T; Ikeda, T; Imai, A

    2011-01-01

    Primary ovarian carcinoid tumor is uncommon and represents less than 0.1% of ovarian malignancies. The strumal carcinoid may be complicated by carcinoid syndrome induced by peptide YY (PYY). We describe a 45-year-old woman with a bilateral ovarian tumor diagnosed through periodical gynecological examination. She presented with severe constipation. Right ovarian cyst laparoscopically resected was diagnosed as a strumal carcinoid tumor; the left one was mature cystic teratoma. No metastatic findings were seen macroscopically on the ovarian surface and pelvic peritoneum. Constipation was drastically improved by resecting the tumor. The carcinoid tumor cells were positive for tumor-producing PYY by mRNA analysis. It is important to be aware of this entity in the pathological diagnosis of ovarian tumors, in the presence of any clinical indicator of carcinoid tumor/syndrome, as it carries a markedly better prognosis and clinical outcome in comparison with most other malignant ovarian tumors.

  16. Fasting and nutrient-stimulated plasma peptide-YY levels are elevated in critical illness and associated with feed intolerance: an observational, controlled study

    PubMed Central

    Nguyen, Nam Q; Fraser, Robert JL; Chapman, Marianne; Bryant, Laura K; Wishart, Judith; Holloway, Richard H; Horowitz, Michael

    2006-01-01

    Introduction Delayed gastric emptying and feed intolerance occur frequently in the critically ill. In these patients, gastric motor responses to nutrients are disturbed. Peptide YY (PYY) slows gastric emptying. The aim of this study was to determine fasting and nutrient-stimulated plasma PYY concentrations and their relationship to cholecystokinin (CCK) in critically ill patients. Methods Studies were performed in 19 unselected mechanically ventilated critically ill patients (12 males; 48 ± 7 years old) in a randomised, single-blind fashion. Subjects received a 60-minute duodenal infusion of Ensure® at either 1 or 2 kcal/minute. Blood samples were collected at baseline and at 20, 40, 60, and 180 minutes following commencement of the nutrient infusion for the measurement of plasma PYY and CCK concentrations (using radioimmunoassay). Patient data were compared to 24 healthy subjects (17 males; 43 ± 2 years old). Results Fasting PYY concentration was higher in patients (P < 0.05), particularly in those with feed intolerance (P < 0.05). Plasma PYY concentrations were higher in patients during nutrient infusion (area under the curve [AUC] at 1 kcal/minute: 2,265 ± 718 versus 1,125 ± 138 pmol/l.min, P < 0.05; at 2 kcal/minute: 2,276 ± 303 versus 1,378 ± 210 pmol/l.min, P = 0.01) compared to healthy subjects. The magnitude of PYY elevation was greater in patients during the 1 kcal/minute infusion (AUC: 441 ± 153 versus 186 ± 58 pmol/l.min, P < 0.05), but not the 2 kcal/minute infusion. Fasting and nutrient-stimulated plasma CCK concentrations were higher in patients (P < 0.05). There was a relationship between plasma PYY and CCK concentrations during fasting (r = 0.52, P < 0.05) and nutrient infusion (r = 0.98, P < 0.0001). Conclusion In critical illness, both fasting and nutrient-stimulated plasma PYY concentrations are elevated, particularly in patients with feed intolerance, in conjunction with increased CCK concentrations. PMID:17173662

  17. Modulation of taste responsiveness by the satiation hormone peptide YY.

    PubMed

    La Sala, Michael S; Hurtado, Maria D; Brown, Alicia R; Bohórquez, Diego V; Liddle, Rodger A; Herzog, Herbert; Zolotukhin, Sergei; Dotson, Cedrick D

    2013-12-01

    It has been hypothesized that the peripheral taste system may be modulated in the context of an animal's metabolic state. One purported mechanism for this phenomenon is that circulating gastrointestinal peptides modulate the functioning of the peripheral gustatory system. Recent evidence suggests endocrine signaling in the oral cavity can influence food intake (FI) and satiety. We hypothesized that these hormones may be affecting FI by influencing taste perception. We used immunohistochemistry along with genetic knockout models and the specific reconstitution of peptide YY (PYY) in saliva using gene therapy protocols to identify a role for PYY signaling in taste. We show that PYY is expressed in subsets of taste cells in murine taste buds. We also show, using brief-access testing with PYY knockouts, that PYY signaling modulates responsiveness to bitter-tasting stimuli, as well as to lipid emulsions. We show that salivary PYY augmentation, via viral vector therapy, rescues behavioral responsiveness to a lipid emulsion but not to bitter stimuli and that this response is likely mediated via activation of Y2 receptors localized apically in taste cells. Our findings suggest distinct functions for PYY produced locally in taste cells vs. that circulating systemically.

  18. The role of peptide YY in gastrointestinal diseases and disorders

    PubMed Central

    EL-SALHY, MAGDY; MAZZAWI, TAREK; GUNDERSEN, DORIS; HATLEBAKK, JAN GUNNAR; HAUSKEN, TRYGVE

    2013-01-01

    Peptide YY (PYY) is affected in several gastrointestinal diseases and disorders. Changes in PYY appear to be an adaptive response to alterations in pathophysiological conditions caused by the disease. This applies to gastrointestinal diseases/disorders such as irritable bowel syndrome, inflammatory bowel disease, celiac disease, systemic sclerosis, and post-intestinal resection. By contrast, the changes in PYY in chronic idiopathic slow transit constipation (CST) seem to be of a primary nature, and may be one etiological factor of the disease. Abnormalities in PYY seem to contribute to the development of symptoms present in irritable bowel syndrome, inflammatory bowel disease, gastroenteropathy in long-standing diabetes and CST. The changes in PYY could, however, be favorable in some gastrointestinal disorders such as celiac disease, systemic sclerosis and post-intestinal resection state. Investigating changes in PYY in gastrointestinal diseases/disorders could be beneficial in clinical practice, where a receptor agonist or an antagonist can be used as a drug, depending on the condition. Similar to other neuroendocrine peptides/amines of the gut, PYY has broad physiological/pharmacological effects: it can bind to and activate several receptors with independent actions. Thus, in order to use PYY as a drug, receptor-specific agonists or antagonists need to be developed. PMID:23292145

  19. Differential effects of laparoscopic sleeve gastrectomy and laparoscopic gastric bypass on appetite, circulating acyl-ghrelin, peptide YY3-36 and active GLP-1 levels in non-diabetic humans.

    PubMed

    Yousseif, Ahmed; Emmanuel, Julian; Karra, Efthimia; Millet, Queensta; Elkalaawy, Mohamed; Jenkinson, Andrew D; Hashemi, Majid; Adamo, Marco; Finer, Nicholas; Fiennes, Alberic G; Withers, Dominic J; Batterham, Rachel L

    2014-02-01

    Laparoscopic Roux-en-Y gastric bypass (LRYGBP) reduces appetite and induces significant and sustainable weight loss. Circulating gut hormones changes engendered by LRYGBP are implicated in mediating these beneficial effects. Laparoscopic sleeve gastrectomy (LSG) is advocated as an alternative to LRYGBP, with comparable short-term weight loss and metabolic outcomes. LRYGBP and LSG are anatomically distinct procedures causing differential entero-endocrine cell nutrient exposure and thus potentially different gut hormone changes. Studies reporting the comparative effects of LRYGBP and LSG on appetite and circulating gut hormones are controversial, with no data to date on the effects of LSG on circulating peptide YY3-36 (PYY3-36) levels, the specific PYY anorectic isoform. In this study, we prospectively investigated appetite and gut hormone changes in response to LRYGBP and LSG in adiposity-matched non-diabetic patients. Anthropometric indices, leptin, fasted and nutrient-stimulated acyl-ghrelin, active glucagon-like peptide-1 (GLP-1), PYY3-36 levels and appetite were determined pre-operatively and at 6 and 12 weeks post-operatively in obese, non-diabetic females, with ten undergoing LRYGBP and eight adiposity-matched females undergoing LSG. LRYGBP and LSG comparably reduced adiposity. LSG decreased fasting and post-prandial plasma acyl-ghrelin compared to pre-surgery and to LRYGBP. Nutrient-stimulated PYY3-36 and active GLP-1 concentrations increased post-operatively in both groups. However, LRYGBP induced greater, more sustained PYY3-36 and active GLP-1 increments compared to LSG. LRYGBP suppressed fasting hunger compared to LSG. A similar increase in post-prandial fullness was observed post-surgery following both procedures. LRYGBP and LSG produced comparable enhanced satiety and weight loss. However, LSG and LRYGBP differentially altered gut hormone profiles.

  20. Short-term effect of gastric resection on circulating levels of ghrelin, peptide YY3-36 and obestatin in patients with early gastric cancer.

    PubMed

    Jeon, T Y; Lee, S Y; Kim, H H; Cho, Y H; Cho, A R

    2015-04-01

    The short-term responses of gut hormones and the compensative interaction during a one-week period after subtotal gastrectomy in early gastric cancer (EGC) patients were assessed. Previous studies have reported gut hormonal changes after Roux-en-Y gastric bypass surgery. Blood samples were collected from 40 patients with EGC preoperatively, at 1 h after gastric resection, and on postoperative day (POD) 1, 3, and 7. Levels of active ghrelin, total ghrelin, obestatin, and PYY3-36 were measured. Total ghrelin level rapidly reached a nadir of 69.1%, while active ghrelin level had increased to 135.5% at 1 h after resection. Then, both returned to preoperative level. On the contrary, active/total ghrelin reached its nadir quickly at 1 h after resection and had returned to the preoperative level by POD 3. The nadir PYY3-36 level was 71.4% on POD 1, followed by a gradual recovery, and had increased to 116.5% by POD 7. The same pattern was observed for obestatin. Active ghrelin/obestatin showed an increase on POD 1 while total ghrelin/obestatin showed a decrease on POD 3. Then, both returned to preoperative level. These results suggest that a rapid interactive compensatory mechanism of gut hormones does exist in the remnant gastrointestinal tract after abrupt changes in the production reservoir in nonobese people.

  1. Peptide YY antagonizes beta-adrenergic-stimulated release of insulin in dogs

    SciTech Connect

    Greeley, G.H. Jr.; Lluis, F.; Gomex, G.; Ishizuka, J.; Holland, B.; Thompson, J.C. )

    1988-04-01

    Peptide YY (PYY) and neuropeptide Y (NPY) are peptides of 36 amino acids that share structural homologies with pancreatic polypeptide (PP). PP is predominantly found in the endocrine pancreas. PYY is primarily found in mucosal endocrine cells of the distal ileum, colon, and rectum, whereas NPY is found in both the peripheral and central nervous system. Previous studies indicate that these peptides can interact with the autonomic nervous system. The objective of the present experiments was to study the effect of PYY on neurally stimulated insulin release in conscious dogs. Intravenous administration of PYY (100, 200, and 400 pmol{center dot}kg{sup {minus}1} {center dot}h{sup {minus}1}) reduced 2-DG-stimulated insulin release in a dose-dependent manner (P <0.05) without affecting plasma glucose levels. Administration of NPY, but not PP, reduced 2-DG-stimulated release of insulin. The inhibitory action of PYY on 2-DG-stimulated insulin release persisted in the presence of atropine or phentolamine treatment; however, hexamethonium alone or phentolamine plus propranolol treatment blocked the inhibitory action of PYY. Release of insulin stimulated by the {beta}-agonist isoproterenol was also inhibited by PYY. These results indicate that PYY can inhibit autonomic neurotransmission by a mechanism that may involve ganglionic or postganglionic inhibition of {beta}-adrenergic stimulation. The findings suggest a role for PYY and NPY in the autonomic regulation of insulin release.

  2. Peptide YY secretion in morbidly obese patients before and after vertical banded gastroplasty.

    PubMed

    Alvarez Bartolomé, Mercedes; Borque, María; Martinez-Sarmiento, Javier; Aparicio, Eugenio; Hernández, Carmen; Cabrerizo, Lucio; Fernández-Represa, J A

    2002-06-01

    The Peptide YY (PYY) secretion pattern was assessed in morbidly obese (MO) patients before and after vertical banded gastroplasty (VBG). 12 MO patients (10 women, 2 men) age 29-62 years, BMI 50.7 +/- 9.6 kg/m2, treated with a VBG were studied. Before surgery, blood samples were taken in basal conditions of fasting and 10, 15, 20, 30 and 60 min after the ingestion of a semiliquid test meal. This was repeated in the same patients 6 and 12 months after VBG. Blood samples were also taken from 6 healthy non-obese subjects as controls. PYY plasma concentration was measured by radioimmunoassay with I125. There were statistically significant differences between the preoperative PYY concentration in MO patients compared to controls. After a VBG, PYY concentration varied significantly compared to the preoperative levels. There was no significant difference between the PYY concentrations in the MO patients after VBG and the controls. PYY concentration is lower in MO patients compared with non-obese. After VBG, PYY concentration gradually rises to the control levels.

  3. Neuropeptide Y, peptide YY and pancreatic polypeptide in the gut–brain axis

    PubMed Central

    Holzer, Peter; Reichmann, Florian; Farzi, Aitak

    2012-01-01

    The gut–brain axis refers to the bidirectional communication between the gut and the brain. Four information carriers (vagal and spinal afferent neurons, immune mediators such as cytokines, gut hormones and gut microbiota-derived signalling molecules) transmit information from the gut to the brain, while autonomic neurons and neuroendocrine factors carry outputs from the brain to the gut. The members of the neuropeptide Y (NPY) family of biologically active peptides, NPY, peptide YY (PYY) and pancreatic polypeptide (PP), are expressed by cell systems at distinct levels of the gut–brain axis. PYY and PP are exclusively expressed by endocrine cells of the digestive system, whereas NPY is found at all levels of the gut–brain and brain–gut axis. The major systems expressing NPY comprise enteric neurons, primary afferent neurons, several neuronal pathways throughout the brain and sympathetic neurons. In the digestive tract, NPY and PYY inhibit gastrointestinal motility and electrolyte secretion and in this way modify the input to the brain. PYY is also influenced by the intestinal microbiota, and NPY exerts, via stimulation of Y1 receptors, a proinflammatory action. Furthermore, the NPY system protects against distinct behavioural disturbances caused by peripheral immune challenge, ameliorating the acute sickness response and preventing long-term depression. At the level of the afferent system, NPY inhibits nociceptive input from the periphery to the spinal cord and brainstem. In the brain, NPY and its receptors (Y1, Y2, Y4, Y5) play important roles in regulating food intake, energy homeostasis, anxiety, mood and stress resilience. In addition, PP and PYY signal to the brain to attenuate food intake, anxiety and depression-related behaviour. These findings underscore the important role of the NPY-Y receptor system at several levels of the gut–brain axis in which NPY, PYY and PP operate both as neural and endocrine messengers. PMID:22979996

  4. 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

  5. Ghrelin and peptide YY in youth: are there race-related differences?

    PubMed

    Bacha, Fida; Arslanian, Silva A

    2006-08-01

    Obesity prevalence is higher in African-American (AA) vs. American white (AW) youth. Ghrelin is a "hunger" peptide that is high preprandially and decreases postprandially, and peptide YY (PYY) is a "satiety" hormone increasing after meals. Impaired regulation of ghrelin/PYY may be conducive to obesity. We hypothesized that racial differences in childhood obesity could partly be explained by differences in ghrelin/PYY dynamics. We investigated: 1) ghrelin suppression/PYY elevation in response to an oral glucose tolerance test (OGTT) in AA vs. AW, and 2) the relationship of ghrelin and PYY dynamics to insulin sensitivity. Thirty-three AA and 54 AW prepubertal children underwent an OGTT measuring ghrelin, PYY, glucose, and insulin. Fasting glucose to insulin ratio (G(F)/I(F)) was used to assess the relationship of insulin sensitivity to fasting and post-OGTT ghrelin and PYY levels. OGTT-induced suppression in ghrelin (Delta ghrelin) was lower in AA youth. Delta ghrelin correlated with G(F)/I(F) (r = 0.47, P < 0.001) and Delta insulin at 30 min (r = -0.47, P < 0.001). In multiple regression analysis, race (P = 0.013) and G(F)/I(F) (P = 0.004) contributed independently to the variance in Delta ghrelin (R(2) = 0.28, P < 0.001). Fasting and post-OGTT PYY levels were lower in AAs and were not related to insulin sensitivity. The lower suppression of ghrelin in AA, but not the lower PYY levels, correlates with insulinemia and insulin resistance. Less ghrelin suppression and PYY elevation after a meal in black youth could be a potential mechanism of race-related differences in hunger/satiety predisposing to risk of obesity.

  6. Diet and gastrointestinal bypass-induced weight loss: the roles of ghrelin and peptide YY.

    PubMed

    Chandarana, Keval; Gelegen, Cigdem; Karra, Efthimia; Choudhury, Agharul I; Drew, Megan E; Fauveau, Veronique; Viollet, Benoit; Andreelli, Fabrizio; Withers, Dominic J; Batterham, Rachel L

    2011-03-01

    Bariatric surgery causes durable weight loss. Gut hormones are implicated in obesity pathogenesis, dietary failure, and mediating gastrointestinal bypass (GIBP) surgery weight loss. In mice, we determined the effects of diet-induced obesity (DIO), subsequent dieting, and GIBP surgery on ghrelin, peptide YY (PYY), and glucagon-like peptide-1 (GLP-1). To evaluate PYY's role in mediating weight loss post-GIBP, we undertook GIBP surgery in PyyKO mice. Male C57BL/6 mice randomized to a high-fat diet or control diet were killed at 4-week intervals. DIO mice underwent switch to ad libitum low-fat diet (DIO-switch) or caloric restriction (CR) for 4 weeks before being killed. PyyKO mice and their DIO wild-type (WT) littermates underwent GIBP or sham surgery and were culled 10 days postoperatively. Fasting acyl-ghrelin, total PYY, active GLP-1 concentrations, stomach ghrelin expression, and colonic Pyy and glucagon expression were determined. Fasting and postprandial PYY and GLP-1 concentrations were assessed 30 days postsurgery in GIBP and sham pair-fed (sham.PF) groups. DIO progressively reduced circulating fasting acyl-ghrelin, PYY, and GLP-1 levels. CR and DIO-switch caused weight loss but failed to restore circulating PYY to weight-appropriate levels. After GIBP, WT mice lost weight and exhibited increased circulating fasting PYY and colonic Pyy and glucagon expression. In contrast, the acute effects of GIBP on body weight were lost in PyyKO mice. Fasting PYY and postprandial PYY and GLP-1 levels were increased in GIBP mice compared with sham.PF mice. PYY plays a key role in mediating the early weight loss observed post-GIBP, whereas relative PYY deficiency during dieting may compromise weight-loss attempts.

  7. Visceral hyperalgesia caused by peptide YY deletion and Y2 receptor antagonism

    PubMed Central

    Hassan, Ahmed M.; Jain, Piyush; Mayerhofer, Raphaela; Fröhlich, Esther E.; Farzi, Aitak; Reichmann, Florian; Herzog, Herbert; Holzer, Peter

    2017-01-01

    Altered levels of colonic peptide YY (PYY) have been reported in patients suffering from functional and inflammatory bowel disorders. While the involvement of neuropeptide Y (NPY) and Y receptors in the regulation of nociception is well established, the physiological role of PYY in somatic and visceral pain is poorly understood. In this work, the role of PYY in pain sensitivity was evaluated using PYY knockout (PYY(−/−)) mice and Y2 receptor ligands. PYY(−/−) mice were more sensitive to somatic thermal pain compared to wild type (WT) mice. Visceral pain was assessed by evaluating pain-related behaviors, mouse grimace scale (MGS) and referred hyperalgesia after intrarectal administration of allyl isothiocyanate (AITC, 1 or 2%) or its vehicle, peanut oil. The pain-related behaviors induced by AITC were significantly exaggerated by PYY deletion, whereas the MGS readout and the referred hyperalgesia were not significantly affected. The Y2 receptor antagonist, BII0246, increased pain-related behaviors in response to intrarectal AITC compared to vehicle treatment while the Y2 receptor agonist, PYY(3–36), did not have a significant effect. These results indicate that endogenous PYY has a hypoalgesic effect on somatic thermal and visceral chemical pain. The effect on visceral pain seems to be mediated by peripheral Y2 receptors. PMID:28106168

  8. In vivo and in vitro degradation of peptide YY3–36 to inactive peptide YY3–34 in humans

    PubMed Central

    Toräng, Signe; Bojsen-Møller, Kirstine Nyvold; Svane, Maria Saur; Hartmann, Bolette; Rosenkilde, Mette Marie; Madsbad, Sten

    2016-01-01

    Peptide YY (PYY) is a 36-amino-acid peptide released from enteroendocrine cells upon food intake. The NH2 terminally truncated metabolite, PYY3–36, exerts anorexic effects and has received considerable attention as a possible antiobesity drug target. The kinetics and degradation products of PYY metabolism are not well described. A related peptide, neuropeptide Y, may be degraded from the COOH terminus, and in vivo studies in pigs revealed significant COOH-terminal degradation of PYY. We therefore investigated PYY metabolism in vitro after incubation in human blood and plasma and in vivo after infusion of PYY1–36 and PYY3–36 in eight young, healthy men. A metabolite, corresponding to PYY3–34, was formed after incubation in plasma and blood and during the infusion of PYY. PYY3–34 exhibited no agonistic or antagonistic effects on the Y2 receptor. PYY1–36 infused with and without coadministration of sitagliptin was eliminated with half-lives of 10.1 ± 0.5 and 9.4 ± 0.8 min (means ± SE) and metabolic clearance rates of 15.7 ± 1.5 and 14.1 ± 1.1 ml·kg−1·min−1 after infusion, whereas PYY3–36 was eliminated with a significantly longer half-life of 14.9 ± 1.3 min and a metabolic clearance rate of 9.4 ± 0.6 ml·kg−1·min−1. We conclude that, upon intravenous infusion in healthy men, PYY is inactivated by cleavage of the two COOH-terminal amino acids. In healthy men, PYY3–36 has a longer half-life than PYY1–36. PMID:26818056

  9. 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.

  10. Peptide YY ameliorates cerulein-induced pancreatic injury in the rat.

    PubMed

    Tito, J M; Rudnicki, M; Jones, D H; Alpern, H D; Gold, M S

    1993-06-01

    Peptide YY (PYY), a known inhibitor of both pancreatic secretion and the release of cholecystokinin (CCK), may play a role in the pathophysiology of acute pancreatitis (AP). Supramaximal stimulation of the pancreas with CCK, or its analogue cerulein, induces edematous AP. We previously documented significant decreases in plasma PYY in sodium taurocholate-induced AP in the anesthetized pig, with exogenous PYY suppressing plasma amylase activity. We hypothesized that PYY may ameliorate cerulein-induced pancreatic injury in a conscious animal model. Thirty-two male Sprague-Dawley rats underwent chronic cannulation of the jugular vein and carotid artery for drug infusion and blood sampling. The animals were allowed to recover from anesthesia for a minimum of 16 hours, after which they were randomized to one of four (n = 8) treatment groups (cerulein 10 micrograms/kg/h, PYY 400 pmol/kg/h, cerulein+PYY, and control-saline 2 mL/kg/h). All treatments were administered by intravenous infusion over the first 6 hours of the experiment. Blood samples were taken prior to infusion and at 1, 3, 6, 9, and 24 hours into the study; the rats were then killed and the pancreata removed for weighing and histologic examination. All pancreatic specimens were graded in a blinded fashion for vacuolization, edema, inflammation, and necrosis. The mean basal plasma amylase level for all animals was 1,171 +/- 100 U/L and was not significantly different between groups. Infusion of cerulein resulted in significant increases in plasma amylase levels at 3, 6, 9, and 24 hours (4,827 +/- 1,022 U/L at 24 hours). In the group receiving both cerulein and PYY, the hyperamylasemia was attenuated with a return to basal values at 24 hours (1,206 +/- 103 U/L). There was significant pancreatic weight gain (1.99 +/- 0.07 g versus 1.03 +/- 0.07 g) and a worsened histologic picture in cerulein-treated animals compared with control animals (worsened edema, necrosis, and vacuolization). The addition of PYY to

  11. Autoradiographic localization of peptide YY and neuropeptide Y binding sites in the medulla oblongata

    SciTech Connect

    Leslie, R.A.; McDonald, T.J.; Robertson, H.A.

    1988-09-01

    Peptide YY is a highly potent emetic when given intravenously in dogs. We hypothesized that the area postrema, a small brain stem nucleus that acts as a chemoreceptive trigger zone for vomiting and lies outside the blood-brain barrier, might have receptors that PYY would bind to, in order to mediate the emetic response. We prepared (/sup 125/I)PYY and used autoradiography to show that high affinity binding sites for this ligand were highly localized in the area postrema and related nuclei of the dog medulla oblongata. Furthermore, the distribution of (/sup 125/I)PYY binding sites in the rat medulla oblongata was very similar to that in the dog; the distribution of (/sup 125/I)PYY binding sites throughout the rat brain was seen to be similar to the distribution of (/sup 125/I)NPY binding sites.

  12. Short term aerobic exercise training increases postprandial pancreatic polypeptide but not peptide YY concentrations in obese individuals

    PubMed Central

    Kanaley, Jill A.; Heden, Timothy D.; Liu, Ying; Whaley-Connell, Adam T.; Chockalingam, Anand; Dellsperger, Kevin C.; Fairchild, Timothy J.

    2013-01-01

    Objective Short-term exercise training improves glycemic control, but the effect of short-term training on postprandial satiety peptide responses or perceived satiety remains unknown. We tested the hypothesis that short-term aerobic exercise training (15 days) would alter postprandial pancreatic and gut peptide [pancreatic polypeptide (PP) and peptide YY (PYY)] responses and perceived appetite and satiety in obese individuals. Subjects Thirteen healthy obese men and women (age: 42±2 y; BMI: 30-45 kg/m2) Measurements Subjects were studied before and after 15 days of training (walking 1 h at 70-75% VO2peak). On the study day, subjects consumed 1500 kcal as 6 meals (250 kcal: 9 g protein, 40 g CHO, 6 g fat) while blood samples and satiety measurements were taken at baseline and every 20 min for 12 h. Blood was analyzed for pancreatic polypeptide (PP), peptide YY (PYY), glucose, and insulin levels. Appetite and satiety was assessed with a visual analog scale throughout the day. Results Incremental area under the curve (iAUC) for PP increased significantly with training (pre 2788±753; post 3845±830 pg/ml·min for 12-h, p<0.001), but there was no difference in the PP response to each meal. The initial PP response to the first meal increased (ΔPPmin 20-0: pre 86±25; post 140±36 pg/ml, p<0.05) with training. PYY iAUC showed no significant changes with training but showed a significant main effect of time across meals, with the largest response being to the first meal (P<0.005). There were no changes in satiety, glucose, or insulin levels with training. Conclusion Short-term exercise training increases postprandial PP concentrations in obese individuals; however, PYY levels and glycemic control remain unaffected. Both PP and PYY show meal-induced increases at all meals but PYY has a greater response at the first meal with reduced responses at subsequent meals. PMID:23736355

  13. Effects of Endurance Running and Dietary Fat on Circulating Ghrelin and Peptide YY

    PubMed Central

    Russell, Ryan D.; Willis, Kentz S.; Ravussin, Eric; Larson-Meyer, Enette D.

    2009-01-01

    Ghrelin and peptide YY (PYY) are newly recognized gut peptides involved in appetite regulation. Plasma ghrelin concentrations are elevated in fasting and suppressed following a meal, while PYY concentrations are suppressed in fasting and elevated postprandially. We determine whether ghrelin and PYY are altered by a low-fat, high-carbohydrate (10% fat, 75% carbohydrate) or moderate-fat, moderate-carbohydrate (35% fat, 50% carbohydrate) diet and; whether these peptides are affected by intense endurance running (which is likely to temporarily suppress appetite). Twenty-one endurance-trained runners followed a controlled diet (25% fat) and training regimen for 3 days before consuming the low-fat or isoenergetic moderate-fat diet for another 3 days in random cross-over fashion. On day 7 runners underwent glycogen restoration and then completed a 90-minute pre-loaded 10-km time trial on day 8, following a control breakfast. Blood samples were obtained on days 4 and 7 (fasting), and day 8 (non-fasting) before and after exercise for analysis of ghrelin, PYY, insulin and growth hormone (GH). Insulin, GH, Ghrelin and PYY changed significantly over time (p < 0.0001) but were not influenced by diet. Ghrelin was elevated during fasting (days 4 and 7), while insulin and PYY were suppressed. Following the pre-exercise meal, ghrelin was suppressed ~17% and insulin and PYY were elevated ~157 and ~40%, respectively, relative to fasting (day 7). Following exercise, PYY, ghrelin, and GH were significantly (p < 0.0001) increased by ~11, ~16 and ~813%, respectively. The noted disruption in the typical inverse relationship between ghrelin and PYY following exercise suggests that interaction of these peptides may be at least partially responsible for post-exercise appetite suppression. These peptides do not appear to be influenced by dietary fat intake. Key points The study presents novel findings which address whether the appetite-stimulating gut peptide ghrelin and the appetite

  14. Nesfatin-1 stimulates cholecystokinin and suppresses peptide YY expression and secretion in mice.

    PubMed

    Ramesh, Naresh; Mortazavi, Sima; Unniappan, Suraj

    2016-03-25

    Nesfatin-1 is an 82 amino acid secreted peptide encoded in the precursor, nucleobindin-2 (NUCB2). It is an insulinotropic anorexigen abundantly expressed in the stomach and hypothalamus. Post-prandial insulin secretion is predominantly regulated by incretins glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Nesfatin-1 was previously reported to modulate GLP-1 and GIP secretion in vitro in an enteroendocrine (STC-1) cell line. Intestine is a source of additional hormones including cholecystokinin (CCK) and peptide YY (PYY) that regulate metabolism. We hypothesized that nesfatin-1 modulates CCK and PYY secretion. Immunofluorescence histochemistry showed NUCB2/nesfatin-1 co-localizing CCK and PYY in the intestinal mucosa of mice. Static incubation of STC-1 cells with nesfatin-1 upregulated both CCK mRNA expression (1 and 10 nM) and secretion (0.1, 1 and 10 nM) at 1 h post-incubation. In contrast, nesfatin-1 treatment for 1 h downregulated PYY mRNA expression (all doses tested) and secretion (0.01 and 0.1 nM) in STC-1 cells. Continuous infusion of nesfatin-1 using osmotic mini-pumps for 12 h upregulated CCK mRNA expression in large intestine, and downregulated PYY mRNA expression in both large and small intestines of male C57BL/6J mice. In these tissues, Western blot analysis found a corresponding increase in CCK and a decrease in PYY content. Collectively, we provide new information on the cell specific localization of NUCB2/nesfatin-1 in the intestinal mucosa, and a novel function for nesfatin-1 in modulating intestinal CCK and PYY expression and secretion in mice.

  15. Duplication of neuropeptide Y and peptide YY in Nile tilapia Oreochromis niloticus and their roles in food intake regulation.

    PubMed

    Yan, Peipei; Jia, Jirong; Yang, Guokun; Wang, Dongfang; Sun, Caiyun; Li, Wensheng

    2017-02-01

    In vertebrates, the neuropeptide Y (NPY) family peptides have been recognized as key players in food intake regulation. NPY centrally promotes feeding, while peptide YY (PYY) and pancreatic polypeptide (PP) mediate satiety. The teleost tetraploidization is well-known to generate duplicates of both NPY and PYY; however, the functional diversification between the duplicate genes, especially in the regulation of food intake, remains unknown. In this study, we identified the two duplicates of NPY and PYY in Nile tilapia (Oreochromis niloticus). Both NPYa and NPYb were primarily expressed in the central nervous system (CNS), but the mRNA levels of NPYb were markedly lower than those of NPYa. Hypothalamic mRNA expression of NPYa, but not NPYb, decreased after feeding and increased after 7-days of fasting. However, both NPYa and NPYb caused a significant increase in food intake after an intracranial injection of 50ng/g body weight dose. PYYb, one of the duplicates of PYY, had an extremely high expression in the foregut and midgut, whereas another form of duplicate PYYa showed only moderate expression in the CNS. Both hypothalamic PYYa and foregut PYYb mRNA expression increased after feeding and decreased after 7-days of fasting. Furthermore, the intracranial injection of PYYb decreased food intake, but PYYa had no significant effect. Our results suggested that although the mature peptides of NPYa and NPYb can both stimulate food intake, NPYa is the main endogenous functional NPY for feeding regulation. A functional division has been identified in the duplicates of PYY, which deems PYYb as a gut-derived anorexigenic peptide and PYYa as a CNS-specific PYY in Nile tilapia. Copyright © 2016 Elsevier Inc. All rights reserved.

  16. Hormonal response to enteral feeding and the possible role of peptide YY in pathogenesis of enteral feeding-related diarrhoea.

    PubMed

    Bowling, T E; Silk, D B

    1996-12-01

    Diarrhoea is a common complication of enteral feeding. Previous studies have demonstrated a secretion of water and electrolytes in the ascending colon during intragastric but not intraduodenal enteral feeding. The cause of this secretion is likely to be neurohumoral in origin. This study was designed to examine the hormonal responses to enteral feeding. In vivo segmental colonic perfusion studies were undertaken. Before and at hourly intervals during these studies serum was taken for estimations of neurotensin (NT), pancreatic glucagon (PG), peptide YY (PYY) and vasoactive intestinal polypeptide (VIP). During fasting there was a median ascending colonic absorption of water in all groups. During feeding there was a net secretion in the ascending colon in both gastric groups and in the high load duodenal group, but not in the low load duodenal group. During these studies the PYY levels remained unchanged from fasting in the low and high load gastric groups. In the low and high load duodenal groups the PYY levels increased. The NT levels increased only in the high load duodenal group. There were no other changes in NT or in PG or VIP levels either between fasting and feeding, or between the gastric and duodenal groups. PYY is known to stimulate intestinal absorption. The absence of a rise during intragastric feeding may be important in the underlying mechanisms of enteral feeding-induced colonic secretion and hence enteral feeding-related diarrhoea.

  17. Cholinergic Regulation of Ghrelin and Peptide YY Release May Be Impaired in Obesity

    PubMed Central

    Maier, Christina; Riedl, Michaela; Vila, Greisa; Nowotny, Peter; Wolzt, Michael; Clodi, Martin; Ludvik, Bernhard; Luger, Anton

    2008-01-01

    OBJECTIVE—Ghrelin and peptide YY (PYY) are both hormones derived from the gastrointestinal tract involved in appetite regulation. The cholinergic part of the vagal nerve is involved in the regulation of glucose and insulin. The aim of this study was to examine the effects of the cholinergic antagonist atropine on ghrelin, PYY, glucose, and insulin under basal conditions and after meal ingestion in lean and obese subjects. REASEARCH DESIGN AND METHODS—Eight lean and eight obese subjects were included in a randomized, double-blind, placebo-controlled crossover study with 4 study days in randomized order (atropine/placebo ± breakfast). Plasma ghrelin, PYY, insulin, and glucose were measured. Hunger and satiety feelings were rated on a 10-cm visual analog scale. RESULTS—In lean individuals, atropine led to a decrease in ghrelin concentrations comparable and nonadditive with breakfast ingestion and a significant decrease in both basal and meal-induced PYY concentrations. In obese subjects, atropine did not significantly change ghrelin or PYY concentrations, whereas it induced a comparable increase in heart rate and meal-induced glucose concentrations in the two study groups. Only lean, not obese, subjects experienced sustained feelings of satiety after breakfast. CONCLUSIONS—The impaired cholinergic regulation of the postprandial drop in ghrelin concentrations and rise in PYY concentrations might be part of the deregulated food intake in obese subjects. PMID:18567824

  18. GSK2374697, a long duration glucagon-like peptide-1 (GLP-1) receptor agonist, reduces postprandial circulating endogenous total GLP-1 and peptide YY in healthy subjects.

    PubMed

    Lin, J; Hodge, R J; O'Connor-Semmes, R L; Nunez, D J

    2015-10-01

    We investigated the effects of a long-duration glucagon-like peptide-1 (GLP-1) receptor agonist, GSK2374697, on postprandial endogenous total GLP-1 and peptide YY (PYY). Two cohorts of healthy subjects, one normal/overweight and one obese, were randomized to receive GSK2374697 2 mg (n = 8 each) or placebo (n = 4 and n = 2) subcutaneously on days 1, 4 and 7. Samples for plasma endogenous GLP-1 and PYY were collected after breakfast on days -1 and 12. Weighted mean area under the curve (0-4 h) of total GLP-1 and PYY in treated subjects was reduced compared with placebo. The least squares mean difference for change from baseline was -1.24 pmol/l [95% confidence interval (CI) -2.33, -0.16] and -4.47 pmol/l (95% CI -8.74, -0.20) for total GLP-1 and PYY, respectively, in normal/overweight subjects (p < 0.05 for both), and -1.56 (95% CI -2.95, -0.16) and -3.02 (95% CI -8.58, 2.55), respectively, in obese subjects (p < 0.05 for GLP-1). In healthy subjects, GSK2374697 reduced postprandial total GLP-1 and PYY levels, suggesting feedback suppression of enteroendocrine L-cell secretion of these peptides.

  19. Neuropeptide Y (NPY) and peptide YY (PYY) receptors in rat brain

    SciTech Connect

    Ohkubo, T.; Niwa, M.; Yamashita, K.; Kataoka, Y.; Shigematsu, K. )

    1990-12-01

    1. Specific binding sites for neuropeptide Y (NPY) and peptide YY (PYY) were investigated in rat brain areas using quantitative receptor autoradiography with {sup 125}I-Bolton-Hunter NPY ({sup 125}I-BH-NPY) and {sup 125}I-PYY, radioligands for PP-fold family peptides receptors. 2. There were no differences between localization of {sup 125}I-BH-NPY and {sup 125}I-PYY binding sites in the rat brain. High densities of the binding sites were present in the anterior olfactory nucleus, lateral septal nucleus, stratum radiatum of the hippocampus, posteromedial cortical amygdaloid nucleus, and area postrema. 3. In cold ligand-saturation experiments done in the presence of increasing concentrations of unlabeled NPY and PYY, {sup 125}I-BH-NPY and {sup 125}I-PYY binding to the stratum radiatum of the hippocampus, layer I of the somatosensory frontoparietal cortex, molecular layer of the cerebellum, and area postrema was single and of a high affinity. There was a significant difference between the affinities of {sup 125}I-BH-NPY (Kd = 0.96 nM) and {sup 125}I-PYY binding (Kd = 0.05 nM) to the molecular layer of the cerebellum. The binding of the two radioligands to the other areas examined had the same affinities. 4. When comparing the potency of unlabeled rat pancreatic polypeptide (rPP), a family peptide of NPY and PYY, to inhibit the binding to the areas examined, rPP displaced {sup 125}I-BH-NPY and {sup 125}I-PYY binding to the area postrema more potently than it did the binding to the stratum radiatum of the hippocampus, layer I of the somatosensory frontoparietal cortex, and molecular layer of the cerebellum. 5. Thus, the quantitative receptor autoradiographic method with {sup 125}I-BH-NPY and {sup 125}I-PYY revealed differences in binding characteristics of specific NPY and PYY binding sites in different areas of the rat brain. The results provide further evidence for the existence of multiple NPY-PYY receptors in the central nervous system.

  20. 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

  1. Ghrelin but not peptide YY is related to change in body weight and energy availability.

    PubMed

    Scheid, Jennifer L; De Souza, Mary Jane; Leidy, Heather J; Williams, Nancy I

    2011-11-01

    The aim of this study was to examine changes in fasting total peptide YY (PYY) and ghrelin in nonobese premenopausal women after an exercise and diet program with and without weight loss. Body composition, energy balance parameters, ghrelin, and PYY were measured before and after a 3-month intervention in nonexercising controls (n = 7) and exercising women who either remained weight stable (n = 5) or lost weight (n = 10). At baseline, subjects were 20.6 ± 2.2 yr, weighed 58.0 ± 4.8 kg, and had 27.2% ± 4.9% body fat. Supervised exercise training occurred five times a week for up to 90 min at 70%-80% of maximum HR. Subjects were fed a controlled diet. Body weight (-3.2 ± 0.8 kg) and fat mass (-2.6 ± 0.7 kg) decreased significantly in the weight-loss exercise group. Neither fasting ghrelin nor PYY changed in response to exercise training in the absence of weight loss, and PYY did not change with exercise and weight loss. Fasting ghrelin did reveal a significant time × experimental group interaction (P = 0.025). The change in ghrelin was inversely correlated with the change in body weight, body mass index, fat-free mass, and energy availability. Neither fasting ghrelin nor fasting PYY seem to play a role in the adaptive changes associated with exercise training when exercise occurs in the absence of weight loss. Fasting ghrelin concentrations increase when body weight is lost and may respond to even smaller changes in energy availability. However, fasting PYY does not seem to play a key role in the regulation of energy balance during diet- and exercise-associated weight loss.

  2. Stimulation of murine peritoneal macrophage functions by neuropeptide Y and peptide YY. Involvement of protein kinase C.

    PubMed Central

    De la Fuente, M; Bernaez, I; Del Rio, M; Hernanz, A

    1993-01-01

    The peptides neuropeptide Y (NPY) and peptide YY (PYY) at concentrations from 10(-12) M to 10(-8) M have been shown in this study to stimulate significantly, in vitro, several functions of resting peritoneal macrophages from BALB/c mice: adherence to substrate, chemotaxis, ingestion of inert particles (latex beads) and foreign cells (Candida albicans), and production of superoxide anion measured by nitroblue tetrazolium reduction. A dose-response relationship was observed, with a maximal stimulation of the macrophage functions studied at 10(-10) M. These effects seem to be produced by specific receptors for the neuropeptides studied in peritoneal macrophages. Whereas the two peptides induced no change of intracellular cyclic AMP, they caused a significant stimulation of protein kinase C (PKC) in murine macrophages. These results suggest that NPY and PYY produce their effects on macrophage function through PKC activation. PMID:8262554

  3. Oral administration of nasturtium affects peptide YY secretion in male subjects.

    PubMed

    Schiess, Sonja; Platz, Stefanie; Kemper, Margrit; Schreiner, Monika; Mewis, Inga; Rohn, Sascha; Bumke-Vogt, Christiane; Pivovarova, Olga; Pfeiffer, Andreas F H

    2017-08-01

    Nasturtium plants contain the glucosinolate glucotropaeolin and its corresponding breakdown product benzyl isothiocyanate (BITC), the latter being intensively studied with regard to cancer chemoprevention and anti-inflammatory properties. In addition, recent research has shown that isothiocyanates are able to activate the release of several gut hormones in vitro and in rodent studies. Here, we tested the effects of a dietary nasturtium administration on circulating levels of gut hormones in humans. Metabolically healthy males (n = 15) received a single oral dose of 10 g freeze-dried nasturtium leaf material suspended in water or only water (control). Blood samples were taken every hour and serum concentrations of insulin, C-peptide, glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), and peptide (PYY) were analyzed. Oral nasturtium intake resulted in an increased release of PYY over a time period of 6 h whereas circulating levels of other hormones were not changed. Given the finding that nasturtium consumption enhances secretion of PYY, a key hormone involved in energy regulation, special diets containing nasturtium, or supplementation with nasturtium or BITC might be considered in the treatment of obesity. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  4. Effects of Meals High in Carbohydrate, Protein, and Fat on Ghrelin and Peptide YY Secretion in Prepubertal Children

    PubMed Central

    Lomenick, Jefferson P.; Melguizo, Maria S.; Mitchell, Sabrina L.; Summar, Marshall L.; Anderson, James W.

    2009-01-01

    Context: Ghrelin and peptide YY (PYY) are two hormones produced by the gastrointestinal tract that have effects on appetite. However, little is known about their secretion in response to meals high in individual macronutrients in prepubertal children. Objective: We sought to understand how meals high in carbohydrate, protein, and fat affect serum concentrations of total ghrelin and total PYY, hypothesizing that these macronutrients would exert differential effects on their secretion. Design and Setting: This was a cross-sectional study at one tertiary care center. Subjects: Subjects were 7- to 11-yr-old healthy normal-weight (NW) and obese (OB) volunteers recruited from local advertisements. Interventions: After an overnight fast, the subjects were given a breakfast high in carbohydrate, protein, or fat at 0800 h. Blood samples for total ghrelin and total PYY were taken at baseline, 30 min, and hourly from 0900 to 1200 h. Main Outcome Measure: We assessed postprandial ghrelin suppression and PYY elevation, as well as changes in reported hunger and satiety, after the three test meals. Results: After the high-protein meal, ghrelin declined gradually in both groups over the study period without subsequent increase, whereas ghrelin suppressed more rapidly to a nadir at 60 min after the high-carbohydrate meal in both NW and OB children, followed by rebound in ghrelin levels. Similarly, after the high-protein meal, PYY concentrations increased steadily over the course of the morning in both groups without decline, whereas PYY levels peaked 30 min after the high-carbohydrate meal in both NW and OB subjects with significant decline thereafter. Ghrelin and PYY responses to the high-fat meal were somewhat intermediate between that observed with high carbohydrate and high protein. The OB children reported higher hunger and lower satiety after the high-carbohydrate meal compared to the NW subjects, whereas appetite ratings were similar between the groups after the high

  5. 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.

  6. Low densities of serotonin and peptide YY cells in the colon of patients with irritable bowel syndrome.

    PubMed

    El-Salhy, M; Gundersen, D; Ostgaard, H; Lomholt-Beck, B; Hatlebakk, J G; Hausken, T

    2012-04-01

    The gut hormones are important in regulating gastrointestinal motility. Disturbances in gastrointestinal motility have been reported in patients with irritable bowel syndrome (IBS). Reduced endocrine cell density, as revealed by chromogranin A, has been reported in the colon of IBS patients. To investigate a possible abnormality in the colonic endocrine cells of IBS patients. A total of 41 patients with IBS according to Rome Criteria III and 20 controls were included in the study. Biopsies from the right and left colon were obtained from both patients and controls during colonoscopy. The biopsies were immunostained for serotonin, peptide YY (PYY), pancreatic polypeptide (PP), entroglucagon, and somatostatin cells. Cell densities were quantified by computerized image analysis. Serotonin and PYY cell densities were reduced in the colon of IBS patients. PP, entroglucagon, and somatostatin-immunoreactive cells were too few to enable reliable quantification. The cause of these observations could be primary genetic defect(s), secondary to altered serotonin and/or PYY signaling systems and/or subclinical inflammation. Serotonin activates the submucosal sensory branch of the enteric nervous system and controls gastrointestinal motility and chloride secretion via interneurons and motor neurons. PYY stimulates absorption of water and electrolytes, and inhibits prostaglandin (PG) E2, and vasoactive intestinal peptide, which stimulates intestinal fluid secretion and is a major regulator of the "ileal brake". Although the cause and effect relationship of these findings is difficult to elucidate, the abnormalities reported here might contribute to the symptoms associated with IBS.

  7. 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.

  8. An Ovarian Carcinoid Tumor With Peptide YY-Positive Insular Component: A Case Report and Review of the Literature.

    PubMed

    Erdenebaatar, Chimeddulam; Yamaguchi, Munekage; Saito, Fumitaka; Motooka, Chisato; Tashiro, Hironori; Katabuchi, Hidetaka

    2016-07-01

    Ovarian carcinoid tumors are uncommon and account for 1% of all carcinoid tumors. The insular type of ovarian carcinoid tumor is common in western countries; in contrast, the strumal and trabecular types seem to be common in Asian countries. Strumal and trabecular types are associated with peptide YY (PYY) production, which may cause constipation. Here, we report the case of a 70-yr-old Japanese woman with chronic constipation who was referred to Kumamoto University Hospital because of a right adnexal mass. Imaging tests suggested that the solid mass might be malignant; therefore, abdominal total hysterectomy, bilateral salpingo-oophorectomy, and omentectomy were performed. A subsequent histopathologic examination confirmed an insular carcinoid tumor with a trabecular component in the right ovary. Both components were positive for PYY but not for serotonin. The patient complained of diarrhea instead of constipation soon after the surgery. Because PYY-positive insular carcinoid tumor in the ovary has not been previously reported, we reviewed 19 reported cases of patients with PYY-positive ovarian carcinoid tumors. The origins, common histologic types and symptoms caused by specific peptides secreted in ovarian carcinoid tumors differ between western and Asian countries.

  9. Role of peptide YY(3-36) in the satiety produced by gastric delivery of macronutrients in rats.

    PubMed

    Reidelberger, Roger; Haver, Alvin; Chelikani, Prasanth K

    2013-05-01

    Peptide YY(3-36) [PYY(3-36)] is postulated to act as a hormonal signal from gut to brain to inhibit food intake. PYY(3-36) potently reduces food intake when administered systemically or into the brain. If action of endogenous PYY(3-36) is necessary for normal satiation to occur, then pharmacological blockade of its receptors should increase food intake. Here, we determined the effects of iv infusion of Y1, Y2, and Y5 receptor antagonists (BIBP 3226, BIIE 0246, CGP 71683) during the first 3 h of the dark period on food intake in non-food-deprived rats. Our results showed that 1) Y2 receptor blockade reversed the anorexic response to iv infusion of PYY(3-36) but did not increase food intake when administered alone; 2) Y1 and Y5 receptor antagonists neither attenuated PYY(3-36)-induced anorexia nor altered food intake when given alone; and 3) Y2 receptor blockade attenuated anorexic responses to gastric infusions of casein hydrolysate and long-chain triglycerides, but not maltodextrin. Previous work showed that Y2 antagonist BIIE 0246 does not penetrate the blood-brain barrier. Together, these results support the hypothesis that gut PYY(3-36) action at Y2 receptors peripheral to the blood brain barrier plays an essential role in mediating satiety responses to gastric delivery of protein and long-chain triglycerides, but not polysaccharide.

  10. Short-term regulation of peptide YY secretion by a mixed meal or peritoneal glucose-based dialysate in patients with chronic renal failure.

    PubMed

    Pérez-Fontán, Miguel; Cordido, Fernando; Rodríguez-Carmona, Ana; Penín, Manuel; Díaz-Cambre, Helena; López-Muñiz, Andrés; Sangiao-Alvarellos, Susana; García-Buela, Jesús

    2008-11-01

    Malnutrition is very prevalent among patients with chronic renal failure. The role of derangements in the gut-brain axis for regulation of appetite in the genesis of anorexia of these patients has not been adequately investigated. Design. Following a randomized, crossover design, we analysed plasma levels of peptide YY (PYY)(1-36) and PYY(3-36) both fasting and after a standardized oral mixed meal or intraperitoneal glucose infusion in 10 stable uraemic patients undergoing peritoneal dialysis and 8 healthy controls, matched for age, gender and body mass index. Main results. Median baseline plasma levels of PYY(1-36) in the different provocation tests oscillated between 406 and 460 pg/mL in patients, as compared with 73 and 100 pg/mL in controls (P < 0.001). Corresponding values for PYY(3-36) oscillated between 235 and 267 pg/mL in patients, versus 56 and 70 pg/mL in controls (P < 0.001). The association of high levels of PYY(3-36) and normal levels of acylated ghrelin (when compared with healthy controls) configurated a markedly pro-anorexigenic pattern in patients. Neither oral intake nor intraperitoneal glucose resulted in significant changes in plasma levels of PYY(1-36) or PYY(3-36) in subjects with renal failure, in contrast with the expected postprandial rise observed in healthy controls (41% for PYY(1-36), P = 0.04 and 32% for PYY(3-36), P = 0.02, median values). Baseline plasma levels of PYY(1-36) or PYY(3-36) are markedly elevated in patients with renal failure undergoing peritoneal dialysis. Provocation studies disclose a marked disregulation in the postprandial secretion of these anorexigenic peptides, when compared with healthy controls. These findings may contribute to clarify the complex pathogenesis of anorexia of chronic renal failure.

  11. Weight loss during oligofructose supplementation is associated with decreased ghrelin and increased peptide YY in overweight and obese adults2

    PubMed Central

    Parnell, Jill A; Reimer, Raylene A

    2013-01-01

    Background Rodent studies show that oligofructose promotes weight loss, stimulates satiety hormone secretion, reduces energy intake, and improves lipid profiles. Objective Our objective was to examine the effects of oligofructose supplementation on body weight and satiety hormone concentrations in overweight and obese adults. Design This study was a randomized, double-blind, placebo-controlled trial. Forty-eight otherwise healthy adults with a body mass index (in kg/m2) > 25 were randomly assigned to receive 21 g oligo-fructose/d or a placebo (maltodextrin) for 12 wk. Body composition (by dual-energy X-ray absorptiometry); meal tolerance tests, including satiety hormone response; food intake; and subjective appetite ratings were determined. Results There was a reduction in body weight of 1.03 ±0.43 kg with oligofructose supplementation, whereas the control group experienced an increase in body weight of 0.45 ± 0.31 kg over 12 wk (P = 0.01). A lower area under the curve (AUC) for ghrelin (P = 0.004) and a higher AUC for peptide YY (PYY) with oligofructose (P = 0.03) coincided with a reduction in self-reported caloric intake (P ≤ 0.05). Glucose decreased in the oligofructose group and increased in the control group between initial and final tests (P ≤ 0.05). Insulin concentrations mirrored this pattern (P ≤ 0.05). Oligofructose supplementation did not affect plasma active glucagon-like peptide 1 secretion. According to a visual analog scale designed to assess side effects, oligofructose was well tolerated. Conclusions Independent of other lifestyle changes, oligofructose supplementation has the potential to promote weight loss and improve glucose regulation in overweight adults. Suppressed ghrelin and enhanced PYY may contribute in part to the reduction in energy intake. The trial was registered at clinicaltrials.gov as NCT00522353. PMID:19386741

  12. Fat digestion is required for suppression of ghrelin and stimulation of peptide YY and pancreatic polypeptide secretion by intraduodenal lipid.

    PubMed

    Feinle-Bisset, Christine; Patterson, Michael; Ghatei, Mohammad A; Bloom, Stephen R; Horowitz, Michael

    2005-12-01

    Stimulation of cholecystokinin and glucagon-like peptide-1 secretion by fat is mediated by the products of fat digestion. Ghrelin, peptide YY (PYY), and pancreatic polypeptide (PP) appear to play an important role in appetite regulation, and their release is modulated by food ingestion, including fat. It is unknown whether fat digestion is a prerequisite for their suppression (ghrelin) or release (PYY, PP). Moreover, it is not known whether small intestinal exposure to fat is sufficient to suppress ghrelin secretion. Our study aimed to resolve these issues. Sixteen healthy young males received, on two separate occasions, 120-min intraduodenal infusions of a long-chain triglyceride emulsion (2.8 kcal/min) 1) without (condition FAT) or 2) with (FAT-THL) 120 mg of tetrahydrolipstatin (THL, lipase inhibitor), followed by a standard buffet-style meal. Blood samples for ghrelin, PYY, and PP were taken throughout. FAT infusion was associated with a marked, and progressive, suppression of plasma ghrelin from t = 60 min (P < 0.001) and stimulation of PYY from t = 30 min (P < 0.01). FAT infusion also stimulated plasma PP (P < or = 0.01), and the release was immediate. FAT-THL completely abolished the FAT-induced changes in ghrelin, PYY, and PP. In response to the meal, plasma ghrelin was further suppressed, and PYY and PP stimulated, during both FAT and FAT-THL infusions. In conclusion, in healthy humans, 1) the presence of fat in the small intestine suppresses ghrelin secretion, and 2) fat-induced suppression of ghrelin and stimulation of PYY and PP is dependent on fat digestion.

  13. The Melanocortin-4 Receptor is Expressed in Enteroendocrine L Cells and Regulates the Release of Peptide YY and Glucagon-Like Peptide 1 In Vivo

    PubMed Central

    Panaro, Brandon L.; Tough, Iain R.; Engelstoft, Maja Storm; Matthews, Robert T.; Digby, Gregory J.; Møller, Cathrine Laustrup; Svendsen, Berit; Gribble, Fiona; Reimann, Frank; Holst, Jens J.; Holst, Birgitte; Schwartz, Thue W.; Cox, Helen M.; Cone, Roger D.

    2014-01-01

    SUMMARY The melanocortin-4 receptor (MC4R) is expressed in the brainstem and vagal afferent nerves, and regulates a number of aspects of gastrointestinal function. Here we show that the receptor is also diffusely expressed in cells of the gastrointestinal system, from stomach to descending colon. Furthermore, MC4R is the second most highly expressed GPCR in peptide YY (PYY) and glucagon-like peptide one (GLP-1) expressing enteroendocrine L cells. When vectorial ion transport is measured across mouse or human intestinal mucosa, administration of α-MSH induces a MC4R-specific PYY-dependent anti-secretory response consistent with a role for the MC4R in paracrine inhibition of electrolyte secretion. Finally, MC4R-dependent acute PYY and GLP-1 release from L cells can be stimulated in vivo by intraperitoneal administration of melanocortin peptides to mice. This suggests physiological significance for MC4R in L cells, and indicates a previously unrecognized peripheral role for the MC4R, complementing vagal and central receptor functions. PMID:25453189

  14. Gastric bypass surgery restores meal stimulation of the anorexigenic gut hormones glucagon-like peptide-1 and peptide YY independently of caloric restriction.

    PubMed

    Evans, Sarah; Pamuklar, Zehra; Rosko, Jonathan; Mahaney, Patrick; Jiang, Ning; Park, Chan; Torquati, Alfonso

    2012-04-01

    The effects of gastric bypass surgery on the secretion of the anorexigenic gut-derived hormones glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), independent of caloric restriction and due to different dietary macronutrients, is not well characterized. This study examines the effects of a mixed-nutrient or high-fat liquid meal on the postprandial stimulation of GLP-1 and PYY following gastric bypass or equivalent hypocaloric diet. Total PYY and active GLP-1 were measured fasting and at multiple points after standardized mixed-nutrient and high-fat liquid meals in two matched groups of obese subjects. The meal stimulation tests were performed before and 14.6 ± 3.3 days after gastric bypass (GBP, n = 10) and before and after a 7-day hypocaloric liquid diet matching the post-GBP diet (control, n = 10). Mixed-nutrient and high-fat postprandial GLP-1 levels increased following GBP (mixed-nutrient peak: 85.0 ± 28.6-323 ± 51 pg/ml, P < 0.01; high-fat peak: 81.8 ± 9.6-278 ± 49 pg/ml, P < 0.01), but not after diet (mixed-nutrient peak: 104.4 ± 9.4-114.9 ± 15.8 pg/ml, P = NS; high-fat peak: 118.1 ± 16.4-104.4 ± 10.8 pg/ml, P = NS). The postprandial PYY response also increased after GBP but not diet, though the increase in peak PYY did not reach statistical significance (GBP mixed-nutrient peak: 134.8 ± 26.0-220.7 ± 52.9 pg/ml, P = 0.09; GBP high-fat peak: 142.1 ± 34.6-197.9 ± 12.7 pg/ml, P = 0.07; diet mixed-nutrient peak: 99.8 ± 8.0-101.1 ± 13.3 pg/ml, P = NS; diet high-fat peak: 105.0 ± 8.8-103.1 ± 11.8 pg/ml, P = NS). The postprandial GLP-1 response was not affected by the macronutrient content of the meal. However, following GBP the mixed-nutrient PYY total area under the curve (AUC(0-120)) was significantly greater than the high-fat PYY AUC(0-120) (22,081 ± 5,662 pg/ml min vs. 18,711 ± 1,811 pg/ml min, P = 0.04). Following GBP there is an increase in the postprandial stimulation of PYY and GLP-1 that is independent of caloric restriction. The

  15. GASTRIC BYPASS SURGERY RESTORES MEAL STIMULATION OF THE ANOREXIGENIC GUT HORMONES GLUCAGON-LIKE PEPTIDE-1 AND PEPTIDE YY INDEPENDENTLY OF CALORIC RESTRICTION

    PubMed Central

    Evans, Sarah; Pamuklar, Zehra; Rosko, Jonathan; Mahaney, Patrick; Jiang, Ning; Park, Chan; Torquati, Alfonso

    2011-01-01

    Background The effects of gastric bypass surgery on the secretion of the anorexogenic gut-derived hormones glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), independent of caloric restriction and due to different dietary macronutrients, is not well-characterized. This study examines the effects of a mixed-nutrient or high-fat liquid meal on the postprandial stimulation of GLP-1 and PYY following gastric bypass or equivalent hypocaloric diet. Methods Total PYY and active GLP-1 were measured fasting and at multiple points after standardized mixed-nutrient and high-fat liquid meals in two matched groups of obese subjects. The meal stimulation tests were performed before and 14.6±3.3 days after gastric bypass (GBP, n=10) and before and after a 7-day hypocaloric liquid diet matching the post-GBP diet (Control, n=10). Results Mixed-nutrient and high-fat postprandial GLP-1 levels increased following GBP (mixed-nutrient peak: 85.0±28.6 pg/ml to 323±51 pg/ml, p<0.01; high-fat peak: 81.8±9.6 pg/ml to 278±49 pg/ml, p<0.01), but not after diet (mixed-nutrient peak: 104.4±9.4 pg/ml to 114.9±15.8 pg/ml, p=NS; high-fat peak: 118.1±16.4 pg/ml to 104.4±10.8 pg/ml, p=NS). The postprandial PYY response also increased after GBP but not diet, though the increase in peak PYY did not reach statistical significance (GBP mixed-nutrient peak: 134.8±26.0 pg/ml to 220.7±52.9 pg/ml, p=0.09; GBP high-fat peak: 142.1±34.6 pg/ml to 197.9±12.7 pg/ml, p=0.07; diet mixed-nutrient peak: 99.8±8.0 pg/ml to 101.1±13.3 pg/ml, p=NS; diet high-fat peak: 105.0±8.8 pg/ml to 103.1±11.8 pg/ml, p=NS). The postprandial GLP-1 response was not affected by the macronutrient content of the meal. However, following GBP the mixed-nutrient PYY AUC0–120 was significantly greater than the high-fat PYY AUC0–120 (22081±5662 pg/ml•min versus 18711±1811 pg/ml•min, p=0.04). Conclusions Following GBP there is an increase in the postprandial stimulation of PYY and GLP-1 that is independent from

  16. Sex-dependent control of murine emotional-affective behaviour in health and colitis by peptide YY and neuropeptide Y

    PubMed Central

    Painsipp, Evelin; Herzog, Herbert; Sperk, Günther; Holzer, Peter

    2011-01-01

    BACKGROUND AND PURPOSE Peptide YY (PYY) and neuropeptide Y (NPY) are involved in regulating gut and brain function. Because gastrointestinal inflammation is known to enhance anxiety, we explored whether experimental colitis interacts with genetic deletion (knockout) of PYY and NPY to alter emotional-affective behaviour. EXPERIMENTAL APPROACH Male and female wild-type, NPY (NPY−/−), PYY (PYY−/−) and NPY−/−; PYY−/− double knockout mice were studied in the absence and presence of mild colitis induced by ingestion of dextran sulphate sodium (2%) in drinking water. Anxiety-like behaviour was tested on the elevated plus maze and open field, and depression-like behaviour assessed by the forced swim test. KEY RESULTS In the absence of colitis, anxiety-like behaviour was increased by deletion of NPY but not PYY in a test- and sex-dependent manner, while depression-like behaviour was enhanced in NPY−/− and PYY−/− mice of either sex. The severity of DSS-induced colitis, assessed by colonic myeloperoxidase content, was attenuated in NPY−/− but not PYY−/− mice. Colitis modified anxiety- and depression-related behaviour in a sex-, genotype- and test-related manner, and knockout experiments indicated that NPY and PYY were involved in some of these behavioural effects of colitis. CONCLUSIONS AND IMPLICATIONS These data demonstrate sex-dependent roles of NPY and PYY in regulation of anxiety- and depression-like behaviour in the absence and presence of colitis. Like NPY, the gut hormone PYY has the potential to attenuate depression-like behaviour but does not share the ability of NPY to reduce anxiety-like behaviour. PMID:21410462

  17. Structural characterization of Y1 and Y2 receptors for neuropeptide Y and peptide YY by affinity cross-linking

    SciTech Connect

    Sheikh, S.P.; Williams, J.A. )

    1990-05-15

    Pharmacological studies indicate that peptide YY (PYY) and neuropeptide Y interact with multiple binding sites, categorized as Y1 and Y2 subtypes. In order to identify and structurally characterize the Y1 and Y2 receptors we covalently cross-linked (125I-Tyr36)PYY to its receptors. The Y2 receptor in rat hippocampus and rabbit kidney membranes was affinity labeled using different homo- and heterobifunctional cross-linking reagents. Analysis by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and autoradiography resulted in a major labeled protein band of Mr = 50,000 in both hippocampal and kidney membranes, which was unaffected by reducing agents. The Y1 receptor was analyzed in membranes from the MC-IXC human neuroblastoma cell line. Autoradiography revealed two labeled bands at Mr = 70,000 and 45,000. As the intensity of the Mr = 45,000 band was reduced by protease inhibitors, it is likely that this band is a degradation product of the larger band. Labeling of these proteins was obtained only when N-5-azido-2-nitrobenzoyloxysuccinimide was employed for cross-linking followed by exposure to UV light. Labeling of the two cross-linked bands was unaffected by reducing agents. The binding of radiolabeled PYY and the intensity of the cross-linked bands, for both the Y1 and Y2 receptors, were inhibited similarly in a dose-dependent manner by increasing concentrations of unlabeled PYY. When exposed to agarose-coupled lectins, the detergent-solubilized Y1 receptor-hormone complex was completely adsorbed by wheat germ agglutinin and partially by ricin communis II. The cross-linked Y2 receptor was almost totally adsorbed by wheat germ agglutinin-agarose and partially adsorbed by concanavalin A. The adsorptions were in all cases blocked by the appropriate hapten sugar.

  18. The functional involvement of gut-expressed sweet taste receptors in glucose-stimulated secretion of glucagon-like peptide-1 (GLP-1) and peptide YY (PYY).

    PubMed

    Steinert, R E; Gerspach, A C; Gutmann, H; Asarian, L; Drewe, J; Beglinger, C

    2011-08-01

    Enteroendocrine cells are thought to directly sense nutrients via α-gustducin coupled taste receptors (originally identified in the oral epithelium) to modulate the secretion of glucagon-like peptide-1 (GLP-1) and peptide YY (PYY). We measured mRNA expression of α-gustducin and T1R3 along the human gut; immunohistochemistry was used to confirm co-localization with GLP-1. Functional implication of sweet taste receptors in glucose-stimulated secretion of GLP-1 and PYY was determined by intragastric infusion of glucose with or without lactisole (a sweet taste receptor antagonist) in 16 healthy subjects. α-gustducin was expressed in a region-specific manner (predominantly in the proximal gut and less in ileum and colon, P < 0.05). Both, T1R3 and α-gustducin were co-localized with GLP-1. Glucose-stimulated secretions of GLP-1 (P = 0.026) and PYY (P = 0.034) were reduced by blocking sweet receptors with lactisole. Key proteins implicated in taste signaling are present in the human gut and co-localized with GLP-1 suggesting that these proteins are functionally linked to peptide secretion from enteroendocrine cells. Glucose-stimulated secretion of GLP-1 and PYY is reduced by a sweet taste antagonist, suggesting the functional involvement of gut-expressed sweet taste receptors in glucose-stimulated secretion of both peptides in humans. Copyright © 2011 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

  19. 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

  20. Peptide YY signaling in the lateral parabrachial nucleus increases food intake through the Y1 receptor

    PubMed Central

    Golub, Danielle; Hayes, Matthew R.; Grill, Harvey J.

    2015-01-01

    Although central PYY delivery potently increases food intake, the sites of action and mechanisms mediating these hyperphagic effects are not fully understood. The present studies investigate the contribution of lateral parabrachial nucleus (lPBN) PYY-Y receptor signaling to food intake control, as lPBN neurons express Y receptors and receive PYY fibers and are known to integrate circulating and visceral sensory signals to regulate energy balance. Immunohistochemical results identified a subpopulation of gigantocellular reticular nucleus PYY-producing neurons that project monosynaptically to the lPBN, providing an endogenous source of PYY to the lPBN. lPBN microinjection of PYY-(1–36) or PYY-(3–36) markedly increased food intake by increasing meal size. To determine which receptors mediate these behavioral results, we first performed quantitative real-time PCR to examine the relative levels of Y receptor expression in lPBN tissue. Gene expression analyses revealed that, while Y1, Y2, and Y5 receptors are each expressed in lPBN tissue, Y1 receptor mRNA is expressed at fivefold higher levels than the others. Furthermore, behavioral/pharmacological results demonstrated that the hyperphagic effects of PYY-(3–36) were eliminated by lPBN pretreatment with a selective Y1 receptor antagonist. Together, these results highlight the lPBN as a novel site of action for the intake-stimulatory effects of central PYY-Y1 receptor signaling. PMID:26330345

  1. Effects of Glycine-Extended and Serine13-Phosphorylated Forms of Peptide YY on Food Intake in Rats

    PubMed Central

    Reidelberger, Roger; Haver, Alvin; Chelikani, Prasanth; Keire, David A.; Reeve, Joseph R.

    2011-01-01

    The gut hormone peptide YY(3–36)-amide [PYY(3–36)-NH2] is significantly more potent than PYY(1–36)-NH2 in reducing food intake in rats and humans. Other Gly-extended and Ser13-phosphorylated PYY forms have been detected or predicted based upon known cellular processes of PYY synthesis and modification. Here we compared the effects of 3-h IV infusion of PYY(1–36)-NH2, PYY(3–36)-NH2, PYY(1–36)-Gly-OH, PYY(3–36)-Gly-OH, Ser13(PO3)-PYY(1–36)-NH2, Ser13(PO3)-PYY(3–36)-NH2, Ser13(PO3)-PYY(1–36)-Gly-OH, and Ser13(PO3)-PYY(3–36)-Gly-OH during the early dark period on food intake in freely-feeding rats. PYY(3–36)-NH2 and Ser13(PO3)-PYY(3–36)-NH2 reduced food intake similarly at 50 pmol/kg/min, while only PYY(3–36)-NH2 reduced food intake at 15 pmol/kg/min. PYY(1–36)-NH2 and Ser13(PO3)-PYY(1–36)-NH2 reduced food intake similarly at 50 and 150 pmol/kg/min. In contrast, PYY(1–36)-Gly-OH, PYY(3–36)-Gly-OH, Ser13(PO3)-PYY(3–36)-Gly-OH, and Ser13(PO3)-PYY(1–36)-Gly-OH had no effect on food intake at doses of 50 or 150 pmol/kg/min. Taken together, these results indicate that i) PYY(3–36)-NH2 is significantly more potent than PYY(1–36)-NH2 in reducing food intake, ii) Gly-extended forms of PYY are significantly less potent than non-extended forms, and iii) Ser13-phosphorylation of PYY(3–36)-NH2 decreases the anorexigenic potency PYY(3–36)-NH2, but not PYY(1–36)-NH2. Thus, PYY(3–36)-NH2 appears to be the most potent PYY form for reducing food intake in rats. PMID:21262301

  2. Peptide YY3-36 Decreases Reinstatement of High-Fat Food Seeking during Dieting in a Rat Relapse Model

    PubMed Central

    Ghitza, Udi E.; Nair, Sunila G.; Golden, Sam A.; Gray, Sarah M.; Uejima, Jamie L.; Bossert, Jennifer M.; Shaham, Yavin

    2007-01-01

    A major problem in treating obesity is high rates of relapse to maladaptive food-taking habits during dieting. This relapse is often provoked by acute re-exposure to palatable food, food-associated cues, or stress. We used a reinstatement model, commonly used to study relapse to abused drugs, to explore the effect of peptide YY3-36 (PYY3-36) on reinstatement of high-fat (35%, 45 mg pellets) food seeking induced by acute exposure to the pellets (pellet priming), a cue previously associated with pellet delivery (pellet cue), or yohimbine (2 mg/kg, a pharmacological stressor). Rats were placed on a restricted diet (16 g of chow per day) and lever-pressed for the pellets for 9 – 12 sessions (6 h/d, every 48 h); pellet delivery was paired with a tone–light cue. They were then given 10 – 20 extinction sessions wherein lever presses were not reinforced with the pellets and subsequently tested for reinstatement of food seeking. Systemic PYY3-36 injections (100 – 200 μg/kg) decreased pellet priming- and pellet cue-induced reinstatement of food seeking but not yohimbine-induced reinstatement. Arcuate nucleus (Arc) injections of PYY3-36 (0.4 μg per side) decreased pellet priming-induced reinstatement. The attenuation of pellet priming-induced reinstatement by systemic PYY3-36 was reversed by systemic (2 mg/kg) but not Arc (0.5 μg per side) injections of the Y2 receptor antagonist BIIE0246. Arc PYY3-36 injections did not decrease pellet cue-induced reinstatement. Finally, systemic PYY3-36 injections had minimal effects on ongoing food self-administration or heroin priming- or heroin cue-induced reinstatement of heroin seeking. These data identify an effect of systemic PYY3-36 on relapse to food seeking that is independent of Y2 receptor activation in Arc and suggest that PYY3-36 should be considered for the treatment of relapse to maladaptive food-taking habits during dieting. PMID:17959795

  3. Medical and surgical treatments for obesity have opposite effects on peptide YY and appetite: a prospective study controlled for weight loss.

    PubMed

    Valderas, Juan P; Irribarra, Verónica; Boza, Camilo; de la Cruz, Rolando; Liberona, Yessica; Acosta, Ana Maria; Yolito, Macarena; Maiz, Alberto

    2010-03-01

    The effects of medical and surgical treatments for obesity on peptide YY (PYY) levels, in patients with similar weight loss, remain unclear. The objective of the study was to assess PYY and appetite before and after Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy (SG), and medical treatment (MED). This was a prospective, controlled, nonrandomized study. The study was conducted at the Departments of Nutrition and Digestive Surgery at a university hospital. PARTICIPANTS included three groups of eight patients with similar body mass indexes (RYGB 37.8 +/- 0.8, SG 35.3 +/- 0.7, and MED 39.1 +/- 1.7 kg/m(2), P = NS) and eight lean controls (body mass index 21.7 +/- 0.7 kg/m(2)). Total plasma PYY, hunger, and satiety visual analog scales in fasting and after ingestion of a standard test meal were measured. At baseline there were no differences in the area under the curve (AUC) of PYY, hunger, or satiety in obese groups. Two months after the interventions, RYGB, SG, and MED groups achieved similar weight loss (17.7 +/- 3, 14.9 +/- 2.4, 16.6 +/- 4%, respectively, P = NS). PYY AUC increased in RYGB (P < 0.001) and SG (P < 0.05) and did not change in MED. PYY levels decreased at fasting, 30 min, and 180 min after a standard test meal in MED (P < 0.05). Hunger AUC decreased in RYGB (P < 0.05). Satiety AUC increased in RYGB (P < 0.05) and SG (P < 0.05). Appetite did not change in MED. PYY AUC correlated with satiety AUC (r = 0.35, P < 0.05). RYGB and SG increased PYY and reduced appetite. MED failed to produce changes. Different effects occur despite similar weight loss. This suggests that the weight-loss effects of these procedures are enhanced by an increase in PYY and satiety.

  4. Ghrelin suppresses cholecystokinin (CCK), peptide YY (PYY) and glucagon-like peptide-1 (GLP-1) in the intestine, and attenuates the anorectic effects of CCK, PYY and GLP-1 in goldfish (Carassius auratus).

    PubMed

    Blanco, Ayelén Melisa; Bertucci, Juan Ignacio; Valenciano, Ana Isabel; Delgado, María Jesús; Unniappan, Suraj

    2017-07-01

    Ghrelin is an important gut-derived hormone with an appetite stimulatory role, while most of the intestinal hormones, including cholecystokinin (CCK), peptide YY (PYY) and glucagon-like peptide-1 (GLP-1), are appetite-inhibitors. Whether these important peptides with opposing roles on food intake interact to regulate energy balance in fish is currently unknown. The aim of this study was to characterize the putative crosstalk between ghrelin and CCK, PYY and GLP-1 in goldfish (Carassius auratus). We first determined the localization of CCK, PYY and GLP-1 in relation to ghrelin and its main receptor GHS-R1a (growth hormone secretagogue 1a) in the goldfish intestine by immunohistochemistry. Colocalization of ghrelin/GHS-R1a and CCK/PYY/GLP-1 was found primarily in the luminal border of the intestinal mucosa. In an intestinal explant culture, a significant decrease in prepro-cck, prepro-pyy and proglucagon transcript levels was observed after 60min of incubation with ghrelin, which was abolished by preincubation with the GHS-R1a ghrelin receptor antagonist [D-Lys3]-GHRP-6 (except for proglucagon). The protein expression of PYY and GLP-1 was also downregulated by ghrelin. Finally, intraperitoneal co-administration of CCK, PYY or GLP-1 with ghrelin results in no modification of food intake in goldfish. Overall, results of the present study show for the first time in fish that ghrelin exerts repressive effects on enteric anorexigens. It is likely that these interactions mediate the stimulatory effects of ghrelin on feeding and metabolism in fish. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. Effects of oligofructose on appetite profile, glucagon-like peptide 1 and peptide YY3-36 concentrations and energy intake.

    PubMed

    Verhoef, Sanne P M; Meyer, Diederick; Westerterp, Klaas R

    2011-12-01

    In rats, oligofructose has been shown to stimulate satiety hormone secretion, reduce energy intake and promote weight loss. The present study aimed to examine the effect of oligofructose supplementation on appetite profiles, satiety hormone concentrations and energy intake in human subjects. A total of thirty-one healthy subjects (ten men and twenty-one women) aged 28 (SEM 3) years with a BMI of 24·8 (SEM 0·3) kg/m(2) were included in a randomised double-blind, cross-over study. The subjects received 10 g oligofructose, 16 g oligofructose or 16 g placebo (maltodextrin) daily for 13 d, with a 2-week washout period between treatments. Appetite profile, active glucagon-like peptide 1 (GLP-1) and peptide YY3-36 (PYY) concentrations and energy intake were assessed on days 0 and 13 of the treatment period. Time × treatment interaction revealed a trend of reduction in energy intake over days 0-13 by oligofructose (P = 0·068). Energy intake was significantly reduced (11 %) over time on day 13 compared with day 0 with 16 g/d oligofructose (2801 (SEM 301) v. 3217 (SEM 320) kJ, P < 0·05). Moreover, energy intake was significantly lower with 16 g/d oligofructose compared with 10 g/d oligofructose on day 13 (2801 (SEM 301) v. 3177 (SEM 276) kJ, P < 0·05). Area under the curve (AUC) for GLP-1 on day 13 was significantly higher with 16 g/d oligofructose compared with 10 g/d oligofructose (45 (SEM 4) v. 41 (SEM 3) pmol/l × h, P < 0·05). In the morning until lunch, AUC(0-230 min) for PYY on day 13 was significantly higher with 16 g/d oligofructose compared with 10 g/d oligofructose and placebo (409 (SEM 35) v. 222 (SEM 19) and 211 (SEM 20) pg/ml × h, P < 0·01). In conclusion, 16 g/d and not 10 g/d oligofructose may be an effective dose to reduce energy intake, possibly supported by higher GLP-1 and PYY concentrations.

  6. Peptide YY and glucagon-like peptide-1 contribute to decreased food intake after Roux-en-Y gastric bypass surgery.

    PubMed

    Svane, M S; Jørgensen, N B; Bojsen-Møller, K N; Dirksen, C; Nielsen, S; Kristiansen, V B; Toräng, S; Wewer Albrechtsen, N J; Rehfeld, J F; Hartmann, B; Madsbad, S; Holst, J J

    2016-11-01

    Exaggerated postprandial secretion of glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) may explain appetite reduction and weight loss after Roux-en-Y gastric bypass (RYGB), but causality has not been established. We hypothesized that food intake decreases after surgery through combined actions from GLP-1 and PYY. GLP-1 actions can be blocked using the GLP-1 receptor antagonist Exendin 9-39 (Ex-9), whereas PYY actions can be inhibited by the administration of a dipeptidyl peptidase-4 (DPP-4) inhibitor preventing the formation of PYY3-36. Appetite-regulating gut hormones and appetite ratings during a standard mixed-meal test and effects on subsequent ad libitum food intake were evaluated in two studies: in study 1, nine patients with type 2 diabetes were examined prospectively before and 3 months after RYGB with and without Ex-9. In study 2, 12 RYGB-operated patients were examined in a randomized, placebo-controlled, crossover design on four experimental days with: (1) placebo, (2) Ex-9, (3) the DPP-4 inhibitor, sitagliptin, to reduce formation of PYY3-36 and (4) Ex-9/sitagliptin combined. In study 1, food intake decreased by 35% following RYGB compared with before surgery. Before surgery, GLP-1 receptor blockage increased food intake but no effect was seen postoperatively, whereas PYY secretion was markedly increased. In study 2, combined GLP-1 receptor blockage and DPP-4 inhibitor mediated lowering of PYY3-36 increased food intake by ~20% in RYGB patients, whereas neither GLP-1 receptor blockage nor DPP-4 inhibition alone affected food intake, perhaps because of concomitant marked increases in the unblocked hormone. Blockade of actions from only one of the two L-cell hormones, GLP-1 and PYY3-36, resulted in concomitant increased secretion of the other, probably explaining the absent effect on food intake on these experimental days. Combined blockade of GLP-1 and PYY actions increased food intake after RYGB, supporting that these hormones have a role in

  7. Hyperglycemia abolishes meal-induced satiety by a dysregulation of ghrelin and peptide YY3-36 in healthy overweight/obese humans.

    PubMed

    Knudsen, Sine H; Karstoft, Kristian; Solomon, Thomas P J

    2014-01-15

    Satiety and satiety-regulating gut hormone levels are abnormal in hyperglycemic individuals. We aimed to determine whether these abnormalities are secondary to hyperglycemia. Ten healthy overweight/obese subjects (age: 56 ± 3 yr; BMI: 30.3 ± 1.2 kg/m(2)) received three equicaloric meals at t = 0, 4, and 8 h in the absence (control trial) and presence of experimental hyperglycemia (hyperglycemia trial; 5.4 mM above basal). Circulating levels of glucose, insulin, ghrelin, and peptide YY (PYY)3-36 and visual analog scale ratings of satiety were measured throughout each trial. In the control trial, glucose, insulin, PYY3-36, and the feeling of fullness were increased in the postprandial periods, whereas ghrelin was decreased. In the hyperglycemia trial, in which plasma glucose was increased to 11.2 ± 0.1 mmol/l, postprandial meal responses (AUC: 0-2, 4-6, and 8-10 h) of PYY3-36 were lower (meal 1, P < 0.0001; meal 2, P < 0.001; meal 3, P < 0.05), whereas insulin (meal 1, P < 0.01; meal 2, P < 0.001; meal 3, P < 0.05) and ghrelin (meal 1, P < 0.05; meal 2, P > 0.05; meal 3, P > 0.05) were higher compared with the control trial. Furthermore, the incremental (Δ0-0.5, 4-4.5, and 8-8.5 h) ghrelin response to the first and third meals was higher in the hyperglycemia trial in contrast to control (Δ: 2.3 ± 8.0, P = 0.05; Δ: 14.4 ± 2.5, P < 0.05). Also, meal-induced fullness was prevented (meal 1, P = 0.06; meal 2, P = 0.01; meal 3, P = 0.08) by experimental hyperglycemia. Furthermore, trends in ghrelin, PYY3-36, and fullness were described by different polynomial functions between the trials. In conclusion, hyperglycemia abolishes meal-induced satiety and dysregulates postprandial responses of the gut hormones PYY3-36 and ghrelin in overweight/obese healthy humans.

  8. Age-related effect of peptide YY (PYY) on paw edema in the rat: the function of Y1 receptors on inflammatory cells.

    PubMed

    Stanojević, Stanislava; Vujić, Vesna; Kovacević-Jovanović, Vesna; Mitić, Katarina; Kosec, Dusko; Hörsten, Stephan von; Dimitrijević, Mirjana

    2006-08-01

    It is well documented that neuropeptides participate in local inflammatory reaction and modulate functions of inflammatory cells. The aim of the study was to determine a link between in vivo and in vitro effects of NPY-related peptides on inflammatory response with respect to ageing. Peptide YY (PYY) intraplantarly applied decreases concanavalin A-induced paw edema in 3 and 8 months, but not in 24 months old male rats of Albino Oxford strain. The use of NPY-related receptor-specific peptides and Y1 receptor antagonist revealed that anti-inflammatory effect of PYY is mediated via NPY Y1 receptors. PYY in vitro decreases adherence of macrophages from 8 months, but not from 3 and 24 months old rats and this effect is also mediated via NPY Y1 receptor. Additionally, PYY (10(-6)M) decreases NBT reduction in macrophages from 3 and 8 months old rats, and suppresses NO production in cells from 24 months old rats, albeit regardless of absence of in vivo effect of PYY on inflammation in aged rats. It is concluded that aged rats are less responsive to anti-inflammatory action of PYY compared to adult and young rats, and that ageing is associated with altered NPY Y1 receptor functioning.

  9. Expression of YY1 in Differentiated Thyroid Cancer.

    PubMed

    Arribas, Jéssica; Castellví, Josep; Marcos, Ricard; Zafón, Carles; Velázquez, Antonia

    2015-05-01

    The transcription factor Yin Yang 1 (YY1) has an important regulatory role in tumorigenesis, but its implication in thyroid cancer has not been yet investigated. In the present study, we have analyzed the expression of YY1 in differentiated thyroid cancer and assessed the association of YY1 expression with clinical features. Expression of YY1 was evaluated in human thyroid cancer cell lines, a series of matched normal/tumor thyroid tissues and in a thyroid cancer tissue microarray, using real-time PCR, Western blot, and/or immunohistochemistry. YY1 was overexpressed in thyroid cancer cells, at transcription and protein levels. A significant increase of YY1 mRNA was also observed in tumor thyroid tissues. Moreover, immunohistochemical analysis of the thyroid cancer tissue microarray revealed that both papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC) present increased YY1 protein levels (48 and 19%, respectively). After stratification by the level of YY1 protein, positive YY1 expression identifies 88% of patients with PTC. The association of YY1 expression with clinicopathological features in PTC and FTC showed that YY1 expression was related with age at diagnosis. Our data indicates for the first time overexpression of YY1 in differentiated thyroid cancer, with YY1 being more frequently overexpressed in the PTC subtype.

  10. The peripheral modulation of duodenal and colonic motility in rats by the pancreatic polypeptide-fold family: neuropeptide Y, peptide YY, and pancreatic polypeptide.

    PubMed

    Wager-Pagé, S A; Ghazali, B; Anderson, W; Veale, W L; Davison, J S

    1993-01-01

    Neuropeptide Y (NPY), peptide YY (PYY), and pancreatic polypeptide (PP) altered intraluminal pressure in the duodenum and colon of fasted anesthetized rats following intravenous bolus administration. There were rapid increases in intraluminal pressure of the duodenum and colon of anesthetized rats following peripheral injections of NPY, PYY and PP. Administration (IV) of NPY, PYY, and PP increased intraduodenal pressure +1.8, +3.2, and +3.7 mmHg compared to saline baseline. Prazosin, an alpha-2 adrenergic antagonist, did not alter the response of the duodenum of urethane-anesthesized rats to any of the PP-fold peptides following peripheral administration. Yohimbine, an alpha 2-adrenergic antagonist, attenuated the excitatory response of rat duodenum following NPY (IV) but did not alter the duodenal response to PP (IV). Intravenous NPY, PYY, and PP increased intracolonic pressure +2.0, +3.3, and +6.2 mmHg compared to saline baseline. In the presence of prazosin, an alpha 1-adrenergic antagonist, the intraluminal pressure of the colon increased +2.6, +2.4, and +8.1 mmHg compared to saline baseline by NPY, PYY, and PP (IV), respectively. In the presence of alpha 2-adrenergic blockade by yohimbine, NPY, PYY, and PP (IV) increased intraluminal pressure of the colon +4.2, +2.9, and +2.5 mmHg compared to saline baseline. The response of the duodenum to the excitatory effect of PYY (IV) was enhanced in the presence of yohimbine. Duodenal and colonic tone were modulated by the PP-fold peptides following peripheral administration. The alpha-adrenergic nervous system played only a minor role in the modulation of GI motility by the PP-fold peptides at peripheral sites.

  11. Neuroendocrine peptide levels in the gastrointestinal tract of mice after unilateral cervical vagotomy.

    PubMed

    El-Salhy, M; Danielsson, A; Axelsson, H; Qian, B F

    2000-03-17

    The effects of left and right unilateral cervical vagotomy on the content of several neuroendocrine peptides were studied in different parts of the murine gastrointestinal tract, known to receive vagal innervation. The neuroendocrine peptides investigated were secretin, gastric inhibitory peptide (GIP), gastrin, motilin, peptide YY (PYY), somatostatin, substance P, VIP, neurotensin, neuropeptide Y (NPY), and galanin. The neuroendocrine peptide concentration was affected after both left and right vagotomy, and that the changes in the concentrations of the neuroendocrine peptide levels occurred in all the gastrointestinal segments investigated, namely antrum, small and large intestine. However, these changes varied, depending on which side was vagotomized and the interval after vagotomy. It is concluded that the vagus nerve had an important impact on the neuroendocrine system in the murine gut. It is suggested, furthermore that the contradictory results obtained earlier on the effect of vagotomy on the gastrointestinal peptides may depend on differences in the vagotomy methods used and on differences in observation time after vagotomy.

  12. 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

  13. Effects of exendin-4 alone and with peptide YY(3-36) on food intake and body weight in diet-induced obese rats.

    PubMed

    Reidelberger, Roger D; Haver, Alvin C; Apenteng, Bettye A; Anders, Krista L; Steenson, Sharalyn M

    2011-01-01

    Significant weight loss following Roux-en-Y gastric bypass surgery (RYGB) in obese humans correlates with enhanced secretion of anorexigenic gut hormones glucagon-like peptide-1 (GLP-1) and peptide YY(3-36) (PYY(3-36)). Our aim here was to identify a dosing strategy for intraperitoneal (IP) infusion of GLP-1 homologue exendin-4 alone and with PYY(3-36) that produces a sustained reduction in daily food intake and body weight in diet-induced obese (DIO) rats. We tested 12 exendin-4 strategies over 10 weeks. Exendin-4 infused during the first and last 3 h of the dark period at 15-20 pmol/h (0.15 nmol/kg/day) produced a sustained 24 ± 1% reduction in daily food intake for 17 days, and decreased body weight by 7%. In a separate group of DIO rats, none of seven dosing strategies combining exendin-4 and PYY(3-36) produced a similar reduction in daily food intake for >10 days. The subsequent decline in efficacies of exendin-4 alone and with PYY(3-36) on food intake and body weight in each experiment suggested possible receptor downregulation and tolerance to treatments. However, when treatments were discontinued for 1 day following losses in efficacies, daily food intake significantly increased. Together, these results demonstrate that (i) intermittent IP infusion of a low dose of exendin-4 can produce a relatively prolonged reduction in daily food intake and body weight in DIO rats, (ii) co-infusion of exendin-4 and PYY(3-36) does not further prolong this response, and (iii) activation of an orexigenic mechanism gradually occurs to counteract the inhibitory effects of exendin-4 alone and with PYY(3-36) on food intake and body weight.

  14. 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

  15. Critical role of YY1 in cardiac morphogenesis.

    PubMed

    Beketaev, Ilimbek; Zhang, Yi; Kim, Eun Young; Yu, Wei; Qian, Ling; Wang, Jun

    2015-05-01

    Yin Yang 1 (YY1), the only DNA binding polycomb group protein, was reported to regulate cardiomyocyte differentiation during early cardiac mesoderm development. However, whether it contributes to cardiac morphogenesis at later developmental stage(s) during embryogenesis is unknown. We excised YY1 in murine hearts during embryogenesis using two temporal-spatially controlled cre activation approaches, and revealed critical roles of YY1 in cardiac structural formation. Alpha-myosin heavy chain-cre (α-MHC-cre)-mediated cardiomyocyte-specific ablation of YY1 (MHC-YY1) resulted in perinatal death of mutant mice, and Nkx2.5-cre-mediated YY1 null embryos (Nkx2.5-YY1) died embryonically. In the Nkx2.5-YY1 mutants, the endocardial cushions (ECs) of both atrioventricular canal (AVC) and outflow tract (OFT) were hypoplastic due to decreased proliferation and increased apoptosis. Endothelial-to-mesenchymal transition (EMT) progress was also compromised in ECs. Nkx2.5-YY1 mutant hearts had normal formation of extracellular matrix, suggesting that the impaired EMT resulted from the direct loss of YY1. We further uncovered that a number of factors that are involved in normal cardiogenesis were downstream targets of YY1. YY1 plays a critical role in cardiac development and occupies a high-level position within the hierarchy of the cardiac transcriptional network that governs normal cardiogenesis. © 2015 Wiley Periodicals, Inc.

  16. Neuropeptide Y, peptide YY, and pancreatic polypeptide modulate duodenal and colonic motility at a thoracic spinal site in rats.

    PubMed

    Wager-Pagé, S A; Ghazali, B; Anderson, W; Veale, W L; Davison, J S

    1992-01-01

    Neuropeptide Y, PYY, and PP (200 pmol) alter intraluminal pressure in the duodenum and colon of rats following their administration into the thoracic (T8-T10) region of the spinal cord. Neuropeptide Y decreases the tone of the duodenum and the colon following intrathecal (T8-T10) administration prior to an increase in tone to baseline or greater. There is no effect on intraluminal pressure of either the duodenum or the colon following intrathecal administration of NPY or PP into the lumbar (L4-L5) region of the spinal cord. Following intrathecal (T8-T10) administration of PYY and PP, increases in intraduodenal pressures are observed (+2.1 and +3.0 mmHg from saline baseline). Phasic contractions of the duodenum are increased following intrathecal administration of PYY into the thoracic spinal cord of rats. Neuropeptide Y, PYY, and PP increase intracolonic pressure +2.2, +3.3, and +3.7 mmHg from saline baseline, respectively. Phasic contractions of the colon are increased following PP intrathecal thoracic administration. Responsiveness of the duodenum or colon to the different ligands of the PP-fold peptide family in the absence of alpha-adrenergic blockade did not vary. The increases in intraluminal pressure of the duodenum and colon following intrathecal administration of the PP-fold peptides are attenuated by both alpha-1 adrenergic (prazosin) and alpha-2 adrenergic (yohimbine) blockade. There is a difference in responsiveness of the colon between the ligands of the PP-fold family in the presence of the alpha-2 adrenergic blockade. The findings of this study indicate that duodenal and colonic motility are modulated by the PP-fold peptides at thoracic spinal sites via alteration of sympathetic outflow.

  17. Vitamin B12 Conjugation of Peptide-YY3–36 Decreases Food Intake Compared to Native Peptide-YY3–36 Upon Subcutaneous Administration in Male Rats

    PubMed Central

    Henry, Kelly E.; Elfers, Clinton T.; Burke, Rachael M.; Chepurny, Oleg G.; Holz, George G.; Blevins, James E.

    2015-01-01

    Challenges to peptide-based therapies include rapid clearance, ready degradation by hydrolysis/proteolysis, and poor intestinal uptake and/or a need for blood brain barrier transport. This work evaluates the efficacy of conjugation of vitamin B12 (B12) on sc administered peptide tyrosine tyrosine (PYY)3–36 function. In the current experiments, a B12-PYY3–36 conjugate was tested against native PYY3–36, and an inactive conjugate B12-PYYC36 (null control) in vitro and in vivo. In vitro experiments demonstrated similar agonism for the neuropeptide Y2 receptor by the B12-PYY3–36 conjugate (EC50 26.5 nM) compared with native PYY3–36 (EC50 16.0 nM), with the null control having an EC50 of 1.8 μM. In vivo experiments were performed in young adult male Sprague Dawley rats (9 wk). Daily treatments were delivered sc in five 1-hour pulses, each pulse delivering 5–10 nmol/kg, by implanted microinfusion pumps. Increases in hindbrain Fos expression were comparable 90 minutes after B12-PYY3–36 or PYY3–36 injection relative to saline or B12-PYYC36. Food intake was reduced during a 5-day treatment for both B12-PYY3–36- (24%, P = .001) and PYY3–36-(13%, P = .008) treated groups relative to baseline. In addition, reduction of food intake after the three dark cycle treatment pulses was more consistent with B12-PYY3–36 treatment (−26%, −29%, −27%) compared with the PYY3–36 treatment (−3%, −21%, −16%), and B12-PYY3–36 generated a significantly longer inhibition of food intake vs PYY3–36 treatment after the first two pulses (P = .041 and P = .036, respectively). These findings demonstrate a stronger, more consistent, and longer inhibition of food intake after the pulses of B12-PYY3–36 conjugate compared with the native PYY3–36. PMID:25658456

  18. Vitamin B12 conjugation of peptide-YY(3-36) decreases food intake compared to native peptide-YY(3-36) upon subcutaneous administration in male rats.

    PubMed

    Henry, Kelly E; Elfers, Clinton T; Burke, Rachael M; Chepurny, Oleg G; Holz, George G; Blevins, James E; Roth, Christian L; Doyle, Robert P

    2015-05-01

    Challenges to peptide-based therapies include rapid clearance, ready degradation by hydrolysis/proteolysis, and poor intestinal uptake and/or a need for blood brain barrier transport. This work evaluates the efficacy of conjugation of vitamin B12 (B12) on sc administered peptide tyrosine tyrosine (PYY)(3-36) function. In the current experiments, a B12-PYY(3-36) conjugate was tested against native PYY(3-36), and an inactive conjugate B12-PYYC36 (null control) in vitro and in vivo. In vitro experiments demonstrated similar agonism for the neuropeptide Y2 receptor by the B12-PYY(3-36) conjugate (EC50 26.5 nM) compared with native PYY(3-36) (EC50 16.0 nM), with the null control having an EC50 of 1.8 μM. In vivo experiments were performed in young adult male Sprague Dawley rats (9 wk). Daily treatments were delivered sc in five 1-hour pulses, each pulse delivering 5-10 nmol/kg, by implanted microinfusion pumps. Increases in hindbrain Fos expression were comparable 90 minutes after B12-PYY(3-36) or PYY3-36 injection relative to saline or B12-PYYC36. Food intake was reduced during a 5-day treatment for both B12-PYY(3-36)- (24%, P = .001) and PYY(3-36)-(13%, P = .008) treated groups relative to baseline. In addition, reduction of food intake after the three dark cycle treatment pulses was more consistent with B12-PYY(3-36) treatment (-26%, -29%, -27%) compared with the PYY(3-36) treatment (-3%, -21%, -16%), and B12-PYY(3-36) generated a significantly longer inhibition of food intake vs. PYY(3-36) treatment after the first two pulses (P = .041 and P = .036, respectively). These findings demonstrate a stronger, more consistent, and longer inhibition of food intake after the pulses of B12-PYY(3-36) conjugate compared with the native PYY(3-36).

  19. Effects of different intermittent peptide YY (3-36) dosing strategies on food intake, body weight, and adiposity in diet-induced obese rats.

    PubMed

    Reidelberger, Roger D; Haver, Alvin C; Chelikani, Prasanth K; Buescher, James L

    2008-08-01

    Chronic administration of anorexigenic substances to experimental animals by injections or continuous infusion typically produces either no effect or a transient reduction in food intake and body weight. Our aim here was to identify an intermittent dosing strategy for intraperitoneal infusion of peptide YY(3-36) [PYY(3-36)] that produces a sustained reduction in daily food intake and adiposity in diet-induced obese rats. Rats (665+/-10 g body wt, 166+/-7 g body fat) with intraperitoneal catheters tethered to infusion swivels had free access to a high-fat diet. Vehicle-treated rats (n=23) had relatively stable food intake, body weight, and adiposity during the 9-wk test period. None of 15 PYY(3-36) dosing regimens administered in succession to a second group of rats (n=22) produced a sustained 15-25% reduction in daily food intake for >5 days, although body weight and adiposity were reduced across the 9-wk period by 12% (594+/-15 vs. 672+/-15 g) and 43% (96+/-7 vs. 169+/-9 g), respectively. The declining inhibitory effect of PYY(3-36) on daily food intake when the interinfusion interval was >or=3 h appeared to be due in part to an increase in food intake between infusions. The declining inhibitory effect of PYY(3-36) on daily food intake when the interinfusion interval was <3 h suggested possible receptor downregulation and tolerance to frequent PYY(3-36) administration; however, food intake significantly increased when PYY(3-36) treatments were discontinued for 1 day following apparent loss in treatment efficacies. Together, these results demonstrate the development of a potent homeostatic response to increase food intake when PYY(3-36) reduces food intake and energy reserves in diet-induced obese rats.

  20. Peptide YY directly inhibits ghrelin-activated neurons of the arcuate nucleus and reverses fasting-induced c-Fos expression.

    PubMed

    Riediger, Thomas; Bothe, Christine; Becskei, Csilla; Lutz, Thomas A

    2004-01-01

    The hypothalamic arcuate nucleus (Arc) monitors and integrates hormonal and metabolic signals involved in the maintenance of energy homeostasis. The orexigenic peptide ghrelin is secreted from the stomach during negative status of energy intake and directly activates neurons of the medial arcuate nucleus (ArcM) in rats. In contrast to ghrelin, peptide YY (PYY) is released postprandially from the gut and reduces food intake when applied peripherally. Neurons in the ArcM express ghrelin receptors and neuropeptide Y receptors. Thus, PYY may inhibit feeding by acting on ghrelin-sensitive Arc neurons. Using extracellular recordings, we (1) characterized the effects of PYY on the electrical activity of ghrelin-sensitive neurons in the ArcM of rats. In order to correlate the effect of PYY on neuronal activity with the energy status, we (2) investigated the ability of PYY to reverse fasting-induced c-Fos expression in Arc neurons of mice. In addition, we (3) sought to confirm that PYY reduces food intake under our experimental conditions. Superfusion of PYY reversibly inhibited 94% of all ArcM neurons by a direct postsynaptic mechanism. The PYY-induced inhibition was dose-dependent and occurred at a threshold concentration of 10(-8)M. Consistent with the opposite effects of ghrelin and PYY on food intake, a high percentage (50%) of Arc neurons was activated by ghrelin and inhibited by PYY. In line with this inhibitory action, peripherally injected PYY partly reversed the fasting-induced c-Fos expression in Arc neurons of mice. Similarly, refeeding of food-deprived mice reversed the fasting-induced activation in the Arc. Furthermore, peripherally injected PYY reduced food intake in 12-hour fasted mice. Thus the activity of Arc neurons correlated with the feeding status and was not only reduced by feeding but also by administration of PYY in non-refed mice. In conclusion, our current observations suggest that PYY may contribute to signaling a positive status of energy intake

  1. /sup 125/I-neuropeptide Y and /sup 125/I-peptide YY bind to multiple receptor sites in rat brain

    SciTech Connect

    Walker, M.W.; Miller, R.J.

    1988-12-01

    We describe the preparation of monoiodinated neuropeptide Y (Tyr1-125I-NPY) and monoiodinated peptide YY (Tyr36-125I-PYY). Using these ligands, we detected high, moderate, and low affinity receptor populations in rat brain. Only high and moderate affinity binding sites were suggested by saturation binding studies. Tyr1-125I-NPY bound to 8 +/- 3% of the sites with a Kd of 54 pM (Bmax = 19.4 fmol/mg of protein) and to 92 +/- 3% of the sites with a Kd of 0.92 nM (Bmax = 220.0 fmol/mg of protein). Tyr36-125I-PYY bound to 14 +/- 3% of the sites with a Kd of 23.5 pM (Bmax = 36.4 fmol/mg of protein) and to 86 +/- 3% of the sites with a Kd of 1.9 nM (Bmax = 220.1 fmol/mg of protein). The fragments NPY 13-36 and PYY 13-36 were able to compete with 10 pM Tyr1-125I-NPY for essentially all the binding sites. The fragments were 1 to 2 orders of magnitude less potent than the native peptides. Approximately 50% of the moderate affinity sites, but not the high affinity sites, were reversibly lost in the presence of 5'-guanylyl imidophosphate (Gpp(NH)p), a nonhydrolyzable analog of GTP. Kinetic studies revealed that Tyr1-125I-NPY dissociation could be best described by three dissociation rates. The proportions of slow and intermediate dissociation matched the proportions of moderate and high affinity binding sites, respectively, as suggested by equilibrium studies. There also existed a phase of fast dissociation. When Gpp(NH)p was added during dissociation, the proportion of slow dissociation decreased to the same extent that the fast dissociation was increased. However, the proportion of intermediate dissociation did not change. We propose that rat brain contains a minor population of high affinity NPY binding sites with an intermediate dissociation rate and no sensitivity to Gpp(NH)p.

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

    PubMed Central

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

    2013-01-01

    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 0800–1000h and 2000–0800h and q20 min from 1000–2000h. 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±0.67kg; p=0.02), and body fat (−2.53±0.83%; p=0.01) decreased from BL to post. Ghrelin AUC (5252±2177pg/ml/24hr; p=0.03), 24h mean (216±90pg/ml; p=0.03) and peak (300±134pg/ml; p=0.047) increased from BL to post. No change occurred in PYY AUC (88.2±163.7pg/ml; p=0.60), 24h mean (4.8±6.9pg/ml; p=0.50) or peak (3.6±6.4pg/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. PMID:24012997

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

    PubMed

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

    2013-11-01

    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 30-40 kg/m(2)) ages 22-60 years received counseling to reduce ED. Fasting blood samples were analyzed for total ghrelin and total PYY by radioimmunoassay at months 0, 3, 6, and 12. Restraint, disinhibition, and hunger were assessed by the Eating Inventory. Body weight (-7.8 ± 0.5 kg), BMI (-2.9 ± 0.2 kg/m(2)), body fat (-3.0 ± 0.3%), and ED (-0.47 ± 0.05 kcal/g or -1.97 ± 0.21 kJ/g) decreased from months 0 to 6 (p<0.05) after which no change occurred from months 6 to 12. Ghrelin increased in a curvilinear fashion (month 0: 973 ± 39, month 3: 1024 ± 37, month 6: 1109 ± 44, and month 12: 1063 ± 45 pg/ml, p<0.001) and PYY increased linearly (month 0: 74.2 ± 3.1, month 3: 76.4 ± 3.2, month 6: 77.2 ± 3.0, month 12: 82.8 ± 3.2 pg/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. Copyright © 2013 Elsevier Inc. All rights reserved.

  4. 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.

  5. Role of capsaicin-sensitive peripheral sensory neurons in anorexic responses to intravenous infusions of cholecystokinin, peptide YY-(3-36), and glucagon-like peptide-1 in rats.

    PubMed

    Reidelberger, Roger; Haver, Alvin; Anders, Krista; Apenteng, Bettye

    2014-10-15

    Cholecystokinin (CCK)-induced suppression of feeding is mediated by vagal sensory neurons that are destroyed by the neurotoxin capsaicin (CAP). Here we determined whether CAP-sensitive neurons mediate anorexic responses to intravenous infusions of gut hormones peptide YY-(3-36) [PYY-(3-36)] and glucagon-like peptide-1 (GLP-1). Rats received three intraperitoneal injections of CAP or vehicle (VEH) in 24 h. After recovery, non-food-deprived rats received at dark onset a 3-h intravenous infusion of CCK-8 (5, 17 pmol·kg⁻¹·min⁻¹), PYY-(3-36) (5, 17, 50 pmol·kg⁻¹·min⁻¹), or GLP-1 (17, 50 pmol·kg⁻¹·min⁻¹). CCK-8 was much less effective in reducing food intake in CAP vs. VEH rats. CCK-8 at 5 and 17 pmol·kg⁻¹·min⁻¹ reduced food intake during the 3-h infusion period by 39 and 71% in VEH rats and 7 and 18% in CAP rats. In contrast, PYY-(3-36) and GLP-1 were similarly effective in reducing food intake in VEH and CAP rats. PYY-(3-36) at 5, 17, and 50 pmol·kg⁻¹·min⁻¹ reduced food intake during the 3-h infusion period by 15, 33, and 70% in VEH rats and 13, 30, and 33% in CAP rats. GLP-1 at 17 and 50 pmol·kg⁻¹·min⁻¹ reduced food intake during the 3-h infusion period by 48 and 60% in VEH rats and 30 and 52% in CAP rats. These results suggest that anorexic responses to PYY-(3-36) and GLP-1 are not primarily mediated by the CAP-sensitive peripheral sensory neurons (presumably vagal) that mediate CCK-8-induced anorexia.

  6. 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.

  7. Discrimination between neuropeptide Y and peptide YY in the rat tail artery by the neuropeptide Y1-selective antagonist, BIBP 3226.

    PubMed Central

    Gicquiaux, H.; Tschöpl, M.; Doods, H. N.; Bucher, B.

    1996-01-01

    1. The ability of the novel, nonpeptide, neuropeptide Y (NPY) Y1-selective antagonist, BIBP 3226 ¿(R)-N2-(diphenylacetyl)-N-[(4-hydroxyphenyl)methyl]-D-arginine amide¿, to antagonize the increase in perfusion pressure induced by NPY and peptide Y (PYY) was tested in the perfused rat tail artery, a postjunctional Y1-receptor bioassay, precontracted by 1 microM phenylephrine. 2. NPY and PYY produced a concentration-dependent enhancement of the vasoconstrictor response evoked by 1 microM phenylephrine. Although NPY and PYY are roughly equipotent, the maximal contractile response elicited by PYY was about twice that elicited by NPY. 3. Increasing concentrations of BIBP 3226 caused a parallel and rightward shift in the NPY concentration-response curve without depressing the maximal response. The contractile effect of NPY was potently inhibited in a competitive manner. The pA2 value for BIBP 3226 was 7.01 +/- 0.08, a value equivalent to that observed in the rabbit saphenous vein. Although increasing concentrations of BIBP 3226 shifted the concentration-response curve of PYY to the right without any significant decrease in the maximal vasoconstrictor response, the antagonism appeared non-competitive as the slope of the Schild plot was significantly different from unity (0.58 +/- 0.04). 4. In conclusion, these data confirm that BIBP 3226 is a potent and selective nonpeptide Y1 receptor antagonist. Moreover, they show that complex interactions occur between BIBP 3226 and postjunctional receptors activated by PYY. We postulate that BIBP 3226 might discriminate between the effects of NPY and PYY at the postjunctional level in the rat tail artery. It may be that distinct receptors for NPY and PYY exist; these may or may not allosterically interact with each other. Another working hypothesis would be that there is a single receptor complex with allosterically interacting binding sites for the two peptides. PMID:8968537

  8. 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.

  9. 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.

  10. CtBP Levels Control Intergenic Transcripts, PHO/YY1 DNA Binding, and PcG Recruitment to DNA

    PubMed Central

    Basu, Arindam; Atchison, Michael L.

    2013-01-01

    Carboxy-terminal binding protein (CtBP) is a well-known corepressor of several DNA binding transcription factors in Drosophila as well as in mammals. CtBP is implicated in Polycomb Group (PcG) complex-mediated transcriptional repression because it can bind to some PcG proteins, and mutation of the ctbp gene in flies results in lost PcG protein recruitment to Polycomb Response Elements (PREs) and lost PcG repression. However, the mechanism of reduced PcG DNA binding in CtBP mutant backgrounds is unknown. We show here that in a Drosophila CtBP mutant background, intergenic transcripts are induced across several PRE sequences and this corresponds to reduced DNA binding by PcG proteins Pleiohomeotic (PHO) and Polycomb (Pc), and reduced trimethylation of histone H3 on lysine 27, a hallmark of PcG repression. Restoration of CtBP levels by expression of a CtBP transgene results in repression of intergenic transcripts, restored PcG binding, and elevated trimethylation of H3 on lysine 27. Our results support a model in which CtBP regulates expression of intergenic transcripts that controls DNA binding by PcG proteins and subsequent histone modifications and transcriptional activity. PMID:20082324

  11. Rapid evolution of a recently retroposed transcription factor YY2 in mammalian genomes

    SciTech Connect

    Luo, C; Lu, X; Stubbs, L; Kim, J

    2005-11-11

    YY2 was originally identified due to its unusual similarity to the evolutionarily well conserved, zinc-finger gene YY1. In this study, we have determined the evolutionary origin and conservation of YY2 using comparative genomic approaches. Our results indicate that YY2 is a retroposed copy of YY1 that has been inserted into another gene locus named Mbtps2 (membrane-bound transcription factor protease site 2). This retroposition is estimated to have occurred after the divergence of placental mammals from other vertebrates based on the detection of YY2 only in the placental mammals. The N-terminal and C-terminal regions of YY2 have evolved under different selection pressures. The N-terminal region has evolved at a very fast pace with very limited functional constraints whereas the DNA-binding, C-terminal region still maintains very similar sequence structure as YY1 and is also well conserved among placental mammals. In situ hybridizations using different adult mouse tissues indicate that mouse YY2 is expressed at relatively low levels in Purkinje and granular cells of cerebellum, and neuronal cells of cerebrum, but at very high levels in testis. The expression levels of YY2 is much lower than YY1, but the overall spatial expression patterns are similar to those of Mbtps2, suggesting a possible shared transcriptional control between YY2 and Mbtps2. Taken together, the formation and evolution of YY2 represent a very unusual case where a transcription factor was first retroposed into another gene locus encoding a protease and survived with different selection schemes and expression patterns.

  12. Increased peptide YY blood concentrations, not decreased acyl-ghrelin, are associated with reduced hunger and food intake in healthy older women: Preliminary evidence.

    PubMed

    Hickson, Mary; Moss, Charlotte; Dhillo, Waljit S; Bottin, Jeanne; Frost, Gary

    2016-10-01

    With ageing there is frequently a loss of appetite, termed anorexia of ageing, which can result in under-nutrition. We do not know how appetite control alters with ageing. The objective of this study was to investigate whether differences in the release of, and response to, gastrointestinal appetite hormones is altered in young compared to old healthy volunteers. We hypothesised that an increase in PYY and GLP-1 or a decrease ghrelin may result in a decreased appetite. A comparative experimental design, using a cross-sectional sample of ages from a healthy population, matched for sex and BMI was used. The study compared total ghrelin, acyl-ghrelin, PYY, GLP-1 and subjective appetite responses to ingestion of a standardised 2781kj (660 kcal) test meal. 31 female volunteers aged between 21 and 92yrs took part. Multiple linear regression showed that both age and sex had an independent effect on energy intake. Subjective appetite scores showed that hunger, pleasantness to eat, and prospective food intake were significantly lower in the older age groups. PYY incremental area under the curve (IAUC) was greater in the oldest old compared to younger ages f(3,27) = 2.9, p = 0.05. No differences in GLP-1, ghrelin or acyl-ghrelin were observed in the older compared to younger age groups. Our data suggest that there may be increases in postprandial PYY(3-36) levels in female octogenarians, potentially resulting in reduced appetite. There does not appear to be any change in ghrelin or acyl-ghrelin concentrations with ageing.

  13. YY1 positively regulates human UBIAD1 expression

    SciTech Connect

    Funahashi, Nobuaki; Hirota, Yoshihisa; Nakagawa, Kimie; Sawada, Natumi; Watanabe, Masato; Suhara, Yoshitomo; Okano, Toshio

    2015-05-01

    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 mouse 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 UBIAD1

  14. A RAPID Method for Blood Processing to Increase the Yield of Plasma Peptide Levels in Human Blood.

    PubMed

    Teuffel, Pauline; Goebel-Stengel, Miriam; Hofmann, Tobias; Prinz, Philip; Scharner, Sophie; Körner, Jan L; Grötzinger, Carsten; Rose, Matthias; Klapp, Burghard F; Stengel, Andreas

    2016-04-28

    Research in the field of food intake regulation is gaining importance. This often includes the measurement of peptides regulating food intake. For the correct determination of a peptide's concentration, it should be stable during blood processing. However, this is not the case for several peptides which are quickly degraded by endogenous peptidases. Recently, we developed a blood processing method employing Reduced temperatures, Acidification, Protease inhibition, Isotopic exogenous controls and Dilution (RAPID) for the use in rats. Here, we have established this technique for the use in humans and investigated recovery, molecular form and circulating concentration of food intake regulatory hormones. The RAPID method significantly improved the recovery for (125)I-labeled somatostatin-28 (+39%), glucagon-like peptide-1 (+35%), acyl ghrelin and glucagon (+32%), insulin and kisspeptin (+29%), nesfatin-1 (+28%), leptin (+21%) and peptide YY3-36 (+19%) compared to standard processing (EDTA blood on ice, p <0.001). High performance liquid chromatography showed the elution of endogenous acyl ghrelin at the expected position after RAPID processing, while after standard processing 62% of acyl ghrelin were degraded resulting in an earlier peak likely representing desacyl ghrelin. After RAPID processing the acyl/desacyl ghrelin ratio in blood of normal weight subjects was 1:3 compared to 1:23 following standard processing (p = 0.03). Also endogenous kisspeptin levels were higher after RAPID compared to standard processing (+99%, p = 0.02). The RAPID blood processing method can be used in humans, yields higher peptide levels and allows for assessment of the correct molecular form.

  15. Appetite regulating peptides in red-bellied piranha, Pygocentrus nattereri: cloning, tissue distribution and effect of fasting on mRNA expression levels.

    PubMed

    Volkoff, Hélène

    2014-06-01

    cDNAs encoding the appetite regulating peptides apelin, cocaine and amphetamine regulated transcript (CART), cholecystokinin (CCK), peptide YY (PYY) and orexin were isolated in red-bellied piranha and their mRNA tissue and brain distributions examined. When compared to other fish, the sequences obtained for all peptides were most similar to that of other Characiforme fish, as well as to Cypriniformes. All peptides were widely expressed within the brain and in several peripheral tissues, including gastrointestinal tract. In order to assess the role of these peptides in the regulation of feeding of red-bellied piranha, we compared the brain mRNA expression levels of these peptides, as well as the gut mRNA expression of CCK and PYY, between fed and 7-day fasted fish. Within the brain, fasting induced a significant increase in both apelin and orexin mRNA expressions and a decrease in CART mRNA expression, but there where were no significant differences for either PYY or CCK brain mRNA expressions between fed and fasted fish. Within the intestine, PYY mRNA expression was lower in fasted fish compared to fed fish but there was no significant difference for CCK intestine mRNA expression between fed and fasted fish. Our results suggest that these peptides, perhaps with the exception of CCK, play a major role in the regulation of feeding of red-bellied piranha.

  16. The Yin Yang-1 (YY1) protein undergoes a DNA-replication-associated switch in localization from the cytoplasm to the nucleus at the onset of S phase.

    PubMed

    Palko, Linda; Bass, Hank W; Beyrouthy, Maroun J; Hurt, Myra M

    2004-01-26

    The essential Yin Yang-1 gene (YY1) encodes a ubiquitous, conserved, multifunctional zinc-finger transcription factor in animals. The YY1 protein regulates initiation, activation, or repression of transcription from a variety of genes required for cell growth, development, differentiation, or tumor suppression, as well as from genes in some retroviruses and DNA viruses. Among the specific functions attributed to YY1 is a role in cell-cycle-specific upregulation of the replication-dependent histone genes. The YY1 protein binds to the histone alpha element, a regulatory sequence found in all replication-dependent histone genes. We therefore examined the abundance, DNA-binding activity and localization of the YY1 protein throughout the cell cycle in unperturbed, shake-off-synchronized Chinese hamster ovary and HeLa cells. We found that, whereas the DNA-binding activity of YY1 increased dramatically early in S phase, the YY1 mRNA and protein levels did not. YY1 changed subcellular distribution patterns during the cell cycle, from mainly cytoplasmic at G1 to mainly nuclear at early and middle S phase, then back to primarily cytoplasmic later in S phase. Nuclear accumulation of YY1 near the G1/S boundary coincided with both an increase in YY1 DNA-binding activity and the coordinate up-regulation of the replication-dependent histone genes. The DNA synthesis inhibitor aphidicolin caused a nearly complete loss of nuclear YY1, whereas addition of caffeine or 2-aminopurine to aphidicolin-treated cells restored both DNA synthesis and YY1 localization in the nucleus. These findings reveal a mechanism by which YY1 localization is coupled to DNA synthesis and responsive to cell-cycle signaling pathways. Taken together, our results provide insight into how YY1 might participate in the cell-cycle control over a variety of nuclear events required for cell division and proliferation.

  17. YY1 Control of AID Dependent Lymphomagenesis

    DTIC Science & Technology

    2016-09-01

    chromosome inactivation. Timed matings are ongoing to more fully establish the importance of YY1 loss in DLBCL at late time points. Finally, we have...therapeutic target for DLBCL. In addition our studies showed that YY1 is crucial for germinal center B cell development, for X- chromosome inactivation in B...development of autoimmune diseases. Females are more prone to autoimmune disorders, perhaps due to the X- chromosome , which contains many immunity

  18. 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.

  19. 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.

  20. YY1 Is Required for Germinal Center B Cell Development.

    PubMed

    Banerjee, Anupam; Sindhava, Vishal; Vuyyuru, Raja; Jha, Vibha; Hodewadekar, Suchita; Manser, Tim; Atchison, Michael L

    2016-01-01

    YY1 has been implicated as a master regulator of germinal center B cell development as YY1 binding sites are frequently present in promoters of germinal center-expressed genes. YY1 is known to be important for other stages of B cell development including the pro-B and pre-B cells stages. To determine if YY1 plays a critical role in germinal center development, we evaluated YY1 expression during B cell development, and used a YY1 conditional knock-out approach for deletion of YY1 in germinal center B cells (CRE driven by the immunoglobulin heavy chain γ1 switch region promoter; γ1-CRE). We found that YY1 is most highly expressed in germinal center B cells and is increased 3 fold in splenic B cells activated by treatment with anti-IgM and anti-CD40. In addition, deletion of the yy1 gene by action of γ1-CRE recombinase resulted in significant loss of GC cells in both un-immunized and immunized contexts with corresponding loss of serum IgG1. Our results show a crucial role for YY1 in the germinal center reaction.

  1. YY1 Is Required for Germinal Center B Cell Development

    PubMed Central

    Vuyyuru, Raja; Jha, Vibha; Hodewadekar, Suchita; Manser, Tim; Atchison, Michael L.

    2016-01-01

    YY1 has been implicated as a master regulator of germinal center B cell development as YY1 binding sites are frequently present in promoters of germinal center-expressed genes. YY1 is known to be important for other stages of B cell development including the pro-B and pre-B cells stages. To determine if YY1 plays a critical role in germinal center development, we evaluated YY1 expression during B cell development, and used a YY1 conditional knock-out approach for deletion of YY1 in germinal center B cells (CRE driven by the immunoglobulin heavy chain γ1 switch region promoter; γ1-CRE). We found that YY1 is most highly expressed in germinal center B cells and is increased 3 fold in splenic B cells activated by treatment with anti-IgM and anti-CD40. In addition, deletion of the yy1 gene by action of γ1-CRE recombinase resulted in significant loss of GC cells in both un-immunized and immunized contexts with corresponding loss of serum IgG1. Our results show a crucial role for YY1 in the germinal center reaction. PMID:27167731

  2. Gastrointestinal peptide levels in obese and anorexic females

    SciTech Connect

    Pasley, J.N.; Rice, R.L.; McCullough, S.S.; McKay, D.W.; Rayford, P.L. )

    1989-01-01

    The role of gastrointestinal peptides in eating disorders has yet to be determined. Methods: In this study we examined plasma levels of gastrin (G), cholecystokinin (CCK), and pancreatic polypeptide (PP) in adolescent anorexic, and obese female subjects hospitalized for feeding behavior disorders. Six anorexic, six obese and six control young females (ages 13-26) were studied after an overnight fast and after consuming a liquid test meal. The liquid test meal (Ensure, Ross Laboratories; Columbus OH) consisted of 14% calories as protein, 31.5% calories as fat and 54.5% calories as carbohydrate in a 240ml volume. Plasma levels of gastrointestinal peptides, G, CCK and PP were determined by specific radioimmunoassay. The data were analyzed by one way analysis of variance and the Student's t-test. Results: show that fasting levels of G were greater in control and obese groups than the anorexic subjects. Postprandial G levels for controls were higher than the anorexic, and obese groups respectively. When fasting and postprandial G levels were compared among the same groups only the controls increased after eating. Fasting CCK levels were lower in control and anorexic groups than the obese group. Postprandial CCK levels were higher among control patients compared to anorexic and obese subjects. When fasting and postprandial CCK levels were compared among groups, only control levels increased after eating. Fasting and postprandial PP levels were not different between groups. Postprandial PP levels increased over fasting PP levels only in controls.

  3. 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

  4. Epithelial inactivation of Yy1 abrogates lung branching morphogenesis.

    PubMed

    Boucherat, Olivier; Landry-Truchon, Kim; Bérubé-Simard, Félix-Antoine; Houde, Nicolas; Beuret, Laurent; Lezmi, Guillaume; Foulkes, William D; Delacourt, Christophe; Charron, Jean; Jeannotte, Lucie

    2015-09-01

    Yin Yang 1 (YY1) is a multifunctional zinc-finger-containing transcription factor that plays crucial roles in numerous biological processes by selectively activating or repressing transcription, depending upon promoter contextual differences and specific protein interactions. In mice, Yy1 null mutants die early in gestation whereas Yy1 hypomorphs die at birth from lung defects. We studied how the epithelial-specific inactivation of Yy1 impacts on lung development. The Yy1 mutation in lung epithelium resulted in neonatal death due to respiratory failure. It impaired tracheal cartilage formation, altered cell differentiation, abrogated lung branching and caused airway dilation similar to that seen in human congenital cystic lung diseases. The cystic lung phenotype in Yy1 mutants can be partly explained by the reduced expression of Shh, a transcriptional target of YY1, in lung endoderm, and the subsequent derepression of mesenchymal Fgf10 expression. Accordingly, SHH supplementation partially rescued the lung phenotype in vitro. Analysis of human lung tissues revealed decreased YY1 expression in children with pleuropulmonary blastoma (PPB), a rare pediatric lung tumor arising during fetal development and associated with DICER1 mutations. No evidence for a potential genetic interplay between murine Dicer and Yy1 genes during lung morphogenesis was observed. However, the cystic lung phenotype resulting from the epithelial inactivation of Dicer function mimics the Yy1 lung malformations with similar changes in Shh and Fgf10 expression. Together, our data demonstrate the crucial requirement for YY1 in lung morphogenesis and identify Yy1 mutant mice as a potential model for studying the genetic basis of PPB.

  5. Loss-of-Function Mutations in YY1AP1 Lead to Grange Syndrome and a Fibromuscular Dysplasia-Like Vascular Disease.

    PubMed

    Guo, Dong-Chuan; Duan, Xue-Yan; Regalado, Ellen S; Mellor-Crummey, Lauren; Kwartler, Callie S; Kim, Dong; Lieberman, Kenneth; de Vries, Bert B A; Pfundt, Rolph; Schinzel, Albert; Kotzot, Dieter; Shen, Xuetong; Yang, Min-Lee; Bamshad, Michael J; Nickerson, Deborah A; Gornik, Heather L; Ganesh, Santhi K; Braverman, Alan C; Grange, Dorothy K; Milewicz, Dianna M

    2017-01-05

    Fibromuscular dysplasia (FMD) is a heterogeneous group of non-atherosclerotic and non-inflammatory arterial diseases that primarily involves the renal and cerebrovascular arteries. Grange syndrome is an autosomal-recessive condition characterized by severe and early-onset vascular disease similar to FMD and variable penetrance of brachydactyly, syndactyly, bone fragility, and learning disabilities. Exome-sequencing analysis of DNA from three affected siblings with Grange syndrome identified compound heterozygous nonsense variants in YY1AP1, and homozygous nonsense or frameshift YY1AP1 variants were subsequently identified in additional unrelated probands with Grange syndrome. YY1AP1 encodes yin yang 1 (YY1)-associated protein 1 and is an activator of the YY1 transcription factor. We determined that YY1AP1 localizes to the nucleus and is a component of the INO80 chromatin remodeling complex, which is responsible for transcriptional regulation, DNA repair, and replication. Molecular studies revealed that loss of YY1AP1 in vascular smooth muscle cells leads to cell cycle arrest with decreased proliferation and increased levels of the cell cycle regulator p21/WAF/CDKN1A and disrupts TGF-β-driven differentiation of smooth muscle cells. Identification of YY1AP1 mutations as a cause of FMD indicates that this condition can result from underlying genetic variants that significantly alter the phenotype of vascular smooth muscle cells.

  6. Glucagon-like peptide-1 (GLP-1) increases in plasma and colon tissue prior to estrus and circulating levels change with increasing age in reproductively competent Wistar rats.

    PubMed

    Johnson, Michelle L; Saffrey, M Jill; Taylor, Victoria J

    2017-02-22

    There is a well-documented association between cyclic changes to food intake and the changing ovarian hormone levels of the reproductive cycle in female mammals. Limited research on appetite-controlling gastrointestinal peptides has taken place in females, simply because regular reproductive changes in steroid hormones present additional experimental factors to account for. This study focussed directly on the roles that gastrointestinal-secreted peptides may have in these reported, naturally occurring, changes to food intake during the rodent estrous cycle and aimed to determine whether peripheral changes occurred in the anorexigenic (appetite-reducing) hormones peptide-YY (PYY) and glucagon-like peptide-1 (GLP-1) in female Wistar rats (32-44 weeks of age). Total forms of each peptide were measured in matched fed and fasted plasma and descending colon tissue samples for each animal during the dark (feeding) phase. PYY concentrations did not significantly change between defined cycle stages, in either plasma or tissue samples. GLP-1 concentrations in fed plasma and descending colon tissue were significantly increased during proestrus, just prior to a significant reduction in fasted stomach contents at estrus, suggesting increased satiety and reduced food intake at this stage of the cycle. Increased proestrus GLP-1 concentrations could contribute to the reported reduction in food intake during estrus and may also have biological importance in providing the optimal nutritional and metabolic environment for gametes at the potential point of conception. Additional analysis of the findings demonstrated significant interactions of ovarian cycle stage and fed/fasted status with age on GLP-1, but not PYY plasma concentrations. Slightly older females had reduced fed plasma GLP-1 suggesting that a relaxation of regulatory control of this incretin hormone may also take place with increasing age in reproductively competent females.

  7. 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

  8. Human INO80/YY1 chromatin remodeling complex transcriptionally regulates the BRCA2- and CDKN1A-interacting protein (BCCIP) in cells.

    PubMed

    Su, Jiaming; Sui, Yi; Ding, Jian; Li, Fuqiang; Shen, Shuang; Yang, Yang; Lu, Zeming; Wang, Fei; Cao, Lingling; Liu, Xiaoxia; Jin, Jingji; Cai, Yong

    2016-10-01

    The BCCIP (BRCA2- and CDKN1A-interacting protein) is an important cofactor for BRCA2 in tumor suppression. Although the low expression of BCCIP is observed in multiple clinically diagnosed primary tumor tissues such as ovarian cancer, renal cell carcinoma and colorectal carcinoma, the mechanism of how BCCIP is regulated in cells is still unclear. The human INO80/YY1 chromatin remodeling complex composed of 15 subunits catalyzes ATP-dependent sliding of nucleosomes along DNA. Here, we first report that BCCIP is a novel target gene of the INO80/YY1 complex by presenting a series of experimental evidence. Gene expression studies combined with siRNA knockdown data locked candidate genes including BCCIP of the INO80/YY1 complex. Silencing or over-expressing the subunits of the INO80/YY1 complex regulates the expression level of BCCIP both in mRNA and proteins in cells. Also, the functions of INO80/YY1 complex in regulating the transactivation of BCCIP were confirmed by luciferase reporter assays. Chromatin immunoprecipitation (ChIP) experiments clarify the enrichment of INO80 and YY1 at +0.17 kb downstream of the BCCIP transcriptional start site. However, this enrichment is significantly inhibited by either knocking down INO80 or YY1, suggesting the existence of both INO80 and YY1 is required for recruiting the INO80/YY1 complex to BCCIP promoter region. Our findings strongly indicate that BCCIP is a potential target gene of the INO80/YY1 complex.

  9. 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

  10. YY1 modulates taxane response in epithelial ovarian cancer

    SciTech Connect

    Matsumura, Noriomi; Huang, Zhiqing; Baba, Tsukasa; Lee, Paula S.; Barnett, Jason C.; Mori, Seiichi; Chang, Jeffrey T.; Kuo, Wen-Lin; Gusberg, Alison H.; Whitaker, Regina S.; Gray, JoeW.; Fujii, Shingo; Berchuck, Andrew; Murphy, Susan K.

    2008-10-10

    The results of this study show that a high YY1 gene signature (characterized by coordinate elevated expression of transcription factor YY1 and putative YY1 target genes) within serous epithelial ovarian cancers is associated with enhanced response to taxane-based chemotherapy and improved survival. If confirmed in a prospective study, these results have important implications for the potential future use of individualized therapy in treating patients with ovarian cancer. Identification of the YY1 gene signature profile within a tumor prior to initiation of chemotherapy may provide valuable information about the anticipated response of these tumors to taxane-based drugs, leading to better informed decisions regarding chemotherapeutic choice. Survival of ovarian cancer patients is largely dictated by their response to chemotherapy, which depends on underlying molecular features of the malignancy. We previously identified YIN YANG 1 (YY1) as a gene whose expression is positively correlated with ovarian cancer survival. Herein we investigated the mechanistic basis of this association. Epigenetic and genetic characteristics of YY1 in serous epithelial ovarian cancer (SEOC) were analyzed along with YY1 mRNA and protein. Patterns of gene expression in primary SEOC and in the NCI60 database were investigated using computational methods. YY1 function and modulation of chemotherapeutic response in vitro was studied using siRNA knockdown. Microarray analysis showed strong positive correlation between expression of YY1 and genes with YY1 and transcription factor E2F binding motifs in SEOC and in the NCI60 cancer cell lines. Clustering of microarray data for these genes revealed that high YY1/E2F3 activity positively correlates with survival of patients treated with the microtubule stabilizing drug paclitaxel. Increased sensitivity to taxanes, but not to DNA crosslinking platinum agents, was also characteristic of NCI60 cancer cell lines with a high YY1/E2F signature. YY1

  11. Elevated levels of natriuretic peptides in patients with pulmonary thromboembolism.

    PubMed

    Kiely, David G; Kennedy, Norman S; Pirzada, Omar; Batchelor, Sheila A; Struthers, Allan D; Lipworth, Brian J

    2005-10-01

    Pulmonary thromboembolism (PTE) occurs in a wide variety of clinical settings and presents a diagnostic challenge to clinicians, often requiring extensive imaging of the vascular bed. Management increasingly requires accurate risk stratification to rapidly identify those with massive and submassive PTE requiring different therapeutic strategies such as thrombolysis. Provision of a rapid blood test that improves diagnostic certainty and helps stratify risk could therefore bridge the gap between uncertainty and delivery of immediate early life-saving treatment. One hundred and fourteen consecutive patients with suspected PTE underwent prospective evaluation. Venous blood samples were obtained from an unselected group referred for ventilation-perfusion scintigraphy. B-type natriuretic peptide (BNP), atrial natriuretic peptide (ANP) and N-terminal pro-ANP (N-ANP) were measured by radioimmunoassay using commercially available kits. The scans were classified into three groups according to standard criteria (PIOPED); normal scan (N) (n=20), low/intermediate probability (L/I) of PTE (n=77) and high probability (H) of PTE (n=17). Comparisons were also made between patients with high probability scans who died (n=3) and those who survived (n=14). Values are quoted for the median and interquartile ranges. There were statistically significant differences between groups for levels of (a) BNP (P<0.001): N=6.7 pmol/l (5.6-11.9), L/I=12.5 pmol/l (6.7-28.2) and H=18.5 pmol/l (12.6-74.6); (b) ANP (P<0.005): N=12.6 pmol/l (7.1-16.0), L/I=19.51 pmol/l (12.5-28.2) and H=19.1 pmol/l (15.7-31.7) and (c) N-ANP (P<0.05): N=177 pmol/l (119-200), L/I=302 pmol/l (152-576) and H=322 pmol/l (223-563). Levels of BNP and ANP were significantly (P<0.05) higher in patients with high probability scans and a diagnosis of PTE who died (n=3) than in those who survived (n=14); BNP: 91.6 pmol/l (77.5-336.2) vs. 14.4 pmol/l (11.9-27.4) and ANP 32.5 pmol/l (21.7-105.5) vs. 17.6 pmol/l (15

  12. NF-kappaB regulation of YY1 inhibits skeletal myogenesis through transcriptional silencing of myofibrillar genes.

    PubMed

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

    2007-06-01

    NF-kappaB 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-kappaB activity. Interestingly, even in proliferating myoblasts, the absence of NF-kappaB caused the pronounced induction of several myofibrillar genes, suggesting that NF-kappaB functions as a negative regulator of late-stage muscle differentiation. Although several myofibrillar promoters contain predicted NF-kappaB binding sites, functional analysis using the troponin-I2 gene as a model revealed that NF-kappaB-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-kappaB stimulated YY1 expression in multiple cell types, genetic ablation of the RelA/p65 subunit of NF-kappaB in both cultured cells and adult skeletal muscle correlated with reduced YY1 transcripts and protein. NF-kappaB 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-kappaB activity. Based on these results, we propose that NF-kappaB regulation of YY1 and transcriptional silencing of myofibrillar genes represent a new mechanism by which NF-kappaB functions in myoblasts to modulate skeletal muscle differentiation.

  13. 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

  14. 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 (ESTEM). 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 ESTEMs 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.

  15. Factors influencing brain natriuretic peptide levels in healthy pregnant women.

    PubMed

    Mayama, Michinori; Yoshihara, Masato; Uno, Kaname; Tano, Sho; Takeda, Takehiko; Ukai, Mayu; Kishigami, Yasuyuki; Oguchi, Hidenori

    2017-02-01

    The normal range of plasma brain natriuretic peptide (BNP) in pregnant women is still unclear. Moreover, pregnant women experience dynamic body weight changes and suffer from anemia, but effects on maternal BNP have not been investigated. This study aimed to reveal the normal plasma BNP range and examine the effects of physiological changes on BNP among pregnant women. Plasma BNP, hemoglobin, plasma creatinine and BMI were measured in 58 non-pregnant control women and in 773 normal pregnant women at late pregnancy, early postpartum and 1-month postpartum. Mean plasma BNP (in pg/mL) was 11.8 (95% confidence interval: 0-27.5) in non-pregnant women, 17.9 (0-44.7, p<0.001) at late pregnancy, 42.5 (0-112.6, p<0.001) early postpartum and 16.1 (0-43.9, p=0.001) 1-month postpartum. Multiple regression analysis revealed that pre-delivery BNP levels were negatively correlated with BMI (p<0.001) and hemoglobin (p=0.002) and positively correlated with creatinine (p<0.001). Post-delivery BNP was positively associated with body weight change during pregnancy (p=0.001) and post-delivery creatinine (p=0.010) but negatively associated with body weight loss at delivery (p<0.001) and post-delivery hemoglobin (p=0.004). Even normal pregnancy affects plasma BNP, particularly in the early postpartum period, indicative of cardiac stress. Plasma BNP levels are affected by BMI, body weight changes, creatinine and hemoglobin levels; therefore, these factors should be considered when analysing cardiac function and the physiological implications of BNP levels in pregnant women. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  16. Acute gastric pH changes alter intraluminal but not plasma peptide levels.

    PubMed

    Mueller, C R; Ure, T; O'Dorisio, T M; Barrie, R J; Woltering, E A

    1991-12-01

    Gastric acidity is influenced by systemic and local peptide effects. Previous work by others has shown that intraluminally secreted peptides may have a role in local control of gastric acidity; however, the response of these peptides to acute changes in gastric pH is unknown. To determine the effects of acute changes in pH on systemic and intraluminal peptide levels, 14 normal volunteers underwent placement of a nasogastric tube after an overnight fast. Blood and gastric fluid were analyzed on a control day, 2 hours after completion of 24 hours of aluminum-magnesium antacid therapy and after 24 hours of H2 blockade. Plasma and acid-alcohol-extracted gastric peptide levels were measured with specific radioimmunoassays. Specimens were subdivided into two groups: 28 gastric fluid specimens with a pH less than 4 and 10 specimens with a pH greater than 4. In the patients with a pH greater than 4, the luminal peptides, motilin, neurotensin, pancreatic polypeptide, somatostatin, substance P, and gastrin, were decreased by 50% to 90% and gastrin-releasing peptide was decreased by 36% compared with specimens with a pH less than 4. Conversely, intraluminal vasoactive intestinal polypeptide and calcitonin levels were elevated by 60% and 27%, respectively, in the samples with a pH greater than 4. Intraluminal peptide concentrations are responsive to changes in intragastric pH; however, this response was not seen in plasma peptide levels.

  17. Transcriptional Regulation of the Astrocytic Excitatory Amino Acid Transporter 1 (EAAT1) via NF-κB and Yin Yang 1 (YY1)*

    PubMed Central

    Karki, Pratap; Kim, Clifford; Smith, Keisha; Son, Deok-Soo; Aschner, Michael; Lee, Eunsook

    2015-01-01

    Astrocytic glutamate transporter excitatory amino acid transporter (EAAT) 1, also known as glutamate aspartate transporter (GLAST) in rodents, is one of two glial glutamate transporters that are responsible for removing excess glutamate from synaptic clefts to prevent excitotoxic neuronal death. Despite its important role in neurophysiological functions, the molecular mechanisms of EAAT1 regulation at the transcriptional level remain to be established. Here, we report that NF-κB is a main positive transcription factor for EAAT1, supported by the following: 1) EAAT1 contains two consensus sites for NF-κB, 2) mutation of NF-κB binding sites decreased EAAT1 promoter activity, and 3) activation of NF-κB increased, whereas inhibition of NF-κB decreased EAAT1 promoter activity and mRNA/protein levels. EGF increased EAAT1 mRNA/protein levels and glutamate uptake via NF-κB. The transcription factor yin yang 1 (YY1) plays a role as a critical negative regulator of EAAT1, supported by the following: 1) the EAAT1 promoter contains multiple consensus sites for YY1, 2) overexpression of YY1 decreased EAAT1 promoter activity and mRNA/protein levels, and 3) knockdown of YY1 increased EAAT1 promoter activity and mRNA/protein levels. Manganese decreased EAAT1 expression via YY1. Epigenetic modifiers histone deacetylases (HDACs) served as co-repressors of YY1 to further decrease EAAT1 promoter activity, whereas inhibition of HDACs reversed manganese-induced decrease of EAAT1 expression. Taken together, our findings suggest that NF-κB is a critical positive regulator of EAAT1, mediating the stimulatory effects of EGF, whereas YY1 is a negative regulator of EAAT1 with HDACs as co-repressors, mediating the inhibitory effects of manganese on EAAT1 regulation. PMID:26269591

  18. Scorpion toxin peptide action at the ion channel subunit level.

    PubMed

    Housley, David M; Housley, Gary D; Liddell, Michael J; Jennings, Ernest A

    2016-10-10

    This review categorizes functionally validated actions of defined scorpion toxin (SCTX) neuropeptides across ion channel subclasses, highlighting key trends in this rapidly evolving field. Scorpion envenomation is a common event in many tropical and subtropical countries, with neuropharmacological actions, particularly autonomic nervous system modulation, causing significant mortality. The primary active agents within scorpion venoms are a diverse group of small neuropeptides that elicit specific potent actions across a wide range of ion channel classes. The identification and functional characterisation of these SCTX peptides has tremendous potential for development of novel pharmaceuticals that advance knowledge of ion channels and establish lead compounds for treatment of excitable tissue disorders. This review delineates the unique specificities of 320 individual SCTX peptides that collectively act on 41 ion channel subclasses. Thus the SCTX research field has significant translational implications for pathophysiology spanning neurotransmission, neurohumoral signalling, sensori-motor systems and excitation-contraction coupling. Copyright © 2016 Elsevier Ltd. All rights reserved.

  19. The prevalence of a YY synaptonemal complex over XY synapsis in an XYY man with exclusive XYY spermatocytes.

    PubMed

    Solari, A J; Rey Valzacchi, G

    1997-11-01

    An infertile XYY man was studied by synaptonemal complex analysis of microspread spermatocytes and by quantitation of germ cells in semithin sections. All the 74 spermatocytes micrographed have an XYY constitution, and the biopsy shows a homogeneous arrest of spermatogenesis at the spermatocyte/young spermatid stages. The overwhelming majority (86%) of spermatocytes showed a Y-Y bivalent plus a univalent X. The Y-Y bivalent is totally synapsed in 48% of the cells. In the remaining cells, the YY bivalent has an average synaptic segment covering 43% of its length that always includes Yp. Another 9% of the spermatocytes showed an XYY trivalent and 4% of the spermatocytes showed univalence of the three gonosomes. Progression through all the pachytene substages was observed in cells with the two main synaptic configurations, but a high level of germ cell death was observed at or immediately after the meiotic divisions. The prevalence of Y-Y synapsis arises from the longer homologous region and the higher speed of pairing between the two Y chromosomes. Germ cell death is probably related to the univalence of the X chromosome. Synaptic competition between three gonosomes seems to be similar to that found in triploid birds but is somewhat different from that of XYY mice.

  20. YY1 plays an essential role at all stages of B-cell differentiation

    PubMed Central

    Kleiman, Eden; Jia, Haiqun; Loguercio, Salvatore; Su, Andrew I.; Feeney, Ann J.

    2016-01-01

    Ying Yang 1 (YY1) is a ubiquitously expressed transcription factor shown to be essential for pro–B-cell development. However, the role of YY1 in other B-cell populations has never been investigated. Recent bioinformatics analysis data have implicated YY1 in the germinal center (GC) B-cell transcriptional program. In accord with this prediction, we demonstrated that deletion of YY1 by Cγ1-Cre completely prevented differentiation of GC B cells and plasma cells. To determine if YY1 was also required for the differentiation of other B-cell populations, we deleted YY1 with CD19-Cre and found that all peripheral B-cell subsets, including B1 B cells, require YY1 for their differentiation. Transitional 1 (T1) B cells were the most dependent upon YY1, being sensitive to even a half-dosage of YY1 and also to short-term YY1 deletion by tamoxifen-induced Cre. We show that YY1 exerts its effects, in part, by promoting B-cell survival and proliferation. ChIP-sequencing shows that YY1 predominantly binds to promoters, and pathway analysis of the genes that bind YY1 show enrichment in ribosomal functions, mitochondrial functions such as bioenergetics, and functions related to transcription such as mRNA splicing. By RNA-sequencing analysis of differentially expressed genes, we demonstrated that YY1 normally activates genes involved in mitochondrial bioenergetics, whereas it normally down-regulates genes involved in transcription, mRNA splicing, NF-κB signaling pathways, the AP-1 transcription factor network, chromatin remodeling, cytokine signaling pathways, cell adhesion, and cell proliferation. Our results show the crucial role that YY1 plays in regulating broad general processes throughout all stages of B-cell differentiation. PMID:27335461

  1. Associations of plasma natriuretic peptide, adrenomedullin, and homocysteine levels with alterations in arterial stiffness: The Framingham Heart Study

    USDA-ARS?s Scientific Manuscript database

    Experimental studies suggest that the natriuretic peptides influence lipid and fatty acid metabolism. Although it has been shown that obese individuals have reduced natriuretic peptide levels, conflicting data exist on the relation of natriuretic peptide levels to other metabolic risk factors. We ex...

  2. YY1 tethers Xist RNA to the inactive X nucleation center

    PubMed Central

    Jeon, Yesu; Lee, Jeannie T.

    2011-01-01

    SUMMARY The long noncoding Xist RNA inactivates one X-chromosome in the female mammal. Current models posit that Xist induces silencing as it spreads along X and recruits Polycomb complexes. However, the mechanisms for Xist loading and spreading are currently unknown. Here, we define the nucleation center for Xist RNA and show that YY1 docks Xist particles onto the X chromosome. YY1 is a ‘bivalent’ protein, capable of binding both RNA and DNA through different sequence motifs. Xist’s exclusive attachment to the inactive X is determined by an epigenetically regulated trio of YY1 sites as well as allelic origin. Specific YY1-to-RNA and YY1-to-DNA contacts are required to load Xist particles onto X. YY1 interacts with Xist RNA through Repeat C. We propose that YY1 acts as adaptor between regulatory RNA and chromatin targets. PMID:21729784

  3. Using Peptide-Level Proteomics Data for Detecting Differentially Expressed Proteins.

    PubMed

    Suomi, Tomi; Corthals, Garry L; Nevalainen, Olli S; Elo, Laura L

    2015-11-06

    The expression of proteins can be quantified in high-throughput means using different types of mass spectrometers. In recent years, there have emerged label-free methods for determining protein abundance. Although the expression is initially measured at the peptide level, a common approach is to combine the peptide-level measurements into protein-level values before differential expression analysis. However, this simple combination is prone to inconsistencies between peptides and may lose valuable information. To this end, we introduce here a method for detecting differentially expressed proteins by combining peptide-level expression-change statistics. Using controlled spike-in experiments, we show that the approach of averaging peptide-level expression changes yields more accurate lists of differentially expressed proteins than does the conventional protein-level approach. This is particularly true when there are only few replicate samples or the differences between the sample groups are small. The proposed technique is implemented in the Bioconductor package PECA, and it can be downloaded from http://www.bioconductor.org.

  4. Ubiquitin Ligase Substrate Identification through Quantitative Proteomics at Both the Protein and Peptide Levels

    PubMed Central

    Lee, Kimberly A.; Hammerle, Lisa P.; Andrews, Paul S.; Stokes, Matthew P.; Mustelin, Tomas; Silva, Jeffrey C.; Black, Roy A.; Doedens, John R.

    2011-01-01

    Protein ubiquitination is a key regulatory process essential to life at a cellular level; significant efforts have been made to identify ubiquitinated proteins through proteomics studies, but the level of success has not reached that of heavily studied post-translational modifications, such as phosphorylation. HRD1, an E3 ubiquitin ligase, has been implicated in rheumatoid arthritis, but no disease-relevant substrates have been identified. To identify these substrates, we have taken both peptide and protein level approaches to enrich for ubiquitinated proteins in the presence and absence of HRD1. At the protein level, a two-step strategy was taken using cells expressing His6-tagged ubiquitin, enriching proteins first based on their ubiquitination and second based on the His tag with protein identification by LC-MS/MS. Application of this method resulted in identification and quantification of more than 400 ubiquitinated proteins, a fraction of which were found to be sensitive to HRD1 and were therefore deemed candidate substrates. In a second approach, ubiquitinated peptides were enriched after tryptic digestion by peptide immunoprecipitation using an antibody specific for the diglycine-labeled internal lysine residue indicative of protein ubiquitination, with peptides and ubiquitination sites identified by LC-MS/MS. Peptide immunoprecipitation resulted in identification of over 1800 ubiquitinated peptides on over 900 proteins in each study, with several proteins emerging as sensitive to HRD1 levels. Notably, significant overlap exists between the HRD1 substrates identified by the protein-based and the peptide-based strategies, with clear cross-validation apparent both qualitatively and quantitatively, demonstrating the effectiveness of both strategies and furthering our understanding of HRD1 biology. PMID:21987572

  5. Molecular level studies on binding modes of labeling molecules with polyalanine peptides

    NASA Astrophysics Data System (ADS)

    Mao, Xiaobo; Wang, Chenxuan; Ma, Xiaojing; Zhang, Min; Liu, Lei; Zhang, Lan; Niu, Lin; Zeng, Qindao; Yang, Yanlian; Wang, Chen

    2011-04-01

    In this work, the binding modes of typical labeling molecules (thioflavin T (ThT), Congo red (CR) and copper(ii) phthalocyanine tetrasulfonic acid tetrasodium salt (PcCu(SO3Na)4)) on pentaalanine, which is a model peptide segment of amyloidpeptides, have been resolved at the molecular level by using scanning tunneling microscopy (STM). In the STM images, ThT molecules are predominantly adsorbed parallel to the peptide strands and two binding modes could be identified. It was found that ThT molecules are preferentially binding on top of the peptide strand, and the mode of intercalated between neighboring peptides also exists. The parallel binding mode of CR molecules can be observed with pentaalaninepeptides. Besides the binding modes of labeling molecules, the CR and PcCu(SO3Na)4 display different adsorption affinity with the pentaalaninepeptides. The results could be beneficial for obtaining molecular level insight of the interactions between labeling molecules and peptides.In this work, the binding modes of typical labeling molecules (thioflavin T (ThT), Congo red (CR) and copper(ii) phthalocyanine tetrasulfonic acid tetrasodium salt (PcCu(SO3Na)4)) on pentaalanine, which is a model peptide segment of amyloidpeptides, have been resolved at the molecular level by using scanning tunneling microscopy (STM). In the STM images, ThT molecules are predominantly adsorbed parallel to the peptide strands and two binding modes could be identified. It was found that ThT molecules are preferentially binding on top of the peptide strand, and the mode of intercalated between neighboring peptides also exists. The parallel binding mode of CR molecules can be observed with pentaalaninepeptides. Besides the binding modes of labeling molecules, the CR and PcCu(SO3Na)4 display different adsorption affinity with the pentaalaninepeptides. The results could be beneficial for obtaining molecular level insight of the interactions between labeling molecules and peptides. Electronic

  6. 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.

  7. [Endogenous levels of somatostatin, C-peptide and insulin in acute pancreatitis].

    PubMed

    Aleryani, S; Huorka, M; Payer, J; Duris, I; Ondrejka, P; Kratochvíl'ová, H

    1997-11-01

    The authors compared in seven patients with acute pancreatitis the levels of endogenous somatostatin, insulin and C-peptide to assess their mutual correlation and relation to the development of the disease and serum amalyse levels. The results were compared with values recorded in 11 healthy volunteers. The levels of endogenous somatostatin were in patients with acute pancreatitis significantly higher (p < 0.05) than in the control group. The authors found an inverse relationship between the somatostatin and amylase level (correlation coefficient 0.75). They did not observe a significant correlation between somatostatin and insulin levels nor between somatostatin and C-peptide levels. The elevated somatostatin level may be due to the counteregulatory reaction during secretion, stimulated by endogenous or exogenous factors (cholecystokinin, alcohol, food).

  8. Optimization of Heavy Chain and Light Chain Signal Peptides for High Level Expression of Therapeutic Antibodies in CHO Cells

    PubMed Central

    Haryadi, Ryan; Ho, Steven; Kok, Yee Jiun; Pu, Helen X.; Zheng, Lu; Pereira, Natasha A.; Li, Bin; Bi, Xuezhi; Goh, Lin-Tang; Yang, Yuansheng; Song, Zhiwei

    2015-01-01

    Translocation of a nascent protein from the cytosol into the ER mediated by its signal peptide is a critical step in protein secretion. The aim of this work was to develop a platform technology to optimize the signal peptides for high level production of therapeutic antibodies in CHO cells. A database of signal peptides from a large number of human immunoglobulin (Ig) heavy chain (HC) and kappa light chain (LC) was generated. Most of the HC signal peptides contain 19 amino acids which can be divided into three domains and the LC signal peptides contain 22 amino acids. The signal peptides were then clustered according to sequence similarity. Based on the clustering, 8 HC and 2 LC signal peptides were analyzed for their impacts on the production of 5-top selling antibody therapeutics, namely, Herceptin, Avastin, Remicade, Rituxan, and Humira. The best HC and LC signal peptides for producing these 5 antibodies were identified. The optimized signal peptides for Rituxan is 2-fold better compared to its native signal peptides which are available in the public database. Substitution of a single amino acid in the optimized HC signal peptide for Avastin reduced its production significantly. Mass spectrometry analyses revealed that all optimized signal peptides are accurately removed in the mature antibodies. The results presented in this report are particularly important for the production of these 5 antibodies as biosimilar drugs. They also have the potential to be the best signal peptides for the production of new antibodies in CHO cells. PMID:25706993

  9. Identification of clustered YY1 binding sites in Imprinting Control Regions

    SciTech Connect

    Kim, J D; Hinz, A; Bergmann, A; Huang, J; Ovcharenko, I; Stubbs, L; Kim, J

    2006-04-19

    Mammalian genomic imprinting is regulated by Imprinting Control Regions (ICRs) that are usually associated with tandem arrays of transcription factor binding sites. In the current study, the sequence features derived from a tandem array of YY1 binding sites of Peg3-DMR (differentially methylated region) led us to identify three additional clustered YY1 binding sites, which are also localized within the DMRs of Xist, Tsix, and Nespas. These regions have been shown to play a critical role as ICRs for the regulation of surrounding genes. These ICRs have maintained a tandem array of YY1 binding sites during mammalian evolution. The in vivo binding of YY1 to these regions is allele-specific and only to the unmethylated active alleles. Promoter/enhancer assays suggest that a tandem array of YY1 binding sites function as a potential orientation-dependent enhancer. Insulator assays revealed that the enhancer-blocking activity is detected only in the YY1 binding sites of Peg3-DMR but not in the YY1 binding sites of other DMRs. Overall, our identification of three additional clustered YY1 binding sites in imprinted domains suggests a significant role for YY1 in mammalian genomic imprinting.

  10. The Yin and Yang of YY1 in the nervous system.

    PubMed

    He, Ye; Casaccia-Bonnefil, Patrizia

    2008-08-01

    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.

  11. Cleavage efficient 2A peptides for high level monoclonal antibody expression in CHO cells.

    PubMed

    Chng, Jake; Wang, Tianhua; Nian, Rui; Lau, Ally; Hoi, Kong Meng; Ho, Steven C L; Gagnon, Peter; Bi, Xuezhi; Yang, Yuansheng

    2015-01-01

    Linking the heavy chain (HC) and light chain (LC) genes required for monoclonal antibodies (mAb) production on a single cassette using 2A peptides allows control of LC and HC ratio and reduces non-expressing cells. Four 2A peptides derived from the foot-and-mouth disease virus (F2A), equine rhinitis A virus (E2A), porcine teschovirus-1 (P2A) and Thosea asigna virus (T2A), respectively, were compared for expression of 3 biosimilar IgG1 mAbs in Chinese hamster ovary (CHO) cell lines. HC and LC were linked by different 2A peptides both in the absence and presence of GSG linkers. Insertion of a furin recognition site upstream of 2A allowed removal of 2A residues that would otherwise be attached to the HC. Different 2A peptides exhibited different cleavage efficiencies that correlated to the mAb expression level. The relative cleavage efficiency of each 2A peptide remains similar for expression of different IgG1 mAbs in different CHO cells. While complete cleavage was not observed for any of the 2A peptides, GSG linkers did enhance the cleavage efficiency and thus the mAb expression level. T2A with the GSG linker (GT2A) exhibited the highest cleavage efficiency and mAb expression level. Stably amplified CHO DG44 pools generated using GT2A had titers 357, 416 and 600 mg/L for the 3 mAbs in shake flask batch cultures. Incomplete cleavage likely resulted in incorrectly processed mAb species and aggregates, which were removed with a chromatin-directed clarification method and protein A purification. The vector and methods presented provide an easy process beneficial for both mAb development and manufacturing.

  12. Racial Differences in Circulating Natriuretic Peptide Levels: The Atherosclerosis Risk in Communities Study

    PubMed Central

    Gupta, Deepak K; Claggett, Brian; Wells, Quinn; Cheng, Susan; Li, Man; Maruthur, Nisa; Selvin, Elizabeth; Coresh, Josef; Konety, Suma; Butler, Kenneth R; Mosley, Thomas; Boerwinkle, Eric; Hoogeveen, Ron; Ballantyne, Christie M; Solomon, Scott D

    2015-01-01

    Background Natriuretic peptides promote natriuresis, diuresis, and vasodilation. Experimental deficiency of natriuretic peptides leads to hypertension (HTN) and cardiac hypertrophy, conditions more common among African Americans. Hospital-based studies suggest that African Americans may have reduced circulating natriuretic peptides, as compared to Caucasians, but definitive data from community-based cohorts are lacking. Methods and Results We examined plasma N-terminal pro B-type natriuretic peptide (NTproBNP) levels according to race in 9137 Atherosclerosis Risk in Communities (ARIC) Study participants (22% African American) without prevalent cardiovascular disease at visit 4 (1996–1998). Multivariable linear and logistic regression analyses were performed adjusting for clinical covariates. Among African Americans, percent European ancestry was determined from genetic ancestry informative markers and then examined in relation to NTproBNP levels in multivariable linear regression analysis. NTproBNP levels were significantly lower in African Americans (median, 43 pg/mL; interquartile range [IQR], 18, 88) than Caucasians (median, 68 pg/mL; IQR, 36, 124; P<0.0001). In multivariable models, adjusted log NTproBNP levels were 40% lower (95% confidence interval [CI], −43, −36) in African Americans, compared to Caucasians, which was consistent across subgroups of age, gender, HTN, diabetes, insulin resistance, and obesity. African-American race was also significantly associated with having nondetectable NTproBNP (adjusted OR, 5.74; 95% CI, 4.22, 7.80). In multivariable analyses in African Americans, a 10% increase in genetic European ancestry was associated with a 7% (95% CI, 1, 13) increase in adjusted log NTproBNP. Conclusions African Americans have lower levels of plasma NTproBNP than Caucasians, which may be partially owing to genetic variation. Low natriuretic peptide levels in African Americans may contribute to the greater risk for HTN and its sequalae in

  13. A Dynamic Noise Level Algorithm for Spectral Screening of Peptide MS/MS Spectra

    PubMed Central

    2010-01-01

    Background High-throughput shotgun proteomics data contain a significant number of spectra from non-peptide ions or spectra of too poor quality to obtain highly confident peptide identifications. These spectra cannot be identified with any positive peptide matches in some database search programs or are identified with false positives in others. Removing these spectra can improve the database search results and lower computational expense. Results A new algorithm has been developed to filter tandem mass spectra of poor quality from shotgun proteomic experiments. The algorithm determines the noise level dynamically and independently for each spectrum in a tandem mass spectrometric data set. Spectra are filtered based on a minimum number of required signal peaks with a signal-to-noise ratio of 2. The algorithm was tested with 23 sample data sets containing 62,117 total spectra. Conclusions The spectral screening removed 89.0% of the tandem mass spectra that did not yield a peptide match when searched with the MassMatrix database search software. Only 6.0% of tandem mass spectra that yielded peptide matches considered to be true positive matches were lost after spectral screening. The algorithm was found to be very effective at removal of unidentified spectra in other database search programs including Mascot, OMSSA, and X!Tandem (75.93%-91.00%) with a small loss (3.59%-9.40%) of true positive matches. PMID:20731867

  14. Potent and Selective BACE-1 Peptide Inhibitors Lower Brain Aβ Levels Mediated by Brain Shuttle Transport.

    PubMed

    Ruderisch, Nadine; Schlatter, Daniel; Kuglstatter, Andreas; Guba, Wolfgang; Huber, Sylwia; Cusulin, Carlo; Benz, Jörg; Rufer, Arne Christian; Hoernschemeyer, Joerg; Schweitzer, Christophe; Bülau, Tina; Gärtner, Achim; Hoffmann, Eike; Niewoehner, Jens; Patsch, Christoph; Baumann, Karlheinz; Loetscher, Hansruedi; Kitas, Eric; Freskgård, Per-Ola

    2017-09-07

    Therapeutic approaches to fight Alzheimer's disease include anti-Amyloidβ (Aβ) antibodies and secretase inhibitors. However, the blood-brain barrier (BBB) limits the brain exposure of biologics and the chemical space for small molecules to be BBB permeable. The Brain Shuttle (BS) technology is capable of shuttling large molecules into the brain. This allows for new types of therapeutic modalities engineered for optimal efficacy on the molecular target in the brain independent of brain penetrating properties. To this end, we designed BACE1 peptide inhibitors with varying lipid modifications with single-digit picomolar cellular potency. Secondly, we generated active-exosite peptides with structurally confirmed dual binding mode and improved potency. When fused to the BS via sortase coupling, these BACE1 inhibitors significantly reduced brain Aβ levels in mice after intravenous administration. In plasma, both BS and non-BS BACE1 inhibitor peptides induced a significant time- and dose-dependent decrease of Aβ. Our results demonstrate that the BS is essential for BACE1 peptide inhibitors to be efficacious in the brain and active-exosite design of BACE1 peptide inhibitors together with lipid modification may be of therapeutic relevance. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  15. The Role of YY1 in Prostate Cancer

    DTIC Science & Technology

    2010-03-01

    activator protein 1. Cancer Res 2007;67:4816-26. 54. Delehouzee S, Yoshikawa T, Sawa C, et al. GABP, HCF-1 and YY1 are involved in Rb gene...expression during myogenesis. Genes Cells 2005;10:717-31. 55. Santiago FS, Ishii H, Shafi S, et al. Yin Yang-1 inhibits vascular smooth muscle cell growth... Ishii H, Shafi S, Khurana R, Kanellakis P, Bhindi R, et al. Yin Yang-1 inhibits vascular smooth muscle cell growth and intimal thickening by

  16. B-type natriuretic peptide level in a patient with constrictive pericarditis.

    PubMed

    Brown, Todd; Hollman, Jay

    2006-12-01

    We report the case of a 35-year-old man with constrictive pericarditis who had a B-type natriuretic peptide (BNP) level of 129 pg/dl despite a left ventricular end diastolic pressure of 35 mmHg. We discuss a possible explanation for the relatively low BNP level given this patient's markedly elevated intracavitary pressures in the setting of constrictive pericarditis.

  17. Beta-glucans and cancer: The influence of inflammation and gut peptide.

    PubMed

    Baldassano, Sara; Accardi, Giulia; Vasto, Sonya

    2017-09-15

    Dietary β-glucans are soluble fibers with potentially health-promoting effects. Gut peptides are important signals in the regulation of energy and glucose homeostasis. This article reviews the effects of different enriched β-glucan food consumption on immune responses, inflammation, gut hormone and cancer. Gut hormones are influenced by enriched β-glucan food consumption and levels of such peptide as YY, ghrelin, glucagon-like peptide 1 and 2 in humans influence serum glucose concentration as well as innate and adaptive immunity. Cancer cell development is also regulated by obesity and glucose dishomeostasy that are influenced by β-glucan food consumption that in turn regulated gut hormones. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  18. Kinetics of chemical degradation in monoclonal antibodies: relationship between rates at the molecular and peptide levels.

    PubMed

    Ionescu, Roxana; Vlasak, Josef

    2010-04-15

    This article describes a method to analyze the kinetics of monoclonal antibody degradation and to determine the quantitative relationship between the degradation rates observed at the molecular and peptide levels. The proposed model can be applied to any degradation pathway that can be well approximated by a first order reaction; if several pathways exist, the model assumes that they are independent. Three examples are presented to illustrate the benefits of this approach. For each case, the calculated fractions of species were compared to one or more data sets to demonstrate the good agreement between experimental results and model prediction. This method can serve as a valuable tool in interpreting chromatograms of degraded samples and predicting the population of species present at the molecular level when only data from degradation observed at the peptide level is available. This method further demonstrates how deviations from predictions of simple models can be used to unravel additional, unforeseen reactions.

  19. Stereospecific effects of morphine on plasma opioid peptide levels and nociception in dogs

    SciTech Connect

    Adams, M.L.; Morris, D.L.; Dewey, W.L.

    1986-03-05

    ..beta..-endorphin, (met)enkephalin, and (leu)enkephalin were quantitated in canine plasma by radioimmunoassay (RIA) after extraction of the peptides on Sep Pak C18 cartridges. Plasma samples were taken one hour after a 10 mg/kg s.c. injection of (-)-morphine SO/sub 4/ or (+)-morphine HBr. Antinociception, measured by a dog tail-flick test, and morphine-induced emesis, salivation, diarrhea, and ataxia were quantitated before sampling. Control levels for each dog were taken one week earlier at the same time of day after saline injections. Antinociception, morphine signs, and opioid peptide levels in plasma were significantly increased by (-)-morphine. Antinociception increased from zero to 83.54 +/- 11.0%. The number of morphine signs increased from zero to 2.9 +/- 0.28 per dog. ..beta..-endorphin levels increased from 44.52 +/- 4.25 to 90.6 +/- 7.38 pg/ml; (met)enkephalin levels increased from 253.56 +/- 22.04 to 497.1 +/- 58.12 pg/ml; (leu)-enkephalin increased from 141.65 +/- 12.9 to 313.24 +/- 35.95 pg/ml. None of these effects were observed in the dogs that received (+)-morphine. The conclude that morphine stereospecifically inhibits nociception, induces observable signs, and increases plasma opioid peptide levels in dogs.

  20. Isolation and characterization of polypeptide at the picomole level. Pre-column formation of peptide derivatives with dimethylaminoazobenzene isothiocyanate.

    PubMed Central

    Chang, J Y

    1981-01-01

    Polypeptides coupled with dimethylaminoazobenzene isothiocyanate through their amino groups to form dimethylaminoazobenzenethiocarbamoyl- (DABTC-)peptides can be separated by reversed-phase high-pressure liquid chromatography and detected in the visible region (436 nm). As little as 1 ng (2 pmol) of a DABTC-pentapeptide can be identified against a stable base-line with the signal-to-noise ratio of 10. The DABTC-peptides can also be recovered from the column, and their N-terminal amino acids (obtained by direct treatment with aqueous acid) and amino acid compositions and sequences can be all analysed at the picomole level. The power of this method is demonstrated by the complete separation and characterization of model peptides, peptide hormones and peptides derived from enzymic fragmentation of proteins. This new technique should provide a sensitive and efficient tool for peptide analysis at the nanogram level. PMID:6803768

  1. An Upstream YY1 Binding Site on the HIV-1 LTR Contributes to Latent Infection

    PubMed Central

    Bernhard, Wendy; Barreto, Kris; Raithatha, Sheetal; Sadowski, Ivan

    2013-01-01

    During HIV-1 infection a population of latently infected cells is established. This population is the major obstacle preventing total eradication of the virus from AIDS patients. HIV-1 latency is thought to arise by various mechanisms including repressive chromatin modifications. Transcription factors such as YY1 have been shown to facilitate repressive chromatin modifications by the recruitment of histone deacetylases. In this study, we identified a novel binding site for YY1 on the HIV-1 LTR, 120 nucleotides upstream of the transcription start site. We show that YY1 can bind to this site in vitro and in vivo and that binding to the LTR is dissociated upon T cell activation. Overexpression of YY1 causes an increase in the proportion of cells that produce latent infections. These observations, in combination with previous results, demonstrate that YY1 plays a prominent role in controlling the establishment and maintenance of latent HIV-1 provirus in unstimulated cells. PMID:24116200

  2. IL-13 Induces YY1 through the AKT Pathway in Lung Fibroblasts

    PubMed Central

    Guo, Jia; Yao, Hongwei; Lin, Xin; Xu, Haodong; Dean, David; Zhu, Zhou; Liu, Gang; Sime, Patricia

    2015-01-01

    A key feature of lung fibrosis is the accumulation of myofibroblasts. Interleukin 13 (IL-13) is a pro-fibrotic mediator that directly and indirectly influences the activation of myofibroblasts. Transforming growth factor beta (TGF-β) promotes the differentiation of fibroblasts into myofibroblasts, and can be regulated by IL-13. However, IL-13’s downstream signaling pathways are not completely understood. We previously reported that the transcription factor Yin Yang 1 (YY1) is upregulated in fibroblasts treated with TGF-β and in the lungs of mice and patients with pulmonary fibrosis. Moreover, YY1 directly regulates collagen and alpha smooth muscle actin (α-SMA) expression in fibroblasts. However, it is not known if IL-13 regulates fibroblast activation through YY1 expression. We hypothesize that IL-13 up-regulates YY1 expression through regulation of AKT activation, leading to fibroblast activation. In this study we found that YY1 was upregulated by IL-13 in lung fibroblasts in a dose- and time-dependent manner, resulting in increased α-SMA. Conversely, knockdown of YY1 blocked IL-13-induced α-SMA expression in fibroblasts. Furthermore, AKT phosphorylation was increased in fibroblasts treated with IL-13, and AKT overexpression upregulated YY1, whereas blockade of AKT phosphorylation suppressed the induction of YY1 by IL-13 in vitro. In vivo YY1 was upregulated in fibrotic lungs from CC10-IL-13 transgenic mice compared to that from wild-type littermates, which was associated with increased AKT phosphorylation. Taken together, these findings demonstrate that IL-13 is a potent stimulator and activator of fibroblasts, at least in part, through AKT-mediated YY1 activation. PMID:25775215

  3. Proteasome Inhibitors Alter Levels of Intracellular Peptides in HEK293T and SH-SY5Y Cells

    PubMed Central

    Dasgupta, Sayani; Castro, Leandro M.; Dulman, Russell; Yang, Ciyu; Schmidt, Marion; Ferro, Emer S.; Fricker, Lloyd D.

    2014-01-01

    The proteasome cleaves intracellular proteins into peptides. Earlier studies found that treatment of human embryonic kidney 293T (HEK293T) cells with epoxomicin (an irreversible proteasome inhibitor) generally caused a decrease in levels of intracellular peptides. However, bortezomib (an antitumor drug and proteasome inhibitor) caused an unexpected increase in the levels of most intracellular peptides in HEK293T and SH-SY5Y cells. To address this apparent paradox, quantitative peptidomics was used to study the effect of a variety of other proteasome inhibitors on peptide levels in HEK293T and SH-SY5Y cells. Inhibitors tested included carfilzomib, MG132, MG262, MLN2238, AM114, and clasto-Lactacystin β-lactone. Only MG262 caused a substantial elevation in peptide levels that was comparable to the effect of bortezomib, although carfilzomib and MLN2238 elevated the levels of some peptides. To explore off-target effects, the proteosome inhibitors were tested with various cellular peptidases. Bortezomib did not inhibit tripeptidyl peptidase 2 and only weakly inhibited cellular aminopeptidase activity, as did some of the other proteasome inhibitors. However, potent inhibitors of tripeptidyl peptidase 2 (butabindide) and cellular aminopeptidases (bestatin) did not substantially alter the peptidome, indicating that the increase in peptide levels due to proteasome inhibitors is not a result of peptidase inhibition. Although we cannot exclude other possibilities, we presume that the paradoxical increase in peptide levels upon treatment with bortezomib and other inhibitors is the result of allosteric effects of these compounds on the proteasome. Because intracellular peptides are likely to be functional, it is possible that some of the physiologic effects of bortezomib and carfilzomib arise from the perturbation of peptide levels inside the cell. PMID:25079948

  4. Regulation of the transcription factor YY1 in mitosis through phosphorylation of its DNA-binding domain.

    PubMed

    Rizkallah, Raed; Hurt, Myra M

    2009-11-01

    Yin-Yang 1 (YY1) is a ubiquitously expressed zinc finger transcription factor. It regulates a vast array of genes playing critical roles in development, differentiation, and cell cycle. Very little is known about the mechanisms that regulate the functions of YY1. It has long been proposed that YY1 is a phosphoprotein; however, a direct link between phosphorylation and the function of YY1 has never been proven. Investigation of the localization of YY1 during mitosis shows that it is distributed to the cytoplasm during prophase and remains excluded from DNA until early telophase. Immunostaining studies show that YY1 is distributed equally between daughter cells and rapidly associates with decondensing chromosomes in telophase, suggesting a role for YY1 in early marking of active and repressed genes. The exclusion of YY1 from DNA in prometaphase HeLa cells correlated with an increase in the phosphorylation of YY1 and loss of DNA-binding activity that can be reversed by dephosphorylation. We have mapped three phosphorylation sites on YY1 during mitosis and show that phosphorylation of two of these sites can abolish the DNA-binding activity of YY1. These results demonstrate a novel mechanism for the inactivation of YY1 through phosphorylation of its DNA-binding domain.

  5. Regulation of the Transcription Factor YY1 in Mitosis through Phosphorylation of Its DNA-binding Domain

    PubMed Central

    Rizkallah, Raed

    2009-01-01

    Yin-Yang 1 (YY1) is a ubiquitously expressed zinc finger transcription factor. It regulates a vast array of genes playing critical roles in development, differentiation, and cell cycle. Very little is known about the mechanisms that regulate the functions of YY1. It has long been proposed that YY1 is a phosphoprotein; however, a direct link between phosphorylation and the function of YY1 has never been proven. Investigation of the localization of YY1 during mitosis shows that it is distributed to the cytoplasm during prophase and remains excluded from DNA until early telophase. Immunostaining studies show that YY1 is distributed equally between daughter cells and rapidly associates with decondensing chromosomes in telophase, suggesting a role for YY1 in early marking of active and repressed genes. The exclusion of YY1 from DNA in prometaphase HeLa cells correlated with an increase in the phosphorylation of YY1 and loss of DNA-binding activity that can be reversed by dephosphorylation. We have mapped three phosphorylation sites on YY1 during mitosis and show that phosphorylation of two of these sites can abolish the DNA-binding activity of YY1. These results demonstrate a novel mechanism for the inactivation of YY1 through phosphorylation of its DNA-binding domain. PMID:19793915

  6. The MeCP2/YY1 interaction regulates ANT1 expression at 4q35: novel hints for Rett syndrome pathogenesis.

    PubMed

    Forlani, Greta; Giarda, Elisa; Ala, Ugo; Di Cunto, Ferdinando; Salani, Monica; Tupler, Rossella; Kilstrup-Nielsen, Charlotte; Landsberger, Nicoletta

    2010-08-15

    Rett syndrome is a severe neurodevelopmental disorder mainly caused by mutations in the transcriptional regulator MeCP2. Although there is no effective therapy for Rett syndrome, the recently discovered disease reversibility in mice suggests that there are therapeutic possibilities. Identification of MeCP2 targets or modifiers of the phenotype can facilitate the design of curative strategies. To identify possible novel MeCP2 interactors, we exploited a bioinformatic approach and selected Ying Yang 1 (YY1) as an interesting candidate. We demonstrate that MeCP2 interacts in vitro and in vivo with YY1, a ubiquitous zinc-finger epigenetic factor regulating the expression of several genes. We show that MeCP2 cooperates with YY1 in repressing the ANT1 gene encoding a mitochondrial adenine nucleotide translocase. Importantly, ANT1 mRNA levels are increased in human and mouse cell lines devoid of MeCP2, in Rett patient fibroblasts and in the brain of Mecp2-null mice. We further demonstrate that ANT1 protein levels are upregulated in Mecp2-null mice. Finally, the identified MeCP2-YY1 interaction, together with the well-known involvement of YY1 in the regulation of D4Z4-associated genes at 4q35, led us to discover the anomalous depression of FRG2, a subtelomeric gene of unknown function, in Rett fibroblasts. Collectively, our data indicate that mutations in MeCP2 might cause the aberrant overexpression of genes located at a specific locus, thus providing new candidates for the pathogenesis of Rett syndrome. As both ANT1 mutations and overexpression have been associated with human diseases, we consider it highly relevant to address the consequences of ANT1 deregulation in Rett syndrome.

  7. C-Peptide Levels Predict the Effectiveness of Dipeptidyl Peptidase-4 Inhibitor Therapy

    PubMed Central

    Demir, Sevin; Sargin, Mehmet

    2016-01-01

    Background. Our aim was to define the conditions that affect therapeutic success when dipeptidyl peptidase-4 (DPP-4) inhibitor is added to metformin monotherapy. Materials and Methods. We reviewed the medical records of 56 patients who had received DPP-4 inhibitor as an add-on to metformin monotherapy and evaluated their response in the first year of therapy. Fasting blood glucose (FBG), HbA1c, C-peptide, and weight of the patients were recorded at 3-month intervals during the first year of treatment. Results. Patients who added DPP-4 inhibitor to metformin monotherapy had significant weight loss (P = 0.004) and FBG and HbA1c levels were significantly lowered during the first 6 months (both P < 0.001). Baseline levels of C-peptide were predictive for success of the treatment (P = 0.02), even after correction for confounding factors, for example, age, gender, or BMI (P = 0.03). Duration of diabetes was not a predictor of response to treatment (P = 0.60). Conclusion. Our study demonstrates that in patients having inadequate glycemic control, the addition of a DPP-4 inhibitor as a second oral agent to metformin monotherapy provides better glycemic control, protects β-cell reserves, and does not cause weight gain. These effects depend on baseline C-peptide levels. PMID:27882332

  8. 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.

  9. Expression levels of MHC class I molecules are inversely correlated with promiscuity of peptide binding

    PubMed Central

    Chappell, Paul E; Meziane, El Kahina; Harrison, Michael; Magiera, Łukasz; Hermann, Clemens; Mears, Laura; Wrobel, Antoni G; Durant, Charlotte; Nielsen, Lise Lotte; Buus, Søren; Ternette, Nicola; Mwangi, William; Butter, Colin; Nair, Venugopal; Ahyee, Trudy; Duggleby, Richard; Madrigal, Alejandro; Roversi, Pietro; Lea, Susan M; Kaufman, Jim

    2015-01-01

    Highly polymorphic major histocompatibility complex (MHC) molecules are at the heart of adaptive immune responses, playing crucial roles in many kinds of disease and in vaccination. We report that breadth of peptide presentation and level of cell surface expression of class I molecules are inversely correlated in both chickens and humans. This relationship correlates with protective responses against infectious pathogens including Marek's disease virus leading to lethal tumours in chickens and human immunodeficiency virus infection progressing to AIDS in humans. We propose that differences in peptide binding repertoire define two groups of MHC class I molecules strategically evolved as generalists and specialists for different modes of pathogen resistance. We suggest that differences in cell surface expression level ensure the development of optimal peripheral T cell responses. The inverse relationship of peptide repertoire and expression is evidently a fundamental property of MHC molecules, with ramifications extending beyond immunology and medicine to evolutionary biology and conservation. DOI: http://dx.doi.org/10.7554/eLife.05345.001 PMID:25860507

  10. Simulations of the periodic flaring rate on YY Gem

    NASA Astrophysics Data System (ADS)

    Gao, D. H.; Chen, P. F.; Ding, M. D.; Li, X. D.

    2008-03-01

    The binary YY Gem shows many interesting properties, one of which is the periodicity in its flaring rate. The period, which is about 48 +/- 3 min, was ever interpreted in terms of the oscillation of a filament. In this paper, we propose a new model to explain this phenomenon by means of 2.5D magnetohydrodynamic (MHD) numerical simulations. It is found that magnetic reconnection is induced as the coronal loops rooted on both stars inflate and approach each other, which is driven by the differential stellar rotation. The magnetic reconnection is modulated by fast-mode magnetoacoustic waves which are trapped between the surfaces of the two stars, so that the reconnection rate presents a periodic behaviour. With the typical parameters for the binary system, the observed period can be reproduced. We also derive an empirical formula to relate the period of the flaring rate to the coronal temperature and density, as well as the magnetic field.

  11. A rediscussion on the eclipsing binary YY Canis Minoris

    NASA Astrophysics Data System (ADS)

    Vivekananda Rao, P.; Sarma, M. B. K.; Abhyankar, K. D.

    1999-10-01

    We have reanalysed the UBV light curves of \\cite[Abhyankar (1962b)]{abh62b} using the 1993 version of Wilson-Devinney computer programme with a view to derive a consistent solution in all the three passbands and to answer the discordant opinions on the general picture of YY CMi. Initially, a preliminary unspotted solution was obtained and a photometric mass ratio was derived. From the present analysis, we obtained a mass ratio of q=0.89 which differs from the mass ratio of 0.8 derived by \\cite[Giuricin & Mardirossian (1981)]{giu81} and 0.65 derived by \\cite[Abhyankar (1962b)]{abh62b} but agrees with the value of 0.885 derived by \\cite[Niarchos et al. (1998)]{nia98}. Finally, the light curves were modelled by introducing a spot on the cooler secondary component to represent the observed light curve asymmetries. Assuming the mass of the primary component to be 1.56 msun(F1V), the absolute elements of YY CMi are found to be mc=1.39 msun, Rh=2.52 Rsun, Rc=2.38 Rsun, Log Lh=1.13 Lsun, Log Lc=0.86 Lsun, Log gh=3.83 and Log gc=3.83. The primary and secondary components are found to be slightly overluminous and bigger in size when compared to stars of the same mass. In the H-R diagram (log Te versus log L, ZAMS), both the components are above but near the ZAMS suggesting that both of them have left the main sequence and have come into contact. Our results essentially agree with those of \\cite[Niarchos et al. (1998)]{nia98} based on V passband only.

  12. Plasma brain natriuretic peptide levels are elevated in patients with cancer.

    PubMed

    Bando, Sachiko; Soeki, Takeshi; Matsuura, Tomomi; Tobiume, Takeshi; Ise, Takayuki; Kusunose, Kenya; Yamaguchi, Koji; Yagi, Shusuke; Fukuda, Daiju; Iwase, Takashi; Yamada, Hirotsugu; Wakatsuki, Tetsuzo; Shimabukuro, Michio; Muguruma, Naoki; Takayama, Tetsuji; Kishimoto, Ichiro; Kangawa, Kenji; Sata, Masataka

    2017-01-01

    Natriuretic peptides have been proposed as biomarkers of cardiovascular disease, especially heart failure. Brain natriuretic peptide (BNP) has also been shown to be upregulated at the transcriptional and translational levels by pro-inflammatory cytokines in cardiac myocytes. Although we often measure plasma BNP levels in cancer patients, it remains unknown whether cancer-related inflammation affects the plasma BNP levels. We investigated the relationship between the BNP and human cancers. We retrospectively studied 2,923 patients in whom the plasma BNP levels and serum C-reactive protein (CRP) were measured and echocardiography was performed. Patients with clinically evident heart failure (NYHA II or higher), heart disease requiring medical treatment or surgery, renal dysfunction, and inflammatory disease were excluded. There were 234 patients in the final analysis. Blood sampling was performed before surgery and chemotherapy. In addition, we evaluated the relationship between the inflammation and plasma BNP levels in mouse models of colon cancer. Of the 234 patients, 80 were diagnosed with cancer. Both the plasma BNP and serum CRP levels were significantly higher in cancer patients than those without. There were no significant differences in the echocardiographic parameters. There was a significant positive correlation between the plasma BNP and serum CRP levels in cancer patients (r = 0.360, P<0.01) but not in those without. In cancer patients, only the CRP correlated with the BNP independent of the age, creatinine level, hypertension, and body mass index. In addition, in nude mice with subcutaneous colon cancer, the plasma BNP level was elevated compared with that in non-cancer mice, and there was a significant relationship between the plasma BNP and serum levels of the inflammatory markers. In cancer patients, as well as colon cancer model mice, the plasma BNP levels were elevated, possibly due to cancer-related inflammation. The effect of cancer on the BNP

  13. 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.

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

    PubMed Central

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

    2016-01-01

    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. PMID:27369384

  15. Molecular-level understanding of the adsorption mechanism of a graphite-binding peptide at the water/graphite interface.

    PubMed

    Penna, M J; Mijajlovic, M; Tamerler, C; Biggs, M J

    2015-07-14

    The association of proteins and peptides with inorganic material has vast technological potential. An understanding of the adsorption of peptides at liquid/solid interfaces on a molecular-level is fundamental to fully realising this potential. Combining our prior work along with the statistical analysis of 100+ molecular dynamics simulations of adsorption of an experimentally identified graphite binding peptide, GrBP5, at the water/graphite interface has been used here to propose a model for the adsorption of a peptide at a liquid/solid interface. This bottom-up model splits the adsorption process into three reversible phases: biased diffusion, anchoring and lockdown. Statistical analysis highlighted the distinct roles played by regions of the peptide studied here throughout the adsorption process: the hydrophobic domain plays a significant role in the biased diffusion and anchoring phases suggesting that the initial impetus for association between the peptide and the interface may be hydrophobic in origin; aromatic residues dominate the interaction between the peptide and the surface in the adsorbed state and the polar region in the middle of the peptide affords a high conformational flexibility allowing strongly interacting residues to maximise favourable interactions with the surface. Reversible adsorption was observed here, unlike in our prior work focused on a more strongly interacting surface. However, this reversibility is unlikely to be seen once the peptide-surface interaction exceeds 10 kcal mol(-1).

  16. Effect of interactions between C peptide levels and insulin treatment on clinical outcomes among patients with type 2 diabetes mellitus

    PubMed Central

    Ko, Gary T.C.; So, Wing-Yee; Tong, Peter C.; Chan, Wing-Bun; Yang, Xilin; Ma, Ronald C.; Kong, Alice P.; Ozaki, Risa; Yeung, Chun-Yip; Chow, Chun-Chung; Chan, Juliana C.

    2009-01-01

    Background A recently halted clinical trial showed that intensive treatment of type 2 diabetes mellitus was associated with increased mortality. Given the phenotypic heterogeneity of diabetes, therapy targeted at insulin status may maximize benefits and minimize harm. Methods In this longitudinal cohort study, we followed 503 patients with type 2 diabetes who were free of cardiovascular disease from 1996 until data on mortality and cardiovascular outcomes were censored in 2005. Phenotype-targeted therapy was defined as use of insulin therapy in patients with a fasting plasma C peptide level of 0.2 nmol/L or less and no insulin therapy in patients with higher C peptide levels. Results The mean age of the cohort was 54.4 (standard deviation 13.1) years, and 56% were women. The mean duration of diabetes was 4.6 years (range 0–35.9 years). Of the 503 patients, 110 (21.9%) had a low C peptide level and 111 (22.1%) were given insulin. Based on their C peptide status, 338 patients (67.2%) received phenotype-targeted therapy (non-insulin-treated, high C peptide level [n = 310] or insulin-treated, low C peptide level [n = 28]), and 165 patients (32.8%) received non-phenotype-targeted therapy (non-insulin-treated, low C peptide level [n = 82] or insulin-treated, high C peptide level [n = 83]). Compared with the insulin-treated, low-C-peptide referent group, the insulin-treated, high-C-peptide group was at a significantly higher risk of cardiovascular events (hazard ratio [HR] 2.85, p = 0.049) and death (HR 3.43, p = 0.043); the risk was not significantly higher in the other 2 groups. These differences were no longer significant after adjusting for age, sex and diabetes duration. Interpretation Patients with low C peptide levels who received insulin had the best clinical outcomes. Patients with normal to high C peptide levels who received insulin had the worst clinical outcomes. The results suggest that phenotype-targeted insulin therapy may be important in treating

  17. Lack of associations between betatrophin/ANGPTL8 level and C-peptide in type 2 diabetic subjects.

    PubMed

    Abu-Farha, Mohamed; Abubaker, Jehad; Noronha, Fiona; Al-Khairi, Irina; Cherian, Preethi; Alarouj, Monira; Bennakhi, Abdullah; Elkum, Naser

    2015-08-20

    Betatrophin has been suggested as an inducer of β-cell proliferation in mice in addition to its function in regulating triglyceride. Recent data showed that betatrophin was increased in Type 2 Diabetes (T2D), however, its ability to induce insulin production has been questioned. We hypothesized that the increased betatrophin in T2D is not affecting insulin production from β-cells. To test this hypothesis, we investigated the association between betatrophin and C-peptide level in humans, which acts as a measure of endogenous insulin production from β-cells. This study was designed to examine the association between plasma betatrophin level and C-peptide in 749 T2D and non-diabetics. Betatrophin and C-peptide levels were higher in T2D subjects compared with non-diabetics subjects. Betatrophin showed strong correlation with C-peptide in non-diabetics subjects (r = 0.28, p = < 0.0001). No association between betatrophin and C-peptide were observed in T2D subjects (r = 0.07, p = 0.3366). Dividing obese and non-obese subjects into tertiles according to betatrophin level showed significantly higher C-peptide levels at higher tertiles of betatrophin in obese non-diabetics subjects P-trend = 0.0046. On the other hand, C-peptide level was significantly higher in subject with higher betatrophin level in non-diabetics subjects across all age groups but not in T2D subjects. Multiple logistic regression models adjusted for age, BMI, gender, ethnicity as well as C-peptide level showed that subjects in the highest tertiles of betatrophin had higher odds of having T2D [odd ratio (OR) = 7.3, 95% confidence interval (CI) 4.0-13.3]. Increased betatrophin level in obese subjects is correlated with an increase in C-peptide level; which is possibly caused by the increased insulin resistance. On the other hand, no correlation is observed between increased betatrophin level and C-peptide in T2D subjects. In conclusion, the increased betatrophin in T2D subject does not cause any increase

  18. [The plasma levels of orexigenic peptides and human platelets phospholipase D activity in anorexia nervosa patients].

    PubMed

    Janas-Kozik, Maģorzata; Krupka-Matuszczyk, Irena; Krzystanek, Marek; Tomasik-Krótki, Jagna

    2006-01-01

    Ghrelin, orexins A and B (OXA, OXB) are neuropeptides engaged in the regulation of energy balance stimulating appetite and feeding. Disturbances in their activity are proposed to be involved in pathomechanism of eating disorders, particularly in anorexia nervosa (AN). The intracellular mechanism of the peptides action remains unclear. It is considered whether the orexigenic peptides may act through second messengers related to phospholipase D (PLD). The aim of the study was to find a hypothetical relation between ghrelin, OXA and OXB levels and human platelets PLD activity. 25 AN females and 20 healthy controls (mean age 17.6 and 18.6, mean BMI 15.03 and 21.41 kg/m(2), respectively) were examined. OXA and OXB plasma levels and total ghrelin plasma level was determinated with RIA. PLD activity in homogenized blood platelets was assessed with modified fluorometric method. All values are presented as the mean values. The data were analyzed using Student-t test, non-parametric U-Mann-Whitney test and Spearman correlation. The p < 0.05 was accepted as the level of significance. There is a correlation between analyzed neuropeptides and PLD in AN patients. In AN patients it is not possible to exclude influence orexins and ghrelin on platelet PLD activity.

  19. Elapid snake venom analyses show the specificity of the peptide composition at the level of genera Naja and Notechis.

    PubMed

    Munawar, Aisha; Trusch, Maria; Georgieva, Dessislava; Hildebrand, Diana; Kwiatkowski, Marcel; Behnken, Henning; Harder, Sönke; Arni, Raghuvir; Spencer, Patrick; Schlüter, Hartmut; Betzel, Christian

    2014-02-28

    Elapid snake venom is a highly valuable, but till now mainly unexplored, source of pharmacologically important peptides. We analyzed the peptide fractions with molecular masses up to 10 kDa of two elapid snake venoms-that of the African cobra, N. m. mossambica (genus Naja), and the Peninsula tiger snake, N. scutatus, from Kangaroo Island (genus Notechis). A combination of chromatographic methods was used to isolate the peptides, which were characterized by combining complimentary mass spectrometric techniques. Comparative analysis of the peptide compositions of two venoms showed specificity at the genus level. Three-finger (3-F) cytotoxins, bradykinin-potentiating peptides (BPPs) and a bradykinin inhibitor were isolated from the Naja venom. 3-F neurotoxins, Kunitz/basic pancreatic trypsin inhibitor (BPTI)-type inhibitors and a natriuretic peptide were identified in the N. venom. The inhibiting activity of the peptides was confirmed in vitro with a selected array of proteases. Cytotoxin 1 (P01467) from the Naja venom might be involved in the disturbance of cellular processes by inhibiting the cell 20S-proteasome. A high degree of similarity between BPPs from elapid and viperid snake venoms was observed, suggesting that these molecules play a key role in snake venoms and also indicating that these peptides were recruited into the snake venom prior to the evolutionary divergence of the snakes.

  20. Engineered glucagon-like peptide-1-producing hepatocytes lower plasma glucose levels in mice.

    PubMed

    Riedel, Michael J; Lee, Corinna Wai Kwan; Kieffer, Timothy J

    2009-04-01

    Glucagon-like peptide (GLP)-1 is an incretin hormone with well-characterized antidiabetic properties, including glucose-dependent stimulation of insulin secretion and enhancement of beta-cell mass. GLP-1 agonists have recently been developed and are now in clinical use for the treatment of type 2 diabetes. Rapid degradation of GLP-1 by enzymes including dipeptidyl-peptidase (DPP)-IV and neutral endopeptidase (NEP) 24.11, along with renal clearance, contribute to a short biological half-life, necessitating frequent injections to maintain therapeutic efficacy. Gene therapy may represent a promising alternative approach for achieving long-term increases in endogenous release of GLP-1. We have developed a novel strategy for glucose-regulated production of GLP-1 in hepatocytes by expressing a DPP-IV-resistant GLP-1 peptide in hepatocytes under control of the liver-type pyruvate kinase promoter. Adenoviral delivery of this construct to hepatocytes in vitro resulted in production and secretion of bioactive GLP-1 as measured by a luciferase-based bioassay developed to detect the NH2-terminally modified GLP-1 peptide engineered for this study. Transplantation of encapsulated hepatocytes into CD-1 mice resulted in an increase in plasma GLP-1 levels that was accompanied by a significant reduction in fasting plasma glucose levels. The results from this study demonstrate that a gene therapy approach designed to induce GLP-1 production in hepatocytes may represent a novel strategy for long-term secretion of bioactive GLP-1 for the treatment of type 2 diabetes.

  1. Altered cerebrospinal fluid levels of amyloid β and amyloid precursor-like protein 1 peptides in Down's syndrome.

    PubMed

    Portelius, Erik; Hölttä, Mikko; Soininen, Hilkka; Bjerke, Maria; Zetterberg, Henrik; Westerlund, Anni; Herukka, Sanna-Kaisa; Blennow, Kaj; Mattsson, Niklas

    2014-06-01

    Down's syndrome (DS) patients develop early Alzheimer's disease pathology with abundant cortical amyloid plaques, likely due to overproduction of the amyloid precursor protein (APP), which subsequently leads to amyloid β (Aβ) aggregation. This is reflected in cerebrospinal fluid (CSF) levels of the 42-amino acid long Aβ peptide (Aβ1-42), which are increased in young DS patients and decreases with age. However, it is unclear whether DS also affects other aspects of Aβ metabolism, including production of shorter C- and N-terminal truncated Aβ peptides, and production of peptides from the amyloid precursor-like protein 1 (APLP1), which is related to APP, and cleaved by the same enzymatic processing machinery. APLP1-derived peptides may be surrogate markers for Aβ1-42 production in the brain. Here, we used hybrid immunoaffinity-mass spectrometry and enzyme-linked immunosorbent assays to monitor several Aβ and APLP1 peptides in CSF from DS patients (n = 12) and healthy controls (n = 20). CSF levels of Aβ1-42 and three endogenous peptides derived from APLP1 (APL1β25, APL1β27 and APL1β28) were decreased in DS compared with controls, while a specific Aβ peptide, Aβ1-28, was increased in a majority of the DS individuals. This study indicates that DS causes previously unknown specific alterations of APP and APLP1 metabolism.

  2. Cellular transcription factor YY1 mediates the varicella-zoster virus (VZV) IE62 transcriptional activation.

    PubMed

    Khalil, Mohamed I; Sommer, Marvin; Arvin, Ann; Hay, John; Ruyechan, William T

    2014-01-20

    Several cellular transcription factors have been shown to be involved in IE62-mediated activation. The YY1 cellular transcription factor has activating and repressive effects on gene transcription. Analysis of the VZV genome revealed 19 postulated YY1 binding sites located within putative promoters of 16 VZV genes. Electrophoretic mobility shift assays (EMSA) confirmed the binding of YY1 to ORF10, ORF28/29 and gI promoters and the mutation of these binding sites inhibited YY1 binding and the promoter activation by IE62 alone or following VZV infection. Mutation of the ORF28/29 YY1 site in the VZV genome displayed insignificant influence on virus growth in melanoma cells; but it inhibited the virus replication significantly at day 5 and 6 post infection in HELF cells. This work suggests a novel role for the cellular factor YY1 in VZV replication through the mediation of IE62 activation of viral gene expression. © 2013 Elsevier Inc. All rights reserved.

  3. A prominent and conserved role for YY1 in Xist transcriptional activation

    PubMed Central

    Navarro, Pablo; Neuillet, Damien; Rougeulle, Claire

    2014-01-01

    Accumulation of the non-coding RNA Xist on one X chromosome in female cells is a hallmark of X-chromosome inactivation in eutherians. Here, we uncovered an essential function for the ubiquitous autosomal transcription factor Yin-Yang 1 (YY1) in the transcriptional activation of Xist in both human and mouse. We show that loss of YY1 prevents Xist up-regulation during the initiation and maintenance of X-inactivation, and that YY1 binds directly the Xist 5′ region to trigger the activity of the Xist promoter. Binding of YY1 to the Xist 5′ region prior to X-chromosome inactivation competes with the Xist repressor REX1 while DNA methylation controls mono-allelic fixation of YY1 to Xist at the onset of X-chromosome inactivation. YY1 is thus the first autosomal activating factor involved in a fundamental and conserved pathway of Xist regulation that ensures the asymmetric transcriptional up-regulation of the master regulator of X-chromosome inactivation. PMID:25209548

  4. YY1 regulates the expression of snail through a distal enhancer

    PubMed Central

    Palmer, Matthew B.; Majumder, Parimal; Cooper, John C.; Yoon, Hyesuk; Wade, Paul A.; Boss, Jeremy M.

    2010-01-01

    Expression of the snail gene is required for the epithelial-mesenchymal transitions that accompany mammalian gastrulation, neural crest migration, and organ formation. Pathological expression of snail contributes to the migratory capacity of invasive tumors, including melanomas. To investigate the mechanism of snail up regulation in human melanoma cells, a conserved enhancer located 3’ of the snail gene was analyzed. An overlapping Ets and YY1 consensus sequence, in addition to a SOX consensus sequence, were required for full enhancer activity. Proteins specifically binding these sequences were detected by EMSA. The Ets/YY1 binding activity was purified by DNA affinity chromatography and identified as YY1. Although ubiquitously expressed, YY1 was bound at the snail 3’ enhancer in vivo in snail-expressing cells but not in cells that did not express snail. Knockdown of YY1 in A375 cells led to decreased snail expression. These results identify a role for YY1 in regulating transcription of snail in melanoma cells through binding to the snail 3’ enhancer. PMID:19208738

  5. 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

  6. Associates of an Elevated Natriuretic Peptide Level in Stable Heart Failure Patients: Implications for Targeted Management

    PubMed Central

    Dawkins, Ian; Murphy, Niamh; Collier, Patrick; Ledwidge, Mark; McDonald, Kenneth; Watson, Chris J.

    2013-01-01

    Background. Persistently elevated natriuretic peptide (NP) levels in heart failure (HF) patients are associated with impaired prognosis. Recent work suggests that NP-guided therapy can improve outcome, but the mechanisms behind an elevated BNP remain unclear. Among the potential stimuli for NP in clinically stable patients are persistent occult fluid overload, wall stress, inflammation, fibrosis, and ischemia. The purpose of this study was to identify associates of B-type natriuretic peptide (BNP) in a stable HF population. Methods. In a prospective observational study of 179 stable HF patients, the association between BNP and markers of collagen metabolism, inflammation, and Doppler-echocardiographic parameters including left ventricular ejection fraction (LVEF), left atrial volume index (LAVI), and E/e prime (E/e′) was measured. Results. Univariable associates of elevated BNP were age, LVEF, LAVI, E/e′, creatinine, and markers of collagen turnover. In a multiple linear regression model, age, creatinine, and LVEF remained significant associates of BNP. E/e′ and markers of collagen turnover had a persistent impact on BNP independent of these covariates. Conclusion. Multiple variables are associated with persistently elevated BNP levels in stable HF patients. Clarification of the relative importance of NP stimuli may help refine NP-guided therapy, potentially improving outcome for this at-risk population. PMID:24453873

  7. Elevated circulating levels of xenopsin-related peptide-1 are associated with polycystic ovary syndrome.

    PubMed

    Temur, Muzaffer; Özün Özbay, Pelin; Aksun, Saliha; Yilmaz, Özgür; Çift, Tayfur; Üstünel, Sibel; Calan, Mehmet

    2017-08-22

    This study was conducted to compare serum xenopsin-related peptide-1 (XP-1) levels in women with polycystic ovary syndrome (PCOS) and in healthy women and to determine the role of XP-1 levels in PCOS. Forty patients with PCOS and 38 healthy women were included in the study and matched with age and body mass index. Fasting blood glucose, insulin, high sensitivity C-reactive protein (hs-CRP), XP-1 and total testosterone levels of all participants were measured. Serum XP-1 levels significantly increased in women with PCOS compared to the control group (6.49 ± 1.57 vs 5.29 ± 1.45 ng/ml, p = 0.001). Serum insulin, hs-CRP, HOMA-IR, total testosterone levels and waist circumference were higher in women with PCOS than in control group. High XP-1 levels were associated with PCOS after adjustment for potential confounders. Receiver operating characteristic (ROC) curve analysis confirmed that the area under ROC curves was 0.703 (95% CI 0.588-0.818, p < 0.002) for XP-1 levels. The optimal cut-off value of XP-1 for detecting PCOS was ≥5.87 ng/ml. Our results indicate that increased XP-1 levels were associated with PCOS after adjustment for potential confounders, which has been shown to be effective in the function of the insulin signaling pathway.

  8. NT-brain natriuretic peptide levels in pleural fluid distinguish between pleural transudates and exudates.

    PubMed

    Tomcsányi, János; Nagy, Erzsébet; Somlói, Miklós; Moldvay, Judit; Bezzegh, Attila; Bózsik, Béla; Strausz, János

    2004-10-01

    Pleural effusion is not pathognomic and distinguishing between transudates and exudates often presents a diagnostic dilemma. The purpose of our study was to examine whether the inclusion of pleural fluid brain natriuretic peptide (BNP) measurement into the analysis improves the diagnostic accuracy of pleural effusion. The pleural effusion of 14 patients with CHF (group A) and 14 subjects with different pleural pathology (group B) were analyzed. Samples of pleural fluid and serum were obtained from all patients on admission and biochemical analysis, bacterial and fungal culture, acid-fast bacilli smear and culture and cytology were performed on the pleural fluid. In vitro quantitative determination of N-terminal pro-Brain natriuretic peptide (NT-proBNP) in serum and pleural fluid were performed by electrochemiluminescence immunoassay proBNP method on an Elecsys 2010 (Roche) analyzer. The median NT-proBNP levels in groups A and B were 6295 pg/ml and 276 pg/ml, respectively: (P=0.0001). There was no overlap between the two groups. While the Light's criteria had a sensitivity of 93% and specificity of 43% for transudates, the pleural fluid NT-proBNP level accurately differentiated between the two groups. The pleural NT-proBNP levels were elevated in all patients who had transudate. Therefore if the NT-proBNP levels of pleural effusion are within the normal range, transudate resulting from congestive heart failure can be ruled out. Our results suggest that the inclusion of pleural fluid NT-proBNP measurement in the routine diagnostic panel would enhance discrimination among the different causes of pleural effusions.

  9. In Situ Molecular Level Studies on Membrane Related Peptides and Proteins in Real Time Using Sum Frequency Generation Vibrational Spectroscopy

    PubMed Central

    Ye, Shuji; Nguyen, Khoi Tan; Le Clair, Stéphanie V.; Chen, Zhan

    2009-01-01

    Sum frequency generation (SFG) vibrational spectroscopy has been demonstrated to be a powerful technique to study the molecular structures of surfaces and interfaces in different chemical environments. This review summarizes recent SFG studies on hybrid bilayer membranes and substrate-supported lipid monolayers and bilayers, the interaction between peptides/proteins and lipid monolayers/bilayers, and bilayer perturbation induced by peptides/proteins. To demonstrate the ability of SFG to determine the orientations of various secondary structures, studies on the interaction between different peptides/proteins (melittin, G proteins, almethicin, and tachyplesin I) and lipid bilayers are discussed. Molecular level details revealed by SFG in these studies show that SFG can provide a unique understanding on the interactions between a lipid monolayer/bilayer and peptides/proteins in real time, in situ and without any exogenous labeling. PMID:19306928

  10. Optimizing production of Fc-amidated peptides by Chinese hamster ovary cells.

    PubMed

    Carlson, Kristina; Pomerantz, Steven C; Vafa, Omid; Naso, Michael; Strohl, William; Mains, Richard E; Eipper, Betty A

    2015-10-16

    Amidation of the carboxyl terminal of many peptides is essential for full biological potency, often increasing receptor binding and stability. The single enzyme responsible for this reaction is peptidylglycine α-amidating monooxygenase (PAM: EC 1.14.17.3), a copper- and ascorbate-dependent Type I membrane protein. To make large amounts of high molecular weight amidated product, Chinese hamster ovary (CHO) cells were engineered to express exogenous PAM. To vary access of the enzyme to its substrate, exogenous PAM was targeted to the endoplasmic reticulum, trans-Golgi network, endosomes and lysosomes or to the lumen of the secretory pathway. PAM was equally active when targeted to each intracellular location and assayed in homogenates. Immunocytochemical analyses of CHO cells and a pituitary cell line demonstrated that targeting of exogenous PAM was partially successful. PAM substrates generated by expressing peptidylglycine substrates (glucagon-like peptide 1-Gly, peptide YY-Gly and neuromedin U-Gly) fused to the C-terminus of immunoglobulin Fc in CHO cell lines producing targeted PAM. The extent of amidation of the Fc-peptides was determined by mass spectrometry and amidation-specific enzyme immunoassays. Amidation was inhibited by copper chelation, but was not enhanced by the addition of additional copper or ascorbate. Peptide amidation was increased over endogenous levels by exogenous PAM, and targeting PAM to the endoplasmic reticulum or trans-Golgi network increased peptide amidation compared to endogenous CHO PAM.

  11. YY1 and CTCF orchestrate a 3D chromatin looping switch during early neural lineage commitment

    PubMed Central

    Beagan, Jonathan A.; Duong, Michael T.; Titus, Katelyn R.; Zhou, Linda; Cao, Zhendong; Ma, Jingjing; Lachanski, Caroline V.; Gillis, Daniel R.; Phillips-Cremins, Jennifer E.

    2017-01-01

    CTCF is an architectural protein with a critical role in connecting higher-order chromatin folding in pluripotent stem cells. Recent reports have suggested that CTCF binding is more dynamic during development than previously appreciated. Here, we set out to understand the extent to which shifts in genome-wide CTCF occupancy contribute to the 3D reconfiguration of fine-scale chromatin folding during early neural lineage commitment. Unexpectedly, we observe a sharp decrease in CTCF occupancy during the transition from naïve/primed pluripotency to multipotent primary neural progenitor cells (NPCs). Many pluripotency gene-enhancer interactions are anchored by CTCF, and its occupancy is lost in parallel with loop decommissioning during differentiation. Conversely, CTCF binding sites in NPCs are largely preexisting in pluripotent stem cells. Only a small number of CTCF sites arise de novo in NPCs. We identify another zinc finger protein, Yin Yang 1 (YY1), at the base of looping interactions between NPC-specific genes and enhancers. Putative NPC-specific enhancers exhibit strong YY1 signal when engaged in 3D contacts and negligible YY1 signal when not in loops. Moreover, siRNA knockdown of Yy1 specifically disrupts interactions between key NPC enhancers and their target genes. YY1-mediated interactions between NPC regulatory elements are often nested within constitutive loops anchored by CTCF. Together, our results support a model in which YY1 acts as an architectural protein to connect developmentally regulated looping interactions; the location of YY1-mediated interactions may be demarcated in development by a preexisting topological framework created by constitutive CTCF-mediated interactions. PMID:28536180

  12. Sex and estrogen receptor expression influence opioid peptide levels in the mouse hippocampal mossy fiber pathway.

    PubMed

    Van Kempen, Tracey A; Kahlid, Sana; Gonzalez, Andreina D; Spencer-Segal, Joanna L; Tsuda, Mumeko C; Ogawa, Sonoko; McEwen, Bruce S; Waters, Elizabeth M; Milner, Teresa A

    2013-09-27

    The opioid peptides, dynorphin (DYN) and enkephalin (L-ENK) are contained in the hippocampal mossy fiber pathway where they modulate synaptic plasticity. In rats, the levels of DYN and L-ENK immunoreactivity (-ir) are increased when estrogen levels are elevated (Torres-Reveron et al., 2008, 2009). Here, we used quantitative immunocytochemistry to examine whether opioid levels are similarly regulated in wildtype (WT) mice over the estrous cycle, and how these compared to males. Moreover, using estrogen receptor (ER) alpha and beta knock-out mice (AERKO and BERKO, respectively), the present study examined the role of ERs in rapid, membrane-initiated (6 h), or slower, nucleus-initiated (48 h) estradiol effects on mossy fiber opioid levels. Unlike rats, the levels of DYN and L-ENK-ir did not change over the estrous cycle. However, compared to males, females had higher levels of DYN-ir in CA3a and L-ENK-ir in CA3b. In WT and BERKO ovariectomized (OVX) mice, neither DYN- nor L-ENK-ir changed following 6 or 48 h estradiol benzoate (EB) administration. However, DYN-ir significantly increased 48 h after EB in the dentate gyrus (DG) and CA3b of AERKO mice only. These findings suggest that cyclic hormone levels regulate neither DYN nor L-ENK levels in the mouse mossy fiber pathway as they do in the rat. This may be due to species-specific differences in the mossy fiber pathway. However, in the mouse, DYN levels are regulated by exogenous EB in the absence of ERα possibly via an ERβ-mediated pathway requiring new gene transcription.

  13. Increased B-type natriuretic peptide levels in early-onset versus late-onset preeclampsia.

    PubMed

    Szabó, Gábor; Molvarec, Attila; Nagy, Bálint; Rigó, János

    2014-02-01

    We compared B-type natriuretic peptide (BNP) levels, clinical and laboratory findings in early-onset preeclampsia (EOP), late-onset preeclampsia (LOP) and healthy pregnant groups. We studied 40 healthy pregnant and 40 preeclamptic patients. Preeclamptics were divided in two groups, the EOP group (n=20) and LOP group (n=20), according to gestational age at the onset of disease. The distinction criterion for early- vs. late-onset was set as week 34 of gestation. The concentration of the BNP levels was measured by a sandwich fluorescence immunoassay. For statistical analysis of the clinical and laboratory findings non-parametric methods were applied. BNP levels were higher in EOP [61.35 (36.95-93.25) pg/mL] and LOP patients [32.4 (19.15-39.2) pg/mL] than in healthy pregnant women [10.05 (6.08-16.03) pg/mL] (both p<0.001). Furthermore, EOPs had significantly higher BNP levels as compared to LOP patients (p<0.001). A BNP cut-off <24.5 pg/mL had a negative-predictive value of 85.1% excluding preeclampsia. There was a significant inverse correlation between plasma BNP levels of EOP patients and sodium (p<0.05) and total protein concentrations (p<0.05). In the EOP group, a significant positive correlation was observed between plasma levels of BNP and hematocrit (p<0.05), serum potassium (p<0.05), urea (p<0.05) and 24-h proteinuria (p<0.05). BNP levels were significantly higher in EOP than in LOP patients. The cut-off value <24.5 pg/mL seems to be a powerful discriminative indicator excluding preeclampsia. The amount of proteinuria and total protein levels correlate with the elevation of the BNP levels. In EOP the extent of proteinuria is higher than in the LOP.

  14. Molecular level detection and localization of mechanical damage in collagen enabled by collagen hybridizing peptides

    PubMed Central

    Zitnay, Jared L.; Li, Yang; Qin, Zhao; San, Boi Hoa; Depalle, Baptiste; Reese, Shawn P.; Buehler, Markus J.; Yu, S. Michael; Weiss, Jeffrey A.

    2017-01-01

    Mechanical injury to connective tissue causes changes in collagen structure and material behaviour, but the role and mechanisms of molecular damage have not been established. In the case of mechanical subfailure damage, no apparent macroscale damage can be detected, yet this damage initiates and potentiates in pathological processes. Here, we utilize collagen hybridizing peptide (CHP), which binds unfolded collagen by triple helix formation, to detect molecular level subfailure damage to collagen in mechanically stretched rat tail tendon fascicle. Our results directly reveal that collagen triple helix unfolding occurs during tensile loading of collagenous tissues and thus is an important damage mechanism. Steered molecular dynamics simulations suggest that a likely mechanism for triple helix unfolding is intermolecular shearing of collagen α-chains. Our results elucidate a probable molecular failure mechanism associated with subfailure injuries, and demonstrate the potential of CHP targeting for diagnosis, treatment and monitoring of tissue disease and injury. PMID:28327610

  15. Molecular level detection and localization of mechanical damage in collagen enabled by collagen hybridizing peptides

    NASA Astrophysics Data System (ADS)

    Zitnay, Jared L.; Li, Yang; Qin, Zhao; San, Boi Hoa; Depalle, Baptiste; Reese, Shawn P.; Buehler, Markus J.; Yu, S. Michael; Weiss, Jeffrey A.

    2017-03-01

    Mechanical injury to connective tissue causes changes in collagen structure and material behaviour, but the role and mechanisms of molecular damage have not been established. In the case of mechanical subfailure damage, no apparent macroscale damage can be detected, yet this damage initiates and potentiates in pathological processes. Here, we utilize collagen hybridizing peptide (CHP), which binds unfolded collagen by triple helix formation, to detect molecular level subfailure damage to collagen in mechanically stretched rat tail tendon fascicle. Our results directly reveal that collagen triple helix unfolding occurs during tensile loading of collagenous tissues and thus is an important damage mechanism. Steered molecular dynamics simulations suggest that a likely mechanism for triple helix unfolding is intermolecular shearing of collagen α-chains. Our results elucidate a probable molecular failure mechanism associated with subfailure injuries, and demonstrate the potential of CHP targeting for diagnosis, treatment and monitoring of tissue disease and injury.

  16. Evaluation of CART peptide level in rat plasma and CSF: Possible role as a biomarker in opioid addiction.

    PubMed

    Bakhtazad, Atefeh; Vousooghi, Nasim; Garmabi, Behzad; Zarrindast, Mohammad Reza

    2016-10-01

    It has been shown previously that cocaine- and amphetamine-regulated transcript (CART) peptide has a modulatory role and homeostatic regulatory effect in motivation to and reward of the drugs of abuse specially psychostimulants. Recent data also showed that in addition to psychostimulants, CART is critically involved in the different stages of opioid addiction. Here we have evaluated the fluctuations in the level of CART peptide in plasma and CSF in different phases of opioid addiction to find out whether CART can serve as a suitable marker in opioid addiction studies. Male rats were randomly distributed in groups of control, acute low-dose (10mg/kg) morphine, acute high-dose morphine (80mg/kg), chronic escalating doses of morphine, withdrawal syndrome precipitated by administration of naloxone (1mg/kg), and abstinent after long-term drug-free maintenance of addicted animals. The level of CART peptide in CSF and plasma samples was measured by enzyme immunoassay. CART peptide concentration in the CSF and plasma was significantly elevated in acute high-dose morphine and withdrawal state animals and down-regulated in addicted rats. In abstinent group, CART peptide level was up-regulated in plasma but not in CSF samples. As the observed results are in agreement with data regarding the CART mRNA and protein expression in the brain reward pathway in opioid addiction phases, it may be suggested that evaluation of CART peptide level in CSF or plasma could be a suitable marker which reflects the rises and falls of the peptide concentration in brain in the development of opioid addiction. Copyright © 2016 Elsevier Inc. All rights reserved.

  17. Ghrelin-related peptides do not modulate vasodilator nitric oxide production or superoxide levels in mouse systemic arteries.

    PubMed

    Ku, Jacqueline M; Sleeman, Mark W; Sobey, Christopher G; Andrews, Zane B; Miller, Alyson A

    2016-04-01

    The ghrelin gene is expressed in the stomach where it ultimately encodes up to three peptides, namely, acylated ghrelin, des-acylated ghrelin and obestatin, which all have neuroendocrine roles. Recently, the authors' reported that these peptides have important physiological roles in positively regulating vasodilator nitric oxide (NO) production in the cerebral circulation, and may normally suppress superoxide production by the pro-oxidant enzyme, Nox2-NADPH oxidase. To date, the majority of studies using exogenous peptides infer that they may have similar roles in the systemic circulation. Therefore, this study examined whether exogenous and endogenous ghrelin-related peptides modulate NO production and superoxide levels in mouse mesenteric arteries and/or thoracic aorta. Using wire myography, it was found that application of exogenous acylated ghrelin, des-acylated ghrelin or obestatin to mouse thoracic aorta or mesenteric arteries failed to elicit a vasorelaxation response, whereas all three peptides elicited vasorelaxation responses of rat thoracic aorta. Also, none of the peptides modulated mouse aortic superoxide levels as measured by L-012-enhanced chemiluminescence. Next, it was found that NO bioactivity and superoxide levels were unaffected in the thoracic aorta from ghrelin-deficient mice when compared with wild-type mice. Lastly, using novel GHSR-eGFP reporter mice in combination with double-labelled immunofluorescence, no evidence was found for the growth hormone secretagogue receptor (GHSR1a) in the throracic aorta, which is the only functional ghrelin receptor identified to date. Collectively these findings demonstrate that, in contrast to systemic vessels of other species (e.g. rat and human) and mouse cerebral vessels, ghrelin-related peptides do not modulate vasodilator NO production or superoxide levels in mouse systemic arteries.

  18. Blood levels and renal effects of atrial natriuretic peptide in normal man.

    PubMed Central

    Weidmann, P; Hasler, L; Gnädinger, M P; Lang, R E; Uehlinger, D E; Shaw, S; Rascher, W; Reubi, F C

    1986-01-01

    Since mammalian atria were recently found to contain vasoactive and natriuretic peptides, we investigated the following in normal humans: plasma human atrial natriuretic peptide concentrations, effective renal plasma flow (ERPF), glomerular filtration rate (GFR), urinary water and electrolyte excretion, blood pressure (BP), and catecholamine, antidiuretic hormone (ADH), angiotensin II, and aldosterone levels before, during, and after intravenous administration of the newly synthetized alpha-human atrial natriuretic peptide (alpha hANP). In 10 subjects alpha hANP given as an initial bolus of 50 micrograms followed by a 45-min maintenance infusion at 6.25 micrograms/min increased plasma alpha hANP from 58 +/- 12 to 625 +/- 87 (mean +/- SEM) pg/ml; caused an acute fall in diastolic BP (-12%, P less than 0.001) and a hemoconcentration (hematocrit +7%, P less than 0.01) not fully explained by a negative body fluid balance; increased GFR (+15%, P less than 0.05) despite unchanged or decreased ERPF (filtration fraction +37%, P less than 0.001); augmented (P less than 0.05- less than 0.001) urinary chloride (+317%), sodium (+224%), calcium (+158%), magnesium (+110%), phosphate excretion (+88%), and free water clearance (from -0.76 to +2.23 ml/min, P less than 0.001) with only little change in potassium excretion; and increased plasma norepinephrine (P less than 0.001) while plasma and urinary epinephrine and dopamine, and plasma ADH, angiotensin II, and aldosterone levels were unchanged. The magnitude and pattern of electrolyte and water excretion during alpha hANP infusion could not be accounted for by increased GFR alone. Therefore, in normal man, endogenous alpha hANP seems to circulate in blood. alpha hANP can cause a BP reduction and hemoconcentration which occur, at least in part, independently of diuresis and are accompanied by sympathetic activation. An increase in GFR that occurs in the presence of unchanged or even decreased total renal blood flow is an important

  19. Identification and characterization of four novel peptide motifs that recognize distinct regions of the transcription factor CP2.

    PubMed

    Kang, Ho Chul; Chung, Bo Mee; Chae, Ji Hyung; Yang, Sung-Il; Kim, Chan Gil; Kim, Chul Geun

    2005-03-01

    Although ubiquitously expressed, the transcriptional factor CP2 also exhibits some tissue- or stage-specific activation toward certain genes such as globin in red blood cells and interleukin-4 in T helper cells. Because this specificity may be achieved by interaction with other proteins, we screened a peptide display library and identified four consensus motifs in numerous CP2-binding peptides: HXPR, PHL, ASR and PXHXH. Protein-database searching revealed that RE-1 silencing factor (REST), Yin-Yang1 (YY1) and five other proteins have one or two of these CP2-binding motifs. Glutathione S-transferase pull-down and coimmunoprecipitation assays showed that two HXPR motif-containing proteins REST and YY1 indeed were able to bind CP2. Importantly, this binding to CP2 was almost abolished when a double amino acid substitution was made on the HXPR sequence of REST and YY1 proteins. The suppressing effect of YY1 on CP2's transcriptional activity was lost by this point mutation on the HXPR sequence of YY1 and reduced by an HXPR-containing peptide, further supporting the interaction between CP2 and YY1 via the HXPR sequence. Mapping the sites on CP2 for interaction with the four distinct CP2-binding motifs revealed at least three different regions on CP2. This suggests that CP2 recognizes several distinct binding motifs by virtue of employing different regions, thus being able to interact with and regulate many cellular partners.

  20. Effects of posture and ageing on circulating atrial natriuretic peptide levels in man.

    PubMed

    Haller, B G; Züst, H; Shaw, S; Gnädinger, M P; Uehlinger, D E; Weidmann, P

    1987-10-01

    Possible influences of posture or age on plasma immunoreactive atrial natriuretic peptide (irANP) levels and potential correlates were assessed in 12 young (age +/- s.e.m. 24 +/- 1 year) and 12 elderly (63 +/- 8 year) healthy subjects on a liberal sodium intake. The groups did not differ significantly in their basal 24-h urinary sodium excretion (210 +/- 23 versus 180 +/- 15 mmol/l). However, plasma irANP was five- to ninefold higher in the elderly (P less than 0.05-0.01). Plasma irANP averaged 167 +/- 31 and 24 +/- 3 pg/ml in the elderly and young, respectively, during recumbency, fell (P less than 0.05) to 101 +/- 21 and 11 +/- 1 pg/ml, respectively, with upright posture, and rose (P less than 0.01) to 250 +/- 51 and 50 +/- 9 pg/ml, respectively, after intravenous (i.v.) loading with 0.9% saline (2.14 l in 3 h). Supine blood pressure (BP) and plasma norepinephrine tended to be higher while renin and aldosterone levels were lower (P less than 0.01) in the elderly; the three latter variables rose (P less than 0.001) with upright posture. These findings demonstrate that in normal humans, circulating irANP levels vary with posture and ageing. These changes may have potential physiological relevance and should be considered when interpreting plasma irANP levels in pathological conditions.

  1. Determinants of low levels of brain natriuretic peptide in morbid obesity.

    PubMed

    Ricci, Maria Anastasia; De Vuono, Stefano; Pucci, Giacomo; Di Filippo, Francesco; Berisha, Sokol; Gentili, Alessandra; Daviddi, Giulia; Ministrini, Stefano; Rondelli, Fabio; Boni, Marcello; Lupattelli, Graziana

    2017-08-01

    morbid obesity is associated with cardiovascular comorbidity. A noteworthy feature of this relationship could regard low levels of brain natriuretic peptide (BNP). The study investigates the relationship between BNP and obesity-related markers in a morbid obese population, along with echocardiographic and vascular parameters. in 154 morbid obese patients we evaluated anthropometric parameters, glycometabolic/lipid profile, bioimpedentiometry, echocardiography, visceral fat area and flow-mediated dilation (FMD) by ultrasonography. we divided population in two groups on the basis of median BMI levels; patients with higher BMI had significantly lower BNP (p = .008), FMD (p = .014) and HDL-C (p = .001) and showed a more impaired heart function. A similar trend emerged subdividing patients on the basis of median visceral fat area. BNP showed a significant inverse correlation with BMI (p < .001), left ventricular mass (p = .026) and inter-ventricular septum thickness (p = .007) and a significant positive correlation with FMD (p = .008), HDL-C (p = .022), and ejection fraction (p = .013). BMI and triglycerides were independent predictors of BNP levels. patients with higher BMI show lower BNP levels associated with greater total body fat amount. The correlation of BNP with endothelium-dependent vasodilation and cardiac impairment could represent another link between obesity and cardiovascular damage. Copyright © 2016 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

  2. Increasing B-type natriuretic peptide levels predict mortality in unselected haemodialysis patients.

    PubMed

    Breidthardt, Tobias; Kalbermatter, Stefan; Socrates, Thenral; Noveanu, Markus; Klima, Theresia; Mebazaa, Alexandre; Mueller, Christian; Kiss, Denes

    2011-08-01

    Cardiac disease is the major cause of death in patients undergoing chronic haemodialysis. Recent studies have found that B-type natriuretic peptide (BNP) levels accurately reflect the cardiovascular burden of dialysis patients. However, the prognostic potential of BNP measurements in dialysis patients remains unknown. The study included 113 chronic dialysis patients who were prospectively followed up. Levels of BNP were measured at baseline and every 6 months thereafter. The potential of baseline BNP and annual BNP changes to predict all-cause and cardiac mortality were assessed as endpoints. Median follow-up was 735 (354-1459) days; 35 (31%) patients died, 17 (15%) of them from cardiac causes. Baseline BNP levels were similar among survivors and non-survivors, and failed to predict all-cause and cardiac death. Cardiac death was preceded by a marked increase in BNP levels. In survivors BNP levels remained stable [median change: +175% (+20-+384%) vs. -14% (-35-+35%) over the 18 months preceding either death or the end of follow-up, P< 0.001]. Hence, annual BNP changes adequately predicted all-cause and cardiac death in the subsequent year {AUC(all-cause) = 0.70 [SD 0.05, 95% CI (0.60-0.81)]; AUC(cardiac) = 0.82 [SD 0.04, 95%CI (0.73-0.90)]}. A BNP increase of 40% provided the best cut-off level. Cox regression analysis confirmed that annual increases over 40% were associated with a seven-fold increased risk for all-cause and cardiac death. Annual BNP increases above 40% predicted all-cause and cardiac death in the subsequent year. Hence, serially measuring BNP levels may present a novel tool for risk stratification and treatment guidance of end-stage renal disease patients on chronic dialysis.

  3. Serum Levels of Vasoactive Intestinal Peptide as a Prognostic Marker in Early Arthritis

    PubMed Central

    Martínez, Carmen; Ortiz, Ana M.; Juarranz, Yasmina; Lamana, Amalia; Seoane, Iria V.; Leceta, Javier; García-Vicuña, Rosario

    2014-01-01

    Objective Suitable biomarkers are essential for the design of therapeutic strategies in personalized medicine. Vasoactive intestinal peptide (VIP) has demonstrated immunomodulatory properties in autoimmune murine and ex vivo human models. Our aim was to study serum levels of VIP during the follow-up of an early arthritis (EA) cohort and to analyze its value as a biomarker predicting severity and therapeutic requirements. Methods Data from 91 patients on an EA register were analyzed (76% rheumatoid arthritis (RA), 24% undifferentiated arthritis, 73% women, and median age 54 years; median disease duration at entry, 5.4 months). We collected per protocol sociodemographic, clinical, and therapeutic data. VIP levels were determined by enzyme immunoassay in sera harvested from the 91 patients (353 visits; 3.9 visit/patient) and from 100 healthy controls. VIP values below the 25th percentile of those assessed in healthy population were considered low. To determine the effect of independent variables on VIP levels, we performed a longitudinal multivariate analysis nested by patient and visit. A multivariate ordered logistic regression was modeled to determine the effect of low VIP serum levels on disease activity at the end of follow-up. Results VIP concentrations varied considerably across EA patients. Those fulfilling the criteria for RA had the lowest values in the whole sample, although no significant differences were observed compared with healthy donors. Disease activity, which was assessed using DAS28, inversely correlated with VIP levels. After a two-year follow-up, those patients with low baseline levels of VIP displayed higher disease activity and received more intensive treatment. Conclusion Patients who are unable to up-regulate VIP seem to have a worse clinical course despite receiving more intense treatment. Therefore, measurement of VIP levels may be suitable as a prognostic biomarker. PMID:24409325

  4. Evaluation of Pericardial Fluid C-Type Natriuretic Peptide Levels in Patients Undergoing Coronary Bypass Surgery.

    PubMed

    Guclu, Orkut; Karahan, Oguz; Karabacak, Mustafa; Yuksel, Volkan; Huseyin, Serhat; Mavitas, Binali

    2017-06-01

    Background Neurohumoral and hemodynamic mechanisms have an effect on cardiac activity. C-type natriuretic peptide (CNP) is accessible in the cardiovascular system. The aim of this study was to determine whether CNP concentrations in pericardial fluid and blood are related to cardiac dysfunction in patients undergoing coronary artery bypass graft surgery. Materials and Methods In this study, 40 patients undergoing coronary artery bypass grafting were enrolled. The patients were separated into two groups according to left ventricular (LV) ejection fraction (EF): group 1 contained 28 patients with normal LV systolic function (LVEF ≥ 50%) and group 2 contained 12 patients with impaired LV systolic function (LVEF < 45%). Plasma and pericardial fluid samples were acquired during surgery to measure CNP levels. Results In group 1, CNP levels were detected to be 0.46 ± 0.10 ng/mL in plasma and 0.66 ± 0.8 ng/mL in pericardial liquid. In group 2, these levels were 0.51 ± 0.09 and 0.79 ± 0.12 ng/mL, respectively. CNP levels were determined to be significantly higher in patients with low EF compared with those with normal EF in pericardial fluid concentrations (p = 0.013). Conclusions CNP level in pericardial fluid is a more sensitive and proper marker of LV dysfunction than CNP levels in plasma. To the best of our knowledge, this study is the first to examine pericardial fluid CNP levels in patients undergoing coronary artery bypass surgery. It may have a valuable role in organizing cardiac remodeling and hypertrophy. Georg Thieme Verlag KG Stuttgart · New York.

  5. Acarbose improves hypoglycaemia following gastric bypass surgery without increasing glucagon-like peptide 1 levels.

    PubMed

    Valderas, Juan Patricio; Ahuad, Jessica; Rubio, Lorena; Escalona, Manuel; Pollak, Felipe; Maiz, Alberto

    2012-04-01

    Postprandial hypoglycaemia is a severe complication of Roux-en-Y gastric bypass (RYGBP). Acarbose, an α-glucosidase inhibitor (AGI), is employed in its treatment. Several studies have shown that AGIs increase the postprandial levels of glucagon-like peptide 1 (GLP-1). However, an excessive level of GLP-1 is one of the factors involved in the physiopathology of this condition. We analysed the effect of acarbose oral administration in eight RYBGP patients with clinically significant hypoglycaemia or dumping syndrome. Glucose, insulin and GLP-1 plasma levels in fasting and after ingestion of a standard meal (Ensure Plus®; 13 g protein, 50 g carbohydrate, 11 g fat) were measured. The test was repeated the following week with the oral administration of 100 mg of acarbose 15 min prior to the meal. Five patients developed asymptomatic hypoglycaemia during the test (glucose level <50 mg/dl) with inappropriately high insulin levels and exaggerated GLP-1 response. Acarbose ingestion avoided hypoglycaemia in all of the patients and increased the lowest plasma glucose level (46.4 ± 4.8 vs. 59.0 ± 2.6 mg/dl, p < 0.01). Acarbose ingestion decreased the area under the curve for serum insulin and GLP-1 levels at 15 min after the meal. Acarbose avoided postprandial hypoglycaemia following RYGBP by decreasing the hyperinsulinemic response. This was associated with a decrease in early GLP-1 secretion, in contrast to that observed in non-surgical subjects. This finding could be explained by the reduction of glucose load in the jejunum produced by the α-glucosidase inhibition, which is the main stimulus for GLP-1 secretion.

  6. Definition of neutralizing sites on African horse sickness virus serotype 4 VP2 at the level of peptides.

    PubMed

    Martínez-Torrecuadrada, J L; Langeveld, J P; Meloen, R H; Casal, J I

    2001-10-01

    The antigenic structure of African horse sickness virus (AHSV) serotype 4 capsid protein VP2 has been determined at the peptide level by PEPSCAN analysis in combination with a large collection of polyclonal antisera and monoclonal antibodies. VP2, the determinant for the virus serotype and an important target in virus neutralization, was found to contain 15 antigenic sites. A major antigenic region containing 12 of the 15 sites was identified in the region between residues 223 and 400. A second domain between residues 568 and 681 contained the three remaining sites. These sites were used for the synthesis of peptides, which were later tested in rabbits. Of the 15 synthetic peptides, three were able to induce neutralizing antibodies for AHSV-4, defining two neutralizing epitopes, 'a' and 'b', between residues 321 and 339, and 377 and 400, respectively. A combination of peptides representing both sites induced a more effective neutralizing response. Still, the relatively low neutralization titres make the possibility of producing a synthetic vaccine for AHSV unlikely. The complex protein-protein interaction of the outer shell of the viral capsid would probably require the presence of either synthetic peptides in the correct conformation or peptide segments from the different proteins VP2, VP5 and VP7.

  7. YY1 restrained cell senescence through repressing the transcription of p16.

    PubMed

    Wang, Xiuli; Feng, Yunpeng; Xu, Liang; Chen, Yuli; Zhang, Yu; Su, Dongmei; Ren, Guoling; Lu, Jun; Huang, Baiqu

    2008-10-01

    The transcription factor YY1 has been implicated to play a role in cell growth control. In this report, we demonstrate that YY1 was able to suppress NCI-H460 cell senescence through regulating the expression of p16(INK4a), a cyclin-dependent kinase inhibitor. We also show that YY1 participated in the repression of p16(INK4a) expression in 293T cells through an epigenetic mechanism involving histone acetylation modification. Specifically, HDAC3 and HDAC4 inhibited the p16(INK4a) promoter activity. The chromatin immunoprecipitation (ChIP) assays verified that HDAC3 and HDAC4 were recruited to p16(INK4a) promoter by YY1. Moreover, co-immunoprecipitation assays revealed that these three protein factors formed a complex. Furthermore, knockdown of these factors induced cell enlargement and flattened morphology and significantly increased the SA-beta-gal activity, a biochemical marker of cell senescence. Overall, data from this study suggest that YY1, HDAC3 and HDAC4 restrained cell senescence by repressing p16(INK4a) expression through an epigenetic modification of histones.

  8. Aurora A Phosphorylation of YY1 during Mitosis Inactivates its DNA Binding Activity.

    PubMed

    Alexander, Karen E; Rizkallah, Raed

    2017-08-30

    Successful execution of mitotic cell division requires the tight synchronisation of numerous biochemical pathways. The underlying mechanisms that govern chromosome segregation have been thoroughly investigated. However, the mechanisms that regulate transcription factors in coordination with mitotic progression remain poorly understood. In this report, we identify the transcription factor YY1 as a novel mitotic substrate for the Aurora A kinase, a key regulator of critical mitotic events, like centrosome maturation and spindle formation. Using in vitro kinase assays, we show that Aurora A directly phosphorylates YY1 at serine 365 in the DNA-binding domain. Using a new phospho-specific antibody, we show that YY1 phosphorylation at serine 365 occurs during mitosis, and that this phosphorylation is significantly reduced upon inhibition of Aurora A. Furthermore, we show, using electrophoretic mobility shift and chromatin immunoprecipitation assays, that phosphorylation of YY1 at this site abolishes its DNA binding activity in vitro and in vivo. In conformity with this loss of binding activity, phosphorylated YY1 also loses its transctivation ability as demonstrated by a luciferase reporter assay. These results uncover a novel mechanism that implicates Aurora A in the mitotic inactivation of transcription factors.

  9. Fully Blind Docking at the Atomic Level for Protein-Peptide Complex Structure Prediction.

    PubMed

    Yan, Chengfei; Xu, Xianjin; Zou, Xiaoqin

    2016-10-04

    Protein-peptide interactions play an important role in many cellular processes. In silico prediction of protein-peptide complex structure is highly desirable for mechanistic investigation of these processes and for therapeutic design. However, predicting all-atom structures of protein-peptide complexes without any knowledge about the peptide binding site and the bound peptide conformation remains a big challenge. Here, we present a docking-based method for predicting protein-peptide complex structures, referred to as MDockPeP, which starts with the peptide sequence and globally docks the all-atom, flexible peptide onto the protein structure. MDockPeP was tested on the peptiDB benchmarking database using both bound and unbound protein structures. The results show that MDockPeP successfully generated near-native peptide binding modes in 95.0% of the bound docking cases and in 92.2% of the unbound docking cases. The performance is significantly better than other existing docking methods. MDockPeP is computationally efficient and suitable for large-scale applications. Copyright © 2016 Elsevier Ltd. All rights reserved.

  10. Effect of C-peptide Alone or in Combination with Nicotinamide on Insulin Levels from Pancreatic Islets in Mouse

    PubMed Central

    Ahangarpour, Akram; Ali Akbari, Fatemeh Ramezani; Moghadam, Hadi Fathi

    2016-01-01

    Background Both c-peptide and nicotinamide are known to increase blood insulin in diabetes. In the present study, we examined the effect of c-peptide alone or in combination with nicotinamide on insulin levels in pancreatic islets in mice. Methods This study was conducted with 60 adult male Naval Medical Research Institute (NMARI) mice weighing 25 to 30 g. Pancreatic islets from normal mice were isolated by the collagenase digestion method. Mice were divided into ten groups of six (n = 6): control, glyburide (1 and 10 μM), C-peptide (50 and 100 nM), nicotinamide (10, 25, and 100 mM), nicotinamide + C-peptide (100 mM and 100 nM), and buffer in different glucose concentrations (2.8, 5.6, and 16.7 mM). Insulin secretion was measured using insulin radioimmunoassay method. Results Insulin secretion significantly increased at 16.7 mM glucose concentration compared with 2.8 and 5.6 mM glucose concentrations. Incubation of islets at 2.8 and 5.6 mM glucose concentrations and nicotinamide + C-peptide, nicotinamide 25 and 100 mM, and C-peptide 100 nM significantly increased insulin secretion compared with the control group. In addition, incubation of islets at 16.7 mM glucose with nicotinamide + C-peptide significantly increased insulin secretion. Glyburide at 10 μM concentration was more effective than nicotinamide at 10 and 100 mM, C-peptide 50 and 100 nM in the presence of 16.7 mM glucose concentration. However, the combination of nicotinamide + C-peptide was more effective than glyburide at a concentration of 10 μM in the presence of a 16.7 mM glucose concentration. Conclusions This paper suggests that c-peptide, nicotinamide, and the combination of c-peptide and nicotinamide in-creases insulin secretion from pancreatic islets. PMID:27540321

  11. B-Type Natriuretic Peptide Levels Predict Ventricular Arrhythmia Post Left Ventricular Assist Device Implantation.

    PubMed

    Hellman, Yaron; Malik, Adnan S; Lin, Hongbo; Shen, Changyu; Wang, I-Wen; Wozniak, Thomas C; Hashmi, Zubair A; Pickrell, Jeanette; Jani, Milena; Caccamo, Marco A; Gradus-Pizlo, Irmina; Hadi, Azam

    2015-12-01

    B-type natriuretic peptide (BNP) levels have been shown to predict ventricular arrhythmia (VA) and sudden death in patients with heart failure. We sought to determine whether BNP levels before left ventricular assist device (LVAD) implantation can predict VA post LVAD implantation in advanced heart failure patients. We conducted a retrospective study consisting of patients who underwent LVAD implantation in our institution during the period of May 2009-March 2013. The study was limited to patients receiving a HeartMate II or HeartWare LVAD. Acute myocardial infarction patients were excluded. We compared between the patients who developed VA within 15 days post LVAD implantation to the patients without VA. A total of 85 patients underwent LVAD implantation during the study period. Eleven patients were excluded (five acute MI, four without BNP measurements, and two discharged earlier than 13 days post LVAD implantation). The incidence of VA was 31%, with 91% ventricular tachycardia (VT) and 9% ventricular fibrillation. BNP remained the single most powerful predictor of VA even after adjustment for other borderline significant factors in a multivariate logistic regression model (P < 0.05). BNP levels are a strong predictor of VA post LVAD implantation, surpassing previously described risk factors such as age and VT in the past.

  12. 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.

  13. Effect of a 4-week weight maintenance diet on circulating hormone levels: implications for clinical weight loss trials.

    PubMed

    Sainsbury, A; Evans, I R; Wood, R E; Seimon, R V; King, N A; Hills, A P; Byrne, N M

    2015-04-01

    The majority of weight loss studies fail to standardize conditions such as diet and exercise via a weight maintenance period prior to commencement of the trial. This study aimed to determine whether a weight stabilization period is necessary to establish stable baseline hormone concentrations. Fifty-one obese male participants with a body mass index of 30-40 kg m(-2) and aged 25-54 years underwent 4 weeks on an energy balance diet that was designed to achieve weight stability. Blood samples were collected in the fasting state at commencement and completion of the 4-week period, and circulating concentrations of 18 commonly measured hormones were determined. During the 4-week weight maintenance period, participants achieved weight stability within -1.5 ± 0.2 kg (-1.4 ± 0.2%) of their initial body weight. Significant reductions in serum insulin (by 18 ± 6.5%) and leptin (by 21 ± 6.0%) levels occurred, but no significant changes were observed for gut-derived appetite-regulating hormones (ghrelin and peptide YY), nor thyroid, adrenal, gonadal or somatotropic hormones. There were no significant correlations between the change in body weight and the change in circulating concentrations of insulin or leptin over the 4-week period, indicating that the observed changes were not due to weight loss, albeit significant negative correlations were observed between the changes in body weight and plasma ghrelin and peptide YY levels. This study demonstrates the need for baseline weight maintenance periods to stabilize serum levels of insulin and leptin in studies specifically investigating effects on these parameters in the obese. However, this does not apply to circulating levels of gut-derived appetite-regulating hormones (ghrelin and peptide YY), nor thyroid, adrenal, gonadal or somatotropic hormones.

  14. Fasting and postprandial levels of a novel anorexigenic peptide nesfatin in childhood obesity.

    PubMed

    Anık, Ahmet; Çatlı, Gönül; Abacı, Ayhan; Küme, Tuncay; Bober, Ece

    2014-07-01

    Nesfatin-1, a recently discovered anorexigenic peptide, is expressed in several tissues, including pancreatic islet cells and central nervous system. However, its pathophysiological role in the development of obesity and insulin resistance remains unknown. To investigate the possible involvement of nesfatin-1 in the pathogenesis of childhood obesity, we examined the relationship between fasting and postprandial nesfatin-1 concentrations and metabolic/antropometric parameters in obese children. The study included obese children with a body mass index >95th percentile. Fasting serum glucose, insulin, lipid profile, fasting and postprandial (120th min) nesfatin-1 levels were measured to evaluate the metabolic parameters. Different cutoff values for prepubertal and pubertal stages were used to determine the status of insulin resistance (HOMA-IR) (prepubertal >2.5, pubertal >4). The percentage of body fat was measured using bioelectric impedance analysis. Seventy-one obese children were included in this study. There was no statistically significant difference between fasting and postprandial nesfatin-1 levels in obese subjects (0.70 ± 0.15 and 0.69 ± 0.14 ng/mL, p>0.05, respectively). Insulin resistance was observed in 58% (41/71) of the cases. There was no significant difference in either fasting or postprandial serum nesfatin-1 levels between the insulin-resistant and non-resistant groups (p>0.05). There was no correlation between fasting and postprandial serum nesfatin-1 levels and anthropometric and metabolic parameters in insulin-resistant and non-resistant groups. In this study, there was no significant increase in the postprandial level of nesfatin-1. This observation suggested that oral glucose load in obese children may not be sufficient for nesfatin-1 response and that nesfatin-1 may not have an effect as a short-term regulator of food intake.

  15. Hierarchical processes in β-sheet peptide self-assembly from the microscopic to the mesoscopic level

    NASA Astrophysics Data System (ADS)

    Li, Deng; Hai, Xu

    2016-01-01

    Under appropriate physicochemical conditions, short peptide fragments and their synthetic mimics have been shown to form elongated cross-β nanostructures through self-assembly. The self-assembly process and the resultant peptide nanostructures are not only related to neurodegenerative diseases but also provide inspiration for the development of novel bionanomaterials. Both experimental and theoretical studies on peptide self-assembly have shown that the self-assembly process spans multiple time and length scales and is hierarchical. β-sheet self-assembly consists of three sub-processes from the microscopic to the mesoscopic level: β-sheet locking, lateral stacking, and morphological transformation. Detailed atomistic simulation studies have provided insight into the early stages of peptide nanostructure formation and the interplay between different non-covalent interactions at the microscopic level. This review gives a brief introduction of the hierarchical peptide self-assembly process and focuses on the roles of various non-covalent interactions in the sub-processes based on recent simulation, experimental, and theoretical studies. Project supported by the National Natural Science Foundation of China (Grant Nos. 21373270 and 11504431) and the Fundamental Research Funds for Central Universities of China (Grant No. 15CX02025A).

  16. Temporal changes in nutritional state affect hypothalamic POMC peptide levels independently of leptin in adult male mice

    PubMed Central

    Mercer, Aaron J.; Stuart, Ronald C.; Attard, Courtney A.; Otero-Corchon, Veronica; Nillni, Eduardo A.

    2014-01-01

    Hypothalamic proopiomelanocortin (POMC) neurons constitute a critical anorexigenic node in the central nervous system (CNS) for maintaining energy balance. These neurons directly affect energy expenditure and feeding behavior by releasing bioactive neuropeptides but are also subject to signals directly related to nutritional state such as the adipokine leptin. To further investigate the interaction of diet and leptin on hypothalamic POMC peptide levels, we exposed 8- to 10-wk-old male POMC-Discosoma red fluorescent protein (DsRed) transgenic reporter mice to either 24–48 h (acute) or 2 wk (chronic) food restriction, high-fat diet (HFD), or leptin treatment. Using semiquantitative immunofluorescence and radioimmunoassays, we discovered that acute fasting and chronic food restriction decreased the levels of adrenocorticotropic hormone (ACTH), α-melanocyte-stimulating hormone (α-MSH), and β-endorphin in the hypothalamus, together with decreased DsRed fluorescence, compared with control ad libitum-fed mice. Furthermore, acute but not chronic HFD or leptin administration selectively increased α-MSH levels in POMC fibers and increased DsRed fluorescence in POMC cell bodies. HFD and leptin treatments comparably increased circulating leptin levels at both time points, suggesting that transcription of Pomc and synthesis of POMC peptide products are not modified in direct relation to the concentration of plasma leptin. Our findings indicate that negative energy balance persistently downregulated POMC peptide levels, and this phenomenon may be partially explained by decreased leptin levels, since these changes were blocked in fasted mice treated with leptin. In contrast, sustained elevation of plasma leptin by HFD or hormone supplementation did not significantly alter POMC peptide levels, indicating that enhanced leptin signaling does not chronically increase Pomc transcription and peptide synthesis. PMID:24518677

  17. Temporal changes in nutritional state affect hypothalamic POMC peptide levels independently of leptin in adult male mice.

    PubMed

    Mercer, Aaron J; Stuart, Ronald C; Attard, Courtney A; Otero-Corchon, Veronica; Nillni, Eduardo A; Low, Malcolm J

    2014-04-15

    Hypothalamic proopiomelanocortin (POMC) neurons constitute a critical anorexigenic node in the central nervous system (CNS) for maintaining energy balance. These neurons directly affect energy expenditure and feeding behavior by releasing bioactive neuropeptides but are also subject to signals directly related to nutritional state such as the adipokine leptin. To further investigate the interaction of diet and leptin on hypothalamic POMC peptide levels, we exposed 8- to 10-wk-old male POMC-Discosoma red fluorescent protein (DsRed) transgenic reporter mice to either 24-48 h (acute) or 2 wk (chronic) food restriction, high-fat diet (HFD), or leptin treatment. Using semiquantitative immunofluorescence and radioimmunoassays, we discovered that acute fasting and chronic food restriction decreased the levels of adrenocorticotropic hormone (ACTH), α-melanocyte-stimulating hormone (α-MSH), and β-endorphin in the hypothalamus, together with decreased DsRed fluorescence, compared with control ad libitum-fed mice. Furthermore, acute but not chronic HFD or leptin administration selectively increased α-MSH levels in POMC fibers and increased DsRed fluorescence in POMC cell bodies. HFD and leptin treatments comparably increased circulating leptin levels at both time points, suggesting that transcription of Pomc and synthesis of POMC peptide products are not modified in direct relation to the concentration of plasma leptin. Our findings indicate that negative energy balance persistently downregulated POMC peptide levels, and this phenomenon may be partially explained by decreased leptin levels, since these changes were blocked in fasted mice treated with leptin. In contrast, sustained elevation of plasma leptin by HFD or hormone supplementation did not significantly alter POMC peptide levels, indicating that enhanced leptin signaling does not chronically increase Pomc transcription and peptide synthesis.

  18. MAXI/GSC detection of a possible X-ray flare from an dMe binary system YY Gem

    NASA Astrophysics Data System (ADS)

    Nakamura, Y.; Kanetou, S.; Tsuboi, Y.; Sasaki, R.; Ueno, S.; Tomida, H.; Nakahira, S.; Kimura, M.; Ishikawa, M.; Nakagawa, Y. E.; Mihara, T.; Sugizaki, M.; Serino, M.; Shidatsu, M.; Sugimoto, J.; Takagi, T.; Matsuoka, M.; Kawai, N.; Arimoto, M.; Yoshii, T.; Tachibana, Y.; Ono, Y.; Fujiwara, T.; Yoshida, A.; Sakamoto, T.; Kawakubo, Y.; Ohtsuki, H.; Tsunemi, H.; Imatani, R.; Negoro, H.; Nakajima, M.; Tanaka, K.; Masumitsu, T.; Ueda, Y.; Kawamuro, T.; Hori, T.; Yamauchi, M.; Itoh, D.; Yamaoka, K.; Morii, M.

    2015-09-01

    MAXI/GSC observed a possible X-ray flare from a dMe binary system YY Gem. The MAXI/GSC nova alert system triggered on the flare-like event from the position consistent with the active binary system YY Gem during a scan transit at 01:29:00 UT on September 24th 2015.

  19. Lateralized Response of Dynorphin A Peptide Levels after Traumatic Brain Injury

    PubMed Central

    Hussain, Zubair Muhammad; Fitting, Sylvia; Watanabe, Hiroyuki; Usynin, Ivan; Yakovleva, Tatjana; Knapp, Pamela E.; Scheff, Stephen W.; Hauser, Kurt F.

    2012-01-01

    Abstract Traumatic brain injury (TBI) induces a cascade of primary and secondary events resulting in impairment of neuronal networks that eventually determines clinical outcome. The dynorphins, endogenous opioid peptides, have been implicated in secondary injury and neurodegeneration in rodent and human brain. To gain insight into the role of dynorphins in the brain's response to trauma, we analyzed short-term (1-day) and long-term (7-day) changes in dynorphin A (Dyn A) levels in the frontal cortex, hippocampus, and striatum, induced by unilateral left-side or right-side cortical TBI in mice. The effects of TBI were significantly different from those of sham surgery (Sham), while the sham surgery also produced noticeable effects. Both sham and TBI induced short-term changes and long-term changes in all three regions. Two types of responses were generally observed. In the hippocampus, Dyn A levels were predominantly altered ipsilateral to the injury. In the striatum and frontal cortex, injury to the right (R) hemisphere affected Dyn A levels to a greater extent than that seen in the left (L) hemisphere. The R-TBI but not L-TBI produced Dyn A changes in the striatum and frontal cortex at 7 days after injury. Effects of the R-side injury were similar in the two hemispheres. In naive animals, Dyn A was symmetrically distributed between the two hemispheres. Thus, trauma may reveal a lateralization in the mechanism mediating the response of Dyn A-expressing neuronal networks in the brain. These networks may differentially mediate effects of left and right brain injury on lateralized brain functions. PMID:22468884

  20. Creation of dialysis vascular access with normal flow increases brain natriuretic peptide levels.

    PubMed

    Malík, Jan; Tuka, Vladimir; Krupickova, Zdislava; Chytilova, Eva; Holaj, Robert; Slavikova, Marcela

    2009-12-01

    Chronic heart failure is very common in hemodialyzed patients due to several factors such as intermittent volume overload, anemia, and hypertension. Dialysis access flow is usually considered to have a minor effect. We hypothesized that creation of dialysis access with "normal" flow would lead to elevation of B-type natriuretic peptide (BNP), which is a sensitive marker of heart failure. We included subjects with a newly created, well-functioning vascular access and normal left ventricular ejection fraction. They were examined before access creation (baseline), then again 6 weeks and 6 months after the surgery. Only subjects with access flow (Qa) < 1500 ml/min were included. Changes of BNP levels and their relation to access flow were studied. We examined 35 subjects aged 60.6 +/- 13.5 years. Qa was 789 +/- 361 and 823 +/- 313 ml/min at 6 weeks and 6 months after the surgery, respectively. Within 6 weeks after access creation, BNP rose from 217 (294) to 267 (550) ng/l (median (quartile range)) with P = 0.003. Qa was significantly related to BNP levels 6 weeks after access creation (r = 0.37, P = 0.036). Six months after access creation, there was only a trend of BNP decrease (235 (308) ng/l, P = 0.44). Creatinine, blood urea nitrogen and hemoglobin levels as well as patients' weight did not change significantly. Creation of dialysis access with "normal" flow volume leads to significant increase of BNP, which is related to the value of access flow. The increase of BNP probably mirrors worsening of clinically silent heart failure.

  1. Brain Natriuretic Peptide Levels in Managing Pediatric Patients with Pulmonary Arterial Hypertension

    PubMed Central

    Bernus, Anna; Wagner, Brandie D.; Accurso, Frank; Doran, Aimee; Kaess, Heidi; Ivy, D. Dunbar

    2009-01-01

    Background Pulmonary arterial hypertension (PAH) is an important determinant of morbidity and mortality in children. In this study we aimed to investigate the value of Brain Natriuretic Peptide (BNP) in a cohort of children with PAH, with respect to monitoring disease severity as assessed by hemodynamic and echocardiographic parameters. Methods We performed a prospective study to determine if BNP varies over time in this population and if these changes track with hemodynamic or echocardiographic parameters. The population included a group of 78 pediatric patients from January 2005 until April 2008. All patients were diagnosed with PAH and had serum BNP, catheterization and echocardiographic variables collected longitudinally. Results The median BNP level, for all observations, was 36.0pg/ml (interquartile range [IQR], 18.0 to 76pg/ml). There was no strong correlation found between commonly used echocardiographic or hemodynamic data and BNP. However, using a bivariate model, the change in BNP measurements over time significantly correlated with the change in the hemodynamic and echocardiographic parameters. Patients with a BNP value greater than 180pg/ml had a decreased survival rate. Conclusions There is indication that BNP could be a useful marker to monitor disease severity in pediatric pulmonary hypertension. We show that simple correlations between variables and BNP are not likely to illustrate its usefulness due to variations in the normative levels. Instead, we propose that patient’s BNP levels should be monitored over time, as changes in BNP within a patient are likely to be more informative. PMID:18849405

  2. Ghrelin, peptide YY and their hypothalamic targets differentially regulate spontaneous physical activity.

    PubMed

    Pfluger, Paul T; Castañeda, Tamara R; Heppner, Kristy M; Strassburg, Sabine; Kruthaupt, Traci; Chaudhary, Nilika; Halem, Heather; Culler, Michael D; Datta, Rakesh; Burget, Lukas; Tschöp, M H; Nogueiras, Ruben; Perez-Tilve, Diego

    2011-11-30

    Recent studies suggest that spontaneous physical activity (SPA) may be under the non-conscious control of neuroendocrine circuits that are known to control food intake. To further elucidate endocrine gut-brain communication as a component of such circuitry, we here analyzed long-term and acute effects of the gastrointestinal hormones ghrelin and PYY 3-36 as well as their hypothalamic neuropeptide targets NPY, AgRP and POMC (alpha-MSH), on locomotor activity and home cage behaviors in rats. For the analysis of SPA, we used an automated infrared beam break activity measuring system, combined with a novel automated video-based behavior analysis system (HomeCageScan (HCS)). Chronic (one-month) peripheral infusion of ghrelin potently increased body weight and fat mass in rats. Such positive energy balance was intriguingly not due to an overall increased caloric ingestion, but was predominantly associated with a decrease in SPA. Chronic intracerebroventricular infusion (7 days) of ghrelin corroborated the decrease in SPA and suggested a centrally mediated mechanism. Central administration of AgRP and NPY increased food intake as expected. AgRP administration led to a delayed decrease in SPA, while NPY acutely (but transiently) increased SPA. Behavioral dissection using HCS corroborated the observed acute and transient increases of food intake and SPA by central NPY infusion. Acute central administration of alpha-MSH rapidly decreased food intake but did not change SPA. Central administration of the NPY receptor agonist PYY 3-36 transiently increased SPA. Our data suggest that the control of spontaneous physical activity by gut hormones or their neuropeptide targets may represent an important mechanistic component of energy balance regulation. Copyright © 2011 Elsevier Inc. All rights reserved.

  3. Molecular Level Characterization of the Structure and Interactions in Peptide-Functionalized Metal-Organic Frameworks.

    PubMed

    Todorova, Tanya K; Rozanska, Xavier; Gervais, Christel; Legrand, Alexandre; Ho, Linh N; Berruyer, Pierrick; Lesage, Anne; Emsley, Lyndon; Farrusseng, David; Canivet, Jérôme; Mellot-Draznieks, Caroline

    2016-11-07

    We use density functional theory, newly parameterized molecular dynamics simulations, and last generation (15) N dynamic nuclear polarization surface enhanced solid-state NMR spectroscopy (DNP SENS) to understand graft-host interactions and effects imposed by the metal-organic framework (MOF) host on peptide conformations in a peptide-functionalized MOF. Focusing on two grafts typified by MIL-68-proline (-Pro) and MIL-68-glycine-proline (-Gly-Pro), we identified the most likely peptide conformations adopted in the functionalized hybrid frameworks. We found that hydrogen bond interactions between the graft and the surface hydroxyl groups of the MOF are essential in determining the peptides conformation(s). DNP SENS methodology shows unprecedented signal enhancements when applied to these peptide-functionalized MOFs. The calculated chemical shifts of selected MIL-68-NH-Pro and MIL-68-NH-Gly-Pro conformations are in a good agreement with the experimentally obtained (15) N NMR signals. The study shows that the conformations of peptides when grafted in a MOF host are unlikely to be freely distributed, and conformational selection is directed by strong host-guest interactions. © 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  4. B-type natriuretic peptide levels in preterm neonates with bronchopulmonary dysplasia: a marker of severity?

    PubMed

    Kalra, Vaneet Kumar; Aggarwal, Sanjeev; Arora, Prem; Natarajan, Girija

    2014-11-01

    B type natriuretic peptide (BNP) is a hormone released in response to stretching of the ventricular wall. The role of BNP as a biomarker of bronchopulmonary dysplasia (BPD) has not been clarified. To determine if plasma BNP concentrations correlate with the severity of BPD. This prospective observational case control study included 60 preterm infants (≤32 weeks); 27 infants had no/mild BPD, 19 had moderate and 14 had severe BPD. BNP levels were measured at 36 ± 2 weeks PMA or within a week of discharge home. Groups were compared using Mann-Whitney's U-test, Kruskal-Wallis, and bivariate regression. Median (IQR) plasma levels of BNP in infants with moderate/severe BPD infants (n = 33) were higher as compared to those with no/mild BPD (n = 27); 27.1 (12.1-43.5) pg/ml versus 9.3 (6-18.5) pg/ml; P < 0.05 (Mann Whitney U). Median (IQR) BNP levels in infants with severe BPD (n = 14), 43.5 (28.4-189) pg/ml differed significantly from levels in those with moderate (n = 19), 22.8 (10.3-27.7) pg/ml; mild (n = 16), 11.5 (6.6-44.5 pg/ml); or no (n = 11), 8.1 (5-12.6 pg/ml) BPD (P < 0.001 Kruskal-Wallis). Based on receiver operating characteristic curves, BNP > 24.4 pg/ml at 36 ± 2 weeks PMA or discharge home was 85.7% sensitive and 76.1% specific for severe BPD. An elevation in plasma BNP was significantly associated with severe BPD. We speculate that plasma BNP measurement in infants with BPD may aid in risk-stratification and further targeted therapies. © 2013 Wiley Periodicals, Inc.

  5. Some Like It Hot: The X-Ray Emission of the Giant Star YY Mensae

    NASA Astrophysics Data System (ADS)

    Audard, Marc; Telleschi, Alessandra; Güdel, Manuel; Skinner, Stephen L.; Pallavicini, Roberto; Mitra-Kraev, Urmila

    2004-12-01

    We present an analysis of the X-ray emission of the rapidly rotating giant star YY Mensae observed by Chandra HETGS and XMM-Newton. The high-resolution spectra display numerous emission lines of highly ionized species; Fe XVII to Fe XXV lines are detected, together with H-like and He-like transitions of lower Z elements. Although no obvious flare was detected, the X-ray luminosity changed by a factor of 2 between the XMM-Newton and Chandra observations taken 4 months apart (from logLX~32.2 to 32.5 ergs s-1, respectively). The coronal abundances and the emission measure distribution have been derived from three different methods using optically thin collisional ionization equilibrium models, which is justified by the absence of opacity effects in YY Men as measured from line ratios of Fe XVII transitions. The abundances show a distinct pattern as a function of the first ionization potential (FIP), suggestive of an inverse FIP effect as seen in several active RS CVn binaries. The low-FIP elements (<10 eV) are depleted relative to the high-FIP elements; when compared to its photospheric abundance, the coronal Fe abundance also appears depleted. We find a high N abundance in YY Men's corona, which we interpret as a signature of material processed in the CNO cycle and dredged up in the giant phase. The corona is dominated by a very high temperature (20-40 MK) plasma, which places YY Men among the magnetically active stars with the hottest coronae. Lower temperature plasma also coexists, albeit with much lower emission measure. Line broadening is reported in some lines, with a particularly strong significance in Ne X Lyα. We interpret such broadening as Doppler thermal broadening, although rotational broadening due to X-ray-emitting material high above the surface could be present as well. We use two different formalisms to discuss the shape of the emission measure distribution. The first one infers the properties of coronal loops, whereas the second formalism uses

  6. The plasma level of brain natriuretic peptide is increased in malnourished hemodialysis patients.

    PubMed

    Chazot, Charles; Jean, Guillaume; Vo-Van, Cyril; Collonge, Cecile; Terrat, Jean Claude; Vanel, Thierry; Lorriaux, Christie; Hurot, Jean Marc; Charra, Bernard

    2009-01-01

    In hemodialysis (HD) patients, the plasma brain natriuretic peptide (BNP) level is associated with left ventricular dysfunction and patients' survival. Malnutrition is common in HD patients, it is associated with inflammation and contributes to the high incidence of cardiovascular (CV) disease in this setting (malnutrition-inflammation-atherosclerosis syndrome). In a cross-sectional study, we assessed the relationship between predialysis plasma BNP level and nutritional markers in chronic HD patients. Of 210 patients receiving HD treatment in our unit, 51 patients who were treated with three times weekly long-hour HD (5-8 h/session) for at least 6 months (mean age 65.8 +/- 15.0 years; F/M ratio 23/28; vintage 71.3 +/- 71.9 months; BMI 24.9 +/- 5.9; session time 6.9 +/- 1.3 h; percentage of diabetic patients 31%) were studied before a mid-week HD session for nutritional markers (plasma albumin 35.3 +/- 3.7 g/l; prealbumin 0.36 +/- 0.09 g/l; CRP 15.3 +/- 14.7 mg/l; nPNA 1.29 +/- 0.29 g/kg/day) and plasma BNP (246.9 +/- 252.2 ng/l, normal <100 ng/l, Bayer(R) kit). The interdialytic weight gain was 2.1 +/- 1.0 kg. In the last 3 months prior to the commencement of the study, the patients' dry weight varied by +0.17 +/- 1.9 kg. Predialysis plasma BNP levels did not differ according to gender and the presence of diabetes. It was not correlated with age and vintage but was found to be negatively associated with the session time (r = -0.34, p = 0.018). Several nutritional markers were negatively correlated with BNP levels: prealbumin (r = -0.46, p = 0.001), BMI (r = -0.33, p = 0.018), nPNA (r = -0.46, p = 0.002). The plasma albumin relationship with the BNP level was close to significance (p = -0.26, p = 0.070). The 3-month dry weight variation was also negatively correlated with BNP levels (r = -0.34, p = 0.018). With multiple stepwise regression analysis, prealbumin and session time remained significant (respectively p = 0.004 and 0.01). BNP levels were higher in a

  7. [High levels of atrial natriuretic peptide and copeptin and mortality risk].

    PubMed

    Rey, Corsino; García-Cendón, Clara; Martínez-Camblor, Pablo; López-Herce, Jesús; Concha-Torre, Andrés; Medina, Alberto; Vivanco-Allende, Ana; Mayordomo-Colunga, Juan

    2016-12-01

    To determine whether high levels of mid-regional pro-atrial natriuretic peptide (MR-proANP), copeptin, and procalcitonin (PCT) plasma concentrations are associated with increased mortality risk. Prospective observational study including 254 critically ill children. MR-proANP, copeptin and PCT were compared between children with high (Group A; n=33) and low (Group B; n=221) mortality risk, and between patients with failure of more than 1 organ (Group 1; n=71) and less than 2 (Group 2; n=183). Median (range) of MR-proANP, copeptin, and PCT levels in group A vs B were, respectively: 209.4 (30.5-1415.8) vs. 75.0 (14.6-867.2) pmol/L (P<.001); 104.4 (7.4-460.9) vs. 26.6 (0.00-613.1) pmol/L (P<.001), and 7.8 (0.3-552.0) vs. 0.3 (0.02-107.0) ng/mL (P<.001). The area under the curve (AUC) for the differentiation of group A and B was 0.764 (95% CI: 0.674-0.854) for MR-proANP; 0.735 (0.642-0.827) for copeptin, and 0.842 (0.744-0.941) for PCT, with no statistical differences. The AUCs for the differentiation of group 1 and 2 were: 0.837 (0.784-0.891) for MR-proANP, 0.735 (0.666-0.804) for copeptin, and 0.804 (0.715-0.892) for PCT, with statistical differences between MR-proANP and copeptin, P=.01. High levels of MR-proANP, copeptin and PCT were associated with increased mortality risk scores. MR-proANP showed a higher association than copeptin with number of organs in failure. Copyright © 2015 Asociación Española de Pediatría. Publicado por Elsevier España, S.L.U. All rights reserved.

  8. 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

  9. Peptides as Quorum Sensing Molecules: Measurement Techniques and Obtained Levels In vitro and In vivo

    PubMed Central

    Verbeke, Frederick; De Craemer, Severine; Debunne, Nathan; Janssens, Yorick; Wynendaele, Evelien; Van de Wiele, Christophe; De Spiegeleer, Bart

    2017-01-01

    The expression of certain bacterial genes is regulated in a cell-density dependent way, a phenomenon called quorum sensing. Both Gram-negative and Gram-positive bacteria use this type of communication, though the signal molecules (auto-inducers) used by them differ between both groups: Gram-negative bacteria use predominantly N-acyl homoserine lacton (AHL) molecules (autoinducer-1, AI-1) while Gram-positive bacteria use mainly peptides (autoinducer peptides, AIP or quorum sensing peptides). These quorum sensing molecules are not only involved in the inter-microbial communication, but can also possibly cross-talk directly or indirectly with their host. This review summarizes the currently applied analytical approaches for quorum sensing identification and quantification with additionally summarizing the experimentally found in vivo concentrations of these molecules in humans. PMID:28446863

  10. Peptides as Quorum Sensing Molecules: Measurement Techniques and Obtained Levels In vitro and In vivo.

    PubMed

    Verbeke, Frederick; De Craemer, Severine; Debunne, Nathan; Janssens, Yorick; Wynendaele, Evelien; Van de Wiele, Christophe; De Spiegeleer, Bart

    2017-01-01

    The expression of certain bacterial genes is regulated in a cell-density dependent way, a phenomenon called quorum sensing. Both Gram-negative and Gram-positive bacteria use this type of communication, though the signal molecules (auto-inducers) used by them differ between both groups: Gram-negative bacteria use predominantly N-acyl homoserine lacton (AHL) molecules (autoinducer-1, AI-1) while Gram-positive bacteria use mainly peptides (autoinducer peptides, AIP or quorum sensing peptides). These quorum sensing molecules are not only involved in the inter-microbial communication, but can also possibly cross-talk directly or indirectly with their host. This review summarizes the currently applied analytical approaches for quorum sensing identification and quantification with additionally summarizing the experimentally found in vivo concentrations of these molecules in humans.

  11. Interaction between Pirenzepine and Ninjinto, a Traditional Japanese Herbal Medicine, on the Plasma Gut-Regulated Peptide Levels in Humans.

    PubMed

    Sato, Yuhki; Hiroki, Itoh; Suzuki, Yosuke; Tatsuta, Ryosuke; Takeyama, Masaharu

    2013-01-01

    The Japanese herbal medicine (Kampo) Ninjinto has been used for the treatment of gastroenteritis, esogastritis, gastric atony, gastrectasis, vomiting, and anorexia. The pharmacological effects of Ninjinto on the gastrointestine are due to changes in the levels of gut-regulated peptide, such as motilin, somatostatin, calcitonin gene-related peptide (CGRP), substance P, and vasoactive intestinal polypeptide (VIP). The release of these peptides is controlled by acetylcholine (ACh) from the preganglionic fibers of the parasympathetic nerve. Thus, we examined the effects of the selective M1 muscarinic receptor antagonist pirenzepine on the elevation of Ninjinto-induced plasma the area under the plasma gut-regulated peptide concentration-time curve from 0 to 240 min (AUC0→240 min) in humans. Oral pretreatment with pirenzepine significantly reduced the Ninjinto-induced elevation of plasma motilin and substance P release (AUC0→240 min). Combined treatment with Ninjinto and pirenzepine significantly increased the release of plasma somatostatin (AUC0→240 min) compared with administration of Ninjinto alone or placebo. Ninjinto appeared to induce the release of substance P and motilin into plasma mainly through the activation of M1 muscarinic receptors, and pirenzepine may affect the pharmacologic action of Ninjinto by the elevation of plasma substance P, motilin, and somatostatin.

  12. YY1 overexpression is associated with poor prognosis and metastasis-free survival in patients suffering osteosarcoma

    PubMed Central

    2011-01-01

    Background The polycomb transcription factor Yin Yang 1 (YY1) overexpression can be causally implicated in experimental tumor growth and metastasization. To date, there is no clinical evidence of YY1 involvement in outcome of patients with osteosarcoma. Prognosis of osteosarcoma is still severe and only few patients survive beyond five years. We performed a prospective immunohistochemistry analysis to correlate YY1 immunostaining with metastatic development and survival in a selected homogeneous group of patients with osteosarcoma. Methods We studied 41 patients suffering from osteosarcoma (stage II-IVa). Multivariate analysis was performed using Cox proportional hazard regression to evaluate the correlation between YY1 expression and both metastasis development and mortality. Results YY1 protein is not usually present in normal bone; in contrast, a high number of patients (61%) showed a high score of YY1 positive cells (51-100%) and 39% had a low score (10-50% positive cells). No statistical difference was found in histology, anatomic sites, or response to chemotherapy between the two degrees of YY1 expression. Cox regression analysis demonstrated that the highest score of YY1 expression was predictive of both low metastasis-free survival (HR = 4.690, 95%CI = 1.079-20.396; p = 0.039) and poor overall survival (HR = 8.353, 95%CI = 1.863-37.451 p = 0.006) regardless of the effects of covariates such as age, gender, histology and chemonecrosis. Conclusion Overexpression of YY1 in primary site of osteosarcoma is associated with the occurrence of metastasis and poor clinical outcome. PMID:22047406

  13. Impact of inulin and oligofructose on gastrointestinal peptides.

    PubMed

    Delzenne, Nathalie M; Cani, Patrice D; Daubioul, Catherine; Neyrinck, Audrey M

    2005-04-01

    In the present paper, we summarise the data supporting the following hypothesis: dietary inulin-type fructans extracted from chicory root may modulate the production of peptides, such as incretins, by endocrine cells present in the intestinal mucosa, this phenomenon being involved in the regulation of food intake and/or systemic effects. To test this hypothesis, male Wistar rats received for 3 weeks either a standard diet or the same diet supplemented with 10 % inulin-type fructans with different degrees of polymerisation. All the effects were most pronounced with the diet containing oligofructose, and consisted of (i) a decrease in mean daily energy intake and in epididymal fat mass; (ii) a higher caecal pool of the anorexigenic glucagon-like peptide-1 (7-36) amide (GLP-1), and peptide YY (PYY), due to caecal tissue proliferation; (iii) an increase in GLP-1 and of its precursor - proglucagon mRNA - concentrations in the proximal colon; (iv) an increase in portal serum level of GLP-1 and PYY; (v) a decrease in serum orexigenic peptide ghrelin. Moreover, oligofructose supplementation improved glucose homeostasis (i.e. decreased glycaemia, increased pancreatic and serum insulin content) in diabetic rats previously treated with streptozotocin, a phenomenon that is partly linked to the reduction in food intake and that correlates with the increase in colic and portal GLP-1 content. Based on these results it appears justified to test, in human subjects, the hypothesis that dietary inulin-type fructans could play a role in the management of obesity and diabetes through their capacity to promote secretion of endogenous gastrointestinal peptides involved in appetite regulation.

  14. High-level expression of nattokinase in Bacillus licheniformis by manipulating signal peptide and signal peptidase.

    PubMed

    Cai, D; Wei, X; Qiu, Y; Chen, Y; Chen, J; Wen, Z; Chen, S

    2016-09-01

    Nattokinase is an enzyme produced by Bacillus licheniformis and has potential to be used as a drug for treating cardiovascular disease due to its beneficial effects of preventing fibrin clots etc. However, the low activity and titre of this protein produced by B. licheniformis often hinders its application of commercial production. The aim of this work is to improve the nattokinase production by manipulating signal peptides and signal peptidases in B. licheniformis. The P43 promoter, amyL terminator and AprN target gene were used to form the nattokinase expression vector, pHY-SP-NK, which was transformed into B. licheniformis and nattokinase was expressed successfully. A library containing 81 predicted signal peptides was constructed for nattokinase expression in B. licheniformis, with the maximum activity being obtained under the signal peptide of AprE. Among four type I signal peptidases genes (sipS, sipT, sipV, sipW) in B. licheniformis, the deletion of sipV resulted in a highest decrease in nattokinase activity. Overexpression of sipV in B. licheniformis led to a nattokinase activity of 35·60 FU ml(-1) , a 4·68-fold improvement over activity produced by the initial strain. This work demonstrates the potential of B. licheniformis for industrial production of nattokinase through manipulation of signal peptides and signal peptidases expression. This study has screened the signal peptides of extracellular proteins of B. licheniformis for nattokinase production. Four kinds of Type I signal peptidases genes have been detected respectively in B. licheniformis to identify which one played the vital role for nattokinase production. This study provided a promising strain for industry production of nattokinase. © 2016 The Society for Applied Microbiology.

  15. Changes in mRNA expression of arcuate nucleus appetite-regulating peptides during lactation in rats.

    PubMed

    Suzuki, Yoshihiro; Nakahara, Keiko; Maruyama, Keisuke; Okame, Rieko; Ensho, Takuya; Inoue, Yoshiyuki; Murakami, Noboru

    2014-04-01

    The contribution of hypothalamic appetite-regulating peptides to further hyperphagia accompanying the course of lactation in rats was investigated by using PCR array and real-time PCR. Furthermore, changes in the mRNA expression for appetite-regulating peptides in the hypothalamic arcuate nucleus (ARC) were analyzed at all stages of pregnancy and lactation, and also after weaning. Food intake was significantly higher during pregnancy, lactation, and after weaning than during non-lactation periods. During lactation, ARC expression of mRNAs for agouti-related protein (AgRP) and peptide YY was increased, whereas that of mRNAs for proopiomelanocortin (POMC) and cholecystokinin (CCK) was decreased, in comparison with non-lactation periods. The increase in AgRP mRNA expression during lactation was especially marked. The plasma level of leptin was significantly decreased during the course of lactation, whereas that of acyl-ghrelin was unchanged. In addition, food intake was negatively correlated with the plasma leptin level during lactation. This study has clarified synchronous changes in the expression of many appetite-regulating peptides in ARC of rats during lactation. Our results suggest that hyperphagia during lactation in rats is caused by decreases in POMC and CCK expression and increases in AgRP expression in ARC, the latter being most notable. Together with the decrease in the blood leptin level, such changes in mRNA expression may explain the further hyperphagia accompanying the course of lactation.

  16. A Nascent Peptide Signal Responsive to Endogenous Levels of Polyamines Acts to Stimulate Regulatory Frameshifting on Antizyme mRNA.

    PubMed

    Yordanova, Martina M; Wu, Cheng; Andreev, Dmitry E; Sachs, Matthew S; Atkins, John F

    2015-07-17

    The protein antizyme is a negative regulator of cellular polyamine concentrations from yeast to mammals. Synthesis of functional antizyme requires programmed +1 ribosomal frameshifting at the 3' end of the first of two partially overlapping ORFs. The frameshift is the sensor and effector in an autoregulatory circuit. Except for Saccharomyces cerevisiae antizyme mRNA, the frameshift site alone only supports low levels of frameshifting. The high levels usually observed depend on the presence of cis-acting stimulatory elements located 5' and 3' of the frameshift site. Antizyme genes from different evolutionary branches have evolved different stimulatory elements. Prior and new multiple alignments of fungal antizyme mRNA sequences from the Agaricomycetes class of Basidiomycota show a distinct pattern of conservation 5' of the frameshift site consistent with a function at the amino acid level. As shown here when tested in Schizosaccharomyces pombe and mammalian HEK293T cells, the 5' part of this conserved sequence acts at the nascent peptide level to stimulate the frameshifting, without involving stalling detectable by toe-printing. However, the peptide is only part of the signal. The 3' part of the stimulator functions largely independently and acts at least mostly at the nucleotide level. When polyamine levels were varied, the stimulatory effect was seen to be especially responsive in the endogenous polyamine concentration range, and this effect may be more general. A conserved RNA secondary structure 3' of the frameshift site has weaker stimulatory and polyamine sensitizing effects on frameshifting.

  17. 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

  18. 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.

  19. VizieR Online Data Catalog: YY Cet UBV differential light curves (Williamon+, 2012)

    NASA Astrophysics Data System (ADS)

    Williamon, R. M.; Sowell, J. R.

    2013-03-01

    Our photometric observations of YY Cet (BD-18 349, SAO 148148) were obtained with the 90cm Cassegrain reflector at the Fernbank Science Center (Atlanta, Georgia) during 1973-1977. More than 540 measurements were made in each UBV bandpass with an unrefrigerated EMI 6256s photomultiplier. A second set of unpublished UBV data were given to us by Carlson Chamblis when he retired. His 152 measurements in each bandpass were obtained in 1972-1973 with the 0.6m telescope at Mount John University Observatory in New Zealand. The improved ephemeris for the primary eclipse of YY Cet is minimum light (HJD)=2442658.94694+/-0.00006+0.790458487+/-0.000000052E (2 data files).

  20. 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.

  1. Molecular forms of peptide histidine isoleucine-like immunoreactivity in the gastrointestinal tract. Nonequimolar levels of peptide histidine isoleucine and vasoactive intestinal peptide in the stomach explained by the presence of a big peptide histidine isoleucine-like molecule.

    PubMed

    Yiangou, Y; Christofides, N D; Blank, M A; Yanaihara, N; Tatemoto, K; Bishop, A E; Polak, J M; Bloom, S R

    1985-09-01

    Regional specific antibodies and chromatography were used to analyze the distributions and molecular forms of peptide histidine isoleucine (PHI) and vasoactive intestinal peptide (VIP) in the porcine intestine. Both peptides were present along the entire length of the intestine, the highest concentrations occurring in the colon. Concentrations of PHI immunoreactivity, measured with three different antisera, and VIP immunoreactivity were approximately equal in all parts of the gastrointestinal tract except in the stomach. In the stomach, the concentration of PHI immunoreactivity, measured with the N-terminally directed antibody R8403, although equal to the corresponding VIP concentration, was two to four times higher than the PHI immunoreactivity detected with the two C-terminally directed PHI antisera T33 and T41. Chromatographic analysis on Sephadex G-50 superfine of gastric extracts revealed only one VIP immunoreactive peak that eluted in the same position as the porcine VIP standard, at Kav 0.53. A PHI immunoreactive peak was also detected with the C-terminally directed PHI antisera in the same position as porcine PHI standard. However, with the N-terminally directed PHI antiserum R8403, an additional PHI immunoreactive peak was detected in gastric extracts constituting the predominant form present, and this peak eluted earlier at Kav 0.37. The PHI immunoreactive material that eluted earlier was present in the rest of the intestine in only small amounts. As VIP and PHI are believed to be derived from a common precursor, it is suggested that in the stomach the posttranslational enzymic processing of the precursor is different from that in the other parts of the intestine.

  2. Mathematical Modeling of Interacting Glucose-Sensing Mechanisms and Electrical Activity Underlying Glucagon-Like Peptide 1 Secretion

    PubMed Central

    Riz, Michela; Pedersen, Morten Gram

    2015-01-01

    Intestinal L-cells sense glucose and other nutrients, and in response release glucagon-like peptide 1 (GLP-1), peptide YY and other hormones with anti-diabetic and weight-reducing effects. The stimulus-secretion pathway in L-cells is still poorly understood, although it is known that GLP-1 secreting cells use sodium-glucose co-transporters (SGLT) and ATP-sensitive K+-channels (K(ATP)-channels) to sense intestinal glucose levels. Electrical activity then transduces glucose sensing to Ca2+-stimulated exocytosis. This particular glucose-sensing arrangement with glucose triggering both a depolarizing SGLT current as well as leading to closure of the hyperpolarizing K(ATP) current is of more general interest for our understanding of glucose-sensing cells. To dissect the interactions of these two glucose-sensing mechanisms, we build a mathematical model of electrical activity underlying GLP-1 secretion. Two sets of model parameters are presented: one set represents primary mouse colonic L-cells; the other set is based on data from the GLP-1 secreting GLUTag cell line. The model is then used to obtain insight into the differences in glucose-sensing between primary L-cells and GLUTag cells. Our results illuminate how the two glucose-sensing mechanisms interact, and suggest that the depolarizing effect of SGLT currents is modulated by K(ATP)-channel activity. Based on our simulations, we propose that primary L-cells encode the glucose signal as changes in action potential amplitude, whereas GLUTag cells rely mainly on frequency modulation. The model should be useful for further basic, pharmacological and theoretical investigations of the cellular signals underlying endogenous GLP-1 and peptide YY release. PMID:26630068

  3. Mathematical Modeling of Interacting Glucose-Sensing Mechanisms and Electrical Activity Underlying Glucagon-Like Peptide 1 Secretion.

    PubMed

    Riz, Michela; Pedersen, Morten Gram

    2015-12-01

    Intestinal L-cells sense glucose and other nutrients, and in response release glucagon-like peptide 1 (GLP-1), peptide YY and other hormones with anti-diabetic and weight-reducing effects. The stimulus-secretion pathway in L-cells is still poorly understood, although it is known that GLP-1 secreting cells use sodium-glucose co-transporters (SGLT) and ATP-sensitive K+-channels (K(ATP)-channels) to sense intestinal glucose levels. Electrical activity then transduces glucose sensing to Ca2+-stimulated exocytosis. This particular glucose-sensing arrangement with glucose triggering both a depolarizing SGLT current as well as leading to closure of the hyperpolarizing K(ATP) current is of more general interest for our understanding of glucose-sensing cells. To dissect the interactions of these two glucose-sensing mechanisms, we build a mathematical model of electrical activity underlying GLP-1 secretion. Two sets of model parameters are presented: one set represents primary mouse colonic L-cells; the other set is based on data from the GLP-1 secreting GLUTag cell line. The model is then used to obtain insight into the differences in glucose-sensing between primary L-cells and GLUTag cells. Our results illuminate how the two glucose-sensing mechanisms interact, and suggest that the depolarizing effect of SGLT currents is modulated by K(ATP)-channel activity. Based on our simulations, we propose that primary L-cells encode the glucose signal as changes in action potential amplitude, whereas GLUTag cells rely mainly on frequency modulation. The model should be useful for further basic, pharmacological and theoretical investigations of the cellular signals underlying endogenous GLP-1 and peptide YY release.

  4. 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.

  5. Phosphorylated C/EBPβ Influences a Complex Network Involving YY1 and USF2 in Lung Epithelial Cells

    PubMed Central

    Viart, Victoria; Varilh, Jessica; Lopez, Estelle; René, Céline; Claustres, Mireille; Taulan-Cadars, Magali

    2013-01-01

    The promoter of the cystic fibrosis transmembrane conductance regulator gene CFTR is tightly controlled by regulators including CCAAT/enhancer binding proteins (C/EBPs). We previously reported that the transcription factors YY1 and USF2 affect CFTR expression. We can now demonstrate that C/EBPβ, a member of the CCAAT family, binds to the CFTR promoter and contributes to its transcriptional activity. Our data reveal that C/EBPβ cooperates with USF2 and acts antagonistically to YY1 in the control of CFTR expression. Interestingly, YY1, a strong repressor, fails to repress the CFTR activation induced by USF2 through DNA binding competition. Collectively, the data strongly suggest a model by which USF2 functionally interacts with YY1 blocking its inhibitory activity, in favour of C/EBPβ transactivation. Further investigation into the interactions between these three proteins revealed that phosphorylation of C/EBPβ influences the DNA occupancy of YY1 and favours the interaction between USF2 and YY1. This phosphorylation process has several implications in the CFTR transcriptional process, thus evoking an additional layer of complexity to the mechanisms influencing CFTR gene regulation. PMID:23560079

  6. YY1 and a unique DNA repeat element regulates the transcription of mouse CS1 (CD319, SLAMF7) gene.

    PubMed

    Dongre, Prachi; Mathew, Stephen; Akopova, Irina; Gryczynski, Ignacy; Mathew, Porunelloor

    2013-07-01

    CS1 (CD319, CRACC, SLAMF7, novel Ly9) activates NK cell-mediated cytotoxicity and proliferation of B lymphocytes during immune responses. The expression of CS1 is up regulated on B cells in multiple myeloma and systemic lupus erythematosus. In this study we describe the transcriptional regulation of mouse CS1 (mCS1) gene. We show that mCS1 gene transcription is regulated by YY1 (Ying Yang 1) and a unique (AG)n=36 DNA repeat element. YY1 is known to play a significant role in B cell development by regulating the pro B cell to pre B cell transition. The consensus DNA binding site for YY1 was detected using TRANSFAQ on the mCS1 promoter region. Mutations in the YY1 site led to a significant increase in mCS1 promoter activity indicating that YY1 represses mCS1 transcription. YY1 binds to the mCS1 promoter at the expected site in vivo and in vitro as tested by chromatin immunoprecipitation assays and super-shift EMSA assays respectively. Unique (CT)n=24 and (AG)n=36 DNA repeat elements are present on mCS1 promoter that are sensitive to S1 nuclease and engage in DNA triplex structure as confirmed by AFM (atomic force microscopy) imaging. Interestingly, the (AG)n=36 repeat element enhances mCS1 promoter activity. Copyright © 2012 Elsevier Ltd. All rights reserved.

  7. Fast voxel-level dosimetry for 177Lu labelled peptide treatments

    NASA Astrophysics Data System (ADS)

    Hippeläinen, E.; Tenhunen, M.; Sohlberg, A.

    2015-09-01

    In peptide receptor radionuclide therapy (PRRT), voxel-level radiation absorbed dose calculations can be performed using several different methods. Each method has it strengths and weaknesses; however, Monte Carlo (MC) simulation is presently considered the most accurate method at providing absorbed dose distributions. Unfortunately MC simulation is time-consuming and often impractical to carry out in a clinical practice. In this work, a fast semi-Monte Carlo (sMC) absorbed dose calculation method for 177Lu PRRT dosimetry is presented. The sMC method is based on a local electron absorption assumption and fast photon MC simulations. The sMC method is compared against full MC simulation code built on PENELOPE (vxlPen) using digital phantoms to assess the accuracy of these assumptions. Due to the local electron absorption assumption of sMC, the potential errors in cross-fire dose from electrons and photons emitted by 177Lu were first evaluated using an ellipsoidal kidney model by comparing vxlPen and sMC. The photon cross-fire dose from background to kidney and kidney to background with varying kidney-to-background activity concentration ratios were calculated. In addition, kidney to kidney photon and electron cross-dose with different kidney to kidney distances were studied. Second, extended cardiac-torso (XCAT) phantoms were created with liver lesions and with realistic activity distributions and tissue densities. The XCAT phantoms were used to simulate SPECT projections and 3D activity distribution images were reconstructed using an OSEM algorithm. Image-based dose rate distributions were calculated using vxlPen and sMC. Total doses and dose rate volume histograms (DrVH) produced by the two methods were compared. The photon cross-fire dose from the kidney increased the background’s absorbed dose by 5% or more up to 5.8 cm distance with 20 : 1 kidney to background activity concentration ratio. On the other hand, the photon cross-fire dose from the background to

  8. Fast voxel-level dosimetry for (177)Lu labelled peptide treatments.

    PubMed

    Hippeläinen, E; Tenhunen, M; Sohlberg, A

    2015-09-07

    In peptide receptor radionuclide therapy (PRRT), voxel-level radiation absorbed dose calculations can be performed using several different methods. Each method has it strengths and weaknesses; however, Monte Carlo (MC) simulation is presently considered the most accurate method at providing absorbed dose distributions. Unfortunately MC simulation is time-consuming and often impractical to carry out in a clinical practice. In this work, a fast semi-Monte Carlo (sMC) absorbed dose calculation method for (177)Lu PRRT dosimetry is presented. The sMC method is based on a local electron absorption assumption and fast photon MC simulations. The sMC method is compared against full MC simulation code built on PENELOPE (vxlPen) using digital phantoms to assess the accuracy of these assumptions.Due to the local electron absorption assumption of sMC, the potential errors in cross-fire dose from electrons and photons emitted by (177)Lu were first evaluated using an ellipsoidal kidney model by comparing vxlPen and sMC. The photon cross-fire dose from background to kidney and kidney to background with varying kidney-to-background activity concentration ratios were calculated. In addition, kidney to kidney photon and electron cross-dose with different kidney to kidney distances were studied. Second, extended cardiac-torso (XCAT) phantoms were created with liver lesions and with realistic activity distributions and tissue densities. The XCAT phantoms were used to simulate SPECT projections and 3D activity distribution images were reconstructed using an OSEM algorithm. Image-based dose rate distributions were calculated using vxlPen and sMC. Total doses and dose rate volume histograms (DrVH) produced by the two methods were compared.The photon cross-fire dose from the kidney increased the background's absorbed dose by 5% or more up to 5.8 cm distance with 20 : 1 kidney to background activity concentration ratio. On the other hand, the photon cross-fire dose from the background to

  9. Synthetic peptides for efficient discrimination of anti-enterovirus antibodies at the serotype level.

    PubMed

    Routsias, John G; Mavrouli, Maria D; Antonaki, Georgia; Spanakis, Nikolaos; Tsakris, Athanassios

    2014-08-01

    Enteroviruses are important human pathogens, causing a broad spectrum of diseases from minor common colds to fatal myocarditis. However, certain disease syndromes are caused by one or few serotypes. Serotype identification is difficult due to the laborious neutralization tests that lack of sensitivity, while in commercial ELISAs homotypic antibodies' activities are largely masked by the recognition of genera-specific epitopes by heterotypic antibodies. In the present study homotypic assays were developed with the ability to discriminate different enterovirus serotypes. Seventy-three children sera, positive for IgM antibodies against enterovirus genus and 49 healthy children were examined for the presence of antibodies against 14 synthetic peptides derived from a non-conserved region of the VP1 protein of coxsackieviruses B2, B3, B4, B5, A9, A16, A24, echoviruses 6, 7, 9, 11, 30, enterovirus 71 and parechovirus 1. 50% of the anti-enterovirus IgM positive sera (>150 BU) reacted with the peptides with the majority of them to preferentially recognize one of them, supporting the homotypic nature of our assay. Inhibition studies yielded homologous inhibition rates 67-95% suggesting that specific peptide recognition actually occurred. The diagnostic value of our assay was tested in blood samples drawn over a 1.5-year period from a 5-year old patient. The anti-enterovirus reactivity was clearly attributed to echovirus serotype 11. The IgM/IgG antibody ratio was reversed 4 months later and subsequently IgM antibodies dropped below the cutoff point. In this paper we demonstrate that our assay can be used to discriminate between antibodies targeting different enterovirus serotypes.

  10. Investigation of Elemental Mass Spectrometry in Pharmacology for Peptide Quantitation at Femtomolar Levels.

    PubMed

    Cordeau, Emmanuelle; Arnaudguilhem, Carine; Bouyssiere, Brice; Hagège, Agnès; Martinez, Jean; Subra, Gilles; Cantel, Sonia; Enjalbal, Christine

    2016-01-01

    In the search of new robust and environmental-friendly analytical methods able to answer quantitative issues in pharmacology, we explore liquid chromatography (LC) associated with elemental mass spectrometry (ICP-MS) to monitor peptides in such complex biological matrices. The novelty is to use mass spectrometry to replace radiolabelling and radioactivity measurements, which represent up-to now the gold standard to measure organic compound concentrations in life science. As a proof of concept, we choose the vasopressin (AVP)/V1A receptor system for model pharmacological assays. The capacity of ICP-MS to provide highly sensitive quantitation of metallic and hetero elements, whatever the sample medium, prompted us to investigate this technique in combination with appropriate labelling of the peptide of interest. Selenium, that is scarcely present in biological media, was selected as a good compromise between ICP-MS response, covalent tagging ability using conventional sulfur chemistry and peptide detection specificity. Applying selenium monitoring by elemental mass spectrometry in pharmacology is challenging due to the very high salt content and organic material complexity of the samples that produces polyatomic aggregates and thus potentially mass interferences with selenium detection. Hyphenation with a chromatographic separation was found compulsory. Noteworthy, we aimed to develop a straightforward quantitative protocol that can be performed in any laboratory equipped with a standard macrobore LC-ICP-MS system, in order to avoid time-consuming sample treatment or special implementation of instrumental set-up, while allowing efficient suppression of all mass interferences to reach the targeted sensitivity. Significantly, a quantification limit of 57 ng Se L-1 (72 femtomoles of injected Se) was achieved, the samples issued from the pharmacological assays being directly introduced into the LC-ICP-MS system. The established method was successfully validated and

  11. Investigation of Elemental Mass Spectrometry in Pharmacology for Peptide Quantitation at Femtomolar Levels

    PubMed Central

    Cordeau, Emmanuelle; Arnaudguilhem, Carine; Bouyssiere, Brice; Hagège, Agnès; Martinez, Jean; Subra, Gilles; Cantel, Sonia

    2016-01-01

    In the search of new robust and environmental-friendly analytical methods able to answer quantitative issues in pharmacology, we explore liquid chromatography (LC) associated with elemental mass spectrometry (ICP-MS) to monitor peptides in such complex biological matrices. The novelty is to use mass spectrometry to replace radiolabelling and radioactivity measurements, which represent up-to now the gold standard to measure organic compound concentrations in life science. As a proof of concept, we choose the vasopressin (AVP)/V1A receptor system for model pharmacological assays. The capacity of ICP-MS to provide highly sensitive quantitation of metallic and hetero elements, whatever the sample medium, prompted us to investigate this technique in combination with appropriate labelling of the peptide of interest. Selenium, that is scarcely present in biological media, was selected as a good compromise between ICP-MS response, covalent tagging ability using conventional sulfur chemistry and peptide detection specificity. Applying selenium monitoring by elemental mass spectrometry in pharmacology is challenging due to the very high salt content and organic material complexity of the samples that produces polyatomic aggregates and thus potentially mass interferences with selenium detection. Hyphenation with a chromatographic separation was found compulsory. Noteworthy, we aimed to develop a straightforward quantitative protocol that can be performed in any laboratory equipped with a standard macrobore LC-ICP-MS system, in order to avoid time-consuming sample treatment or special implementation of instrumental set-up, while allowing efficient suppression of all mass interferences to reach the targeted sensitivity. Significantly, a quantification limit of 57 ng Se L-1 (72 femtomoles of injected Se) was achieved, the samples issued from the pharmacological assays being directly introduced into the LC-ICP-MS system. The established method was successfully validated and

  12. Memantine Lowers Amyloid-beta Peptide Levels in Neuronal Cultures and in APP/PS1 Transgenic Mice

    PubMed Central

    Alley, George M.; Bailey, Jason A; Chen, DeMao; Ray, Balmiki; Puli, Lakshman K.; Tanila, Heikki; Banerjee, Pradeep K; Lahiri, Debomoy K.

    2009-01-01

    Memantine is a moderate-affinity, uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist that stabilizes cognitive, functional, and behavioral decline in patients with moderate to severe Alzheimer’s disease (AD). In AD, the extracellular deposition of fibrillogenic amyloid-beta peptides (Aβ) occurs due to aberrant processing of the full-length Aβ precursor protein (APP). Memantine protects neurons from the neurotoxic effects of Aβ and improves cognition in transgenic mice with high brain levels of Aβ. However, it is unknown how memantine protects cells against neurodegeneration and affects APP processing and Aβ production. We report the effects of memantine in three different systems. In human neuroblastoma cells, memantine, at therapeutically relevant concentrations (1-4 μM), decreased levels of secreted APP and Aβ1-40. Levels of the potentially amylodogenic Aβ1-42 were undetectable in these cells. In primary rat cortical neuronal cultures, memantine treatment lowered Aβ1-42 secretion. At the concentrations used, memantine treatment was not toxic to neuroblastoma or primary cultures and increased cell viability and/or metabolic activity under certain conditions. In APP/presenilin-1 (PS1) transgenic mice exhibiting high brain levels of Aβ1-42, oral dosing of memantine (20 mg/kg/day for 8 days) produced plasma drug concentration of 0.96 μM and significantly reduced the cortical levels of soluble Aβ1-42. The ratio of Aβ1-40/Aβ1-42 increased in treated mice, suggesting effects on the γ-secretase complex. Thus, memantine reduces the levels of Aβ peptides at therapeutic concentrations and may inhibit the accumulation of fibrillogenic Aβ in mammalian brains. Memantine’s ability to preserve neuronal cells against neurodegeneration, increase metabolic activity, and lower Aβ level has therapeutic implications for neurodegenerative disorders. PMID:19642202

  13. 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

  14. A Casein Kinase II Phosphorylation Site in AtYY1 Affects Its Activity, Stability, and Function in the ABA Response

    PubMed Central

    Wu, Xiu-Yun; Li, Tian

    2017-01-01

    The phosphorylation and dephosphorylation of proteins are crucial in the regulation of protein activity and stability in various signaling pathways. In this study, we identified an ABA repressor, Arabidopsis Ying Yang 1 (AtYY1) as a potential target of casein kinase II (CKII). AtYY1 physically interacts with two regulatory subunits of CKII, CKB3, and CKB4. Moreover, AtYY1 can be phosphorylated by CKII in vitro, and the S284 site is the major CKII phosphorylation site. Further analyses indicated that S284 phosphorylation can enhance the transcriptional activity and protein stability of AtYY1 and hence strengthen the effect of AtYY1 as a negative regulator in the ABA response. Our study provides novel insights into the regulatory mechanism of AtYY1 mediated by CKII phosphorylation. PMID:28348572

  15. No association of plasma levels of adiponectin and c-peptide with risk of aggressive prostate cancer in the Cancer Prevention Study II Nutrition Cohort.

    PubMed

    Stevens, Victoria L; Jacobs, Eric J; Sun, Juzhong; Gapstur, Susan M

    2014-05-01

    Obesity is associated with a higher risk of aggressive prostate cancer and alters circulating levels of insulin and adiponectin, two hormones that influence biologic processes implicated in carcinogenesis. Results of some studies showed associations of circulating levels of adiponectin, insulin, and c-peptide (a marker of insulin secretion) with aggressive prostate cancer, but the size of these studies was limited. A nested case-control study of 272 aggressive prostate cancer cases [Gleason score ≥ 7 (4+3) or T3-T4] and 272 age- and race-matched controls from the Cancer Prevention Study II Nutrition Cohort was conducted to determine the associations of prediagnostic plasma levels of c-peptide and adiponectin with risk of aggressive prostate cancer. Neither circulating adiponectin nor c-peptide was associated with risk of aggressive prostate cancer. In analyses of the highest-risk aggressive prostate cancer (Gleason score ≥ 8 or T3-T4), the highest quartile of c-peptide, compared with the lowest, was associated with an OR of 1.41 [95% confidence interval (CI), 0.72-2.78]. Our findings provide no support for the hypothesis that adiponectin is associated with risk of aggressive prostate cancer but a possible association of high levels of c-peptide with particularly high-risk prostate cancer cannot be ruled out. These results indicate that changes in circulating levels of adiponectin and c-peptide do not play an important role in risk of aggressive prostate cancer. ©2014 AACR.

  16. A Nascent Peptide Signal Responsive to Endogenous Levels of Polyamines Acts to Stimulate Regulatory Frameshifting on Antizyme mRNA*

    PubMed Central

    Yordanova, Martina M.; Wu, Cheng; Andreev, Dmitry E.; Sachs, Matthew S.; Atkins, John F.

    2015-01-01

    The protein antizyme is a negative regulator of cellular polyamine concentrations from yeast to mammals. Synthesis of functional antizyme requires programmed +1 ribosomal frameshifting at the 3′ end of the first of two partially overlapping ORFs. The frameshift is the sensor and effector in an autoregulatory circuit. Except for Saccharomyces cerevisiae antizyme mRNA, the frameshift site alone only supports low levels of frameshifting. The high levels usually observed depend on the presence of cis-acting stimulatory elements located 5′ and 3′ of the frameshift site. Antizyme genes from different evolutionary branches have evolved different stimulatory elements. Prior and new multiple alignments of fungal antizyme mRNA sequences from the Agaricomycetes class of Basidiomycota show a distinct pattern of conservation 5′ of the frameshift site consistent with a function at the amino acid level. As shown here when tested in Schizosaccharomyces pombe and mammalian HEK293T cells, the 5′ part of this conserved sequence acts at the nascent peptide level to stimulate the frameshifting, without involving stalling detectable by toe-printing. However, the peptide is only part of the signal. The 3′ part of the stimulator functions largely independently and acts at least mostly at the nucleotide level. When polyamine levels were varied, the stimulatory effect was seen to be especially responsive in the endogenous polyamine concentration range, and this effect may be more general. A conserved RNA secondary structure 3′ of the frameshift site has weaker stimulatory and polyamine sensitizing effects on frameshifting. PMID:25998126

  17. PARP-1 and YY1 are important novel regulators of CXCL12 gene transcription in rat pancreatic beta cells.

    PubMed

    Marković, Jelena; Grdović, Nevena; Dinić, Svetlana; Karan-Djurašević, Teodora; Uskoković, Aleksandra; Arambašić, Jelena; Mihailović, Mirjana; Pavlović, Sonja; Poznanović, Goran; Vidaković, Melita

    2013-01-01

    Despite significant progress, the molecular mechanisms responsible for pancreatic beta cell depletion and development of diabetes remain poorly defined. At present, there is no preventive measure against diabetes. The positive impact of CXCL12 expression on the pancreatic beta cell prosurvival phenotype initiated this study. Our aim was to provide novel insight into the regulation of rat CXCL12 gene (Cxcl12) transcription. The roles of poly(ADP-ribose) polymerase-1 (PARP-1) and transcription factor Yin Yang 1 (YY1) in Cxcl12 transcription were studied by examining their in vitro and in vivo binding affinities for the Cxcl12 promoter in a pancreatic beta cell line by the electrophoretic mobility shift assay and chromatin immunoprecipitation. The regulatory activities of PARP-1 and YY1 were assessed in transfection experiments using a reporter vector with a Cxcl12 promoter sequence driving luciferase gene expression. Experimental evidence for PARP-1 and YY1 revealed their trans-acting potential, wherein PARP-1 displayed an inhibitory, and YY1 a strong activating effect on Cxcl12 transcription. Streptozotocin (STZ)-induced general toxicity in pancreatic beta cells was followed by changes in Cxcl12 promoter regulation. PARP-1 binding to the Cxcl12 promoter during basal and in STZ-compromised conditions led us to conclude that PARP-1 regulates constitutive Cxcl12 expression. During the early stage of oxidative stress, YY1 exhibited less affinity toward the Cxcl12 promoter while PARP-1 displayed strong binding. These interactions were accompanied by Cxcl12 downregulation. In the later stages of oxidative stress and intensive pancreatic beta cell injury, YY1 was highly expressed and firmly bound to Cxcl12 promoter in contrast to PARP-1. These interactions resulted in higher Cxcl12 expression. The observed ability of PARP-1 to downregulate, and of YY1 to upregulate Cxcl12 promoter activity anticipates corresponding effects in the natural context where the functional

  18. Integrative genomics identifies YY1AP1 as an oncogenic driver in EpCAM(+) AFP(+) hepatocellular carcinoma.

    PubMed

    Zhao, X; Parpart, S; Takai, A; Roessler, S; Budhu, A; Yu, Z; Blank, M; Zhang, Y E; Jia, H-L; Ye, Q-H; Qin, L-X; Tang, Z-Y; Thorgeirsson, S S; Wang, X W

    2015-09-24

    Identification of key drivers and new therapeutic targets is important given the poor prognosis for hepatocellular carcinoma (HCC) patients, particularly those ineligible for surgical resection or liver transplant. However, the approach to identify such driver genes is facing significant challenges due to the genomically heterogenous nature of HCC. Here we tested whether the integrative genomic profiling of a well-defined HCC subset that is classified by an extreme EpCAM(+) AFP(+) gene expression signature and associated with poor prognosis, all attributes of a stem cell-like phenotype, could uncover survival-related driver genes in HCC. Following transcriptomic analysis of the well-defined HCC cases, a Gene Set Enrichment Analysis coupled with genomic copy number alteration assessment revealed that YY1-associated protein 1 (YY1AP1) is a critical oncoprotein specifically activated in EpCAM(+) AFP(+) HCC. YY1AP1 silencing eliminates oncogene addiction by altering the chromatin landscape and triggering massive apoptosis in vitro and tumor suppression in vivo. YY1AP1 expression promotes HCC proliferation and is required for the maintenance of stem cell features. We revealed that YY1AP1 cooperates with YY1 to alter the chromatin landscape and activate transcription of stemness regulators. Thus YY1AP1 may serve as a key molecular target for EpCAM(+) AFP(+) HCC subtype. Our results demonstrate the feasibility and power of a new strategy by utilizing well-defined patient samples and integrative genomics to uncover critical pathways linked to HCC subtypes with prognostic impact.

  19. High environmental salinity induces memory enhancement and increases levels of brain angiotensin-like peptides in the crab Chasmagnathus granulatus.

    PubMed

    Delorenzi, A; Dimant, B; Frenkel, L; Nahmod, V E; Nässel, D R; Maldonado, H

    2000-11-01

    Previous work on the brackish-water crab Chasmagnathus granulatus demonstrated that an endogenous peptide similar to angiotensin II plays a significant role in enhancing long-term memory that involves an association between context and an iterative danger stimulus (context-signal memory). The present results show that this memory enhancement could be produced by moving crabs from brackish water to sea water (33.0%) and keeping them there for at least 4 days. The possibility that such a facilitatory effect is due to osmotic stress is ruled out. Coincidentally, the level of angiotensin-II-like peptides in crab brain, measured by radioimmunoassay, increases with the length of exposure to sea water, reaching a significantly different level at the fourth day. The presence of angiotensin-II-like immunoreactive material in neural structures of the supraoesophageal and eyestalk ganglia was confirmed by immunohistochemical analysis. The results are interpreted as supporting the hypothesis that exposure to water of high salinity is an external cue triggering a process mediated by angiotensins that leads to enhanced memory in these crabs.

  20. Amyloid Beta Peptides Affect Pregnenolone and Pregnenolone Sulfate Levels in PC-12 and SH-SY5Y Cells Depending on Cholesterol.

    PubMed

    Calan, Ozlem Gursoy; Akan, Pinar; Cataler, Aysenur; Dogan, Cumhur; Kocturk, Semra

    2016-07-01

    Increased amyloid beta (AB) peptide concentration is one of the initiating factors in the neurodegeneration process. It has been suggested that cholesterol induces the synthesis of AB peptide from amyloid precursor protein or facilitates the formation of amyloid plaque by lowering the aggregation threshold of the peptide. It is also shown that AB peptides may affect cholesterol metabolism and the synthesis of steroid hormones such as progesterone and estradiol. Pregnenolone (P) and pregnenolone sulfate (PS) are the major steroids produced from cholesterol in neural tissue. In toxicity conditions, the effect of AB peptides on P and PS levels has not yet been determined. Furthermore, it has not been clearly defined how changes in cellular P and PS levels affect neuronal cell survival. The aim of this study was to determine the effects of AB peptides on cellular changes in P and PS levels depending on the level of their main precursor, cholesterol. Cholesterol and toxic concentrations of AB fragments (AB 25-35, AB 1-40 and AB 1-42) were applied to PC-12 and SH-SY5Y cells. Changes in cellular cholesterol, P and PS levels were determined simultaneously in a dose-and time-dependent manner. The cell viability and cell death types were also evaluated. AB peptides affected both cell viability and P/PS levels. Steroid levels were altered depending on AB fragment type and the cholesterol content of the cells. Treatment with each of the AB fragments alone increased P levels by twofold. However, combined treatment with AB peptides and cholesterol increased P levels by approximately sixfold, while PS levels were increased only about 2.5 fold in both cell lines. P levels in the groups treated with AB 25-35 were higher than those in AB 1-40 and AB 1-42 groups. The cell viabilities were significantly low in the group treated by AB and cholesterol (9 mM). The effect of AB peptides on P levels might be a result of cellular self-defense. On the other hand, the rate of P increase

  1. The transcription factor YY1 is a novel substrate for Aurora B kinase at G2/M transition of the cell cycle.

    PubMed

    Kassardjian, Ari; Rizkallah, Raed; Riman, Sarah; Renfro, Samuel H; Alexander, Karen E; Hurt, Myra M

    2012-01-01

    Yin Yang 1 (YY1) is a ubiquitously expressed and highly conserved multifunctional transcription factor that is involved in a variety of cellular processes. Many YY1-regulated genes have crucial roles in cell proliferation, differentiation, apoptosis, and cell cycle regulation. Numerous mechanisms have been shown to regulate the function of YY1, such as DNA binding affinity, subcellular localization, and posttranslational modification including phosphorylation. Polo-like kinase 1(Plk1) and Casein kinase 2α (CK2 α) were the first two kinases identified to phosphorylate YY1. In this study, we identify a third kinase. We report that YY1 is a novel substrate of the Aurora B kinase both in vitro and in vivo. Serine 184 phosphorylation of YY1 by Aurora B is cell cycle regulated and peaks at G2/M and is rapidly dephosphorylated, likely by protein phosphatase 1 (PP1) as the cells enter G1. Aurora A and Aurora C can also phosphorylate YY1 in vitro, but at serine/threonine residues other than serine 184. We present evidence that phosphorylation of YY1 in the central glycine/alanine (G/A)-rich region is important for DNA binding activity, with a potential phosphorylation/acetylation interplay regulating YY1 function. Given their importance in mitosis and overexpression in human cancers, Aurora kinases have been identified as promising therapeutic targets. Increasing our understanding of Aurora substrates will add to the understanding of their signaling pathways.

  2. [Prospective study of gluco-lipidic hormone and peptide levels in morbidly obese patients after sleeve gastrectomy].

    PubMed

    Bruna, Marcos; Gumbau, Verónica; Guaita, Marcos; Canelles, Enrique; Mulas, Claudia; Basés, Carla; Celma, Isabel; Puche, José; Marcaida, Goitzane; Oviedo, Miguel; Vázquez, Antonio

    2014-03-01

    Different hormones and peptides involved in lipid and carbohydrate metabolism have been studied in relation to morbid obesity and its variation after bariatric surgery. The aim of this study is toevaluate variations in different molecules related to glico-lipidic metabolism during the first year after sleeve gastrectomy in morbidly obese patients. Prospective study in patients undergoing sleeve gastrectomy between November 2009 and January 2011. We analyzed changes in different clinical, anthropometric and analytic parameters related with glico-lipidic metabolism in all patients in the preoperative period, first postoperative day, fifth day, one month, 6 months and one year after surgery. Statistical analysis was performed using SPSS 20.0. We included 20 patients, 60% were women with a median of age of 45 years. Median of body mass index (IMC) was 48,5 kg/m(2) and 70% had obstructive sleep apnea syndrome (SAOS), 65% arterial hypertension (HTA), 45% dyslipidemia and 40% diabetes mellitus. One year after surgery, the percentage of excess of BMI loss was 72% and the rate of cure or improvement of dyslipidemia was 100%, diabetes 87,5%, HTA 84,6% and SAOS 57,1%. At this time, glycemia levels decreased significantly (P<.001), and levels of IGF-1 and HDL-cholesterol increased significantly. Levels of adiponectine increased and leptine (P=.003), insulin (P=.004) and triglycerides (P=.016) decreased significantly one year after the surgery. ACTH levels (that decreased during first 6 months after surgery), glycosilated hemoglobin, total cholesterol and LDL-cholesterol had no changes one year after surgery. Sleeve gastrectomy is a surgical technique with good results of weight loss and cure of comorbidities. This procedure induces significant modifications in blood levels of glico-lipidic metabolism related peptides and hormones, such as glucose, IGF-1, insulin, leptin, triglycerides and HDL-cholesterol. Copyright © 2013 AEC. Published by Elsevier Espana. All rights reserved.

  3. The role of the stomach in the control of appetite and the secretion of satiation peptides.

    PubMed

    Steinert, Robert E; Meyer-Gerspach, Anne C; Beglinger, Christoph

    2012-03-15

    It is widely accepted that gastric parameters such as gastric distention provide a direct negative feedback signal to inhibit eating; moreover, gastric and intestinal signals have been reported to synergize to promote satiation. However, there are few human data exploring the potential interaction effects of gastric and intestinal signals in the short-term control of appetite and the secretion of satiation peptides. We performed experiments in healthy subjects receiving either a rapid intragastric load or a continuous intraduodenal infusion of glucose or a mixed liquid meal. Intraduodenal infusions (3 kcal/min) were at rates comparable with the duodenal delivery of these nutrients under physiological conditions. Intraduodenal infusions of glucose elicited only weak effects on appetite and the secretion of glucagon-like peptide-1 (GLP-1) and peptide YY (PYY). In contrast, identical amounts of glucose delivered intragastrically markedly suppressed appetite (P < 0.05) paralleled by greatly increased plasma levels of GLP-1 and PYY (≤3-fold, P < 0.05). Administration of the mixed liquid meal showed a comparable phenomenon. In contrast to GLP-1 and PYY, plasma ghrelin was suppressed to a similar degree with both intragastric and intraduodenal nutrients. Our data confirm that the stomach is an important element in the short-term control of appetite and suggest that gastric and intestinal signals interact to mediate early fullness and satiation potentially by increased GLP-1 and PYY secretions.

  4. A PTP4A3 peptide PIMAP39 modulates TNF-alpha levels and endotoxic shock.

    PubMed

    Tang, Xiaoren; Woodward, Timothy; Amar, Salomon

    2010-01-01

    Lipopolysaccharide (LPS) stimulation of macrophages initiates intracellular signaling pathways leading to activation of MAPK and its subsequent influence on cytokine production. We recently identified a LITAF-STAT6(B) complex regulated by p38 MAPK in response to LPS stimulation. However, the LPS-induced cascade in the p38/LITAF/TNF signaling pathway remains unclear. Here, we identified PTP4A3, a protein tyrosine phosphotase, as a novel negative regulator of LPS-induced LITAF/TNF-alpha production. PTP4A3 exerts its negative role by dephosphorylating p38 alpha MAPK in response to LPS stimulation of primary macrophages. PTP4A3 expression is upregulated in primary macrophages. Further structure-function analysis revealed that a unique short peptide (PIMAP39) derived from PTP4A3 is capable of mimicking the functionality of full-length PTP4A3 to selectively dephosphorylate p38 alpha and indirectly suppress LPS-induced LITAF-STAT6B complex when it is translocated from the cytoplasmic region to the nucleus of the cell. Treatment of mice with PIMAP39 significantly attenuates the severity of adverse host responses to LPS stimulation, and in some cases provides complete resistance to a lethal dose of LPS due to suppression of TNF-alpha production. All together, these results reveal a previously unrecognized role for the PTP4A3 pathway in response to LPS.

  5. Expression levels of antimicrobial peptide tachyplesin I in transgenic Ornithogalum lines affect the resistance to Pectobacterium infection.

    PubMed

    Lipsky, Alexander; Joshi, Janak Raj; Carmi, Nir; Yedidia, Iris

    2016-11-20

    The genus Ornithogalum includes several ornamental species that suffer substantial losses from bacterial soft rot caused by Pectobacteria. The absence of effective control measures for use against soft rot bacteria led to the initiation of a project in which a small antimicrobial peptide from an Asian horseshoe crab, tachyplesin (tpnI), was introduced into two commercial cultivars: O. dubium and O. thyrsoides. Disease severity and bacterial colonization were examined in transgenic lines expressing this peptide. Disease resistance was evaluated in six lines of each species by measuring bacterial proliferation in the plant tissue. Three transgenic lines of each species were subjected to further analysis in which the expression level of the transgene was evaluated using RT-PCR and qRT-PCR. The development of disease symptoms and bacterial colonization of the plant tissue were also examined using GFP-expressing strain of P. carotovorum subsp. brasiliense Pcb3. Confocal-microscopy imaging revealed significantly reduced quantities of bacterial cells in the transgenic plant lines that had been challenged with the bacterium. The results clearly demonstrate that tpnI expression reduces bacterial proliferation, colonization and disease symptom (reduced by 95-100%) in the transgenic plant tissues. The quantity of tpnI transcripts, as measured by qRT-PCR, was negatively correlated with the protection afforded to the plants, as measured by the reduced severity of disease symptoms in the tissue.

  6. Preliminary Examination of Glucagon-Like Peptide-1 Levels in Women with Purging Disorder and Bulimia Nervosa

    PubMed Central

    Dossat, Amanda M.; Bodell, Lindsay P.; Williams, Diana L.; Eckel, Lisa A.; Keel, Pamela K.

    2014-01-01

    Objective This study examined pre- and post-prandial glucagon-like peptide 1 (GLP-1) levels in women with bulimia nervosa (BN), purging disorder (PD), and non-eating disorder control women to better understand whether alterations in satiation-related hormones in BN may be linked to binge-eating episodes or other altered ingestive behaviors. Method Participants included women with BN (n = 19), PD (n = 14), or controls (n = 14). Participants provided subjective ratings for hunger and fullness and plasma samples before and after consumption of a standardized test meal. Results As expected, GLP-1 levels increased significantly following test meal consumption; however, participants with BN displayed significantly lower GLP-1 levels compared to PD and control participants both before and after consumption of the test meal. There were no significant differences between PD and control participants in GLP-1 levels, but individuals with PD displayed significantly higher levels of fullness throughout the test meal as compared to both control and BN participants. Discussion Our findings provide preliminary evidence that reduced GLP-1 levels in individuals with BN may be associated with binge-eating episodes. Additionally, increased fullness in individuals with PD does not appear to be accounted for by exaggerated post-prandial GLP-1 release. PMID:24590464

  7. Predictive value of B-type natriuretic peptide level on the postoperative course of infants with congenital heart disease.

    PubMed

    Nahum, Elhanan; Pollak, Uri; Dagan, Ovdi; Amir, Gabriel; Frenkel, George; Birk, Einat

    2013-05-01

    B-type natriuretic peptide (BNP) has been shown to have prognostic value for morbidity and mortality after cardiac surgery. Less is known about its prognostic value in infants. To investigate the predictive value of BNP levels regarding the severity of the postoperative course in infants undergoing surgical repair of congenital heart disease. We conducted a prospective comparative study. Plasma BNP levels in infants aged 1-12 months with congenital heart disease undergoing complete repair were measured preoperatively and 8, 24 and 48 hours postoperatively. Demographic and clinical data included postoperative inotropic support and lactate level, duration of mechanical ventilation, intensive care unit (ICU) and hospitalization stay. Cardiac surgery was performed in 19 infants aged 1-12 months. Preoperative BNP level above 170 pg/ml had a positive predictive value of 100% for inotropic score > or = 7.5 at 24 hours (specificity 100%, sensitivity 57%) and 48 hours (specificity 100%, sensitivity 100%), and was associated with longer ICU stay (P = 0.05) and a trend for longer mechanical ventilation (P = 0.12). Similar findings were found for 8 hours postoperative BNP above 1720 pg/ml. BNP level did not correlate with measured fractional shortening. In infants undergoing heart surgery, preoperative and 8 hour BNP levels were predictive of inotropic support and longer ICU stay. These findings may have implications for preplanning ICU loads in clinical practice. Further studies with larger samples are needed.

  8. Protein C and procollagen III peptide levels in patients with hepatic dysfunction after allogeneic hematopoietic stem cell transplantation.

    PubMed

    Pihusch, M; Wegner, H; Goehring, P; Salat, C; Pihusch, V; Andreesen, R; Kolb, H-J; Holler, E; Pihusch, R

    2005-10-01

    Veno-occlusive disease (VOD) is one of the most serious complications following hematopoietic stem cell transplantation (HSCT) and is associated with a high mortality. We conducted a large trial on the clinical significance of protein C (PC) and procollagen III peptide (PNPIII) levels, which have been described as possible diagnostic markers of VOD. In total, 350 patients undergoing allogeneic HSCT were included. PC and PNPIII levels were analyzed prior to conditioning and weekly until 8 weeks after the HSCT. Signs of VOD and other transplantation-related complications (graft-versus-host disease (GVHD), toxicity, microangiopathic hemolytic anemia, infection) were recorded weekly throughout the trial. Patients showed a significant drop of the PC levels in VOD (70.3 vs 96.3%, P<0.001) and with increasing severity of aGVHD. Steroids increased the PC levels (69.4% vs 109.4%, P<0.001). The highest PNPIII levels were registered in patients with VOD (mean 6.3 IU/ml). Patients with aGVHD showed an elevation of PNPIII, especially patients with hepatic aGVHD. PC levels during conditioning do not predict VOD (98.5 vs 76.5%, NS). Although PC and PNPIII may play a role in the pathogenesis of VOD they cannot discriminate between complications with jaundice and are only of limited help in the differential diagnosis of VOD.

  9. Complete genome sequence and transcriptomics analyses reveal pigment biosynthesis and regulatory mechanisms in an industrial strain, Monascus purpureus YY-1.

    PubMed

    Yang, Yue; Liu, Bin; Du, Xinjun; Li, Ping; Liang, Bin; Cheng, Xiaozhen; Du, Liangcheng; Huang, Di; Wang, Lei; Wang, Shuo

    2015-02-09

    Monascus has been used to produce natural colorants and food supplements for more than one thousand years, and approximately more than one billion people eat Monascus-fermented products during their daily life. In this study, using next-generation sequencing and optical mapping approaches, a 24.1-Mb complete genome of an industrial strain, Monascus purpureus YY-1, was obtained. This genome consists of eight chromosomes and 7,491 genes. Phylogenetic analysis at the genome level provides convincing evidence for the evolutionary position of M. purpureus. We provide the first comprehensive prediction of the biosynthetic pathway for Monascus pigment. Comparative genomic analyses show that the genome of M. purpureus is 13.6-40% smaller than those of closely related filamentous fungi and has undergone significant gene losses, most of which likely occurred during its specialized adaptation to starch-based foods. Comparative transcriptome analysis reveals that carbon starvation stress, resulting from the use of relatively low-quality carbon sources, contributes to the high yield of pigments by repressing central carbon metabolism and augmenting the acetyl-CoA pool. Our work provides important insights into the evolution of this economically important fungus and lays a foundation for future genetic manipulation and engineering of this strain.

  10. Promoter-region hypermethylation and expression downregulation of Yy1 (Yin yang 1) in preneoplastic liver lesions in a thioacetamide rat hepatocarcinogenesis model

    SciTech Connect

    Abe, Hajime; Ogawa, Takashi; Wang, Liyun; Kimura, Masayuki; Tanaka, Takeshi; Morita, Reiko; Yoshida, Toshinori; Shibutani, Makoto

    2014-11-01

    Thioacetamide (TAA) has been used to develop a rodent model for hepatocarcinogenesis. To determine the genes with epigenetic modifications in early hepatocarcinogenesis, we did a genome-wide scan for hypermethylated promoter regions using CpG island microarrays in TAA-promoted rat liver tissue. Eight genes were selected based on the microarray profile; of these, Yy1 and Wdr45b were confirmed to be hypermethylated by methylation-specific polymerase chain reaction (PCR) and pyrosequencing and downregulated by real-time reverse transcription PCR. Non-neoplastic liver cells had nuclear Yy1 immunoreactivity, while preneoplastic foci with glutathione S-transferase placental form (GST-P) immunoreactivity had decreased Yy1 immunoreactivity. The incidence of these foci was proportional to the dose of TAA administered. Co-expression analysis of gene products downstream of Yy1 revealed increased nuclear phospho-c-Myc{sup +} foci as well as nuclear and cytoplasmic p21{sup Cip1+} foci in Yy1{sup −} or GST-P{sup +} foci in response to TAA-promotion dose. Although the absolute number of cells was low, the incidence of death receptor 5{sup −} foci was increased in Yy1{sup −} foci in proportion to the TAA dose. Yy1{sup −}/GST-P{sup +} foci revealed a higher number of proliferating cell nuclear antigen (PCNA)-immunoreactive cells than Yy1{sup +}/GST-P{sup +} foci, while cleaved caspase-3{sup +} cells were unchanged between Yy1{sup –}/GST-P{sup +} and Yy1{sup +}/GST-P{sup +} foci. In the case of Wdr45b, most GST-P{sup +} foci were Wdr45b{sup –} and were not increased by TAA promotion. These results suggest involvement of Yy1 in the epigenetic gene regulation at the early stages of TAA promoted cell proliferation and concomitant cell cycle arrest in preneoplastic lesions. - Highlights: • Epigenetically downregulated genes were searched in TAA-promnoted rat livers. • Yy1 and Wdr45b showed promoter-region hypermethylation and mRNA downregulation. • TAA promoted

  11. Signal-3L 2.0: A Hierarchical Mixture Model for Enhancing Protein Signal Peptide Prediction by Incorporating Residue-Domain Cross-Level Features.

    PubMed

    Zhang, Yi-Ze; Shen, Hong-Bin

    2017-04-24

    Signal peptides play key roles in targeting and translocation of integral membrane proteins and secretory proteins. However, signal peptides present several challenges for automatic prediction methods. One challenge is that it is difficult to discriminate signal peptides from transmembrane helices, as both the H-region of the peptides and the transmembrane helices are hydrophobic. Another is that it is difficult to identify the cleavage site between signal peptides and mature proteins, as cleavage motifs or patterns are still unclear for most proteins. To solve these problems and further enhance automatic signal peptide recognition, we report a new Signal-3L 2.0 predictor. Our new model is constructed with a hierarchical protocol, where it first determines the existence of a signal peptide. For this, we propose a new residue-domain cross-level feature-driven approach, and we demonstrate that protein functional domain information is particularly useful for discriminating between the transmembrane helices and signal peptides as they perform different functions. Next, in order to accurately identify the unique signal peptide cleavage sites along the sequence, we designed a top-down approach where a subset of potential cleavage sites are screened using statistical learning rules, and then a final unique site is selected according to its evolution conservation score. Because this mixed approach utilizes both statistical learning and evolution analysis, it shows a strong capacity for recognizing cleavage sites. Signal-3L 2.0 has been benchmarked on multiple data sets, and the experimental results have demonstrated its accuracy. The online server is available at www.csbio.sjtu.edu.cn/bioinf/Signal-3L/ .

  12. Investigating AP-2 and YY1 protein expression as a cause of high HER2 gene transcription in breast cancers with discordant HER2 gene amplification.

    PubMed

    Powe, Desmond G; Akhtar, Gulfareen; Habashy, Hany Onsy; Abdel-Fatah, Tarek; Rakha, Emad A; Green, Andrew R; Ellis, Ian O

    2009-01-01

    Candidacy for anti-HER2 adjuvant therapy in breast cancer is assessed using tumour HER2 status but recently it has been proposed that the transcription factors AP-2alpha and YY1 may cause Her2 protein overexpression independently of gene amplification. We characterised AP-2alpha/beta, AP-2alpha and YY1 with HER2 gene and protein expression, other relevant biomarkers, and clinical outcome using tissue microarrays (TMAs) and immunohistochemistry in a large (n = 1,176) clinically annotated series of early stage operable breast cancer. The associations and prognostic independence of AP-2 and YY1 was assessed in all patients and an oestrogen receptor negative subgroup. Nuclear expression of AP-2alpha/beta, AP-2alpha and YY1 was detected in 23%, 44% and 33% of cases respectively. AP-2alpha/beta significantly correlated with YY1 and both markers were increased in luminal oestrogen receptor (ER) positive tumours of small size and low grade but only AP-2alpha/beta correlated with good prognosis breast cancer specific survival and disease free interval (BCSS and DFI). These characteristics were lost in oestrogen receptor negative patients. AP-2alpha also correlated with luminal-type tumours but not with YY1 expression or good prognosis. AP-2alpha and YY1 showed a significant correlation with Her2 protein expression and in addition, YY1 correlated with HER2 gene expression. Discordant HER2 gene and protein expression was identified in six cases (0.71% of the study group) with four of these showing AP-2alpha but absence of AP-2alpha/beta and YY1 expression. AP-2alpha/beta and YY1 are markers of good prognosis principally due to their association with oestrogen receptor but are not independent predictors. Discordant HER2 protein/gene expression is a rare event that is not always explained by the actions of AP-2 and YY1.

  13. FACTORS ASSOCIATED WITH SERUM BRAIN NATRIURETIC PEPTIDE LEVELS AFTER THE FONTAN PROCEDURE

    PubMed Central

    Atz, Andrew M.; Zak, Victor; Breitbart, Roger E.; Colan, Steven D.; Pasquali, Sara K.; Hsu, Daphne T.; Lu, Minmin; Mahony, Lynn; Paridon, Stephen M.; Puchalski, Michael D.; Geva, Tal; McCrindle, Brian W.

    2011-01-01

    Objective Although a useful marker of heart failure in adults, the utility of brain natriuretic peptide concentration (BNP) for children after the Fontan procedure is not well studied. Design BNP was measured in 510 patients aged 6–18 years in the Pediatric Heart Network Fontan cross-sectional study at a median of 8.2 years after Fontan. Patients underwent echocardiography, exercise testing, magnetic resonance imaging (MRI) and functional health status questionnaires. Associations of BNP with baseline patient characteristics, medical history and cross-sectional assessment were examined with multivariable linear regression analyses. Results The distribution of BNP was highly skewed, median 13.0 pg/mL (inter-quartile range: 7.1, 25.9), and was normalized with logarithmic transformation (logBNP). Among medical history variables, logBNP was greater in females (p=0.02) and older patients (p<0.001). Presence of pre-Fontan systolic ventricular dysfunction, greater number of post-Fontan complications, and thrombosis after Fontan were independently associated with higher logBNP (R2=0.16). Age-adjusted logBNP was significantly related to Fontan connection type, (lower with extracardiac conduits, higher with atriopulmonary connection; p<0.001). Lower physical functioning health status (R2=0.05), lower chronotropic index during exercise (R2=0.17), indices of diastolic dysfunction measured by echocardiography (R2=0.15), and higher total ventricular mass on MRI (R2=0.33) were related to higher logBNP. Conclusions Despite a markedly abnormal circulation, BNP was variable but within a normal range in the majority of Fontan patients in this large outpatient cohort. Higher BNP was associated with several markers of suboptimal outcome, although associations were weak. The routine use of BNP as an outpatient surveillance tool in asymptomatic Fontan patients is not warranted. PMID:21435188

  14. Growth of Streptococcus mutans in Biofilms Alters Peptide Signaling at the Sub-population Level

    PubMed Central

    Shields, Robert C.; Burne, Robert A.

    2016-01-01

    Streptococcus mutans activates multiple cellular processes in response to the formation of a complex between comX-inducing peptide (XIP) and the ComR transcriptional regulator. Bulk phase and microfluidic experiments previously revealed that ComR-dependent activation of comX is altered by pH and by carbohydrate source. Biofilm formation is a major factor in bacterial survival and virulence in the oral cavity. Here, we sought to determine the response of S. mutans biofilm cells to XIP during different stages of biofilm maturation. Using flow cytometry and confocal microscopy, we showed that exogenous addition of XIP to early biofilms resulted in robust comX activation. However, as the biofilms matured, increasing amounts of XIP were required to activate comX expression. Single-cell analysis demonstrated that the entire population was responding to XIP with activation of comX in early biofilms, but only a sub-population was responding in mature biofilms. The sub-population response of mature biofilms was retained when the cells were dispersed and then treated with XIP. The proportion and intensity of the bi-modal response of mature biofilm cells was altered in mutants lacking the Type II toxins MazF and RelE, or in a strain lacking the (p)ppGpp synthase/hydrolase RelA. Thus, competence signaling is markedly altered in cells growing in mature biofilms, and pathways that control cell death and growth/survival decisions modulate activation of comX expression in these sessile populations. PMID:27471495

  15. NT-pro Brain Natriuretic Peptide Levels and the Risk of Death in the Cooperative Study of Sickle Cell Disease

    PubMed Central

    Machado, Roberto F.; Hildesheim, Mariana; Mendelsohn, Laurel; Remaley, Alan T.; Kato, Gregory J.; Gladwin, Mark T.

    2011-01-01

    Epidemiological studies support a hypothesis that pulmonary hypertension (PH) is a common complication of sickle cell disease (SCD) that is associated with a high risk of death and evolves as a complication of haemolytic anaemia. This fundamental hypothesis has been recently challenged and remains controversial. In order to further test this hypothesis in a large and independent cohort of SCD patients we obtained plasma samples from the Cooperative Study of Sickle Cell Disease (CSSCD) for analysis of a biomarker, N-terminal-pro brain natriuretic peptide (NT-proBNP), which is elevated in the setting of pulmonary arterial and venous hypertension. A NT-pro-BNP value previously identified to predict PH in adults with SCD was used to determine the association between the risk of mortality in 758 CSSCD participants (428 children and 330 adults). An abnormally high NT-proBNP level ≥160 ng/l was present in 27.6 % of adult SCD patients. High levels were associated with markers of haemolytic anaemia, such as low haemoglobin level (P<0.001), high lactate dehydrogenase (P<0.001), and high total bilirubin levels (P<0.007). A NT-proBNP level ≥160 ng/l was an independent predictor of mortality (RR 6.24, 95% CI 2.9–13.3, P<0.0001). These findings provide further support for an association between haemolytic anaemia and cardiovascular complications in this patient population. PMID:21689089

  16. Differences in basal and ethanol-induced levels of opioid peptides in Wistar rats from five different suppliers.

    PubMed

    Palm, Sara; Roman, Erika; Nylander, Ingrid

    2012-07-01

    One major cause for discrepancies in results from animal experimental studies is the use of different animal strains and suppliers. We have previously reported that Wistar rats from five different suppliers display profound differences in ethanol intake and behavior. One of the neurobiological processes that could be underlying these differences is the endogenous opioid system, which has been implicated in the rewarding and reinforcing effects of alcohol. We therefore hypothesized that the differences between the supplier groups would also be evident in the endogenous opioid system. Radioimmunoassay was used to determine the levels of the opioid peptides Met-enkephalin-Arg(6)Phe(7) and dynorphin B in several brain areas of ethanol-drinking and ethanol naïve Wistar rats from five different suppliers. In the ethanol naïve animals, differences between the supplier groups were found in the pituitary gland, hypothalamus, frontal cortex, dorsal striatum and hippocampus. In the ethanol-drinking rats, differences were found in the same structures, with the addition of medial prefrontal cortex and substantia nigra. Correlations between ethanol intake and peptide levels were also found in several of the areas examined. The structures in which differences were found have all been implicated in the transition from drug use to addiction and these differences may lead to different propensities and vulnerability to this transition. Because the endogenous opioids have been suggested to be involved in a number of neurobiological disorders the results do not only have implications for research on alcohol or drug addiction, but many other fields as well.

  17. Effects of atrial and brain natriuretic peptides upon cyclic GMP levels, potassium transport, and receptor binding in rat astrocytes

    SciTech Connect

    Beaumont, K.; Tan, P.K. )

    1990-02-01

    The ability of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) to alter cyclic GMP levels and NaKCl cotransport in rat neocortical astrocytes was determined. At concentrations of 10(-9)-10(-6) M, rat ANP99-126 (rANF), rat ANP102-126 (auriculin B), and rat ANP103-126 (atriopeptin III) stimulated 6- to 100-fold increases in cyclic GMP levels. Porcine BNP (pBNP) and rat BNP (rBNP) were 20%-90% as effective as rANF over most of this concentration range, although 10(-6) M pBNP produced a greater effect than rANF. NaKCl cotransport as measured by bumetanide-sensitive 86Rb+ influx was not altered by exposure of astrocytes to 10(-6)M rANF, pBNP, or rBNP. Both pBNP and rBNP, as well as rat ANP103-123 (atriopeptin I) and des(gl18, ser19, gly20, leu21, gly22) ANF4-23-NH2 (C-ANF4-23) strongly competed for specific 125I-rANF binding sites in astrocyte membranes with affinities ranging from 0.03 to 0.4 nM, suggesting that virtually all binding sites measured at subnanomolar concentrations of 125I-rANF were of the ANP-C (ANF-R2) receptor subtype. These receptors are thought to serve a clearance function and may be linked to a guanylate cyclase activity that is chemically and pharmacologically distinct from that coupled to ANP-A (ANF-R1) receptors. ANP receptors on astrocytes may function in limiting the access of ANP and BNP to neurons involved in body fluid and cardiovascular regulation.

  18. Plasma B-type natriuretic peptide levels and recurrent arrhythmia after successful ablation of lone atrial fibrillation.

    PubMed

    Hussein, Ayman A; Saliba, Walid I; Martin, David O; Shadman, Mazyar; Kanj, Mohamed; Bhargava, Mandeep; Dresing, Thomas; Chung, Mina; Callahan, Thomas; Baranowski, Bryan; Tchou, Patrick; Lindsay, Bruce D; Natale, Andrea; Wazni, Oussama M

    2011-05-17

    Plasma B-type natriuretic peptide (BNP) is abnormally elevated in patients with lone atrial fibrillation (AF). The exact significance and prognostic implications of this elevation have yet to be determined. Little is known about BNP in lone AF patients undergoing arrhythmia ablation. We sought to determine the relationship between BNP levels and the risk of recurrent arrhythmia after ablation of lone AF. We followed up 726 patients with lone AF undergoing first-time arrhythmia ablation. All had BNP levels measured on the day of ablation with of the point-of-care Triage Meter assay (Biosite Diagnostics, San Diego, CA). At baseline, factors associated with elevated BNP levels in multivariable linear regression analysis (with log BNP being the dependent variable) were older age (β regression coefficient for +1-year change, 0.025; P<0.0001), longer duration of AF (β for +1-year change, 0.031; P=0.01), nonparoxysmal AF (versus paroxysmal; β, 0.52; P<0.0001), and larger left atrial size (β for +1-cm(2) change, 0.040; P<0.0001). The BNP levels were strongly associated with arrhythmia recurrence in univariate- (hazard ratio for +1-log-BNP change, 2.32; 95% confidence interval, 2.11 to 2.74; P<0.001) and covariate- (hazard ratio for +1-log-BNP change, 2.13; 95% confidence interval, 2.06 to 2.38; P<0.001) adjusted Cox proportional hazards analysis. The covariate-adjusted hazard ratios for recurrent arrhythmia were 1.6, 2.7, 4.3, and 5.7 for the second, third, fourth, and fifth quintiles, respectively, compared with patients in the lowest quintile (P for trend across quintiles <0.001). B-type natriuretic peptide levels correlate with AF burden (chronicity, altered hemodynamics, and anatomic remodeling) in patients with lone AF and are strong predictors of recurrent arrhythmia after ablation. Elevated BNP levels may reflect increased cardiac chamber wall stress and/or intrinsic atrial disease, thus increasing the risk of arrhythmia recurrence.

  19. Interactions of gastrointestinal peptides: ghrelin and its anorexigenic antagonists.

    PubMed

    Wisser, Anna-Sophia; Habbel, Piet; Wiedenmann, Bertram; Klapp, Burghard F; Mönnikes, Hubert; Kobelt, Peter

    2010-01-01

    Food intake behaviour and energy homeostasis are strongly regulated by a complex system of humoral factors and nerval structures constituting the brain-gut-axis. To date the only known peripherally produced and centrally acting peptide that stimulates food intake is ghrelin, which is mainly synthesized in the stomach. Recent data indicate that the orexigenic effect of ghrelin might be influenced by other gastrointestinal peptides such as cholecystokinin (CCK), bombesin, desacyl ghrelin, peptide YY (PYY), as well as glucagon-like peptide (GLP). Therefore, we will review on the interactions of ghrelin with several gastrointestinal factors known to be involved in appetite regulation in order to elucidate the interdependency of peripheral orexigenic and anorexigenic peptides in the control of appetite.

  20. Interactions of Gastrointestinal Peptides: Ghrelin and Its Anorexigenic Antagonists

    PubMed Central

    Wisser, Anna-Sophia; Habbel, Piet; Wiedenmann, Bertram; Klapp, Burghard F.; Mönnikes, Hubert; Kobelt, Peter

    2010-01-01

    Food intake behaviour and energy homeostasis are strongly regulated by a complex system of humoral factors and nerval structures constituting the brain-gut-axis. To date the only known peripherally produced and centrally acting peptide that stimulates food intake is ghrelin, which is mainly synthesized in the stomach. Recent data indicate that the orexigenic effect of ghrelin might be influenced by other gastrointestinal peptides such as cholecystokinin (CCK), bombesin, desacyl ghrelin, peptide YY (PYY), as well as glucagon-like peptide (GLP). Therefore, we will review on the interactions of ghrelin with several gastrointestinal factors known to be involved in appetite regulation in order to elucidate the interdependency of peripheral orexigenic and anorexigenic peptides in the control of appetite. PMID:20798884

  1. A prospective study of brain natriuretic peptide levels in three subgroups: Stroke with hypertension, stroke without hypertension, and hypertension alone

    PubMed Central

    Cakir, Zeynep; Saritas, Ayhan; Emet, Mucahit; Aslan, Sahin; Akoz, Ayhan; Gundogdu, Fuat

    2010-01-01

    Aim: To study brain natriuretic peptide (BNP) levels in three subgroups: patients having stroke with hypertension (HT), those having stroke without HT, and those with HT alone. We also tried to identify whether BNP levels predict the length of stay in hospital and mortality. Materials and Methods: The groups were formed by patients who had been admitted to the emergency department in the first 4–12 h after the onset of symptoms. There were 30 stroke patients with a history of HT (group I), 30 stroke patients without a history of HT (group II), and 20 HT patients without stroke (group III). Patients with congestive heart failure, chronic cor pulmonale, severe valvular heart disease, chronic renal failure, liver insufficiency, diabetes mellitus, atrial fibrillation, and those with a history of stroke were excluded from the study since these diseases can affect the plasma BNP levels. Results: The demographic characteristics, except the age distribution, were similar among the groups. The mean BNP levels in the three groups were 168.8 ± 223.9 pg/ml, 85.0 ± 75.1 pg/ml, and 84.8 ± 178.3 pg/ml, respectively. The differences between the groups were statistically significant. Conclusion: The mean BNP levels were affected by HT and/or stroke. The simultaneous presence of HT and stroke results in a more significant increase BNP than the presence of either stroke or HT alone. When diseases that can affect the plasma BNP levels are excluded, the BNP levels in stroke patients without a history of HT are similar to the levels seen in patients with only HT. PMID:20436747

  2. Serum asymmetric dimethylarginine levels are independently associated with procollagen III N-terminal peptide in nonalcoholic fatty liver disease patients.

    PubMed

    Hyogo, Hideyuki; Yamagishi, Sho-Ichi; Maeda, Sayaka; Fukami, Kei; Ueda, Seiji; Okuda, Seiya; Nakahara, Takashi; Kimura, Yuki; Ishitobi, Tomokazu; Chayama, Kazuaki

    2014-02-01

    Although impaired synthesis and/or bioavailability of nitric oxide are considered to contribute to insulin resistance and the progression of liver disease in nonalcoholic fatty liver disease, role of asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase, has not been examined. We examined retrospectively which anthropometric and metabolic parameters were independently associated with serum levels of asymmetric dimethylarginine in nonalcoholic fatty liver disease. A total of 194 consecutive biopsy-proven nonalcoholic fatty liver disease patients with or without type 2 diabetes were enrolled. Serum asymmetric dimethylarginine levels in nonalcoholic fatty liver disease patients were significantly higher, irrespective of the presence or absence of diabetes, than those in healthy control. Multiple stepwise regression analysis showed that decreased total protein and procollagen N-terminal peptide levels, markers of advanced liver disease and hepatic fibrosis, respectively, were independently associated with asymmetric dimethylarginine levels in nonalcoholic fatty liver disease subjects without diabetes, whereas soluble form of receptor for advanced glycation end products and density ratio of liver to spleen in computed tomography were independent correlates of asymmetric dimethylarginine in diabetic patients. The present study suggests that asymmetric dimethylarginine may be associated with nonalcoholic fatty liver disease, especially subjects without diabetes.

  3. Glutinous rice amylopectin can adjust the plasma gut-regulated peptide levels in rhubarb-induced spleen deficiency rats.

    PubMed

    Zhang, Huijuan; Wang, Jing; Liu, Yingli; Sun, Baoguo

    2016-02-01

    The pharmacological effects of glutinous rice (GR) and GR amylopectin (GRA) on the gastrointestine were investigated in rhubarb-induced spleen deficiency rats by determining the levels of gastrointestinal hormones such as the peptides serum gastrin, amylase motilin, and somatostatin. GR and GRA were given by gavage at various doses of GR (7.5, 15, and 30 g per kg body weight) and GRA (3.8, 7.6, and 15 g per kg body weight) every day for 4 weeks, respectively. The results indicated that the final body weight of rats in the highest-dose GR (GRH) group and all the GRA groups significantly (P < 0.05) increased (7.2-12.1%) compared with the model control (MC) group. All the GR and GRA treated groups had significantly (P < 0.05) higher gastrin contents (32.8-51.2%), motilin levels (13.8-39.2%), and amylase contents (22.5-39.4%) and the GRH and highest-dose GRA (GRAH) groups had significantly (P < 0.05) lower somatostatin contents compared with the MC group. Meanwhile, the somatostatin contents were negatively correlated with the motilin levels (r = -0.964, P < 0.01) and amylase contents (r = -0.981, P < 0.01). The GRAH treatment group had the highest final body weight, gastrin contents, motilin levels, and amylase contents and the lowest somatostatin contents, which demonstrated that GRA might play the most important role in the spleen-regulating activities of GR.

  4. Events at the transition between cell cycle exit and oligodendrocyte progenitor differentiation: the role of HDAC and YY1.

    PubMed

    He, Ye; Sandoval, Juan; Casaccia-Bonnefil, Patrizia

    2007-08-01

    The complexity of the adult brain is the result of an integrated series of developmental events that depends on appropriate timing of differentiation. The importance of transcriptional regulatory networks and epigenetic mechanisms of regulation of gene expression is becoming increasingly evident. Among these mechanisms, previous work has revealed the importance of histone deacetylation in oligodendrocyte differentiation. In this manuscript we define the region of interaction between transcription factor Yin-Yang 1 (YY1) and histone deacetylase 1, and characterize the functional consequences of YY1 overexpression on the differentiation of oligodendrocyte progenitors.

  5. YY1 and GATA-1 interaction modulate the chicken 3'-side alpha-globin enhancer activity.

    PubMed

    Rincón-Arano, Héctor; Valadez-Graham, Viviana; Guerrero, Georgina; Escamilla-Del-Arenal, Martín; Recillas-Targa, Félix

    2005-06-24

    Studying the chicken alpha-globin domain as a model system of gene regulation, we have previously identified contiguous silencer-enhancer elements located on the 3'-side of the domain. To better characterize the enhancer we performed a systematic functional analysis to define its expression influence range and the ubiquitous and stage-specific transcriptional regulators interacting with this control element. In contrast to previous reports, we found that, in addition to a core element that includes three GATA-1 binding sites, the enhancer incorporates a 120 base-pair DNA fragment where EKLF, NF-E2 and a fourth GATA-1 factor could interact. Functional experiments demonstrate that the enhancer activity over the adult alpha(D) promoter is differentially regulated. We found that the transcriptional factor Ying Yang 1 (YY1) binds to the 120 base-pair DNA fragment and its effect over the enhancer activity is GATA-1-dependent. In addition, we characterize a novel physical interaction between GATA-1 and YY1 that influences the enhancer function. Experiments using a histone deacetylation inhibitor indicate that, in pre-erythroblasts, the enhancer down-regulation could be influenced by a closed chromatin conformation. Our observations show that the originally defined enhancer possesses a more complex composition than previously assumed. We propose that its activity is modulated through differential nuclear factor interactions and chromatin modifications at distinct erythroid stages.

  6. AZTECA, a y-y diagram oriented interactive computer program for optical system design and optimization

    NASA Astrophysics Data System (ADS)

    Flores-Hernandez, Ricardo

    1995-09-01

    The Centro de Investigaciones en Optica is developing the AZTECA optical design program to exploit the full synthesis capabilities intrinsic to Delano's y-y method. Both the y- y diagram and its dual the (omega) -(omega) diagram, are manipulated in real time to introduce changes at any point or line in those diagrams. These changes result in altered new versions of the optical system by means of a specialized subroutine that incorporates the fundamental synthesis equations for those diagrams. To display results on the computer's screen as the optimization process progress, AZTECA makes wide use of the fact that the y-y and the (omega) -(omega) diagrams display graphically all the first order attributes of an optical system. This program adjoins to these features the calculation of Buchdahl's 3rd, 5th, and 7th order aberration coefficients to the output. This results in a real time display of the system's paraxial and aberrational behavior. Efficient graphic displays, the program's modular structure and an interactive mode of operation, also contribute to make the AZTECA a versatile platform. It will be further developed as a new tool for efficient optical system design.

  7. Relationship of serum elastin peptide level to single breath transfer factor for carbon monoxide in French coal miners

    PubMed Central

    Frette, C.; Jacob, M. P.; Wei, S. M.; Bertrand, J. P.; Laurent, P.; Kauffmann, F.; Pham, Q. T.

    1997-01-01

    BACKGROUND: Clinical and epidemiological studies have given discordant results on the usefulness of the level of circulating elastin peptide (EP), a potential marker of both elastin destruction (a key phenomenon in pulmonary emphysema) and neosynthesis, for assessing structural changes in the lung extracellular matrix. The aim of the present study was to explore the relationship between levels of EP and forced expiratory volume in one second (FEV1) and single breath transfer factor for carbon monoxide (TLCO and KCO) in coal miners. METHODS: The study population comprised 227 working coal miners aged 34-50 years consisting of 75 miners heavily exposed to underground coal dust with pulmonary radiographs classified as 0/1 or 1/0 by the International Labour Office classification, 75 exposed miners with radiographs classified as normal (0/0), and 77 miners slightly exposed to coal dust with normal radiographs. The subjects answered a standardised questionnaire and performed spirometric tests and a carbon monoxide (CO) transfer test. RESULTS: No association was observed between EP levels and % predicted FEV1 (or FEV1/FVC). The level of EP increased significantly with decreased % predicted TLCO (r = -0.20). Miners in the lowest % predicted KCO quintile had higher EP levels than the rest (3.28 (1.37) vs 2.47 (1.16)). A significantly lower EP level was observed in miners with radiographs classified as 1/0 or 0/1, especially in those with round opacities, compared with miners with a normal radiograph, and in current smokers compared with the rest. CONCLUSIONS: The results of this study suggest that the level of EP may reflect some remodelling activity in emphysema and lung fibrosis. 


 PMID:9516897

  8. Caffeinated coffee, decaffeinated coffee, and caffeine in relation to plasma C-peptide levels, a marker of insulin secretion, in U.S. women.

    PubMed

    Wu, Tianying; Willett, Walter C; Hankinson, Susan E; Giovannucci, Edward

    2005-06-01

    Coffee consumption is associated with reduced risk of type 2 diabetes, but the mechanism is not clearly understood. Elevated C-peptide, as a marker of insulin secretion, has been linked to insulin-resistant type 2 diabetes. In this study, we examined consumption of caffeinated and decaffeinated coffee and total caffeine in relation to concentrations of plasma C-peptide. Plasma C-peptide concentrations were measured in a cross-sectional setting among 2,112 healthy women from the Nurses' Health Study I who provided blood samples in 1989-1990. Consumption of caffeinated and decaffeinated coffee and total caffeine was assessed using a semiquantitative food-frequency questionnaire in 1990. Intakes of caffeinated and decaffeinated coffee and caffeine in 1990 were each inversely associated with C-peptide concentration in age-adjusted, BMI-adjusted, and multivariable-adjusted analyses. In multivariable analysis, concentrations of C-peptide were 16% less in women who drank >4 cups/day of caffeinated or decaffeinated coffee compared with nondrinkers (P < 0.005 for each). Women in the highest quintile compared with the lowest quintile of caffeine intake had 10% lower C-peptide levels (P = 0.02). We did not find any association between tea and C-peptide. The inverse association between caffeinated coffee and C-peptide was considerably stronger in obese (27% reduction) and overweight women (20% reduction) than in normal weight women (11% reduction) (P = 0.005). Our findings suggest a potential reduction of insulin secretion by coffee in women. This reduction may be related to other components in coffee rather than caffeine.

  9. Blood serum levels of CART peptide in patients with schizophrenia on clozapine monotherapy.

    PubMed

    Wysokiński, Adam; Kłoszewska, Iwona

    2014-12-15

    CART (cocaine- and amphetamine-regulated transcript) is an endogenous inhibitor of food intake. We compared fasting serum CART levels in subjects with schizophrenia on clozapine monotherapy (n=24) with sex- and age-matched healthy controls (n=24). CART levels were higher in the clozapine group (262.76±359.91 vs. 90.40±169.90 pg/mL). CART levels were higher in subjects with metabolic syndrome compared to subjects without metabolic syndrome in the clozapine group (415.63±416.93 vs. 122.62±237.17 pg/mL, n=12 and 12, respectively) and in the whole study group (377.73±401.09 vs. 88.58±172.35 pg/mL, n=16 and 32, respectively). In the control group CART levels were higher in subjects with total body fat lower than the target maximum compared to subjects with total body fat below the target maximum (121.71±154.91 vs. 66.32±182.96 pg/mL, n=14 and 10, respectively). CART levels did not correlate with age, weight, BMI, abdominal, waist and hip circumferences, WHR, blood pressure, laboratory tests, clozapine dose, antipsychotic or clozapine treatment duration, body composition, and markers of insulin resistance in the study group. Further studies are required to confirm whether increased levels of circulating CART are compensatory in response to treatment-induced weight gain and abdominal obesity or a primary feature of schizophrenia. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  10. A study of low level selenium determination by hydride generation atomic fluorescence spectrometry in water soluble protein and peptide fractions.

    PubMed

    Stibilj, V; Mazej, D; Falnoga, I

    2003-12-01

    Development of a method for very low level selenium determination in water soluble protein and peptide fractions, obtained after various separation procedures, is presented. A hydride generation atomic fluorescence spectrometry (HG-AFS) detection system was optimised and the influence of Cu(II), Sb(V), As(III) and HNO3 interferences in the measurement of Se by HG-AFS was investigated. A destruction procedure using HNO3 and H2O2 was also optimised and the average recovery of the digestion of a solution of selenomethioneine was 92 +/- 4% (n=14). Combination of this digestion with the detection system gave reliable results. Accuracy was tested by comparison with two independent methods. A very low detection limit (DL) of 0.2 ng/g of measuring solution was achieved. The whole procedure from weighing to measuring was performed in the same Teflon tube. The addition of HNO3 to the fractions before long term storage at -20 degrees C was necessary to prevent adsorption on the test tubes. Selenium was measured in water soluble protein and peptide fractions obtained after extraction, and Sephadex G-75 chromatography performed on liver samples from: i) hens exposed to As2O3, ii) hens fed with a high fat feed and iii) the certified reference material dogfish liver (CRM DOLT-2). Because of the very low DL we were able to observe the Se distribution in chromatographic fractions of samples of organisms which were not exposed to excess amounts of Se. The presence of selenium associated with metallothioneins was observed.

  11. Short-term treatment with rivastigmine and plasma levels of Abeta peptides in Alzheimer's disease.

    PubMed

    Sobow, Tomasz; Kloszewska, Iwona

    2005-01-01

    Deregulation of APP metabolism is considered to be a key pathogenic event in Alzheimer's disease. Data from cell cultures indicate that the secretion of Abeta1-42 might be inhibited by cholinesterase inhibitors, possibly via M1 receptors stimulation. Treatment with tacrine, a dual acetyl- and butyrylcholinesterase inhibitor, had no significant effect on mean plasma Abeta species concentrations. However, a correlation was observed between higher drug concentrations and lower Abeta levels that might indicate an effect on APP metabolism with an increased alpha-cleavage. Abeta1-40 and Abeta1-42 levels were measured in the plasma of 28 AD subjects by means of a commercially available ELISA before rivastigmine treatment and at week 2 after the first dose of the drug (3 mg/day) had been administered. Treatment with rivastigmine exhibited a significant effect on mean plasma concentrations of Abeta1-42 (mean difference 7.8+/-8.4, t=-4.9, pmean difference 7.8+/-8.4, t=-4.9, p<0.001) with a negative correlation with the patients age (Pearson's R=-0.40, p=0.035). No significant effect on plasma Abeta1-40 was observed. The observed increase of mean levels of plasma Abeta1-42 after rivastigmine treatment might indicate an effect of the drug on Abeta metabolism, mobilization of Abeta1-42 from deposits in the affected brain areas and a consecutive Ab1-42 brain-to-plasma efflux. The negative correlation between Abeta1-42 plasma levels changes and age may be a sign of impairment of this process in the older patients. A large individual variation of the observed response, however, excludes drawing definite conclusions. Whether those subjects who respond to rivastigmine in terms of Abeta1-42 plasma levels changes also respond clinically needs to be established.

  12. One-year prognosis and the role of brain natriuretic peptide levels in patients with chronic cor pulmonale.

    PubMed

    Park, So Young; Lee, Chang Youl; Kim, Changhwan; Jang, Seung Hun; Park, Yong Bum; Park, Sunghoon; Hwang, Yong Il; Lee, Myung Goo; Jung, Ki-Suck; Kim, Dong-Gyu

    2015-04-01

    Data on the clinical outcomes and role of brain natriuretic peptide (BNP) levels in patients with chronic cor pulmonale are limited. A total of 69 patients with chronic cor pulmonale, admitted for dyspnea (January 2007 to September 2011) to three university hospitals, were retrospectively reviewed. All of the patients had right ventricular (RV) dysfunction on echocardiography. The median age was 70.0 yr, and chronic obstructive pulmonary disease (40.6%) and tuberculosis-destroyed lung (TDL, 27.5%) were the leading causes of chronic cor pulmonale. At the 1-yr follow-up, the mortality rate was 15.9%, and the readmission rate was 53.7%; patients with TDL had higher mortality (31.6% vs. 10.0%; P=0.059) and readmission rates (78.9% vs. 43.8%; P=0.009) than those with non-TDL diseases. The area under the receiver operating characteristic curve for admission BNP levels to predict readmission was 0.788 (95% confidence interval [CI], 0.673-0.904), and the sensitivity and specificity of the cut-off value were 80.6% and 77.4%, respectively. In multivariate analysis, high admission BNP levels were a significant risk factor for subsequent readmission (hazard ratio, 1.049; 95% CI, 1.005-1.094). Additionally, admission BNP levels were well correlated with cardiac troponin I (r=0.558), and delta BNP also correlated with delta RV systolic pressure (n=25; r=0.562). In conclusion, among hospitalized patients with chronic cor pulmonale, admission high BNP levels are a significant risk factor for subsequent readmission. Therefore, more intensive monitoring and treatment are needed in patients with higher BNP levels.

  13. High levels of the proNGF peptides LIP1 and LIP2 in the serum and synovial fluid of rheumatoid arthritis patients: evidence for two new cytokines.

    PubMed

    Dicou, Eleni

    2008-02-01

    The proNGF peptides LIP1 and LIP2 display multiple biological and physiological properties several of which share common features with the nerve growth factor (NGF). The objective of this study was firstly to demonstrate the presence of these peptides in the human sera and secondly to provide evidence for their involvement in inflammatory diseases. Their levels measured by specific enzyme-linked immunosorbent assays (ELISA) were found to be more than 10-fold higher in sera of patients with rheumatoid arthritis (RA), as compared to healthy controls. High levels of LIP1 and LIP2 were also detected in the synovial fluid (SF) of RA patients. These results provide first evidence for a cytokine-like role of the LIP1 and LIP2 peptides.

  14. iProphet: Multi-level Integrative Analysis of Shotgun Proteomic Data Improves Peptide and Protein Identification Rates and Error Estimates*

    PubMed Central

    Shteynberg, David; Deutsch, Eric W.; Lam, Henry; Eng, Jimmy K.; Sun, Zhi; Tasman, Natalie; Mendoza, Luis; Moritz, Robert L.; Aebersold, Ruedi; Nesvizhskii, Alexey I.

    2011-01-01

    The combination of tandem mass spectrometry and sequence database searching is the method of choice for the identification of peptides and the mapping of proteomes. Over the last several years, the volume of data generated in proteomic studies has increased dramatically, which challenges the computational approaches previously developed for these data. Furthermore, a multitude of search engines have been developed that identify different, overlapping subsets of the sample peptides from a particular set of tandem mass spectrometry spectra. We present iProphet, the new addition to the widely used open-source suite of proteomic data analysis tools Trans-Proteomics Pipeline. Applied in tandem with PeptideProphet, it provides more accurate representation of the multilevel nature of shotgun proteomic data. iProphet combines the evidence from multiple identifications of the same peptide sequences across different spectra, experiments, precursor ion charge states, and modified states. It also allows accurate and effective integration of the results from multiple database search engines applied to the same data. The use of iProphet in the Trans-Proteomics Pipeline increases the number of correctly identified peptides at a constant false discovery rate as compared with both PeptideProphet and another state-of-the-art tool Percolator. As the main outcome, iProphet permits the calculation of accurate posterior probabilities and false discovery rate estimates at the level of sequence identical peptide identifications, which in turn leads to more accurate probability estimates at the protein level. Fully integrated with the Trans-Proteomics Pipeline, it supports all commonly used MS instruments, search engines, and computer platforms. The performance of iProphet is demonstrated on two publicly available data sets: data from a human whole cell lysate proteome profiling experiment representative of typical proteomic data sets, and from a set of Streptococcus pyogenes experiments

  15. N-Terminal pro-brain natriuretic peptide levels in dichorionic diamniotic twins with selective intrauterine growth restriction.

    PubMed

    Fujioka, Kazumichi; Mizobuchi, Masami; Sakai, Hitomi; Iwatani, Sota; Wada, Keiko; Yoshimoto, Seiji; Nakao, Hideto

    2014-03-04

    Monochorionic diamniotic (MD) twins with selective intrauterine growth restriction (sIUGR) have known associations with cardiac complications. However, the cardiac load of dichorionic diamniotic (DD) twins with sIUGR (DD-sIUGR) remains unclear. N-terminal pro-brain natriuretic peptide (NT-pro BNP) is a convenient marker of cardiac dysfunction in neonates, and is elevated in MD twins with sIUGR (MD-sIUGR). However, there are no reports assessing serum NT-pro BNP levels in DD-sIUGR. Here, we aimed to clarify serum NT-pro BNP levels at birth in DD-sIUGR, and to compare them with those of MD-sIUGR. Forty-one DD twin pairs admitted to our center between October 2007 and January 2013 were enrolled in this study and separated into two groups: nine twins with sIUGR (DD-sIUGR group) and 32 twins without sIUGR (DD without sIUGR group). Sixteen MD twins with sIUGR (MD-sIUGR group) served as positive controls. Serum NT-pro BNP levels at birth in DD-sIUGR [median 2,115 pg/ml (range, 443-6,590 pg/ml)] were significantly higher than in DD without sIUGR [1,080 pg/ml (range, 313-3,470 pg/ml); p=0.001], and significantly lower than in MD twins with sIUGR [4,520 pg/ml (range, 529-62,400 pg/ml); p=0.04]. Serum NT-pro BNP levels between larger and smaller DD co-twins were significantly correlated (r = 0.582; p<0.0001). In conclusion, serum NT-pro BNP levels at birth in DD twins with sIUGR were higher than those without, and lower than in MD twins with sIUGR.

  16. B-type natriuretic peptide (BNP) serum levels in rats after forced repeated swimming stress.

    PubMed

    Hadzovic-Dzuvo, Almira; Valjevac, Amina; Avdagić, Nesina; Lepara, Orhan; Zaćiragić, Asija; Jadrić, Radivoj; Alajbegović, Jasmin; Prnjavorac, Besim

    2011-02-01

    To estimate the effects of forced repeated swimming stress on BNP serum levels in rats. Adult male Wistar rats weighting between 280-330 g were divided into two groups: control group (n = 8) and stress group (n = 8). Rats in the stress group were exposed to forced swimming stress daily, for 7 days. The rats were forced to swim in plastic tanks (90 cm wide, 120 cm deep) containing tap water (temperature ca. 25 degrees C). The depth of water was 40 cm. Duration of each swimming session progressively increased from 10 minutes on the first day to 40 minutes on days 6 and 7. Rats were sacrificed and blood was drawn from abdominal aorta for BNP analysis immediately after the last swimming session. B-type natriuretic serum level was determined by ELISA method using RAT BNP-32 kit (Phoenix Pharmaceutical Inc.). There was no statistically significant difference between mean BNP serum level in the stress group after the swimming period (0.81 +/- 0.14 ng/ml) as compared to the unstressed group of rats (0.8 +/- 0.08 ng/ml). After the swimming period mean body weight slightly decreased in the stress group in comparison with values before stress period (296.3 g vs. 272.8 g), but this difference was not statistically significant. The stress period had no influence on food intake in the stress rat group. The workload consisting of 40-minutes long swimming session is not sufficient to provoke BNP release from myocardium in rats.

  17. Elevated parathyroid hormone-related peptide levels after human gestation: relationship to changes in bone and mineral metabolism.

    PubMed

    Dobnig, H; Kainer, F; Stepan, V; Winter, R; Lipp, R; Schaffer, M; Kahr, A; Nocnik, S; Patterer, G; Leb, G

    1995-12-01

    PTH-related peptide (PTHrP) can be found in high concentrations in human breast milk and has been implicated in material calcium regulation postpartum. We studied the relationship of plasma PTHrP levels of serum markers of bone turnover and selective cancellous bone density in 35 women (age, 25 +/- 3 yr) 2-3 days postpartum and after 3 and 6 months of lactation. The mean postpartum plasma PTHrP levels measured by immunoradiometric assay was 2.64 +/- 0.19 pmol/L (mean +/- SE) and were elevated compared to that in 35 age- and sex-matched controls (1.34 +/- 0.14; P < 0.0001). PTHrP remained significantly elevated, but decreased during the lactation period of 6 +/- 1 months. Immediately postpartum, serum protein levels were lowest, and serum ionized calcium levels highest. At that time, PTH was suppressed to 50% of control values (P < 0.001). Two or 3 days postpartum, serum ionized calcium was negatively correlated with total serum protein (r = -0.47; P < 0.0001) and positively correlated with plasma PTHrP (r = -0.32; P < 0.008). PTH was inversely correlated with ionized calcium (r = -0.24; P = 0.03) and PTHrP (r = -0.31; P < 0.01). Three and 6 months postpartum, serum protein and PTH levels had returned to normal, and ionized calcium concentrations decreased. There was no indication that PTHrP may have any significant systemic effect after 3 and 6 months of lactation. Long term lactation led to a significant decrease in radial cancellous bone density (-4.5%; P < 0.05) at 6 months and to elevations in serum markers of bone resorption (2- to 3-fold for serum carboxy-terminal telopeptide of type I collagen) and formation (1- to 2-fold for osteocalcin and serum carboxy-terminal propeptide of type I procollagen). Bone turnover balance was clearly negative after 3 months of lactation compared to the control value and indicated net bone loss at a time when estrogen levels were low. With ongoing lactation, estrogen levels increased, and bone turnover balance improved

  18. Regulation of the microRNA processor DGCR8 by hepatitis B virus proteins via the transcription factor YY1.

    PubMed

    Shan, Xuefeng; Ren, Min; Chen, Ke; Huang, Ailong; Tang, Hua

    2015-03-01

    MicroRNAs (miRNAs) are a new class of well-conserved small noncoding RNAs that mediate posttranscriptional gene regulation. Hepatitis B virus (HBV) causes various liver diseases, including chronic hepatitis, liver cirrhosis and hepatocellular cancer. Recent data have indicated HBV alters miRNAs expression patterns, but the underlying mechanisms have not been fully established so far. Here, we provide a hypothesis that HBV alters the expressions of miRNAs by playing a role in the microRNA production process. In this study, we demonstrate that HBV downregulates miRNAs processor DGCR8 mRNA and protein expression in stable and transient HBV-expressing cells. HBV downregulates DGCR8 expression by inhibiting its promoter activity, and HBs and HBx may be involved in this process. Ectopic expression and knockdown of YY1 revealed that YY1 suppresses the activity of the DGCR8 promoter, while YY1 expression is significantly upregulated by HBV. In conclusion, our data show that HBV proteins repress DGCR8 promoter activity by upregulating the expression of transcription factor YY1. This provides a new insight into the mechanism of HBV-induced miRNA dysregulation.

  19. 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

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

    PubMed

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

    2015-10-26

    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. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

  1. Peptidomics of Cpe fat/fat mouse hypothalamus: effect of food deprivation and exercise on peptide levels.

    PubMed

    Che, Fa-Yun; Yuan, Quan; Kalinina, Elena; Fricker, Lloyd D

    2005-02-11

    Carboxypeptidase E is a major enzyme in the biosynthesis of numerous neuroendocrine peptides. Previously, we developed a technique for the isolation of neuropeptide-processing intermediates from mice that lack carboxypeptidase E activity (Cpe fat/fat mice) due to a naturally occurring point mutation. In the present study, we used a differential labeling procedure with stable isotopic tags and mass spectrometry to quantitate the relative changes in a number of hypothalamic peptides in Cpe fat/fat mice in two different paradigms that each cause an approximately 10% decrease in body mass. One paradigm involved a 2-day fast under normal sedentary conditions (i.e. standard mouse cages); the other involved giving mice access to an exercise wheel for 4 weeks with free access to food. Approximately 50 peptides were detected in both studies, and over 80 peptides were detected in at least one of the two studies. Twenty-eight peptides were increased >50% by food deprivation, and some of these were increased by 2- to 3-fold. In contrast, only three peptides were increased >50% in the group with exercise wheels, and many peptides showed a slight 15-30% decrease upon exercise. Approximately one-half of the peptides detected in both studies were identified by tandem mass spectrometry. Peptides found to be elevated by food deprivation but not exercise included a number of fragments of proenkephalin, prothyrotropin-releasing hormone, secretogranin II, chromogranin B, and pro-SAAS. Taken together, the differential regulation of these peptides in the two paradigms suggests that the regulation is not due to the lower body weight but to the manner in which the paradigms achieved this lower body weight.

  2. Control of Food Intake by Gastrointestinal Peptides: Mechanisms of Action and Possible Modulation in the Treatment of Obesity

    PubMed Central

    Prinz, Philip; Stengel, Andreas

    2017-01-01

    This review focuses on the control of appetite by food intake-regulatory peptides secreted from the gastrointestinal tract, namely cholecystokinin, glucagon-like peptide 1, peptide YY, ghrelin, and the recently discovered nesfatin-1 via the gut-brain axis. Additionally, we describe the impact of external factors such as intake of different nutrients or stress on the secretion of gastrointestinal peptides. Finally, we highlight possible conservative—physical activity and pharmacotherapy—treatment strategies for obesity as well as surgical techniques such as deep brain stimulation and bariatric surgery also altering these peptidergic pathways. PMID:28096522

  3. Non-linear Equation using Plasma Brain Natriuretic Peptide Levels to Predict Cardiovascular Outcomes in Patients with Heart Failure

    NASA Astrophysics Data System (ADS)

    Fukuda, Hiroki; Suwa, Hideaki; Nakano, Atsushi; Sakamoto, Mari; Imazu, Miki; Hasegawa, Takuya; Takahama, Hiroyuki; Amaki, Makoto; Kanzaki, Hideaki; Anzai, Toshihisa; Mochizuki, Naoki; Ishii, Akira; Asanuma, Hiroshi; Asakura, Masanori; Washio, Takashi; Kitakaze, Masafumi

    2016-11-01

    Brain natriuretic peptide (BNP) is the most effective predictor of outcomes in chronic heart failure (CHF). This study sought to determine the qualitative relationship between the BNP levels at discharge and on the day of cardiovascular events in CHF patients. We devised a mathematical probabilistic model between the BNP levels at discharge (y) and on the day (t) of cardiovascular events after discharge for 113 CHF patients (Protocol I). We then prospectively evaluated this model on another set of 60 CHF patients who were readmitted (Protocol II). P(t|y) was the probability of cardiovascular events occurring after >t, the probability on t was given as p(t|y) = ‑dP(t|y)/dt, and p(t|y) = pP(t|y) = αyβP(t|y), along with p = αyβ (α and β were constant); the solution was p(t|y) = αyβ exp(‑αyβt). We fitted this equation to the data set of Protocol I using the maximum likelihood principle, and we obtained the model p(t|y) = 0.000485y0.24788 exp(‑0.000485y0.24788t). The cardiovascular event-free rate was computed as P(t) = 1/60Σi=1,…,60 exp(‑0.000485yi0.24788t), based on this model and the BNP levels yi in a data set of Protocol II. We confirmed no difference between this model-based result and the actual event-free rate. In conclusion, the BNP levels showed a non-linear relationship with the day of occurrence of cardiovascular events in CHF patients.

  4. Non-linear Equation using Plasma Brain Natriuretic Peptide Levels to Predict Cardiovascular Outcomes in Patients with Heart Failure

    PubMed Central

    Fukuda, Hiroki; Suwa, Hideaki; Nakano, Atsushi; Sakamoto, Mari; Imazu, Miki; Hasegawa, Takuya; Takahama, Hiroyuki; Amaki, Makoto; Kanzaki, Hideaki; Anzai, Toshihisa; Mochizuki, Naoki; Ishii, Akira; Asanuma, Hiroshi; Asakura, Masanori; Washio, Takashi; Kitakaze, Masafumi

    2016-01-01

    Brain natriuretic peptide (BNP) is the most effective predictor of outcomes in chronic heart failure (CHF). This study sought to determine the qualitative relationship between the BNP levels at discharge and on the day of cardiovascular events in CHF patients. We devised a mathematical probabilistic model between the BNP levels at discharge (y) and on the day (t) of cardiovascular events after discharge for 113 CHF patients (Protocol I). We then prospectively evaluated this model on another set of 60 CHF patients who were readmitted (Protocol II). P(t|y) was the probability of cardiovascular events occurring after >t, the probability on t was given as p(t|y) = −dP(t|y)/dt, and p(t|y) = pP(t|y) = αyβP(t|y), along with p = αyβ (α and β were constant); the solution was p(t|y) = αyβ exp(−αyβt). We fitted this equation to the data set of Protocol I using the maximum likelihood principle, and we obtained the model p(t|y) = 0.000485y0.24788 exp(−0.000485y0.24788t). The cardiovascular event-free rate was computed as P(t) = 1/60Σi=1,…,60 exp(−0.000485yi0.24788t), based on this model and the BNP levels yi in a data set of Protocol II. We confirmed no difference between this model-based result and the actual event-free rate. In conclusion, the BNP levels showed a non-linear relationship with the day of occurrence of cardiovascular events in CHF patients. PMID:27845390

  5. The role of ranitidine infusion on glucose, insulin and C-peptide serum levels induced by oral glucose tolerance test in healthy subjects.

    PubMed

    Gentile, S; Marmo, R; Costume, A; Orlando, C; D'Alessandro, R; De Bellis, G; Porcellini, M; Coltorti, M

    1986-01-01

    In 9 healthy subjects we evaluated the effect of a constant ranitidine infusion (100 mg) on glucose (mg/dl), insulin (microU/ml) and C-peptide (ng/ml) serum levels promoted by oral glucose tolerance test (75 g). Ranitidine significantly increased the area under concentration/time curves for glucose and insulin but not that of C-peptide. Our data indicate that ranitidine does not affect pancreatic insulin release nor peripheral glucose utilization and are consistent with the hypothesis that ranitidine influences the hepatic clearance of glucose and insulin both of which undergo high first-pass liver extraction.

  6. Hormone, metabolic peptide, and nutrient levels in the earliest phases of rheumatoid arthritis-contribution of free fatty acids to an increased cardiovascular risk during very early disease.

    PubMed

    Tang, Man Wai; Koopman, Frieda A; Visscher, Jan P M; de Hair, Maria J; Gerlag, Danielle M; Tak, Paul Peter

    2017-02-01

    Rheumatoid arthritis (RA) is a chronic autoimmune disease associated with changes in several hormones and metabolic peptides. Crosstalk between these factors and the immune system may be important for homeostasis during inflammation. Here, we studied the levels of hormones, metabolic peptides, and nutrients in individuals at risk for developing RA (at risk). In total, 18 hormones, metabolic peptides, and nutrients were measured in fasting serum samples from 45 autoantibody-positive individuals at risk, 22 RA patients, and 16 healthy subjects. Triglyceride (TG) levels were also measured in an independent validation cohort of 32 individuals at risk, 20 early arthritis patients, and 20 healthy controls. We found an elevated TG level in individuals at risk and significantly higher TG levels in RA patients compared to healthy controls. These results were confirmed in the validation cohort. Similarly, free fatty acid (FFA) levels showed an increase in individuals at risk and were significantly higher in RA patients compared to healthy controls. In RA patients, FFA levels were positively correlated with disease activity. Pancreatic polypeptide (PP) and norepinephrine levels were highly significantly increased in individuals at risk and RA patients compared to healthy controls. TG and FFA levels are increased in RA patients and positively correlated with disease activity parameters. The results presented here suggest a role for FFAs in the pathogenesis of RA. Furthermore, PP and norepinephrine may be a biomarker that could assist in the identification of individuals at risk.

  7. In hemodialysis, adiponectin, and pro-brain natriuretic peptide levels may be subjected to variations in body mass index.

    PubMed

    Trimarchi, Hernan; Muryan, Alexis; Dicugno, Mariana; Forrester, Mariano; Lombi, Fernando; Young, Pablo; Pomeranz, Vanesa; Iriarte, Romina; Barucca, Nanci; Campolo-Girard, Vicente; Alonso, Mirta; Lindholm, Bengt

    2011-10-01

    Adiponectin exerts cardiovascular protective actions, although some studies have shown the opposite. In hemodialysis, obese subjects display lower mortality rates despite hypoadiponectinemia, while higher adiponectin concentrations correlate with an elevated cardiovascular risk in nonobese subjects. The aim of the study is to suggest that adiponectin level variations are associated with differences in the body mass index (BMI). The interplay between adiponectin and pro-brain natriuretic peptide (Pro-BNP) levels may vary according to body fat mass. Fifty-two chronic hemodialysis patients were divided into three groups. Group A, BMI<25 (n=20); Group B, BMI 25 to 30 (n=21), and Group C, BMI>30 (n=11). Diabetics: Group A 10%; Group B 6 29%; Group C 55%, P=0.027. Determinations: Adiponectin, Pro-BNP, insulin, insulin resistance (HOMA), troponin T, nutritional status, ultrafiltration rates, C-reactive protein (CRP), vascular accesses, and echocardiography. Group A: adiponectinemia positively and significantly correlated with Pro-BNP, CRP, and troponin T. As BMI increased, adiponectin, Pro-BNP, and malnutrition significantly decreased, while insulin, HOMA, and ultrafiltration rates significantly increased. Cardiac restriction was significantly higher in obese patients. In all groups, Pro-BNP and troponin T displayed a strong positive correlation. In low-BMI subjects, high Pro-BNP and adiponectin, low myocardial restriction, and worse nutritional status were prevalent. In obesity, hypoadiponectinemia stimulates cardiac remodeling, cardiac hypertrophy, and decreased stretching, rendering Pro-BNP levels low despite high ultrafiltration rates. Thus, adiponectin correlates inversely with BMI, probably playing different cardiovascular roles as BMI changes. © 2011 The Authors. Hemodialysis International © 2011 International Society for Hemodialysis.

  8. Alterations in the neuropeptide galanin system in major depressive disorder involve levels of transcripts, methylation, and peptide

    PubMed Central

    Barde, Swapnali; Rüegg, Joelle; Prud’homme, Josée; Ekström, Tomas J.; Palkovits, Miklos; Turecki, Gustavo; Bagdy, Gyorgy; Ihnatko, Robert; Theodorsson, Elvar; Juhasz, Gabriella; Diaz-Heijtz, Rochellys; Mechawar, Naguib; Hökfelt, Tomas G. M.

    2016-01-01

    Major depressive disorder (MDD) is a substantial burden to patients, families, and society, but many patients cannot be treated adequately. Rodent experiments suggest that the neuropeptide galanin (GAL) and its three G protein-coupled receptors, GAL1–3, are involved in mood regulation. To explore the translational potential of these results, we assessed the transcript levels (by quantitative PCR), DNA methylation status (by bisulfite pyrosequencing), and GAL peptide by RIA of the GAL system in postmortem brains from depressed persons who had committed suicide and controls. Transcripts for all four members were detected and showed marked regional variations, GAL and galanin receptor 1 (GALR1) being most abundant. Striking increases in GAL and GALR3 mRNA levels, especially in the noradrenergic locus coeruleus and the dorsal raphe nucleus, in parallel with decreased DNA methylation, were found in both male and female suicide subjects as compared with controls. In contrast, GAL and GALR3 transcript levels were decreased, GALR1 was increased, and DNA methylation was increased in the dorsolateral prefrontal cortex of male suicide subjects, however, there were no changes in the anterior cingulate cortex. Thus, GAL and its receptor GALR3 are differentially methylated and expressed in brains of MDD subjects in a region- and sex-specific manner. Such an epigenetic modification in GALR3, a hyperpolarizing receptor, might contribute to the dysregulation of noradrenergic and serotonergic neurons implicated in the pathogenesis of MDD. Thus, one may speculate that a GAL3 antagonist could have antidepressant properties by disinhibiting the firing of these neurons, resulting in increased release of noradrenaline and serotonin in forebrain areas involved in mood regulation. PMID:27940914

  9. Alterations in the neuropeptide galanin system in major depressive disorder involve levels of transcripts, methylation, and peptide.

    PubMed

    Barde, Swapnali; Rüegg, Joelle; Prud'homme, Josée; Ekström, Tomas J; Palkovits, Miklos; Turecki, Gustavo; Bagdy, Gyorgy; Ihnatko, Robert; Theodorsson, Elvar; Juhasz, Gabriella; Diaz-Heijtz, Rochellys; Mechawar, Naguib; Hökfelt, Tomas G M

    2016-12-27

    Major depressive disorder (MDD) is a substantial burden to patients, families, and society, but many patients cannot be treated adequately. Rodent experiments suggest that the neuropeptide galanin (GAL) and its three G protein-coupled receptors, GAL1-3, are involved in mood regulation. To explore the translational potential of these results, we assessed the transcript levels (by quantitative PCR), DNA methylation status (by bisulfite pyrosequencing), and GAL peptide by RIA of the GAL system in postmortem brains from depressed persons who had committed suicide and controls. Transcripts for all four members were detected and showed marked regional variations, GAL and galanin receptor 1 (GALR1) being most abundant. Striking increases in GAL and GALR3 mRNA levels, especially in the noradrenergic locus coeruleus and the dorsal raphe nucleus, in parallel with decreased DNA methylation, were found in both male and female suicide subjects as compared with controls. In contrast, GAL and GALR3 transcript levels were decreased, GALR1 was increased, and DNA methylation was increased in the dorsolateral prefrontal cortex of male suicide subjects, however, there were no changes in the anterior cingulate cortex. Thus, GAL and its receptor GALR3 are differentially methylated and expressed in brains of MDD subjects in a region- and sex-specific manner. Such an epigenetic modification in GALR3, a hyperpolarizing receptor, might contribute to the dysregulation of noradrenergic and serotonergic neurons implicated in the pathogenesis of MDD. Thus, one may speculate that a GAL3 antagonist could have antidepressant properties by disinhibiting the firing of these neurons, resulting in increased release of noradrenaline and serotonin in forebrain areas involved in mood regulation.

  10. Serum C peptide and IRI levels after administration of glucagon and glucose in non-insulin-dependent diabetics.

    PubMed

    Jayyab, A K; Heding, L G; Czyzyk, A; Malczewski, B; Królewski, A S

    1982-03-01

    A comparative study was carried out on B cell response to alternative intravenous glucagon (1.0 mg) and intravenous glucose (0.33 g per kg body weight) in healthy non-obese persons (c-NOb), healthy obese persons (C-Ob), non-obese non-insulin-dependent diabetics (NIDD-NOb) and obese non-insulin-dependent diabetics (NIDD-Ob). Each group comprised ten subjects. C-peptide (CP immunoassay using antiserum M 1230) and IRI in the serum were measured for each test. After glucose load in B-cell responses were significantly lower in both the diabetic groups than in the normal groups. After glucagon injection there were no significant differences in IRI and CP levels between NIDD-NOb and C-NOb, however, significantly lower levels of serum CP were noted among NIDD-Ob in comparison to C-Ob with a lack of these differences in IRI levels. This phenomenon is well reflected by the molar IRI/CP ratio expressed as a percentage. In the fasting state IRI accounted in C-Ob for 8.8 +/- 3.5 per cent of CP, while in NIDD-Ob for up to 25. +/- 10.4 percent of CP (P = 0.0004). In the latter group of patients, the IRI/CP ratio after glucagon reached the highest values (over 30 per cent) observed in this study. These data suggest the important role in insulin disposal played by the liver in non-insulin-dependent diabetes associated with obesity. Another explanation for these data is that more proinsulin is secreted in this group of patients as compared to other groups.

  11. 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

  12. Genetic manipulation of sex ratio for the large-scale breeding of YY super-male and XY all-male yellow catfish (Pelteobagrus fulvidraco (Richardson)).

    PubMed

    Liu, Hanqin; Guan, Bo; Xu, Jiang; Hou, Changchun; Tian, Hua; Chen, Hongxi

    2013-06-01

    Yellow catfish has become one of the most important freshwater aquaculture species in China. The mono-sex male yellow catfish has important application value in aquaculture because the male grows generally faster than the sibling females under the same conditions. This study has screened YY super-male and YY physiological female yellow catfish by sex reversal, gynogenesis, and progeny testing, which can help to achieve the large-scale production of YY super-male and XY all-male. From 2008 to 2010, about 123,000 YY super-male were produced, and about 81 million XY all-male fry were produced with 100% male rate by random sampling. Therefore, these results indicate that YY super-male and YY physiological female yellow catfish can be viable and fertile. We conclude that the mono-sex breeding technique by YY super-male yellow catfish is stable and reliable, which has great potential for application in yellow catfish aquaculture.

  13. Identifying the Atomic-Level Effects of Metal Composition on the Structure and Catalytic Activity of Peptide-Templated Materials.

    PubMed

    Merrill, Nicholas A; McKee, Erik M; Merino, Kyle C; Drummy, Lawrence F; Lee, Sungsik; Reinhart, Benjamin; Ren, Yang; Frenkel, Anatoly I; Naik, Rajesh R; Bedford, Nicholas M; Knecht, Marc R

    2015-12-22

    Bioinspired approaches for the formation of metallic nanomaterials have been extensively employed for a diverse range of applications including diagnostics and catalysis. These materials can often be used under sustainable conditions; however, it is challenging to control the material size, morphology, and composition simultaneously. Here we have employed the R5 peptide, which forms a 3D scaffold to direct the size and linear shape of bimetallic PdAu nanomaterials for catalysis. The materials were prepared at varying Pd:Au ratios to probe optimal compositions to achieve maximal catalytic efficiency. These materials were extensively characterized at the atomic level using transmission electron microscopy, extended X-ray absorption fine structure spectroscopy, and atomic pair distribution function analysis derived from high-energy X-ray diffraction patterns to provide highly resolved structural information. The results confirmed PdAu alloy formation, but also demonstrated that significant surface structural disorder was present. The catalytic activity of the materials was studied for olefin hydrogenation, which demonstrated enhanced reactivity from the bimetallic structures. These results present a pathway to the bioinspired production of multimetallic materials with enhanced properties, which can be assessed via a suite of characterization methods to fully ascertain structure/function relationships.

  14. [B-type natriuretic peptide (BNP) levels and the effects of carvedilol on BNP levels in juvenile rats with right heart failure].

    PubMed

    An, Jin-Dou; Liang, Fang; Feng, Song

    2009-07-01

    To examine serum B-type natriuretic peptide (BNP) levels and BNP expression of protein and mRNA in the right ventricular myocardium in juvenile rats with right heart failure (RHF) and the effects of beta-adrenergic receptor blocker carvedilol on serum and myocardial BNP levels in order to investigate the role of BNP in the diagnosis and treatment of RHF. Fifty-one four-week-old Sprague-Dawley rats were randomly assigned to 5 groups: RHF 1, RHF 2, carvedilol-treated RHF, control 1 and control 2. RHF was developed 4 weeks after an intraperitoneal injection of monocrotaline in the RHF 1, RHF 2 and carvedilol-treated RHF groups. The rats in the RHF 1 and the control 1 groups were sacrificed after the RHF event for observing pathological changes in the myocardium. After the RHF event, the carvedilol-treated group was given intragastric administration of carvedilol (3.5 mg/kg/d) for 2 weeks. The RHF 2 and the control 2 groups were given distilled water of equal dose instead. The rats were sacrificed 2 weeks after carvedilol or distilled water administration. Serum BNP levels were measured using ELISA. BNP protein and mRNA expression in the right ventricular myocardium were measured by immunohistochemistry and RT-PCR, respectively. Haemodynamics and some physiological indexes were measured. Serum BNP levels and BNP protein and mRNA expression in the right ventricular myocardium were significantly higher in the RHF 1 group than those in the control 1 group (p<0.01). Serum BNP levels and BNP protein and mRNA expression in the right ventricular myocardium increased more significantly in the RHF 2 group. There was a positive correlation between serum BNP levels and myocardial BNP protein expression in the RHF group (r=0.698, p<0.01). Serum BNP levels and BNP protein and mRNA expression in the carvedilol-treated RHF group were significantly reduced when compared with the RHF 2 group (p<0.05). Carvedilol treatment also resulted in improved hemodynamics and relieved right

  15. The effect of global ischemia and reperfusion on the plasma levels of vasoactive peptides. The neuroendocrine response to cardiac arrest and resuscitation.

    PubMed

    Paradis, N A; Rose, M I; Garg, U

    1993-12-01

    Return of spontaneous circulation with CPR is a function of coronary perfusion pressure, which is determined by vasomotor tone and the force of compression. Vasomotor tone is affected by the relative stimulation of arterial vasoconstricting and vasorelaxing receptors by vasoactive substances. We measured the plasma levels of the endogenous vasoactive peptides arginine vasopressin (AVP) angiotensin II (ANG-II) and atrial natriuretic peptide (ANP) during cardiac arrest and resuscitation. A fibrillatory canine model of canine arrest was used. 'Down time' was greater than 10 min, during which no therapy, including BLS, was given. Standard ACLS was initiated at the end of the down time with manual external chest compression standardized to an esophageal pulse pressure of 50 mmHg. Blood samples were collected through an aortic catheter during spontaneous circulation and 3 min after initiation of ACLS. Peptide levels were measured using standard RIA techniques. Results are reported as the mean +/- S.D. in pg/ml. AVP levels increased from a baseline of 1.7 +/- 1.0 pg/ml during spontaneous circulation to 29.9 +/- 33.3 during cardiac arrest and CPR (P = 0.01). There was a moderate positive correlation between aortic pressure and circulating AVP levels after the first dose of epinephrine (R = 0.5). There was a trend towards higher AVP levels in animals with return of spontaneous circulation (P = 0.12). ANG-II levels increased from a baseline of 14.7 +/- 12.9 pg/ml during spontaneous circulation to 151 +/- 105 during cardiac arrest and CPR (P < 0.05). ANP levels increased from a baseline of 55 +/- 46 pg/ml during spontaneous circulation to 293 +/- 73 during cardiac arrest and CPR (P < 0.01). There were significant increases in the levels of these endogenous vasoactive peptides. This reflects the neuroendocrine response to global ischemia and CPR reperfusion. Plasma levels of these peptides may effect the vital organ perfusion pressures, response to exogenous vasopressors, and

  16. Cationic Membrane Peptides: Atomic-Level Insight of Structure-Activity Relationships from Solid-State NMR

    PubMed Central

    Su, Yongchao; Li, Shenhui; Hong, Mei

    2012-01-01

    Many membrane-active peptides, such as cationic cell-penetrating peptides (CPPs) and antimicrobial peptides (AMPs), conduct their biological functions by interacting with the cell membrane. The interactions of charged residues with lipids and water facilitate membrane insertion, translocation or disruption of these highly hydrophobic species. In this mini-review we will summarize high-resolution structural and dynamic findings towards the understanding of the structure-activity relationship of lipid membrane-bound CPPs and AMPs, as examples of the current development of solid-state NMR (SSNMR) techniques for studying membrane peptides. We will present the most recent atomic-resolution structure of the guanidinium-phosphate complex, as constrained from experimentally measured site-specific distances. These SSNMR results will be valuable specifically for understanding the intracellular translocation pathway of CPPs and antimicrobial mechanism of AMPs, and more generally broaden our insight into how cationic macromolecules interact with and cross the lipid membrane. PMID:23108593

  17. Brain Natriuretic Peptide Levels and the Occurrence of Subclinical Pulmonary Edema in Healthy Lowlanders at High Altitude.

    PubMed

    Pagé, Maude; Henri, Christine; Pagé, Pierre; Sauvé, Claude; Schampaert, Erick

    2015-08-01

    High altitude (HA) pulmonary edema (PE) results from complex and misunderstood interactions between adaptation mechanisms. We assessed the occurrence of subclinical PE and brain natriuretic peptide (BNP) levels among nonacclimatized individuals during an expedition on Mount Elbrus (5642 m). Seven subjects underwent assessment of vital signs, Lake Louise Score, ultrasound lung comets using handheld echography and circulating BNP using capillary testing at different stages of ascension, in addition to baseline echocardiography. Friedman tests were used to compare serial measurements. Heart rate, Lake Louise Score (P < 0.0001) and blood pressure (P = 0.037) increased during ascension; oxygen saturation decreased (P < 0.0001). BNP increased (40.7 ± 16.8 vs 19.7 ± 3.04 pg/mL; P < 0.01) after the summit, as did ultrasound lung comet count throughout ascension (P < 0.0001), but both parameters were not correlated (r = 0.36; P = 0.42). Post-summit peak BNP correlated with baseline left ventricular mass index (r = -0.79; P = 0.033). This study confirms the high incidence of subclinical PE during subacute exposure to hypobaric hypoxia and enhancement of this phenomenon after exertion. Although not correlated with the degree of PE, BNP levels increased after sustained effort at HA, but not at rest. Further investigation is needed to determine the mechanisms underlying the BNP response at HA and its usefulness as a monitoring tool during expeditions. Copyright © 2015 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.

  18. The low level of glucagon-like peptide-1 (glp-1) is a risk factor of type 2 diabetes mellitus.

    PubMed

    Lastya, Agus; Saraswati, Made Ratna; Suastika, Ketut

    2014-11-26

    Glucagon like peptide-1 (GLP-1), an incretin hormone, regulates glucose metabolism by inducing insulin secretion and suppressing glucagon secretion. The aim of the study is to assess the levels of fasting and post-prandial GLP-1 and their risk for T2DM. A case control study was conducted at the diabetes clinic Sanglah Hospital Denpasar Bali, involving 40 subjects who were native Indonesian citizens and 18-70 years of age. Twenty subjects were allocated as the case group (subjects with T2DM) and 20 subjects were allocated as the control group (subjects with normal glucose tolerance [NGT]). Both fasting intact GLP-1 (FGLP-1) and 60 minutes post-75 gram glucose loading intact GLP-1 (1hGLP-1) levels were measured. Both fasting and post-prandial GLP-1 levels were significantly lower in subjects with T2DM than those with NGT (2.06 ± 0.43 vs. 2.87 ± 0.67 pg/L, p < 0.01; and 2.49 ± 0.60 vs. 3.42 ± 0.85 pg/L, p = 0.02; respectively). Low levels of FGLP-1 (OR, 13.5; p = 0.001) and 1hGLP-1 (OR, 5.667, p = 0.018), with no response after glucose loading (∆GLP-1), were a significant risk for T2DM. According to the ∆GLP-1, there was a tendency of decreasing response of GLP-1 after glucose loading among subjects with T2DM (∆ = 0.43 pg/L) compared to subjects with NGT (∆ = 0.55 pg/L). From this study it can be concluded that levels of intact GLP-1 are an important risk factor for T2DM in the Indonesian population.

  19. Dose-dependent changes in the levels of free and peptide forms of hydroxyproline in human plasma after collagen hydrolysate ingestion.

    PubMed

    Shigemura, Yasutaka; Kubomura, Daiki; Sato, Yoshio; Sato, Kenji

    2014-09-15

    The presence of hydroxyproline (Hyp)-containing peptides in human blood after collagen hydrolysate ingestion is believed to exert beneficial effects on human health. To estimate the effective beneficial dose of these peptides, we examined the relationship between ingested dose and food-derived Hyp levels in human plasma. Healthy volunteers (n=4) ingested 30.8, 153.8 and 384.6 mg per kg body weight of collagen hydrolysate. The average plasma concentration of Hyp-containing peptides was dose-dependent, reaching maximum levels of 6.43, 20.17 and 32.84 nmol/ml following ingestion of 30.8, 153.8 and 384.6-mg doses of collagen hydrolysate, respectively. Ingesting over 153.8 mg of collagen hydrolysate significantly increased the average concentrations of the free and peptide forms of Hyp in plasma. The Hyp absorption limit was not reached with ingestion of as much as 384.6 mg of collagen hydrolysate. These finding suggest that ingestion of less than 30.8 mg of collagen hydrolysate is not effective for health benefits. Copyright © 2014 Elsevier Ltd. All rights reserved.

  20. Effects of exercise on gut peptides, energy intake and appetite.

    PubMed

    Martins, Catia; Morgan, Linda M; Bloom, Stephen R; Robertson, M Denise

    2007-05-01

    This study investigated the acute effects of exercise on the postprandial levels of appetite-related hormones and metabolites, energy intake (EI) and subjective measures of appetite. Ghrelin, polypeptide YY (PYY), glucagon-like peptide-1 (GLP-1) and pancreatic polypeptide (PP) were measured in the fasting state and postprandially in 12 healthy, normal-weight volunteers (six males and six females) using a randomised crossover design. One hour after a standardised breakfast, subjects either cycled for 60 min at 65% of their maximal heart rate or rested. Subjective appetite was assessed throughout the study using visual analogue scales and subsequent EI at a buffet meal was measured at the end (3-h post-breakfast and 1-h post-exercise). Exercise significantly increased mean PYY, GLP-1 and PP levels, and this effect was maintained during the post-exercise period for GLP-1 and PP. No significant effect of exercise was observed on postprandial levels of ghrelin. During the exercise period, hunger scores were significantly decreased; however, this effect disappeared in the post-exercise period. Exercise significantly increased subsequent absolute EI, but produced a significant decrease in relative EI after accounting for the energy expended during exercise. Hunger scores and PYY, GLP-1 and PP levels showed an inverse temporal pattern during the 1-h exercise/control intervention. In conclusion, acute exercise, of moderate intensity, temporarily decreased hunger sensations and was able to produce a short-term negative energy balance. This impact on appetite and subsequent energy homeostasis was not explained by changes in postprandial levels of ghrelin; however, 'exercise-induced anorexia' may potentially be linked to increased PYY, GLP-1 and PP levels.

  1. Fasting C-peptide levels and death resulting from all causes and breast cancer: the health, eating, activity, and lifestyle study.

    PubMed

    Irwin, Melinda L; Duggan, Catherine; Wang, Ching-Yun; Smith, Ashley Wilder; McTiernan, Anne; Baumgartner, Richard N; Baumgartner, Kathy B; Bernstein, Leslie; Ballard-Barbash, Rachel

    2011-01-01

    To examine the association between serum C-peptide, a marker of insulin secretion, measured 3 years after a breast cancer diagnosis, and death resulting from all causes and breast cancer. This was a prospective, observational study of 604 women enrolled onto the Health, Eating, Activity, and Lifestyle (HEAL) Study who were diagnosed with local or regional breast cancer between 1995 and 1998 and observed until death or December 31, 2006, whichever came first. The hazard ratio (HR) for all deaths and deaths owing to breast cancer and 95% CIs for the HR were estimated using multivariable stratified Cox regression analyses. Among women without type 2 diabetes, fasting C-peptide levels were associated with an increased risk of death resulting from all causes and from breast cancer. A 1-ng/mL increase in C-peptide was associated with a 31% increased risk of any death (HR = 1.31; 95% CI, 1.06 to 1.63; P = .013) and a 35% increased risk of death as a result of breast cancer (HR = 1.35; 95% CI, 1.02 to 1.87, P = .048). Associations between C-peptide levels and death as a result of breast cancer were stronger in certain subgroups, including women with type 2 diabetes, women with a body mass index less than 25 kg/m(2), women diagnosed with a higher stage of disease, and women whose tumors were estrogen receptor positive. Treatment strategies to reduce C-peptide levels in patients with breast cancer, including dietary-induced weight loss, physical activity, and/or use of insulin-lowering medications, should be explored.

  2. Elevated levels of calcitonin gene-related peptide in upper spinal cord promotes sensitization of primary trigeminal nociceptive neurons.

    PubMed

    Cornelison, Lauren E; Hawkins, Jordan L; Durham, Paul L

    2016-12-17

    Orofacial pain conditions including temporomandibular disorder (TMD) and migraine are characterized by peripheral and central sensitization of trigeminal nociceptive neurons. The goal of this study was to investigate the role of calcitonin gene-related peptide (CGRP) in promoting bidirectional signaling within the trigeminal system to mediate sensitization of primary nociceptive neurons. Adult male Sprague-Dawley rats were injected intercisternally with CGRP or co-injected with the receptor antagonist CGRP8-37 or KT 5720, a protein kinase A (PKA) inhibitor. Nocifensive head withdrawal response to mechanical stimulation was investigated using von Frey filaments. Expression of PKA, glial fibrillary acidic protein (GFAP), and ionized calcium-binding adapter molecule 1 (Iba1) in the spinal cord and phosphorylated extracellular signal-regulated kinase (P-ERK) in the ganglion was studied using immunohistochemistry. Some animals were co-injected with CGRP and Fast Blue dye and the ganglion was imaged using fluorescent microscopy. CGRP increased nocifensive responses to mechanical stimulation when compared to control. Co-injection of CGRP8-37 or KT 5720 with CGRP inhibited the nocifensive response. CGRP stimulated PKA and GFAP expression in the spinal cord, and P-ERK in ganglion neurons. Seven days post injection, Fast Blue was observed in ganglion neurons and satellite glial cells. Our results demonstrate that elevated levels of CGRP in the upper spinal cord promote sensitization of primary nociceptive neurons via a mechanism that involves activation of PKA centrally and P-ERK in ganglion neurons. Our findings provide evidence of bidirectional signaling within the trigeminal system that facilitate increased neuron-glia communication within the ganglion associated with trigeminal sensitization.

  3. Liraglutide promotes natriuresis but does not increase circulating levels of atrial natriuretic peptide in hypertensive subjects with type 2 diabetes.

    PubMed

    Lovshin, Julie A; Barnie, Annette; DeAlmeida, Ariana; Logan, Alexander; Zinman, Bernard; Drucker, Daniel J

    2015-01-01

    GLP-1 receptor (GLP-1R) agonists induce natriuresis and reduce blood pressure (BP) through incompletely understood mechanisms. We examined the effects of acute and 21-day administration of liraglutide on plasma atrial natriuretic peptide (ANP), urinary sodium excretion, office and 24-h BP, and heart rate (HR). Liraglutide or placebo was administered for 3 weeks to hypertensive subjects with type 2 diabetes in a double-blinded, randomized, placebo-controlled crossover clinical trial in the ambulatory setting. End points included within-subject change from baseline in plasma ANP, Nt-proBNP, office BP, and HR at baseline and over 4 h following a single dose of liraglutide (0.6 mg) and after 21 days of liraglutide (titrated to 1.8 mg) versus placebo administration. Simultaneous 24-h ambulatory BP and HR monitoring and 24-h urine collections were measured at baseline and following 21 days of treatment. Plasma ANP levels did not change significantly after acute (+16.72 pg/mL, P = 0.24, 95% CI [-12.1, +45.5] at 2 h) or chronic (-17.42 pg/mL, 95% CI [-36.0, +1.21] at 2 h) liraglutide administration. Liraglutide significantly increased 24-h and nighttime urinary sodium excretion; however, 24-h systolic BP was not significantly different. Small but significant increases in 24-h and nighttime diastolic BP and HR were observed with liraglutide. Body weight, HbA1c, and cholesterol were lower, and office-measured HR was transiently increased (for up to 4 h) with liraglutide administration. Sustained liraglutide administration for 3 weeks increases urinary sodium excretion independent of changes in ANP or BP in overweight and obese hypertensive patients with type 2 diabetes. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

  4. A peptide identification-free, genome sequence-independent shotgun proteomics workflow for strain-level bacterial differentiation

    PubMed Central

    Shao, Wenguang; Zhang, Min; Lam, Henry; Lau, Stanley C. K.

    2015-01-01

    Shotgun proteomics is an emerging tool for bacterial identification and differentiation. However, the identification of the mass spectra of peptides to genome-derived peptide sequences remains a key issue that limits the use of shotgun proteomics to bacteria with genome sequences available. In this proof-of-concept study, we report a novel bacterial fingerprinting method that enjoys the resolving power and accuracy of mass spectrometry without the burden of peptide identification (i.e. genome sequence-independent). This method uses a similarity-clustering algorithm to search for mass spectra that are derived from the same peptide and merge them into a unique consensus spectrum as the basis to generate proteomic fingerprints of bacterial isolates. In comparison to a traditional peptide identification-based shotgun proteomics workflow and a PCR-based DNA fingerprinting method targeting the repetitive extragenic palindromes elements in bacterial genomes, the novel method generated fingerprints that were richer in information and more discriminative in differentiating E. coli isolates by their animal sources. The novel method is readily deployable to any cultivable bacteria, and may be used for several fields of study such as environmental microbiology, applied microbiology, and clinical microbiology. PMID:26395646

  5. Physiological levels of A-, B- and C-type natriuretic peptide shed the endothelial glycocalyx and enhance vascular permeability.

    PubMed

    Jacob, Matthias; Saller, Thomas; Chappell, Daniel; Rehm, Markus; Welsch, Ulrich; Becker, Bernhard F

    2013-05-01

    Atrial natriuretic peptide (ANP) is a peptide hormone released from the cardiac atria during hypervolemia. Though named for its well-known renal effect, ANP has been demonstrated to acutely increase vascular permeability in vivo. Experimentally, this phenomenon was associated with a marked shedding of the endothelial glycocalyx, at least for supraphysiological intravascular concentrations. This study investigates the impact and mechanism of action of physiological doses of ANP and related peptides on the vascular barrier. In isolated guinea pig hearts, prepared and perfused in a modified Langendorff mode with and without the intravascular presence of the colloid hydroxyethyl starch (HES), we measured functional changes in vascular permeability and glycocalyx shedding related to intracoronary infusion of physiological concentrations of A-, B- and C-type natriuretic peptide (ANP, BNP and CNP). Significant coronary venous washout of glycocalyx constituents (syndecan-1 and heparan sulfate) was observed. As tested for ANP, this effect was positively related to the intracoronary concentration. Intravascular shedding of the glycocalyx was morphologically confirmed by electron microscopy. Also, functional vascular barrier competence decreased, as indicated by significant increases in transudate formation and HES extravasation. Ortho-phenanthroline, a non-specific inhibitor of matrix metalloproteases, was able to reduce ANP-induced glycocalyx shedding. These findings suggest participation of natriuretic peptides in pathophysiological processes like heart failure, inflammation or sepsis. Inhibition of metalloproteases might serve as a basis for future therapeutical options.

  6. A peptide identification-free, genome sequence-independent shotgun proteomics workflow for strain-level bacterial differentiation.

    PubMed

    Shao, Wenguang; Zhang, Min; Lam, Henry; Lau, Stanley C K

    2015-09-23

    Shotgun proteomics is an emerging tool for bacterial identification and differentiation. However, the identification of the mass spectra of peptides to genome-derived peptide sequences remains a key issue that limits the use of shotgun proteomics to bacteria with genome sequences available. In this proof-of-concept study, we report a novel bacterial fingerprinting method that enjoys the resolving power and accuracy of mass spectrometry without the burden of peptide identification (i.e. genome sequence-independent). This method uses a similarity-clustering algorithm to search for mass spectra that are derived from the same peptide and merge them into a unique consensus spectrum as the basis to generate proteomic fingerprints of bacterial isolates. In comparison to a traditional peptide identification-based shotgun proteomics workflow and a PCR-based DNA fingerprinting method targeting the repetitive extragenic palindromes elements in bacterial genomes, the novel method generated fingerprints that were richer in information and more discriminative in differentiating E. coli isolates by their animal sources. The novel method is readily deployable to any cultivable bacteria, and may be used for several fields of study such as environmental microbiology, applied microbiology, and clinical microbiology.

  7. Investigating AP-2 and YY1 protein expression as a cause of high HER2 gene transcription in breast cancers with discordant HER2 gene amplification

    PubMed Central

    2009-01-01

    Introduction Candidacy for anti-HER2 adjuvant therapy in breast cancer is assessed using tumour HER2 status but recently it has been proposed that the transcription factors AP-2α and YY1 may cause Her2 protein overexpression independently of gene amplification. Methods We characterised AP-2α/β, AP-2α and YY1 with HER2 gene and protein expression, other relevant biomarkers, and clinical outcome using tissue microarrays (TMAs) and immunohistochemistry in a large (n = 1,176) clinically annotated series of early stage operable breast cancer. The associations and prognostic independence of AP-2 and YY1 was assessed in all patients and an oestrogen receptor negative subgroup. Results Nuclear expression of AP-2α/β, AP-2α and YY1 was detected in 23%, 44% and 33% of cases respectively. AP-2α/β significantly correlated with YY1 and both markers were increased in luminal oestrogen receptor (ER) positive tumours of small size and low grade but only AP-2α/β correlated with good prognosis breast cancer specific survival and disease free interval (BCSS and DFI). These characteristics were lost in oestrogen receptor negative patients. AP-2α also correlated with luminal-type tumours but not with YY1 expression or good prognosis. AP-2α and YY1 showed a significant correlation with Her2 protein expression and in addition, YY1 correlated with HER2 gene expression. Discordant HER2 gene and protein expression was identified in six cases (0.71% of the study group) with four of these showing AP-2α but absence of AP-2α/β and YY1 expression. Conclusions AP-2α/β and YY1 are markers of good prognosis principally due to their association with oestrogen receptor but are not independent predictors. Discordant HER2 protein/gene expression is a rare event that is not always explained by the actions of AP-2 and YY1. PMID:20025767

  8. Reciprocal localization of transcription factors YY1 and CP2c in spermatogonial stem cells and their putative roles during spermatogenesis.

    PubMed

    Kim, Ji Sook; Chae, Ji Hyung; Cheon, Yong-Pil; Kim, Chul Geun

    2016-09-01

    Maintaining stemness and permitting differentiation mediated by combinations of transcription factors (TFs) are key aspects of mammalian spermatogenesis. It has been established that yin yang 1 (YY1), a target factor of mammalian polycomb repressive complex 2 (PRC2) and a regulator of stemness, is involved in the stable maintenance of prophase stage spermatocytes. Recently, we have demonstrated that the TF CP2c partners with YY1 in some cells to antagonistically regulate the other protein's function. To date, the functional roles of YY1 and CP2c in spermatogonial stem cells and their derived germ cells remain unclear. Here, we investigated the expression of YY1 and CP2c in mouse gonocytes and germ cells using tissue immunohistochemical and immunofluorescence analyses. At E14.5, both YY1 and CP2c were stained in gonocytes and Sertoli cells in testicular cords, showing different proportion and density of immunoreactivity. However, in adult testes, YY1 was localized in the nuclei of spermatogonial stem cells and spermatocytes, but not in spermatozoa. It was also detected in spermatogonia and spermatids in a stage-specific manner during spermatogenic cycle. CP2c could be detected mostly in the cytoplasm of spermatocytes but not at all in spermatogonial stem cells, indicating mutually exclusive expression of CP2c and YY1. Interestingly, however, CP2c was stained in the cytoplasm and nucleus of spermatogonia at elongation and release stages, and co-localized with YY1 in the nucleus at grouping, maturation, and releasing stages. Neither YY1 nor CP2c was expressed in spermatozoa. Our data indicate that YY1 strongly localizes in the spermatogonial stem cells and co-localizes heterogeneously with CP2c to permit spermatogenesis, and also suggest that YY1 is essential for stemness of spermatogonial stem cells (SCs) whereas CP2c is critical for the commitment of spermatogonia and during the progression of spermatogonia to spermatids. This evaluation expands our understanding of

  9. Airway lipoxin A4/formyl peptide receptor 2-lipoxin receptor levels in pediatric patients with severe asthma.

    PubMed

    Gagliardo, Rosalia; Gras, Delphine; La Grutta, Stefania; Chanez, Pascal; Di Sano, Caterina; Albano, Giusy D; Vachier, Isabelle; Montalbano, Angela M; Anzalone, Giulia; Bonanno, Anna; Riccobono, Loredana; Gjomarkaj, Mark; Profita, Mirella

    2016-06-01

    Lipoxins are biologically active eicosanoids with anti-inflammatory properties. Lipoxin A4 (LXA4) signaling blocks asthmatic responses in human and experimental model systems. There is evidence that patients with respiratory diseases, including severe asthma (SA), display defective generation of lipoxin signals despite glucocorticoid therapy. We investigated airway levels of formyl peptide receptor 2-lipoxin receptor (FPR2/ALXR), LXA4, and its counterregulatory compound, leukotriene B4 (LTB4), in patients with childhood asthma. We addressed the potential interplay of the LXA4-FPR2/ALXR axis and glucocorticoids in the resolution of inflammation. We examined LXA4 and LTB4 concentrations in induced sputum supernatants from children with intermittent asthma (IA), children with SA, and healthy control (HC) children. In addition, we investigated FPR2/ALXR expression in induced sputum cells obtained from the study groups. Finally, we evaluated in vitro the molecular interaction between LXA4 and glucocorticoid receptor-based mechanisms. We found that children with SA have decreased LXA4 concentrations in induced sputum supernatants in comparison with children with IA. In contrast to decreases in LXA4 concentrations, LTB4 concentrations were increased in children with asthma independent of severity. LXA4 concentrations negatively correlated with LTB4 concentrations and with exacerbation numbers in children with SA. FPR2/ALXR expression was reduced in induced sputum cells of children with SA compared with that seen in HC subjects and children with IA. Finally, we describe in vitro the existence of crosstalk between LXA4 and glucocorticoid receptor at the cytosolic level mediated by G protein-coupled FPR2/ALXR in peripheral blood granulocytes isolated from HC subjects, children with IA, and children with SA. Our findings provide evidence for defective LXA4 generation and FPR2/ALXR expression that, associated with increased LTB4, might be involved in a reduction in the

  10. Cilostazol Upregulates Autophagy via SIRT1 Activation: Reducing Amyloid-β Peptide and APP-CTFβ Levels in Neuronal Cells

    PubMed Central

    Lee, Hye Rin; Shin, Hwa Kyoung; Park, So Youn; Kim, Hye Young; Bae, Sun Sik; Lee, Won Suk; Rhim, Byung Yong; Hong, Ki Whan; Kim, Chi Dae

    2015-01-01

    Autophagy is a vital pathway for the removal of β-amyloid peptide (Aβ) and the aggregated proteins that cause Alzheimer’s disease (AD). We previously found that cilostazol induced SIRT1 expression and its activity in neuronal cells, and thus, we hypothesized that cilostazol might stimulate clearances of Aβ and C-terminal APP fragment β subunit (APP-CTFβ) by up-regulating autophagy.When N2a cells were exposed to soluble Aβ1–42, protein levels of beclin-1, autophagy-related protein5 (Atg5), and SIRT1 decreased significantly. Pretreatment with cilostazol (10–30 μM) or resveratrol (20 μM) prevented these Aβ1–42 evoked suppressions. LC3-II (a marker of mammalian autophagy) levels were significantly increased by cilostazol, and this increase was reduced by 3-methyladenine. To evoke endogenous Aβ overproduction, N2aSwe cells (N2a cells stably expressing human APP containing the Swedish mutation) were cultured in medium with or without tetracycline (Tet+ for 48 h and then placed in Tet- condition). Aβ and APP-CTFβ expressions were increased after 12~24 h in Tet- condition, and these increased expressions were significantly reduced by pretreating cilostazol. Cilostazol-induced reductions in the expressions of Aβ and APP-CTFβ were blocked by bafilomycin A1 (a blocker of autophagosome to lysosome fusion). After knockdown of the SIRT1 gene (to ~40% in SIRT1 protein), cilostazol failed to elevate the expressions of beclin-1, Atg5, and LC3-II, indicating that cilostazol increases these expressions by up-regulating SIRT1. Further, decreased cell viability induced by Aβ was prevented by cilostazol, and this inhibition was reversed by 3-methyladenine, indicating that the protective effect of cilostazol against Aβ induced neurotoxicity is, in part, ascribable to the induction of autophagy. In conclusion, cilostazol modulates autophagy by increasing the activation of SIRT1, and thereby enhances Aβ clearance and increases cell viability. PMID:26244661

  11. A ghrelin receptor (GHS-R1A) antagonist attenuates the rewarding properties of morphine and increases opioid peptide levels in reward areas in mice.

    PubMed

    Engel, Jörgen A; Nylander, Ingrid; Jerlhag, Elisabet

    2015-12-01

    Gut-brain hormones such as ghrelin have recently been suggested to have a role in reward regulation. Ghrelin was traditionally known to regulate food intake and body weight homoeostasis. In addition, recent work has pin-pointed that this peptide has a novel role in drug-induced reward, including morphine-induced increase in the extracellular levels of accumbal dopamine in rats. Herein the effect of the ghrelin receptor (GHS-R1A) antagonist, JMV2959, on morphine-induced activation of the mesolimbic dopamine system was investigated in mice. In addition, the effects of JMV2959 administration on opioid peptide levels in reward related areas were investigated. In the present series of experiment we showed that peripheral JMV2959 administration, at a dose with no effect per se, attenuates the ability of morphine to cause locomotor stimulation, increase the extracellular levels of accumbal dopamine and to condition a place preference in mice. JMV2959 administration significantly increased tissue levels of Met-enkephalin-Arg(6)Phe(7) in the ventral tegmental area, dynorphin B in hippocampus and Leu-enkephalin-Arg(6) in striatum. We therefore hypothesise that JMV2959 prevents morphine-induced reward via stimulation of delta receptor active peptides in striatum and ventral tegmental areas. In addition, hippocampal peptides that activate kappa receptor may be involved in JMV2959׳s ability to regulate memory formation of reward. Given that development of drug addiction depends, at least in part, of the effects of addictive drugs on the mesolimbic dopamine system the present data suggest that GHS-R1A antagonists deserve to be elucidated as novel treatment strategies of opioid addiction.

  12. [Reference the YY/T 0841-2011 standard to improve preventive maintenance of medical electrical equipment and experience].

    PubMed

    Liu, Xiang; Ge, Bin; Liu, Jinchu

    2014-09-01

    In this paper, we interpret the new YY/T 0841-2011 standard and contrast the difference between it and GB9706.1-2007 standard. Then, we improved the current preventive maintenance work. After the improvement, we not only have more effective detection of the electrical safety performance of all kinds of medical electrical equipment, but also reduce the workload of clinical engineers, improve efficiency, and reduce the risk of electrical shock.

  13. Cholecystokinin-Induced Gallbladder Emptying and Metformin Elicit Additive Glucagon-Like Peptide-1 Responses.

    PubMed

    Rohde, Ulrich; Sonne, David Peick; Christensen, Mikkel; Hansen, Morten; Brønden, Andreas; Toräng, Signe; Rehfeld, Jens Frederik; Holst, Jens Juul; Vilsbøll, Tina; Knop, Filip Krag

    2016-05-01

    Bile acids have been suggested to mediate glucagon-like peptide-1 (GLP-1) secretion. Metformin, too, has been shown to increase GLP-1 levels. The effect of gallbladder emptying, metformin, or a combination has, however, never been studied. We hypothesized that cholecystokinin (CCK)-8-induced gallbladder emptying stimulates human GLP-1 secretion and that metformin would potentiate this effect. A double-blinded, randomized study. The study was conducted at a specialized research unit. Ten healthy male subjects with no family history of diabetes (age, 22 [range, 20-32] years; body mass index, 21.7 [19.3-24.2] kg/m(2); fasting plasma glucose, 4.9 [4.7-5.3] mm; and glycosylated hemoglobin A1c, 5.1 [4.4-5.8] %). On 4 separate days, the subjects received metformin or placebo and a concomitant 60-minute intravenous infusion of saline or CCK. Blood was sampled for 4 hours, and gallbladder volume was measured by ultrasound. Plasma levels of GLP-1. CCK-induced gallbladder emptying and metformin alone (no observed effect on gallbladder emptying) both elicited significant and additive GLP-1 responses. Metformin alone or combined with gallbladder emptying elicited a significant peptide YY response. CCK-induced gallbladder emptying resulted in a short-lasting glucose-dependent insulinotropic polypeptide response independent of metformin. No effects were seen on plasma glucose, insulin, C-peptide, or gastrin. CCK-induced gallbladder emptying in healthy subjects elicits significant GLP-1 secretion, which can be potentiated by metformin.

  14. Evolutionary Conserved Motif Finder (ECMFinder) for genome-wide identification of clustered YY1- and CTCF-binding sites

    PubMed Central

    Kang, Keunsoo; Chung, Jae Hoon; Kim, Joomyeong

    2009-01-01

    We have developed a new bioinformatics approach called ECMFinder (Evolutionary Conserved Motif Finder). This program searches for a given DNA motif within the entire genome of one species and uses the gene association information of a potential transcription factor-binding site (TFBS) to screen the homologous regions of a second and third species. If multiple species have this potential TFBS in homologous positions, this program recognizes the identified TFBS as an evolutionary conserved motif (ECM). This program outputs a list of ECMs, which can be uploaded as a Custom Track in the UCSC genome browser and can be visualized along with other available data. The feasibility of this approach was tested by searching the genomes of three mammals (human, mouse and cow) with the DNA-binding motifs of YY1 and CTCF. This program successfully identified many clustered YY1- and CTCF-binding sites that are conserved among these species but were previously undetected. In particular, this program identified CTCF-binding sites that are located close to the Dlk1, Magel2 and Cdkn1c imprinted genes. Individual ChIP experiments confirmed the in vivo binding of the YY1 and CTCF proteins to most of these newly discovered binding sites, demonstrating the feasibility and usefulness of ECMFinder. PMID:19208640

  15. Placenta Peptide Can Protect Mitochondrial Dysfunction through Inhibiting ROS and TNF-α Generation, by Maintaining Mitochondrial Dynamic Network and by Increasing IL-6 Level during Chronic Fatigue

    PubMed Central

    Muluye, Rekik A.; Bian, Yuhong; Wang, Li; Alemu, Paulos N.; Cui, Huantian; Peng, Xiaofei; Li, Shanshan

    2016-01-01

    Background: Level of fatigue is related to the metabolic energy available to tissues and cells, mainly through mitochondrial respiration, as well fatigue is the most common symptom of poorly functioning mitochondria. Hence, dysfunction of these organelles may be the cause of the fatigue seen in Chronic fatigue (CF). Placenta has been used for treatment of fatigue and various disease, moreover peptides has known protect mitochondrial viability, and alleviate fatigue. These properties of placenta and peptides may link with its effect on mitochondria; therefore, it is highly important to investigate the effectiveness of placenta peptide on fatigue and mitochondrial dysfunction. Methods: After administration of sheep placenta peptide (SPP) for 1 month, mice’s were forced to swim till exhaustion for 90 min to induce chronic fatigue. Electron microscopic examination of skeletal muscle mitochondrial structure, tissue Malondialdehyde (MDA), mitochondrial SOD and serum inflammatory cytokines level were investigated in order to determine the potential effect of SPP on mitochondria during CF. Rat skeletal muscle (L6 cell) were also treated with different concentration of SPP to determine the effect of SPP on cell viability using Thiazoyl blue tetrazolium assay. Results: Our finding revealed that forced swimming induced fatigue model can cause mitochondrial damage through Reactive oxygen species (ROS) mediated lipid peroxidation and Tumor Necrosis factor alpha (TNF-α) elevation. Whereas SPP protected fatigue induced mitochondrial dysfunction through preventing ROS and TNF-α generation, by maintaining mitochondrial dynamic network and by increasing serum IL-6 level. Conclusion: SPP can protect damage in mitochondrial components which will allow proper functioning of mitochondria that will in turn inhibit progression of chronic fatigue. Therefore, SPP may represent a novel therapeutic advantage for preventing mitochondrial dysfunction in patients with chronic fatigue. PMID

  16. Early effects of Roux-en-Y gastric bypass on peptides and hormones involved in the control of energy balance.

    PubMed

    Molin Netto, Bárbara Dal; Earthman, Carrie P; Cravo Bettini, Solange; Grotti Clemente, Ana Paula; Landi Masquio, Deborah Cristina; Farias, Gisele; Boritza, Katia; da Silva, Larissa Gabrielle; von der Heyde, Maria Emilia; Dâmaso, Ana Raimunda

    2016-09-01

    Body weight varies depending on the prevailing direction of environmental pressures; however, physiological factors also play a significant role in the control of body weight. The aim of the present study was to assess the impact of Roux-en-Y gastric bypass (RYGB) on hormones and peptides involved in the control of energy balance and their possible implications in appetite/satiety. The sample included 39 individuals with extreme obesity (37 women and two men) who underwent RYGB. Anthropometric and biochemical markers were collected before surgery and 6 months after RYGB. The BMI decreased from 44.3±6.4 to 31.7±5.7 kg/m (P<0.001) at the sixth month. Percentage of excess weight lost was 63.2±25.0%. Leptin and glucose levels decreased significantly 6 months after RYGB (P<0.001). Interestingly, a significant correlation was confirmed between the anorexigenic gut hormone peptide YY (PYY) and the central anorexigenic mediator α-melanocyte-stimulating hormone after 6 months of RYGB (r=0.35, P=0.004). In contrast, PYY concentrations were correlated negatively with BMI (r=-0.34, P=0.002). In the present investigation, it was found that there is a relationship between α-melanocyte-stimulating hormone and PYY concentrations, and it supports the role of the PYY to POMC signal in appetite regulation after RYGB.

  17. Two groups of phenylalanine biosynthetic operon leader peptides genes: a high level of apparently incidental frameshifting in decoding Escherichia coli pheL

    PubMed Central

    Gurvich, Olga L.; Näsvall, S. Joakim; Baranov, Pavel V.; Björk, Glenn R.; Atkins, John F.

    2011-01-01

    The bacterial pheL gene encodes the leader peptide for the phenylalanine biosynthetic operon. Translation of pheL mRNA controls transcription attenuation and, consequently, expression of the downstream pheA gene. Fifty-three unique pheL genes have been identified in sequenced genomes of the gamma subdivision. There are two groups of pheL genes, both of which are short and contain a run(s) of phenylalanine codons at an internal position. One group is somewhat diverse and features different termination and 5′-flanking codons. The other group, mostly restricted to Enterobacteria and including Escherichia coli pheL, has a conserved nucleotide sequence that ends with UUC_CCC_UGA. When these three codons in E. coli pheL mRNA are in the ribosomal E-, P- and A-sites, there is an unusually high level, 15%, of +1 ribosomal frameshifting due to features of the nascent peptide sequence that include the penultimate phenylalanine. This level increases to 60% with a natural, heterologous, nascent peptide stimulator. Nevertheless, studies with different tRNAPro mutants in Salmonella enterica suggest that frameshifting at the end of pheL does not influence expression of the downstream pheA. This finding of incidental, rather than utilized, frameshifting is cautionary for other studies of programmed frameshifting. PMID:21177642

  18. Candidate genes for Alzheimer’s disease are associated with individual differences in plasma levels of beta amyloid peptides in adults with Down syndrome

    PubMed Central

    Schupf, Nicole; Lee, Annie; Park, Naeun; Dang, Lam-Ha; Pang, Deborah; Yale, Alexander; Oh, David Kyung-Taek; Krinsky-McHale, Sharon J.; Jenkins, Edmund C.; Luchsinger, José A.; Zigman, Warren B.; Silverman, Wayne; Tycko, Benjamin; Kisselev, Sergey; Clark, Lorraine; Lee, Joseph H.

    2015-01-01

    We examined the contribution of candidate genes for Alzheimer’s disease (AD) on Chromosome 21 and other chromosomes to differences in Aβ peptide levels in a cohort of adults with DS, a population at high risk for AD. Participants were 254 non-demented adults with Down syndrome, 30–78 years of age. Genomic DNA was genotyped using an Illumina GoldenGate custom array. We used linear regression to examine differences in levels of Aβ peptides associated with the number of risk alleles, adjusting for age, sex, level of intellectual disability, race/ethnicity and the presence of the APOE ε4 allele. For Aβ42 levels, the strongest gene-wise association was found for a SNP on CAHLM1; for Aβ40 levels the strongest gene-wise associations were found for SNPs in IDE and SOD1, while the strongest gene-wise associations with levels of the Aβ42/Aβ40 ratio were found for SNPs in SORCS1. Broadly classified, variants in these genes may influence APP processing (CALHM1, IDE), vesicular trafficking (SORCS1), and response to oxidative stress (SOD1). PMID:26166206

  19. Plasmatic levels of N-terminal pro-atrial natriuretic peptide in preeclamptic patients and healthy normotensive pregnant women.

    PubMed

    Reyna-Villasmil, Eduardo; Mejia-Montilla, Jorly; Reyna-Villasmil, Nadia; Mayner-Tresol, Gabriel; Herrera-Moya, Pedro; Fernández-Ramírez, Andreina; Rondón-Tapía, Marta

    2017-08-31

    To compare plasma N-terminal pro-atrial natriuretic peptide concentrations in preeclamptic patients and healthy normotensive pregnant women. A cases-controls study was done with 180 patients at Hospital Central Dr. Urquinaona, Maracaibo, Venezuela, that included 90 preeclamptic patients (group A; cases) and 90 healthy normotensive pregnant women selected with the same age and body mass index similar to group A (group B; controls). Blood samples were collected one hour after admission and prior to administration of any medication in group A to determine plasma N-terminal pro-atrial natriuretic peptide and other laboratory parameters. Plasma N-terminal pro-atrial natriuretic peptide concentrations in group A (mean 1.01 [0.26] pg/mL) showed a significant difference when compared with patients in group B (mean 0.55 [0.07] pg/mL; P<.001]. There was no significant correlation with systolic and diastolic blood pressure values in preeclamptic patients (P=ns). A cut-off value of 0.66ng/mL had an area under the curve of 0.93, sensitivity of 87.8%, specificity of 83.3%, a positive predictive value of 84.0% and a negative predictive value of 87.2%, with a diagnostic accuracy of 85.6%. Preeclamptic patients have significantly higher concentrations of plasma N-terminal pro-atrial natriuretic peptide compared with healthy normotensive pregnant women, with high predictive values for diagnosis. Copyright © 2017 Elsevier España, S.L.U. All rights reserved.

  20. Inhibition of sympathetic vasoconstriction in pigs in vivo by the neuropeptide Y-Y1 receptor antagonist BIBP 3226.

    PubMed Central

    Lundberg, J. M.; Modin, A.

    1995-01-01

    nerve stimulation. Both BIBP 3435 and BIBP 3226 caused a slight transient decrease in mean arterial blood pressure (by about 5 and 15 mmHg at 1 mg kg-1 and 3 mg kg-1, respectively), accompanied by splenic and mesenteric vasodilatation, suggesting that this effect was unrelated to Y1 receptor blockade. 6. The peptide YY (PYY)- and NPY-evoked vasoconstriction in the kidney of reserpine-treated pigs was markedly reduced (by 95%) by BIBP 3226 while the vasoconstrictor effect in the spleen was attenuated by only 20%. BIBP 3226 did not influence stimulation-evoked NPY release. The vasoconstrictor response in reserpine-treated pigs to single impulse stimulation, which is observed only in nasal mucosa and hind limb, was unchanged regarding maximal amplitude and the integrated effect was only moderately reduced (by about 25%) in the presence of BIBP 3226 (1 mg kg-1). BIBP 3226 (1 mg kg-1) markedly reduced (by 55-70%) the long-lasting vascular response (total integrated blood flow reduction) evoked by sympathetic nerve stimulation at high frequency (40 impulses at 20 Hz) in spleen, kidney, nasal mucosa and hind limb. Furthermore, the maximal amplitude of the vasoconstriction was reduced mainly in the kidney (by 60%) and also in the spleen (by 40%). 7. It is concluded that BIBP 3226 can act as a selective Y1 receptor antagonist in the pig. Endogenous NPY via Y1 receptor activation may play a role in evoking the long-lasting vasoconstriction seen in nasal mucosa, hind limb and skin after high frequency stimulation of sympathetic nerves in control pigs. Furthermore, NPY via Y1 receptor mechanisms seems to be of major importance for the long-lasting component of the reserpine resistant sympathetic vasoconstriction in many vascular beds, and for the maximal vasoconstrictor response in the kidney. Circulating NPY and PYY induce splenic vasoconstriction via Y2-receptors in contrast to neuronally released NPY which mainly activates Y1 receptors. Images Figure 3 Figure 4 Figure 5 Figure 7

  1. Mice deficient in endothelin-converting enzyme-2 exhibit abnormal responses to morphine and altered peptide levels in the spinal cord.

    PubMed

    Miller, Lydia K; Hou, Xiaowen; Rodriguiz, Ramona M; Gagnidze, Khatuna; Sweedler, Jonathan V; Wetsel, William C; Devi, Lakshmi A

    2011-12-01

    An increasing body of evidence suggests that endothelin-converting enzyme-2 (ECE-2) is a non-classical neuropeptide processing enzyme. Similar to other neuropeptide processing enzymes, ECE-2 exhibits restricted neuroendocrine distribution, intracellular localization, and an acidic pH optimum. However, unlike classical neuropeptide processing enzymes, ECE-2 exhibits a non-classical cleavage site preference for aliphatic and aromatic residues. We previously reported that ECE-2 cleaves a number of neuropeptides at non-classical sites in vitro; however its role in peptide processing in vivo is poorly understood. Given the recognized roles of neuropeptides in pain and opiate responses, we hypothesized that ECE-2 knockout (KO) mice might show altered pain and morphine responses compared with wild-type mice. We find that ECE-2 KO mice show decreased response to a single injection of morphine in hot-plate and tail-flick tests. ECE-2 KO mice also show more rapid development of tolerance with prolonged morphine treatment and fewer signs of naloxone-precipitated withdrawal. Peptidomic analyses revealed changes in the levels of a number of spinal cord peptides in ECE-2 KO as compared to wild-type mice. Taken together, our findings suggest a role for ECE-2 in the non-classical processing of spinal cord peptides and morphine responses; however, the precise mechanisms through which ECE-2 influences morphine tolerance and withdrawal remain unclear. © 2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry.

  2. Mice deficient in Endothelin-Converting Enzyme-2 exhibit abnormal responses to morphine and altered peptide levels in the spinal cord

    PubMed Central

    Miller, L.K.; Hou, X.; Rodriguiz, R.M.; Gagnidze, K.; Sweedler, J. V.; Wetsel, W.C.; Devi, L.A.

    2011-01-01

    An increasing body of evidence suggests that Endothelin-converting enzyme-2 (ECE-2) is a non-classical neuropeptide processing enzyme. Similar to other neuropeptide processing enzymes, ECE-2 exhibits restricted neuroendocrine distribution, intracellular localization, and an acidic pH optimum. However, unlike classical neuropeptide processing enzymes, ECE-2 exhibits a non-classical cleavage site preference for aliphatic and aromatic residues. We previously reported that ECE-2 cleaves a number of neuropeptides at non-classical sites in vitro; however its role in peptide processing in vivo is poorly understood. Given the recognized roles of neuropeptides in pain and opiate responses, we hypothesized that ECE-2 knockout (KO) mice might show altered pain and morphine responses compared to wild-type (WT) mice. We find that ECE-2 KO mice show decreased response to a single injection of morphine in hot-plate and tail-flick tests. ECE-2 KO mice also show more rapid development of tolerance with prolonged morphine treatment and fewer signs of naloxone-precipitated withdrawal. Peptidomic analyses revealed changes in the levels of a number of spinal cord peptides in ECE-2 KO as compared to WT mice. Taken together, our findings suggest a role for ECE-2 in the non-classical processing of spinal cord peptides and morphine responses; however, the precise mechanisms through which ECE-2 influences morphine tolerance and withdrawal remain unclear. PMID:21972895

  3. Free Enthalpy Differences between α-, π-, and 310-Helices of an Atomic Level Fine-Grained Alanine Deca-Peptide Solvated in Supramolecular Coarse-Grained Water.

    PubMed

    Lin, Zhixiong; Riniker, Sereina; van Gunsteren, Wilfred F

    2013-03-12

    Atomistic molecular dynamics simulations of peptides or proteins in aqueous solution are still limited to the multi-nanosecond time scale and multi-nanometer range by computational cost. Combining atomic solutes with a supramolecular solvent model in hybrid fine-grained/coarse-grained (FG/CG) simulations allows atomic detail in the region of interest while being computationally more efficient. We used enveloping distribution sampling (EDS) to calculate the free enthalpy differences between different helical conformations, i.e., α-, π-, and 310-helices, of an atomic level FG alanine deca-peptide solvated in a supramolecular CG water solvent. The free enthalpy differences obtained show that by replacing the FG solvent by the CG solvent, the π-helix is destabilized with respect to the α-helix by about 2.5 kJ mol(-1), and the 310-helix is stabilized with respect to the α-helix by about 9 kJ mol(-1). In addition, the dynamics of the peptide becomes faster. By introducing a FG water layer of 0.8 nm around the peptide, both thermodynamic and dynamic properties are recovered, while the hybrid FG/CG simulations are still four times more efficient than the atomistic simulations, even when the cutoff radius for the nonbonded interactions is increased from 1.4 to 2.0 nm. Hence, the hybrid FG/CG model, which yields an appropriate balance between reduced accuracy and enhanced computational speed, is very suitable for molecular dynamics simulation investigations of biomolecules.

  4. Biliopancreatic diversion in rats is associated with intestinal hypertrophy and with increased GLP-1, GLP-2 and PYY levels.

    PubMed

    Borg, Cynthia M; le Roux, Carel W; Ghatei, Mohammad A; Bloom, Stephen R; Patel, Ameet G

    2007-09-01

    Factors leading to weight loss and weight stabilization after bariatric surgery are not fully understood. The aims of this study were to develop an animal model for biliopancreatic diversion (BPD) and to determine changes in gut hormones, malabsorption and small bowel histology postoperatively. 2 groups of Wistar rats underwent sham and BPD surgery. Daily postoperative weights and food intake were measured. 24-hour fecal collections were performed at Day 6 and 21. Bomb calorimetry was performed to determine the fecal calorific values. At day 23, levels of peptide YY (PYY), glucagon-like peptide 1 (GLP-1) and glucagon-like peptide 2 (GLP-2) were determined and small bowel biopsies were taken. Animals in the BPD group had significant reduction in weight (P<0.001) and in food intake (P<0.001) compared to the sham group. Serum levels of PYY, GLP-1 and GLP-2 in the BPD group were significantly higher (P<0.005). Animals in the BPD group had significantly higher fecal energy content at Day 6 (P<0.001) but not at Day 21 when compared to the sham group. Small bowel histology confirmed the presence of significantly increased mitosis (P=0.03) and labelled cells (P=0.002) in the BPD animals when compared to sham. In our animal model, the higher levels of PYY, GLP-1 and GLP-2 after BPD may be due to gut adaptation and hypertrophy and could be important in inducing and maintaining weight loss after bariatric surgery.

  5. Isotopologue Distributions of Peptide Product Ions by Tandem Mass Spectrometry: Quantitation of Low Levels of Deuterium Incorporation1

    PubMed Central

    Wang, Benlian; Sun, Gang; Anderson, David R.; Jia, Minghong; Previs, Stephen; Anderson, Vernon E.

    2007-01-01

    Protonated molecular peptide ions and their product ions generated by tandem mass spectrometry appear as isotopologue clusters due to the natural isotopic variations of carbon, hydrogen, nitrogen, oxygen and sulfur. Quantitation of the isotopic composition of peptides can be employed in experiments involving isotope effects, isotope exchange, isotopic labeling by chemical reactions, and studies of metabolism by stable isotope incorporation. Both ion trap and quadrupole-time of flight mass spectrometry are shown to be capable of determining the isotopic composition of peptide product ions obtained by tandem mass spectrometry with both precision and accuracy. Tandem mass spectra obtained in profile-mode of clusters of isotopologue ions are fit by non-linear least squares to a series of Gaussian peaks (described in the accompanying manuscript) which quantify the Mn/M0 values which define the isotopologue distribution (ID). To determine the isotopic composition of product ions from their ID, a new algorithm that predicts the Mn/M0 ratios is developed which obviates the need to determine the intensity of all of the ions of an ID. Consequently a precise and accurate determination of the isotopic composition a product ion may be obtained from only the initial values of the ID, however the entire isotopologue cluster must be isolated prior to fragmentation. Following optimization of the molecular ion isolation width, fragmentation energy and detector sensitivity, the presence of isotopic excess (2H, 13C, 15N, 18O) is readily determined within 1%. The ability to determine the isotopic composition of sequential product ions permits the isotopic composition of individual amino acid residues in the precursor ion to be determined. PMID:17559791

  6. The natriuretic peptides.

    PubMed

    Baxter, Gary F

    2004-03-01

    The natriuretic peptides are a family of widely distributed, but evolutionarily conserved, polypeptide mediators that exert a range of actions throughout the body. In cardiovascular homeostasis, the endocrine roles of the cardiac-derived atrial and B-type natriuretic peptide (ANP and BNP) in regulating central fluid volume and blood pressure have been recognised for two decades. However, there is a growing realisation that natriuretic peptide actions go far beyond their volume regulating effects. These pleiotropic actions include local (autocrine/paracrine) regulatory actions of ANP and BNP within the heart, and of another natriuretic peptide, CNP, within the vessel wall. Effects on function and growth of the local tissue environment are likely to be of great importance, especially in disease states where tissue and circulating levels of ANP and BNP rise markedly. At present, the relevance of other natriuretic peptides (notably uroguanylin and DNP) to human physiology and pathology remain uncertain. Other articles in this issue of Basic Research in Cardiology review the molecular physiology of natriuretic peptide signalling, with a particular emphasis on the lessons from genetically targetted mice; the vascular activity of natriuretic peptides; the regulation and roles of natriuretic peptides in ischaemic myocardium; and the diagnostic, prognostic and therapeutic roles of natriuretic peptides in heart failure.

  7. Biochemical studies in Normal Pressure Hydrocephalus (NPH) patients: change in CSF levels of amyloid precursor protein (APP), amyloid-beta (Aβ) peptide and phospho-tau.

    PubMed

    Ray, Balmiki; Reyes, Patricio F; Lahiri, Debomoy K

    2011-04-01

    Normal Pressure Hydrocephalus (NPH) is one of the causes of dementia of the elderly characterized by impaired mental function, gait difficulties and urinary incontinence. Previously, it was proposed that some of the NPH patients may develop Alzheimer's disease (AD) like pathology. Aim of this study was to compare levels of different CSF biomarkers, including total secreted β-amyloid precursor protein (sAPP), sAPP-alpha form (sAPPα), amyloid-beta (Aβ) peptide, total-tau protein and hyperphosphorylated-tau protein in subjects from NPH and Non-NPH Control (NNC). CSF was collected from 23 NPH patients and 13 Non-NPH controls by lumber puncture. Western blot analysis was performed to measure levels of sAPP-total. ELISA was used separately to determine levels of sAPPα, Aβ peptide, total-tau and phospho-tau proteins. We found a significant decrease in levels of total secreted APP, sAPPα and Aβ (1-42) in the CSF sample of NPH patients vs. NNC. We did not observe any change in levels of total-tau or phospho-tau in NPH vs. NNC subjects. Notably, phospho-tau level was significantly increased in the NPH patients, who were suffering from the disease for more than one year, vs. NNC. Among five biomarkers studied, decreased sAPP, sAPPα and Aβ (1-42) levels in CSF can be molecular markers to distinguish NPH cases from NNC. Disease severity can also be assessed by increased levels of CSF phospho-tau protein and the ratio of phospho-tau to Aβ (1-42), which might be a useful tool for predicting conversion of NPH individuals to other neurodegenerative disorders including Alzheimer's disease (AD).

  8. 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.

  9. Mining for Nonribosomal Peptide Synthetase and Polyketide Synthase Genes Revealed a High Level of Diversity in the Sphagnum Bog Metagenome

    PubMed Central

    Müller, Christina A.; Oberauner-Wappis, Lisa; Peyman, Armin; Amos, Gregory C. A.; Wellington, Elizabeth M. H.

    2015-01-01

    Sphagnum bog ecosystems are among the oldest vegetation forms harboring a specific microbial community and are known to produce an exceptionally wide variety of bioactive substances. Although the Sphagnum metagenome shows a rich secondary metabolism, the genes have not yet been explored. To analyze nonribosomal peptide synthetases (NRPSs) and polyketide synthases (PKSs), the diversity of NRPS and PKS genes in Sphagnum-associated metagenomes was investigated by in silico data mining and sequence-based screening (PCR amplification of 9,500 fosmid clones). The in silico Illumina-based metagenomic approach resulted in the identification of 279 NRPSs and 346 PKSs, as well as 40 PKS-NRPS hybrid gene sequences. The occurrence of NRPS sequences was strongly dominated by the members of the Protebacteria phylum, especially by species of the Burkholderia genus, while PKS sequences were mainly affiliated with Actinobacteria. Thirteen novel NRPS-related sequences were identified by PCR amplification screening, displaying amino acid identities of 48% to 91% to annotated sequences of members of the phyla Proteobacteria, Actinobacteria, and Cyanobacteria. Some of the identified metagenomic clones showed the closest similarity to peptide synthases from Burkholderia or Lysobacter, which are emerging bacterial sources of as-yet-undescribed bioactive metabolites. This report highlights the role of the extreme natural ecosystems as a promising source for detection of secondary compounds and enzymes, serving as a source for biotechnological applications. PMID:26002894

  10. Mining for Nonribosomal Peptide Synthetase and Polyketide Synthase Genes Revealed a High Level of Diversity in the Sphagnum Bog Metagenome.

    PubMed

    Müller, Christina A; Oberauner-Wappis, Lisa; Peyman, Armin; Amos, Gregory C A; Wellington, Elizabeth M H; Berg, Gabriele

    2015-08-01

    Sphagnum bog ecosystems are among the oldest vegetation forms harboring a specific microbial community and are known to produce an exceptionally wide variety of bioactive substances. Although the Sphagnum metagenome shows a rich secondary metabolism, the genes have not yet been explored. To analyze nonribosomal peptide synthetases (NRPSs) and polyketide synthases (PKSs), the diversity of NRPS and PKS genes in Sphagnum-associated metagenomes was investigated by in silico data mining and sequence-based screening (PCR amplification of 9,500 fosmid clones). The in silico Illumina-based metagenomic approach resulted in the identification of 279 NRPSs and 346 PKSs, as well as 40 PKS-NRPS hybrid gene sequences. The occurrence of NRPS sequences was strongly dominated by the members of the Protebacteria phylum, especially by species of the Burkholderia genus, while PKS sequences were mainly affiliated with Actinobacteria. Thirteen novel NRPS-related sequences were identified by PCR amplification screening, displaying amino acid identities of 48% to 91% to annotated sequences of members of the phyla Proteobacteria, Actinobacteria, and Cyanobacteria. Some of the identified metagenomic clones showed the closest similarity to peptide synthases from Burkholderia or Lysobacter, which are emerging bacterial sources of as-yet-undescribed bioactive metabolites. This report highlights the role of the extreme natural ecosystems as a promising source for detection of secondary compounds and enzymes, serving as a source for biotechnological applications.

  11. Less increase of BNP and NT-proBNP levels in obese patient with decompensated heart failure: interpretation of natriuretic peptides in obesity.

    PubMed

    Kälsch, Hagen; Neumann, Till; Erbel, Raimund

    2009-03-20

    Plasma brain natriuretic peptide (BNP) is a useful adjunct to diagnose and monitor patient with heart failure, but there are comorbidities such as chronic kidney disease or chronic pulmonary disease, which influence the interpretation of BNP levels. We present a case of a young and very obese patient (body mass index [BMI] 72.6 kg/m(2)), who was presented with acute global heart decompensation. Echocardiography revealed a dilated left ventricle with an ejection fraction of 20% by global distributed heart with enlarged right heart caves. Computed tomography and X-ray demonstrated an extreme cardiomegaly with cardio-thoracic ratio of 0.71. Remarkably, laboratory measurements revealed only a slight elevated concentrations of brain natriuretic peptide (BNP) (443.2 pg/ml) and his inactive component NT-proBNP (1710 pg/ml). Despite maximized heart care clinical condition of the patient aggravated continuously so that the patient died after 6 days because of heart insufficiency. Obese patients (body mass index [BMI] >30 kg/m(2)) with any given severity of heart failure obviously express lower levels of BNP. Until now, the cause for this phenomenon is unclear. Therefore caution should be exercised in interpreting BNP levels in such patients.

  12. Analysis of Different Fragmentation Strategies on a Variety of Large Peptides: Implementation of a Low Level of Theory in Fragment-Based Methods Can Be a Crucial Factor.

    PubMed

    Saha, Arjun; Raghavachari, Krishnan

    2015-05-12

    We have investigated the performance of two classes of fragmentation methods developed in our group (Molecules-in-Molecules (MIM) and Many-Overlapping-Body (MOB) expansion), to reproduce the unfragmented MP2 energies on a test set composed of 10 small to large biomolecules. They have also been assessed to recover the relative energies of different motifs of the acetyl(ala)18NH2 system. Performance of different bond-cutting environments and the use of Hartree-Fock and different density functionals (as a low level of theory) in conjunction with the fragmentation strategies have been analyzed. Our investigation shows that while a low level of theory (for recovering long-range interactions) may not be necessary for small peptides, it provides a very effective strategy to accurately reproduce the total and relative energies of larger peptides such as the different motifs of the acetyl(ala)18NH2 system. Employing M06-2X as the low level of theory, the calculated mean total energy deviation (maximum deviation) in the total MP2 energies for the 10 molecules in the test set at MIM(d=3.5Å), MIM(η=9), and MOB(d=5Å) are 1.16 (2.31), 0.72 (1.87), and 0.43 (2.02) kcal/mol, respectively. The excellent performance suggests that such fragment-based methods should be of general use for the computation of accurate energies of large biomolecular systems.

  13. Gender differences in normal left ventricle of adult FVB/N mice due to variation in interleukins and natriuretic peptides expression levels.

    PubMed

    Haroon, Javeria; Foureaux, Giselle; Martins, Almir S; Ferreira, Anderson J; Reis, Adelina M; Javed, Qamar

    2015-01-01

    This study examined the sex differences for physical, morphological, histological, mRNA, and protein expression levels changes for interleukins and natriuretic peptides in left ventricle (LV) of two groups of adult FVB/N mice; males (WM) and females (WF). LV morphological, histological, reverse transcription and quantitative real-time PCR (RT-PCR), and immunohistochemical (IHC) alterations were determined in FVB/N mice at 34-35 weeks on gender basis. Confirming the gender dimorphism, FVB/N males (WM) illustrated a significant reduction in ANP and IL1-A levels as well as significantly increased body weight (BW (gm)), tibia length (TL (mm)), heart weight (HW (mg)), heart weight-to-body weight (HW/BW (mg/gm)) ratio, heart weight-to-tibia length (HW/TL (mg/mm)) ratio, left ventricle weight (LV (mg)), left ventricle-to-body weight (LV/BW (mg/gm)) ratio, and left ventricle-to-tibia length (LV/TL (mg/mm)) ratio, left ventricular (LV) cardiomyocyte diameter, high BNP, NPRA, IL-1B, and IL1R1 expression in comparison with FVB/N females (WF). Gender differences in relation to left ventricle (LV) may be due to differences in the interleukins and natriuretic peptides levels as an outcome of sex related hormones. Copyright © 2014 Elsevier Ltd. All rights reserved.

  14. 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

    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/m(2)) at 4-5 weeks postpartum and 20 never-pregnant controls (BMI = 24.0 ± 3.1 kg/m(2)). 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.

  15. 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

  16. Development of an isotope dilution assay for precise determination of insulin, C-peptide, and proinsulin levels in non-diabetic and type II diabetic individuals with comparison to immunoassay.

    PubMed

    Kippen, A D; Cerini, F; Vadas, L; Stöcklin, R; Vu, L; Offord, R E; Rose, K

    1997-05-09

    We describe the application of a stable isotope dilution assay (IDA) to determine precise insulin, C-peptide, and proinsulin levels in blood by extraction from serum and quantitation by mass spectrometry using analogues of each target protein labeled with stable isotopes. Insulin and C-peptide levels were also determined by immunoassay, which gave consistently higher results than by IDA, the relative difference being larger at low concentrations. Insulin, C-peptide, and proinsulin levels were all shown by IDA to be higher in type II diabetics than in non-diabetics, with mean values rising from 22 (+/- 2) to 92 (+/- 8), 335 (+/- 11) to 821 (+/- 24), and 6 (+/- 1) to 37 (+/- 3) pM, respectively. Interestingly, the ratio between IDA and immunoassay values for insulin levels increased from 1.3 in non-diabetics to 1.7 in type II diabetics. The ratio between proinsulin and insulin levels by IDA increased from 0.24 in non-diabetics to 0.36 in type II diabetics, whereas the ratio between C-peptide and insulin levels by IDA decreased from 17.6 to 10.7. This disproportionate change in protein levels between different types of individuals has implications for the metabolism of insulin in the diabetics studied (type II) and suggests that C-peptide levels are not always a reliable guide as to pancreatic insulin secretion. In addition, levels of the 33-residue C-peptide (partially trimmed form) were shown to be less than 10% that of the fully trimmed 31-residue C-peptide levels, and we tested IDA in a clinical context by two post-pancreatic graft studies. IDA was shown to give direct, positive identification of the target protein with unrivaled accuracy, avoiding many of the problems associated with present methodology for protein determination.

  17. High levels of anti-cyclic citrullinated peptide autoantibodies are associated with co-occurrence of pulmonary diseases with rheumatoid arthritis.

    PubMed

    Aubart, Fleur; Crestani, Bruno; Nicaise-Roland, Pascale; Tubach, Florence; Bollet, Caroline; Dawidowicz, Karen; Quintin, Emilie; Hayem, Gilles; Palazzo, Elisabeth; Meyer, Olivier; Chollet-Martin, Sylvie; Dieudé, Philippe

    2011-06-01

    To investigate whether levels of anti-cyclic citrullinated peptide antibodies (anti-CCP2) in patients with rheumatoid arthritis (RA) are associated with the co-occurrence of lung diseases. A total of 252 RA patients were included in a cross-sectional study. Pulmonary disease was confirmed by high-resolution chest computed tomography scan. Circulating anti-CCP2 were quantified using ELISA. Multivariate logistic regression was conducted to identify independent risk factors for lung disease. Male sex (OR 3.29, 95% CI 1.59-6.80) and high anti-CCP2 levels (OR 1.49, 95% CI 1.25-1.78) were identified as independent risk factors for lung disease in the RA population. High anti-CCP2 levels are associated with lung disease in the RA population.

  18. Cardiac tamponade as an independent condition affecting the relationship between the plasma B-type natriuretic peptide levels and cardiac function.

    PubMed

    Minai, Kosuke; Komukai, Kimiaki; Arase, Satoshi; Nagoshi, Tomohisa; Matsuo, Seiichiro; Ogawa, Kazuo; Kayama, Yosuke; Inada, Keiichi; Tanigawa, Shin-Ichi; Takemoto, Tomoyuki; Sekiyama, Hiroshi; Date, Taro; Ogawa, Takayuki; Taniguchi, Ikuo; Yoshimura, Michihiro

    2013-07-01

    Plasma B-type natriuretic peptide (BNP) is finely regulated by the cardiac function and several extracardiac factors. Therefore, the relationship between the plasma BNP levels and the severity of heart failure sometimes seems inconsistent. The purpose of the present study was to investigate the plasma BNP levels in patients with cardiac tamponade and their changes after pericardial drainage. This study included 14 patients with cardiac tamponade who underwent pericardiocentesis. The cardiac tamponade was due to malignant diseases in 13 patients and uremia in 1 patient. The plasma BNP levels were measured before and 24-48 h after drainage. Although the patients reported severe symptoms of heart failure, their plasma BNP levels were only 71.2 ± 11.1 pg/ml before drainage. After appropriate drainage, the plasma BNP levels increased to 186.0 ± 22.5 pg/ml, which was significantly higher than that before drainage (P = 0.0002). In patients with cardiac tamponade, the plasma BNP levels were low, probably because of impaired ventricular stretching, and the levels significantly increased in response to the primary condition after drainage. This study demonstrates an additional condition that affects the relationship between the plasma BNP levels and cardiac function. If inconsistency is seen in the relationship between the plasma BNP levels and clinical signs of heart failure, the presence of cardiac tamponade should therefore be considered.

  19. 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.

  20. Increased extracellular water measured by bioimpedance and by increased serum levels of atrial natriuretic peptide in RA patients-signs of volume overload.

    PubMed

    Straub, Rainer H; Ehrenstein, Boris; Günther, Florian; Rauch, Luise; Trendafilova, Nadezhda; Boschiero, Dario; Grifka, Joachim; Fleck, Martin

    2017-05-01

    The aim of the study is to investigate water compartments in patients with rheumatoid arthritis (RA). Acute inflammatory episodes such as infection stimulate water retention, chiefly implemented by the sympathetic nervous system (SNS) and hypothalamic-pituitary-adrenal (HPA) axis. This is an important compensatory mechanism due to expected water loss (sweating etc.). Since SNS and HPA axis are activated in RA, inflammation might be accompanied by water retention. Using bioimpedance analysis, body composition was investigated in 429 controls and 156 treatment-naïve RA patients between January 2008 and December 2014. A group of 34 RA patients was tested before and after 10 days of intensified therapy. Levels of pro-atrial natriuretic peptide (proANP) and expression of atrial natriuretic peptide in synovial tissue were investigated in 15 controls and 14 RA patients. Extracellular water was higher in RA patients than controls (mean ± SEM: 49.5 ± 0.3 vs. 36.7 ± 0.1, % of total body water, p < 0.0001). Plasma levels of proANP were higher in RA than controls. RA patients expressed ANP in synovial tissue, but synovial fluid levels and synovial tissue superfusate levels were much lower than plasma levels indicating systemic origin. Systolic/diastolic blood pressure was higher in RA patients than controls. Extracellular water levels did not change in RA patients despite 10 days of intensified treatment. This study demonstrates signs of intravascular overload in RA patients. Short-term intensification of anti-inflammatory therapy induced no change of a longer-lasting imprinting of water retention indicating the requirement of additional treatment. The study can direct attention to the area of volume overload.

  1. An important role for the activation peptide domain in controlling factor IX levels in the blood of haemophilia B mice.

    PubMed

    Begbie, Megan E; Mamdani, Asif; Gataiance, Sharon; Eltringham-Smith, Louise J; Bhakta, Varsha; Hortelano, Gonzalo; Sheffield, William P

    2005-12-01

    The factors responsible for the removal of injected factor IX (fIX) from the blood of individuals with haemophilia B are only partly understood, and may include binding to endothelial or subendothelial sites, passive extravasation related to size or charge, or interactions requiring fIX activation. To investigate these issues, we have produced and characterised recombinant fIX proteins with amino acid changes: delta155-177, an internal deletion which removes most of the activation peptide while retaining the activation cleavage sites; S365A, which inactivates the serine protease activity of fIXa; and K5A, previously shown to eliminate fIX binding of endothelial/subendothelial collagen IV. All proteins were expressed in stably transfected HEK 293 cells, purified by immunoaffinity chromatography, and compared to the wild type HEK 293-derived protein (fIX (WT)). Mutant fIX proteins K5A and delta155-177 exhibited 72 and 202% of the specific activity of fIX (WT), respectively; S365A was without activity. Following intravenous injection in haemophilia B (fIX knockout) mice, recoveries did not differ for fIX (WT) and delta155-177, but were higher for K5A and S365A. The terminal catabolic half-life of delta155-177, alone among the mutants, was increased, by 45% versus fIX (WT). Nine hours post-injection, the observed areas under the clearance curve (AUCs) of delta155-177 and K5, but not S365A, were elevated 2-fold. delta155-177 was equally effective as fIX (WT) in reducing blood loss following tail vein transection in haemophilia B mice. Our results suggest that deletion of the multiple sites of fIX post-translational modification found within the activation peptide eliminated important fIX clearance motifs.

  2. Low Levels of IgM Antibodies against an Advanced Glycation Endproduct-Modified Apolipoprotein B100 Peptide Predict Cardiovascular Events in Nondiabetic Subjects.

    PubMed

    Engelbertsen, Daniel; Vallejo, Jenifer; Quách, Tâm Dan; Fredrikson, Gunilla Nordin; Alm, Ragnar; Hedblad, Bo; Björkbacka, Harry; Rothstein, Thomas L; Nilsson, Jan; Bengtsson, Eva

    2015-10-01

    Increased glucose levels are associated with the generation of advanced glycation endproduct (AGE) modifications. Interaction between AGE-modified plaque components and immune cells is believed to have an important role in the development of vascular complications in diabetes. Methylglyoxal (MGO) is one type of reactive aldehyde that gives rise to AGE modification. The present study analyzed whether autoantibodies against MGO-modified epitopes of the low-density lipoprotein apolipoprotein B (apoB) 100 predict cardiovascular events. A library consisting of 302 peptides comprising the complete apoB100 molecule was screened to identify peptides targeted by MGO-specific autoantibodies. Peptide (p) 220 (apoB amino acids 3286-3305) was identified as a major target. Baseline IgM and IgG against MGO-peptide 220 (p220) were measured in 700 individuals from the Malmö Diet and Cancer Cohort. A total of 139 cardiovascular events were registered during the 15-y follow-up period. Controlling for major cardiovascular risk factors demonstrated that subjects in the lowest tertile of MGO-p220 IgM had an increased risk for cardiovascular events (hazard ratio [95% confidence interval]: 2.07 [1.22-3.50]; p(trend) = 0.004). Interestingly, the association between MGO-p220 IgM and cardiovascular events remained and even tended to become stronger when subjects with prevalent diabetes were excluded from the analysis (2.51 [1.37-4.61]; p(trend) = 0.002). MGO-p220 IgM was inversely associated with blood glucose, but not with oxidized low-density lipoprotein. Finally, we demonstrate that anti-MGO-p220 IgM is produced by B1 cells. These data show that subjects with low levels of IgM recognizing MGO-modified p220 in apoB have an increased risk to develop cardiovascular events and that this association is present in nondiabetic subjects.

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

    PubMed Central

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

    2016-01-01

    Aim: 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. Methods: 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. Results: 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. Conclusion: 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. PMID:26687936

  4. Intermedin in rat uterus: changes in gene expression and peptide levels across the estrous cycle and its effects on uterine contraction

    PubMed Central

    2013-01-01

    Background The present study demonstrates the expression of intermedin (IMD) and its receptor components in the uterus of the female rat during the estrous cycle and its effect on uterine contraction. Methods The gene expression level of intermedin and its receptor components and the peptide level of intermedin were studied by real-time RT-PCR and enzyme immunoassay (EIA) respectively. The separation of precursor and mature IMD was studied by gel filtration chromatography and EIA. The localization of IMD in the uterus was investigated by immunohistochemistry. The effect of IMD on in vitro uterine contraction was studied by organ bath technique. Results Uterine mRNAs of Imd and its receptor components and IMD levels displayed cyclic changes across the estrous cycle. Imd mRNA level was the highest at proestrus while the IMD level was the highest at diestrus. IMD was found in the luminal and glandular epithelia and IMD treatment significantly reduced the amplitude and frequency of uterine contraction but not the basal tone. Both calcitonin gene-related peptide (CGRP) receptor antagonist hCGRP8-37 and adrenomedullin (ADM) receptor antagonist hADM22-52 partially abolished the inhibitory effect of IMD on uterine contraction while the specific IMD receptor antagonist hIMD17-47 completely blocked the actions. The enzyme inhibitors of NO (L-NAME) and PI3K (Wortmannin) pathways diminished the IMD effects on uterine contraction while the cAMP/PKA blocker, KT5720, had no effect, indicating an involvement of NO and PI3K/Akt but not PKA. Conclusions IMD and the gene expression of its receptor components are differentially regulated in the uterus during the estrous cycle and IMD inhibits uterine contraction by decreasing the amplitude and frequency. PMID:23442365

  5. The presence of the peptides apelin, ghrelin and nesfatin-1 in the human breast milk, and the lowering of their levels in patients with gestational diabetes mellitus.

    PubMed

    Aydin, Suleyman

    2010-12-01

    Numerous bioactive peptides (such as ghrelins) have been identified in breast milk but there is no information concerning apelin and nesfatin-1. Therefore, present study was designated to explore whether breast milk contains apelin and nesfatin-1, to determine the concentrations and to compare these with serum levels. In addition, the concentrations of these peptides were compared in patients with gestational diabetes and normal lactating samples. Furthermore, this study explored the effectivity of various commercial diagnostic kits for determining ghrelin concentrations in breast milk. Ten gestational diabetic lactating women (29.1±2.2 years old and BMI: 33.2±4.8) and 10 control lactating women (28.2±1.8 years old and BMI: 39.48±1.7) were enrolled in the study. An ELISA was used to determine concentrations of apelin-36 and -12, nesfatin-1, and acylated and desacylated ghrelin in serum, colostrum and mature milk. Serum apelin-36 and -12 concentrations were correlated with colostrum and mature milk, and the same trends were observed for nesfatin-1. Apelins and nesfatin-1 concentrations were higher in mature milk than in colostrum (P<0.05). The concentration of apelins, ghrelins and nesfatin-1 in serum and milk in gestational diabetic lactating women was lower than in control samples. The majority of ghrelin circulating and in milk was the free form (desacylated) in both groups of women. This is the first report to describe the presence of apelins and nesfatin-1 in breast milk. It is suggested that the source of ghrelins, apelins and nesfatin-1 in breast milk is likely to be breast tissue (autonomous production). These bioactive peptides found in breast milk could be important for growth, energy regulation and maturation of the gastrointestinal system in neonates. Copyright © 2010 Elsevier Inc. All rights reserved.

  6. A new expression vector for high level protein production, one step purification and direct isotopic labeling of calmodulin-binding peptide fusion proteins.

    PubMed

    Zheng, C F; Simcox, T; Xu, L; Vaillancourt, P

    1997-02-20

    Calmodulin-binding peptide (CBP), a peptide of 26 amino acids derived from muscle myosin light chain kinase (MLCK), binds to calmodulin with nanomolar affinity. Proteins fused in frame with CBP can be purified from crude E. coli lysates in a single step using calmodulin affinity chromatography (Stofko-Hahn et al., 1992). Because the binding between CBP and calmodulin is calcium-dependent, the fusion protein can be eluted from the resin with virtually any buffer containing EGTA (2 mM) and used directly for many applications. To take full advantage of this affinity purification system, we constructed the versatile CBP fusion protein expression vector pCAL-n. The CBP coding sequence was positioned for fusion at the N-terminus, an advantage that ensures consistent high level synthesis of fusion proteins due to the efficient translation of the CBP in E. coli. The production of fusion proteins from pCAL-n is controlled by the tightly regulated T7(lac)O promoter. A versatile multiple cloning site (MCS) was included to facilitate the cloning of genes of interest. The protein coding sequence for the enzyme c-Jun N-terminal kinase (JNK) was inserted into the MCS of pCAL-n, and the resulting fusion protein CBP-JNK synthesized in E. coli cells at 15-20 mg/1 culture. CBP-JNK was purified to near homogeneity in one step with calmodulin affinity resin. Purified CBP-JNK is fully active, and the CBP peptide tag can be removed by cleavage with thrombin. We also show that CBP can be efficiently phosphorylated by cAMP-dependent protein kinase. Hence, the purified fusion proteins can be labeled directly with [gamma-32P]ATP and used to probe protein-protein or protein-nucleic acid interactions.

  7. The effect of bariatric surgery on gastrointestinal and pancreatic peptide hormones.

    PubMed

    Meek, Claire L; Lewis, Hannah B; Reimann, Frank; Gribble, Fiona M; Park, Adrian J

    2016-03-01

    Bariatric surgery for obesity has proved to be an extremely effective method of promoting long-term weight reduction with additional beneficial metabolic effects, such as improved glucose tolerance and remission of type 2 diabetes. A range of bariatric procedures are in common use, including gastric banding, sleeve gastrectomy and the Roux-en-Y gastric bypass. Although the mechanisms underlying the efficacy of bariatric surgery are unclear, gastrointestinal and pancreatic peptides are thought to play an important role. The aim of this review is to summarise the effects of different bariatric surgery procedures upon gastrointestinal and pancreatic peptides, including ghrelin, gastrin, cholecystokinin (CCK), glucose-dependent insulinotropic hormone (GIP), glucagon-like peptide 1 (GLP-1), peptide YY (PYY), oxyntomodulin, insulin, glucagon and somatostatin.

  8. Variation of plasma levels of endothelin, calcitonin gene-related peptide, nitric oxide, and malondialdehyde in acute myocardial ischemia reperfusion injury in a rabbit model.

    PubMed

    Zhao, Y B; Wang, Y Z; Yue, Y H; Zhao, W C; Feng, G X

    2015-05-25

    We examined the variation in plasma levels of endothelin (ET), calcitonin gene-related peptide (CGRP), nitric oxide (NO), and malondialdehyde (MDA), as well as superoxide dismutase (SOD) activity, in acute myocardial ischemia reperfusion injury in a rabbit model. Seventy rabbits were randomly assigned into 3 groups. Open-chest surgery (OCS) was performed for all rabbits. Group A (N = 20) received sham-surgery, group B (N = 25) was the reperfusion group, and group C (N = 25) was the infarction group. At 12 h after chest clo-sure, plasma ET levels in groups B and C were clearly increased, while CGRP levels were clearly decreased, particularly in group B. At 24 h after chest closure, ET levels were higher than before OCS, while there was no significant difference between groups B and C. ET in group B was decreased, while that in group C was increased at 12 h. No significant difference in CGRP was observed between 12 and 24 h after chest closure. NO levels in groups B and C at 12 h after chest closure were significantly decreased compared to those before OCS. NO levels in group B at 24, 48, and 72 h were significantly lower than those at 12 h, while those of group C were not significantly changed after 12 h. Dynamic monitoring and comparison of plasma levels of ET, CGRP, NO, and MDA as well as SOD activity revealed that appropriate intervention of these factors may reduce reperfusion injury.

  9. Calcitonin gene-related peptide elevates cyclic AMP levels in chick skeletal muscle: possible neurotrophic role for a coexisting neuronal messenger.

    PubMed Central

    Laufer, R; Changeux, J P

    1987-01-01

    Recent immunocytochemical studies have shown that calcitonin gene-related peptide (CGRP) coexists with the neurotransmitter acetylcholine in spinal motoneurons of the chick. Moreover, CGRP causes an increase in the number of acetylcholine receptors on the surface of cultured chick myotubes. CGRP might thus serve as one of the signals by which motoneurons regulate endplate development. In a search for the second messengers involved, we now demonstrate that CGRP stimulates accumulation of cyclic AMP (cAMP) in cultured chick myotubes. This effect is, at least in part, mediated by an increase in cAMP synthesis, as the peptide also activates adenylate cyclase in chick muscle membranes. Nanomolar concentrations of CGRP elicit significant increases in both cellular cAMP levels and acetylcholine receptor numbers. The present findings suggest that cAMP is one of the second messengers which mediate the increase in acetylcholine receptor number elicited by CGRP. Furthermore, CGRP might be implicated in other trophic actions mediated by cAMP in skeletal muscle cells. PMID:3036493

  10. High-level secretion and very efficient isotopic labeling of tick anticoagulant peptide (TAP) expressed in the methylotrophic yeast, Pichia pastoris.

    PubMed

    Laroche, Y; Storme, V; De Meutter, J; Messens, J; Lauwereys, M

    1994-11-01

    Tick anticoagulant peptide (TAP) is a potent and specific inhibitor of the blood coagulation protease Factor Xa. We designed and assembled a synthetic TAP-encoding gene (tapo) based on codons preferentially observed in the highly expressed Pichia pastoris alcohol oxidase 1 gene (AOX1), and fused it to a novel hybrid secretory prepro leader sequence. Expression from this gene yielded biologically active rTAP, which was correctly processed at the amino-terminal fusion site, and accumulated in the medium to approximately 1.7 g/l. This corresponds to a molar concentration of 0.24 mM, and is the highest yet described for a recombinant product secreted from P. pastoris. It also represents a seven-fold improvement in productivity compared to rTAP secretion from Saccharomyces cerevisiae, making P. pastoris an attractive host for the industrial-scale production of this potential therapeutic agent. This system was also used to prepare 21 mg 15N-rTAP, 11 mg 13C-rTAP and 27 mg 15N/13C-rTAP, with isotope incorporation levels higher than 98%, and purities sufficient to allow their use in determining the solution structure of the tick anticoagulant peptide using high field NMR.

  11. Plasma brain natriuretic peptide and troponin levels in severe sepsis and septic shock: relationships with systolic myocardial dysfunction and intensive care unit mortality.

    PubMed

    Klouche, Kada; Pommet, Stephane; Amigues, Laurent; Bargnoux, Anne Sophie; Dupuy, Anne Marie; Machado, Sonia; Serveaux-Delous, Marianne; Morena, Marion; Jonquet, Olivier; Cristol, Jean Paul

    2014-01-01

    The aim of this study was to evaluate and compare brain natriuretic peptide (BNP) and cardiac troponin I (cTnI) levels as mortality prognosticator and predictor for myocardial dysfunction in severe sepsis and septic shock. Baseline clinical and biological variables were collected from 47 patients with severe sepsis or septic shock. Ventricular systolic function assessed by echocardiography was measured over a 5-day period. Both cTnI and BNP plasmatic levels were determined at intensive care unit (ICU) admission and during the following 15 days. At admission, cTnI and BNP levels were compared to those of 12 control critically ill nonseptic patients. The plasma levels of BNP and cTnI in patients with sepsis were elevated at admission and significantly higher than in the controls. Among patients with sepsis, BNP levels were significantly more elevated in nonsurvivors compared to survivors at admission and 1 day later. The cTnI levels were also significantly more elevated in nonsurvivors compared to survivors, but only at admission. From admission to day 5, patients with sepsis with left ventricular systolic dysfunction had higher BNP plasmatic concentrations than those without; differences were significant at days 3 and 4. In contrast, plasma cTnI levels were similar between the 2 groups. In critically ill patients, sepsis induces significant increase in BNP and cTnI levels. High BNP and cTnI plasma levels during ICU admission appear to be associated with poor outcome of sepsis. Time course of BNP levels seems helpful to discriminate between surviving and nonsurviving patients with sepsis and to detect myocardial dysfunction where troponin levels fail to do so.

  12. Diagnostic utility of plasma N-terminal pro-B-type natriuretic peptide and C-reactive protein levels in differential diagnosis of pericardial constriction and restrictive cardiomyopathy.

    PubMed

    Karaahmet, Tansu; Yilmaz, Fatih; Tigen, Kursat; Mutlu, Bulent; Cevik, Cihan; Basaran, Yelda

    2009-01-01

    The authors investigated the diagnostic utility of plasma N-terminal pro-B-type natriuretic peptide (NT proBNP) and C-reactive protein (CRP) levels in the differential diagnosis of constrictive pericarditis (CP) and restrictive cardiomyopathy (RC). Twenty-five patients with high clinical suspicion of either CP or RC were enrolled. Mean plasma NT proBNP levels were significantly higher in patients with RC compared to those with CP (2641 +/- 2902 pg/mL vs 628 +/- 678 pg/mL; P=.003). The NT proBNP level that provided the best sensitivity and specificity for the differentiation of CP and RC was 800 pg/mL. Mean CRP levels were higher in patients with CP than with RC (1.41 +/- 1.73 mg/dL vs 0.38 +/- 0.21 mg/dL; P=.03). The CRP level that provided the best sensitivity and specificity for the differentiation of CP and RC was 0.57 mg/dL. Plasma NT proBNP and CRP levels can be useful in the differential diagnosis of RC and CP.

  13. Amelioration of Cardiac Function and Activation of Anti-Inflammatory Vasoactive Peptides Expression in the Rat Myocardium by Low Level Laser Therapy

    PubMed Central

    Manchini, Martha Trindade; Serra, Andrey Jorge; Feliciano, Regiane dos Santos; Santana, Eduardo Tadeu; Antônio, Ednei Luis; de Tarso Camillo de Carvalho, Paulo; Montemor, Jairo; Crajoinas, Renato Oliveira; Girardi, Adriana Castello Costa; Tucci, Paulo José Ferreira; Silva, José Antônio

    2014-01-01

    Low-level laser therapy (LLLT) has been used as an anti-inflammatory treatment in several disease conditions, even when inflammation is a secondary consequence, such as in myocardial infarction (MI). However, the mechanism by which LLLT is able to protect the remaining myocardium remains unclear. The present study tested the hypothesis that LLLT reduces inflammation after acute MI in female rats and ameliorates cardiac function. The potential participation of the Renin-Angiotensin System (RAS) and Kallikrein-Kinin System (KKS) vasoactive peptides was also evaluated. LLLT treatment effectively reduced MI size, attenuated the systolic dysfunction after MI, and decreased the myocardial mRNA expression of interleukin-1 beta and interleukin-6 in comparison to the non-irradiated rat tissue. In addition, LLLT treatment increased protein and mRNA levels of the Mas receptor, the mRNA expression of kinin B2 receptors and the circulating levels of plasma kallikrein compared to non-treated post-MI rats. On the other hand, the kinin B1 receptor mRNA expression decreased after LLLT. No significant changes were found in the expression of vascular endothelial growth factor (VEGF) in the myocardial remote area between laser-irradiated and non-irradiated post-MI rats. Capillaries density also remained similar between these two experimental groups. The mRNA expression of the inducible nitric oxide synthase (iNOS) was increased three days after MI, however, this effect was blunted by LLLT. Moreover, endothelial NOS mRNA content increased after LLLT. Plasma nitric oxide metabolites (NOx) concentration was increased three days after MI in non-treated rats and increased even further by LLLT treatment. Our data suggest that LLLT diminishes the acute inflammation in the myocardium, reduces infarct size and attenuates left ventricle dysfunction post-MI and increases vasoactive peptides expression and nitric oxide (NO) generation. PMID:24991808

  14. The importance of the olfactory rosettes in maintaining pituitary prolactin and prolactin-releasing peptide levels during hyposmotic acclimation in silver sea bream (Sparus sarba).

    PubMed

    Kwong, Anna K Y; Woo, Norman Y S

    2012-04-01

    A potential role of the olfactory rosettes in maintaining prolactin (PRL) and prolactin-releasing peptide (PrRP) levels was examined in the euryhaline silver sea bream (Sparus sarba). The olfactory rosettes were surgically removed in silver sea bream adapted to hypo- (6 ppt) and hyper-osmotic (33 ppt) salinities and the mRNA expression of the two previously identified freshwater-adapting factors, prolactin (PRL) and prolactin-releasing peptide (PrRP), in silver sea bream was measured. The elevation of pituitary PRL and PrRP mRNA expression levels as seen in 6 ppt-adapted fish was abolished by surgical removal of the olfactory rosettes. The PRL and PrRP expression levels in fish adapted to 6 ppt were significantly lowered following olfactory rosette removal. On the other hand, hypothalamic PrRP mRNA expression in 6 ppt-adapted fish did not change. Specific signals for Na(+)-K(+)-ATPase but not CFTR mRNA expression were detected in the surface layers of olfactory epithelial cells by in situ hybridization. The mRNA abundance of CFTR and Na(+)-K(+)-ATPase α and β subunits remained unchanged in the olfactory rosette of silver sea bream adapted to 0, 6, 12, 33 and 50 ppt for 4 weeks and in fish abruptly transferred from 33 ppt to 6 ppt. Data obtained from the olfactory rosette removal experiments suggest a possible role of the olfactory system for maintaining PRL and PrRP expression during hyposmotic acclimation in sea bream.

  15. Changes in anti-cyclic citrullinated peptide antibodies and rheumatoid factor isotypes serum levels in patients with rheumatoid arthritis following treatment with different biological drugs.

    PubMed

    Iannone, Florenzo; Tampoia, Marilina; Giannini, Margherita; Lopalco, Giuseppe; Cantarini, Luca; Villalta, C Danilo; Galeazzi, Mauro; Lapadula, Giovanni

    2016-01-01

    Anti-cyclic citrullinated peptide antibodies (anti-CCP) are a serological marker of rheumatoid arthritis (RA), and also have a prognostic value for more aggressive disease. Whether anti-CCP levels may change during treatment according to clinical response is matter of debate. Likewise, it is unknown whether different biological drugs have peculiar effects on anti-CCP levels. This study aimed to investigate changes in anti-CCP serum levels in RA patients on biological drugs with different mechanism of action. We studied 71 patients with active RA tested positive for anti-CCP who started a first biological drug (54 anti-TNF-α drug, 9 rituximab, 8 tocilizumab). In 14 patients stopping anti-TNF-α treatment for ineffectiveness, rituximab was started. Anti-CCP and rheumatoid factor (RF) isotypes (IgM, IgA, IgG) levels were measured at entry, 12 months and again at 12 months after swapping to rituximab. After 1 year of therapy of the first biological drug, patients taking anti-TNF-α drugs showed a significant reduction of the anti-CCP levels (p=0.002), and all RF isotypes (p=0.003). Also patients treated with rituximab or tolicizumab had a significant decrease in anti-CCP (p=0.01) and RF isotype levels (p=0.01). Anti-CCP levels did not correlated with DAS28 over time. In patients switching to rituximab after failure of TNF-α blockers, anti-CCP levels did not change at 12 months (p=0.06), despite of the reduction of DAS28 (p=0.02) and RFs levels (p=0.02). Our study showed that anti-CCP levels may change during RA course, regardless of the biological drug used and the clinical response.

  16. Selective intracellular release of copper and zinc ions from bis(thiosemicarbazonato) complexes reduces levels of Alzheimer disease amyloid-beta peptide.

    PubMed

    Donnelly, Paul S; Caragounis, Aphrodite; Du, Tai; Laughton, Katrina M; Volitakis, Irene; Cherny, Robert A; Sharples, Robyn A; Hill, Andrew F; Li, Qiao-Xin; Masters, Colin L; Barnham, Kevin J; White, Anthony R

    2008-02-22

    Copper and zinc play important roles in Alzheimer disease pathology with recent reports describing potential therapeutics based on modulation of metal bioavailability. We examined the ability of a range of metal bis(thiosemicarbazonato) complexes (MII(btsc), where M=CuII or ZnII) to increase intracellular metal levels in Chinese hamster ovary cells overexpressing amyloid precursor protein (APP-CHO) and the subsequent effect on extracellular levels of amyloid-beta peptide (Abeta). The CuII(btsc) complexes were engineered to be either stable to both a change in oxidation state and dissociation of metal or susceptible to intracellular reduction and dissociation of metal. Treatment of APP-CHO cells with stable complexes resulted in elevated levels of intracellular copper with no effect on the detected levels of Abeta. Treatment with complexes susceptible to intracellular reduction increased intracellular copper levels but also resulted in a dose-dependent reduction in the levels of monomeric Abeta. Treatment with less stable ZnII(btsc) complexes increased intracellular zinc levels with a subsequent dose-dependent depletion of monomeric Abeta levels. The increased levels of intracellular bioavailable copper and zinc initiated a signaling cascade involving activation of phosphoinositol 3-kinase and c-Jun N-terminal kinase. Inhibition of these enzymes prevented Abeta depletion induced by the MII(btsc) complexes. Inhibition of metalloproteases also partially restored Abeta levels, implicating metal-driven metalloprotease activation in the extracellular monomeric Abeta depletion. However, a role for alternative metal-induced Abeta metabolism has not been ruled out. These studies demonstrate that MII(btsc) complexes have potential for Alzheimer disease therapy.

  17. Coronal density diagnostics with Helium-like triplets: CHANDRA-LETGS observations of Algol, Capella, Procyon, epsilon Eri, alpha Cen A&B, UX Ari, AD Leo, YY Gem, and HR 1099

    NASA Astrophysics Data System (ADS)

    Ness, J.-U.; Schmitt, J. H. M. M.; Burwitz, V.; Mewe, R.; Raassen, A. J. J.; van der Meer, R. L. J.; Predehl, P.; Brinkman, A. C.

    2002-11-01

    We present an analysis of ten cool stars (Algol, Capella, Procyon, epsilon Eri, alpha Cen A&B, UX Ari, AD Leo, YY Gem, and HR 1099) observed with the Low Energy Transmission Grating Spectrometer (LETGS) on board the Chandra X-ray Observatory. This sample contains all cools stars observed with the LETGS presently available to us with integration times sufficiently long to warrant a meaningful spectral analysis. Our sample comprises inactive, moderately active, and hyperactive stars and samples the bulk part of activity levels encountered in coronal X-ray sources. We use the LETGS spectra to carry out density and temperature diagnostics with an emphasis on the H-like and the He-like ions. We find a correlation between line flux ratios of the Lyalpha and He-like resonance lines with the mean X-ray surface flux. We determine densities using the He-like triplets. For all stars we find no significant deviations from the low-density limit for the ions of Ne, Mg, and Si, while the measured line ratios for the ions of C, N, and O do show evidence for departures from the low-density limit in the active stars, but not in the inactive stars. Best measurements can be made for the O VII triplet where we find significant deviations from the low-density limit for the stars Algol, Procyon, YY Gem, epsilon Eri, and HR 1099. We discuss the influence of radiation fields on the interpretation of the He-like triplet line ratios in the low-Z ions, which is relevant for Algol, and the influence of dielectronic satellite lines, which is relevant for Procyon. For the active stars YY Gem, epsilon Eri, and HR 1099 the low f/i ratios can unambiguously be attributed to high densties in the range 1-3*E10 cm-3 at O VII temperatures. We find our LETGS spectra to be an extremely useful tool for plasma diagnostics of stellar coronae.

  18. Nurses' performance in classifying heart failure patients based on physical exam: comparison with cardiologist's physical exam and levels of N-terminal pro-B-type natriuretic peptide.

    PubMed

    Sauer, Jaquelini; Rabelo, Eneida R; Castro, Raquel A; Goldraich, Livia; Rohde, Luis E; Clausell, Nadine; Beck-da-Silva, Luis

    2010-12-01

    The purpose of this study is to compare clinical assessment of congestion performed by a nurse to that performed by cardiologist and correlate them with NT-ProBNP levels. The nurses' role in heart failure has been strongly focused in therapeutic, educational and self-care interventions. The diagnostic performance of nurses in heart failure outpatients is not well explored. N-terminal pro-B-type natriuretic peptide is a cardiac marker that reflects elevated filling pressures. Cross-sectional contemporaneous study. Heart failure outpatients underwent a systematic clinical assessment of clinical congestion score performed by cardiologist and nurse during the same visit. Assessments were performed independently and N-terminal pro-B-type natriuretic peptide levels obtained. The nurses' ability to classify patients in hemodynamic profile was compared to the cardiologist's. Eighty-nine assessments were performed in 63 patients with heart failure. The correlation of clinical congestion scores obtained by nurse with those obtained by cardiologist was rs=0.86; p<0.001. The correlation of clinical congestion scores from nurse and cardiologist with levels of N-terminal pro-B-type natriuretic peptide were as follows: rs=0.45; p<0.0001 and rs=0.51, respectively, p<0.0001. Patients with clinical congestion score≥3 had levels of NT-ProBNP significantly higher than those with clinical congestion score<3, in the assessment performed by the cardiologist (1866 SD 1151 vs. 757 SD 988 pg/ml; p<0.0001) and by the nurse (1720 SD 1228 vs. 821 SD 914 pg/ml; p<0.0001). The nurse and cardiologist had similar capacity in classifying patients in congested quadrants (p=0.027) or in dry quadrants (p=0.03), according to the levels of N-terminal pro-B-type natriuretic peptide. Area under the receiver-operating characteristic curve of the nurse and cardiologist to detect congestion was, respectively, 0.77 and 0.72. Our data suggests that nurses trained in heart failure may have a similar

  19. Plasma and hypothalamic peptide-hormone levels regulating somatotroph function and energy balance in fed and fasted states: a comparative study in four strains of rats.

    PubMed

    Kappeler, L; Zizzari, P; Grouselle, D; Epelbaum, J; Bluet-Pajot, M T

    2004-12-01

    Both growth hormone (GH)/insulin growth factor (IGF)-1 axis and energy balance have been implicated in longevity independently. The aim of the present study was to characterize the effect of a 72-h fasting period at 3 months of age in four different rat strains: (i) Wistar and (ii) Fischer 344 rats, which develop obesity with age, and (iii) Brown Norway and (iv) Lou C rats, which do not. Wistar rats ate more, were significantly bigger, and presented with higher plasma leptin and lower ghrelin levels and hypothalamic growth hormone-releasing hormone (GHRH) content than rats from the three other strains. Plasma insulin and IGF-1 levels were lower in Brown Norway and Lou C rats, and somatostatin content was lower in Brown Norway rats only. Glycaemia was lower in Lou C rats that displayed a lower relative food intake compared to Fischer and Wistar rats. Brown Norway rats showed a greater caloric efficiency than the three other strains. Concerning major hypothalamic neuropeptides implicated in feeding, similar amounts were detected in the four strains for neuropeptide Y, agouti-related peptide, galanin, melanin-concentrating hormone, alpha-melanocortin-stimulating hormone (alpha-MSH) and corticotropin-releasing hormone. Orexin A appeared to be slightly elevated in Fischer rats and cocaine amphetamine-regulated transcript (CART)(55-102) diminished in Brown Norway. At the mRNA level, orexin A, GHSR1, alpha-MSH and CART expression were higher in Wistar and Lou C rats. Principal component analysis confirmed the presence of two main factors in the ad libitum rat population; the first being associated with growth-related parameters and the second being associated with food intake regulation. Hypothalamic GHRH and somatostatin content were positively correlated with feeding-related neuropeptides such as alpha-MSH for GHRH, and orexin A and CART for both peptides. Plasma ghrelin levels were negatively correlated with leptin and IGF-1 levels. Finally, a 72-h fasting period

  20. Amino-Terminal proB-Type Natriuretic Peptide Levels in the Umbilical Cord Blood of Neonates Differ According to the Type of Prenatally Diagnosed Congenital Heart Disease.

    PubMed

    Bae, Jin Young; Cha, Hyun-Hwa; Seong, Won Joon

    2015-12-01

    The aim of this study was to investigate differences in amino-terminal proB-type natriuretic peptide (NT-proBNP) levels in the cord blood of neonates according to the type of congenital heart disease (CHD) and to evaluate the usefulness of NT-proBNP as a prognostic marker. We included 76 neonates with prenatally diagnosed CHD and 45 controls without CHD. Neonates were classified into five groups based on echocardiographic findings. The levels of NT-proBNP in the cord blood were examined and analyzed according to the neonatal outcomes. The levels of NT-proBNP were significantly elevated in the cord blood of neonates with CHD compared with that in the cord blood of controls. The levels of NT-proBNP in the group with right ventricular outflow tract obstruction without a ventricular septal defect were significantly increased compared to that in the other groups. The neonates that required acute surgical correction had higher levels of NT-proBNP in the cord blood, though they were not statistically significant. Meanwhile, NT-proBNP levels in the cord blood of neonates with functional single ventricle were significantly higher than that in the cord blood of those with functional biventricles. Significant differences in the levels of NT-proBNP between survivors and nonsurvivors were observed within 1 year of birth. In this study, we found that the levels of NT-proBNP in the cord blood of neonates with CHD were higher than the levels in controls. This finding was striking in the group with right ventricular outflow tract obstruction, and it was associated with surgery for functional single ventricle and 1-year survival.

  1. A retrospective study of the fluctuation in serum levels of anti-cyclic citrullinated peptide antibody in patients with rheumatoid arthritis.

    PubMed

    Aotsuka, S; Okawa-Takatsuji, M; Nagatani, K; Nagashio, C; Kano, T; Nakajima, K; Ito, K; Mimori, A

    2005-01-01

    To investigate the fluctuation in serum levels of anti-cyclic citrullinated peptide antibody (anti-CCP) retrospectively in patients with rheumatoid arthritis (RA). Serum levels of anti-CCP were measured retrospectively in 131 patients with RA and 90 patients with non-RA rheumatic diseases using a commercially available kit. All sera were collected from patients during the 22-year period, 1982-2004. To analyze the fluctuation in anti-CCP levels, 17 RA patients were selected on the basis of showing a significantly higher anti-CCP level in a serum sample taken at the first visit (> 80 U/ml), and availability of preserved serum samples that had been taken from each patient at 10 time points. The test gave a sensitivity of 88% (115/131) and a specificity of 81% (73/90). The longitudinal study of 17 RA patients showed that anti-CCP levels were elevated at the first visit in 12 (71%) patients and then decreased gradually, whereas those in the other five (29%) patients fluctuated substantially. In both cases, anti-CCP levels tended to fluctuate in parallel with the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level, reflecting the spontaneous aggravation of arthritis and the efficacy of anti-rheumatic drugs. The courses of three representative RA patients are illustrated in detail along with their therapeutic regimens, and these further confirm the correlation of anti-CCP levels with laboratory parameters (ESR and CRP) as well as the activity of arthritis. Measurement of serum anti-CCP levels was found to be useful for not only the diagnosis but also the management of RA.

  2. [Levels of some auto-antibodies and C-peptide in insulin-treated patients with diabetes mellitus (DM) depending on gender of the patients and disease duration].

    PubMed

    Likhonosov, P N; Khalangot, N D

    2007-01-01

    Determination of antibodies to thyroid peroxidase was recently proposed to single out subgroups among patients with DM1 for following clinical and genetic studies. 73 men and 64 women who are being treated with insulin and included in territorial register of patients with DM of Mariupol city, Donetsk region, Ukraine. Average age of patients at the stage of investigation was 35.17+/-1.16, the duration of the disease was 11.85+/-0.74, BMI-23.13+/-0.32 kg/m2, HBA1c9.23+/-0.25, C-peptide 0.48+/-0.09 nmol/l, glutaminic acid decarboxylase antibodies-GADAs-0.63+/-0.04 units/ml and did not depend on gender. Patients aged less then 30 years had their level of GADAbs and TPOAbs changed linearly correlated with the duration of diabetes mellitus. Obtained data can be used to assess subgroups among patients with DM1.

  3. 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…

  4. 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…

  5. Relationship of Left Atrial Global Peak Systolic Strain with Left Ventricular Diastolic Dysfunction and Brain Natriuretic Peptide Level in Patients Presenting with Non-ST Elevation Myocardial Infarction

    PubMed Central

    Değirmenci, Hüsnü; Bakırcı, Eftal Murat; Demirtaş, Levent; Duman, Hakan; Hamur, Hikmet; Ceyhun, Gökhan; Topal, Ergün

    2014-01-01

    Background In patients presenting with non-ST elevation myocardial infarction, we investigated the relationship of left atrial deformational parameters evaluated by 2-dimensional speckle tracking imaging (2D-STI) with conventional echocardiographic diastolic dysfunction parameters and brain natriuretic peptide level. Material/Methods We enrolled 74 non-ST segment elevation myocardial infarction patients who were treated with percutaneous coronary intervention and 58 healthy control subjects. Non-ST segment elevation myocardial infarction patients had echocardiographic examination 48 h after the percutaneous coronary intervention procedure and venous blood samples were drawn simultaneously. In addition to conventional echocardiographic parameters, left atrial strain curves were obtained for each patient. Average peak left atrial strain values during left ventricular systole were measured. Results BNP values were higher in non-ST segment elevation myocardial infarction patients compared to controls. Mean left atrium peak systolic global longitudinal strain in Group 2 (the control group) was higher than in the non-ST segment elevation myocardial infarction group. Left atrium peak systolic global longitudinal strain was significantly correlated with left ventricular ejection fraction. There was a significant inverse correlation between left atrium peak systolic global longitudinal strain and brain natriuretic peptide level, left atrium volume maximum, and left atrium volume minimum. Conclusions Our study shows that Left atrium peak systolic global longitudinal strain values decreased consistently with deteriorating systolic and diastolic function in non-ST segment elevation myocardial infarction patients treated with percutaneous coronary intervention. Left atrium peak systolic global longitudinal strain measurements may be helpful as a complimentary method to evaluate diastolic function in this patient population. PMID:25338184

  6. Relationship of left atrial global peak systolic strain with left ventricular diastolic dysfunction and brain natriuretic peptide level in patients presenting with non-ST elevation myocardial infarction.

    PubMed

    Değirmenci, Hüsnü; Bakırcı, Eftal Murat; Demirtaş, Levent; Duman, Hakan; Hamur, Hikmet; Ceyhun, Gökhan; Topal, Ergün

    2014-10-22

    In patients presenting with non-ST elevation myocardial infarction, we investigated the relationship of left atrial deformational parameters evaluated by 2-dimensional speckle tracking imaging (2D-STI) with conventional echocardiographic diastolic dysfunction parameters and brain natriuretic peptide level. We enrolled 74 non-ST segment elevation myocardial infarction patients who were treated with percutaneous coronary intervention and 58 healthy control subjects. Non-ST segment elevation myocardial infarction patients had echocardiographic examination 48 h after the percutaneous coronary intervention procedure and venous blood samples were drawn simultaneously. In addition to conventional echocardiographic parameters, left atrial strain curves were obtained for each patient. Average peak left atrial strain values during left ventricular systole were measured. BNP values were higher in non-ST segment elevation myocardial infarction patients compared to controls. Mean left atrium peak systolic global longitudinal strain in Group 2 (the control group) was higher than in the non-ST segment elevation myocardial infarction group. Left atrium peak systolic global longitudinal strain was significantly correlated with left ventricular ejection fraction. There was a significant inverse correlation between left atrium peak systolic global longitudinal strain and brain natriuretic peptide level, left atrium volume maximum, and left atrium volume minimum. Our study shows that Left atrium peak systolic global longitudinal strain values decreased consistently with deteriorating systolic and diastolic function in non-ST segment elevation myocardial infarction patients treated with percutaneous coronary intervention. Left atrium peak systolic global longitudinal strain measurements may be helpful as a complimentary method to evaluate diastolic function in this patient population.

  7. Differential effects of the peptides Stomagen, EPF1 and EPF2 on activation of MAP kinase MPK6 and the SPCH protein level.

    PubMed

    Jewaria, Pawan Kumar; Hara, Toshiaki; Tanaka, Hirokazu; Kondo, Tatsuhiko; Betsuyaku, Shigeyuki; Sawa, Shinichiro; Sakagami, Youji; Aimoto, Saburo; Kakimoto, Tatsuo

    2013-08-01

    The positioning and density of leaf stomata are regulated by three secretory peptides, EPIDERMAL PATTERNING FACTOR 1 (EPF1), EPF2 and stomagen. Several lines of published evidence have suggested a regulatory pathway as follows. EPF1 and EPF2 are perceived by receptor complexes consisting of a receptor-like protein, TOO MANY MOUTHS (TMM), and receptor kinases, ERECTA (ER), ERECTA-LIKE (ERL) 1 and ERL2. These receptors activate a mitogen-activated protein (MAP) kinase module. MAP kinases phosphorylate and destabilize the transcription factor SPEECHLESS (SPCH), resulting in a decrease in the number of stomatal lineage cells. Stomagen acts antagonistically to EPF1 and EPF2. However, there is no direct evidence that EPF1 and EPF2 activate or that stomagen inactivates the MAP kinase cascade, through which they might regulate the SPCH level. Experimental modulation of these peptides in Arabidopsis thaliana would change the number of stomatal lineage cells in developing leaves, which in turn would change the expression of SPCH, making the interpretation difficult. Here we reconstructed this signaling pathway in differentiated leaf cells of Nicotiana benthamiana to examine signaling without the confounding effect of cell type change. We show that EPF1 and EPF2 are able to activate the MAP kinase MPK6, and that both EPF1 and EPF2 are able to decrease the SPCH level, whereas stomagen is able to increase it. Our data also suggest that EPF1 can be recognized by TMM together with any ER family receptor kinase, whereas EPF2 can be recognized by TMM together with ERL1 or ERL2, but not by TMM together with ER.

  8. The amount of citrullinated proteins in synovial tissue is related to serum anti-cyclic citrullinated peptide (anti-CCP) antibody levels.

    PubMed

    Olivares-Martínez, Elizabeth; Hernández-Ramírez, Diego F; Núñez-Álvarez, Carlos A; Cabral, Antonio R; Llorente, Luis

    2016-01-01

    The objective of this study was to determine the relationship between citrullinated proteins in synovial tissue with peripheral anti-citrullinated peptides autoantibodies (ACPA) and peptidylarginine deiminase (PADI) PADI2, PADI3, and PADI4 messenger RNA (mRNA) expressions in synovial tissue and fibroblast-like synoviocytes in rheumatoid arthritis (RA) patients. Eleven RA and 12 osteoarthritis (OA) patients who underwent knee replacement surgery were studied. We detected citrullinated proteins in synovial tissue homogenates by western blot and serum ACPA by ELISA to anti-cyclic citrullinated peptide (anti-CCP) antibodies, and PADI2, PADI3, and PADI4 mRNA expressions in synovial tissue and in fibroblast-like synoviocytes. Patients with high amount of citrullinated proteins in synovial tissue (3 out of 7) have high levels of anti-CCP in serum. However, in the remaining 4 patients, the amount of synovial citrullinated proteins was minimal and their sera showed low levels of anti-CCP antibodies. Furthermore, we observed an increase in PADI2 mRNA expression in RA synovial tissue compared with OA patients (p = 0.02). We detected PADI3 mRNA in the synovial tissue of RA patients, but not in the tissue of OA patients. Even though fibroblast-type synoviocytes in RA are not the main source of PADs in the synovial tissue, they express PADI2 mRNA moderately, PADI4 mRNA weakly, while there is no detectable expression of PADI3 mRNA. In conclusion, we found a variety of citrullinated proteins in the synovial tissue of RA patients and the amount of such proteins is related to serum concentration of anti-CCP antibodies. We identified the presence of PADI3 mRNA expression in synovial tissue and PADI2 and PADI4 mRNA expressions in fibroblast-like synoviocytes from patients with RA.

  9. An improved method for high-level soluble expression and purification of recombinant amyloid-beta peptide for in vitro studies.

    PubMed

    Chhetri, Gaurav; Pandey, Tripti; Chinta, Ramesh; Kumar, Awanish; Tripathi, Timir

    2015-10-01

    Amyloid-beta (Aβ) peptide mediates several neurodegenerative diseases. The 42 amino acid (Aβ1-42) is the predominant form of peptide found in the neuritic plaques and has been demonstrated to be neurotoxic in vivo and in vitro. The availability of large quantities of Aβ peptide will help in several biochemical and biophysical studies that may help in exploring the aggregation mechanism and toxicity of Aβ peptide. We report a convenient and economical method to obtain such a peptide biologically. Synthetic oligonucleotides encoding Aβ1-42 were constructed and amplified through the polymerase cycling assembly (also known as assembly PCR), followed by the amplification PCR. Aβ1-42 gene was cloned into pET41a(+) vector for expression. Interestingly, the addition of 3% (v/v) ethanol to the culture medium resulted in the production of large amounts of soluble Aβ fusion protein. The Aβ fusion protein was subjected to a Ni-NTA affinity chromatography followed by enterokinase digestion, and the Aβ peptide was purified using glutathione Sepharose affinity chromatography. The peptide yield was ∼15mg/L culture, indicating the utility of this method for high-yield production of soluble Aβ peptide. Sodium dodecyl sulfate polyacrylamide gel electrophoresis analysis and immunoblotting with anti-His antibody confirmed the identity of purified Aβ fusion protein and Aβ peptide. In addition, this method provides an advantage over the chemical synthesis and other conventional methods used for large-scale production of recombinant Aβ peptide.

  10. Active ghrelin levels and active to total ghrelin ratio in cancer-induced cachexia.

    PubMed

    Garcia, Josè M; Garcia-Touza, Mariana; Hijazi, Rabih A; Taffet, George; Epner, Daniel; Mann, Douglas; Smith, Roy G; Cunningham, Glenn R; Marcelli, Marco

    2005-05-01

    Anorexia and weight loss are negative prognostic factors in patients with cancer. Although total ghrelin levels are increased in energy-negative states, levels of the biologically active octanoylated ghrelin and the anorexigenic peptide YY (PYY) have not been reported in patients with cancer-induced cachexia. We hypothesized that abnormal ghrelin and/or PYY levels contribute to cancer-induced cachexia. We evaluated 21 patients with cancer-induced cachexia; 24 cancer patients without cachexia; and 23 age-, sex-, race-, and BMI-matched subjects without cancer. Active ghrelin levels and the active to total ghrelin ratio were significantly increased in subjects with cancer-induced cachexia, compared with cancer and noncancer controls. PYY levels were similar among groups. Appetite measured by a visual analog scale was not increased in subjects with cachexia. The increase in active ghrelin levels is likely to be a compensatory response to weight loss. Cachexia may be a state of ghrelin resistance because appetite does not correlate with ghrelin levels. Changes in the active to total ghrelin ratio suggest that a mechanism other than increased secretion must be responsible for the increase in active ghrelin levels. PYY is unlikely to play an important role in cancer-induced cachexia.

  11. Usefulness of N-terminal pro-brain natriuretic peptide levels to predict success of weaning from intra-aortic balloon pumping.

    PubMed

    Tokita, Yukichi; Yamamoto, Takeshi; Sato, Naoki; Hosokawa, Yusuke; Munakata, Ryo; Akutsu, Koichi; Shimizu, Wataru; Tanaka, Keiji

    2014-09-15

    There is currently no reliable method of predicting the success of weaning from intra-aortic balloon pumping (IABP). The aim of this study was to investigate the ability of serum N-terminal pro-brain natriuretic peptide (NT-proBNP) level to predict the success of weaning from IABP. Consecutive patients scheduled for weaning from IABP were prospectively enrolled. NT-proBNP levels were measured at baseline (before the start of weaning) and cessation (just before cessation of IABP). Changes in NT-proBNP level between baseline and cessation were analyzed in 2 groups of patients: those who were successfully weaned and those who were not successfully weaned for any reason, including a decision to discontinue weaning, worsening of pulmonary edema after cessation of IABP, or unstable hemodynamics after cessation of IABP. A total of 30 patients were enrolled (mean age 66 ± 12 years, 16 men, 16 with acute myocardial infarctions, and 14 with acute exacerbation of chronic heart failure). Median (interquartile range) baseline NT-proBNP levels were not significantly different between the successful and unsuccessful weaning groups (4,200 [1,400 to 8,752] pg/ml vs (5,620 [2,035 to 13,950] pg/ml, p = 0.30). In the unsuccessful weaning group, the median NT-proBNP level was significantly higher at cessation (9,995 [2,920 to 15,100] pg/ml) than at baseline (p = 0.008). All patients with decreases in NT-proBNP level between baseline and cessation were successfully weaned from IABP. In conclusion, these results show that NT-proBNP levels were useful for predicting the success of weaning from IABP. If the NT-proBNP level increases during weaning from IABP, more intense management should be considered.

  12. Single vagus nerve stimulation reduces early postprandial C-peptide levels but not other hormones or postprandial metabolism.

    PubMed

    Tang, M W; van Nierop, F S; Koopman, F A; Eggink, H M; Gerlag, D M; Chan, M W; Zitnik, R; Vaz, F M; Romijn, J A; Tak, P P; Soeters, M R

    2017-04-08

    A recent study in rheumatoid arthritis (RA) patients using electrical vagus nerve stimulation (VNS) to activate the inflammatory reflex has shown promising effects on disease activity. Innervation by the autonomic nerve system might be involved in the regulation of many endocrine and metabolic processes and could therefore theoretically lead to unwanted side effects. Possible effects of VNS on secretion of hormones are currently unknown. Therefore, we evaluated the effects of a single VNS on plasma levels of pituitary hormones and parameters of postprandial metabolism. Six female patients with RA were studied twice in balanced assignment (crossover design) to either VNS or no stimulation. The patients selected for this substudy had been on VNS therapy daily for at least 3 months and at maximum of 24 months. We compared 10-, 20-, and 30-min poststimulus levels to baseline levels, and a 4-h mixed meal test was performed 30 min after VNS. We also determined energy expenditure (EE) by indirect calorimetry before and after VNS. VNS did not affect pituitary hormones (growth hormone, thyroid stimulating hormone, adrenocorticotropic hormone, prolactin, follicle-stimulating hormone, and luteinizing hormone), postprandial metabolism, or EE. Of note, VNS reduced early postprandial insulin secretion, but not AUC of postprandial plasma insulin levels. Cortisol and catecholamine levels in serum did not change significantly. Short stimulation of vagal activity by VNS reduces early postprandial insulin secretion, but not other hormone levels and postprandial response. This suggests VNS as a safe treatment for RA patients.

  13. Urinary Peptides in Rett Syndrome.

    ERIC Educational Resources Information Center

    Solaas, K. M.; Skjeldal, O.; Gardner, M. L. G.; Kase, B. F.; Reichelt, K. L.

    2002-01-01

    A study found a significantly higher level of peptides in the urine of 53 girls with Rett syndrome compared with controls. The elevation was similar to that in 35 girls with infantile autism. Levels of peptides were lower in girls with classic Rett syndrome than those with congenital Rett syndrome. (Contains references.) (Author/CR)

  14. Urinary Peptides in Rett Syndrome.

    ERIC Educational Resources Information Center

    Solaas, K. M.; Skjeldal, O.; Gardner, M. L. G.; Kase, B. F.; Reichelt, K. L.

    2002-01-01

    A study found a significantly higher level of peptides in the urine of 53 girls with Rett syndrome compared with controls. The elevation was similar to that in 35 girls with infantile autism. Levels of peptides were lower in girls with classic Rett syndrome than those with congenital Rett syndrome. (Contains references.) (Author/CR)

  15. Bioactive Peptides

    PubMed Central

    Daliri, Eric Banan-Mwine; Oh, Deog H.; Lee, Byong H.

    2017-01-01

    The increased consumer awareness of the health promoting effects of functional foods and nutraceuticals is the driving force of the functional food and nutraceutical market. Bioactive peptides are known for their high tissue affinity, specificity and efficiency in promoting health. For this reason, the search for food-derived bioactive peptides has increased exponentially. Over the years, many potential bioactive peptides from food have been documented; yet, obstacles such as the need to establish optimal conditions for industrial scale production and the absence of well-designed clinical trials to provide robust evidence for proving health claims continue to exist. Other important factors such as the possibility of allergenicity, cytotoxicity and the stability of the peptides during gastrointestinal digestion would need to be addressed. This review discusses our current knowledge on the health effects of food-derived bioactive peptides, their processing methods and challenges in their development. PMID:28445415

  16. Bioactive Peptides.

    PubMed

    Daliri, Eric Banan-Mwine; Oh, Deog H; Lee, Byong H

    2017-04-26

    The increased consumer awareness of the health promoting effects of functional foods and nutraceuticals is the driving force of the functional food and nutraceutical market. Bioactive peptides are known for their high tissue affinity, specificity and efficiency in promoting health. For this reason, the search for food-derived bioactive peptides has increased exponentially. Over the years, many potential bioactive peptides from food have been documented; yet, obstacles such as the need to establish optimal conditions for industrial scale production and the absence of well-designed clinical trials to provide robust evidence for proving health claims continue to exist. Other important factors such as the possibility of allergenicity, cytotoxicity and the stability of the peptides during gastrointestinal digestion would need to be addressed. This review discusses our current knowledge on the health effects of food-derived bioactive peptides, their processing methods and challenges in their development.

  17. The developmental regulator protein Gon4l associates with protein YY1, co-repressor Sin3a, and histone deacetylase 1 and mediates transcriptional repression.

    PubMed

    Lu, Ping; Hankel, Isaiah L; Hostager, Bruce S; Swartzendruber, Julie A; Friedman, Ann D; Brenton, Janet L; Rothman, Paul B; Colgan, John D

    2011-05-20

    Genetic studies involving zebrafish and mice have demonstrated that the protein Gon4l (Gon4-like) is essential for hematopoiesis. These studies also suggested that Gon4l regulates gene expression during hematopoietic development, yet the biochemical function of Gon4l has not been defined. Here, we describe the identification of factors that interact with Gon4l and may cooperate with this protein to regulate gene expression. As predicted by polypeptide sequence conservation, Gon4l interacted and co-localized with the DNA-binding protein YY1 (Yin Yang 1). Density gradient sedimentation analysis of protein lysates from mouse M12 B cells showed that Gon4l and YY1 co-sediment with the transcriptional co-repressor Sin3a and its functional partner histone deacetylase (HDAC) 1. Consistent with these results, immunoprecipitation studies showed that Gon4l associates with Sin3a, HDAC1, and YY1 as a part of complexes that form in M12 cells. Sequential immunoprecipitation studies demonstrated that Gon4l, YY1, Sin3a, and HDAC1 could all associate as components of a single complex and that a conserved domain spanning the central portion of Gon4l was required for formation of this complex. When targeted to DNA, Gon4l repressed the activity of a nearby promoter, which correlated with the ability to interact with Sin3a and HDAC1. Our data suggest that Sin3a, HDAC1, and YY1 are co-factors for Gon4l and that Gon4l may function as a platform for the assembly of complexes that regulate gene expression.

  18. Polymorphisms of delta-aminolevulinic acid dehydratase (ALAD) and peptide transporter 2 (PEPT2) genes in children with low-level lead exposure

    PubMed Central

    Sobin, Christina; Gutierrez, Marisela; Alterio, Heather

    2009-01-01

    Low-level lead exposure during early childhood has long been associated with altered neurocognitive development and diminished cognitive functions. Over nine thousand U.S. industrial facilities annually emit significant amounts of lead, creating exposure risk particularly for minority children. The mechanisms by which low-level lead exerts neurotoxic effects are poorly understood. Once absorbed, the only intervention is source removal, thus primary prevention is key. Genetic biomarkers could provide an efficient means of identifying children at greatest risk. Common functional variants of genes that alter lead's neurotoxic potential have been identified and include delta-aminolevulinic acid dehydratase (ALAD2) and peptide transporter 2 (PEPT2*2). These polymorphisms have not been examined previously in Hispanic minority samples, or with regard to lowest level lead exposure. In 116 children of Mexican-American/Hispanic descent residing in zip codes previously designated as “high risk” for lead exposure (mean age = 8.1, S.D. = 1.9), blood lead level was measured at three time points over a 3-month period and averaged. DNA extraction was completed using buccal swab samples. The frequencies of the ALAD2 and PEPT2*2 polymorphisms observed in this sample closely approximated those previously reported for Anglo, European and Asian samples. As compared to children heterozygous for the PEPT2*2 polymorphism, and without the PEPT2*2 polymorphism, the geometric mean blood lead level of children homozygous for the PEPT2*2 polymorphism was significantly higher. In contrast to past studies, mean blood lead level of children heterozygous and homozygous for the ALAD2 polymorphism in this sample did not differ from that of children without the ALAD2 polymorphism. Higher blood lead burden in children with the PEPT2*2 mutation may suggest that this common genetic variant is a biomarker of increased vulnerability to the neurotoxic effects of lowest level lead exposure. PMID

  19. Can signal peptide-CUB-EGF domain-containing protein (SCUBE) levels be a marker of angiogenesis in patients with psoriasis?

    PubMed

    Capkin, Arzu Aydın; Demir, Selim; Mentese, Ahmet; Bulut, Çağlar; Ayar, Ahmet

    2017-04-01

    Angiogenesis is an important process being involved in the pathogenesis of psoriasis and promises new potential parameter for diagnosis and screening of treatment. This study investigated the levels of signal peptide-CUB-EGF (epidermal growth factor-like protein) family domain-containing protein (SCUBE) 1 and 3. Potential value as a novel marker of angiogenesis in patients with psoriasis is also evaluated by assessing possible relation of SCUBE-1 and 3 with disease activity in conjunction with vascular endothelial growth factor (VEGF) levels, as an established marker of angiogenesis. Forty-eight patients with psoriasis (aged >18 years) and 48 age- and gender-matched healthy controls were included. Detailed information was obtained through history and physical examination. Psoriasis area and severity index (PASI) scores were calculated. Blood SCUBE 1 and 3, and VEGF levels were measured by enzyme-linked immunosorbent assay. The mean PASI score of the patients was 6.7 ± 4.1. Patients' serum SCUBE 1 and 3 and VEGF levels were significantly higher than those of the controls (P = 0.001). The sensitivity and specificity were calculated as 83 and 62% for the 0.67 ng/ml cut-off level of SCUBE 1, and 63 and 71% for the 2.57 ng/ml cut-off level of SCUBE 3, respectively. A cut-off VEGF level of 310 ng/mL predicted the presence of psoriasis with a sensitivity of 50% and specificity of 77%. The results of this pioneering study indicate that SCUBE protein family appears to have a probable role in the pathogenesis and angiogenesis development in psoriasis and SCUBE 1 and 3 may be novel markers of angiogenesis in psoriasis.

  20. Right ventricular function and N-terminal pro-brain natriuretic peptide levels in adult patients with simple dextro-transposition of the great arteries.

    PubMed

    Martínez-Quintana, Efrén; Marrero-Negrín, Natalia; Gopar-Gopar, Silvia; Rodríguez-González, Fayna

    2017-06-01

    Dextro-transposition of the great arteries (d-TGA) patients is at high risk of developing right ventricular dysfunction and tricuspid regurgitation in adulthood. Determining the relation between echocardiographic parameters, N-terminal pro-brain natriuretic peptide (NT-pro-BNP) levels and the New York Heart Association (NYHA) functional class may help determining the best time to operate them. Patients with simple d-TGA operated in infancy with an atrial switch procedure (Mustard or Senning operation) were followed up in our Adult Congenital Heart Disease Unit. Analytical, echocardiographic, and clinical parameters were determined to evaluate the correlation between right echocardiographic ventricular function, NT-pro-BNP levels, and NYHA functional class. Twenty-four patients with d-TGA were operated in infancy of whom 17 alive patients had simple d-TGA. Nine patients had NT-pro-BNP levels lower than 200 pg/mL and eight patients were above 200 pg/mL. Patients with lower hemoglobin concentration, higher right ventricular diameter or under diuretic treatment showed significant higher NT-pro-BNP levels (above 200 pg/dL). The Spearman test showed a positive correlation between basal right ventricular diameter and tricuspid regurgitation with pro NT BNP levels (correlation coefficient of .624; P=.017 and .490; P=.046, respectively) and a negative correlation with the right ventricle fractional area change (-.508, P=.045). No correlation was seen between NT-pro-BNP levels and the rest of echocardiographic parameters or the NYHA functional class. NT-pro-BNP levels showed a positive correlation with basal right ventricular diameter and tricuspid regurgitation but not with NYHA association functional class in d-TGA patients. © 2017, Wiley Periodicals, Inc.

  1. N-Terminal pro-B-Type Natriuretic Peptide Levels are Linked with Modified Child-Pugh Classification in Patients with Nonalcoholic Cirrhosis [NT-ProBNP and Liver Cirrhosis].

    PubMed

    Kumbasar, Abdulbaki; Navdar, Mehtap; Ataoglu, Esra; Uzunhasan, Isil; Ergen, Kadir; Poturoglu, Sule; Basinoglu, Filiz; Yilmaz, Fatih; Yenigun, Mustafa; Sar, Fuat; Tanriverdi, Ozgur

    2017-03-01

    Excess N-terminal pro-brain natriuretic peptide secretion has been linked to cirrhosis in previously studies. The relationship of plasma N-terminal pro-brain natriuretic peptide levels and cardiac dysfunction determined by echocardiography were investigated in patients with nonalcoholic cirrhosis and a control group of chronic hepatitis. This study was designed as a cross-sectional study. Thirty-two men and thirty-three women who gave informed consent who were followed-up for chronic liver failure were enrolled. All patients gave clinical history, physical examination was carried out and information about ongoing medication has been obtained. Serum N-terminal pro-brain natriuretic peptide level was measured in all patients. The same cardiologist determined ejection fraction, end-diastolic left ventricular diameter, interventricular septum, and posterior wall on transthoracic echocardiography. Patients with extensive liver disease according to Child-Pugh classification from A to C had increasing N-terminal pro-brain natriuretic peptide levels in association (P < .001). According to the Child-Pugh classification there were no significant difference between groups for echocardiographic measurements (P > .05). N-terminal pro-brain natriuretic peptide may be an important marker for cardiac dysfunction in patients with chronic liver failure in accordance with Child-Pugh stage.

  2. Interleukin-7 Plasma Levels in Human Differentiate Anorexia Nervosa, Constitutional Thinness and Healthy Obesity

    PubMed Central

    Germain, Natacha; Viltart, Odile; Loyens, Anne; Bruchet, Céline; Nadin, Katia; Wolowczuk, Isabelle; Estour, Bruno; Galusca, Bogdan

    2016-01-01

    Introduction Interleukin-7 (IL-7) is a cytokine involved in energy homeostasis as demonstrated in rodents. Anorexia nervosa is characterized by restrained eating behavior despite adaptive orexigenic regulation profile including high ghrelin plasma levels. Constitutional thinness is a physiological condition of resistance to weight gain with physiological anorexigenic profile including high Peptide YY plasma level. Healthy obesity can be considered as a physiological state of resistance to weight loss with opposite appetite regulating profile to constitutional thinness including low Peptide YY plasma level. No studies in IL-7 are yet available in those populations. Therefore we evaluated circadian plasma levels of IL-7 in anorexia nervosa compared to constitutional thinness, healthy obese and control females. Materials and Methods 10 restrictive-type anorexia nervosa women, 5 bingeing/purging anorexia nervosa woman, 5 recovered restrictive anorexia nervosa women, 4 bulimic females, 10 constitutional thinness women, 7 healthy obese females, and 10 normal weight women controls were enrolled in this cross-sectional study, performed in endocrinology unit and academic laboratory. Twelve-point circadian profiles of plasma IL-7 levels were measured in each subject. Results 24h mean IL-7 plasma levels (pg/ml, mean±SEM) were decreased in restrictive-type anorexia nervosa (123.4±14.4, p<0.0037), bingeing/purging anorexia nervosa (24.2±5.6, p<0.001), recovered restrictive anorexia nervosa (64.2±16.1, p = 0.01) and healthy obese patients (51±3.2, p<0.001) compared to controls (187.7±28.6). Bulimic patients (197.4±42.7) and constitutional thinness patients (264.3±35.8) were similar to controls. Conclusions Low IL-7 is part of the adaptive profile in restrictive-type anorexia nervosa, confirming its difference with constitutional thinness. Healthy obesity, with low IL-7, is once again in mirror image of constitutional thinness with normal high IL-7. PMID:27611669

  3. A Peptide Filtering Relation Quantifies MHC Class I Peptide Optimization

    PubMed Central

    Goldstein, Leonard D.; Howarth, Mark; Cardelli, Luca; Emmott, Stephen; Elliott, Tim; Werner, Joern M.

    2011-01-01

    Major Histocompatibility Complex (MHC) class I molecules enable cytotoxic T lymphocytes to destroy virus-infected or cancerous cells, thereby preventing disease progression. MHC class I molecules provide a snapshot of the contents of a cell by binding to protein fragments arising from intracellular protein turnover and presenting these fragments at the cell surface. Competing fragments (peptides) are selected for cell-surface presentation on the basis of their ability to form a stable complex with MHC class I, by a process known as peptide optimization. A better understanding of the optimization process is important for our understanding of immunodominance, the predominance of some T lymphocyte specificities over others, which can determine the efficacy of an immune response, the danger of immune evasion, and the success of vaccination strategies. In this paper we present a dynamical systems model of peptide optimization by MHC class I. We incorporate the chaperone molecule tapasin, which has been shown to enhance peptide optimization to different extents for different MHC class I alleles. Using a combination of published and novel experimental data to parameterize the model, we arrive at a relation of peptide filtering, which quantifies peptide optimization as a function of peptide supply and peptide unbinding rates. From this relation, we find that tapasin enhances peptide unbinding to improve peptide optimization without significantly delaying the transit of MHC to the cell surface, and differences in peptide optimization across MHC class I alleles can be explained by allele-specific differences in peptide binding. Importantly, our filtering relation may be used to dynamically predict the cell surface abundance of any number of competing peptides by MHC class I alleles, providing a quantitative basis to investigate viral infection or disease at the cellular level. We exemplify this by simulating optimization of the distribution of peptides derived from Human

  4. Influence of the amount of co-infused amino acids on post-therapeutic potassium levels in peptide receptor radionuclide therapy

    PubMed Central

    2014-01-01

    Background Peptide receptor radionuclide therapy (PRRT) is routinely used for advanced or metastasized neuroendocrine tumours (NET). To prevent nephrotoxicity, positively charged amino acids (AA) are co-infused. The aim of this study was to correlate the risk for therapy-related hyperkalaemia with the total amount of AA infused. Methods Twenty-two patients undergoing PRRT with standard activities of 177Lu-DOTATATE/-TOC were monitored during two following treatment cycles with co-infusion of 75 and 50 g of AA (l-arginine and l-lysine), respectively. Mean serum levels of potassium and other parameters (glomerular filtration rate [GFR], creatinine, blood urea nitrogen [BUN], phosphate, chloride, lactate dehydrogenase) prior to, 4 h and 24 h after AA infusion were compared. Results Self-limiting hyperkalaemia (>5.0 mmol/l) resolving after 24 h occurred in 91% (20/22) of patients in both protocols. Potassium levels, BUN, creatinine, GFR, phosphate, chloride and LDH showed a similar range at 4 h after co-infusion of 75 or 50 g of AA, respectively (p?>?0.05). Only GFR and creatinine levels at 24 h varied significantly between the two co-infusion protocols (p?

  5. Effect of left ventricular dyssynchrony on plasma B-type natriuretic peptide levels in patients with long-term right ventricular apical pacing.

    PubMed

    Kawanishi, Yasunori; Ito, Takahide; Suwa, Michihiro; Terasaki, Fumio; Futai, Rie; Kitaura, Yasushi

    2008-03-01

    Right ventricular apical pacing (RAP) has been reported to have the potential to lead to left ventricular (LV) dyssynchrony and impaired LV function. The plasma level of B-type natriuretic peptide (BNP) is increased in the state of abnormal ventricular wall stretch. Therefore, the aim of the present study was to examine the effect of LV dyssynchrony on BNP levels in patients with chronic RAP. Thirty-four patients (17 women, age 69 +/- 11 years) with preserved LV systolic function on permanent RAP (duration, 7.0 +/- 4.7 years) underwent conventional echo-Doppler assessment and tissue Doppler imaging. Twenty-two normal subjects (8 women, age 66 +/- 9 years) served as controls. The standard deviation (SD) and dispersion of the time-to-peak systolic velocity (TPV) among the 6 basal LV segments were used as the indexes of LV dyssynchrony. Compared with control subjects, RAP patients had prolonged TPVs and heterogeneous LV contraction with greater values of TPV-SD (18 +/- 8 ms versus 39 +/- 15 ms, P < 0.001) and TPV-dispersion (42 +/- 20 ms versus 93 +/- 31 ms, P < 0.001). There were significant correlations between BNP levels and the indexes of LV dyssynchrony (r = 0.41, P = 0.017 for TPV-SD; r = 0.46, P = 0.006 for TPV-dispersion). RAP is associated with LV dyssynchrony, which may accelerate BNP secretion.

  6. Elevations in growth hormone and glucagon-like peptide-2 levels on admission are associated with increased mortality in trauma patients

    SciTech Connect

    Rowan, Matthew P.; Beckman, Darrick J.; Rizzo, Julie A.; Isbell, Claire L.; White, Christopher E.; Cohn, Stephen M.; Chung, Kevin K.

    2016-10-04

    Burn and trauma patients present a clinical challenge due to metabolic derangements and hypermetabolism that result in a prolonged catabolic state with impaired healing and secondary complications, including ventilator dependence. Previous work has shown that circulating levels of growth hormone (GH) are predictive of mortality in critically ill adults, but few studies have examined the prognostic potential of GH levels in adult trauma patients. Here, our objective is to investigate the utility of GH and other endocrine responses in the prediction of outcomes, we conducted a prospective, observational study of adult burn and trauma patients. We evaluated the serum concentration of GH, insulin-like growth factor 1 (IGF-1), IGF binding protein 3 (IGFBP-3), and glucagon-like peptide-2 (GLP-2) weekly for up to 6 weeks in 36 adult burn and trauma patients admitted between 2010 and 2013. As a result, non-survivors had significantly higher levels of GH and GLP-2 on admission than survivors. This study demonstrates that GH has potential as a predictor of mortality in critically ill trauma and burn patients. Future studies will focus on not only the role of GH, but also GLP-2, which was shown to correlate with mortality in this study with a goal of offering early, targeted therapeutic interventions aimed at decreasing mortality in the critically injured. GH and GLP-2 may have clinical utility for outcome prediction in adult trauma patients.

  7. Elevations in growth hormone and glucagon-like peptide-2 levels on admission are associated with increased mortality in trauma patients

    DOE PAGES

    Rowan, Matthew P.; Beckman, Darrick J.; Rizzo, Julie A.; ...

    2016-10-04

    Burn and trauma patients present a clinical challenge due to metabolic derangements and hypermetabolism that result in a prolonged catabolic state with impaired healing and secondary complications, including ventilator dependence. Previous work has shown that circulating levels of growth hormone (GH) are predictive of mortality in critically ill adults, but few studies have examined the prognostic potential of GH levels in adult trauma patients. Here, our objective is to investigate the utility of GH and other endocrine responses in the prediction of outcomes, we conducted a prospective, observational study of adult burn and trauma patients. We evaluated the serum concentrationmore » of GH, insulin-like growth factor 1 (IGF-1), IGF binding protein 3 (IGFBP-3), and glucagon-like peptide-2 (GLP-2) weekly for up to 6 weeks in 36 adult burn and trauma patients admitted between 2010 and 2013. As a result, non-survivors had significantly higher levels of GH and GLP-2 on admission than survivors. This study demonstrates that GH has potential as a predictor of mortality in critically ill trauma and burn patients. Future studies will focus on not only the role of GH, but also GLP-2, which was shown to correlate with mortality in this study with a goal of offering early, targeted therapeutic interventions aimed at decreasing mortality in the critically injured. GH and GLP-2 may have clinical utility for outcome prediction in adult trauma patients.« less

  8. Inverse relationship of bone mineral density and serum level of N-terminal pro-B-type natriuretic peptide in peritoneal dialysis patients.

    PubMed

    Wang, Chih-Hsien; Tsai, Jen-Pi; Lai, Yu-Hsien; Lin, Yu-Li; Kuo, Chiu-Huang; Hsu, Bang-Gee

    2016-01-01

    Chronic kidney disease is associated with decreased bone mineral density (BMD). In this study, the relationship between BMD and the fasting serum concentration of N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) was evaluated in peritoneal dialysis (PD) patients. Fasting blood samples were obtained from 52 PD patients. BMD was measured by dual energy X-ray absorptiometry of the lumbar vertebrae (L2-L4). The serum NT-pro-BNP level was measured by an electrochemiluminescence immunoassay. Ten patients (19.2%) had osteoporosis, 23 patients (44.2%) had osteopenia, and 19 patients had normal BMD. Increased serum NT-pro-BNP (p < 0.001), advanced age (p = 0.012), decreased body mass index (p = 0.006), body height (p = 0.018), and body weight (p = 0.004) were associated with lower lumbar T-scores, but sex, menopausal status, PD modality, diabetes mellitus, and hypertension were not. Multivariate forward stepwise linear regression analysis with adjustment for age, body height, body weight, body mass index, and log-NT-pro-BNP indicated that a high serum level of log-NT-pro-BNP (R(2) change = 0.346; p < 0.001) and low body weight (R(2) change = 0.208; p < 0.001) were significantly and independently associated with poor lumbar BMD. A high serum level of NT-pro-BNP and low body weight were associated with poor BMD in PD patients.

  9. Expression of human uncoupling protein-3 in Drosophila insulin-producing cells increases insulin-like peptide (DILP) levels and shortens lifespan.

    PubMed

    Humphrey, Dickon M; Toivonen, Janne M; Giannakou, Maria; Partridge, Linda; Brand, Martin D

    2009-05-01

    Uncoupling proteins (UCPs) can dissipate mitochondrial protonmotive force by increasing the proton conductance of the inner membrane and through this effect could decrease ROS production, ameliorate oxidative stress and extend lifespan. We investigated whether ubiquitous, pan-neuronal or neurosecretory cell-specific expression of human UCP3 (hUCP3) in adult Drosophila melanogaster affected lifespan. Low, ubiquitous expression of hUCP3 at levels found in rodent skeletal muscle mitochondria did not affect proton conductance in mitochondria isolated from whole flies, but high pan-neuronal expression of hUCP3 increased the proton conductance of mitochondria isolated from fly heads. Expression of hUCP3 at moderate levels in adult neurons led to a marginal lifespan-extension in males. However, high expression of hUCP3 in neuronal tissue shortened lifespan. The life-shortening effect was replicated when hUCP3 was expressed specifically in median neurosecretory cells (mNSC), which express three of the Drosophila insulin-like peptides (DILPs). Expression of hUCP3 in the mNSC did not alter expression of dilp2, dilp3 or dilp5 mRNA, but led to increased amounts of DILP2 in fly heads. These data suggest that lowering mitochondrial coupling by high expression of hUCP3 alters mNSC function in a way that appears to increase DILP-levels in fly heads and lead to a concomitant decrease in lifespan.

  10. COPS5 (Jab1) protein increases β site processing of amyloid precursor protein and amyloid β peptide generation by stabilizing RanBP9 protein levels.

    PubMed

    Wang, Hongjie; Dey, Debleena; Carrera, Ivan; Minond, Dmitriy; Bianchi, Elisabetta; Xu, Shaohua; Lakshmana, Madepalli K

    2013-09-13

    Increased processing of amyloid precursor protein (APP) and accumulation of neurotoxic amyloid β peptide (Aβ) in the brain is central to the pathogenesis of Alzheimer's disease (AD). Therefore, the identification of molecules that regulate Aβ generation is crucial for future therapeutic approaches for AD. We demonstrated previously that RanBP9 regulates Aβ generation in a number of cell lines and primary neuronal cultures by forming tripartite protein complexes with APP, low-density lipoprotein-related protein, and BACE1, consequently leading to increased amyloid plaque burden in the brain. RanBP9 is a scaffold protein that exists and functions in multiprotein complexes. To identify other proteins that may bind RanBP9 and regulate Aβ levels, we used a two-hybrid analysis against a human brain cDNA library and identified COPS5 as a novel RanBP9-interacting protein. This interaction was confirmed by coimmunoprecipitation experiments in both neuronal and non-neuronal cells and mouse brain. Colocalization of COPS5 and RanBP9 in the same subcellular compartments further supported the interaction of both proteins. Furthermore, like RanBP9, COPS5 robustly increased Aβ generation, followed by increased soluble APP-β (sAPP-β) and decreased soluble-APP-α (sAPP-α) levels. Most importantly, down-regulation of COPS5 by siRNAs reduced Aβ generation, implying that endogenous COPS5 regulates Aβ generation. Finally, COPS5 levels were increased significantly in AD brains and APΔE9 transgenic mice, and overexpression of COPS5 strongly increased RanBP9 protein levels by increasing its half-life. Taken together, these results suggest that COPS5 increases Aβ generation by increasing RanBP9 levels. Thus, COPS5 is a novel RanBP9-binding protein that increases APP processing and Aβ generation by stabilizing RanBP9 protein levels.

  11. The possible link between elevated serum levels of epithelial cell-derived neutrophil-activating peptide-78 (ENA-78/CXCL5) and autoimmunity in autistic children.

    PubMed

    Mostafa, Gehan Ahmed; Al-Ayadhi, Laila Yousef

    2015-03-19

    In autoimmune disorders, the underlying pathogenic mechanism is the formation of antigen-antibody complexes which trigger an inflammatory response by inducing the infiltration of neutrophils. Epithelial cell-derived neutrophil-activating peptide-78 (ENA-78) is a chemokine that recruits and activates neutrophils, thus it could play a pathogenic role in inflammation and autoimmune disorders. Some autistic children have elevated levels of brain specific auto-antibodies. We are the first to evaluate serum expression of ENA-78 and its relation to antineuronal auto-antibodies in autistic children. Serum ENA-78 and antineuronal auto-antibodies were measured by ELISA test in 62 autistic children aged between 4-11 years and 62 health-matched controls. Serum levels of ENA-78 were significantly higher in autistic children than healthy controls (P < 0.001). Increased serum levels of ENA-78 have been found in 69.35% of autistic patients. In addition, autistic children had significantly higher percent positivity of serum antineuronal auto-antibodies (64.5%) than healthy controls (6.45%), P < 0.001. There was a significant positive association between the positivity of serum antineuronal auto-antibodies and the elevated levels of serum ENA-78 (P < 0.001) in autistic children. Serum levels of ENA-78 were elevated in autistic children and they were significantly associated with the increased levels of serum antineuronal auto-antibodies. However, these data should be treated with caution until further research is conducted to determine the pathogenic role of ENA-78 in autism and its relation to brain specific auto-antibodies that have been found in some autistic children. The possible therapeutic role of ENA-78 antagonist in autistic children should be also studied.

  12. Vitamin D3 administration to MS patients leads to increased serum levels of latency activated peptide (LAP) of TGF-beta.

    PubMed

    Åivo, Julia; Hänninen, Arno; Ilonen, Jorma; Soilu-Hänninen, Merja

    2015-03-15

    Deficiency of vitamin D is an environmental risk factor for MS. Vitamin D has immunomodulatory effects, including promotion of T-cell differentiation into T-regulatory cells, which produces regulatory cytokines including TGF-β. Increasing serum vitamin D levels have been associated with decreased disease activity in MS patients, but there are only few studies concerning the immunological effects of vitamin D supplementation in MS. In this study we investigated the effect of weekly supplementation of vitamin D3 or placebo on serum levels of multiple cytokines in patients with relapsing remitting MS. The study was conducted on the patient cohort of the Finnish Vitamin D study. All patients were using IFN-beta-1b and were randomized to add-on treatment with either cholecalciferol 20,000 IU/week or placebo. Concentrations of LAP (TGF-β), INF-γ, IL-17A, IL-2, IL-10, IL-9, IL-22, IL-6, IL-13, IL-4, IL-5, IL-1β and TNF-α were determined at screening and at 12 months using commercial fluorescent bead immunoassay kits. LAP (TGF-β) levels increased significantly in the vitamin D treated group from a mean of 47 (SE 11) pg/ml to 55 (SE 14) pg/ml in 12 months (p-value=0.0249). Placebo treatment had no significant effect on LAP levels. The levels of the other cytokines did not change significantly in either group. We showed increased serum latency activated peptide (LAP) of TGF-β levels in MS patients treated with vitamin D3. The immune regulatory effects of TGF-beta may play a role in the improved MRI outcomes that we observed earlier in the vitamin D treated group of patients. Copyright © 2015 Elsevier B.V. All rights reserved.

  13. Sardine protein diet increases plasma glucagon-like peptide-1 levels and prevents tissue oxidative stress in rats fed a high-fructose diet.

    PubMed

    Madani, Zohra; Sener, Abdullah; Malaisse, Willy J; Dalila, Ait Yahia

    2015-11-01

    The current study investigated whether sardine protein mitigates the adverse effects of fructose on plasma glucagon‑like peptide-1 (GLP-1) and oxidative stress in rats. Rats were fed casein (C) or sardine protein (S) with or without high‑fructose (HF) for 2 months. Plasma glucose, insulin, GLP‑1, lipid and protein oxidation and antioxidant enzymes were assayed. HF rats developed obesity, hyperglycemia, hyperinsulinemia, insulin resistance and oxidative stress despite reduced energy and food intakes. High plasma creatinine and uric acid levels, in addition to albuminuria were observed in the HF groups. The S‑HF diet reduced plasma glucose, insulin, creatinine, uric acid and homeostasis model assessment‑insulin resistance index levels, however increased GLP‑1 levels compared with the C‑HF diet. Hydroperoxides were reduced in the liver, kidney, heart and muscle of S‑HF fed rats compared with C‑HF fed rats. A reduction in liver, kidney and heart carbonyls was observed in S‑HF fed rats compared with C‑HF fed rats. Reduced levels of nitric oxide (NO) were detected in the liver, kidney and heart of the S‑HF fed rats compared with C‑HF fed rats. The S diet compared with the C diet reduced levels of liver hydroperoxides, heart carbonyls and kidney NO. The S‑HF diet compared with the C‑HF diet increased the levels of liver and kidney superoxide dismutase, liver and muscle catalase, liver, heart and muscle glutathione peroxidase and liver ascorbic acid. The S diet prevented and reversed insulin resistance and oxidative stress, and may have benefits in patients with metabolic syndrome.

  14. Effects of sleeve gastrectomy and medical treatment for obesity on glucagon-like peptide 1 levels and glucose homeostasis in non-diabetic subjects.

    PubMed

    Valderas, Juan Patricio; Irribarra, Veronica; Rubio, Lorena; Boza, Camilo; Escalona, Manuel; Liberona, Yessica; Matamala, Andrea; Maiz, Alberto

    2011-07-01

    The effects of medical and surgical treatments for obesity on glucose metabolism and glucagon-like peptide 1 (GLP-1) levels independent of weight loss remain unclear. This study aims to assess plasma glucose levels, insulin sensitivity and secretion, and GLP-1 levels before and after sleeve gastrectomy (SG) or medical treatment (MED) for obesity. This study is a prospective, controlled, non-randomised study. Two groups of non-diabetic obese patients with similar BMIs, including a SG group (BMI, 35.5 ± 0.9 kg/m(2); n = 6) and a MED group (BMI, 37.7 ± 1.9 kg/m(2); n = 6) and a group of lean subjects (BMI, 21.7 ± 0.7 kg/m(2); n = 8). Plasma glucose, insulin, and total GLP-1 levels at fasting and after the intake of a standard liquid meal at baseline and at 2 months post-intervention. At baseline, total GLP-1 levels were similar, but obese patients had lower insulin sensitivity and higher insulin secretion than lean subjects. At 2 months post-intervention, SG and MED patients achieved similar weight loss (14.4 ± 0.8%, 15.3 ± 0.9%, respectively). Insulin sensitivity increased in SG and MED patients; however, postprandial insulin secretion decreased after MED, but not after SG. The incremental area under the curve of GLP-1 increased after SG (P = 0.04), but not after MED. Weight loss by medical or surgical treatment improved insulin sensitivity. However, only MED corrected the hyperinsulinemic postprandial state associated to obesity. Postprandial GLP-1 levels increased significantly after SG without duodenal exclusion, which may explain why insulin secretion did not decrease following this surgery.

  15. ECL-cell histamine mobilization in conscious rats: effects of locally applied regulatory peptides, candidate neurotransmitters and inflammatory mediators.

    PubMed

    Norlén, P; Bernsand, M; Konagaya, T; Håkanson, R

    2001-12-01

    1. The ECL cells control gastric acid secretion by mobilizing histamine in response to circulating gastrin. In addition, the ECL cells are thought to operate under nervous control and to be influenced by local inflammatory processes. 2. The purpose of the present study was to monitor histamine mobilization from ECL cells in conscious rats in response to locally applied regulatory peptides, candidate neurotransmitters and inflammatory mediators. 3. Microdialysis probes were implanted in the submucosa of the acid-producing part of the rat stomach. Three days later, the agents to be tested were administered via the microdialysis probe and their effects on basal (48 h fast) and stimulated (intravenous infusion of gastrin-17, 3 nmol kg(-1) h(-1)) mobilization of ECL-cell histamine was monitored by continuous measurement of histamine in the perfusate (radioimmunoassay). 4. Locally administered gastrin-17 and sulfated cholecystokinin-8 mobilized histamine as did pituitary adenylate cyclase-activating peptide-27, vasoactive intestinal peptide, peptide YY, met-enkephalin, endothelin and noradrenaline, adrenaline and isoprenaline. 5. While gastrin, sulfated-cholecystokinin-8, met-enkephalin and isoprenaline induced a sustained elevation of the submucosal histamine concentration, endothelin, peptide YY, pituitary adenylate cyclase activating peptide, vasoactive intestinal peptide, noradrenaline and adrenaline induced a transient elevation. 6. Calcitonin gene-related peptide, galanin, somatostatin and the prostanoid misoprostol inhibited gastrin-stimulated histamine mobilization. 7. The gut hormones neurotensin and secretin and the neuropeptides gastrin-releasing peptide, neuropeptide Y and substance P failed to affect ECL-cell histamine mobilization, while motilin and neuromedin U-25 had weak stimulatory effects. Also acetylcholine, carbachol, serotonin and the amino acid neurotransmitters aspartate, gamma-aminobutyric acid, glutamate and glycine were inactive or weakly

  16. Pro-Brain Natriuretic Peptide and Troponin T-Hypersensitivity Levels Correlate With the Severity of Liver Dysfunction in Liver Cirrhosis.

    PubMed

    Zhao, Jiancheng; Li, Sai; Ren, Linan; Guo, Xiaozhong; Qi, Xingshun

    2017-08-01

    Increased pro-brain natriuretic peptide (pro-BNP) or troponin T-hypersensitivity (TnT-HSST) levels are common in liver cirrhosis. We conducted a retrospective observational study aimed to evaluate the correlation of pro-BNP and TnT-HSST levels with the clinical characteristics, laboratory data and in-hospital outcomes of patients with liver cirrhosis. We selected cirrhotic patients admitted to our hospital between January 2011 and June 2014. All eligible patients had pro-BNP or TnT-HSST data, or both. The pro-BNP and TnT-HSST data were further divided according to the presence of cardiac diseases. The prevalence of pro-BNP level >900pg/mL was 41.72% (63 of 151 patients). The prevalence of TnT-HSST level >0.05ng/mL was 11.22% (45 of 401 patients). In the overall analysis, pro-BNP level significantly correlated with red blood cell (RBC), platelet, ascites, blood urea nitrogen (BUN), creatinine (Cr), Child-Pugh score, model for end-stage liver disease (MELD) score and in-hospital death; TnT-HSST level significantly correlated with white blood cell, ascites, albumin (ALB), BUN, Cr, Child-Pugh score, MELD score and in-hospital death. In patients with cardiac diseases, pro-BNP level significantly correlated with RBC, ascites, BUN, Cr, Child-Pugh score and MELD score; TnT-HSST level significantly correlated with sex, ascites, white blood cell, ALB, BUN, Cr, Child-Pugh score, MELD score and in-hospital death. In patients without cardiac diseases, pro-BNP level significantly correlated with ascites, RBC, platelet, BUN, Cr, MELD score and in-hospital death; TnT-HSST level significantly correlated with age, ascites, RBC, ALB, BUN, Cr, Child-Pugh score, MELD score and in-hospital death. Pro-BNP and TnT-HSST levels significantly correlated with the severity of liver dysfunction and in-hospital mortality in cirrhosis. Copyright © 2017 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.

  17. High Serum Levels of Pro-Brain Natriuretic Peptide (pro BNP) Identify Cardioembolic Origin in Undetermined Stroke

    PubMed Central

    Rodríguez-Yáñez, Manuel; Sobrino, Tomás; Blanco, Miguel; de la Ossa, Natalia Pérez; Brea, David; Rodríguez-González, Raquel; Leira, Rogelio; Dávalos, Antonio; Castillo, José

    2009-01-01

    Background: Stroke subtype diagnosis leads to specific therapies to reduce recurrences. Because nearly one third of patients remain with unknown etiology after a complete screening workup, we aim to investigate whether molecular markers of myocardial damage were associated with cardioembolic stroke and if they were useful to reclassify strokes of undetermined etiology. Methods: We included 262 patients with first ischemic stroke within the first 12 hours. Stroke subtype was evaluated by TOAST criteria. Stroke of undetermined origin were reclassified into likely atherothrombotic or likely cardioembolic according to a predefined non-validated algorithm. Blood samples were obtained on admission to determine serum levels of molecular markers (pro-BNP, pro-ANP and CK-MB) of myocardial damage. Results: Patients with cardioembolic infarct showed higher levels of pro-BNP, pro-ANP and CK-MB. Pro-BNP > 360 pg/mL was independently associated with cardioembolic stroke (OR: 28.51, CI95%: 5.90–136.75, p < 0.0001). Stroke etiology was undetermined in 82 patients (31%); 34 were reclassified as likely cardioembolic, 22 as likely atherothrombotic, and 26 remained as undetermined. Pro-BNP > 360 pg/mL was the only factor independently associated with likely cardioembolic stroke. Conclusions: Pro-BNP levels higher than 360 pg/mL are associated with cardioembolic stroke and may be useful to reclassify undetermined strokes as of cardioembolic origin. PMID:19729800

  18. Self-assembled peptide nanotubes as electronic materials: An evaluation from first-principles calculations

    SciTech Connect

    Akdim, Brahim E-mail: ruth.pachter@us.af.mil; Pachter, Ruth E-mail: ruth.pachter@us.af.mil; Naik, Rajesh R.

    2015-05-04

    In this letter, we report on the evaluation of diphenylalanine (FF), dityrosine (YY), and phenylalanine-tryptophan (FW) self-assembled peptide nanotube structures for electronics and photonics applications. Realistic bulk peptide nanotube material models were used in density functional theory calculations to mimic the well-ordered tubular nanostructures. Importantly, validated functionals were applied, specifically by using a London dispersion correction to model intertube interactions and a range-separated hybrid functional for accurate bandgap calculations. Bandgaps were found consistent with available experimental data for FF, and also corroborate the higher conductance reported for FW in comparison to FF peptide nanotubes. Interestingly, the predicted bandgap for the YY tubular nanostructure was found to be slightly higher than that of FW, suggesting higher conductance as well. In addition, the band structure calculations along the high symmetry line of nanotube axis revealed a direct bandgap for FF. The results enhance our understanding of the electronic properties of these material systems and will pave the way into their application in devices.

  19. A combination of P wave electrocardiography and plasma brain natriuretic peptide level for predicting the progression to persistent atrial fibrillation: comparisons of sympathetic activity and left atrial size.

    PubMed

    Akutsu, Yasushi; Kaneko, Kyouichi; Kodama, Yusuke; Miyoshi, Fumito; Li, Hui-Ling; Watanabe, Norikazu; Asano, Taku; Tanno, Kaoru; Suyama, Jumpei; Namiki, Atsuo; Gokan, Takehiko; Kobayashi, Youichi

    2013-11-01

    Development of atrial fibrillation (AF) is complexly associated with electrical and structural remodeling and other factors every stage of AF development. We hypothesized that P wave electrocardiography with an elevated brain natriuretic peptide (BNP) level would be associated with the progression to persistence from paroxysmal AF. P wave electrocardiography such as a maximum P wave duration (MPWD) and dispersion by 12-leads ECG, heart/mediastinum (H/M) ratio by delayed iodine-123 metaiodobenzylguanidine scintigraphic imaging, left ventricular ejection fraction (LVEF), and left atrial dimension (LAD) by echocardiography, and plasma BNP level were measured to evaluate the electrical and structural properties and sympathetic activity in 71 patients (mean ± standard deviation, age: 67 ± 13 years, 63.4 % males) with idiopathic paroxysmal AF. Over a 12.9-year follow-up period, AF developed into persistent AF in 30 patients. A wider MPWD (>129 ms) (p = 0.001), wider P wave dispersion (>60 ms) (p = 0.001), LAD enlargement (>40 mm) (p = 0.001), higher BNP level (>72 pg/mL) (p = 0.002), lower H/M ratio (≤2.7) (p = 0.025), and lower LVEF (≤60 %) (p = 0.035) were associated with the progression to persistent AF, and the wide MPWD was an independently powerful predictor of the progression to persistent AF with a hazard ratio (HR) of 5.49 [95 % confidence interval (CI) 2.38-12.7, p < 0.0001] after adjusting for potential confounding variables, such as age and sex. The combination of wide MPWD and elevated BNP level was additive and incremental prognostic power with 13.3 [2.16-13, p < 0.0001]. The wide MPWD with elevated BNP level was associated with the progression to persistent AF.

  20. Urinary C-peptide levels in male bonobos (Pan paniscus) are related to party size and rank but not to mate competition.

    PubMed

    Surbeck, Martin; Deschner, Tobias; Behringer, Verena; Hohmann, Gottfried

    2015-05-01

    Within- and between-species variation in male mating strategies has been attributed to a multitude of factors including male competitive ability and the distribution of fertile females across space and time. Differences in energy balance across and within males allow for the identification of some of the trade-offs associated with certain social and mating strategies. Bonobos live in groups with a high degree of fission-fusion dynamics, there is co-dominance between the sexes and a linear dominance hierarchy among males. Males compete over access to females, breeding is aseasonal, and females exhibit sexual swellings over extended time periods. In this study we use urinary C-peptide (UCP) levels in male bonobos (Pan paniscus) obtained from 260 urine samples from a wild bonobo community, to quantify male energy balance during mate competition and levels of gregariousness in the species. Although high ranking males are more aggressive, spend more time in proximity to maximally tumescent females, and have higher mating frequencies, we found no indication that mate guarding or mate competition affected male energy balance. Our results showed a positive correlation between monthly mean UCP levels and mean party size. When traveling in large parties, high ranking males had higher UCP levels than those of the low ranking males. These results support the hypothesis that patterns of fission-fusion dynamics in bonobos are either linked to energy availability in the environment or to the energetic costs of foraging. The finding of a rank-bias in UCP levels in larger parties could also reflect an increase in contest competition among males over access to food.

  1. Mosapride citrate, a 5-HT₄ receptor agonist, increased the plasma active and total glucagon-like peptide-1 levels in non-diabetic men.

    PubMed

    Aoki, Kazutaka; Kamiyama, Hiroshi; Masuda, Kiyomi; Togashi, Yu; Terauchi, Yasuo

    2013-01-01

    Mosapride citrate, a selective agonist of the 5-hydroxytryptaine (5-HT)₄ receptor, is typically used to treat heartburn, nausea, and vomiting associated with chronic gastritis or to prepare for a barium enema X-ray examination. Mosapride citrate reportedly improves insulin sensitivity in patients with type 2 diabetes. As mosapride citrate activates the motility of the gastrointestinal tract, we hypothesized that mosapride citrate affects incretin secretion. We examined the effect of the administration of mosapride citrate on the plasma glucose, serum insulin, plasma glucagon, and plasma incretin levels before breakfast and at 60, 120, and 180 min after breakfast in men with normal glucose tolerance (NGT) or impaired glucose tolerance (IGT) to exclude gastropathy. Mosapride citrate was administered according to two different intake schedules (C: control (no drug), M: mosapride citrate 20 mg) in each of the subject groups. The area under the curve (AUC) of the plasma glucose levels was smaller in the M group than in the C group. The time profiles for the serum insulin levels at 60 and 120 min after treatment with mosapride citrate tended to be higher, although the difference was not statistically significant. The AUCs of the plasma active and total glucagon-like peptide-1 (GLP-1) levels were significantly larger in the M group than in the C group. No significant difference in the AUC of the plasma glucose-dependent insulinotropic polypeptide (GIP) level was observed between the two groups. Our results suggest that mosapride citrate may have an antidiabetic effect by increasing GLP-1 secretion.

  2. The effects of orbital spaceflight on bone histomorphometry and messenger ribonucleic acid levels for bone matrix proteins and skeletal signaling peptides in ovariectomized growing rats

    NASA Technical Reports Server (NTRS)

    Cavolina, J. M.; Evans, G. L.; Harris, S. A.; Zhang, M.; Westerlind, K. C.; Turner, R. T.

    1997-01-01

    A 14-day orbital spaceflight was performed using ovariectomized Fisher 344 rats to determine the combined effects of estrogen deficiency and near weightlessness on tibia radial bone growth and cancellous bone turnover. Twelve ovariectomized rats with established cancellous osteopenia were flown aboard the space shuttle Columbia (STS-62). Thirty ovariectomized rats were housed on earth as ground controls: 12 in animal enclosure modules, 12 in vivarium cages, and 6 killed the day of launch for baseline measurements. An additional 18 ovary-intact rats were housed in vivarium cages as ground controls: 8 rats were killed as baseline controls and the remaining 10 rats were killed 14 days later. Ovariectomy increased periosteal bone formation at the tibia-fibula synostosis; cancellous bone resorption and formation in the secondary spongiosa of the proximal tibial metaphysis; and messenger RNA (mRNA) levels for the prepro-alpha2(1) subunit of type 1 collagen, osteocalcin, transforming growth factor-beta, and insulin-like growth factor I in the contralateral proximal tibial metaphysis and for the collagen subunit in periosteum pooled from tibiae and femora and decreased cancellous bone area. Compared to ovariectomized weight-bearing rats, the flight group experienced decreases in periosteal bone formation, collagen subunit mRNA levels, and cancellous bone area. The flight rats had a small decrease in the cancellous mineral apposition rate, but no change in the calculated bone formation rate. Also, spaceflight had no effect on cancellous osteoblast and osteoclast perimeters or on mRNA levels for bone matrix proteins and signaling peptides. On the other hand, spaceflight resulted in an increase in bone resorption, as ascertained from the diminished retention of a preflight fluorochrome label. This latter finding suggests that osteoclast activity was increased. In a follow-up ground-based experiment, unilateral sciatic neurotomy of ovariectomized rats resulted in cancellous

  3. The effects of orbital spaceflight on bone histomorphometry and messenger ribonucleic acid levels for bone matrix proteins and skeletal signaling peptides in ovariectomized growing rats

    NASA Technical Reports Server (NTRS)

    Cavolina, J. M.; Evans, G. L.; Harris, S. A.; Zhang, M.; Westerlind, K. C.; Turner, R. T.

    1997-01-01

    A 14-day orbital spaceflight was performed using ovariectomized Fisher 344 rats to determine the combined effects of estrogen deficiency and near weightlessness on tibia radial bone growth and cancellous bone turnover. Twelve ovariectomized rats with established cancellous osteopenia were flown aboard the space shuttle Columbia (STS-62). Thirty ovariectomized rats were housed on earth as ground controls: 12 in animal enclosure modules, 12 in vivarium cages, and 6 killed the day of launch for baseline measurements. An additional 18 ovary-intact rats were housed in vivarium cages as ground controls: 8 rats were killed as baseline controls and the remaining 10 rats were killed 14 days later. Ovariectomy increased periosteal bone formation at the tibia-fibula synostosis; cancellous bone resorption and formation in the secondary spongiosa of the proximal tibial metaphysis; and messenger RNA (mRNA) levels for the prepro-alpha2(1) subunit of type 1 collagen, osteocalcin, transforming growth factor-beta, and insulin-like growth factor I in the contralateral proximal tibial metaphysis and for the collagen subunit in periosteum pooled from tibiae and femora and decreased cancellous bone area. Compared to ovariectomized weight-bearing rats, the flight group experienced decreases in periosteal bone formation, collagen subunit mRNA levels, and cancellous bone area. The flight rats had a small decrease in the cancellous mineral apposition rate, but no change in the calculated bone formation rate. Also, spaceflight had no effect on cancellous osteoblast and osteoclast perimeters or on mRNA levels for bone matrix proteins and signaling peptides. On the other hand, spaceflight resulted in an increase in bone resorption, as ascertained from the diminished retention of a preflight fluorochrome label. This latter finding suggests that osteoclast activity was increased. In a follow-up ground-based experiment, unilateral sciatic neurotomy of ovariectomized rats resulted in cancellous

  4. Effect of Sodium Glucose Cotransporter 2 Inhibitors With Low SGLT2/SGLT1 Selectivity on Circulating Glucagon-Like Peptide 1 Levels in Type 2 Diabetes Mellitus

    PubMed Central

    Takebayashi, Kohzo; Inukai, Toshihiko

    2017-01-01

    Sodium glucose cotransporter 2 (SGLT2) inhibitors are a new class of antidiabetic drugs that improve glycemic control by inhibiting reabsorption of glucose filtered through the renal glomerulus. Use of drugs in this class has increased because of their effect of decreasing body weight and a low risk for hypoglycemia, in addition to a relatively strong glucose-lowering effect. SGLT2 inhibitors such as canagliflozin and sotagliflozin (a SGLT1/SGLT2 dual inhibitor) also have a mild or moderate intestinal and renal SGLT1 inhibitory effect because of their relatively weak selectivity for SGLT2 over SGLT1. Recent evidence shows that these SGLT2 inhibitors with low SGLT2/SGLT1 selectivity elevate the level of circulating glucagon like peptide-1 (GLP-1), an incretin hormone that promotes insulin secretion in pancreatic β cells. This effect probably occurs partly via inhibition of intestinal SGLT1, and the elevation of active GLP-1 levels is especially apparent when these drugs are co-administered with dipeptidyl peptidase 4 (DPP4) inhibitors. These findings suggest that a combination of canagliflozin or sotagliflozin and a DPP4 inhibitor can provide a beneficial effect associated with elevation of circulating active GLP-1 and may serve as a treatment for patients with type 2 diabetes. PMID:28811850

  5. Effect of Sodium Glucose Cotransporter 2 Inhibitors With Low SGLT2/SGLT1 Selectivity on Circulating Glucagon-Like Peptide 1 Levels in Type 2 Diabetes Mellitus.

    PubMed

    Takebayashi, Kohzo; Inukai, Toshihiko

    2017-09-01

    Sodium glucose cotransporter 2 (SGLT2) inhibitors are a new class of antidiabetic drugs that improve glycemic control by inhibiting reabsorption of glucose filtered through the renal glomerulus. Use of drugs in this class has increased because of their effect of decreasing body weight and a low risk for hypoglycemia, in addition to a relatively strong glucose-lowering effect. SGLT2 inhibitors such as canagliflozin and sotagliflozin (a SGLT1/SGLT2 dual inhibitor) also have a mild or moderate intestinal and renal SGLT1 inhibitory effect because of their relatively weak selectivity for SGLT2 over SGLT1. Recent evidence shows that these SGLT2 inhibitors with low SGLT2/SGLT1 selectivity elevate the level of circulating glucagon like peptide-1 (GLP-1), an incretin hormone that promotes insulin secretion in pancreatic β cells. This effect probably occurs partly via inhibition of intestinal SGLT1, and the elevation of active GLP-1 levels is especially apparent when these drugs are co-administered with dipeptidyl peptidase 4 (DPP4) inhibitors. These findings suggest that a combination of canagliflozin or sotagliflozin and a DPP4 inhibitor can provide a beneficial effect associated with elevation of circulating active GLP-1 and may serve as a treatment for patients with type 2 diabetes.

  6. Peptide identification

    DOEpatents

    Jarman, Kristin H [Richland, WA; Cannon, William R [Richland, WA; Jarman, Kenneth D [Richland, WA; Heredia-Langner, Alejandro [Richland, WA

    2011-07-12

    Peptides are identified from a list of candidates using collision-induced dissociation tandem mass spectrometry data. A probabilistic model for the occurrence of spectral peaks corresponding to frequently observed partial peptide fragment ions is applied. As part of the identification procedure, a probability score is produced that indicates the likelihood of any given candidate being the correct match. The statistical significance of the score is known without necessarily having reference to the actual identity of the peptide. In one form of the invention, a genetic algorithm is applied to candidate peptides using an objective function that takes into account the number of shifted peaks appearing in the candidate spectrum relative to the test spectrum.

  7. Treatment of hypertension with perindopril reduces plasma atrial natriuretic peptide levels, left ventricular mass, and improves echocardiographic parameters of diastolic function

    NASA Technical Reports Server (NTRS)

    Yalcin, F.; Aksoy, F. G.; Muderrisoglu, H.; Sabah, I.; Garcia, M. J.; Thomas, J. D.

    2000-01-01

    BACKGROUND: Hypertension is a major independent risk factor for cardiac deaths, and diastolic dysfunction is a usual finding during the course of this disease. HYPOTHESIS: This study was designed to investigate the effects of chronic therapy with perindopril on left ventricular (LV) mass, left atrial size, diastolic function, and plasma level of atrial natriuretic peptide (ANP) in patients with hypertension. METHODS: Twenty four patients who had not been previously taking any antihypertensive medication and without prior history of angina pectoris, myocardial infarction, congestive heart failure, dysrhythmias, valvular heart disease, or systemic illnesses received 4-8 mg/day of perindopril orally. Echocardiographic studies were acquired at baseline and 6 months after the initiation of therapy. RESULTS: Systolic and diastolic blood pressure decreased from 174 +/- 19.7 and 107.5 +/- 7.8 mmHg to 134 +/- 10.6 and 82 +/- 6.7 mmHg, respectively (p < 0.001). Left ventricular mass decreased from 252.4 +/- 8.3 to 205.7 +/- 7.08 g and left atrial volume from 20.4 +/- 5.1 to 17.6 +/- 5.2 ml, respectively (p < 0.001). Transmitral Doppler early and atrial filling velocity ratio (E/A) increased from 0.69 +/- 0.06 to 0.92 +/- 0.05 m/s and plasma ANP level decreased from 71.9 +/- 11.7 to 35.3 +/- 7.8 pg/ml (p < 0.001). Reduction of LV mass correlated positively with a reduction in ANP levels (r = 0.66, p < 0.0005). CONCLUSIONS: Perindopril caused a significant reduction of LV mass, left atrial volume, and plasma ANP levels, as well as improvement in Doppler parameters of LV filling in this group of patients with hypertension.

  8. Impact of decreased serum albumin levels on acute kidney injury in patients with acute decompensated heart failure: a potential association of atrial natriuretic peptide.

    PubMed

    Takaya, Yoichi; Yoshihara, Fumiki; Yokoyama, Hiroyuki; Kanzaki, Hideaki; Kitakaze, Masafumi; Goto, Yoichi; Anzai, Toshihisa; Yasuda, Satoshi; Ogawa, Hisao; Kawano, Yuhei; Kangawa, Kenji

    2017-02-07

    Although hypoalbuminemia at admission is a risk for acute kidney injury (AKI) and mortality in patients with acute decompensated heart failure (ADHF), the clinical significance of decreased serum albumin levels (DAL) during ADHF therapy has not been elucidated. This study aimed to evaluate whether DAL was associated with AKI, and whether intravenous atrial natriuretic peptide (ANP) administration, which provides an effective treatment for ADHF but promotes albumin extravasation, was associated with DAL and AKI. A total of 231 consecutive patients with ADHF were enrolled. AKI was defined as ≥0.3 mg/dl absolute or 1.5-fold increase in serum creatinine levels within 48 h. AKI occurred in 73 (32%) of the 231 patients during ADHF therapy. The median value of decreases in serum albumin levels was 0.3 g/dl at 7 days after admission. When DAL was defined as ≥0.3 g/dl decrease in serum albumin levels, DAL occurred in 113 patients, and was independently associated with AKI. Of the 231 patients, 73 (32%) were treated with intravenous ANP. DAL occurred more frequently in patients receiving ANP than in those not receiving ANP (77 vs. 36%, p < 0.001), and ANP was independently associated with DAL. The incidence of AKI was higher in patients receiving ANP than in those not receiving ANP (48 vs. 24%, p < 0.001). ANP was independently associated with AKI. In conclusion, DAL is associated with AKI. Intravenous ANP administration may be one of the promoting factors of DAL, which leads to AKI, indicating a possible novel mechanism of AKI.

  9. Combination of Urinary Sodium/Creatinine Ratio and Plasma Brain Natriuretic Peptide Level Predicts Successful Tolvaptan Therapy in Patients With Heart Failure and Volume Overload.

    PubMed

    Sato, Yuichi; Dohi, Kaoru; Watanabe, Kiyotaka; Tanimura, Muneyoshi; Takeuchi, Tetsushiro; Sugiura, Emiyo; Sugimoto, Tadafumi; Kumagai, Naoto; Ogura, Toru; Nakamori, Shiro; Fujimoto, Naoki; Yamada, Norikazu; Ito, Masaaki

    2016-01-01

    To evaluate the short-term clinical and hemodynamic effects of tolvaptan therapy and to identify predictors of the therapeutic outcomes, we retrospectively recruited 60 consecutive hospitalized heart failure (HF) patients (70 ± 11 years) with volume overload. The subjects were divided into two groups on the basis of the changes in HF symptom scores and hemodynamic status assessed by right heart catheterization after tolvaptan therapy (median: 7 days). The majority of patients were successfully treated (group 1). However, 22% of patients (group 2) were unsuccessfully treated, in whom 1) the HF symptom score worsened or 2) there was a stationary HF symptom score ≥ 6 points, and mean PCWP > 18 mmHg and mean RAP > 10 mmHg, after tolvaptan therapy. HF symptom scores, hemodynamic parameters, and plasma brain natriuretic peptide (BNP) level improved in group 1, but all of these parameters remained unchanged in group 2. Lower urine sodium/creatinine ratio (UNa/UCr) and higher BNP level at baseline were independently associated with unsuccessful tolvaptan therapy, and UNa/UCr best predicts unsuccessful tolvaptan therapy with a cut-off value of 46.5 mEq/g·Cr (AUC 0.847, 95% CI: 0.718-0.976, sensitivity 77%, specificity 81%, P < 0.01). Double-positive results of UNa/UCr < 46.5 mEq/g·Cr and plasma BNP level > 778 pg/mL predicted unsuccessful tolvaptan therapy with high diagnostic accuracy (sensitivity 54%, specificity 100%, positive predictive value 100%, negative predictive value 89%, and accuracy 90%). In summary, short-term tolvaptan therapy ameliorated HF symptoms and provided hemodynamic improvement in the majority of patients, and UNa/UCr and BNP level strongly predicted the therapeutic outcomes.

  10. Posiphen as a candidate drug to lower CSF amyloid precursor protein, amyloid-β peptide and τ levels: target engagement, tolerability and pharmacokinetics in humans

    PubMed Central

    Maccecchini, Maria L; Chang, Mee Young; Pan, Catherine; John, Varghese; Zetterberg, Henrik

    2012-01-01

    Aim A first in human study to evaluate tolerability and pharmacokinetics followed by an early proof of mechanism (POM) study to determine whether the small orally, available molecule, Posiphen tartrate (Posiphen), lowers secreted (s) amyloid-β precursor protein (APP) α and -β, amyloid-β peptide (Aβ), tau (τ) and inflammatory markers in CSF of patients with mild cognitive impairment (MCI). Study design Posiphen single and multiple ascending dose phase 1 randomised, double blind, placebo-controlled safety, tolerance, pharmacokinetic studies were undertaken in a total of 120 healthy volunteers to define a dose that was then used in a small non-randomised study of five MCI subjects, used as their own controls, to define target engagement. Main outcome measures Pharmacodynamic: sAPPα, sAPPβ, Aβ42, τ (total (t) and phosphorylated (p)) and inflammatory marker levels were time-dependently measured over 12 h and compared prior to and following 10 days of oral Posiphen treatment in four MCI subjects who completed the study. Pharmacokinetic: plasma and CSF drug and primary metabolite concentrations with estimated brain levels extrapolated from steady-state drug administration in rats. Results Posiphen proved well tolerated and significantly lowered CSF levels of sAPPα, sAPPβ, t-τ, p-τ and specific inflammatory markers, and demonstrated a trend to lower CSF Aβ42. Conclusions These results confirm preclinical POM studies, demonstrate that pharmacologically relevant drug/metabolite levels reach brain and support the continued clinical optimisation and evaluation of Posiphen for MCI and Alzheimer's disease. PMID:22791904

  11. Increased procollagen type I C-terminal peptide levels indicate diastolic dysfunction in end-stage renal disease patients undergoing maintenance dialysis therapy.

    PubMed

    Su, Chi-Ting; Liu, Yen-Wen; Lin, Jou-Wei; Chen, Shih-I; Yang, Chun-Shin; Chen, Jyh-Hong; Hung, Kuan-Yu; Tsai, Wei-Chuan; Huang, Jenq-Wen

    2012-08-01

    Cardiac dysfunction is common among patients with end-stage renal disease. The aim of this study was to explore the determinants of diastolic dysfunction in patients with end-stage renal disease on maintenance hemodialysis. Patients with asymptomatic end-stage renal disease undergoing hemodialysis underwent Doppler tissue imaging analysis and two-dimensional speckle-tracking echocardiography with strain analysis. Blood studies included albumin, cardiac troponin T, and procollagen type I C-terminal peptide (PICP). All enrolled patients had left ventricular (LV) diastolic dysfunction and were stratified into two groups by a cutoff value of 13 for the ratio of early transmitral flow velocity to the average early diastolic annular velocity (E/e'). Seventy-two of the enrolled patients (87%) had grade 1 diastolic dysfunction, and 11 patients (13%) had higher grades of diastolic dysfunction. The study population did not include a representative sample of patients with the pseudonormal or restrictive filling patterns of diastolic dysfunction. There were no significant differences in gender, age, LV geometric change, ejection fraction, global systolic longitudinal strain and strain rate, and prevalence of comorbidities between groups. Patients with average E/e' ≥ 13 had higher PICP, which was significantly correlated with cardiac troponin T, average E/e', and systolic circumferential strain rate. By multivariate regression analysis, average E/e' level was an independent factor of PICP level (P = .047). Hemodialysis patients with high average E/e' ratios showed increased levels of LV filling pressure and higher severity levels of cardiac fibrosis, which occurred before the development of systolic dysfunction. PICP was a potential indicator of diastolic dysfunction and increased LV filling pressure. Copyright © 2012 American Society of Echocardiography. Published by Mosby, Inc. All rights reserved.

  12. Treatment of hypertension with perindopril reduces plasma atrial natriuretic peptide levels, left ventricular mass, and improves echocardiographic parameters of diastolic function

    NASA Technical Reports Server (NTRS)

    Yalcin, F.; Aksoy, F. G.; Muderrisoglu, H.; Sabah, I.; Garcia, M. J.; Thomas, J. D.

    2000-01-01

    BACKGROUND: Hypertension is a major independent risk factor for cardiac deaths, and diastolic dysfunction is a usual finding during the course of this disease. HYPOTHESIS: This study was designed to investigate the effects of chronic therapy with perindopril on left ventricular (LV) mass, left atrial size, diastolic function, and plasma level of atrial natriuretic peptide (ANP) in patients with hypertension. METHODS: Twenty four patients who had not been previously taking any antihypertensive medication and without prior history of angina pectoris, myocardial infarction, congestive heart failure, dysrhythmias, valvular heart disease, or systemic illnesses received 4-8 mg/day of perindopril orally. Echocardiographic studies were acquired at baseline and 6 months after the initiation of therapy. RESULTS: Systolic and diastolic blood pressure decreased from 174 +/- 19.7 and 107.5 +/- 7.8 mmHg to 134 +/- 10.6 and 82 +/- 6.7 mmHg, respectively (p < 0.001). Left ventricular mass decreased from 252.4 +/- 8.3 to 205.7 +/- 7.08 g and left atrial volume from 20.4 +/- 5.1 to 17.6 +/- 5.2 ml, respectively (p < 0.001). Transmitral Doppler early and atrial filling velocity ratio (E/A) increased from 0.69 +/- 0.06 to 0.92 +/- 0.05 m/s and plasma ANP level decreased from 71.9 +/- 11.7 to 35.3 +/- 7.8 pg/ml (p < 0.001). Reduction of LV mass correlated positively with a reduction in ANP levels (r = 0.66, p < 0.0005). CONCLUSIONS: Perindopril caused a significant reduction of LV mass, left atrial volume, and plasma ANP levels, as well as improvement in Doppler parameters of LV filling in this group of patients with hypertension.

  13. Elevated Serum Levels of Interleukin-29 Are Associated with Disease Activity in Rheumatoid Arthritis Patients with Anti-Cyclic Citrullinated Peptide Antibodies.

    PubMed

    Chang, Qiong-Jie; Lv, Cheng; Zhao, Feng; Xu, Ting-Shuang; Li, Ping

    2017-02-01

    Rheumatoid arthritis (RA) is an inflammatory autoimmune disease that may lead to progressive joint destruction. The anti-cyclic citrullinated peptide (anti-CCP) antibody is an essential marker for the diagnosis of RA and has a crucial role in the bone destruction in RA. Recent studies have shown that interleukin (IL)-29, a vital member of type III interferon (IFN) family, could enhance proinflammatory cytokine production and might be involved in the joint destruction in RA. Therefore, in this study, we aimed to examine the role of IL-29 in RA patients with anti-CCP antibodies. The result showed that the serum IL-29 levels were higher in RA patients (n = 68) compared with healthy controls (HC, n = 68, P = 0.019). Correlation analysis demonstrated a significant positive correlation among serum IL-29 level, rheumatoid factor (RF, P < 0.001) and anti-CCP antibodies (P = 0.042). However, when RA patients were divided into two groups according to anti-CCP antibodies, the serum IL-29 levels were significantly higher in anti-CCP-antibodies positive RA patients (n = 54) than those in HC (n = 68) and anti-CCP-antibodies negative RA patients (n = 14). Furthermore, the serum IL-29 levels were positively correlated with the disease activity (P < 0.05) and significantly declined after 6 months of treatment (P < 0.01) in the anti-CCP-antibodies positive RA patients, whereas no significant change was found in the anti-CCP-antibodies negative RA patients (P > 0.05). The findings indicate that IL-29 is a potential biomarker for disease activity in anti-CCP-antibodies positive RA patients.

  14. C-peptide blood levels in keto-acidosis and in hyperosmolar non-ketotic diabetic coma.

    PubMed

    Chupin, M; Charbonnel, B; Chupin, F

    1981-01-01

    For further evaluation of B-cell secretion in diabetic keto-acidosis (KA) and in non-ketotic hyperosmolar coma (NKHC), basal and post-i.v. tolbutamide blood CPR and IRI values were measured in 34 patients (22 KA and 12 NKHC). FFA, cortisol and HGH measurements were also performed. IRI was low in both KA and NKHC (0.07 +/- 0.01 and 0.082 +/- 0.01 nmol/l) as opposed to CPR which was significantly higher in NKHC (1.14 +/- 0.1 nmol/l) than in KA (0.21 +/- 0.03 nmol/l). After tolbutamide injection, CPR and IRI levels did not change in any of the KA cases, whereas they significantly increased in half of the NKHC cases. Cortisol and FFA values were similarly increased in both situations, as opposed to HGH which was significantly higher (6.1 +/- 1.2 ng/ml) in KA than in NKHC (1.9 +/- 0.2 ng/ml). These results suggest that B-cell function is less deficient in NKHC than in KA. Residual insulin amounts reaching the liver via the portal vein could partly account for the absence of ketosis in NKHC.

  15. 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 una