Regulatory Peptides[JOURNAL]
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200 papers
Vasotocin analogues with selective natriuretic, kaliuretic and antidiuretic effects in rats.
Kutina AV, Marina AS, Shakhmatova EI … +1 more , Natochin YV
Regul Pept · 2013 Aug · PMID 23835093 · Publisher ↗
The aim of the present study was an investigation of mechanisms mediating selective effect of vasotocin analogues on water, sodium, and potassium excretion. We tested vasotocin analogues: Mpa(1)-vasotocin (dAVT), Mpa(1)-...
The aim of the present study was an investigation of mechanisms mediating selective effect of vasotocin analogues on water, sodium, and potassium excretion. We tested vasotocin analogues: Mpa(1)-vasotocin (dAVT), Mpa(1)-Arg(4)-vasotocin (dAAVT) and Mpa(1)-DArg(8)-vasotocin (dDAVT). The effects on water, sodium, and potassium transport were evaluated in experiments using normal and water-loaded Wistar rats. It was shown that all tested peptides exerted antidiuretic activity. Vasotocin and dAVT induced natriuresis and kaliuresis in rats. V1a agonist (Phe(2)-Ile(3)-Orn(8)-vasopressin) reproduced the renal effects of dAVT on sodium and potassium excretion but not on water reabsorption. dAAVT, dDAVT and V2 agonist (desmopressin) induced kaliuresis without any effect on sodium excretion. Natriuresis was associated with increase in cGMP excretion, whereas kaliuresis was correlated with rise of cAMP excretion. V1a antagonist (Pmp(1)-Tyr(Me)(2)-vasopressin) significantly reduced the dAVT-stimulated natriuresis and did not influence on urinary potassium excretion. V2 antagonist (Pmp(1)-DIle(2)-Ile(4)-vasopressin) significantly reduced the dAVT- and dAAVT-induced kaliuresis. It is assumed that effects of the nonapeptides on sodium and potassium transport are independent of their antidiuretic activity and mediated by different subtypes of V receptors (the V1a or V1a-like receptor for natriuretic effect and V2 or V2-like one for kaliuretic). In accordance to the data obtained, there is a possibility of selective regulation of renal water reabsorption and urinary sodium and potassium excretion with involvement of neurohypophysial hormones.
Association of weight regain with specific methylation levels in the NPY and POMC promoters in leukocytes of obese men: a translational study.
Crujeiras AB, Campion J, Díaz-Lagares A … +5 more , Milagro FI, Goyenechea E, Abete I, Casanueva FF, Martínez JA
Regul Pept · 2013 Sep · PMID 23831408 · Publisher ↗
Specific methylation of appetite-related genes in leukocytes could serve as a useful biomarker to predict weight regain after an energy restriction program. We aimed to evaluate whether the pre-intervention DNA methylati...
Specific methylation of appetite-related genes in leukocytes could serve as a useful biomarker to predict weight regain after an energy restriction program. We aimed to evaluate whether the pre-intervention DNA methylation patterns involved in the epigenetic control of appetite-regulatory genes in leukocytes are associated with the weight regain process. Eighteen men who lost ≥5% of body weight after an 8-week nutritional intervention were categorized as "regainers" (≥10% weight regain) and "non-regainers" (<10% weight regain) 32weeks after stopping dieting. At baseline, leukocytes were isolated and DNA was analyzed for epigenetic methylation patterns of appetite-related gene promoters by MALDI-TOF mass spectrometry. Regainers showed higher methylation levels than non-regainers in proopiomelanocortin (POMC) CpG sites +136bp and +138bp (fold change from non-regainers=26%; p=0.020) and lower methylation of the whole analyzed region of neuropeptide Y (NPY; fold change from non-regainers=-22%; p=0.033), as well as of several individual NPY-promoter CpG sites. Importantly, total baseline NPY methylation was associated with weight-loss regain (r=-0.76; p<0.001), baseline plasma ghrelin levels (r=0.60; p=0.011) and leptin/ghrelin ratio (r=-0.52; p=0.046). Lower methylation levels of POMC CpG sites +136bp and +138bp were associated with success in weight-loss maintenance (odds ratio=0.042 [95% CI 0.01-0.57]; p=0.018), whereas lower total methylation levels in NPY promoter were associated with higher risk of weight regain (odds ratio=14.0 [95% CI 1.13-172]; p=0.039). Therefore, the study of leukocyte methylation levels reflects a putative epigenetic regulation of NPY and POMC, which might be implicated in the weight regain process and be used as biomarkers for predicting weight regain after dieting.
Exposure to the endocrine disruptor nonylphenol alters structure and function of thyroid gland in rats.
Xi Y, Li D, San W
Regul Pept · 2013 Aug · PMID 23830829 · Publisher ↗
OBJECTIVE: Nonylphenol (NP) is an estrogenic-like compound which can induce vitellogenin synthesis in males and immature teleostean species. Known as an endocrine disruptor, it has been reported to affect endocrine gland...
OBJECTIVE: Nonylphenol (NP) is an estrogenic-like compound which can induce vitellogenin synthesis in males and immature teleostean species. Known as an endocrine disruptor, it has been reported to affect endocrine glands; however, little is known about its effects on thyroid function. The present study aimed to evaluate whether exposure to NP alters the structure and function of the thyroid gland of rats and/or the underlying mechanisms. METHODS: Rats were gavaged with NP (40, 80 and 200 mg/kg/d) for 15 days. Serum levels of thyroid-stimulating hormone were determined by radioimmunoassay. Ultramicroscopic structure of follicular cells was examined by a transmission electron microscope. Histopathology was conducted with hematoxylin-eosin (HE) staining. RESULTS: We found that NP exposure induced a decrease in serum levels of free tetraiodothyronine (FT) 3 and FT4 while it induced an increase in serum levels of thyroid-stimulating hormone (TSH) in a dose-dependent manner. There was a negative correlation between different doses of NP with serum levels of FT3 and FT4 (FT4 r=-0.932; FT3 r=-0.926) and a positive correlation with serum levels of TSH (r=0.967). Histological and morphometric study in the NP-exposed group revealed dilation of endoplasmic reticulum into cystic in thyroid follicular cells. Mitochondrion was damaged in the 80 and 200 mg/kg/d groups. CONCLUSIONS: Exposure to NP may lead to thyroid dysfunction. It may be a potential contributor to thyroid disruption.
Desensitization of human CRF2(a) receptor signaling governed by agonist potency and βarrestin2 recruitment.
Hauger RL, Olivares-Reyes JA, Braun S … +5 more , Hernandez-Aranda J, Hudson CC, Gutknecht E, Dautzenberg FM, Oakley RH
Regul Pept · 2013 Sep · PMID 23820308 · Full text
The primary goal was to determine agonist-specific regulation of CRF2(a) receptor function. Exposure of human retinoblastoma Y79 cells to selective (UCN2, UCN3 or stresscopins) and non-selective (UCN1 or sauvagine) agoni...
The primary goal was to determine agonist-specific regulation of CRF2(a) receptor function. Exposure of human retinoblastoma Y79 cells to selective (UCN2, UCN3 or stresscopins) and non-selective (UCN1 or sauvagine) agonists prominently desensitized CRF2(a) receptors in a rapid, concentration-dependent manner. A considerably slower rate and smaller magnitude of desensitization developed in response to the weak agonist CRF. CRF1 receptor desensitization stimulated by CRF, cortagine or stressin1-A had no effect on CRF2(a) receptor cyclic AMP signaling. Conversely, desensitization of CRF2(a) receptors by UCN2 or UCN3 did not cross-desensitize Gs-coupled CRF1 receptor signaling. In transfected HEK293 cells, activation of CRF2(a) receptors by UCN2, UCN3 or CRF resulted in receptor phosphorylation and internalization proportional to agonist potency. Neither protein kinase A nor casein kinases mediated CRF2(a) receptor phosphorylation or desensitization. Exposure of HEK293 or U2OS cells to UCN2 or UCN3 (100nM) produced strong βarrestin2 translocation and colocalization with membrane CRF2(a) receptors while CRF (1μM) generated only weak βarrestin2 recruitment. βarrestin2 did not internalize with the receptor, however, indicating that transient CRF2(a) receptor-arrestin complexes dissociate at or near the cell membrane. Since deletion of the βarrestin2 gene upregulated Gs-coupled CRF2(a) receptor signaling in MEF cells, a βarrestin2 mechanism restrains Gs-coupled CRF2(a) receptor signaling activated by urocortins. We further conclude that the rate and extent of homologous CRF2(a) receptor desensitization are governed by agonist-specific mechanisms affecting GRK phosphorylation, βarrestin2 recruitment, and internalization thereby producing unique signal transduction profiles that differentially affect the stress response.
Ectopic expression of ghrelin affects gastric H(+)-K(+)-ATPase activity and expression of GHR/IGF-1 system in weaned mice.
Du GM, Liu MJ, Parvizi N … +1 more , Zhao RQ
Regul Pept · 2013 Sep · PMID 23820307 · Publisher ↗
OBJECTIVES: Ghrelin has been implicated in the regulation of gastric growth and functional development, but it is yet to be determined whether and how ghrelin over-expression may modify gastric growth, gastric acid secre...
OBJECTIVES: Ghrelin has been implicated in the regulation of gastric growth and functional development, but it is yet to be determined whether and how ghrelin over-expression may modify gastric growth, gastric acid secretion and mRNA expression of other gastric endocrine hormones. 25-day-old mice were injected intramuscularly with vacant plasmid (VP) or recombinant plasmid expressing secretory ghrelin at the doses of 50μg (LG) and 100μg (HG). RESULTS: Expression of ghrelin mRNA was detected in muscles 15days post-injection, being most abundant in HG mice. In accordance with the ghrelin expression, gastric weight increased (P<0.05) in HG mice, compared with VP control group. Significant increase of gastric mucosa H(+)-K(+)-ATPase mRNA expression was detected in HG mice compared to VP control group (P<0.05). Compared with VP mice, gastric somatostatin (SS) mRNA expression decreased in LG and HG mice (P<0.05), while gastric gastrin expression had no significant difference. CONCLUSIONS: I.M. injection of plasmid encoding ghrelin improved gastric growth and gastric acid secretion with decreased SS mRNA in weaned mice.
Beta-arrestin2 is involved in the increase of distal colonic contraction in diabetic rats.
Xie DP, Li S, Li L … +5 more , Chang XW, Xi TF, Yang X, Jin Z, Zeng Y
Regul Pept · 2013 Aug · PMID 23816471 · Publisher ↗
Colonic dysmotility occurs in diabetes and the patients exhibit diarrhea or constipation. The pathogenetic mechanisms underlying colonic dysmotility in diabetic patients remain poorly understood. The effects of β-arresti...
Colonic dysmotility occurs in diabetes and the patients exhibit diarrhea or constipation. The pathogenetic mechanisms underlying colonic dysmotility in diabetic patients remain poorly understood. The effects of β-arrestin2 on colonic contraction in diabetic rats were investigated for the first time. Male SD rats were treated with a single intraperitoneally injected dose of streptozotocin, and those displaying sustained high blood glucose were selected as diabetes mellitus models. Longitudinal muscle strips of the distal colon were prepared to monitor contraction of the colon in vitro. Expression of β-arrestin2 was investigated by Western blot analysis. Anti-β-arrestin2 antibody had no direct effect on the contraction of distal colonic strips in both normal and diabetic rats. Carbachol-induced contractions of distal colonic strips were higher in diabetic rats than in normal rats. Anti-β-arrestin2 antibody partly blocked carbachol-induced increases of distal colonic strips in diabetic rats. The expression level of β-arrestin2 protein in the colon was higher in diabetic rats than in normal rats. These results suggest that β-arrestin2 is involved in the increase of distal colonic contraction in diabetic rats.
Alpha-calcitonin gene-related peptide is protective against pressure overload-induced heart failure.
Li J, Levick SP, DiPette DJ … +2 more , Janicki JS, Supowit SC
Regul Pept · 2013 Aug · PMID 23816470 · Publisher ↗
The sensory neuropeptide, α-calcitonin gene-related peptide (α-CGRP) is protective against hypertension-induced heart damage and cardiac ischemia/reperfusion injury. To determine whether this neuropeptide is also cardiop...
The sensory neuropeptide, α-calcitonin gene-related peptide (α-CGRP) is protective against hypertension-induced heart damage and cardiac ischemia/reperfusion injury. To determine whether this neuropeptide is also cardioprotective in heart failure, this study examined whether the absence of α-CGRP exacerbated the adverse cardiac remodeling, dysfunction and mortality in pressure overload heart failure induced by transverse aortic constriction (TAC). Male α-CGRP knockout (KO) and wild type (WT) mice had TAC or sham surgery at day 0 and were studied on days 3, 14, 21, and 28. The survival rate of TAC α-CGRP KO mice was lower than the TAC WT mice over the duration of the protocol. Left ventricular α-CGRP content in TAC WT mice was higher at days 3, 14, and 21 than sham WT mice. Echocardiography demonstrated greater adverse cardiac remodeling and dysfunction in the TAC α-CGRP KO compared to the TAC WT mice. The lung/body weight ratios and left ventricular masses were higher in TAC α-CGRP KO compared to the TAC WT mice. While there was increased cardiac fibrosis in the TAC WT mice compared to shams, the TAC α-CGRP KO mice had markedly increased fibrosis above that of the TAC WT mice. TAC WT mice had greater cardiac inflammation, cell death, and adaptive angiogenesis compared to sham mice. Importantly, the TAC α-CGRP KO mice had greater inflammation, cell death, and attenuation of angiogenesis compared to TAC WT hearts. Thus, α-CGRP plays a significant protective role in TAC-induced heart failure which may be mediated by decreased inflammation, cell death, and fibrosis.
Plasminogen activator inhibitor (PAI)-1 suppresses inhibition of gastric emptying by cholecystokinin (CCK) in mice.
Gamble J, Kenny S, Dockray GJ
Regul Pept · 2013 Aug · PMID 23816469 · Full text
The intestinal hormone cholecystokinin (CCK) delays gastric emptying and inhibits food intake by actions on vagal afferent neurons. Recent studies suggest plasminogen activator inhibitor (PAI)-1 suppresses the effect of...
The intestinal hormone cholecystokinin (CCK) delays gastric emptying and inhibits food intake by actions on vagal afferent neurons. Recent studies suggest plasminogen activator inhibitor (PAI)-1 suppresses the effect of CCK on food intake. In this study we asked whether PAI-1 also modulated CCK effects on gastric emptying. Five minute gastric emptying of liquid test meals was studied in conscious wild type mice (C57BL/6) and in transgenic mice over-expressing PAI-1 in gastric parietal cells (PAI-1H/Kβ mice), or null for PAI-1. The effects of exogenous PAI-1 and CCK8s on gastric emptying were studied after ip administration. Intragastric peptone delayed gastric emptying in C57BL/6 mice by a mechanism sensitive to the CCK-1 receptor antagonist lorglumide. Peptone did not delay gastric emptying in PAI-1-H/Kβ mice. Exogenous CCK delayed gastric emptying of a control test meal in C57BL/6 mice and this was attenuated by administration of PAI-1; exogenous CCK had no effect on emptying in PAI-1-H/Kβ mice. Prior administration of gastrin to increase gastric PAI-1 inhibited CCK-dependent effects on gastric emptying in C57BL/6 mice but not in PAI-1 null mice. Thus, both endogenous and exogenous PAI-1 inhibit the effects of CCK (whether exogenous or endogenous) on gastric emptying. The data are compatible with emerging evidence that gastric PAI-1 modulates vagal effects of CCK.
Angiotensin-converting enzyme 2 attenuates oxidative stress and VSMC proliferation via the JAK2/STAT3/SOCS3 and profilin-1/MAPK signaling pathways.
Song B, Jin H, Yu X … +12 more , Zhang Z, Yu H, Ye J, Xu Y, Zhou T, Oudit GY, Ye JY, Chen C, Gao P, Zhu D, Penninger JM, Zhong JC
Regul Pept · 2013 Aug · PMID 23816468 · Publisher ↗
Angiotensin (Ang) II plays a vital role in vascular smooth muscle cell (VSMC) growth and proliferation. Angiotensin-converting enzyme 2 (ACE2) is a specific Ang II-degrading enzyme but its role in VSMC proliferation rema...
Angiotensin (Ang) II plays a vital role in vascular smooth muscle cell (VSMC) growth and proliferation. Angiotensin-converting enzyme 2 (ACE2) is a specific Ang II-degrading enzyme but its role in VSMC proliferation remains largely unknown. We hypothesized that ACE2 might suppress Ang II-mediated oxidative stress and VSMC proliferation. Human umbilical artery smooth muscle cells (HUASMCs) were pretreated with Ang II (100nM) for 6h and 24h, respectively. Exposure to Ang II resulted in significant increases in suppressor of cytokine signaling 3 (SOCS3) expression and phosphorylation levels of JAK2, STAT3 and ERK1/2 linked with elevated superoxide production and cell proliferation in HUASMCs. These changes were strikingly prevented by administration of ERK1/2 inhibitor PD98059 (10μM) and JAK/STAT inhibitor WP1066 (5 μM) but were largely aggravated by ACE2 inhibitor DX600 (0.5 μM). More importantly, treatment with human recombinant ACE2 (hrACE2; 1mg/ml) dramatically prevented Ang II-mediated SOCS3 expression and the JAK2-STAT3 and ERK1/2 signaling, and resulted in attenuation of superoxide production and cell proliferation in HUASMCs. Intriguingly, downregulation of profilin-1 with profilin-1 siRNA (50 nM) was able to abolish Ang II-induced upregulations of profilin-1 expression, ERK1/2 phosphorylation and superoxide production with attenuation of VSMC proliferation. In conclusion, treatment with hrACE2 prevents Ang II-mediated activation of the JAK2/STAT3/SOCS3 and profilin-1/MAPK signaling pathways, contributing to attenuation of superoxide generation and cell proliferation in HUASMCs, suggesting a protective mechanism of ACE2 against Ang II-mediated oxidative stress and VSMC proliferation. ACE2 may represent a potential candidate to prevent and treat vascular disorders.
Effect of short- and long-term physical activities on circulating granin protein levels.
Røsjø H, Opstad PK, Hoff JE … +4 more , Godang K, Christensen G, Stridsberg M, Omland T
Regul Pept · 2013 Aug · PMID 23816467 · Publisher ↗
BACKGROUND: The classic chromogranin-secretogranin (granin) proteins are produced in the myocardium and throughout the neuroendocrine system, but while chromogranin (Cg) A and B levels are high in the adrenal medulla, se...
BACKGROUND: The classic chromogranin-secretogranin (granin) proteins are produced in the myocardium and throughout the neuroendocrine system, but while chromogranin (Cg) A and B levels are high in the adrenal medulla, secretogranin (Sg) II production is higher in the pituitary gland. Whether these differences may influence the response to physical activity is not known. METHODS: We measured circulating granin proteins during (1) a short-term maximal bicycle exercise stress test and (2) a 7 day military ranger course of continuous physical activity and sleep and energy deprivation. RESULTS: In 9 healthy subjects performing the exercise stress test (7 male, age 45±5 y [mean±SEM], duration 10.13±1.14 min), CgB levels increased from before to immediately after the test: 1.20±0.12 vs. 1.45±0.09 nmol/L, p=0.013. Metabolic equivalents, representing an index of performed work, were closely associated with the change (∆) in CgB levels during stress testing and explained 74% of the variability in ∆CgB levels (p=0.004). CgA and SgII levels were not increased after exercise stress testing. In the second cohort of 8 male subjects (age 25±1 y) participating in the ranger course, CgB levels increased from day 1 and were significantly elevated on days 5 and 7. CgA also increased gradually with levels significantly elevated on day 7, while SgII was markedly increased on day 5 whereas levels on days 3 and 7 were unchanged compared to baseline levels. CONCLUSION: We demonstrate a heterogeneous response to short- and long-term physical activities among circulating granin proteins with the most potent effect on CgB levels.
Increased thymosin β4 levels in the serum and SF of knee osteoarthritis patients correlate with disease severity.
Wei M, Duan D, Liu Y … +2 more , Wang Z, Li Z
Regul Pept · 2013 Aug · PMID 23816466 · Publisher ↗
OBJECTIVE: Thymosin β4, a member of a large family of thymic proteins, plays an important role in the process of articular cartilage degeneration which is a common cause of osteoarthritis (OA). This study aims to determi...
OBJECTIVE: Thymosin β4, a member of a large family of thymic proteins, plays an important role in the process of articular cartilage degeneration which is a common cause of osteoarthritis (OA). This study aims to determine thymosin β4 levels in the serum and synovial fluid (SF) of patients with knee OA and analyze the correlation of thymosin β4 levels with the radiographic severity of OA. METHODS: This study consisted of 216 patients with knee OA and 152 healthy controls. OA progression was classified based on Kellgren-Lawrence by evaluating x-ray changes observed in anteroposterior knee radiography. Thymosin β4 levels in the serum and SF were measured by enzyme-linked immunosorbent assay method. RESULTS: The knee OA patients had higher levels of serum thymosin β4 than the healthy controls. Knee OA patients with KL grade 4 showed significantly elevated thymosin β4 levels in the serum and SF compared with those with KL grades 2 and 3. Knee OA patients with KL grade 3 had significantly higher SF levels of thymosin β4 than those with KL grade 2. Thymosin β4 levels in the serum and SF of knee OA patients were significantly correlated with disease severity according to KL grading criteria. CONCLUSION: The thymosin β4 levels in the serum and SF may serve as effective biomarkers for the severity of OA.
Leptin modulates enteric neurotransmission in the rat proximal colon: an in vitro study.
Florian V, Caroline F, Francis C … +2 more , Camille S, Fabielle A
Regul Pept · 2013 Aug · PMID 23816465 · Publisher ↗
Leptin has been shown to modulate gastrointestinal functions including nutrient absorption, growth, and inflammation and to display complex effects on gut motility. Leptin receptors have also been identified within the e...
Leptin has been shown to modulate gastrointestinal functions including nutrient absorption, growth, and inflammation and to display complex effects on gut motility. Leptin receptors have also been identified within the enteric nervous system (ENS), which plays a crucial role in digestive functions. Although leptin has recently been shown to activate neurons in the ENS, the precise mechanisms involved are so far unknown. Therefore, the aim of the present study was to determine the effects of leptin on rat proximal colon smooth muscle and enteric neuron activities. The effects of exogenous leptin on tone and on responses to transmural nerve stimulation (TNS) of isolated circular smooth muscle of proximal colon in rats were investigated using an organ bath technique. The effects of a physiological concentration (0.1 μM) of leptin were also studied on tone and TNS-induced relaxation in the presence of atropine, hexamethonium, L-N(G)-nitroarginine methyl ester (L-NAME) and capsazepine. Leptin caused a slight but significant decrease in tone, TNS-induced relaxation and contraction in a concentration-dependent manner in colonic preparations. Cholinergic antagonists abolished the effects of 0.1 μM leptin on TNS-induced relaxation. This concentration of leptin had no further effect on relaxation in the presence of L-NAME. In the presence of capsazepine, leptin had no further effect either on tone or relaxation compared to the drug alone. In conclusion, leptin modulates the activity of enteric inhibitory and excitatory neurons in proximal colon. These effects may be mediated through nitrergic neurons. Intrinsic primary afferent neurons may be involved.
Central insulin-angiotensin II interaction in blood pressure regulation in fructose overloaded rats.
Mayer MA, Höcht C, Giani JF … +6 more , Muñoz MC, Carranza A, Taira CA, Dominici FP, Puyó AM, Fernández BE
Regul Pept · 2013 Aug · PMID 23816464 · Publisher ↗
The aim of the present study was to determine if insulin is able to modulate the pressor response to intracerebroventricularly administered angiotensin II in insulin resistant fructose overloaded rats. Male Sprague-Dawle...
The aim of the present study was to determine if insulin is able to modulate the pressor response to intracerebroventricularly administered angiotensin II in insulin resistant fructose overloaded rats. Male Sprague-Dawley rats were divided into two groups: 1) Control group (C) with tap water to drink for 6 weeks (n=36); and 2) fructose treated (F), with fructose solution (10% w/v) to drink for 6 weeks (n=36). On the day of the experiment, anesthetized male C and F rats were intracerebroventricularly infused with insulin (12 mU/h, n=15) or Ringer's solution as vehicle (n=15) for 2h. Immediately, changes in mean arterial pressure (MAP) in response to an intracerebroventricular subpressor dose of angiotensin II (5 pmol, n=10) or vehicle (n=5) were measured for 10 min. Then, hypothalami were removed and Akt and ERK1/2 phosphorylation levels were determined. In a subset of C (n=10) and F (n=20) animals, PD98059 (p44/42 MAPK inhibitor) or vehicle was administered intracerebroventricularly at a flow rate of 5 μl/min for 1 min. Ten minutes later, insulin (12 mU/h, n=5 for each group) or vehicle (Ringer's solution, only in the F group, n=5) was perfused for 2h at a flow rate of 4 μl/h, and cardiovascular parameters were measured every 15 min. Immediately, changes in MAP and HR in response to a subpressor dose of Ang II (5 pmol/2 μl) were evaluated for 10 min (n=5 for each group). In other subset of animals (n=6 for each group), AT1 and AT2 hypothalamic receptor levels were measured by Western blotting. Intracerebroventricular insulin pre-treatment increased the pressor response to angiotensin II in C rats. In F rats (with or without insulin pretreatment), the pressor response to angiotensin II was higher than that in vehicle pre-treated C animals, but similar to that observed in C after insulin infusion. In C rats phospho-ERK 1/2 hypothalamic levels significantly increased after angiotensin II injection in insulin pretreated animals compared to vehicle pre-treated rats, suggesting that MAPK activation might be involved in insulin potentiation of blood pressure response to angiotensin II in the brain. Phospho-ERK 1/2 hypothalamic levels were significantly increased in vehicle treated F rats compared to C, suggesting that basal MAPK activation might play a role in the enhanced response to angiotensin II observed in these animals. Finally, in F rats, either after vehicle or insulin infusion, angiotensin II injection was associated with a similar increase in phospho-ERK 1/2 hypothalamic levels, comparable to that observed after angiotensin II injection in insulin pre-treated C animals. ERK 1/2 blockade significantly reduced MAP in F rats compared to C. Moreover, ERK 1/2 inhibition completely abolished the Ang II pressor response in F rats and in insulin pre-treated C animals. All these findings suggest that insulin-angiotensin II interaction at hypothalamic level might be involved in the increase in blood pressure observed in the insulin resistant state.
Effects of lixisenatide once daily on gastric emptying in type 2 diabetes--relationship to postprandial glycemia.
Lorenz M, Pfeiffer C, Steinsträsser A … +4 more , Becker RH, Rütten H, Ruus P, Horowitz M
Regul Pept · 2013 Aug · PMID 23665027 · Publisher ↗
OBJECTIVES: To determine the effects of lixisenatide, a new once-daily (QD) glucagon-like peptide-1 receptor agonist, on postprandial glucose (PPG) and gastric emptying, and the relationship between these effects in pati...
OBJECTIVES: To determine the effects of lixisenatide, a new once-daily (QD) glucagon-like peptide-1 receptor agonist, on postprandial glucose (PPG) and gastric emptying, and the relationship between these effects in patients with type 2 diabetes mellitus (T2DM). METHODS: Data were obtained from a randomized, double-blind, placebo-controlled, parallel-group study with treatment duration of 28 days in patients with T2DM receiving ≤2 oral antidiabetic drugs. Lixisenatide was injected subcutaneously using an ascending dose range (5-20 μg) increased every fifth day in increments of 2.5 μg. Blood glucose was determined before and after three standardized meals (breakfast, lunch, and dinner). Gastric emptying of the standardized breakfast was determined by a (13)C-octanoic acid breath test at baseline (Day-1) and at Day 28. RESULTS: A total of 21 and 22 patients were randomized to lixisenatide 20 μg QD and placebo, respectively. With lixisenatide 20 μg QD, there was a reduction in PPG when compared with placebo after breakfast (p<0.0001), lunch (p<0.001) and dinner (p<0.05). Hence, lixisenatide 20 μg administered in the morning exhibited a pharmacodynamic effect on blood glucose throughout the day. Gastric emptying (50% emptying time) increased substantially from baseline with lixisenatide 20 μg QD, but not with placebo (change from baseline ± SD: -24.1 ± 133.1 min for placebo and 211.5 ± 278.5 min for lixisenatide; p<0.01). There was an inverse relationship between PPG area under the curve after breakfast and gastric emptying with lixisenatide 20 μg QD (n=17, r(2)=0.51, p<0.05), but not with placebo. CONCLUSIONS: In this study, lixisenatide at a dose of 20 μg QD reduced postprandial glycemic excursions in patients with T2DM, possibly as a result of sustained slowing of gastric emptying.
Retraction notice to “Erythropoietin as a possible mechanism for the effects of intermittent hypoxia on bodyweight, serum glucose and leptin in mice” [Regul. Pept. 165(2–3) (2010) 168–173].
Regul Pept · 2013 Mar · PMID 23616999 · Publisher ↗
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Characterization of signaling pathways coupled to melatonin receptors in gastrointestinal smooth muscle.
Ahmed R, Mahavadi S, Al-Shboul O … +3 more , Bhattacharya S, Grider JR, Murthy KS
Regul Pept · 2013 Jun · PMID 23541890 · Full text
Melatonin, a close derivative of serotonin, is involved in physiological regulation of circadian rhythms. In the gastrointestinal (GI) system, melatonin exhibits endocrine, paracrine and autocrine actions and is implicat...
Melatonin, a close derivative of serotonin, is involved in physiological regulation of circadian rhythms. In the gastrointestinal (GI) system, melatonin exhibits endocrine, paracrine and autocrine actions and is implicated in the regulation of GI motility. However, it is not known whether melatonin can also act directly on GI smooth muscle cells. The aim of the present study was to determine the expression of melatonin receptors in smooth muscle and identify their signaling pathways. MT1, but not MT2 receptors are expressed in freshly dispersed and cultured gastric smooth muscle cells. Melatonin selectively activated Gq and stimulated phosphoinositide (PI) hydrolysis in freshly dispersed and cultured muscle cells. PI hydrolysis was blocked by the expression of Gq, but not Gi minigene in cultured muscle cells. Melatonin also caused rapid increase in cytosolic Ca(2+) as determined by epifluorescence microscopy in fura-2 loaded single smooth muscle cells, and induced rapid contraction. Melatonin-induced PI hydrolysis and contraction were blocked by a non-selective MT1/MT2 antagonist luzindole (1 μM), but not by a selective MT2 antagonist 4P-PDOT (100 nM), and by the PLC inhibitor U73122. MT2 selective agonist IIK7 (100 nM) had no effect on PI hydrolysis and contraction. We conclude that rabbit gastric smooth muscle cells express melatonin MT1 receptors coupled to Gq. Activation of these receptors causes stimulation of PI hydrolysis and increase in cytosolic Ca(2+), and elicits muscle contraction.
Five functional adipokinetic peptides expressed in the corpus cardiacum of the moth genus Hippotion (Lepidoptera, Sphingidae).
Gäde G, Simek P, Clark KD … +1 more , Marco HG
Regul Pept · 2013 Jun · PMID 23541889 · Publisher ↗
This is the first study that finds five adipokinetic hormones (AKHs) in the corpus cardiacum of an insect. From two species of the sphingid moth genus Hippotion, eson and celerio, three novel and two known AKHs were isol...
This is the first study that finds five adipokinetic hormones (AKHs) in the corpus cardiacum of an insect. From two species of the sphingid moth genus Hippotion, eson and celerio, three novel and two known AKHs were isolated and sequenced by deduction from multiple MS(n) electrospray mass data: two octapeptides are pGlu-Leu-Thr-Phe-Thr-Ser-Ser-Trp amide (denoted Hipes-AKH-I) and its Thr(7) analogue (Hipes-AKH-II); two nonapeptides are pGlu-Leu-Thr-Phe-Thr-Ser-Ser-Trp-Gly amide (Manse-AKH) and its Thr(7) analogue (Hipes-AKH-III), as well as a decapeptide pGlu-Leu-Thr-Phe-Ser-Ser-Gly-Trp-Gly-Gln amide (Manse-AKH-II). All sequences were confirmed by identical behaviour of natural and synthetic peptides in reversed-phase HPLC and liquid chromatography coupled to electrospray mass spectrometry, resulting in identical retention times and tandem mass spectral data. High resolution mass spectrometry and retention time data also confirmed that the amino acid at position 10 in Manse-AKH-II is Gln and not the isobaric Lys. Conspecific injections of all five peptides in synthetic form and low doses caused hyperlipaemia in H. eson. Our results and pertaining literature suggest that five genes code for the mature peptides, which are very likely released during flight to provide energy for long distance migration in this genus via lipid oxidation; as all five peptides are active at low doses in a conspecific bioassay, it may be speculated, but not proven, that there is only one AKH receptor present in Hippotion that can bind all five peptides with high affinity.
Evaluation of melatonin and prostaglandin E1 combination on necrotizing enterocolitis model in neonatal rats.
Cekmez F, Cetinkaya M, Tayman C … +5 more , Canpolat FE, Kafa IM, Uysal S, Tunc T, Sarıcı SÜ
Regul Pept · 2013 Jun · PMID 23524022 · Publisher ↗
BACKGROUND: Necrotizing enterocolitis (NEC) is one of the most common gastrointestinal emergencies in newborn infants but up to now there is no completely effective treatment for it. OBJECTIVE: In order to show that a co...
BACKGROUND: Necrotizing enterocolitis (NEC) is one of the most common gastrointestinal emergencies in newborn infants but up to now there is no completely effective treatment for it. OBJECTIVE: In order to show that a combination of melatonin and prostaglandins may be useful to save lives, we use newborn rat as a model of necrotizing enterocolitis to test the hypothesis of using the combination therapy might have more potential effect on mucosal cytoprotection and healing. PATIENTS AND METHODS: A total of 60 newborn pups from 5 time-mated Sprague-Dawley pregnant rats were divided equally into 5 groups as follows: NEC (subjected to NEC), NEC+Melatonin, NEC+Prostaglandin, NEC+Prostaglandin+Melatonin and control. These animals were fed with hyperosmolar formula 3 times daily and subjected to 100% CO2 inhalation for 10 min, +4°C cold exposure for 5 min, and 97% O2 for 5 min twice daily to induce NEC. This procedure was applied to the pups for 3 days. RESULTS: The macroscopic scoring, intestinal injury scoring and apoptosis index scoring were all found to be significantly lower in NEC+Prostaglandin+Melatonin group compared with NEC group. Anti-oxidant enzyme activities were significantly higher, whereas lipid peroxidation was significantly lower in NEC+Prostaglandin+Melatonin group compared with NEC group. CONCLUSION: This combination therapy showed cytoprotective and healing effects on mucosa in the intestinal tissue of rat pups in necrotizing enterocolitis model. Therefore, this therapy might also show benefit in preterm infants with NEC. After confirmation of this data by other clinical and experimental studies, it may be a novel therapeutic option for the prevention of NEC in preterm infants.
Thymosin β4 enhances the healing of medial collateral ligament injury in rat.
Xu B, Yang M, Li Z … +4 more , Zhang Y, Jiang Z, Guan S, Jiang D
Regul Pept · 2013 Jun · PMID 23523891 · Publisher ↗
The role played by thymosin β4 (Tβ4) in the process of wound healing was reported in several organs. However, there have been no reports that investigated the role of Tβ4 in the repair process after ligament injury. The...
The role played by thymosin β4 (Tβ4) in the process of wound healing was reported in several organs. However, there have been no reports that investigated the role of Tβ4 in the repair process after ligament injury. The purpose of this study was to determine whether administration of Tβ4 would improve ligament repair following injury. The medial collateral ligament (MCL) was sharply transected on the day of surgery. Then, the treatment group received 100 μL of fibrin sealant containing 1 μg of Tβ4 placed in the ligament gap. Healing tissues were evaluated by hematoxylin and eosin stain, transmission electron microscopy, and biomechanical test at 4 weeks after surgery. Histologically, healing tissues in Tβ4-treated group exhibited uniform and evenly spaced fiber bundles. However, the collagen fibers were not evenly spaced in control rats. Moreover, diameters of collagen fibrils within granulation tissue from the Tβ4-treated rats were significantly increased. In Tβ4-treated MCLs, the mechanical properties of these healing tissues were significantly higher at 4 weeks after surgery. In terms of the mechanical properties of the healing femur-medial collateral ligament-tibia complexes, the Tβ4-treated group had significantly better biomechanical properties than the control group at 4 weeks after surgery. Local administration of Tβ4 promotes the healing process of MCL, both histologically and mechanically, in a rat model. These findings provide a basis for potential clinical use of Tβ4 in repairing ligaments.
Effects of felodipine combined with puerarin on ACE2-Ang (1-7)-Mas axis in renovascular hypertensive rat.
Bai S, Huang ZG, Chen L … +2 more , Wang JT, Ding BP
Regul Pept · 2013 Jun · PMID 23523569 · Publisher ↗
This study aimed to investigate the effect of combination of felodipine+puerarin on ACE2-Ang (1-7)-Mas axis, and to explore the protective effect of the combination against kidney in renovascular hypertensive rats. Goldb...
This study aimed to investigate the effect of combination of felodipine+puerarin on ACE2-Ang (1-7)-Mas axis, and to explore the protective effect of the combination against kidney in renovascular hypertensive rats. Goldblatt rats were randomly divided into 5 groups as follows: 4 groups which were treated with felodipine (Felo), puerarin (Pue), Felo+Pue, and Felo+captopril (Cap), respectively, and a control group of animals that were administrated with distilled water. Contents of Ang II and Ang (1-7) in renal tissues were determined by ELISA kit. The mRNA expression of ACE2/Mas and ACE/AT1 in kidneys was analyzed by RT-PCR. After 8weeks of treatment, compared with Goldblatt group, Felo+Pue reduced SBP, DBP and HR (p<0.01 or p<0.05), ameliorated renal interstitial fibrosis, decreased the level of Ang II and increased that of Ang (1-7), upregulated mRNA expression of ACE2 and Mas, decreased that of ACE and AT1, and downregulated protein expression of TGF-β1 in kidneys (p<0.01). Compared with Felo group, Felo+Pue decreased DBP and HR more markedly, attenuated fibrosis, decreased Ang II levels and increased those of Ang (1-7), upregulated mRNA expression of ACE2 in bilateral kidneys and that of Mas in ischemic kidney, downregulated that of ACE in bilateral kidneys and that of AT1 in ischemic kidney, and decreased expression of TGF-β1 protein significantly. In a word, a combination of Felo+Pue has a more efficient therapeutic effect on DBP and HR, and contributes to a better protection against renal interstitial fibrosis.
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