Peptides (v.58, #C)

Differences in acute anorectic effects of long-acting GLP-1 receptor agonists in rats by Stephanie Sisley; Kathleen Smith; Darleen A. Sandoval; Randy J. Seeley (1-6).
Long-acting glucagon-like peptide-1 receptor (GLP-1R) agonists have both glucose- and weight-lowering effects. The brain is poised to mediate both of these actions since GLP-1Rs are present in key areas known to control weight and glucose. Although some research has been performed on the effects of exendin-4 in the brain, little data exists on the central effects of liraglutide, a long-acting GLP-1R agonist with much closer structural homology to native GLP-1. In lean, Long-Evans rats, we found that direct intra-third cerebroventricular (i3vt) administration of 0.26 nmol liraglutide caused a 50% reduction in food intake. However, exendin-4 produced the same reduction in food intake with 10-fold greater potency (0.02 nmol). These data are supported by similar c-Fos immunoreactivity in the hypothalamic paraventricular nuclei by exendin-4 as compared to liraglutide despite differing doses. The anorectic effects of both drugs were blocked with i3vt pre-treatment of a GLP-1R competitive antagonist, exendin(9-39), indicating that both drugs required the GLP-1R for their effects. Exendin-4, and not liraglutide, caused hyperglycemia when given i3vt prior to an oral glucose tolerance test, although liraglutide did not lower glucose. Thus, these data show that GLP-1R agonists have differing anorectic potencies in the CNS, which may account for some of their clinical differences. Additionally, we show here that the glucose lowering properties of acute administration of GLP-1R agonists are not accounted for by their central effects.
Keywords: GLP-1R; Liraglutide; Brain; Exendin-4;

This study aims to evaluate the therapeutic effect of polyethylene glycosylated porcine glucagon-like peptide-2 (pGLP-2), a long-acting form of pGLP-2, in lipopolysaccharide (LPS)-challenged piglets. Eighteen 21-day-old weaning piglets were randomly assigned into three groups: control (saline solution), LPS (100 μg/kg LPS), and PEG–pGLP-2 (10 nmol/kg PEG–pGLP-2 + 100 μg/kg LPS). All treatments were administered intraperitoneally. Compared with the control treatment, LPS treatment significantly decreased (P  < 0.05) the villus heights of the duodenum and jejunum, as well as the villus height/crypt depth ratio of the jejunum. However, PEG–pGLP-2 therapy reduced these effects (P  > 0.05). Specifically, PEG–pGLP-2 infusion significantly increased the villus height/crypt depth ratio of the duodenum (P  < 0.05) compared with LPS treatment. Compared with the control treatment, LPS treatment significantly increased (P  < 0.05) the mRNA expression levels of interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) in the jejunum. However, PEG–pGLP-2 therapy reduced these effects (P  < 0.05). Specifically, PEG–pGLP-2 infusion significantly decreased (P  < 0.05) the mRNA expression levels of interleukin (IL)-8 and TNF-α in the duodenum and jejunum, IL-10 in the duodenum, and IFN-γ in the jejunum compared with the LPS treatment. LPS treatment increased the caspase-3 activity of the ileum mucosal (P  < 0.05), and this effect was significantly reduced by PEG–pGLP-2 treatment. These results indicate that PEG–pGLP-2 infusion alleviates the severity of intestinal injury in weaning piglets by reducing the secretion of inflammatory cytokines and the caspase-3 activity, and increasing the villus height/crypt depth ratio.
Keywords: PEGylated; Porcine glucagon-like peptide-2; Tight junction protein; Inflammatory cytokines; Caspase-3; Piglet;

α-Calcitonin gene related peptide (α-CGRP) mediated lipid mobilization in 3T3-L1 adipocytes by Christopher S. Walker; Debbie L. Hay; Sandra M. Fitzpatrick; Garth J.S. Cooper; Kerry M. Loomes (14-19).
The neuropeptide, α-calcitonin gene-related peptide (α-CGRP), is expressed from sensory nerves that innervate fat. However, how α-CGRP may act in adipose tissue is unclear. Using 3T3-L1 adipocytes we observed that rat α-CGRP (rα-CGRP) evoked either a biphasic or monophasic reduction in intracellular free fatty acid (FFA) content. cAMP production was always monophasic and occurred when FFA responses were absent. Taken together with the observed potencies, these findings suggest that adipose tissue is a physiological target for α-CGRP. However, uncoupling of the FFA and CGRP-signaling responses with increasing passage number limits 3T3-L1 adipocytes as a suitable cellular model.
Keywords: CGRP; Adipose; Lipolysis; Lipid; cAMP;

Melanin-concentrating hormone in the medial preoptic area reduces active components of maternal behavior in rats by Luciana Benedetto; Mariana Pereira; Annabel Ferreira; Pablo Torterolo (20-25).
Melanin-concentrating hormone (MCH) is an inhibitory neuropeptide mainly synthesized in neurons of the lateral hypothalamus and incerto-hypothalamic area of mammals that has been implicated in behavioral functions related to motivation. During lactation, this neuropeptide is also expressed in the medial preoptic area (mPOA), a key region of the maternal behavior circuitry. Notably, whereas MCH expression in the mPOA progressively increases during lactation, maternal behavior naturally declines, suggesting that elevated MCHergic activity in the mPOA inhibit maternal behavior in the late postpartum period. To explore this idea, we assessed the maternal behavior of early postpartum females following bilateral microinfusions of either MCH (50 and 100 ng/0.2 μl/side) or the same volume of vehicle into the mPOA. As expected, females receiving 100 ng MCH into the mPOA exhibited significant deficits in the active components of maternal behavior, including retrieving and nest building. In contrast, nursing, as well as other behaviors, including locomotor activity, exploration, and anxiety-like behavior, were not affected by intra-mPOA MCH infusion. The present results, together with previous findings showing elevated expression of this neuropeptide toward the end of the postpartum period, suggest that modulation of mPOA function by MCH may contribute to the weaning of maternal responsiveness characteristic of the late postpartum period.
Keywords: MCH; mPOA; Lactation; Motivation;

Plasma copeptin level predicts acute traumatic coagulopathy and progressive hemorrhagic injury after traumatic brain injury by Ding-Bo Yang; Wen-Hua Yu; Xiao-Qiao Dong; Quan Du; Yong-Feng Shen; Zu-Yong Zhang; Qiang Zhu; Zhi-Hao Che; Qun-Jie Liu; Hao Wang; Li Jiang; Yuan-Feng Du (26-29).
Higher plasma copeptin levels correlate with poor clinical outcomes after traumatic brain injury. Nevertheless, their links with acute traumatic coagulopathy and progressive hemorrhagic injury are unknown. Therefore, we aimed to investigate the relationship between plasma copeptin levels, acute traumatic coagulopathy and progressive hemorrhagic injury in patients with severe traumatic brain injury. We prospectively studied 100 consecutive patients presenting within 6 h from head trauma. Progressive hemorrhagic injury was present when the follow-up computerized tomography scan reported any increase in size or number of the hemorrhagic lesion, including newly developed ones. Acute traumatic coagulopathy was defined as an activated partial thromboplastic time greater than 40 s and/or international normalized ratio greater than 1.2 and/or a platelet count less than 120 × 109/L. We measured plasma copeptin levels on admission using an enzyme-linked immunosorbent assay in a blinded fashion. In multivariate logistic regression analysis, plasma copeptin level emerged as an independent predictor of progressive hemorrhagic injury and acute traumatic coagulopathy. Using receiver operating characteristic curves, we calculated areas under the curve for progressive hemorrhagic injury and acute traumatic coagulopathy. The predictive performance of copeptin was similar to that of Glasgow Coma Scale score. However, copeptin did not obviously improve the predictive value of Glasgow Coma Scale score. Thus, copeptin may help in the prediction of progressive hemorrhagic injury and acute traumatic coagulopathy after traumatic brain injury.
Keywords: Copeptin; Traumatic brain injury; Acute traumatic coagulopathy; Progressive hemorrhagic injury; Biomarker;

Neurons expressing the leptin receptor (Ob-R) exist within the caudal nucleus of the solitary tract (NTS). Additionally, afferent neurons expressing the Ob-R have been identified within the nodose ganglion and NTS. Furthermore, systemic injections or focal injections of leptin directly into NTS potentiate the response of NTS neurons to carotid chemoreceptor activation. However, the distribution of carotid body afferents in relation to Ob-R containing neurons within NTS is not known. In this study, chemoreceptor afferent fibers were labeled following microinjection of the anterograde tract tracer biotinylated dextran amine (BDA) into the carotid body or petrosal/nodose ganglion of Wistar rats. After a survival period of 10–14 days, the NTS was processed for BDA and Ob-R immunoreactivity. Afferent axons originating in the carotid body were found to project to the lateral (Slt), gelantinosa (Sg), and medial (Sm) subnuclei of the NTS complex. A similar, but more robust distribution of BDA labeled fibers was observed in the NTS complex after injections into the petrosal/nodose ganglion. Carotid body BDA labeled fibers were observed in close apposition to Ob-R immunoreactive neurons in the region of Slt, Sg and Sm. In addition, a small number of carotid body afferents were found to contain both BDA and express Ob-R-like immunoreactivity within the regions of Slt, Sg and Sm. Taken together, these data suggest that leptin may modulate carotid chemoreceptor function not only through direct effects on NTS neurons, but also through a direct effect on carotid body primary afferent fibers that innervate NTS neurons.
Keywords: Leptin receptors; Arterial chemoreceptors; Carotid body; Nodose ganglion; Cardiovascular reflex pathways;

The Zucker rat is an animal model used to study obesity and the control of food intake by various satiety peptides. The amphibian peptide bombesin (Bn) reduces cumulative food intake similarly in both obese and lean weanling Zucker rats. Here, we hypothesized that intraperitoneal (i.p) administration of gastrin-releasing peptides-10, -27 and -29 (GRP-10, GRP-27, GRP-29), which are the mammalian forms of Bn, would reduce first meal size (MS, 10% sucrose) and prolong the intermeal interval (IMI, time between first and second meals) similarly in obese and lean adult Zucker rats. To test this hypothesis, we administered GRP-10, GRP-27 and GRP-29 (0, 2.1, 4.1 and 10.3 nmol/kg) i.p. to obese and lean male Zucker rats (who were deprived of overnight food but not water) and then measured the first and second MS, IMI and satiety ratio (SR, IMI/MS). We found that in both obese and lean rats, all forms of GRP reduced the first MS, and in lean rats, they also decreased the second MS. Additionally, GRP-10 and GRP-29 prolonged the IMI in both obese and lean rats, but GRP-27 only prolonged it in lean rats. Finally, we found that all forms of GRP increased the SR in both obese and lean rats. In agreement with our hypothesis, we conclude that all forms of GRP reduce food intake in obese and lean adult Zucker rats similar to Bn in weanling rats.
Keywords: Zucker rats; GRP; Meal size; Intermeal interval; Satiety ratio;

High plasma proenkephalin A levels have been associated with poor clinical outcome of aneurysmal subarachnoid hemorrhage. This prospective observatory study was designed to investigate the relationship between plasma proenkephalin A levels and 1-week mortality, 6-month mortality and 6-month unfavorable outcome (defined as Glasgow Outcome Scale score of 1–3) in patients with severe traumatic brain injury. This study recruited 128 patients and 128 sex- and age-matched healthy controls. Plasma proenkephalin A levels, as measured by chemoluminescence sandwich immunoassay, were statistically significantly higher in patients than in healthy controls (239.1 ± 93.0 pmol/L vs.81.3 ± 22.1 pmol/L; P  < 0.001) and were correlated with Glasgow Coma Scale scores (r  = −0.540, P  < 0.001). It was identified as an independent prognostic predictor of 1-week mortality [odds ratio (OR), 1.214; 95% confidence interval (CI), 1.103–1.425; P  < 0.001], 6-month mortality (OR, 1.162; 95% CI, 1.101–1.372; P  < 0.001) and 6-month unfavorable outcome (OR, 1.116; 95% CI, 1.097–1.281; P  < 0.001). Moreover, it had high predictive value for 1-week mortality [area under curve (AUC), 0.852; 95% CI, 0.778–0.908], 6-month mortality (AUC, 0.841; 95% CI, 0.766–0.899) and 6-month unfavorable outcome (AUC, 0.830; 95% CI, 0.754–0.891). Furthermore, its predictive value was similar to Glasgow Coma Scale score's (all P  > 0.05). Yet, a combined logistic-regression model did not show that it statistically significantly improved the predictive value of Glasgow Coma Scale score (all P  > 0.05). Thus, it was proposed that enhanced plasma proenkephalin A could be a useful, complementary tool to predict short- or long-term clinical outcome after severe traumatic brain injury.
Keywords: Proenkephalin A; Traumatic brain injury; Clinical outcome;

High plasma proenkephalin A (PENK-A) levels are associated with poor clinical outcome after ischemic stroke. However, not much is known regarding the change of its level in acute intracerebral hemorrhage. Thus, we sought to determine PENK-A in plasma of patients with acute spontaneous basal ganglia hemorrhage and evaluate its relation with disease severity and in-hospital mortality. One hundred and two patients and 100 healthy controls were recruited. Plasma samples were obtained on admission for patients and at study entry for controls. Its concentration was measured by chemoluminescence sandwich immunoassay. Plasma PENK-A levels were substantially higher in patients than in healthy controls (235.5 ± 85.4 pmol/L vs. 90.1 ± 31.3 pmol/L; P  < 0.0001). A forward stepwise logistic regression selected plasma PENK-A as an independent predictor for in-hospital mortality of patients (odds ratio 1.080, 95% confidence interval 1.018–1.147, P  < 0.001). A multivariate linear regression demonstrated that plasma PENK-A level was positively associated with National Institutes of Health Stroke Scale (NIHSS) score (t  = 6.189, P  < 0.001) and hematoma volume (t  = 5.388, P  < 0.001). A receiver operating characteristic curve identified a plasma PENK-A level > 267.1 pmol/L predicted in-hospital mortality of patients with 80.0% sensitivity and 74.7% specificity (area under curve, 0.836; 95% confidence interval, 0.750–0.902). Its predictive value was similar to NIHSS score's and hematoma volume's (both P  > 0.05). However, it did not statistically significantly improve the predictive values of NIHSS score and hematoma volume (both P  > 0.05). Thus, increased plasma PENK-A levels are associated with disease severity and in-hospital mortality after acute intracerebral hemorrhage.
Keywords: Proenkephalin A; Intracerebral hemorrhage; Severity; Mortality;

Synthetic peptides for efficient discrimination of anti-enterovirus antibodies at the serotype level by John G. Routsias; Maria D. Mavrouli; Georgia Antonaki; Nikolaos Spanakis; Athanassios Tsakris (52-59).
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.
Keywords: Enterovirus; Coxsackievirus; Serotypes; Homotypic antibodies; Heterotypic antibodies; VP1 protein;

Elevated plasma visfatin levels correlate with poor prognosis of gastric cancer patients by Guo-Wen Lu; Qi-Jun Wang; Min-Ming Xia; Jiao Qian (60-64).
Visfatin is a proinflammmatory cytokine with accumulating evidence for its rise in circulation of cancer patients. This study aimed to evaluate the relationship between preoperative plasma visfatin level and prognosis of gastric cancers. Preoperative plasma visfatin levels of 262 patients with gastric cancers and plasma visfatin levels of 262 healthy individuals were determined using enzyme-linked immunosorbent assay. Preoperative plasma visfatin level was substantially higher in patients than in healthy subjects. Plasma visfatin levels were associated with invasion depth, lymph node metastasis, distant metastasis, peritoneal dissemination, tumor size and tumor node metastasis stage. Multivariate analysis revealed that high plasma visfatin level was an independent factor for death. Receiver operating characteristic curve analysis showed that plasma visfatin level predicted death with high area under curve. Multivariate Cox regression analysis identified plasma visfatin level as an independent predictor of overall survival. Thus, our results suggest that high preoperative plasma visfatin level is associated with prognostic factors for gastric cancer as well as may play a role as prognostic biomarker in gastric cancer survival.
Keywords: Visfatin; Gastric cancer; Prognosis; Biomarker;

Adipokinetic hormone induces changes in the fat body lipid composition of the beetle Zophobas atratus by Marek Gołębiowski; Magdalena Cerkowniak; Aleksandra Urbanek; Małgorzata Słocińska; Grzegorz Rosiński; Piotr Stepnowski (65-73).
In insects, neuropeptide adipokinetic hormone (AKH) released from the corpora cardiaca mobilizes lipids and carbohydrates in the fat body. We examined the developmental differences in the action of Tenmo-AKH, a bioanalogue belonging to the adipokinetic/hypertrahelosemic family (AKH/HrTH), on the lipid composition of larval and pupal fat bodies in the beetle Zophobas atratus. Tenmo-AKH was administered to the beetle larvae and pupae either as a single dose or as two doses of 20 pmol during a 24 h interval. Extracts of fat bodies were used to analyse the lipid composition by gas chromatography (GC) combined with mass spectrometry (GC–MS). Control extracts were analyzed using the same method. Fatty acids (FA) and fatty acid methyl esters (FAME) were the most abundant compounds in the fat bodies from both developmental stages. We observed significant differences in their concentrations following hormonal treatment. Tenmo-AKH also induced a distinct increase in larval sterols, fatty alcohols and benzoic acid.
Keywords: Adipokinetic hormone; Fat body; Lipids; GC–MS; Zophobas atratus;

The expression and the role of renin angiotensin aldosterone system (RAAS) components on regulation of cell volume and water transport on vertebrates and invertebrates were reviewed. The presence of these components even in simple organisms like leeches and their relevance for the control of cellular volume and water transport supports the view that the expression of these components, at cellular level, is an acquisition which was preserved throughout evolution.
Keywords: Renin; Angiotensin; Aldosterone; Invertebrates; Vertebrates;

Expression of peptide YY by human blood leukocytes by Julia Pia Natascha Holler; Jessica Schmitz; Rainer Roehrig; Sigrid Wilker; Andreas Hecker; Winfried Padberg; Veronika Grau (78-82).
Peptide YY is produced by L cells in the mucosa of the distal ileum, colon, and rectum and may have systemic and paracrine functions. We hypothesized that peptide YY is expressed by peripheral blood mononuclear cells. The purpose of the present study was to evaluate the expression of peptide YY mRNA and peptide by peripheral blood mononuclear cells and differentiated THP-1 cells after lipopolysaccharide treatment as an in vitro model of inflammation. Blood was drawn by venipuncture from 18- to 63-year-old healthy male blood donors (n  = 63); peptide YY mRNA expression levels were detected in peripheral blood mononuclear cells from all healthy male subjects. In 3 subjects, peripheral blood mononuclear cells were cultured for 3 and 24 h and peptide YY was detected in the cell culture supernatant. In human monocytic THP-1 cells treated with phorbol-12-myristate-13-acetate to induce differentiation to macrophages, treatment with lipopolysaccharide caused down-regulation of peptide YY mRNA levels. In summary, freshly isolated peripheral blood mononuclear cells from healthy humans expressed peptide YY. In vitro data suggested that peptide YY expression is down-regulated by differentiation of monocytes to macrophages and proinflammatory stimuli.
Keywords: Neuropeptide Y; Pancreatic polypeptide; Inflammation; Differentiation;

Arginine-rich, cell penetrating peptide–anti-microRNA complexes decrease glioblastoma migration potential by Yu Zhang; Melanie Köllmer; Jason S. Buhrman; Mary Y. Tang; Richard A. Gemeinhart (83-90).
MicroRNAs (miRNAs) are a class of gene regulators originating from non-coding endogenous RNAs. Altered expression, both up- and down-regulation, of miRNAs plays important roles in many human diseases. Correcting miRNA dysregulation by either inhibiting or restoring miRNA function may provide therapeutic benefit. However, efficient, nontoxic miRNA delivery systems are in need. Cell penetrating peptides (CPPs) have been widely exploited for protein, DNA, and RNA delivery. Few have examined CPP transfection efficiency with single stranded anti-miRNA. The R8 peptide condensed both siRNA and anti-miRNA. Greater than 50% of cells had anti-miRNA/R8 complexes associated and in these cells 68% of anti-miRNA escapes the endosome/lysosome. Single-stranded antisense miR-21 inhibitor (anti-miR-21) administered using the R8 peptide elicited efficient downstream gene upregulation. Glioblastoma cell migration was inhibited by 25% compared to the negative control group. To our knowledge, this is the first demonstration of miRNA modulation with anti-miR-21/R8 complexes, which has laid the groundwork for further exploring octaarginine as intracellular anti-miRNAs carrier.
Keywords: miRNAs; miRNA-21; Glioblastoma; Anti-miRNAs; Cell penetrating peptide;

Elevated adropin: A candidate diagnostic marker for myocardial infarction in conjunction with troponin-I by Suna Aydin; Tuncay Kuloglu; Suleyman Aydin; Mehmet Kalayci; Musa Yilmaz; Tolga Çakmak; Mehmet Nesimi Eren (91-97).
Myocardial infarction (MI; “heart attack”) can cause injury to or death of heart muscle tissue (myocardium) owing to prolonged ischemia and hypoxia. Troponins and CK-MB are released from heart muscle cells during MI. It has been demonstrated that energy expenditure is regulated by adropin expressed in the endocardium, myocardium, and epicardium. We hypothesized that adropin is released into the bloodstream during myocardial muscle injury caused by MI, so the serum level rises as myocytes die. Therefore, we examined the association between adropin expression and myocardial infarction in isoproterenol-induced myocardial infarction. Rats were randomly allocated to six groups. After treatment they were decapitated and their blood and tissues were collected for adropin measurement. Changes in adropin synthesis in rat heart, kidney and liver tissues in isoproterenol (ISO)-induced MI were demonstrated immunohistochemically. Serum adropin concentrations were measured by ELISA, and troponin-I, CK and CK-MB concentrations by autoanalysis. The results demonstrated that cardiac muscle cells, glomerular, peritubular and renal cortical interstitial cells, hepatocytes and liver sinusoidal cells all synthesize adropin, and synthesis increased 1–24 h after MI except in the liver cells. The findings elucidate the pathogenesis of MI, and the gradual increase in serum adropin could be a novel diagnostic marker and serve as an alternative to troponin-I measurement for diagnosing MI.
Keywords: Myocardial infarction; Adropin; Cardiac muscle cells; Hepatocytes; Kidneys;

Intermedin functions systemically as a potent vasodilator and its plasma levels have been shown to be elevated in patients with acute myocardial infarction. This study aimed to evaluate the prognostic value of plasma intermedin level in the patients with ST-segment elevation acute myocardial infarction. Plasma intermedin concentrations of 128 patients and 128 healthy controls were determined using a radioimmunoassay. Patients were followed up for 6 months for major adverse cardiovascular events (MACE) consisting of cardiovascular mortality, reinfarction, hospitalization for decompensated heart failure, and lift-threatening arrhythmia. The association of plasma intermedin levels with MACE was investigated by univariate and multivariate analyses. Plasma intermedin levels were significantly higher in patients than in healthy subjects. Elevated plasma level of intermedin was identified as an independent predictor of MACE. Receiver operating characteristic curve analysis showed that plasma intermedin levels had high predictive value for MACE. Moreover, its predictive value was similar to Global Registry of Acute Coronary Events scores’ based on area under curve. Meantime, it obviously improved Global Registry of Acute Coronary Events scores’ predictive value in a combined logistic-regression model. In multivariate Cox's proportional hazard analysis, plasma intermedin level emerged as an independent predictor of MACE-free survival. Thus, our results suggest that high plasma intermedin level is associated with poor outcomes of patients and may be a useful prognostic biomarker in ST-segment elevation acute myocardial infarction.
Keywords: Intermedin; Acute myocardial infarction; Major adverse cardiovascular event; Prognosis; Biomarker;

Previous studies have shown that repeated central injections of neurotensin, or its active analog, d-Tyr[11]neurotensin, sensitize to the locomotor stimulant effect of amphetamine. The development of sensitization to amphetamine can be modulated by contextual stimuli associated with the drug and as a consequence the expression of sensitization becomes context-dependent. The present study was thus aimed at determining whether the induction of amphetamine sensitization by neurotensin is modulated by the context in which neurotensin is administered. Different groups of adult male Long Evans rats were injected on four occasions with d-Tyr[11]neurotensin (18 nmol/10 μl; i.c.v.) in the locomotor activity cages (paired group) or in their home cage (unpaired group); control group received vehicle injection in both environments. One week after the last central injection, the locomotor response to a single dose of amphetamine (0.75 mg/kg; i.p.) was measured in all the rats. Results show that amphetamine induced higher ambulatory, non-ambulatory and vertical activity in the paired group than in the control group confirming the sensitization effect. The paired group also displayed significant higher ambulatory activity than those in the unpaired group, confirming that the expression of sensitization was context-dependent. This context-dependency was not found however for amphetamine-induced non-ambulatory and vertical activity suggesting that neurotensin can induce both a context-dependent and context-independent sensitization.
Keywords: Amphetamine; Context; Neurotensin; Sensitization;

Atrial natriuretic peptide (ANP) a cardiovascular hormone mainly secreted by heart atria in response to stretching forces induces potent diuretic, natriuretic and vasorelaxant effects and plays a major role in the homeostasis of blood pressure as well as of water and salt balance. The hormone can also act as autocrine/paracrine factor and modulate several immune functions as well as cytoprotective effects. ANP contributes to innate immunity being able to: (i) stimulate the host defense against extracellular microbes by phagocytosis and Reactive Oxygen Species (ROS) release; (ii) inhibit the synthesis and release of proinflammatory markers such as TNF-α, IL-1, MCP-1, nitric oxide (NO), cyclooxygenase-2 (COX-2); (iii) inhibit the expression of adhesion molecules such as ICAM-1 and E-selectin. ANP can also affect the adaptive immunity being able to: (i) reduce the number of CD4+ CD8+ lymphocytes as well as to increase the CD4 CD8 cells; (ii) stimulate the differentiation of naïve CD4+ cells toward the Th2 and/or Th17 phenotype. The hormone shows protective effects during: (i) ventricular hypertrophy and myocardial injury; (ii) atherosclerosis and hypertension by the induction of antiproliferative effects; (iii) oxidative stress counteracting the dangerous effects of ROS; (iv) growth of tumors cells by the induction of apoptosis or necrosis. Since not much is known about of the role of ANP locally produced and released by non-cardiac cells, this review outlines the contribution of ANP in different aspect of innate as well as adaptive immunity also with respect to the excessive cell growth in physiological and/or pathological conditions.
Keywords: Atrial natriuretic peptide; Cytokines; Reactive oxygen species; Cell proliferation; Cytoprotective effects;