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Publication date: January 2014 Source:Peptides, Volume 51

Author(s): Carla de Oliveira , Vanessa Leal Scarabelot , Andressa de Souza , Cleverson Moraes de Oliveira , Liciane Fernandes Medeiros , Isabel Cristina de Macedo , Paulo Ricardo Marques Filho , Stefania Giotti Cioato , Wolnei Caumo , Iraci L.S. Torres

Disruption of the circadian system can lead to metabolic dysfunction as a response to environmental alterations. This study assessed the effects of the association between obesity and chronic stress on the temporal pattern of serum levels of adipogenic markers and corticosterone in rats. We evaluated weekly weight, delta weight, Lee index, and weight fractions of adipose tissue (mesenteric, MAT; subcutaneous, SAT; and pericardial, PAT) to control for hypercaloric diet-induced obesity model efficacy. Wistar rats were divided into four groups: standard chow (C), hypercaloric diet (HD), stress plus standard chow (S), and stress plus hypercaloric diet (SHD), and analyzed at three time points: ZT0, ZT12, and ZT18. Stressed animals were subjected to chronic stress for 1h per day, 5 days per week, during 80 days. The chronic exposure to a hypercaloric diet was an effective model for the induction of obesity and metabolic syndrome, increasing delta weight, Lee index, weight fractions of adipose tissue, and triglycerides and leptin levels. We confirmed the presence of a temporal pattern in the release of triglycerides, corticosterone, leptin, and adiponectin in naïve animals. Chronic stress reduced delta weight, MAT weight, and levels of triglycerides, total cholesterol, and leptin. There were interactions between chronic stress and obesity and serum total cholesterol levels, between time points and obesity and adiponectin and corticosterone levels, and between time points and chronic stress and serum leptin levels. In conclusion, both parameters were able to desynchronize the temporal pattern of leptin and triglyceride release, which could contribute to the development of metabolic diseases such as obesity and metabolic syndrome.

Publication date: February 2014 Source:Peptides, Volume 52

Author(s): Vo Nguyen Trung , Hiroshi Yamamoto , Tsuyoshi Yamaguchi , Satoshi Murata , Yoshinari Aimi , Atsukazu Kuwahara , Tohru Tani

The portal neural system may have an important role on the regulation of glucose homeostasis since activation of the gut–brain–liver neurocircuit by nutrient sensing in the proximal intestine reduces hepatic glucose production through enhanced liver insulin sensitivity. Although there have been many studies investigating the role of portal neural system, surgical denervation of the sole portal vein has not been reported to date. The aim of this study was to clarify the role of the portal neural system on the regulation of glucose homeostasis and food intake in the physiological condition. Surgical denervation of portal vein (DV) was performed in 10 male 12 week-old Wistar rats. The control was a sham operation (SO). One week after surgery, food intake and body weight were monitored; an oral glucose tolerance test (OGTT) was performed; and glucagon-like peptide-1 (GLP-1) and insulin levels during OGTT were assayed. In addition, insulinogenic index, homeostatic model assessment, and Matsuda index were calculated. All rats regained the preoperative body weight at one week after surgery. There was no significant difference in food intake between DV and SO rats. DV rats exhibited increased blood glucose levels associated with decreased insulin sensitivity but increased GLP-1 and insulin secretion during OGTT. In summary, in the physiological state, loss of the portal neural system leads to decreased insulin sensitivity and increased blood glucose levels but does not affect food intake. These data indicate that an intact portal neural system is important for maintaining normal glucose metabolism.

Publication date: February 2014 Source:Peptides, Volume 52

Author(s): A.E. Pekary , Albert Sattin

Women are at greater risk for major depression, PTSD, and other anxiety disorders. ERβ-selective agonists for the treatment of these disorders are the focus of pharmacologic development and clinical testing. Estradiol and its metabolites contribute to the neuroprotective effects of this steroid class, particularly in men, due to local conversion of testosterone to estiradiol in key brain regions which are predisposed to neurodegenerative diseases. We have used young adult female Sprague–Dawley rats to assess the role of TRH and TRH-like peptides, with the general structure pGlu-X-Pro-NH2 where “X” can be any amino acid residue, as mediators of the neurobiochemical effects of estradiol. The neuroprotective TRH and TRH-like peptides are coreleased with excitotoxic glutamate by glutamatergic neurons which contribute importantly to the regulation of the estrus cycle. The levels of TRH and TRH-like peptides during proestrus and/or estrus in the 12 brain regions analyzed were significantly decreased (due to accelerated release) 106 times but increased only 25 times when compared to the corresponding levels during diestrus days 1 and 2. These changes, listed by brain region in the order of decreasing number of significant decreases (↓) and/or increases (↑), were: striatum (20↓,1↑), medulla oblongata (16↓,2↑), amygdala (14↓,1↑), cerebellum (13↓,1↑), hypothalamus (12↓,1↑), entorhinal cortex (6↓,6↑), posterior cingulate (10↓,1↑), frontal cortex (3↓,5↑), nucleus accumbens (5↓,3↑), hippocampus (5↓,2↑), anterior cingulate (2↓,1↑), and piriform cortex (1↑). In peripheral tissues the corresponding changes were: ovaries (23↓), uterus (16↓,1↑), adrenals (11↓,3↑), and pancreas (1↓,6↑). We conclude that these peptides may be downstream mediators of some of the therapeutic effects of estrogen.

Publication date: February 2014 Source:Peptides, Volume 52

Author(s): Hao Zhang , Bo Tang , Cong-Guo Yin , Yan Chen , Qing-Lian Meng , Lin Jiang , Wei-Ping Wang , Guo-Zhong Niu

Plasma adrenomedullin concentration has been found to be enhanced in ischemic stroke. Up to now, little is known about the association of plasma adrenomedullin concentration with clinical outcomes of ischemic stroke. This study recruited 138 patients with ischemic stroke and 138 healthy volunteers. Unfavorable outcome was defined as modified Rankin Scale score >2 at 3 months. Plasma adrenomedullin concentrations were determined by enzyme-linked immunosorbent assay. Plasma adrenomedullin concentrations were statistically significantly higher in patients than in healthy individuals (79.9±27.3pg/mL vs. 36.8±10.4pg/mL; P <0.001). 3-Month mortality was 20.3% (28/138) and sixty-six patients (47.8%) had unfavorable outcome in 3 months. A logistic regression analysis identified plasma adrenomedullin concentration as an independent predictor of 3-month mortality (odds ratio, 1.211; 95% confidence interval, 1.101–1.582; P =0.004) and unfavorable outcome (odds ratio, 1.193; 95% confidence interval, 1.082–1.447; P =0.006). Receiver operating characteristic curve analysis showed that plasma adrenomedullin concentration predicted 3-month mortality (area under curve, 0.806; 95% confidence interval, 0.730–0.868) and unfavorable outcome (area under curve, 0.816; 95% confidence interval, 0.742–0.877) with the high predictive value. Its predictive performance was similar to that of National Institutes of Health Stroke Scale score (P =0.694 or 0.206). Its combined use with National Institutes of Health Stroke Scale score did not improve the predictive value (P =0.236 or 0.590). Thus, adrenomedullin may aid to predict long-term clinical outcomes of patients with ischemic stroke.

Publication date: Available online 20 January 2014 Source:Peptides

Author(s): Balazs Suto , Istvan Szitter , Terez Bagoly , Erika Pinter , Janos Szolcsányi , Csaba Loibl , Timea Nemeth , Krisztian Tanczos , Tihamer Molnar , Tamas Leiner , Bianka Varnai , Zsofia Bardonicsek , Zsuzsanna Helyes

Alterations of somatostatin-like immunoreactivity (SST-LI) in the plasma of 11 systemic inflammatory response syndrome (SIRS) patients were investigated in correlation with cytokines, adhesion molecules and coagulation markers repeatedly during 4 days. The origin and role of SST were studied in the cecum ligation and puncture (CLP) rat SIRS model. Capsaicin-sensitive peptidergic sensory nerves were defunctionalized by resiniferatoxin (RTX) pretreatment 2 weeks earlier, in a separate group animals were treated with the somatostatin receptor antagonist cyclo-somatostatin (C-SOM). Plasma SST-LI significantly elevated in septic patients compared to healthy volunteers during the whole 4-day period. Significantly decreased Horowitz score showed severe lung injury, increased plasma C-reactive protein and Procalcitonin confirmed SIRS. Soluble P-selectin, tissue plasminogen activator and the interleukin 8 and monocyte chemotactic protein-1 significantly increased, interleukin 6 and soluble CD40 ligand did not change, and soluble Vascular Adhesion Molecule-1 decreased. SST-LI significantly increased in rats both in the plasma and the lung 6h after CLP compared to sham-operation. After RTX pretreatment SST-LI was not altered in intact animals, but the SIRS-induced elevation was absent. Lung MPO activity significantly increased 6h following CLP compared to sham operation, which was significantly higher both after RTX-desensitization and C-SOM-treatment. Most non-pretreated operated rats survived the 6h, but 60% of the RTX-pretreated ones died showing a significantly worse survival. This is the first comprehensive study in humans and animal experiments providing evidence that SST is released from the activated peptidergic sensory nerves. It gets into the bloodstream and mediates a potent endogenous protective mechanism.

Publication date: February 2014 Source:Peptides, Volume 52

Author(s): S.S. Bhandari , J.E. Davies , J. Struck , L.L. Ng

Endothelin-1 (ET-1) is a short chained peptide primarily of endothelial origin. Concentrations of this peptide are increased in subjects with hypertension, primary pulmonary hypertension and myocardial infarction, however its short half-life makes quantification difficult. The C-terminal of proET-1 (CTproET-1) is stoichiometrically secreted with its bioactive peptide and would be a valid method of measuring the active peptide as it has a stable half-life and is less resistant to proteolytic cleavage. The objective of this study was to understand the factors (clinical, echocardiographic and biochemical) that specifically influence plasma CTproET-1 in healthy subjects. 518 healthy volunteers were recruited from a screening study. Plasma CTproET-1 concentrations were quantified using a novel immunoluminometric sandwich assay. In multivariate analyses, age (P <0.001), diastolic BP (P =0.007), LA size (P =0.001) and eGFR (P <0.001) were independently predictive of plasma CTproET-1 levels in the healthy subjects. Therefore the interpretation of plasma CTproET-1 levels in such individuals should take into account these variables to avoid potential confounding.

Publication date: Available online 10 January 2014 Source:Peptides

Author(s): Yuko Tashiro , Kengo Sato , Takuya Watanabe , Kyoko Nohtomi , Michishige Terasaki , Masaharu Nagashima , Tsutomu Hirano

Macrophage foam cell formation, characterized by cholesterol ester accumulation catalyzed by acyl-CoA:cholesterol acyltransferase 1 (ACAT1), is the hallmark of early atherogenesis. We previously demonstrated the suppressive effects of incretins, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), on the development of atherosclerotic lesions in apolipoprotein E-deficient (apoE^−/−) mice. The present study was performed to evaluate the suppressive effects of these incretins and GLP-1 analogs, such as exendin-4 and liraglutide, on human macrophage foam cell formation in vitro and those of liraglutide on atherosclerotic lesion development in apoE^−/− mice. We investigated the suppressive effects of GLP-1, GIP, exendin-4, and liraglutide against oxidized low-density lipoprotein (oxLDL)-induced foam cell formation in primary cultured human monocyte-derived macrophages. Seventeen-week-old apoE^−/− mice were administered a long-acting GLP-1 analog liraglutide by osmotic mini-pumps for 4 weeks. Aortic atherosclerosis, oxLDL-induced foam cell formation, and related gene expression in exudate peritoneal macrophages were determined in vivo and ex vivo. Receptors for GLP-1 and GIP were expressed at high levels in human aortic smooth muscle cells and monocytes, but at relatively low levels in human macrophages and foam cells. GLP-1, GIP, exendin-4, and liraglutide significantly suppressed oxLDL-induced foam cell formation mainly associated with ACAT1 down-regulation in human monocyte-derived macrophages. The infusion of liraglutide into apoE^−/− mice significantly retarded atherosclerotic lesions with monocyte/macrophage infiltration in the aortic wall and suppressed foam cell formation and ACAT1 expression in macrophages. These findings indicate that liraglutide could prevent the development of atherosclerotic lesions by suppressing macrophage foam cell formation mainly associated with ACAT1 down-regulation.

Publication date: February 2014 Source:Peptides, Volume 52

Author(s): Yonglin Ding , Wei Wang , Meng Fan , Zhongchun Tong , Rong Kuang , WenKai Jiang , Longxing Ni

Dental caries is a common oral bacterial infectious disease. Its prevention and treatment requires control of the causative pathogens within dental plaque, especially Streptococcus mutans (S. mutans). Antimicrobial peptides (AMPs), one of the promising substitutes for conventional antibiotics, have been widely tested and used for controlling bacterial infections. The present study focuses on evaluating the potential of the novel AMPs cyclic bactenecin and its derivatives against bacteria associated with dental caries. The results indicate that Bac8c displayed highest activity against the bacteria tested, whereas both cyclic and linear bactenecin had weak antimicrobial activity. The cytotoxicity assay showed that Bac8c did not cause detectable toxicity at concentrations of 32–128μg/ml for 5min or 32–64μg/ml for 60min. S. mutans and Lactobacillus fermenti treated with Bac8c showed variable effects on bacterial structure via scanning electron microscopy and transmission electron microscopy. There appeared to be a large amount of extracellular debris and obvious holes on the cell surface, as well as loss of cell wall and nucleoid condensation. The BioFlux system was employed to generate S. mutans biofilms under a controlled flow, which more closely resemble the formation process of natural biofilms. Bac8c remarkably reduced the viability of cells in biofilms formed in the BioFlux system. This phenomenon was further analyzed and verified by real-time PCR results of a significant suppression of the genes involved in S. mutans biofilm formation. Taken together, this study suggests that Bac8c has a potential clinical application in preventing and treating dental caries.

Publication date: Available online 3 January 2014 Source:Peptides

Author(s): Olivier Christiaens , Luc Swevers , Guy Smagghe

Over the past decade, RNA interference (RNAi), the sequence-specific suppression of gene expression, has proven very promising for molecular research in many species, including model insects as Tribolium castaneum and Apis mellifera. It showed its usefulness to analyze gene function and its potential to manage pest populations and reduce disease pathogens. However, in several insects, the efficiency of RNAi is low or very variable at best. One of the factors that could influence RNAi efficiency in insects is degradation of dsRNA after administration to the insect. In this paper, we report on the importance of dsRNA breakdown in the pea aphid (Acyrthosiphon pisum) associated with the absence of an RNAi response upon oral feeding and injection with dsRNA targeting different genes such as the ecdysone hormone receptor and ultraspiracle. In essence, we discovered that both the salivary secretions of aphids and the hemolymph were able to degrade the dsRNA. In parallel, introduction of dsRNA in the aphid body was not able to provoke a response in the expression of the siRNA core machinery genes.

Graphical abstract

Publication date: February 2014 Source:Peptides, Volume 52

Author(s): Suna Aydin , Tuncay Kuloglu , Suleyman Aydin , Mehmet Nesimi Eren , Ahmet Celik , Musa Yilmaz , Mehmet Kalayci , İbrahim Sahin , Orhan Gungor , Ali Gurel , Murat Ogeturk , Ozlem Dabak

Irisin converts white adipose tissue (WAT) into brown adipose tissue (BAT), as regulated by energy expenditure. The relationship between irisin concentrations after exercise in rats compared humans after exercise remains controversial. We therefore: (1) measured irisin expression in cardiac and skeletal muscle, liver, kidney, peripheral nerve sheath and skin tissues, as also serum irisin level in 10 week-old rats without exercise, and (2) measured tissue supernatant irisin levels in cardiac and skeletal muscle, and in response to exercise in young and old rats to establishing which tissues produced most irisin. Young (12 months) and old rats (24 months) with or without 10min exercise (water floating) and healthy 10 week-old Sprague-Dawley rats without exercise were used. Irisin was absent from sections of skeletal muscle of unexercised rats, the only part being stained being the perimysium. In contrast, cardiac muscle tissue, peripheral myelin sheath, liver, kidneys, and skin dermis and hypodermis were strongly immunoreactivity. No irisin was seen in skeletal muscle of unexercised young and old rats, but a slight amount was detected after exercise. Strong immunoreactivity occurred in cardiac muscle of young and old rats with or without exercise, notably in pericardial connective tissue. Serum irisin increased after exercise, being higher in younger than older rats. Irisin in tissue supernatants (cardiac and skeletal muscle) was high with or without exercise. High supernatant irisin could come from connective tissues around skeletal muscle, especially nerve sheaths located within it. Skeletal muscle is probably not a main irisin source.