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Publication date: January 2014 Source:Peptides, Volume 51

Author(s): Hirokazu Mizoguchi , Hirokazu Takagi , Chizuko Watanabe , Akihiko Yonezawa , Takumi Sato , Tsukasa Sakurada , Shinobu Sakurada

The involvement of the μ-opioid receptor subtypes on the presynaptic or postsynaptic inhibition of spinal pain transmission was characterized in ddY mice using endomorphins. Intrathecal treatment with capsaicin, N-methyl-d-aspartate (NMDA) or substance P elicited characteristic nociceptive behaviors that consisted primarily of vigorous biting and/or licking with some scratching. Intrathecal co-administration of endogenous μ-opioid peptide endomorphin-1 or endomorphin-2 resulted in a potent antinociceptive effect against the nociceptive behaviors induced by capsaicin, NMDA or substance P, which was eliminated by i.t. co-administration of the μ-opioid receptor antagonist D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP). The antinociceptive effect of endomorphin-1 was significantly suppressed by i.t.-co-administration of the μ2-opioid receptor antagonist Tyr-D-Pro-Trp-Phe-NH2 (D-Pro²-endomorphin-1) but not the μ1-opioid receptor antagonist Tyr-D-Pro-Phe-Phe-NH2 (D-Pro²-endomorphin-2) on capsaicin- or NMDA-elicited nociceptive behaviors. In contrast, the antinociceptive effect of endomorphin-2 was significantly suppressed by i.t.-co-administration of D-Pro²-endomorphin-2 but not D-Pro²-endomorphin-1 on capsaicin-, NMDA- or substance P-elicited nociceptive behaviors. Interestingly, regarding substance P-elicited nociceptive behaviors, the antinociceptive effect of endomorphin-1 was significantly suppressed by i.t.-co-administration of another μ2-opioid receptor antagonist, Tyr-D-Pro-Trp-Gly-NH2 (D-Pro²-Tyr-W-MIF-1), but not D-Pro²-endomorphin-1 or D-Pro²-endomorphin-2. The present results suggest that the multiple μ-opioid receptor subtypes are involved in the presynaptic or postsynaptic inhibition of spinal pain transmission.

Publication date: February 2014 Source:Peptides, Volume 52

Author(s): Xue-Jia Su , Rui-Xin Dong , Yan-Peng Li , Shu-Guang Yang , Zhao-Feng Li

Obestatin, encoded by the same gene as ghrelin, was first described as a physiological opponent of ghrelin through an interaction with the orphan receptor GPR39. However, the effects of obestatin were not totally contrary to the effects of ghrelin in cardiovascular regulations based on the recent studies. We summarize here the current evidences surrounding the cardiovascular actions of obestatin, and the possible implications of obestatin as a therapeutic agent in common conditions such as hypertension and heart failure.

Publication date: January 2014 Source:Peptides, Volume 51

Author(s): Marek Ruchala , Edyta Gurgul , Adam Stangierski , Elzbieta Wrotkowska , Jerzy Moczko

Ghrelin is a multifunctional peptide of widespread expression. Since it has been shown to influence energy homeostatis, its potential role in thyroid dysfunction may have clinical significance. In this study, plasma ghrelin changes have been analyzed in the same patients in three different thyroid states for the first time. The study group consisted of 16 patients who had been diagnosed with hyperthyroidism, were treated with radioiodine, developed hypothyroidism after treatment, and finally became euthyroid on l-thyroxine substitution. In the initial state of hyperthyroidism plasma ghrelin levels correlated negatively with fT3 and fT4. In hypothyroidism ghrelin concentration increased significantly (p <0.05). Although the mean value of plasma ghrelin tended to decrease in the euthyroid state, the individual difference between hypothyroidism and euthyroidism was not significant. Plasma ghrelin in euthyroidism was still significantly higher than in hyperthyroidism (p <0.05), and correlated positively with ghrelin levels in hyperthyroidism and hypothyroidism. In our opinion, plasma ghrelin fluctuations may reflect metabolic changes in patients with thyroid dysfunction. Moreover, it cannot be excluded that in thyroid disorders ghrelin acts as a compensatory factor, helping to balance metabolic disturbances.

Publication date: Available online 24 January 2014 Source:Peptides

Author(s): Joost Overduin , James Gibbs , David E. Cummings , Jr. Joseph R. Reeve

Reduction of food intake by exogenous cholecystokinin (CCK) has been demonstrated primarily for its short molecular form, CCK-8. Mounting evidence, however, implicates CCK-58 as a major physiologically active CCK form, with different neural and exocrine response profiles than CCK-8. In three studies, we compared meal-pattern effects of intraperitoneal injections CCK-8 vs. CCK-58 in undeprived male Sprague-Dawley rats consuming sweetened condensed milk. In study one, rats (N=10) received CCK-8, CCK-58 (0.45, 0.9, 1.8 and 3.6 nmole/kg) or vehicle before a 4-hour test-food presentation. At most doses, both CCK-8 and CCK-58 reduced meal size relative to vehicle. Meal-size reduction prompted a compensatory shortening of the intermeal interval (IMI) after CCK-8, but not after CCK-58, which uniquely increased the satiety ratio (IMI/size of the preceding meal). In the second study, lick patterns were monitored after administration of 0.9nmole/kg CCK-58, CCK-8 or vehicle. Lick cluster size, lick efficiency and interlick-interval distribution remained unaltered compared to vehicle, implying natural satiation, rather than illness, following both CCK forms. In study 3, threshold satiating doses of the two CCK forms were given at 5 and 30minutes after meal termination, respectively. CCK 58, but not CCK-8 increased the intermeal interval and satiety ratio compared to vehicle. In conclusion, while CCK 58 and CCK-8 both stimulate satiation, thereby reducing meal size, CCK-58 consistently exerts a satiety effect, prolonging IMI. Given the physiological prominence of CCK-58, these results suggest that CCK's role in food intake regulation may require re-examination.

Publication date: January 2014 Source:Peptides, Volume 51

Author(s): Lennart Righard , Anna Carlsson-Jonsson , Fred Nyberg

An incorrect, superficial suckling technique in breastfeeding frequently leads to milk congestion and sometimes mastitis. In the present study we have examined whether milk congestion may affect levels of the atypical opioid β-casomorphin-8 in milk and in plasma. We also investigated whether the rate of acute psychosis during the first half year after parturition has declined in Sweden over the years. Milk and plasma samples were collected for peptide analysis from 14 women with mastitis and 10 controls. We found that in a group of 14 late cases of mastitis (median 48 days post partum) the detected mean level of β-casomorphin-8 in milk was significantly higher and somewhat higher in plasma at the acute stage compared with 2–3 weeks later, after recovery when the symptoms had disappeared, as well as compared to the control subjects. Swedish official statistics show that the incidence of acute psychosis in the first month and in the first half year after birth has declined by a half during the last 30 years. A relationship between postpartum psychosis and elevated β-casomorphin-8 levels in CSF has been suggested from earlier studies. In this study, milk congestion led to enhanced levels of β-casomorphin-8 in milk, which may be related to postpartum psychosis and probably also to ‘the postnatal blues’.

Publication date: Available online 24 January 2014 Source:Peptides

Author(s): Bulent Gogebakan , Vedat Uruc , Raif Ozden , Ibrahim Gokhan Duman , Abdullah Erman Yagiz , Hamza Malik Okuyan , Ozgur Aldemir , Yunus Dogramaci , Aydiner Kalaci

Synovial fibrosis is one of the main outcomes of osteoarthritis. Some authors have reported that urotensin-II (U-II) may cause pathologic fibrosis in cardiovascular system, lung and liver. However there are no previous reports available in the literature about its relationship with the synovial fibrosis in osteoarthritis. The aim of this study was to compare the U-II levels in knee synovial fluids obtained from osteoarthritic and non-osteoarthritic patients. Two groups were created, the osteoarthritis group and non-osteoarthritic control group. The control group was consisted of patients who underwent arthroscopic surgery for other reasons than cartilage disorders. In the osteoarthritis group all patients had grade 4 primer degenerative osteoarthritis and were treated with total knee arthroplasty. Minimum 1ml knee synovial fluids were obtained during operation. Levels of U-II were measured by using ELISA kit U-II levels were significantly higher in the osteoarthritic group than that in the control group. No correlation was found between U-II levels and age. In conclusion, the significantly high U-II levels in the knee synovial fluid of osteoarthritic patients supported our hypothesis that “U-II may be associated with the synovial fibrosis in osteoarthritis”. Further studies are needed to elucidate the whole mechanism.

Publication date: January 2014 Source:Peptides, Volume 51

Author(s): Mariane Bertagnolli , Karina R. Casali , Frederico B. De Sousa , Katya Rigatto , Lenice Becker , Sergio H.S. Santos , Lucinara D. Dias , Graziela Pinto , Daniela R. Dartora , Beatriz D. Schaan , Ruben Dario Sinisterra Milan , Maria Claudia Irigoyen , Robson A.S. Santos

Low angiotensin-(1–7) (Ang-(1–7)) concentration is observed in some cardiovascular diseases and exercise training seems to restore its concentration in the heart. Recently, a novel formulation of an orally active Ang-(1–7) included in hydroxy-propyl-beta-cyclodextrin (HPB-CD) was developed and chronically administered in experimental models of cardiovascular diseases. The present study examined whether chronic administration of HPB-CD/Ang-(1–7) produces beneficial cardiovascular effects in spontaneously hypertensive rats (SHR), as well as to compare the results obtained with those produced by exercise training. Male SHR (15-week old) were divided in control (tap water) or treated with HPB-CD/Ang-(1–7) (corresponding to 30μgkg⁻¹ day⁻¹ of Ang-(1–7)) by gavage, concomitantly or not to exercise training (treadmill, 10 weeks). After chronic treatment, hemodynamic, morphometric and molecular analysis in the heart were performed. Chronic HPB-CD/Ang-(1–7) decreased arterial blood pressure (BP) and heart rate in SHR. The inclusion compound significantly improved left ventricular (LV) end-diastolic pressure, restored the maximum and minimum derivatives (dP/dT) and decreased cardiac hypertrophy index in SHR. Chronic treatment improved autonomic control by attenuating sympathetic modulation on heart and vessels and the SAP variability, as well as increasing parasympathetic modulation and HR variability. Overall results were similar to those obtained with exercise training. These results show that chronic treatment with the HPB-CD/Ang-(1–7) inclusion compound produced beneficial effects in SHR resembling the ones produced by exercise training. This observation reinforces the potential cardiovascular therapeutic effect of this novel peptide formulation.

Publication date: Available online 24 January 2014 Source:Peptides

Author(s): Dongmei Wang , Yuanhui Huo , Rémi Quirion , Yanguo Hong

Adrenomedullin (AM) is a member of calcitonin gene-related peptide (CGRP) family and a pain-related peptide. We have shown that chronic administration of morphine (20μg) upregulates AM activity contributing to morphine tolerance. The present study investigated if AM is involved in acute morphine-induced analgesia. Single intrathecal (i.t.) injection of morphine at a dose of 5μg increased the tail-flick latency (TFL). This analgesic effect was potentiated by the co-administration of the AM receptor antagonist AM22-52 (5 and 10 nmol). Exposure of sensory ganglion culture to morphine increased AM content in the ganglia in concentration (0.33 - 10μM)- and time (10 - 240min)-dependent manners. However, treatment with morphine (3.3μM) for 30-240min did not alter AM mRNA levels in the cultured ganglia. Furthermore, exposure of ganglion cultures to morphine (3.3μM) for 30-240, but not 10, min induced an increase in AM content in the culture medium. These results reveal that a single morphine treatment potentiates post-translational change and the release of AM in sensory ganglia masking morphine-induced analgesia. Thus, targeting AM and its receptors should be considered as a novel approach to improve the analgesic potency of opiates during their acute use.

Publication date: January 2014 Source:Peptides, Volume 51

Author(s): Nikolaos D. Roupas , Laurent Maïmoun , Irene Mamali , Olivier Coste , Alexandra Tsouka , Krishna Kunal Mahadea , Thibault Mura , Pascal Philibert , Laura Gaspari , Denis Mariano-Goulart , Michel Leglise , Charles Sultan , Neoklis A. Georgopoulos

Elite Rhythmic Gymnasts (RGs) constitute a unique metabolic model and they are prone to developing Anorexia Athletica. The aim of the present study was to evaluate the effect of training intensity on salivary adiponectin levels and assess a possible role of salivary adiponectin levels as a predictive factor of reproductive dysfunction and bone mass acquisition in elite RGs. The study included 80 elite female RGs participating in the World Rhythmic Gymnastics Championship tournament held in Montpellier, France on September 2011. Anthropometric values were assessed, training data and menstrual pattern were recorded, bone mass was measured with Broadband ultrasound attenuation (dB/Mhz) and baseline salivary adiponectin levels were determined. The athletes were classified as intensely and very intensely trained, considering the mean training intensity (40.84h/week). Moreover, considering their reproductive status, they were divided into RG's with normal menstruation, primary amenorrhea and oligomenorrhea. All comparisons were adjusted to age, BMI and body fat percentage differences. Very intensely trained RGs showed higher salivary adiponectin levels (p =0.05). Moreover, salivary adiponectin levels showed significant correlation with training intensity (r =0.409, p =0.003). On the other hand, no association of salivary adiponectin levels was documented with either reproductive function or bone mass acquisition. The results of the present study suggest that, in elite RGs, salivary adiponectin levels are associated with the intensity of training, possibly reflecting the deterioration of energy balance rather than the training stress. On the other hand, a predictive role of salivary adiponectin levels in reproductive dysfunction or bone mass acquisition could not be supported.

Publication date: Available online 24 January 2014 Source:Peptides

Author(s): Nishikant K. Subhedar , Kartik T. Nakhate , Manoj A. Upadhya , Dadasaheb M. Kokare

Cocaine- and amphetamine-regulated transcript peptide (CART) with its wide distribution in the brain of mammals has been the focus of considerable research in recent years. Last two decades have witnessed a steady rise in the information on the genes that encode this neuropeptide and regulation of its transcription and translation. CART is highly enriched in the hypothalamic nuclei and its relevance to energy homeostasis and neuroendocrine control has been understood in great details. However, the occurrence of this peptide in a range of diverse circuitries for sensory, motor, vegetative, limbic and higher cortical areas has been confounding. Evidence that CART peptide may have role in addiction, pain, reward, learning and memory, cognition, sleep, reproduction and development, modulation of behavior and regulation of autonomic nervous system are accumulating, but an integration has been missing. A steady stream of papers has been pointing at the therapeutic potentials of CART. The current review is an attempt at piecing together the fragments of available information, and seeks meaning out of the CART elements in their anatomical niche. We try to put together the CART containing neuronal circuitries that have been conclusively demonstrated as well as those which have been proposed, but need confirmation. With a view to finding out the evolutionary antecedents, we visit the CART systems in sub-mammalian vertebrates and seek the answer why the system is shaped the way it is. We enquire into the conservation of the CART system and appreciate its functional diversity across the phyla.