Peptides. 2010 Nov 29. [Epub ahead of print]
CORONARY VASOCONSTRICTOR EFFECT OF GHRELIN IS NOT MEDIATED BY GROWTH HORMONE SECRETAGOGUE RECEPTOR 1A TYPE IN DOGS.
Sax B, Nadasy GL, Turi K, Hirschberg K, Furjesz D, Nagy A, Merkely B, Szabo G, Monos E, Kekesi V.
Heart Center, Semmelweis University, Budapest, Hungary.
Abstract
Ghrelin (GHR) is a recently discovered endocrine regulatory peptide of gastrointestinal origin with multiple functions including cardiovascular effects. However, contradictory data are available on the vascular actions of GHR in different organs and species. The aim of this study was to characterize the direct effect of the peptide on the canine coronary bed and to evaluate the role of the growth hormone secretagogue receptor (GHS-R) in the effect of GHR on coronary arterioles. Presence of GHS-R 1a and 1b subtypes in canine coronary arterioles was investigated using Western blotting and immunohistochemistry. Responses of coronary arterioles with spontaneous and elevated vascular tone (the latter evoked by the thromboxane mimetic agent U46619, 10(-7) to 10(-6) mol/l) to GHR (10(-9) to 3*10(-7) nmol/l) were recorded by video-microscopy as changes of vessel diameter. Positive immunostaining for both GHS-R subtypes was found in the wall of intramural arterioles. The microarteriographic study results showed that GHR alone could not elicit any significant effect on vessel diameter of arterioles with spontaneous tone. However, when vascular smooth muscle was preconstricted by the thromboxane mimetic agent U46619, administration of GHR induced further constriction (+31±9% increase in contraction p<0.01).>Copyright © 2010. Published by Elsevier Inc.
PMID: 21126551 [PubMed - as supplied by publisher]
Peptides. 2010 Nov 29. [Epub ahead of print]
Investigation of Gastrin-Releasing Peptide as a Mediator for 5'-Guanidinonaltrindole-Induced Compulsive Scratching in Mice.
Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
Abstract
Gastrin-releasing peptide (GRP) has been implicated in the itch-scratch cycle. We investigated if this gut-brain-skin peptide plays a role in the compulsive, hindleg scratching of the neck of mice by 5'-guanidinonaltrindole (GNTI), the kappa opioid receptor antagonist, and in the antipruritic activity of nalfurafine, the kappa opioid agonist. Previously, we showed that GNTI (0.03-1mg/kg,s.c.) elicits dose-related scratching and that nalfurafine (0.001-0.02mg/kg,s.c.) inhibits this behavior in mice. Utilizing immunohistochemistry, GRP positive nerve fibers were detected in mouse skin and superficial layer of the dorsal horn of the spinal cord as well as GRP positive cells in the dorsal root ganglion. Pretreating mice with either a pseudopeptide GRP receptor antagonist, RC-3095 (10-30mg/kg,s.c. at -15min), or a peptide GRP receptor antagonist, [D-Phe(6)]bombesin(6-13) methyl ester (2-100 nmoles, i.t. at -10min), did not suppress GNTI-induced scratching. However, pretreating mice with either antagonist inhibited scratching precipitated by the GRP receptor agonist, GRP(18-27) (2 nmoles, i.t.). Pretreating mice with a muscarinic M(1) receptor agonist, McN-A-343 (1.5-15μg/5μl, i.t. at -10min) antagonized GNTI-induced scratching. Norbinaltorphimine (20mg/kg, i.p. at -18 to -20h), a kappa opioid antagonist, countered the antiscratch activity of nalfurafine. We conclude that (a) the GRP receptor system does not mediate GNTI-induced scratching, and (b) the kappa opioid system is involved, at least in part, in the scratch suppressing activity of nalfurafine.
Copyright © 2010. Published by Elsevier Inc.PMID: 21126550 [PubMed - as supplied by publisher]
Peptides. 2010 Nov 29. [Epub ahead of print]
Structure-function relationship of conotoxin lt14a; a potential analgesic with low cytotoxicity.
Sun D, Ren Z, Zeng X, You Y, Pan W, Zhou M, Wang L, Xu A.
State Key Laboratory of Biocontrol, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, National Engineering Research Center of South China Sea Marine Biotechnology, Department of Biochemistry, College of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, People's Republic of China.
Abstract
A novel conotoxin lt14a containing 13 amino acid residues with an amidated C-terminus derived from Conus litteratus, belongs to C-C-C-C cysteine pattern. As the smallest peptide of conotoxin framework 14, lt14a could inhibit nicotinic acetylcholine r eceptor and suppress pain. To elucidate structure-function relationship, we determine the solution structure by NMR and find that lt14a comprises a short duple β-strand region and β-turn motif. An analogue [K7A]-lt14a of Ala substitution for Lys in position 7 is designed. Interestingly, [K7A]-lt14a exhibits higher activity than lt14a as long-lasting analgesic in the hotplate pain model in mice. Additionally, MTT assay reveals that the two peptides have low toxicity to human cells. The studies suggest that positively charged residue may be not involved in the blocking mechanism. However, due to the Ala substitution, hydrophobic residues patch expansion strengthens the binding ability. A hypothesis is given that in conotoxin lt14a, hydrophobic residues rather than charged residues play a key role during target binding.
Copyright © 2010. Published by Elsevier Inc.PMID: 21126549 [PubMed - as supplied by publisher]
Peptides. 2010 Nov 29. [Epub ahead of print]
Dermorphin tetrapeptide analogs as potent and long-lasting analgesics with pharmacological profiles distinct from morphine.
Mizoguchi H, Bagetta G, Sakurada T, Sakurada S.
Department of Physiology and Anatomy, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.
Abstract
Dermorphin (Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH(2)) is a heptapeptide isolated from amphibian skin. With a very high affinity and selectivity for μ-opioid receptors, dermorphin shows an extremely potent antinociceptive effect. The structure-activity relationship studies of dermorphin analogs clearly suggest that the N-terminal tetrapeptide is the minimal sequence for agonistic activity at μ-opioid receptors, and that the replacement of the D-Ala(2) residue with D-Arg(2) makes the tetrapeptides resistant to enzymatic metabolism. At present, only a handful of dermorphin N-terminal tetrapeptide analogs containing D-Arg(2) have been developed. The analogs show potent antinociceptive activity that is greater than that of morphine with various injection routes, and retain high affinity and selectivity for μ-opioid receptors. Interestingly, some analogs show pharmacological profiles that are distinct from the traditional μ-opioid receptor agonists morphine and [D-Ala(2),NMePhe(4),Gly-ol(5)]enkephalin (DAMGO). These analogs stimulate the release of dynorphins through the activation of μ-opioid receptors. The activation of κ-opioid receptors by dynorphins is suggested to reduce the side effects of μ-opioid receptor agonists, e.g., dependence or antinociceptive tolerance. The dermorphin N-terminal tetrapeptide analogs containing D-Arg(2) may provide a new target molecule for developing novel analgesics that have fewer side effects.
Copyright © 2010. Published by Elsevier Inc.PMID: 21126548 [PubMed - as supplied by publisher]
Peptides. 2010 Nov 29. [Epub ahead of print]
Intraspecies variability and conopeptide profiling of the injected venom of Conus ermineus.
Rivera-Ortiz JA, Cano H, Marí F.
Department of Chemistry and Biochemistry, Florida Atlantic University, 777 Glades Road, Boca Raton, FL 33431-0991, USA.
Abstract
The venom of cone snails (ssp. Conus), a genus of predatory venomous mollusks, is a vast source of bioactive peptides. Conus venom expression is complex and can vary considerably depending upon method of extraction and the species of cone snail in question. The injected venom from Conus ermineus, the only fish-hunting cone snail species that inhabits the Atlantic Ocean, was characterized using nanoNMR spectroscopy, MALDI-TOF mass spectrometry, RP-HPLC, nanoLC-ESI-MS. These methods allowed us to evaluate the variability of the venom within this species. Single individual specimens of a C. ermineus show unchanged injected venom mass spectra and HPLC profiles overtime. However, there was significant variability of the injected venom composition from specimen to specimen, in spite of their common biogeographic origin. The uneven distribution of fifteen conopeptides with known sequences among the individuals also attests for the differential expression of components. Using nanoLC-ESI-MS we determined that over 800 unique conopeptides are expressed by this reduced set of specimens of C. ermineus. This number of conopeptides is considerably larger than previous estimates on the molecular repertoire available to cone snails to immobilize prey. These results support the idea of the existence of a complex regulatory mechanism to express specific venom peptides for injection into prey. These intraspecies differences can be a result of a combination of genetic and environmental factors. The differential expression of venom components represents a neurochemical paradigm that warrants further investigation.
Copyright © 2010. Published by Elsevier Inc.PMID: 21126547 [PubMed - as supplied by publisher]
Peptides. 2010 Nov 29. [Epub ahead of print]
Guinea pig ileum motility stimulation elicited by N-formyl-Met-Leu-Phe (fMLF) involves neurotransmitters and prostanoids.
Colucci M, Mastriota M, Maione F, Di Giannuario A, Mascolo N, Palmery M, Severini C, Perretti M, Pieretti S.
Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, viale Regina Elena 299, 00161 Rome, Italy.
Abstract
In guinea-pig ileum (GPI), the chemotactic peptide N-formyl-Met-Leu-Phe-OH (fMLF) possess spasmogenic properties through the activation of formyl peptide receptors (FPRs). Despite this, the mediators involved remain to be elucidated. fMLF (1 nM-1μM) induced a dose-dependent contraction of GPI (EC(50)=24nM), that is blocked by pre-treatment with the FPRs antagonist Boc(2). The pre-treatment with tetrodotoxin (TTX) atropine or with SR140333 reduced the fMLF-induced contraction, whereas with hexamethonium, MEN10627, SB222200, mepyramine, cimetidine, thioperamide or methysergide did not produce any effect. With DuP697 pre-treatment, but not with piroxicam, reduced the fMLF-induced contraction. After stimulation with 24nM fMLF, a strong increase in the PGE(2) levels was observed. Finally, the concomitant blocking of the NK(1) receptor, the muscarinic receptors and COX-2 abolished the GPI contractions induced by fMLF. fMLF induced a concentration-dependent contraction of guinea-pig jejunum (EC(50)=11nM), proximal colon (EC(50)=3.5nM) and distal colon (EC(50)=2.2nM), with a time-course similar to that observed in GPI. In these preparations as well, the co-administration of atropine, SR140333 and DuP697 abolished the contractions induced by fMLF. Intraperitoneal injection of fMLF (0.1 or 1μmol/kg) enhanced the gastrointestinal motility in mice, abolished by the co-administration of atropine, SR140333 and DuP697. In conclusion, we showed that fMLF exerts spasmogenic actions on guinea-pig intestine both in vitro and in vivo through the release of acetylcholine and substance P from myenteric motorneurons and through prostanoids, probably from the inflammatory cells of the enteric immune system.
Copyright © 2010. Published by Elsevier Inc.PMID: 21126546 [PubMed - as supplied by publisher]
Peptides. 2010 Nov 29. [Epub ahead of print]
Change in plasma copeptin level after acute spontaneous basal ganglia hemorrhage.
Dong XQ, Huang M, Yu WH, Zhang ZY, Zhu Q, Che ZH, Du Q, Wang H.
Department of Neurosurgery, The First Hangzhou Municipal People's Hospital, Nanjing Medical University, 261 Huansha Road, Hangzhou 310000, China.
Abstract
High plasma copeptin levels are associated with mortality after intracerebral hemorrhage (ICH). However, there is a paucity of data available on whether copeptin is an independent prognostic marker of mortality. Thus, we sought to furthermore evaluate this relation. Thirty healthy controls and 86 patients with acute ICH were included. Plasma samples were obtained on admission and at days 1, 2, 3, 5, and 7 after ICH. Its concentration was measured by enzyme-linked immunosorbent assay. After ICH, plasma copeptin level in patients increased during the 6-hour period immediately, peaked in 24hours, decreased gradually thereafter, and was substantially higher than that in healthy controls during the 7-day period. A multivariate analysis showed plasma copeptin level was an independent predictor for 1-week mortality (odds ratio, 1.013; 95% confidence interval (CI), 1.003 - 1.023; P=0.009) and positively associated with hematoma volume (t= 6.616, P<0.001).>577.5pg/mL predicted 1-week mortality with 87.5% sensitivity and 72.2% specificity (area under curve (AUC), 0.873; 95% CI, 0.784-0.935). The AUC of the copeptin concentration was similar to those of Glasgow Coma Scale (GCS) scores and hematoma volumes (P=0.136 and 0.280). However, Copeptin did not statistically significantly improve the AUCs of GCS scores and hematoma volumes (P=0.206 and 0.333). Hence, increased plasma copeptin level is associated with hematoma volume and an independent prognostic marker of mortality after ICH.
Copyright © 2010. Published by Elsevier Inc.PMID: 21126545 [PubMed - as supplied by publisher]
Biochim Biophys Acta. 2010 Nov 29. [Epub ahead of print]
Transport and proofreading of proteins by the twin-arginine translocation (Tat) system in bacteria.
Robinson C, Matos CF, Beck D, Chao R, Lawrence J, Vasisht N, Mendel S.
Abstract
The twin-arginine translocation (Tat) system operates in plant thylakoid membranes and the plasma membranes of most free-living bacteria. In bacteria, it is responsible for the export of a number of proteins to the periplasm, outer membrane or growth medium, selecting substrates by virtue of cleavable N-terminal signal peptides that contain a key twin-arginine motif together with other determinants. Its most notable attribute is its ability to transport large folded proteins (even oligomeric proteins) across the tightly sealed plasma membrane. In Gram-negative bacteria, TatABC subunits appear to carry out all of the essential translocation functions in the form of two distinct complexes at steady state: a TatABC substrate-binding complex and separate TatA complex. Several studies favour a model in which these complexes transiently coalesce to generate the full translocase. Most Gram-positive organisms possess an even simpler 'minimalist' Tat system which lacks a TatB component and contains, instead, a bifunctional TatA component. These Tat systems may involve the operation of a TatAC complex together with a separate TatA complex, although a radically different model for TatAC-type systems has also been proposed. While bacterial Tat systems appear to require the presence of only a few proteins for the actual translocation event, there is increasing evidence for the operation of ancillary components that carry out sophisticated 'proofreading' activities. These activities ensure that redox proteins are only exported after full assembly of the cofactor, thereby avoiding the futile export of apo-forms.
Copyright © 2010. Published by Elsevier B.V.PMID: 21126506 [PubMed - as supplied by publisher]
FEBS J. 2010 Dec;277(24):4998-5005. doi: 10.1111/j.1742-4658.2010.07932.x.
Roles of prolactin-releasing peptide and RFamide related peptides in the control of stress and food intake.
Division of Brain and Neurophysiology, Department of Physiology, Jichi Medical University, Japan.
Abstract
Subsequent to the isolation of the first recognized RFamide neuropeptide, FMRFamide, from the clam, a large number of these peptides have been identified. There are now five groups of RFamide peptides identified in mammals. RFamide peptides show diversity with respect to their N-terminal sequence and biological activity. RFamide peptides have been implicated in a variety of roles, including energy metabolism, stress and pain modulation, as well as effects in the neuroendocrine and cardiovascular systems. In the present minireview, we focus on prolactin-releasing peptide (PrRP) and RFamide related peptide (RFRP) with respect to their roles in the control of energy metabolism and stress responses. Both food intake and stressful stimuli activate PrRP neurons. The administration of PrRP affects energy metabolism and neuroendocrine systems. PrRP-deficient or PrRP receptor-deficient mice show abnormal energy metabolism and/or stress responses. On the other hand, RFRP neurons are activated by stressful stimuli and the administration of RFRP induces neuroendocrine and behavioral stress responses. Taken together, these data suggests that PrRP and RFRP neurons play a role in the control of energy metabolism and/or stress responses.
© 2010 The Authors Journal compilation © 2010 FEBS.PMID: 21126313 [PubMed - in process]
Hum Gene Ther. 2010 Dec 2. [Epub ahead of print]
Systemic Pro-opiomelanocortin Expression Induces Melanogenic Differentiation and Inhibits Tumor Angiogenesis in Established Mouse Melanoma.
Liu GS, Tsai HE, Weng WT, Liu LF, Weng CH, Chuang MR, Lam HC, Wu CS, Tee R, Wen ZH, Howng SL, Tai MH.
Kaohsiung Veterans General Hospital, Department of Medical Education & Research , Kaohsiung, Taiwan; gsliu@unimelb.edu.au.
Abstract
Malignant melanoma is one of the leading causes of cancer mortality worldwide, undermining the need for effective novel therapies. In this study, the therapeutic efficacy and mechanism of systemic POMC therapy was evaluated in mice bearing established melanoma. Injection of adenovirus encoding POMC (Ad-POMC) led to hepatic POMC overexpression and elevated corticotropin (ACTH) levels in circulation. Systemic POMC therapy significantly attenuated the growth of established melanoma and prolonged the survival of tumor-bearing mice. Histological analysis revealed that systemic POMC therapy induced melanogenic differentiation while reducing melanoma growth. Besides, POMC therapy also elicited a significant reduction in the neovascular network of melanoma. Finally, we demonstrated that POMC-derived peptides, including ACTH, α-MSH and β-MSH, are involved in the POMC-mediated melanogenic differentiation and angiogenesis inhibition. In summary, systemic POMC therapy suppresses melanoma growth via induction of melanogenic differentiation and angiogenesis blockade, thereby demonstrating its potential as a novel treatment modality for melanoma.
PMID: 21126174 [PubMed - as supplied by publisher]
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