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The gastrin‐releasing peptide receptor (GRPR) is overexpressed in prostate cancer and other solid malignancies. Following up on our work on [68Ga]Ga‐ProBOMB1 that had better imaging characteristics than [68Ga]Ga‐NeoBOMB1, we investigated the effects of substituting 68Ga for 177Lu to determine if the resulting radiopharmaceuticals could be used with a therapeutic aim. We radiolabeled the bombesin antagonist ProBOMB1 (DOTA‐pABzA‐DIG‐D‐Phe‐Gln‐Trp‐Ala‐Val‐Gly‐His‐Leu‐ψ‐Pro‐NH2) with lutetium‐177 and compared it with [177Lu]Lu‐NeoBOMB1 (obtained in 54.2 ± 16.5% isolated radiochemical yield with >96% radiochemical purity and 440.8 ± 165.1 GBq/μmol molar activity) for GRPR targeting. Lu‐NeoBOMB1 had better binding affinity for GRPR than Lu‐ProBOMB1 (Ki values: 2.26 ± 0.24 and 30.2 ± 3.23nM). [177Lu]Lu‐ProBOMB1 was obtained in 53.7 ± 5.4% decay‐corrected radiochemical yield with 444.2 ± 193.2 GBq/μmol molar activity and >95% radiochemical purity. In PC‐3 prostate cancer xenograft mice, tumor uptake of [177Lu]Lu‐ProBOMB1 was 3.38 ± 1.00, 1.32 ± 0.24, and 0.31 ± 0.04%ID/g at 1, 4, and 24 hours pi. However, the uptake in tumor was lower than [177Lu]Lu‐NeoBOMB1 at all time points. [177Lu]Lu‐ProBOMB1 was inferior to [177Lu]Lu‐NeoBOMB1, which had better therapeutic index for the organs receiving the highest doses. [ABSTRACT FROM AUTHOR]

Neuropeptides function as neuromodulators in the brain, whereby they are released in a paracrine manner and activate G protein–coupled receptors (GPCRs) in adjacent cells. Because neuropeptides are made in, and secreted from, cancer cells, then bind to cell surface receptors, they function in an autocrine manner. Bombesin (BB)‐like peptides synthesized by neuroendocrine tumor small cell lung cancer (SCLC) bind to BB receptors (BBRs), causing phosphatidylinositol turnover and phosphorylation of extracellular signal–regulated kinase (ERK). Phosphorylated ERK enters the nucleus and alters gene expression of SCLC cells, stimulating growth. Vasoactive intestinal peptide (VIP) addition to SCLC cells increases their release rate of BB‐like peptides via activation of VIP receptors (VIPR), leading to activation of adenylyl cyclase and subsequent elevation of cAMP. Protein kinase A is then stimulated, leading to phosphorylation of cyclic AMP response element binding protein (CREB), which alters gene expression and stimulates proliferation. The growth of SCLC is inhibited by BBR and VIPR antagonists. This review will focus on how GPCRs for VIP and BB are molecular targets for early detection and treatment of cancer. [ABSTRACT FROM AUTHOR]

Gastrin‐releasing peptide receptors (GRPRs) are overexpressed in prostate cancer, representing attractive targets for diagnosis and therapy with bombesin (BBN)‐like radioligands. GRPR‐antagonists have lately attracted much attention owing to inherent biosafety and favorable pharmacokinetics. We herein present the GRPR‐antagonist SB9 structurally resembling the known BBN‐based agonist AMBA (SB9 = [Leu13NHEt‐desMet14]AMBA). The profiles of 111In‐SB9 and 111In‐AMBA were directly compared in PC‐3 cells and tumor‐bearing mice. SB9 and AMBA displayed high GRPR affinities. 111In‐AMBA strongly internalized in PC‐3 cells, while 111In‐SB9 remained bound on the cell surface showing a typical GRPR‐radioantagonist profile. 111In‐SB9 was more stable than 111In‐AMBA, but coinjection of the neprilysin (NEP) inhibitor phosphoramidon (PA) stabilized both in vivo. The radioligands displayed high tumor uptake (20.23 ± 3.41 %ID/g and 18.53 ± 1.54 %ID/g, respectively, at 4 hours pi), but 111In‐SB9 washed faster from background. PA coinjection led to significant increase of tumor uptake, combined with better clearance for 111In‐SB9. In short, this study has revealed superior pharmacokinetics and higher stability for the GRPR‐antagonist 111In‐SB9 vs the corresponding agonist 111In‐AMBA consolidating previous evidence that GRPR antagonists are preferable to agonists for tumor imaging and therapy. It has also demonstrated that further pharmacokinetic improvements were feasible by in situ metabolic radioligand stabilization using PA. [ABSTRACT FROM AUTHOR]

Cancer targeting can be used for both tumor diagnosis and therapy. Recently, gold nanoparticles (AuNPs) have found utility in this field as they are very small in size, and thus display an enhanced permeability and retention effect, allowing them to be taken up by tumor cells through 'passive targeting.' However, this accumulation is non-specific. Conversely, AuNPs functionalized with targeting entities such as peptides, antibodies, or small molecules can specifically target tumors through interaction with cancer-specific protein receptors. In this study, targeted AuNPs were developed using an azide-modified peptide that was able to react with alkyne-functionalized AuNPs through an interfacial strain-promoted azide-alkyne cycloaddition. Small (3 nm) AuNPs were made water-soluble through PEGylation and functionalized with dibenzocyclooctyne to add the alkyne functionality. For the targeting entity, a pan-bombesin peptide ([D-Phe6,β-Ala11,Phe13,Nle14]bombesin(6-14)) was chosen as it binds to all four receptor subtypes of the gastrin releasing peptide receptor, which is highly expressed in prostate cancer. Prostate cancer (PC-3) cells were incubated with the targeted AuNPs and studied via transmission electron microscopy. AuNPs conjugated with bombesin showed higher accumulation in PC-3 cells than either the blocking or control studies. These results suggest that these small, water-soluble, bombesin-functionalized AuNPs have potential applications in targeting prostate cancer as diagnostic or therapeutic entities. [ABSTRACT FROM AUTHOR]

Background and Purpose: Psychological stress exacerbates symptoms of urinary bladder dysfunction; however, the underlying brain mechanisms are unclear. We have demonstrated that centrally administered bombesin, a stress-related neuropeptide, facilitates the rat micturition reflex. Brain bombesin-like peptides modulate the serotoninergic nervous system activity under stress conditions; therefore, we examined whether brain 5-HT is involved in the bombesin-induced increased frequency of urination in urethane-anaesthetised male Sprague-Dawley rats.Experimental Approach: Evaluation of intercontraction intervals (ICI) and maximal voiding pressure (MVP) during cystometrograms were started 1 h before i.c.v. administration of bombesin or i.c.v. pretreatment with the 5-HT receptor antagonists.Key Results: Bombesin (0.03 nmol per animal, i.c.v.) significantly reduced ICI without affecting MVP. The bombesin-induced response was significantly suppressed by acute depletion of brain 5-HT, which was induced by pretreatment with p-chlorophenylalanine, a 5-HT synthesis inhibitor. Bombesin at a lower dose (0.01 nmol per animal, i.c.v.) showed no significant effect on ICI, while it significantly reduced ICI in the presence of WAY-100635 (5-HT1A receptor antagonist, 0.1 or 0.3 μg per animal, i.c.v.), which can block the negative feedback control of 5-HT release. Bombesin (0.03 nmol per animal)-induced ICI reduction was significantly attenuated by SB269970 (5-HT7 receptor antagonist, 0.1 or 0.3 μg per animal, i.c.v.) but not by ritanserin (5-HT2 receptor antagonist, 0.3 or 1 μg per animal, i.c.v.).Conclusions and Implications: The brain serotoninergic nervous system is involved in the facilitation of the rat micturition reflex induced by bombesin-like peptides at least in part through brain 5-HT7 receptors. [ABSTRACT FROM AUTHOR]

Aims We have analysed levels of bombesin-positive neuroendocrine cells ( NECs) in neuroendocrine cell hyperplasia of infancy ( NEHI) and other childhood interstitial lung diseases (ch ILDs) in order to validate proposed histological criteria for NEHI and investigate its aetiology. Methods and results The extent of bombesin-positive cells within airway epithelium was analysed in lung biopsies from seven patients diagnosed with NEHI, including two classified previously as non-diagnostic, and other ch ILDs ( n = 64) with age ranges of 1 month-18 years. NECs were counted and calculated as a percentage of airways containing NECs, average percentage of NECs per airway, percentage of airways with >10% NECs and number of neuroendocrine bodies ( NEBs). Correlation with age and gender was also undertaken. Patients with NEHI had the highest average percentage of bombesin-positive NECs per airway compared to other ch ILDs. However, NEH was also seen in many other ch ILDs, and appears to be most prominent in disorders associated with lung immaturity such as histological patterns associated with surfactant protein-related disorders and pulmonary interstitial glycogenosis. Conclusions NEH may, to a degree, be a marker of airway immaturity rather than the direct cause of NEHI. This possibility is supported by the fact that the number of bombesin-positive NECs decreased with age in this cohort, independent of disease type. The average percentage of bombesin-positive NECs per airway appears to be the best histological criterion for assessing the extent of NECs in the context of NEHI. [ABSTRACT FROM AUTHOR]

Key points Retinoic acid (RA) and ghrelin levels are altered in human hypoplastic lungs when compared to healthy lungs. Although considerable data have been obtained about RA, ghrelin and bombesin in the congenital diaphragmatic hernia (CDH) rat model, neuroendocrine factors have never been associated with the RA signalling pathway in this animal model., In this study, the interaction between neuroendocrine factors and RA was explored in the CDH rat model., The authors found that normal fetal lung explants treated with RA, bombesin and ghrelin showed an increase in lung growth. Hypoplastic lungs presented higher expression levels of the RA receptors α and γ. Moreover bombesin and ghrelin supplementation, in vitro, to normal lungs increased RA receptor α/γ expression whereas administration of bombesin and ghrelin antagonists to normal and hypoplastic lungs decreased it., These data reveal for the first time that there is a link between neuroendocrine factors and RA, and that neuroendocrine factors sensitise the lung to the RA action through RA receptor modulation., Abstract Congenital diaphragmatic hernia (CDH) is characterised by a spectrum of lung hypoplasia and consequent pulmonary hypertension, leading to high morbidity and mortality rates. Moreover, CDH has been associated with an increase in the levels of pulmonary neuroendocrine factors, such as bombesin and ghrelin, and a decrease in the action of retinoic acid (RA). The present study aimed to elucidate the interaction between neuroendocrine factors and RA. In vitro analyses were performed on Sprague-Dawley rat embryos. Normal lung explants were treated with bombesin, ghrelin, a bombesin antagonist, a ghrelin antagonist, dimethylsulfoxide (DMSO), RA dissolved in DMSO, bombesin plus RA and ghrelin plus RA. Hypoplastic lung explants (nitrofen model) were cultured with bombesin, ghrelin, bombesin antagonist or ghrelin antagonist. The lung explants were analysed morphometrically, and retinoic acid receptor (RAR) α, β and γ expression levels were assessed via Western blotting. Immunohistochemistry analysis of RAR was performed in normal and hypoplastic lungs 17.5 days post-conception (dpc). Compared with the controls, hypoplastic lungs exhibited significantly higher RARα/γ expression levels. Furthermore considering hypoplastic lungs, bombesin and ghrelin antagonists decreased RARα/γ expression. Normal lung explants (13.5 dpc) treated with RA, bombesin plus RA, ghrelin plus RA, bombesin or ghrelin exhibited increased lung growth. Moreover, bombesin and ghrelin increased RARα/γ expression levels, whereas the bombesin and ghrelin antagonists decreased RARα/γ expression. This study demonstrates for the first time that neuroendocrine factors function as lung growth regulators, sensitising the lung to the action of RA through up-regulation of RARα and RARγ. [ABSTRACT FROM AUTHOR]

Objective To determine the expression and biology of the neuroendocrine growth factor gastrin-releasing peptide ( GRP) and other proGRP-derived peptides in renal cancer. Materials and Methods Receptor binding studies, enzyme-linked immunosorbent assay ( ELISA) and radioimmunoassay, were used to quantitate the presence of proGRP-derived peptide receptors and their ligands in renal cancer cell lines and human renal cancers. Biological activity of proGRP peptides was confirmed with proliferation, migration, and extracellular-signal-regulated kinases 1 and 2 ( ERK1/2) activation assays in vitro. In vivo, ACHN renal cancer xenografts were treated with proGRP-derived peptides to assess tumour size and necrosis. hypoxia-inducible factor 1α ( HIF1α) and vascular endothelial growth factor ( VEGF) expression were investigated with Western blotting and ELISA respectively, to determine the possible contribution of the proGRP peptides to tumour viability. Results In ACHN cells that expressed both proGRP- and GRP-receptors, the expression of proGRP binding sites was 80-fold greater than the GRP-receptor ( GRPR). C-terminal proGRP-derived peptides stimulated the activation of ERK1/2, but with a different time course to GRP, consistent with the suggestion that these peptides may have unique cellular functions. Both GRP and proGRP47-68 stimulated proliferation and migration of ACHN cells in vitro, but only GRP reduced the extent of tumour necrosis in ACHN xenografts. GRP, but not proGRP47-68, was able to induce HIF1α and VEGF expression in ACHN cells. This may account in part for the reduction in necrosis after GRP treatment. C-terminal proGRP-derived peptides were present in all three renal cancer cell lines and a panel of human renal cancers, but mature amidated GRP was absent. Conclusion C-terminal proGRP peptides are more abundant in renal cancers and their cell lines than the more extensively studied amidated peptide, GRP. These results suggest that C-terminal proGRP-derived peptides may be a better target for novel renal cancer treatments. [ABSTRACT FROM AUTHOR]

The replacement of amide bonds in the backbone of peptides by proteolytically stable 1,2,3-triazole isosteres can provide novel peptidomimetics with promising properties for the development of tumor-targeting radiopeptides. On the basis of our previous work with radiolabeled agonistic bombesin (BBN) derivatives of the sequence [Nle14]BBN(7-14), we substituted selected amide bonds of the structurally closely related antagonistic peptide analog JMV594. With the exception of the C-terminal modification, amide-to-triazole substitutions tolerated by [Nle14]BBN(7-14) without loss of biological function led to abolished receptor affinity in the case of JMV594. These findings provide an additional piece of evidence for the currently disputed differences in the modes of action of agonistic and antagonistic gastrin-releasing peptide receptor (GRPR)-targeting radiopeptides. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Gastrin-releasing peptide ( GRP) acts as an important regulatory peptide in several normal physiological processes and as a growth factor in certain cancers. In this review we provide a comprehensive overview of the current state of knowledge of GRP in urological tissues under both normal and cancerous conditions. GRP and its receptor, GRP- R, are expressed in the normal kidney and renal cancers. GRP can stimulate the growth of renal cancer cells. GRP and GRP- R are expressed in prostate cancer and GRP can stimulate the growth of prostate cancer cell lines. Importantly, GRP is a key neuroendocrine peptide, which may be involved in the progression of advanced prostate cancer and in the neuroendocrine differentiation of prostate cancer. Recent animal studies have shown that GRP and GRP- R are an integral part of male sexual function and play a crucial role in spinal control of erections and ejaculation. [ABSTRACT FROM AUTHOR]

Background and Purpose Haemopressin and RVD-haemopressin, derived from the haemoglobin α-chain, are bioactive peptides found in brain and are ligands for cannabinoid CB1 receptors. Activation of brain CB1 receptors inhibited the secretion of adrenal catecholamines (noradrenaline and adrenaline) induced by i.c.v. bombesin in the rat. Here, we investigated the effects of two haemoglobin-derived peptides on this bombesin-induced response Experimental Approach Anaesthetised male Wistar rats were pretreated with either haemoglobin-derived peptide, given i.c.v., 30 min before i.c.v. bombesin and plasma catecholamines were subsequently measured electrochemically after HPLC. Direct effects of bombesin on secretion of adrenal catecholamines were examined using bovine adrenal chromaffin cells. Furthermore, activation of haemoglobin α-positive spinally projecting neurons in the rat hypothalamic paraventricular nucleus ( PVN, a regulatory centre of central adrenomedullary outflow) after i.c.v. bombesin was assessed by immunohistochemical techniques. Key Results Bombesin given i.c.v. dose-dependently elevated plasma catecholamines whereas incubation with bombesin had no effect on spontaneous and nicotine-induced secretion of catecholamines from chromaffin cells. The bombesin-induced increase in catecholamines was inhibited by pretreatment with i.c.v. RVD-haemopressin ( CB1 receptor agonist) but not after pretreatment with haemopressin ( CB1 receptor inverse agonist). Bombesin activated haemoglobin α-positive spinally projecting neurons in the PVN. Conclusions and Implications The haemoglobin-derived peptide RVD-haemopressin in the brain plays an inhibitory role in bombesin-induced activation of central adrenomedullary outflow via brain CB1 receptors in the rat. These findings provide basic information for the therapeutic use of haemoglobin-derived peptides in the modulation of central adrenomedullary outflow. [ABSTRACT FROM AUTHOR]

Radiolabeled gold nanoparticles may function simultaneously as radiotherapy and thermal ablation systems. The gastrin-releasing peptide receptor (GRP-r) is overexpressed in prostate cancer, and Lys3-bombesin is a peptide that binds with high affinity to the GRP-r. HIV Tat(49-57) is a cell-penetrating peptide that reaches the DNA. In cancer cells, 177Lu shows efficient crossfire effect, whereas 99mTc that is internalized in the cancer cell nuclei acts as an effective system of targeted radiotherapy because of the biological Auger effect. The aim of this research was to evaluate the in vitro potential of 99mTc-labeled and 177Lu-labeled gold nanoparticles conjugated to Tat(49-57)-Lys3-bombesin peptides (99mTc/177Lu-AuNP-Tat-BN) as a plasmonic photothermal therapy and targeted radiotherapy system in PC3 prostate cancer cells. Peptides were conjugated to AuNPs (5 nm) by spontaneous reaction with the thiol group of cysteine (Cys). The effect on PC3 cell viability after laser heating of the AuNP-Tat-BN incubated with the cancer cells was conducted using an Nd:YAG laser pulsed for 5 ns at 532 nm (0.65 W/cm2). For the 99mTc/177Lu-AuNP-Tat-BN to be obtained, the 177Lu-DOTA-Gly-Gly-Cys and 99mTc-HYNIC-octreotide radiopeptides were first prepared and added simultaneously to a solution of AuNP-Tat-BN. 99mTc/177Lu-AuNP-Tat-BN (20 Bq/cell) was incubated with PC3 cells, and the effect on the cell proliferation was evaluated after 3 days. Fluorescence images of 99mTc/177Lu-AuNP-Tat-BN internalized in nuclei of PC3 were also obtained. After laser irradiation, the presence of AuNP-Tat-BN caused a significant increase in the temperature of the medium (46.4 vs 39.5 °C of that without AuNP) resulting in a significant decrease in PC3 cell viability down to 1.3%. After treatment with 99mTc/177Lu-AuNP-Tat-BN, the PC3 cell proliferation was inhibited. The nanosystem exhibited properties suitable for plasmonic photothermal therapy and targeted radiotherapy in the treatment of prostate cancer. [ABSTRACT FROM AUTHOR]

The triazole makes the difference: Replacement of amide bonds in the backbone of peptides by 1,4‐disubstituted 1,2,3‐triazole isosteres affords peptidomimetics with retained receptor affinity and cell‐internalization properties, enhanced proteolytic stability, and improved tumor‐targeting capabilities. [ABSTRACT FROM AUTHOR]

The reaction of the C-functionalized cyclam chelating agent 1,4,8,11-tetraazacyclotetradecane-6-carboxylic acid ( 1) with CuCl2 generated a stable and neutral complex 2, which was characterized by elemental analysis, UV/Vis and IR spectroscopy, electrospray ionization mass spectrometry (ESI-MS), EPR spectroscopy and X-ray crystallography. The secondary amine groups of 1 were protected to generate 3, which was further conjugated with the bombesin (BN) derivative H2N-(Ornithine)3-BN(2-14) by a solid phase peptide synthesis method. After cleavage from the resin and deprotection, the resulting product 5 was obtained and characterized with ESI-MS and NMR spectroscopy, and was subsequently complexed under mild conditions with CuCl2 to generate complex 6 in high yield. Complex 6 was characterized with UV/Vis spectroscopy, ESI-MS and EPR spectroscopy. The stability of complexes 2 and 6 was tested against cysteine, histidine and glutathione, and both complexes were found to be stable. The cyclam BN conjugate 5 and its CuII complex 6 were suitable for targeting the gastrin releasing peptide receptors (GRPrs) that are over expressed on PC-3 cells. Both 5 and 6 showed high binding affinity to GRPrs during in vitro cell assays with human PC-3 prostate cancer cells. The half maximal inhibitory concentration ( IC50) values observed for 5 and 6 (0.30 ± 0.03 and 0.33 ± 0.03 n M, respectively) were similar to that of the [Tyr]4-BN peptide (0.45 ± 0.04 n M), which was used as standard. [ABSTRACT FROM AUTHOR]

Objectives: Neuropeptides are important signal initiators in advanced prostate cancer, partially acting through activation of nuclear factor kappa B. Central to nuclear factor kappa B regulation is the ubiquitin-proteasome system, pharmacological inhibition of which has been proposed as an anticancer strategy. We investigated the putative role of the proteasome inhibitor bortezomib in neuropeptides signaling effects on prostate cancer cells. Methods: Human prostate cancer cell lines, LNCaP and PC-3, were used to examine cell proliferation, levels of proapoptotic (caspase-3, Bad) and cell cycle regulatory proteins (p53, p27, p21), as well as total and phosphorylated Akt and p44/42 mitogen-activated protein kinase proteins. Furthermore, 20S proteasome activity, subcellular localization of nuclear factor kappa B and transcription of nuclear factor kappa B target genes, interleukin-8 and vascular endothelial growth factor, were assessed. Results: Neuropeptides (endothelin-1, bombesin) increased cell proliferation, whereas bortezomib decreased proliferation and induced apoptosis, an effect maintained after cotreatment with neuropeptides. Bad, p53, p21 and p27 were downregulated by neuropeptides in PC-3, and these effects were reversed with the addition of bortezomib. Neuropeptides increased proteasomal activity and nuclear factor kappa B levels in PC-3, and these effects were prevented by bortezomib. Interleukin-8 and vascular endothelial growth factor transcripts were induced after neuropeptides treatment, but downregulated by bortezomib. These results coincided with the ability of bortezomib to reduce mitogen-activated protein kinase signaling in both cell lines. Conclusions: These findings are consistent with bortezomib-mediated abrogation of neuropeptides-induced proliferative and antiapoptotic signaling. Thus, the effect of the drug on the neuropeptides axis needs to be further investigated, as neuropeptide action in prostate cancer might entail involvement of the proteasome. [ABSTRACT FROM AUTHOR]

Targeted drug delivery to specific group of cells offers an attractive strategy to minimize the undesirable side effects and achieve the therapeutic effect with a lower dose. Both linear and cyclic peptides have been explored as trafficking moiety due to ease of synthesis, structural simplicity, and low probability of undesirable immunogenicity. Peptides derived from sequence of cell surface proteins, such as intercellular adhesion molecule-1 (ICAM-1), LHRH, Bombesin, and LFA-1, have shown potent binding affinity to the target cell surface receptors. Moreover, peptides derived from ICAM-1 receptor can be internalized by the leukemic T-cells along with the conjugated moiety offering the promise to selectively treat cancers and autoimmune diseases. Systematic analyses have revealed that physicochemical properties of the drug-peptide conjugates and their mechanism of receptor-mediated cellular internalization are important controlling factors for developing a successful targeting system. This review is focused on understanding the factors involved in the development of an effective drug-peptide conjugate with an emphasis on the chemistry and biology of the conjugates. Reported results on several promising drug-peptide conjugates have been critically evaluated. The approaches and results presented here will serve as a guide to systematically approach targeted delivery of cytotoxic drug molecules using peptides for treatment of several diseases. © 2010 Wiley Periodicals, Inc. Med Res Rev, 32, No. 3, 637-658, 2012 [ABSTRACT FROM AUTHOR]

The article presents a study on the physiological effects of degranulated mast cells (MCs) in rainbow trout. The study found that the degranulation of MCs dosed with compound 48/80 indicates a concentration-dependent intestinal contraction in the intestinal strips of rainbow trout. The study demonstrated that histological modification on MCs are characterized through gray-levels and texture analysis. It adds that anticeras are tested on intestinal sections, while no MCs positive to serotonin and bombesin are found.

The article describes the von economo neurons (VENs), large bipolar neurons that are found in frontoinsular (FI) and anterior cingulate cortex (ACC) in great apes and humans. Stereological analysis revealed that there are more VENs in FI and the limbic anterior (LA) area of ACC of human than in apes. VENs in humans were found to be rare at birth and increase during the first eight months after birth. The authors concluded that VENs and fork cells selectively express bombesin peptides neuromedin B (NMB) and gastrin releasing peptide, relevant for satiety.

All forms of the neuropeptide gastrin-releasing peptide (GRP) are derived from the precursor proGRP1-125. Amidated GRP18-27, which together with amidated GRP1-27 was long thought to be the only biologically relevant product of the GRP gene, is involved in a multitude of physiological functions and acts as a mitogen, morphogen, and proangiogenic factor in certain cancers. Recently, GRP has been implicated in several psychiatric conditions, in the maintenance of circadian rhythm, in spinal transmission of the itch sensation, and in inflammation and wound repair. The actions of GRP are mediated by the GRP receptor. Over the last decade, nonamidated peptides derived from proGRP, such as the glycine-extended form GRP18-28 and recombinant and synthetic fragments from proGRP31-125, have been shown to be biologically active in a range of tissues and in cancer cell lines. While GRP18-28 acts via the GRP receptor, the identity of the receptor for proGRP31-125 and its fragments has not yet been established. Nonamidated fragments are also present in normal tissues and in various cancers. In fact, proGRP31-98 is the most sensitive serum biomarker in patients with small cell lung cancer and is a significant predictor of poor survival in patients with advanced prostate cancer. © 2009 International Union of Biochemistry and Molecular Biology, Inc. [ABSTRACT FROM AUTHOR]

The overexpression of peptide receptors in a variety of human carcinomas has generated considerable interest in peptide-based radiopharmaceuticals for peptide receptor imaging and peptide receptor radiotherapy. The gastrin-releasing peptide receptor is overexpressed in human prostate-, breast-, colon- and small cell lung carcinoma cells. We have developed metabolically stable 99mTc-radiolabeled bombesin ([Cha13, Nle14]BBS(7–14)) analogs, which bind with high affinity to the gastrin-releasing peptide receptors. However, because of their lipophilicity, they showed unfavorable biodistribution with high hepatic accumulation and hepatobiliary excretion. We now report a study of different glycation methods for [Cha13, Nle14]BBS(7–14) analogs to improve their biodistribution profile. Whereas the glycation using the Maillard reaction was problematic, resulting in low yields, selective introduction of the glycomimetic shikimic acid to the side chain of a Lys residue was possible. A chemoselective ligation of α-d-glucose to an amino-oxyacetylated [Cha13, Nle14]BBS(7–14) analog could be achieved, but was complicated by the co-elution of starting peptide and glycopeptide. The best procedure consisted of the [1,3]-cycloaddition of N3-β-d-glucose to a propargylglycine-containing [Cha13, Nle14]BBS(7–14) analog, using a catalytic amount of Cu(I)I. All glycated [Cha13, Nle14]BBS(7–14) analogs showed high affinity for the gastrin-releasing peptide receptor and rapid accumulation into PC-3 tumor cells. [ABSTRACT FROM AUTHOR]

Gastrin-releasing peptide (GRP) is produced by pulmonary neuroendocrine cells (PNECs), with highest numbers of GRP-positive cells present in fetal lung. Normally GRP-positive PNECs are relatively infrequent after birth, but PNEC hyperplasia is frequently associated with chronic lung diseases. To address the hypothesis that GRP mediates chronic lung injury, we present the cumulative evidence implicating GRP in bronchopulmonary dysplasia (BPD), the chronic lung disease of premature infants who survive acute respiratory distress syndrome. The availability of well-characterized animal models of BPD was a critical tool for demonstrating that GRP plays a direct role in the early pathogenesis of this disease. Potential mechanisms by which GRP contributes to injury are analyzed, with the main focus on innate immunity. Autoreactive T cells may contribute to lung injury late in the course of disease. A working model is proposed with GRP triggering multiple cell types in both the innate and adaptive immune systems, promoting cascades culminating in chronic lung disease. These observations represent a paradigm shift in the understanding of the early pathogenesis of BPD, and suggest that GRP blockade could be a novel treatment to prevent this lung disease in premature infants. [ABSTRACT FROM AUTHOR]

Previous research has shown that chronic corticosterone treatment increases the expression of corticotrophin-releasing hormone (CRH) mRNA at the central nucleus of the amygdala (CeA). Like CRH, gastrin-releasing peptide (GRP) appears to be involved in mediation of the stress response and is released at the CeA during exposure to an acute stressor. Using in-vivo microdialysis, this study examined the effects of corticosterone treatment on the release of CRH and GRP in response to an airpuff challenge at two forebrain regions, the CeA and medial prefrontal cortex. Adrenally intact rats were treated with corticosterone by systemic implants over a 14-day period prior to microdialysis probe insertion. We found that, at both regions, the airpuff-induced CRH and GRP release were enhanced in the corticosterone pellet-implanted rats as compared with the release observed in the vehicle-implanted control rats. These findings suggest that chronic corticosterone exposure potentiates the stressor-elicited release of CRH and GRP. As cortisol dysregulation has frequently been reported in people with psychiatric conditions, such as anxiety disorders or depression, a better understanding of the glucocorticoid-mediating regulation of CRH and GRP may provide insight into the underlying neurochemical mechanisms involved in both adaptive fear-type responses and maladaptive responses leading to pathology. [ABSTRACT FROM AUTHOR]

Interference with the effects of neuropeptides may be of potential therapeutic value for the treatment of rheumatoid arthritis (RA). Two neuropeptides that can be discussed in this context are bombesin/gastrin-releasing peptide (BN/GRP) and substance P (SP). In order to obtain new information on the possible importance of these two peptides, the patterns of immunohistochemical expression of BN/GRP and SP and their related receptors in the mouse knee joint from healthy and arthritic mice were examined. Positive staining for GRP receptor and the SP preferred receptor (the neurokinin-1 receptor [NK-1 R]) was observed in articular chondrocytes. On the whole, there was a decrease in immunoreactions for both the GRP- and the NK-1 receptors in the articular chondrocytes in joints exhibiting severe arthritis. Staining for BN/GRP and GRP receptor was seen in the inflammatory infiltrates of the arthritic joints. New evidence for the occurrence of marked effects of BN/GRP concerning both the articular chondrocytes and the inflammatory process is obtained in this study. With these findings and previous observations of neuropeptide expression patterns and functions we discuss the possibility that interventions with the effects of BN/GRP, SP, and other neuropeptides might be worthwhile in RA. [ABSTRACT FROM AUTHOR]

Protein kinase D (PKD) plays an important role in mediating cellular DNA synthesis in response to G protein-coupled receptor (GPCR) agonists but the function of other isoforms of the PKD family has been much less explored. Here, we examined whether PKD2 overexpression in Swiss 3T3 cells facilitates DNA synthesis and the activation of the extracellular regulated protein kinase (ERK) pathway in response to the mitogenic GPCR agonist bombesin. We show that PKD2 overexpression markedly potentiated the ability of this agonist to induce DNA synthesis. Addition of bombesin to Swiss 3T3 cells overexpressing PKD2 also induced a striking increase in the duration of MEK/ERK/RSK activation as compared with cultures of control cells. In contrast, neither DNA synthesis nor the duration of ERK activation in response to epidermal growth factor, which acts via protein kinase C/PKD2-independent pathways, was increased. Furthermore, bombesin promoted a striking accumulation of c-Fos protein in cells overexpressing PKD2. Our study demonstrates that PKD2, like PKD, facilitates mitogenesis and supports the hypothesis that an increase in the duration of the ERK signaling leading to accumulation of immediate gene products is one of the mechanisms by which isoforms of the PKD family enhance re-initiation of DNA synthesis by Gq-coupled receptor activation. J. Cell. Physiol. 211: 781–790, 2007. © 2007 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

The article offers information on several seven transmembrane receptors. They include 5-HT receptors, muscarinic acetycholine receptors, adenosine receptors, adiponectin receptors and anaphylatoxin and chemotactic peptide receptors and bombesin receptors. Data are given on nomenclature, selective agonists, principal transduction and probes.

One of the mechanisms that has been put forward for the development of the androgen-resistant status is neuroendocrine differentiation. Neuroendocrine cells secrete neuropeptides that may represent one of the possible molecular bases by which hormone-dependent prostate cancer cells could escape treatment. LNCaP prostate cancer cells were treated with either etoposide or neuropeptides. Morphological changes related to apoptosis and cell viability were assessed. Changes in intracellular ion content were quantitatively analyzed by electron probe X-ray microanalysis. Etoposide treatment consistently induces a decrease in K and an increase in Na, which are inhibited by bombesin or calcitonin. The Na/K ratio increased markedly after exposure to etoposide, and both bombesin and calcitonin blocked this increase. Etoposide also caused changes in the intracellular P and S concentrations that to a large extent could be blocked by neuropeptides. These results support the hypothesis that neuropeptides confer anti-apoptotic capabilities onto non-neuroendocrine cells in close proximity to neuroendocrine cells. [Copyright &y& Elsevier]

On their plasma membranes, cells express receptor proteins with high affinity for regulatory peptides, such as somatostatin. Changes in the density of these receptors during disease, for example, overexpression in many tumors, provide the basis for new imaging methods. The first peptide analogues successfully applied for visualization of receptor-positive tumors were radiolabeled somatostatin analogues. The next step was to label these analogues with therapeutic radionuclides for peptide receptor radionuclide therapy (PRRT). Results from preclinical and clinical multicenter studies already have shown an effective therapeutic response when using radiolabeled somatostatin analogues to treat receptor-positive tumors. Infusion of positively charged amino acids reduces kidney uptake, enlarging the therapeutic window. For PRRT of CCK-B receptor-positive tumors, such as medullary thyroid carcinoma, radiolabeled minigastrin analogues currently are being successfully applied. The combination of different therapy modalities holds interest as a means of improving the clinical therapeutic effects of radiolabeled peptides. The combination of different radionuclides, such as 177Lu-and 90Y-labeled somatostatin analogues, to reach a wider tumor region of high curability, has been described. A variety of other peptide-based radioligands, such as bombesin and NPY(Y1) analogues, receptors for which are expressed on common cancers such as prostate and breast cancer, are currently under development and in different phases of (pre)clinical investigation. Multireceptor tumor targeting using the combination of bombesin and NPY(Y1) analogues is promising for scintigraphy and PRRT of breast carcinomas and their lymph node metastases. [ABSTRACT FROM AUTHOR]

Several receptor and intracellular signalling systems in the basolateral amygdala (BLA) regulate memory formation. In the present study, we show that bombesin/gastrin-releasing peptide (GRP) receptors in the BLA are involved in the consolidation of affectively motivated memory. Adult male rats were trained in a single-trial step-down inhibitory avoidance task and tested for retention 24 h later. Post-training systemic injection of the bombesin/GRP receptor antagonist (D-Tpi6, Leu13 psi[CH2NH]-Leu14) bombesin (6–14) (RC-3095) impaired memory retention. In rats implanted under thionembutal anaesthesia with guide cannulae aimed at the BLA, post-training bilateral infusion of RC-3095 into the BLA dose-dependently impaired retention. Pre-training unilateral muscimol inactivation of the BLA blocked the memory-impairing effect of post-training systemic administration of RC-3095. The results suggest that bombesin/GRP receptors in the BLA are involved in the consolidation of aversive memory, and the BLA mediates the memory-impairing effect of systemic bombesin/GRP receptor blockade. [ABSTRACT FROM AUTHOR]

Reports on molecular cloning and characterization of avian bombesin-like peptide receptors. Novel tools for investigating molecular basis for ligand selectivity; Amino acid-sequence of chick; Physiological importance of the peptides.

We have investigated whether low affinity cholecystokinin (CCK) receptors suppress agonist-induced rises of cytosolic free Ca2+ concentration ([Ca2+]c) in pancreatic acinar cells by using properties of caffeine. A high concentration of caffeine (20 mM) completely blocked inositol 1,4,5-trisphosphate (InsP3)-induced [Ca2+]c rises but spared the InsP3-independent long-lasting [Ca2+]c oscillations. In the presence of 20 mM caffeine, only high concentrations of CCK, but not bombesin or JMV-180, suppressed the caffeine-resistant CCK or bombesin-induced [Ca2+]c oscillations, indicating that low affinity CCK receptors inhibit agonist-induced [Ca2+]c oscillations. It could be one of the underlying mechanisms by which low affinity CCK receptors suppress secretion in pancreatic acinar cells. [Copyright &y& Elsevier]

Bombesin receptor antagonists are potential therapeutic agents due to their ability to act as inhibitors of cellular proliferation. On the basis of our hypothesis concerning the mechanism of action of gastrin associating an activating enzyme to the receptor and on the results reported in the literature, we have synthesized bombesin analogs which have been modified in the C-terminal part. Potent bombesin receptor antagonists were obtained by replacement of Leu-13 with a statyl residue or with a residue bearing an hydroxyl group in place of the carbonyl function of Leu-13. Several inhibitors were able to recognize the bombesin receptor on rat pancreatic acini and antagonized bombesin stimulated amylase secretion in the nanomolar range. These compounds were also able to recognize the bombesin receptor and to inhibit [[sup 3]H] thymidine incorporation in 3T3 cells with the same potency. [ABSTRACT FROM AUTHOR]

Cholecystokinin octapeptide (CCK-8) and bombesin tetradecapeptide (BBS-14) are brain-gut neuropeptides shown to inhibit intake and choice of alcohol solutions and foods in a variety of species. Recently, Draski and colleagues selectively bred strains descended from N/Nih outbred Norway rats that differ in sleep time after injection of ethanol. The intake of 5% w/v ethanol, food, and water was measured in these rats with high, low, and control alcohol sensitivity (HAS, US, and CAS), after intraperitoneal injection of randomized sequences of doses of CCK-8 or BBS-14 (0-8 μg/kg). During baseline adaptation to water deprivation-induced consumption of alcohol, LAS rats consumed reliably more ethanol than HAS or CAS rats. Injection of CCK-8 or BBS-14 significantly and equivalently suppressed intake of ethanol and food at 30 min after presentation in each group of rats. Water intake and food intake at 30-60 min following alcohol access was not affected by prior injection of either neuropeptide. Large differences in alcohol neurosensitivity (HAS > CAS > LAS) were observed in these rats' resting behavior for 1 hr after intraperitoneal injection of 1 g/kg of ethanol. These selectively bred alcohol neurosensitivity differences cannot be explained by corresponding differences in sensitivity to the inhibitory behavioral effects of CCK-8 or BBS-14. However, differences in alcohol intake and resting behavior do correspond to artificially selected sensitivities to ethanol's hypnotic effect. [ABSTRACT FROM AUTHOR]

Endothelial cells were isolated from rat brain microvessels and grown in vitro. They expressed a high density of [125]-Tyr4]bombesin receptors (Bmax = 0.9 pmol/mg protein) with an apparent Kd value of 10 nM. The pharmacological profile of inhibition of the specific [125I-Tyr4]bombesin binding [bombesin = neuromedin B > gastrin releasing peptide (GRP)] was consistent with the presence of a neuromedin-B-preferring receptor. Addition of bombesin, neuromedin B and GRP increased the activity of phospholipase C as measured by the production of total inositol phosphates and from intracellular Ca2+ measurements. They increase 86Rb+ uptake by the Na+, K+, 2C1-cotransporter and by a charybdo-toxin-sensitive, Ca2+-activated K+ channel and 22Na+ uptake by the Na+/H+ exchanger. The pharmacologyical profiles of activation of phospholipase C, Na+, K+, 2C1- cotransport and Na+/H+ exchange by bombesin-like peptide were consistent with an involvement of the neuromedin-B-preferring receptor characterized in binding experiments. It is suggested that one of the actions of neuromedin B in brain vessels could be to control K+ secretion by the blood/brain barrier. [ABSTRACT FROM AUTHOR]

We analyzed the effect of growth factors on the localization of the 80-kDa acidic myristoylated alanine-rich C-kinase substrate (80-kDa MARCKS), the major protein kinase C (PKC) substrate, in Swiss 3T3 fibroblasts. Virtually all 80-kDa MARCKS of quiescent cultures of these cells was membrane bound. However, within 40 min after addition of bombesin (10 nM) to these cells, the content of 80-kDa MARCKS in the cytoplasmic fraction increased 25-fold. Phosphorylated 80-kDa MARCKS was detectable in the cytoplasmic fraction as early as 30 s after addition of bombesin and the translocation was sustained for 6 h i.e. until 80-kDa MARCKS became down-regulated. The ability of bombesin to stimulate translocation of 80-kDa MARCKS was dose-dependent (concentration required to produce 50% of the effect was 0.6 nM bombesin) and was abolished by the specific antagonist [Leu14,13 Ψ 14CH2NH]bombesin. Furthermore, platelet-derived growth factor (PDGF) stimulated a dose-dependent (concentration required to produce 50% of the effect was 3 ng/ml) translocation which was comparable to that induced by bombesin in terms of kinetics and magnitude. Translocation was independent of continuous protein synthesis, but dependent on active PKC. Depletion or inhibition of PKC activity abolished the 80-kDa MARCKS translocation induced by either bombesin or PDGF. Furthermore, the neuropeptides β-endothelin, bradykinin, and vasopressin, which are known to stimulate PKC activity, also promoted translocation. In contrast, epidermal growth factor, insulin and forskolin, which do not activate PKC, failed to cause such an effect. Translocation of 80-kDa MARCKS was also observed in Rat1 cells treated with phorbol ester, PDGF and β-endothelin. We conclude that the translocation of 80-kDa MARCKS from the membrane to the cytosol is an early response to a variety of growth-promoting factors that stimulate PKC through different signal-transduction pathways. [ABSTRACT FROM AUTHOR]

The homology screening approach has been used to clone a new member of the guanine-nucleotide-binding-protein-coupled receptor superfamily from guinea pig uterus. The cloned cDNA encodes a 399-amino-acid protein and shows the highest amino acid similarity to members of the bombesin receptor family; 52% and 47% similarity to the gastrin-releasing-peptide (GRP) receptor and the neuromedin-B receptor, respectively. Binding experiments with the stably transfected LLC-PK1 cell line expressing the new receptor protein confirmed the bombesin-like nature of the cloned receptor. The relative order of ligand affinity, GRP = neuromedin C [This symbol cannot be presented in ASCII format] neuromedin B, suggests that the cloned cDNA represents the GRP subtype rather than the neuromedin-B subtype of bombesin receptors. Northern-blot analysis of mRNA species from several guinea-pig tissues showed that the mRNA for the new bombesin receptor subtype is expressed mainly in uteri of pregnant animals. [ABSTRACT FROM AUTHOR]

The conformation of bombesin in trifluoroethanol/water mixtures has been studied using ¹H-NMR spectroscopy. By a combination of two-dimensional ¹H-NMR techniques and measurement of vicinal NH-α-CH spin-spin coupling constants, the secondary structure of the molecule has been determined. Bombesin adopts a helical structure in the region from Asn-6 to Met-14 with the remaining N-terminal portion existings as a more extended structures. The structure is very similar to that proposed from Fourier-transform infrared spectroscopic measurements for bombesin inserted into lipid bilayers [D. Erne & R. Schwyzer (1987) Biochemistry 26.6316–6319]. The absence of a hydrogen bond between the sidechains of Trp-8 and His-12 is discussed in terms of the ionization slate of His-12. Stabilisalion of the helix results when His-12 is in the ionized state. [ABSTRACT FROM AUTHOR]

The mode of action of bombesin on amylase secretion was investigated in rat pancreatic acini. Bombesin induced a dose-dependent increase in inositol 1,4,5-trisphosphate and cytosolic free Ca2+. The threshold concentration capable of inducing both effects was 0.1 nM and the half-maximal dose of the peptide for Ca2+ mobilization was approximately 0.6 nM. By contrast, amylase release was approximately 30 times more sensitive than inositol 1,4,5-trisphosphate production and Ca2+ mobilization to bombesin action, with 1 pM being the first stimulatory concentration and a half-maximal effect at approximately 20 pM. The ability of low bombesin doses to trigger enzyme secretion was unaffected by chelation of extracellular Ca2+ with EGTA. In order to test whether the stimulation of amylase release was truly a Ca2+-independent response, the intracellular Ca2+ stores were depleted by retreating acini with EGTA plus ionomycin, the Ca2+ ionophore. Under these conditions bombesin was still capable of eliciting a significant twofold enhancement of the secretory activity. These results indicate that bombesin, an agonist thought to activate secretion mainly through mobilization of Ca2+ from intracellular stores, elicits amylase release at low concentrations, independently of a concomitant rise in cytosolic free Ca2+. The relevance of these findings to the physiological regulation of pancreatic exocrine secretion is discussed. [ABSTRACT FROM AUTHOR]

The ¹H nuclear magnetic resonance spectrum of the tetradecapeptide, bombesin, has been assigned in (²H6)dimethyl sulphoxide solution and aqueous solution using two-dimensional techniques. The chemical shifts in both solvents indicate that the molecule has little secondary structure and adopts a random coil conformation. A comparison is made between the spectra of various smaller bombesin fragments and the intact polypeptide. [ABSTRACT FROM AUTHOR]

The gastro-intestinal tract of Polypterus senegalus was investigated by means of electron microscopy and immunohistochemistry. Cilia-bearing cells can be observed over the whole length of the intestine. All enterocytes along the intestinal tract are characterized by apical pinocytotic vesicles. However, a typical intestinal region, which in other fish is characterized by large supranuclear vacuoles, is lacking. By means of electron microscopy, four types of endocrine cells and three types of nerve cell processes can be identified. By means of immunohistochemistry, endocrine cells with immunoreactivity for bombesin-, enkephalin-, G/CCK-. 5-HT-, somatostatin- and substance P-antisera can be found Nerve cell processes show immunoreactivity for bombesin-, enkephalin-, 5-HT-, substance P- and VIP-antisera. The number of immunoreactive endocrine cells, nerve cells and nerve cell processes is different for each part of the gut. [ABSTRACT FROM AUTHOR]

Bombesin, as well as the two mammalian bombesin-like peptides gastrin-releasing peptide and neuromedin C, have been shown in this study to stimulate in vitro all steps of the phagocytic process in murine peritoneal macrophages: adherence to substrate, chemotaxis, ingestion of cells (Candida albicans) and inert particles (latex beads), and production of superoxide anion as measured by nitroblue tetrazolium reduction. A dose-response relationship was observed, with maximal stimulation of phagocytic process between 10-12M and 10-9M. Gastrin-releasing peptide (GRP) and neuromedin C caused a higher activation of adherence. chemotaxis and ingestion of C. albicans than bombesin. The three neuropcptides induced in murine macrophages a significant, but transient, increase of inositol 1,4,5,-trisphosphate (IP3) levels at 60 seconds. On the contrary, these neuropeptides produced a rapid, transient and significant decrease of cAMP at 30 seconds. These results suggest that there are close relations between IP1 and cAMP messenger systems and the phagocytic process in murine peritoneal macrophages when these cells are incubated in the presence of bombesin, GRP or neuromedin C. [ABSTRACT FROM AUTHOR]

The article presents information on the effects of serotonin on airways. Serotonin is an endogenous autacoid that can modulate activity in visceral sensory nerves. It produces complex physiologic cardiopulmonary system by interacting with both vascular and airway smooth-muscle 5-HT receptors. Although the effects of 5-HT on airways are today better defined, major. points, remain to be clarified to define the role of 5-HT, if any, in asthma in this regard, the relationships. between 5-HT and other inflammatory mediators, such as platelet-activating factor and adenosine, or substance P and bombesin should be investigated.

The article focuses on the efficacy of luteinizing hormone-releasing hormone (LHRH) analogues and hormone ablation in treating prostate cancer. It discusses the oncological and gynecological utilization of LHRH agonists. The triptorelin, a LHRH agonist, provides and effective palliative for prostate cancer. It also discusses the use of cytotoxic analogues of LHRH, somatostatin and bombesin that can be targeted to prostate cancer tumors in the improvement of the treatment.

Gastrin and cholecystokinin (CCK) are hormones released from endocrine cells in the antral stomach (gastrin), the duodenum, and the jejunum (CCK). Recent reports, based on secretion experiments in an enteroendocrine cell line (NCI‐H716) and gastrin receptor expression in proglucagon‐expressing cells from the rat colon, suggested that gastrin could be a regulator of glucagon‐like peptide‐1 (GLP‐1) secretion. To investigate these findings, we studied the acute effects of CCK‐8 (a CCK1/CCK2 (gastrin) receptor agonist) and gastrin‐17 (a CCK2(gastrin) receptor agonist) in robust ex vivo models: the isolated perfused rat small intestine and the isolated perfused rat colon. Small intestines from Wistar rats (n = 6), were perfused intraarterially over 80 min. During the perfusion, CCK (1 nmol/L) and gastrin (1 nmol/L) were infused over 10‐min periods separated by washout/baseline periods. Colons from Wistar rats (n = 6) were perfused intraarterially over 100 min. During the perfusion, CCK (1 nmol/L), vasoactive intestinal peptide (VIP) (10 nmol/L), and glucose‐dependent insulinotropic polypeptide (GIP) (1 nmol/L) were infused over 10‐min periods separated by washout/baseline periods. In the perfused rat small intestines neither CCK nor gastrin stimulated the release of GLP‐1 or neurotensin. In the perfused rat colon, neither CCK or VIP stimulated GLP‐1 or peptide YY (PYY) release, but GIP stimulated both GLP‐1 and PYY release. In both sets of experiments, bombesin, a gastrin‐releasing peptide analog, served as a positive control. Our findings do not support the suggestion that gastrin or CCK participate in the acute regulation of intestinal GLP‐1 secretion, but that GIP may play a role in the regulation of hormone secretion from the colon. [ABSTRACT FROM AUTHOR]

Peripheral bronchial carcinoids sometimes arise as single solid or nodular lesions in the periphery of the lung. We encountered a 74-year-old Japanese male with bronchial carcinoids that were widely disseminated throughout the lung parenchyma. Pulmonary function tests revealed mild airflow obstruction. A metastatic process was ruled out from primary malignancy and a histological examination revealed findings consistent with a peripheral bronchial carcinoid. Based on these findings, we concluded that this patient had a primary multifocal peripheral bronchial carcinoid. An immunohistochemical examination revealed immunoreactivity for chromogranin A and bombesin. The present case appears to be an unusual case of diffuse multifocal peripheral bronchial carcinoid, confirmed by immunohistochemistry. [ABSTRACT FROM AUTHOR]

The gastrin‐releasing peptide receptor (GRPR) is part of the bombesin receptor family and a well‐known target in cancer diagnosis and therapy. In the last decade, promising results have been achieved by using peptide‐drug conjugates, which allow selective targeting of GRPR expressing tumor cells. Most ligands, however, have been antagonists even though agonists can lead to higher tumor uptake owing to their internalization. So far, only a few studies focused on the identification of small GRPR‐selective agonists that are metabolically stable. Here, we developed novel bombesin analogs with high selectivity for the GRPR and improved blood plasma stability. The most promising analog [d‐Phe6, β‐Ala11, NMe‐Ala13, Nle14]Bn(6‐14) displays an activity of 0.3nM at the GRPR, a more than 4000‐fold selectivity over the other two bombesin receptors and more than 75% stability in human blood plasma after 24 hours. This analog is proposed as a promising drug shuttle for the intracellular delivery of different payloads in targeted tumor therapy approaches. [ABSTRACT FROM AUTHOR]

The aim of the article was to study the effects of Bornhesin vs. Saccharomyces boulardii on the translocations of Candida albicans (CA) a model of immunosuppressed rats. CA is an important opportunistic fungal pathogen causing life-threatening infections in immuno-compromised patients. CA resides as a commensal yeast of the mucosae and the gastrointestinal tract. In disseminated candidosis, CA is thought to originate from the gut. Its passage across the bowel wall into the bloodstream is an important portal of entry leading to systemic or disseminated candidosis.

Of all the non-somatosensory G protein-coupled receptors (GPCRs), about 100 are "orphan receptors": GPCRs whose natural ligands have not yet been identified. Their physiological functions therefore remain obscure and difficult to investigate directly. Bombesin receptor subtype-3 (BRS-3) is an early orphan receptor that has been resistant to "deorphanization". However, BRS-3 deficient mice have been created and shown to develop a late-onset mild obesity with metabolic defects. This implicates BRS-3 as having a role in regulating feeding and metabolism. In order to search for the physiological function of BRS-3, we first investigated the anatomical distribution of BRS-3 and found that BRS-3 is mostly expressed in the central nervous system. We show that the highest levels of BRS-3 mRNA expression are found in the hypothalamus, in the testis and in the bone marrow. We then screened for BRS-3 selective agonists and found a synthetic small molecule compound which proved to act as a selective high-affinity agonist for BRS-3 and does not activate the other bombesin receptors, the gastrin-releasing peptide- and neuromedin B- receptors. Intracerebroventricular administration of this agonist in rats showed however no effect on normal food intake. It also did not affect locomotor activity. This suggests that the anorexigenic effect of the BRS-3 system might be mediated through a novel mechanism which we are investigating. [ABSTRACT FROM AUTHOR]

Examines the effect of dexamethasone treatment after adrenalectomy on the bombesin content in the rat spinal cord. Connections between steroid hormones and the nervous system; Measurement of the plasma levels of corticosterone; Detection of bombesin-like immunoreactivity.