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BMB Reports Nov 2021Vascular calcification is the heterotopic accumulation of calcium phosphate salts in the vascular tissue and is highly correlated with increased cardiovascular morbidity...
Vascular calcification is the heterotopic accumulation of calcium phosphate salts in the vascular tissue and is highly correlated with increased cardiovascular morbidity and mortality. In this study, we found that the expression of neuromedin B (NMB) and NMB receptor is upregulated in phosphate-induced calcification of vascular smooth muscle cells (VSMCs). Silencing of NMB or treatment with NMB receptor antagonist, PD168368, inhibited the phosphate-induced osteogenic differentiation of VSMCs by inhibiting Wnt/β-catenin signaling and VSMC apoptosis. PD168368 also attenuated the arterial calcification in cultured aortic rings and in a rat model of chronic kidney disease. The results of this study suggest that NMB-NMB receptor axis may have potential therapeutic value in the diagnosis and treatment of vascular calcification. [BMB Reports 2021; 54(11): 569-574].
Topics: Animals; Calcium; Cell Differentiation; Cells, Cultured; Male; Muscle, Smooth, Vascular; Neurokinin B; Osteogenesis; Phosphates; Rats; Rats, Wistar; Receptors, Bombesin; Renal Insufficiency, Chronic; Vascular Calcification; Wnt Signaling Pathway
PubMed: 34674793
DOI: 10.5483/BMBRep.2021.54.11.089 -
Biomedicine & Pharmacotherapy =... May 2023The gastrin-releasing peptide receptor (GRPR), a member of the G protein-coupled receptors (GPCRs), binds to ligands such as gastrin-releasing peptide (GRP) and plays a... (Review)
Review
The gastrin-releasing peptide receptor (GRPR), a member of the G protein-coupled receptors (GPCRs), binds to ligands such as gastrin-releasing peptide (GRP) and plays a variety of biological roles. GRP/GRPR signalling is involved in the pathophysiological processes of many diseases, including inflammatory diseases, cardiovascular diseases, neurological diseases, and various cancers. In the immune system, the unique function of GRP/GRPR in neutrophil chemotaxis suggests that GRPR can be directly stimulated through GRP-mediated neutrophils to activate selective signalling pathways, such as PI3K, PKC, and MAPK, and participate in the occurrence and development of inflammation-related diseases. In the cardiovascular system, GRP increases intercellular adhesion molecule 1 (ICAM-1) and induces vascular cell adhesion molecule-1 (VCAM-1). GRP activates ERK1/2, MAPK, and AKT, leading to cardiovascular diseases, including myocardial infarction. Central nervous system signal transduction mediated by the GRP/GRPR axis plays a vital role in emotional responses, social interaction, and memory. The GRP/GRPR axis is elevated in various cancers, including lung, cervical, colorectal, renal cell, and head and neck squamous cell carcinomas. GRP is a mitogen in a variety of tumour cell lines. Its precursor, pro-gastrin-releasing peptide (ProGRP), may play an important role as an emerging tumour marker in early tumour diagnosis. GPCRs serve as therapeutic targets for drug development, but their function in each disease remains unclear, and their involvement in disease progression has not been well explored or summarised. This review lays out the above mentioned pathophysiological processes based on previous research conclusions. The GRP/GRPR axis may be a potential target for treating multiple diseases, and the study of this signalling axis is particularly important.
Topics: Humans; Receptors, Bombesin; Gastrin-Releasing Peptide; Cardiovascular Diseases; Signal Transduction; Cell Line, Tumor
PubMed: 36933382
DOI: 10.1016/j.biopha.2023.114497 -
Current Opinion in Endocrinology,... Feb 2008Mammalian bombesin-related peptides, gastrin-releasing peptide and neuromedin B actions are mediated by two receptors (BB1-receptor, BB2-receptor), which are closely... (Review)
Review
PURPOSE OF REVIEW
Mammalian bombesin-related peptides, gastrin-releasing peptide and neuromedin B actions are mediated by two receptors (BB1-receptor, BB2-receptor), which are closely related to the orphan receptor BRS-3 (BB3-receptor). The purpose of this review is to highlight advances in the understanding of these peptides in physiology/disease states.
RECENT FINDINGS
Pharmacologic/receptor-knockout studies show involvement of these receptors in a number of new processes/diseases. Neuromedin B/BB1-receptor is an important physiological regulator of pituitary-thyroid function; in mediating behavior, especially feas/anxiety; in mediating satiety through different cascades than gastrin-releasing peptide/BB2 receptors and for its autocrine tumor-growth effects. Gastrin-releasing peptide/BB2-receptor plays important roles in mediating signals for pruritus, lung development/injury, small intestinal mucosal defense, and central nervous system processes such as learning/memory. The signaling mechanisms of its potent growth effects are being elucidated and their possible therapeutic targets identified. BB3-receptor knockout mice provided insights for their obesity/glucose intolerance and demonstrated that this receptor may be important in the lung response to injury, tumor growth and gastrointestinal motility. Each receptor is frequently overexpressed in human tumors and has potent growth effects. This effect is being explored to develop new antitumor treatments, such as bombesin-receptor ligands conjugated to cytotoxic agents.
SUMMARY
This receptor family is involved in an increasing number of central nervous system/peripheral processes physiologically and in disease states, and increased understanding of its role may lead to novel treatments.
Topics: Animals; Antineoplastic Agents; Bombesin; Cell Proliferation; Humans; Neoplasms; Peptide Fragments; Receptors, Bombesin
PubMed: 18185064
DOI: 10.1097/MED.0b013e3282f3709b -
Trends in Endocrinology and Metabolism:... Sep 2016Bombesin-like receptor 3 (BRS-3) is an X-linked orphan Gq-coupled receptor that regulates food intake, metabolic rate, body temperature, heart rate, blood pressure, and... (Review)
Review
Bombesin-like receptor 3 (BRS-3) is an X-linked orphan Gq-coupled receptor that regulates food intake, metabolic rate, body temperature, heart rate, blood pressure, and insulin secretion. Most BRS-3 actions occur via the brain, through mechanisms including regulating sympathetic outflow. Ablation of Brs3 causes obesity, while synthetic agonists produce weight loss.
Topics: Animals; Blood Pressure; Eating; Energy Metabolism; Heart Rate; Humans; Insulin; Receptors, Bombesin
PubMed: 27055378
DOI: 10.1016/j.tem.2016.03.003 -
Biomedicine & Pharmacotherapy =... Mar 2017Despite efforts, cancer is still one of the leading causes of morbidity and mortality worldwide, with approximately 14 million new cases and 8.2 million cancer-related... (Review)
Review
Despite efforts, cancer is still one of the leading causes of morbidity and mortality worldwide, with approximately 14 million new cases and 8.2 million cancer-related deaths each year, according to the World Health Organization. Among the strategies to reduce cancer progression and improving its management, implementing early detection technologies is crucial. Based on the fact that several types of cancer cells overexpress surface receptors, small molecule ligands, such as peptides, have been developed to allow tumor identification at earlier stages. Allied with imaging techniques such as PET and SPECT, radiolabeled peptides play a pivotal role in nuclear medicine. Bombesin, a peptide of 14 amino acids, is an amphibian homolog to the mammalian gastrin-releasing peptide (GRP), that has been extensively studied as a targeting ligand for diagnosis and therapy of GRP positive tumors, such as breast, pancreas, lungs and prostate cancers. In this context, herein we provide a review of reported bombesin derivatives radiolabeled with a multitude of radioactive isotopes for diagnostic purposes in the preclinical setting. Moreover, since animal models are highly relevant for assessing the potential of clinical translation of this radiopeptides, a brief report of the currently used GRP-positive tumor-bearing animal models is described.
Topics: Animals; Bombesin; Diagnostic Imaging; Humans; Neoplasms; Positron-Emission Tomography; Radiopharmaceuticals; Receptors, Bombesin; Tomography, Emission-Computed, Single-Photon
PubMed: 28040598
DOI: 10.1016/j.biopha.2016.12.083 -
European Journal of Nuclear Medicine... Feb 2012Radiolabelled receptor-binding peptides targeting receptors (over)expressed on tumour cells are widely under investigation for tumour diagnosis and therapy. The concept... (Review)
Review
Radiolabelled receptor-binding peptides targeting receptors (over)expressed on tumour cells are widely under investigation for tumour diagnosis and therapy. The concept of using radiolabelled receptor-binding peptides to target receptor-expressing tissues in vivo has stimulated a large body of research in nuclear medicine. The (111)In-labelled somatostatin analogue octreotide (OctreoScan) is the most successful radiopeptide for tumour imaging, and was the first to be approved for diagnostic use. Based on the success of these studies, other receptor-targeting peptides such as cholecystokinin/gastrin analogues, glucagon-like peptide-1, bombesin (BN), chemokine receptor CXCR4 targeting peptides, and RGD peptides are currently under development or undergoing clinical trials. In this review, we discuss some of these peptides and their analogues, with regard to their potential for radionuclide imaging of tumours.
Topics: Animals; Bombesin; Cholecystokinin; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Ligands; Neoplasms; Octreotide; Pentetic Acid; Peptides; Radionuclide Imaging; Radiopharmaceuticals; Receptor, Cholecystokinin B; Receptors, Bombesin; Receptors, CXCR4; Receptors, Cholecystokinin; Receptors, Glucagon
PubMed: 22388627
DOI: 10.1007/s00259-011-2014-7 -
American Journal of Physiology. Heart... Apr 2016Bombesin-like receptor 3 (BRS-3) is an orphan G protein-coupled receptor that regulates energy expenditure, food intake, and body weight. We examined the effects of...
Bombesin-like receptor 3 (BRS-3) is an orphan G protein-coupled receptor that regulates energy expenditure, food intake, and body weight. We examined the effects of BRS-3 deletion and activation on blood pressure and heart rate. In free-living, telemetered Brs3 null mice the resting heart rate was 10% lower than wild-type controls, while the resting mean arterial pressure was unchanged. During physical activity, the heart rate and blood pressure increased more in Brs3 null mice, reaching a similar heart rate and higher mean arterial pressure than control mice. When sympathetic input was blocked with propranolol, the heart rate of Brs3 null mice was unchanged, while the heart rate in control mice was reduced to the level of the null mice. The intrinsic heart rate, measured after both sympathetic and parasympathetic blockade, was similar in Brs3 null and control mice. Intravenous infusion of the BRS-3 agonist MK-5046 increased mean arterial pressure and heart rate in wild-type but not in Brs3 null mice, and this increase was blocked by pretreatment with clonidine, a sympatholytic, centrally acting α2-adrenergic agonist. In anesthetized mice, hypothalamic infusion of MK-5046 also increased both mean arterial pressure and heart rate. Taken together, these data demonstrate that BRS-3 contributes to resting cardiac sympathetic tone, but is not required for activity-induced increases in heart rate and blood pressure. The data suggest that BRS-3 activation increases heart rate and blood pressure via a central sympathetic mechanism.
Topics: Adrenergic Agents; Animals; Blood Pressure; Heart Rate; Mice; Mice, Inbred C57BL; Receptors, Bombesin; Sympathetic Nervous System
PubMed: 26801314
DOI: 10.1152/ajpheart.00963.2015 -
Peptides Jan 2016Bombesin receptor subtype-3 (BRS-3) is an orphan G-protein coupled receptor which is classified in the bombesin receptor (BnR) family with which it shares high homology....
Bombesin receptor subtype-3 (BRS-3) is an orphan G-protein coupled receptor which is classified in the bombesin receptor (BnR) family with which it shares high homology. It is present widely in the central nervous system and peripheral tissues and primarily receptor-knockout studies suggest it is involved in metabolic-glucose-insulin homeostasis, feeding and other CNS behaviors, gastrointestinal motility and cancer growth. However, the role of BRS-3 physiologically or in pathologic disorders has been not well defined because the natural ligand is unknown. Until recently, no selective agonists/antagonists were available; however, recently synthetic high-affinity agonists, chiral-diazepines nonpeptide-analogs (3F, 9D, 9F, 9G) with low CNS penetrance, were described, but are not well-categorized pharmacologically or in different labarotory species. The present study characterizes the affinities, potencies, selectivities of the chiral-diazepine BRS-3 agonists in human and rodents (mice,rat). In human BRS-3 receptors, the relative affinities of the chiral-diazepines was 9G>9D>9F>3F; each was selective for BRS-3. For stimulating PLC activity, in h-BRS-3 each of the four chiral diazepine analogs was fully efficacious and their relative potencies were: 9G (EC50: 9 nM)>9D (EC50: 9.4 nM)>9F (EC50: 39 nM)>3F (EC50: 48 nM). None of the four chiral diazepine analogs activated r,m,h-GRPR/NMBR. The nonpeptide agonists showed marked differences from each other and a peptide agonist in receptor-coupling-stiochiometry and in affinities/potencies in different species. These results demonstrate that chiral diazepine analogs (9G, 9D, 9F, 3F) have high/affinity/potency for the BRS-3 receptor in human and rodent cells, but different coupling-relationships and species differences from a peptide agonist.
Topics: Animals; Azepines; BALB 3T3 Cells; Drug Evaluation, Preclinical; Gastrin-Releasing Peptide; Humans; Inhibitory Concentration 50; Inositol 1,4,5-Trisphosphate; Mice; Neurokinin B; Rats; Receptors, Bombesin; Second Messenger Systems; Species Specificity
PubMed: 26524625
DOI: 10.1016/j.peptides.2015.10.007 -
Physiology (Bethesda, Md.) Aug 2011Itch is a major somatic sensation, along with pain, temperature, and touch, detected and relayed by the somatosensory system. Itch can be an acute sensation, associated... (Review)
Review
Itch is a major somatic sensation, along with pain, temperature, and touch, detected and relayed by the somatosensory system. Itch can be an acute sensation, associated with mosquito bite, or a chronic condition, like atopic dermatitis (29, 59). The origins of the stimulus can be localized in the periphery or systemic, and associated with organ failure or cancer. Itch is also a perception originating in the brain. Itch is broadly characterized as either histamine-dependent (histaminergic) or histamine-independent (nonhistaminergic), both of which are relayed by subsets of C fibers and by the second-order neurons expressing gastrin-releasing peptide receptor (GRPR) and spinothalamic track (STT) neurons in the spinal cord of rodents. Historically, itch research has been primarily limited to clinical and psychophysical studies and to histamine-mediated mechanisms. In contrast, little is known about the signaling mechanisms underlying nonhistaminergic itch, despite the fact that the majority of chronic itch are mediated by nonhistaminergic mechanisms. During the past few years, important progress has been made in understanding the molecular signaling of itch, largely due to the introduction of mouse genetics. In this review, we examine some of the molecular mechanisms underlying itch sensation with an emphasis on recent studies in rodents.
Topics: Animals; Humans; Nervous System; Pruritus; Receptors, Bombesin; Sensation; Signal Transduction
PubMed: 21841076
DOI: 10.1152/physiol.00007.2011 -
Scientific Reports Jun 2021Bombesin is a putative antibacterial peptide isolated from the skin of the frog, Bombina bombina. Two related (bombesin-like) peptides, gastrin-releasing peptide (GRP)...
Bombesin is a putative antibacterial peptide isolated from the skin of the frog, Bombina bombina. Two related (bombesin-like) peptides, gastrin-releasing peptide (GRP) and neuromedin B (NMB) have been found in mammals. The history of GRP/bombesin discovery has caused little attention to be paid to the evolutionary relationship of GRP/bombesin and their receptors in vertebrates. We have classified the peptides and their receptors from the phylogenetic viewpoint using a newly established genetic database and bioinformatics. Here we show, by using a clawed frog (Xenopus tropicalis), that GRP is not a mammalian counterpart of bombesin and also that, whereas the GRP system is widely conserved among vertebrates, the NMB/bombesin system has diversified in certain lineages, in particular in frog species. To understand the derivation of GRP system in the ancestor of mammals, we have focused on the GRP system in Xenopus. Gene expression analyses combined with immunohistochemistry and Western blotting experiments demonstrated that GRP peptides and their receptors are distributed in the brain and stomach of Xenopus. We conclude that GRP peptides and their receptors have evolved from ancestral (GRP-like peptide) homologues to play multiple roles in both the gut and the brain as one of the 'gut-brain peptide' systems.
Topics: Animals; Anura; Bombesin; Gastrin-Releasing Peptide; Mammals; Neurokinin B; Phylogeny; Receptors, Bombesin; Xenopus laevis
PubMed: 34172791
DOI: 10.1038/s41598-021-92528-x