An immunoreactive peptide in milk contains bombesin-like bioactivity

Parallel in vitro bioassays using rat uterus and guinea pig large intestine tissues specific for the bombesin family of peptides, demonstrated that the bombesin-like peptides present in bovine milk can produce a dose-related response similar to bombesin and litorin. The bioactivity of this type of milk peptide appeared to be approximately 20-50% as active as the amphibian peptides. These data support the proposal that a bombesin immunoreactive peptide in milk contains bombesin bioactivity.     

New approaches to therapy of cancers of the stomach,colon and pancreas based on peptide analogs

Cancers of the stomach, colon and exocrine pancreas are major international health problems and result in more than a million deaths worldwide each year. The therapies for these malignancies must be improved. The effects of gastrointestinal (GI) hormonal peptides and endogenous growth factors on these cancers were reviewed. Some GI peptides, including gastrin and gastrin-releasing peptide (GRP) (mammalian bombesin), appear to be involved in the growth of neoplasms of the GI tract. Certain growth factors such as insulin-like growth factor (IGF)-I, IGF-II and epidermal growth factor and their receptors that regulate cell proliferation are also implicated in the development and progression of GI cancers. Experimental investigations on gastric, colorectal and pancreatic cancers with analogs of somatostatin, antagonists of bombesin/GRP, antagonists of growth hormone-releasing hormone as well as cytotoxic peptides that can be targeted to peptide receptors on tumors were summarized. Clinical trials on peptide analogs in patients with gastric, colorectal and pancreatic cancers were reviewed and analyzed. It may be possible to develop new approaches to hormonal therapy of GI malignancies based on various peptide analogs.Received 20 November 2003; accepted 6 January 2004     

Regulatory peptides in the respiratory system

Summary Many regulatory peptides have been described in the respiratory tract of animals and humans. Some peptides (bombesin, calcitonin, calcitonin gene-related peptide) are localised to neuroendocrine cells and may have a trophic or transmitter role. Others are localised to motor nerves. Vasoactive intestinal peptide and peptide histidine isoleucine are candidates for neurotransmitters of non-adrenergic inhibitory fibres and may be cotransmitters in cholinergic nerves. These peptides may regulate airway smooth muscle tone, bronchial blood flow and airway secretions. Sensory neuropeptides (substance P, neurokinin A and B, calcitonin gene-related peptide) may contract airway smooth muscle, stimulate mucus secretion and regulate bronchial blood flow and microvascular permeability. If released by an axon reflex mechanism these peptides may be involved in the pathogenesis of asthma. Other peptides, such as galanin and neuropeptide Y, are also present but their function is not yet known.     

Regulatory peptides in the respiratory system

Many regulatory peptides have been described in the respiratory tract of animals and humans. Some peptides (bombesin, calcitonin, calcitonin gene-related peptide) are localised to neuroendocrine cells and may have a trophic or transmitter role. Others are localised to motor nerves. Vasoactive intestinal peptide and peptide histidine isoleucine are candidates for neurotransmitters of non-adrenergic inhibitory fibres and may be cotransmitters in cholinergic nerves. These peptides may regulate airway smooth muscle tone, bronchial blood flow and airway secretions. Sensory neuropeptides (substance P, neurokinin A and B, calcitonin gene-related peptide) may contract airway smooth muscle, stimulate mucus secretion and regulate bronchial blood flow and microvascular permeability. If released by an axon reflex mechanism these peptides may be involved in the pathogenesis of asthma. Other peptides, such as galanin and neuropeptide Y, are also present but their function is not yet known.     

Bombesin,calcitonin and leu-enkephalin immunoreactivity in endocrine cells of human lung

Summary By immunohistochemistry, bombesin, calcitonin and leu-enkephalin was localized in endocrine cells of human lungs from various age groups. It is suggested that at least 3 different peptide containing endocrine cells may be present in human lung.Acknowledgments. The authors thank Dr Camille Vaillant, University of Liverpool, for advice with immunohistochemical methods and Dr G. Dockray for his generous gift of bombesin antiserum. This work has been supported by Medical Research Council of Canada (MA-7054) and Ontario Thoracic Society.     

Peptides and epithelial growth regulation

Summary There is now considerable evidence implicating several peptides in the control of gastrointestinal epithelial cell proliferation and cell renewal. While some of these may act directly, many may be involved in regulating the powerful trophic effects of the intake and digestion of foold on the gut epithelium.—Several peptides have been associated with the regulation of intestinal cell proliferation. There is little doubt that gastrin is trophic to the stomach, but, its role in the rest of the gastrointestinal tract is debatable. Enteroglucagon has often been associated with increased intestinal epithelial proliferation, but at the moment all the evidence for this is circumstantial. The effects of peptide YY and bombesin warrant further study. The availability of recombinant epidermal growth factor (EGF) has recently enabled us to demonstrate a powerful trophic response to infused EGF throughout the gastrointestinal tract. The increasing availability of peptides will eventually allow the rigorous in vivo evaluation of the trophic role of these potentially very important peptides.     

Peptides and epithelial growth regulation

There is now considerable evidence implicating several peptides in the control of gastrointestinal epithelial cell proliferation and cell renewal. While some of these may act directly, many may be involved in regulating the powerful trophic effects of the intake and digestion of food on the gut epithelium. Several peptides have been associated with the regulation of intestinal cell proliferation. There is little doubt that gastrin is trophic to the stomach, but, its role in the rest of the gastrointestinal tract is debatable. Enteroglucagon has often been associated with increased intestinal epithelial proliferation, but at the moment all the evidence for this is circumstantial. The effects of peptide YY and bombesin warrant further study. The availability of recombinant epidermal growth factor (EGF) has recently enabled us to demonstrate a powerful trophic response to infused EGF throughout the gastrointestinal tract. The increasing availability of peptides will eventually allow the rigorous in vivo evaluation of the trophic role of these potentially very important peptides.     

Effects of enterally- and parenterally-administered bombesin on intestinal luminal tryptic activity and protein in the suckling rat

Because of the presence of bombesin-like immunoreactivity in milk, we investigated if enteral administration of bombesin affects the intestinal luminal content of trypsin and protein in 12-14-day-old rats. Bombesin (40 micrograms/kg), given either orogastrically or subcutaneously, produced a significant elevation in the intestinal content of trypsin activity. Thus, enterally-administered bombesin can produce acute biologic effects in suckling rats.     

Effects of enterally- and parenterally-administered bombesin on intestinal luminal tryptic activity and protein in the suckling rat

Summary Because of the presence of bombesin-like immunoreactivity in milk we investigated if enteral administration of bombesin affects the intestinal luminal content of trypsin and protein in 12-14-day-old rats. Bombesin (40 g/kg), given either orogastrically or subcutaneously, produced a significant elevation in the intestinal content of trypsin activity. Thus, enterally-administered bombesin can produce acute biologic effects in suckling rats.     

Bombesin-like immunoreactivity in the pancreas of man and other mammalian species

Summary Bombesin-like immunoreactivity has been measured in pancreatic tissues of man (12.4±1.2 pmol/g), pig (15.8±3.2), calf (4.3±0.9), rat (8.5±1.2) and guinea-pig (2.8±0.6) by a specific radioimmunoassay. Gel filtration of the pancreatic extracts revealed 2 major immunoreactive peaks: the earlier peak was eluted in the position of porcine gastrin-releasing peptide, and the later peak was eluted just after the amphibian bombesin standard. Immunocytochemistry demonstrated the presence of bombesin-like immunoreactivity in nerves in the rat pancreas, particularly in the exocrine pancreas, and occasionally in the peri-insular spaces. Isolated rat pancreatic islets were found to contain small quantities of bombesin-like immunoreactivity (0.037±0.003 fmol/islet) suggesting that mammalian bombesin-like peptides may be invovled in the regulation of endocrine as well as exocrine pancreatic secretion.Acknowledgments. We are grateful to Dr. A. V. Edwards, Physiological Laboratory, Cambridge, U. K. for providing the calf tissues, and the British Diabetic Association, U. K. for support.To whom reprint requests should be addressed.     

Effect of bombesin on glucose transport system in biomembranes

Summary Bombesin is able to stimulate the glucose transport system supported by a contractile glucose binding protein (GBP) in biomembranes. The increase of glucose transport indicates that bombesin affects GBP.     

Structure and function of RGD peptides involved in bone biology

This review focuses on recent papers that describe the involvement of the RGD sequence in bone biology and incorporate the use of synthetic RGD peptides to develop new drugs or control the bioactivity of materials used for bone regeneration. Because in vivo bone function is completely dependent on angiogenesis and vessels, the present publication is focused on physiology, pathophysiology and therapeutics of RGD peptides dedicated to bone cells and endothelial systems. It appears that alphavbeta3, alphavbeta5 and alphaIIbbeta3 are the integrins most reported to be involved in bone function and RGD sequence binding. The specificity of RGD peptides depends on backbone conformation, orientations of the charged side chains of Arg and Asp residues, and hydrophobic moieties flanking the Asp residue. Despite of recent progress in integrins and RGD peptide structures and function, future work should focus on integrin selectivity of RGD-based agents, model structure and activity-selectivity relationships.     

Cardiomyokines from the heart

The heart is regarded as an endocrine organ as well as a pump for circulation, since atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) were discovered in cardiomyocytes to be secreted as hormones. Both ANP and BNP bind to their receptors expressed on remote organs, such as kidneys and blood vessels; therefore, the heart controls the circulation by pumping blood and by secreting endocrine peptides. Cardiomyocytes secrete other peptides besides natriuretic peptides. Although most of such cardiomyocyte-derived peptides act on the heart in autocrine/paracrine fashions, several peptides target remote organs. In this review, to overview current knowledge of endocrine properties of the heart, we focus on cardiomyocyte-derived peptides (cardiomyokines) that act on the remote organs as well as the heart. Cardiomyokines act on remote organs to regulate cardiovascular homeostasis, systemic metabolism, and inflammation. Therefore, through its endocrine function, the heart can maintain physiological conditions and prevent organ damage under pathological conditions.     

Endocrine cells producing regulatory peptides

Recent data on the immunolocalization of regulatory peptides and related propeptide sequences in endocrine cells and tumors of the gastrointestinal tract, pancreas, lung, thyroid, pituitary (ACTH and opioids), adrenals and paraganglia have been revised and discussed. Gastrin, xenopsin, cholecystokinin (CCK), somatostatin, motilin, secretin, GIP (gastric inhibitory polypeptide), neurotensin, glicentin/glucagon-37 and PYY (peptide tyrosine tyrosine) are the main products of gastrointestinal endocrine cells; glucagon, CRF (corticotropin releasing factor), somatostatin, PP (pancreatic polypeptide) and GRF (growth hormone releasing factor), in addition to insulin, are produced in pancreatic islet cells; bombesin-related peptides are the main markers of pulmonary endocrine cells; calcitonin and CGRP (calcitonin gene-related peptide) occur in thyroid and extrathyroid C cells; ACTH and endorphins in anterior and intermediate lobe pituitary cells, alpha-MSH and CLIP (corticotropin-like intermediate lobe peptide) in intermediate lobe cells; met- and leu-enkephalins and related peptides in adrenal medullary and paraganglionic cells as well as in some gut (enterochromaffin) cells; NPY (neuropeptide Y) in adrenaline-type adrenal medullary cells, etc.. Both tissue-appropriate and tissue-inappropriate regulatory peptides are produced by endocrine tumours, with inappropriate peptides mostly produced by malignant tumours.     

Relaxin family peptide systems and the central nervous system

Since its discovery in the 1920s, relaxin has enjoyed a reputation as a peptide hormone of pregnancy. However, relaxin and other relaxin family peptides are now associated with numerous non-reproductive physiologies and disease states. The new millennium bought with it the sequence of the human genome and subsequently new directions for relaxin research. In 2002, the ancestral relaxin gene RLN3 was identified from genome databases. The relaxin-3 peptide is highly expressed in a small region of the brain and in species from teleost to primates and has both conserved sequence and sites of expression. Combined with the discovery of the relaxin family peptide receptors, interest in the role of the relaxin family peptides in the central nervous system has been reignited. This review explores the relaxin family peptides that are expressed in or act upon the brain, the receptors that mediate their actions, and what is currently known of their functions.     

Regulatory peptide receptors: visualization by autoradiography

Summary The receptors for regulatory peptides have been extensively characterized using radioligand binding techniques. By combining these binding techniques with autoradiography it is possible to visualize at the light and electron microscopic levels the anatomical and cellular localization of these receptors. In this review we discuss the procedures used to label peptide receptors for autoradiography and the peculiarities of peptides as ligands. The utilization of autoradiography in mapping peptide receptors in brain and peripheral tissues, some of the new insights revealed by these studies particularly the problem of mismatch between endogenous peptides and receptors, the existence of multiple receptors for a given peptide family and the use of peptide receptor autoradiography in human tissues are also reviewed.     

Casein, a prohormone with an immunomodulating role for the newborn?

Maternal colostrum and milk, the earliest food of the newborn, should not only be considered as supplying nutrients, but also as agents providing protection against aggressions from the new environment. Indeed by enzymatic digestion of the main milk proteins, the caseins, biologically active peptides are released; they may be implicated in the stimulation of the newborn's immune system. From this point of view a 'strategic active zone' has been characterized in beta-casein. A possible role of casein as a 'prohormone' for the newborn is suggested.     

Regulatory peptide receptors: visualization by autoradiography

The receptors for regulatory peptides have been extensively characterized using radioligand binding techniques. By combining these binding techniques with autoradiography it is possible to visualize at the light and electron microscopic levels the anatomical and cellular localization of these receptors. In this review we discuss the procedures used to label peptide receptors for autoradiography and the peculiarities of peptides as ligands. The utilization of autoradiography in mapping peptide receptors in brain and peripheral tissues, some of the new insights revealed by these studies particularly the problem of 'mismatch' between endogenous peptides and receptors, the existence of multiple receptors for a given peptide family and the use of peptide receptor autoradiography in human tissues are also reviewed.     

Peptide antigens for gamma/delta T cells

γδ T cells express adaptive antigen receptors encoded by rearranging genes. Their diversity is highest in the small region of TCR V–J junctions, especially in the δ chain, which should enable the γδ TCRs to distinguish differences in small epitopes. Indeed, recognition of small molecules, and of an epitope on a larger protein has been reported. Responses to small non-peptides known as phospho-antigens are multi-clonal yet limited to a single γδ T cell subset in humans and non-human primates. Responses to small peptides are multi-clonal or oligo-clonal, include more than one subset of γδ T cells, and occur in rodents and primates. However, less effort has been devoted to investigate the peptide responses. To settle the questions of whether peptides can be ligands for the γδ TCRs, and whether responses to small peptides might occur normally, peptide binding will have to be demonstrated, and natural peptide ligands identified.     

Relation between stimulus intensity and neutrophil chemotactic response

Summary The effect of chemotactic peptides which lack chemokinetic activity has been investigated. The neutrophil response is proportional to the logarithm of the stimulus intensity, or alternatively a power function with an exponent of 0.3. Equal responses are obtained for equal ratios between the peptide concentration in the lower compartment and the threshold concentration. The significance of Weber-Fechner's law in leucocyte chemotaxis is discussed.We thank Miss B. Zanolari, Mrs M. Marti, Mrs Hauck and Mr Dietz for excellent technical assistance. This work was supported by the Swiss National Foundation for Scientific Research.