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PubMed1992

Identification of a novel type of processing sites in the precursor for the sea anemone neuropeptide Antho-RFamide (<Glu-Gly-Arg-Phe-NH2) from Anthopleura elegantissima.

Neuropeptides are synthesized as large precursor proteins that undergo posttranslational cleavages and modifications to produce bioactive peptides. Here, we have cloned two closely related precursor proteins for the sea anemone neuropeptide Antho-RFamide (<Glu-Gly-Arg-Phe-NH2) from Anthopleura elegantissima. The first precursor (435 amino acids long) contains 13 copies of immature Antho-RFamide (Gln-Gly-Arg-Phe-Gly) and nine other, Antho-RFamide-related neuropeptide sequences that are in the C-terminal part of the protein. The second precursor (429 amino acid residues) harbors 14 copies of immature Antho-RFamide and eight other related peptide sequences. Each copy of Antho-RFamide or Antho-RFamide-related peptide is followed, at its C-terminal side, by a single Arg residue, which is an established signal for posttranslational cleavage. At the N terminus of each Antho-RFamide sequence, however, basic residues are lacking, and instead one or more acidic residues occur. These acidic residues are the cleavage sites for a new type of processing enzyme occurring in neurons. This enzyme could either be an amino- or endopeptidase hydrolyzing at the C-terminal side of Asp or Glu residues. The N-terminal regions of the two precursor proteins harbor eight copies of the putative neuropeptide sequence Pro-Gln-Phe-Trp-Lys-Gly-Arg-Phe-Ser and three additional, closely related sequences. The total number of all established and putative neuropeptides that may be cleaved from the precursors is 33. Thus, the Antho-RFamide precursors beong to the most complex peptide precursor proteins known so far.

Amino Acid Sequence↗

PubMed1992

Gene structures of pepsinogens A and C.

Pepsinogen is an inactive precursor of pepsin, a typical aspartic proteinases, synthesized in the chief cells of gastric glands. There are two major groups of pepsinogen, namely pepsinogen A (PGA) and pepsinogen C (PGC) (or progastricsin), and each frequently has isozymogens. The relative extents of expression of the two pepsinogens vary among animal species and, moreover, their biosynthesis is known to be affected by such bioactive peptides as gastrin and secretin; however, the regulation mechanism of pepsinogen biosynthesis, hence pepsinogen gene expression is not yet clear. Therefore, it is thought to be of fundamental importance to elucidate the primary structures of the pepsinogen gene for such studies. This report describes the primary structures of human PGA and PGC genes and rat PGC gene. The organization of the genes is essentially the same; each gene was found to be separated into nine exons by eight introns of various lengths, encoding the amino acid sequence of the corresponding prepepsinogen. These results show that these genes are all derived from a common ancestral gene. The 5'-flanking region of human PGA gene, however, was different from those of human and rat PGC genes, whereas those of human and rat PGC genes were similar to each other. Thus, it is suggested that the expression of the PGA and PGC genes are somewhat differently regulated.

Amino Acid Sequence↗

PubMed2003

[Review: functional foods and ingredients derived from milk].

The objective of this paper is to review the main research works related to functional foods and ingredients derived from milk. Research in functional foods has increased during last twelve years with the intention of increasing life expectancy and improving human health conditions. Probiotics, prebiotics, bioactive peptides or proteins, dietetic fibers and fatty acids, as well as the addition of fitochemical compounds in dairy products and a record of some allergic compounds are also discussed. The demand of this kind of products is increasing due to intense advertising campaigns posted in many countries. Basically, these campaigns promise better health and/or the prevention of certain illnesses. Milk contains diverse constituents with physiological functionality, which might change the traditional view point that we have about drugs. The topic of functional foods in general, and specifically that from milk and dairy products, has still not been completely exploited, and in the future it will be found that the best work has not been carried out in this area.

Animals↗

PubMed2005

[Adipose tissue: a new endocrine organ].

In the recent years we have begun to appreciate that adipose tissue is more than just a passive repository for excess energy. It is a highly active endocrine organ secreting a range of bioactive peptides with both local and distant action collectively called 'adipokines' or 'adipose tissue hormones'. They include leptin, adiponectin, resistin, acylation-stimulating protein (ASP), plasminogen activator inhibitor-1 (PAI-1), tumor necrosis factor alpha (TNFalpha), interleukin 6, and angiotensinogen. Some of these are specific fat-related hormones that are involved in regulating energy homeostasis, carbohydrate and lipid metabolism, vascular homeostasis and immune response. Moreover, the tissue is implicated in the metabolism of some steroid hormones. Disturbances in adipokine production may have potential repercussions in the pathophysiology of obesity, insulin resistance, and dyslipidemia. Reversal or alleviation of these changes seem to be a promising target for management of the mentioned disorders. The objective of this review is to summarise the most important aspects of biology, actions and regulation of these hormones with a special emphasis on the most recent literature.

Acylation↗

PubMed2005

Pre-clinical and clinical experiences with novel somatostatin ligands: advantages, disadvantages and new prospects.

Since the cloning and characterization of the five human somatostatin receptor (SSTR) subtypes, our understanding of the expression and functional role of the five SSTR subtypes in human (neuro-)endocrine tumors has increased significantly. The majority of human (neuro-)endocrine tumors express multiple SSTR. GH-secreting pituitary adenomas preferentially express SSTR2 and SSTR5, prolactinomas SSTR1 and SSTR5, and corticotroph adenomas express SSTR2 (low number) and predominantly SSTR5s. In addition, gastroenteropancreatic (GEP) neuroendocrine tumors frequently express multiple SSTR as well, with SSTR2 being expressed at the highest level. Treatment with the current generation of octapeptide somatostatin-analogs, e.g. octreotide and lanreotide, normalizes circulating GH- and IGF-I levels in approximately 60-70% of acromegalic patients, thereby remaining about one-third of patients uncontrolled. In patients with GEP neuroendocrine tumors, both somatostatin-analogs effectively suppress the production of bioactive peptides and hormones by the tumor cells, resulting in an important improvement of the related clinical symptomatology. However, a considerable proportion of patients experience an escape from treatment within months to several years. Altogether, the current generation of somatostatin analogs are effective medical tools in the treatment of acromegalic patients and of patients with neuroendocrine GEP tumors, but there is certainly a need for novel somatostatin analogs. In recent years, a significant number of novel somatostatin-ligands has been developed. These ligands include SSTR selective-, bi-specific, universal, as well as chimeric dopamine (DA)-somatostatin ligands. In vitro studies using human pituitary adenoma cells demonstrate a more profound inhibition of GH, PRL and ACTH secretion by somatostatin-analogs targeting both SSTR2s and SSTR5s, compared with SSTR2-preferential somatostatin-analogs. This likely reflects the SSTR subtype expression pattern in the adenoma cells. A first proof-of-concept trial with the more universal somatostatin-ligand SOM230 in 12 acromegalic patients shows that a single dose of SOM230 is effective in suppressing circulating GH concentrations in a significant larger number of patients compared with octreotide. In animal models, SOM230 has a better effect on GH and IGF-I level with less signs of tachyphylaxis compared with octreotide. Depending on the SSTR expression pattern on neuroendocrine GEP tumors, somatostatin-analogs targeting multiple SSTRs may play a future role in the more long-term control of patients with neuroendocrine GEP tumors. The first clinical trial comparing octreotide and SOM230 is ongoing. However, every advantage has its disadvantage. Targeting multiple SSTR potentially induces more adverse effects as well. Especially, glucose homeostasis might induce new problems in the long-term use of universal ligands.

Acromegaly↗

PubMed2006

Identification of cancer targets and therapeutics using phage display.

Phage display is a well-established approach for the identification of bioactive peptides and antibody fragments through the use of high diversity libraries. One major advantage of phage display lies in its ability to rapidly identify target-specific reagents with pharmacological activity as agonists or antagonists. Peptides and antibodies have several clinical advantages over traditional small-molecule chemotherapeutics, including specificity, selectivity and potency. Thus, phage display can be used to generate 'targeted therapeutics', which is the current clinical paradigm of choice in the field of oncology.

Animals↗

PubMed1991

The renin-angiotensin system: a multidimensional source of control over alcohol consumption.

While the renin-angiotensin system has traditionally been considered part of a larger homeostatic process that regulates blood pressure and fluid/electrolyte balance, the data summarized in this review suggest a new and different kind of function- that of regulating the behavior of alcohol consumption. Using a wide variety of drug, genetic, dietary, surgical and neurosurgical manipulations all of which share the common property of altering activity in the renin-angiotensin system, the picture emerges of an inverse relationship between activity in the renin-angiotensin system and alcohol consumption. One possible mechanism of this effect may be a process of satiety where levels of the bioactive peptide angiotensin II exceeding a critical level, set behavioral processes into action that lead to a cessation in alcohol intake.

Alcohol Drinking↗

PubMed1992

Acylpeptide hydrolase: inhibitors and some active site residues of the human enzyme.

Acylpeptide hydrolase may be involved in N-terminal deacetylation of nascent polypeptide chains and of bioactive peptides. The activity of this enzyme from human erythrocytes is sensitive to anions such as chloride, nitrate, and fluoride. Furthermore, blocked amino acids act as competitive inhibitors of the enzyme. Acetyl leucine chloromethyl ketone has been employed to identify one active site residue as His-707. Diisopropylfluorophosphate has been used to identify a second active site residue as Ser-587. Chemical modification studies with a water-soluble carbodiimide implicate a carboxyl group in catalytic activity. These results and the sequence around these active site residues, especially near Ser-587, suggest that acylpeptide hydrolase contains a catalytic triad. The presence of a cysteine residue in the vicinity of the active site is suggested by the inactivation of the enzyme by sulfhydryl-modifying agents and also by a low amount of modification by the peptide chloromethyl ketone inhibitor. Ebelactone A, an inhibitor of the formyl aminopeptidase, the bacterial counterpart of eukaryotic acylpeptide hydrolase, was found to be an effective inhibitor of this enzyme. These findings suggest that acylpeptidase hydrolase is a member of a family of enzymes with extremely diverse functions.

Acetylation↗

PubMed1991

Progesterone-regulated cyclic modulation of membrane metalloendopeptidase (enkephalinase) in human endometrium.

Membrane metalloendopeptidase (MMEP; EC 3.4.24.11; enkephalinase) catalyzes the degradation of endothelins, enkephalins, atrial natriuretic factor, substance P, and other small bioactive peptides. We found that MMEP is present in human endometrium, localized primarily in stromal cells of this tissue, and that the specific activity of MMEP (and immunoreactive MMEP protein) in endometrial tissue is correlated in a highly significant positive manner with the concentration of progesterone in plasma. In estrogen-treated, human endometrial stromal cells in monolayer culture, the specific activity of MMEP increases in response to treatment with progestin; and, this increase is accompanied by increases in immunoreactive MMEP protein, newly synthesized MMEP, and MMEP mRNA.

Adult↗

PubMed1990

Three main components in plasma proteases and their relation to the renin-angiotensin system.

The relation of plasma renin activity (PRA) and plasma levels of angiotensin I (AI) and II (AII) to those of various proteases, including eight endopeptidases and four aminopeptidases, was investigated in 51 normal control subjects. The multivariate study using factor analysis showed that the plasma proteases can be classified into three main components: the aminopeptidase, the plasmin, and the kinin-kallikrein. PRA and AI were related almost exclusively to the aminopeptidase component, while the AII level was related not only to the same component but also to the kallikrein-kinin component. This kind of multivariate study may help in the elucidation of the role of proteases and bioactive peptides, such as angiotensin derivatives, in essential hypertension through a comparison of multivariate relationships in controls and patients.

Amino Acid Sequence↗

PubMed1987

Immunohistochemical demonstration of simple epithelia-type keratin intermediate filament in a case of Merkel cell carcinoma.

A case of Merkel cell carcinoma that developed on the right cheek of a 77-year-old woman is reported. The diagnosis was ultrastructurally made by demonstrating dense-core granules in the cytoplasm of the tumor cells. Immunohistochemically, the tumor cells were shown to possess simple epithelia-type keratin intermediate filaments, but no neurofilaments. This finding was in accordance with that obtained on normal Merkel cells. No bioactive peptides examined could be detected in the tumor cells. Typing of intermediate filaments in tumor cells may be one of the important markers, along with the ultrastructural findings, in diagnosing Merkel cell carcinoma.

Adenocarcinoma↗

PubMed1989

[Significance of endothelin in shock pathogenesis].

Endothelin is a recently discovered bioactive peptide produced by vascular endothelial cells. By means of specific radioimmunoassay we found that plasma endothelin level in patients with late septic shock was significantly increased. And a typical shock model in healthy rats was reproduced by continuous infusion of endothelin (endothelin shock). Infusion of endothelin at a small dose to hemorrhagic shocked rats deteriorated the shock process and resulted in an irreversible development. From these results it is suggested that endothelin may be an endogenous injury-inducing factor, acting as one of the important humoral factors involved in shock pathogenesis.

Animals↗

PubMed1989

Cleavage of parathyroid hormone in macrophage endosomes illustrates a novel pathway for intracellular processing of proteins.

Most ligands which are taken up by macrophages are transported to lysosomes where they are degraded to their constituents by a concert of acid hydrolases. This process requires a number of intracellular events which result in the transport of ligands from light density endosomes to the more dense lysosomes. In contrast, our studies have shown that macrophages may process some incoming ligands in endosomes (Diment, S., and Stahl, P. D. (1985) J. Biol. Chem. 260, 15311-15317) and that cathepsin D, an aspartyl protease, is localized in these organelles (Diment, S., Leech, M. S., and Stahl, P. D. (1988) J. Biol. Chem. 263, 6901-6907). Using rabbit alveolar macrophages, which can be subjected to subcellular fractionation, we have traced the intracellular transport and processing of bovine parathyroid hormone (PTH-(1-84]. We present evidence that macrophages internalize PTH-(1-84). Once in endosomes the hormone is cleaved to fragments which include a bioactive peptide, PTH-(1-34), and then the fragments are returned to the extracellular medium, without delivery to lysosomes. The entire cycle from initial binding to release of PTH-(1-34) is achieved within 10-15 min, a time period consistent with findings in vivo. Our data provide evidence for a novel route for processing of an endocytosed ligand.

Animals↗

PubMed1988

[The nonadrenergic, noncholinergic neuropeptide system and asthma].

An understanding of the non adrenergic non cholinergic nervous system and its implication in the pathogenesis of asthma would benefit by the identification and localisation of the numerous natural bioactive peptides at the pulmonary level. In the past few years two components of the non adrenergic non cholinergic nervous system have been characterised. A bronchodilator component which would be mediated by "vaso-active intestinal peptide" (VIP) and the "peptide histidine methionine" (PHM). A broncho-constrictor component which would be mediated by the neurokinins (substance P (SP), neurokinin A (NKA) and the "calcitonin gene related peptide" (CGRP)). These neuropeptides, in vitro as well as in vivo, have effects which are not limited to the regulation of bronchial smooth muscle tone. In effect, they may intervene in the regulation of vascular tone, in the production of mucous and in the expression of immediate hypersensitivity reactions at pulmonary level. Several neuropeptides are present or co-exist with classical neurotransmitter in the afferent nerve endings of the pulmonary efferents. This co-existence of several neurotransmitters in the same nervous fibres raised the questions as to their interactions at the pre or post synaptic level. The implication of these neuropeptides in the pathogenesis of asthma rests on numerous experimental arguments. This recent aspect in the pathophysiology of asthma allows us to hope for new therapeutic approaches.

Asthma↗

PubMed1982

Identification of proctolin-containing neurons.

Proctolin (H-Arg-Tyr-Leu-Pro-Thr-OH), a highly bioactive peptide found first in insects, is shown to be localized to specific neurons in the central nervous system (CNS) of the cockroach Periplaneta americana. Application of an antiproctolin serum to whole ganglia in a whole-mount immunohistochemical technique reveals the presence of proctolin immunoreactive neurons throughout the CNS. These neurons can be mapped and appear in consistent positions in different individuals. Some have been uniquely identified by intracellular dye injection combined with immunological localization. The presence of proctolin in individually identified neurons has been determined by high-pressure liquid chromatography combined with proctolin bioassay detection performed on extracts made from single identified cells. Some proctolin-containing neurons contain large vacuolelike inclusions in their cell bodies. These vacuoles appear to be the greatly enlarged lumena of the rough endoplasmic reticulum and may be part of the morphological substrate for the manufacture of proctolin. Electrophysiological studies suggest that some proctolin-containing neurons in different segmental ganglia, although not all, are normally recruited together as a functional unit by shared presynaptic input. This characterization of individual proctolin neurons is a prelude to a cellular study of the physiological role of a neuropeptide.

Animals↗

PubMed1993

[The expression of CD57 immunoreactivity in endocrine cells of human pancreas].

CD57, a glycoprotein, is a specific antigen presented on the surface of human natural killer cells and killer cells. The monoclonal antibody to CD57 has been available. In this study, the avidin-biotin-peroxidase complex (ABC) technique visualized with glucose oxidase-DAB-nickle (GDN) was used to detect the expression of CD57 in endocrine cells of human pancreas. The results showed that the CD57 immunoreactive (CD57-IR) cells were scattered throughout human pancreas. Most of positive cells were localized in the pancreatic islets. Grouped or single cells occurred intercalated between acinar cells, as well as in the epithelium of pancreatic ducts. The anti-CD57-monoclonal antibody stained the myelin sheaths of nerve fibers in all tissues investigated. Alternative sections immunostained with antibodies against bioactive peptides proved the coexistence of CD57 and Glu, SS, HPP or PS in endocrine cells. The significance of the expression of CD57 immunoreactivity in endocrine cells of human pancreas was discussed.

Antibodies, Monoclonal↗

PubMed1994

Potential indirect anti-inflammatory effects of IL-4. Stimulation of human monocytes, macrophages, and endothelial cells by IL-4 increases aminopeptidase-N activity (CD13; EC 3.4.11.2).

IL-4 up-regulates various monocytic properties that are associated with pro-inflammatory functions. Paradoxically, IL-4 may also act as an anti-inflammatory agent by down-regulating the production of several inflammatory mediators. As the activity of some mediators has recently been shown to be regulated by peptidases, we examined whether IL-4 was able to modulate the expression of a cell membrane-associated peptidase, aminopeptidase-N (CD13). IL-4 caused a dose-dependent increase in the expression of CD13 Ag on highly purified human blood monocytes. Maximal expression was observed around 48 h of culture. This IL-4-induced increase was completely blocked by anti-IL-4 antiserum. Furthermore, the increase in surface expression was preceded by increased mRNA levels of CD13, which was maximal around 24 h of culture. We also observed that CD13-mediated leucine-aminopeptidase activity of monocytes was induced by IL-4. Other CD13-expressing cells were also sensitive to IL-4, as CD13 Ag expression and CD13 mRNA levels were up-regulated in human alveolar macrophages and endothelial cells upon IL-4 treatment. The increased expression of cell membrane aminopeptidase-N represents a potentially increased cellular ability to inactivate inflammatory mediators. Therefore, these findings represent further evidence of IL-4-mediated anti-inflammatory actions. We postulate that up-regulation of aminopeptidase-N expression may be an indirect mechanism of IL-4 to modulate the action of bioactive peptides. This mechanism may underlie, at least partially, the anti-inflammatory effects of IL-4 in vivo.

Aminopeptidases↗

PubMed1994

Dominant chymotrypsin-like esterase activity in human lymphocyte granules is mediated by the serine carboxypeptidase called cathepsin A-like protective protein.

We identified a chymotrypsin-like activity in the granules of IL-2 lymphokine-activated killer (LAK) cells and a NK cell line (YT) that reacted preferentially with the oligopeptide substrate succinyl-Phe-Leu-Phe-thiobenzyl ester (Suc-Phe-Leu-Phe-SBzl). The enzyme was isolated by detergent extraction of sedimented cytotoxic granules and then by a sequence of sieve, hydrophobic, and anion exchange chromatography. On SDS-PAGE, the protein migrated at 42 kDa in nonreduced form and became two bands (31 and 19 kDa, respectively) after reduction. Amino-terminal sequencing of the reduced protein bands revealed 100% homology with cathepsin A-like protective protein (CAPP), a lysosomal enzyme that expresses serine carboxypeptidase and deamidase activities. The carboxypeptidase activity of lymphocyte CAPP was verified by showing that the protease preferred hydrophobic amino acids in the penultimate position of the C terminus (i.e., cleaved arginine from dansyl-Phe-Leu-Arg). The presence of lymphocyte CAPP in secretory lysosomes was demonstrated by showing that Suc-Phe-Leu-Phe-SBzl activity co-migrated with tryptase and Asp-ase activities on Percoll density gradients and that 95% of the Suc-Phe-Leu-Phe-SBzl activity in granule fractions of cavitated YT cells could be immunoprecipitated with an anti-CAPP antiserum. In addition, calcium ionophore-stimulated YT cells were shown to secrete immunoprecipitable CAPP. As proposed for platelets, lymphocyte CAPP may be secreted to function extracellularly by inactivating bioactive peptides.

Amino Acid Sequence↗