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PubMed2004

Expression and bioactivity analysis of recombinant beta-CPP dimer.

Beta-casein phosphopeptide (beta-CPP) is a bioactive peptide that carries different minerals, especially calcium. To investigate more effects of beta-CPP, eukaryotic expression vector of beta-CPP dimer was constructed and transfected into Chinese hamster ovary (CHO) cells. After selection, the cell lines stably expressing beta-CPP dimer were obtained, and the recombinant product was identified and purified. Activity assay of recombinant protein indicated that the recombinant beta-CPP dimer could improve Ca(2+) uptake of sperm, stimulate the proliferation of spleen cells, and induce apoptosis of some malignant tumor cells.

Animals↗

PubMed1997

Antiproliferative effects of yogurt fractions obtained by membrane dialysis on cultured mammalian intestinal cells.

The consumption of yogurt has been associated with a reduced incidence of colon cancer in population groups. Bioactive peptides produced during bacterial fermentation may alter the risk of colon cancer via modification of cell proliferation in the colon. Using our previously described cell culture model system, we have isolated a yogurt fraction that decreases cell proliferation. Yogurt was fractionated using 10,000- and 500-Da membrane dialysis. When the yogurt fraction was incubated with IEC-6 or Caco-2 cells, cell division was decreased compared with control treatments, as determined by thymidine incorporation. Cell division was not inhibited in response to a similarly produced milk fraction or in response to solutions of lactic acid. The determination of cell kinetics by flow cytometry revealed a decrease in the number of cells in the initial growth phase in response to the yogurt fraction for the IEC-6 cells, but not the Caco-2 cells. Alpha-Lactalbumin inhibited cell division of both cell lines, but beta-casein did not.

Animals↗

PubMed2000

The antithrombotic effect of angiotensin-(1-7) closely resembles that of losartan.

Angiotensin-(1-7) [Ang-(1-7)] is the bioactive peptide which may be responsible for some of the pharmacological effects of losartan. Our previous study has demonstrated the antithrombotic action of losartan in a model of experimental thrombosis. In the present study, we compared the antithrombotic action of losartan and Ang-(1-7). Acute (10 mg/kg, p.o.) and chronic (10 mg/kg, p.o., three weeks) losartan administration to spontaneously hypertensive rats (SHR) induced a decrease in thrombus weight (1.6 +/- 0.6 mg and 1.2 +/- 0.3 mg respectively vs. control 2.9 +/- 0.8 mg; p<0.05, p<0.05). A similar reduction was observed in two-kidney, one-clip hypertensive rats (2K-IC)receiving acute losartan administration (1.39 +/- 0.29 mg vs. 3.25 +/- 0.62 mg; p<0.01). Infusion of Ang-(1-7) to2K-lC rats also reduced the thrombus weight(1.01 +/- 0.34 mg, 1.23 +/- 0.38 mg and 2.17 +/- 0.36 mg for 1, 10, 100 pmol/kg/min, respectively vs. 3.58 +/- 0.6 mg control; p<0.01, p<0.01, p<0.05). Losartan produced a decrease in systolic blood pressure (BP) in SHR as well as in 2K-1C rats, while Ang-(1-7) infusion had no effect on BP. Acute losartan dosing to 2K-1C rats decreased platelet adhesion to fibrillar collagen(24.9 +/- 1.0% vs. control 31.5 +/- 1.1%, p<0.001). The incubation of platelet samples with Ang-(1-7) (10-6 and 10 5 M) also reduced adhesion to fibrillar collagen(38.4 +/- 0.1% and 33.8 +/- 0.8% respectively vs. control 40.0 +/- 0.6%; p<0.05, p<0.001). There were no apparent changes in prothrombin time, activated partial thromboplastin time and euglobulin clot lysis time in losartan and Ang-(1-7)-treated groups. We conclude that, like losartan, Ang-(1-7) is able to act as an antithrombotic agent.

Angiotensin I↗

PubMed1999

Dipeptidyl peptidase IV: a cell surface peptidase involved in regulating T cell growth (review).

The CD26 antigen is identical with the cell surface ectopeptidase dipeptidyl peptidase IV (DP IV, EC 3.4.14.5). The post proline cleaving substrate specificity makes DP IV relatively unique among other proteases. Numerous cytokines, chemokines and other bioactive peptides are potential substrates of DP IV, but knowledge about the real in vivo substrates is still very limited. CD26 represents an accessory surface molecule playing an important role in the process of activation and proliferation of human lymphocytes. The molecular events mediated by this ectoenzyme are only partly established and the necessity of DP IV enzymatic activity for its signalling capacity has been controversial. This review out-lines evidence for an involvement of DP IV in the regulation of immune response and focuses on the putative role of the catalytic domain of this peptidase. Inhibition of the catalytic activity can provoke many cellular effects, including induction of tyrosine phosphorylations and p38 MAP kinase activation as well as suppression of DNA synthesis and reduced production of various cytokines. TGF-beta1, the production and secretion of which is increased after DP IV inhibition, supposedly mediates the observed suppressive effects by maintaining p27kip expression levels which leads to a cell cycle arrest in G1. Moreover, anti-CD3-induced signalling pathways can be strongly affected by DP IV inhibition. Thus, the enzymatic activity or at least the interaction of effectors with the catalytic domain of CD26 seem to be important for crucial functions of this cell surface antigen.

Adenosine Deaminase↗

PubMed1998

Chymase: its pathophysiological roles and inhibitors.

Chymase is a chymotrypsin-type serine protease mainly localized in mast cells (MCs). Human, primate, and dog chymase generate angiotensin II (Ang II) from Ang I, while mouse and rat chymases degrade Ang II. It is suggested that chymase generating Ang II might be an alternative Ang II-forming enzyme to angiotensin-converting enzyme (ACE) in the renin-angiotensin system in tissues, but not in blood, and cause hypertrophy and remodeling of cardiovascular tissues. Chymase also degrades extracellular matrix, and processes procollagenase, inflammatory cytokines and other bioactive peptides. As a result, chymase plays important roles in inflammatory tissues through its proteolytic activities to cause tissue remodeling, that is, a chymase inhibitor may have the ability to prevent diseases caused by the above inflammatory reactions. The investigation of chymase inhibitors by pharmaceutical companies has yielded peptide and peptide mimetic inhibitors. We also found potent non-peptide low molecular inhibitors. However, the in vivo functions of chymase have not been verified so far by applying a chymase inhibitor to in vivo pathological models. In this article, we overview the pathophysiological roles of chymase and chymase inhibitors proposed to date, and discuss the structure-activity relationships of substituted 3-phenylsulfonyl-1-phenylimidazolidine-2,4-dione derivatives.

Angiotensin I↗

PubMed1999

Cloning and characterization of Aplysia neutral endopeptidase, a metallo-endopeptidase involved in the extracellular metabolism of neuropeptides in Aplysia californica.

Cell surface metallo-endopeptidases play important roles in cell communication by controlling the levels of bioactive peptides around peptide receptors. To understand the relative relevance of these enzymes in the CNS, we characterized a metallo-endopeptidase in the CNS of Aplysia californica, whose peptidergic pathways are well described at the molecular, cellular, and physiological levels. The membrane-bound activity cleaved Leu-enkephalin at the Gly3-Phe4 bond with an inhibitor profile similar to that of the mammalian neutral endopeptidase (NEP). This functional homology was supported by the molecular cloning of cDNAs from the CNS, which demonstrated that the Aplysia and mammalian NEPs share all the same amino acids that are essential for the enzymatic activity. The protein is recognized both by specific anti-Aplysia NEP (apNEP) antibodies and by the [125I]-labeled NEP-specific inhibitor RB104, demonstrating that the apNEP gene codes for the RB104-binding protein. In situ hybridization experiments on sections of the ganglia of the CNS revealed that apNEP is expressed in neurons and that the mRNA is present both in the cell bodies and in neurites that travel along the neuropil and peripheral nerves. When incubated in the presence of a specific NEP inhibitor, many neurons of the buccal ganglion showed a greatly prolonged physiological response to stimulation, suggesting that NEP-like metallo-endopeptidases may play a critical role in the regulation of the feeding behavior in Aplysia. One of the putative targets of apNEP in this behavior is the small cardioactive peptide, as suggested by RP-HPLC experiments. More generally, the presence of apNEP in the CNS and periphery may indicate that it could play a major role in the modulation of synaptic transmission in Aplysia and in the metabolism of neuropeptides close to their point of release.

Amino Acid Sequence↗

PubMed1999

Proteolytic processing of big endothelin-3 by the kell blood group protein.

Kell blood group protein shares a consensus sequence (H.E.X.X.H) with a large family of zinc-dependent endopeptidases. Kell has closest homology with neutral endopeptidase 24.11, endothelin converting enzyme-1 (ECE-1), and the PEX gene product that, as a group, comprise the M13 subfamily of mammalian neutral endopeptidases. The proteolytic activity of the M13 members, but not of Kell, has been previously demonstrated. A secreted form of wild-type Kell protein (s-Kell), devoid of the intracellular and transmembrane domains, was expressed in sf9 cells. As a negative control, an inactive mutant Kell protein (E582G) was expressed. As determined by N-terminal amino acid sequencing and mass spectrometry of the cleaved products, wild-type s-Kell, but not the control mutant protein, specifically cleaved big endothelin-3 (ET-3) at Trp(21)-Ile(22), yielding ET-3, and, to a much lesser extent, also cleaved big ET-1 and big ET-2 at Trp(21)-Val(22), yielding ET-1 and ET-2. Enzymatic activity was partially inhibited by phosphoramidon. s-Kell has an acidic pH optimum (pH 6.0 to 6.5). Like the recombinant protein, red blood cells of common Kell phenotype also preferentially process big ET-3, in contrast to Ko (null) cells that do not. These data demonstrate that the Kell blood group protein is a proteolytic enzyme that processes big ET-3, generating ET-3, a potent bioactive peptide with multiple biological roles.

Endothelin-3↗

PubMed2000

Expression of Kell blood group protein in nonerythroid tissues.

The Kell blood group protein is a zinc endopeptidase that yields endothelin-3, a potent bioactive peptide, by cleavage of big endothelin-3, a larger intermediate precursor. On red cells, Kell protein is linked by a single disulfide bond to XK, a protein that traverses the membrane 10 times and whose absence, as occurs in the McLeod phenotype, is associated with a set of clinical symptoms that include nerve and muscle disorders and red cell acanthocytosis. Previous studies indicated that Kell is primarily expressed in erythroid tissues, whereas XK has a wider tissue distribution. The tissue distribution of Kell protein has been further investigated by Northern blot analysis, PCR-screening of tissue complementary DNAs (cDNAs), and Western immunoblots. Screening of an RNA dot-blot panel confirmed that Kell is primarily expressed in erythroid tissues but is also expressed in a near equal amount in testis, with weaker expression in a large number of other tissues. PCR-screening of cDNAs from different tissues and DNA sequencing of the products gave similar results. In 2 of the nonerythroid tissues tested, testis and skeletal muscle, Kell protein was detected by Western immunoblotting. In skeletal muscle, isolation of XK with a specific antibody coisolated Kell protein. These studies demonstrate that Kell is expressed in both erythroid and nonerythroid tissues and is associated with XK.

Amino Acid Transport Systems, Neutral↗

PubMed2000

Prohormone transport through the secretory pathway of neuroendocrine cells.

En route through the secretory pathway of neuroendocrine cells, prohormones pass a series of membrane-bounded compartments. During this transport, the prohormones are sorted to secretory granules and proteolytically cleaved to bioactive peptides. Recently, progress has been made in a number of aspects concerning secretory protein transport and sorting, particularly with respect to transport events in the early regions of the secretory pathway. In this review we will deal with some of these aspects, including: i) selective exit from the endoplasmic reticulum via COPII-coated vesicles and the potential role of p24 putative cargo receptors in this process, ii) cisternal maturation as an alternative model for protein transport through the Golgi complex, and iii) the mechanisms that may be involved in the sorting of regulated secretory proteins to secretory granules. Although much remains to be learned, interesting new insights into the functioning of the secretory pathway have been obtained.

Animals↗

PubMed2000

Neuropeptidases regulating gonadal function.

The generation and metabolism of bioactive peptides involves a series of highly ordered proteolytic events. This post-translational processing can occur either within the cell, at the cell surface or after secretion. In the central nervous system a number of extracellular peptidases have been implicated in the regulated processing of peptides, particularly in the regulation of neuroendocrine function. The aim of this study has been to identify the peptidases involved in the metabolism of gonadotropin-releasing hormone (GnRH) and to characterize the factors and the mechanisms by which the activity of these peptidases are regulated. We have shown that both prolylendopeptidase and the thimet oligopeptidase EC 3.4. 24.15 are involved in GnRH metabolism and that both oestrogen and thiol-based reductants could be involved in the physiological regulation of their activities.

Animals↗

PubMed2000

Comparative aspects of invertebrate neuropeptides.

1. We searched for bioactive peptides, most of which were considered to be neuropeptides, in various animals of several phyla. These peptides were compared with each other and with peptides identified by many other investigators. Consequently, we found that structures of neuropeptides are generally conserved in each phylum. 2. We also found some exceptional interesting aspects. First, there are a number of peptide groups whose members are distributed among several phyla. Second, there are many structural similarities between molluscan and annelidan peptides as if molluscs and annelids were the animals in a phylum. Third, certain toxic peptides of invertebrates are closely related to vertebrate neuropeptides. 3. In addition to the above phylogenetic aspects, we found some other interesting aspects. A wide structural variety of members of a peptide group is generally found in invertebrate species. Invertebrate muscles seem to be generally regulated not only by some or several classical non-peptidic neuromediators but also by various peptidic neuromediators. Peptides containing a D-amino acid residue are not rare.

Amino Acid Sequence↗

PubMed2001

Transmembrane proteases in focus: diversity and redundancy?

Recent advances have led to the identification and characterization of an array of transmembrane proteases that mediate the proteolysis of various substrates (including bioactive peptides, components of the extracellular matrix, and integral proteins) and cell-cell or cell-matrix adhesion. The membrane proteases known to participate in these processes currently include the ectopeptidases, the membrane-type matrix metalloproteases (MT-MMPs), the ADAM (a disintegrin and metalloprotease) family, the meprins, and the secretases, and this list may be expected to grow. The roles that these molecules play within neoplastic and inflammatory sites are being investigated actively. The capacity of these ectoenzymes to transmit intracellular-transduction signals through the plasma membrane has to be considered. An appreciation of their functional redundancy is emerging.

Animals↗

PubMed2001

[RGD peptides and endothelialization of biomaterials].

Endothelialization can remarkably improve blood compatibility of biomaterials and promote their clinical application, especially the uses of cardiovascular grafts. The attachment and growth of endothelial cells on artificial surfaces is the critical factor affecting the process of endothelialization. Many adhesive proteins contain the Arg-Gly-Asp(RGD) sequence which plays an important role in cell adhesion, migration and growth. In this review, the interaction of RGD peptides sequence and integrins, the influential factors of RGD peptides bioactivity and its application in endothelialization of biomaterials were discussed.

Biocompatible Materials↗

PubMedDate not supplied

Transmembrane proteases as disease markers and targets for therapy.

Transmembrane proteases (i.e. membrane-associated proteases, ectoproteases) are present in a wide variety of tissues and cell types including endothelial, epithelial and hematopoietic cells. Natural and synthetic inhibitors have been characterized and have revealed that certain ectoenzymes are able to modulate bioactive peptide responses and to influence major biological events such as cell proliferation, survival and invasiveness. Dysregulated expression of some of them in human diseases triggers research on their role in pathophysiology, on their value as disease markers and as putative targets for therapy.

Animals↗

PubMed2001

Immunohistochemical demonstration of chromogranin A in endocrine organs of the rat and horse by use of region-specific antibodies.

Chromogranin A (CgA) is an acidic glycoprotein that is co-stored with hormones or neurotransmitters in granular components of endocrine cells and neurons, and released together with them in response to adequate stimulation. In addition to acting as a packaging protein, CgA functions as a precursor molecule that yields several bioactive peptides by proteolytic cleavage. The purpose of this study is to elucidate how different the processing of CgA is among endocrine tissues by immunostaining using multiple region-specific antisera, and to evaluate the availability of region-specific antisera. When various endocrine organs of rats were immunostained with four region-specific antisera against rat CgA (CgA 1-28, 94-130, 296-314, and 359-389), all amine/peptide-secreting endocrine tissues except the pineal body were stained positively. The adrenal medulla and gastric endocrine cells were equally intensely immunoreactive to all four antisera, while the other endocrine tissues, represented by pancreatic islets, showed different staining patterns depending on the antiserum. These results suggest that the processing of CgA differs from tissue to tissue. An antiserum against horse CgA 335-365, corresponding to rat CgA 359-389 which shows the highest concentration in the plasma and urine of the rat, again stained all endocrine tissues of the horse except the pineal body. Therefore, the anti-horse CgA 335-365 serum is useful for immunohistochemical survey of horse CgA, and may make possible the establishment of a CgA assay system for the measurement of CgA in the plasma, urine and saliva.

Animals↗

PubMed2001

The enterins: a novel family of neuropeptides isolated from the enteric nervous system and CNS of Aplysia.

To identify neuropeptides that have a broad spectrum of actions on the feeding system of Aplysia, we searched for bioactive peptides that are present in both the gut and the CNS. We identified a family of structurally related nonapeptides and decapeptides (enterins) that are present in the gut and CNS of Aplysia, and most of which share the HSFVamide sequence at the C terminus. The structure of the enterin precursor deduced from cDNA cloning predicts 35 copies of 20 different enterins. Northern analysis, in situ hybridization, and immunocytochemistry show that the enterins are abundantly present in the CNS and the gut of Aplysia. Using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry we characterized the enterin-precursor processing, demonstrated that all of the precursor-predicted enterins are present, and determined post-translational modifications of various enterins. Enterin-positive neuronal somata and processes were found in the gut, and enterins inhibited contractions of the gut. In the CNS, the cerebral and buccal ganglia, which control feeding, contained the enterins. Enterin was also present in the nerve that connects these two ganglia. Enterins reduced the firing of interneurons B4/5 during feeding motor programs. Such enterin-induced reduction of firing also occurred when excitability of B4/5 was tested directly. Because reduction of B4/5 activity corresponds to a switch from egestive to ingestive behaviors, enterin may contribute to such program switching. Furthermore, because enterins are present throughout the nervous system, they may also play a regulatory role in nonfeeding behaviors of Aplysia.

Amino Acid Sequence↗

PubMed2001

A study of plasma alpha-2-macroglobulin levels in type 2 diabetic subjects with microalbuminuria.

BACKGROUND: Alpha-2 macroglobulin (Alpha-2-M) is a major plasma protease inhibitor that also regulates the activity of a variety of bioactive peptides including interleukins and exerts a range of immunomodulatory effects. OBJECTIVE: We conducted the present study with the objective to study the alpha-2-M levels in type 2 diabetic subjects with microalbuminuria in an attempt to establish alpha-2-M as a predictor of microvascular complications in diabetes. MATERIAL AND METHODS: Plasma Alpha-2-M levels were assayed in 100 (53 males and 47 females) randomly selected type 2 diabetic subjects with microalbuminuria. Diabetes was diagnosed according to the expert committee report of 1998. Patients with any acute metabolic complication like hypoglycemia, ketoacidosis, cerebrovascular accident or any acute infection were not included in the study group. RESULTS: Majority of patients belonged to 40-60 years age group. In our study alpha-2-M levels indicated a clear increase in diabetic subjects with the increasing age of subjects confirmed by multiple logistical analysis. Alpha-2-M levels were not found to be significantly different between males and females (55.6 +/- 11.3 vs. 53.7 +/- 10.5). Duration of diabetes was found to be an important confounding variable showing a direct positive correlation with alpha-2-M levels and also a significant correlation was found between alpha-2-M levels with different levels of microalbuminuria on multiple logistical analysis. No significant relation of alpha-2-M levels with either fasting blood sugar or HbA1 was observed. CONCLUSION: The increase in plasma alpha-2 macroglobulin levels in diabetes may be a correlative measure to encounter the potential proteolytic challenge associated with diabetic microangiopathy, even very early in the course of the disease. Alph-2 macroglobulin may yet be one of the most specific markers of microvascular complications in diabetes than any other serum protein.

Aged↗

PubMed1994

Optimization of pharmaceutical formulations for therapy.

A pharmaceutical formulation is aimed at ensuring drug delivery at the site of action in order to produce the desired therapeutic effect. The design of a pharmaceutical formulation must reflect the chemical reactivity of the drug substance as well as those of any other substances that are used in the formulation. Standardized manufacturing procedures that conform to accepted codes of Good Manufacturing Practices are prerequisites for the preparation of pharmaceutical formulations for optimal drug delivery. Drug formulations produced by such methods are expected to have the desired bioavailability characteristics for pharmacotherapy. The different types of pharmaceutical formulations usually prepared for administration by various routes are aimed at achieving the most appropriate drug delivery system for each drug. When necessary, special drug delivery systems are designed to achieve this objective. Advances in biotechnology has led to production of labile substances for use as drugs in therapy and this has created new challenges in the development of novel drug delivery systems. The sublingual, buccal, nasal and oropharyngeal routes of drug delivery have become of great interest in the delivery of bioactive peptides like insulin and interferons and pharmaceutical formulations have to be designed to meet such challenges. Of no less importance are the traditional herbal preparations whose formulation strategies have been much less understood and their therapeutic significance underestimated. Greater interest in, and investment on research on these herbal preparations will open new avenues for pharmacotherapy.

Journal Article↗