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PubMed1985

Structure of the human vasoactive intestinal polypeptide gene.

Vasoactive intestinal polypeptide (VIP) is a 28-amino-acid hormone produced primarily by neural tissues. The amino acid sequence of VIP is similar to that of a number of gastrointestinal hormones, including glucagon and secretin. VIP is synthesized as part of a polyprotein, pre-proVIP, which generates, in addition to VIP, an additional bioactive peptide known as PHM. As a first step toward understanding the molecular basis of pre-proVIP gene expression, we have isolated the pre-proVIP gene and have determined its structure. The gene is approximately 9 kb long and is interrupted by six introns which appear to divide the gene into functional domains. One of the introns occurs within the 3'-untranslated region of the gene.

Amino Acid Sequence↗

PubMed2001

The gut as the largest endocrine organ in the body.

Secretin, gastrin and cholecystokinin were the first discovered gut hormones. Today we recognize more than 30 gut hormone genes and a multitude of bioactive peptides, which make the gut the largest endocrine organ in the body. Due to structural homologies gut peptide hormones/growth factors have been divided into separate families. It has been emphasized that those peptides are widely distributed, but have a specific expression in different cell types. The intestine can also be regarded as a sensory organ operating via neurons, endocrine cells and immune cells with gut peptides as signalling substances. Expression studies of peptide receptors in gut neuroendocrine tumours in combination with tailored peptide analogs have been helpful in developing new diagnostic and therapeutic strategies. New fields of research will relate to gut peptides associated with deficiency diseases and as potential growth factors in malignancies. Enterochromaffin cells, interspersed throughout the entire gastrointestinal mucosa, form the largest endocrine cell system. The physiological role of hormonal messengers, peptide receptors and amine transporters is currently under investigation as well as their potential involvement in disease, e.g. the secretory diarrhea associated with midgut carcinoid tumours.

Amines↗

PubMed2005

Angiotensin type 1a receptor signaling-dependent induction of vascular endothelial growth factor in stroma is relevant to tumor-associated angiogenesis and tumor growth.

Angiotensin II is a multi-functional bioactive peptide and recent reports have suggested that angiotensin II is a proangiogenic growth factor. A retrospective cohort study revealed that angiotensin converting enzyme inhibitors decreased cancer risk, however, the precise mechanism is unknown. We hypothesized that endogenous angiotensin II plays a crucial role in tumor-associated angiogenesis. Tumors implanted in the subcutaneous tissue of wild-type mice developed intensive angiogenesis with vascular endothelial growth factor (VEGF) induction in tumor stroma. AT1a receptor (AT1a-R), but not AT1b receptor or AT2 receptor was expressed in tumor stroma and systemic administration of an AT1-R antagonist reduced tumor-associated angiogenesis and VEGF expression in tumor stroma. Angiotensin II up-regulates VEGF expression through the pathway including protein kinase C, AP-1 and NF-kappaB in fibroblasts, the major cellular component of tumor stroma. VEGF is a major determinant of tumor-associated angiogenesis in the present model, since angiogenesis was markedly reduced by either a VEGF neutralizing antibody or a VEGF receptor kinase inhibitor. Compared with the wild-type, tumor-associated angiogenesis was reduced in AT1a-R null mice, with reduced expression of VEGF in the stroma, and this reduction in AT1a-R null mice was not inhibited by an AT1-R antagonist. These suggest that host stromal VEGF induction by AT1a-R signaling is a key regulator of tumor-associated angiogenesis and tumor growth. AT1a-R signaling blockade may be a novel and effective therapeutic strategy against cancers.

Angiotensin II↗

PubMed1997

Aging impairs release of central and peripheral cholecystokinin (CCK) in male but not in female rats.

BACKGROUND: Cholecystokinin (CCK) is an important bioactive peptide which stimulates pancreatic enzyme secretion and is also a neuromodulator in the central nervous system. We examined whether CCK release from the central and peripheral tissues was decreased in old animals, and whether there were sex-related differences. METHODS: Young (5-10-month-old) and old (25-29-month-old) male and female Wistar rats were used. Synaptosomes were prepared from the cerebral cortex, and the vascularly perfused duodenojejunum was isolated to examine central and peripheral CCK release, respectively. In some young female rats, 21 days after bilateral ovariectomy, the peripheral CCK release and the changes in CCK mRNA levels were examined. RESULTS: The central CCK release was impaired in response to the higher concentration of KCl, and the peripheral CCK response to the highest dose of neuromedin C was impaired in old male rats. However, no aging effect was observed in female rats, and ovariectomy did not affect CCK release or CCK mRNA level. CONCLUSIONS: CCK release from both central and peripheral tissues was decreased in old male rats, but not in old female rats.

Aging↗

PubMed2006

Translation initiation by using various N-acylaminoacyl tRNAs.

Bioactive peptides isolated from natural sources have diverse acyl groups on the N-terminus. It is difficult to synthesize these peptides in vitro translation system because ribosomal peptide synthesis generally limits the N-terminal group to be N-formylmethionine (fMet). To overcome this restriction, we developed a novel methodology for the ribosomal synthesis of peptides having various terminal N-acyl groups with desired amino acids. In this methodology, two technologies, Flexizyme system consisting of artificial ribozymes and a reconstitute E. coli cell-free translation system (PURE system), were used. First, an amino acid carrying a desired N-acyl group was charged onto an initiation tRNA by the Flexizyme system. The addition of this N-acyl-aminoacyl-tRNA (N-acyl-aa-tRNA) to the PURE system allowed us to initiate the peptide synthesis with the designated N-acyl-amino acid. By means of this methodology, the translation was exclusively initiated by various N-terminal acyl groups as well as amino acids without contamination of N-formylmethionine.

Aminoacylation↗

PubMed2000

Characterization of recombinant human adipocyte-derived leucine aminopeptidase expressed in Chinese hamster ovary cells.

Adipocyte-derived leucine aminopeptidase (A-LAP) is a recently identified novel member of the M1 family of zinc-metallopeptidases. Transfection of the A-LAP cDNA into COS-7 cells resulted in the secretion of the enzyme. In this study, recombinant A-LAP was expressed in Chinese hamster ovary cells, purified to homogeneity and its enzymatic properties were characterized. The purified enzyme was active towards a synthetic substrate, L-leucyl-p-nitroanilide, yielding a V(max) of 3.55 micromol/min/mg and a K(m) of 1.28 mM, and was shown to be a monomeric protein with molecular mass of 120 kDa in solution. By monitoring the sequential N-terminal amino acid liberation, it was found that the enzyme hydrolyzes a variety of bioactive peptides, including angiotensin II and kallidin. Immunohistochemical analysis indicated that the enzyme is expressed in the cortex of the human kidney, where tissue kallikrein is localized. Taken together, these results indicate that A-LAP possesses a broad substrate specificity towards naturally occurring peptide hormones and suggest that it plays a role in the regulation of blood pressure through the inactivation of angiotensin II and/or the generation of bradykinin in the kidney.

Adipocytes↗

PubMed1988

Porcine muscle prolyl endopeptidase and its endogenous substrates.

Prolyl endopeptidase [EC 3.4.21.26] was purified 4,675-fold with a yield of 26.3% from porcine muscle. The purified enzyme was shown to be very similar to the liver enzyme with respect to its molecular weight (72,000-74,000), antigenicity, substrate specificity, and susceptibility to protease inhibitors. Among several bioactive peptides, angiotensins I, II, and III had the lowest Km of 0.6 to 3 microM with the lowest kcat of 0.19 to 0.85 s-1, while thyrotropin-releasing hormone had the highest Km of 98 microM with the highest kcat of 14.4 s-1. Interestingly, mastoparan was hydrolyzed at alanyl bonds, but insulin was only slightly hydrolyzed and glucagon was not hydrolyzed although the latter two peptides contain prolyl and/or alanyl bonds. Muscle prolyl endopeptidase failed to hydrolyze proteins with high molecular weight such as albumin, immunoglobulin G, elastin, collagen, and muscle soluble and insoluble proteins. However, 8 of 14 peptides with molecular weights lower than 3,000, which were isolated from muscle extract, were digested by this enzyme, and they were proved to contain prolyl and/or alanyl residues in their molecules. The data suggest that they are probable endogenous substrates for prolyl endopeptidase.

Amino Acid Sequence↗

PubMed1991

Evidence that differentiates between precursor cleavages at dibasic and Arg-X-Lys/Arg-Arg sites.

It is well known that precursor cleavage at paired basic amino acids (e.g., Lys-Arg, Arg-Arg) within the regulated secretory pathway is one of the key steps to produce bioactive peptides. On the other hand, we have recently shown that precursors with an Arg residue at the fourth residue upstream of the cleavage site besides the basic pair, i.e. with the Arg-X-Lys/Arg-Arg (RXK/RR) motif, are cleaved within the constitutive secretory pathway. To discriminate between the precursor cleavage at RXK/RR sites within the constitutive pathway and that at dibasic sites within the regulated pathway, we examined the effects of drugs affecting the secretory process, intracellular Ca2+ depletion, and a protease inhibitor on these cleavages. Chloroquine (a weak base), depletion of intracellular Ca2+ by A23187 (a Ca2+ ionophore), and the Pittsburgh-type mutant of alpha 1-protease inhibitor differentially affected these two cleavages. Brefeldin A, which impedes protein transport from the endoplasmic reticulum to the Golgi complex, inhibited both cleavages. Colchicine (an anti-microtubular drug) had no discernible effect on either cleavage. These observations support the notion that the precursor cleavages at dibasic and RXK/RR sites occur in different subcellular compartments, and are catalyzed by different processing endoproteases.

Amino Acid Sequence↗

PubMed1998

Folding motifs induced and stabilized by distinct cystine frameworks.

Bioactive peptides of different sources and biological functionalities, like endothelins, sarafotoxins, bee and scorpion venom toxins, contain a consensus cystine framework, Cys-(X)1-Cys/Cys-(X)3-Cys, which has been found to induce and stabilize a homologous folding motif named the cystine-stabilized alpha-helix (CSH). This is composed of an alpha-helical segment spanning the Cys-(X)3-Cys sequence portion that is crosslinked by two disulfide bridges to the sequence portion Cys-(X)1-Cys, itself folded in an extended beta-strand type structure. Search for sequence homologies of peptides and proteins in the SWISS-PROT and PDB data banks provided additional multiple examples of this type of cystine framework in serine proteinase inhibitors, in insect and plant defense proteins, as well as in members of the growth factor family with the cystine-knot. A comparative analysis of the known 3D-structures of these peptides and proteins confirmed that the presence of this peculiar cystine framework leads in all cases to a high degree of local structural homology that consists of the CSH motif, except for the cystine-knot, of the superfamily of the growth factors. In this case the cyclic structure formed by the parallel cysteine connectivities of Cys-(X)1-Cys/Cys-(X)3-Cys framework is penetrated by a third disulfide bond with formation of a concatenated knot, and the two disulfide-bridged peptide chains Cys-(X)1-Cys and Cys-(X)3-Cys are located in beta-strands. Conversely, peptides and proteins containing Cys-(X)m-Cys/Cys-(X)n-Cys cystine frameworks that differ from m/n = 1/3 were found to fold only sporadically into local alpha-helical structures.

Amino Acid Sequence↗

PubMed2002

Pituitary adenylate cyclase-activating polypeptide modulates plasminogen activator expression in rat granulosa cell.

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a bioactive peptide isolated from ovine hypothalamus. It has been demonstrated to be transiently expressed in preovulatory follicles and to positively affect several parameters correlated with the ovulatory process. The aim of the present study was to investigate whether PACAP influences the plasminogen/plasmin system in rat ovary. Plasminogen activators (PAs) are serine proteases, modulated by gonadotropins and several peptides in preovulatory follicles, that appear to be involved in ovulation. Granulosa cells obtained from immature eCG-treated rats were cultured for 24 h in the presence of increasing concentrations of PACAP and vasoactive intestinal peptide (VIP). A significant, dose-dependent increase in tissue-type PA (tPA) activity and decrease in urokinase-type (uPA) PA activity were observed in PACAP-treated cells. These effects were exerted at the mRNA level. The use of cycloheximide, a protein synthesis inhibitor, suggested that PACAP requires an intermediary protein to decrease uPA-mRNA, but not to induce tPA-mRNA. However, no significant modulation of PAs was observed in the presence of VIP. When granulosa cells were stimulated within the intact follicle (i.e., maintaining the three-dimensional structure and in the presence of the theca cell layers), both PACAP and VIP dose-dependently stimulated tPA. These data suggest that, in addition to the PACAP type I receptor present on granulosa cells, different subtypes of PACAP receptors are present in the different ovarian compartments.

Animals↗

PubMed1994

Bacterial endotoxin: molecular relationships of structure to activity and function.

Endotoxins of Gram-negative microbes fulfill as components of the outer membrane a vital function for bacterial viability and, if set free, induce in mammalians potent pathophysiological effects. Chemically, they are lipopolysaccharides (LPS) consisting of an O-specific chain, a core oligosaccharide, and a lipid component, termed lipid A. The latter determines the endotoxic activities and, together with the core constituent Kdo, essential functions for bacteria. The primary structure of lipid A of various bacterial origin has been elucidated and lipid A of Escherichia coli has been chemically synthesized. The biological analysis of synthetic lipid A partial structures proved that the expression of endotoxic activity depends on a unique primary structure and a peculiar endotoxic conformation. The biological lipid A effects are mediated by macrophage-derived bioactive peptides such as tumor necrosis factor alpha (TNF). Macrophages possess LPS receptors, and the lipid A regions involved in specific binding and cell activation have been characterized. Synthetic lipid A partial structures compete the specific binding of LPS or lipid A and antagonistically inhibit the production of LPS-induced TNF. LPS toxicity, in general, and the ability of LPS to induce TNF are also suppressed by a recently developed monoclonal antibody (IgG2a), which is directed against an epitope located in the core oligosaccharide. At present we determine molecular and submolecular details of the specificity of the interaction of lipid A with responsive host cells with the ultimate aim to provide pharmacological or immunological therapeutics that reduce or abolish the fatal inflammatory consequences of endotoxicosis.

Animals↗

PubMed2002

Human proprotein convertase 2 homologue from a plant nematode: cloning, characterization, and comparison with other species.

Proprotein convertases (PCs) are evolutionarily conserved enzymes responsible for processing the precursors of many bioactive peptides in mammals. The invertebrate homologues of PC2 play important roles during development that makes the enzyme a good target for practical applications in pest management. Screening of a plant nematode Heterodera glycines cDNA library resulted in isolation of a full-length clone encoding a PC2-like precursor. The deduced protein (74.2 kD) exhibits strong amino acid homology to all known PC2s, including human, and shares the main structural characteristics: signal peptide; prosegment; catalytic domain, with D/H/S catalytic triad, PC2-specific residues, and 7B2 binding sites; P domain (with RRGDT pentapeptide); and carboxyl terminus. Comparative analysis of PC2s from 15 species discloses the presence of an insert in the catalytic domain unique to nematodes. Expression of PC2-like mRNA found in eggs and juveniles was undetectable in adult stages of H. glycines. Nucleotide analysis reveals distinctive differences in base composition and codon usage between H. glycines and Caenorhabditis elegans PC2s. The H. glycines cDNA clone encoding PC2 is the first one isolated from plant-parasitic nematodes.

Animals↗

PubMed2003

Neutral endopeptidase/CD10 expression in the stroma of epithelial ovarian carcinoma.

This study investigated the immunohistochemical expression and localization of neutral endopeptidase (NEP) (CD10), which plays a functional role by degrading bioactive peptides, in ovarian tumors. In normal ovaries and benign cystadenomas, NEP was not detected in any epithelial or stromal cells. In borderline tumors, NEP was detected in the stromal cells in 6 of 7 serous tumors, but not in those from mucinous tumors. In ovarian carcinomas, NEP in the stromal cells was observed in 13 of 20 serous, 8 of 10 endometrioid, and 7 of 10 clear-cell adenocarcinomas. NEP was weakly detected in only 1 of 9 mucinous adenocarcinomas. The staining intensity of stromal NEP was decreased in grades 2 and 3 serous carcinomas compared with that in grade 1 serous carcinomas. In conclusion, NEP was specifically expressed in the stroma of borderline and malignant ovarian tumors, but not in adenomas. Furthermore, stromal NEP was downregulated as the histological grade advanced. These results suggest that NEP may play a role in the regulation of neoplastic transformation and tumor differentiation in epithelial ovarian carcinomas.

Adenocarcinoma, Clear Cell↗

PubMed2001

Altered expression of the neuropeptide-processing enzyme carboxypeptidase E in the rat brain after global ischemia.

Carboxypeptidase E, an exoprotease involved in the processing of bioactive peptides released by a regulated secretory pathway, was identified in a subtractive complementary DNA library derived from an ischemic rat brain by differential screening. In situ hybridization and immunocytochemical analysis showed the presence of carboxypeptidase E messenger RNA and protein in the cerebral cortex, thalamus, striatum, and hippocampus of a healthy rat brain. After 15 minutes of transient global ischemia followed by 8 hours of reperfusion, increased levels of carboxypeptidase E messenger RNA and protein were observed in the hippocampal CA1 and CA3 regions and in the cortex, as detected by Northern and Western blot analyses and in situ hybridization. After extended reperfusion (24 to 72 hours), both carboxypeptidase E messenger RNA and protein levels were decreased. The ischemia-induced changes in carboxypeptidase E expression suggest that this enzyme may play a role in modulating the brain's response to ischemia.

Animals↗

PubMed1996

Matrix metalloproteinases in the normal human central nervous system, microglial nodules, and multiple sclerosis lesions.

Matrix metalloproteinases (MMPs) comprise a family of proteolytic enzymes that are involved in remodeling of the extracellular matrix (ECM) of many tissues. They have been implicated in degradation of vascular basement membranes thereby facilitating leukocyte migration into inflammatory sites. To determine the cellular localization and levels of MMPs in the normal human central nervous system (CNS), multiple sclerosis (MS) lesions, and other conditions, cryostat sections of CNS samples were immunostained with antisera to MMP-1, -2, -3 and -9. In control white matter the principal cells that express the MMPs were perivascular and parenchymal microglia. Cellular MMP expression was also found in sporadic microglial nodules in MS white matter. Most CNS microvessel endothelial cells expressed MMP-3 and -9 but not MMP-1 or -2. The majority of macrophages in active MS and necrotic lesions were MMP-l-, -2-, -3-, and -9-positive whereas chronic MS lesions had fewer MMP-positive macrophages. Small numbers of astrocytes were MMP-2-, -3- and -9-positive in acute and chronic MS lesions. These data suggest that microglia-derived MMPs may mediate turnover of the CNS ECM under normal conditions and in microglial nodules. In sites of CNS tissue injury there is complex and dynamic regulation of MMP expression by different cell populations. In MS lesions MMP-mediated proteolysis may contribute to breakdown of the blood-brain barrier and leukocyte migration into the CNS, in situ immune activation, demyelination, metabolism of bioactive peptides, and the formation of an ECM that does not promote remyelination or axonal repair.

Adult↗

PubMed1997

Standardization of procedure for efficient ex vivo gene transfer into porcine pancreatic islets with cationic liposomes.

BACKGROUND: New strategies to improve the outcome of encapsulated porcine islet transplantation may involve the transfer of gene sequences affecting islet viability. While adenoviral vectors appear as the most efficient gene transfer system so far established for islets, non-viral-based vectors are most likely to fulfill microbiological safety criteria and be retained in the clinical setting. Our aim was to standardize the procedures of gene transfer into adult porcine islets using cationic liposome DOTAP. METHODS: Porcine islets obtained by collagenase digestion and density gradient purification were lipofected with plasmids coding for luciferase or beta-galactosidase under the control of simian virus 40 or cytomegalovirus promoter. The following parameters were explored: exposure time to vector (1-48 hr), DNA amount (1-15 microg/500 islets), and DOTAP to DNA ratio (2-16). Reporter gene expression was determined 48-72 hr after lipofection. RESULTS: Efficiency and reproducibility of transfection were maximal with the following procedure: 3-hr exposure time followed by islet washing, 12 microg of DNA per 500 islets (150 microm equivalent), and DOTAP to DNA ratio of 12 microl/microg. Freshly isolated islets in large aliquots (n=4000 in 50-ml tubes) were efficiently transduced with this procedure, and distribution of gene expression was homogenous when islets were subsequently plated in 500-islet aliquots. Luciferase gene expression was detected for a minimum of 7 days after lipofection. Gene expression was also evident up to 4 weeks after islet transplantation beneath the kidney capsule of athymic mice. Transfection of islets using the beta-galactosidase vector yielded 25% positive islets. Islet viability was not adversely affected. CONCLUSIONS: This islet lipofection procedure may help achieve the local release of a bioactive peptide in the graft environment and have therapeutic applications in islet transplantation.

Animals↗

PubMed2006

Salusins protect neonatal rat cardiomyocytes from serum deprivation-induced cell death through upregulation of GRP78.

Salusin-alpha and salusin-beta are newly identified bioactive peptides with hemodynamic and mitogenic activities. Recent studies have shown that salusins improve calcium uptake and protein synthesis in neonatal rat cardiomyocytes, suggesting that salusins may be regulatory factors for myocardial growth and hypertrophy. In this study, we investigated whether salusins improve the survival of cardiomyocytes after serum deprivation. Cultured neonatal cardiomyocytes were treated with or without salusins (salusin-alpha or salusin-beta) at a concentration range of 10 to 10 mol/L for 24 h under serum deprivation conditions. Cardiomyocytes viability was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazonium bromide assay. Cell death or apoptosis rate was identified by flow cytometry analysis. Compared to serum deprivation-only groups, cardiomyocyte viability was significantly increased in salusin-alpha or salusin-beta groups. Cell death rate was decreased after administration of 10 mol/L salusin-alpha or salusin-beta. Salusin-beta was able to decrease the apoptotic rate. Salusins also increased the expression of cardiomyocyte glucose-regulated protein 78 (GRP78) as estimated by Western blot. Furthermore, antisense oligodeoxynucleotide specifically against GRP78 attenuated or abrogated antiapoptosis or survival effects of salusin-beta. These findings suggest that salusin-alpha and salusin-beta may be a potential survival factor against serum deprivation-induced myocardial cell death and that this cardioprotective effect may involve an upregulation of GRP78 expression in cardiomyocytes.

Adenosine Triphosphatases↗

PubMed2006

Dairy products and cardiovascular disease.

PURPOSE OF REVIEW: Although it has often been postulated that the consumption of dairy products is associated with a high risk of coronary heart disease, study results have been conflicting. This review summarizes recent observational and human intervention trial findings on dairy products and cardiovascular disease. RECENT FINDINGS: Results from more recent observational studies on dairy products and milk disagree. This may be because of the very different methods used combined with several methodological problems. A somewhat surprising beneficial association between the intake of dairy products and the metabolic syndrome was observed in some studies, although not in a single study of elderly women. Milk may have the same cholesterol-raising properties as butter, whereas cheese does not seem to increase plasma cholesterol. Some milk products fermented by specific bacterial strains have been shown to have rather moderate cholesterol-reducing properties. There is also good evidence that certain fermented products (especially by Lactobacillus helveticus) have a mildly decreasing effect on hypertension, probably because of bioactive peptides. SUMMARY: When guiding principles such as balance, variety and moderation are stressed, there is no strong evidence that dairy products increase the risk of coronary heart disease in healthy men of all ages or young and middle-aged healthy women. Human studies should investigate the role of dairy products with respect to sex and age by including classic and novel risk markers of coronary heart disease. Specific fermented milks may be beneficial in the future prevention of hypertension. The beneficially neutral effect of cheese on coronary heart disease risk factors should be elucidated further.

Age Factors↗