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PubMed2006

The inhibitory effect of opioids on HepG2 cells is mediated via interaction with somatostatin receptors.

Opioids, acting via G-protein coupled membrane receptors, induce analgesia. However their role is not limited to their anti-nociceptive action. They are found in several peripheral tissues acting as negative regulators of cellular processes. Even though that is not fully elucidated, it becomes obvious that opioids exert their effects in close relation to other neuropeptides such as somatostatin. Hepatocellular carcinoma is one tumor, among others, which secrete bioactive peptides while somatostatin analogs exert an inhibitory effect. We have used the human hepatocyte-derived cancer cell line HepG2, in order to examine the effect of opioids on cell growth and their possible mode of action. Our results show that the opioid ethylketocyclazocine (EKC) inhibits cell proliferation and induces apoptosis. This inhibitory effect is not exerted via opioids receptors since it was not reversed by the opioid antagonist diprenorphine and functional opioid receptors were not found on HepG2 cells. On the contrary, we show that EKC binds to somatostatin receptors, and activates a PTP signalling cascade. In this respect, the interaction of opioids with somatostatin receptors on hepatocellular carcinoma cells, and the fact that they are widely used for pain control, may provide some additional clues for the discrepancies during treatment with somatostatin analogues.

Analgesics, Opioid↗

PubMed2004

Expression of proprotein convertase 2 mRNA in the ovarian follicles of the medaka, Oryzias latipes.

Proprotein convertases (PCs) are enzymes responsible for processing the precursors of many bioactive peptides in vertebrates and invertebrates. In the present study, a cDNA for proprotein convertase 2 (PC2) was cloned for the first time from a fish. The clone, which was isolated from the ovary of the medaka, Oryzias latipes, by a combination of RT-PCR cloning and 5'- and 3'-rapid amplification of cDNA ends, codes for a protein of 641 amino acid residues highly homologous to other vertebrate PC2. The medaka preproPC2 consists of a signal sequence, a propeptide with sites for autocatalytic activation, a Kex2-like catalytic domain, and a P-domain. The catalytic triad residues (Asp-169, His-210, and Ser-386) were all conserved. Northern blot analysis revealed that PC2 was expressed in the brain, ovary, and kidney of the fish. The size of PC2 mRNA expressed in the ovary was 2.3 kb, whereas those of the brain and kidney were 2.8 kb. This size difference was attributed to the lack of an approximately 300-bp nucleotide sequence just before the poly(A)+ tail of the ovarian PC2 mRNA. Ovarian expression of the PC2 gene was found in the medaka but not in the mouse, and therefore further analysis was conducted for the fish ovary. The greatest expression of PC2 mRNA in the oocytes of small growing follicles in the mature medaka was demonstrated by Northern blotting, RT-PCR and in situ hybridization analysis. These results suggest that PC2 may play a role in the processing of proproteins and/or pro-hormones expressed in the growing oocytes.

Amino Acid Sequence↗

PubMed2026

Gloeotrichia echinulata genomes from the United States are nontoxigenic and likely geosmin producers.

Six Gloeotrichia echinulata genomes derived from planktonic harmful algal blooms (HABs) with similar colonial morphology have been sequenced from lakes in the west and northeast regions of USA, four of them to completion. The c. 7 Mbp genomes exhibit a high level of conservation, with 98-99% pairwise genome-wide average nucleotide identity and high levels of synteny, representing a single species cluster. We observed strong conservation of gene clusters responsible for the synthesis of the secondary metabolites and bioactive peptides that are characteristic of HAB-forming cyanobacteria. All six G. echinulata genomes lack genes for the synthesis of classic cyanotoxins, including microcystin, but possess genes responsible for the synthesis of the taste and odor compound geosmin. Interestingly, the geoA geosmin synthase gene in three genomes is homologous to other cyanobacterial geoA genes, while the other three geoA genes are related to actinomyces geoA. Phylogenomic analysis places the G. echinulata genomes within a clade of benthic Nostocales, reflecting an ecological niche featuring extensive growth on the sediment surface before colonies disperse into the epilimnion for planktonic growth. We identify genes conserved in all six genomes that could represent physiological adaptations supporting active growth on sediments and pelagic recruitment independent of wind-driven mixing: phycoerythrin light harvesting complexes for optimal photosynthesis at depth; gliding motility to access patchy nutrient distributions; and gas vesicles with relatively small GvpC proteins that predict resistance to higher hydrostatic pressure. The strong genomic similarity across geographically distant populations suggests that G. echinulata in the United States is a tightly related non-toxigenic species group with predictable properties relevant to public health and drinking water management.

Cyanobacteria↗

PubMed2006

Immunomodulating capacity of commercial fish protein hydrolysate for diet supplementation.

Dietary proteins harbour bioactive peptides that can be released by a fermentation process. Fish proteins are a valuable and little-exploited source of potentially active biopeptides. The aim of this research was to evaluate the effects of a commercially available fermented fish protein concentrate (Seacure) (FPC) derived from a fermentation process, on the mucosal immune response in a murine model. BALB/c mice received the FPC or the non-fermented powder at different concentrations (0.20, 0.25 or 0.30mg/ml) for 2, 5 or 7 consecutive days. At the end of each feeding period, histological studies of the gut were carried out and the phagocytic activity of peritoneal macrophages, the number of IgA+ cells in the small intestine lamina propria and bronchial tissue and the number of IL-4+, IL-6+, IL-10+, IFNgamma+ and TNFalpha+ cells in the small intestine lamina propria were determined. Different accumulative doses of FPC did not induce any inflammatory immune response and the normal morphology of the small intestine was not affected. Phagocytic activity of peritoneal macrophages was enhanced following FPC administration at 0.3mg/ml for 7 consecutive days. The number of IgA+ cells increased in the small intestine lamina propria but not in the bronchial tissue. IL-4, IL-6 and IL-10 were all significantly increased in the lamina propria of the small intestine of animals that received FPC. At the same time, some pro-inflammatory cytokines such as IFNgamma and TNFalpha also increased, but the intestinal homoeostasis was maintained and no tissue damage was observed. We conclude that FPC is an immunomodulating food with a demonstrated capacity to enhance non-specific host defense mechanisms.

Administration, Oral↗

PubMed2005

Roles of N-terminal pyroglutamate in maintaining structural integrity and pKa values of catalytic histidine residues in bullfrog ribonuclease 3.

Many proteins and bioactive peptides contain an N-terminal pyroglutamate residue (Pyr1). This residue reduces the susceptibility of the protein to aminopeptidases and often has important functional roles. The antitumor ribonuclease RC-RNase 3 (RNase 3) from oocytes of Rana catesbeiana (bullfrog) is one such protein. We have produced recombinant RNase 3 containing the N-terminal Pyr1 (pRNase 3) and found it to be indistinguishable from the native RNase 3 by mass spectrometry and a variety of other biochemical and immunological criteria. We demonstrated by NMR analysis that the Pyr1 of pRNase 3 forms hydrogen bonds with Lys9 and Ile96 and stabilizes the N-terminal alpha-helix in a rigid conformation. In contrast, the N-terminal alpha-helix becomes flexible and the pKa values of the catalytic residues His10 and His97 altered when Pyr1 formation is blocked by an extra methionine at the N terminus in the recombinant mqRNase 3. Thus, our results provide a mechanistic explanation on the essential role of Pyr1 in maintaining the structural integrity, especially at the N-terminal alpha-helix, and in providing the proper environment for the ionization of His10 and His97 residues for catalysis and cytotoxicity against HeLa cells.

Animals↗

PubMed2005

Dynamic and differential changes in myocardial and plasma endothelin in patients undergoing cardiopulmonary bypass.

OBJECTIVE: The bioactive peptide endothelin modulates left ventricular function by changing afterload, coronary vascular tone, and myocardial contractility. However, whether increased plasma endothelin levels observed in patients during and after coronary revascularization and cardiopulmonary bypass reflect actual myocardial interstitial levels are unknown. METHODS: A microdialysis probe (outer diameter: 0.77 mm; length: 4 mm) was placed in the left ventricular apical midmyocardium in 20 patients and myocardial interstitial fluid was collected (2.5 microL/min) at baseline and up to 30 minutes after cardiopulmonary bypass. Myocardial interstitial and systemic arterial endothelin were measured by radioimmunoassay. RESULTS: Baseline myocardial interstitial endothelin was over 6-fold higher than plasma (20.11 +/- 2.07 vs 3.19 +/- 0.25 fmol/mL, P < .05). Plasma endothelin increased by 23% +/- 12% at 60 minutes of cardiopulmonary bypass whereas myocardial interstitial endothelin increased by 105% +/- 24%, P < .05), and this change was higher than in the plasma ( P < .05). Although no further change in plasma endothelin occurred during cardiopulmonary bypass, myocardial interstitial levels increased further after crossclamp removal (400% +/- 75%) and remained significantly higher than plasma at separation from cardiopulmonary bypass. CONCLUSION: The unique findings of this study were 2-fold: First, significant compartmentalization of endothelin exists within the human myocardium. Second, a significantly higher and temporally disparate change in myocardial interstitial endothelin occurs during and after cardiopulmonary bypass when compared with systemic levels. These dynamic changes in myocardial endothelin likely influence coronary vascular tone and contractility.

Aged↗

PubMed2004

Orexins/hypocretins cause sharp wave- and theta-related synaptic plasticity in the hippocampus via glutamatergic, gabaergic, noradrenergic, and cholinergic signaling.

Orexins (OX), also called hypocretins, are bioactive peptides secreted from glucose-sensitive neurons in the lateral hypothalamus linking appetite, arousal and neuroendocrine-autonomic control. Here, OX-A was found to cause a slow-onset long-term potentiation of synaptic transmission (LTPOX) in the hippocampus of young adult mice. LTPOX was induced at Schaffer collateral-CA1 but not mossy fiber-CA3 synapses, and required transient sharp wave-concurrent population field-burst activity generated by the autoassociative CA3 network. Exogenous long theta-frequency stimulation of Schaffer collateral axons erased LTPOX in intact hippocampal slices but not mini slices devoid of the CA3 region. Pharmacological analysis revealed that LTPOX requires co-activation of ionotropic and metabotropic glutamatergic, GABAergic, as well as noradrenergic and cholinergic receptors. Together these data indicate that OX-A induces a state-dependent metaplasticity in the CA1 region associated with sharp-wave and theta rhythm activity as well as glutamatergic, GABAergic, aminergic, and cholinergic transmission. Thus, orexins not only regulate arousal threshold and body weight but also threshold and weight of synaptic connectivity, providing a molecular prerequisite for homeostatic and behavioral state-dependent control of neuronal plasticity and presumably memory functions.

Acetylcholine↗

PubMed2005

Optimization of anabaenopeptin extraction from cyanobacteria and the effect of methanol on laboratory manipulation.

Anabaenopeptins are commonly occurring bioactive peptides of cyanobacterial origin. Cyanobacteria (blue-green algae) are known to be capable of producing a large number of biologically active peptides, but the widespread occurrence of anabaenopeptins in particular, makes them ideal candidates for investigating the reasons that cyanobacteria produce such a complex spectrum of peptides and the wider implications of their natural function(s). Despite the identification of these peptides in cyanobacterial samples, little is known about the concentrations produced. For this reason, methods for the quantitative extraction of anabaenopeptins from lyophilized cyanobacterial cells were optimized. Higher yields of anabaenopeptins were obtained using aqueous methanol extraction than using water alone. However, repeat extractions using 50, 70 or 90% aqueous methanol did not result in significantly different total yields of the anabaenopeptin variants, ABPN-A and -B. Similarly, little difference was found in the quantification of purified ABPN-A and -B by high performance liquid chromatography with photodiode array detection (HPLC-PDA) when analyzed in methanol solutions of different concentrations. The effects of solvent concentration on the laboratory handling of ABPN-A and -B in glass and plastic containers were also investigated. Significantly lower concentrations of dissolved ABPN-A and -B were found when aqueous solutions came into contact with plastics, but not 50 or 100% methanol.

Anabaena↗

PubMed2005

Development and immunochemical evaluation of antibodies Y for the poorly immunogenic polypeptide prothymosin alpha.

Since conserved mammalian polypeptides are believed to exhibit enhanced immunogenicity in avian species, hens were immunized against the poorly immunogenic, highly conserved mammalian polypeptide prothymosin alpha (ProTalpha), i.e. against either non-conjugated ProTalpha (isolated from bovine thymus) or ProTalpha conjugated to keyhole limpet hemocyanin (ProTalpha/KLH). The antibodies Y were isolated from the egg yolk and evaluated through suitable dot-blot and ELISA systems in parallel with antibodies G isolated from the antiserum of rabbits immunized against the same immunogens. As revealed, antibodies Y and G of low titer and/or affinity were obtained against non-conjugated ProTalpha, while antibodies Y against ProTalpha/KLH had a better apparent titer, could better discriminate between ProTalpha and the closely related bioactive peptide thymosin alpha 1, and were obtained at much larger quantities than the corresponding antibodies G.

Amino Acid Sequence↗

PubMed2005

Tachykinins and ovarian function in mammals.

Tachykinins are bioactive peptides whose presence has been demonstrated in endocrine glands, where they likely exert a paracrine modulatory activity on hormonal secretions. In the ovary, tachykinins have been shown to be present in nerve fibers, blood vessels, and in granulosa, luteal and interstitial cells. Tachykinin gene expression was shown in granulosa and luteal cells. Tachykinins have also been found in the follicular fluid. Substance P (SP) has been demonstrated to significantly affect the release of hormonal steroids by ovarian cells in vitro. While some authors found that SP stimulated the release of steroids, others found an inhibitory effect by the same tachykinin. Gonadotropins decrease tachykinin concentrations in the ovary. The neonatal treatment of rats with capsaicin, a drug that depletes SP in primary afferent neurons, resulted in a modest reduction in the reproductive success in rats. The experimental results listed in this review suggest that tachykinins are synthesized in the ovary, in the granulosa and luteal cells. Tachykinins are likely intraovarian modulators of the secretion of hormonal steroids. Their stores in the ovary are likely regulated by pituitary gonadotropins.

Animals↗

PubMed2006

Elements of the granular gland peptidome and transcriptome persist in air-dried skin of the South American orange-legged leaf frog, Phyllomedusa hypocondrialis.

The defensive strategy of amphibians against predator attack relies heavily on the secretion of noxious/toxic chemical cocktails from specialized skin granular glands. Bioactive peptides constitute a major component of secretions in many species and the most complex are produced by neotropical leaf frogs of the sub-family Phyllomedusinae. We recently reported that these skin secretions contain elements of both the granular gland peptidome and transcriptome and that polyadenylated mRNAs constituting the latter are protected from degradation by interactions with endogenous amphipathic peptides. This thus permits parallel amino acid sequencing of peptides and nucleic acid sequencing of cloned precursor transcripts from single lyophilized samples of secretion. Here we report that the protection afforded is sufficiently robust to permit transcriptome studies by cloning of full-length polyadenylated peptide precursor encoding mRNAs from libraries constructed using ambient temperature air-dried skin from recently deceased specimens as source material. The technique was sufficiently sensitive to permit the identification of cDNAs encoding antimicrobial peptides constituted by six different isoforms of phylloseptin and two dermaseptins. Also, for the first time, establishment of the nucleic acid and amino acid sequence of the precursor encoding the phyllomedusine frog skin bradykinin-related peptide, phyllokinin, from cloned cDNA, was achieved. These data unequivocally demonstrate that the granular gland transcriptome persists in air-dried amphibian skin--a finding that may have fundamental implications in the study of archived materials but also in the wider field of molecular biology.

Amino Acid Sequence↗

PubMed2006

Presence of immunoreactive salusin-alpha in human serum and urine.

Salusins, identified from a full-length enriched human cDNA library by bioinformatics analyses, show mitogenic, neuromodulatory and hemodynamic activities in rats. They are expressed in a wide variety of human tissues, but their precise structures and levels in human body fluids remain unknown. We developed a radioimmunoassay suitable for the detection of immunoreactive human salusin-alpha and characterized the molecular forms and concentrations of salusin-alpha in human serum and urine. The assay allowed for measurement of immunoreactive salusin-alpha concentrations as low as 1 fmol/tube after extraction of serum with an octyl-silica column, and the concentration required for 50% inhibition of binding was 40 fmol/tube. Cross-reactivities with salusin-beta and other bioactive peptides were negligible. Salusin-alpha-like immunoreactivity in normal human serum and urine ranged from 11.0 to 40.4 pmol/l (mean+/-S.D., 23.3+/-8.1 pmol/l, n=31) and from 18.6 to 367.3 pmol/l (mean+/-S.D., 156.8+/-95.8 pmol/l), respectively. Reverse-phase high performance liquid chromatography coupled with radioimmunoassay detection revealed a major immunoreactive component that coeluted with authentic salusin-alpha. These data indicate the presence of salusin-alpha in human serum and urine, thereby verifying the initially predicted processing sites for salusin-alpha in humans.

Adult↗

PubMed2006

Effect of beta-lactotensin on acute stress and fear memory.

beta-Lactotensin (beta-LT) is a bioactive peptide derived from bovine milk beta-lactoglobulin and is a natural ligand for neurotensin receptors. We examined the effect of beta-LT on restraint stress and fear memory in mice. Mice subjected to acute restraint stress exhibited a decreased number of head-dips and increased head-dip latency compared to non-stressed controls in the hole-board test, reflecting increased stress-induced behaviors. However, prior administration of beta-LT improved the behaviors caused by stress. The anti-stress effect of beta-LT was blocked by levocabastine, a neurotensin receptor subtype 2 (NTR2) antagonist. In the fear-conditioning test, the duration of freezing responses by cued fear conditioning was significantly reduced in mice administered beta-LT compared with control mice. These results suggest that beta-LT has an anti-stress effect and promotes the extinction of fear memory, which may be mediated by NTR2.

Animals↗

PubMedDate not supplied

Signal pathway involved in increased expression of neutral endopeptidase 24.11 by gonadotropin releasing hormone in choriocarcinoma cells.

Neutral endopeptidase 24.11 (NEP) is known to regulate cellular functions by degrading several bioactive peptides, such as gonadotropin-releasing hormone (GnRH). The present study was performed to clarify the mechanisms of NEP expression by GnRH in human choriocarcinoma (BeWo) cells. GnRH increased NEP expression and enzyme activity in a dose- and time-dependent manner in BeWo cells. The phosphorylation levels of protein kinase C (PKC) delta, p38 mitogen-activated protein kinase (MAPK), and c-Jun N-terminal kinase (JNK1 and 2) were enhanced after 10 min exposure of 10(-6)m GnRH. The effect of GnRH on both NEP expression and enzyme activity was completely inhibited by inhibitors of PKC, PKC delta, and p38MAPK. Cell number was reduced by 54.4 per cent of the control by culture with 10(-6)m GnRH for 24 h. However, phosphoramidon, a NEP specific inhibitor, inhibited antiproliferative effect of GnRH and reverted to the control level. In conclusion, GnRH induces NEP expression by PKC delta and p38MAPK, and increased NEP expression may be involved in antiproliferative effect in BeWo cells.

Adult↗

PubMed2005

Cloning of novel bombesin precursor cDNAs from skin of Bombina maxima.

Amphibian skin is a rich resource of bioactive peptides like proline-rich bombesin from frog Bombina maxima. A novel cDNA clone encoding a precursor protein that comprises proline-rich bombesin and a novel peptide, designated as bombestatin, was isolated from a skin cDNA library of B. maxima. The predicted primary structure of the novel peptide is WEVLLNVALIRLELLSCRSSKDQDQKESCGMHSW, in which two cysteines form a disulfide bond. A BLAST search of databases did not detect sequences with significant similarity. Bombestatin possesses dose-dependent contractile activity on rat stomach strips. The differences between cDNAs encoding PR-bombesin plus bombestatin and PR-bombesin alone are due to fragment insertions located in 3'-coding region and 3'-untranslational region, respectively.

Amino Acid Sequence↗

PubMed2005

Mass spectrometry in identification of ecotoxicants including chemical and biological warfare agents.

Mass spectrometry is a unique tool to detect and identify trace levels of organic and bioorganic compounds as well as microorganisms in the environment. The range of potential chemical warfare (CW) and biological warfare (BW) agents is very broad. An important advantage of mass spectrometry over other techniques involves potential for full spectrum detection of chemical and biological agents including mid-spectrum materials (i.e. bioactive peptides, toxins, etc.) for which biological approaches are inadequate. Being very fast (seconds and minutes), extremely sensitive (zeptomoles 10(-21)), and informative (detailed qualitative and quantitative composition of mixtures containing hundreds of chemicals), mass spectrometry is a principal analytical tool at the sites of destruction of CW. Due to its unique features, mass spectrometry is applied not only for the detection of CW agents, but for the analysis of products of metabolism and degradation of these agents in organisms or environment as well. The present paper deals with some examples of successful application of mass spectrometry for the analyses of ecotoxicants, chemical warfare agents, explosives, and microorganisms including biology warfare agents.

Animals↗

PubMed2005

Cutting back on pro-protein convertases: the latest approaches to pharmacological inhibition.

The secretory pathway in cells possesses an elaborate set of endoproteolytic enzymes that carry out a crucial step in protein precursor maturation. This step is proteolytic activation by cleavage at specific pairs of basic residues. These enzymes, named pro-protein convertases (PCs), are responsible for generating bioactive peptides and activating several enzymes and growth factors that are implicated in many important physiological events. PCs have roles in several pathologies including viral infections and cancers and, thus, are promising targets for therapeutic applications. Recent structural and homology-modeling studies demonstrate more similarity than expected at the catalytic site of the seven PCs, which makes the development of selective drugs to target individual PCs frustrating. Based on this information, we review the latest strategies to inhibit PCs, which might lead to the development of specific compounds.

Animals↗

PubMed2004

Seasonal cyclicity of secretogranin-II expression and its modulation by sex steroids and GnRH in the female goldfish pituitary.

The secretory vesicle protein secretogranin-II (SgII), a precursor for the bioactive peptide secretoneurin, is expressed at all levels of the goldfish reproductive axis, including the hypothalamus, pituitary and ovaries. These findings led us to hypothesize that SgII is involved in reproduction and is physiologically regulated. We investigated the effects of different sex steroids on pituitary SgII expression throughout the seasonal reproductive cycle of the female goldfish, as well as the effects of GnRH and testosterone on pituitary LHbeta subunit, GH, and SgII expression in sexually recrudescent female fish using northern blot analysis. We demonstrated that SgII expression levels vary seasonally, with levels being highest in winter and lowest in spring. Sex steroids did not alter SgII expression at any of the time periods studied. In sexually mature goldfish, injection of a GnRH agonist stimulated the expression of LHbeta and SgII specifically in the pars distalis but not the neurointermediate lobe of the pituitary. Although testosterone alone did not alter the expression of either of these genes, it did abolish the stimulatory effects of GnRH on both LHbeta and SgII expression. This represents the first study where testosterone is shown to modulate SgII expression in the pituitary.

Animals↗