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Opioide peptiders virkemåte i kroppen, og dyrestudier med opioide peptider fra matproteiner

How does the opioid system control pain, reward and addictive behavior?
Professor Brigitte L. Kieffer (14-Oct-2007)
European College of Neuropsychopharmacology

Transport Systems for Opioid Peptides in Mammalian Tissues
Vadivel Ganapathy and Seiji Miyauchi
AAPS Journal. 2005; 7(4): E852-E856. DOI:  10.1208/aapsj070482
 

Peptides. 2009 Jun 30. [Epub ahead of print]
Beta-Casomorphins-7 in infants on different type of feeding and different levels of psychomotor development.
Kost NV, Sokolov CO, Kurasova CO, Dmitriev AD, Tarakanova JN, Gabaeva CE, Zolotarev YA, Dadayan CA, Grachev SA, Korneeva CI, Mikheeva IG, Zozulya CA.  National Research Center for Mental Health RAMS, 113152, Moscow, Zagorodnoe shosse 2/2.
 
Casomorphins are the most important during the first year of life, when postnatal formation is most active and milk is the main source of both nutritive and biologically active material for infants. This study was conducted on a total of 90 infants, of which 37 were fed with breast milk and 53 were fed with formula containing cow milk. The study has firstly indicated substances with immunoreactivity of human (irHCM) and bovine (irBCM) beta-casomorphins-7 in blood plasma of naturally and artificially fed infants, respectively. irHCM and irBCM were detected both in the morning before feeding (basal level), and 3hours after feeding. Elevation of irHCM and irBCM levels after feeding was detected mainly in infants in the first 3 months of life. Chromatographic characterization of the material with irBCM has demonstrated that it has the same molecular mass and polarity as synthetic bovine beta-casomorphin-7. The highest basal irHCM was observed in breast fed infants with normal psychomotor development and muscle tone. In contrast, elevated basal irBCM was found in formula-fed infants showing delay in psychomotor development and heightened muscle tone. Among formula-fed infants with normal development, the rate of this parameter directly correlated to basal irBCM. The data indicate that breast feeding has an advantage over artificial feeding for infants' development during the first year of life and support the hypothesis for deterioration of bovine casomorphin elimination as a risk factor for delay in psychomotor development and other diseases such as autism.

PMID: 19576256 [PubMed - as supplied by publisher]

 



Eksp Klin Farmakol. 2009 Mar-Apr;72(2):3-5.Links
[Naloxone-induced suppression of the behavioral manifestation of serotoninergic system hyperactivation by beta-casomorphins-7 in mice][Article in Russian]
Zozulia AA, Meshavkin VK, Sokolov OIu, Kost NV.

 

The effect of human and bovine beta-casomorphins-7 on the behavior of mice under conditions of 5-hydroxytryptophan (5-HT) induced hyperactivation of the serotoninergic system (head twitch test) has been studied. Intraperitoneal administration of each peptide in a dose of 1 mg/kg was shown to suppress the head twitch response in mice approximately by half (p < 0.01). This effect was completely blocked by the opioid receptor antagonist naloxone (10 mg/kg), which did not alter the behavior of mice in the head twitch test by itself. Thus, the influence of casomorphins on the serotoninergic system in vivo has been demonstrated for the first time. The role of 5-HT and opioid receptors in the mechanism of casomorphin action is discussed.

PMID: 19441718 [PubMed - indexed for MEDLINE]

 



J Chromatogr B Analyt Technol Biomed Life Sci. 2007 Jun 1;852(1-2):485-90. Epub 2007 Feb 15.
Liquid chromatography-mass spectrometry assay for quantification of Gluten Exorphin B5 in cerebrospinal fluid.
Fanciulli G, Azara E, Wood TD, Delitala G, Marchetti M. Dipartimento-Struttura Clinica Medica-Patologia Speciale Medica, University of Sassari, Viale San Pietro 8, 07100 Sassari, Italy.

 

A sensitive, precise and accurate method for the quantification of the alimentary opioid peptide Gluten Exorphin B5 (GE-B5, Tyr-Gly-Gly-Trp-Leu) in cerebrospinal fluid (CSF) was developed using liquid chromatography-mass spectrometry (LC-MS). Aliquots (10muL) of sheep CSF were injected into a LC-MS instrument equipped with a reversed-phase C12 column at a flow rate of 250muL/min. The mobile phase consisted of Eluent A water with 0.01% acetic acid as an ion-pairing reagent, and Eluent B acetonitrile. The LC-MS system was programmed to divert column flow to waste for 3.5min after injection, after which time flow was directed into the mass spectrometer that operated in positive ion mode. DADLE (Tyr-D-Ala-Gly-Phe-D-Leu) was used as Internal Standard. No significant interfering peaks were detected at the retention times of GE-B5 in CSF blanks. The calibration curves were linear in the range of 0.39-78.00ng/mL. The lower limit of detection and the lower limit of quantitation values for GE-B5 in CSF were established at 0.30 and 0.78ng/mL, respectively. The intra-day and inter-day precision values were <12% relative standard deviation. The intra-day and inter-day accuracy were 99.46-100.86% and 98.95-100.02%, respectively. Recovery of GE-B5 in CSF samples was greater than 80%. Stability studies indicate that GE-B5 in CSF undergoes significant degradation (>55% after 600min), which is reduced by the addition of protease inhibitors. This is the first reported method for the quantification of GE-B5 in CSF.

PMID: 17336169 [PubMed - in process]

Kommentar: Metode for påvisning av glutensekvens med opioid virkning i CSF

 


 

Journal of Applied Genetics 48(3),2007, pp. 189 - 198
Polymorphism of bovine beta-casein and its potential effect on human health
Stanislaw Kaminski, Anna Cieslinska, Elzbieta Kostyra

Abstract: Proteins in bovine milk are a common source of bioactive peptides. The peptides are released by the digestion of caseins and whey proteins. In vitro the bioactive peptide beta-casomorphin 7 (BCM-7) is yielded by the successive gastrointestinal proteolytic digestion of bovine beta-casein variants A1 and B, but this was not seen in variant A2. In hydrolysed milk with variant A1 of beta-casein, BCM-7 level is 4-fold higher than in A2 milk. Variants A1 and A2 of beta-casein are common among many dairy cattle breeds. A1 is the most frequent in Holstein-Friesian (0.310-0.660), Ayrshire (0.432-0.720) and Red (0.710) cattle. In contrast, a high frequency of A2 is observed in Guernsey (0.880-0.970) and Jersey (0.490-0.721) cattle. BCM-7 may play a role in the aetiology of human diseases. Epidemiological evidence from New Zealand claims that consumption of beta-casein A1 is associated with higher national mortality rates from ischaemic heart disease. It seems that the populations that consume milk containing high levels of beta-casein A2 have a lower incidence of cardiovascular disease and type 1 diabetes. BCM-7 has also been suggested as a possible cause of sudden infant death syndrome. In addition, neurological disorders, such as autism and schizophrenia, seem to be associated with milk consumption and a higher level of BCM-7. Therefore, careful attention should be paid to that protein polymorphism, and deeper research is needed to verify the range and nature of its interactions with the human gastrointestinal tract and whole organism.

Key words: beta-casein, beta-casomorphin 7, diabetes, ischaemic heart disease, polymorphism.

Correspondence: S. Kaminski, Department of Animal Genetics, University of Warmia and Mazury, M. Oczapowskiego 5, 10-718 Olsztyn, Poland; e-mail: Denne e-postadressen er beskyttet mot programmer som samler e-postadresser. Du må aktivere javaskript for å kunne se den.
[URL til artikkel]

 



Bull Exp Biol Med. 2005 Nov;140(5):582-4.Links
Reactions between beta-casomorphins-7 and 5-HT2-serotonin receptors.
Sokolov OY, Pryanikova NA, Kost NV, Zolotarev YA, Ryukert EN, Zozulya AA. Research Center of Mental Health, Russian Academy of Medical Sciences, Moscow. Denne e-postadressen er beskyttet mot programmer som samler e-postadresser. Du må aktivere javaskript for å kunne se den.

 

Radioreceptor analysis showed that human beta-casomorphin-7 displaced 3H-spiperone from 5-HT2-serotonin receptors of the rat cerebral frontal cortex: EC50 8 +/- 1 microM. Human and bovine beta-casomorphin-7 dose-dependently blocked serotonin-induced human platelet aggregation: IC50 5 +/- 1 and 20 +/- 4 microM, respectively. It was proved that beta-casomorphins-7 act as 5-HT2-serotonin receptor antagonists; one of the mechanisms of their biological effects is presumably associated with modulation of the serotoninergic system.

PMID: 16758631 [PubMed - indexed for MEDLINE]

 



Clin Diagn Lab Immunol. 2004 May;11(3):515-24.Links
Heat shock protein and gliadin peptide promote development of peptidase antibodies in children with autism and patients with autoimmune disease.
Vojdani A, Bazargan M, Vojdani E, Samadi J, Nourian AA, Eghbalieh N, Cooper EL.
Section of Neuroimmunology, Immunosciences Lab., Inc., 8693 Wilshire Blvd., Suite 200, Beverly Hills, CA 90211, USA. Denne e-postadressen er beskyttet mot programmer som samler e-postadresser. Du må aktivere javaskript for å kunne se den.

 

Searching for a mechanism underlying autoimmunity in autism, we postulated that gliadin peptides, heat shock protein 60 (HSP-60), and streptokinase (SK) bind to different peptidases resulting in autoantibody production against these components. We assessed this hypothesis in patients with autism and in those with mixed connective tissue diseases. Associated with antigliadin and anti-HSP antibodies, children with autism and patients with autoimmune disease developed anti-dipeptidylpeptidase I (DPP I), anti-dipeptidylpeptidase IV (DPP IV [or CD26]) and anti-aminopeptidase N (CD13) autoantibodies. A significant percentage of autoimmune and autistic sera were associated with elevated immunoglobulin G (IgG), IgM, or IgA antibodies against three peptidases, gliadin, and HSP-60. These antibodies are specific, since immune absorption demonstrated that only specific antigens (e.g., DPP IV absorption of anti-DPP IV), significantly reduced IgG, IgM, and IgA antibody levels. For direct demonstration of SK, HSP-60, and gliadin peptide binding to DPP IV, microtiter wells coated with DPP IV were reacted with SK, HSP-60, and gliadin. They were then reacted with anti-DPP IV or anti-SK, anti-HSP, and antigliadin antibodies. Adding SK, HSP-60, and gliadin peptides to DPP IV resulted in 27 to 43% inhibition of the DPP IV-anti-DPP IV reaction, but DPP IV-positive peptides caused 18 to 20% enhancement of antigen-antibody reactions. We propose that (i) superantigens (e.g., SK and HSP-60) and dietary proteins (e.g., gliadin peptides) in individuals with predisposing HLA molecules bind to aminopeptidases and (ii) they induce autoantibodies to peptides and tissue antigens. Dysfunctional membrane peptidases and autoantibody production may result in neuroimmune dysregulation and autoimmunity.

PMID: 15138176 [PubMed - indexed for MEDLINE]

Kommentar: Kobling mellom gliadin (glutenprotein) og utvikling av autisme/ autoimmune sykdommer

 



Life Sci. 2002 Oct 4;71(20):2383-90.
Prolactin and growth hormone response to intracerebroventricular administration of the food opioid peptide gluten exorphin B5 in rats.
Fanciulli G, Dettori A, Tomasi PA, Demontis MP, Gianorso S, Anania V, Delitala G. Dipartimento-Struttura Clinica Medica-Patologia Speciale Medica, Istituto di Patologia Medica, University of Sassari, Viale San Pietro 8, 07100, Sassari, Italy. Denne e-postadressen er beskyttet mot programmer som samler e-postadresser. Du må aktivere javaskript for å kunne se den.

 

Although it has long been known that opioid peptides cause marked changes of pituitary hormone secretion in both animals and humans, little is known about the possible effect(s) of food-derived opioids (exorphins) on pituitary function. In order to investigate the possible role of exorphins derived from wheat gluten on pituitary function, we gave the following treatments to four groups of male rats: intracerebroventricular (ICV) vehicle, Gluten Exorphin B5 (GE-B5) 200 microg ICV, naloxone intraperitoneally (IP) followed by vehicle ICV, naloxone IP followed by GE-B5 ICV. Blood samples for Prolactin (PRL) and Growth Hormone (GH) were taken at intervals for 90 minutes after vehicle or GE-B5 administration. GE-B5 strongly stimulated PRL secretion; its effect was completely abolished by naloxone administration. GH secretion was unaffected by GE-B5 under these experimental conditions. The present study shows for the first time that an opioid peptide derived from wheat gluten, GE-B5, has an effect on pituitary function when administered ICV; its mechanism of action appears to be mediated via classical opioid receptors.
Publication Types:
Research Support, Non-U.S. Gov't

PMID: 12231399 [PubMed - indexed for MEDLINE]

Kommentar: Forhøyet prolaktin-nivå finner man igjen i flere autoimmune sykdommer.

 



Vitam Horm. 2002;65:257-79.Links
Endomorphins and related opioid peptides.
Okada Y, Tsuda Y, Bryant SD, Lazarus LH. Faculty of Pharmaceutical Sciences, High Technology Research Center, Kobe Gakuin University, Kobe 651-2180, Japan.

Opioid peptides and their G-protein-coupled receptors (delta, kappa, mu) are located in the central nervous system and peripheral tissues. The opioid system has been studied to determine the intrinsic mechanism of modulation of pain and to develop uniquely effective pain-control substances with minimal abuse potential and side effects. Two types of endogenous opioid peptides exist, one containing Try-Gly-Gly-Phe as the message domain (enkephalins, endorphins, dynorphins) and the other containing the Tyr-Pro-Phe/Trp sequence (endomorphins-1 and -2). Endomorphin-1 (Tyr-Pro-Trp-Phe-NH2), which has high mu receptor affinity (Ki = 0.36 nM) and remarkable selectivity (4000- and 15,000-fold preference over the delta and kappa receptors, respectively), was isolated from bovine and human brain. In addition, endomorphin-2 (Tyr-Pro-Phe-Phe-NH2), isolated from the same sources, exhibited high mu receptor affinity (Ki = 0.69 nM) and very high selectivity (13,000- and 7500-fold preference relative to delta and kappa receptors, respectively). Both opioids bind to mu-opioid receptors, thereby activating G-proteins, resulting in regulation of gastrointestinal motility, manifestation of antinociception, and effects on the vascular systems and memory. To develop novel analgesics with less addictive properties, evaluation of the structure-activity relationships of the endomorphins led to the design of more potent and stable analgesics. Opioidmimetics and opioid peptides containing the amino acid sequence of the message domain of endomorphins, Tyr-Pro-Phe/Trp, could exhibit unique binding activity and lead to the development of new therapeutic drugs for controlling pain.

PMID: 12481550 [PubMed - indexed for MEDLINE]

Kommentar: NPIF-medlemmer, og enkeltcasus fra autisme-studier kan bekrefte at proteinintolerante har unormal høy smerteterskel under jevn tilførsel av gluten- og melkeproteiner.

 


 

2007 The American Society for Nutrition J. Nutr. 137:953-958, April 2007
Nutrient Physiology, Metabolism, and Nutrient-Nutrient Interactions
Angiotensin Converting Enzyme Inhibitory Peptides from a Lactotripeptide-Enriched Milk Beverage Are Absorbed Intact into the Circulation1
Unilever Food and Health Research Institute, 3133 AR Vlaardingen, The Netherlands
Martin Foltz*, Evelyne E. Meynen, Veronique Bianco, Chris van Platerink, Thea M. M. G. Koning and Joris Kloek  * To whom correspondence should be addressed. E-mail: Denne e-postadressen er beskyttet mot programmer som samler e-postadresser. Du må aktivere javaskript for å kunne se den. .

Food products containing angiotensin converting enzyme (ACE) inhibitory peptides reportedly play a role in treatment of mild hypertension. The aim of this placebo-controlled crossover study was to assess the bioavailability of Ile-Pro-Pro and 7 other ACE-inhibiting peptides present in a lactotripeptide (LTP)-enriched yogurt beverage and whether meal intake affects Ile-Pro-Pro bioavailability. Six male and female subjects randomly consumed an LTP-enriched yogurt beverage or a placebo in the fasted state and an LTP-enriched yogurt beverage in the fed or fasted state. The area under the curve (AUC) of Ile-Pro-Pro after the LTP treatment in the fasted state was 2.1-fold of that after the placebo treatment (P < 0.001). The maximum peptide plasma concentration (Cmax) value was greater after consumption of the LTP-enriched beverage (897 ± 157 pmol/L) than after the placebo treatment (555 ± 0.09 pmol/L; P < 0.001) with a greater time after ingestion when reaching Cmax (Tmax) in the placebo treatment. Plasma concentrations of the peptides Leu-Trp, Phe-Tyr, Ile-Tyr, and Leu-Pro-Pro increased compared with baseline (P < 0.05) in the LTP-enriched and placebo treatment when consumed in the fasted state. However, Cmax values differed significantly between the placebo and LTP-enriched treatment only for Leu-Pro-Pro. Meal intake affected Ile-Pro-Pro concentrations. When the beverage was consumed after a meal, the AUC of Ile-Pro-Pro was 1.3-fold (P < 0.05) of the AUC derived from premeal intake. This was due to an increase in the plasma elimination half-life (P < 0.05); Cmax and Tmax were not affected by meal intake. In summary, this is the first demonstration, to our knowledge, that the tripeptide Ile-Pro-Pro selectively escapes from intestinal degradation and reaches the circulation undegraded.

[link til publikasjonen]

Kommentar: Påvisning av tripeptid som går gjennom tarm-blodbarrieren uspaltet

 


 

Journal of Pediatric Gastroenterology & Nutrition:Volume 25 Supplement 11997p 43
LONG-TERM EEG-EXAMINATIONS IN CHILDREN WITH COELIAC DISEASE
[Gut Interactions with Brain and Environment in Children; First International Symposium on Pediatric Neurogastroenterology Capri, Italy, September 18-20, 1997]
Henker, J.; Paul, K.-D.; Todt, H. Dept. of Pediat., Medical Faculty of Technical University, Dresden, Germany

Neurological manifestations in coeliac disease (CD) have been known for a long time. In generally they are the consequence of malabsorption.

In a previous study we could show by using EEG-examinations, that a gluten-containing diet in children with CD can lead to cerebral alterations (1).

Long-term EEG-investigations have been carried out in 19 of these patients (up to 7.8 year). We found, despite re-introduc tion of a strict glutenfree diet and normalization of small intestinal architecture the EEG disturbances can persist. We assume, there is primarily in the floride phase of disease a functional-metabolic disturbance followed by morphologic changes. Gluten challenge tests to confirm the diagnosis, if necessary, should therefore not be performed until the age of 6, that is after the completion of cell differentiation in the brain and last as short as possible.  [Context Link]

Reference
1. Paul K-D, Henker J, Todt H, Eysold R: EEG-Befunde bei zöliakiekranken Kindern in Abhängigkeit von der Ernährung Z Klin Med 1985; 40:707-709


Z Klin Med 1985; 40:707-709
EEG-Befunde bei zöliakiekranken Kindern in Abhängigkeit von der Ernährung
Paul K-D, Henker J, Todt H, Eysold R

A total of 90 EEGs was performed in 58 children with coeliac disease and evaluated taking into consideration the alimentary status and biopsy findings of the small intestine. Patological electro-encephalographic curves were found more frequently with gluten-containing food and hence also in cases of mucosal lesions. The proportion of pathological EEGs increased with rising duration of gluten-containing diet for a longer period of time, the tendency of regression of pathological EEG is minimal in spite of new glutenfree diet. In cases of typical initial symptoms, of paraclinical parameters suggesting a malabsorption syndrome and total atrophy of villi in biopsies of the small intestine gluten-provocation should only be performed after the 6th years of life and should not exceed 5 months. Even if there are no signs of subjective symptoms under gluten-containing food, impairment of the child´s organism may exist. Thus our findings support the demand to keep a life-long gluten-free diet when coeliac disease has been diagnosed. The EEG has no diagnstic value as far as the coeliac disease is concerned and it is not suitable for therapeutic control.  [Link to study]

Kommentar: Hos barn med Cøliaki har en sett EEG (elektriske avledninger fra hjernen) forandringer hos 42%. Hvis man provoserer barn med cøliaki under 7 år med gluten er det påvist EEG effekter i 72% av tilfellene som vedvarte opptil et helt år.

 


 

Beta-casomorfiner fra kumelkproteiner

Pediatr Allergy Immunol. 2008 Jan 16 [Epub ahead of print]
Content of beta-casomorphins in milk of women with a history of allergy.
Sidor K, Jarmołowska B, Kaczmarski M, Kostyra E, Iwan M, Kostyra H. Third Department of Paediatric Diseases, Medical University, Bialystok, Poland.

The prevalence of food allergies increased over the past decade. Most symptoms of food allergy appear during the first 2 yr of life. The aim of this study was to determine the beta-casomorphin-5 and -7 (BCMs) in colostrum and milk of 12 breast-feeding women with a history and clinical manifestation of food allergy. The results were compared with the data obtained from a control group of healthy age-matched breast-feeding women. The level of BCM in women with food allergy was constant during lactation, whereas the highest level of opioid peptides was found in colostrums of healthy women with a subsequent rapid decrease in mature milk. These differences in BCMs profile between allergic and healthy breast-feeding women suggest that BCM content in the human milk may be an indicator of allergic conditions.

PMID: 18208459 [PubMed - as supplied by publisher]

 



J Agric Food Chem. 2008 Jan 15 [Epub ahead of print]Links
Producibility and Digestibility of Antihypertensive beta-Casein Tripeptides, Val-Pro-Pro and Ile-Pro-Pro, in the Gastrointestinal Tract: Analyses Using an in Vitro Model of Mammalian Gastrointestinal Digestion.
Ohsawa K, Satsu H, Ohki K, Enjoh M, Takano T, Shimizu M.
Denne e-postadressen er beskyttet mot programmer som samler e-postadresser. Du må aktivere javaskript for å kunne se den. .

 

Val-Pro-Pro (VPP) and Ile-Pro-Pro (IPP) are antihypertensive tripeptides isolated from milk fermented with Lactobacillus helveticus and inhibit angiotensin-converting enzyme (ACE). We investigated whether these peptides were generated from beta-casein by digestive enzymes and whether they were resistant to enzymatic hydrolysis, using an in vitro model. VPP and IPP were not generated from beta-casein by gastrointestinal enzymes; instead, a number of longer peptides including VPP and IPP sequences were detected. The fermentation step would therefore be necessary to produce these antihypertensive tripeptides. VPP and IPP themselves were hardly digested by digestive enzymes, suggesting that orally administered VPP and IPP remain intact in the intestine, retaining their activity until adsorption. The present study also demonstrated that various functional peptide sequences in beta-casein were resistant to gastrointestinal enzymes. There may be a strong correlation between the resistance of peptides to gastrointestinal digestion and their real physiological effects after oral administration.

PMID: 18193838 [PubMed - as supplied by publisher]

 



J Appl Genet. 2007;48(3):189-98.
Polymorphism of bovine beta-casein and its potential effect on human health.
Kaminski S, Cieslinska A, Kostyra E.
Department of Animal Genetics, University of Warmia and Mazury, M. Oczapowskiego 5, 10-718 Olsztyn, Poland.

 

Proteins in bovine milk are a common source of bioactive peptides. The peptides are released by the digestion of caseins and whey proteins. In vitro the bioactive peptide beta-casomorphin 7 (BCM-7) is yielded by the successive gastrointestinal proteolytic digestion of bovine beta-casein variants A1 and B, but this was not seen in variant A2. In hydrolysed milk with variant A1 of beta-casein, BCM-7 level is 4-fold higher than in A2 milk. Variants A1 and A2 of beta-casein are common among many dairy cattle breeds. A1 is the most frequent in Holstein-Friesian (0.310-0.660), Ayrshire (0.432-0.720) and Red (0.710) cattle. In contrast, a high frequency of A2 is observed in Guernsey (0.880-0.970) and Jersey (0.490-0.721) cattle. BCM-7 may play a role in the aetiology of human diseases. Epidemiological evidence from New Zealand claims that consumption of beta-casein A1 is associated with higher national mortality rates from ischaemic heart disease. It seems that the populations that consume milk containing high levels of beta-casein A2 have a lower incidence of cardiovascular disease and type 1 diabetes. BCM-7 has also been suggested as a possible cause of sudden infant death syndrome. In addition, neurological disorders, such as autism and schizophrenia, seem to be associated with milk consumption and a higher level of BCM-7. Therefore, careful attention should be paid to that protein polymorphism, and deeper research is needed to verify the range and nature of its interactions with the human gastrointestinal tract and whole organism.

PMID: 17666771 [PubMed - in process]

Kommentar: Norske kuer produserer A1-melk

 



Bull Exp Biol Med. 2005 Nov;140(5):582-4.Links
Reactions between beta-casomorphins-7 and 5-HT2-serotonin receptors.
Sokolov OY, Pryanikova NA, Kost NV, Zolotarev YA, Ryukert EN, Zozulya AA.
Research Center of Mental Health, Russian Academy of Medical Sciences, Moscow.

 

Radioreceptor analysis showed that human beta-casomorphin-7 displaced 3H-spiperone from 5-HT2-serotonin receptors of the rat cerebral frontal cortex: EC50 8 +/- 1 microM. Human and bovine beta-casomorphin-7 dose-dependently blocked serotonin-induced human platelet aggregation: IC50 5 +/- 1 and 20 +/- 4 microM, respectively. It was proved that beta-casomorphins-7 act as 5-HT2-serotonin receptor antagonists; one of the mechanisms of their biological effects is presumably associated with modulation of the serotoninergic system.

PMID: 16758631 [PubMed]

Kommentar: Forstyrrelser i 5-HT(2A) er knyttet til blant annet schizofreni [Pubmed]

 



Int J Immunopathol Pharmacol. 2003 Sep-Dec;16(3):189-99.Links
Infections, toxic chemicals and dietary peptides binding to lymphocyte receptors and tissue enzymes are major instigators of autoimmunity in autism.
Vojdani A, Pangborn JB, Vojdani E, Cooper EL.
Lab. Comparative Immunology, Dept. Neurobiology, UCLA Medical Center, Los Angeles, CA, USA. Denne e-postadressen er beskyttet mot programmer som samler e-postadresser. Du må aktivere javaskript for å kunne se den.

 

Similar to many complex autoimmune diseases, genetic and environmental factors including diet, infection and xenobiotics play a critical role in the development of autism. In this study, we postulated that infectious agent antigens such as streptokinase, dietary peptides (gliadin and casein) and ethyl mercury (xenobiotic) bind to different lymphocyte receptors and tissue enzyme (DPP IV or CD26). We assessed this hypothesis first by measuring IgG, IgM and IgA antibodies against CD26, CD69, streptokinase (SK), gliadin and casein peptides and against ethyl mercury bound to human serum albumin in patients with autism. A significant percentage of children with autism developed anti-SK, anti-gliadin and casein peptides and anti-ethyl mercury antibodies, concomitant with the appearance of anti-CD26 and anti-CD69 autoantibodies. These antibodies are synthesized as a result of SK, gliadin, casein and ethyl mercury binding to CD26 and CD69, indicating that they are specific. Immune absorption demonstrated that only specific antigens, like CD26, were capable of significantly reducing serum anti-CD26 levels. However, for direct demonstration of SK, gliadin, casein and ethyl mercury to CD26 or CD69, microtiter wells were coated with CD26 or CD69 alone or in combination with SK, gliadin, casein or ethyl mercury and then reacted with enzyme labeled rabbit anti-CD26 or anti-CD69. Adding these molecules to CD26 or CD69 resulted in 28-86% inhibition of CD26 or CD69 binding to anti-CD26 or anti-CD69 antibodies. The highest % binding of these antigens or peptides to CD26 or CD69 was attributed to SK and the lowest to casein peptides. We, therefore, propose that bacterial antigens (SK), dietary peptides (gliadin, casein) and Thimerosal (ethyl mercury) in individuals with pre-disposing HLA molecules, bind to CD26 or CD69 and induce antibodies against these molecules. In conclusion, this study is apparently the first to demonstrate that dietary peptides, bacterial toxins and xenobiotics bind to lymphocyte receptors and/or tissue enzymes, resulting in autoimmune reaction in children with autism.

PMID: 14611720 [PubMed - indexed for MEDLINE]

 


 

Opioide peptider fra gluten

FEBS Lett. 1997 Aug 4;412(3):475-9.Links
Release of opioid peptides, gluten exorphins by the action of pancreatic elastase.
Fukudome S, Jinsmaa Y, Matsukawa T, Sasaki R, Yoshikawa M.
Food Research Laboratory, Nisshin Flour Milling Co. Ltd., Saitama, Japan.

The release of opioid peptides, gluten exorphins A, which have been isolated from the pepsin-thermolysin digest of wheat gluten, with gastrointestinal proteases was examined. High levels of gluten exorphin A5 (Gly-Tyr-Tyr-Pro-Thr) immunoreactive materials were detected in the pepsin-pancreatic elastase digest by a competitive ELISA. From this digest, gluten exorphin A5, B5 and B4 were isolated. This means that these peptides are released in the gastrointestinal tracts after ingestion of wheat gluten. The yield of gluten exorphin A5 in the pepsin-elastase digest was larger than that in the pepsin-thermolysin digest. The gluten exorphin A5 sequence is found 15 times in the primary structure of the high molecular weight glutenin. The region from which gluten exorphin A5 was released by the action of pancreatic elastase was identified using synthetic fragment peptides.

PMID: 9276449 [PubMed - indexed for MEDLINE]

 


 

Dyrestudier med opioide peptider fra matproteiner

World J Gastroenterol. 2007 Apr 14;13(14):2094-9.Links
Effects of intra-gastric beta-casomorphin-7 on somatostatin and gastrin gene expression in rat gastric mucosa.
 Zong YF, Chen WH, Zhang YS, Zou SX.
Department of Animal Physiology and Biochemistry, Nanjing Agricultural University, Nanjing 210095, Jiangshu Province, China. Denne e-postadressen er beskyttet mot programmer som samler e-postadresser. Du må aktivere javaskript for å kunne se den. .

AIM: To investigate the in vivo effect of beta-casomorphin-7 on the regulation of gastric somatostatin and gastrin messenger RNA in rat gastric mucosa. METHODS: Somatostatin and gastrin mRNA were quantified by RT-PCR and in situ hybridization (ISH) in 24 rats. The rats were divided into three treatment groups: basal diet + physiological saline (n = 8), basal diet + beta-casomorphin-7 (7.5 multiply 10(-7) mol) (n = 8), and basal diet + poly-Gly-7 (containing equal mol of N with 7.5 multiply 10(-7) mol beta-casomorphin-7) (n = 8). After oral administration for 30 days, rats were killed by exsanguinations. RESULTS: After intra-gastric administration of beta-casomorphin-7 for 30 d, gastrin mRNA increased by 52.8% (P < 0.05, n = 8), and somatostatin mRNA levels decreased by 30.7% compared with the controls (P < 0.01, n = 8). No significant differences in the expression of the two genes were observed in the poly-Gly-treated group, although gastrin mRNA expression was elevated by 35.6% as against the control group (P = 0.15, n = 8). The long-term oral administration of a casomorphin solution significantly decreased the even gray of D-cells, but did not lower the number of D-cells both in the antrum and fundus. Interestingly, the number of G-cells increased in the antrum and fundus, but its average density was augmented only in the antrum. CONCLUSION: Beta-casomorphin-7 is capable of modulating gene expression of the regulatory peptides from G and D cells. Data from in situ hybridization studies indicate that beta-casomorphin-7 affects gastrin gene expression indirectly by means of the paracrine action of somatostatin, and depends on its intrinsic molecular function.

PMID: 17465454 [PubMed - in process]

 


 

Ross Fiziol Zh Im I M Sechenova. 2005 Jan;91(1):80-8.Links
[Influence of acute and chronic administrations of beta-casomorphins on the maternal motivation in albino rats][Article in Russian]
Dubynin VA, Ivleva IuA, Beliaeva IuA, Dobriakova IuV, Andreeva LA, Kamenskiĭ AA.

The influence of food-derived opioid peptides beta-casomorphines on the manifestation of nursing albino rats maternal behavior was investigated. It was shown that both acute and chronic (during the postnatal period) administration of beta-casomorphin-7 (Tyr-Pro-Phe-Pro-Gly-Pro), the typical representative of this group of peptides, decreases the level of the parental motivation. The effects of beta-casomorphin-7 were naloxone-dependent; N-terminal-reduced analogues had a significantly lesser activity. The obtained results testify in favor of the probable role of casein opioid fragments which were formed in mammary glands of a nursing female, in the development of maternal behavior abnormalities. At the same time, beta-casomorphins could be considered as the limiting factors to the excessive manifestation of the parental motivation.

PMID: 15773583 [PubMed - indexed for MEDLINE]

 


 

Life Sci. 2005 Feb 25;76(15):1713-9. Epub 2004 Dec 20.Links
Gluten exorphin B5 stimulates prolactin secretion through opioid receptors located outside the blood-brain barrier.
Fanciulli G, Dettori A, Demontis MP, Tomasi PA, Anania V, Delitala G.
Dipartimento-Struttura Clinica Medica-Patologia Speciale Medica, University of Sassari, Viale San Pietro 8, 07100 Sassari, Italy. Denne e-postadressen er beskyttet mot programmer som samler e-postadresser. Du må aktivere javaskript for å kunne se den.

Gluten exorphin B5 (GE-B5) is a food-derived opioid peptide identified in digests of wheat gluten. We have recently shown that GE-B5 stimulates prolactin (PRL) secretion in rats; this effect is abolished by preadministration of the opioid receptor antagonist naloxone. However, since the structure of naloxone allows it to cross the blood-brain barrier (BBB) and antagonize opioid effects centrally as well as peripherally, it could not established, on the basis of those data, if GE-B5-induced PRL release is exerted through sites located inside or outside the BBB. In this study, we sought to determine the site of action of GE-B5 on PRL secretion, by pretreating male rats with naloxone methobromide (NMB), an opioid antagonist that does not cross the BBB. Four groups of rats were given the following treatments: 1) intravenous vehicle; 2) intravenous GE-B5 (3 mg kg(-1) body weight); 3) intraperitoneal NMB (5 mg kg(-1) body weight), followed by vehicle; 4) NMB, followed by GE-B5. Blood samples for PRL were taken at intervals for 40 minutes after vehicle or GE-B5 administration. GE-B5 stimulated PRL secretion; the effect was statistically significant at time 20. NMB preadministration completely abolished PRL response. Our experiment indicates that GE-B5 stimulates PRL secretion through opioid receptors located outside the BBB. Since opioid peptides do not exert their effect on PRL secretion directly, but via a reduced dopaminergic tone, our data suggest that GE-B5 can modify brain neurotransmitter release without crossing the BBB.

PMID: 15698850 [PubMed - indexed for MEDLINE]

 


 

Nutr Neurosci. 2004 Feb;7(1):53-5.Links
Serum prolactin levels after administration of the alimentary opioid peptide gluten exorphin B4 in male rats.
Fanciulli G, Dettori A, Demontis MP, Anania V, Delitala G.
Dipartimento-Struttura Clinica Medica-Patologia Speciale Medica, University of Sassari, Viale San Pietro 8, 07100 Sassari, Italy. Denne e-postadressen er beskyttet mot programmer som samler e-postadresser. Du må aktivere javaskript for å kunne se den.

Gluten Exorphins are opioid peptides identified in enzymatic digests of gluten. The effects of Gluten Exorphins are still largely unknown. It has been shown that Gluten Exorphin B5 (Tyr-Gly-Gly-Trp-Leu) stimulates Prolactin secretion in male rats. In this study, we have evaluated the Prolactin response to Gluten Exorphin B4, another exorphin whose structure (Tyr-Gly-Gly-Trp) is identical to that of the NH(2)-terminal sequence of Gluten Exorphin B5. To this aim, five groups of male rats were given the following intravenous treatments: vehicle, Gluten Exorphin B5 3 mg kg-1 body weight, Gluten Exorphin B4 at the doses of 3, 6 and 9 mg kg-1 body weight. At the dose of 3 mg kg-1 body weight, Gluten Exorphin B5 induced a significant increase in Prolactin levels. Gluten Exorphin B4 could not modify Prolactin secretion, even when administered at doses three times higher than those effective for Gluten Exorphin B5. The present study: (1) indicates that Gluten Exorphin B4 does not modify Prolactin secretion in male rats; (2) confirms the ability of Gluten Exorphin B5 to exert a stimulatory action on Prolactin release; (3) suggests that the presence of the carboxy-terminal leucine in Gluten Exorphin B5 is essential for its action on Prolactin secretion.

PMID: 15085559 [PubMed - indexed for MEDLINE]

 


 

Abstract A115.16, published in FENS Forum Abstracts, vol. 2, 2004.
Ref.: FENS Abstr., vol.2, A115.16, 2004
Author(s) Slusarenko J., Dobryakova J., Stovolosov I., Dybinin V. & Kamensky A.
Addresse(s) Lab. of Neuropharmacology, Moscow, Russia
Influence of food-derived opioid peptides on the level of defence motivation and learning ability of white rat pups.

As known, the opioid system is available to decrease level of defence motivation and to increase resistance of nervous system to stress. Influence of morphin, met-enkephalin, beta-endorphin decreases stress-induced release of noradrenaline in hypothalamus, amigdala, locus coeruleus. The idea of our experiments was to investigate the behavioral effects of food-derived opioid peptides - beta-casomorphin-7 (from beta-casein of cow milk; YPFPGPI) and exorphin C (the fragment of gluten; YPISL). Rat pups in different age had received peripheral injections of peptides as a model of consuming by newborns substitutions of maternal milk. As was shown the effects of beta-casomorphin-7 are anxiolytic that is typical for mu-agonists. The peptide increases exploration and decreases defence motivation in various modifications of 'open field'test and in X-maze. Beta-casomorphin-7 also changes the learning process- it improves acquisition in food-reinforced task and impares acquisition in pain-reinforced task. The peptide is effective when injected acute (from rats age 28 days) and chronically (long-lasting effects). Now we investigate properties of gluten exorphin C. It was discovered that peptide influence is anxiogenic: the level of defence motivation increases exploration decreases. In result exorphin C impaires acquisition in food-reinforced task increasing the number of errors in maze. Like beta-casomorphins exorphin C is effective when injected acute and chronically. In whole our results show that effects of beta-casomorphins and exorphin C on rats behavior are opposite. Seems exorphin C when binding to opioid receptors works as compete antagonist to endorphins. The reason is the difference in primary structure of peptide molecules mainly the absense of Phe as 3 residue in molecule of exorphin C. The facts support the idea that consumption of food with high content of gluten may lead to unfavourable consequences.

 


 

Life Sci. 2005 Feb 25;76(15):1713-9. Epub 2004 Dec 20.Links
Gluten exorphin B5 stimulates prolactin secretion through opioid receptors located outside the blood-brain barrier.
Fanciulli G, Dettori A, Demontis MP, Tomasi PA, Anania V, Delitala G.
Dipartimento-Struttura Clinica Medica-Patologia Speciale Medica, University of Sassari, Viale San Pietro 8, 07100 Sassari, Italy. Denne e-postadressen er beskyttet mot programmer som samler e-postadresser. Du må aktivere javaskript for å kunne se den.

Gluten exorphin B5 (GE-B5) is a food-derived opioid peptide identified in digests of wheat gluten. We have recently shown that GE-B5 stimulates prolactin (PRL) secretion in rats; this effect is abolished by preadministration of the opioid receptor antagonist naloxone. However, since the structure of naloxone allows it to cross the blood-brain barrier (BBB) and antagonize opioid effects centrally as well as peripherally, it could not established, on the basis of those data, if GE-B5-induced PRL release is exerted through sites located inside or outside the BBB. In this study, we sought to determine the site of action of GE-B5 on PRL secretion, by pretreating male rats with naloxone methobromide (NMB), an opioid antagonist that does not cross the BBB. Four groups of rats were given the following treatments: 1) intravenous vehicle; 2) intravenous GE-B5 (3 mg kg(-1) body weight); 3) intraperitoneal NMB (5 mg kg(-1) body weight), followed by vehicle; 4) NMB, followed by GE-B5. Blood samples for PRL were taken at intervals for 40 minutes after vehicle or GE-B5 administration. GE-B5 stimulated PRL secretion; the effect was statistically significant at time 20. NMB preadministration completely abolished PRL response. Our experiment indicates that GE-B5 stimulates PRL secretion through opioid receptors located outside the BBB. Since opioid peptides do not exert their effect on PRL secretion directly, but via a reduced dopaminergic tone, our data suggest that GE-B5 can modify brain neurotransmitter release without crossing the BBB.

PMID: 15698850 [PubMed - indexed for MEDLINE]

 


 

Life Sci. 1995;57(7):729-34.Links
Effect of gluten exorphins A5 and B5 on the postprandial plasma insulin level in conscious rats.
Fukudome S, Shimatsu A, Suganuma H, Yoshikawa M.
Research Control Department, Nisshin Flour Milling Co., Ltd., Tokyo, Japan.

The effect of exogenous opioid peptides, gluten exorphins A5 and B5, which were isolated from the enzymatic digest of wheat gluten, on the postprandial insulin level were examined in rats. The oral administration of gluten exorphin A5 at a dose of 30 mg/kg w. potentiated the postprandial plasma insulin level and the effect was reversed by naloxone. The administration of gluten exorphin B5 showed a similar effect at a higher dose (300 mg/kg w). Furthermore, intravenous administration of gluten exorphin A5 at a dose of 30 mg/kg w. also stimulated the postprandial insulin release. The fact that orally and intravenously administered gluten exorphin A5 stimulates insulin release suggests that it modulates pancreatic endocrine function by the action after the absorption rather than within the the gastrointestinal tract.

PMID: 7637543 [PubMed - indexed for MEDLINE]

 


 

 

Zh Vyssh Nerv Deiat Im I P Pavlova. 1995 Nov-Dec;45(6):1143-50.Links
The effect of beta-casomorphin-7 on the level of food and defense motivations in different types of learning
Maklakova AS, Nazarenko IV, Dubynin VA, Nezavibat'ko VN, Alfeeva LA, Kamenskiĭ AA.

The effects of intraperitoneal administration of the heptapeptide beta-casomorphin-7 (beta-C-7) on learning were investigated in white rats using T-maze, active and passive avoidance tests. The substance injected in the dose of 5 mg/kg 5 min prior to training accelerated the acquisition of food-reinforced task increasing the number of correct trials in T-maze. The same injection in the dose of 1 mg/kg impaired the acquisition of avoidance tasks. The heptapeptide didn't influence food motivation and consolidation of memory trace. The data obtained support the idea that beta-C-7 attenuated manifestations of defensive motivation.

PMID: 8585304 [PubMed]

 



Endocrinology, Vol 112, 885-889, Copyright © 1983 by Endocrine Society
Effect of beta-casomorphins and analogs on insulin release in dogs
V Schusdziarra, A Schick, A de la Fuente, J Specht, M Klier, V Brantl and EF Pfeiffer

 

Opioid-active substances have been isolated from bovine beta-casein peptone (beta-casomorphin). Since the ingestion of beta-casomorphin- containing foodstuff elicits an increase in postprandial insulin release, the present study was designed to determine the effect of iv infused beta-casomorphins on insulin release. The infusion of beta- casomorphin-7, -5, -4, and -3 did not alter basal insulin secretion. During prestimulation of insulin release with amino acids and glucose the infusion of beta-casomorphin-7, -5, -4, and -3 at a dose of 1 nmol/ kg . h augmented insulin release, whereas at a concentration of 100 nmol/kg . h no further stimulatory effect was observed except for the infusion of beta-casomorphin-4. In comparison, the infusion of morphine elicited a potentiation of insulin release at the lower dose, whereas no effect was observed at the higher infusion rate. Leucine-enkephalin had no effect at the lower dose but elicited an inhibitory effect at the higher rate. The infusion of opiate-active and inactive analogs of beta-casomorphin-4 resulted in a loss of its stimulatory effect, indicating that the full tetrapeptide structure of the molecule is important for its stimulatory activity on beta-cell secretion. All stimulatory and inhibitory effects of the opioid-active substances were blocked by the specific opiate-receptor antagonist naloxone. Additionally, the present data support the concept that beta-cell secretion is stimulated by mu-receptor activation and inhibited by delta-receptor activation. The K-receptor antagonist ethyl- ketocyclazocine did not alter insulin secretion. The fact that iv administered beta-casomorphins stimulate insulin release raises the possibility that ingested food-derived opioid-active substances modulate pancreatic endocrine function also after their absorption, provided the doses employed in the present study reflect physiological concentrations of circulating beta-casomorphins.  [Url til artikkel]

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