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Bioactive peptides from milk proteins: focusing on peptides displaying immunomodulatory activity
Full text linkMilk-derived peptides are milk components able to influence specific physiologicalfunctions, finally acting on body health condition. At present, the bioactivitiesdescribed for milk-derived peptides include opiate, antithrombotic, antihypertensive,
immunomodulating, antioxidative, antimicrobial, anticancer, mineral-carrying andgrowth-promoting activities. In this thesis, special attention has been given to bioactive peptides with ACE-inhibitory and immunomodulatory activities.
In the Experiment 1 Enterococcus faecalis TH563 (E. faecalis TH563) and Lactobacillus delbrueckii subsp. bulgaricus LA2 (L. delb. bulgaricus LA2), two bacterial strains isolated from traditional North Eastern Italy dairy products, have been evaluated for their ability to produce fermented milk rich in ACE-inhibitory and immunomodulatory activities. The preliminary results obtained from this experiment demonstrated that E. faecalis TH563 produced a fermented milk with high ACEinhibitory activity while L. delb. bulgaricus LA2 showed an immunomodulatory activity on bovine lymphocytes.
To better understand the mechanisms underlying the immunomodulatory activity of fermented milks, in the Experiment 2 the immunomodulatory effects of the milkderived
bioactive tri-peptide YGG have been examined. YGG could be generated during milk fermentation from a–lactalbumin hydrolysis operated by bacterial enzymes, so it could be present in milk fermented by L. delb. bulgaricus LA2. YGG
has been administered to purified peripheral blood lymphocytes in different culture conditions (presence/absence of activators of lymphocyte proliferation, different concentration of newborn calf serum) and its effects on lymphocyte proliferation and
cytokine RNA expression (IL2 and INFg) have been analyzed. YGG modulated lymphocytes proliferation, in a manner dependent from culture conditions but its effects did not seem mediated by the modulation of IL2 or INFg RNA expression.
An important limiting factor of the large-scale diffusion of food carrying potential bioactivities is the bioavailability of the peptides responsible of such bioactivities. The main factors influencing the bioavailability of peptides are the resistance to digestion enzymes of and the absorption by the intestinal epithelium. In the Experiments 3 and 4 the sensitivity to gastrointestinal enzymes and the mechanisms of absorption of the peptide b-CN (193-209) have been evaluated. b-CN (193-209) is a long hydrophobic peptide derived from b-casein that has been already isolated and identified from fermented milks and yogurt and displayed immunomodulatory properties. The pattern of digestion and the mechanisms of absorption have been evaluated in well-known in vitro models for the intestinal epithelium, as the brush border membrane vesicles (BBMV) and the Caco-2 cell line. The results of these studies demonstrated that the b-CN (193-209) peptide is absorbed intact by the Caco-2 monolayer, probably via a vesicles-mediated mechanism. In conclusion, the main contribution of this PhD thesis was to provide new knowledge about milk-derived products with bioactivities. In particular, original contributions are in relation to the mechanisms by which milk-derived bioactive peptides are generated, express their bioactivities, and their fate in the gastrointestinal tract. As a result, new questions have arisen on this area that could constitute the objective of further research programs in the future.I peptidi bioattivi derivati dal latte costituiscono una parte importante del latte, in grado di influenzare lo stato di salute. Attualmente nel latte e nei suoi derivati sono stati identificati e caratterizzati peptidi ad azione oppioide, anti-trombotica, antiipertensiva, immunomodulatoria, antiossidante, antimicrobica, anticancro, stimolanti l’assorbimento di minerali e la crescita. In questa tesi particolare attenzione è stata
rivolta ai peptidi bioattivi ad attività ACE-inibitoria e immunomodulatoria.
Nell'Esperimento 1 Enterococcus faecalis TH563 (E. faecalis TH563) e Lactobacillus delbrueckii subsp. bulgaricus LA2 (L. delb. bulgaricus LA2), due ceppi batterici isolati da formaggi tradizionali del Nord Italia, sono stati caratterizzati per la
loro capacità di produrre latti fermentati arricchiti in attività ACE-inibitoria e immunomodulatoria. I risultati preliminari hanno dimostrato che il ceppo E. faecalis TH563 è in grado di produrre un latte fermentato con elevata attività ACE-inibitoria
mentre il ceppo L. delb. bulgaricus LA2 produce un latte fermentato con attività immunomodulatoria su linfociti bovini.
Per meglio comprendere i meccanismi che regolano l’attività immunomodulatoria manifestata dal latte fermentato, nell’Esperimento 2 sono stati riportati i risultati di un
esperimento atto a valutare gli effetti immunomodulatori del peptide bioattivo YGG.
Tale tripeptide può essere generato durante il processo di fermentazione del latte dalla proteina alfa–lattoalbumina mediante l’azione proteolitica degli enzimi batterici, e
quindi anche durante la fermentazione operata dai ceppi E. faecalis TH563 e L. delb. bulgaricus LA2. YGG è stato somministrato a linfociti isolati da sangue bovino
e ne è stata studiata la capacità di modulare la proliferazione dei linfociti e l’espressione (RNA) di due citochine (IL2 e INFg) in diverse condizioni di coltura (presenza/assenza di attivatori della proliferazione, diverse concentrazioni di siero bovino). Lo studio ha dimostrato che il peptide YGG è in grado di modulare la proliferazione delle cellule e che tale modulazione è influenzata dalle condizioni di coltura ma non sembra essere mediata dalle citochine oggetto di studio.
Un fattore importante che limita l’impiego su larga scala di alimenti con proprietà bioattive è la biodisponibilità dei peptidi portatori di tali bioattività. I fattori che maggiormente influenzano la biodisponibilità dei peptidi sono la resistenza alla
digestione operata dagli enzimi gastrointestinali e la possibilità che tali peptidi possano essere assorbiti dall’epitelio intestinale. A questo scopo, negli Esperimenti 3 e 4 sono stati esaminati il profilo di digestione e i meccanismi di assorbimento del
peptide b-CN (193-209). b-CN (193-209) è un peptide bioattivo lungo e idrofobico,derivato dalla b-caseina ed è già stato isolato e identificato in diversi prodotti derivati dal latte come yogurt e latte fermentati. Tale peptide possiede inoltre diverse attività
immunomodulatorie. Il profilo di digestione di tale peptide e i meccanismi di assorbimento intestinale sono stati studiati in modelli in vitro adatti a rappresentare la mucosa intestinale, come le vescicole della membrana a orletto a spazzola
(BBMV) e la linea cellulare Caco-2. Tali esperimenti hanno dimostrato che il peptide viene assorbito intatto dalle cellule Caco-2, probabilmente attraverso un trasporto
mediato da vescicole. In conclusione, il contributo principale di questa tesi di dottorato è stato il fornire nuova conoscenza sui prodotti derivati dal latte ad azione bioattiva. Più specificatamente, questa tesi ha permesso di ottenere nuove informazioni sui meccanismi di produzione dei peptidi bioattivi derivati dal latte, sul loro meccanismo d’azione e sulla loro stabilità nel sistema gastrointestinale. Infine, i risultati ottenuti
hanno contribuito a generare nuove idee che potranno costituire nuovi spunti per futuri progetti di ricerca
B-casokinin 10 (YGG peptide) modulates proliferation and cytokine expression in bovine peripheral blood lymphocytes.
No full textThe pathogenic role of the GIP/GIPR axis in human endocrine tumors: emerging clinical mechanisms beyond diabetes
No full textThe glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone produced in the gastrointestinal tract in response to nutrients. GIP has a variety of effects on different systems, including the potentiation of insulin secretion from pancreatic β-cells after food intake (i.e. incretin effect), which is probably the most important. GIP effects are mediated by the GIP receptor (GIPR), a G protein-coupled receptor expressed in several tissues, including islet β-cells, adipocytes, bone cells, and brain. As well as its involvement in metabolic disorders (e.g. it contributes to the impaired postprandial insulin secretion in type 2 diabetes (T2DM), and to the pathogenesis of obesity and associated insulin resistance), an inappropriate GIP/GIPR axis activation of potential diagnostic and prognostic value has been reported in several endocrine tumors in recent years. The ectopic GIPR expression seen in patients with overt Cushing syndrome and primary bilateral macronodular adrenal hyperplasia or unilateral cortisol-producing adenoma has been associated with an inverse rhythm of cortisol secretion, with low fasting morning plasma levels that increase after eating. On the other hand, most acromegalic patients with an unusual GH response to oral glucose suppression have GIPR-positive somatotropinomas, and a milder phenotype, and are more responsive to medical treatment. Neuroendocrine tumors are characterized by a strong GIPR expression that may correlate positively or inversely with the proliferative index MIB-1, and that seems an attractive target for developing novel radioligands. The main purpose of this review is to summarize the role of the GIP/GIPR axis in endocrine neoplasia, in the experimental and the clinical settings
Peptides contained in milk and fermented milk as a potential source of regulators of bioactivities.
No full textDifferent therapeutic options in patients with Cushing's syndrome due to bilateral macronodular adrenal hyperplasia
No full textBilateral macronodular adrenal hyperplasia (BMAH) is a relatively rare cause of Cushing's syndrome (CS). In recent years, growing evidence has shown that steroidogenesis is regulated by aberrant G-protein-coupled receptors (GPCR) expression and their ligands, in a significant proportion of patients with BMAH. The screening of patients with overt or subclinical CS demonstrate the frequent expression of several GPCR that opened the option to potential therapeutic applications. Thus, several studies have demonstrated that targeting the involved receptor with specific antagonists, may result in a more or less effective control of cortisol excess. Bilateral adrenalectomy has traditionally been considered the treatment of choice for BMAH. However, unilateral adrenalectomy has been recently proposed as an alternative in selective patients to avoid the long-term necessity of gluco/mineralocorticoid replacement. Adrenal steroidogenesis inhibitors remains a valid option when medical treatment is needed due to high surgical risk
The Role of Glucocorticoid Receptor in the Pathophysiology of Pituitary Corticotroph Adenomas
Full text linkAdrenocorticotropic Hormone (ACTH)-secreting pituitary adenomas are rare tumors characterized by autonomous ACTH secretion with a consequent increase in circulating cortisol levels. The resulting clinical picture is called Cushing’s disease (CD), a severe condition burdened with high morbidity and mortality. Apart from increased cortisol levels, CD patients exhibit a partial resistance to the negative glucocorticoid (GC) feedback, which is of paramount clinical utility, as the lack of suppression after dexamethasone administration is one of the mainstays for the differential diagnosis of CD. Since the glucocorticoid receptor (GR) is the main regulator of negative feedback of the hypothalamic–pituitary–adrenal axis in normal conditions, its implication in the pathophysiology of ACTH-secreting pituitary tumors is highly plausible. In this paper, we review GR function and structure and the mechanisms of GC resistance in ACTH-secreting pituitary tumors and assess the effects of the available medical therapies targeting GR on tumor growth
Angiotensin I converting enzyme-inhibitory peptides in Asiago d'Allevo cheese.
No full textAsiago d’Allevo (AA) is an Italian PDO cheese produced with raw skimmed milk and ripened from 6 to 18 months. This study aimed at evaluating the Angiotensin-I-converting enzyme (ACE)-inhibitory activity (IA) of water-soluble extracts (WSEs) from AA cheeses. The samples analysed were obtained from milk produced by cows fed with a total mixed ration or alpine pasture plus concentrate and ripened for 6, 12 or 18 months. WSEs were ultrafiltrated onto 10000 Da cut-off membrane and subsequently onto 3000 Da cut-off to obtain small peptides which probably make a considerable contribution to ACE-IA. This bioactivity was determined with a rapid in vitro enzymatic test. Values of ACE-inhibition were submitted to ANOVA considering also the peptide concentration tested as covariate. Preliminary results showed no differences among ripening groups while the concentration of peptides resulted statistically significant (P<0.05). In addition, the interaction between ripening and feeding system was also statistically significant. This finding suggests that alpine grazing condition influences microbial enzymes activity and the derived biopeptides. Furthermore gastro-intestinal digestion will be simulated in order to evaluate whether digestive enzymes generate peptides with high ACE-I
No von Willebrand factor domains other than A1 are involved in type 2B von Willebrand disease: what the p.R924Q and p.A2178S variants teach us
Full text linkCaratterizzazione di peptidi ACE-inibitori prodotti ad opera di batteri proteolitici impiegati per la realizzazione di latte-fermentati.
No full textI latte-fermentati suscitano interesse per il loro contenuto in peptidi bioattivi.
Questi esercitano la loro funzione fisiologica solo quando vengono liberati
dalle proteine del latte. L’obiettivo del presente lavoro è di sviluppare un
metodo rapido di caratterizzazione dei peptidi ACE-inibitori derivati dal latte
per mezzo di batteri selezionati per la loro capacità proteolitica. L’enzima ACE
catalizza la conversione dell’angiotensina I in angiotensina II, sostanza ad
azione ipertensiva. Il metodo si avvale di un sistema HPLC impiegato per
individuare un profilo standard di eluizione di alcuni peptidi con attività ACEinibitoria
nota e per identificare i peptidi negli idrolizzati proteici ottenuti dopo
la fermentazione con i ceppi microbici. Ciò permette la valutazione dei ceppi
più adatti a produrre peptidi ACE-inibitori. L’attività ACE-inibitoria dei lattefermentati
è poi confermata mediante test enzimatico
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