Alpha-2-macroglobulin loaded microcapsules enhance human leukocyte functions and innate immune response

Synthetic microstructures can be engineered to deliver bioactive compounds impacting on their pharmacokinetics and pharmacodynamics. Herein, we applied dextran-based layer-by-layer (LbL) microcapsules to deliver alpha-2-macroglobulin (α2MG), a protein with modulatory properties in inflammation. Extending recent observations made with dextran-microcapsules loaded with α2MG in experimental sepsis, we focused on the physical and chemical characteristics of these microstructures and determined their biology on rodent and human cells. We report an efficient encapsulation of α2MG into microcapsules, which enhanced i) human leukocyte recruitment to inflamed endothelium and ii) human macrophage phagocytosis: in both settings microcapsules were more effective than soluble α2MG or empty microcapsules (devoid of active protein). Translation of these findings revealed that intravenous administration of α2MG-microcapsules (but not empty microcapsules) promoted neutrophil migration into peritoneal exudates and augmented macrophage phagocytic functions, the latter response being associated with alteration of bioactive lipid mediators as assessed by mass spectrometry. The present study indicates that microencapsulation can be an effective strategy to harness the complex biology of α2MG with enhancing outcomes on fundamental processes of the innate immune response paving the way to potential future development in the control of sepsis

Context Preserving Focal Probes for Exploration of Volumetric Medical Datasets

During real-time medical data exploration using volume rendering, it is often difficult to enhance a particular region of interest without losing context information. In this paper, we present a new illustrative technique for focusing on a user-driven region of interest while preserving context information. Our focal probes define a region of interest using a distance function which controls the opacity of the voxels within the probe, exploit silhouette enhancement and use non-photorealistic shading techniques to improve shape depiction.187-19

Formyl Peptide Receptor as a Novel Therapeutic Target for Anxiety-Related Disorders

Formyl peptide receptors (FPR) belong to a family of sensors of the immune system that detect microbe-associated molecules and inform various cellular and sensorial mechanisms to the presence of pathogens in the host. Here we demonstrate that Fpr2/3-deficient mice show a distinct profile of behaviour characterised by reduced anxiety in the marble burying and light-dark box paradigms, increased exploratory behaviour in an open-field, together with superior performance on a novel object recognition test. Pharmacological blockade with a formyl peptide receptor antagonist, Boc2, in wild type mice reproduced most of the behavioural changes observed in the Fpr2/3(-/-) mice, including a significant improvement in novel object discrimination and reduced anxiety in a light/dark shuttle test. These effects were associated with reduced FPR signalling in the gut as shown by the significant reduction in the levels of p-p38. Collectively, these findings suggest that homeostatic FPR signalling exerts a modulatory effect on anxiety-like behaviours. These findings thus suggest that therapies targeting FPRs may be a novel approach to ameliorate behavioural abnormalities present in neuropsychiatric disorders at the cognitive-emotional interface

Bioactive Molecules Released in Food by Lactic Acid Bacteria: Encrypted Peptides and Biogenic Amines

Lactic acid bacteria (LAB) can produce a huge amount of bioactive compounds. Since their elective habitat is food, especially dairy but also vegetal food, it is frequent to find bioactive molecules in fermented products. Sometimes these compounds can have adverse effects on human health such as biogenic amines (tyramine and histamine), causing allergies, hypertensive crises, and headache. However, some LAB products also display benefits for the consumers. In the present review article, the main nitrogen compounds produced by LAB are considered. Besides biogenic amines derived from the amino acids tyrosine, histidine, phenylalanine, lysine, ornithine, and glutamate by decarboxylation, interesting peptides can be decrypted by the proteolytic activity of LAB. LAB proteolytic system is very efficient in releasing encrypted molecules from several proteins present in different food matrices. Alpha and beta-caseins, albumin and globulin from milk and dairy products, rubisco from spinach, beta-conglycinin from soy and gluten from cereals constitute a good source of important bioactive compounds. These encrypted peptides are able to control nutrition (mineral absorption and oxidative stress protection), metabolism (blood glucose and cholesterol lowering) cardiovascular function (antithrombotic and hypotensive action), infection (microbial inhibition and immunomodulation) and gut-brain axis (opioids and anti-opioids controlling mood and food intake). Very recent results underline the role of food-encrypted peptides in protein folding (chaperone-like molecules) as well as in cell cycle and apoptosis control, suggesting new and positive aspects of fermented food, still unexplored. In this context, the detailed (transcriptomic, proteomic, and metabolomic) characterization of LAB of food interest (as starters, biocontrol agents, nutraceuticals, and probiotics) can supply a solid evidence-based science to support beneficial effects and it is a promising approach as well to obtain functional food. The detailed knowledge of the modulation of human physiology, exploiting the health-promoting properties of fermented food, is an open field of investigation that will constitute the next challenge

Post-ischemic intestinal inflammation: a role for histamine and serine proteases

L’ischemia mesenterica acuta è una condizione patologica causata dallo scompenso tra la perfusione di ossigeno al distretto intestinale da una parte e la domanda metabolica tissutale dall’altra. L’incidenza in aumento nel corso di questi ultimi anni, l’eziologia multifattoriale, la complessità della patogenesi e la mancanza di terapie risolventi riservano a questa patologia una posizione di rilievo negli attuali studi di ricerca. In questo lavoro di tesi in un modello sperimentale di ischemia e riperfusione intestinale nel topolino è stato indagato il ruolo svolto dall’istamina nella patogenesi del danno associato ad una condizione di ischemia mesenterica acuta. La principale fonte intestinale di istamina è rappresentata dalla degranulazione dei mastociti mucosali. I risultati hanno dimostrato che il trattamento con il Cromolyn, uno stabilizzatore dei mastociti, ha esercitato un effetto protettivo sul reclutamento granulocitario che segue un evento ischemico intestinale. Sulla base di queste indicazioni, sembra logico ritenere che l’istamina liberata in risposta alla degranulazione dei mastociti possa contribuire alla patogenesi del danno da ischemia e riperfusione intestinale. Infatti, abbiamo evidenziato che l’istamina svolge un ruolo determinante durante le prime ore di riperfusione mediante l’attivazione del recettore H4 il cui blocco è il solo in grado di svolgere un effetto protettivo e preventivo nei confronti della chemiotassi dei granulociti neutrofili. Nel presente lavoro, in un analogo modello di infiammazione intestinale, è stato dimostrato che anche le proteasi svolgono un ruolo decisivo nella patogenesi di questa malattia. Infatti, è stata rilevata un’aumentata attività serin-proteasica nel plasma e nel tessuto intestinale associata al danno da ischemia e riperfusione. L’inibizione di questa attività protegge l’intestino dall’infiltrazione granulocitaria post-ischemica ed aumenta il grado di sopravvivenza degli animali. Inoltre, abbiamo dimostrato che l’effetto proinfiammatorio delle proteasi seriniche associate al danno tissutale dipende dall’attivazione del recettore PAR1 e PAR2 Lo sviluppo di terapie complementari in grado di bloccare selettivamente l’attività del recettore istaminico H4 e di inibire l’attività delle proteasi seriniche può rappresentare un ulteriore approccio terapeutico nella prevenzione dal danno locale e sistemico determinato da una condizione di ischemia e riperfusione intestinale