Nicotinamide enhances myelin production after demyelination through reduction of astrogliosis and microgliosis

Caloric restriction is the chronic reduction of total caloric intake without malnutrition and has attracted a lot of attention as, among multiple other effects, it attenuates demyelination and stimulates remyelination. In this study we have evaluated the effect of nicotinamide (NAM), a well-known caloric restriction mimetic, on myelin production upon demyelinating conditions. NAM is the derivative of nicotinic acid (vitamin B3) and a precursor of nicotinamide adenine dinucleotide (NAD+), a ubiquitous metabolic cofactor. Here, we use cortical slices ex vivo subjected to demyelination or cultured upon normal conditions, a lysolecithin (LPC)-induced focal demyelination mouse model as well as primary glial cultures. Our data show that NAM enhances both myelination and remyelination ex vivo, while it also induces myelin production after LPC-induced focal demyelination ex vivo and in vivo. The increased myelin production is accompanied by reduction in both astrogliosis and microgliosis in vivo. There is no direct effect of NAM on the oligodendrocyte lineage, as no differences are observed in oligodendrocyte precursor cell proliferation or differentiation or in the number of mature oligodendrocytes. On the other hand, NAM affects both microglia and astrocytes as it decreases the population of M1-activated microglia, while reducing the pro-inflammatory phenotype of astrocytes as assayed by the reduction of TNF-α. Overall, we show that the increased myelin production that follows NAM treatment in vivo is accompanied by a decrease in both astrocyte and microglia accumulation at the lesion site. Our data indicate that NAM influences astrocytes and microglia directly, in favor of the remyelination process by promoting a less inflammatory environment

Diet supplementation with fish‐derived extracts suppresses diabetes and modulates intestinal microbiome in a murine model of diet‐induced obesity

Metabolic syndrome-related diseases affect millions of people worldwide. It is well established that changes in nutritional habits and lifestyle can improve or prevent metabolic-related pathologies such as type-2 diabetes and obesity. Previous reports have shown that nutritional supplements have the capacity to limit glucose intolerance and suppress diabetes development. In this study, we investigated the effect of dietary supplementation with fish-derived extracts on obesity and type 2 diabetes and their impact on gut microbial composition. We showed that nutritional supplements containing Fish Complex (FC), Fish Complex combined with Cod Powder (FC + CP), or Cod Powder combined with Collagen (CP + C) improved glucose intolerance, independent of abdominal fat accumulation, in a mouse model of diet-induced obesity and type 2 diabetes. In addition, collagen-containing supplements distinctly modulate the gut microbiome in high-fat induced obesity in mice. Our results suggest that fish-derived supplements suppress diet-induced type 2 diabetes, which may be partly mediated through changes in the gut microbiome. Thus, fish-derived supplements and particularly the ones containing fish collagen have potential beneficial properties as dietary supplements in managing type 2 diabetes and metabolic syndrome via modulation of the gut microbiome.publishedVersio

Diet supplementation with fish‐derived extracts suppresses diabetes and modulates intestinal microbiome in a murine model of diet‐induced obesity

Metabolic syndrome-related diseases affect millions of people worldwide. It is well established that changes in nutritional habits and lifestyle can improve or prevent metabolic-related pathologies such as type-2 diabetes and obesity. Previous reports have shown that nutritional supplements have the capacity to limit glucose intolerance and suppress diabetes development. In this study, we investigated the effect of dietary supplementation with fish-derived extracts on obesity and type 2 diabetes and their impact on gut microbial composition. We showed that nutritional supplements containing Fish Complex (FC), Fish Complex combined with Cod Powder (FC + CP), or Cod Powder combined with Collagen (CP + C) improved glucose intolerance, independent of abdominal fat accumulation, in a mouse model of diet-induced obesity and type 2 diabetes. In addition, collagen-containing supplements distinctly modulate the gut microbiome in high-fat induced obesity in mice. Our results suggest that fish-derived supplements suppress diet-induced type 2 diabetes, which may be partly mediated through changes in the gut microbiome. Thus, fish-derived supplements and particularly the ones containing fish collagen have potential beneficial properties as dietary supplements in managing type 2 diabetes and metabolic syndrome via modulation of the gut microbiome.publishedVersio

Ανοσολογικοί μηχανισμοί άμυνας των μακροφάγων έναντι παθογόνων μικροοργανισμών κατά τα αρχικά στάδια της ζωής

Neonatal sepsis is a major cause of morbidity and mortality among term and preterm infants in both developed and developing countries worldwide. Several studies have identified E. coli and Streptococcus agalactiae (GBS) as the leading causative agents of sepsis in this vulnerable age group. Though these pathogens are commensals for healthy adults, in neonates such infections have particularly devastating outcomes for both infant hosts and their families. Despite antibiotic treatment there are no other available therapies for the management of neonatal sepsis. A major contributor of neonatal susceptibility to infections is the immature state of neonatal adaptive and innate immune responses. During this tender period of life, adaptive immunity is still underdeveloped, whereas innate immune responses are untrained and partly disarmed compared to those of adults. Since the molecular and cellular mechanisms of neonatal innate immune defense against pathogens and sepsis have not been clearly elucidated, their understanding is crucial to develop new targeted and effective therapies for this detrimental condition. DEL-1 is a molecule with profound immunomodulatory and anti-inflammatory properties with fundamental role in inflammatory disease pathology. By utilizing wild type (WT) healthy and septic mice of adult and neonatal age, we observed that DEL-1 expression was systemically elevated in healthy neonates compared to adults and further increased under septic conditions as opposed to septic adults. To investigate the role of DEL-1 in the context of neonatal sepsis, we utilized WT and DEL-1-/- that we subjected to polymicrobial sepsis. We found that DEL-1 -/- mice displayed profound neutropenia, exaggerated bacteremia and overall diminished survival in response to sepsis, defects that were rescued by the exogenous administration of DEL-1. The basis of these defects relies on the diminished numbers of myeloid-biased hematopoietic stem cells, granulocyte progenitors and neutrophils in the bone marrow of septic DEL-1 -/- mice, indicating the importance of DEL-1 as an integral component of the neonatal bone marrow niche that exerts its protective effects via supporting emergency granulopoiesis. We also demonstrate that the sustained tissue production of DEL-1 in newborn sepsis was attributed to the high IL-10/IL-17A ratio that neonates display. Specifically, we provide evidence that as IL-10 upregulates DEL-1, as blockade of IL-10 signaling diminished both the expression and the beneficial effects of DEL-1. Consistent with the mouse findings, DEL-1 and neutrophil numbers were higher in septic human adult and neonate patients with high IL-10/IL-17A ratio. Furthermore, septic patients with high DEL-1 exhibited lower mortality rates compared to patients with low DEL-1. In conclusion, we highlight the role of a hitherto unappreciated IL-10–DEL-1 axis in the maintenance of the bone marrow neutrophil pool, which is inadequate in infancy, by supporting emergency granulopoiesis, thus preventing neutropenia and promoting sepsis survival in early life. Next, we studied the role of adult and neonatal macrophages in response to GBS infection. GBS is a commensal for healthy adults but a leading cause of sepsis and meningitis among neonates and young infants. To study the molecular mechanisms of macrophage immunity against GBS we utilized thioglycolate elicited peritoneal macrophages from adult and neonate mice that we stimulated with GBS. Unlike adult macrophages, GBS infection in neonatal macrophages was characterized by elevated intracellular bacterial load, enhanced cytoplasmic escape and decreased targeting to lysosomes for degradation. Using confocal microscopy analysis and a series of siRNA molecules we demonstrated that LC3 Associated Phagocytosis (LAP) is the driver immune mechanism mediating GBS clearance in adult macrophages. However, neonatal macrophages suffer from profound deficits in LAP pathway as indicated by the diminished co-localization of GBS with LC3. GBS infected neonatal macrophages acquired a unique metabolic and inflammatory profile, baring both pro- and anti-inflammatory characteristics. RNA-seq analysis revealed that neonatal macrophages produce exacerbated amounts of IL-6 in response to infections that negatively impact LAP. In fact, the administration of IL-6 in murine adult macrophages impeded their antibacterial activity. In contrast, the universal inhibition of IL-6 or the selective inhibition of its trans signaling mode improved the bactericidal capacity of the GBS infected macrophages in a LAP dependent manner. Similarly, the inhibition of the downstream signaling mediators JAK1/2 and STAT-3 significantly decreased intracellular load and cytoplasmic escape of GBS, while enhancing LC3 deposition on internalized bacteria. In accordance with our findings on the murine model, the inhibition of IL-6R with Tocilizumab, augments the capacity of human cord blood macrophages to eliminate GBS. Finally, we demonstrate that the IL-6 targeting therapies can have potential in vivo and prolong the survival of GBS infected murine pups. Hence, the administration of immunomodulatory therapies targeting the IL-6/JAK1&2/STAT-3 axis may confer protection from invasive GBS infection in newborns by effectively activating the intracellular defense mechanisms of macrophages against invading pathogens. The findings of the current study can potentially lead to the development of targeted therapies that may improve neonatal sepsis prognosis and morbidity that remain too dismal.Η νεογνική σήψη είναι μια από τις βασικές αιτίες θνητότητας και θνησιμότητας βρεφών παγκοσμίως, τόσο στις αναπτυσσόμενες όσο και στις ανεπτυγμένες χώρες. Πλήθος μελετών έχουν αναδείξει τα παθογόνα E. coli και Streptococcus agalactiae (GBS) ως τους κύριους λοιμώδεις παράγοντες που προκαλούν σήψη σε αυτή την ευαίσθητη ηλικιακή ομάδα. Παρά το γεγονός ότι και τα δύο αυτά παθογόνα είναι αβλαβή για τους υγιείς ενήλικες οργανισμούς, οι λοιμώξεις αυτών των παθογόνων στα νεογνά έχουν σοβαρές επιπτώσεις τόσο για τους ίδιους τους ξενιστές όσο και για τις οικογένειές τους. Μέχρι στιγμής, η μόνη διαθέσιμη θεραπεία για τη διαχείριση της νεογνικής σήψης είναι η χορήγηση αντιβιοτικών. Ένας βασικός παράγοντας που καθιστά τα νεογνά επιρρεπή στην ανάπτυξη λοιμώξεων είναι η ανωριμότητα του νεογνικού ανοσοποιητικού συστήματος, τόσο της έμφυτης όσο και της επίκτητης ανοσίας. Σε αυτή τη τρυφερή περίοδο της ζωής, η γραμμή της επίκτητης ανοσίας δεν έχει αναπτυχθεί επαρκώς, ενώ οι έμφυτες ανοσολογικές αποκρίσεις παραμένουν μερικώς εκπαιδευμένες και ανεπαρκείς, σε σχέση με αυτές των ενήλικων οργανισμών. Καθώς οι μοριακοί και κυτταρικοί μηχανισμοί άμυνας της νεογνικής έμφυτης ανοσίας δεν είναι επαρκώς χαρακτηρισμένοι, η σε βάθος κατανόηση τους είναι απαραίτητη για το σχεδιασμό νέων στοχευμένων και αποτελεσματικών θεραπευτικών προσεγγίσεων έναντι της νεογνικής σήψης. Η πρωτεΐνη DEL-1 είναι ένα μόριο με χαρακτηριστικές ανοσοτροποποιητικές και αντιφλεγμονώδεις ιδιότητες, που διαδραματίζει σημαντικό ρόλο στη παθολογία φλεγμονωδών νόσων. Χρησιμοποιώντας αγρίου τύπου (WT) υγιή και σηπτικά, νεογνά και ενήλικα ποντίκια παρατηρήσαμε ότι έκφραση αυτού του παράγοντα είναι συστημικά αυξημένη στα νεογνά σε σχέση με τα ενήλικα ποντίκια, ενώ παρουσία σήψης αυξήθηκαν ακόμη περισσότερο σε αντίθεση με τα επίπεδα των σηπτικών ενήλικων ποντικών. Προκειμένου να διερευνήσουμε το ρόλο της πρωτεΐνης DEL-1 στο πλαίσιο της νεογνικής σήψης, χρησιμοποιήσαμε νεογνά WT και DEL-1 -/- γονοτύπου τα οποία υποβάλαμε σε πολυμικροβιακή σήψη. Παρατηρήσαμε ότι τα DEL-1 -/- νεογνά ποντίκια παρουσίασαν έντονη ουδετεροπενία, οξυμένη βακτηριαιμία και σημαντικά μειωμένη επιβίωση στη σήψη, συμπτώματα τα οποία αναστράφηκαν έπειτα από τη χορήγηση εξωγενούς DEL-1. Η βάση αυτών των συμπτωμάτων βρίσκεται στο μειωμένο αριθμό των μυελικών αιμοποιητικών βλαστοκυττάρων και των πρόγονων ουδετερόφιλων στο μυελό των οστών των σηπτικών DEL-1 -/- νεογνών, αναδεικνύοντας τη σημασία της πρωτεΐνης DEL-1 ως αναπόσπαστο συστατικό του νεογνικού μυελού που διαμεσολαβεί τις προστατευτικές του ιδιότητες, στηρίζοντας την επείγουσα μυελοποίηση. Επιπλέον αναδεικνύουμε ότι η αυξημένη ιστική παραγωγή της DEL-1 στα σηπτικά νεογνά αποδίδεται στην αυξημένη αναλογία IL-10/IL-17A κυτταροκινών. Συγκεκριμένα, δείχνουμε ότι η κυτταροκίνη IL-10 ρυθμίζει θετικά την DEL-1, καθώς η παρεμπόδιση του σηματοδοτικού μονοπατιού της IL-10 μείωσε τόσο την έκφραση όσο και τις ευεργετικές δράσεις της DEL-1. Σε συμφωνία με τα δεδομένα μας από τα πειραματικά μας μοντέλα, τόσο η DEL-1 όσο και ο αριθμός των κυκλοφορόντων ουδετερόφιλων είναι αυξημένα στους σηπτικούς ασθενείς που χαρακτηρίζονται από υψηλή αναλογία IL-10/IL-17A. Επιπλέον, οι σηπτικοί ασθενείς με υψηλότερα επίπεδα DEL-1 παρουσιάζουν καλύτερη επιβίωση σε σχέση με τους ασθενείς με χαμηλά επίπεδα DEL-1. Συμπερασματικά, σε αυτή τη μελέτη αναδεικνύουμε του σηματοδοτικού άξονα IL-10–DEL-1 στη διατήρηση των αποθεμάτων ουδετερόφιλων στο μυελό των οστών, τα οποία είναι ανεπαρκή κατά τη νεογνική ηλικία, στηρίζοντας την επείγουσα μυελοποίηση και την επιβίωση των σηπτικών νεογνών. Έπειτα μελετήσαμε το ρόλο των ενήλικων και των νεογνικών μακροφάγων στην λοίμωξη με το Στρεπτόκοκκο Βήτα Ομάδας (GBS). Ο GBS είναι ένα ευκαιριακό παθογόνο για τους υγιείς ενήλικες οργανισμούς, όμως για τα νεογνά και να νεαρά βρέφη αποτελεί μία από τις κύριες αιτίες σήψης και μηνιγγίτιδας παγκοσμίως. Για να διερευνήσουμε τους μοριακούς μηχανισμούς άμυνας των μακροφάγων έναντι του GBS χρησιμοποιήσαμε περιτοναϊκά μακροφάγα από νεογνά και ενήλικα ποντίκια τα οποία στη συνέχεια μολύναμε με GBS. Σε αντίθεση με τα μακροφάγα των ενηλίκων, η λοίμωξη του GBS στα νεογνικά μακροφάγα οδήγησε σε αύξηση του ενδοκυττάριου βακτηριακού φορτίου, μεγαλύτερη κυτταροπλασματική διαφυγή των βακτηρίων και μειωμένη στόχευσή τους στα λυσοσώματα για καταστροφή. Με τη χρήση συνεστιακής μικροσκοπίας και μίας σειράς μορίων siRNA, αποδείξαμε ότι ο μηχανισμός της LC3 εξαρτώμενης φαγοκυττάρωσης (LAP) είναι ο βασικός διαμεσολαβητής της βακτηριοκτόνου δράσης των ενήλικων μακροφάγων κυττάρων έναντι του GBS. Ωστόσο, στα νεογνικά μακροφάγα ο μηχανισμός αυτός είναι μη λειτουργικός όπως καταδεικνύεται από τον μειωμένο συν εντοπισμό του GBS με την LC3. Κατά τη μόλυνσή τους με GBS τα νεογνικά μακροφάγα αποκτούν ένα διακριτό μεταβολικό και φλεγμονώδες προφίλ, το οποίο παρουσιάζει προφλεγμονώδη και αντιφλεγμονώδη χαρακτηριστικά. Σύμφωνα με τα αποτελέσματα της RNA-seq ανάλυσης, έπειτα από τη διέγερσή τους με τον GBS τα νεογνικά μακροφάγα παρουσιάζουν υπέρμετρη παραγωγή της κυτταροκίνης IL-6, η οποία έχει ανασταλτική δράση στο μονοπάτι της LAP. Πράγματι, η χορήγηση εξωγενούς IL-6 σε ενήλικα μακροφάγα κύτταρα, παρεμποδίζει τη βακτηριοκτόνο δράση τους. Αντιθέτως η στόχευση της IL-6 ή πιο συγκεκριμένα του trans σηματοδοτικού της μονοπατιού, ενισχύει την αντιβακτηριακή δραστηριότητα των νεογνικών μακροφάγων έναντι του GBS μέσω του μηχανισμού της LAP. Ομοίως, η παρεμπόδιση των κάτωθεν σηματοδοτικών μορίων της IL-6, JAK1/2 και STAT-3, μείωσε σημαντικά το ενδοκυττάριο βακτηριακό φορτίο και τη κυτταροπλασματική διαφυγή του GBS στα νεογνικά μακροφάγα, ενισχύοντας παράλληλα τον συν-εντοπισμό των ενδοκυττάριων βακτηρίων με την πρωτεΐνη LC3. Σε συμφωνία με τα μέχρι τώρα δεδομένα μας από το πειραματικό μοντέλο των ποντικών, η χημική αναστολή του IL-6R με τον παράγοντα Tocilizumab στα μακροφάγα ομφάλιου λώρου, βελτιώνει την ικανότητα τους να καταπολεμήσουν τον GBS. Τέλος, σε αυτή τη μελέτη παραθέτουμε στοιχεία ότι η στόχευση του σηματοδοτικού άξονα της IL-6 έχει τη δυνατότητα να παρατείνει την επιβίωση των μολυσμένων με GBS νεογνών ποντικών. Για το λόγο αυτό, η χορήγηση ανοσοτροποποιητικών θεραπειών που θα στοχεύσουν συγκεκριμένα τον άξονα IL-6/JAK1&2/STAT-3 θα μπορούσε να προστατεύσει τα νεογνά ενάντια λοιμώξεων από τον GBS, ενισχύοντας τους ενδοκυττάριους μηχανισμούς άμυνας των μακροφάγων έναντι των οπορτουνιστικών παθογόνων. Τα ευρήματα της παρούσας μελέτης θα μπορούσαν μελλοντικά να οδηγήσουν στην ανάπτυξη στοχευμένων θεραπευτικών προσεγγίσεων που θα συνεισφέρουν στη πρόγνωση και θεραπεία της νεογνικής σήψης που παραμένει πενιχρή

Fish Sidestream-Derived Protein Hydrolysates Suppress DSS-Induced Colitis by Modulating Intestinal Inflammation in Mice

publishedVersio

Data_Sheet_1_Nicotinamide enhances myelin production after demyelination through reduction of astrogliosis and microgliosis.docx

Caloric restriction is the chronic reduction of total caloric intake without malnutrition and has attracted a lot of attention as, among multiple other effects, it attenuates demyelination and stimulates remyelination. In this study we have evaluated the effect of nicotinamide (NAM), a well-known caloric restriction mimetic, on myelin production upon demyelinating conditions. NAM is the derivative of nicotinic acid (vitamin B3) and a precursor of nicotinamide adenine dinucleotide (NAD+), a ubiquitous metabolic cofactor. Here, we use cortical slices ex vivo subjected to demyelination or cultured upon normal conditions, a lysolecithin (LPC)-induced focal demyelination mouse model as well as primary glial cultures. Our data show that NAM enhances both myelination and remyelination ex vivo, while it also induces myelin production after LPC-induced focal demyelination ex vivo and in vivo. The increased myelin production is accompanied by reduction in both astrogliosis and microgliosis in vivo. There is no direct effect of NAM on the oligodendrocyte lineage, as no differences are observed in oligodendrocyte precursor cell proliferation or differentiation or in the number of mature oligodendrocytes. On the other hand, NAM affects both microglia and astrocytes as it decreases the population of M1-activated microglia, while reducing the pro-inflammatory phenotype of astrocytes as assayed by the reduction of TNF-α. Overall, we show that the increased myelin production that follows NAM treatment in vivo is accompanied by a decrease in both astrocyte and microglia accumulation at the lesion site. Our data indicate that NAM influences astrocytes and microglia directly, in favor of the remyelination process by promoting a less inflammatory environment.</p

Secondary Metabolites with Anti-Inflammatory Activity from <i>Laurencia majuscula</i> Collected in the Red Sea

The chemical investigation of the organic extract of the red alga Laurencia majuscula collected from Hurghada reef in the Red Sea resulted in the isolation of five C15 acetogenins, including four tricyclic ones of the maneonene type (1–4) and a 5-membered one (5), 15 sesquiterpenes, including seven lauranes (6–12), one cuparane (13), one seco-laurane (14), one snyderane (15), two chamigranes (16, 17), two rearranged chamigranes (18, 19) and one aristolane (20), as well as a tricyclic diterpene (21) and a chlorinated fatty acid derivative (22). Among them, compounds 1–3, 5, 7, 8, 10, 11 and 14 are new natural products. The structures and the relative configurations of the isolated natural products have been established based on extensive analysis of their NMR and MS data, while the absolute configuration of maneonenes F (1) and G (2) was determined on the basis of single-crystal X-ray diffraction analysis. The anti-inflammatory activity of compounds 1, 2, 4–8, 10, 12–16, 18 and 20–22 was evaluated by measuring suppression of nitric oxide (NO) release in TLR4-activated RAW 264.7 macrophages in culture. All compounds, except 6, exhibited significant anti-inflammatory activity. Among them, metabolites 1, 4 and 18 did not exhibit any cytostatic activity at the tested concentrations. The most prominent anti-inflammatory activity, accompanied by absence of cytostatic activity at the same concentration, was exerted by compounds 5 and 18, with IC50 values of 3.69 μM and 3.55 μΜ, respectively

Secondary Metabolites with Anti-Inflammatory Activity from Laurencia majuscula Collected in the Red Sea

The chemical investigation of the organic extract of the red alga Laurencia majuscula collected from Hurghada reef in the Red Sea resulted in the isolation of five C15 acetogenins, including four tricyclic ones of the maneonene type (1&ndash;4) and a 5-membered one (5), 15 sesquiterpenes, including seven lauranes (6&ndash;12), one cuparane (13), one seco-laurane (14), one snyderane (15), two chamigranes (16, 17), two rearranged chamigranes (18, 19) and one aristolane (20), as well as a tricyclic diterpene (21) and a chlorinated fatty acid derivative (22). Among them, compounds 1&ndash;3, 5, 7, 8, 10, 11 and 14 are new natural products. The structures and the relative configurations of the isolated natural products have been established based on extensive analysis of their NMR and MS data, while the absolute configuration of maneonenes F (1) and G (2) was determined on the basis of single-crystal X-ray diffraction analysis. The anti-inflammatory activity of compounds 1, 2, 4&ndash;8, 10, 12&ndash;16, 18 and 20&ndash;22 was evaluated by measuring suppression of nitric oxide (NO) release in TLR4-activated RAW 264.7 macrophages in culture. All compounds, except 6, exhibited significant anti-inflammatory activity. Among them, metabolites 1, 4 and 18 did not exhibit any cytostatic activity at the tested concentrations. The most prominent anti-inflammatory activity, accompanied by absence of cytostatic activity at the same concentration, was exerted by compounds 5 and 18, with IC50 values of 3.69 &mu;M and 3.55 &mu;&Mu;, respectively

Fish-Derived Protein Hydrolysates Increase Insulin Sensitivity and Alter Intestinal Microbiome in High-Fat-Induced Obese Mice

Obesity and type 2 diabetes are characterized by low-grade systemic inflammation and glucose intolerance, which can be partially controlled with nutritional interventions. Protein-containing nutritional supplements possess health-promoting benefits. Herein, we examined the effect of dietary supplementation with protein hydrolysates derived from fish sidestreams on obesity and diabetes, utilizing a mouse model of High-Fat Diet-induced obesity and type 2 diabetes. We examined the effect of protein hydrolysates from salmon and mackerel backbone (HSB and HMB, respectively), salmon and mackerel heads (HSH and HMH, respectively), and fish collagen. The results showed that none of the dietary supplements affected weight gain, but HSH partially suppressed glucose intolerance, while HMB and HMH suppressed leptin increase in the adipose tissue. We further analyzed the gut microbiome, which contributes to the metabolic disease implicated in the development of type 2 diabetes, and found that supplementation with selected protein hydrolysates resulted in distinct changes in gut microbiome composition. The most prominent changes occurred when the diet was supplemented with fish collagen since it increased the abundance of beneficial bacteria and restricted the presence of harmful ones. Overall, the results suggest that protein hydrolysates derived from fish sidestreams can be utilized as dietary supplements with significant health benefits in the context of type 2 diabetes and diet-induced changes in the gut microbiome

An IL-10/DEL-1 axis supports granulopoiesis and survival from sepsis in early life

Abstract The limited reserves of neutrophils are implicated in the susceptibility to infection in neonates, however the regulation of neutrophil kinetics in infections in early life remains poorly understood. Here we show that the developmental endothelial locus (DEL-1) is elevated in neonates and is critical for survival from neonatal polymicrobial sepsis, by supporting emergency granulopoiesis. Septic DEL-1 deficient neonate mice display low numbers of myeloid-biased multipotent and granulocyte-macrophage progenitors in the bone marrow, resulting in neutropenia, exaggerated bacteremia, and increased mortality; defects that are rescued by DEL-1 administration. A high IL-10/IL-17A ratio, observed in newborn sepsis, sustains tissue DEL-1 expression, as IL-10 upregulates while IL-17 downregulates DEL-1. Consistently, serum DEL-1 and blood neutrophils are elevated in septic adult and neonate patients with high serum IL-10/IL-17A ratio, and mortality is lower in septic patients with high serum DEL-1. Therefore, IL-10/DEL-1 axis supports emergency granulopoiesis, prevents neutropenia and promotes sepsis survival in early life