13 research outputs found

    Immunomodulatory effects of resveratrol on human intestinal mast cell signaling in vitro and mast cell associated enteritis and colitis in mice

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    By releasing their pre-stored or de novo synthesized mediators, mast cells (MC) are important immunoregulatory cells responsible for a variety of inflammatory reactions. Although known to be major effector cells in immunoglobuline (Ig) E dependent allergic reactions, MC have been widely shown to play a role in various inflammations of the gut. Diseases of the gastrointestinal tract (GIT) are widespread and multicausal. Those affected suffer from the sometimes severe symptoms and may experience restrictions on their daily life. Even if conventional medication is applied routinely, aim of the past and current research is to establish supportive and/or alternative medication that is based on natural substances. These may be on the basis of small natural components like resveratrol, a stilbene mostly found in grapes. Numerous positive properties are attributed to resveratrol. These are anti-inflammatory, anti-cancerogenic, anti-oxidative, as well as neuroprotective effects. The use of substances of natural origin as so-called nutraceuticals can help to increase the acceptance of medication by those affected, but also to reduce and overcome the side effects associated with conventional treatment. Effects of resveratrol were examined on the reactivity of MC isolated from patients tissue undergoing bowel resection. The results of this work show that resveratrol exhibited potent inhibitory effects on high affinity IgE receptor mediated activation of MC, strongly inhibiting not only MC degranulation, but also gene expression of the pro-inflammatory cytokines C-X-C motif chemokine ligand (CXCL) 8, C-C motif chemokine ligand (CCL) 2, CCL3, CCL4 and tumor necrosis factor (TNF-) α. Ultimately, the intracellular signaling cascade triggered during MC activation via IgE receptor leads to mediator release. Following IgE receptor mediated activation, phosphorylation of signaling molecules like extracellular signal-regulated kinase (ERK) 1/2 and signal transducer and activator of transcription (STAT) 3, occurs. ERK1/2 was found to be responsible for phosphorylation of mitochondrial STAT3, which contributes significantly to MC degranulation. Treatment with resveratrol was able to inhibit the phosphorylation of STAT3 by more than 50 % and that of ERK1/2 by almost 100 %. Furthermore, the experiments performed succeeded in isolating the mitochondrial fraction from relatively low human intestinal MC (hiMC) numbers. Also, in this fraction we could detect phosphorylation of STAT3 and ERK1/2 after MC activation, which was reduced after treatment with resveratrol. Having shown the strong inhibitory effects in vitro, we set out to examine immunomodulatory effects of resveratrol in vivo. Presence and activity of MC are closely related to intestinal inflammations in consequence of food allergy (FA) and inflammatory bowel disease (IBD). In mice, FA can be studied using the ovalbumin (OVA)-induced allergic enteritis model and colitis can be studied using the IL-10 knockout (-/-) mice, which develop a spontaneous form of chronic colitis. We could show that the oral application of resveratrol inhibited the increase of MC numbers in the colon and duodenum of affected animals in both experimental settings. Less pronounced but still visible effects of resveratrol administration were observed in the colon with regard to epithelial damage, cell infiltration and reduction of goblet cell numbers. In all cases, based on a scoring system, the damage decreased to the level of the corresponding controls receiving no additive and in which no allergic enteritis was induced or nor colitis developed. Overall, allergic enteritis resulted in a weaker symptomatology, and IL-10-/- animals showed a delayed appearance of the typical symptoms. The results of this thesis show a strong inhibitory effect of resveratrol on hiMC. This could be detected for mediator release as well as on gene expression levels and in the phosphorylation of the signaling molecules ERK1/2 and STAT3, which we could also identify in the mitochondria of hiMC. We observed positive influences on MC-associated parameters in the OVA enteritis and IL-10-/- colitis mouse models. With regard to its use as nutraceutical, resveratrol could therefore come more of a focus in the future.Mastzellen sind wichtige immunregulatorische Zellen, die durch Freisetzung ihrer in den Granula gespeicherten oder der de novo synthetisierten Mediatoren fĂŒr eine Vielzahl von EntzĂŒndungsreaktionen verantwortlich sind. Mastzellen, die in erster Linie als Haupteffektorzellen bei von Immunoglobulin (Ig) E abhĂ€ngigen allergischen Reaktionen bekannt sind, spielen auch bei diversen EntzĂŒndungen des Darmes eine Rolle. Erkrankungen des Gastrointestinaltraktes sind weit verbreitet und multikausal. Betroffene leiden aber immer mit unter der teils stark auftretenden Symptomatik und erfahren EinschrĂ€nkungen im alltĂ€glichen Leben. Auch wenn die herkömmliche Medikation zur Behandlung dieser Störungen routinemĂ€ĂŸig Anwendung findet, ist es Ziel der Wissenschaft, eine unterstĂŒtzende sowie Alternativmedikation zu entwickeln, die auf natĂŒrlichen Ausgangssubstanzen, wie z.B. dem in Trauben vorkommenden Stilben Resveratrol, basiert. Resveratrol werden zahlreiche positive Eigenschaften zugeschrieben. Darunter fallen anti-inflammatorische, anti-kanzerogene, antioxidative, als auch neuroprotektive Eigenschaften. Ein Einsatz von Substanzen natĂŒrlichen Ursprungs als sogenanntes Nutraceutical kann einerseits dazu dienen, die Akzeptanz der Medikation bei Betroffenen zu erhöhen, aber auch, die mit der herkömmlichen Behandlungsmethode verbundenen, Nebenwirkungen zu mindern und zu ĂŒberwinden. Effekte von Resveratrol wurden auf die ReaktivitĂ€t von Mastzellen, isoliert aus humanen intestinalen ResektionsprĂ€paraten (hiMC), geprĂŒft. Die Ergebnisse dieser Arbeit verdeutlichen, dass das Stilben starke inhibitorische Wirkung auf IgE-Rezeptor vermittelte Aktivierung von Mastzellen zeigt und dabei nicht nur die Mastzelldegranulation, sondern auch die Genexpression der pro-inflammatorischen Zytokine C-X-C motif chemokine ligand (CXCL) 8, C-C motif chemokine ligand (CCL) 2, CCL3, CCL4 und tumor necrosis factor (TNF-) α stark hemmt. Die, im Zuge der Mastzellaktivierung via IgE-Rezeptor, ausgelöste intrazellulĂ€re Signalkaskade fĂŒhrt letztlich zur MediatorausschĂŒttung. Im Verlauf der Signalkaskade kommt es zur Phosphorylierung, d.h. der Aktivierung der SignalmolekĂŒle extracellular signal-regulated kinase (ERK) 1/2 und signal transducer and activator of transcription (STAT) 3. Dabei ist ERK1/2 fĂŒr die Phosphorylierung von mitochondrialem STAT3 verantwortlich, welches maßgeblich zur Mastzelldegranulation beitrĂ€gt. Die Behandlung mit Resveratrol fĂŒhrte dabei zur Hemmung der Phosphorylierung von STAT3 um mehr als 50 %, sowie die von ERK1/2 um fast 100 %. Des Weiteren gelang es uns, die mitochondriale Fraktion aus relativ geringen Mengen humaner intestinaler Mastzellen (hiMC) zu isolieren. Auch in dieser Fraktion konnten wir die Phosphorylierung von ERK1/2 und STAT3 nach Mastzellaktivierung detektieren, die nach einer Behandlung mit Resveratrol ebenfalls verringert war. Nachdem die stark hemmende Wirkung von Resveratrol in vitro gezeigt wurde, sollten die immunmodulatorischen Wirkungen auch in vivo ĂŒberprĂŒft werden. Das Vorhandensein und die AktivitĂ€t von MC stehen in engem Zusammenhang mit EntzĂŒndungen des Darms als Ursache von Nahrungsmittelallergien sowie chronisch-entzĂŒndlicher Darmerkrankungen (CED). Im Mausmodell kann man Nahrungsmittelallergie mit Hilfe einer Ovalbumin (OVA)-induzierten allergischen Enteritis und CED mit Hilfe der IL-10 knockout (-/-) Maus, bei der es zu einer spontan auftretenden chronischen Colitis kommt, experimentell untersuchen. Wir konnten zeigen, dass die orale Gabe von Resveratrol bei betroffenen Tieren im Allergiemodell (OVA) als auch im Modell der murinen Colitis (IL-10-/-) zu einer Hemmung des Anstiegs der Mastzellanzahl im Gewebe von Colon und Duodenum betroffener Tiere fĂŒhrte. Weniger stark ausgeprĂ€gte, aber dennoch sichtbare Effekte bei einer Resveratrol-Gabe konnten im Colon im Hinblick auf EpithelschĂ€digung und bei der IL-10-/- Colitis auch im Hinblick auf Zellinfiltration sowie Reduktion der Anzahl an Gobletzellen beobachtet werden. In allen FĂ€llen verringerten sich die SchĂ€digungen auf das Level der jeweiligen Kontrolltiere ohne allergische Enteritis bzw. Colitis. Insgesamt kam es bei der allergischen Enteritis zu einer schwĂ€cher ausgeprĂ€gten Symptomatik, bei IL-10-/- Tieren kam es insgesamt zu einem verzögerten Auftreten der typischen Symptomatiken. Die Ergebnisse dieser Promotionsarbeit zeigen eine stark inhibitorische Wirkung von Resveratrol auf hiMC. Diese ließen sich sowohl bei der Mediatorfreisetzung als auch auf Genexpressionslevel und in der Phosphorylierung der SignalmolekĂŒle ERK1/2 und STAT3 zeigen, bei denen es gelungen ist, sie auch in den Mitochondrien von hiMC nachzuweisen. Auch im Mausmodell bei der Untersuchung einer allergisch induzierten Enteritis sowie einer murinen Colitis aufgrund eines IL-10-/- konnten wir positive EinflĂŒsse auf Mastzell-assoziierte Parameter beobachten. Im Hinblick auf die Verwendung als Nutraceutical könnte Resveratrol deshalb zukĂŒnftig mehr in den Fokus rĂŒcken

    A novel splice variant of the protein tyrosine phosphatase PTPRJ that encodes for a soluble protein involved in angiogenesis

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    PTPRJ is a receptor protein tyrosine phosphatase with tumor suppressor activity. Very little is known about the role of PTPRJ ectodomain, although recently both physiological and synthetic PTPRJ ligands have been identified. A putative shorter spliced variant, coding for a 539 aa protein corresponding to the extracellular N-terminus of PTPRJ, is reported in several databases but, currently, no further information is available. Here, we confirmed that the PTPRJ short isoform (named sPTPRJ) is a soluble protein secreted into the supernatant of both endothelial and tumor cells. Like PTPRJ, also sPTPRJ undergoes post-translational modifications such as glycosylation, as assessed by sPTPRJ immunoprecipitation. To characterize its functional activity, we performed an endothelial cell tube formation assay and a wound healing assay on HUVEC cells overexpressing sPTPRJ and we found that sPTPRJ has a proangiogenic activity. We also showed that sPTPRJ expression down-regulates endothelial adhesion molecules, that is a hallmark of proangiogenic activity. Moreover, sPTPRJ mRNA levels in human high-grade glioma, one of the most angiogenic tumors, are higher in tumor samples compared to controls. Further studies will be helpful not only to clarify the way sPTPRJ works but also to supply clues to circumvent its activity in cancer therapy

    Resveratrol Treatment Prevents Increase of Mast Cells in Both Murine OVA Enteritis and IL-10−/− Colitis

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    Mast cells are involved in allergic and other inflammatory diseases. The polyphenol resveratrol is known for its anti-inflammatory properties and may be used as nutraceutical in mast cell associated diseases. We analyzed the effect of resveratrol on mast cells in vivo in ovalbumin-induced allergic enteritis as well as experimental colitis in IL-10−/− mice which received resveratrol via drinking water. Treatment with resveratrol prevented the increase in mast cells in both allergic enteritis and chronic colitis in duodenum as well as in colon. Further, it delayed the onset of diseases symptoms and ameliorated diseases associated parameters such as tissue damage as well as inflammatory cell infiltration in affected colon sections. In addition to the findings in vivo, resveratrol inhibited IgE-dependent degranulation and expression of pro-inflammatory cytokines such as TNF-α in IgE/DNP-activated as well as in LPS-activated bone marrow-derived mast cells. These results indicate that resveratrol may be considered as an anti-allergic and anti-inflammatory plant-derived component for the prevention or treatment of mast cell-associated disorders of the gastrointestinal tract

    Dimensions and correlates of quality of life according to frailty status: a cross-sectional study on community-dwelling older adults referred to an outpatient geriatric service in Italy

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    BACKGROUND: There is a lack of knowledge concerning the relationship between two closely-linked multidimensional variables: frailty and quality of life (QOL). The aim of this study was to investigate dimensions and correlates of QOL associated with frailty status among community-dwelling older outpatients. METHODS: We conducted a cross-sectional survey of 239 community-dwelling outpatients aged 65+ (mean age 81.5 years) consecutively referred to a geriatric medicine clinic in Italy between June and November 2009. Participants underwent a comprehensive geriatric assessment, including assessment of their frailty status according to the Study of Osteoporotic Fractures (SOF) criteria, and QOL, which was evaluated by using the Older People's QOL (OPQOL) questionnaire. One-way ANOVA and chi-squared tests were used to find correlates of frailty, including QOL dimensions, after stratification of participants in the "robust" (n = 72), "pre-frail" (n = 89) and "frail" (n = 78) groups. Multiple linear regression analyses were performed to find correlates of QOL in the overall sample and among "frail" and "robust" participants. RESULTS: A negative trend of QOL with frailty status was found for almost all dimensions of QOL (health, independence, home and neighbourhood, psychological and emotional well-being, and leisure, activities and religion) except for social relationships and participation and financial circumstances. Independent correlates of a poor QOL in the total sample were "reduced energy level" (SOF criterion for frailty), depressive status, dependence in transferring and bathing abilities and money management (adjusted R squared 0.39); among "frail" participants the associations were with depressive status and younger age, and among "robust" participants the association was with lower body mass index. CONCLUSIONS: Five out of seven dimensions of QOL were negatively affected by frailty, but only one SOF criterion for frailty was independently related to QOL, after correction for age, functional status and depression. A more advanced age as well as a better affective status were correlates of a better QOL among frail elders. Interventions targeting the QOL in frail community-dwelling older outpatients should consider as outcomes, not only health-related QOL, but also other domains of the QOL

    Resveratrol Treatment Prevents Increase of Mast Cells in Both Murine OVA Enteritis and IL-10<sup>−/−</sup> Colitis

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    Mast cells are involved in allergic and other inflammatory diseases. The polyphenol resveratrol is known for its anti-inflammatory properties and may be used as nutraceutical in mast cell associated diseases. We analyzed the effect of resveratrol on mast cells in vivo in ovalbumin-induced allergic enteritis as well as experimental colitis in IL-10−/− mice which received resveratrol via drinking water. Treatment with resveratrol prevented the increase in mast cells in both allergic enteritis and chronic colitis in duodenum as well as in colon. Further, it delayed the onset of diseases symptoms and ameliorated diseases associated parameters such as tissue damage as well as inflammatory cell infiltration in affected colon sections. In addition to the findings in vivo, resveratrol inhibited IgE-dependent degranulation and expression of pro-inflammatory cytokines such as TNF-α in IgE/DNP-activated as well as in LPS-activated bone marrow-derived mast cells. These results indicate that resveratrol may be considered as an anti-allergic and anti-inflammatory plant-derived component for the prevention or treatment of mast cell-associated disorders of the gastrointestinal tract

    Resveratrol Is a Natural Inhibitor of Human Intestinal Mast Cell Activation and Phosphorylation of Mitochondrial ERK1/2 and STAT3

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    Mast cells play a critical role as main effector cells in allergic and other inflammatory diseases. Usage of anti-inflammatory nutraceuticals could be of interest for affected patients. Resveratrol, a natural polyphenol found in red grapes, is known for its positive properties. Here, we analyzed the effects of resveratrol on FcΔRI-mediated activation of mature human mast cells isolated from intestinal tissue (hiMC). Resveratrol inhibited degranulation and expression of cytokines and chemokines such as CXCL8, CCL2, CCL3, CCL4, and TNF-α in a dose-dependent manner. Further, resveratrol inhibited the phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 and signal transducer and activator of transcription (STAT) 3. ERK1/2 is known to be involved in cytokine expression of hiMC and to directly interact with STAT3. Mitochondrial STAT3 is phosphorylated by ERK1/2 and contributes to mast cell degranulation. We were able to isolate mitochondrial fractions from small hiMC numbers and could show that activation of mitochondrial STAT3 and ERK1/2 in hiMC was also inhibited by resveratrol. Our results indicate that resveratrol inhibits hiMC activation by inhibiting the phosphorylation of mitochondrial and nuclear ERK1/2 and STAT3, and it could be considered as an anti-inflammatory nutraceutical in the treatment of mast cell-associated diseases

    A comprehensive evaluation of elderly people discharged from an Emergency Department

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    Elderly people make extensive use of the Emergency Department (ED). After discharge from the ED, these patients are at high risk of short-term adverse outcomes such as functional decline, readmission to the ED, hospitalization and death. We investigated whether a comprehensive geriatric evaluation (CGE) and follow-up of the elderly discharged from the ED can provide them with better diagnosis and treatment, and thus reduce adverse outcomes. Out of 423 elderly patients over 75 years of age discharged from an ED we evaluated 222 of them. The patients were evaluated and treated, based on testing for physical, functional, cognitive and emotional status. A comparison was made between scale scores at baseline and 3 months later. We observed a significant improvement in physical and emotional status in all the studied patients, a significant improvement in behavioural status in the elderly patients with cognitive dysfunction, and a reduction of distress in the caregivers of the elderly patients with cognitive dysfunction and behavioural disturbances. We also found that the rate of ED readmission or hospitalization was lower than in the 3 months preceding the CGE. The experience of older patients with the ED system can be greatly improved if their complex needs are given due attention by developing interdisciplinary programs between emergency physicians, geriatricians, and primary care physicians

    Design, Synthesis, Biological Activity, and Structural Analysis of Lactam-Constrained PTPRJ Agonist Peptides

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    PTPRJ is a receptor-like protein tyrosine phosphatase mainly known for its antiproliferative and tumor-suppressive functions. PTPRJ dephosphorylates several growth factors and their receptors, negatively regulating cell proliferation and migration. We recently identified a disulfide-bridged nonapeptide, named PTPRJ-19 (H-[Cys-His-His-Asn-Leu-Thr-His-Ala-Cys]-OH), which activates PTPRJ, thereby causing cell growth inhibition and apoptosis of both cancer and endothelial cells. With the aim of replacing the disulfide bridge by a chemically more stable moiety, we have synthesized and tested a series of lactam analogues of PTPRJ-19. This replacement led to analogues with higher activity and greater stability than the parent peptide

    Progetto per il concorso internazionale per il waterfront di La Spezia.

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    Progetto per il concorso internazionale per il waterfront di La Spezia. Progetto: Jose Maria Tomas Llavador, Studio Schiattarella, Aldo Mazzanobile Consulenti: Mario Manfroni (progetto urbano) Christian Rocchi (progetto urbano) Valeria Caramagno (verde) Maria Emanuela Lo Monaco (pr.financing) Exa Engineering (strutture e op.marittime) Patrizia Burlando (paesaggio) Collaboratori: Pilar MartÏ Rodrigo, Paola Schiattarella, Fabrizio Battistelli, Daniela Biavati, Gianluca Bilotta, Gabriele Cossetto, Emidio Di Nicola, Alberto Greti, Ernesto Iacangelo, Sabrina Leone, Carla Maresca, Angela Pizzuti, Alessandra Rapaccini, Alberto Riccioni, Giacomo Sanna, Giorgia Semprini, Vicenç Ferrer
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