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Espressione e attività del recettore nicotinico α7nAchR in macrofagi intestinali di pazienti con malattie infiammatorie croniche intestinali ed in modelli murini di neuropatie del sistema nervoso enterico
Get PDFThe α7 nicotinic receptor is involved in the cholinergic anti-inflammatory pathway, the mechanism through which the nervous system influences leukocytes inflammatory responses. Vagus nerve releases the neurotransmitter acetylcholine which binds to the α7 nicotinic receptors on the surface of macrophages inhibiting pro-inflammatory mediators release, such as TNFα and ILβ.
Intestinal Bowel diseases (IBD), which comprise Crohnâs disease (CD) and ulcerative colitis (UC), are chronic immune mediated diseases characterized by a deregulated immune response to commensal flora in a genetically susceptible host. Epidemiologic studies revealed the dual effect of smoke on IBD patients: smoke ameliorates CU, by suppressing macrophages and lymphocytes activity, but worsen the symptoms and the histologic damage in CD patients.
This thesis aimed to study the mechanism underlying the nicotine anti-inflammatory effect on CU patients (but not in CD patients), verifying the hypothesis that different expression levels of nicotinic receptor in IBD patients are responsible for its antithetic effects on diseases progress. Our main purpose was to verify first nicotinic receptor levels on mucosal macrophages during inflammation, and consequently whether macrophagesâ sensibility to the anti-inflammatory pathway, could be influenced by the integrity of the enteric nervous system (ENS).
Expression levels and functionality of α7nAchR in UC and CD patients in clinical remission or mild activity was compared to control subjects (HV, healthy volunteers or patients in screening for colonic cancer) in peripheral blood-derived macrophages and intestinal macrophages isolated from colon-sigma biopsies. In blood-derived macrophages α7nAchR levels were comparable between the three groups both at mRNA, quantified by Real Time-PCR, and protein, quantified by α-bungarotoxin-Alexa Fluor 488 binding, levels. On the contrary, the nicotinic receptors were more expressed in intestinal mucosal macrophages in UC patients than in healthy subjects and CD patients. Moreover, nicotine, the exogenous ligand of α7nAchR, significantly reduced LPS-induced TNFα synthesis in mucosal macrophages from UC but not MC and HV.
To determine the mechanism responsible for the altered expression of α7nAchR in CD patients, we studied the cholinergic anti-inflammatory pathway in murine models of ENS neuropathy, since structural and functional damages in enteric neurons is well established in IBD patients. Our neuropathy models comprise TLR2 deficient mice (TLR2-/-) and mice infected by Herpes Simplex Virus type-1 (HSV-1). We quantified α7nAchR expression and inflammatory activation markers (F4/80 and caspase-1 activation) of intestinal macrophages in basal conditions and during early and late phases of experimental colitis induced by DSS. Mucosal macrophages showed no significant differences in α7nAchR expression in WT and TLR2-/- mice, while HSV-1 induced neuropathy caused a significant increase of α7nAchR levels. However, after three days of DSS administration, a significant increase of α7nAchR occurred in WT mice, but not in mice with enteric neuropathy. In parallel, in mucosal macrophages of WT mice, but not in mice with ENS neuropathy, we observed the activation of caspase-1 and surface F4/80 overexpression. Moreover, only in WT mice, nicotine reduced caspase-1 activation induced by LPS+ATP in mucosal macrophages. Furthermore, in vivo nicotine administration reduced the gravity of colitis in WT mice, but was ineffective in TLR2-/- mice. Finally, by correcting the integrity of ENS of TLR2-/- mice by administration in vivo of glial-derived neurotrophic factor (GDNF), caspase-1 activation in mucosal macrophages during colitis was normalized.
All together our data suggest that for the cholinergic anti-inflammatory pathway to have an optimal action, it is required an increased expression of α7nAchR in mucosal macrophages in response to an inflammatory stimulus. Lack of α7nAchR up-regulation in mucosal macrophages, such as in MC patients, causes the loss of nicotine anti-inflammatory effects. The presence of a neuropathy might contribute to the inadequate expression of α7nAchR in mucosal macrophages during inflammatory processes, thus paving the way to amplified mucosal damage. Mediators that directly regulate α7nAchR expression in mucosal macrophages are now under investigation
Adaptive immune responses triggered by herpes simplex virus type 1 cause enteric nervous system dysfunction
No full textDiet-induced obesity alters nerochemical code in enteric glial cells and injures enteric plexuses causing intestinal dysfunctions
No full textObjective: Alterations in intestinal motility and in gut mucosal barrier function, two gastrointestinal activities coordinated by the enteric nervous system (ENS), take place in metabolic syndrome. Since derangements
in the ENS have not been evaluated in obese subjects, iin this study we investigated the structural and neurochemical alterations in the enteric plexus during dietinduced obesity. Methods: Male C57Bl/6 mice received either regular
chow diet (RCD) or high fat diet (HFD) for 9 weeks.
Enteric plexus architecture was investigated by
immuno-fluorescence on ileal whole mount preparations.
Trans-mucosal resistance and neuromuscular
contractility of isolated ileal segments were evaluated
by Ussing’s chambers and pharmacological/electrical
(EFS) stimulation, respectively. Neurochemical code
was studied by quantitative RT-PCR in longitudinal
muscle myenteric plexus preparations and in cultured
enteric glial cells. Results: At the seventh week of diet, mice receiving HFD registered a significant increase in body weight gain and altered glucose tolerance test as compared to mice fed on RCD. HFD administration drastically reduced peripherin and HuC/D expression in the enteric neurons, affecting both neuronal nitric oxide synthase and Chat expression in myenteric and submucosal plexuses. Intestinal mucosal resistance decreased early during HFD administration (P = 0.01 vs RCD at 4 weeks). EFS-induced ileal contractility was significantly reduced at 6 weeks on HFD in a neuronally-mediated manner since contractions were completely abolished by TTX (1 microM). On the second week of HFD, the levels of glia-derived neurotrophic factor (GDNF) mRNA transcript were significantly reduced as compared to RCD fed animals. In cultured enteric glial cells interleukin 6 (10 ng mL)1) and stearic acid (20 micromol) significantly reduced GDNF levels. Conclusion: In summary following HFD administration, changes in ENS integrity and function develop before the occurrence of the metabolic syndrome. We speculate that dietary fatty acids and inflammatory soluble factors alter the neurochemical code in enteric glial cells driving the ENS neuroplasticity in obesity
HSV-1 infection of enteric nervous system evokes inflammation-mediated myenteric plexus injury.
No full textObjective: Enteric neuropathies are characterized by marked infiltration of neutrophils and cytotoxic lymphocytes into the myenteric plexus. We previously reported that Herpes simplex virus (HSV)-1 infection of the enteric nervous system (ENS) results in neuro-dysfunction and gastrointestinal dysmotility. Since the mechanisms of neuronal injury remain unclear, in the present study we investigated whether innate and/or acquired immune responses against HSV-1 harm neuronal functional integrity. Methods: Adult C57Bl/6 mice were intranasally inoculated with HSV-1, after 4 weeks (W) intragastrically (IG), and sacrificed 1–8 W post IG. Molecular analysis was performed to ascertain viral transcripts in longitudinal muscle myenteric plexus (LMMP). Immune cells isolated from mucosa and LMMP were characterized using fluorescent activated flow cytometry (FACS). Muscular contractility and gut motility were evaluated by electric field stimulation (EFS) of isolated ileal segments and gastrointestinal transit, respectively. ENS integrity was assessed by immunofluorescence on LMMP whole mount preparations for peripherin expression. Results: In the ENS of infected mice, HSV-1 latencyassociated transcripts (LATs) correlated with the infiltration of activated macrophages (CD11b+CD49d+F4/80+ cells) and CD4+CD25+Foxp3+ regulatory T cells at 2 and 6 W post IG viral inoculum. Abortive viral replication was associated to HSV-1 reactive CD3+CD8+IFNgamma+ lymphocytes at 8 W post IG. EFS-evoked contractions were reduced at 2 W post infection but increased at 8 W. Intestinal transit time was reduced only at 8 W post IG infection as compared to sham infected animals. In myenteric plexus, peripherin expression augmented during the early time of infection but resulted highly fragmented at 8 W. Administration of anti-serum anti-CD8 at 6 W post IG infection ameliorated intestinal contractility in mice sacrificed at 8 W. Conclusion: In the ENS, HSV-1 infection triggers innate and acquired immune responses in a timedependent fashion. Thus, following neurotropic viral infection the recruitment of different immune-competent cellular populations into the myenteric plexus may account for the time-dependent neuronal damage and intestinal dismotility during enteric neuropathies
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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