Modulazione farmacologica del sistema dell’adenosina nella fisiopatologia dell’infiammazione intestinale

Le normali funzioni gastrointestinali, quali l’attività contrattile e secretiva, risultano alterate in pazienti affetti da malattie infiammatorie intestinali. L’adenosina è fisiologicamente coinvolta nella regolazione di numerosi processi a livello del tratto digerente, ma diverse evidenze sperimentali ne hanno ipotizzato anche un coinvolgimento nella fisiopatologia delle malattie infiammatorie intestinali. Sulla base di queste evidenze, le nostre ricerche sono state indirizzate alla caratterizzazione dell’espressione e del ruolo funzionale dei recettori dell’adenosina nel comparto neuromuscolare del colon umano e del ratto, e alla valutazione degli effetti dell’infiammazione intestinale sull’espressione e sulla funzione di questi recettori in un modello di colite sperimentale. Una parte del programma di ricerca è stata inoltre dedicata alla caratterizzazione dei possibili effetti antinfiammatori derivanti dal blocco dell’attività dell’adenosina deaminasi per mezzo di APP, un nuovo inibitore di questo enzima, in un modello di colite nel ratto. I risultati ottenuti da studi funzionali nel ratto hanno permesso di osservare che: a) la colite si associa ad un aumento dell’espressione dei recettori A2A, b) in presenza di infiammazione intestinale il potenziamento del controllo inibitore esercitato dal recettore A2A può essere attribuito a variazioni della sua espressione; c) il recettore A1 e A2B cooperano nella modulazione diretta del controllo colinergico dell’attività motoria del colon in condizioni normali; d) in presenza di infiammazione è soprattutto il recettore A2A a partecipare al controllo inibitore dell’attività motoria colica attraverso la stimolazione della via nitrergica. I risultati ottenuti nell’uomo sostengono il concetto che: a) l’adenosina partecipa alla regolazione dei circuiti neuromuscolari enterici deputati alla regolazione inibitrice delle risposte contrattili attraverso l’attivazione dei recettori A2A; b) l’attività del recettore A2A si esplica prevalentemente a livello neuronale attraverso la modulazione del sistema nitrergico. Inoltre da una serie di esperimenti è emerso che il trattamento con APP è in grado di contrastare l’infiammazione intestinale con una potenza maggiore rispetto a EHNA (farmaco inibitore di adenosina deaminasi di riferimento), e che le differenze nell’attività anti-infiammatoria di questi farmaci riflettono le loro rispettive potenze nell’inibire in vitro l’attività dell’adenosina deaminasi. L’APP può quindi rappresentare un farmaco di riferimento per lo sviluppo di nuovi inibitori dell’adenosina deaminasi caratterizzati da buoni profili di potenza e selettività. Nell’insieme, queste osservazioni possono costituire una base per l’interpretazione dei meccanismi tramite i quali il sistema dell’adenosina controlla le funzioni neuromotorie enteriche, sia in condizioni fisiologiche che in presenza di patologie infiammatorie intestinali. In particolare, i risultati ottenuti nel modello di colite sperimentale forniscono evidenze originali a sostegno dell’importanza di questo autacoide nella fisiopatologia delle disfunzioni motorie associate ai processi infiammatori enterici, e inoltre evidenziano che la modulazione farmacologica dei livelli di adenosina endogena può rappresentare un possibile bersaglio per lo sviluppo di nuovi farmaci ad attività anti-infiammatoria, utili per contrastare il processo flogistico, e per correggere i disturbi della motilità intestinale caratteristici delle malattie infiammatorie intestinali

Myeloid cells in the tumor microenvironment: Role of adenosine

Adenosine, deriving from ATP released by dying cancer cells and then degradated in the tumor environment by CD39/CD73 enzyme axis, is linked to the generation of an immunosuppressed niche favoring the onset of neoplasia. The effects of adenosine are mediated by four adenosine receptors, named A1, A2A, A2B and A3 that are widely expressed on several immune cell populations. A critical role of this nucleoside is emerging in the modulation of myeloid cell subsets accumulation and functions into tumor microenvironment, providing new insights that might be useful for the development of novel therapeutic approaches aimed to undermine the immune privileged sites where cancer cells grow and proliferate

Pathophysiology of Gastric Ulcer Development and Healing: Molecular Mechanisms and Novel Therapeutic Options

Peptic ulcer disease is one of the most common chronic infections in human population. Despite centuries of study, it still troubles a lot of people, especially in the third world countries, and it can lead to other more serious complications such as cancers or even to death sometimes. This book is a snapshot of the current view of peptic ulcer disease. It includes 5 sections and 25 chapters contributed by researchers from 15 countries spread out in Africa, Asia, Europe, North America and South America. It covers the causes of the disease, epidemiology, pathophysiology, molecular-cellular mechanisms, clinical care, and alternative medicine. Each chapter provides a unique view. The book is not only for professionals, but also suitable for regular readers at all levels

Histochemical Detection of Collagen Fibers by Sirius Red/Fast Green Is More Sensitive than van Gieson or Sirius Red Alone in Normal and Inflamed Rat Colon

Collagen detection in histological sections and its quantitative estimation by computer-aided image analysis represent important procedures to assess tissue localization and distribution of connective fibers. Different histochemical approaches have been proposed to detect and quantify collagen deposition in paraffin slices with different degrees of satisfaction. The present study was performed to compare the qualitative and quantitative efficiency of three histochemical methods available for collagen staining in paraffin sections of colon. van Gieson, Sirius Red and Sirius Red/Fast Green stainings were carried out for collagen detection and quantitative estimation by morphometric image analysis in colonic specimens from normal rats or animals with 2,4-dinitrobenzenesulfonic acid (DNBS) induced colitis. Haematoxylin/eosin staining was carried out to assess tissue morphology and histopathological lesions. Among the three investigated methods, Sirius Red/Fast Green staining allowed to best highlight well-defined red-stained collagen fibers and to obtain the highest quantitative results by morphometric image analysis in both normal and inflamed colon. Collagen fibers, which stood out against the green-stained non-collagen components, could be clearly appreciated, even in their thinner networks, within all layers of normal or inflamed colonic wall. The present study provides evidence that, as compared with Sirius Red alone or van Gieson staining, the Sirius Red/Fast Green method is the most sensitive, in terms of both qualitative and quantitative evaluation of collagen fibers, in paraffin sections of both normal and inflamed colon

InSAR full-resolution analysis of the 2017–2018 M>6 earthquakes in Mexico

Abstract The present study analyzes the sequence of 4 important earthquakes occurred in Mexico from September 2017 to February 2018, exploiting the large availability of InSAR data and analytical models, with a twofold goal: to privede new solutions for seismogenic sources, completely independent from seismological data, and to discuss methodological aspects related to the non-linear and linear inverse problem. We review and update an earlier study, focused on the concept of resolution, showing the level of detail achievable in the investigation of the slip distribution based on geodetic observations, according to data availability, fault locations and event magnitudes. We further give new insights into the relationship between fault resolution and parameter uncertainty, demonstrating that a realistic assessment is strictly related to a proper fault subdivision. We eventually discourage the use of qualitative approaches, such as the checkerboard test, to evaluate the data resolving power and suggest the adoption of quantitative indicators, like the Dirichlet Spread Function, normalized, easy to calculate and mathematically robust

Transanal Minimally Invasive Surgery: A Promising Alternative for Certain Advanced Rectal Cancer Patients

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Alteration of colonic excitatory tachykininergic motility and enteric inflammation following dopaminergic nigrostriatal neurodegeneration

Background: Parkinson's disease (PD) is frequently associated with gastrointestinal (GI) symptoms, including constipation and defecatory dysfunctions. The mechanisms underlying such disorders are still largely unknown, although the occurrence of a bowel inflammatory condition has been hypothesized. This study examined the impact of central dopaminergic degeneration, induced by intranigral injection of 6-hydroxydopamine (6-OHDA), on distal colonic excitatory tachykininergic motility in rats. Methods: Animals were euthanized 4 and 8 weeks after 6-OHDA injection. Tachykininergic contractions, elicited by electrical stimulation or exogenous substance P (SP), were recorded in vitro from longitudinal muscle colonic preparations. SP, tachykininergic NK1 receptor, and glial fibrillary acidic protein (GFAP) expression, as well as the density of eosinophils and mast cells in the colonic wall, were examined by immunohistochemical analysis. Malondialdehyde (MDA, colorimetric assay), TNF, and IL-1 beta (ELISA assay) levels were also examined. The polarization of peritoneal macrophages was evaluated by real-time PCR. Results: In colonic preparations, electrically and SP-evoked tachykininergic contractions were increased in 6-OHDA rats. Immunohistochemistry displayed an increase in SP and GFAP levels in the myenteric plexus, as well as NK1 receptor expression in the colonic muscle layer of 6-OHDA rats. MDA, TNF, and IL-1 beta levels were increased also in colonic tissues from 6-OHDA rats. In 6-OHDA rats, the number of eosinophils and mast cells was increased as compared with control animals, and peritoneal macrophages polarized towards a pro-inflammatory phenotype. Conclusions: The results indicate that the induction of central nigrostriatal dopaminergic degeneration is followed by bowel inflammation associated with increased oxidative stress, increase in pro-inflammatory cytokine levels, activation of enteric glia and inflammatory cells, and enhancement of colonic excitatory tachykininergic motility

Enteric dysfunctions in experimental Parkinson's disease: alterations of excitatory cholinergic neurotransmission regulating colonic motility in rats

Parkinson's disease (PD) is frequently associated with gastrointestinal symptoms, mostly represented by constipation and defecatory dysfunctions. This study examined the impact of central dopaminergic denervation, induced by injection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle, on distal colonic excitatory cholinergic neuromotor activity in rats. Animals were euthanized 4 and 8 weeks after 6-OHDA injection. In vivo colonic transit was evaluated by radiological assay. Electrically and carbachol-induced cholinergic contractions were recorded in vitro from longitudinal and circular muscle colonic preparations, while acetylcholine levels were assayed in their incubation media. Choline acetyltransferase (ChAT), HuC/D (pan-neuronal marker), muscarinic M2 and M3 receptors. As compared with control rats, at week 4 6-OHDA-treated animals displayed the following changes: decreased in vivo colonic transit rate; impaired electrically evoked neurogenic cholinergic contractions; enhanced carbachol-induced contractions; decreased basal and electrically stimulated acetylcholine release from colonic tissues; decreased ChAT immunopositivity in the neuromuscular layer; unchanged density of HuC/D immunoreactive myenteric neurons; increased expression of colonic muscarinic M2 and M3 receptors. The majority of such alterations were detected also at week 8 post-6-OHDA injection. These findings indicate that central nigrostriatal dopaminergic denervation is associated with an impaired excitatory neurotransmission characterized by a loss of myenteric neuronal ChAT positivity and decrease in acetylcholine release, resulting in a dysregulated smooth muscle motor activity, which likely contributes to the concomitant decrease in colonic transit rate

The natural history of multiple osteochondromas in a large Italian cohort of pediatric patients.

Abstract Importance Multiple osteochondromas is a rare hereditary skeletal disorder, characterized by bony protrusions arising from growth plates on long bones during skeletal development. The disorder frequently leads to diminished stature, deformities and functional limitations. Understanding of the natural history of multiple osteochondromas and its evolution in children and adolescents is limited. Objective To provide valuable information on the natural history of multiple osteochondromas, to inform recommendations for treatment and prevent impairments caused by osteochondromas. Design This retrospective cohort study in children with multiple osteochondromas includes longitudinal data collected from first to last follow-up visit for patient demographics, and over 36 months for disease evolution. Setting Data were collected from the Registry of Multiple Osteochondromas, which includes data from circa 1200 patients with multiple osteochondromas treated from 2003 to 2017 at IRCCS Istituto Ortopedico Rizzoli in Bologna. Participants Patients ≤18 years with multiple osteochondromas, who provided written informed consent and had data for ≥1 12-month follow-up visit. Main outcome(s) and measurement(s) Demographics, clinical features, incidence of surgeries, and disease evolution (progression or regression) were assessed. Results were summarized using descriptive statistics, annual rates of new clinical features and surgeries, and Kaplan-Meier estimates. Patient height was evaluated following Italian growth charts. Results 158 patients were included in these analyses. Throughout follow-up, 80.4% of patients developed new osteochondromas, 57.6% developed new deformities, 23.4% developed new functional limitation(s). New osteochondroma(s) were developed by 28.5% patients by Month 12, 39.9% at Month 24, 50% at Month 36. Most new osteochondromas were detected in the younger population; patients aged 0–4 years underwent a significantly higher number of lesions within 12, 24 and 36 months of follow-up. The overall incidence of patients with ≥1 new deformity within 12 months was 17.7%, with incidences decreasing with increasing age (p = .023). In addition, the analyses on height highlight that 13 years is a cut off age for slow growth of the stature (p  Conclusions and relevance This natural history study reports the main set of clinically relevant data for patients with multiple osteochondromas during skeletal development, providing insight for patient management and development of therapeutic interventions

"Cecal Resection with Bipolar Sealing in a Rat Model": A Promising Approach for Future Human Studies.

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