S100B and PGE2: key enteric glial-derived signalling molecules in the gut pathophysiology

The present research is focused on providing new insights in the pathophysiological functions of enteric glia identifying novel molecular target for the intervention of gastrointestinal disorders. Specifically, we focused on the role of two different glial mediators: S100B and PGE2. S100B is a calciumbinding protein physiologically release by EGCs acting as neurotrophic factor. An aberrant production of S100B represents a key step in several intestinal diseases, including ulcerative colitis, celiac diseases and melanoma. However, evidences about the implication of S100B in colon cancer outcome are still missing. On the other hand, PGE2 is a bioactive lipid belonging to prostanoid family exhibiting different actions in intestinal inflammation, tissue repair as well as colon cancer. Although the involvement of PGE2 in the homeostasis and pathological conditions of gastrointestinal tract is well established, any investigations about PGE2 as glial mediator have been reported yet. In this scenario, the present study aimed to: i) elucidate the role of S100B in ex vivo culture of human colorectal cancer; ii) evaluate the impact of glial-derived PGE2 on intestinal functions in both physiological and pathological conditions in mPGES1-S100B-deleted mice

Endocannabinoid-related compounds in gastrointestinal diseases

The endocannabinoid system (ECS) is an endogenous signalling pathway involved in the control of several gastrointestinal (GI) functions at both peripheral and central levels. In recent years, it has become apparent that the ECS is pivotal in the regulation of GI motility, secretion and sensitivity, but endocannabinoids (ECs) are also involved in the regulation of intestinal inflammation and mucosal barrier permeability, suggesting their role in the pathophysiology of both functional and organic GI disorders. Genetic studies in patients with irritable bowel syndrome (IBS) or inflammatory bowel disease have indeed shown significant associations with polymorphisms or mutation in genes encoding for cannabinoid receptor or enzyme responsible for their catabolism, respectively. Furthermore, ongoing clinical trials are testing EC agonists/antagonists in the achievement of symptomatic relief from a number of GI symptoms. Despite this evidence, there is a lack of supportive RCTs and relevant data in human beings, and hence, the possible therapeutic application of these compounds is raising ethical, political and economic concerns. More recently, the identification of several EC-like compounds able to modulate ECS function without the typical central side effects of cannabinomimetics has paved the way for emerging peripherally acting drugs. This review summarizes the possible mechanisms linking the ECS to GI disorders and describes the most recent advances in the manipulation of the ECS in the treatment of GI diseases

The rapid moving Capriglio earth flow (Parma Province, North Italy): multi-temporal mapping and GB-InSAR monitoring

This research presents the main findings of the multi-temporal mapping and of the long-term, real-time monitoring of the Capriglio landslide in the Emilian Apennines (Northern Italy). The landslide, triggered by prolonged rainfall and rapid snowmelt, activated of April 6th 2013. It is constituted by two main adjacent enlarging bodies with a roto-translational kinematics. They activated in sequence and subsequently joined into a large fast moving earth flow, channelizing downstream the Bardea Creek, for a total length of about 3600 meters. The landslide completely destroyed a 450 m sector of the provincial roadway S.P. 101, and its retrogression tendency put at high risk the Capriglio and Pianestolla villages, located in the upper watershed area of the Bardea River. Furthermore, the advancing toe seriously threatened the Antria bridge, representing the "Massese" provincial roadway S.P. 665R transect over the Bardea Creek, the only strategic roadway left able to connect the above-mentioned villages. With the final aim of supporting local authorities in the hazard assessment and risk management during the emergency phase, on May 5th 2013 aerial optical surveys were conducted to accurately map the landslide extension and evolution. Moreover, a GB-InSAR monitoring campaign was started in order to assess displacements of the whole landslide area. The versatility and flexibility of the GB-InSAR sensors allowed acquiring data with two different configurations, designed and set up to continuously retrieve information on the landslide movements rates (both in its upper slow-moving sectors and in its fast-moving toe). The first acquisition mode revealed that the Capriglio and Pianestolla villages were affected by minor displacements (order of magnitude of few millimetres per month). The second acquisition mode allowed to acquire data every 28'', reaching very high temporal resolution values by applying GB-InSAR technique (Monserrat et al., 2014; Caduff et al., 2015)

Predictors of Bluetongue development in Sardinia (Italy) identification, using multilevel logistic mixed model

Objectives: The Bluetongue Virus is one of the most studied ruminant diseases, affecting particularly sheep and goats. This study aims to identify, for the first time, the specific risk factors influencing the disease development in Sardinia, using multilevel logistic regression model, in order to give a contribution to the sanitary programs and favour the early detection.   Methods: The data of the present retrospective study, collected from informatics systems of Istituto Zooprofilattico della Sardegna, are referred to all 15,780 Sardinian sheep farms observed for 3 years (2012-2014). The outcome of interest was dichotomous and defined the development of Bluetongue outbreak, after serological test or clinical signs. The effect of several region-specific prognostic factors on disease spread was investigated. Results: The final model indicated that Bluetongue development was significantly associated with an increase in number of animals (P < 0.0001), number of cattle around farm (P  < 0.0001), water surface area (P =0.002), and amount of rainfall in the previous days (P < 0.0001). Furthermore, the altitude over 450 MASL (P < 0.0001), the vaccination prophylaxis (P < 0.0001) and the previous outbreak event (P < 0.0001) had a protective effect against the outcome. Conclusion: The results of this study indicated that number of animals and the amount of rainfall were the most important risk factors that affected the Bluetongue development, while the vaccination prophylaxis was found to be an effective measure in decelerating the disease spread.&nbsp

Rifaximin improves Clostridium difficile toxin A-induced toxicity in Caco-2 cells by the PXR-dependent TLR4/MyD88 /NF-?B pathway

Background: Clostridium difficile infections (CDIs) caused by Clostridium difficile toxin A (TcdA) lead to severe ulceration, inflammation and bleeding of the colon, and are difficult to treat. Aim: The study aimed to evaluate the effect of rifaximin on TcdA-induced apoptosis in intestinal epithelial cells and investigate the role of PXR in its mechanism of action. Methods: Caco‐2 cells were incubated with TcdA and treated with rifaximin (0.1−10 μM) with or without ketoconazole (10 μM). The transepithelial electrical resistance (TEER) and viability of the treated cells was determined. Also, the expression of zona occludens‐1 (ZO‐1), toll‐like receptor 4 (TLR4), Bcl‐2‐associated X protein (Bax), transforming growth factor‐β‐activated kinase‐1 (TAK1), myeloid differentiation factor 88 (MyD88) and nuclear factor‐kappaB (NF‐κB) was determined. Results Rifaximin treatment (0.1, 1.0 and 10 μM) caused a significant and concentration-dependent increase in the TEER of Caco-2 cells (360%, 480% and 680% vs TcdA treatment) 24 hours after the treatment and improved their viability (61%, 79% and 105%). Treatment also concentration-dependently decreased the expression of Bax protein (–29%, –65% and –77%) and increased the expression of ZO-1 (25%, 54% and 87%) and occludin (71%, 114% and 262%) versus TcdA treatment. The expression of TLR4 (–33%, –50% and –75%), MyD88 (–29%, –60% and –81%) and TAK1 (–37%, –63% and –79%) were also reduced with rifaximin versus TcdA treatment. Ketoconazole treatment inhibited these effects. Conclusions: Rifaximin improved TcdA‐induced toxicity in Caco‐2 cells by the PXR‐dependent TLR4/MyD88/NF‐κB pathway mechanism, and may be useful in the treatment of CDIs

HIV-1 Tat-induced diarrhea is improved by the PPARalpha agonist, palmitoylethanolamide, by suppressing the activation of enteric glia

Diarrhea is a severe complication in HIV-1-infected patients with Trans-activator of transcription (HIV-1 Tat) protein being recognized as a major underlying cause. Beside its direct enterotoxic effects, Tat protein has been recently shown to affect enteric glial cell (EGC) activity. EGCs regulate intestinal inflammatory responses by secreting pro-inflammatory molecules; nonetheless, they might also release immune-regulatory factors, as palmytoilethanolamide (PEA), which exerts anti-inflammatory effects by activating PPARα receptors. We aimed at clarifying whether EGCs are involved in HIV-1 Tat-induced diarrhea and if PEA exerts antidiarrheal activity