Heparanase and macrophage interplay in the onset of liver fibrosis

Abstract The heparan sulfate endoglycosidase heparanase (HPSE) is involved in tumor growth, chronic inflammation and fibrosis. Since a role for HPSE in chronic liver disease has not been demonstrated to date, the current study was aimed at investigating the involvement of HPSE in the pathogenesis of chronic liver injury. Herein, we revealed that HPSE expression increased in mouse livers after carbon tetrachloride (CCl4)-mediated chronic induction of fibrosis, but with a trend to decline during progression of the disease. In mouse fibrotic liver tissues HPSE immunostaining was restricted in necro-inflammatory areas, co-localizing with F4/80 macrophage marker and TNF-α. TNF-α treatment induced HPSE expression as well as HPSE secretion in U937 macrophages. Moreover, macrophage-secreted HPSE regulated the expression of α-SMA and fibronectin in hepatic stellate LX-2 cells. Finally, HPSE activity increased in the plasma of patients with liver fibrosis but it inversely correlated with liver stiffness. Our results suggest the involvement of HPSE in early phases of reaction to liver damage and inflammatory macrophages as an important source of HPSE. HPSE seems to play a key role in the macrophage-mediated activation of hepatic stellate cells (HSCs), thus suggesting that HPSE targeting could be a new therapeutic option in the treatment of liver fibrosis

Financial exposure to the euro area before and after the crisis: home bias and institutions at home

This paper investigates whether global investors are over or under exposed to- wards the euro area and the role of home bias and institutions at home in shaping this exposure. According to a simple benchmark from standard portfolio theory, euro area investors - in particular those from euro area low-rating economies - are overexposed to euro area securities. Instead, investors outside the EU are underexposed to euro area securities in their total portfolio, proportionally to their degree of home bias, but not in their foreign portfolio. Nevertheless, once we account for gravity factors, the largest foreign investors overweigh euro area securities, especially debt of euro area high rating economies. Crucially, this overexposure was resilient to the euro area crisis. Moreover, we show that institutions at home are important to explain exposure to euro area securities. In particular, the higher the standards of governance at home, the greater the exposure to the euro area debt

METHANE AND CARBON DIOXIDE FLUXES FROM LIMONIUM RESIDUES DECOMPOSITION IN SALTMARSH SOILS: EFFECTS OF TIDE REGIME

The flooding regime of saltmarshes strongly affects organic matter mineralisation, representing a unique situation where oxygen diffusion is either impeded by submersion or favoured by retreating water in regular cycles within the same day. Decomposition of Limonium vulgare Mill. residues in saltmarsh soils was evaluated measuring CO2 and CH4 emissions. Four different saltmarshes from the Grado Lagoon (Northern Adriatic Sea) were investigated. Soils were characterised by a similar vegetation (Sarcocornietea class) and similar high coverage of L. vulgare (70-75%) but differed in redox potential, texture and organic carbon content. Hydromorphic conditions were reproduced in mesocosms, and soils were incubated under fully aerobic, fully anaerobic and transient (6 hours cycles) tidal states. Partially decomposed litter (leaves) of L. vulgare was added and decomposition processes were monitored through CO2 and CH4 emissions. Larger CO2 emissions were measured under aerobic conditions, in particular in soil samples with coarse texture. Fully anoxic and tidal regimes showed a similar behaviour. On the contrary, CH4 emissions were less dependent upon flooding, showing only slightly larger values under completely submerged conditions. Larger CH4 emissions have been obtained in fine textured soils. Soil organic matter content also influenced gas emissions: larger values corresponded to higher emissions of both CO2 and CH4

Polyclonal and monoclonal B lymphocytes response in HCV-infected patients treated with direct-acting antiviral agents

Hepatitis C virus (HCV) chronic infection can be associated with extrahepatic manifestations such as mixed cryoglobulinaemia and lymphoproliferative disorders that are endowed with increased rates of morbidity and all-cause mortality. In this study, we used flow cytometry to evaluate the effect of interferon-free antiviral treatment on peripheral blood lymphocytes in HCV-infected patients with or without associated lymphoproliferative disorders. Flow cytometry analysis of peripheral blood lymphocytes was performed at baseline and at the end of treatment. In HCV-infected patients with lymphoproliferative disorders, we evaluated immunoglobulin (Ig) light chain \u3ba/\u3bb ratio variations as a measure of monoclonal B-cell response to antiviral therapy. Healthy volunteers were enrolled as controls. A total of 29 patients were included, nine with and 20 without lymphoproliferative disorders. Sustained virological response was achieved in 29 of 29 patients. We observed a significant reduction in the B-cell compartment (39% global reduction) in eight of nine HCV-infected patients with lymphoproliferative disorders after viral clearance. We recognized the same trend, even if less pronounced, in HCV-infected patients without lymphoproliferative disorders (9% global reduction). Among HCV-infected patients with lymphoproliferative disorders, three showed an improvement/normalization of the immunoglobulin light chain ratio, whereas in the remaining six patients monoclonal B cells persisted to be clonally restricted even 1\ua0year after the end of treatment. Our data show that DAAs treatment can be effective in reducing the frequency of pathological B cells in the peripheral blood of HCV-infected patients affected by HCV-associated lymphoproliferative disorders; however, monoclonal populations can persist after viral eradication

Pregnane X receptor and constitutive androstane receptor modulate differently CYP3A-mediated metabolism in earlyand late-stage cholestasis

AIM: To ascertain whether cholestasis affects the expression of two CYP3A isoforms (CYP3A1 and CYP3A2) and of pregnane X receptor (PXR) and constitutive androstane receptor (CAR). METHODS: Cholestasis was induced by bile duct ligation in 16 male Wistar rats; whereas 8 sham-operated rats were used as controls. Severity of cholestasis was assessed on histological examination of liver sections, and serum concentrations of albumin, AST, ALT, GGT, ALPK and bilirubin. Gene and protein expressions of PXR, CAR, CYP3A1 and CYP3A2 were assessed by means of qRT-PCR and Western blot, respectively. Alterations in CYP3A activity were measured by calculating the kinetic parameters of 4-OH and 1'-OH-midazolam hydroxylation, marker reactions for CYP3A enzymes. RESULTS: The mRNA and protein expression of CYP3A1 increased significantly in mild cholestasis (P < 0.01). At variance, mRNA and protein expression of CYP3A2 didn't change in mild cholestasis, whereas the expression and activity of both CYP3A1 and CYP3A2 decreased dramatically when cholestasis became severe. Consistently with these observations, the nuclear expression of both PXR and CAR, which was measured because they both translocate into the cell nucleus after their activation, virtually disappeared in the late stage of cholestatic injury, after an initial increase. These results indicate that early- and late-stage cholestasis affects CYP3A-mediated drug metabolism differently, probably as consequence of the different activation of PXR and CAR. CONCLUSION: Early- and late-stage cholestasis affects CYP3A-mediated drug metabolism differently. PXR and CAR might be targeted therapeutically to promote CYP3A-mediated liver detoxification

Leukemia inhibitory factor protects cholangiocarcinoma cells from drug-induced apoptosis via a PI3K/AKT-dependent Mcl-1 activation

Cholangiocarcinoma is an aggressive, strongly chemoresistant liver malignancy. Leukemia inhibitory factor (LIF), an IL-6 family cytokine, promotes progression of various carcinomas. To investigate the role of LIF in cholangiocarcinoma, we evaluated the expression of LIF and its receptor (LIFR) in human samples. LIF secretion and LIFR expression were assessed in established and primary human cholangiocarcinoma cell lines. In cholangiocarcinoma cells, we tested LIF effects on proliferation, invasion, stem cell-like phenotype, chemotherapy-induced apoptosis (gemcitabine+cisplatin), expression levels of pro-apoptotic (Bax) and anti-apoptotic (Mcl-1) proteins, with/without PI3K inhibition, and of pSTAT3, pERK1/2, pAKT. LIF effect on chemotherapy-induced apoptosis was evaluated after LIFR silencing and Mcl-1 inactivation. Results show that LIF and LIFR expression were higher in neoplastic than in control cholangiocytes; LIF was also expressed by tumor stromal cells. LIF had no effects on cholangiocarcinoma cell proliferation, invasion, and stemness signatures, whilst it counteracted drug-induced apoptosis. Upon LIF stimulation, decreased apoptosis was associated with Mcl-1 and pAKT up-regulation and abolished by PI3K inhibition. LIFR silencing and Mcl-1 blockade restored drug-induced apoptosis. In conclusion, autocrine and paracrine LIF signaling promote chemoresistance in cholangiocarcinoma by up-regulating Mcl-1 via a novel STAT3- and MAPK-independent, PI3K/AKT-dependent pathway. Targeting LIF signaling may increase CCA responsiveness to chemotherapy

Approaches towards C-H carboxylations mediated by group 11 metal centres.

openStudio sulle principali metodolgie di carbossilazione con metalli e complessi metallici del gruppo 11

Clinical Variants of Primary Sclerosing Cholangitis: When Does Liver Biopsy Make the Diagnosis?

Non

Effects of muscle disuse/hospitalization and physical training/retraining on the neuromuscular function in healthy older adults: iso-inertial resistance exercise training as a potential countermeasure form

Population ageing is a global phenomenon and it is causing many concerns regarding the economic, social and health consequences that it might bring to individual countries. Ageing is associated with the decline of the physical performance and the greater risk for the occurrence of physical disabilities. Everyday tasks require good levels of muscle performance, such as muscle force and power abilities. Hence, older people, due to their reduced physical capability levels, might have difficulties in performing these daily actions. Even the walking ability might result impaired in this population which might be associated with a loss in physical independence and, in extreme cases, death. Physical performance deterioration depends on primary ageing processes and lifestyle habits, as well. Within the lifestyle factors, periods of inactivity (i.e. defined as periods where muscles are not stimulated adequately, muscle disuse) are frequent in older people and this might exacerbate performance deterioration in this population. Indeed, muscle disuse causes further impairments in muscle force and power abilities which, added to the intrinsic alterations brought about by ageing processes, might influence everyday tasks to a greater extent. However, influences of muscle disuse on the walking ability in older people are not well studied. Weather muscle disuse can produce negative consequences to this well established and natural motor action in older people is investigated in this thesis. Muscle disuse effects on muscle power and force of the lower limb in older people are studied as well in the current work. Furthermore, to better understand how muscle performance changes with muscle disuse, investigations on the motor control, muscle volume and muscle fibers characteristics accompany the previous analyses. Information about how muscle disuse influences the neuromuscular function of older people might be of clinical importance. Indeed, muscle disuse might be associated to hospitalization periods due to health problems. Interventions that preserve the deterioration of muscle performance before and even after hospitalization might be required to rapidly reintegrate older patients into society. Thus, studying the effects of potential countermeasures, that might be involved before and after hospitalization, on the neuromuscular function of older individuals, is another theme that the current thesis faces. In particular, physical training has been chosen as the promising countermeasure that might help older people to recover from hospitalization or even other muscle disuse periods. As muscle power performance decreases to a greater extent compared to muscle force due to both ageing and muscle disuse conditions, attention is given to a particular form of resistance training: the flywheel iso-inertial resistance training. Although this training has been shown to call for greater muscle power improvements, compared to traditional gravity dependent trainings, its effects on other neuromuscular function features (i.e. muscle force, architecture, etc.) and on the walking ability are not studied in depth. Hence, the current thesis provides new evidence on this topic by further compared it with traditional resistance training adaptations