Silybin-Phosphatidylcholine Complex Protects Human Gastric and Liver Cells from Oxidative Stress

Silybin is the main component of silymarin with antioxidant, anti-inflammatory and cytoprotective actions. Our aim was to compare the effect of silybin used as single substance, silybin-phosphatidylcholine complex (SilPho), and derivatives of silybin (MannpSil, GalpSil, GlcpSil, LactpSil) on MKN28 and HepG2 cell viability and cell death, in vitro, after induction of oxidative stress

Urotensin-II Receptor: A Double Identity Receptor Involved in Vasoconstriction and in the Development of Digestive Tract Cancers and other Tumors

Urotensin II and Urotensin-II receptors are important molecular factors that regulate vasoconstriction and all the diseases that are linked to abnormalities in blood pressure regulation (i.e.: hypertension, kidney diseases, cirrhosis etc.). Recently, Urotensin II and its receptor have also been involved in metabolic syndrome, diabetes and schizophrenia. Recent strong findings suggest that Urotensin II and its receptor are involved in the onset and development of different epithelial cancers. Indeed, it was reported that cell growth, motility and invasion in human breast, bladder, prostate, colorectal and glioblastoma cancer cells were regulated by Urotensin II and Urotensin-II receptor axis. This axis also regulated focal adhesion kinase and small Guanosine-5'-triphosphate binding proteins that likely had a role in motility and invasion mediated by Urotensin-II receptor. Additionally, its expression on tumour tissues is variably associated to the prediction of the clinical outcome of the patients and it can be considered an alternative molecular marker to be used as prognostic factor in human cancers. In conclusion, a new weapon in the treatment of human cancers is highlighting a new scenario for the future

A 60-Year-Old Woman with Primary Biliary Cholangitis and Crohn's Ileitis Following the Suspension of Ursodeoxycholic Acid

BACKGROUND There is a recognized association between inflammatory bowel disease (IBD) and hepatobiliary autoimmune disease, particularly primary sclerosing cholangitis (PSC). There have been fewer reported cases of IBD and primary biliary cholangitis (PBC), which is treated with ursodeoxycholic acid (UDCA). This report presents the case of a 60-year-old woman with PBC who was diagnosed with Crohn's ileitis after suspension of UDCA treatment. CASE REPORT A 66-year-old female patient with PBC was admitted to our department for irrepressible chronic diarrhea and recurrent abdominal pain. PBC was diagnosed on the basis of serological data: chronic (>6 months) increase in alkaline phosphatase (ALP) associated with positivity for specific anti-nuclear antibodies (sp100 and gp210), without requiring a liver biopsy and a magnetic resonance cholangiopancreatography to rule out PSC. Given the intolerance and non-responsiveness according to the Toronto criteria (ALP <1.67 times the normal limit after 2 years) to UDCA at 15 mg/kg/day, an oral monotherapy treatment using obeticholic acid at 5 mg/day was prescribed. The patient complained of abdominal pain and upper gastrointestinal symptoms. The endoscopic/histologic and radiologic examinations supported the diagnosis of Crohn's ileitis. Given the potential benefits to PBC patients of what is described as off-label therapy, budesonide at a dosage of 9 mg/day p.o. was also administered. One month after discharge, an improvement was observed both in the cholestasis indices and in gastrointestinal symptoms. CONCLUSIONS This report presents a case of PBC in which the patient was diagnosed with Crohn's ileitis after cessation of treatment with UDCA, and highlights the importance of recognizing the association between autoimmune hepatobiliary disease and IBD

The Role of Insulin Resistance in Fueling NAFLD Pathogenesis: From Molecular Mechanisms to Clinical Implications

Non-alcoholic fatty liver disease (NAFLD) represents a predominant hepatopathy that is rapidly becoming the most common cause of hepatocellular carcinoma worldwide. The close association with metabolic syndrome's extrahepatic components has suggested the nature of the systemic metabolic-related disorder based on the interplay between genetic, nutritional, and environmental factors, creating a complex network of yet-unclarified pathogenetic mechanisms in which the role of insulin resistance (IR) could be crucial. This review detailed the clinical and pathogenetic evidence involved in the NAFLD-IR relationship, presenting both the classic and more innovative models. In particular, we focused on the reciprocal effects of IR, oxidative stress, and systemic inflammation on insulin-sensitivity disruption in critical regions such as the hepatic and the adipose tissue, while considering the impact of genetics/epigenetics on the regulation of IR mechanisms as well as nutrients on specific insulin-related gene expression (nutrigenetics and nutrigenomics). In addition, we discussed the emerging capability of the gut microbiota to interfere with physiological signaling of the hormonal pathways responsible for maintaining metabolic homeostasis and by inducing an abnormal activation of the immune system. The translation of these novel findings into clinical practice could promote the expansion of accurate diagnostic/prognostic stratification tools and tailored pharmacological approaches

Beneficial Effects of Silybin Treatment After Viral Eradication in Patients With HCV-Related Advanced Chronic Liver Disease: A Pilot Study

Introduction and Aims: HCV eradication by direct-acting antivirals (DAAs) improves liver outcomes and reduces overall liver mortality. However, patients with advanced chronic liver disease (ACLD) may experience a progression of liver disease despite viral clearance. Silybin has shown hepatoprotective effects in experimental models, but clinical data are limited. The aim of this study is to evaluate the effect of a highly bioavailable form of silybin on liver fibrosis in patients with HCV-related ACLD after viral eradication with DAAs, in comparison with the standard of care. Methods: In this multicenter and prospective study, HCV patients with ACLD achieving SVR12 were treated with the combination of silybinphospholipid complex with vitamin D and vitamin E (Realsil 100D(®), Ibi Lorenzini S.p.A., Aprilia, Italy) for 12 months (R group) compared to controls (C group). Patients were submitted to transient elastography (TE) and to the enhanced liver fibrosis (ELF) test at baseline, week 24, and week 48. Results: One hundred sixteen patients were enrolled, 56 in the R group and 60 in the C group. The median age was 68 years, and 53% were male, with no differences between groups. In both groups, liver stiffness improved at 6 and 12 months compared to baseline. However, patients in the R group compared to those in the C group showed a higher reduction of liver stiffness after 6 months (−2.05, 95% CI −3.89 to −0.22, p < 0.05) and 12 months of treatment (−2.79, 95% CI −4.5 to −1.09, p < 0.01) in comparison with baseline. No significant difference in the reduction of ELF was observed between the two groups. During the follow-up, four patients developed HCC, all in the C group. Conclusions: In HCV-related ACLD, the hepatoprotective effects of silybin may represent a tool to counteract liver disease progression

Regorafenib in combination with silybin as a novel potential strategy for the treatment of metastatic colorectal cancer

Regorafenib, an oral multikinase inhibitor, has demonstrated survival benefit in metastatic colorectal cancer (mCRC) patients that have progressed after all standard therapies. However, novel strategies to improve tolerability and enhance anti-cancer efficacy are needed

Environmental bisphenol A exposure triggers trained immunity-related pathways in monocytes

IntroductionTrained Immunity represents a novel revolutionary concept of the immunological response involving innate immune cells. Bisphenol A is a well-known endocrine disrupter, widely disseminated worldwide and accumulated in the human body. Due to the increased interest regarding the effects of plastic-derived compounds on the immune system, our purpose was to explore whether BPA was able to induce trained immunity in human primary monocytes in vitro using low environmental concentrations.Materials and methodsWe extracted BPA from the serum of 10 healthy individuals through a liquid-liquid extraction followed by a solid phase extraction and measured the concentration using an HPLC system coupled to a triple quadrupole mass spectrometer. In parallel, monocytes were isolated from whole blood and acutely stimulated or trained with BPA at three different concentrations (1 nM, 10 nM, 20 nM). Pro- and anti-inflammatory cytokines (IL-1β, TNF-α, IL-6, and IL-10) production were assessed after 24 hours of acute stimulation and after Lipopolysaccharide (LPS) rechallenge. A comprehensive overview of the metabolic changes after BPA acute stimulation and trained immunity induction was assessed through extracellular lactate measurements, Seahorse XFb metabolic flux analysis and ROS production.ResultsMonocytes primed with BPA showed increased pro- and anti-inflammatory cytokine responses upon restimulation, sustained by the modulation of the immunometabolic circuits. Moreover, we proved the non-toxic effect of BPA at each experimental concentration by performing an MTT assay. Additionally, correlation analysis were performed between pro- and anti-inflammatory cytokines production after LPS acute stimulation or BPA-mediated trained immunity and BPA serum concentrations showing a significant association between TNF-α and BPA circulating levels.DiscussionOverall, this study pointed out for the first time the immunological effects of an environmental chemical and plastic-derived compound in the induction of trained immunity in a healthy cohort

Performance of the model for end-stage liver disease score for mortality prediction and the potential role of etiology

Bakground &amp; aims Although discrimination of the model for end stage liver disease (MELD) is generally considered acceptable, its calibration is still unclear. In a validation study, we assessed the discrimination and calibration performance of 3 versions of the model: original MELD-TIPS, used to predict survival after transjugular intra-hepatic portosystemic shunt (TIPS); classic MELD-Mayo; MELD-UNOS, used by United Network for Organ Sharing (UNOS). Recalibration and model updating were also explored. Methods 776 patients submitted to elective TIPS (TIPS cohort), and 445 unselected patients (non-TIPS cohort) were included. Three, 6 and 12-month mortality predictions were calculated by the 3 MELD versions: discrimination was assessed by c-statistics and calibration by comparing deciles of predicted and observed risks. Cox and Fine and Grey models were used for recalibration and prognostic analyses. Results Major patient characteristics in TIPS/non-TIPS cohorts were: viral etiology 402/188, alcoholic 185/130, NASH 65/33; mean follow-up± SD 25±9/19±21months; 3-6-12 month mortality were respectively, 57-102-142/31-47-99. C-statistics ranged from 0.66 to 0.72 in TIPS and 0.66 to 0.76 in non-TIPS cohorts across prediction times and scores. A post-hoc analysis revealed worse c-statistics in non-viral cirrhosis with more pronounced and significant worsening in non-TIPS cohort. Calibration was acceptable with MELD-TIPS but largely unsatisfactory with MELD-Mayo and -UNOS whose performance improved much after recalibration. A prognostic analysis showed that age, albumin, and TIPS indication might be used for a MELD updating. Conclusions In this validation study the MELD performance was largely unsatisfactory, particularly in non-viral cirrhosis. MELD recalibration and candidate variables for a MELD updating are proposed. Lay summary While discrimination performance of the Model for End Stage Liver Disease (MELD) is credited to be fair to good, its calibration, the correspondence of observed to predicted mortality, is still unsettled. We found that application of 3 different versions of the MELD in two independent cirrhosis cohorts yielded largely imprecise mortality predictions particularly in non-viral cirrhosis and propose a validated model recalibration. Candidate variables for a MELD updating are proposed