Papers by Claudio Tiribelli
Nutrients, Sep 12, 2017
The increasing prevalence of non-alcoholic fatty liver disease (NAFLD) in adolescents is challeng... more The increasing prevalence of non-alcoholic fatty liver disease (NAFLD) in adolescents is challenging the global care system. No therapeutic strategies have been defined so far, and changes in the lifestyle remain the only alternative. In this study, we assessed the protective effects of silymarin in a juvenile non-alcoholic steatohepatitis (NASH) model and the in vitro effects on fat-laden human hepatocytes. C57Bl/6 mice were exposed to HFHC diet immediately after weaning. After eight weeks, animals showed histological signs of NASH. Silymarin was added to the HFHC diet, the treatment continued for additional 12 weeks and the effects on BMI, hepatomegaly, visceral fat, lipid profile, transaminases, HOMA-IR, steatosis, inflammation, fibrosis, oxidative stress, and apoptosis were determined. The switch from HFHC to control diet was used to mimic lifestyle changes. In vitro experiments were performed in parallel in human hepatocytes. HFHC diet supplemented with silymarin showed a significant improvement in glycemia, visceral fat, lipid profile, and liver fibrosis. Moreover, it reduced (both in vitro and in vivo) ALT, hepatic inflammation, oxidative stress, and apoptosis. Lifestyle changes restored the control group parameters. The data presented show the beneficial effects of the oral administration of silymarin in the absence of changes in the dietary habits in a juvenile model of NASH.
Biomedicines, Mar 17, 2022
Bilirubin has been regarded as a powerful endogenous antioxidant and anti-inflammatory molecule, ... more Bilirubin has been regarded as a powerful endogenous antioxidant and anti-inflammatory molecule, able to act on cellular pathways as a hormone. Diabetic kidney disease (DKD) is a common chronic complication of diabetes, and it is the leading cause of end-stage renal disease. Here, we will review the clinical and molecular features of mild hyperbilirubinemia in DKD. The pathogenesis of DKD involves oxidative stress, inflammation, fibrosis, and apoptosis. Serum bilirubin levels are positively correlated with the levels of the antioxidative enzymes as superoxide dismutase, catalase, and glutathione peroxidase, while it is inversely correlated with C-reactive protein, TNFα, interleukin (IL)-2, IL-6, and IL-10 release in diabetic kidney disease. Bilirubin downregulates NADPH oxidase, reduces the induction of pro-fibrotic factor HIF-1α expression, cleaved caspase-3, and cleaved PARP induction showing lower DNA fragmentation. Recent experimental and clinical studies have demonstrated its effects in the development and progression of renal diseases, pointing out that only very mild elevations of bilirubin concentrations result in real clinical benefits. Future controlled studies are needed to explore the precise role of bilirubin in the pathogenesis of DKD and to understand if the use of serum bilirubin levels as a marker of progression or therapeutic target in DKD is feasible and realistic.
Antioxidants, Aug 23, 2022
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
Biochemical and Biophysical Research Communications, Nov 1, 2003
Earlier studies suggest that Mrp1 may mediate ATP-dependent cellular extrusion of unconjugated bi... more Earlier studies suggest that Mrp1 may mediate ATP-dependent cellular extrusion of unconjugated bilirubin (UCB). We studied the serial responses of expression of Mrp1 mRNA and protein in rats with increased bilirubin production due to hemolysis induced by phenylhydrazine (PHZ) treatment. Mrp1 mRNA was analyzed by quantitative PCR and protein by Western blot. Hepatic expression of Mrp1 mRNA and protein peaked at day 3 of PHZ treatment. Splenic expression of Mrp1 mRNA peaked within 24 h and returned to baseline at day 5 whereas Mrp1 protein expression peaked at day 3. Pretreatment with heme-oxygenase inhibitor, tin mesoporphyrin, blunted the increase in serum UCB and erased the overexpression of Mrp1 both in liver and spleen. Thus, the upregulation of Mrp1 in hemolysis is mediated by UCB and/or other products of heme oxygenase, further supporting a role of Mrp1 in UCB transport and protection from its cellular toxicity.
Current Pharmaceutical Design, Sep 1, 2009
Digestive and Liver Disease, Feb 1, 2016
Digestive and Liver Disease, Oct 1, 2015
Digestive and Liver Disease, Oct 1, 2015
Results: H-IR was significantly higher in moderate/severe steatosis than in the mild steatosis gr... more Results: H-IR was significantly higher in moderate/severe steatosis than in the mild steatosis group (p < 0.0001). In contrast, MISI did not differ between the two groups. There was a significant correlation between H-IR, MISI and all of the components of MS. H-IR was significantly correlated with carotid IMT (r = 0.35; p < 0.0001) and the apoB/apoAI ratio (r = 0.43; p < 0.0001). Otherwise, a significant correlation was observed only between MISI and apoB/apoAI ratio. Multivariate analysis revealed that H-IR is related to early markers of atherosclerosis independently to MS components. Conclusions: In our study population, NAFLD was positively associated with carotid IMT. This association is independent of MS components but strictly related to H-IR that might contribute to the development of atherosclerosis through an impairment of the lipid profile in terms of the apoB/apoAI ratio.
Current Drug Abuse Reviews, Jun 11, 2018
Drinking more than the recommended limits is a worldwide emerging problem, difficult to circumscr... more Drinking more than the recommended limits is a worldwide emerging problem, difficult to circumscribe, and alcohol related brain damages are an under-recognized health problem. Alcohol-cognitive disruption can be considered as transient and recoverable if the alcohol consumption is limited and occasional; if not, it can progress to the so-called alcohol-related dementia (ARD), or to the Wernicke encephalopathy, or it can even induce the Korsakoff syndrome, an irreversible and long-lasting medical condition. ARD still remains poorly diagnosed and addressed, even if it had recently raised increased research interest. That is a frustrating condition, being ARD a relatively non-progressive, or even partially reversible condition in abstinent ex-drinkers. On the contrary, Wernicke encephalopathy, with its neurological symptoms (ocular coordination imbalance and gait ataxia), is a dramatic medical condition, potentially lethal which can lead towards Korsakoff dementia. The alcohol consumption is a strong reinforcing condition of the thiamine deficit, the main biochemical determinant factor that starts the cascade of the brain irreversible damaging events. Our review focus on the possible common neural pathways of these three condition, on the biochemical basis of the damages, and tries to underline the strong need of better understanding the pathogenesis of the brain lesions, including epigenetics and the nutritional aspects of the problem.
Journal of Clinical Medicine, 2021
As in adults, obesity also plays a central role in the development of metabolic syndrome (MS) in ... more As in adults, obesity also plays a central role in the development of metabolic syndrome (MS) in children. Non-alcoholic fatty liver disease (NAFLD) is considered a manifestation of MS. Not only MS but also NAFLD seem to be inversely associated with serum bilirubin concentrations, an important endogenous tissue protector when only mild elevated. The aim of the study was to evaluate the association between serum bilirubin levels and the prevalence of MS and NAFLD in Italian obese children and adolescents. A retrospective cross-sectional study was performed in 1672 patients aged from 5 to 18 years. Clinical and laboratory parameters were assessed. NAFLD was measured by liver ultrasonography. The study was approved by the Ethical Committee of the Istituto Auxologico Italiano (research project code 1C021_2020, acronym BILOB). MS was present in 24% and fatty liver (FL) in 38% of this population. Bilirubin was not associated with FL and MS as a whole, but it was inversely associated only ...
Background: Mildly elevated serum bilirubin in Gilbert Syndrome (GS) protects against diabetes, c... more Background: Mildly elevated serum bilirubin in Gilbert Syndrome (GS) protects against diabetes, cardiovascular diseases (CVD) and metabolic syndrome (MetS). GS is a benign condition in which unconjugated hyperbilirubinemia occurs in the absence of structural liver disease and without hemolysis. It is caused by a genetic mutation that decreased the hepatic UGT1A1, the enzyme that mediates bilirubin glucuronidation. UGT1A1 variants in GS may confer a strong genetic advantage. Bilirubin, the final endogenous product of oxidative degradation of heme, plays a role in the cellular protection via scavenging peroxyl radicals and it prevents the oxidative modification of lipoproteins and lipids. Strategies to mimic GS may prove to be an attractive intervention in cardiovascular disease and metabolic syndrome. Aim: The aim is to study the protective role of mild hyperbilirubinemia on oxidative stress, inflammation and ER-stress in two in vitro models of MetS. Methods: Human kidney tubular epithelial HK-2 and murine heart endothelial H5V cell lines were treated respectively with Advanced Glycated End Products (AGE) and palmitic acid (PA). Cell viability, gene and protein expression, and intracellular ROS were evaluated. Results: PA treatments on H5V cells cause cell necrosis and mRNA induction of HO-1, IL-6, GRP78, CHOP, E-Selectin, V-CAM, ICAM and iNOS. UCB pre-treatment reverts cell necrosis, reduces CHOP, IL-6 and iNOS mRNA induction and increases HO-1 mRNA expression. CHOP protein induction by PA was also reduced. AGE treatment on HK-2 cells causes significative variation of IL-8, HIF1a, HO-1, GPX and Catalase mRNA expression and increases intracellular ROS. UCB pre-treatment increases the HO-1 and GPX mRNA, and reduces IL-8 and HIF1a mRNA induction and ROS intracellular levels. Conclusions: UCB plays a role in the modulation of cell viability, intracellular ROS production and mRNA gene expression in the in vitro models of diabetic nephropathy and atherosclerosis studied. Biography Annalisa Bianco, after her Bachelor's at Urbino University in Biological Sciences, attended the Master's Degree Course in Functional Genomics at the University of Trieste. She graduated on 20th October 2017 with the final evaluation of 109/110. From 1st November 2017 she enrolls in the PhD School of Molecular Biomedicine at the University of Trieste. She developed her Master's Degree Thesis work at Italian Liver Foundation where she produced the results presented in the present abstract.
International Journal of Molecular Sciences, 2020
Background: Severe hyperbilirubinemia can cause permanent neurological damage in particular in ne... more Background: Severe hyperbilirubinemia can cause permanent neurological damage in particular in neonates, whereas mildly elevated serum bilirubin protects from various oxidative stress-mediated diseases. The present work aimed to establish the intracellular unconjugated bilirubin concentrations (iUCB) thresholds differentiating between anti- and pro-oxidant effects. Methods: Hepatic (HepG2), heart endothelial (H5V), kidney tubular (HK2) and neuronal (SH-SY5Y) cell lines were exposed to increasing concentration of bilirubin. iUCB, cytotoxicity, intracellular reactive oxygen species (ROS) concentrations, and antioxidant capacity (50% efficacy concentration (EC50)) were determined. Results: Exposure of SH-SY5Y to UCB concentration > 3.6 µM (iUCB of 25 ng/mg) and >15 µM in H5V and HK2 cells (iUCB of 40 ng/mg) increased intracellular ROS production (p < 0.05). EC50 of the antioxidant activity was 21 µM (iUCB between 5.4 and 21 ng/mg) in HepG2 cells, 0.68 µM (iUCB between 3.3 and ...
International Journal of Molecular Sciences, 2019
The current treatments of Parkinson disease (PD) are ineffective mainly due to the poor understan... more The current treatments of Parkinson disease (PD) are ineffective mainly due to the poor understanding of the early events causing the decline of dopaminergic neurons (DOPAn). To overcome this problem, slow progressively degenerating models of PD allowing the study of the pre-clinical phase are crucial. We recreated in a short ex vivo time scale (96 h) all the features of human PD (needing dozens of years) by challenging organotypic culture of rat substantia nigra with low doses of rotenone. Thus, taking advantage of the existent knowledge, the model was used to perform a time-dependent comparative study of the principal possible causative molecular mechanisms undergoing DOPAn demise. Alteration in the redox state and inflammation started at 3 h, preceding the reduction in DOPAn number (pre-diagnosis phase). The number of DOPAn declined to levels compatible with diagnosis only at 12 h. The decline was accompanied by a persistent inflammation and redox imbalance. Significant microglia...
Annals of Hepatology, 2019
The interleukin-33/interleukin-13 pathway is involved in the immunopathology of liver fibrosis an... more The interleukin-33/interleukin-13 pathway is involved in the immunopathology of liver fibrosis and recently characterized group 2 innate lymphoid cells (ILC2) were identified as profibrotic immune cells in the liver of mouse models. Our aim was to elucidate whether ILC2 might be present in human liver tissue and whether ILC2 contribute to liver fibrosis. Materials and methods: To identify ILC2 in liver tissue and blood, we purified mononuclear immune cells from needle biopsies, cirrhotic explant specimen, and paired peripheral blood samples. Cell suspensions were incubated with specific markers for ILC2 and analyzed by flow cytometry. The CD69 marker was included to assess the activation level of ILC2. In addition, we determined the IL-33 plasma level. Results: Results were correlated with the METAVIR fibrotic score of patients enrolled in this study. We detected ILC2 in a higher percentage of CD45 + cells in liver tissue than in paired peripheral blood. The number of ILC2 was significantly increased in fibrotic tissue, but only slightly increased in paired peripheral blood. A higher percentage of CD69 + ILC2 was observed in fibrotic tissue, and this increase correlates positively with aggravation of liver fibrosis measured by fibrotic METAVIR score. A higher level of plasma IL-33 was only detected in samples obtained from cirrhotic patients. Conclusion: Our study indicates that ILC2 are present in the human liver and are activated in tissue contributing to the immunopathology of human liver fibrosis, independently of the etiology; which might be a potential new therapeutic target.
Journal of Hepatology, 2016
Scientific Reports, 2018
Phototherapy was introduced in the early 1950’s, and is the primary treatment of severe neonatal ... more Phototherapy was introduced in the early 1950’s, and is the primary treatment of severe neonatal jaundice or Crigler-Najjar syndrome. Nevertheless, the potential biological effects of the products generated from the photodegradation of bilirubin during phototherapy remain unknown. This is very relevant in light of recent clinical observations demonstrating that the use of aggressive phototherapy can increase morbidity or even mortality, in extremely low birthweight (ELBW) infants. The aim of our study was to investigate the effects of bilirubin, lumirubin (LR, its major photo-oxidative product), and BOX A and B (its monopyrrolic oxidative products) on the central nervous system (CNS) using in vitro and ex vivo experimental models. The effects of bilirubin photoproducts on cell viability and expression of selected genes were tested in human fibroblasts, three human CNS cell lines (neuroblastoma SH-SY5Y, microglial HMC3, and glioblastoma U-87 cell lines), and organotypic rat hippocamp...
Oxidative Medicine and Cellular Longevity, 2018
Unconjugated bilirubin is considered a potent antioxidant when present at moderate levels. Howeve... more Unconjugated bilirubin is considered a potent antioxidant when present at moderate levels. However, at high concentrations, it produces severe neurological damage and death associated with kernicterus due to oxidative stress and other mechanisms. While it is widely recognized that oxidative stress by different toxic insults results in severe damage to cellular macromolecules, especially to DNA, no data are available either on DNA damage in the brain triggered by hyperbilirubinemia during the neonatal period or on the activation of DNA repair mechanisms. Here, using a mouse model of neonatal hyperbilirubinemia, we demonstrated that DNA damage occursin vivoin the cerebellum, the brain region most affected by bilirubin toxicity. We studied the mechanisms associated with potential toxic action of bilirubin on DNA inin vitromodels, which showed significant increases in DNA damage when neuronal and nonneuronal cells were treated with 140 nM of free bilirubin (Bf), as determined byγH2AX We...
Current Nutrition & Food Science, 2017
Vitamin B12 and folate induced, via two major pathways, the conversion of homocysteine to methion... more Vitamin B12 and folate induced, via two major pathways, the conversion of homocysteine to methionine and the conversion of methylmalonyl coenzyme A to succinyl coenzyme A. Therefore, the defect of both vitamins result in an increase of both serum homocysteine and methylmalonic acid. Hence, homocysteine, vitamin B12, and folate are closely linked together in the so-called one-carbon cycle, being vitamin B12 the necessary co-enzyme for the methyl donation from 5-methyl-tetra-hydrofolate in tetra-hydro-folate, necessary for methionine synthetase. Folate is a cofactor in one-carbon metabolism, and it promotes, the remethylation of homocysteine, which can cause DNA strand breakage, oxidative stress and apoptosis. Vitamin B12 and folate are involved in nucleic acid synthesis and in the methylation reactions, and their deficit cause the inhibition of S-adenosylmethionine mediated methylation reactions, and through the related toxic effects of homocysteine a possible direct alteration of the vascular endothelium and inhibition of N-methyl-D-Aspartate receptors. We discuss the possible and still controversial role of homocysteine accumulation in cerebral pathologies, starting from vascular events up to neurodegeneration and to endothelium damage mechanism.
Gene Therapy, 2017
Repeated AAV-mediated gene transfer by serotype switching enables long-lasting therapeutic levels... more Repeated AAV-mediated gene transfer by serotype switching enables long-lasting therapeutic levels of hUgt1a1 enzyme in a mouse model of Crigler-Najjar syndrome type I, Gene Therapy accepted article preview
British Journal of Medicine and Medical Research, 2016
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Papers by Claudio Tiribelli