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1. Genome-wide DNA methylation and transcriptomic analysis of liver tissues subjected to early ischemia/reperfusion injury upon human liver transplantation

Author

Pablo J. Giraudi, Allen A. Laraño, Simeone Dal Monego, Riccardo Pravisani, Deborah Bonazza, Gabriel Gondolesi, Claudio Tiribelli, Francisco Baralle, Umberto Baccarani, and Danilo Licastro

Subjects
Ischemia-reperfusion injury, DNA methylation, Transcriptomics, Liver transplantation, Functional enrichment, Cell-type enrichment, Specialties of internal medicine, RC581-951
Abstract

Introduction and Objectives: Epigenetic changes represent a mechanism connecting external stresses with long-term modifications of gene expression programs. In solid organ transplantation, ischemia-reperfusion injury (IRI) appears to induce epigenomic changes in the graft, although the currently available data are extremely limited. The present study aimed to characterize variations in DNA methylation and their effects on the transcriptome in liver transplantation from brain-dead donors. Patients and Methods: 12 liver grafts were evaluated through serial biopsies at different timings in the procurement-transplantation process: T0 (warm procurement, in donor), T1 (bench surgery), and T2 (after reperfusion, in recipient). DNA methylation (DNAm) and transcriptome profiles of biopsies were analyzed using microarrays and RNAseq. Results: Significant variations in DNAm were identified, particularly between T2 and T0. Functional enrichment of the best 1000 ranked differentially methylated promoters demonstrated that 387 hypermethylated and 613 hypomethylated promoters were involved in spliceosomal assembly and response to biotic stimuli, and inflammatory immune responses, respectively. At the transcriptome level, T2 vs. T0 showed an upregulation of 337 and downregulation of 61 genes, collectively involved in TNF-α, NFKB, and interleukin signaling. Cell enrichment analysis individuates macrophages, monocytes, and neutrophils as the most significant tissue-cell type in the response. Conclusions: In the process of liver graft procurement-transplantation, IRI induces significant epigenetic changes that primarily act on the signaling pathways of inflammatory responses dependent on TNF-α, NFKB, and interleukins. Our DNAm datasets are the early IRI methylome literature and will serve as a launch point for studying the impact of epigenetic modification in IRI.

Published
2024
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2. Proteome profiling identifies circulating biomarkers associated with hepatic steatosis in subjects with Prader-Willi syndrome

Author

Devis Pascut, Pablo J. Giraudi, Cristina Banfi, Stefania Ghilardi, Claudio Tiribelli, Adele Bondesan, Diana Caroli, Alessandro Minocci, Graziano Grugni, and Alessandro Sartorio

Subjects
proteomics, proteome, circulating biomarkers, PWS, steatosis, cardiovascular, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract

IntroductionPrader-Willi syndrome (PWS) is a rare genetic disorder characterized by loss of expression of paternal chromosome 15q11.2-q13 genes. Individuals with PWS exhibit unique physical, endocrine, and metabolic traits associated with severe obesity. Identifying liver steatosis in PWS is challenging, despite its lower prevalence compared to non-syndromic obesity. Reliable biomarkers are crucial for the early detection and management of this condition associated with the complex metabolic profile and cardiovascular risks in PWS.MethodsCirculating proteome profiling was conducted in 29 individuals with PWS (15 with steatosis, 14 without) using the Olink Target 96 metabolism and cardiometabolic panels. Correlation analysis was performed to identify the association between protein biomarkes and clinical variables, while the gene enrichment analysis was conducted to identify pathways linked to deregulated proteins. Receiver operating characteristic (ROC) curves assessed the discriminatory power of circulating protein while a logistic regression model evaluated the potential of a combination of protein biomarkers.ResultsCDH2, CTSO, QDPR, CANT1, ALDH1A1, TYMP, ADGRE, KYAT1, MCFD, SEMA3F, THOP1, TXND5, SSC4D, FBP1, and CES1 exhibited a significant differential expression in liver steatosis, with a progressive increase from grade 1 to grade 3. FBP1, CES1, and QDPR showed predominant liver expression. The logistic regression model, -34.19 + 0.85 * QDPR*QDPR + 0.75 * CANT1*TYMP - 0.46 * THOP1*ALDH1A, achieved an AUC of 0.93 (95% CI: 0.63-0.99), with a sensitivity of 93% and specificity of 80% for detecting steatosis in individuals with PWS. These biomarkers showed strong correlations among themselves and were involved in an interconnected network of 62 nodes, related to seven metabolic pathways. They were also significantly associated with cholesterol, LDL, triglycerides, transaminases, HbA1c, FLI, APRI, and HOMA, and showed a negative correlation with HDL levels.ConclusionThe biomarkers identified in this study offer the potential for improved patient stratification and personalized therapeutic protocols.

Published
2023
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3. Sex differences in non-alcoholic fatty liver disease: hints for future management of the disease

Author

Noel C. Salvoza, Pablo J. Giraudi, Claudio Tiribelli, and Natalia Rosso

Subjects
nonalcoholic fatty liver disease, sex differences, hormones, inflammation, oxidative stress, insulin resistance, lipid metabolism, gut microbiota, metabolites, Other systems of medicine, RZ201-999
Abstract

Non-alcoholic fatty liver disease (NAFLD) remains a major cause of chronic liver disease worldwide. Despite extensive studies, the heterogeneity of the risk factors as well as different disease mechanisms complicate the goals toward effective diagnosis and management. Recently, it has been shown that sex differences play a role in the prevalence and progression of NAFLD. In vitro, in vivo, and clinical studies revealed that the lower prevalence of NAFLD in premenopausal as compared to postmenopausal women and men is mainly due to the protective effects of estrogen and body fat distribution. It has been also described that males and females present differential pathogenic features in terms of biochemical profiles and histological characteristics. However, the exact molecular mechanisms for the gender differences that exist in the pathogenesis of NAFLD are still elusive. Lipogenesis, oxidative stress, and inflammation play a key role in the progression of NAFLD. For NAFLD, only a few studies characterized these mechanisms at the molecular level. Therefore, we aim to review the reported differential molecular mechanisms that trigger such different pathogenesis in both sexes. Differences in lipid metabolism, glucose homeostasis, oxidative stress, inflammation, and fibrosis were discussed based on the evidence reported in recent publications. In conclusion, with this review, we hope to provide a new perspective for the development of future practice guidelines as well as a new avenue for the management of the disease.

Published
2020
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4. Network Analysis for the Discovery of Common Oncogenic Biomarkers in Liver Cancer Experimental Models

Author

Loraine Kay D. Cabral, Pablo J. Giraudi, Gianluigi Giannelli, Francesco Dituri, Roberto Negro, Claudio Tiribelli, and Caecilia H. C. Sukowati

Subjects
hepatocellular carcinoma, cellular heterogeneity, targeted therapies, experimental models, Biology (General), QH301-705.5
Abstract

Hepatocellular carcinoma (HCC) is a malignancy marked by heterogeneity. This study aimed to discover target molecules for potential therapeutic efficacy that may encompass HCC heterogeneity. In silico analysis using published datasets identified 16 proto-oncogenes as potential pharmacological targets. We used an immortalized hepatocyte (IHH) and five HCC cell lines under two subtypes: S1/TGFβ-Wnt-activated (HLE, HLF, and JHH6) and the S2/progenitor subtype (HepG2 and Huh7). Three treatment modalities, 5 µM 5-Azacytidine, 50 µM Sorafenib, and 20 nM PD-L1 gene silencing, were evaluated in vitro. The effect of treatments on the proto-oncogene targets was assessed by gene expression and Western blot analysis. Our results showed that 10/16 targets were upregulated in HCC cells, where cells belonging to the S2/progenitor subtype had more upregulated targets compared to the S1/TGFβ-Wnt-activated subtype (81% vs. 62%, respectively). Among the targets, FGR was consistently down-regulated in the cell lines following the three different treatments. Sorafenib was effective to down-regulate targets in S2/progenitor subtype while PD-L1 silencing was able to decrease targets in all HCC subtypes, suggesting that this treatment strategy may comprise cellular heterogeneity. This study strengthens the relevance of liver cancer cellular heterogeneity in response to cancer therapies.

Published
2023
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5. Natural Compounds for Counteracting Nonalcoholic Fatty Liver Disease (NAFLD): Advantages and Limitations of the Suggested Candidates

Author

Noel Salvoza, Pablo J. Giraudi, Claudio Tiribelli, and Natalia Rosso

Subjects
coffee, caffeine, caffeic acid, chicoric acid, tormentic acid, verbascoside, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

The booming prevalence of nonalcoholic fatty liver disease (NAFLD) in adults and children will threaten the health system in the upcoming years. The “multiple hit” hypothesis is the currently accepted explanation of the complex etiology and pathophysiology of the disease. Some of the critical pathological events associated with the development of NAFLD are insulin resistance, steatosis, oxidative stress, inflammation, and fibrosis. Hence, attenuating these events may help prevent or delay the progression of NAFLD. Despite an increasing understanding of the mechanisms involved in NAFLD, no approved standard pharmacological treatment is available. The only currently recommended alternative relies on lifestyle modifications, including diet and physical activity. However, the lack of compliance is still hampering this approach. Thus, there is an evident need to characterize new therapeutic alternatives. Studies of food bioactive compounds became an attractive approach to overcome the reticence toward lifestyle changes. The present study aimed to review some of the reported compounds with beneficial properties in NAFLD; namely, coffee (and its components), tormentic acid, verbascoside, and silymarin. We provide details about their protective effects, their mechanism of action in ameliorating the critical pathological events involved in NAFLD, and their clinical applications.

Published
2022
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6. Ficolin-2 Plasma Level Assesses Liver Fibrosis in Non-Alcoholic Fatty Liver Disease

Author

Pablo J. Giraudi, Noel Salvoza, Deborah Bonazza, Carlo Saitta, Daniele Lombardo, Biagio Casagranda, Nicolò de Manzini, Teresa Pollicino, Giovanni Raimondo, Claudio Tiribelli, Silvia Palmisano, and Natalia Rosso

Subjects
biomarkers, in silico, non-alcoholic fatty liver disease, discovery strategy, omics, blood-based tests, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

Fibrosis is the strongest predictor for disease-specific mortality in non-alcoholic fatty liver diseases (NAFLD), but the need for liver biopsy limits its diagnosis. We assessed the performance of plasma ficolin-2 (FCN-2) as a biomarker of fibrosis identified by an in silico discovery strategy. Two hundred and thirty-five morbidly obese (MO) subjects with biopsy-proven NAFLD stratified by fibrosis stage (F0, n = 44; F1, n = 134; F2, n = 46; F3/F4, n = 11) and 40 cirrhotic patients were enrolled. The cohort was subdivided into discovery (n = 76) and validation groups (n = 159). The plasma level of FCN-2 and other candidate markers was determined. FCN-2 was inversely correlated with the stage of liver fibrosis (ρ = −0.49, p < 0.001) independently of steatosis (p = 0.90), inflammation (p = 0.57), and ballooning (p = 0.59). In the global cohort, FCN-2 level decreased significantly in a stepwise fashion from F0/F1 (median 4753 ng/mL) to F2–F3–F4 (2760 ng/mL) and in cirrhotic subjects (1418 ng/mL). The diagnostic performance of FCN-2 in detecting F ≥ 2 was higher than other indexes (APRI, FIB-4) (AUROC 0.82, 0.68, and 0.6, respectively). The accuracy improved when combined with APRI score and HDL values (FCNscore, AUROC 0.85). Overall, the FCN-2 plasma level can accurately discriminate liver fibrosis status (minimal vs. moderate/advanced) significantly improving the fibrosis diagnostic algorithms.

Published
2022
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7. Silybin Modulates Collagen Turnover in an In Vitro Model of NASH

Author

Beatrice Anfuso, Pablo J. Giraudi, Claudio Tiribelli, and Natalia Rosso

Subjects
NAFLD, NASH, Silybin, fibrogenesis, coculture model, hepatic stellate cells, Organic chemistry, QD241-441
Abstract

Silybin has been proposed as a treatment for nonalcoholic steatohepatitis (NASH). In this study, we assessed the effect of Silybin in a well-established in vitro coculture model of early-stage NASH. LX2 and Huh7 cells were exposed to free fatty acid (FFA) and Silybin as mono- or coculture (SCC). Cell viability, LX2 activation, collagen deposition, metalloproteinase 2 and 9 (MMP2-9) activity, and ROS generation were determined at 24, 96, and 144 h. Exposure to FFA induced the activation of LX2 as shown by the increase in cell viability and upregulation of collagen biosynthesis. Interestingly, while cotreatment with Silybin did not affect collagen production in LX2, a significant reduction was observed in SCC. MMP2-9 activity was reduced in FFA-treated Huh7 and SCC and cotreatment with Silybin induced a dose-dependent increase, while no effect was observed in LX2. Silybin also showed antioxidant properties by reducing the FFA-induced production of ROS in all the cell systems. Based on these data, Silybin exerts its beneficial effects by reducing LX2 proliferation and ROS generation. Moreover, MMP2-9 modulation in hepatocytes represents the driving mechanism for the net reduction of collagen in this NASH in vitro model, highlighting the importance of hepatic cells interplay in NASH development and resolution.

Published
2019
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8. Effects of Oral Administration of Silymarin in a Juvenile Murine Model of Non-alcoholic Steatohepatitis

Author

Veronica Marin, Silvia Gazzin, Sabrina E. Gambaro, Matteo Dal Ben, Sonia Calligaris, Monica Anese, Alan Raseni, Claudio Avellini, Pablo J. Giraudi, Claudio Tiribelli, and Natalia Rosso

Subjects
NAFLD, NASH, fibrosis, silymarin, in vivo model, in vitro model, therapeutic approach, Nutrition. Foods and food supply, TX341-641
Abstract

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 life style 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.

Published
2017
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9. Hepatology highlights

Author

Sabrina E. Gambaro, Pablo J. Giraudi, Claudio Tiribelli, M.D.,Ph.D., and Natalia Rosso

Subjects
Specialties of internal medicine, RC581-951
Published
2015
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10. Modifications of IGF2 and EGFR plasma protein concentrations in NAFLD patients after bariatric surgery

Author

Michela Giuricin, Natalia Rosso, Pablo J. Giraudi, Silvia Palmisano, Claudio Tiribelli, Deborah Bonazza, Nicolò de Manzini, Giraudi, P. J., Giuricin, M., Bonazza, D., de Manzini, N., Tiribelli, C., Palmisano, S., and Rosso, N.

Subjects
Adult, Male, medicine.medical_specialty, Bilirubin, bariatric surgery, plasmatic proteins, Endocrinology, Diabetes and Metabolism, Bariatric Surgery, Medicine (miscellaneous), 030209 endocrinology & metabolism, 03 medical and health sciences, Liver disease, chemistry.chemical_compound, 0302 clinical medicine, Insulin-Like Growth Factor II, Non-alcoholic Fatty Liver Disease, Nonalcoholic fatty liver disease, medicine, Humans, 030212 general & internal medicine, NASH, Nutrition and Dietetics, medicine.diagnostic_test, business.industry, Albumin, Middle Aged, medicine.disease, Blood proteins, Obesity, Obesity, Morbid, Surgery, ErbB Receptors, Treatment Outcome, chemistry, Liver biopsy, Female, Glycated hemoglobin, business
Abstract

Background: Nonalcoholic fatty liver disease (NAFLD) is strictly associated with the epidemic of obesity and is becoming the most prevalent liver disease worldwide. In severe obesity, bariatric surgery (BS) is the most effective treatment not only for obesity but also for the associated metabolic co-morbidities, NAFLD, among others. To date, noninvasive diagnostic/prognostic methods cannot evaluate hepatic improvements following surgery. Objectives: We aimed to measure plasma level of insulin-growth factor-2 protein (IGF2) and epithermal growth factor receptor (EGFR), and to assess their relationship with clinical and biochemical parameters during the 12 months follow-up. Methods: Demographic, clinical–biochemical data, and plasma IGF2 and EGFR were measured in 69 patients preoperatively (T0) and 6 and 12 months (T6M and T12M, respectively) after BS. Liver biopsy was performed at T0. Relationships between IGF2, EGFR, and several biochemical parameters were performed using Pearson or Spearman correlation analysis. Results: IGF2 plasma level increases during follow-up, passing from 2.5 (1.8–15.5) at baseline to 13.3 (8.6–19.1) at T12M, p < 0.001. Conversely, EGFR showed a not significant reduction. At T12M, the plasma level of both markers was comparable to those of lean subjects. The clinical–biochemical parameters (BMI, glycated hemoglobin, HOMA-IR) also return to the normal range at T12M. Correlation analysis demonstrated that IGF2 was significantly associated with total bilirubin, direct bilirubin, and albumin at T0 while with blood glucose, ALT, GGT, and AST/ALT ratio at T6M and T12M. Conclusions: IGF2 plasma levels increase after bariatric surgery, and these changes are associated with the modification of hepatic biochemical parameters, even if other clinic or metabolic improvements cannot be excluded.

Published
2020

11. Sex differences in non-alcoholic fatty liver disease: hints for future management of the disease

Author

Pablo J. Giraudi, Noel C. Salvoza, Claudio Tiribelli, and Natalia Rosso

Subjects
nonalcoholic fatty liver disease, sex differences, 0301 basic medicine, hormones, gut microbiota, business.industry, Fatty liver, Physiology, 030209 endocrinology & metabolism, Non alcoholic, Disease, medicine.disease, Other systems of medicine, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, inflammation, insulin resistance, lipid metabolism, oxidative stress, Medicine, business, metabolites, RZ201-999
Abstract

Non-alcoholic fatty liver disease (NAFLD) remains a major cause of chronic liver disease worldwide. Despite extensive studies, the heterogeneity of the risk factors as well as different disease mechanisms complicate the goals toward effective diagnosis and management. Recently, it has been shown that sex differences play a role in the prevalence and progression of NAFLD. In vitro, in vivo, and clinical studies revealed that the lower prevalence of NAFLD in premenopausal as compared to postmenopausal women and men is mainly due to the protective effects of estrogen and body fat distribution. It has been also described that males and females present differential pathogenic features in terms of biochemical profiles and histological characteristics. However, the exact molecular mechanisms for the gender differences that exist in the pathogenesis of NAFLD are still elusive. Lipogenesis, oxidative stress, and inflammation play a key role in the progression of NAFLD. For NAFLD, only a few studies characterized these mechanisms at the molecular level. Therefore, we aim to review the reported differential molecular mechanisms that trigger such different pathogenesis in both sexes. Differences in lipid metabolism, glucose homeostasis, oxidative stress, inflammation, and fibrosis were discussed based on the evidence reported in recent publications. In conclusion, with this review, we hope to provide a new perspective for the development of future practice guidelines as well as a new avenue for the management of the disease.

Published
2020

12. Global multi-stakeholder endorsement of the MAFLD definition

Author

Nahum Méndez-Sánchez, Elisabetta Bugianesi, Robert G Gish, Frank Lammert, Herbert Tilg, Mindie H Nguyen, Shiv K Sarin, Núria Fabrellas, Shira Zelber-Sagi, Jian-Gao Fan, Gamal Shiha, Giovanni Targher, Ming-Hua Zheng, Wah-Kheong Chan, Shlomo Vinker, Takumi Kawaguchi, Laurent Castera, Yusuf Yilmaz, Marko Korenjak, C Wendy Spearman, Mehmet Ungan, Melissa Palmer, Mortada El-Shabrawi, Hans-Juergen Gruss, Jean-François Dufour, Anil Dhawan, Heiner Wedemeyer, Jacob George, Luca Valenti, Yasser Fouad, Manuel Romero‐Gomez, Mohammed Eslam, Maria Lorena Abate, Bahaa Abbas, Ahmed Amr Abbassy, Waleed Abd El Ghany, Amira Abd Elkhalek, Emad Abd ElMajeed, Mohammad Abdalgaber, Mohamed AbdAllah, Marwa Abdallah, Nourhan Abdallah, Shereen Abdelaleem, Yasser Abdelghani, Wael Abdelghany, Safaa Mohamed Abdelhalim, Wafaa Abdelhamid, Nehal Abdelhamid, Nadia A. Abdelkader, Elsayed Abdelkreem, Aly Mohamed Abdelmohsen, Awny Ali Abdelrahman, Sherief M Abd-elsalam, Doaa Abdeltawab, Abdulbaset Abduh, Nada Abdulhakam, Maheeba Abdulla, Navid Abedpoor, Ludovico Abenavoli, Fredrik Åberg, Omala Ablack, Mostafa Abo elftouh, Yousry Esam-Eldin Abo-Amer, Ashraf Aboubkr, Alaa Aboud, Amr M. Abouelnaga, Galal A. Aboufarrag, Ashraf Aboutaleb, Leticia Abundis, Gupse Adalı, Enrique Adames, Leon Adams, Danjuma Adda, Noor Adel, Nada Adel, Muhammad Adel Sayed, Taiba Jibril Afaa, Nawal Afredj, Gulnara Aghayeva, Alessio Aghemo, Carlos A. Aguilar-Salinas, Golo Ahlenstiel, Walid Ahmady, Wafaa Ahmed, Amira Ahmed, Samah Nasser Ahmed, Heba Mostafa Ahmed, Rasha Ahmed, Elmar Aigner, Mesut Akarsu, Maisam Akroush, Umit Akyuz, Mamun Al Mahtab, Tahani Al Qadiri, Yusriya Al Rawahi, Razzaq AL rubaee, Muna Al Saffar, Shahinul Alam, Zaid Al-Ani, Agustín Albillos, Mohamed Alboraie, Said Al-Busafi, Mohamed Al-Emam, Jawaher Alharthi, Kareem Ali, Basma Abdelmoez Ali, Mohammad Ali, Raja Affendi Raja Ali, Anna Alisi, Ali Raad AL-Khafaji, Maryam Alkhatry, Rocio Aller, Yahya Almansoury, Khalid Al-Naamani, Alaa Alnakeeb, Anna Alonso, Saleh A. Alqahtani, Leina Alrabadi, Khalid Alswat, Mahir Altaher, Turki Altamimi, Jose Altamirano, Mario R. Alvares-da-Silva, Elsragy Adel M. Aly, Amgad Alzahaby, Ahmed Alzamzamy, Keisuke Amano, Maysa A. Amer, Mona A. Amin, Sayed A. Amin, Ashraf A. Amir, Javier Ampuero, Noha Anas, Pietro Andreone, Soa Fy Andriamandimby, Mahmoud Anees, Peltec Angela, Manal Antonios, Wael Arafat, Jose Moreno Araya, Juan Armendariz-Borunda, Matthew J. Armstrong, Hassan Ashktorab, Patricia Aspichueta, Fathia Assal, Mira Atef, Dina Attia, Hoda Atwa, Reham Awad, Mohyeldeen Abd Elaziz Awad, Sally Awny, Obafemi Awolowo, Yaw Asante Awuku, Ibrahim Ayada, Than Than Aye, Sherif Ayman, Hedy Ayman, Hesham Ayoub, Hosny M. Azmy, Romiro P. Babaran, Omneya Badreldin, Ahmed Badry, İbrahim Halil Bahçecioğlu, Amira Bahour, Jiajia Bai, Yasemin Balaban, Muthuswamy Balasubramanyam, Khaled Bamakhrama, Jesus M Banales, Babu Bangaru, Jianfeng Bao, Jorge Suazo Barahona, Salma Barakat, Sandra Maria Barbalho, Bikwa Barbra, Beatriz Barranco, Francisco Barrera, Ulrich Baumann, Shamardan Bazeed, Eva Bech, Aourarh Benayad, Andreas Benesic, David Bernstein, Fernando Bessone, Susie Birney, Cyrille Bisseye, Martin Blake, Bilal Bobat, Leonilde Bonfrate, Dmitry S Bordin, Francisco Bosques-Padilla, Jerome Boursier, Boushab Mohamed Boushab, David Bowen, Patricia Medina Bravo, Paul N Brennan, Bisi Bright, Ilse Broekaert, Xabier Buque, Diego Burgos-Santamaría, Julio Burman, Luca Busetto, Chris D. Byrne, Patricia Anne I. Cabral-Prodigalidad, Guillermo Cabrera-Alvarez, Wei Cai, Francesca Cainelli, Ali Riza Caliskan, Ali Canbay, Ana Cano-Contreras, Hai-Xia Cao, Zhujun Cao, Andres Carrion, Francesca Carubbi, Teresa Casanovas, Marlen Ivón Castellanos Fernández, Jin Chai, Siew Pheng Chan, Phunchai Charatcharoenwitthaya, Norberto Chavez-Tapia, Kazuaki Chayama, Jinjun Chen, Lin Chen, Zhong-Wei Chen, Huiting Chen, Sui-Dan Chen, Qiang Chen, Yaxi Chen, Gang Chen, En-Quang Chen, Fei Chen, Pei-Jer Chen, Robert Cheng, Wendy Cheng, Jack Tan Wei Chieh, Imad Chokr, Evangelos Cholongitas, Ashok Choudhury, Abhijit Chowdhury, Evaristus Sunday Chukwudike, Stefano Ciardullo, Michelle Clayton, Karine Clement, Marie Michelle Cloa, Cecilia Coccia, Cristina Collazos, Massimo Colombo, Arif Mansur Cosar, Helma Pinchemel Cotrim, Joris Couillerot, Alioune Coulibaly, Gonzalo Crespo, Javier Crespo, Maria Cruells, Ian Homer Y. Cua, Hesham K. Dabbous, George N Dalekos, Patricia D'Alia, Li Dan, Viet Hang Dao, Mostafa Darwish, Christian Datz, Milagros B Davalos-Moscol, Heba Dawoud, Blanca Olaechea de Careaga, Robert de Knegt, Victor de Ledinghen, Janaka de Silva, Nabil Debzi, Marie Decraecker, Elvira Del Pozo, Teresa C Delgado, Manuel Delgado-Blanco, Łukasz Dembiński, Adilson Depina, Moutaz Derbala, Hailemichael Desalegn, Christèle Desbois-Mouthon, Mahmoud Desoky, Anouk Dev, Agostino Di Ciaula, Moisés Diago, Ibrahima Diallo, Luis Antonio Díaz, Melisa Dirchwolf, Paola Dongiovanni, Andrriy Dorofeyev, Xiaoguang Dou, Mark W. Douglas, Michael Doulberis, Cecil K. Dovia, Adam Doyle, Ivana Dragojević, Joost PH Drenth, Xuefei Duan, Audrius Dulskas, Dan L Dumitrascu, Oliver Duncan, Vincent Dusabejambo, Rev. Shem N.A. Dwawhi, Sho Eiketsu, Doaa El Amrousy, Ahmed El Deeb, Ghada El Deriny, Hesham Salah El Din, Salwa El Kamshishy, Mohamed El Kassas, Maissa El Raziky, Osama A Elagamy, Wafaa Elakel, Dina Elalfy, Hanaa Elaraby, Heba ElAwady, Reda Elbadawy, Hanaa Hassan Eldash, Manal S. Eldefrawy, Carol Lezama Elecharri, Amel Elfaramawy, Mohammed Elfatih, Mahmoud Elfiky, Mohamed Elgamsy, Mohamed Elgendy, Mohamed A. El-Guindi, Nagi Elhussieny, Ahmed Maher Eliwa, Zeineb Elkabbany, Hesham El-Khayat, Nehal M. El-Koofy, Alaa Elmetwalli, Amr Elrabat, Fathiya El-Raey, Fatma Elrashdy, Medhat Elsahhar, Esraa M. Elsaid, Shimaa Elsayed, Hany Elsayed, Aly Elsayed, Amr M. Elsayed, Hamdy Elsayed, Magdy El-Serafy, Ahmed M. Elsharkawy, Reem Yehia Elsheemy, Eman Elsayed Elshemy, Sara Elsherbini, Naglaa Eltoukhy, Reda Elwakil, Ola Emad, Shaimaa Emad, Mohamed Embabi, Ilkay Ergenç, Tatiana Ermolova, Gamal Esmat, Doaa M. Esmat, Enrique Carrera Estupiñan, Said Ettair, Tcaciuc Eugen, Mohammed Ezz-Eldin, Lidia Patricia Valdivieso Falcón, Yu-Chen Fan, Samah Fandari, Mahmoud Farag, Taghreed Mohamed Farahat, Eman M. Fares, Michael Fares, Eduardo Fassio, Hayam Fathy, Dina Fathy, Wael Fathy, Soheir Fayed, Dan Feng, Gong Feng, Miguel Fernández-Bermejo, Cristina Targa Ferreira, Javier Díaz Ferrer, Alastair Forbes, Rabab Fouad, Hanan M. Fouad, Tove Frisch, Hideki Fujii, Shuhei Fukunaga, Shinya Fukunishi, Hacer Fulya, Masato Furuhashi, Yasmine Gaber, Augusto Jose G. Galang, Jacqueline Cordova Gallardo, Rocío Galloso, Mahmoud Gamal, Reham Gamal, Hadeel Gamal, Jian Gan, Anar Ganbold, Xin Gao, George Garas, Tony Garba, Miren García-Cortes, Carmelo García-Monzón, Javier García-Samaniego, Amalia Gastaldelli, Manuel Gatica, Elizabeth Gatley, Tamar Gegeshidze, Bin Geng, Hasmik Ghazinyan, Salma Ghoneem, Luca Giacomelli, Gianluigi Giannelli, Edoardo G. Giannini, Matthew Giefer, Pere Ginès, Marcos Girala, Pablo J Giraudi, George Boon-Bee Goh, Ahmed Ali Gomaa, Benbingdi Gong, Dina Hilda C. Gonzales, Humberto C. Gonzalez, Maria Saraí Gonzalez-Huezo, Isabel Graupera, Ivica Grgurevic, Henning Grønbæk, Xuelian Gu, Lin Guan, Ibrahima Gueye, Alice Nanelin Guingané, Ozen Oz Gul, Cuma Bulent Gul, Qing Guo, Pramendra Prasad Gupta, Ahmet Gurakar, Juan Carlos Restrepo Gutierrez, Ghada Habib, Azaa Hafez, Emilia Hagman, Eman Halawa, Osama Hamdy, Abd Elkhalek Hamed, Dina H. Hamed, Saeed Hamid, Waseem Hamoudi, Yu Han, James Haridy, Hanan Haridy, David C H Harris Harris, Michael Hart, Fuad Hasan, Almoutaz Hashim, Israa Hassan, Ayman Hassan, Essam Ali Hassan, Adel Ahmed Hassan, Magda Shehata Hassan, Fetouh Hassanin, Alshymaa Hassnine, John Willy Haukeland, Amr Ismael M. Hawal, Jinfan He, Qiong He, Yong He, Fang-Ping He, Mona Hegazy, Adham Hegazy, Osama Henegil, Nelia Hernández, Manuel Hernández-Guerra, Fatima Higuera-de-la-Tijera, Ibrahim Hindy, Keisuke Hirota, Lee Chi Ho, Alexander Hodge, Mohamed Hosny, Xin Hou, Jiao-Feng Huang, Yan Huang, Zhifeng Huang, Yuan Huang, Ang Huang, Xiao-Ping Huang, Sheng Hui-ping, Bela Hunyady, Mennatallah A. Hussein, Osama Hussein, Shahinaz Mahmoud Hussien, Luis Ibáñez-Samaniego, Jamal Ibdah, Luqman Ibrahim, Miada Ibrahim, Ibrahim Ibrahim, Maria E. 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Khalaf, Rofida Khalefa, Sherin Khamis, Doaa Khater, Hamed khattab, Anatoly Khavkin, Olga Khlynova, Nabil Khmis, Nazarii Kobyliak, Apostolos Koffas, Kazuhiko Koike, Kenneth Y.Y. Kok, Tomas Koller, Narcisse Patrice Komas, Nataliya V. Korochanskaya, Yannoula Koulla, Shunji Koya, Colleen Kraft, Bledar Kraja, Marcin Krawczyk, Mohammad Shafi Kuchay, Anand V Kulkarni, Ashish Kumar, Manoj Kumar, Sulaiman Lakoh, Philip Lam, Ling Lan, Naomi F. Lange, Kamran Bagheri Lankarani, Nicolas Lanthier, Kateryna Lapshyna, Sameh A. Lashen, Konang Nguieguia Justine Laure, Leonid Lazebnik, Didier Lebrec, Samuel S. 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Mina, Milan Mishkovik, Amal Mishriki, Tim Mitchell, Alshaimaa Mohamed, Mona Mohamed, Sofain Mohamed, Shady Mohammed, Ahmed Mohammed, Viswanathan Mohan, Sara Mohie, Aalaa Mokhtar, Reham Moniem, Mabel Segura Montilla, Jose Antonio Orozco Morales, María María Sánchez Morata, Jose Maria Moreno-Planas, Silvia Morise, Sherif Mosaad, Mohamed Moselhy, Alaa Mohamed Mostafa, Ebraheem Mostafa, Nezha Mouane, Nasser Mousa, Hamdy Mahfouz Moustafa, Abeer Msherif, Kate Muller, Christopher Munoz, Ana Beatriz Muñoz-Urribarri, Omar Alfaro Murillo, Feisul Idzwan Mustapha, Emir Muzurović, Yehia Nabil, Shaymaa Nafady, Ayu Nagamatsu, Atsushi Nakajima, Dan Nakano, Yuemin Nan, Fabio Nascimbeni, Mirella S. Naseef, Nagwa Nashat, Taran Natalia, Francesco Negro, Alexander V. 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Hasan, F, Hashim, A, Hassan, I, Hassan, A, Hassan, E, Hassan, M, Hassanin, F, Hassnine, A, Haukeland, J, Hawal, A, He, J, He, Q, He, Y, He, F, Hegazy, M, Hegazy, A, Henegil, O, Hernandez, N, Hernandez-Guerra, M, Higuera-de-la-Tijera, F, Hindy, I, Hirota, K, Ho, L, Hodge, A, Hosny, M, Hou, X, Huang, J, Huang, Y, Huang, Z, Huang, A, Huang, X, Hui-ping, S, Hunyady, B, Hussein, M, Hussein, O, Hussien, S, Ibanez-Samaniego, L, Ibdah, J, Ibrahim, L, Ibrahim, M, Ibrahim, I, Icaza-Chavez, M, Idelbi, S, Idilman, R, Ikeda, M, Indolfi, G, Invernizzi, F, Irshad, I, Isa, H, Iskandar, N, Ismaiel, A, Ismail, M, Ismail, Z, Ismail, F, Iwamoto, H, Jack, K, Jacob, R, Jafarov, F, Jafri, W, Jahshan, H, Jalal, P, Jancoriene, L, Janicko, M, Jayasena, H, Jefferies, M, Jha, V, Ji, F, Ji, Y, Jia, J, Jiang, C, Jiang, N, Jiang, Z, Jin, X, Jin, Y, Jing, X, Jingyu, Q, Jinjolava, M, Jong, F, Jucov, A, Julius, I, Kaddah, M, Kamada, Y, Kamal, A, Kamal, E, Kamel, A, Kao, J, Karin, M, Karlas, T, Kashwaa, M, Katsidzira, L, Kaya, E, Kayasseh, M, Keenan, B, Keklikkiran, C, Keml, W, Khalaf, D, Khalefa, R, Khamis, S, Khater, D, Khattab, H, Khavkin, A, Khlynova, O, Khmis, N, Kobyliak, N, Koffas, A, Koike, K, Kok, K, Koller, T, Komas, N, Korochanskaya, N, Koulla, Y, Koya, S, Kraft, C, Kraja, B, Krawczyk, M, Kuchay, M, Kulkarni, A, Kumar, A, Kumar, M, Lakoh, S, Lam, P, Lan, L, Lange, N, Lankarani, K, Lanthier, N, Lapshyna, K, Lashen, S, Laure, K, Lazebnik, L, Lebrec, D, Lee, S, Lee, W, Lee, Y, Leeming, D, Leite, N, Leon, R, Lesmana, C, Li, J, Li, Q, Li, Y, Li, L, Li, M, Liang, H, Lijuan, T, Lim, S, Lim, L, Lin, S, Lin, H, Lin, R, Lithy, R, Liu, Y, Liu, X, Liu, W, Liu, S, Liu, K, Liu, T, Lonardo, A, Lopez, M, Lopez-Benages, E, Lopez-Jaramillo, P, Lu, H, Lu, L, Lu, Y, Lubel, J, Lui, R, Lupasco, I, Luzina, E, Lv, X, Lynch, K, Ma, H, Machado, M, Maduka, N, Madzharova, K, Magdaong, R, Mahadeva, S, Mahfouz, A, Mahmood, N, Mahmoud, E, Mahrous, M, Maiwall, R, Majeed, A, Majumdar, A, Mak, L, Maklouf, M, Malekzadeh, R, Mandato, C, Mangia, A, Mann, J, Mansour, H, Mansouri, A, Mantovani, A, Mao, J, Maramag, F, Marchesini, G, Marcus, C, Marinho, R, Martinez-Chantar, M, Martins, A, Marwan, R, Mason, K, Masoud, G, Massoud, M, Matamoros, M, Mateos, R, Mawed, A, Mbanya, J, Mbendi, C, Mccolaugh, L, Mcleod, D, Medina, J, Megahed, A, Mehrez, M, Memon, I, Merat, S, Mercado, R, Mesbah, A, Meskini, T, Metwally, M, Metwaly, R, Miao, L, Micah, E, Miele, L, Milivojevic, V, Milovanovic, T, Mina, Y, Mishkovik, M, Mishriki, A, Mitchell, T, Mohamed, A, Mohamed, M, Mohamed, S, Mohammed, S, Mohammed, A, Mohan, V, Mohie, S, Mokhtar, A, Moniem, R, Montilla, M, Morales, J, Morata, M, Moreno-Planas, J, Morise, S, Mosaad, S, Moselhy, M, Mostafa, A, Mostafa, E, Mouane, N, Mousa, N, Moustafa, H, Msherif, A, Muller, K, Munoz, C, Munoz-Urribarri, A, Murillo, O, Mustapha, F, Muzurovic, E, Nabil, Y, Nafady, S, Nagamatsu, A, Nakajima, A, Nakano, D, Nan, Y, Nascimbeni, F, Naseef, M, Nashat, N, Natalia, T, Negro, F, Nersesov, A, Neuman, M, Ng'Wanasayi, M, Ni, Y, Nicoll, A, Niizeki, T, Nikolova, D, Ningning, W, Niriella, M, Nogoibaeva, K, Nordien, R, O Sullivan, C, O'Beirne, J, Obekpa, S, Ocama, P, Ochwoto, M, Ogolodom, M, Ojo, O, Okrostsvaridze, N, Oliveira, C, Omana, R, Omar, O, Omar, H, Omar, M, Omran, S, Omran, R, Osman, M, Owise, N, Owusu-Ansah, T, Padilla- Machaca, P, Palle, S, Pan, Z, Pan, X, Pan, Q, Papaefthymiou, A, Paquissi, F, Par, G, Parkash, A, Payawal, D, Peltekian, K, Peng, X, Peng, L, Peng, Y, Pengoria, R, Perez, M, Perez, J, Perez, N, Persico, M, Pessoa, M, Petta, S, Philip, M, Plaz Torres, M, Polavarapu, N, Poniachik, J, Portincasa, P, Pu, C, Purnak, T, Purwanto, E, Qi, X, Qian, Z, Qiang, Z, Qiao, Z, Qiao, L, Queiroz, A, Rabiee, A, Radwan, M, Rahetilahy, A, Ramadan, Y, Ramadan, D, Ramli, A, Ramm, G, Ran, A, Rankovic, I, Rao, H, Raouf, S, Ray, S, Reau, N, Refaat, A, Reiberger, T, Remes-Troche, J, Reyes, E, Richardson, B, Ridruejo, E, Riestra Jimenez, S, Rizk, I, Roberts, S, Roblero, J, Robles, J, Rockey, D, Rodriguez, M, Rodriguez Hernandez, H, Roman, E, Romeiro, F, Romeo, S, Rosales-Zabal, J, Roshdi, G, Rosso, N, Ruf, A, Ruiz, P, Runes, N, Ruzzenente, A, Ryan, M, Saad, A, Sabbagh, E, Sabbah, M, Saber, S, Sabrey, R, Sabry, R, Saeed, M, Said, D, Said, E, Sakr, M, Salah, Y, Salama, R, Salama, A, Saleh, H, Saleh, A, Salem, A, Salifou, A, Salih, A, Salman, A, Samouda, H, Sanai, F, Sanchez-Avila, J, Sanker, L, Sano, T, Sanz, M, Saparbu, T, Sawhney, R, Sayed, F, Sayed, S, Sayed, A, Sayed, M, Sebastiani, G, Secadas, L, Sediqi, K, Seif, S, Semida, N, Senates, E, Serban, E, Serfaty, L, Seto, W, Sghaier, I, Sha, M, Shabaan, H, Shalaby, L, Shaltout, I, Sharara, A, Sharma, V, Shawa, I, Shawkat, A, Shawky, N, Shehata, O, Sheils, S, Shewaye, A, Shi, G, Shi, J, Shimose, S, Shirono, T, Shou, L, Shrestha, A, Shui, G, Sievert, W, Sigurdardottir, S, Sira, M, Siradj, R, Sison, C, Smyth, L, Soliman, R, Sollano, J, Sombie, R, Sonderup, M, Sood, S, Soriano, G, Stedman, C, Stefanyuk, O, Stimac, D, Strasser, S, Strnad, P, Stuart, K, Su, W, Su, M, Sumida, Y, Sumie, S, Sun, D, Sun, J, Suzuki, H, Svegliati-Baroni, G, Swar, M, Taharboucht, S, Taher, Z, Takamura, S, Tan, L, Tan, S, Tanwandee, T, Tarek, S, Tatiana, G, Tavaglione, F, Tecson, G, Tee, H, Teschke, R, Tharwat, M, Thong, V, Thursz, M, Tine, T, Tiribelli, C, Tolmane, I, Tong, J, Tongo, M, Torkie, M, Torre, A, Torres, E, Trajkovska, M, Treeprasertsuk, S, Tsutsumi, T, Tu, T, Tur, J, Turan, D, Turcan, S, Turkina, S, Tutar, E, Tzeuton, C, Ugiagbe, R, Uygun, A, Vacca, M, Vajro, P, Van der Poorten, D, Van Kleef, L, Vashakidze, E, Velazquez, C, Velazquez, M, Vento, S, Verhoeven, V, Vespasiani-Gentilucci, U, Vethakkan, S, Vilaseca, J, Vitek, L, Volkanovska, A, Wallace, M, Wan, W, Wang, Y, Wang, X, Wang, C, Wang, M, Wangchuk, P, Weltman, M, White, M, Wiegand, J, Wifi, M, Wigg, A, Wilhelmi, M, William, R, Wittenburg, H, Wu, S, Wubeneh, A, Xia, H, Xiao, J, Xiao, X, Xiaofeng, W, Xiong, W, Xu, L, Xu, J, Xu, W, Xu, K, Xu, Y, Xu, S, Xu, M, Xu, A, Xu, C, Yan, H, Yang, J, Yang, R, Yang, Y, Yang, Q, Yang, N, Yao, J, Yara, J, Yaras, S, Yilmaz, N, Younes, R, Younes, H, Young, S, Youssef, F, Yu, Y, Yu, M, Yuan, J, Yue, Z, Yuen, M, Yun, W, Yurukova, N, Zakaria, S, Zaky, S, Zaldastanishvili, M, Zapata, R, Zare, N, Zerem, E, Zeriban, N, Zeshuai, X, Zhang, H, Zhang, X, Zhang, Y, Zhang, W, Zhang, Z, Zhao, J, Zhao, R, Zhao, H, Zheng, C, Zheng, Y, Zheng, R, Zheng, T, Zheng, K, Zhou, X, Zhou, Y, Zhou, H, Zhou, L, Zhu, L, Zhu, Y, Zhu, P, Ziada, E, Ziring, D, Ziyi, L, Zou, S, Zou, Z, Zou, H, Zuart Ruiz, R, and Global Multi-Stakeholder Consensus on the Redefinition of Fatty Liver Disease

Subjects
Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], Hepatology, Non-alcoholic Fatty Liver Disease, NAFLD, consensu, Gastroenterology, MAFLD, definition, Humans, MAFLD, NAFLD, Human medicine
Abstract

Contains fulltext : 252162.pdf (Publisher’s version ) (Closed access)

Published
2022

14. Diagnostic management of nonalcoholic fatty liver disease: a transformational period in the development of diagnostic and predictive tools-a narrative review

Author

Natalia Rosso, Claudio Tiribelli, Pablo J. Giraudi, and Adam M. Stephenson

Subjects
medicine.medical_specialty, business.industry, medicine.medical_treatment, General Medicine, Disease, Liver transplantation, Diagnostic tools, medicine.disease, Transformational leadership, Nonalcoholic fatty liver disease, Health care, medicine, Profiling (information science), Narrative review, Intensive care medicine, business, Review Article on Unresolved Basis Issues in Hepatology
Abstract

NAFLD is an emerging healthcare epidemic that is causing predictable adverse consequences for healthcare systems, societies and individuals. Whilst NAFLD is recognized as a multi-system disease with compound pathways that are both benign and pernicious in their unfolding; NASH is generally understood as a deleterious follow-on condition with path-specific tendencies that progress to cirrhosis, HCC and liver transplantation. Recent evidence is beginning to challenge this interpretation demanding more attention to the personalized nature of the disease and its pathogenesis across multiple different cohorts. This means that we need better diagnostic and prognostic tools not only to capture those 'at risk' disease phenotypes; but for better stratification and monitoring of patients according to their treatment strategies. With the advent of pipeline therapies for NASH underway, the medical profession looks to adopt more accurate non-invasive diagnostic tools that can help to delineate and eliminate NASH histology. This review looks at the search for the killer application revealing this particular moment in time as a transformational period; one that is pushing the boundaries of technology to integrate diverse panels of species through sensitive profiling and multi-omics approaches that cast wide, yet powerful diagnostic nets that have the potential to elucidate pathway specific biomarkers that are personalized and predictable.

Published
2021

16. Optimization of Point-Shear Wave Elastography by Skin-to-Liver Distance to Assess Liver Fibrosis in Patients Undergoing Bariatric Surgery

Author

Fabrizio Zanconati, Lory Saveria Crocè, Stefano Palmucci, Antonio Basile, Claudio Tiribelli, Natalia Rosso, Nicolò de Manzini, Pablo J. Giraudi, Silvia Palmisano, Mauro Giuffrè, Deborah Bonazza, Michela Giuricin, Flora Masutti, Giuffre, Mauro, Giuricin, M., Bonazza, D., Rosso, N., Giraudi, P. J., Masutti, F., Palmucci, S., Basile, A., Zanconati, F., De Manzini, N., Tiribelli, C., Palmisano, S., and Croce, L. S.

Subjects
medicine.medical_specialty, bariatric surgery, Clinical Biochemistry, Logistic regression, Abdominal wall, Abdominal wall thickness, Bariatric surgery, Liver biopsy, Liver elastography, Liver fibrosis, Liver histology, NAFLD, Non-alcoholic fatty liver disease, Non-alcoholic steatohepatitis, Likelihood ratios in diagnostic testing, Article, 03 medical and health sciences, 0302 clinical medicine, Region of interest, abdominal wall thickness, medicine, liver elastography, liver fibrosis, non-alcoholic fatty liver disease, abdominal wall, liver biopsy, liver histology, non-alcoholic steatohepatitis, lcsh:R5-920, Fibrous capsule of Glisson, medicine.diagnostic_test, business.industry, Ultrasound, Liver fibrosi, Surgery, Abdominal wall thickne, 030220 oncology & carcinogenesis, 030211 gastroenterology & hepatology, Elastography, lcsh:Medicine (General), business, Body mass index
Abstract

Background: Obesity is a primary limiting factor in liver stiffness measurement (LSM). The impact of obesity has always been evaluated in terms of body mass index (BMI), without studying the effects of skin-to-liver distance (SLD) on LSM. We studied the impact of SLD on LSM in a cohort of obese patients undergoing bariatric surgery and intra-operatory liver biopsy. Materials and Methods: 299 patients underwent LSM by point-shear wave elastography (ElastPQ protocol), with two different ultrasound machines. SLD was measured as the distance between the skin and the liver capsule, perpendicular to where the region of interest (ROI) was positioned. We used the following arbitrary cut-offs

Published
2020

17. Differentiation between stages of non-alcoholic fatty liver diseases using surface-enhanced Raman spectroscopy

Author

Michela Giuricin, Claudio Tiribelli, Valter Sergo, Elisa Gurian, Alois Bonifacio, Fabrizio Zanconati, Nicolò de Manzini, Deborah Bonazza, Pablo J. Giraudi, Silvia Palmisano, Natalia Rosso, Gurian, E., Giraudi, P., Rosso, N., Tiribelli, C., Bonazza, D., Zanconati, F., Giuricin, M., Palmisano, S., de Manzini, N., Sergo, V., and Bonifacio, A.

Subjects
Adult, Male, medicine.medical_specialty, Cirrhosis, Surface Properties, 02 engineering and technology, Spectrum Analysis, Raman, digestive system, 01 natural sciences, Biochemistry, Gastroenterology, Analytical Chemistry, symbols.namesake, chemistry.chemical_compound, Non-alcoholic Fatty Liver Disease, Internal medicine, NAFLD, medicine, Humans, Environmental Chemistry, Spectroscopy, Hypoxanthine, SERS, Surface enhanced Raman spectroscopy, 010401 analytical chemistry, Fatty liver, NASH, nutritional and metabolic diseases, Non alcoholic, Middle Aged, Surface-enhanced Raman spectroscopy, 021001 nanoscience & nanotechnology, medicine.disease, digestive system diseases, 0104 chemical sciences, chemistry, symbols, Uric acid, Female, Steatohepatitis, 0210 nano-technology, Raman spectroscopy
Abstract

Non-alcoholic fatty liver disease (NAFLD) is a chronic disorder progressing from an initial benign accumulation of fat (NAFL) towards steatohepatitis (NASH), a degenerative form that can lead to liver cirrhosis and cancer. The development of non-invasive, rapid and accurate method to diagnose NASH is of high clinical relevance. Surface-enhanced Raman spectroscopy (SERS) of plasma was tested as a method to distinguish NAFL from NASH. SERS spectra from plasma of female patients diagnosed with NAFL (n = 32) and NASH (n = 35) were obtained in few seconds, using a portable Raman spectrometer. The sample consisted of 5 μL of biofluid deposited on paper coated with Ag nanoparticles. The spectra show consistent differences between the NAFL and NASH patients, with the uric acid/hypoxanthine band area ratio statistically different (p-value

Published
2020

18. Occult hepatitis B virus infection predicts non-alcoholic steatohepatitis in severely obese individuals from Italy

Author

Carlo Saitta, Daniele Lombardo, Giovanni Raimondo, Giuseppe Navarra, Antonio Ieni, Angela Alibrandi, Natalia Rosso, Deborah Bonazza, Pablo J. Giraudi, Silvia Palmisano, Claudio Tiribelli, Lazzara S, Teresa Pollicino, Raimondo, Giovanni, Saitta, Carlo, Lombardo, Daniele, Giraudi, Pablo J, Rosso, Natalia, Ieni, Antonio, Lazzara, Salvatore, Palmisano, Silvia, Bonazza, Deborah, Alibrandi, Angela, Navarra, Giuseppe, Tiribelli, Claudio, and Pollicino, Teresa

Subjects
Adult, Male, medicine.medical_specialty, Hepatitis B virus, obesity, Cirrhosis, Carcinoma, Hepatocellular, Chronic liver disease, Gastroenterology, Liver disease, genetic polymorphisms, Non-alcoholic Fatty Liver Disease, Diabetes mellitus, Internal medicine, medicine, Humans, genetic polymorphism, diabetes, genetic polymorphisms, non-alcoholic fatty liver, obesity, occult HBV infection, diabetes, non-alcoholic fatty liver, occult HBV infection, Aged, Hepatology, medicine.diagnostic_test, business.industry, Fatty liver, Liver Neoplasms, medicine.disease, Hepatitis B, digestive system diseases, Italy, diabete, Liver biopsy, Hepatocellular carcinoma, Female, Steatohepatitis, business
Abstract

Background & aims Obesity is associated with non-alcoholic fatty liver (NAFL), which may progress towards non-alcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma (HCC). Occult hepatitis B virus infection (OBI) may contribute to hepatic damage in patients with chronic liver disease of different aetiologies (eg HCV, alcohol). However, information on the prevalence and clinical impact of OBI in obese individuals is lacking. The aims of this study were to investigate NASH prevalence and risk factors in obese people who underwent bariatric surgery. Methods Two-hundred and twenty-six subjects (160 females; mean age 42.9 years ±10.8 SD) without evidence of any further cause of liver disease consecutively underwent bariatric surgery in two Italian liver centers. During surgery, all patients underwent liver biopsy for histological evaluation and molecular studies. Liver DNA extracts were tested for PNPLA3, TM6SF2, MBOAT7, IRGM polymorphisms and for OBI. Univariate and multivariate analyses were used to identify predictors of NASH. Results Histology showed NASH in 115 (50.9%) and NAFL in 111 cases (49.1%). Twenty-nine/226 (12.8%) cases had OBI, 24 (82.8%) of whom had NASH and 5 (17.2%) NAFL, whereas among the 197 OBI-negative cases, 91 (46.2%) had NASH and 106 (53.8%) NAFL (P = .0002). Multivariate analysis showed that older age (P = .03, OR 1.034), alanine aminotransferase values (P = .005, OR 1.023), insulin resistance/diabetes (P = .02, OR 2.257), TM6SF2 polymorphism (P = .04, OR 3.168) and OBI (P = .004, OR 5.503) were independent predictors of NASH. Conclusion NASH is highly prevalent in obese individuals undergoing bariatric surgery. OBI is one of the strongest risk factors of NASH in these patients.

Published
2020

19. Differences in circulating microRNA signature in Prader–Willi syndrome and non-syndromic obesity

Author

Claudio Tiribelli, Alessandro Minocci, Silvia Bresolin, Alessandro Sartorio, Giuseppe Basso, Sofia Tamini, Pablo J. Giraudi, Graziano Grugni, and Devis Pascut

Subjects
0301 basic medicine, congenital, hereditary, and neonatal diseases and abnormalities, Prader–Willi syndrome, Endocrinology, Diabetes and Metabolism, Array, microRNA, miRNA, Non-syndromic obesity, Obese, Prader-Willi syndrome, Serum miRNA, Population, array, Bioinformatics, lcsh:Diseases of the endocrine glands. Clinical endocrinology, 03 medical and health sciences, Endocrinology, Internal Medicine, medicine, education, education.field_of_study, lcsh:RC648-665, obese, Microarray analysis techniques, business.industry, Research, nutritional and metabolic diseases, medicine.disease, Phenotype, Obesity, Circulating MicroRNA, 030104 developmental biology, non-syndromic obesity, Gene chip analysis, serum miRNA, Steatosis, business
Abstract

Prader–Willi syndrome (PWS) represents the most common genetic-derived obesity disorder caused by the loss of expression of genes located on the paternal chromosome 15q11.2-q13. The PWS phenotype shows peculiar physical, endocrine and metabolic characteristics compared to those observed in non-syndromic essential obesity. Since miRNAs have now a well-established role in many molecular pathways, including regulatory networks related to obesity, this pilot study was aimed to characterize the expression of circulating miRNAs in PWS compared to essential obesity. The circulating miRNome of 10 PWS and 10 obese subjects, adequately matched for age, BMI and sex, was profiled throughout Genechip miRNA 4.0 microarray analysis. We identified 362 out of 2578 mature miRNAs to be expressed in serum of the studied population. The circulating miRNA signature significantly characterising the two populations include 34 differently expressed RNAs. Among them, miR-24-3p, miR-122 and miR-23a-3p highly differ between the two groups with a FC >10 in obese compared to PWS. In the obese subjects, miR-7107-5p, miR-6880-3p, miR-6793-3p and miR-4258 were associated to the presence of steatosis. A different signature of miRNAs significantly distinguished PWS with steatosis from PWS without steatosis, involving miR-619-5p, miR-4507, miR-4656, miR-7847-3p and miR-6782-5p. The miRNA target GO enrichment analysis showed the different pathway involved in these two different forms of obesity. Although the rarity of PWS actually represents a limitation to the availability of large series, the present study provides novel hints on the molecular pathogenesis of syndromic and non-syndromic obesity.

Published
2018

20. Taste perception and expression in stomach of bitter taste receptor tas2r38 in obese and lean subjects

Author

Pio Corleone, Claudio Tiribelli, Paolo Gasparini, Nicolò de Manzini, Martina La Bianca, Pablo J. Giraudi, Silvia Palmisano, Biagio Casagranda, Martina Guerra, Fabio Monica, C. Simeth, Antonietta Robino, Natalia Rosso, Robino, Antonietta, Rosso, Natalia, Guerra, Martina, Corleone, Pio, Casagranda, Biagio, Giraudi, Pablo J., Tiribelli, Claudio, Simeth, Catrin, Monica, Fabio, La Bianca, Martina, Gasparini, Paolo, de Manzini, Nicolò, and Palmisano, Silvia

Subjects
Taste, medicine.medical_specialty, Receptors, G-Protein-Coupled, TAS2R38 gene, Taste perception, Obesity, Stomach, Taste receptor, Internal medicine, medicine, Gastric mucosa, Humans, General Psychology, Gastrointestinal tract, Nutrition and Dietetics, business.industry, medicine.disease, medicine.anatomical_structure, TAS2R38, Endocrinology, Propylthiouracil, Digestion, business
Abstract

Differences in taste perception have been related to eating behavior, nutritional status, and diseases. Recently, taste receptors have been identified in several extra-oral tissues, such as the gastrointestinal tract, where they seem to influence processes like digestion, sense of satiety as well as energy balance and intraluminal changes occurring in obesity. Our study aims to analyze differences in taste perception among 42 obese patients (OB) and 41 normal-weight subjects (LEAN). Polymorphisms in the gene codifying for the bitter taste receptor TAS2R38 and its expression on the surface of the gastric mucosa were tested and compared among OB and LEAN. Taste intensity of PROP (6-n-propylthiouracil), quinine, sucrose, citric acid and NaCl were measured on a labeled magnitude scale. DNA from peripheral whole blood was extracted and three polymorphisms in the TAS2R38 gene (rs713598, rs1726866, rs10246939) analyzed. Gastric biopsies were collected during bariatric surgery in OB and during endoscopy in LEAN. RNA was extracted and TAS2R38 gene expression assessed by RT-Real-Time qPCR. Anamnestic and anthropometric data were recorded in all participants during baseline visits. Logistic regression analysis showed that OB perceives sweet (sucrose) and bitter (PROP or 6-n-propylthiouracil) taste more intensely than LEAN (p-value = 0.02 and p-value = 0.005, respectively). While polymorphisms in TAS2R38 gene did not differ among OB and LEAN, we observed a significant increase of TAS2R38 mRNA levels in the stomach of OB compared to LEAN (p = 0.01). Our results provide new evidence of a link between obesity and altered taste perception as well as TAS2R38 expression in the stomach.

Published
2021

21. Silybin Modulates Collagen Turnover in an In Vitro Model of NASH

Author

Claudio Tiribelli, Beatrice Anfuso, Natalia Rosso, and Pablo J. Giraudi

Subjects
Antioxidant, Cell Survival, medicine.medical_treatment, Cell, Pharmaceutical Science, Fatty Acids, Nonesterified, Article, Analytical Chemistry, Cell Line, lcsh:QD241-441, 03 medical and health sciences, 0302 clinical medicine, Downregulation and upregulation, lcsh:Organic chemistry, Non-alcoholic Fatty Liver Disease, NAFLD, Drug Discovery, medicine, Hepatic Stellate Cells, Humans, Viability assay, Physical and Theoretical Chemistry, chemistry.chemical_classification, Metalloproteinase, Chemistry, Organic Chemistry, coculture model, NASH, Fatty acid, fibrogenesis, In vitro, Coculture Techniques, Cell biology, medicine.anatomical_structure, Liver, Matrix Metalloproteinase 9, Chemistry (miscellaneous), 030220 oncology & carcinogenesis, Silybin, Hepatic stellate cell, Hepatocytes, Molecular Medicine, Matrix Metalloproteinase 2, 030211 gastroenterology & hepatology, Collagen, Reactive Oxygen Species
Abstract

Silybin has been proposed as a treatment for nonalcoholic steatohepatitis (NASH). In this study, we assessed the effect of Silybin in a well-established in vitro coculture model of early-stage NASH. LX2 and Huh7 cells were exposed to free fatty acid (FFA) and Silybin as mono- or coculture (SCC). Cell viability, LX2 activation, collagen deposition, metalloproteinase 2 and 9 (MMP2-9) activity, and ROS generation were determined at 24, 96, and 144 h. Exposure to FFA induced the activation of LX2 as shown by the increase in cell viability and upregulation of collagen biosynthesis. Interestingly, while cotreatment with Silybin did not affect collagen production in LX2, a significant reduction was observed in SCC. MMP2-9 activity was reduced in FFA-treated Huh7 and SCC and cotreatment with Silybin induced a dose-dependent increase, while no effect was observed in LX2. Silybin also showed antioxidant properties by reducing the FFA-induced production of ROS in all the cell systems. Based on these data, Silybin exerts its beneficial effects by reducing LX2 proliferation and ROS generation. Moreover, MMP2-9 modulation in hepatocytes represents the driving mechanism for the net reduction of collagen in this NASH in vitro model, highlighting the importance of hepatic cells interplay in NASH development and resolution.

Published
2019

22. A simple in silico strategy identifies candidate biomarkers for the diagnosis of liver fibrosis in morbidly obese subjects

Author

Pablo J. Giraudi, Silvia Palmisano, C.M. Chackelevicius, Sabrina Eliana Gambaro, Giorgio Soardo, Fabrizio Zanconati, Sofia Ornelas Arroyo, Natalia Rosso, Marta Silvestri, Daniele Macor, Lory Saveria Crocè, Claudio Tiribelli, Deborah Bonazza, Nicolò de Manzini, Michela Giuricin, Giraudi, Pablo J., Gambaro, Sabrina E., Arroyo, Sofia O., Chackelevicius, Carla M., Giuricin, Michela, Silvestri, Marta, Macor, Daniele, Crocé, S. L., Bonazza, Deborah, Soardo, Giorgio, de Manzini, Nicolo', Zanconati, Fabrizio, Tiribelli, Claudio, Palmisano, Silvia, and Rosso, NATALIA CAROLINA

Subjects
0301 basic medicine, Liver Cirrhosis, Male, Pathology, Biología, Biopsy, LIVER FIBROSIS, Gastroenterology, Severity of Illness Index, Liver disorder, 0302 clinical medicine, Fibrosis, Non-alcoholic Fatty Liver Disease, Prospective Studies, Protein Interaction Maps, Morbid, liver fibrosis, medicine.diagnostic_test, Fatty liver, Middle Aged, biomarkers, in silico strategy, morbid obese, Obesity, Morbid, ErbB Receptors, Liver biopsy, Cohort, biomarker, 030211 gastroenterology & hepatology, Female, Adult, medicine.medical_specialty, CIENCIAS MÉDICAS Y DE LA SALUD, BIOMARKERS, Biotecnología de la Salud, 03 medical and health sciences, Insulin-Like Growth Factor II, Predictive Value of Tests, Internal medicine, medicine, Humans, Computer Simulation, Obesity, morbidly obese, Aged, Biomarkers, Case-Control Studies, Reproducibility of Results, Hepatology, Receiver operating characteristic, business.industry, liver fibrosi, Gold standard (test), medicine.disease, MORBIDLY OBESE, 030104 developmental biology, Steatohepatitis, business, Otras Biotecnologías de la Salud
Abstract

Background & aims: Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disorder, tightly associated with obesity. The histological spectrum of the disease ranges from simple steatosis to steatohepatitis, with different stages of fibrosis, and fibrosis stage is the most significant predictor of mortality in NAFLD. Liver biopsy continues to be the gold standard for its diagnosis and reliable non-invasive diagnostic tools are unavailable. We investigated the accuracy of candidate proteins, identified by an in silico approach, as biomarkers for diagnosis of fibrosis. Methods: Seventy-one morbidly obese (MO) subjects with biopsy-proven NAFLD were enrolled, and the cohort was subdivided according to minimal (F0/F1) or moderate (F2/F3) fibrosis. The plasmatic level of CD44 antigen (CD44), secreted protein acidic and rich in cysteine (SPARC), epidermal growth factor receptor (EGFR) and insulin-like growth factor 2 (IGF2) were determined by ELISA. Significant associations between plasmatic levels and histological fibrosis were determined by correlation analysis and the diagnostic accuracy by the area under receiver operating characteristic curves (AUROC). Results: Eighty-two percentage of the subjects had F0/F1 and 18% with F2/F3 fibrosis. Plasmatic levels of IGF2, EGFR and their ratio (EGFR/IGF2) were associated with liver fibrosis, correlating inversely for IGF2 (P < .006) and directly (P < .018; P < .0001) for EGFR and EGFR/IGF2 respectively. The IGF2 marker had the best diagnostic accuracy for moderate fibrosis (AUROC 0.83), followed by EGFR/IGF2 ratio (AUROC 0.79) and EGFR (AUROC 0.71). Conclusions: Our study supports the potential utility of IGF2 and EGFR as non-invasive diagnostic biomarkers for liver fibrosis in morbidly obese subjects., Facultad de Ciencias Exactas

Published
2018

23. The interplay between hepatic stellate cells and hepatocytes in an in vitro model of NASH

Author

Natalia Rosso, Misael Uribe, Claudio Tiribelli, Varenka J. Barbero-Becerra, Pablo J. Giraudi, Norberto C. Chávez-Tapia, Barbero Becerraa, Varenka J., Giraudi, PABLO JOSÈ, Chávez Tapia, Norberto C., Uribe, Misael, Tiribelli, Claudio, and Rosso, NATALIA CAROLINA

Subjects
Extracellular matrix, Fatty acids, Hepatic stellate cells, NAFLD, Cell Communication, Fatty Acids, Nonesterified, Biology, Toxicology, Collagen Type I, Cell Line, Flow cytometry, Paracrine signalling, Non-alcoholic Fatty Liver Disease, Cell Line, Tumor, medicine, Humans, RNA, Messenger, HSP47 Heat-Shock Proteins, Hepatic stellate cell, Regulation of gene expression, Tissue Inhibitor of Metalloproteinase-2, Tissue Inhibitor of Metalloproteinase-1, medicine.diagnostic_test, General Medicine, Fatty acid, Actins, Coculture Techniques, Cell biology, Collagen Type I, alpha 1 Chain, medicine.anatomical_structure, Biochemistry, Cell culture, Hepatocyte, Hepatocytes, Matrix Metalloproteinase 2, Intracellular
Abstract

Background & aim A complex interplay exists between hepatocytes and hepatic stellate cells (HSC) in hepatic fibrogenesis. The activation of HSCs after liver injury leads to production of extracellular matrix (ECM). Co-culture models could be useful to mimic the liver microenvironment. This study evaluates the effect of free fatty acids (FFA) on HSC cells and the interplay with hepatocytes via both soluble-mediator and cell–cell contact. Methods The human hepatocyte cell line (HuH7) and HSC cells (LX2) were exposed to FFA for 24 h in 3 different experimental set-ups: (A) monoculture of HSC; (B) Transwell® system (effect of soluble mediators); and (C) Simultaneous Co-Culture (SCC) (cell-to-cell connections). Intracellular FFA accumulation was assessed qualitatively (microscopy) and quantitatively (flow cytometry); the activation of HSC (alpha smooth muscle actin, α-SMA) expression of ECM components were quantified by RT-PCR. Results FFA exposure induces intracellular fat accumulation in all the experimental set-up but the expression of α-SMA was significantly increased only in SCC. On the contrary, the expression of ECM was substantially decreased in the transwell® system. Conclusions The HSC activation is independent of FFA accumulation but requires cell-to-cell interaction with hepatocyte. On the contrary, the gene regulation of ECM components seems to occur through paracrine mediators.

Published
2015

24. Effects of oral administration of silymarin in a juvenile murine model of non-alcoholic steatohepatitis

Author

Claudio Avellini, Silvia Gazzin, Natalia Rosso, Matteo Dal Ben, Claudio Tiribelli, Pablo J. Giraudi, Sonia Calligaris, Monica Anese, Alan Raseni, Sabrina Eliana Gambaro, V. Marin, Marin, Veronica, Gazzin, Silvia, Gambaro, SABRINA ELIANA, DAL BEN, Matteo, Calligaris, Sonia, Anese, Monica, Raseni, Alan, Avellini, Claudio, Giraudi, PABLO JOSÈ, Tiribelli, Claudio, and Rosso, NATALIA CAROLINA

Subjects
Liver Cirrhosis, Male, Fibrosi, Administration, Oral, Ciencias de la Salud, Apoptosis, medicine.disease_cause, Mice, 0302 clinical medicine, Non-alcoholic Fatty Liver Disease, Fibrosis, Oral administration, NAFLD, NASH, fibrosis, silymarin, in vivo model, in vitro model, therapeutic approach, Insulin, FIBROSIS, IN VITRO MODEL, Nutrition and Dietetics, medicine.diagnostic_test, Fatty liver, Alanine Transaminase, Organ Size, Liver, 030220 oncology & carcinogenesis, Female, 030211 gastroenterology & hepatology, purl.org/becyt/ford/3 [https], lcsh:Nutrition. Foods and food supply, Silymarin, medicine.medical_specialty, CIENCIAS MÉDICAS Y DE LA SALUD, lcsh:TX341-641, Diet, High-Fat, Article, Therapeutic approach, 03 medical and health sciences, purl.org/becyt/ford/3.3 [https], In vitro model, Internal medicine, medicine, Animals, Humans, Weaning, In vivo model, SILYMARIN, Aspartate Aminotransferases, Inflammation, Salud Ocupacional, business.industry, medicine.disease, Mice, Inbred C57BL, Disease Models, Animal, Oxidative Stress, THERAPEUTIC APPROACH, Endocrinology, Hepatocytes, IN VIVO MODEL, Insulin Resistance, Steatosis, Steatohepatitis, Reactive Oxygen Species, business, Lipid profile, Biomarkers, Oxidative stress, Food Science
Abstract

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 fatladen 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 life style 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. Fil: Marin, Veronica. Centro Studi Fegato; Italia Fil: Gazzin, Silvia. Centro Studi Fegato; Italia Fil: Gambaro, Sabrina Eliana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Centro Studi Fegato; Italia Fil: Dal Ben, Matteo. Centro Studi Fegato; Italia Fil: Calligaris, Sonia. Università degli Studi di Trieste; Italia Fil: Anese, Monica. Università degli Studi di Trieste; Italia Fil: Raseni, Alan. Università degli Studi di Trieste; Italia Fil: Avellini, Claudio. Azienda Ospedaliero-Universitaria “Santa Maria della Misericordia”; Italia Fil: Giraudi, Pablo. Centro Studi Fegato; Italia Fil: Tiribelli, Claudio. Centro Studi Fegato; Italia Fil: Rosso, Natalia. Centro Studi Fegato; Italia

Published
2017

25. Risk factors associated with NASH in obese people who underwent bariatric surgery

Author

Natalia Rosso, Teresa Pollicino, Giuseppe Navarra, Claudio Tiribelli, Carlo Saitta, S. Lazzara, Deborah Bonazza, Daniele Lombardo, Pablo J. Giraudi, Silvia Palmisano, A. Ieni, and G. Raimondo

Subjects
medicine.medical_specialty, Hepatology, business.industry, Gastroenterology, Medicine, business, Surgery
Published
2019

26. Liver and adipose tissue interplay through the up-regulation of the Th17 pathway

Author

C.M. Chackelevicius, N. Demanzini, Sabrina Eliana Gambaro, Claudio Tiribelli, Natalia Rosso, Pablo J. Giraudi, Silvia Palmisano, Deborah Bonazza, Michela Giuricin, Fabrizio Zanconati, Chackelevicius, CARLA MELISA, Giraudi, PABLO JOSÈ, Gambaro, SABRINA ELIANA, Palmisano, Silvia, Giuricin, Michela, de Manzini, Nicolo', Bonazza, Deborah, Zanconati, Fabrizio, Tiribelli, Claudio, and Rosso, NATALIA CAROLINA

Subjects
Th17 cell, medicine.medical_specialty, Hepatology, business.industry, Gastroenterology, Adipose tissue, White adipose tissue, Morbid obesity, liver and adipose tissue, Endocrinology, Downregulation and upregulation, Internal medicine, medicine, business
Published
2016

27. Kinetics and Specificity of Feline Leukemia Virus Subgroup C Receptor (FLVCR) Export Function and Its Dependence on Hemopexin

Author

Claudio Tiribelli, Raymond T. Doty, Zhantao Yang, Ann Smith, John D. Philips, Janis L. Abkowitz, J. Donald Ostrow, Pablo J. Giraudi, Z., Yang, J. D., Philip, R. T., Doty, P., Giraudi, J. D., Ostrow, Tiribelli, Claudio, A., Smith, and J. L., Abkowitz

Subjects
genetics/metabolism, Hemorrhage, genetics/metabolism, Protoporphyrins, Biochemistry, genetics, Humans, Iron, genetics/metabolism, Homeostasi, chemistry.chemical_compound, Hemopexin, Receptors, Homeostasis, genetics, Heme, chemistry.chemical_classification, biology, Protoporphyrin IX, Membrane transport protein, Viru, Transferrin, metabolism, Membrane Transport Protein, genetics, Hemopexin, Virus, genetics/metabolism, Transferrin, Liver, Receptors, Virus, metabolism, Liver, Rabbits, Animals, Biological Transport, genetics, Cell Line, Coproporphyrins, genetics/metabolism, Heme, genetics/metabolism, Hemolysis, genetics/metabolism, Homeostasis, metabolism, Macrophages, metabolism, Membrane Transport Proteins, genetics/metabolism, Protoporphyrins, genetics/metabolism, Rabbits, Rats, Receptors, genetics, Cell Line, Coproporphyrin, Coproporphyrins, Iron, genetics/metabolism, Rabbits, Rats, Receptor, Hemorrhage, Hemolysis, Cell Line, Animals, Humans, Heme export, Molecular Biology, Macrophages, Membrane Transport Proteins, Biological Transport, Cell Biology, genetics/metabolism, Hemolysi, Major facilitator superfamily, Rats, chemistry, genetics/metabolism, Protoporphyrin, biology.protein, Protoporphyrin, metabolism, Macrophage, metabolism
Abstract

The feline leukemia virus subgroup C receptor (FLVCR) is a heme export protein that is required for proerythroblast survival and facilitates macrophage heme iron recycling. However, its mechanism of heme export and substrate specificity are uncharacterized. Using [(55)Fe]heme and the fluorescent heme analog zinc mesoporphyrin, we investigated whether export by FLVCR depends on the availability and avidity of extracellular heme-binding proteins. Export was 100-fold more efficient when the medium contained hemopexin (K(d) < 1 pm) compared with albumin (K(d) = 5 nm) at the same concentration and was not detectable when the medium lacked heme-binding proteins. Besides heme, FLVCR could export other cyclic planar porphyrins, such as protoporphyrin IX and coproporphyrin. However, FLVCR has a narrow substrate range because unconjugated bilirubin, the primary breakdown product of heme, was not transported. As neither protoporphyrin IX nor coproporphyrin export improved with extracellular hemopexin (versus albumin), our observations further suggest that hemopexin, an abundant protein with a serum concentration (6.7-25 mum) equivalent to that of the iron transport protein transferrin (22-31 mum), by accepting heme from FLVCR and targeting it to the liver, might regulate macrophage heme export and heme iron recycling in vivo. Final studies show that hemopexin directly interacts with FLVCR, which also helps explain why FLVCR, in contrast to some major facilitator superfamily members, does not function as a bidirectional gradient-dependent transporter. Together, these data argue that hemopexin has a role in assuring systemic iron balance during homeostasis in addition to its established role as a scavenger during internal bleeding or hemolysis.

Published
2010

28. Gene expression and activity of urea cycle enzymes of rat hepatocytes cold stored up to 120h in University of Wisconsin solution

Author

María E. Mamprin, Pablo J. Giraudi, Claudio Tiribelli, Luciana L. Almada, Joaquín V. Rodríguez, María Gabriela Mediavilla, Cristina Bellarosa, and Edgardo E. Guibert

Subjects
Male, Adenosine, Urea cycle disorder, Allopurinol, Organ Preservation Solutions, Carbamoyl-Phosphate Synthase (Ammonia), Ornithine transcarbamylase, Gene Expression, General Biochemistry, Genetics and Molecular Biology, law.invention, chemistry.chemical_compound, Raffinose, law, medicine, Animals, Insulin, Urea, Ammonium, Viaspan, RNA, Messenger, Rats, Wistar, Cells, Cultured, Ornithine Carbamoyltransferase, chemistry.chemical_classification, L-Lactate Dehydrogenase, Bioartificial liver device, General Medicine, medicine.disease, Glutathione, Rats, Cold Temperature, Quaternary Ammonium Compounds, Transplantation, Enzyme, chemistry, Biochemistry, Urea cycle, Hepatocytes, Tissue Preservation, General Agricultural and Biological Sciences
Abstract

Urea cycle (UC) is the main pathway of ammonium removal. A deficiency in any of the five classical enzymes of the pathway causes a urea cycle disorder. Hepatocellular transplantation is one of the techniques applicable to treat this disorder. In the present work, we investigated the activities and the relative expression levels of two of the UC enzymes: Carbamyl phosphate synthetase I (CPSI) and ornithine transcarbamylase (OTC), in isolated hepatocytes preserved up to 120 h in University of Wisconsin (UW) solution at 0 degrees C, and during the rewarming of these suspensions. During preservation, CPSI showed differences in mRNA levels respect to time 0, while ornithine transcarbamylase remained unchanged. At the end of the rewarming, CPSI showed values of enzymatic activity and relative mRNA level comparable with the control, meanwhile, there was an increment in OTC activity. In line with these results, we found that hepatocytes cold preserved up to 120h in UW solution maintained their ability to remove an ammonium load comparable to freshly isolated hepatocytes. These data indicated that our preservation conditions up to 120h in UW solution followed by rewarming, preserves UC enzymes at levels similar to freshly isolated hepatocytes, allowing the use of these cells in bioartificial liver devices or hepatocellular transplantation.

Published
2006

29. In Silico Identification and in Vivo Validation of Non-Invasive Biomarkers for Liver Fibrosis

Author

Claudio Tiribelli, Giorgio Soardo, Michela Giuricin, Deborah Bonazza, Pablo J. Giraudi, Silvia Palmisano, C.M. Chackelevicius, Natalia Rosso, L.S. Crocè, Sabrina Eliana Gambaro, and N. de Manzini

Subjects
Hepatology, business.industry, In vivo, Liver fibrosis, In silico, Non invasive biomarkers, Medicine, Identification (biology), Computational biology, business
Published
2016

30. Adipose Tissue-Liver Axis: Involvement of the TH17 Pathway in the Progression of Human NAFLD

Author

N. de Manzini, Fabrizio Zanconati, Claudio Tiribelli, C.M. Chackelevicius, Sabrina Eliana Gambaro, Michela Giuricin, Deborah Bonazza, Natalia Rosso, Pablo J. Giraudi, and Silvia Palmisano

Subjects
03 medical and health sciences, Pathology, medicine.medical_specialty, 0302 clinical medicine, Hepatology, business.industry, Adipose tissue, Medicine, 030212 general & internal medicine, 030206 dentistry, business
Published
2016

31. Bilirubin accumulation and Cyp mRNA expression in selected brain regions of jaundiced Gunn rat pups

Author

Andrea Lorena Berengeno, Carlos D Coda Zabetta, Libor Vítek, Claudio Tiribelli, Jaroslav Zelenka, Renata Koníčková, Pablo J. Giraudi, María Celeste Robert, Lucie Zdrahalova, Alan Raseni, Silvia Gazzin, S., Gazzin, J., Zelenka, L., Zdrahalova, R., Konickova, C. C., Zabetta, P. J., Giraudi, A. L., Berengeno, A., Raseni, M. C., Robert, L., Vitek, and Tiribelli, Claudio

Subjects
Cerebellum, medicine.medical_specialty, Superior Colliculi, ATP Binding Cassette Transporter, Subfamily B, Bilirubin, brain, Rats, Gunn, Jaundice, Cytochrome P-450 CYP2A6, chemistry.chemical_compound, Cytochrome P-450 Enzyme System, Cytochrome P-450 CYP1A2, Internal medicine, Albumins, medicine, Cytochrome P-450 CYP1A1, Animals, RNA, Messenger, Cerebral Cortex, Messenger RNA, biology, Sulfadimethoxine, Neurotoxicity, Cytochrome P450, toxicity, Monooxygenase, bilirubin, medicine.disease, Gunn rat, Rats, Disease Models, Animal, medicine.anatomical_structure, Real-time polymerase chain reaction, Endocrinology, chemistry, Animals, Newborn, Pediatrics, Perinatology and Child Health, biology.protein, Aryl Hydrocarbon Hydroxylases, Multidrug Resistance-Associated Proteins
Abstract

Few data exist on regional brain bilirubin content in the neonatal period when acute bilirubin-induced neurologic damage (BIND) may occur, and no information is available on regional brain expression of cytochrome P450 monooxygenases (Cyps) that oxidize bilirubin. Bilirubin content was analyzed by high-performance liquid chromatography and Cyp1a1, 1a2, and 2a3 mRNA expression was analyzed by quantitative PCR (qPCR) in cortex (Cx), cerebellum (Cll), superior colliculi (SC), and inferior colliculi (IC) of 17-d-old hyperbilirubinemic (jj) Gunn rat pups before and after administration of sulphadimethoxine to acutely displace bilirubin from plasma albumin. There was no difference in bilirubin content among brain regions in untreated rats. After intraperitoneal sulphadimethoxine, bilirubin content peaked at fourfold in Cx and SC at 1 h; but at 11- to 13-fold in Cll and IC at 24 h; returning to control levels at 72 h. The Cyp mRNA peaked at 30–70 times control at 1 h in Cx and SC, but at 3–9 times control at 24 h in Cll and IC. The close relationship in distinct brain regions between the extent of bilirubin accumulation and induction of mRNA of Cyps suggests Cyps may have a role in protecting selected brain areas from bilirubin neurotoxicity.

Published
2012

32. Rescue of bilirubin-induced neonatal lethality in a mouse model of Crigler-Najjar syndrome type I by AAV9-mediated gene transfer

Author

Andrés F. Muro, Cristina Bellarosa, Giulia Bortolussi, Mauro Giacca, Lorena Zentilin, Gabriele Baj, Pablo J. Giraudi, Claudio Tiribelli, Bortolussi, Giulia, Zentilin, Lorena, Baj, Gabriele, Giraudi, PABLO JOSÈ, Bellarosa, Cristina, Giacca, Mauro, Tiribelli, Claudio, and Muro, A. F.

Subjects
Western, Cerebellum, Enzymologic, Glucuronosyltransferase, Crigler–Najjar syndrome, Genetic enhancement, Mutant, enzymology/metabolism/pathology, Crigler-Najjar Syndrome, Inbred C57BL, Biochemistry, Transgenic, Research Communications, Mice, Cerebellum, Northern, genetics, Unconjugated hyperbilirubinemia, Crigler-Najjar Syndrome, enzymology/genetics/mortality, biology, Blotting, Reverse Transcriptase Polymerase Chain Reaction, Gene Transfer Techniques, Gene Therapy, Skeletal, Jaundice, Transgenic, Muscle, enzymology/metabolism/pathology, Dependovirus, deficiency/genetics, Animal, Gene Expression Regulation, Survival Rate, Newborn, Bilirubin, Animals, Animals, blood, Blotting, Northern, Blotting, enzymology/genetics/mortality, Dependovirus, classification/genetics, Disease Models, Enzymologic, Gene Therapy, methods, Gene Transfer Techniques, Genetic Vectors, genetics, Glucuronosyltransferase, deficiency/genetics, Humans, Mice, Mice, Inbred C57BL, Mice, enzymology/metabolism, Mutation, Reverse Transcriptase Polymerase Chain Reaction, Survival Rate, Muscle, medicine.symptom, Western, Biotechnology, medicine.medical_specialty, classification/genetics, methods, Gene Transfer Techniques, Genetic Vector, Transgene, Blotting, Western, Genetic Vectors, Mice, Transgenic, enzymology/genetics/mortality, Dependoviru, Gene Expression Regulation, Enzymologic, methods, blood, Internal medicine, medicine, kernicterus, Animals, Humans, Muscle, Skeletal, Molecular Biology, Animals, Animal, Animal, Bilirubin, Genetic Therapy, medicine.disease, Blotting, Northern, Newborn, enzymology/metabolism, classification/genetics, Disease Model, Mice, Inbred C57BL, Disease Models, Animal, Endocrinology, Animals, Newborn, Gene Expression Regulation, Immunology, Disease Models, Mutation, biology.protein, Kernicterus, UGT1A1, phototherapy
Abstract

Crigler-Najjar type I (CNI) syndrome is a recessively inherited disorder characterized by severe unconjugated hyperbilirubinemia caused by uridine diphosphoglucuronosyltransferase 1A1 (UGT1A1) deficiency. The disease is lethal due to bilirubin-induced neurological damage unless phototherapy is applied from birth. However, treatment becomes less effective during growth, and liver transplantation is required. To investigate the pathophysiology of the disease and therapeutic approaches in mice, we generated a mouse model by introducing a premature stop codon in the UGT1a1 gene, which results in an inactive enzyme. Homozygous mutant mice developed severe jaundice soon after birth and died within 11 d, showing significant cerebellar alterations. To rescue neonatal lethality, newborns were injected with a single dose of adeno-associated viral vector 9 (AAV9) expressing the human UGT1A1. Gene therapy treatment completely rescued all AAV-treated mutant mice, accompanied by lower plasma bilirubin levels and normal brain histology and motor coordination. Our mouse model of CNI reproduces genetic and phenotypic features of the human disease. We have shown, for the first time, the full recovery of the lethal effects of neonatal hyperbilirubinemia. We believe that, besides gene-addition-based therapies, our mice could represent a very useful model to develop and test novel technologies based on gene correction by homologous recombination.—Bortolussi, G., Zentilin, L., Baj, G., Giraudi, P., Bellarosa, C., Giacca, M., Tiribelli, C., Muro, A. F. Rescue of bilirubin-induced neonatal lethality in a mouse model of Crigler-Najjar syndrome type I by AAV9-mediated gene transfer.

Published
2012

33. A transcriptome analysis identifies molecular effectors of unconjugated bilirubin in human neuroblastoma SH-SY5Y cells

Author

Rossana Foti, Cristina Bellarosa, Raffaella Calligaris, H Krmac, Pablo J. Giraudi, Paola Roncaglia, Stefano Gustincich, Claudio Tiribelli, Calligaris, R, Bellarosa, C, Foti, R, Roncaglia, P, Giraudi, P, Krmac, H, Tiribelli, Claudio, and Gustincich, S.

Subjects
X-Box Binding Protein 1, metabolism, Autophagy, SH-SY5Y, Transcription, Genetic, chemistry/pharmacology, pathology, Neuron, Endoplasmic Reticulum, metabolism, Endoplasmic Reticulum, Transcriptome, Neuroblastoma, drug effects/genetics, Bilirubin, Homeostasis, Amino Acids, chemistry/pharmacology, Cell Line, Tumor, Cell Survival, drug effects, DNA-Binding Proteins, drug effects/genetics/metabolism, Gene Expression Profiling, Homeostasis, drug effects, Humans, Neuroblastoma, pathology, Neurons, drug effects/metabolism/pathology, Oligonucleotide Array Sequence Analysis, Protein Biosynthesis, drug effects/genetics, Protein Splicing, drug effects, Protein Transport, drug effects/genetics, Reproducibility of Results, Reverse Transcriptase Polymerase Chain Reaction, Transcription Factor CHOP, metabolism, Transcription Factors, metabolism, Transcription, Genetic, drug effects, Unfolded Protein Response, drug effects, Oligonucleotide Array Sequence Analysis, Neurons, Tumor, Reverse Transcriptase Polymerase Chain Reaction, drug effects/genetics, drug effects/metabolism/pathology, Cell biology, DNA-Binding Proteins, Amino Acid, Protein Transport, Transcription, Intracellular, Biotechnology, XBP1, lcsh:QH426-470, Cell Survival, lcsh:Biotechnology, Regulatory Factor X Transcription Factors, Biology, Cell Line, lcsh:TP248.13-248.65, Cell Line, Tumor, Research article, drug effects/metabolism/pathology, Oligonucleotide Array Sequence Analysis, Protein Biosynthesi, Autophagy, Genetics, Humans, Protein Splicing, drug effects, DNA-Binding Protein, Gene Expression Profiling, Endoplasmic reticulum, Reproducibility of Results, Bilirubin, Subcellular localization, Molecular biology, Gene expression profiling, lcsh:Genetics, Protein Biosynthesis, Unfolded Protein Response, Unfolded protein response, drug effects/genetics/metabolism, pathology, drug effects/genetics/metabolism, Gene Expression Profiling, Homeostasi, metabolism, metabolism, Transcription Factor, Transcription Factor CHOP, Transcription Factors
Abstract

Background The deposition of unconjugated bilirubin (UCB) in selected regions of the brain results in irreversible neuronal damage, or Bilirubin Encephalopathy (BE). Although UCB impairs a large number of cellular functions in other tissues, the basic mechanisms of neurotoxicity have not yet been fully clarified. While cells can accumulate UCB by passive diffusion, cell protection may involve multiple mechanisms including the extrusion of the pigment as well as pro-survival homeostatic responses that are still unknown. Results Transcriptome changes induced by UCB exposure in SH-SY5Y neuroblastoma cell line were examined by high density oligonucleotide microarrays. Two-hundred and thirty genes were induced after 24 hours. A Gene Ontology (GO) analysis showed that at least 50 genes were directly involved in the endoplasmic reticulum (ER) stress response. Validation of selected ER stress genes is shown by quantitative RT-PCR. Analysis of XBP1 splicing and DDIT3/CHOP subcellular localization is presented. Conclusion These results show for the first time that UCB exposure induces ER stress response as major intracellular homeostasis in surviving neuroblastoma cells in vitro.

Published
2009

34. Cytotoxicity is predicted by unbound and not total bilirubin concentration

Author

Claudio Tiribelli, Richard P. Wennberg, Sebastian Calligaris, Cristina Bellarosa, Pablo J. Giraudi, and J. Donald Ostrow

Subjects
Bilirubin, Cell Survival, Pharmacology, chemistry.chemical_compound, Mice, Animals, Humans, Cytotoxicity, Cells, Cultured, Serum Albumin, Photolysis, biology, Dose-Response Relationship, Drug, Chemistry, Sulfadimethoxine, Albumin, Serum Albumin, Bovine, Unconjugated bilirubin, Bilirubin concentration, Biochemistry, Cell culture, Pediatrics, Perinatology and Child Health, Toxicity, biology.protein, Peroxidase, HeLa Cells, Protein Binding
Abstract

Although it has been suggested that the unbound, free, (B(f)) rather than total (B(T)) bilirubin level correlates with cell toxicity, direct experimental evidence supporting this conclusion is limited. In addition, previous studies never included a direct measurement of B(f), using newer, accurate methods. To test "the free bilirubin hypothesis", in vitro cytotoxicity was assessed in four cell lines exposed to different B(f) concentrations obtained by varying B(T)/Albumin ratio, using serum albumins with different binding affinities, and/or displacing unconjugated bilirubin (UCB) from albumin with a sulphonamide. B(f) was assessed by the modified, minimally diluted peroxidase method. Cytotoxicity varied among cell lines but was invariably related to B(f) and not B(T). Light exposure decreased toxicity parallel to a decrease in B(f). In the absence of albumin, no cytotoxicity was found at a B(f) of 150 nM whereas in the presence of albumin a similar B(f) resulted in a 40% reduction of viability indicating the importance of total cellular uptake of UCB in eliciting toxic effect. In the presence of albumin-bound UCB, bilirubin-induced cytotoxicity in a given cell line is accurately predicted by B(f) irrespective of the source and concentration of albumin, or total bilirubin level.

Published
2007

35. Identification and evaluation of novel non-invasive biomarkers for non-alcoholic fatty liver disease

Author

L.S. Crocè, N. de Manzini, M. Belgrano, Sabrina Eliana Gambaro, Deborah Bonazza, Claudio Tiribelli, Michela Giuricin, C.M. Chackelevicius, Pablo J. Giraudi, Silvia Palmisano, Flora Masutti, Natalia Rosso, Giraudi, PABLO JOSÈ, Gambaro, SABRINA ELIANA, Chackelevicius, CARLA MELISA, Giuricin, Michela, Croce', Saveria, Bonazza, Deborah, Masutti, Flora, Belgrano, MANUEL GIANVALERIO, de Manzini, Nicolo', Tiribelli, Claudio, Palmisano, Silvia, and Rosso, NATALIA CAROLINA

Subjects
Hepatology, business.industry, Non invasive biomarkers, Fatty liver, Gastroenterology, biomarkers, Non alcoholic, Disease, Bioinformatics, medicine.disease, Liver disease, biomarker, Medicine, Identification (biology), Biomarker discovery, liver disease, business
Published
2015

37. The assessment of viability in isolated rat hepatocytes subjected to cold or subzero non-freezing preservation protocols using a propidium iodide modified test

Author

Pablo J, Giraudi, Luciana L, Almada, María E, Mamprin, Edgardo E, Guibert, Graciela, Furno, and Joaquín V, Rodriguez

Subjects
Cold Temperature, Cryopreservation, Male, Cell Survival, Hepatocytes, Animals, Rats, Wistar, Fluorescent Dyes, Propidium, Rats
Abstract

A rapid and simple assay (6 min, two steps) is described for determination of cell viability of hepatocytes subjected to cold preservation protocols. In this method, cells are incubated with the fluorescent marker propidium iodide (PI) and the fluorescence intensity is measured before (direct fluorescence--Fd) and after (total fluorescence--Ft) addition of digitonin, which allows the dye to enter the hepatocytes. The Fd originated from non-viable cells that have membrane damage and taken up PI. The Ft originated from all cells in the sample. The ratio between the two fluorescence values is used as an indicator of cell viability. The assay was challenged versus two classical viability tests: LDH retention and Trypan Blue exclusion. Our assay shows good correlation only with Trypan Blue test. In addition, a fluorescence confocal microscopy protocol was used to evaluate the possible toxicity of PI in hepatocyte suspensions.

Published
2005

38. 586 Differential Regional Dynamics of Unconjugated Bilirubin Entry and Clearance in the Brain of Gunn Rats

Author

Renata Koníčková, Silvia Gazzin, Jaroslav Zelenka, Claudio Tiribelli, Libor Vítek, Pablo J. Giraudi, Alan Raseni, L Zdrahalova, and Andrea Lorena Berengeno

Subjects
Nervous system, Cerebellum, medicine.medical_specialty, business.industry, Bilirubin, Sulfadimethoxine, medicine.disease, Cortex (botany), chemistry.chemical_compound, medicine.anatomical_structure, Endocrinology, chemistry, Internal medicine, Pediatrics, Perinatology and Child Health, Toxicity, medicine, Distribution (pharmacology), Kernicterus, business, medicine.drug
Abstract

Background: “Kernicterus” historically describes the unconjugated bilirubin (UCB) accumulation in selective brain regions, leading to neurological damage in hyperbilirubinemic newborn babies and in Crigler-Najjar type I patients. Hyperbilirubinemic (jj) Gunn rats develop neurological deficits that parallels the human pathology and a similar pattern of regional brain UCB distribution under displacing agents treatment. Aims: Methods: Cortex (Cx), superior collicula (SC), inferior collicula (IC), cerebellum (CLL) and the rest of the brain (RB) were collected 1, 6, 24, 48 and 72 hrs after injection of sulfadimethoxine (200 mg/Kg; IP) in 17 days-old jj animals and in not treated JJ, Jj and jj rats. TUCB was analyzed by the HPLC based method (Zelenska_2008). Results: In untreated jj animals TUCB brain amounts was about 80 times higher than in Jj and JJ, and no regional differences were detected. After sulphadimethoxine administration TUCB picked differently in the regions analyzed: 1 hr in Cx and SC, 6 hrs in RB, 24 hrs in IC, 6 - 24 hrs in CLL. 72 hrs after injection, TUCB content was lower than in not treated littermates. Conclusions: The differential entry and clearance across brain areas show regional difference in cellular mechanisms modulating tissue UCB concentration. The different kinetics might be involved in the tissue resistance/sensitivity to bilirubin toxicity of nervous system.

Published
2010

40. Functional Induction of the Cystine-Glutamate Exchanger System Xc- Activity in SH-SY5Y Cells by Unconjugated Bilirubin

Author

Claudio Tiribelli, Pablo J. Giraudi, Carlos D. Coda-Zabetta, Cristina Bellarosa, Paolo Peruzzo, P. J., Giraudi, C., Bellarosa, C. D., Coda Zabetta, P., Peruzzo, and Tiribelli, Claudio

Subjects
SH-SY5Y, Amino Acid Transport System y+, Bilirubin, Cystine, lcsh:Medicine, SLC7A11, Biosynthesis, Real-Time Polymerase Chain Reaction, medicine.disease_cause, Biochemistry, chemistry.chemical_compound, Cell Line, Tumor, cell biology, Molecular Cell Biology, medicine, Humans, RNA, Messenger, RNA, Small Interfering, lcsh:Science, Biology, Cellular Stress Responses, DNA Primers, Multidisciplinary, Base Sequence, biology, lcsh:R, bilirubim toxicity, Biological Transport, Neurochemistry, Glutathione, Molecular biology, Metabolism, chemistry, Cell culture, biology.protein, lcsh:Q, Metabolic Pathways, Neurochemicals, Oxidative stress, Research Article, Neuroscience, Cysteine
Abstract

We have previously reported that exposure of SH-SY5Y neuroblastoma cells to unconjugated bilirubin (UCB) resulted in a marked up-regulation of the mRNA encoding for the Na(+)-independent cystine∶glutamate exchanger System X(c)(-) (SLC7A11 and SLC3A2 genes). In this study we demonstrate that SH-SY5Y cells treated with UCB showed a higher cystine uptake due to a significant and specific increase in the activity of System X(c)(-), without the contribution of the others two cystine transporters (X(AG)(-) and GGT) reported in neurons. The total intracellular glutathione content was 2 folds higher in the cells exposed to bilirubin as compared to controls, suggesting that the internalized cystine is used for gluthathione synthesis. Interestingly, these cells were significantly less sensitive to an oxidative insult induced by hydrogen peroxide. If System X(c)(-) is silenced the protection is lost. In conclusion, these results suggest that bilirubin can modulate the gluthathione levels in neuroblastoma cells through the induction of the System X(c)(-), and this renders the cell less prone to oxidative damage.

Published
2011

41. Functional induction of the cystine-glutamate exchanger system Xc(-) activity in SH-SY5Y cells by unconjugated bilirubin.

Author

Pablo J Giraudi, Cristina Bellarosa, Carlos D Coda-Zabetta, Paolo Peruzzo, and Claudio Tiribelli

Subjects
Medicine, Science
Abstract

We have previously reported that exposure of SH-SY5Y neuroblastoma cells to unconjugated bilirubin (UCB) resulted in a marked up-regulation of the mRNA encoding for the Na(+)-independent cystine∶glutamate exchanger System X(c)(-) (SLC7A11 and SLC3A2 genes). In this study we demonstrate that SH-SY5Y cells treated with UCB showed a higher cystine uptake due to a significant and specific increase in the activity of System X(c)(-), without the contribution of the others two cystine transporters (X(AG)(-) and GGT) reported in neurons. The total intracellular glutathione content was 2 folds higher in the cells exposed to bilirubin as compared to controls, suggesting that the internalized cystine is used for gluthathione synthesis. Interestingly, these cells were significantly less sensitive to an oxidative insult induced by hydrogen peroxide. If System X(c)(-) is silenced the protection is lost. In conclusion, these results suggest that bilirubin can modulate the gluthathione levels in neuroblastoma cells through the induction of the System X(c)(-), and this renders the cell less prone to oxidative damage.

Published
2011
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