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Maria Jose Gomezlechon - One of the best experts on this subject based on the ideXlab platform.
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human neonatal hepatocyte transplantation induces long term rescue of unconjugated hyperbilirubinemia in the Gunn Rat
Liver Transplantation, 2015Co-Authors: Laia Tolosa, Silvia Lopez, Eugenia Pareja, M T Donato, Anne Myara, Tuan Huy Nguyen, Jose V Castell, Maria Jose GomezlechonAbstract:Crigler-Najjar type 1 disease is a rare inherited metabolic disease characterized by high levels of unconjugated bilirubin due to the complete absence of hepatic uridine diphosphoglucuronate–glucuronosyltransferase activity. Hepatocyte transplantation (HT) has been proposed as an alternative treatment for Crigler-Najjar syndrome, but it is still limited by the quality and the low engraftment and repopulation ability of the cells used. Because of their attachment capability and expression of adhesion molecules as well as the higher proportion of hepatic progenitor cells, neonatal hepatocytes may have an advantage over adult cells. Adult or neonatal hepatocytes were transplanted into Gunn Rats, a model for Crigler-Najjar disease. Engraftment and repopulation were studied and compared by immunofluorescence (IF). Additionally, the serum bilirubin levels, the presence of bilirubin conjugates in Rat serum, and the expression of uridine diphosphate glucuronosyltransferase 1 family polypeptide A1 (UGT1A1) in Rat liver samples were also analyzed. Here we show that neonatal HT results in long-term correction in Gunn Rats. In comparison with adult cells, neonatal cells showed better engraftment and repopulation capability 3 days and 6 months after transplantation, respectively. Bilirubinemia decreased in the transplanted animals during the whole experimental follow-up (6 months). Bilirubin conjugates were also present in the serum of the transplanted animals. Western blots and IF confirmed the presence and expression of UGT1A1 in the liver. This work is the first to demonstRate the advantage of using neonatal hepatocytes for the treatment of Crigler-Najjar in vivo. Liver Transpl 21:801-811, 2015. © 2015 AASLD.
Laia Tolosa - One of the best experts on this subject based on the ideXlab platform.
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human neonatal hepatocyte transplantation induces long term rescue of unconjugated hyperbilirubinemia in the Gunn Rat
Liver Transplantation, 2015Co-Authors: Laia Tolosa, Silvia Lopez, Eugenia Pareja, M T Donato, Anne Myara, Tuan Huy Nguyen, Jose V Castell, Maria Jose GomezlechonAbstract:Crigler-Najjar type 1 disease is a rare inherited metabolic disease characterized by high levels of unconjugated bilirubin due to the complete absence of hepatic uridine diphosphoglucuronate–glucuronosyltransferase activity. Hepatocyte transplantation (HT) has been proposed as an alternative treatment for Crigler-Najjar syndrome, but it is still limited by the quality and the low engraftment and repopulation ability of the cells used. Because of their attachment capability and expression of adhesion molecules as well as the higher proportion of hepatic progenitor cells, neonatal hepatocytes may have an advantage over adult cells. Adult or neonatal hepatocytes were transplanted into Gunn Rats, a model for Crigler-Najjar disease. Engraftment and repopulation were studied and compared by immunofluorescence (IF). Additionally, the serum bilirubin levels, the presence of bilirubin conjugates in Rat serum, and the expression of uridine diphosphate glucuronosyltransferase 1 family polypeptide A1 (UGT1A1) in Rat liver samples were also analyzed. Here we show that neonatal HT results in long-term correction in Gunn Rats. In comparison with adult cells, neonatal cells showed better engraftment and repopulation capability 3 days and 6 months after transplantation, respectively. Bilirubinemia decreased in the transplanted animals during the whole experimental follow-up (6 months). Bilirubin conjugates were also present in the serum of the transplanted animals. Western blots and IF confirmed the presence and expression of UGT1A1 in the liver. This work is the first to demonstRate the advantage of using neonatal hepatocytes for the treatment of Crigler-Najjar in vivo. Liver Transpl 21:801-811, 2015. © 2015 AASLD.
Silvia Gazzin - One of the best experts on this subject based on the ideXlab platform.
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Histone acetylation as a new mechanism for bilirubin-induced encephalopathy in the Gunn Rat
Nature Publishing Group, 2018Co-Authors: Eleonora Vianello, Stefania Zampieri, Thomas Marcuzzo, Fabio Tordini, Cristina Bottin, Andrea Dardis, Fabrizio Zanconati, Claudio Tiribelli, Silvia GazzinAbstract:Abstract Bilirubin neurotoxicity has been studied for decades and has been shown to affect various mechanisms via significant modulation of gene expression. This suggests that vital regulatory mechanisms of gene expression, such as epigenetic mechanisms, could play a role in bilirubin neurotoxicity. Histone acetylation has recently received attention in the CNS due to its role in gene modulation for numerous biological processes, such as synaptic plasticity, learning, memory, development and differentiation. Aberrant epigenetic regulation of gene expression in psychiatric and neurodegeneRative disorders has also been described. In this work, we followed the levels of histone 3 lysine 14 acetylation (H3K14Ac) in the cerebellum (Cll) of the developing (2, 9, 17 days after the birth) and adult Gunn Rat, the natural model for neonatal hyperbilirubinemia and kernicterus. We observed an age-specific alteRation of the H3K14Ac in the hyperbilirubinemic animals. The GeneOntology analysis of the H3K14Ac linked chromatin revealed that almost 45% of H3K14Ac ChiP-Seq TSS-promoter genes were involved in CNS development including matuRation and differentiation, morphogenesis, dendritogenesis, and migRation. These data suggest that the hallmark Cll hypoplasia in the Gunn Rat occurs also via epigenetically controlled mechanisms during the matuRation of this brain structure, unraveling a novel aspect of the bilirubin-induced neurotoxicity
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alteRations in the cell cycle in the cerebellum of hyperbilirubinemic Gunn Rat a possible link with apoptosis
PLOS ONE, 2013Co-Authors: Maria Celeste Robert, Eleonora Vianello, Claudio Tiribelli, Giulia Furlan, Natalia Rosso, S E Gambaro, Faina Apitsionak, Silvia GazzinAbstract:Severe hyperbilirubinemia causes neurological damage both in humans and rodents. The hyperbilirubinemic Gunn Rat shows a marked cerebellar hypoplasia. More recently bilirubin ability to arrest the cell cycle progression in vascular smooth muscle, tumour cells, and, more importantly, cultured neurons has been demonstRated. However, the involvement of cell cycle perturbation in the development of cerebellar hypoplasia was never investigated before. We explored the effect of sustained spontaneous hyperbilirubinemia on cell cycle progression and apoptosis in whole cerebella dissected from 9 day old Gunn Rat by Real Time PCR, Western blot and FACS analysis. The cerebellum of the hyperbilirubinemic Gunn Rats exhibits an increased cell cycle arrest in the late G0/G1 phase (p < 0.001), characterized by a decrease in the protein expression of cyclin D1 (15%, p < 0.05), cyclin A/A1 (20 and 30%, p < 0.05 and 0.01, respectively) and cyclin dependent kinases2 (25%, p < 0.001). This was associated with a marked increase in the 18 kDa fragment of cyclin E (67%, p < 0.001) which amplifies the apoptotic pathway. In line with this was the increase of the cleaved form of Poly (ADP-ribose) polymerase (54%, p < 0.01) and active Caspase3 (two fold, p < 0.01). These data indicate that the characteristic cerebellar alteRation in this developing brain structure of the hyperbilirubinemic Gunn Rat may be partly due to cell cycle perturbation and apoptosis related to the high bilirubin concentRation in cerebellar tissue mainly affecting granular cells. These two phenomena might be intimately connected.
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AlteRations in the Cell Cycle in the Cerebellum of Hyperbilirubinemic Gunn Rat: A Possible Link with Apoptosis?
2013Co-Authors: Maria Celeste Robert, Eleonora Vianello, Claudio Tiribelli, Giulia Furlan, Natalia Rosso, S E Gambaro, Faina Apitsionak, Silvia GazzinAbstract:Severe hyperbilirubinemia causes neurological damage both in humans and rodents. The hyperbilirubinemic Gunn Rat shows a marked cerebellar hypoplasia. More recently bilirubin ability to arrest the cell cycle progression in vascular smooth muscle, tumour cells, and, more importantly, cultured neurons has been demonstRated. However, the involvement of cell cycle perturbation in the development of cerebellar hypoplasia was never investigated before. We explored the effect of sustained spontaneous hyperbilirubinemia on cell cycle progression and apoptosis in whole cerebella dissected from 9 day old Gunn Rat by Real Time PCR, Western blot and FACS analysis. The cerebellum of the hyperbilirubinemic Gunn Rats exhibits an increased cell cycle arrest in the late G0/G1 phase (p < 0.001), characterized by a decrease in the protein expression of cyclin D1 (15%, p < 0.05), cyclin A/A1 (20 and 30%, p < 0.05 and 0.01, respectively) and cyclin dependent kinases2 (25%, p < 0.001). This was associated with a marked increase in the 18 kDa fragment of cyclin E (67%, p < 0.001) which amplifies the apoptotic pathway. In line with this was the increase of the cleaved form of Poly (ADP-ribose) polymerase (54%, p < 0.01) and active Caspase3 (two fold, p < 0.01). These data indicate that the characteristic cerebellar alteRation in this developing brain structure of the hyperbilirubinemic Gunn Rat may be partly due to cell cycle perturbation and apoptosis related to the high bilirubin concentRation in cerebellar tissue mainly affecting granular cells. These two phenomena might be intimatel
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mRNA relative expression of Cyclin D1, Cyclin E1, Cyclin A, A1 and Cdk2.
2013Co-Authors: Maria Celeste Robert, Eleonora Vianello, Claudio Tiribelli, Giulia Furlan, Natalia Rosso, S E Gambaro, Faina Apitsionak, Silvia GazzinAbstract:□ Normal homozygous JJ and ■ Hyperbilirubinemic homozygous jj Gunn Rat. Data are expressed as mean ± SD. Statistical significance: ** p < 0.01.
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Representative Western blot and protein relative expression of p18-Cyclin E, Parp-1, cParp-1 and cCasp3.
2013Co-Authors: Maria Celeste Robert, Eleonora Vianello, Claudio Tiribelli, Giulia Furlan, Natalia Rosso, S E Gambaro, Faina Apitsionak, Silvia GazzinAbstract:A) Representative Western blot, and B) protein relative quantification. cParp-1: cleaved Parp-1. cCasp3: active caspase3 □ Normal homozygous JJ and ■ Hyperbilirubinemic homozygous jj Gunn Rat. Data are expressed as mean ± SD. Statistical significance: * p < 0.05, ** p < 0.01.
Clifford J Steer - One of the best experts on this subject based on the ideXlab platform.
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correction of the udp glucuronosyltransferase gene defect in the Gunn Rat model of crigler najjar syndrome type i with a chimeric oligonucleotide
Proceedings of the National Academy of Sciences of the United States of America, 1999Co-Authors: Betsy T Kren, Jayanta Roy Chowdhury, Bhupesh Parashar, Paramita T Bandyopadhyay, Namita Roy Chowdhury, Clifford J SteerAbstract:Crigler–Najjar syndrome type I is characterized by unconjugated hyperbilirubinemia resulting from an autosomal recessive inherited deficiency of hepatic UDP-glucuronosyltransferase (UGT) 1A1 activity. The enzyme is essential for glucuronidation and biliary excretion of bilirubin, and its absence can be fatal. The Gunn Rat is an excellent animal model of this disease, exhibiting a single guanosine (G) base deletion within the UGT1A1 gene. The defect results in a frameshift and a premature stop codon, absence of enzyme activity, and hyperbilirubinemia. Here, we show permanent correction of the UGT1A1 genetic defect in Gunn Rat liver with site-specific replacement of the absent G residue at nucleotide 1206 by using an RNA/DNA oligonucleotide designed to promote endogenous repair of genomic DNA. The chimeric oligonucleotide was either complexed with polyethylenimine or encapsulated in anionic liposomes, administered i.v., and targeted to the hepatocyte via the asialoglycoprotein receptor. G insertion was determined by PCR amplification, colony lift hybridizations, restriction endonuclease digestion, and DNA sequencing, and confirmed by genomic Southern blot analysis. DNA repair was specific, efficient, stable throughout the 6-month observation period, and associated with reduction of serum bilirubin levels. Our results indicate that correction of the UGT1A1 genetic lesion in the Gunn Rat restores enzyme expression and bilirubin conjugating activity, with consequent improvement in the metabolic abnormality.
Anne Myara - One of the best experts on this subject based on the ideXlab platform.
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human neonatal hepatocyte transplantation induces long term rescue of unconjugated hyperbilirubinemia in the Gunn Rat
Liver Transplantation, 2015Co-Authors: Laia Tolosa, Silvia Lopez, Eugenia Pareja, M T Donato, Anne Myara, Tuan Huy Nguyen, Jose V Castell, Maria Jose GomezlechonAbstract:Crigler-Najjar type 1 disease is a rare inherited metabolic disease characterized by high levels of unconjugated bilirubin due to the complete absence of hepatic uridine diphosphoglucuronate–glucuronosyltransferase activity. Hepatocyte transplantation (HT) has been proposed as an alternative treatment for Crigler-Najjar syndrome, but it is still limited by the quality and the low engraftment and repopulation ability of the cells used. Because of their attachment capability and expression of adhesion molecules as well as the higher proportion of hepatic progenitor cells, neonatal hepatocytes may have an advantage over adult cells. Adult or neonatal hepatocytes were transplanted into Gunn Rats, a model for Crigler-Najjar disease. Engraftment and repopulation were studied and compared by immunofluorescence (IF). Additionally, the serum bilirubin levels, the presence of bilirubin conjugates in Rat serum, and the expression of uridine diphosphate glucuronosyltransferase 1 family polypeptide A1 (UGT1A1) in Rat liver samples were also analyzed. Here we show that neonatal HT results in long-term correction in Gunn Rats. In comparison with adult cells, neonatal cells showed better engraftment and repopulation capability 3 days and 6 months after transplantation, respectively. Bilirubinemia decreased in the transplanted animals during the whole experimental follow-up (6 months). Bilirubin conjugates were also present in the serum of the transplanted animals. Western blots and IF confirmed the presence and expression of UGT1A1 in the liver. This work is the first to demonstRate the advantage of using neonatal hepatocytes for the treatment of Crigler-Najjar in vivo. Liver Transpl 21:801-811, 2015. © 2015 AASLD.