Karpen S.J.,Texas Childrens Liver Center |
Trauner M.,Laboratory of Experimental and Molecular Hepatology
Journal of Hepatology | Year: 2010
A joint EASL/AASLD Monothematic Conference on 'Nuclear Receptors and Liver Disease' was held from February 27th to March 1st, 2009, in Vienna, Austria, to discuss the latest advances at the forefront of basic and clinical nuclear receptor research and its potential implications for liver diseases. This article reports the highlights of the conference and summarizes the main conclusions emphasizing the relevance for clinical and experimental hepatology. The confluence of nuclear receptors as central transcriptional regulators, acting as sensors and adaptors to many of the small molecules present in the intracellular milieu of all the cells of the liver, provides a current framework to address a broader physiological understanding of the liver. The next stage will be the design and testing of safe and effective therapeutics.
McLin V.A.,University of Geneva |
McLin V.A.,Texas Childrens Liver Center |
Anand R.,EMMES Corporation |
Daniels S.R.,University of Colorado at Denver |
And 2 more authors.
American Journal of Transplantation | Year: 2012
As pediatric liver transplant (LT) recipients come of age, additional insight into long-term medical complications of immunosuppression is warranted. The aims of this study were to estimate the prevalence of elevated blood pressure (BP) in long-term survivors of pediatric LT using the data from the Studies in Pediatric Liver Transplantation (SPLIT) database and to identify predictive factors. Patients enrolled in the BP arm of the SPLIT cohort participated in the study. All patients were of at least 5 years but ≤10 years post-LT. Automated BP measurements were obtained at anniversary visits. BP measures were classified as normal, borderline or elevated according to standard criteria. Patients taking antihypertensive medications were classified as " Eight hundred and fifteen patients participated. The prevalence of elevated BP measurements 5 to 10 years post-LT was 17.5 to 27.5%. Of total 62.5% patients presented with at least one additional elevated BP at a later follow up visit. Multivariate analysis revealed the following parameters to be predictive of elevated BP: age at transplant, steroid use at last BP measurement and cGFR at last BP measurement. Pediatric LT patients show a high prevalence of elevated BP measurements 5 to 10 years following LT, which is related to age at LT, decreased cGFR and recent steroid use. Pediatric liver transplant recipients show a high prevalence of elevated blood pressure measurements 5-10 years following liver transplantation, which are related to age at transplantation, decreased cGFR and recent steroid use. © Copyright 2011 The American Society of Transplantation and the American Society of Transplant Surgeons.
Baghdasaryan A.,Medical University of Graz |
Claudel T.,Medical University of Graz |
Kosters A.,Texas Childrens Liver Center |
Gumhold J.,Medical University of Graz |
And 7 more authors.
Gut | Year: 2010
Background and aim: Chronic cholangiopathies have limited therapeutic options and represent an important indication for liver transplantation. Curcumin, the yellow pigment of the spice turmeric, has pleiotropic actions and attenuates hepatic damage in animal models of chemically-induced liver injury. Whether curcumin has beneficial effects in cholangiopathies is unknown. Methods: Potential anticholestatic, anti-inflammatory and antifibrotic mechanisms of curcumin were explored in vivo in Mdr2-/- mice as a murine model of chronic cholangiopathy; as well as in vitro in a cholangiocyte cell line (HuCCT1) and portal myofibroblasts (MFBs) isolated from Mdr2-/- mice. Results: Liver damage, cholestasis and fibrosis were reduced in Mdr2 -/- mice after curcumin feeding. Moreover, curcumin inhibited cholangiocyte proliferation and expression of activation marker vascular cell adhesion molecule-1 in Mdr2-/- mice. Curcumin - similar to PPARγ synthetic agonist troglitazone - directly inhibited TNF-α-induced inflammatory activation of cholangiocytes in vitro, whereas these beneficial effects of curcumin were largely blocked by a PPARγ synthetic antagonist. In addition, curcumin blocked proliferation and activation of portal MFBs by inhibiting ERK1/2 phosphorylation, thus contributing to reduced fibrogenesis. Conclusions: These results show that curcumin may have multiple targets in liver including activation of PPARγ in cholangiocytes and inhibition of ERK1/2 signalling in MFBs, thereby modulating several central cellular events in a mouse model of cholangiopathy. Targeting these pathways may be a promising therapeutic approach to cholangiopathies.
Maynard J.P.,Texas Childrens Liver Center |
Maynard J.P.,Baylor College of Medicine |
Lee J.-S.,University of Texas M. D. Anderson Cancer Center |
Sohn B.H.,University of Texas M. D. Anderson Cancer Center |
And 6 more authors.
Oncotarget | Year: 2015
P2 purinergic receptors are overexpressed in certain cancer tissues, but the pathophysiologic relevance of purinergic signaling in hepatocellular carcinoma (HCC) remains unknown. To examine the role of P2 purinergic signaling in the pathogenesis of HCC and characterize extracellular nucleotide effects on HCC cell proliferation, two independent HCC patient cohorts were analyzed for P2 purinergic receptor expression, and nucleotide treated HCC cell lines were evaluated for effects on proliferation and cell cycle progression. Our studies suggest that multiple P2 purinergic receptor isoforms are overexpressed in liver tumors, as compared to uninvolved liver, and dysregulation of P2 purinergic receptor expression is apparent in HCC cell lines, as compared to human primary hepatocytes. High P2X3 purinergic receptor expression is associated with poor recurrence-free survival (RFS), while high P2Y13 expression is associated with improved RFS. Extracellular nucleotide treatment alone is sufficient to induce cell cycle progression, via activation of JNK signaling, and extracellular ATPmediated activation of P2X3 receptors promotes proliferation in HCC cells. Conclusion: Our analysis of HCC patient livers and HCC cells in vitro identifies a novel role for dysregulation of P2 purinergic signaling in the induction of hyper-proliferative HCC phenotype and identifies P2X3 purinergic receptors as potential new targets for therapy.
Tackett B.C.,Texas Childrens Liver Center |
Tackett B.C.,Baylor College of Medicine |
Sun H.,Texas Childrens Liver Center |
Mei Y.,Texas Childrens Liver Center |
And 10 more authors.
American Journal of Physiology - Gastrointestinal and Liver Physiology | Year: 2014
Extracellular nucleotides via activation of P2 purinergic receptors influence hepatocyte proliferation and liver regeneration in response to 70% partial hepatectomy (PH). Adult hepatocytes express multiple P2Y (G protein-coupled) and P2X (ligand-gated ion channels) purinergic receptor subtypes. However, the identity of key receptor subtype(s) important for efficient hepatocyte proliferation in regenerating livers remains unknown. To evaluate the impact of P2Y2 purinergic receptor-mediated signaling on hepatocyte proliferation in regenerating livers, wild-type (WT) and P2Y2 purinergic receptor knockout (P2Y2—/—) mice were subjected to 70% PH. Liver tissues were analyzed for activation of early events critical for hepatocyte priming and subsequent cell cycle progression. Our findings suggest that early activation of p42/44 ERK MAPK (5 min), early growth response-1 (Egr-1) and activator protein-1 (AP-1) DNA-binding activity (30 min), and subsequent hepatocyte proliferation (24-72 h) in response to 70% PH were impaired in P2Y2—/— mice. Interestingly, early induction of cytokines (TNF-a, IL-6) and cytokine-mediated signaling (NF-kB, STAT-3) were intact in P2Y2—/— remnant livers, uncovering the importance of cytokine-independent and nucleotide-dependent early priming events critical for subsequent hepatocyte proliferation in regenerating livers. Hepatocytes isolated from the WT and P2Y2—/— mice were treated with ATP or ATP7S for 5-120 min and 12-24 h. Extracellular ATP alone, via activation of P2Y2 purinergic receptors, was sufficient to induce ERK phosphorylation, Egr-1 protein expression, and key cyclins and cell cycle progression of hepatocytes in vitro. Collectively, these findings highlight the functional significance of P2Y2 purinergic receptor activation for efficient hepatocyte priming and proliferation in response to PH. © 2014 the American Physiological Society.