ORCID Profile
0000-0001-7058-6201
Current Organisations
QIMR Berghofer Medical Research Institute
,
University of Queensland
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Research Topics
In Research Link Australia (RLA), "Research Topics" refer to ANZSRC FOR and SEO codes. These topics are either sourced from ANZSRC FOR and SEO codes listed in researchers' related grants or generated by a large language model (LLM) based on their publications.
Top 5 Research Topics
ANZSRC Field of Research (FoR)
Animal Physiology - Systems | Biochemistry and Cell Biology | Biochemistry and Cell Biology not elsewhere classified
ANZSRC Socio-Economic Objective (SEO)
Behaviour and Health | Endocrine Organs and Diseases (excl. Diabetes) |
Related Links
Publications
Risk of Liver Cancer in HFE-Hemochromatosis
Publisher: Elsevier BV
Date: 11-2021
A New Look at Ferritin Metabolism
Publisher: Springer US
Date: 1994
Evidence for a sub-morphological inflammatory process in the liver in haemochromatosis
Publisher: Elsevier BV
Date: 04-2003
DOI: 10.1016/S0168-8278(02)00444-0
Abstract: The role of cytokines in hepatic injury has been examined for many liver diseases however little is known of the cytokine involvement in haemochromatosis. The aim of the current study was to examine the hepatic gene expression of potential proinflammatory and profibrogenic cytokines in haemochromatosis. Interferon-gamma, interleukin-10, transforming growth factor-beta(1) and tumor necrosis factor-alpha mRNA expression was assessed in liver tissue from 20 haemochromatosis patients, eight controls and eight chronic hepatitis C patients. To assess the immunophenotype of the inflammatory infiltrate in haemochromatosis, liver sections were subjected to immunohistochemistry using markers for macrophages (CD68, HAM56, MAC387) or T cells (CD3 and CD45RO). Interferon-gamma mRNA was increased in both haemochromatosis (0.29+/-0.08%, P=0.01) and hepatitis C patients (1.02+/-0.32%, P=0.03) compared to controls (0.04+/-0.01%). Interleukin-10 mRNA was significantly decreased in both haemochromatosis and hepatitis C patients (0.01+/-0.003%, P=0.008 and 0.03+/-0.015%, P=0.02, respectively) compared to controls (0.12+/-0.01%). CD3 positive T-cell number was significantly correlated with increasing hepatic iron concentration (r=0.56, P=0.03). This study has demonstrated a distinct pattern of cytokine gene expression in haemochromatosis, which resembles that of inflammatory conditions such as chronic hepatitis C. These factors may play a role in the development of iron-induced hepatic fibrosis in haemochromatosis.
A Role for Serotonin (5-HT) in Hepatic Stellate Cell Function and Liver Fibrosis
Publisher: Elsevier BV
Date: 09-2006
DOI: 10.2353/AJPATH.2006.050767
Abstract: Hepatic stellate cells (HSCs) are key cellular components of hepatic wound healing and fibrosis. There is emerging evidence that the fibrogenic function of HSCs may be influenced by neurochemical and neurotrophic factors. This study addresses the potential for the serotonin (5-HT) system to influence HSC biology. Rat and human HSCs express the 5-HT1B, 5-HT1F 5-HT2A 5-HT2B, and 5-HT7 receptors, with expression of 5-HT1B 5-HT2A and 5-HT2B being induced on HSC activation. Induction of 5-HT2A and 5-HT2B was 106+/-39- and 52+/-8.5-fold that of quiescent cells, respectively. 5-HT2B was strongly associated with fibrotic tissue in diseased rat liver. Treatment of HSCs with 5-HT2 antagonists suppressed proliferation and elevated their rate of apoptosis by contrast 5-HT was protective against nerve growth factor-induced apoptosis. 5-HT synergized with platelet-derived growth factor to stimulate increased HSC proliferation. HSCs were shown to express a functional serotonin transporter and to participate in both active uptake and release of 5-HT. We conclude that HSCs express key regulatory components of the 5-HT system enabling them to store and release 5-HT and to respond to the neurotransmitter in a profibrogenic manner. Antagonists that selectively target the 5-HT class of receptors may be exploited as antifibrotic drugs.
RELATIVELY FEW CLINICIANS IN MEDICAL RESEARCH IN AUSTRALIA: A PROBLEM?
Publisher: Wiley
Date: 10-1989
Utility and limitations of Hepascore and transient elastography to detect advanced hepatic fibrosis in HFE hemochromatosis
Publisher: Springer Science and Business Media LLC
Date: 19-07-2021
DOI: 10.1038/S41598-021-94083-X
Abstract: Aspartate aminotransferase-to-platelet ratio index (APRI) and Fibrosis-4 Index (Fib4) have been validated against liver biopsy for detecting advanced hepatic fibrosis in HFE hemochromatosis. We determined the diagnostic utility for advanced hepatic fibrosis of Hepascore and transient elastography compared with APRI and Fib4 in 134 newly diagnosed HFE hemochromatosis subjects with serum ferritin levels 300 µg/L using area under the receiver operator characteristic curve (AUROC) analysis and APRI- ( 0.44) or Fib4- ( 1.1) cut-offs for AHF, or a combination of both. Compared with APRI, Hepascore demonstrated an AUROC for advanced fibrosis of 0.69 (95% CI 0.56–0.83 sensitivity = 69%, specificity = 65% P = 0.01) at a cut-off of 0.22. Using a combination of APRI and Fib4, the AUROC for Hepascore for advanced fibrosis was 0.70 (95% CI 0.54–0.86, P = 0.02). Hepascore was not diagnostic for detection of advanced fibrosis using the Fib4 cut-off. Elastography was not diagnostic using either APRI or Fib4 cut-offs. Hepascore and elastography detected significantly fewer true positive or true negative cases of advanced fibrosis compared with APRI and Fib4, except in subjects with serum ferritin levels 1000 µg/L. In comparison with APRI or Fib4, Hepascore or elastography may underdiagnose advanced fibrosis in HFE Hemochromatosis, except in in iduals with serum ferritin levels 1000 µg/L.
Reply: The utility of noninvasive imaging in cystic fibrosis liver disease
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 22-04-2011
DOI: 10.1002/HEP.24288
Vitamin A-poor lipocytes: a novel desmin-negative lipocyte subpopulation, which can be activated to myofibroblasts
Publisher: American Physiological Society
Date: 10-1995
DOI: 10.1152/AJPGI.1995.269.4.G532
Abstract: Lipocytes have been classified as vitamin A-storing, desmin-positive cells. In hepatic fibrogenesis, lipocytes transform into myofibroblasts, which express alpha-smooth muscle actin (alpha-SMA) and produce increased amounts of collagen. We isolated a population of vitamin A-poor lipocytes (VAPL) from normal rat liver and examined the morphological and biochemical differences between VAPL and vitamin A-replete lipocytes (VARL). Desmin and alpha-SMA expression were determined by Western blot in quiescent cells and in cells activated by culture on uncoated plastic. Both cell types were alpha-SMA-negative however, in contrast to VARL, freshly isolated VAPL did not contain desmin. Desmin expression was induced in VAPL on activation. With time in culture, both VAPL and VARL expressed alpha-SMA and produced collagen, indicative of transformation to myofibroblasts. Ferritin receptor expression was demonstrated in cultured VARL after 1 day and in VAPL after 5 days, indicating that this is an early marker of lipocyte activation. After 7 days, VARL and VAPL were indistinguishable in terms of desmin, ferritin receptor expression, and collagen production. This study demonstrates the first isolation and characterization of two distinct quiescent subpopulations of lipocytes from normal rat liver: desmin-negative VAPL and desmin-positive VARL. Both populations of cells can be activated to myofibroblasts, the phenotype associated with hepatic fibrogenesis.
Mechanism of pancreatic and liver malformations in human fetuses with short‐rib polydactyly syndrome
Publisher: Wiley
Date: 11-03-2016
DOI: 10.1002/BDRA.23495
Abstract: The short-rib polydactyly (SRP) syndromes are rare skeletal dysplasias caused by abnormalities in primary cilia, sometimes associated with visceral malformations. The pathogenesis of ductal plate malformation (DPM) varies in different syndromes and has not been investigated in SRP. We have studied liver development in five SRP fetuses and pancreatic development in one SRP fetus, with genetically confirmed mutations in cilia related genes, with and without DPMs, using the immunoperoxidase technique, and compared these to other syndromes with DPM. Acetylated tubulin expression was abnormal in DPM in SRP, Meckel syndrome, and autosomal recessive polycystic kidney disease (ARPKD), confirming ciliary anomalies. SDF-1 was abnormally expressed in SRP and two of three cases of autosomal dominant polycystic kidney disease (ADPKD) but not ARPKD or Meckel. Increased density of quiescent hepatic stellate cells was seen in SRP, Meckel, one of three cases of ARPKD, and two of three cases of ADPKD with aberrant hepatocyte expression of keratin 19 in SRP and ADPKD. Immunophenotypic abnormalities were present even in fetal liver without fully developed DPMs. The SRP case with DPM and pancreatic malformations showed abnormalities in the pancreatic head (influenced by mesenchyme from the septum transversum, similar to liver) but not pancreatic body (influenced by mesenchyme adjacent to the notochord). In SRP, there are differentiation defects of hepatocytes, cholangiocytes, and liver mesenchyme and, in rare cases, pancreatic mesenchymal anomalies. The morphological changes were subtle in early gestation but immunophenotypic abnormalities were present. Mesenchymal-epithelial interactions may contribute to the malformations. Birth Defects Research (Part A) 106:549-562, 2016. © 2016 Wiley Periodicals, Inc.
Serum MicroRNAs as Biomarkers in Hepatitis C: Preliminary Evidence of a MicroRNA Panel for the Diagnosis of Hepatocellular Carcinoma
Publisher: MDPI AG
Date: 17-02-2019
DOI: 10.3390/IJMS20040864
Abstract: Early diagnosis of cirrhosis and hepatocellular carcinoma (HCC) due to chronic Hepatitis C (CHC) remain clinical priorities. In this pilot study, we assessed serum microRNA (miRNA) expression to distinguish cirrhosis and HCC, alone and in combination with the aminotransferase-to-platelet ratio (APRI), Fibrosis 4 (FIB-4), and alpha-fetoprotein (AFP). Sixty CHC patients were sub ided into 3 cohorts: Mild disease (fibrosis stage F0-2 n = 20) cirrhosis (n = 20) and cirrhosis with HCC (n = 20). Circulating miRNA signatures were determined using a liver-specific real-time quantitative reverse transcription PCR (qRT-PCR) microarray assessing 372 miRNAs simultaneously. Differentially-expressed miRNA candidates were independently validated using qRT-PCR. Serum miRNA-409-3p was increased in cirrhosis versus mild disease. In HCC versus cirrhosis, miRNA-486-5p was increased, whereas miRNA-122-5p and miRNA-151a-5p were decreased. A logistic regression model-generated panel, consisting of miRNA-122-5p + miRNA-409-3p, distinguished cirrhosis from mild disease (area under the curve, AUC = 0.80 sensitivity = 85%, specificity = 70% p 0.001). When combined with FIB-4 or APRI, performance was improved with AUC = 0.89 (p 0.001) and 0.87 (p 0.001), respectively. A panel consisting of miRNA-122-5p + miRNA-486-5p + miRNA-142-3p distinguished HCC from cirrhosis (AUC = 0.94 sensitivity = 80%, specificity = 95% p 0.001), outperforming AFP (AUC = 0.64, p = 0.065). Serum miRNAs are differentially expressed across the spectrum of disease severity in CHC. MicroRNAs have great potential as diagnostic biomarkers in CHC, particularly in HCC where they outperform the only currently-used biomarker, AFP.
Attenuated liver progenitor (oval) cell and fibrogenic responses to the choline deficient, ethionine supplemented diet in the BALB/c inbred strain of mice
Publisher: Elsevier BV
Date: 2007
DOI: 10.1016/J.JHEP.2006.08.015
Abstract: Liver regeneration following chronic injury is associated with inflammation, the proliferation of liver progenitor (oval) cells and fibrosis. Previous studies identified interferon-gamma as a key mediator of oval cell proliferation. Interferon-gamma is known to regulate Th1 cell activities during immune challenge. Therefore, we hypothesised that progenitor cell-mediated regeneration is associated with a Th1 immune response. C57Bl/6 (normal Th1 response) and BALB/c mice (deficient in Th1 signalling) were placed on a carcinogenic diet to induce liver injury, progenitor cell proliferation and fibrosis. Serum transaminases and mortality were elevated in BALB/c mice fed the diet. Proliferation of liver progenitor cells was significantly attenuated in BALB/c animals. The pattern of cytokine expression and inflammation differed between strains. Liver fibrosis and hepatic stellate cell activation were significantly inhibited in BALB/c mice compared to C57Bl/6. In addition, interferon-gamma knockout mice also showed reduced fibrosis compared to wild type. These findings are in contrast to published results, in which interferon-gamma is shown to be anti-fibrogenic. Our data demonstrate that the hepatic progenitor cell response to a CDE diet is inhibited in mice lacking Th1 immune signalling and further show that this inhibition is associated with reduced liver fibrosis.
Screening for Hemochromatosis in Asymptomatic Subjects With or Without a Family History
Publisher: American Medical Association (AMA)
Date: 13-02-2006
DOI: 10.1001/ARCHINTE.166.3.294
Abstract: Hemochromatosis in white subjects is mostly due to homozygosity for the common C282Y substitution in HFE. Although clinical symptoms are preventable by early detection of the genetic predisposition and prophylactic treatment, population screening is not currently advocated because of the discrepancy between the common mutation prevalence and apparently lower frequency of clinical disease. This study compared screening for hemochromatosis in subjects with or without a family history. We assessed disease expression by clinical evaluation and liver biopsy in 672 essentially asymptomatic C282Y homozygous subjects identified by either family screening or health checks. We also observed a subgroup of untreated homozygotes with normal serum ferritin levels for up to 24 years. Prevalence of hepatic iron overload and fibrosis were comparable between the 2 groups. Disease-related conditions were more common in male subjects identified by health checks, but they were older. Hepatic iron overload (grades 2-4) was present in 56% and 34.5% of male and female subjects, respectively hepatic fibrosis (stages 2-4) in 18.4% and 5.4% and cirrhosis in 5.6% and 1.9%. Hepatic fibrosis and cirrhosis correlated significantly with the hepatic iron concentration, and except in cases of cirrhosis, there was a 7.5-fold reduction in the mean fibrosis score after phlebotomy. All subjects with cirrhosis were asymptomatic. Screening for hemochromatosis in apparently healthy subjects homozygous for the C282Y mutation with or without a family history reveals comparable levels of hepatic iron overload and disease. Significant hepatic fibrosis is frequently found in asymptomatic subjects with hemochromatosis and, except when cirrhosis is present, is reversed by iron removal.
Effect of colchicine on the clearance of ferritin in vivo
Publisher: American Physiological Society
Date: 05-1990
DOI: 10.1152/AJPGI.1990.258.5.G707
Abstract: The effect of the microtubular inhibitor colchicine, administered at either 0.036 (dose 1) or 5 mumol/kg (dose 2), on hepatic ferritin uptake was determined over a 5-h period of ferritin infusion in normal and iron-loaded rats. In the absence of colchicine, the serum ferritin concentration of normal rats was reduced after 5 h to 20 +/- 9% and in iron-loaded rats to 30 +/- 1% of the expected values, indicating ferritin clearance. After colchicine (dose 1), a similar result was observed in normal rats however, in iron-loaded rats, an increase in serum ferritin to 77 +/- 16% of the expected value indicated a decreased ferritin clearance and/or increased ferritin release. The administration of the higher dose to normal rats also resulted in an increase in serum ferritin to 72 +/- 2% of the expected value. In iron-loaded rats, after dose 2 the ferritin concentration rose to 359 +/- 108% of the expected value, consistent with the release of endogenous ferritin. Colchicine administration had no effect on biliary ferritin in normal rats however, in iron-loaded rats, both doses resulted in a fivefold increase in the release of biliary ferritin. The results suggest that ferritin uptake is facilitated by receptor-mediated endocytosis, which is partially inhibited by colchicine. Release of ferritin also occurs as a result of colchicine administration, and this is dependent on both the dose of colchicine and the iron status of the animal.
Iron and Hepatic Carcinogenesis
Publisher: Begell House
Date: 2013
DOI: 10.1615/CRITREVONCOG.2013007759
Abstract: Iron is an essential co-factor for life however, a physiologically optimal balance is critical. Too much or too little iron can have detrimental effects on human health. In this article, we explore the relationships between iron and hepatocellular carcinoma (HCC). Iron can act as a modulating co-factor in a range of chronic liver diseases and can accelerate the development of liver injury, fibrosis, cirrhosis, and ultimately HCC. Iron can, however, also act as a sole factor in the causation of liver cirrhosis and HCC in in iduals with hereditary hemochromatosis (HH). We overview the regulation of normal iron metabolism and the role of iron in wound healing and associated cell types as well as in pathophysiologies that predispose to HCC. We review how these injury processes are inextricably linked, providing a mechanistic basis for understanding how iron and hepatic injury potentially result in HCC.
Function and Regulation of MicroRNAs and Their Potential as Biomarkers in Paediatric Liver Disease
Publisher: MDPI AG
Date: 27-10-2016
DOI: 10.3390/IJMS17111795
Aspartate aminotransferase to platelet ratio and fibrosis‐4 as biomarkers in biopsy‐validated pediatric cystic fibrosis liver disease
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 28-09-2015
DOI: 10.1002/HEP.28016
Abstract: Up to 10% of cystic fibrosis (CF) children develop cirrhosis by the first decade. We evaluated the utility of two simple biomarkers, aspartate aminotransferase to platelet ratio index (APRI) and FIB-4, in predicting degree of fibrosis in pediatric CF liver disease (CFLD) validated by liver biopsy. In this retrospective, cross-sectional study, 67 children with CFLD had dual-pass liver biopsies and 104 age- and sex-matched CF children without liver disease (CFnoLD) had serum to calculate APRI and FIB-4 collected at enrollment. CFLD was defined as having two of the following: (1) hepatomegaly±splenomegaly (2)>6 months elevation of ALT (>1.5× upper limit of normal ULN) or (3) abnormal liver ultrasound findings. Biopsies were staged according to Metavir classification by two blinded pathologists. Receiver operating characteristic (ROC) analysis and continuation ratio logistic regression were performed to assess the predictability of these biomarkers to distinguish CFLD from CFnoLD and determine fibrosis stage-specific cut-off values. The AUC for APRI was better than FIB-4 (0.75 vs. 0.60 P=0.005) for predicting CFLD and severe CFLD (F3-F4) (0.81). An APRI score>0.264 demonstrated a sensitivity (95% confidence interval [CI]) of 73.1% (60.9, 83.2) and specificity of 70.2% (60.4, 78.8) in predicting CFLD. A 50% increase in APRI was associated with a 2.4-fold (95% CI: 1.7, 3.3) increased odds of having CFLD. APRI demonstrated full agreement with histology staging 37% of the time, but was within one stage 73% of the time. Only FIB-4 predicted portal hypertension at diagnosis (area under the receiver operator characteristic curve [AUC 0.91 P<0.001). This is the first liver biopsy-validated study of APRI and FIB-4 in pediatric CFLD. APRI appears superior to FIB-4 in differentiating CFLD versus CFnoLD. APRI also exhibited a high AUC in predicting severe liver fibrosis with specific cutoffs for lower stages.
HFE gene and hemochromatosis
Publisher: Wiley
Date: 18-05-2004
Extracellular vesicles in the development of organ‐specific metastasis
Publisher: Wiley
Date: 07-2021
DOI: 10.1002/JEV2.12125
Abstract: Distant organ metastasis, often termed as organotropic metastasis or metastatic organotropism, is a fundamental feature of malignant tumours and accounts for most cancer‐related mortalities. This process is orchestrated by many complex biological interactions and processes that are mediated by a combination of anatomical, genetic, pathophysiological and biochemical factors. Recently, extracellular vesicles (EVs) are increasingly being demonstrated as critical mediators of bi‐directional tumour‐host cell interactions, controlling organ‐specific infiltration, adaptation and colonization at the secondary site. EVs govern organotropic metastasis by modulating the pre‐metastatic microenvironment through upregulation of pro‐inflammatory gene expression and immunosuppressive cytokine secretion, induction of phenotype‐specific differentiation and recruitment of specific stromal cell types. This review discusses EV‐mediated metastatic organotropism in visceral (brain, lung, liver, and lymph node) and skeletal (bone) metastasis, and discusses how the pre‐metastatic education by EVs transforms the organ into a hospitable, tumour cell–friendly milieu that supports the growth of metastatic cells. Decoding the organ‐specific traits of EVs and their functions in organotropic metastasis is essential in accelerating the clinical application of EVs in cancer management.
Transcriptional profiling of chronic clinical hepatic schistosomiasis japonica indicates reduced metabolism and immune responses
Publisher: Cambridge University Press (CUP)
Date: 28-07-2015
DOI: 10.1017/S0031182015000682
Abstract: Schistosomiasis is a significant cause of human morbidity and mortality. We performed a genome-wide transcriptional survey of liver biopsies obtained from Chinese patients with chronic schistosomiasis only, or chronic schistosomiasis with a current or past history of viral hepatitis B. Both disease groups were compared with patients with no prior history or indicators of any liver disease. Analysis showed in the main, downregulation in gene expression, particularly those involved in signal transduction via EIF2 signalling and mTOR signalling , as were genes associated with cellular remodelling. Focusing on immune associated pathways, genes were generally downregulated. However, a set of three genes associated with granulocytes, MMP7, CLDN7, CXCL6 were upregulated. Differential gene profiles unique to schistosomiasis included the gene Granulin which was decreased despite being generally considered a marker for liver disease, and IGBP2 which is associated with increased liver size, and was the most upregulated gene in schistosomiasis only patients, all of which presented with hepatomegaly. The unique features of gene expression, in conjunction with previous reports in the murine model of the cellular composition of granulomas, granuloma formation and recovery, provide an increased understanding of the molecular immunopathology and general physiological processes underlying hepatic schistosomiasis.
Hepatocellular carcinoma surveillance in Australia: time to improve the diagnosis of cirrhosis and use liver ultrasound
Publisher: AMPCo
Date: 08-10-2020
DOI: 10.5694/MJA2.50808
Characterization of CFTR mutations in people with cystic fibrosis and severe liver disease who are not eligible for CFTR modulators
Publisher: Elsevier BV
Date: 03-2023
Possible Role of WT1 in a Human Fetus with Evolving Bronchial Atresia, Pulmonary Malformation and Renal Agenesis
Publisher: SAGE Publications
Date: 2012
Abstract: The association of peripheral bronchial atresia and congenital pulmonary airway malformation (CPAM) has recently been recognised, but the pathology of the lesions evolving together has not been described. We present autopsy findings in a 20 week fetus showing areas of peripheral bronchial destruction and airway malformation consistent with developing CPAM in the right lung supporting a causal relationship between these lesions. This fetus also had congenital heart defect, bilateral renal agenesis and syndactyly. We identified another fetus from our autopsy files, with bilateral renal agenesis, similar right sided pulmonary malformation and cardiac defects. Similar bilateral renal agenesis and defects of the heart and lungs are found in wt1 −-/– mice and we have investigated the expression of WT1 in these fetuses. We hypothesise that the cardiac, liver, renal and possibly lung lesions in these two cases may arise due to mesenchymal defects consequent to WT1 misexpression and discuss evidence for this from the scientific literature. We used immunoperoxidase stains to analyse WT1 expression in autopsy hepatic tissue in both fetuses. We also investigated the expression of α-smooth muscle actin (α-SMA), a marker of activated hepatic stellate cells/myofibroblasts, and desmin in hepatic mesenchyme and compare these findings with control fetuses, without congenital malformations. We found reduced WT1 expression in hepatic mesothelium in both fetuses with malformations. There was also increased expression of α-SMA in liver perisinusoidal cells, as seen in the wt1 −-/– mouse model. We therefore propose that abnormality of WT1 signalling may be an underlying factor, as WT1 is expressed in coelomic lining cells from which mesenchyme is derived in many organs.
Activation of Pancreatic Stellate Cells in Human and Experimental Pancreatic Fibrosis
Publisher: Elsevier BV
Date: 10-1999
The structural conformation of the tachykinin domain drives the anti-tumoural activity of an octopus peptide in melanoma BRAFV600E.
Publisher: Wiley
Date: 29-07-2022
DOI: 10.1111/BPH.15923
Abstract: Over past decades, targeted therapies and immunotherapy have improved survival and reduced the morbidity of patients with BRAF‐mutated melanoma. However, drug resistance and relapse hinder overall success. Therefore, there is an urgent need for novel compounds with therapeutic efficacy against BRAF‐melanoma. This prompted us to investigate the antiproliferative profile of a tachykinin‐peptide from the Octopus kaurna , Octpep‐1 in melanoma. We evaluated the cytotoxicity of Octpep‐1 by MTT assay. Mechanistic insights on viability and cellular damage caused by Octpep‐1 were gained via flow cytometry and bioenergetics. Structural and pharmacological characterization was conducted by molecular modelling, molecular biology, CRISPR/Cas9 technology, high‐throughput mRNA and calcium flux analysis. In vivo efficacy was validated in two independent xerograph animal models (mice and zebrafish). Octpep‐1 selectively reduced the proliferative capacity of human melanoma BRAF V600E ‐mutated cells with minimal effects on fibroblasts. In melanoma‐treated cells, Octpep‐1 increased ROS with unaltered mitochondrial membrane potential and promoted non‐mitochondrial and mitochondrial respiration with inefficient ATP coupling. Molecular modelling revealed that the cytotoxicity of Octpep‐1 depends upon the α‐helix and polyproline conformation in the C‐terminal region of the peptide. A truncated form of the C‐terminal end of Octpep‐1 displayed enhanced potency and efficacy against melanoma. Octpep‐1 reduced the progression of tumours in xenograft melanoma mice and zebrafish. We unravel the intrinsic anti‐tumoural properties of a tachykinin peptide. This peptide mediates the selective cytotoxicity in BRAF‐mutated melanoma in vitro and prevents tumour progression in vivo, providing a foundation for a therapy against melanoma.
Gomesin inhibits melanoma growth by manipulating key signaling cascades that control cell death and proliferation
Publisher: Springer Science and Business Media LLC
Date: 08-2018
DOI: 10.1038/S41598-018-29826-4
Abstract: Consistent with their erse pharmacology, peptides derived from venomous animals have been developed as drugs to treat disorders as erse as hypertension, diabetes and chronic pain. Melanoma has a poor prognosis due in part to its metastatic capacity, warranting further development of novel targeted therapies. This prompted us to examine the anti-melanoma activity of the spider peptides gomesin (AgGom) and a gomesin-like homolog (HiGom). AgGom and HiGom dose-dependently reduced the viability and proliferation of melanoma cells whereas it had no deleterious effects on non-transformed neonatal foreskin fibroblasts. Concordantly, gomesin-treated melanoma cells showed a reduced G0/G1 cell population. AgGom and HiGom compromised proliferation of melanoma cells via activation of the p53 21 cell cycle check-point axis and the Hippo signaling cascade, together with attenuation of the MAP kinase pathway. We show that both gomesin peptides exhibit antitumoral activity in melanoma AVATAR-zebrafish xenograft tumors and that HiGom also reduces tumour progression in a melanoma xenograft mouse model. Taken together, our data highlight the potential of gomesin for development as a novel melanoma-targeted therapy.
Phenotypic analysis of hemochromatosis subtypes reveals variations in severity of iron overload and clinical disease
Publisher: American Society of Hematology
Date: 05-07-2018
DOI: 10.1182/BLOOD-2018-02-830562
Abstract: This comprehensive comparison of the genetic subtypes of hemochromatosis reveals more severe iron overload and disease in non-HFE forms. Arthropathy is more common in HFE-related hemochromatosis, suggesting that joint disease may not be associated with iron.
Endogenous ursodeoxycholic acid and cholic acid in liver disease due to cystic fibrosis
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2004
DOI: 10.1002/HEP.20238
Abstract: Focal biliary cirrhosis causes significant morbidity and mortality in cystic fibrosis (CF). Although the mechanisms of pathogenesis remain unclear, bile acids have been proposed as potential mediators of liver injury. This study examined bile acid composition in CF and assessed altered bile acid profiles to determine if they are associated with incidence and progression of liver injury in CF-associated liver disease (CFLD). Bile acid composition was determined by gas-liquid chromatography/mass spectrometry in bile, urine, and serum s les from 30 children with CFLD, 15 children with CF but without liver disease (CFnoLD), and 43 controls. Liver biopsies from 29 CFLD subjects were assessed histologically by grading for fibrosis stage, inflammation, and disruption of the limiting plate. A significantly greater proportion of endogenous biliary ursodeoxycholic acid (UDCA) was demonstrated in CFnoLD subjects vs. both CFLD subjects and controls (2.4- and 2.2-fold, respectively ANOVA, P =.04), and a 3-4 fold elevation in endogenous serum UDCA concentration was observed in both CFLD subjects and CFnoLD subjects vs. controls (ANOVA, P <.05). In CFLD, there were significant correlations between serum cholic acid and hepatic fibrosis, inflammation, and limiting plate disruption as well as the ratio of serum cholic acid/chenodeoxycholic acid to hepatic fibrosis, inflammation, and limiting plate disruption. In conclusion, elevated endogenous UDCA in CFnoLD suggests a possible protective role against liver injury in these patients. The correlation between both cholic acid and cholic acid/chenodeoxycholic acid levels with histological liver injury and fibrosis progression suggests a potential monitoring role for these bile acids in CFLD.
Evidence that 'myofibroblast-like' cells are the cellular source of capsular collagen in hepatocellular carcinoma
Publisher: Elsevier BV
Date: 04-1997
DOI: 10.1016/S0168-8278(97)80245-0
Abstract: The prognosis for patients with hepatocellular carcinoma is poor although tumour encapsulation has been associated with improved survival and disease-free rates. While the source of the tumour capsule is unclear, the major role that activated hepatic stellate cells play in the deposition of liver matrix in normal and diseased states suggests the possible involvement of these cells in tumour encapsulation. Twenty-four liver tumours (seven encapsulated HCC, seven non-encapsulated HCC, 10 colorectal metastases) were studied. Activated hepatic stellate cells were identified by immunohistochemistry for alpha-smooth muscle actin (alpha-SMA) and in situ hybridization for pro-collagen alpha1 (I) mRNA. Collagen deposition was localized using Masson's trichrome stain. Pro-collagen alpha1 (I) mRNA co-localized to alpha-SMA positive hepatic stellate cells within the region of increased collagen deposition in (i) the tumour capsule of encapsulated HCC, and (ii) the tumour junction of non-encapsulated HCC and colorectal metastasis. In addition, there was marked peritumour expression of alpha-SMA and procollagen alpha1 (I) mRNA, which diminished with distance away from the tumour in all tumour groups. The degree of expression was greatest with encapsulated HCC, less with non-encapsulated HCC and least with colorectal metastasis. This contrasted with the absence of alpha-SMA expression in normal liver from the same patients. Within the tumours, colorectal metastases differed from HCC by demonstrating marked alpha-SMA expression and collagen deposition in the septa. Our findings demonstrate that activated hepatic stellate cells (i) are responsible for increased peritumour collagen production in non-encapsulated HCC and colorectal metastasis, and (ii) may be implicated in tumour capsule formation in HCC and metastasis stroma development. Thus, stellate cells may influence the local hepatic invasion by these tumours.
Lipid peroxidation in hepatic steatosis in humans is associated with hepatic fibrosis and occurs predominately in acinar zone 3
Publisher: Wiley
Date: 06-2001
DOI: 10.1046/J.1440-1746.2001.02445.X
Abstract: Hepatic steatosis has been shown to be associated with lipid peroxidation and hepatic fibrosis in a variety of liver diseases including non-alcoholic fatty liver disease. However, the lobular distribution of lipid peroxidation associated with hepatic steatosis, and the influence of hepatic iron stores on this are unknown. The aim of this study was to assess the distribution of lipid peroxidation in association with these factors, and the relationship of this to the fibrogenic cascade. Liver biopsies from 39 patients with varying degrees of hepatic steatosis were assessed for evidence of lipid peroxidation (malondialdehyde adducts), hepatic iron, inflammation, fibrosis, hepatic stellate cell activation (alpha-smooth muscle actin and TGF-beta expression) and collagen type I synthesis (procollagen alpha1 (I) mRNA). Lipid peroxidation occurred in and adjacent to fat-laden hepatocytes and was maximal in acinar zone 3. Fibrosis was associated with steatosis (P < 0.04), lipid peroxidation (P < 0.05) and hepatic iron stores (P < 0.02). Multivariate logistic regression analysis confirmed the association between steatosis and lipid peroxidation within zone 3 hepatocytes (P < 0.05), while for hepatic iron, lipid peroxidation was seen within sinusoidal cells (P < 0.05), particularly in zone 1 (P < 0.02). Steatosis was also associated with acinar inflammation (P < 0.005). alpha-Smooth muscle actin expression was present in association with both lipid peroxidation and fibrosis. Although the effects of steatosis and iron on lipid peroxidation and fibrosis were additive, there was no evidence of a specific synergistic interaction between them. These observations support a model where steatosis exerts an effect on fibrosis through lipid peroxidation, particularly in zone 3 hepatocytes.
Absorbed aluminium is found with two cytosolic protein fractions, other than ferritin, in the rat duodenum.
Publisher: BMJ
Date: 05-1993
DOI: 10.1136/GUT.34.5.643
Abstract: After in vivo perfusion of the upper intestine of the rat with a range of concentrations of aluminium chloride, entry of the metal into the portal system was only detected when the perfusate exceeded 400 mumol/l, suggesting a mucosal block. Using gel filtration of a mucosal cytosol extract, two consistently appearing aluminium peaks were identified which may represent aluminium binding proteins. Both were heat stable at 60 degrees C and had molecular sizes of about 700 (kilo daltons) (kD) and 17 kD respectively. The larger molecule was distinct from ferritin. Neither molecule associated with 59Fe nor 45Ca. It is suggested that the aluminium peaks are relatively specific aluminium binding proteins that have a scavenging role, reducing entry of the metal from the intestinal contents into the portal blood.
Serum ferritin concentration predicts hepatic fibrosis better than hepatic iron concentration in human HFE- Haemochromatosis
Publisher: Wiley
Date: 13
DOI: 10.1111/LIV.13395
Abstract: Ferritin is purported to have proinflammatory and profibrogenic effects on hepatic stellate cells. Thus, rather than acting as a passive indicator of hepatic iron concentration (HIC) in haemochromatosis, ferritin may directly influence fibrosis. This study evaluated whether serum ferritin is a better predictor of hepatic fibrosis compared to variables previously associated with increased fibrosis risk in haemochromatosis. We identified 291 C282Y HFE-homozygous patients who had undergone liver biopsy for histological fibrosis staging and measurement of HIC. Ordinal logistic regression determined the best model for fibrosis stage not including serum ferritin. Then, serum ferritin was introduced into this model to assess whether the predictive power of the model was significantly increased and to evaluate the effect on other predictors of fibrosis. Ordinal logistic regression analyses without serum ferritin demonstrated that log HIC (OR 2.89 P < .001), male gender (OR 2.93 P = .005), alcohol consumption (g/day) (OR 1.01 P = .004), steatosis (OR 2.86 P = .01), arthritis (OR 2.46 P = .01) predicted increasing fibrosis stage (n=217). Addition of serum ferritin in multivariate analysis substantially improved the predictive power of the model (χ In haemochromatosis, serum ferritin is a better predictor of fibrosis stage than HIC, gender, steatosis and alcohol. These data support a hypothesis that ferritin may play a role in fibrosis rather than simply acting as a passive indicator of iron storage.
Cost-Effectiveness of a Serum Biomarker Test for Risk-Stratified Liver Ultrasound Screening for Hepatocellular Carcinoma
Publisher: Elsevier BV
Date: 10-2021
DOI: 10.1016/J.JVAL.2021.04.1286
Abstract: Risk-stratified ultrasound screening for hepatocellular carcinoma (HCC), informed by a serum biomarker test, enables resources to be targeted to patients at the highest risk of developing cancer. We aimed to investigate the cost-effectiveness of risk-stratified screening for HCC in the Australian healthcare system. A Markov cohort model was constructed to test 3 scenarios for patients with compensated cirrhosis: (1) risk-stratified screening for high-risk patients, (2) all-inclusive screening, and (3) no formal screening. Probabilistic sensitivity analyses were undertaken to determine the impact of uncertainty. Scenario analyses were used to assess cost-effectiveness in Australia's Aboriginal and Torres Strait Islander peoples and to determine the impact of including productivity-related costs of mortality. Both risk-stratified screening and all-inclusive screening programs were cost-effective compared with no formal screening, with incremental cost-effectiveness ratios of A$39 045 and A$23 090 per quality-adjusted life-year (QALY), respectively. All-inclusive screening had an incremental cost-effectiveness ratio of A$4453 compared with risk-stratified screening and had the highest probability of being cost-effective at a willingness-to-pay (WTP) threshold of A$50 000 per QALY. Risk-stratified screening had the highest likelihood of cost-effectiveness when the WTP was between A$25 000 and A$35 000 per QALY. Cost-effectiveness results were further strengthened when applied to an Aboriginal and Torres Strait Islander cohort and when productivity costs were included. Cirrhosis population-wide screening for HCC is likely to be cost-effective in Australia. Risk-stratified screening using a serum biomarker test may be cost-effective at lower WTP thresholds.
Taurocholate Induces Biliary Differentiation of Liver Progenitor Cells Causing Hepatic Stellate Cell Chemotaxis in the Ductular Reaction Role in Pediatric Cystic Fibrosis Liver Disease
Publisher: Elsevier BV
Date: 12-2017
DOI: 10.1016/J.AJPATH.2017.08.024
Abstract: Cystic fibrosis liver disease (CFLD) in children causes progressive fibrosis leading to biliary cirrhosis however, its cause(s) and early pathogenesis are unclear. We hypothesized that a bile acid-induced ductular reaction (DR) drives fibrogenesis. The DR was evaluated by cytokeratin-7 immunohistochemistry in liver biopsies, staged for fibrosis, from 60 children with CFLD, and it demonstrated that the DR was significantly correlated with hepatic fibrosis stage and biliary taurocholate levels. To examine the mechanisms involved in DR induction, liver progenitor cells (LPCs) were treated with taurocholate, and key events in DR evolution were assessed: LPC proliferation, LPC biliary differentiation, and hepatic stellate cell (HSC) chemotaxis. Taurocholate induced a time-dependent increase in LPC proliferation and expression of genes associated with cholangiocyte differentiation (cytokeratin 19, connexin 43, integrin β4, and γ-glutamyltranspeptidase), whereas the hepatocyte specification marker HNF4α was suppressed. Functional cholangiocyte differentiation was demonstrated via increased acetylated α-tubulin and SOX9 proteins, the number of primary cilia
Serum hyaluronic acid with serum ferritin accurately predicts cirrhosis and reduces the need for liver biopsy in C282Y hemochromatosis
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 22-09-2008
DOI: 10.1002/HEP.22650
Abstract: Diagnosing the presence of cirrhosis is crucial for the management of patients with C282Y hereditary hemochromatosis (HH). HH patients with serum ferritin >1,000 microg/L are at risk of cirrhosis however, the majority of these patients do not have cirrhosis. Noninvasive markers of hepatic fibrosis may assist in determining which patients with a serum ferritin >1,000 microg/L have cirrhosis and require liver biopsy. This study evaluated the utility of current diagnostic algorithms for detecting cirrhosis, including serum ferritin concentration, platelet counts, and aspartate aminotransferase (AST) levels, in combination with serum markers of fibrosis, hyaluronic acid and collagen type IV (CLIV), in predicting cirrhosis in HH patients. Stage of fibrosis, serum hyaluronic acid and CLIV levels, were measured in 56 patients with HH. No patient with a serum ferritin 1,000 microg/L were cirrhotic. A combination of platelet count ( 1,000 microg/L did not detect 30% of cirrhotic subjects. Serum hyaluronic acid was increased in HH compared with controls (42.0 +/- 9.8 ng/mL versus 19.3 +/- 1.8 ng/mL P = 0.02). A hyaluronic acid concentration >46.5 ng/mL was 100% sensitive and 100% specific in identifying patients with cirrhosis. In patients with serum ferritin >1,000 microg/L, hyaluronic acid levels were significantly elevated in patients with cirrhosis versus those without cirrhosis (137 +/- 34.4 ng/mL versus 18.6 +/- 1.5 ng/mL, respectively P = 0.006). CLIV >113 ng/mL was 100% sensitive but only 56% specific for cirrhosis (area under the curve = 0.78 P = 0.01). In HH, the measurement of hyaluronic acid in patients with serum ferritin >1,000 microg/L is a noninvasive, accurate, and cost-effective method for the diagnosis of cirrhosis. (HEPATOLOGY 2009 :418-425.).
Vitamin A status in human fetuses with congenital diaphragmatic hernia
Publisher: Elsevier BV
Date: 2018
Transcriptional Basis for Hepatic Fibrosis in Cystic Fibrosis–associated Liver Disease
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2012
Risk factors for more rapid progression of severe liver fibrosis in children with cystic fibrosis‐related liver disease: A multi‐center study validated by liver biopsy
Publisher: Wiley
Date: 10-04-2023
DOI: 10.1111/LIV.15572
Abstract: Early identification of risk factors for the development of severe fibrosis in children with cystic fibrosis‐related liver disease (CFLD) is crucial as promising therapies emerge. This multi‐center cohort study of children with a priori defined CFLD from 1999 to 2016, was designed to evaluate the clinical utility of CF‐specific characteristics and liver biomarkers assessed years prior to liver biopsy‐proven CFLD to predict risk of developing severe fibrosis (F3‐4) over time. Fibrosis was staged by Metavir classification. The overall study cohort of 42 patients (F0‐2 ( n = 22) and F3‐4 ( n = 20)) was 57% male ( n = 24) with median age of 7.6 years at baseline visit versus 10.3 years at biopsy. Median FEV 1 % predicted was lower in F3‐4 participants at baseline versus F0‐2 (59% vs. 85% p = .002), while baseline FIB‐4, APRI and GGT were higher in F3‐4. Median splits for FIB‐4 (≥.13), APRI (≥.36), GPR (≥.09), GGT (≥25.5), and FEV 1 % ( %) were associated with more rapid progression to F3‐4 ( p .01 for all). Using a combination of change/year in FIB‐4, APRI, and GPR to predict F3‐4, the AUROC was .81 (95% CI, .66, .96 p .0001). For up to 5.8 years prior, thresholds for GPR were met 6.5‐fold more rapidly, and those for APRI and FIB‐4 were met 2.5‐fold more rapidly, in those who progressed to F3‐4 than those that did not. This study suggests mild–moderate pulmonary dysfunction and higher liver biomarker indices at baseline may be associated with faster progression of CFLD.
Reply
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 18-12-2015
DOI: 10.1002/HEP.28260
Hepatocellular carcinoma surveillance in Australia: time to improve the diagnosis of cirrhosis and use liver ultrasound
Publisher: AMPCo
Date: 24-02-2020
DOI: 10.5694/MJA2.50521
Aldehydic products of lipid peroxidation do not directly activate rat hepatic stellate cells
Publisher: Wiley
Date: 07-2002
DOI: 10.1046/J.1440-1746.2002.02798.X
Abstract: Activation of hepatic stellate cells (HSC) results in the transdifferentiation of the resting (quiescent) phenotype to one characterized by loss of vitamin A droplets, increased alpha-smooth muscle actin (SMA) expression and increased collagen production. Aldehydic products of lipid peroxidation have been shown to increase collagen production by cultured fibroblasts and by passaged HSC, but it is unclear whether these products of lipid peroxidation can initiate the activation of HSC. In the present study the effects were examined of two aldehydic products of lipid peroxidation, malondialdehyde (MDA) and 4-hydroxynonenal (HNE), on activation of rat HSC in early culture as measured by SMA and desmin expression, and collagen production. The HSC from normal rat liver were plated in plastic wells and exposed to either MDA (5-200 micromol/L), HNE (0.1-20 micromol/L) or vehicle for either 3 or 7 days. The cells were then harvested SMA and desmin levels were measured by western blotting. Collagen production was measured by radiolabeled proline incorporation after 6 h of aldehyde exposure. Malondialdehyde (100 and 200 micromol/L) decreased SMA expression during the 3-day and 7-day exposures compared with controls. 4-Hydroxynonenal (20 micromol/L) decreased SMA expression significantly while no effects were observed with lower concentrations compared with controls during the 3-day exposure. Seven-day exposure to HNE (0.1-20 micromol/L) failed to alter SMA expression compared with controls. Exposure to MDA or HNE did not influence desmin expression or collagen production. Aldehydic products of lipid peroxidation do not directly activate HSC in early culture and alternative pathways may be responsible for HSC activation during oxidative stress.
Repair after cholestatic liver injury correlates with neutrophil infiltration and matrix metalloproteinase 8 activity
Publisher: Elsevier BV
Date: 08-2005
DOI: 10.1016/J.SURG.2005.04.009
Abstract: Although timely surgical treatment of liver disease can interrupt inflammation and reduce fibrosis, the mechanisms of repair are unknown. We questioned whether these mechanisms of repair include changes in the inflammatory infiltrate and associated biological activity of matrix metalloproteinases (MMPs) 8 and 2. Rats (n >or= 3) underwent biliary ductal suspension for 7 days followed by decompression. Livers were collected after 7 days of obstruction (d0) and after 2, 5, and 7 days of repair (d2, d5, d7, respectively), and assessed morphometrically for collagen, polymorphonuclear cells (PMNs), Kupffer cells (KCs), and inflammatory mononuclear phagocytes (MNPs). In situ zymography was performed by using fluorogenic substrates for MMP-8 and MMP-2 to spatially localize enzymatic activity. Cholestatic injury resulted in significantly elevated (P <or= .001) collagen deposition (3-fold), and elevated numbers of MNPs (10-fold), KCs (5-fold), and PMNs (4-fold), compared with shams. PMNs remained elevated through d7, while collagen deposition, KCs, and MNPs returned to sham levels by d2. In situ zymography showed no significant changes in MMP-2 activity after cholestatic injury and repair. MMP-8 activity was significantly (P <or= .05) elevated only during repair. Activity was localized to fibrotic portal triads containing PMNs. Cholestatic injury results in increased fibrosis, MNPs, KCs, and PMNs but no MMP-2 or MMP-8 activity. Biliary decompression results in increased MMP-8 activity co-localized to areas of portal fibrosis and PMN accumulation. We conclude that secretion of MMP-8 by neutrophils may play a critical role in resolving the fibrotic scar generated during cholestasis.
Role of resident liver cells in the pathogenesis of schistosomiasis
Publisher: Elsevier BV
Date: 12-2012
Abstract: Pathology in schistosomiasis occurs as a result of eggs deposited in the liver by the schistosome parasite. A granulomatous reaction occurs, resulting in portal hypertension and hepatic fibrosis. Resident non-parenchymal cells within the liver take part in this process, including hepatic stellate cells, which are responsible for collagen production, and Kupffer cells, the liver macrophages involved in both host protection and in pathology. Other cells such as liver sinusoidal endothelial cells or portal fibroblasts may also be involved in this process. This review discusses the possible role of these resident liver cells in the pathology associated with schistosomiasis and provides information which may assist our understanding of the mechanisms associated with chronic liver disease in general.
Cellular Plasticity in Liver Regeneration: Spotlight on Cholangiocytes
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 19-02-2019
DOI: 10.1002/HEP.30340
Desmoplastic Reaction in Pancreatic Cancer
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2004
DOI: 10.1097/00006676-200410000-00002
Abstract: Pancreatic cancer has a very poor prognosis, largely due to its propensity for early local and distant spread. Histopathologically, most pancreatic cancers are characterized by a prominent stromal/fibrous reaction in and around tumor tissue. The aims of this study were to determine whether (1) the cells responsible for the formation of the stromal reaction in human pancreatic cancers are activated pancreatic stellate cells (PSCs) and (2) an interaction exists between pancreatic cancer cells and PSCs that may facilitate local and distant invasion of tumor. Serial sections of human pancreatic cancer tissue were stained for desmin and glial fibrillary acidic protein (stellate cell selective markers) and alpha-smooth muscle actin (alphaSMA), a marker of activated PSC activation, by immunohistochemistry, and for collagen using Sirius Red. Correlation between the extent of positive staining for collagen and alphaSMA was assessed by morphometry. The cellular source of collagen in stromal areas was identified using dual staining methodology, ie, immunostaining for alphaSMA and in situ hybridization for procollagen alpha1I mRNA. The possible interaction between pancreatic cancer cells and PSCs was assessed in vitro by exposing cultured rat PSCs to control medium or conditioned medium from 2 pancreatic cancer cell lines (PANC-1 and MiaPaCa-2) for 24 hours. PSC activation was assessed by cell proliferation and alphaSMA expression. Stromal areas of human pancreatic cancer stained strongly positive for the stellate cell selective markers desmin and GFAP (indicating the presence of PSCs), for alphaSMA (suggesting that the PSCs were in their activated state) and for collagen. Morphometric analysis demonstrated a close correlation (r = 0.77 P < 0.04 8 paired sections) between the extent of PSC activation and collagen deposition. Procollagen mRNA expression was localized to alphaSMA-positive cells in stromal areas indicating that activated PSCs were the predominant source of collagen in stromal areas. Exposure of PSCs to pancreatic cancer cell secretions in vitro resulted in PSC activation as indicated by significantly increased cell proliferation and alphaSMA expression. Activated PSCs are present in the stromal reaction in pancreatic cancers and are responsible for the production of stromal collagen. PSC function is influenced by pancreatic cancer cells. Interactions between tumor cells and stromal cells (PSCs) may play an important role in the pathobiology of pancreatic cancer.
Reply
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-06-2015
DOI: 10.1002/HEP.27851
TWEAK and LTβ Signaling during Chronic Liver Disease
Publisher: Frontiers Media SA
Date: 2014
Advanced but not mild liver disease is a predictor of decreased survival in children with cystic fibrosis, with far greater impact in females: A 27-year real-life cohort study
Publisher: Elsevier BV
Date: 03-2021
DOI: 10.1016/J.JCF.2021.11.015
Abstract: Improved survival of children with CF has increased our need to understand the relevance of cystic fibrosis-associated liver disease (CFLD). We assessed the impact of liver disease and disease severity on the survival of children with cystic fibrosis. A real life, single center cohort study with 27 years follow up was conducted. Mild CFLD was diagnosed as children with abnormal serum liver function tests and abnormal ultrasound. Advanced CFLD was established by detection of cirrhosis or portal hypertension. A directed acyclic graph, Kaplan-Meier (KM) and Cox regression analysis were used to model survival. 290 patients were enrolled, 48 (16.5%) had mild CFLD and 55 (19%) had advanced CFLD. Ten children with advanced CFLD and 1 with mild CFLD died. Based on the KM analysis, the mean (SE) overall survival age of all CF children was 29.1 years (0.50). The mean (SE) survival among females with advanced CFLD was 24.7 years (1.58) compared to 30.4 years (0.66) for females without advanced CFLD (p = 0.0027). Advanced CFLD was a predictor of decreased survival when adjusted for sex and diabetes (HR 2.54, 95%CI 1.05-6.15, p = 0.039). Mild CFLD was not associated with decreased survival. The effect of advanced CFLD on survival was mainly borne by females (HR = 6.37, 95%CI 1.62-25.06 vs. males, HR = 1.00, 95%CI 0.25-4.01). Advanced but not mild CFLD was associated with an increased risk of death when adjusted for sex and diabetes, and resulted in premature death in females with cystic fibrosis by approximately 6 years.
Role of myofibroblasts in tumour encapsulation of hepatocellular carcinoma in haemochromatosis
Publisher: Wiley
Date: 04-2001
DOI: 10.1034/J.1600-0676.2001.021002096.X
Abstract: Hepatocellular carcinoma is a common malignancy and a major complication of untreated haemochromatosis. Encapsulation of liver tumours has been associated with a better prognosis and longer disease-free periods following resection. This study investigated the source of the tumour capsule in patients with haemochromatosis and coexisting hepatocellular carcinoma and examined potential factors influencing development. Five haemochromatosis patients with encapsulated hepatocellular carcinoma were studied. Myofibroblasts were identified using combined immunohistochemistry and in situ hybridisation for alpha-smooth muscle actin and procollagen alpha1(I) mRNA, respectively. Immunohistochemistry was also performed for transforming growth factor (TGF)-beta1, platelet-derived growth factor (PDGF)-beta receptor and malondialdehyde. Procollagen alpha1(I) mRNA co-localised to alpha-smooth muscle actin positive myofibroblasts. The number of myofibroblasts was maximal within the capsule and decreased away from the tumour. TGF-beta1 protein was expressed in iron-loaded cells in non-tumour liver at the interface of tumour capsule. PDGF-beta receptor expression was observed in mesenchymal cells in the tumour capsule and in portal tracts. Malondialdehyde adducts were observed in the tumour, non-tumour tissue and in the capsule. This study provides evidence that myofibroblasts are the cell type responsible for collagen production within the tumour capsule surrounding hepatocellular carcinoma in haemochromatosis. The production of TGF-beta1 by iron-loaded hepatic cells at the tumour capsule interface may perpetuate the myofibroblastic phenotype, resulting in the formation of the tumour capsule.
Ethanol and leucine oxidation—II. Leucine oxidation by rat tissue in vitro
Publisher: Elsevier BV
Date: 1985
DOI: 10.1016/0020-711X(85)90114-4
Abstract: The effect of ethanol upon leucine oxidation by rat tissues in vitro is reported. The activities of branched chain amino acid aminotransferase and 2-oxo acid dehydrogenase were decreased by chronic administration of ethanol (20% v/v solution as drinking water for 35 d) in muscle and kidney but were increased, although not significantly, in liver. Acute administration of ethanol (8 g kg-1 body-weight 0.73) did not affect enzyme activities. Tissue NAD+:NADH ratios, calculated from lactate:pyruvate ratios, were significantly decreased in the liver and kidney of rats receiving ethanol acutely. These data are consistent with the view that ethanol decreases leucine oxidation by decreasing availability of NAD+ when given acutely and by decreasing enzyme activity when administered chronically.
Identification of Ferritin Receptors: Their Role in Iron Homeostasis, Hepatic Injury, and Inflammation
Publisher: Elsevier BV
Date: 11-2029
A novel mutation in ferroportin implicated in iron overload
Publisher: Elsevier BV
Date: 05-2007
DOI: 10.1016/J.JHEP.2007.01.033
Abstract: Hereditary iron overload is associated with mutations in a number of genes involved in the regulation of iron metabolism. In this study we examined the molecular basis of iron overload in an in idual from New Zealand and characterised the molecular and cellular defect. We analysed the ferroportin gene and a control population was screened using allele-specific PCR and denaturation analysis. Molecular characterisation was performed by immunofluorescence microscopy analysis of transfected cells. We analysed the ferritin levels of cells expressing wild-type and mutant ferroportin to define the nature of the molecular defect on iron transport. We identified a novel nucleotide substitution (c. 1014T>G) in the ferroportin gene leading to the S338R mutation. This mutation is not a common polymorphism. Cellular analysis of the mutant protein indicates that this amino acid change does not affect the localisation of the protein or its ability to transport iron. The S338R mutation results in a mutated ferroportin associated with iron overload and is predicted insensitive to regulation by the iron regulatory hormone hepcidin.
Value of the 8-oxodG/dG ratio in chronic liver inflammation of patients with hepatocellular carcinoma
Publisher: Elsevier BV
Date: 08-2016
Effect of the microtubular inhibitor vinblastine on ferritin clearance and release in the rat
Publisher: Wiley
Date: 11-1996
DOI: 10.1111/J.1440-1746.1996.TB00039.X
Abstract: We have previously demonstrated that colchicine inhibits ferritin clearance from the circulation of normal and iron-loaded rats and stimulates endogenous ferritin release into both the serum and bile of iron-loaded rats. The aim of the present study was to determine the effect of vinblastine on ferritin clearance and release in normal and iron-loaded rats. Vinblastine was administered at either 1 or 10 mg/kg to both normal and iron-loaded rats, infused over a 5 h period with either a rat liver ferritin or saline solution. Serum and biliary ferritin levels were determined every 30 min. After 5 h, 90% of the infused ferritin was cleared from the circulation in the absence of vinblastine. Low-dose vinblastine decreased ferritin uptake 10-20% in iron-loaded rats. High-dose vinblastine inhibited ferritin clearance by 25% in normal rats and 20-40% in iron-loaded rats. Vinblastine administration caused a 2-3-fold increase in the serum ferritin concentration and a 3-5-fold peak in biliary ferritin levels. Thus, vinblastine caused the release of endogenous ferritin into both the serum and bile of iron-loaded rats in the presence of a ferritin load. We therefore conclude that disturbed microtubule function accounts for the observed inhibition of ferritin uptake and intracellular transport however, the mechanism of increased ferritin release remains unclear.
Effect of phorbol ester and platelet‐derived growth factor on protein kinase C in rat hepatic stellate cells
Publisher: Wiley
Date: 20-08-2007
DOI: 10.1111/J.1478-3231.2007.01573.X
Abstract: Hepatic stellate cells (HSC) play a key role in hepatic fibrogenesis and thus, it is important to understand the intracellular signalling pathways that influence their behaviour. This study investigated the expression and regulation of protein kinase C (PKC) in HSC. Western blot analysis indicates that rat HSC express at least four PKC isoforms, PKC-alpha, PKC-delta, PKC-epsilon and PKC-zeta. PKC-alpha and PKC-zeta were located predominantly in the cytosol and were redistributed to the membrane by the PKC agonist, phorbol 12-myristate 13-acetate (PMA), while PKC-delta and PKC-epsilon were highly membrane-bound and did not undergo translocation by PMA. PKC-alpha, PKC-delta and PKC-zeta were rapidly downregulated by PMA. However, PKC-epsilon was resistant to downregulation. We also examined phosphorylation of myristoylated alanine-rich C kinase substrate (MARCKS), a specific substrate of PKC, as another approach to assess activation of PKC. Platelet-derived growth factor (PDGF) and PMA increased the phosphorylation of MARCKS, suggesting that PDGF can induce PKC activation. PDGF-induced stimulation of extracellular signal-regulated kinase, phosphatidylinositol 3-kinase and p70-S6 kinase was not abrogated by downregulation of PKC-alpha, PKC-delta and PKC-zeta. Prolonged PKC inhibition did not inhibit the fibrogenic phenotype. Multiple PKC isoforms are expressed in rat HSC and are differentially regulated by PMA. PDGF activates certain mitogenic signalling pathways independent of PKC-alpha, PKC-delta and PKC-zeta. Specific PKC isoforms may modulate different cell functions in HSC.
Should HFE p.C282Y homozygotes with moderately elevated serum ferritin be treated? A randomised controlled trial comparing iron reduction with sham treatment (Mi-iron)
Publisher: BMJ
Date: 08-2015
Reduction of body iron in HFE -related haemochromatosis and moderate iron overload (Mi-Iron): a multicentre, participant-blinded, randomised controlled trial
Publisher: Elsevier BV
Date: 12-2017
Paediatric cholestatic liver disease: Diagnosis, assessment of disease progression and mechanisms of fibrogenesis
Publisher: Baishideng Publishing Group Inc.
Date: 2010
Chemokine (C-C motif) receptors in fibrogenesis and hepatic regeneration following acute and chronic liver disease
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 29-10-2009
DOI: 10.1002/HEP.23338
Extracellular vesicles for personalized therapy decision support in advanced metastatic cancers and its potential impact for prostate cancer
Publisher: Wiley
Date: 29-08-2017
DOI: 10.1002/PROS.23403
Abstract: The use of circulating tumor cells (CTCs) and circulating extracellular vesicles (EVs), such as exosomes, as liquid biopsy-derived biomarkers for cancers have been investigated. CTC enumeration using the CellSearch based platform provides an accurate insight on overall survival where higher CTC counts indicate poor prognosis for patients with advanced metastatic cancer. EVs provide information based on their lipid, protein, and nucleic acid content and can be isolated from biofluids and analyzed from a relatively small volume, providing a routine and non-invasive modality to monitor disease progression. Our pilot experiment by assessing the level of two subpopulations of small EVs, the CD9 positive and CD63 positive EVs, showed that the CD9 positive EV level is higher in plasma from patients with advanced metastatic prostate cancer with detectable CTCs. These data show the potential utility of a particular EV subpopulation to serve as biomarkers for advanced metastatic prostate cancer. EVs can potentially be utilized as biomarkers to provide accurate genotypic and phenotypic information for advanced prostate cancer, where new strategies to design a more personalized therapy is currently the focus of considerable investigation.
TWEAK/Fn14 signalling promotes cholangiocarcinoma niche formation and progression
Publisher: Elsevier BV
Date: 04-2021
DOI: 10.1016/J.JHEP.2020.11.018
Abstract: Cholangiocarcinoma (CCA) is a cancer of the hepatic bile ducts that is rarely resectable and is associated with poor prognosis. Tumour necrosis factor-like weak inducer of apoptosis (TWEAK) is known to signal via its receptor fibroblast growth factor-inducible 14 (Fn14) and induce cholangiocyte and myofibroblast proliferation in liver injury. We aimed to characterise its role in CCA. The expression of the TWEAK ligand and Fn14 receptor was assessed immunohistochemically and by bulk RNA and single cell transcriptomics of human liver tissue. Spatiotemporal dynamics of pathway regulation were comprehensively analysed in rat and mouse models of thioacetamide (TAA)-mediated CCA. Flow cytometry, qPCR and proteomic analyses of CCA cell lines and conditioned medium experiments with primary macrophages were performed to evaluate the downstream functions of TWEAK/Fn14. In vivo pathway manipulation was assessed via TWEAK overexpression in NICD/AKT-induced CCA or genetic Fn14 knockout during TAA-mediated carcinogenesis. Our data reveal TWEAK and Fn14 overexpression in multiple human CCA cohorts, and Fn14 upregulation in early TAA-induced carcinogenesis. TWEAK regulated the secretion of factors from CC-SW-1 and SNU-1079 CCA cells, inducing polarisation of proinflammatory CD206 These novel data provide evidence for the action of TWEAK/Fn14 on macrophage recruitment and phenotype, and cancer-associated fibroblast proliferation in CCA. Targeting TWEAK/Fn14 and its downstream signals may provide a means to inhibit CCA niche development and tumour growth. Cholangiocarcinoma is an aggressive, chemotherapy-resistant liver cancer. Interactions between tumour cells and cells that form a supportive environment for the tumour to grow are a source of this aggressiveness and resistance to chemotherapy. Herein, we describe interactions between tumour cells and their supportive environment via a chemical messenger, TWEAK and its receptor Fn14. TWEAK/Fn14 alters the recruitment and type of immune cells in tumours, increases the growth of cancer-associated fibroblasts in the tumour environment, and is a potential target to reduce tumour formation.
Peritoneal hepatoid carcinoma with chemotherapy response and possible stem cell involvement
Publisher: Elsevier BV
Date: 06-2018
Outcome after Portoenterostomy in Biliary Atresia: Pivotal Role of Degree of Liver Fibrosis and Intensity of Stellate Cell Activation
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2006
DOI: 10.1097/01.MPG.0000189324.80323.A6
Abstract: Biliary atresia (BA), a congenital idiopathic obliterative cholangiopathy, rapidly leads to liver cirrhosis and liver failure if untreated. A timely Kasai portoenterostomy (KP) variably alters this natural history. We evaluated liver fibrogenesis by the intensity of alpha-smooth-muscle actin (SMA) expression, which is a marker for hepatic stellate cell activation. We hypothesized that liver fibrogenesis as determined by intensity of alpha-SMA is already progressing at the time of KP, is related to age and degree of fibrosis at KP, and predicts outcome after KP. BA patients at KP (n = 22, age 22-84 days, median 59) had wedge liver biopsies assessed by quantitative morphometry of immunohistochemistry for alpha-SMA expression. Fibrosis was scored by blinded pathologists. Outcome, reflected by conjugated bilirubin concentration 3 months after KP (CBili3m), survival of the native liver, need for liver transplant, or death, were assessed for 2 to 10 years after KP. At KP, age, fibrosis score, and alpha-SMA expression were significantly correlated. Moderate-severe fibrosis and intense alpha-SMA expression was observed in 15 of 22 (68%) patients. Severe fibrosis and high alpha-SMA expression were significantly associated with CBili3m greater than 2 g/dL and unfavorable liver survival (>90% of these ultimately underwent liver transplantation or died). Conversely, those with mild fibrosis and low alpha-SMA expression had normal CBili3m and favorable liver survival. Intense liver fibrogenesis is already established in many cases of BA at the time of KP. Fibrosis scores and intensity of alpha-SMA expression may be predictors of outcome after KP and may indicate those patients who might benefit from trials of potential antifibrotic agents early in the course of BA.
The role of liver progenitor cells during liver regeneration, fibrogenesis, and carcinogenesis
Publisher: American Physiological Society
Date: 02-2016
Abstract: The growing worldwide challenge of cirrhosis and hepatocellular carcinoma due to increasing prevalence of excessive alcohol consumption, viral hepatitis, obesity, and the metabolic syndrome has sparked interest in stem cell-like liver progenitor cells (LPCs) as potential candidates for cell therapy and tissue engineering, as an alternative approach to whole organ transplantation. However, LPCs always proliferate in chronic liver diseases with a predisposition to cancer they have been suggested to play major roles in driving fibrosis, disease progression, and may even represent tumor-initiating cells. Hence, a greater understanding of the factors that govern their activation, communication with other hepatic cell types, and bipotential differentiation as opposed to their potential transformation is needed before their therapeutic potential can be harnessed.
Sensitive and rapid colorimetric immunoenzymometric assay of ferritin in biological samples
Publisher: Oxford University Press (OUP)
Date: 06-1990
DOI: 10.1093/CLINCHEM/36.6.837
Abstract: We describe a rapid and sensitive enzyme-linked immunosorbent assay (ELISA) for quantifying ferritin in human and rat biological fluids. We used chlorophenol red beta-D-galactopyranoside as the colorimetric substrate of beta-galactosidase (EC 3.2.1.23), which is coupled to specific antibodies to either human or rat liver ferritin. The assay is sensitive (detection limit for human assay = 0.58 micrograms/L and for rat assay = 0.37 micrograms/L), accurate (average recovery for human assay = 93% and for rat assay = 92%), and precise (total CVs for human assay = 2.3-12.2% and for rat assay = 5.6-11.3%). The results correlated well with those of an established immunoradiometric technique (r = 0.99691). This assay has a prolonged shelf-life, is inexpensive, and utilizes a stable colorimetric substrate that requires relatively short incubation.
Reply:
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-02-2017
DOI: 10.1002/HEP.29002
Self-assembling asymmetric peptide-dendrimer micelles - A platform for effective and versatile in vitro nucleic acid delivery
Publisher: Springer Science and Business Media LLC
Date: 19-03-2018
DOI: 10.1038/S41598-018-22902-9
Abstract: Despite advancements in the development of high generation cationic-dendrimer systems for delivery of nucleic acid-based therapeutics, commercially available chemical agents suffer from major drawbacks such as cytotoxicity while being laborious and costly to synthesize. To overcome the aforementioned limitations, low-generation cationic peptide asymmetric dendrimers with side arm lipid (cholic and decanoic acid) conjugation were designed, synthesized and systematically screened for their ability to self-assemble into micelles using dynamic light scattering. Cytotoxicity profiling revealed that our entire asymmetric peptide dendrimer library when trialled alone, or as asymmetric dendrimer micelle-nucleic acid complexes, were non-cytotoxic across a broad concentration range. Further, the delivery efficiency of asymmetric peptide dendrimers in H-4-II-E (rat hepatoma), H2K (mdx mouse myoblast), and DAOY (human medulloblastoma) cells demonstrated that cholic acid-conjugated asymmetric dendrimers possess far superior delivery efficiency when compared to the commercial standards, Lipofectamine 2000 or Lipofectin ® .
Type 2 Diabetes Mellitus: Limitations of Conventional Therapies and Intervention with Nucleic Acid-Based Therapeutics
Publisher: American Chemical Society (ACS)
Date: 28-04-2015
DOI: 10.1021/CR5002832
Utility of hepatic or total body iron burden in the assessment of advanced hepatic fibrosis in HFE hemochromatosis
Publisher: Springer Science and Business Media LLC
Date: 27-12-2019
DOI: 10.1038/S41598-019-56732-0
Abstract: Development of advanced hepatic fibrosis in HFE Hemochromatosis (HH) is influenced by hepatic iron concentration (HIC) and age. In patients with HH, it is important to assess the likelihood of cirrhosis and thus the need for confirmatory liver biopsy. Therapeutic phlebotomy also provides an estimate of mobilisable iron stores. We determined whether mobilisable iron stores may predict the presence of advanced fibrosis. Retrospective analysis of 137 male and 65 female HH subjects was undertaken. Biochemical, histological and phlebotomy data were available on all subjects. The mean values of HIC, HIC × [age], mobilisable iron, mobilisable iron × [age] and serum ferritin in the cohort were higher in the group with advanced fibrosis. HIC had an optimum sensitivity and specificity of 73% for the diagnosis of advanced liver fibrosis, with a cut-off HIC level of 200 µmol/g (AUROC 0.83, p 0.0001). AUROC for HIC was greater in females (0.93) than males (0.79). Mobilisable iron had an optimum sensitivity and specificity both of 83% at a cut-off of 9.6 g for the prediction of advanced fibrosis in all subjects (AUROC 0.92, p 0.0001). Mobilisable iron stores provide a simple, clinically useful indication of the risk of advanced fibrosis and should routinely be considered.
Haemochromatosis
Publisher: Elsevier BV
Date: 1999
DOI: 10.1016/S1043-2760(98)00103-9
Abstract: Haemochromatosis is one of the most common inherited diseases in Caucasian populations. The disease is characterized by an inappropriately high rate of iron absorption, and excess iron is deposited in the liver, pancreas, heart and other organs of affected in iduals. If untreated, cirrhosis of the liver can develop and result in premature death from complications of portal hypertension, hepatic failure or hepatocellular carcinoma.
The function of serotonin within the liver
Publisher: Elsevier BV
Date: 04-2008
DOI: 10.1016/J.JHEP.2008.01.006
Abstract: Serotonin or 5-hydroxytryptamine (5-HT) is known to regulate several key aspects of liver biology and these functions include hepatic blood flow, innervation and wound healing. Given the importance of these functions it is surprising that relatively little time has been dedicated to studying the precise function and mechanisms of serotonin within the liver. Here we describe what is known about serotonin and the liver and those receptor types that mediate the observed effects with an aim to stimulating new interest in the field of serotonin and liver biology.
Contribution of hepatic parenchymal and nonparenchymal cells to hepatic fibrogenesis in biliary atresia
Publisher: Elsevier BV
Date: 08-1998
Liquid Biopsies for Hepatocellular Cancer and Their Potential in Clinical Practice
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 30-05-2020
DOI: 10.1002/HEP.31168
Hepatic stellate cell activation in genetic haemochromatosis
Publisher: Elsevier BV
Date: 03-1997
DOI: 10.1016/S0168-8278(97)80424-2
Abstract: Activated hepatic stellate cells produce increased levels of collagen in animal models of chronic iron overload however, their role in human genetic haemochromatosis is unknown. This study examined the relationship between hepatic iron concentration and hepatic stellate cell activation in genetic haemochromatosis. Liver biopsies from 75 patients (55 with haemochromatosis, 14 haemochromatosis patients both pre- and post-phlebotomy and six non iron-loaded disease control subjects) were stained for iron using Perls' Prussian Blue. Thirty biopsies in which there was no evidence of either steatosis or inflammation were subjected to immunohistochemistry for alpha-smooth muscle actin and desmin and counterstained for iron. Forty-five biopsies demonstrated either steatosis or inflammation, in addition to excess iron. Stellate cells were identified by light microscopy as perisinusoidal cells containing numerous intracellular fat droplets. alpha-Smooth muscle actin was detected in biopsies with an hepatic iron concentration >60 micromol/g dry weight. Increasing hepatic iron concentration and hepatic iron index correlated with an increase in alpha-smooth muscle actin expression (r=0.81 and 0.72, respectively). Phlebotomy resulted in a significant decrease in alpha-smooth muscle actin expression. In early disease prior to histological evidence of collagen deposition, whilst activated stellate cells were located in Zone 1, greater numbers were found in Zones 2 and 3 distal to the region of heaviest iron overload. This study has demonstrated for the first time in humans a correlation between hepatic iron concentration and stellate cell activation in haemochromatosis, which is reversed by iron removal. Humoral factors from either iron-loaded hepatocytes or activated Kupffer cells may be responsible for early stellate cell activation in areas of the liver remote from heavy iron loading.
Synthetic peptides derived from the Schistosoma mansoni secretory protein Sm16 induce contrasting responses in hepatic stellate cells
Publisher: Elsevier BV
Date: 05-2022
DOI: 10.1016/J.EXPPARA.2022.108255
Abstract: Sm16 is a 16 KDa protein released by Schistosoma mansoni that modulates inflammatory responses in host cells. Sm16 is expressed by several life cycle stages of S. mansoni, including the egg stage. Schistosome eggs are known to provoke chronic schistosomiasis pathology, which involves the development of liver fibrosis. Hepatic stellate cells (HSCs), which are responsible for this fibrosis, are susceptible to immunomodulation by S. mansoni whole egg secretions. To define the effects of Sm16 exposure on HSCs, two synthetic peptide derivatives of Sm16, coined "KS-84″ and "KS-66″, were tested against LX-2 cells, an immortalised human HSC line, and RNA sequencing was used to assess the transcriptional changes induced by each peptide. In total, 78 and 798 genes were found to be significantly differentially expressed by KS-84 and KS-66 treatment, respectively. In silico pathway analysis of these genes revealed that KS-84 reduced LX-2 cell activation and fibrotic potential, whereas KS-66 increased both processes. Reduced transforming growth factor-β1 (TGF-β1) signalling was identified as a potential mechanism of KS-84-induced inhibition of LX-2 activation. Taken together, these findings indicate a potential role for Sm16 in combatting fibrotic liver disease.
Proposed international standard of human ferritin for the serum ferritin assay
Publisher: Wiley
Date: 09-1985
DOI: 10.1111/J.1365-2141.1985.TB04060.X
Abstract: A marine furanoterpenoid derivative, 10-acetylirciformonin B (10AB), was found to inhibit the proliferation of leukemia, hepatoma, and colon cancer cell lines, with selective and significant potency against leukemia cells. It induced DNA damage and apoptosis in leukemia HL 60 cells. To fully understand the mechanism behind the 10AB apoptotic induction against HL 60 cells, we extended our previous findings and further explored the precise molecular targets of 10AB. We found that the use of 10AB increased apoptosis by 8.9%-87.6% and caused disruption of mitochondrial membrane potential (MMP) by 15.2%-95.2% in a dose-dependent manner, as demonstrated by annexin-V/PI and JC-1 staining assays, respectively. Moreover, our findings indicated that the pretreatment of HL 60 cells with N-acetyl-l-cysteine (NAC), a reactive oxygen species (ROS) scavenger, diminished MMP disruption and apoptosis induced by 10AB, suggesting that ROS overproduction plays a crucial rule in the cytotoxic activity of 10AB. The results of a cell-free system assay indicated that 10AB could act as a topoisomerase catalytic inhibitor through the inhibition of topoisomerase IIα. On the protein level, the expression of the anti-apoptotic proteins Bcl-xL and Bcl-2, caspase inhibitors XIAP and survivin, as well as hexokinase II were inhibited by the use of 10AB. On the other hand, the expression of the pro-apoptotic protein Bax was increased after 10AB treatment. Taken together, our results suggest that 10AB-induced apoptosis is mediated through the overproduction of ROS and the disruption of mitochondrial metabolism.
Evidence for altered hepatic matrix degradation in genetic haemochromatosis
Publisher: BMJ
Date: 05-1998
DOI: 10.1136/GUT.42.5.715
Abstract: Background —Altered matrix degradation contributes to fibrosis in some liver diseases but the role of matrix degradation in fibrogenesis associated with genetic haemochromatosis has not previously been addressed. Aims —To measure serum concentrations of tissue inhibitor of metalloproteinase 1 (TIMP-1) and matrix metalloproteinases (MMP), MMP-1, MMP-2, and MMP-3 in patients with haemochromatosis and control subjects. Patients —Forty patients with haemochromatosis and 19 healthy control subjects. Ten of the 40 patients were studied before and after venesection therapy. Methods —Serum levels of TIMP-1, MMP-1, MMP-2, and MMP-3 were measured by enzyme immunoassay and correlated to hepatic iron concentration and degree of histological fibrosis. Results —Serum TIMP-1 was increased in patients with haemochromatosis compared with controls (163 (30) versus 123 (28) ng/ml, p .0002). Mean serum TIMP-1 concentration of patients with haemochromatosis without fibrosis was significantly higher than in controls (153 (16) versus 123 (28) ng/ml, p=0.03). Serum TIMP-1 concentration correlated with both hepatic iron concentration and hepatic iron index ( r =0.42, p .01 r =0.42, p .01). Serum MMP-2 concentrations correlated with increasing degree of fibrosis in patients with haemochromatosis ( r =0.38, p=0.01). The mean MMP-1:TIMP-1, MMP-2:TIMP-1 and age/sex matched MMP-3:TIMP-1 ratios were significantly lower in patients with haemochromatosis than controls (0.11 (0.06) versus 0.2 (0.14), p=0.02 3.32 (0.9) versus 3.91 (0.81), p=0.05 and 0.26 (0.12) versus 0.47 (0.27), p=0.007, respectively). Following venesection, MMP-2 and MMP-3 concentrations increased by 11% (p=0.03) and 19% (p=0.03), respectively. Conclusions —This study provides the first evidence of an alteration in matrix degradation in haemochromatosis that may be a contributing factor to hepatic fibrogenesis in this disease.
Schistosoma japonicum Eggs Induce a Proinflammatory, Anti-Fibrogenic Phenotype in Hepatic Stellate Cells
Publisher: Public Library of Science (PLoS)
Date: 19-06-2013
Disrupted hepcidin regulation in HFE -associated haemochromatosis and the liver as a regulator of body iron homoeostasis
Publisher: Elsevier BV
Date: 02-2003
Fibrogenesis in pediatric cholestatic liver disease: Role of taurocholate and hepatocyte-derived monocyte chemotaxis protein-1 in hepatic stellate cell recruitment
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 19-09-2008
DOI: 10.1002/HEP.22637
Abstract: Cholestatic liver diseases, such as cystic fibrosis (CF) liver disease and biliary atresia, predominate as causes of childhood cirrhosis. Despite erse etiologies, the stereotypic final pathway involves fibrogenesis where hepatic stellate cells (HSCs) are recruited, producing excess collagen which initiates biliary fibrosis. A possible molecular determinant of this recruitment, monocyte chemotaxis protein-1 (MCP-1), an HSC-responsive chemokine, was investigated in CF liver disease and biliary atresia. The bile-duct-ligated rat and in vitro coculture models of cholestatic liver injury were used to further explore the role of MCP-1 in HSC recruitment and proposed mechanism of induction via bile acids. In both CF liver disease and biliary atresia, elevated hepatic MCP-1 expression predominated in scar margin hepatocytes, closely associated with activated HSCs, and was also expressed in cholangiocytes. Serum MCP-1 was elevated during early fibrogenesis. Similar observations were made in bile-duct-ligated rat liver and serum. Hepatocytes isolated from cholestatic rats secreted increased MCP-1 which avidly recruited HSCs in coculture. This HSC chemotaxis was markedly inhibited in interventional studies using anti-MCP-1 neutralizing antibody. In CF liver disease, biliary MCP-1 was increased, positively correlating with levels of the hydrophobic bile acid, taurocholate. In cholestatic rats, increased MCP-1 positively correlated with taurocholate in serum and liver, and negatively correlated in bile. In normal human and rat hepatocytes, taurocholate induced MCP-1 expression. These observations support the hypothesis that up-regulation of hepatocyte-derived MCP-1, induced by bile acids, results in HSC recruitment in erse causes of cholestatic liver injury, and is a key early event in liver fibrogenesis in these conditions. Therapies aimed at neutralizing MCP-1 or bile acids may help reduce fibro-obliterative liver injury in childhood cholestatic diseases.
The Role of Hepatic Stellate Cells and Transforming Growth Factor-β1 in Cystic Fibrosis Liver Disease
Publisher: Elsevier BV
Date: 05-2002
DOI: 10.1016/S0002-9440(10)61117-0
Abstract: Liver disease causes significant morbidity and mortality from multilobular cirrhosis in patients with cystic fibrosis. Abnormal bile transport and biliary fibrosis implicate abnormal biliary physiology in the pathogenesis of cystic fibrosis-associated liver disease (CFLD), yet the mediators linking biliary events to fibrosis remain unknown. Activated hepatic stellate cells (HSCs) are the pre-eminent mediators of fibrosis in a range of hepatic disorders. The dominant stimulus for matrix production by HSCs is the cytokine transforming growth factor (TGF)-beta(1). In CFLD, the role of HSCs and the source of TGF-beta(1) have not been evaluated. Liver biopsy tissue obtained from 38 children with CFLD was analyzed. Activated HSCs, identified by co-localization of procollagen alpha(1)(I) mRNA and alpha-smooth muscle actin, were demonstrated as the cellular source of excess collagen production in the fibrosis surrounding the bile ducts and the advancing edge of scar tissue. TGF-beta protein and TGF-beta(1) mRNA expression were shown to be predominantly expressed by bile duct epithelial cells. TGF-beta(1) expression was significantly correlated with both hepatic fibrosis and the percentage of portal tracts showing histological abnormalities associated with CFLD. This study demonstrates a definitive role for HSCs in fibrogenesis associated with CFLD and establishes a potential mechanism for the induction of HSC collagen gene expression through the production of TGF-beta(1) by bile duct epithelial cells.
Pathophysiology of Iron Toxicity
Publisher: Springer US
Date: 1994
DOI: 10.1007/978-1-4615-2554-7_26
Abstract: There are several inherited and acquired disorders that can result in chronic iron overload in humans, and the major clinical consequences are hepatic fibrosis, cirrhosis, hepatocellular cancer, cardiac disease, and diabetes. It is clear that lipid peroxidation occurs in experimental iron overload if sufficiently high levels of iron within hepatocytes are achieved. Lipid peroxidation is associated with hepatic mitochondrial and microsomal dysfunction in experimental iron overload, and lipid peroxidation may underlie the increased lysosomal fragility that has been detected in liver s les from both iron-loaded human subjects and experimental animals. Reduced cellular ATP levels, impaired cellular calcium homeostasis, and damage to DNA may all contribute to hepatocellular injury in iron overload. Long-term dietary iron overload in rats can lead to increased collagen gene expression and hepatic fibrosis, perhaps due to activation of hepatic lipocytes. The mechanisms whereby lipocytes are activated in iron overload remain to be elucidated possible mediators include aldehydic products of iron-induced lipid peroxidation produced in hepatocytes, tissue ferritin, and/or cytokines released by activated Kupffer cells.
Therapeutic potential of macrophage colony-stimulating factor in chronic liver disease
Publisher: The Company of Biologists
Date: 04-2022
DOI: 10.1242/DMM.049387
Abstract: Resident and recruited macrophages control the development and proliferation of the liver. We have previously shown in multiple species that treatment with a macrophage colony stimulating factor (CSF1)-Fc fusion protein initiated hepatocyte proliferation and promoted repair in models of acute hepatic injury in mice. Here, we investigated the impact of CSF1-Fc on resolution of advanced fibrosis and liver regeneration, using a non-resolving toxin-induced model of chronic liver injury and fibrosis in C57BL/6J mice. Co-administration of CSF1-Fc with exposure to thioacetamide (TAA) exacerbated inflammation consistent with monocyte contributions to initiation of pathology. After removal of TAA, either acute or chronic CSF1-Fc treatment promoted liver growth, prevented progression and promoted resolution of fibrosis. Acute CSF1-Fc treatment was also anti-fibrotic and pro-regenerative in a model of partial hepatectomy in mice with established fibrosis. The beneficial impacts of CSF1-Fc treatment were associated with monocyte-macrophage recruitment and increased expression of remodelling enzymes and growth factors. These studies indicate that CSF1-dependent macrophages contribute to both initiation and resolution of fibrotic injury and that CSF1-Fc has therapeutic potential in human liver disease.
The development of hepatic stellate cells in normal and abnormal human fetuses - an immunohistochemical study
Publisher: Wiley
Date: 08-2015
DOI: 10.14814/PHY2.12504
Filling the Gap on Caveolin-1 in Liver Carcinogenesis
Publisher: Elsevier BV
Date: 12-2016
DOI: 10.1016/J.TRECAN.2016.10.011
Abstract: Caveolin-1 (CAV1) has emerged as a promoter of proliferation, metastasis, and chemoresistance in hepatoma cells, as well as a marker of poor prognosis in liver cancer. We discuss here current knowledge and future approaches to elucidating the molecular mechanisms underlying CAV1 action during hepatocarcinogenesis and evaluate its potential use in clinical therapies.
How much iron is too much?
Publisher: Informa UK Limited
Date: 06-2008
Lymphotoxin-β receptor signaling regulates hepatic stellate cell function and wound healing in a murine model of chronic liver injury
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 22-08-2008
DOI: 10.1002/HEP.22597
Abstract: Lymphotoxin-beta (LTbeta) is a proinflammatory cytokine and a member of the tumor necrosis factor (TNF) superfamily known for its role in mediating lymph node development and homeostasis. Our recent studies suggest a role for LTbeta in mediating the pathogenesis of human chronic liver disease. We hypothesize that LTbeta co-ordinates the wound healing response in liver injury via direct effects on hepatic stellate cells. This study used the choline-deficient, ethionine-supplemented (CDE) dietary model of chronic liver injury, which induces inflammation, liver progenitor cell proliferation, and portal fibrosis, to assess (1) the cellular expression of LTbeta, and (2) the role of LTbeta receptor (LTbetaR) in mediating wound healing, in LTbetaR(-/-) versus wild-type mice. In addition, primary isolates of hepatic stellate cells were treated with LTbetaR-ligands LTbeta and LTbeta-related inducible ligand competing for glycoprotein D binding to herpesvirus entry mediator on T cells (LIGHT), and mediators of hepatic stellate cell function and fibrogenesis were assessed. LTbeta was localized to progenitor cells immediately adjacent to activated hepatic stellate cells in the periportal region of the liver in wild-type mice fed the CDE diet. LTbetaR(-/-) mice fed the CDE diet showed significantly reduced fibrosis and a dysregulated immune response. LTbetaR was demonstrated on isolated hepatic stellate cells, which when stimulated by LTbeta and LIGHT, activated the nuclear factor kappa B (NF-kappaB) signaling pathway. Neither LTbeta nor LIGHT had any effect on alpha-smooth muscle actin, tissue inhibitor of metalloproteinase 1, transforming growth factor beta, or procollagen alpha(1)(I) expression however, leukocyte recruitment-associated factors intercellular adhesion molecule 1 and regulated upon activation T cells expressed and secreted (RANTES) were markedly up-regulated. RANTES caused the chemotaxis of a liver progenitor cell line expressing CCR5. This study suggests that LTbetaR on hepatic stellate cells may be involved in paracrine signaling with nearby LTbeta-expressing liver progenitor cells mediating recruitment of progenitor cells, hepatic stellate cells, and leukocytes required for wound healing and regeneration during chronic liver injury.
GNPAT p.D519G is independently associated with markedly increased iron stores in HFE p.C282Y homozygotes
Publisher: Elsevier BV
Date: 03-2017
The Clinical Relevance of Compound Heterozygosity for the C282Y and H63D Substitutions in Hemochromatosis
Publisher: Elsevier BV
Date: 11-2006
DOI: 10.1016/J.CGH.2006.07.009
Abstract: Two major mutations are defined within the hemochromatosis gene, HFE. Although the effects of the C282Y substitution have been well characterized, the clinical significance of the C282Y/H63D state remains unclear. This study assessed the phenotypic expression in C282Y/H63D subjects as compared with C282Y homozygotes. Data were obtained from 91 C282Y/H63D probands, 158 C282Y/H63D subjects identified through family screening, and 483 C282Y homozygotes. Subjects underwent clinical evaluation, genotyping, biochemical assessment, and liver biopsy examination where clinically indicated. C282Y/H63D probands had significantly less clinical and biochemical expression than C282Y homozygotes. Biochemical expression was higher in C282Y/H63D probands than in C282Y/H63D subjects identified through family screening (P < .001). Of the C282Y/H63D subjects with serum ferritin levels greater than 1000 mug/L, all had known comorbid factors that could have contributed to the increased ferritin level. Of the 51 C282Y/H63D subjects who underwent liver biopsy examination, significantly increased iron stores were present in 9 subjects and hepatic fibrosis was present in 13. Twelve of the 13 had evidence of hepatic steatosis, excess alcohol consumption, or diabetes. The mobilizable iron level was significantly higher in C282Y homozygous males than in compound heterozygous males (P < .001). Genetic screening of C282Y/H63D first-degree relatives detected 5 C282Y homozygotes. C282Y/H63D subjects referred for assessment had a high prevalence of increased iron indices but did not develop progressive clinical disease without comorbid factors such as steatosis, diabetes, or excess alcohol consumption. When fibrosis was seen, 1 or more comorbid factors almost always were present. Thus, phlebotomy therapy is warranted and cascade screening of relatives should be performed because expressing C282Y homozygotes may be detected.
Characterising granuloma regression and liver recovery in a murine model of schistosomiasis japonica
Publisher: Elsevier BV
Date: 04-2016
DOI: 10.1016/J.IJPARA.2015.12.004
Abstract: For hepatic schistosomiasis the egg-induced granulomatous response and the development of extensive fibrosis are the main pathologies. We used a Schistosoma japonicum-infected mouse model to characterise the multi-cellular pathways associated with the recovery from hepatic fibrosis following clearance of the infection with the anti-schistosomal drug, praziquantel. In the recovering liver splenomegaly, granuloma density and liver fibrosis were all reduced. Inflammatory cell infiltration into the liver was evident, and the numbers of neutrophils, eosinophils and macrophages were significantly decreased. Transcriptomic analysis revealed the up-regulation of fatty acid metabolism genes and the identification of Peroxisome proliferator activated receptor alpha as the upstream regulator of liver recovery. The aryl hydrocarbon receptor signalling pathway which regulates xenobiotic metabolism was also differentially up-regulated. These findings provide a better understanding of the mechanisms associated with the regression of hepatic schistosomiasis.
Importance of Hepatic Fibrosis in Cystic Fibrosis and the Predictive Value of Liver Biopsy
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 17-11-2011
DOI: 10.1002/HEP.24014
Abstract: Cystic fibrosis liver disease (CFLD), which results from progressive hepatobiliary fibrosis, is an important cause of morbidity and mortality, but it is difficult to identify before portal hypertension (PHT) ensues. Clinical signs, serum alanine aminotransferase (ALT) levels, and ultrasound (US) are widely applied, but their value in predicting the presence of cirrhosis, the development of PHT, or adverse outcomes is undetermined. The potential gold standard, liver biopsy, is not standard practice and, notwithstanding s ling error considerations, has not been systematically evaluated. Forty patients with cystic fibrosis (median age = 10.6 years) with abnormal clinical, biochemical, and US findings were subjected to dual-pass percutaneous liver biopsy. Clinical outcomes were recorded over 12 years of follow-up (median = 9.5 years for survivors). Logistic regression and receiver operating characteristic analyses were applied to predict hepatic fibrosis (which was assessed by fibrosis staging and quantitative immunohistochemistry) and the occurrence of PHT. PHT occurred in 17 of 40 patients (42%), including 6 of 7 (17%) who died during follow-up. Clinical examination, serum ALT levels, and US findings failed to predict either the presence of liver fibrosis or the development of PHT. Fibrosis staging on liver biopsy, where the accuracy was improved by dual passes (P = 0.002, nonconcordance = 38%), predicted the development of PHT (P < 0.001), which occurred more frequently and at a younger age in those with severe fibrosis. Clinical modalities currently employed to evaluate suspected CFLD help to identify a cohort of children at risk for liver disease and adverse outcomes but do not predict an in idual's risk of liver fibrosis or PHT development. Liver fibrosis on biopsy predicts the development of clinically significant liver disease. Dual passes help to address s ling concerns. Liver biopsy has a relevant role in the management of patients with suspected CFLD and deserves more widespread application.
Regression of Fibrosis Stage With Treatment Reduces Long-Term Risk of Liver Cancer in Patients With Hemochromatosis Caused by Mutation in HFE
Publisher: Elsevier BV
Date: 07-2020
DOI: 10.1016/J.CGH.2019.10.010
Abstract: Fibrosis stage can decrease following treatment in patients with hemochromatosis caused by mutations in the homeostatic iron regulator gene (HFE), but the effects on cirrhosis are not clear. We assessed regression of severe fibrosis and the ensuing risk of liver cancer after treatment. We performed a retrospective analysis of data from 106 patients in France or Australia who were homozygous for the C282Y mutation in HFE with F3 fibrosis (n = 40) or F4 fibrosis (n = 66) at diagnosis and from whom at least 1 liver biopsy was collected during follow up. We collected data from the time of first biopsy and during follow-up period on patient demographics, treatment, smoking habits, alcohol consumption, infection with hepatitis B or C viruses, and other diseases. The median time between first and last liver biopsy was 9.5 years (range, 3.5-15.6 years). We collected results of tests for liver function, markers of iron stores, and platelet levels. Patients were followed for a median 17.6 years (range, 9.8-24.1 years) for development of liver cancer occurrence. At last liver biopsy, 41 patients (38.6%) had fibrosis scores of F2 or less. Liver cancer occurred in 34 patients (52.3%) with F3 or F4 fibrosis at last liver biopsy vs 2 patients (4.8%) with fibrosis scores of F2 or less at last liver biopsy (P < .001). Liver cancer incidences were 32.8 per 1000 person-years (95% CI, 22.7-45.9 per 1000 person-years) in patients with F3 or F4 fibrosis and 2.3 per 1000 person-years (95% CI, 0.2-8.6 per 1000 person-years) in patients with fibrosis scores of F2 or less (P < .001). In multivariate analysis, male sex (hazard ratio [HR], 6.09 95% CI, 1.21-30.4), age at diagnosis (HR, 1.16 95% CI, 1.09-1.25), presence of diabetes (HR, 3.07 95% CI, 1.35-6.97), excess alcohol consumption (HR, 3.1 95% CI, 1.47-6.35), serum level of ferritin at diagnosis (P < .01), and regression to fibrosis scores of F2 or less (HR, 0.08 95% CI, 0.01-0.62) were significantly associated with risk of liver cancer. In a retrospective analysis of patients with hemochromatosis caused by the C282Y mutation in HFE, we found that severe liver fibrosis can regress with treatment. In patients with fibrosis regression to a stage F2 or less, the long-term risk for liver cancer is significantly reduced.
Hepatic Pathobiology of Iron Overload
Publisher: Humana Press
Date: 24-11-2011
Co-ordinated gene expression in the liver and spleen during schistosoma japonicum infection regulates cell migration
Publisher: Public Library of Science (PLoS)
Date: 18-05-2010
Assessment of hepatic steatosis: comparison of quantitative and semiquantitative methods in 108 liver biopsies
Publisher: Wiley
Date: 10-03-2009
DOI: 10.1111/J.1478-3231.2008.01874.X
Abstract: There is growing interest in the role of hepatic steatosis in liver injury. The current standard for steatosis assessment is histological grading, although there is variability in the scoring systems used. The aim of this study was to compare steatosis assessment by image analysis and histological grading. Three methods were used to measure steatosis: histological grading (from 0 to 4) estimation of the percentage of hepatocytes (to nearest 5%) with steatosis and computer-assisted image analysis. Image analysis was performed on multiple fields for each biopsy with image pro plus 4.5, with steatotic droplets identified on the basis of shape, colour and size. Computer-selected objects were reviewed to ensure that these were steatotic droplets. The predictive accuracy of the three techniques was assessed using measures of obesity and insulin resistance (homeostasis model assessment) as the outcome variables. There was a strong correlation between the results of image analysis and histological grade (r(s)=0.89, P<0.01), and estimated per cent steatosis (r(s)=0.93, P<0.01). The variability in the area of steatosis calculated by image analysis in different fields of a biopsy correlated with the total steatosis area (r(s)=0.93, P<0.01). Image analysis did not offer any additional predictive value when the association between degree of obesity or insulin resistance was correlated with the different methods of assessing steatosis. Image analysis allows measurement of area of steatosis in liver biopsy material and generates a continuous variable that facilitates statistical analysis. These aspects may prove beneficial in research settings.
Reduced expression of chemokine (C-C motif) ligand-2 (CCL2) in ovarian adenocarcinoma
Publisher: Springer Science and Business Media LLC
Date: 17-05-2005
Chronic iron overload causes activation of rat lipocytes in vivo
Publisher: American Physiological Society
Date: 03-1995
DOI: 10.1152/AJPGI.1995.268.3.G451
Abstract: Chronic iron overload can result in hepatic fibrosis and cirrhosis. Activated lipocytes, through increased production of collagen and extracellular matrix, play an important role in hepatic fibrogenesis in several types of experimental liver injury, but their contribution to hepatic injury after iron overload is unknown. This study examines the effect of iron overload on lipocyte activation, in vivo. Male Sprague-Dawley rats were fed a chow diet supplemented with 1% carbonyl iron for up to 20 mo. Controls were fed the chow diet alone. Lipocytes were prepared by sequential pronase and collagenase perfusion of the livers, followed by density-gradient centrifugation. Lipocyte activation was assessed by immunohistochemistry of liver sections and by Western blot analysis of alpha-smooth muscle actin expression in freshly isolated lipocytes. In addition, to measure the biosynthetic capability of these lipocytes, collagen and noncollagen protein production was determined after 3 days in culture, using [3H]proline incorporation. The hepatic iron concentration was increased by eightfold in the iron-loaded rats, and lipocytes from these animals expressed alpha-smooth muscle actin. Collagen production was increased by 2.5-fold, and noncollagen protein production was elevated by twofold in lipocytes isolated from iron-loaded rats. In the iron-loaded livers, autofluorescent material with the characteristics of lipofusion was present in periportal zones. Chronic iron overload expression results in the activation of lipocytes, as determined by increased expression of alpha-smooth muscle actin and by increased production of both collagen and noncollagen protein. This activation may contribute to iron-induced hepatic fibrogenesis.
Morphology of liver repair following cholestatic liver injury: resolution of ductal hyperplasia, matrix deposition and regression of myofibroblasts Note
Publisher: Wiley
Date: 10-2000
DOI: 10.1034/J.1600-0676.2000.020005387.X
Abstract: Myofibroblasts are the primary cells responsible for increased matrix deposition in hepatic fibrosis. Activation of hepatic stellate cells and portal fibroblasts to myofibroblasts during cholestatic liver injury is accompanied by increased expression of the activation marker, alpha-smooth muscle actin (SMA), and collagen genes. In contrast to our understanding of injury, the cellular mechanisms of liver repair are not well defined. This study was designed to examine the morphological relationship between bile duct hyperplasia, matrix deposition and myofibroblast phenotype in a model of chronic cholestatic liver injury and repair. Reversible extrahepatic obstruction was accomplished in rats using a soft vessel loop suspended from the anterior abdominal wall: duct manipulation alone was performed in sham-operated controls. After 7 days, rats were either sacrificed or decompressed by release of the loop and subsequently sacrificed 2-10 days after reversal. Liver sections were obtained for in situ hybridization for procollagen alpha1(I) mRNA, immunohistochemical staining for SMA and cytokeratin 19, and histochemical staining for reticulin. Cholestatic livers demonstrated bile duct hyperplasia, which reversed to normal within 10 days after decompression. Fibrosis was also substantially reduced during this period. SMA-positive myofibroblasts were abundant and localized to regions adjacent to proliferating ducts and excess matrix in the obstructed animals. Decompressed livers showed a dramatic time-dependent reduction in the number of SMA-positive cells and in the expression of procollagen I mRNA. Our results show that the disappearance of bile duct hyperplasia after biliary decompression is accompanied by a similarly rapid loss of SMA-positive myofibroblasts. Both cellular events may abrogate enhanced matrix synthesis and allow repair to occur.
Growth Hormone Stops Excessive Inflammation After Partial Hepatectomy, Allowing Liver Regeneration and Survival Through Induction of H2-Bl/HLA-G
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-11-2020
DOI: 10.1002/HEP.31297
Abstract: Growth hormone (GH) is important for liver regeneration after partial hepatectomy (PHx). We investigated this process in C57BL/6 mice that express different forms of the GH receptor (GHR) with deletions in key signaling domains. PHx was performed on C57BL/6 mice lacking GHR ( Ghr −/− ), disabled for all GH‐dependent Janus kinase 2 signaling ( Box1 −/− ), or lacking only GH‐dependent signal transducer and activator of transcription 5 (STAT5) signaling ( Ghr391 −/− ), and wild‐type littermates. C57BL/6 Ghr −/− mice showed striking mortality within 48 hours after PHx, whereas Box1 −/− or Ghr391 −/− mice survived with normal liver regeneration. Ghr −/− mortality was associated with increased apoptosis and elevated natural killer/natural killer T cell and macrophage cell markers. We identified H2‐Bl, a key immunotolerance protein, which is up‐regulated by PHx through a GH‐mediated, Janus kinase 2–independent, SRC family kinase–dependent pathway. GH treatment was confirmed to up‐regulate expression of the human homolog of H2‐Bl (human leukocyte antigen G [ HLA‐G ]) in primary human hepatocytes and in the serum of GH‐deficient patients. We find that injury‐associated innate immune attack by natural killer/natural killer T cell and macrophage cells are instrumental in the failure of liver regeneration, and this can be overcome in Ghr −/− mice by adenoviral delivery of H2‐Bl or by infusion of HLA‐G protein. Further, H2‐Bl knockdown in wild‐type C57BL/6 mice showed elevated markers of inflammation after PHx, whereas Ghr −/− backcrossed on a strain with high endogenous H2 ‐ Bl expression showed a high rate of survival following PHx. GH induction of H2‐Bl expression is crucial for reducing innate immune‐mediated apoptosis and promoting survival after PHx in C57BL/6 mice. Treatment with HLA‐G may lead to improved clinical outcomes following liver surgery or transplantation.
Circulating MicroRNAs as Noninvasive Diagnostic Biomarkers of Liver Disease in Children With Cystic Fibrosis
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2015
Gomesin peptides prevent proliferation and lead to the cell death of devil facial tumour disease cells
Publisher: Springer Science and Business Media LLC
Date: 14-02-2018
DOI: 10.1038/S41420-018-0030-0
Abstract: The Tasmanian devil faces extinction due to devil facial tumour disease (DFTD), a highly transmittable clonal form of cancer without available treatment. In this study, we report the cell-autonomous antiproliferative and cytotoxic activities exhibited by the spider peptide gomesin (AgGom) and gomesin-like homologue (HiGom) in DFTD cells. Mechanistically, both peptides caused a significant reduction at G0/G1 phase, in correlation with an augmented expression of the cell cycle inhibitory proteins p53, p27, p21, necrosis, exacerbated generation of reactive oxygen species and diminished mitochondrial membrane potential, all hallmarks of cellular stress. The screening of a novel panel of AgGom-analogues revealed that, unlike changes in the hydrophobicity and electrostatic surface, the cytotoxic potential of the gomesin analogues in DFTD cells lies on specific arginine substitutions in the eight and nine positions and alanine replacement in three, five and 12 positions. In conclusion, the evidence supports gomesin as a potential antiproliferative compound against DFTD disease.
Previous liver regeneration induces fibro-protective mechanisms during thioacetamide-induced chronic liver injury
Publisher: Elsevier BV
Date: 05-2021
Quantitative analysis of the expression of ACAT genes in human tissues by real-time PCR2
Publisher: Elsevier BV
Date: 04-2004
Role of TWEAK in coregulating liver progenitor cell and fibrogenic responses
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 27-01-2014
DOI: 10.1002/HEP.26701
Overexpression of miRNA-25-3p inhibits Notch1 signaling and TGF-β-induced collagen expression in hepatic stellate cells
Publisher: Springer Science and Business Media LLC
Date: 12-06-2019
DOI: 10.1038/S41598-019-44865-1
Abstract: During chronic liver injury hepatic stellate cells (HSCs), the principal source of extracellular matrix in the fibrotic liver, transdifferentiate into pro-fibrotic myofibroblast-like cells - a process potentially regulated by microRNAs (miRNAs). Recently, we found serum miRNA-25-3p (miR-25) levels were upregulated in children with Cystic Fibrosis (CF) without liver disease, compared to children with CF-associated liver disease and healthy in iduals. Here we examine the role of miR-25 in HSC biology. MiR-25 was detected in the human HSC cell line LX-2 and in primary murine HSCs, and increased with culture-induced activation. Transient overexpression of miR-25 inhibited TGF-β and its type 1 receptor (TGFBR1) mRNA expression, TGF-β-induced Smad2 phosphorylation and subsequent collagen1α1 induction in LX-2 cells. Pull-down experiments with biotinylated miR-25 revealed Notch signaling (co-)activators ADAM-17 and FKBP14 as miR-25 targets in HSCs. NanoString analysis confirmed miR-25 regulation of Notch- and Wnt-signaling pathways. Expression of Notch signaling pathway components and endogenous Notch1 signaling was downregulated in miR-25 overexpressing LX-2 cells, as were components of Wnt signaling such as Wnt5a. We propose that miR-25 acts as a negative feedback anti-fibrotic control during HSC activation by reducing the reactivity of HSCs to TGF-β-induced collagen expression and modulating the cross-talk between Notch, Wnt and TGF-β signaling.
Repetitive Acute Pancreatic Injury in the Mouse Induces Procollagen α1(I) Expression Colocalized to Pancreatic Stellate Cells
Publisher: Elsevier BV
Date: 02-2000
DOI: 10.1038/LABINVEST.3780018
Abstract: Pancreatic stellate cells may be a major source of extracellular matrix deposition during injury. This study was undertaken to establish whether pancreatic stellate cells are a source of Type I collagen in vivo and whether they continue to be a source of matrix production in the post-injury fibrotic pancreas. To induce pancreatic fibrogenesis, acute pancreatic injury was induced in mice three times weekly with supraphysiologic doses of cerulein. Animals were treated for 6 weeks and allowed to recover for an additional 6 weeks. Stellate cell activation and pancreatic collagen expression were measured by immunohistochemistry, whole tissue RNA analysis, and in situ hybridization. Histology and digital image analysis demonstrated the development of substantial pancreatic fibrosis after 6 weeks of treatment. During recovery, incomplete resolution of the fibrosis was found. Procollagen alpha1(I) mRNA increased more than 15-fold during treatment and continued to be 5-fold elevated during the post-injury phase. In situ hybridization studies demonstrated that collagen gene expression was colocalized to activated pancreatic stellate cells. Collagen expression and fibrosis persisted in focal areas during recovery. These findings show that pancreatic stellate cells are the major source of collagen during repetitive injury in vivo. Additionally, focal areas of sustained pancreatic fibrogenesis persist after cessation of cerulein treatment, and these areas may contribute to sustained total organ collagen expression in the absence of ongoing injury.
Arthritis Prediction of Advanced Hepatic Fibrosis in HFE Hemochromatosis
Publisher: Elsevier BV
Date: 09-2022
DOI: 10.1016/J.MAYOCP.2022.02.017
Abstract: To evaluate whether arthritis predicts the likelihood of advanced hepatic fibrosis in HFE hemochromatosis. We conducted a retrospective, cross-sectional analysis of 112 well-characterized patients with HFE hemochromatosis and liver biopsy-validated fibrosis staging recruited between January 1, 1983, and December 31, 2013. Complete clinical, biochemical, hematologic, and noninvasive serum biochemical indices (aspartate aminotransferase to platelet ratio index [APRI] and fibrosis 4 index [FIB4]) were available. Scheuer fibrosis stages 3 and 4, APRI greater than 0.44, or FIB4 greater than 1.1 were used to define advanced hepatic fibrosis. Comparisons between groups were performed using categorical analysis, unpaired or paired t test. Male (n=76) and female (n=36) patients were similar in age. Nineteen patients had advanced hepatic fibrosis, and 47 had hemochromatosis arthritis. Arthritis was significantly associated with the presence of advanced hepatic fibrosis as determined by liver biopsy (sensitivity, 84%, [95% CI, 62% to 95%] negative predictive value, 95% [95% CI, 87% to 99%] relative risk, 7.4 [95% CI, 2.5 to 23] P<.001), APRI (sensitivity, 75% [95% CI, 55% to 88%] negative predictive value, 91% [95% CI, 81% to 96%] relative risk, 4.5 [95% CI, 2.0 to 10.2] P<.001), or FIB4 (sensitivity, 61% [95% CI, 41% to 78%] negative predictive value, 67% [95% CI, 68% to 90%] relative risk, 2.2 [95% CI, 1.1 to 4.6] P=.03). Mean cell volume values were significantly higher pretreatment in patients with F3-4 fibrosis (96.7±1.1 fL) compared with F0-2 fibrosis (93.4±0.5 fL P=.004) and declined following treatment (F3-4, 93.2±0.9 fL, P=.01 F0-2, 91.7±0.6 fL, P=.01). Advanced hepatic fibrosis is strongly associated with arthritis in HFE hemochromatosis. The absence of arthritis predicts a low likelihood of advanced hepatic fibrosis, supporting its use as a clinical marker for advanced hepatic fibrosis in HFE hemochromatosis.
Transforming growth factor-β and toll-like receptor-4 polymorphisms are not associated with fibrosis in haemochromatosis
Publisher: Baishideng Publishing Group Inc.
Date: 2013
Hereditary hemochromatosis in the post-HFEera
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2008
DOI: 10.1002/HEP.22507
A commentary on: Career paths for basic scientists in medical research
Publisher: Wiley
Date: 09-1996
DOI: 10.1111/J.1440-1746.1996.TB00099.X
Abstract: For basic scientists, the choice of starting a career in medical research is one made through a genuine interest in understanding the human disease processes and a desire to be at the forefront of new knowledge acquisition. However, more often than not, this decision is made without a great understanding of the career path one must follow to be successful in medical research or of the potential hurdles that may lay in wait in attaining one's career goals. The present paper outlines the optimum career path a basic scientist may follow through the National Health and Medical Research Council of Australia career awards and fellowship schemes. The document also highlights a number of potential problems in the career progression of basic scientists to Research Fellow, which appear to be due, in part, to the lack of appropriate funding to support these schemes.
Ductular reaction in hereditary hemochromatosis: The link between hepatocyte senescence and fibrosis progression
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 27-01-2014
DOI: 10.1002/HEP.26706
Abstract: The development of portal fibrosis following the iron loading of hepatocytes is the first stage of fibrogenesis in hereditary hemochromatosis. In other chronic liver diseases it has been shown that a ductular reaction (DR) appears early, correlates with fibrosis progression, and is a consequence of activation of an alternative pathway of hepatocyte replication. This study was designed to investigate the presence of the DR in hemochromatosis and describe its associations. Liver biopsies from 63 C282Y homozygous patients were assessed for hepatic iron concentration (HIC) and graded for iron loading, fibrosis stage, steatosis, and inflammation. Immunostaining allowed quantification of the DR, hepatocyte senescence and proliferation, and analysis incorporated clinical data. Hepatocyte senescence was positively correlated with HIC, serum ferritin, and oxidative stress. A DR was demonstrated and occurred prior to histological fibrosis. HIC, age, hepatocyte senescence and proliferation, portal inflammation, and excessive alcohol consumption all had significant associations with the extent of the DR. In multivariate analysis, iron loading, hepatocyte replicative arrest, and portal inflammation remained independently and significantly associated with the DR. Of factors associated with fibrosis progression, the DR (odds ratio [OR] 10.86 P<0.0001) and the presence of portal inflammation (OR 4.31, P=0.028) remained significant after adjustment for cofactors. The extent of the DR regressed following therapeutic venesection. Iron loading of hepatocytes leads to impaired replication, stimulating the development of the DR in hemochromatosis and this correlates strongly with hepatic fibrosis. Portal inflammation occurs in hemochromatosis and is independently associated with the DR and fibrosis, and thus its role in this disease should be evaluated further.
LXR stimulates a metabolic switch and reveals cholesterol homeostasis as a statin-target against Tasmanian Devil Facial Tumor Disease
Publisher: Elsevier BV
Date: 03-2021
DOI: 10.1016/J.CELREP.2021.108851
Abstract: Devil facial tumor disease (DFTD) and its lack of available therapies are propelling the Tasmanian devil population toward extinction. This study demonstrates that cholesterol homeostasis and carbohydrate energy metabolism sustain the proliferation of DFTD cells in a cell-type-dependent manner. In addition, we show that the liver-X nuclear receptor-β (LXRβ), a major cholesterol cellular sensor, and its natural ligand 24S-hydroxycholesterol promote the proliferation of DFTD cells via a metabolic switch toward aerobic glycolysis. As a proof of concept of the role of cholesterol homeostasis on DFTD proliferation, we show that atorvastatin, an FDA-approved statin-drug subtype used against human cardiovascular diseases that inhibits cholesterol synthesis, shuts down DFTD energy metabolism and prevents tumor growth in an in vivo DFTD-xenograft model. In conclusion, we show that intervention against cholesterol homeostasis and carbohydrate-dependent energy metabolism by atorvastatin constitutes a feasible biochemical treatment against DFTD, which may assist in the conservation of the Tasmanian devil.
Isolation and culture of rat hepatic stellate cells
Publisher: Wiley
Date: 08-1998
Spatial and temporal transcriptomics of Schistosoma japonicum-induced hepatic granuloma formation reveals novel roles for neutrophils
Publisher: Oxford University Press (OUP)
Date: 24-05-2013
DOI: 10.1189/JLB.1212653
Abstract: The severity of schistosome egg-induced hepatic granulomatous pathology depends markedly on the nature of the host immune responses. In this study, we used LMM and microarray analysis to compare gene expression profiles of histologically distinct zones within, and directly proximal to, hepatic granulomas that developed in C57BL/6 mice infected with Schistosoma japonicum. There was significant up-regulation of type-1, type-2, and type-17 immune-associated genes within the granuloma core (adjacent to eggs), followed by increased expression of type-2 and fibrotic genes at the outer zones of granulomas. Neutrophil-associated genes were also found to be expressed differentially in the core and at the peripheral zone of granulomas, present at 7 weeks p.i., demonstrating a significant role of neutrophils in S. japonicum granulomatous pathology. The release of NETs was observed microscopically in granulomas obtained from the livers of infected mice and when human neutrophils were incubated in vitro in the presence of S. japonicum eggs. These finding are the first to suggest a novel, dual role for neutrophils in the mediation of tissue damage and repair in S. japonicum egg-induced hepatic granulomatous lesions. Together, these results provide an overview of the local events occurring within the granuloma microenvironment.
Supersonic shear-wave elastography and APRI for the detection and staging of liver disease in pediatric cystic fibrosis
Publisher: Elsevier BV
Date: 05-2020
DOI: 10.1016/J.JCF.2019.06.017
Abstract: Current diagnostic methods for the diagnosis of Cystic fibrosis (CF)-associated liver disease (CFLD) are non-specific and assessment of disease progression is difficult prior to the advent of advanced disease with portal hypertension. This study investigated the potential of Supersonic shear-wave elastography (SSWE) to non-invasively detect CFLD and assess hepatic fibrosis severity in children with CF. 125 children were enrolled in this study including CFLD (n = 55), CF patients with no evidence of liver disease (CFnoLD = 41) and controls (n = 29). CFLD was diagnosed using clinical, biochemical and imaging best-practice guidelines. Advanced CFLD was established by the presence of portal hypertension and/or macronodular cirrhosis on ultrasound. Liver stiffness measurements (LSM) were acquired using SSWE and diagnostic performance for CFLD detection was evaluated alone or combined with aspartate aminotransferase-to-platelet ratio index (APRI). LSM was significantly higher in CFLD (8.1 kPa, IQR = 6.7-11.9) versus CFnoLD (6.2 kPa, IQR = 5.6-7.0 P < 0.0001) and Controls (5.3 kPa, IQR = 4.9-5.8 P < 0.0001). LSM was also increased in CFnoLD versus Controls (P = 0.0192). Receiver Operating Characteristic (ROC) curve analysis demonstrated good diagnostic accuracy for LSM in detecting CFLD using a cut-off = 6.85 kPa with an AUC = 0.79 (Sensitivity = 75%, Specificity = 71%, P < 0.0001). APRI also discriminated CFLD (AUC = 0.74, P = 0.004). Classification and regression tree modelling combining LSM + APRI showed 14.8 times greater odds of accurately predicting CFLD (AUC = 0.84). The diagnostic accuracy of SSWE for discriminating advanced disease was excellent with a cut-off = 9.05 kPa (AUC = 0.95 P < 0.0001). SSWE-determined LSM shows good diagnostic accuracy in detecting CFLD in children, which was improved when combined with APRI. SSWE alone discriminates advanced CFLD.
Hepatotoxicity of Iron Overload: Mechanisms of Iron-Induced Hepatic Fibrogenesis
Publisher: Georg Thieme Verlag KG
Date: 2005
Abstract: While iron is a vital requirement for normal cellular physiology, excessive intestinal absorption of iron as seen in hemochromatosis leads to its deposition in parenchymal cells of various organs such as the liver, heart, and pancreas, resulting in cellular toxicity, tissue injury, and organ fibrosis. Cellular injury is induced by iron-generated oxyradicals and peroxidation of lipid membranes. In the liver, lipid peroxidation results in damage to hepatocellular organelles, such as mitochondria and lysosomes, which is thought to contribute to hepatocyte necrosis and apoptosis, and ultimately lead to the development of hepatic fibrogenesis. Hepatic stellate cells are central to the development of hepatic fibrosis, as they can be activated into collagen-producing myofibroblasts. Numerous potential stimuli associated with hepatic iron overload and iron-induced hepatocellular injury have been assessed in an attempt to explain stellate cell transformation in hemochromatosis. Stellate cell activation and fibrosis appear to be regulated by a series of events involving cellular interaction between resident and nonresident cells of the liver, the sequestration of free iron versus the transport and storage of mobilizable iron, and extracellular matrix remodeling as well as intracellular signaling events associated with inflammatory and fibrogenic cytokines.
Gamma-glutamyl transpeptidase-to-platelet ratio as a biomarker of liver disease and hepatic fibrosis severity in paediatric Cystic Fibrosis
Publisher: Elsevier BV
Date: 03-2021
DOI: 10.1016/J.JCF.2021.10.014
Abstract: Cystic fibrosis (CF)-associated liver disease (CFLD) causes significant morbidity and mortality in children with CF. Diagnosis of liver disease prior to development of cirrhosis or portal hypertension (PHT) is challenging. While imaging modalities using Elastography show great promise they are still not widely available to all clinicians. This study investigated gamma-glutamyl transpeptidase-to-platelet ratio (GPR) as a non-invasive biomarker to detect liver disease and stage fibrosis severity in children with CF. 237 children were enroled including 76 with CFLD and 161 with CF and no detectable liver disease (CFnoLD). CFLD was diagnosed using standard clinical, biochemical and imaging practice guidelines. Hepatic fibrosis was staged on liver biopsies available from 54 children with CFLD. Serum liver biochemistry was used to calculate GPR (median, [IQR]) and receiver operating characteristics (ROC) analysis assessed utility to detect liver disease and stage fibrosis severity. GPR was significantly increased in CFLD versus CFnoLD (0.33 [0.19-0.96] vs. 0.15 [0.11-0.21], P<0.0001). GPR demonstrated good diagnostic utility for detecting CFLD with an area under the curve (AUC) of 0.81 (95% confidence Interval [CI] [0.75-0.87] P<0.0001), with sensitivity of 74% and specificity of 73%, using a cut-off of 0.20. GPR increased with increasing hepatic fibrosis stage. GPR discriminated both moderate-advanced (F2-F4) fibrosis vs. F0-F1 (AUC=0.82 95%CI [0.71-0.94] P 0.84 was predictive of PHT at diagnosis of CFLD (AUC=0.81 95%CI [0.67-0.95] P = 0.0003). GPR demonstrates good diagnostic utility for assessing the presence of liver disease, PHT and hepatic fibrosis severity in children with CF. These findings will aid in better identification of patients at risk for CF-related liver involvement and the potential for more targeted and timely follow-up and treatment.
Abnormal WT1 expression in human fetuses with bilateral renal agenesis and cardiac malformations
Publisher: Wiley
Date: 13-01-2012
DOI: 10.1002/BDRA.22881
Abstract: Bilateral renal agenesis has multiple etiologies. Animal models have provided useful information on possible causes of this condition, but its etiology in humans is less clear. We recently described autopsy findings of two human fetuses with bilateral renal agenesis and abnormal expression of WT1 (Wilms tumor 1) in liver mesothelium. We have identified 14 additional fetuses with bilateral renal agenesis from autopsies performed in our institution over the past 10 years and subjected archival liver biopsy specimens from these cases to immunohistochemistry for WT1, as well as α-smooth muscle actin (α-SMA) and desmin to assess liver mesenchymal abnormalities. Six of seven fetuses with combined bilateral renal agenesis and cardiac anomalies showed abnormalities of WT1 expression in liver mesothelial cells, which was not seen in other fetuses with bilateral renal agenesis. Except in one case, the fetuses with renal agenesis and cardiac defects also showed liver mesenchymal anomalies (assessed by increased α-SMA expression), which was not present in other renal agenesis fetuses. WT1 is widely expressed in mesothelial cells during development, and we hypothesized that some of the defects are caused by abnormal function of mesenchyme derived from mesothelial cells, similar to the mesothelium-derived defects proposed in animal models. The methods we used are available to many laboratories and can be applied to archival paraffin tissue blocks. We suggest that future similar studies could help to expand the understanding of renal agenesis in humans and could help to subclassify this condition. This would be useful in patient management and counseling.
Lymphotoxin-beta production following bile duct ligation: Possible role for Kupffer cells
Publisher: Wiley
Date: 12-10-2005
DOI: 10.1111/J.1440-1746.2005.04065.X
Abstract: Lymphotoxin-beta (LT-beta) may play a role in the pathogenesis of chronic liver injury. The aim of this study was to determine in an animal model of bile duct ligation liver injury whether LT-beta expression is induced and whether Kupffer cells are an intrahepatic source of LT-beta. Sprague-Dawley rats were ided into two groups: one group received a single dose of GdCl (a Kupffer cell-blocking agent, 10 mg/kg i.v.), whereas the other group received saline. One day later, the groups underwent bile duct ligation or a sham operation. Liver tissue was obtained on days 1, 3, 5, and 8 for assessment of Kupffer cell numbers, early fibrogenic events and LT-beta gene expression. Kupffer cells were isolated using pronase/collagenase perfusion and centrifugal elutriation. Hepatic LT-beta mRNA expression increased early following bile duct ligation. Pretreatment of bile duct-ligated animals with GdCl significantly reduced the number of Kupffer cells, delayed the rise in LT-beta expression, but had no effect on fibrogenesis. Recovery of the Kupffer cell population in these animals was accompanied by increased hepatic LT-beta expression. The LT-beta ligand and receptor were expressed by isolated normal Kupffer cells. Hepatic LT-beta expression is induced early following bile duct ligation. Kupffer cells may be an intrahepatic source of LT-beta.
Temporal expression of chemokines dictates the hepatic inflammatory infiltrate in a murine model of schistosomiasis
Publisher: Public Library of Science (PLoS)
Date: 09-02-2010
Identification and characterization of a receptor for tissue ferritin on activated rat lipocytes.
Publisher: American Society for Clinical Investigation
Date: 07-1994
DOI: 10.1172/JCI117353
Hepcidin in HFE-associated hemochromatosis: Another piece of the “iron” puzzle
Publisher: Elsevier BV
Date: 02-2004
Utility of Serum Biomarker Indices for Staging of Hepatic Fibrosis Before and After Venesection in Patients With Hemochromatosis Caused by Variants in HFE
Publisher: Elsevier BV
Date: 07-2021
A contributory role for activated hepatic stellate cells in the dynamics of Schistosoma japonicum egg-induced fibrosis
Publisher: Elsevier BV
Date: 08-2006
DOI: 10.1016/J.IJPARA.2006.04.015
Abstract: The disease manifestations of schistosomiasis arise from the mammalian host-mediated type 2 T-helper cell-induced (Th2) fibro-granulomatous inflammatory response to eggs trapped within host tissues. Activated hepatic stellate cells are well described as the effector cells of hepatic fibrosis in a variety of human diseases and rodent models. The aim of this study was to further understand the mechanism of fibrosis and the role of hepatic stellate cells in hepatic schistosomiasis progression. Groups of female CBA mice, which produce an intermediate degree of Schistosoma japonicum-induced liver fibrosis, were infected with S. japonicum, perfused at fortnightly time points and the liver tissue and contained egg granulomas examined by immunohistochemistry and cytokine and chemokine analysis using quantitative PCR. Immunohistochemistry demonstrated the presence of activated hepatic stellate cells in the periphery of egg granulomas, adjacent to fibrotic areas. Time course analysis demonstrated that the transcription of smooth muscle actin-alpha type 1 collagen, IL-4, IL-13, IL-13Ralpha2 and tissue inhibitor of metalloproteinase-1 mirrored the initial increase and subsequent down-modulation of granuloma diameter in mice. However, the transcription of monocyte chemo-attractant protein-1, Regulated upon Activation Normal T Cell Expressed and Secreted (RANTES), TNF-alpha, IFN-gamma and matrix metalloproteinase-9 paralleled the evolution of the total liver disease burden. Transforming growth factor-beta1 transcription did not appear to be of biological significance in this mouse model. Immunohistochemical analysis of human hepatic granulomas showed close association of smooth muscle actin-alpha-expressing cells with fibrosis in five available cases of end-stage (advanced) schistosomiasis japonica. We conclude that activated hepatic stellate cells play a contributory role in the granulomatous, fibrotic process induced by S. japonicum eggs, both in the murine model and in human disease.
Role of iron in hepatic fibrosis: One piece in the puzzle
Publisher: Baishideng Publishing Group Inc.
Date: 2007
Abstract: Iron is an essential element involved in various biological pathways. When present in excess within the cell, iron can be toxic due to its ability to catalyse the formation of damaging radicals, which promote cellular injury and cell death. Within the liver, iron related oxidative stress can lead to fibrosis and ultimately to cirrhosis. Here we review the role of excessive iron in the pathologies associated with various chronic diseases of the liver. We also describe the molecular mechanism by which iron contributes to the development of hepatic fibrosis.
Environmental and genetic modifiers of the progression to fibrosis and cirrhosis in hemochromatosis
Publisher: American Society of Hematology
Date: 05-2008
DOI: 10.1182/BLOOD-2007-11-122374
Abstract: Hereditary hemochromatosis is a genetic disorder of iron metabolism leading to inappropriate iron absorption and iron loading in various organs especially the liver. Despite the genetic mutation being relatively common in those of Anglo Celtic descent, cirrhosis of the liver occurs in only a small proportion of affected in iduals. The risk of hepatic fibrosis and cirrhosis relates to the degree of iron loading with threshold hepatic iron concentrations being identified from population studies. However, other environmental and possibly genetic factors appear to modify this risk. Excess alcohol consumption appears to be one of the most important cofactors with steatosis and coexistent viral infection also implicated. Genetic polymorphisms in genes associated with fibrogenesis, antioxidant activity, and inflammation have been investigated in several different forms of chronic liver disease. The variability in the expression of these genes that predispose patients with hemochromatosis to increased risk of severe liver disease is the subject of ongoing investigations. Clearly the progression of iron loading to cirrhosis marks a crucial stage in the natural history of a patient's disease and therefore therapy and prognosis. This review explores recent developments in knowledge of environmental and genetic modifiers of this process.
The nexus of iron and inflammation in hepcidin regulation: SMADs, STATs, and ECSIT
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2006
DOI: 10.1002/HEP.21526
Abstract: Hereditary hemochromatosis, characterized by iron overload in multiple organs, is one of the most common genetic disorders among Caucasians. Hepcidin, which is synthesized in the liver, plays important roles in iron overload syndromes. Here, we show that a Cre-loxP-mediated liver-specific disruption of SMAD4 results in markedly decreased hepcidin expression and accumulation of iron in many organs, which is most pronounced in liver, kidney, and pancreas. Transcript levels of genes involved in intestinal iron absorption, including Dcytb, DMT1, and ferroportin, are significantly elevated in the absence of hepcidin. We demonstrate that ectopic overexpression of SMAD4 activates the hepcidin promoter and is associated with epigenetic modification of histone H3 to a transcriptionally active form. Moreover, transcriptional activation of hepcidin is abrogated in SMAD4-deficient hepatocytes in response to iron overload, TGF-beta, BMP, or IL-6. Our study uncovers a novel role of TGF-beta/SMAD4 in regulating hepcidin expression and thus intestinal iron transport and iron homeostasis [corrected]
Transient liver elastography in unsedated control children: Impact of age and intercurrent illness
Publisher: Wiley
Date: 20-05-2016
DOI: 10.1111/JPC.13151
Abstract: Transient elastography (TE) is a rapid, non-invasive, reproducible assessment of liver fibrosis by liver stiffness measurement (LSM). Uncertainty remains regarding utility in children, unsedated and 2 years reliable results were obtained in ~80%. LSM increased with age 0-2 years (3.5 ± 0.5 kPa), 3-5 years (3.8 ± 0.3 kPa) and 6-11 years (4.1 ± 0.2 kPa) with healthy older children 12-18 years similar to adults (4.5 ± 0.2 kPa). LSM did not vary with gender (female, 4.5 ± 0.2 vs. male, 4.8 ± 0.2 kPa). Children with intercurrent, non-hepatological illnesses had higher LSM (5.2 ± 0.2 kPa (range, 2.8-11.1 kPa)) compared to healthy children ((4.1 ± 0.1 kPa, range, 2.1-6.3 kPa) P = 0.0001). TE in unsedated children is feasible from infancy but most reliable after 2 years. Intercurrent illness increases LSM hence, study context is important when interpreting results.
Signals for hepatic figrogenesis in pediatric cholestatic liver disease: review and hypothesis
Publisher: Springer Science and Business Media LLC
Date: 2004
Caveolin-1 Function in Liver Physiolocy and Disease
Publisher: Elsevier BV
Date: 10-2016
DOI: 10.1016/J.MOLMED.2016.08.007
Abstract: Caveolin-1 (CAV1), the structural protein of caveolae in the plasma membrane, has emerged as a regulator of liver function. CAV1 modulates several molecular pathways leading to the regulation of hepatic lipid accumulation, lipid and glucose metabolism, mitochondrial biology, and hepatocyte proliferation. CAV1 thus plays a crucial role in maintaining hepatic physiology during metabolic adaptation to fasting, liver steatosis, and hepatocyte proliferation associated with liver regeneration. With failure of such processes, CAV1 has been implicated in the modulation of cholestasis, hepatitis, cirrhosis, and hepatocarcinogenesis. This review discusses the latest research in CAV1 biology and related proteins, aiming to guide future endeavors that explore their role in liver physiology and disease.
Case Report: Fetal Bilateral Diaphragmatic Agenesis, Ectopic Liver and Abnormal Pancreas
Publisher: Informa UK Limited
Date: 06-2015
DOI: 10.3109/15513815.2015.1042605
Abstract: Congenital bilateral diaphragm agenesis is a very rare condition. We describe limited (abdomen only) autopsy findings of a case of bilateral diaphragm agenesis in a 27-week male fetus with unusual findings of fibrosis of the pancreatic head and ectopic liver nodules in a mass at the upper abdomen that may represent a possible diaphragm anlage. We have correlated our observations with data from experimental and embryological studies to suggest possible mechanisms for the malformations that were present and their implications for our understanding of pancreas, liver and diaphragm development in the human fetus.
Increased frequency of GNPAT p.D519G in compound HFE p.C282Y/p.H63D heterozygotes with elevated serum ferritin levels
Publisher: Elsevier BV
Date: 11-2020
Pathways of intracellular trafficking and release of ferritin by the liver in vivo: The effect of chloroquine and cytochalasin D
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-1994
Excess iron induces hepatic oxidative stress and transforming growth factor ?1 in genetic hemochromatosis
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-1997
Abstract: Genetic hemochromatosis (GH) is associated with excess iron deposition in hepatocytes, which results in progressive hepatic injury. The pathogenesis of hepatic injury in GH is poorly understood. In this study, we found enhanced oxidative stress in patients with GH, as evidenced by hepatic malondialdehyde (MDA)-protein adducts and by increased oxidatively modified serum proteins. MDA-lysine epitopes and oxidatively modified serum proteins, as well as immunoglobulin G autoantibodies against MDA-lysine epitopes, were increased in untreated GH patients and to a lesser extent in GH heterozygotes compared with normal in iduals. These markers of ongoing oxidative stress decreased with phlebotomy treatment in GH patients. In addition, TGF-beta1 colocalized with hepatic iron and MDA protein adducts in hepatocytes and sinusoidal cells of hepatic acinar zone 1 and normalized after iron removal. Our data suggest that iron overload increases both lipid peroxidation and TGF-beta1 expression, which together could promote hepatic injury and fibrogenesis.
Clinical cofactors and hepatic fibrosis in hereditary hemochromatosis: The role of diabetes mellitus
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 19-06-2012
DOI: 10.1002/HEP.25720
Abstract: The risk of hepatic fibrosis and cirrhosis in hereditary hemochromatosis relates to the degree of iron loading, but iron alone does not explain the variability in disease penetrance. This study sought to identify clinical cofactors that increase the risk of progressive liver disease. We identified 291 patients from our database who were homozygous for the C282Y mutation in HFE and had undergone a liver biopsy with quantification of hepatic iron concentration (HIC) and fibrosis staging. Data were collected from a retrospective chart review, including age, gender, alcohol consumption, medical therapy, smoking history, metabolic risk factors, mobilizable iron, and laboratory results. Male gender, excess alcohol consumption, HIC, and the presence of diabetes were independently associated with increasing fibrosis stage in multivariate analysis. Of these, the presence of diabetes showed the strongest association (odds ratio, 7.32 P = 0.03). The presence of steatosis was associated with higher fibrosis scores, but this was of borderline statistical significance. Risk factors for hepatic steatosis were male gender, impaired glucose tolerance, and increased body mass index. The presence of diabetes was associated with more severe hepatic fibrosis independent of iron loading, male gender, and alcohol consumption. The mechanism for this association is unknown and deserves further evaluation however, it is possible that diabetes produces an additional hepatic oxidative injury from hyperglycemia. Thus, management of such cofactors in patients with hemochromatosis is important to reduce the risk of liver injury and fibrosis.
The Role of Sonic Hedgehog in Human Holoprosencephaly and Short-Rib Polydactyly Syndromes
Publisher: MDPI AG
Date: 12-09-2021
DOI: 10.3390/IJMS22189854
Abstract: The Hedgehog (HH) signalling pathway is one of the major pathways controlling cell differentiation and proliferation during human development. This pathway is complex, with HH function influenced by inhibitors, promotors, interactions with other signalling pathways, and non-genetic and cellular factors. Many aspects of this pathway are not yet clarified. The main features of Sonic Hedgehog (SHH) signalling are discussed in relation to its function in human development. The possible role of SHH will be considered using ex les of holoprosencephaly and short-rib polydactyly (SRP) syndromes. In these syndromes, there is wide variability in phenotype even with the same genetic mutation, so that other factors must influence the outcome. SHH mutations were the first identified genetic causes of holoprosencephaly, but many other genes and environmental factors can cause malformations in the holoprosencephaly spectrum. Many patients with SRP have genetic defects affecting primary cilia, structures found on most mammalian cells which are thought to be necessary for canonical HH signal transduction. Although SHH signalling is affected in both these genetic conditions, there is little overlap in phenotype. Possible explanations will be canvassed, using data from published human and animal studies. Implications for the understanding of SHH signalling in humans will be discussed.
High Parasite Burdens Cause Liver Damage in Mice following Plasmodium berghei ANKA Infection Independently of CD8+T Cell-Mediated Immune Pathology
Publisher: American Society for Microbiology
Date: 05-2011
DOI: 10.1128/IAI.01210-10
Abstract: Infection of C57BL/6 mice with Plasmodium berghei ANKA induces a fatal neurological disease commonly referred to as experimental cerebral malaria. The onset of neurological symptoms and mortality depend on pathogenic CD8 + T cells and elevated parasite burdens in the brain. Here we provide clear evidence of liver damage in this model, which precedes and is independent of the onset of neurological symptoms. Large numbers of parasite-specific CD8 + T cells accumulated in the liver following P. berghei ANKA infection. However, systemic depletion of these cells at various times during infection, while preventing neurological symptoms, failed to protect against liver damage or ameliorate it once established. In contrast, rapid, drug-mediated removal of parasites prevented hepatic injury if administered early and quickly resolved liver damage if administered after the onset of clinical symptoms. These data indicate that CD8 + T cell-mediated immune pathology occurs in the brain but not the liver, while parasite-dependent pathology occurs in both organs during P. berghei ANKA infection. Therefore, we show that P. berghei ANKA infection of C57BL/6 mice is a multiorgan disease driven by the accumulation of parasites, which is also characterized by organ-specific CD8 + T cell-mediated pathology.
Additive‐Free Nb2O5−TiO2 Hybrid Anode towards Low‐Cost and Safe Lithium‐Ion Batteries: A Green Electrode Material Produced in an Environmentally Friendly Process
Publisher: Wiley
Date: 20-11-2018
Anti-chemokine therapy for the treatment of hepatic fibrosis: An attractive approach
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 26-06-2011
DOI: 10.1002/HEP.24353
Detection of HFE Haemochromatosis in the clinic and community using standard erythrocyte tests
Publisher: Elsevier BV
Date: 02-2019
DOI: 10.1016/J.BCMD.2018.10.003
Abstract: Detection of HFE Haemochromatosis (HH) is challenging in the absence of clinical features. HH subjects have elevated erythrocyte parameters compared to those without HH, but it remains unclear how this could be applied in clinical practice. Thus, we determined the sensitivity, specificity and clinical utility of erythrocyte parameters in 144 HH subjects with (n = 122) or without (n = 22) clinical and/or biochemical expression of iron overload, 1844 general population controls, and 700 chronic disease subjects. For both expressing and non-expressing HH subjects, the mean pre- and post-phlebotomy values of mean cell volume (MCV) and mean cell haemoglobin (MCH) were always significantly higher when compared to all other groups and demonstrated excellent diagnostic utility for detection of HH in men and women (AUROC 0.83-0.9 maximal sensitivity and specificity 82% and 78%) using cut-off values for MCV >91 fL or MCH >31 pg, respectively. Between 34 and 62% of all HH subjects would be detected, and 94 fL or 32.2 pg, respectively, were evaluated.
Live imaging of collagen deposition during experimental hepatic schistosomiasis and recovery: a view on a dynamic process
Publisher: Elsevier BV
Date: 02-2019
DOI: 10.1038/S41374-018-0154-0
Abstract: Hepatic fibrosis is the central cause of chronic clinical pathology resulting from infection by the blood flukes Schistosoma japonicum or S. mansoni. Much has been elucidated regarding the molecular, cellular and immunological responses that correspond to the formation of the granulomatous response to trapped schistosome eggs. A central feature of this Th2 response is the deposition of collagen around the periphery of the granuloma. To date, traditional histology and transcriptional methods have been used to quantify the deposition of collagen and to monitor the formation of the hepatic granuloma during experimental animal models of schistosomiasis. We have investigated the dynamic nature of granuloma formation through the use of a transgenic mouse model (B6.Collagen 1(A) luciferase mice (B6.Coll 1A-luc
Hepatic macrophages promote the neutrophil-dependent resolution of fibrosis in repairing cholestatic rat livers
Publisher: Elsevier BV
Date: 05-2008
DOI: 10.1016/J.SURG.2008.01.008
Abstract: Cholestatic liver injury from extrahepatic biliary obstruction is well characterized by inflammatory and fibrogenic mechanisms. Little is known, however, about mechanisms required to reverse injury and effect liver repair. We sought to determine the cellular and molecular requirements for repair after biliary decompression, focusing on the role of hepatic macrophages in regulating inflammation and matrix resolution. Male Sprague-Dawley rats underwent bile duct obstruction for 7 days followed by ductular decompression. Rats were treated with gadolinium chloride (GdCl(3)) to deplete the macrophage populations 24 or 48 hours before decompression. Liver tissue obtained at the time of decompression or after 2 days of repair was processed for morphometric analysis, immunohistochemistry, quantitative RT-PCR and in situ hybridization. GdCl(3) treatment for either 24 or 48 hours before decompression reduced the numbers of ED2(+) Kupffer cells and ED1(+) inflammatory macrophages in obstructed livers only 48 hours of pretreatment, however, reduced the neutrophil counts. Furthermore, 48-hour GdCl(3) pretreatment blocked matrix degradation. Quantitative polymerase chain reaction demonstrated decreased cytokine-induced neutrophil chemoattractant-1 (CINC-1 CXCL1) and intercellular adhesion molecule-1 mRNA expression after GdCl(3) treatment and the elimination of hepatic macrophages. Immunohistochemistry and in situ hybridization revealed that neutrophils and CINC-1 mRNA localize within regions of fibrotic activity during both injury and repair. We conclude that the macrophage population is not directly involved in fibrotic liver repair. Rather, hepatic macrophages regulate the influx of neutrophils, which may play a direct role in matrix degradation.
Clinical practice guidelines on hemochromatosis: Asian Pacific Association for the Study of the Liver
Publisher: Springer Science and Business Media LLC
Date: 17-04-2023
Global multi-stakeholder endorsement of the MAFLD definition
Publisher: Elsevier BV
Date: 05-2022
HPP1: A transmembrane protein-encoding gene commonly methylated in colorectal polyps and cancers
Publisher: Proceedings of the National Academy of Sciences
Date: 19-12-2001
Abstract: Adenomas are the precursors of most colorectal cancers. Hyperplastic polyps have been linked to the subset of colorectal cancers showing DNA microsatellite instability, but little is known of their underlying genetic etiology. Using a strategy that isolates differentially methylated sequences from hyperplastic polyps and normal mucosa, we identified a 370-bp sequence containing the 5′ untranslated region and the first exon of a gene that we have called HPP1. Rapid lification of cDNA ends was used to isolate HPP1 from normal mucosa. Using reverse transcription–PCR, HPP1 was expressed in 28 of 30 (93%) normal colonic s les but in only seven of 30 (23%) colorectal cancers ( P 0.001). The 5′ region of HPP1 included a CpG island containing 49 CpG sites, of which 96% were found to be methylated by bisulfite sequencing of DNA from colonic tumor s les. By COBRA analysis, methylation was detected in six of nine (66%) adenomas, 17 of 27 (63%) hyperplastic polyps, and 46 of 55 (84%) colorectal cancers. There was an inverse relationship between methylation level and mRNA expression in cancers ( r = −0.67 P 0.001), and 5-aza-2-deoxycytidine treatment restored HPP1 expression in two colorectal cancer cell lines. In situ hybridization of HPP1 indicated that expression occurs in epithelial and stromal elements in normal mucosa but is silenced in both cell types in early colonic neoplasia . HPP1 is predicted to encode a transmembrane protein containing follistatin and epidermal growth factor-like domains. Silencing of HPP1 by methylation may increase the probability of neoplastic transformation.
Single Nucleus RNA Sequencing of Pre-Malignant Liver Reveals Disease-Associated Hepatocyte State with HCC Prognostic Potential
Publisher: Cold Spring Harbor Laboratory
Date: 27-03-2022
DOI: 10.1101/2022.03.25.485695
Abstract: Current approaches to stage chronic liver diseases have limited utility to directly predict liver cancer risk. Here, we employed single nucleus RNA sequencing (snRNA-seq) to characterize the cellular microenvironment of healthy and chronically injured pre-malignant livers using two distinct mouse models. Analysis of 40,748 hepatic nuclei unraveled a previously uncharacterized disease-associated hepatocyte transcriptional state (daHep). These cells were absent in healthy livers, but were increasingly prevalent as chronic liver disease progressed towards hepatocarcinogenesis. Gene expression deconvolution of 1,439 human liver transcriptomes from publicly available datasets revealed that daHep frequencies highly correlate with current histopathological liver disease staging systems. Importantly, we show that high daHep levels precede carcinogenesis in mice and humans and predict a higher risk of hepatocellular carcinoma (HCC) development. This novel transcriptional signature with diagnostic and, more importantly, prognostic significance has the potential to change the way chronic liver disease patients are staged, surveilled and risk-stratified.
A novel mutation in ferroportin1 is associated with haemochromatosis in a Solomon Islands patient
Publisher: BMJ
Date: 08-2003
Abstract: A severe form of iron overload with the clinicopathological features of haemochromatosis inherited in an autosomal dominant manner has been described in the Solomon Islands. The genetic basis of the disorder has not been identified. The disorder has similarities to type 4 haemochromatosis, which is caused by mutations in ferroportin1. The aims of this study were to identify the genetic basis of iron overload in a patient from the Solomon Islands. Genomic DNA was isolated from peripheral blood leucocytes of a Solomon Islands man with severe iron overload. The entire coding region and splice sites of the ferroportin1 gene was sequenced. A novel missense mutation (431A>C N144T) was identified in exon 5 of the ferroportin1 gene. A novel restriction endonuclease based assay which identifies both the N144T and N144H mutations was developed which will simplify the diagnosis and screening of patients for iron overload in the Solomon Islands and other populations. This is the first identified mutation associated with haemochromatosis in the Solomon Islands population.
Elevated serum type IV collagen: a sensitive indicator of the presence of cirrhosis in haemochromatosis
Publisher: Elsevier BV
Date: 07-1999
DOI: 10.1016/S0168-8278(99)80162-7
Abstract: Hereditary haemochromatosis can now be diagnosed by genetic testing, although determining the presence or absence of cirrhosis remains crucial to patient management. While many studies have investigated the utility of various serum markers of cirrhosis in chronic liver diseases, few have examined specifically patients with hereditary haemochromatosis. The aim of this study was to assess the utility of serum type IV collagen and serum laminin in diagnosing hepatic fibrosis and cirrhosis in patients with hereditary haemochromatosis. The study group consisted of 42 patients with hereditary haemochromatosis and 19 Caucasian controls. Serum type IV collagen, laminin, matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of metalloproteinase (TIMP-1) concentrations were measured by enzyme-linked immunosorbant assay in serum from patients with haemochromatosis and control subjects. Liver biopsies from patients with haemochromatosis were graded for fibrosis and correlated with serum markers of hepatic fibrosis. Serum type IV collagen concentration was significantly increased in haemochromatosis patients compared to controls (130+/-79 ng/ml vs 81 +/- 17 ng/ml, p<0.05) and was significantly correlated with both the grade of histological fibrosis (r=0.67, p<0.0001) and serum MMP-2 levels (r=0.42, p 115 ng/ml (mean+2 SD of controls) was 100% sensitive and 69% specific in detecting severe (grade 3) fibrosis and cirrhosis. The sensitivity results of serum laminin and TIMP-1 were 11% and 56% respectively. Elevated serum type IV collagen is a sensitive indicator of the presence of severe fibrosis and cirrhosis in patients with haemochromatosis. Useful markers of hepatic fibrosis in other chronic liver diseases may not be applicable to haemochromatosis.
The ancestral haplotype markers HLA -A3 and B7 do not influence the likelihood of advanced hepatic fibrosis or cirrhosis in HFE hemochromatosis
Publisher: Springer Science and Business Media LLC
Date: 13-05-2023
DOI: 10.1038/S41598-023-35028-4
Abstract: Advanced hepatic fibrosis occurs in up to 25% of in iduals with C282Y homozygous hemochromatosis. Our aim was to determine whether human leukocyte antigen (HLA)-A3 and B7 alleles act as genetic modifiers of the likelihood of advanced hepatic fibrosis. Between 1972 and 2013, 133 HFE C282Y homozygous in iduals underwent clinical and biochemical evaluation, HLA typing, liver biopsy for fibrosis staging and phlebotomy treatment. Hepatic fibrosis was graded according to Scheuer as F0–2 (low grade hepatic fibrosis), F3–4 (advanced hepatic fibrosis), and F4 cirrhosis. We analysed associations between the severity of fibrosis and HLA-A3 homozygosity, heterozygosity or absence, with or without the presence of HLA-B7 using categorical analysis. The mean age of HLA-A3 homozygotes (n = 24), heterozygotes (n = 65) and HLA-A3 null in iduals (n = 44) was 40 years. There were no significant differences between the groups for mean(± SEM) serum ferritin levels (1320 ± 296, 1217 ± 124, 1348 ± 188 $$\\upmu$$ μ g/L), hepatic iron concentration (178 ± 26, 213 ± 22, 199 ± 29 $$\\upmu$$ μ mol/g), mobilizable iron stores (9.9 ± 1.5, 9.5 ± 1.5, 11.5 ± 1.7 g iron removed via phlebotomy), frequency of advanced hepatic fibrosis (5/24[12%], 13/63[19%], 10/42[19%]) or cirrhosis (3/24[21%], 12/63[21%], 4/42[24%]), respectively. The presence or absence of HLA-B7 did not influence the outcome. Thus, HLA-A3 and HLA-B7 alleles are not associated with the risk of advanced hepatic fibrosis or cirrhosis in C282Y hemochromatosis.
Murine precision-cut liver slices as an ex vivo model of liver biology
Publisher: MyJove Corporation
Date: 14-03-2020
DOI: 10.3791/60992
Single-nucleus RNA sequencing of pre-malignant liver reveals disease-associated hepatocyte state with HCC prognostic potential
Publisher: Elsevier BV
Date: 05-2023
Differential regulation of ferritin H and L subunit mRNA during inflammation and long‐term iron overload
Publisher: Wiley
Date: 02-1993
DOI: 10.1111/J.1440-1746.1993.TB01170.X
Abstract: Iron overload, such as occurs in the genetic disease haemochromatosis, leads to synthesis of ferritin containing an increased proportion of L subunits. Inflammation also leads to clinically important increases in ferritin synthesis but the predominant subunit involved is unclear. Elevation of serum ferritin concentration during the acute phase response confounds its use as an indicator of body iron stores and identification of the major subunit involved may allow distinction of the ferritin associated with inflammation from the synthesized during iron overload. The present study examined H and L ferritin subunit mRNA levels in rats with: (i) longstanding iron overload, both parenteral and oral, in which changes should be maximal and stable and (ii) inflammation of 24 and 48 h duration. A two-fold increase in L mRNA level was found in both groups of iron loaded animals while H mRNA level was unchanged. This finding would account for the observed preponderance of L subunits in ferritin during iron overload. During the course of inflammation there was a progressive decrease in L mRNA level in the liver but not the spleen. H mRNA relative to total RNA level was unchanged in both liver and spleen. It is concluded that the differential regulation of the two ferritin subunits in response to different stimuli and in different tissues occurs at the level of alteration in mRNA concentration.
Genetics of Hemochromatosis
Publisher: Annual Reviews
Date: 02-1999
DOI: 10.1146/ANNUREV.MED.50.1.87
Abstract: Hereditary hemochromatosis (HHC) is a common autosomal recessive disorder of iron metabolism that results in progressive iron overload and can be fatal if untreated. The hemochromatosis gene (HFE) was identified by positional cloning in 1996. Two missense mutations have been described in HFE. The majority of HHC patients are homozygous for a cysteine-to-tyrosine substitution (C282Y) however, a small number are homozygous for a histidine-to-aspartic-acid substitution (H63D) or are heterozygous for both of these mutations. Mechanisms by which C282Y and H63D may disrupt the normal functioning of HFE have been suggested, but the role of HFE in the process of normal iron metabolism has yet to be clearly defined.
Pathogenesis of Viral Hepatitis-Induced Chronic Liver Disease: Role of Extracellular Vesicles
Publisher: Frontiers Media SA
Date: 10-11-2020
Schistosome-Induced Fibrotic Disease: The Role of Hepatic Stellate Cells
Publisher: Elsevier BV
Date: 06-2018
Abstract: Hepatic fibrosis is a common pathology in various liver diseases. Hepatic stellate cells (HSCs) are the main cell type responsible for collagen deposition and fibrosis formation in the liver. Schistosomiasis is characterised by granulomatous fibrosis around parasite eggs trapped within the liver and other host tissues. This response is facilitated by the recruitment of immune cells and the activation of HSCs. The interactions between HSCs and schistosome eggs are complex and erse, and a better understanding of these interactions could lead to improved resolution of fibrotic liver disease, including that associated with schistosomiasis. Here, we discuss recent advances in HSC biology and the role of HSCs in hepatic schistosomiasis.
Diagnosing schistosomiasis-induced liver morbidity: implications for global control
Publisher: Elsevier BV
Date: 2017
DOI: 10.1016/J.IJID.2016.10.024
Abstract: Subclinical morbidity due to schistosomiasis was evaluated in 565 patients, and the enhanced liver fibrosis (ELF) test was assessed for the first time as a potential screening tool for disease. The prevalence and intensity of infection were determined by Kato-Katz thick smear stool examination at baseline and 2 years after curative treatment. The degree of hepatic fibrosis was assessed by ultrasound. Non-invasive serum biomarkers of hepatic fibrosis were also evaluated. The baseline human prevalence and infection intensity were found to be moderately high at 34% and 123 eggs per gram, respectively. However, hepatic parenchymal fibrosis occurred in 50% of subjects, with grade II fibrosis in 19% and grade III in 6%. The ELF score and higher serum levels of tissue inhibitor of metalloproteinase 1 (TIMP-1) and hyaluronic acid (HA) correlated with the grade of liver fibrosis. The findings of this study demonstrated that praziquantel treatment had a short-term impact on both the prevalence and intensity of infection, but less of an impact on established morbidity. Higher TIMP-1 and HA serum levels, and an ELF cut-off score of 8 were found to be correlated with the grade of liver fibrosis these values may, therefore, assist physicians in identifying in iduals at greater risk of disease.
A membrane vesicle-based dual vaccine against melanoma and Lewis lung carcinoma
Publisher: Elsevier BV
Date: 09-2012
DOI: 10.1016/J.BIOMATERIALS.2012.05.034
Abstract: In the past few years, cell-derived membrane vesicle-based tumor vaccines have been considered as valuable new tools for cancer immunotherapy. Despite promising results in cancer clinical trails, an improved method is urgently needed for high efficiency tumor vaccines for a broad spectrum of tumors. Here we developed a single membrane vesicle-based vaccine, which is active in repressing both melanoma (B16) and Lewis lung carcinoma (LLC) tumor growth. By using the intrinsic function of dendritic cells in the processing and presentation of antigens, we generated dendritic cell (DC)-derived membrane vesicles (DC-mv) bearing tumor antigens from both B16 and LLC cells. Vaccination with this DC-mv-based dual vaccine induced specific cytotoxic T lymphocytes (CTL)-dependent tumor rejection and suppressed the growth of both types of tumor xenografts in mice. In addition, induction of CTL by this vaccine resulted in cross-protection responses and consequently enabled significant enhanced anti-tumor effects, indicating the synergistic anti-tumor activity. Our study suggests that the DC-mv-based vaccine holds great potential as a highly effective, versatile, cell-free vaccine for inhibition of multiple types of tumor growth.
Identification and Characterization of the Hepatic Stellate Cell Transferrin Receptor
Publisher: Elsevier BV
Date: 05-2003
An Ex Vivo Model for Studying Hepatic Schistosomiasis and the Effect of Released Protein from Dying Eggs
Publisher: Public Library of Science (PLoS)
Date: 12-05-2015
The Murine Choline-Deficient, Ethionine-Supplemented (CDE) Diet Model of Chronic Liver Injury
Publisher: MyJove Corporation
Date: 21-10-2017
DOI: 10.3791/56138
Serum markers of hepatic fibrogenesis in cystic fibrosis liver disease
Publisher: Elsevier BV
Date: 10-2004
DOI: 10.1016/J.JHEP.2004.06.032
Abstract: Hepatic fibrosis contributes to adverse outcome in cystic fibrosis (CF). Early detection of CF liver disease (CFLD) may identify patients at risk of significant complications. To evaluate the utility of serum markers to detect hepatic fibrosis in children with CFLD vs. CF patients without liver disease (CFnoLD) and controls. Sera from 36 CFLD, 30 CFnoLD and 39 controls were assessed for tissue inhibitor of matrix metalloproteinase (MMP) (TIMP)-1, collagen (CL)-IV, MMP-2, hyaluronic acid (HA) and prolyl hydroxylase (PH) by enzyme immunoassay and were correlated with hepatic fibrosis score in CFLD. TIMP-1, PH and CL-IV were increased in CFLD vs. CFnoLD and controls. Fibrosis score was negatively correlated with TIMP-1 (r=-0.34, P=0.06) and PH (r=-0.48, P=0.008). Receiver-operating characteristics analysis showed CL-IV (AUC 0.785, P<0.0001) and TIMP-1 (AUC 0.765, P<0.0001) differentiated CFLD from CFnoLD and controls, while PH (AUC 0.814, P<0.0001) predicted early fibrogenesis. Diagnostic accuracy improved using logistic regression combining (i) CL-IV, TIMP-1, PH to identify CFLD (AUC 0.831, P<0.0001) and (ii) TIMP-1, PH to identify CFLD patients with no fibrosis (AUC 0.852, P<0.02). Elevated TIMP-1, CL-IV, PH may be indicators of hepatic fibrogenesis in CF. Increased TIMP-1, PH may be early markers of CFLD.
MicroRNA Sequencing Identifies a Serum MicroRNA Panel, Which Combined With Aspartate Aminotransferase to Platelet Ratio Index Can Detect and Monitor Liver Disease in Pediatric Cystic Fibrosis
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 15-11-2018
DOI: 10.1002/HEP.30156
Abstract: Cystic fibrosis (CF)‐associated liver disease (CFLD) is a hepatobiliary complication of CF. Current diagnostic modalities rely on nonspecific assessments, whereas liver biopsy is the gold standard to assess severity of fibrosis. MicroRNAs (miRNAs) regulate liver disease pathogenesis and are proposed as diagnostic biomarkers. We investigated the combined use of serum miRNAs and aspartate aminotransferase (AST) to platelet ratio (APRI) to diagnose and assess CFLD severity. This was a cross‐sectional cohort study of the circulatory miRNA signature of 124 children grouped by clinical, biochemical, and imaging assessments as follows: CFLD (n = 44), CF patients with no evidence of liver disease (CFnoLD n = 40), and healthy controls (n = 40). Serum miRNAs were analyzed using miRNA sequencing (miRNA‐Seq). Selected differentially expressed serum miRNA candidates were further validated by qRT‐PCR and statistical analysis performed to evaluate utility to predict CFLD and fibrosis severity validated by liver biopsy, alone or in combination with APRI. Serum miR‐122‐5p, miR‐365a‐3p, and miR‐34a‐5p levels were elevated in CFLD compared to CFnoLD, whereas miR‐142‐3p and let‐7g‐5p were down‐regulated in CFLD compared to CFnoLD. Logistic regression analysis combining miR‐365a‐3p, miR‐142‐3p, and let‐7g‐5p with APRI showed 21 times greater odds of accurately predicting liver disease in CF with an area under the receiver operating characteristics curve (AUROC) = 0.91 (sensitivity = 83%, specificity = 92% P 0.0001). Expression levels of serum miR‐18a‐5p were correlated with increasing hepatic fibrosis (HF) stage in CFLD (r s = 0.56 P 0.0001), showing good diagnostic accuracy for distinguishing severe (F3‐F4) from mild/moderate fibrosis (F0‐F2). A unit increase of miR‐18a‐5p showed a 7‐fold increased odds of having severe fibrosis with an AUROC = 0.82 (sensitivity = 93%, specificity = 73% P = 0.004), indicating its potential to predict fibrosis severity. Conclusion: We identified a distinct circulatory miRNA profile in pediatric CFLD with potential to accurately discriminate liver disease and fibrosis severity in children with CF.
Hepatic Iron Deposition Does Not Predict Extrahepatic Iron Loading in Mouse Models of Hereditary Hemochromatosis
Publisher: Elsevier BV
Date: 10-2012
DOI: 10.1016/J.AJPATH.2012.06.025
Abstract: Hereditary hemochromatosis is characterized by tissue iron loading and associated organ damage. However, the phenotype can be highly variable. The relationship between iron loading of different organs and the temporal nature of its deposition is still not well understood. We examined the progression of tissue iron loading in three mouse models to advance our understanding of the natural history of iron deposition in hereditary hemochromatosis. Wild-type, Hfe(-/-), Tfr2(-/-), and Hfe(-/-)/Tfr2(-/-) mice were analyzed at 3, 5, 10, 26, and 52 weeks, respectively. Hepatic, splenic, cardiac, and pancreatic iron concentrations were determined. Expression of both iron-regulatory and fibrosis genes was determined by quantitative real-time PCR in livers and hearts of 52-week-old mice. In all models, hepatic iron increased rapidly, plateauing before 10 weeks at different levels, depending on the genotype. Iron deposition in the pancreas and heart occurred after maximal iron loading of the liver was reached and was most marked in the Hfe(-/-)/Tfr2(-/-) mice. Although a significant positive correlation was identified between pancreatic and cardiac iron in all models at 52 weeks, there was no correlation between hepatic and either pancreatic or cardiac iron. There is variability in the timing and extent of tissue iron loading within a genotype, suggesting that hepatic iron levels in hereditary hemochromatosis may not accurately predict the iron content of other organs.
TWEAK/Fn14 Signalling Regulates the Tissue Microenvironment in Chronic Pancreatitis
Publisher: MDPI AG
Date: 16-03-2023
Abstract: Chronic pancreatitis increases the risk of developing pancreatic cancer through the upregulation of pathways favouring proliferation, fibrosis, and sustained inflammation. We established in previous studies that the ligand tumour necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) signals through its cognate receptor fibroblast growth factor-inducible 14 (Fn14) to regulate these underlying cellular processes in the chronic liver injury niche. However, the role of the TWEAK/Fn14 signalling pathway in pancreatic disease is entirely unknown. An analysis of publicly available datasets demonstrated that the TWEAK receptor Fn14 is upregulated in pancreatitis and pancreatic adenocarcinoma, with single cell RNA sequencing revealing pancreatic ductal cells as the main Fn14 producers. We then used choline-deficient, ethionine-supplemented (CDE) diet feeding of wildtype C57BL/6J and Fn14 knockout littermates to (a) confirm CDE treatment as a suitable model of chronic pancreatitis and (b) to investigate the role of the TWEAK/Fn14 signalling pathway in pancreatic ductal proliferation, as well as fibrotic and inflammatory cell dynamics. Our time course data obtained at three days, three months, and six months of CDE treatment reveal that a lack of TWEAK/Fn14 signalling significantly inhibits the establishment and progression of the tissue microenvironment in CDE-induced chronic pancreatitis, thus proposing the TWEAK/Fn14 pathway as a novel therapeutic target.
Reply
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 15-03-2016
DOI: 10.1002/HEP.28479
Extracellular Vesicles in the Adaptive Process of Prostate Cancer during Inhibition of Androgen Receptor Signaling by Enzalutamide
Publisher: Wiley
Date: 12-2017
Abstract: Current treatments for advanced prostate cancer focus on inhibition of the androgen receptor (AR) by androgen deprivation therapy (ADT). However, complex interactions mediated by tumor suppressors, oncogenes, aberrations of AR expression, or de novo androgen production have been shown to induce the adaptive response of prostate cancer, leading to the development of castration resistant prostate cancer. In this study, we report the effects of AR antagonist, enzalutamide on the protein contents of extracellular vesicles (EVs). EVs mediate cell-to-cell communication and increasing evidence shows the role of EVs in promoting cancer survival and metastasis. We found that treatment with enzalutamide alters the secretion of EVs, one of which is a plasma membrane calcium pump, ATP2B1/PMCA ATPase, as an AR-regulated EV protein. We highlight the networks of interactions between AR, Ca
Hemochromatosis
Publisher: Massachusetts Medical Society
Date: 08-12-2022
Lung and liver growth and retinoic acid status in human fetuses with congenital diaphragmatic hernia
Publisher: Elsevier BV
Date: 2018
DOI: 10.1016/J.EARLHUMDEV.2017.10.005
Abstract: Abnormal retinoic acid (RA) signalling is considered a major cause of congenital diaphragmatic hernia (CDH). Pulmonary hypoplasia and pulmonary hypertension are the major causes of morbidity and mortality in infants born with CDH. Experimental studies in animals have found that RA signalling is involved in lung and liver development, but animal models of CDH do not directly correlate with CDH in human fetuses. This study investigated if RA status is also linked to lung and liver growth in human fetuses with CDH. Hepatic stellate cells (HSC) in autopsy human fetal liver tissue were identified using cRBP-1 immunohistochemistry and the numbers of HSC manually counted. In mammals, RA is principally stored in HSC complexed to cRBP-1 and therefore cRBP-1 The number of cRBP-1 Fetal RA stores, reflected in the number of cRBP-1
Ferritin functions as a proinflammatory cytokine via iron-independent protein kinase C zeta/nuclear factor kappaB-regulated signaling in rat hepatic stellate cells
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-11-2008
DOI: 10.1002/HEP.22716
Effect of protein kinase C activation and inhibition on rat hepatic stellate cell activation
Publisher: Springer Science and Business Media LLC
Date: 2003
Abstract: Protein kinase C (PKC) may play a role in the intracellular signaling pathways responsible for transforming hepatic stellate cells into myofibroblasts. This study examined the effects of inhibitors and activators of PKC on hepatic stellate cell activation. Stellate cells isolated from normal rats were incubated with either 10(-5) M chelerythrine, 10(-7) M bisindolylmaleimide I hydrochloride (BIM), or 10(-6) M staurosporine (PKC inhibitors), or 10(-7) M phorbol myristate acetate (PMA) or 10(-6) M thymeleatoxin (PKC activators). Chelerythrine suppressed alpha-smooth muscle actin expression and proliferation by 49% and 33%, respectively. BIM inhibited alpha-smooth muscle actin expression by 60%, but had no significant effect on proliferation. Staurosporine decreased proliferation by 86% and completely prevented alpha-smooth muscle actin expression. PKC activators had ergent effects on proliferation and alpha-smooth muscle actin expression. PMA and thymeleatoxin caused a 2.8- to 3.2-fold increase in proliferation, while suppressing alpha-smooth muscle actin expression by 50-70%. The demonstration that hepatic stellate cell activation can be suppressed by PKC inhibitors suggests a role for PKC in the regulation of hepatic stellate cell activation.
Effect of vitamin E supplementation on hepatic fibrogenesis in chronic dietary iron overload
Publisher: American Physiological Society
Date: 1997
DOI: 10.1152/AJPGI.1997.272.1.G116
Abstract: It has been suggested that lipid peroxidation plays an important role in hepatic fibrogenesis resulting from chronic iron overload. Vitamin E is an important lipid-soluble antioxidant that has been shown to be decreased in patients with hereditary hemochromatosis and in experimental iron overload. The aim of this study was to determine the effects of vitamin E supplementation on hepatic lipid peroxidation and fibrogenesis in an animal model of chronic iron overload. Rats were fed the following diets for 4, 8, or 14 mo: standard laboratory diet (control), diet with supplemental vitamin E (200 IU/kg, control + E), diet with carbonyl iron (Fe), and diet with carbonyl iron supplemented with vitamin E (200 IU/kg. Fe + E). Iron loading resulted in significant decreases in hepatic and plasma vitamin E levels at all time points, which were overcome by vitamin E supplementation. Thiobarbituric acid-reactive substances (an index of lipid peroxidation) were increased three- to fivefold in the iron-loaded livers supplementation with vitamin E reduced these levels by at least 50% at all time points. Hepatic hydroxyproline levels were increased twofold by iron loading. Vitamin E did not affect hydroxyproline content at 4 or 8 mo but caused an 18% reduction at 14 mo in iron-loaded livers. At 8 and 14 mo, vitamin E decreased the number of alpha-smooth muscle actin-positive stellate cells in iron-loaded livers. These results demonstrate a dissociation between lipid peroxidation and collagen production and suggest that the profibrogenic action of iron in this model is mediated through effects which cannot be completely suppressed by vitamin E.
Alcohol and the Pancreas
Publisher: Wiley
Date: 05-2001
Is HFE involved in increased hepcidin expression and hypoferremia in inflammation and anemia of chronic disease?
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2005
DOI: 10.1002/HEP.20652
Cystic fibrosis-cirrhosis, portal hypertension, and liver biopsy: Reply
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2011
DOI: 10.1002/HEP.24212
Differential expression of chemokine and matrix re-modelling genes is associated with contrasting schistosome-induced hepatopathology in murine models
Publisher: Public Library of Science (PLoS)
Date: 07-06-2011
Accuracy of Transient Elastography Data Combined With APRI in Detection and Staging of Liver Disease in Pediatric Patients With Cystic Fibrosis
Publisher: Elsevier BV
Date: 11-2019
DOI: 10.1016/J.CGH.2019.03.015
Abstract: Liver disease develops in 15%-72% of patients with cystic fibrosis, and 5%-10% develop cirrhosis or portal hypertension, usually during childhood. Transient elastography (TE) is a noninvasive method to measure liver stiffness. We aimed to validate its accuracy in detection of liver disease and assessment of fibrosis in children with cystic fibrosis. We performed a cross-sectional study to evaluate the accuracy of TE in analysis of liver disease in 160 consecutive children who presented with cystic fibrosis (9.0 ± 0.4 years old, 53% male) at a tertiary referral pediatric center in Australia, from 2011 through 2016. Patients were classified as having cystic fibrosis-associated liver disease (CFLD) or cystic fibrosis without liver disease (CFnoLD) based on clinical, biochemical, and imaging features. Fibrosis severity was determined from histologic analysis of dual-pass liver biopsies from children with CFLD, as the reference standard. Data from healthy children without cystic fibrosis (n = 64, controls) were obtained from a separate study. Liver stiffness measurements (LSMs) were made by Fibroscan analysis, using the inter-quartile range/median ≤30% of 10 valid measurements. Children with macronodularity or portal hypertension with heterogeneous changes on ultrasound without available biopsy were assigned to the category of stage F3-F4 fibrosis. LSM was made reliably in 86% of children accuracy increased with age. LSMs were significantly higher in children with CFLD (10.7 ± 2.4 kPa, n = 33) than with CFnoLD (4.6 ± 0.1 kPa, n = 105) (P < .0001) or controls (4.1 ± 0.1kPa) (P < .0001) LSMs were higher in children with CFnoLD than controls (P < .05). At a cut-off value of 5.55kPa, LSM identified children with CFLD with an area under the receiver operating characteristic (AUROC) curve of 0.82, 70% sensitivity, and 82% specificity (P < .0001). Classification and regression tree models that combined LSM and aspartate aminotransferase to platelet ratio index (APRI) identified children with CFLD with an AUROC curve of 0.89, 87% sensitivity, and 74% specificity (odds ratio, 18.6). LSMs correlated with fibrosis stage in patients with CFLD (r = 0.67, P = .0001). A cut-off value of 8.7kPa differentiated patients with stage F3-F4 fibrosis from patients with stage F1-F2 fibrosis (AUROC, 0.87 75% sensitivity 100% specificity, P=.0002). The combination of LSMs and APRI improved the differentiation of patients with F3-F4 fibrosis vs F1-F2 fibrosis (AUROC, 0.92 83% sensitivity and 100% specificity (P < .01). LSMs made by TE accurately detect liver disease in children with cystic fibrosis diagnostic accuracy increases when LSMs are combined with APRI. LSMs also differentiate between children with cystic fibrosis with mild-moderate fibrosis vs advanced fibrosis.
Reduced mortality due to phlebotomy in moderately iron-loaded HFE haemochromatosis? The need for clinical trials
Publisher: Elsevier BV
Date: 07-2015
Rat liver ferritin selectively inhibits expression of alpha-smooth muscle actin in cultured rat lipocytes
Publisher: American Physiological Society
Date: 02-1996
DOI: 10.1152/AJPGI.1996.270.2.G370
Abstract: The role of ferritin in lipocyte activation is unknown. This study examined the effect of rat liver ferritin (RLF), human recombinant H-ferritin (HrHF), human recombinant L-ferritin (HrLF), apo-ferritin (apo-RLF), and hemin on lipocyte activation. Lipocytes were cultured on uncoated plastic and were incubated with these agents for 7 days, at concentrations ranging from 10(-14) to 10(-7) M (0.5 to 50 microM for hemin). Collagen/noncollagen protein production and lipocyte proliferation were determined by [3H]proline and [3H]thymidine incorporation, respectively, and the expression of alpha-smooth muscle actin (alpha-SMA) and desmin was determined by Western blot. RLF, at concentrations ranging from 10(-10) to 10(-7) M, decreased alpha-SMA expression by 65-88%. Apo-RLF, HrHF, and HrLF decreased alpha-SMA by 17-45% at 10(-7) and 10(-8) M. Hemin (10 or 50 microM) inhibited alpha-SMA by 37 and 54%, respectively. Desmin expression was not altered by ferritin or hemin. Collagen and noncollagen protein production were not altered by either RLF or apo-RLF. Lipocyte proliferation was decreased by 54, 32, and 40%, by 10(-7) M RLF, HrHF, and HrLF, respectively, whereas apo-RLF had no effect. Thus RLF inhibited lipocyte alpha-SMA expression, which may be due to an effect of sequestered iron, since neither apo-RLF, HrHF, nor HrLF had a potent effect on alpha-SMA expression and all are essentially iron-free. The inhibitory effect of iron-loaded RLF on alpha-SMA expression suggests that tissue ferritin does not initiate lipocyte activation in iron overload, but rather may have a suppressive action on this process.
Iron Homeostasis, Hepatocellular Injury, and Fibrogenesis in Hemochromatosis: The Role of Inflammation in a Noninflammatory Liver Disease
Publisher: Georg Thieme Verlag KG
Date: 21-07-2010
Abstract: Iron is a crucially important element in normal cellular function and thus the regulation of iron homeostasis is tightly controlled. When this regulation is disrupted, for instance in hereditary hemochromatosis, abnormal intestinal absorption of iron leads to cellular toxicity, tissue injury, and organ fibrosis via the deposition of this iron in parenchymal cells of a number of different organs such as the heart, pancreas, and liver. Iron-generated oxyradicals contribute to the peroxidation of lipid membranes leading to organelle fragility and cellular toxicity. This process is thought to contribute to hepatocellular necrosis and/or apoptosis in the liver with the subsequent activation of hepatic stellate cells and the development of hepatic fibrosis and cirrhosis. Understanding the processes associated with normal iron homeostasis is crucially important as this will ultimately provide clues as to how altered iron uptake and delivery leads to tissue injury and organ dysfunction in diseases of disordered iron metabolism. This review highlights recent advances in identifying major regulators associated with hepatic iron homeostasis and examines the potential mechanisms involved in the development of iron overload-induced hepatic injury and fibrogenesis.
RNA sequencing of LX-2 cells treated with TGF-β1 identifies genes associated with hepatic stellate cell activation
Publisher: Springer Science and Business Media LLC
Date: 14-10-2021
DOI: 10.1007/S11033-021-06774-3
Abstract: Hepatic stellate cells (HSCs) are liver-resident myofibroblast precursors responsible for the production of collagen and maintenance of the hepatic extracellular matrix (ECM). As such, they are generally associated with fibrotic liver diseases. HSCs become “activated” in response to tissue damage or pathogen invasion, a process most commonly driven by transforming growth factor-β1 (TGF-β1). Despite this, the full extent of TGF-β1 signalling in these cells is poorly understood. Clarifying the range and ersity of this signalling will further improve our understanding of the process of HSC activation. RNA sequencing was used to quantitate the transcriptomic changes induced in LX-2 cells, an activated human HSC line, following TGF-b1 treatment. In total, 5,258 genes were found to be significantly differentially expressed with a false discovery rate cut-off of 0.1. The topmost deregulated of these genes included those with no currently characterised role in either HSC activation or fibrotic processes, including CIITA and SERPINB2. In silico analysis revealed the prominent signalling pathways downstream of TGF-β1 in LX-2 cells. In this study, we describe the genes and signalling pathways significantly deregulated in LX-2 cells following TGF-β1 treatment. We identified several highly deregulated genes with no currently characterised role in HSC activation, which may represent novel mediators of fibrotic responses in HSCs or the liver macroenvironment. This work may be of use in the identification of new markers of liver fibrosis and could provide insight into prospective genes or pathways that might be targeted for the amelioration of fibrotic liver disease in the future.
Neutrophil Depletion Blocks Early Collagen Degradation in Repairing Cholestatic Rat Livers
Publisher: Elsevier BV
Date: 03-2010
Androgens alter the heterogeneity of small extracellular vesicles and the small RNA cargo in prostate cancer
Publisher: Wiley
Date: 08-2021
DOI: 10.1002/JEV2.12136
Abstract: Proliferation and survival of prostate cancer cells are driven by the androgen receptor (AR) upon binding to androgen steroid hormones. Manipulating the AR signalling axis is the focus for prostate cancer therapy thus, it is crucial to understand the role of androgens and AR on extracellular vesicle (EV) secretion and cargo. In this study, we report that plasma‐derived circulating vesicles consisting of CD9 and double‐positive for CD9 and Prostate Specific Membrane Antigen (PSMA) are increased in patients with advanced metastatic prostate cancer, whereas double positives for CD9 and CD63 small extracellular vesicles (S‐EVs) are significantly higher in patients with localised prostate cancer. Androgen manipulation by dihydrotestosterone (DHT) and the clinical antagonist enzalutamide (ENZ) altered the heterogeneity and size of CD9 positive S‐EVs in AR expressing prostate cancer cells, while assessment of the total number and protein cargo of total S‐EVs was unaltered across different treatment groups. Furthermore, hormone stimulation caused strong and specific effects on the small RNA cargo of S‐EVs. A total of 543 small RNAs were found to be regulated by androgens including miR‐19‐3p and miR‐361‐5p. Analysis of S‐EVs heterogeneity and small RNA cargo may provide clinical utility for prostate cancer and be informative to understand further the mechanism of resistance to androgen targeted therapy in castration‐resistant prostate cancer.
Exome sequencing in HFE C282Y homozygous men with extreme phenotypes identifies a GNPAT variant associated with severe iron overload
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 18-03-2015
DOI: 10.1002/HEP.27711
Abstract: To identify polymorphisms associated with variability of iron overload severity in HFE ‐associated hemochromatosis, we performed exome sequencing of DNA from 35 male HFE C282Y homozygotes with either markedly increased iron stores (n = 22 cases) or with normal or mildly increased iron stores (n = 13 controls). The 35 participants, residents of the United States, Canada, and Australia, reported no or light alcohol consumption. Sequencing data included 82,068 single‐nucleotide variants, and 10,337 genes were tested for a difference between cases and controls. A variant in the GNPAT gene showed the most significant association with severe iron overload ( P = 3 × 10 −6 P = 0.033 by the likelihood ratio test after correction for multiple comparisons). Sixteen of twenty‐two participants with severe iron overload had glyceronephosphate O‐acyltransferase ( GNPAT ) polymorphism p.D519G (rs11558492 15 heterozygotes, one homozygote). No control participant had this polymorphism. To examine functional consequences of GNPAT deficiency, we performed small interfering RNA–based knockdown of GNPAT in the human liver‐derived cell line, HepG2/C3A. This knockdown resulted in a ‐fold decrease in expression of the messenger RNA encoding the iron‐regulatory hormone, hepcidin. Conclusion: GNPAT p.D519G is associated with a high‐iron phenotype in HFE C282Y homozygotes and may participate in hepcidin regulation. (H epatology 2015 :429–439
Reply: Utility of platelets and aspartate aminotransferase vs serum ferritin and serum hyaluronic acid as markers of cirrhosis in hemochromatosis
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-04-2009
DOI: 10.1002/HEP.22948
Analysis Of The Intrahepatic Ductular Reaction And Progenitor Cell Responses In Hepatitis C Virus Recurrence Post-Liver Transplantation
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 24-11-2014
DOI: 10.1002/LT.24007
Abstract: Fibrosis in livers with hepatitis C virus (HCV) recurrence after liver transplantation (LT) can be rapidly progressive, and the mechanisms underlying this process are poorly understood. In livers with HCV infections in the non-LT setting, there is a significant relationship between the development of structures known as the ductular reaction (DR), hepatic progenitor cells (HPCs), and fibrosis. This study characterizes the DR, HPCs, and fibrosis associated with HCV recurrence after LT. Immunohistochemistry and confocal microscopy were used to characterize the DR, HPC, and fibrosis in liver biopsy specimens. Key findings were confirmed in a separate, independent cohort. The initial characterization cohort had 194 biopsy s les from 105 in iduals with HCV recurrence after LT. The immunophenotype, morphology, and location of the DR were consistent with an HPC origin. The DR correlated with intrahepatic fibrosis (rs = 0.529, P < 0.001) and the number of activated hepatic stellate cells (HSCs rs = 0.446, P < 0.001). There was an early occurrence of hepatocyte replicative arrest as well as increased hepatocyte proliferation that correlated with the DR (rs = 0.295, P < 0.001). Replicative arrest preceded hepatocyte proliferation in early-stage injury. Hepatocyte proliferation decreased with advanced fibrosis in contrast, the extent of the DR and the number of activated HSCs continued to increase. In the second cohort of 37 in iduals, the DR and the number of HPCs similarly correlated with fibrosis and inflammation after LT. In conclusion, this is the first characterization of the DR in HCV-associated liver injury after LT. There was a significant correlation between the DR and the development of progressive fibrosis in HCV recurrence. These results suggest a pivotal role for both the DR and the HPC responses in the aggressive fibrosis seen with HCV recurrence after LT.
Cirrhosis in Hemochromatosis: Independent Risk Factors in 368 HFE p.C282Y Homozygotes
Publisher: Elsevier BV
Date: 09-2018
Divergent Inflammatory, Fibrogenic, and Liver Progenitor Cell Dynamics in Two Common Mouse Models of Chronic Liver Injury
Publisher: Elsevier BV
Date: 07-2016
DOI: 10.1016/J.AJPATH.2016.03.005
Abstract: Complications of end-stage chronic liver disease signify a major cause of mortality worldwide. Irrespective of the underlying cause, most chronic liver diseases are characterized by hepatocellular necrosis, inflammation, fibrosis, and proliferation of liver progenitor cells or ductular reactions. Vast differences exist between experimental models that mimic these processes, and their identification is fundamental for translational research. We compared two common murine models of chronic liver disease: the choline-deficient, ethionine-supplemented (CDE) diet versus thioacetamide (TAA) supplementation. Markers of liver injury, including serum alanine transaminase levels, apoptosis, hepatic fat loading, and oxidative stress, as well as inflammatory, fibrogenic and liver progenitor cell responses, were assessed at days 3, 7, 14, 21, and 42. This study revealed remarkable differences between the models. It identified periportal injury and fibrosis with an early peak and slow normalization of all parameters in the CDE regimen, whereas TAA-treated mice had pericentral patterns of progressive injury and fibrosis, resulting in a more severe hepatic injury phenotype. This study is the first to resolve two different patterns of injury and fibrosis in the CDE and TAA model and to indisputably identify the fibrosis pattern in the TAA model as driven from the pericentral vein region. Our data provide a valuable foundation for future work using the CDE and TAA regimens to model a variety of human chronic liver diseases.
Ursodeoxycholic acid and liver disease associated with cystic fibrosis: A multicenter cohort study
Publisher: Elsevier BV
Date: 03-2022
DOI: 10.1016/J.JCF.2021.03.014
Abstract: The efficacy and safety of ursodeoxycholic acid (UDCA) for the treatment of liver disease associated with cystic fibrosis (CF) are under discussion, and clinical practice varies among centers. The study aimed at evaluating if the incidence of severe liver disease differs between CF centers routinely prescribing or not prescribing UDCA. We carried out a retrospective multicenter cohort study including 1591 CF patients (1192 patients from UDCA-prescribing centers and 399 from non-prescribing centers) born between 1990 and 2007 and followed from birth up to 31 December 2016. We computed the crude cumulative incidence (CCI) of portal hypertension (PH) at the age of 20 years in the two groups and estimated the subdistribution hazard ratio (HR) through a Fine and Gray model. Over the observation period, 114 patients developed PH: 90 (7.6%) patients followed-up in UDCA prescribing centers and 24 (6.0%) in non-prescribing centers. The CCI of PH at 20 years was 10.1% (95% CI: 7.9-12.3) in UDCA-prescribing and 7.7% (95% CI: 4.6-10.7) in non-prescribing centers. The HR among patients followed in prescribing centers indicated no significant difference in the rate of PH either in the unadjusted model (HR: 1.21, 95% CI: 0.69-2.11) or in the model adjusted for pancreatic insufficiency (HR: 1.28, 95% CI: 0.77-2.12). CF patients followed-up in UDCA prescribing centers did not show a lower incidence of PH as compared to those followed in centers not prescribing UDCA. These results question the utility of UDCA in reducing the occurrence of severe liver disease in CF.
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