Iron levels in hepatocytes and portal tract cells predict progression and outcomes of patients with advanced chronic hepatitis C.

Background & Aims: Iron may influence severity and progression of non-hemochromatotic liver diseases. Our aim was to assess the relationship of iron and HFE genetic variations to progression and outcomes in the HALT-C Trial and whether PegIFN therapy influenced iron variables.

Methods: Participants were randomized to receive long-term PegIFN [n = 400] or no therapy [n = 413] for 3.

Altered folate availability modifies the molecular environment of the human colorectum: implications for colorectal carcinogenesis.

Low folate status increases colorectal cancer risk. Paradoxically, overly abundant folate supplementation, which is not uncommon in the United States, may increase risk. The mechanisms of these effects are unknown.

Increased frequency of serrated aberrant crypt foci among smokers.

Objectives: The American College of Gastroenterology has published guidelines recently that suggest that smokers with a history of >20 pack years may need screening for colorectal cancer (CRC) at an earlier age than non-smokers. Aberrant crypt foci (ACF) may represent important precursors for colorectal neoplasms and potential surrogate biomarkers. Clarifying the role of ACF in relation to known CRC risk factors such as smoking may have important implications for screening as well as our understanding of tobacco use and colorectal carcinogenesis.

Iron increases HMOX1 and decreases hepatitis C viral expression in HCV-expressing cells.

Aim: To investigate effects of iron on oxidative stress, heme oxygenase-1 (HMOX1) and hepatitis C viral (HCV) expression in human hepatoma cells stably expressing HCV proteins.

Methods: Effects of iron on oxidative stress, HMOX1, and HCV expression were assessed in CON1 cells. Measurements included mRNA by quantitative reverse transcription-polymerase chain reaction, and protein levels by Western blots.

Differential regulation of human ALAS1 mRNA and protein levels by heme and cobalt protoporphyrin.

5-Aminolevulinic acid synthase 1 (ALAS1) is the first and rate-controlling enzyme of heme biosynthesis. This study was to determine the effects of heme and selected nonheme metalloporphyrins on human ALAS1 gene expression in hepatocytes. We found that, upon heme and cobalt protoporphyrin (CoPP) treatments, ALAS1 mRNA levels were down-regulated significantly by ca.

Effects of silymarin on hepatitis C virus and haem oxygenase-1 gene expression in human hepatoma cells.

Background/aims: Hepatitis C virus (HCV) infection is a global medical problem. The current standard treatment of chronic hepatitis C (CHC), pegylated interferon plus ribavirin, is prolonged, expensive, has serious side effects and, at best, is only 50% effective. Silymarin (SI) is a natural antioxidant often used by patients with CHC, although its efficacy for decreasing HCV levels or ameliorating CHC remains uncertain.

DNA polymorphisms and response to treatment in patients with chronic hepatitis C: results from the HALT-C trial.

Background/aims: Certain host genetic polymorphisms reportedly affect the likelihood of a sustained virological response (SVR) to interferon treatment in subjects infected with hepatitis C virus (HCV). As part of the HALT-C trial we evaluated genetic associations among patients infected with HCV genotype 1 who had failed previous interferon treatment.

Methods: SVR was determined 24 weeks after completing treatment with pegylated interferon alfa-2a and ribavirin.

Zinc mesoporphyrin induces rapid and marked degradation of the transcription factor Bach1 and up-regulates HO-1.

Heme oxygenase 1 (HO-1) is the first and rate-controlling enzyme in heme degradation. Bach1 is a mammalian transcriptional repressor of HO-1. To understand how zinc mesoporphyrin (ZnMP) induces the expression of HO-1, we investigated the effects of ZnMP on Bach1 mRNA and protein levels in human hepatoma Huh-7 cells by quantitative RT-PCR and Western blots.

Reciprocal effects of micro-RNA-122 on expression of heme oxygenase-1 and hepatitis C virus genes in human hepatocytes.

Background & Aims: Heme oxygenase-1 (HO-1) is an antioxidant defense and key cytoprotective enzyme, which is repressed by Bach1. Micro-RNA-122 (miR-122) is specifically expressed and highly abundant in human liver and required for replication of hepatitis C virus (HCV) RNA. This study was to assess whether a specific miR-122 antagomir down-regulates HCV protein replication and up-regulates HO-1.

Serum measures of iron status and HFE gene mutations in patients with hepatitis B virus infection.

Aim: We tested associations between HFE mutations and hepatitis B virus (HBV) infection. We also explored measures of total body iron status and their association with chronic HBV infection.

Methods: Serum measures of iron status and HFE mutations (C282Y, H63D, and S65C) were assessed in 344 Iranian patients with chronic HBV infection (214 asymptomatic carriers, 130 patients with chronic progressive liver disease [CPLD]) and 302 controls.

Genetic aspects of porphyria cutanea tarda.

Porphyria cutanea tarda (PCT) is caused by disruption of heme biosynthesis at the step catalyzed by uroporphyrinogen decarboxylase. The patients present with photosensitive cutaneous lesions, hepatic pathology (including elevated porphyrin levels), and increased excretion of porphyrins. Therapy consists of removing the exacerbating factors of PCT (reduced sunlight exposure, abstinence from alcohol use, decreased estrogen exposure, and treatment for viral infections), decreasing body iron stores (by therapeutic phlebotomy or by the use of the new orally active iron chelators), and, in some instances, the use of low-dose antimalarials.

Roles of iron and HFE mutations on severity and response to therapy during retreatment of advanced chronic hepatitis C.

Background & Aims: Iron overload may cause or contribute to hepatic injury and fibrosis. Mutations in the HFE gene may influence development or progression of chronic liver disease by increasing iron stores or modulating immune responses. The aim of this work was to assess the influence of HFE mutations and serum and hepatic measures of iron status on baseline features and response to lead-in therapy in subjects with advanced chronic hepatitis C enrolled in the Hepatitis C Anti-viral Long-term Treatment to prevent Cirrhosis (HALT-C) Trial.

Role of Bach1 and Nrf2 in up-regulation of the heme oxygenase-1 gene by cobalt protoporphyrin.

Heme oxygenase (HO) catalyzes the conversion of heme to biliverdin with the release of iron and carbon monoxide. HO-1 is highly inducible by a large number of physical and chemical factors. CoPP is known to be a potent and effective inducer of HO-1 activity in many tissues.

HCV proteins increase expression of heme oxygenase-1 (HO-1) and decrease expression of Bach1 in human hepatoma cells.

Background/aims: Hepatitis C infection induces hepatic oxidative stress. Heme oxygenase (HO), the rate-controlling enzyme of heme catabolism, plays a key role as a protector against oxidative, and other stresses. Other recent work has implicated Bach1, a heme binding protein that represses gene expression, in the regulation of HO-1 gene expression.

Association of hepatitis C virus infection with serum iron status: analysis of data from the third National Health and Nutrition Examination Survey.

Background: There is growing evidence that mildly increased amounts of iron in the liver can increase hepatic injury, particularly if combined with other hepatotoxic factors, such as alcohol use, use of porphyrogenic drugs, or chronic viral hepatitis. In the present study, the association of hepatitis C virus (HCV) infection with serum measurements of iron status was assessed in the US population.

Methods: We analyzed data from a total of 14,462 participants in the Third National Health and Nutrition Examination Survey.

Role of Bach-1 in regulation of heme oxygenase-1 in human liver cells: insights from studies with small interfering RNAS.

Heme oxygenase-1 is an antioxidant defense enzyme that converts heme to biliverdin, iron, and carbon monoxide. Bach-1 is a bZip protein that forms heterodimers with small Maf proteins and was reported recently to down-regulate the HO-1 gene in mice. Using small interfering RNAs targeted to human Bach-1 mRNA, we investigated whether modulation of human hepatic Bach-1 expression by small interfering (si)RNA technology influences heme oxygenase-1 gene expression.

Identification of key elements that are responsible for heme-mediated induction of the avian heme oxygenase-1 gene.

Unlabelled: Heme oxygenase (HO) catalyzes the conversion of heme to biliverdin with the release of iron and carbon monoxide. HO-1 is highly inducible by a large number of physical and chemical factors. In recent work, we had identified a metalloporphyrin-responsive element (MPRE) that localized at -3.

Iron as a co-morbid factor in nonhemochromatotic liver disease.

Heavy iron overload, in both primary and secondary hemochromatosis, may cause fibrosis of parenchymal organs, especially the liver. The toxicity of iron is believed to involve increased oxidative stress, with iron-catalyzed production of reactive oxygen species causing oxidative damage to lipids, proteins, and nucleic acids. Lesser degrees of hepatic iron deposition are also associated with, and seem to be risk factors for, certain nonhemochromatotic liver diseases.

Hemochromatosis and porphyria.

A 52-year-old man presented to his primary care physician with blisters and sores on the backs of his hands. Laboratory studies supported a diagnosis of porphyria cutanea tarda, complicated by the presence of both the C282Y and H63D mutations in the HFE gene, with susequent iron over-load. This case illustrates the need to understand the pathogenesis of porphyria cutanea tarda, particularly the role of excess iron in the overproduction of uroporphyrin.

Mapping of the chick heme oxygenase-1 proximal promoter for responsiveness to metalloporphyrins.

Heme oxygenase (HO) catalyzes the rate-controlling step of physiologic heme catabolism, namely, the oxidation of the alpha-methene bridge of the macrocycle with formation of CO, Fe, and biliverdin. HO-1, the first isoform of HO to be identified, is highly inducible by a large number of physical and chemical factors. Many of these factors cause oxidative or other stresses to cells.