Heme oxygenase-1 (HMOX1) and bilirubin UDP-glucuronosyltransferase (UGT1A1) enzymes, both involved in bilirubin homeostasis, play an important role in the oxidative stress defense. The objective of our study was to assess the effect of promoter variations of HMOX1 and UGT1A1 genes and of serum bilirubin on the risk of sporadic colorectal cancer (CRC). This exploratory case-control study was based on 777 CRC patients and 986 controls from the Czech Republic. The (GT)(n) and (TA)(n) dinucleotide variations in HMOX1 and UGT1A1 gene promoters, respectively, were determined by fragment analysis. In addition, the A(-413)T variant in HMOX1 promoter was also analyzed using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Serum bilirubin levels were compared in a subset of 174 cases and 247 controls, for whom biochemical data were available. After adjustment for age, a significant association between CRC risk and UGT1A1*28 allele carrier status was detected [odds ratio (95% confidence intervals) = 0.80 (0.60-0.97), p = 0.022]. No association between CRC risk and individual HMOX1 gene variants was observed, although a diplotype analysis revealed an increased risk for a specific HMOX1 genotype combination. These effects were more pronounced in males. Substantially lower serum bilirubin levels were detected in CRC patients compared to the controls (p < 0.001); each 1 μmol/L decrease in serum bilirubin was associated with a 7% increase of CRC risk (p < 0.001). In conclusion, UGT1A1*28 allele carrier status might be a protective factor against the development of CRC in the male population, whereas low serum bilirubin levels are associated with an increased risk of CRC in both genders.

• MeSH
• Alleles MeSH
• Bilirubin blood   MeSH
• Genetic Predisposition to Disease MeSH
• Genotype MeSH
• Glucuronosyltransferase genetics   MeSH
• Heme Oxygenase-1 genetics   MeSH
• Colorectal Neoplasms blood   genetics   MeSH
• Middle Aged MeSH
• Humans MeSH
• Polymorphism, Genetic * MeSH
• Promoter Regions, Genetic * MeSH
• Aged MeSH
• Sex Factors MeSH
• Case-Control Studies MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Bilirubin MeSH
• Glucuronosyltransferase MeSH
• Heme Oxygenase-1 MeSH
• HMOX1 protein, human MeSH Browser

BACKGROUND: Heme oxygenase-1 (HMOX1) and bilirubin UDP-glucuronosyltransferase (UGT1A1), both enzymes involved in bilirubin homeostasis, play an important role in oxidative stress defense. OBJECTIVE: To assess the effect of promoter variations of HMOX1 and UGT1A1 genes on the progression of fibrosis in patients chronically infected with the hepatitis C virus (HCV). MATERIAL AND METHODS: The study was performed on146 chronic HCV infection patients, plus 146 age- and sex-matched healthy subjects. The (GT)n and (TA)n dinucleotide variations in HMOX1 and UGT1A1 gene promoters, respectively, were determined by fragment analysis in all subjects. RESULTS: No differences were found in the frequencies of each particular allele of both genes, between HCV patients and a control group (p > 0.05). Furthermore, no association was detected (p > 0.05) between either the HMOX1 or the UGT1A1 promoter variants and the individual histological stages of liver disease in the HCV positive patients. Finally, no differences in the HMOX1 and UGT1A1 genotype prevalence rates were found between pre-cirrhotic and cirrhotic patients (p > 0.05). CONCLUSION: Based on our data, microsatellite variations in the HMOX1 and UGT1A1 genes are not likely to protect from progression of liver disease in patients with chronic hepatitis C.

• MeSH
• Biopsy MeSH
• Hepatitis C, Chronic enzymology   genetics   pathology   MeSH
• Phenotype MeSH
• Gene Frequency MeSH
• Genetic Predisposition to Disease MeSH
• Genetic Variation * MeSH
• Glucuronosyltransferase genetics   MeSH
• Heme Oxygenase-1 genetics   MeSH
• Hepacivirus genetics   MeSH
• Liver Cirrhosis enzymology   genetics   pathology   virology   MeSH
• Liver enzymology   pathology   virology   MeSH
• Humans MeSH
• Microsatellite Repeats MeSH
• Promoter Regions, Genetic * MeSH
• RNA, Viral blood   MeSH
• Case-Control Studies MeSH
• Viral Load MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Geographicals
• Czech Republic MeSH
• Names of Substances
• Glucuronosyltransferase MeSH
• Heme Oxygenase-1 MeSH
• HMOX1 protein, human MeSH Browser
• RNA, Viral MeSH
• UGT1A1 enzyme MeSH Browser

Bilirubin has potent biological beneficial effects, protecting against atherosclerosis, obesity, and metabolic syndrome. The aim of this study was to assess serum bilirubin concentrations and (TA)n and (GT)n microsatellite variations in the promoter regions of the UGT1A1 and HMOX1 genes, respectively, in patients with type 2 diabetes mellitus (T2DM). The study was carried out in 220 patients with T2DM and 231 healthy control subjects, in whom standard biochemical tests were performed. The (TA)n and (GT)n dinucleotide variations were determined by means of fragment (size-based) analysis using an automated capillary DNA sequencer. Compared to controls, both male and female patients with T2DM had lower serum bilirubin concentrations (9.9 vs. 12.9 μmol/L, and 9.0 vs. 10.6 μmol/L, in men and women, respectively, p < 0.001). Phenotypic Gilbert syndrome was much less prevalent in T2DM patients, as was the frequency of the (TA)7/7UGT1A1 genotype in male T2DM patients. (GT)nHMOX1 genetic variations did not differ between diabetic patients and controls. Our results demonstrate that the manifestation of T2DM is associated with lower serum bilirubin concentrations. Consumption of bilirubin due to increased oxidative stress associated with T2DM seems to be the main explanation, although (TA)n repeat variations in UGT1A1 partially contribute to this phenomenon.

• Keywords
• Gilbert syndrome, HMOX1, UGT1A1, benign hyperbilirubinemia, bilirubin, heme oxygenase, type 2 diabetes mellitus,
• MeSH
• Bilirubin metabolism   MeSH
• Diabetes Mellitus, Type 2 * genetics   MeSH
• Genotype MeSH
• Glucuronosyltransferase genetics   metabolism   MeSH
• Heme Oxygenase-1 genetics   metabolism   MeSH
• Humans MeSH
• Polymorphism, Genetic * MeSH
• Promoter Regions, Genetic MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• Czech Republic epidemiology   MeSH
• Names of Substances
• Bilirubin MeSH
• Glucuronosyltransferase MeSH
• Heme Oxygenase-1 MeSH
• HMOX1 protein, human MeSH Browser

The aim of our study was to assess the possible relationships among heme oxygenase (HMOX), bilirubin UDP-glucuronosyl transferase (UGT1A1) promoter gene variations, serum bilirubin levels, and Fabry disease (FD). The study included 56 patients with FD (M : F ratio = 0.65) and 185 healthy individuals. Complete standard laboratory and clinical work-up was performed on all subjects, together with the determination of total peroxyl radical-scavenging capacity. The (GT)n and (TA)n dinucleotide variations in the HMOX1 and UGT1A1 gene promoters, respectively, were determined by DNA fragment analysis. Compared to controls, patients with FD had substantially lower serum bilirubin levels (12.0 versus 8.85 μmol/L, p = 0.003) and also total antioxidant capacity (p < 0.05), which showed a close positive relationship with serum bilirubin levels (p = 0.067) and the use of enzyme replacement therapy (p = 0.036). There was no association between HMOX1 gene promoter polymorphism and manifestation of FD. However, the presence of the TA7 allele UGT1A1 gene promoter, responsible for higher systemic bilirubin levels, was associated with a twofold lower risk of manifestation of FD (OR = 0.51, 95% CI = 0.27-0.97, p = 0.038). Markedly lower serum bilirubin levels in FD patients seem to be due to bilirubin consumption during increased oxidative stress, although UGT1A1 promoter gene polymorphism may modify the manifestation of FD as well.

• MeSH
• Antioxidants metabolism   MeSH
• Bilirubin blood   MeSH
• Adult MeSH
• Fabry Disease blood   enzymology   genetics   MeSH
• Glucuronosyltransferase genetics   MeSH
• Heme Oxygenase-1 genetics   MeSH
• Humans MeSH
• Polymorphism, Genetic MeSH
• Promoter Regions, Genetic MeSH
• Case-Control Studies MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Antioxidants MeSH
• Bilirubin MeSH
• Glucuronosyltransferase MeSH
• Heme Oxygenase-1 MeSH
• HMOX1 protein, human MeSH Browser
• UGT1A1 enzyme MeSH Browser

OBJECTIVES: Our aim was to establish a reliable, rapid, and inexpensive method for the simultaneous genotyping of the HMOX-1 (heme oxygenase-1) and UGT1A1 (bilirubin UDP-glucuronosyltransferase) gene promoter variations. RESULTS: The HMOX1 (GT)(n) and UGT1A1 (TA)(n) gene promoter variations were determined by fragment analysis using a single duplex PCR, with different fluorescent dye-labeled primers; followed by multicolored capillary electrophoresis. CONCLUSION: This novel method provides simultaneous genotyping of key tandem repeat variations in the HMOX1 and UGT1A1 promoters.

• MeSH
• Electrophoresis, Capillary methods   MeSH
• Genotype MeSH
• Glucuronosyltransferase genetics   MeSH
• Heme Oxygenase-1 genetics   MeSH
• Polymorphism, Single Nucleotide genetics   MeSH
• Humans MeSH
• Microsatellite Repeats genetics   MeSH
• Reproducibility of Results MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Glucuronosyltransferase MeSH
• Heme Oxygenase-1 MeSH
• UGT1A1 enzyme MeSH Browser

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disorder worldwide. The aim of our study was to assess the role of bilirubin, and the heme oxygenase 1 (HMOX1) and bilirubin UDP-glucuronosyl transferase (UGT1A1) promoter gene variants, which are involved in bilirubin homeostasis, in the NAFLD development in adult patients. The study was performed on 84 patients with NAFLD and 103 age/sex-matched controls. Routine biochemistry, inflammatory markers, adipokines, and the fibrosis/steatohepatitis stage were determined in the NAFLD patients. The (GT)n/(TA)n dinucleotide variations in HMOX1/UGT1A1 gene promoters, respectively, were analyzed by fragment analysis. Compared to controls, serum bilirubin concentrations in NAFLD patients tended to be decreased, while the prevalence of phenotypic Gilbert syndrome was significantly low. Genetic variations in HMOX1 and UGT1A1 gene promoters did not differ between NAFLD patients and controls, and no relationship was found in the NAFLD patients between these gene variants and any of the laboratory or histological parameters. In conclusion, metabolism of bilirubin is dysregulated in NAFLD patients, most likely due to increased oxidative stress, since frequencies of the major functional variants in the HMOX1 or UGT1A1 gene promoters did not have any effect on development of NAFLD in adult patients.

• Keywords
• HMOX1, NAFLD, NASH, UGT1A1, bilirubin, bilirubin UDP-glucuronosyl transferase, heme oxygenase 1, oxidative stress,
• Publication type
• Journal Article MeSH

We analyzed gene expression in THP-1 cells exposed to metal-based nanomaterials (NMs) [TiO2 (NM-100), ZnO (NM-110), SiO2 (NM-200), Ag (NM-300 K)]. A functional enrichment analysis of the significant differentially expressed genes (DEGs) identified the key modulated biological processes and pathways. DEGs were used to construct protein-protein interaction networks. NM-110 and NM-300 K induced changes in the expression of genes involved in oxidative and genotoxic stress, immune response, alterations of cell cycle, detoxification of metal ions and regulation of redox-sensitive pathways. Both NMs shared a number of highly connected protein nodes (hubs) including CXCL8, ATF3, HMOX1, and IL1B. NM-200 induced limited transcriptional changes, mostly related to the immune response; however, several hubs (CXCL8, ATF3) were identical with NM-110 and NM-300 K. No effects of NM-100 were observed. Overall, soluble nanomaterials NM-110 and NM-300 K exerted a wide variety of toxic effects, while insoluble NM-200 induced immunotoxicity; NM-100 caused no detectable changes on the gene expression level.

• Keywords
• THP-1 cells, gene expression, metal-based nanoparticles, protein-protein interactions,
• MeSH
• Heme Oxygenase-1 MeSH
• Interleukin-8 metabolism   genetics   MeSH
• Metal Nanoparticles toxicity   MeSH
• Humans MeSH
• Protein Interaction Maps * drug effects   MeSH
• Nanostructures toxicity   MeSH
• Silicon Dioxide toxicity   MeSH
• Zinc Oxide toxicity   chemistry   MeSH
• Silver * toxicity   MeSH
• THP-1 Cells MeSH
• Titanium * toxicity   MeSH
• Activating Transcription Factor 3 genetics   metabolism   MeSH
• Transcriptome drug effects   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• ATF3 protein, human MeSH Browser
• CXCL8 protein, human MeSH Browser
• Heme Oxygenase-1 MeSH
• HMOX1 protein, human MeSH Browser
• Interleukin-8 MeSH
• Silicon Dioxide MeSH
• Zinc Oxide MeSH
• Silver * MeSH
• Titanium * MeSH
• titanium dioxide MeSH Browser
• Activating Transcription Factor 3 MeSH

Carbon monoxide (CO), a product of heme oxygenase (HMOX), has many beneficial biological functions and is a promising therapeutic agent for many pathological conditions. However, the kinetics of inhaled CO and its protective role in endotoxin-induced cholestasis is not fully known. Thus, our objective was to characterize the kinetics of inhaled CO and then investigate its use in early phase experimental endotoxin-induced cholestasis. Female Wistar rats were randomly divided into 4 groups: CON (control), LPS (lipopolysaccharide, 6 mg/kg), CO (250 ppm COx1h), and CO + LPS. Rats were sacrificed at 0-12 h after LPS administration. Tissues and blood were collected for liver injury markers and tissue CO distribution measurements. Livers were harvested for measurements of Hmox activity, Hmox1 mRNA expression, cytokines (IL10, IL6, TNF), and bile lipid and pigment transporters. Half-lives of CO in spleen, blood, heart, brain, kidney, liver, and lungs were 2.4 ± 1.5, 2.3 ± 0.8, 1.8 ± 1.6, 1.5 ± 1.2, 1.1 ± 1.1, 0.6 ± 0.3, 0.6 ± 0.2 h, respectively. CO treatment increased liver IL10 mRNA and decreased TNF expression 1 h after LPS treatment and prevented the down-regulation of bile acid and bilirubin hepatic transporters (Slc10a1, Abcb11, and Abcc2, p < 0.05), an effect closely related to the kinetics. The protective effect of CO against cholestatic liver injury persisted even 12 h after CO exposure, as shown by attenuation of serum cholestatic markers in CO-treated animals. CO exposure substantially attenuated endotoxin-induced cholestatic liver injury and was directly related to the kinetics of inhaled CO. This data underscores the importance of the kinetics of inhaled CO for the proper design of experimental and clinical studies of using CO as a treatment strategy.

• Keywords
• Carbon monoxide, Cholestasis, Endotoxin, Heme oxygenase,
• MeSH
• Cholestasis chemically induced   drug therapy   metabolism   pathology   MeSH
• Gene Expression MeSH
• Heme Oxygenase (Decyclizing) genetics   metabolism   MeSH
• Interleukin-10 genetics   metabolism   MeSH
• Interleukin-6 genetics   metabolism   MeSH
• Liver drug effects   metabolism   pathology   MeSH
• Rats MeSH
• Lipopolysaccharides MeSH
• RNA, Messenger genetics   metabolism   MeSH
• Carbon Monoxide pharmacokinetics   pharmacology   MeSH
• Half-Life MeSH
• Rats, Wistar MeSH
• Tumor Necrosis Factor-alpha genetics   metabolism   MeSH
• Carrier Proteins genetics   metabolism   MeSH
• Bile chemistry   MeSH
• Bile Ducts drug effects   metabolism   pathology   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Heme Oxygenase (Decyclizing) MeSH
• Hmox1 protein, rat MeSH Browser
• Interleukin-10 MeSH
• Interleukin-6 MeSH
• Lipopolysaccharides MeSH
• RNA, Messenger MeSH
• Carbon Monoxide MeSH
• Tumor Necrosis Factor-alpha MeSH
• Carrier Proteins MeSH

Silybum marianum (milk thistle) is a medicinal plant used for the treatment of various liver disorders. This study examined whether the main flavonolignans from S. marianum (i.e. silybin, silychristin, silydianin) and their 2,3-dehydro derivatives (i.e. 2,3-dehydrosilybin, 2,3-dehydrosilychristin, 2,3-dehydrosilydianin) activate the Nrf2 pathway, which regulates the expression of genes encoding many cytoprotective enzymes, including NAD(P)H:quinone oxidoreductase 1 (NQO1). After 48h of exposure, 2,3-dehydrosilydianin at concentrations of 25μM and higher significantly elevated the activity of NQO1 in murine hepatoma Hepa1c1c7 cells. In contrast, other tested compounds at non-cytotoxic concentrations had a mild or negligible effect on the NQO1 activity. Using a luciferase reporter assay, 2,3-dehydrosilydianin was found to significantly activate transcription via the antioxidant response element in stably transfected human AREc32 reporter cells. Moreover, 2,3-dehydrosilydianin caused the accumulation of Nrf2 and significantly induced the expression of the Nqo1 gene at both the mRNA and protein levels in Hepa1c1c7 cells. We found that 2,3-dehydrosilydianin also increased to some extent the expression of other Nrf2 target genes, namely of the heme oxygenase-1 gene (Hmox1) and the glutamate-cysteine ligase modifier subunit gene (Gclm). We conclude that 2,3-dehydrosilydianin activates Nrf2 and induces Nrf2-mediated gene expression in Hepa1c1c7 cells.

• Keywords
• Flavonolignans, NQO1, Nrf2, Silybin, Silybum marianum, Silymarin,
• MeSH
• Gene Expression drug effects   MeSH
• NF-E2-Related Factor 2 metabolism   MeSH
• Glutamate-Cysteine Ligase genetics   metabolism   MeSH
• Heme Oxygenase-1 genetics   metabolism   MeSH
• Humans MeSH
• Membrane Proteins genetics   metabolism   MeSH
• Molecular Structure MeSH
• Mice MeSH
• NAD(P)H Dehydrogenase (Quinone) genetics   metabolism   MeSH
• Cell Line, Tumor MeSH
• Silybum marianum chemistry   MeSH
• Silybin MeSH
• Silymarin pharmacology   MeSH
• Up-Regulation MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• NF-E2-Related Factor 2 MeSH
• GCLM protein, mouse MeSH Browser
• Glutamate-Cysteine Ligase MeSH
• Heme Oxygenase-1 MeSH
• Hmox1 protein, mouse MeSH Browser
• Membrane Proteins MeSH
• NAD(P)H Dehydrogenase (Quinone) MeSH
• NFE2L2 protein, human MeSH Browser
• Nqo1 protein, mouse MeSH Browser
• Silybin MeSH
• silidianin MeSH Browser
• silychristin MeSH Browser
• Silymarin MeSH

UNLABELLED: Introduction and aim. Hepatocellular carcinoma (HCC) is the most common primary malignant liver tumor. It is primarily caused by hepatic cirrhosis or chronic viral hepatitis. Hepatic carcinogenesis is associated with increased oxidative stress. Thus, the aim of our study was to assess expression of the genes involved in the homeostasis of oxidative stress in patients with HCC. MATERIAL AND METHODS: The study was performed on 32 patients with primary HCC (verified by liver histology in 29 patients) and 27 control subjects (in 11 subjects, liver histology was available either with no or minimal changes in the liver tissue). Gene expressions of heme oxygenase 1 (HMOX1), biliverdin reductase A/B (BLVRA/B), NADPH oxidase 2 (NOX2) and p22phox were analyzed in the liver and peripheral blood leukocytes (PBL) in the subjects. RESULTS: Compared to controls, almost a 3 times higher mRNA level of BLVRA was detected in livers of HCC patients (p = 0.002); while those of BLVRB as well as HMOX1 were unchanged (p > 0.05). In accord with these results in the liver tissue, BLVRA mRNA levels in PBL were also significantly increased in HCC patients (p = 0.012). mRNA levels of NOX2 and p22phox in the liver tissue, although higher in HCC patients, did not differ significantly compared to control subjects (p > 0.05). Nevertheless, NOX2 mRNA level in PBL was significantly higher in HCC patients (p = 0.003). CONCLUSIONS: BLVRA mRNA levels in the liver as well as in PBL are significantly higher in HCC patients most likely as a feedback mechanism to control increased oxidative stress associated with HCC progression.

• MeSH
• Heme Oxygenase-1 genetics   MeSH
• Carcinoma, Hepatocellular blood   enzymology   genetics   pathology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Membrane Glycoproteins genetics   MeSH
• RNA, Messenger genetics   MeSH
• Biomarkers, Tumor blood   genetics   MeSH
• Liver Neoplasms blood   enzymology   genetics   pathology   MeSH
• NADPH Oxidase 2 MeSH
• NADPH Oxidases genetics   MeSH
• Oxidative Stress genetics   MeSH
• Oxidoreductases Acting on CH-CH Group Donors blood   genetics   MeSH
• Disease Progression MeSH
• Gene Expression Regulation, Enzymologic MeSH
• Gene Expression Regulation, Neoplastic MeSH
• Aged MeSH
• Signal Transduction MeSH
• Case-Control Studies MeSH
• Up-Regulation MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• biliverdin reductase MeSH Browser
• CYBA protein, human MeSH Browser
• CYBB protein, human MeSH Browser
• Heme Oxygenase-1 MeSH
• HMOX1 protein, human MeSH Browser
• Membrane Glycoproteins MeSH
• RNA, Messenger MeSH
• Biomarkers, Tumor MeSH
• NADPH Oxidase 2 MeSH
• NADPH Oxidases MeSH
• Oxidoreductases Acting on CH-CH Group Donors MeSH