Hennie M J Roelofs

Radboud University Medical Centre (Radboudumc), Nymegen, Gelderland, Netherlands

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Publications (104)457.61 Total impact

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    ABSTRACT: The use of thiopurines is frequently accompanied by hepatotoxicity. Studies on hepatocyte cultures showed a time- and dose-dependent increase of thiopurine toxicity. 5-Aminosalicylic acid (5-ASA) and allopurinol can influence thiopurine metabolism; however, it is unknown whether this affects in vitro cytotoxicity. Human hepatoma cells (Huh7, HepG2 and HepaRG) were incubated with increasing concentrations of thiopurines, 5-ASA or allopurinol. Water-soluble tetrazolium salt-1 (WST-1) cytotoxicity assays were used to calculate cell survival curves and half maximal inhibitory concentrations (IC50). Combination experiments with thiopurines with a fixed dose of 200 μM 5-ASA or 100 μM allopurinol were conducted in HepaRG cells. Caspase-3/7 activation was evaluated, and single cell electrophoresis analysis was performed. A time- and dose-related cytotoxic effect was seen with azathioprine (AZA) in all hepatoma cells, whereas Huh7 and HepG2 cells did not show toxicity to 6-mercaptopurine (6-MP). HepaRG cells expressed the highest levels of drug metabolising enzymes, and therefore, combination experiments were conducted in HepaRG cells. Addition of a non-toxic dose of allopurinol resulted in a twofold to threefold increased cytotoxicity of all thiopurines, which seemed to be mediated by apoptosis/DNA damage. The addition of allopurinol to thiopurines leads to a two-threefold increased cytotoxicity in HepaRG cells.
    Cell Biology and Toxicology 04/2015; 31(3). DOI:10.1007/s10565-015-9301-1 · 1.97 Impact Factor
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    ABSTRACT: Home parenteral nutrition (HPN) patients depend on lipid emulsions as part of their parenteral nutrition regimen to provide essential fatty acids (EFAs). Mixed-oil sources are used in modern lipid emulsions to decrease the amount of proinflammatory EFAs, mainly linoleic acid, which is present in large amounts in soybean oil. It is unknown whether patients who fully depend on such mixed lipids have adequate EFA supply. We therefore evaluated whether HPN patients who depend on mixed olive oil- and soybean oil-based HPN show clinical or biochemical evidence of EFA deficiency. Fatty acid status was assessed in plasma phosphatidylcholine (PC) and peripheral blood mononuclear cells from 30 patients receiving mixed olive oil- and soybean oil-based HPN (>3 months, ≥5 times per week) and 30 healthy controls. Innate immune cell functions were evaluated by assessing expression of surface membrane molecules, and reactive oxygen species, and cytokine production. None of the patients or controls showed clinical evidence (skin rash) or biochemical evidence (increased Holman index [>0.2]) for EFA deficiency. The Holman index in plasma PC (median [25th-75th percentile]) was significantly higher in patients (0.019 [0.015-0.028]) compared with controls (0.015 [0.011-0.017]). No differences were found in innate immune cell functions between groups, except for a 3.6-fold higher tumor necrosis factor-α production in patients. We found no clinical or biochemical evidence that HPN patients who fully and long-term depend on mixed olive oil- and soybean oil-based lipids have an increased risk for EFA deficiency. © 2015 American Society for Parenteral and Enteral Nutrition.
    Journal of Parenteral and Enteral Nutrition 04/2015; DOI:10.1177/0148607115581375 · 3.14 Impact Factor
  • Gastroenterology 04/2015; 148(4):S-699. DOI:10.1016/S0016-5085(15)32369-6 · 13.93 Impact Factor
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    ABSTRACT: Glutathione S-transferases (GSTs) are important in the detoxification of many compounds, including reactive oxygen species. Polymorphisms in GSTs resulting in a decreased enzyme activity might enhance the risk for inflammatory bowel disease by eliciting a state of oxidative stress. Previous case-control studies showed divergent results and were frequently limited in sample size; therefore we conducted a meta-analysis including results from our case-control study. For the case-control study, we genotyped 552 patients with Crohn's disease (CD), 223 patients with ulcerative colitis (UC) and 972 healthy controls by PCR for functional deletions in GST Mu and GST Theta. Both were not analyzed in recent genome-wide association studies. For the meta-analysis, PubMed, EMBASE and Web of Science were searched. In this meta-analysis, we show an enhanced susceptibility for UC in individuals with the GSTT1null genotype (odds ratio (OR) 2.27, 95% confidence interval (CI) 1.31-3.92). In our case-control study, a reduced risk for CD was seen with the GSTT1null genotype (OR 0.58, 95% CI 0.43-0.77); however, pooled analysis showed an OR of 1.67, 95% CI 0.81-3.45. In this meta-analysis, we showed an increased risk for UC in individuals with the GSTT1null genotype.Journal of Human Genetics advance online publication, 4 September 2014; doi:10.1038/jhg.2014.77.
    Journal of Human Genetics 09/2014; 59(10). DOI:10.1038/jhg.2014.77 · 2.53 Impact Factor
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    ABSTRACT: Gastrointestinal (GI) cancer is responsible for the majority of deaths among all types of cancer. Lifestyle factors may not only be the main risk factor for GI cancer but reactive oxygen species (ROS) may also be involved. The single-nucleotide polymorphisms (SNPs) 609C>T (rs1800566) and 465C>T (rs1131341) in the NAD(P)H:quinone oxidoreductase 1 (NQO1) gene lead to a decline in NQO1 enzyme activity. NQO1 catalyzes the two-electron reduction of quinones to hydroquinones, thereby preventing the formation of ROS. Such polymorphisms in NQO1 may increase the risk of GI cancer. The aim of this study was to evaluate the influence of the SNPs rs1800566 and rs1131341 in the NQO1 gene on the risk of GI cancer in the Netherlands. Real-time polymerase chain reaction techniques were conducted to determine the NQO1 genotypes of 1457 patients with GI cancer and 1457 age- and gender-matched controls in a case-control study. Binary logistic regression analyses showed no statistically significant difference in genotype distributions between patients and controls: odds ratios (ORs) with 95% confidence interval (CI) for rs1800566 were 1.09 (0.93-1.28) and 1.17 (0.77-1.77) for the CT and TT genotypes, respectively. ORs for rs1131341 CT and TT genotypes were 1.21 (0.90-1.63) and 0.54 (0.05-5.94), respectively. For rs1800566, a significant association between the CT genotype and proximal colon cancer was detected (OR=1.60; 95% CI=1.09-2.35). The NQO1*2 T allele of SNP rs1800566 was found associated with an increased risk for proximal colorectal cancer, whereas SNP rs1131341 was rare in our Dutch population and was not associated with GI cancer.Journal of Human Genetics advance online publication, 15 May 2014; doi:10.1038/jhg.2014.38.
    Journal of Human Genetics 05/2014; DOI:10.1038/jhg.2014.38 · 2.53 Impact Factor
  • Gastroenterology 05/2014; 146(5):S-582. DOI:10.1016/S0016-5085(14)62106-5 · 13.93 Impact Factor
  • Gastroenterology 05/2014; 146(5):S-583. DOI:10.1016/S0016-5085(14)62112-0 · 13.93 Impact Factor
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    ABSTRACT: Numerous factors influence the development of gastrointestinal (GI) cancer. The insulin-like growth factor (IGF) axis plays a role in embryonic and postnatal growth and tissue repair. Elevated levels of IGFs, low levels of IGF binding proteins (IGFBPs) and over-expression of IGF receptor (IGFR-I) were associated with several stages of cancer. Here, the prevalence of the single nucleotide polymorphisms (SNPs) rs6214 in the IGF type I (IGF-I) gene and rs6898743 in the growth hormone receptor (GHR) gene in patients with GI cancer and controls was studied. In this Dutch case-control study, DNA isolated from blood of 1,457 GI cancer patients; 438 patients with head and neck cancer (HNC), 475 with esophageal cancer (EC) and 544 with colorectal cancer (CRC) and 1,457 matched controls, was used to determine the rs6214 and rs6898743 genotypes by polymerase chain reaction. The association between these SNPs and GI cancer, HNC, esophageal adenocarcinoma (EAC), esophageal squamous-cell carcinoma (ESCC) and proximal or distal CRC was studied. Odds ratios (ORs) with 95% confidence interval (95% CI) were calculated via unconditional logistic regression. Overall for GI cancer, the ORs for SNPs rs6214 and rs6898743 were approximately 1.0 (p-value>0.05), using the most common genotypes GG as reference. An OR of 1.54 (95% CI, 1.05-2.27) was found for EC for genotype AA of rs6214. The ORs for EAC were 1.45 (95% CI, 1.04-2.01) and 1.71 (95% CI, 1.10-2.68), for genotypes GA and AA, respectively. Genotype GC of rs6898743 showed an OR of 0.47 (95% CI, 0.26-0.86) for ESCC. The A allele of SNP rs6214 in the IGF-I gene was associated with EAC, and with HNC in women. The GC genotype of rs6898743 in the GHR gene was negatively associated with ESCC.
    PLoS ONE 03/2014; 9(3):e90916. DOI:10.1371/journal.pone.0090916 · 3.53 Impact Factor
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    ABSTRACT: Background & aims It remains unclear whether impaired host defenses contribute to the increased risk for infectious complications seen in patients on home parenteral nutrition (HPN). The aim of this study was to compare the innate immune function of patients on olive oil-based HPN with that of healthy controls. Methods Innate immune functions and (anti-)oxidant balance were studied in 20 patients on olive oil-based HPN without an active underlying immune-mediated disease (Clinoleic®, ≥6 months; >3 times/week), and 21 age- and sex-matched healthy controls. Results Neutrophils of patients and controls had a similar capacity to eliminate Streptococcus pneumoniae. Also, levels of activation markers (CD66b, CD11b, CD62L) in granulocytes and monocytes, phorbol ester- and zymosan-induced neutrophil oxygen radical production were not different between patients and controls. No differences in (anti-)oxidant status were found, except for higher concentrations of oxidized glutathione and lower plasma selenium and vitamin C in patients compared to controls. Conclusion Compromised innate immune function does not seem to explain the increased risk for infectious complications in HPN patients using olive oil-based lipid emulsions.
    Clinical nutrition (Edinburgh, Scotland) 08/2013; 32(4):643–649. DOI:10.1016/j.clnu.2012.08.009 · 3.94 Impact Factor
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    ABSTRACT: BACKGROUND: Combinations of genetic polymorphisms in biotransformation enzymes might modify the individual risk for head and neck cancer. METHODS: Blood from 432 patients with head and neck cancer and 437 controls was investigated for genetic polymorphisms in 9 different phase I and II biotransformation enzymes. Analysis of the risk-modifying effect was performed according to predicted enzyme activities, based on genetic polymorphisms in the corresponding genes. RESULTS: Combination of polymorphisms in COX-2 or EPHX1 with high activity polymorphisms in UGT1A1, UGT1A6, or UGT1A7 showed a risk-modulating effect in head and neck carcinogenesis, especially among heavy smokers and patients with laryngeal cancer. However, no additional effect for the combination of these polymorphisms was discovered when compared to the impact of polymorphism in UGT1A1, UGT1A6, and UGT1A7 individually. CONCLUSION: Predicted high activity polymorphisms in the phase II enzymes UGT1A1, UGT1A6, and UGT1A7 are associated with an increased risk of head and neck cancer. Head Neck, 2012.
    Head & Neck 06/2013; 35(6). DOI:10.1002/hed.23054 · 3.01 Impact Factor
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    ABSTRACT: Barrett's esophagus, with gastroesophageal reflux disease and obesity as risk factors, predisposes to esophageal adenocarcinoma (EAC). Recently a British genome wide association study identified two Barrett's esophagus susceptibility loci mapping within the major histocompatibility complex (MHC; rs9257809) and closely to the Forkhead‐F1 (FOXF1; rs9936833) coding gene. An interesting issue is whether polymorphisms associated with Barrett's esophagus, are also implicated in esophageal carcinoma (EC), and more specifically EAC genesis. Assessing the individual genetic susceptibility can help identify high risk patients more prone to benefit from surveillance programs. Our hypothesis: Barrett associated MHC and FOXF1 variants modify EC risk in Caucasians. In a Dutch case‐control study, 431 patients with EC and 605 healthy controls were included. Polymorphisms at chromosomes 6p21 (MHC) and 16q24 (FOXF1) were determined by means of real‐time polymerase chain reaction (RT‐PCR). Logistic regression analysis was used to calculate odds ratios with 95% confidence intervals. The FOXF1 rs9936833 variant C allele was associated with an increased EAC susceptibility; OR, [95% CI]; 1.21, [0.99–1.47]. A sex‐stratified analysis revealed a similar association in males; 1.24 [1.00–1.55]. The variant MHC rs9257809 G allele as well as the MHC heterozygous AG genotype significantly increased ESCC risk; 1.76 [1.16–2.66] and 1.74 [1.08–2.80], respectively. Sex‐stratification showed that the variant G allele was especially present in female patients; 2.32 [1.04–5.20]. In conclusion, this study provides evidence that MHC rs9257809 and FOXF1 rs9936833 variants, associated with Barrett's esophagus, also increase ESCC and EAC susceptibility in Caucasians. FOX proteins are transcription factors involved in organogenesis of the GI tract, while MHC haplotypes are strongly associated with smoking behavior, a crucial risk factor for ESCC. Assessing the individual genetic susceptibility can help identify high risk patients more prone to benefit from (Barrett) surveillance programs.
    International Journal of Cancer 01/2013; 133(7). · 5.01 Impact Factor
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    ABSTRACT: Susceptibility to esophageal carcinoma (EC) is influenced by the interaction between genetic and environmental factors. To clarify the etiology of EC, several genome-wide association studies have identified single nucleotide polymorphisms (SNPs) in PCLE1 and RFT2 genes as esophageal squamous cell carcinoma (ESCC) susceptibility loci in Asian populations. This study aimed to determine whether these SNPs also modify the risk of esophageal adenocarcinoma (EAC) and ESCC in western populations of Caucasian ethnicity. A European case-control study including 349 EC patients and 580 controls matched for age, sex, geographical location, and race was carried out. The SNPs rs2274223 in the PCLE1 gene at chromosome 10q23 and rs13042395 in the RFT2 gene at chromosome 20p13 were determined using PCR. Genotype distributions were compared between patients and controls, and odds ratios with 95% confidence intervals were calculated. The total EC group included 86 patients with ESCC and 258 patients with EAC. The distribution of PLCE1 and RFT2 genotypes did not differ between patients with EAC or ESSC, and the controls. In contrast to the modulation of the risk of ESCC in Asians, it is unlikely that the PLCE1 rs2274223 and RFT2 13042395 SNPs play a role in EAC or ESCC susceptibility in Dutch Caucasians.
    European journal of cancer prevention: the official journal of the European Cancer Prevention Organisation (ECP) 12/2012; DOI:10.1097/CEJ.0b013e32835c7f53 · 2.76 Impact Factor
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    ABSTRACT: Curcumin, quercetin, and eicosapentaenoic acid (EPA) are 3 natural compounds with the capacity to reduce adenoma burden in patients with familial adenomatous polyposis (FAP). The mechanistic basis of this anticarcinogenic capacity is largely unknown, but it was suggested that induction of detoxification enzymes is involved. Therefore, the effects of low-dose curcumin, quercetin, and EPA on phase II detoxification enzymes UDP-glucuronosyltransferase (UGT), glutathione S-transferase (GST), as well as on glutathione (GSH) content were analyzed in 4 cell line models of intestinal carcinogenesis. HT-29, HuTu 80, and Caco-2 intestinal cancer cells and LT97 colon adenoma cells from a patient with FAP were treated with low-dose noncytotoxic concentrations of curcumin, quercetin, and EPA. GST enzyme activity was measured by spectrophotometry, and expression of GSTA1, GSTM1, GSTP1, GSTT1, and UGT1 by Western blotting. Cytosolic GSH levels were determined by high performance liquid chromatography. An inducing effect of curcumin and quercetin on GST or UGT was seen in Caco-2, LT97, and HuTu 80 cells. GSH levels were reduced by quercetin and EPA in HT-29 cells and induced by curcumin in Caco-2 cells. In LT97 cells, GST activity and expression was reduced, but UGT1 expression was induced by curcumin and quercetin; whereas EPA only decreased GST or UGT levels. In summary, enhancement of the detoxification capacity by low dose of the potential anticarcinogens curcumin, quercetin, or EPA seems only a minor factor in explaining their anticarcinogenic properties.
    Nutrition and Cancer 07/2012; 64(6):856-63. DOI:10.1080/01635581.2012.700994 · 2.47 Impact Factor
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    ABSTRACT: Esophageal cancer (EC) has a globally increasing incidence with poor curative treatment options and survival rates. Crucial risk factors are exposure to toxins or carcinogens. Microsomal epoxide hydrolase (mEH) is a biotransformation enzyme essential for the detoxification of xenobiotics. Polymorphisms in exon 3 and exon 4 of the microsomal epoxide hydrolase gene (EPHX1) modify catalytic activity of this enzyme and subsequently may play a role in EC etiology. This case-control study investigated whether these polymorphisms in the EPHX1 gene influence esophageal cancer susceptibility in a Dutch Caucasian population. A case-control study including 349 Caucasian EC patients and 581 Caucasian healthy controls was conducted and the polymorphisms Tyr113His (exon 3) and His139Arg (exon 4) in the EPHX1 gene were determined, using polymerase chain reaction. The distribution of exon 3 and exon 4 genotypes were compared between cases and controls. Analyses included a stratification according to tumor histology; esophageal adenocarcinoma (EAC) or squamous cell carcinoma (ESCC). Furthermore, on the basis of allelic in vitro enzyme activity assays, exon 3 and 4 genotypes were combined and categorized according to their predicted high, medium or low enzyme activity. Homozygosity and heterozygosity for both exon 3 and 4 polymorphisms were correlated with a decreased esophageal squamous cell carcinoma risk. Heterozygosity and homozygosity for both polymorphisms correlated with an increased and a decreased esophageal adenocarcinoma risk, respectively. Predicted intermediate and high activity genotypes were risk and protective factors for esophageal squamous cell carcinoma and esophageal adenocarcinoma, respectively. However, none of these associations were statistically significant. In conclusion, the polymorphisms in exon 3 and exon 4 of the EPHX1 gene do not seem to be modifiers of esophageal squamous cell carcinoma or esophageal adenocarcinoma risk in Dutch Caucasians.
    Oncology Reports 03/2012; 27(6):1710-6. DOI:10.3892/or.2012.1734 · 2.19 Impact Factor
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    ABSTRACT: Esophageal cancer (EC) has a globally increasing incidence with poor curative treatment options and survival rates. Environmental and dietary factors have crucial roles in esophageal carcinogenesis. Polymorphisms in the UGT genes, a superfamily of enzymes essential for the detoxification of carcinogens, may alter enzyme activity and subsequently may play a role in EC etiology. Rather than solely establishing differences in genotype distribution, we investigated whether functional polymorphisms in UGT genes that can predict enzyme activity in vivo, may influence EC risk. A case-control study including 351 Caucasian EC patients and 592 Caucasian controls was conducted and polymorphisms in seven UGT genes were determined, using the polymerase chain reaction. On the basis of allelic in vitro enzyme activity measurements, genotypes were categorized according to their predicted in vivo enzyme activity into high, medium and low categories. Predicted enzyme activity groups were combined and compared between patients and controls. The UGT1A1 and UGT1A8 predicted high enzyme activity genotypes were significantly more (OR=1.62; 95% CI, 1.02-2.56) and less frequent (OR=0.36; 95% CI, 0.15-0.84) among patients with esophageal squamous cell carcinoma (ESCC), respectively. High (OR=0.42; 95% CI, 0.22-0.84) and medium (OR=0.25; 95% CI, 0.12-0.52) activity UGT2B4 genotypes were significantly less often present in ESCC patients. No association was detected between UGT genotypes and esophageal adenocarcinoma (EAC) risk. Polymorphisms in UGT genes, resulting in altered enzyme activity genotypes, do not seem modifiers of EAC risk. However, the predicted high activity UGT1A1 genotype, associated with low serum levels of the antioxidant bilirubin, was associated with an increased ESCC risk. The UGT1A8 and UGT2B4 genotypes associated with decreased predicted enzyme activities, were significantly associated with an increased risk of ESCC, probably by a decreased detoxification of carcinogens.
    International Journal of Oncology 02/2012; 40(6):1789-96. DOI:10.3892/ijo.2012.1385 · 2.77 Impact Factor
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    ABSTRACT: Chemoprevention would be a desirable strategy to avoid duodenectomy in patients with familial adenomatous polyposis (FAP) suffering from duodenal adenomatosis. We investigated the in vitro effects on cell proliferation, apoptosis, and COX-2 expression of the potential chemopreventives celecoxib and tauro-ursodeoxycholic acid (UDCA). HT-29 colon cancer cells and LT97 colorectal micro-adenoma cells derived from a patient with FAP, were exposed to low dose celecoxib and UDCA alone or in combination with tauro-cholic acid (CA) and tauro-chenodeoxycholic acid (CDCA), mimicking bile of FAP patients treated with UDCA. In HT-29 cells, co-treatment with low dose celecoxib and UDCA resulted in a decreased cell growth (14-17%, p<0.01). A more pronounced decrease (23-27%, p<0.01) was observed in LT97 cells. Cell growth of HT-29 cells exposed to 'artificial bile' enriched with UDCA, was decreased (p<0.001), either in the absence or presence of celecoxib. In LT97 cells incubated with 'artificial bile' enriched with UDCA, cell growth was decreased only in the presence of celecoxib (p<0.05). No clear evidence was found for involvement of proliferating cell nuclear antigen, caspase-3, or COX-2 in the cellular processes leading to the observed changes in cell growth. In conclusion, co-treatment with low dose celecoxib and UDCA has growth inhibitory effects on colorectal adenoma cells derived from a patient with FAP, and further research on this combination as promising chemopreventive strategy is desired.
    Experimental Cell Research 02/2012; 318(7):819-27. DOI:10.1016/j.yexcr.2012.02.004 · 3.37 Impact Factor
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    ABSTRACT: In order to define future chemoprevention strategies for adenomas or carcinomas in the pouch of patients with familial adenomatous polyposis (FAP), a 4-weeks intervention with (1) sulindac, (2) inulin/VSL#3, and (3) sulindac/inulin/VSL#3 was performed on 17 patients with FAP in a single center intervention study. Primary endpoints were the risk parameters cell proliferation and glutathione S-transferase (GST) detoxification capacity in the pouch mucosa; secondary endpoints were the short chain fatty acid (SCFA) contents, pH, and cytotoxicity of fecal water. Before the start and at the end of each 4-week intervention period, six biopsies of the pouch were taken and feces was collected during 24 h. Cell proliferation and GST enzyme activity was assessed in the biopsies and pH, SCFA contents, and cytotoxicity were assessed in the fecal water fraction. The three interventions (sulindac, inulin/VSL#3, sulindac/inulin/VSL#3) were compared with the Mann-Whitney U test. Cell proliferation was lower after sulindac or VSL#3/inulin, the combination treatment with sulindac/inulin/VSL#3 showed the opposite. GST enzyme activity was increased after sulindac or VSL#3/inulin, the combination treatment showed the opposite effect. However, no significance was reached in all these measures. Cytotoxicity, pH, and SCFA content of fecal water showed no differences at all among the three treatment groups. Our study revealed non-significant decreased cell proliferation and increased detoxification capacity after treatment with sulindac or VSL#3/inulin; however, combining both regimens did not show an additional effect.
    International Journal of Colorectal Disease 05/2011; 26(5):575-82. DOI:10.1007/s00384-010-1127-y · 2.42 Impact Factor
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    ABSTRACT: Oxidative stress is presumed to play an important role in inflammatory bowel disease (IBD). Accordingly, antioxidant supplementation might be protective. Dietary calcium inhibited colitis development in HLA-B27 transgenic rats, an animal model mimicking IBD. As antioxidants might act at mucosa level and calcium predominantly in the gut lumen, we hypothesize that the combination has additive protective effects on colitis development. HLA-B27 rats were fed a control diet or the same diet supplemented with the antioxidants glutathione, vitamin C, and vitamin E, or supplemented with both antioxidants and calcium. Oxidative stress in colonic mucosa, colonic inflammation, intestinal permeability, and diarrhea were quantified. Intestinal permeability, diarrhea, myeloperoxidase, and interleukin-1β levels were significantly lower in rats fed both antioxidants and calcium compared to rats supplemented with antioxidants only. No beneficial effects were observed in rats fed the diet supplemented with antioxidants only. Strikingly, despite extremely low colonic mucosal glutathione levels in HLA-B27 rats, there was no oxidative stress-related damage. Subsequent analyses showed no defect in expression of glutathione synthesis genes. Additional experiments, comparing young and older HLA-B27 rats, showed that glutathione levels and also reactive oxygen species production decreased with progression of intestinal inflammation. Antioxidant supplementation was ineffective in HLA-B27 rats despite low mucosal glutathione levels, because colitis development did not coincide with oxidative stress in this model. This indicates that the neutrophilic respiratory burst, and thus innate immune defense, is compromised in HLA-B27 rats. As supplementation with both calcium and antioxidants attenuated colitis development, we speculate that this protective effect is attributed to calcium only.
    Inflammatory Bowel Diseases 01/2011; 17(10):2065-75. DOI:10.1002/ibd.21584 · 5.48 Impact Factor
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    ABSTRACT: UDP-glucuronosyltransferase 1A1 (UGT1A1) is an enzyme which catalyses not only the glucuronidation of tobacco smoke carcinogens like benzopyrene, but also of the endogenous substrate bilirubin. Bilirubin for a long time was considered to be only a toxic waste product of hemoglobin degradation, but recent findings have shown that bilirubin is a potent antioxidant, which may play a protective role against cancer. We investigated whether a genetic polymorphism in UGT1A1 (UGT1A1*28), associated with a reduced UGT1A1 enzyme activity, may have a risk-modifying effect on head and neck carcinogenesis. Blood samples from 421 patients with oral, pharyngeal or laryngeal carcinoma, and 417 healthy controls were investigated for the UGT1A1*28 polymorphism. On the basis of the occurrence of this polymorphism, patients and controls were divided according to predicted UGT1A1 enzyme activity (low, intermediate, high). Logistic regression analysis showed a significant increased distribution of predicted high activity UGT1A1*1 polymorphisms among the patients (OR: 1.37; 95% CI: 1.02-1.83). Stratified analyses demonstrated that predicted high activity UGT1A1 polymorphisms were present even more significantly in patients with laryngeal cancer, older patients, heavy smokers and heavy drinkers. In conclusion, the predicted high activity UGT1A1*1 polymorphism, which results in lower serum levels of the endogenous antioxidant bilirubin, was associated with an increased risk of head and neck cancer.
    International Journal of Cancer 12/2010; 127(12):2815-21. DOI:10.1002/ijc.25296 · 5.01 Impact Factor
  • International journal of antimicrobial agents 11/2009; 34(4):385-6. DOI:10.1016/j.ijantimicag.2009.06.003 · 4.26 Impact Factor

Publication Stats

2k Citations
457.61 Total Impact Points

Institutions

  • 1985–2015
    • Radboud University Medical Centre (Radboudumc)
      • Department of Human Genetics
      Nymegen, Gelderland, Netherlands
  • 1984–2014
    • Radboud University Nijmegen
      • • Department of Gastroenterology and Hepatology
      • • Medical Centre
      • • Pharmacology and Toxicology
      Nymegen, Gelderland, Netherlands
  • 2012
    • Canisius-Wilhelmina Ziekenhuis
      Nymegen, Gelderland, Netherlands