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    Keywords: Germany ; COMPONENTS ; IDENTIFICATION ; DERIVATIVES ; phenolic compounds ; PLANTS ; High-performance liquid chromatography ; ACETOGENINS ; gas chromatography-mass spectometry ; hypoxanthine/xanthine oxidase assay ; SQUAMOSA
    Abstract: The root bark of Annona cuneata Oliv. is traditionally used in the Democratic Republic of Congo to treat several debilitating conditions, such as hernia, female sterility, sexual asthenia, and parasitic infections. However, little is known about the composition of the secondary plant substances, which may contribute to these traditional medicinal effects. We conducted an ethnobotanical study and then evaluated the composition of the secondary plant substances in extracts of the root bark by using spectroscopic methods. After delipidation, the root bark was lixiviated in methanol, and components in the extract were studied by gas chromatography-mass spectometry, high-performance liquid chromatography (HPLC)-electrospray ionization-MS and nano-electrospray ionization-MS-MS. These methods identified 13 secondary plant substances (almost exclusively phenolic compounds): p-hydroxybenzaldehyde (I), vanillin (II), tyrosol (III), 3,4-dihydroxybenzaldehyde (IV), p-hydroxybenzoic acid (V), vanillyl alcohol (VI), syringaldehyde (VII), 4-hydroxy-3-methoxyphenylethanol (VIII), vanillic acid (IX), 3,4-dihydroxybenzoic acid (X), syringic acid (XI), and ferulic acid (XII), along with the phytosterol squalene (XIII). In the HPLC-based hypoxanthine/xanthine oxidase antioxidant assay system, the methanolic extract exhibited potent antioxidant capacity, with a 50% inhibitory concentration of 72 muL, equivalent to 1.38 mg/mL of raw extract. Thus, a methanol extract of A. cuneata Oliv. contained a range of polyphenolic compounds, which may be partly responsible for its known traditional medicinal effects. More detailed studies on the phytochemistry of this important plant species are therefore warranted.
    Type of Publication: Journal article published
    PubMed ID: 21870939
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  • 4
    Keywords: CANCER ; EXPRESSION ; DISEASES ; GENE ; GENE-EXPRESSION ; REPAIR ; DAMAGE ; LIPID-PEROXIDATION ; HUMAN-DISEASE ; HYPOMETHYLATION ; METHYLTRANSFERASE ; 3,N-4-ETHENOCYTOSINE ; LIVER DNA ; ADDUCT TYPES
    Abstract: Methylation of cytidine at dCpdG sequences regulates gene expression and is altered in many chronic inflammatory diseases. Inflammation generates lipid peroxidation (LPO) products which can react with deoxycytidine, deoxyadenosine, and deoxyguanosine in DNA to form pro-mutagenic exocyclic etheno-nucleoside residues. Since 5-methyl-2'-deoxycytidine (5mdC) residues exhibit increased nucleophilicity at N3, they should be even better targets for LPO products. We synthesized and characterized 3,N(4)-etheno-5-methyl-2'-deoxycytidine-3'-phosphate and showed that LPO products can indeed form the corresponding etheno-5mdC (epsilon 5mdC) lesion in DNA in vitro. Our newly developed (32)P-postlabeling method was subsequently used to detect epsilon 5mdC lesions in DNA from human white blood cells, lung, and liver at concentrations 4-10 times higher than that observed for etheno adducts on nonmethylated cytidine. Our new detection method can now be used to explore the hypothesis that this DNA lesion perturbs the DNA methylation status
    Type of Publication: Journal article published
    PubMed ID: 22148471
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  • 5
    Keywords: liver ; RISK ; NITRIC-OXIDE ; COLORECTAL-CANCER ; OLIVE OIL ; PHENOLIC-COMPOUNDS ; WHITE BLOOD-CELLS ; 1,N-6-ETHENODEOXYADENOSINE ; ARACHIDONIC-ACID METABOLISM ; BASE ADDUCTS
    Abstract: Molecular pathways to colorectal cancer involve multiple genetic changes, whereby extensive oxyradical damage causes mutations in cancer-related genes and leads to a cycle of cell death and regeneration. Besides direct oxidative DNA-damage, reactive oxygen and nitrogen species can induce etheno (epsilon)-DNA adducts mainly via trans-4-hydroxy-2-nonenal, generated as the major aldehyde by lipid peroxidation (LPO) of omega-6 PUFAs. Patients with familial adenomatous polyposis (FAP) develop multiple colorectal adenomas. In affected tissues increased LPO could be triggered due to increased arachidonic acid metabolism as a result of elevated cyclooxygenases. Our studies demonstrated an increased epsilon-DNA adduct level in affected colon epithelia of FAP patients. Epsilon-DNA adducts are promutagenic and can cause genomic instability that drives colorectal adenoma to malignancy. We have further investigated the potential chemopreventive properties of olive oil and its polyphenolic components. 'Mediterranean diet', of which olive oil is a major fatty acid source, has protective effects against human breast and colorectal cancers. Olive oil extracts and the newly identified lignan fractions showed high antioxidant capacity in vitro. As epsilon-DNA adducts are biomarkers for oxidative stress and LPO induced DNA damage, they can verify the efficacy of newly identified antioxidants, e.g. from olive oil, as chemopreventive agents against colon carcinogenesis.
    Type of Publication: Journal article published
    PubMed ID: 12222681
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  • 6
    Keywords: CARCINOGENESIS ; TISSUES ; BREAST-CANCER ; HUMANS ; DAMAGE ; WHITE BLOOD-CELLS ; PRODUCTS ; MALONALDEHYDE ; DEOXYGUANOSINE ; OXYRADICALS
    Abstract: A diet high in linoleic acid (an omega-6 PUFA) increased the formation of miscoding etheno (epsilon) - DNA adducts in WBC-DNA of women, but not in men (Nair et al., Cancer Epidemiol Biomark Prev 1997;6:597-601). This gender specificity could result from an interaction between omega-6 PUFA intake and estrogen catabolism, via redox-cycling of 4-hydroxyestradiol (4-OH-E(2) ) and subsequent lipid peroxidation (LPO). In this study, we investigated whether in premenopausal women LPO-derived adducts in WBC-DNA are affected by serum concentration of 2- and 4-hydroxyestradiol metabolites and by fatty acid intake. DNA extracted from buffy coat and plasma samples, both blindly coded from healthy women (N = 124, median age 40 year) participating in the EPIC-Heidelberg cohort study were analyzed. Three LPO-derived exocyclic DNA adducts, epsilondA, epsilondC and M(1) dG were quantified by immuno-enriched (32) P-postlabelling and estradiol metabolites by ultra-sensitive GC-mass spectrometry. Mean M(1) dG levels in WBC-DNA were distinctly higher than those of epsilondA and epsilondC, and all were positively and significantly interrelated. Serum levels of 4-OH-E(2) , but not of 2-OH-E(2) , metabolites were positively related to etheno DNA adduct formation. Positive correlations existed between M(1) dG levels and linoleic acid intake or the ratios of dietary linoleic acid/oleic acid and PUFA/MUFA. Aerobic incubation of 4-OH-E(2) , arachidonic acid and calf thymus DNA yielded two to threefold higher etheno DNA adduct levels when compared with assays containing 2-OH-E(2) instead. In conclusion, this study is the first to compare M(1) dG and etheno-DNA adducts and serum estradiol metabolites in human samples in the same subjects. Our results support a novel mechanistic link between estradiol catabolism, dietary omega-6 fatty acid intake and LPO-induced DNA damage supported by an in vitro model. Similar studies in human breast epithelial tissue and on amplification of DNA-damage in breast cancer patients are in progress.
    Type of Publication: Journal article published
    PubMed ID: 22322480
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  • 7
    Keywords: IN-VITRO ; PROTEINS ; MOLECULAR-CLONING ; BIOCHEMICAL-CHARACTERIZATION ; STAUDINGER LIGATION ; MYRISTOYLTRANSFERASE ACTIVITY ; FATTY ACYLATION ; MYRISTIC ACID ; DRUG TARGET ; COA
    Abstract: Myristoyl-CoA (CoA):protein N-myristoyltransferase (NMT) catalyzes protein modification through covalent attachment of a C14 fatty acid (myristic acid) to the N-terminal glycine of proteins, thus promoting protein-protein and protein-membrane interactions. NMT is essential for the viability of numerous human pathogens and is also up-regulated in several tumors. Here we describe a new, nonradioactive, ELISA-based method for measuring NMT activity. After the NMT-catalyzed reaction between a FLAG-tagged peptide and azido-dodecanoyl-CoA (analog of myristoyl-CoA), the resulting azido-dodecanoyl-peptide-FLAG was coupled to phosphine-biotin by Staudinger ligation, captured by plate-bound anti-FLAG antibodies and detected by streptavidin-peroxidase. The assay was validated with negative controls (including inhibitors), corroborated by HPLC analysis, and demonstrated to function with fresh or frozen tissues. Recombinant murine NMT1 and NMT2 were characterized using this new method. This versatile assay is applicable for exploring recombinant NMTs with regard to their activity, substrate specificity, and possible inhibitors as well as for measuring NMT-activity in tissues.
    Type of Publication: Journal article published
    PubMed ID: 22829651
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  • 8
    Abstract: Pancreatic phospholipase A2, product of PLA2G1B, catalyzes the release of fatty acids from dietary phospholipids.Diet is the ultimate source of arachidonic acid in cellular phospholipids, precursor of eicosanoid signaling molecules, linked to inflammation, cell proliferation and colorectal carcinogenesis. We evaluated the association of PLA2G1B tagging single-nucleotide polymorphisms with colorectal neoplasia risk. A linkage-disequilibrium-based tagSNP algorithm (r(2)=0.90, MAF〉/=4%) identified three tagSNPs. The SNPs were genotyped on the Illumina platform in three population-based, case-control studies: colon cancer (1424 cases/1780 controls); rectal cancer (583/775); colorectal adenomas (485/578). Evaluating gene-wide associations, principal-component and haplotype analysis were conducted, individual SNPs were evaluated by logistic regression. Two PLA2G1B variants were statistically significantly associated with reduced risk of rectal cancer (rs5637, 3702 G〉A Ser98Ser, p-trend=0.03; rs9657930, 1593 C〉T, p-trend=0.01); principal component analysis showed that genetic variation in the gene overall was statistically significantly associated with rectal cancer (p=0.02). NSAID users with the rs2070873 variant had a reduced rectal cancer risk (P-inter=0.02). Specific associations were observed with tumor subtypes (TP53/KRAS). The results suggest that genetic polymorphisms in PLA2G1B affect susceptibility to rectal cancer.
    Type of Publication: Journal article published
    PubMed ID: 24046806
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  • 9
    Keywords: IN-VITRO ; CANCER GROWTH ; LIPID-PEROXIDATION ; ANTIOXIDANT CAPACITY ; HUMAN PLASMA ; ELLAGIC ACID ; POMEGRANATE JUICE ; POLYPHENOLIC COMPOUNDS ; PROSTATE-GLAND ; GUT MICROBIOTA
    Abstract: A pilot intervention study was conducted in human volunteers (n = 4) to establish the bioavailability of urolithins, which are the terminal end-products of ellagitannin metabolism by the gastrointestinal microflora. Biospecimens (blood, feces, and urine) along with urolithins purified therefrom were analyzed for their antioxidant capacity in a range of in vitro assays. Urolithin metabolites were identified and quantitated in the biospecimens by negative ion mode HPLC-ESI-MS analysis. The data in this pilot study show that the metabolism of ellagitannins in the four volunteers gave rise to a diverse profile and a highly variable concentration of urolithins in urine. The concentration of glucuronidated urolithins in blood and urine did not correlate with antioxidant capacity. However, the antioxidant capacity of urine, but not plasma biospecimens, was highly correlated with uric acid concentration. The antioxidant capacity of fecal extracts correlated positively with the concentration of urolithin D in both the DPPH and FRAP assays, but not in the ORAC assay, which was entirely consistent with the in vitro assays for pure urolithin D.
    Type of Publication: Journal article published
    PubMed ID: 25275327
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  • 10
    Keywords: EXPRESSION ; PROSTATE-CANCER ; BINDING-PROTEIN ; ESTERS ; ESTERIFICATION ; ISOMEROHYDROLASE ; PUTATIVE RECEPTOR ; REDUCED LECITHIN ; RETINOIC ACID RECEPTORS ; VISUAL CYCLE
    Abstract: Disturbance in vitamin A metabolism seems to be an important attribute of cancer cells. Retinoids, particularly retinoic acid, have critical regulatory functions and appear to modulate tumor development and progression. The key step of vitamin A metabolism is the esterification of all-trans retinol, catalyzed by lecithin/retinol acyltransferase (LRAT). In this work, we show that malignant melanoma cells are able to esterify all-trans retinol and subsequently isomerize all-trans retinyl esters (RE) into 11-cis retinol, whereas their benign counterparts-melanocytes are not able to catalyze these reactions. Besides, melanoma cell lines express lecithin/retinol acyltranseferase both at the mRNA and protein levels. In contrast, melanocytes do not express this enzyme at the protein level, but mRNA of lecithin/retinol acyltransefrase could still be present at mRNA level. RPE65 is expressed in both melanocytic counterparts, and could be involved in the subsequent isomerization of RE produced by lecithin/retinol acyltransefrase to 11-cis retinol. Cellular retinol-binding protein 2 does not appear to be involved in the regulation of all-trans retinol esterification in these cells. Expression of LRAT and RPE65 can be modulated by retinoids. We propose that the post-transcriptional regulation of lecithin/retinol acyltransefrase could be involved in the differential expression of this enzyme. Besides, activities of LRAT and RPE65 may be important for removal of all-trans retinal which is the substrate for retinoic acid production in skin cells. Consequently, the decreasing cellular amount of retinoic acid and its precursor molecules could result in a change of gene regulation. J. Cell. Physiol. (c) 2011 Wiley Periodicals, Inc.
    Type of Publication: Journal article published
    PubMed ID: 21465477
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