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Ciguatoxins (CTX) are potent marine neurotoxins, which can bioaccumulate in seafood, causing a severe and prevalent human illness known as ciguatera poisoning (CP). Despite the worldwide impact of ciguatera, effective disease management is hindered by a lack of knowledge regarding the movement and biotransformation of CTX congeners in marine food webs, particularly in the Caribbean and Western Atlantic. In this study we investigated the hepatic biotransformation of C-CTX across several fish and mammalian species through a series of in vitro metabolism assays focused on phase I (CYP P450; functionalization) and phase II (UGT; conjugation) reactions. Using liquid chromatography high-resolution mass spectrometry to explore potential C-CTX metabolites, we observed two glucuronide products of C-CTX-1/-2 and provided additional evidence from high-resolution tandem mass spectrometry to support their identification. Chemical reduction experiments confirmed that the metabolites were comprised of four distinct glucuronide products with the sugar attached at two separate sites on C-CTX-1/-2 and excluded the C-56 hydroxyl group as the conjugation site. Glucuronidation is a novel biotransformation pathway not yet reported for CTX or other related polyether phycotoxins, yet its occurrence across all fish species tested suggests that it could be a prevalent and important detoxification mechanism in marine organisms. The absence of glucuronidation observed in this study for both rat and human microsomes suggests that alternate biotransformation pathways may be dominant in higher vertebrates.
Jessica Kay Gwinn; Silvio Uhlig; Lada Ivanova; Christiane Kruse Fæste; Fedor Kryuchkov; Alison Robertson. In Vitro Glucuronidation of Caribbean Ciguatoxins in Fish: First Report of Conjugative Ciguatoxin Metabolites. Chemical Research in Toxicology 2021, 34, 1910 -1925.
AMA StyleJessica Kay Gwinn, Silvio Uhlig, Lada Ivanova, Christiane Kruse Fæste, Fedor Kryuchkov, Alison Robertson. In Vitro Glucuronidation of Caribbean Ciguatoxins in Fish: First Report of Conjugative Ciguatoxin Metabolites. Chemical Research in Toxicology. 2021; 34 (8):1910-1925.
Chicago/Turabian StyleJessica Kay Gwinn; Silvio Uhlig; Lada Ivanova; Christiane Kruse Fæste; Fedor Kryuchkov; Alison Robertson. 2021. "In Vitro Glucuronidation of Caribbean Ciguatoxins in Fish: First Report of Conjugative Ciguatoxin Metabolites." Chemical Research in Toxicology 34, no. 8: 1910-1925.
The plant parasitic fungus Claviceps purpurea sensu lato produces sclerotia containing toxic ergot alkaloids and uncharacterized indole diterpenoids in grasses including cereals. The aim of this study was to detect as many peptide ergot alkaloids and indole diterpenoids in ergot sclerotia as possible by using a liquid chromatography–high-resolution mass spectrometry (LC–HRMS/MS) approach and applying filtering of diagnostic fragment ions for data extraction. The sample set consisted of 66 Claviceps sclerotia from four different geographic locations in southeastern Norway as well as Saskatchewan, Canada. The host plants included both wild grasses and important cereal grains such as rye. DNA sequencing showed that the sclerotia were from three Claviceps species, i.e., Claviceps purpurea sensu stricto (s.s.), Claviceps humidiphila, and Claviceps arundinis (former C. purpurea genotypes G1, G2, and G2a, respectively). All sclerotia from cereal grains were from C. purpurea s.s. Diagnostic fragment filtering was based on detecting specific product ions in MS/MS data sets that are well-conserved across the different ergot alkaloid subgroups and indole diterpenoids of the paspaline/paxilline type. The approach extracted mass spectra from 67 peptide ergot alkaloids (including C-8 epimers and lactam variants) and five indole diterpenoids. In addition, three clavines were detected by using targeted analysis. The sum of the peak areas for ergot alkaloids, which have been assigned as “major” analogues by the European Food Safety Authority (ergometrine, ergosine, ergotamine, α-ergocryptine, ergocornine, ergocristine, and their 8-S epimers), accounted for at least 50% of the extracted total ergot alkaloid metabolome. Univariate and multivariate statistical analyses showed that several of the alkaloids were specific for certain species within the C. purpurea species complex and could be used as chemotaxonomic markers for species assignment.
Silvio Uhlig; Oscar Daniel Rangel-Huerta; Hege H. Divon; Elin Rolén; Kari Pauchon; Mark W. Sumarah; Trude Vrålstad; Justin B. Renaud. Unraveling the Ergot Alkaloid and Indole Diterpenoid Metabolome in the Claviceps purpurea Species Complex Using LC–HRMS/MS Diagnostic Fragmentation Filtering. Journal of Agricultural and Food Chemistry 2021, 1 .
AMA StyleSilvio Uhlig, Oscar Daniel Rangel-Huerta, Hege H. Divon, Elin Rolén, Kari Pauchon, Mark W. Sumarah, Trude Vrålstad, Justin B. Renaud. Unraveling the Ergot Alkaloid and Indole Diterpenoid Metabolome in the Claviceps purpurea Species Complex Using LC–HRMS/MS Diagnostic Fragmentation Filtering. Journal of Agricultural and Food Chemistry. 2021; ():1.
Chicago/Turabian StyleSilvio Uhlig; Oscar Daniel Rangel-Huerta; Hege H. Divon; Elin Rolén; Kari Pauchon; Mark W. Sumarah; Trude Vrålstad; Justin B. Renaud. 2021. "Unraveling the Ergot Alkaloid and Indole Diterpenoid Metabolome in the Claviceps purpurea Species Complex Using LC–HRMS/MS Diagnostic Fragmentation Filtering." Journal of Agricultural and Food Chemistry , no. : 1.
Mycotoxin intoxication is in general an acknowledged and tackled issue in animals. However, in several parts of the world, mycotoxicoses in humans still remain a relevant issue. The efficacy of two mycotoxin detoxifying animal feed additives, an aflatoxin bentonite clay binder and a fumonisin esterase, was investigated in a human child gut model, i.e. the in vitro Simulator of the Human Intestinal Microbial Ecosystem (SHIME®). Additionally, the effect of the detoxifiers on gut microbiota was examined in the SHIME. After an initial two weeks of system stabilisation, aflatoxin B1 (AFB1) and fumonisin B1 (FB1) were added to the SHIME diet during one week. Next, the two detoxifiers and mycotoxins were added to the system for an additional week. The AFB1, FB1, hydrolysed FB1 (HFB1), partially hydrolysed FB1a and FB1b concentrations were determined in SHIME samples using a validated ultra-performance liquid chromatography-tandem mass spectrometry method. The short-chain fatty acid (SCFA) concentrations were determined by a validated gas chromatography–mass spectrometry method. Colonic bacterial communities were analysed using metabarcoding, targeting the hypervariable V1-V3 regions of the 16S rRNA genes. The AFB1 and FB1 concentrations significantly decreased after the addition of the detoxifiers. Likewise, the concentration of HFB1 significantly increased. Concentrations of SCFAs remained generally stable throughout the experiment. No major changes in bacterial composition occurred during the experiment. The results demonstrate the promising effect of these detoxifiers in reducing AFB1 and FB1 concentrations in the human intestinal environment, without compromising the gastrointestinal microbiota.
Kaat Neckermann; Gregor Claus; Siegrid De Baere; Gunther Antonissen; Sarah Lebrun; Céline Gemmi; Bernard Taminiau; Caroline Douny; Marie-Louise Scippo; Dian Schatzmayr; James Gathumbi; Silvio Uhlig; Siska Croubels; Véronique Delcenserie. The efficacy and effect on gut microbiota of an aflatoxin binder and a fumonisin esterase using an in vitro simulator of the human intestinal microbial ecosystem (SHIME®). Food Research International 2021, 145, 110395 .
AMA StyleKaat Neckermann, Gregor Claus, Siegrid De Baere, Gunther Antonissen, Sarah Lebrun, Céline Gemmi, Bernard Taminiau, Caroline Douny, Marie-Louise Scippo, Dian Schatzmayr, James Gathumbi, Silvio Uhlig, Siska Croubels, Véronique Delcenserie. The efficacy and effect on gut microbiota of an aflatoxin binder and a fumonisin esterase using an in vitro simulator of the human intestinal microbial ecosystem (SHIME®). Food Research International. 2021; 145 ():110395.
Chicago/Turabian StyleKaat Neckermann; Gregor Claus; Siegrid De Baere; Gunther Antonissen; Sarah Lebrun; Céline Gemmi; Bernard Taminiau; Caroline Douny; Marie-Louise Scippo; Dian Schatzmayr; James Gathumbi; Silvio Uhlig; Siska Croubels; Véronique Delcenserie. 2021. "The efficacy and effect on gut microbiota of an aflatoxin binder and a fumonisin esterase using an in vitro simulator of the human intestinal microbial ecosystem (SHIME®)." Food Research International 145, no. : 110395.
The aim of this study was to investigate the potential interference of cyanobacterial metabolites, in particular microcystins (MCs), with steroid hormone biosynthesis. Steroid hormones control many fundamental processes in an organism, thus alteration of their tissue concentrations may affect normal homeostasis. We used liquid chromatography–tandem mass spectrometry (LC–MS/MS) to investigate the modulation of 14 hormones involved in the adrenal steroid biosynthesis pathway using forskolin-treated H295R cells, following exposure with either microcystin-LR (MC-LR) alone, a mixture made up of MC-LR together with eight other MCs and nodularin-R (NOD-R), or extracts from the MC-LR-producing Microcystis aeruginosa PCC7806 strain or its MC-deficient mutant PCC7806mcyB−. Production of 17-hydroxypregnenolone and dehydroepiandrosterone (DHEA) was increased in the presence of MC-LR in a dose-dependent manner, indicating an inhibitory effect on 3β-hydroxysteroid dehydrogenase (3β-HSD). This effect was not observed following exposure with a MCs/NOD-R mixture, and thus the effect of MC-LR on 3β-HSD appears to be stronger than for other congeners. Exposure to extracts from both M. aeruginosa PCC7806 and M. aeruginosa PCC7806mcyB− had an opposite effect on 3β-HSD, i.e. concentrations of pregnenolone, 17-hydroxypregnenolone and DHEA were significantly decreased, showing that there are other cyanobacterial metabolites that outcompete the effect of MC-LR, and possibly result instead in net-induction. Another finding was a possible concentration-dependent inhibition of CYP21A2 or CYP11β1, which catalyse oxidation reactions leading to cortisol and cortisone, by MC-LR and the MCs/NOD-R mixture. However, both M. aeruginosa PCC7806 and M. aeruginosa PCC7806mcyB− extracts had an opposite effect resulting in a substantial increase in cortisol levels. Our results suggest that MCs can modulate steroidogenesis, but the net effect of the M. aeruginosa metabolome on steroidogenesis is different from that of pure MC-LR and independent of MC production.
Vittoria Mallia; Steven Verhaegen; Bjarne Styrishave; Gunnar Sundstøl Eriksen; Malene Louise Johannsen; Erik Ropstad; Silvio Uhlig. Microcystins and Microcystis aeruginosa PCC7806 extracts modulate steroidogenesis differentially in the human H295R adrenal model. PLOS ONE 2020, 15, e0244000 .
AMA StyleVittoria Mallia, Steven Verhaegen, Bjarne Styrishave, Gunnar Sundstøl Eriksen, Malene Louise Johannsen, Erik Ropstad, Silvio Uhlig. Microcystins and Microcystis aeruginosa PCC7806 extracts modulate steroidogenesis differentially in the human H295R adrenal model. PLOS ONE. 2020; 15 (12):e0244000.
Chicago/Turabian StyleVittoria Mallia; Steven Verhaegen; Bjarne Styrishave; Gunnar Sundstøl Eriksen; Malene Louise Johannsen; Erik Ropstad; Silvio Uhlig. 2020. "Microcystins and Microcystis aeruginosa PCC7806 extracts modulate steroidogenesis differentially in the human H295R adrenal model." PLOS ONE 15, no. 12: e0244000.
This study determined the presence, levels and co-occurrence of mycotoxins in fish feeds in Kenya. Seventy-eight fish feeds and ingredients were sampled from fish farms and fish feed manufacturing plants and analysed for 40 mycotoxins using high-performance liquid chromatography-high resolution mass spectrometry. Twenty-nine (73%) mycotoxins were identified with 76 (97%) samples testing positive for mycotoxins presence. Mycotoxins with the highest prevalences were enniatin B (91%), deoxynivalenol (76%) and fumonisin B1 (54%) while those with the highest maximum levels were sterigmatocystin (<30.5–3517.1 µg/kg); moniliformin (<218.9–2583.4 µg/kg) and ergotamine (<29.3–1895.6 µg/kg). Mycotoxin co-occurrence was observed in 68 (87%) samples. Correlations were observed between the fumonisins; enniatins B and zearalenone and its metabolites. Fish dietary exposure estimates ranged between <0.16 and 43.38 µg/kg body weight per day. This study shows evidence of mycotoxin presence and co-occurrence in fish feeds and feed ingredients in Kenya. Fish exposure to these levels of mycotoxins over a long period of time may lead to adverse health effects due to their possible additive, synergistic or antagonist toxic effects. Measures to reduce fish feed mycotoxin contamination should be taken to avoid mycotoxicosis in fish and subsequently in humans and animals through residues.
Evalyn Wanjiru Mwihia; Jan Ludvig Lyche; Paul Gichohi Mbuthia; Lada Ivanova; Silvio Uhlig; James K. Gathumbi; Joyce G. Maina; Eric Emali Eshitera; Gunnar Sundstøl Eriksen. Co-Occurrence and Levels of Mycotoxins in Fish Feeds in Kenya. Toxins 2020, 12, 627 .
AMA StyleEvalyn Wanjiru Mwihia, Jan Ludvig Lyche, Paul Gichohi Mbuthia, Lada Ivanova, Silvio Uhlig, James K. Gathumbi, Joyce G. Maina, Eric Emali Eshitera, Gunnar Sundstøl Eriksen. Co-Occurrence and Levels of Mycotoxins in Fish Feeds in Kenya. Toxins. 2020; 12 (10):627.
Chicago/Turabian StyleEvalyn Wanjiru Mwihia; Jan Ludvig Lyche; Paul Gichohi Mbuthia; Lada Ivanova; Silvio Uhlig; James K. Gathumbi; Joyce G. Maina; Eric Emali Eshitera; Gunnar Sundstøl Eriksen. 2020. "Co-Occurrence and Levels of Mycotoxins in Fish Feeds in Kenya." Toxins 12, no. 10: 627.
Juveniles are considered as one of the most vulnerable population groups concerning mycotoxins and their modified forms. The weaning stage is a particularly vulnerable period in the life of mammals, reflected in intestinal and immune dysfunction. The current study investigated the toxicokinetic (TK) characteristics of zearalenone (ZEN), zearalenone-14-glucoside (ZEN14G), and zearalenone-14-sulfate (ZEN14S) in weaned (4-week-old) piglets, by means of oral and intravenous administration of equimolar doses, i.e., 331, 500, and 415 μg/kg bodyweight, respectively. Plasma and urine were sampled pre- and post-administration and were quantitatively analyzed for ZEN, ZEN14G, ZEN14S, and in vivo metabolites by liquid chromatography–high-resolution mass spectrometry. Tailor-made TK models were elaborated to process data. A statistical comparison of the results was performed with TK data obtained in a previously reported study in pigs of 8 weeks of age. Additionally, porcine plasma protein binding was determined to support TK findings. The TK results for ZEN, ZEN14G, and ZEN14S, obtained in 4- and 8-week-old pigs, revealed significant age-related differences, based on differences in intestinal permeability, body fat content, gastrointestinal transit time, and biotransformation, with a special emphasis on an increased absorbed fraction of ZEN14G, i.e., 94 vs 61% in 4- compared to 8-week-old pigs. Since the growing pig has been reported to be a suitable pediatric animal model for humans concerning TK processes, these results may contribute to refine the risk assessment concerning modified ZEN forms in juvenile animals and humans.
Amelie Catteuw; Mathias Devreese; Siegrid De Baere; Gunther Antonissen; Bart Huybrechts; Lada Ivanova; Silvio Uhlig; Ann Martens; Sarah De Saeger; Marthe De Boevre; Siska Croubels. Toxicokinetic Studies in Piglets Reveal Age-Related Differences in Systemic Exposure to Zearalenone, Zearalenone-14-Glucoside, and Zearalenone-14-Sulfate. Journal of Agricultural and Food Chemistry 2020, 68, 7757 -7764.
AMA StyleAmelie Catteuw, Mathias Devreese, Siegrid De Baere, Gunther Antonissen, Bart Huybrechts, Lada Ivanova, Silvio Uhlig, Ann Martens, Sarah De Saeger, Marthe De Boevre, Siska Croubels. Toxicokinetic Studies in Piglets Reveal Age-Related Differences in Systemic Exposure to Zearalenone, Zearalenone-14-Glucoside, and Zearalenone-14-Sulfate. Journal of Agricultural and Food Chemistry. 2020; 68 (29):7757-7764.
Chicago/Turabian StyleAmelie Catteuw; Mathias Devreese; Siegrid De Baere; Gunther Antonissen; Bart Huybrechts; Lada Ivanova; Silvio Uhlig; Ann Martens; Sarah De Saeger; Marthe De Boevre; Siska Croubels. 2020. "Toxicokinetic Studies in Piglets Reveal Age-Related Differences in Systemic Exposure to Zearalenone, Zearalenone-14-Glucoside, and Zearalenone-14-Sulfate." Journal of Agricultural and Food Chemistry 68, no. 29: 7757-7764.
The tremorgenic mycotoxin penitrem A is produced by Penicillium species as a secondary metabolite on moldy food and feed. Dogs are sometimes exposed to penitrem A by consumption of spoiled food waste or fallen fruit. The lipophilic toxin crosses the blood-brain barrier and targets neuroreceptors and neurotransmitter release mechanisms in the central and peripheral nervous systems. Typical symptoms of penitrem A intoxication are periodical or continuous tremors, which can be passing, persistent or lethal, depending on the absorbed dose. There is presently no information on the biotransformation and toxicokinetics of penitrem A in dogs. The aim of the present study was therefore to identify potential metabolites of the toxin by performing in vitro biotransformation assays in dog liver microsomes. Analyses by liquid chromatography coupled to high-resolution mass spectrometry led to the provisional identification of eleven penitrem A phase I metabolites, which were tentatively characterized as various oxidation products. Furthermore, elimination parameters determined in in vitro assays run under linear kinetics were used for in vitro-to-in vivo extrapolation of the toxicokinetic data, predicting a maximal bioavailability of more than 50%. The metabolite profile detected in the in vitro assays was similar to that observed in the plasma of an intoxicated dog, confirming the predictive capability of the in vitro approach.
Silvio Uhlig; Lada Ivanova; Pauline Voorspoels; Christiane Kruse Fæste. In Vitro Toxicokinetics and Phase I Biotransformation of the Mycotoxin Penitrem A in Dogs. Toxins 2020, 12, 293 .
AMA StyleSilvio Uhlig, Lada Ivanova, Pauline Voorspoels, Christiane Kruse Fæste. In Vitro Toxicokinetics and Phase I Biotransformation of the Mycotoxin Penitrem A in Dogs. Toxins. 2020; 12 (5):293.
Chicago/Turabian StyleSilvio Uhlig; Lada Ivanova; Pauline Voorspoels; Christiane Kruse Fæste. 2020. "In Vitro Toxicokinetics and Phase I Biotransformation of the Mycotoxin Penitrem A in Dogs." Toxins 12, no. 5: 293.
Cyanobacteria are cosmopolitan photosynthetic prokaryotes that can form dense accumulations in aquatic environments. They are able to produce many bioactive metabolites, some of which are potentially endocrine disrupting compounds, i.e., compounds that interfere with the hormonal systems of animals and humans. Endocrine disruptors represent potential risks to both environmental and human health, making them a global challenge. The aim of this study was to investigate the potential endocrine disrupting activities with emphasis on estrogenic effects of extracts from cultures of Microcystis or Planktothrix species. We also assessed the possible role of microcystins, some of the most studied cyanobacterial toxins, and thus included both microcystin-producing and non-producing strains. Extracts from 26 cyanobacterial cultures were initially screened in estrogen-, androgen-, and glucocorticoid-responsive reporter-gene assays (RGAs) in order to identify endocrine disruption at the level of nuclear receptor transcriptional activity. Extracts from selected strains were tested repeatedly in the estrogen-responsive RGAs, but the observed estrogen agonist and antagonist activity was minor and similar to that of the cyanobacteria growth medium control. We thus focused on another, non-receptor mediated mechanism of action, and studied the 17β-estradiol (natural estrogen hormone) biotransformation in human liver microsomes in the presence or absence of microcystin-LR (MC-LR), or an extract from the MC-LR producing M. aeruginosa PCC7806 strain. Our results show a modulating effect on the estradiol biotransformation. Thus, while 2-hydroxylation was significantly decreased following co-incubation of 17β-estradiol with MC-LR or M. aeruginosa PCC7806 extract, the relative concentration of estrone was increased.
Vittoria Mallia; Lada Ivanova; Gunnar S. Eriksen; Emma Harper; Lisa Connolly; Silvio Uhlig. Investigation of In Vitro Endocrine Activities of Microcystis and Planktothrix Cyanobacterial Strains. Toxins 2020, 12, 228 .
AMA StyleVittoria Mallia, Lada Ivanova, Gunnar S. Eriksen, Emma Harper, Lisa Connolly, Silvio Uhlig. Investigation of In Vitro Endocrine Activities of Microcystis and Planktothrix Cyanobacterial Strains. Toxins. 2020; 12 (4):228.
Chicago/Turabian StyleVittoria Mallia; Lada Ivanova; Gunnar S. Eriksen; Emma Harper; Lisa Connolly; Silvio Uhlig. 2020. "Investigation of In Vitro Endocrine Activities of Microcystis and Planktothrix Cyanobacterial Strains." Toxins 12, no. 4: 228.
Ciguatera poisoning is linked to the ingestion of seafood that is contaminated with ciguatoxins (CTXs). The structural variability of these polyether toxins in nature remains poorly understood due to the low concentrations present even in highly toxic fish, which makes isolation and chemical characterization difficult. We studied the mass spectrometric fragmentation of Caribbean CTXs, i.e., the epimers C-CTX-1 and -2 (1 and 2), using a sensitive UHPLC–HRMS/MS approach in order to identify product ions of diagnostic value. We found that the fragmentation of the ladder-frame backbone follows a characteristic pattern and propose a generalized nomenclature for the ions formed. These data were applied to the structural characterization of a pair of so far poorly characterized isomers, C-CTX-3 and -4 (3 and 4), which we found to be reduced at C-56 relative to 1 and 2. Furthermore, we tested and applied reduction and oxidation reactions, monitored by LC–HRMS, in order to confirm the structures of 3 and 4. Reduction of 1 and 2 with NaBH4 afforded 3 and 4, thereby unambiguously confirming the identities of 3 and 4. In summary, this work provides a foundation for mass spectrometry-based characterization of new C-CTXs, including a suite of simple chemical reactions to assist the examination of structural modifications.
Fedor Kryuchkov; Alison Robertson; Christopher O. Miles; Elizabeth M. Mudge; Silvio Uhlig. LC–HRMS and Chemical Derivatization Strategies for the Structure Elucidation of Caribbean Ciguatoxins: Identification of C-CTX-3 and -4. Marine Drugs 2020, 18, 182 .
AMA StyleFedor Kryuchkov, Alison Robertson, Christopher O. Miles, Elizabeth M. Mudge, Silvio Uhlig. LC–HRMS and Chemical Derivatization Strategies for the Structure Elucidation of Caribbean Ciguatoxins: Identification of C-CTX-3 and -4. Marine Drugs. 2020; 18 (4):182.
Chicago/Turabian StyleFedor Kryuchkov; Alison Robertson; Christopher O. Miles; Elizabeth M. Mudge; Silvio Uhlig. 2020. "LC–HRMS and Chemical Derivatization Strategies for the Structure Elucidation of Caribbean Ciguatoxins: Identification of C-CTX-3 and -4." Marine Drugs 18, no. 4: 182.
Deoxynivalenol (DON) is a trichothecene mycotoxin that is produced by several species of Fusarium, which may infect grain crops. DON, as well as other type-B trichothecenes, contain an α,β-unsaturated carbonyl group that may react with sulfhydryl groups in e.g. amino acids and peptides. Such conjugates have been shown to occur in plants. Nucleophilic addition of thiols to the conjugated double bond in DON afforded several isomeric reaction products, and the thermodynamically favored isomers of DON-10-cysteine and DON-10-glutathione have been prepared and characterized previously. This study reports the preparation and characterization of the kinetically favored DON-10-cysteine isomer. We subsequently studied and compared the rate of the deconjugation reaction of the two DON-10-cysteine isomers and the thermodynamically favored DON-10-glutathione adduct. The deconjugation rate of the thermodynamically favored thiol conjugates was slow with half-lives of weeks even at pH 10.7, while the kinetically favored DON-10-cysteine isomer deconjugated within few hours affording free DON. We adapted a simple and rapid oxidation protocol in which the sulfide linkage was oxidized to a sulfoxide or sulfone that, when treated with base, rapidly eliminated the adducted thiol as its sulfenate or sulfinate to afford free DON. The deconjugation reactions of the sulfoxides and sulfones of thermodynamically favored DON-10–thiols were complete within hours or minutes at pH 10.7, respectively. The increase in deconjugation rates for the kinetically favored DON-10-cysteine were less dramatic. Oxidation of sulfides to sulfoxides is known to occur in vivo, and thus our data shows that thiol-conjugated DON might become bioavailable via sulfide oxidation followed by elimination to regenerate DON. The oxidation-elimination approach could also be useful for the indirect quantification of DON-10–thiol conjugates in plant and animal tissues.
Silvio Uhlig; Lada Ivanova; Christopher O. Miles. Oxidative Release of Thiol-Conjugated Forms of the Mycotoxin 4-Deoxynivalenol. Chemical Research in Toxicology 2019, 33, 515 -521.
AMA StyleSilvio Uhlig, Lada Ivanova, Christopher O. Miles. Oxidative Release of Thiol-Conjugated Forms of the Mycotoxin 4-Deoxynivalenol. Chemical Research in Toxicology. 2019; 33 (2):515-521.
Chicago/Turabian StyleSilvio Uhlig; Lada Ivanova; Christopher O. Miles. 2019. "Oxidative Release of Thiol-Conjugated Forms of the Mycotoxin 4-Deoxynivalenol." Chemical Research in Toxicology 33, no. 2: 515-521.
Age-related differences in toxicokinetic processes of deoxynivalenol (DON) and deoxynivalenol-3-glucoside (DON3G) were studied. DON3G [55.7 µg/kg bodyweight (BW)] and an equimolar dose of DON (36 µg/kg BW) were administered to weaned piglets (4 weeks old) by single intravenous and oral administration in a double two-way cross-over design. Systemic and portal blood was sampled at different time points pre- and post-administration and plasma concentrations of DON, DON3G and their metabolites were quantified using validated liquid chromatography-tandem mass spectrometry (LC–MS/MS) and liquid chromatography–high-resolution mass spectrometry (LC–HRMS) methods. Data were processed using tailor-made compartmental toxicokinetic (TK) models to accurately estimate TK parameters. Results were statistically compared to data obtained in a previous study on 11-week-old pigs using identical experimental conditions. Significant age-related differences in intestinal and systemic exposure to both DON and DON3G were noted. Most remarkably, a significant difference was found for the absorbed fraction of DON3G, after presystemic hydrolysis to DON, in weaned piglets compared to 11-week-old piglets (83% vs 16%, respectively), assumed to be mainly attributed to the higher intestinal permeability of weaned piglets. Other differences in TK parameters could be assigned to a higher water/fat body ratio and longer gastrointestinal transit time of weaned piglets. Results may further refine current risk assessment concerning DON and DON3G in animals. Additionally, since piglets possibly serve as a human paediatric surrogate model, results may be extrapolated to human infants.
Amelie Catteuw; Mathias Devreese; Siegrid De Baere; Gunther Antonissen; Lada Ivanova; Silvio Uhlig; Ann Martens; Sarah De Saeger; Marthe De Boevre; Siska Croubels. Investigation of age-related differences in toxicokinetic processes of deoxynivalenol and deoxynivalenol-3-glucoside in weaned piglets. Archives of Toxicology 2019, 94, 417 -425.
AMA StyleAmelie Catteuw, Mathias Devreese, Siegrid De Baere, Gunther Antonissen, Lada Ivanova, Silvio Uhlig, Ann Martens, Sarah De Saeger, Marthe De Boevre, Siska Croubels. Investigation of age-related differences in toxicokinetic processes of deoxynivalenol and deoxynivalenol-3-glucoside in weaned piglets. Archives of Toxicology. 2019; 94 (2):417-425.
Chicago/Turabian StyleAmelie Catteuw; Mathias Devreese; Siegrid De Baere; Gunther Antonissen; Lada Ivanova; Silvio Uhlig; Ann Martens; Sarah De Saeger; Marthe De Boevre; Siska Croubels. 2019. "Investigation of age-related differences in toxicokinetic processes of deoxynivalenol and deoxynivalenol-3-glucoside in weaned piglets." Archives of Toxicology 94, no. 2: 417-425.
Microcystins are cyclic heptapeptides from cyanobacteria that are potent inhibitors of protein phosphatases and are toxic to animals and humans. At present, more than 250 microcystin variants are known, with variants reported for all seven peptide moieties. While d-glutamic acid (d-Glu) is highly-conserved at position-6 of microcystins, there has been only one report of a cyanobacterium (Anabaena) producing microcystins containing l-Glu at the variable 2- and 4-positions. Liquid chromatography–mass spectrometry analyses of extracts from Planktothrix prolifica NIVA-CYA 544 led to the tentative identification of two new Glu-containing microcystins, [d-Asp3]MC-ER (12) and [d-Asp3]MC-EE (13). Structure determination was aided by thiol derivatization of the Mdha7-moiety and esterification of the carboxylic acid groups, while 15N-labeling of the culture and isotopic profile analysis assisted the determination of the number of nitrogen atoms present and the elemental composition of molecular and product-ions. The major microcystin analog in the extracts was [d-Asp3]MC-RR (1). A microcystin with an unprecedented high-molecular-mass (2116 Da) was also detected and tentatively identified as a sulfide-linked conjugate of [d-Asp3]MC-RR (15) by LC–HRMS/MS and sulfide oxidation, together with its sulfoxide (16) produced via autoxidation. Low levels of [d-Asp3]MC-RW (14), [d-Asp3]MC-LR (4), [d-Asp3,Mser7]MC-RR (11), [d-Asp3]MC-RY (17), [d-Asp3]MC-RF (18), [d-Asp3]MC-RR–glutathione conjugate (19), and [d-Asp3]MC-RCit (20), the first reported microcystin containing citrulline, were also identified in the extract, and an oxidized derivative of [d-Asp3]MC-RR and the cysteine conjugate of 1 were partially characterized.
Vittoria Mallia; Silvio Uhlig; Cheryl Rafuse; Juris Meija; Christopher O. Miles. Novel Microcystins from Planktothrix prolifica NIVA-CYA 544 Identified by LC-MS/MS, Functional Group Derivatization and 15N-labeling. Marine Drugs 2019, 17, 643 .
AMA StyleVittoria Mallia, Silvio Uhlig, Cheryl Rafuse, Juris Meija, Christopher O. Miles. Novel Microcystins from Planktothrix prolifica NIVA-CYA 544 Identified by LC-MS/MS, Functional Group Derivatization and 15N-labeling. Marine Drugs. 2019; 17 (11):643.
Chicago/Turabian StyleVittoria Mallia; Silvio Uhlig; Cheryl Rafuse; Juris Meija; Christopher O. Miles. 2019. "Novel Microcystins from Planktothrix prolifica NIVA-CYA 544 Identified by LC-MS/MS, Functional Group Derivatization and 15N-labeling." Marine Drugs 17, no. 11: 643.
Beauvericin is a depsipeptide mycotoxin. The production of several beauvericin analogues has previously been shown among various genera among Hypocreales fungi. This includes so-called beauvenniatins, in which one or more N-methyl-phenylalanine residues is exchanged with other amino acids. In addition, a range of "unnatural" beauvericins has been prepared by a precursor addition to growth medium. Our aim was to get insight into the natural production of beauvericin analogues among different Hypocreales fungi, such as Fusarium and Isaria spp. In addition to beauvericin, we tentatively identified six earlier described analogues in the extracts; these were beauvericin A and/or its structural isomer beauvericin F, beauvericin C, beauvericin J, beauvericin D, and beauvenniatin A. Other analogues contained at least one additional oxygen atom. We show that the additional oxygen atom(s) were due to the presence of one to three N-methyl-tyrosine moieties in the depsipeptide molecules by using different liquid chromatography⁻mass spectrometry-based approaches. In addition, we also tentatively identified a beauvenniatin that contained N-methyl-leucine, which we named beauvenniatin L. This compound has not been reported before. Our data show that N-methyl-tyrosine containing beauvericins may be among the major naturally produced analogues in certain fungal strains.
Monika Urbaniak; Łukasz Stępień; Silvio Uhlig. Evidence for Naturally Produced Beauvericins Containing N-Methyl-Tyrosine in Hypocreales Fungi. Toxins 2019, 11, 182 .
AMA StyleMonika Urbaniak, Łukasz Stępień, Silvio Uhlig. Evidence for Naturally Produced Beauvericins Containing N-Methyl-Tyrosine in Hypocreales Fungi. Toxins. 2019; 11 (3):182.
Chicago/Turabian StyleMonika Urbaniak; Łukasz Stępień; Silvio Uhlig. 2019. "Evidence for Naturally Produced Beauvericins Containing N-Methyl-Tyrosine in Hypocreales Fungi." Toxins 11, no. 3: 182.
Deoxynivalenol (DON) contamination of feed may result in reduced growth, feed refusal, immunosuppression, and health problems in swine. Piglets can be exposed to DON via placenta before birth and via milk during lactation. The extent of early-life exposure of piglets to DON is, however, not fully known. This study was therefore aimed at investigating DON uptake in sows fed with naturally contaminated diets, DON transfer across placenta during late gestation, and transfer of DON to piglets via colostrum and milk. Forty-four crossbred sows were evaluated from day 93 ± 1 of gestation until weaning of piglets and fed with feed made from naturally DON-contaminated oats at three concentration levels: (1) control (DON < 0.2 mg/kg), (2) DON level 1 (1.4 mg DON/kg), and (3) DON level 2 (1.7 mg DON/kg). The transfer of DON to the piglets was evaluated in 15 sows, with repeated sampling of blood and milk from the sows and blood samples from five piglets of each litter. The piglet/sow plasma DON ratio and milk/plasma (M/P) DON ratio in sows were calculated to estimate the degree of transfer. Piglet/sow plasma ratios were 2.14 at birth, 2.30 within 12–36 h after parturition, 0.08 on day 7, 0.16 on day 21, and 0.20 at weaning. M/P ratios were 0.92, 1.11, 0.94, 1.21, and 0.90, respectively. The results indicate that DON is efficiently transferred across placenta and into milk. However, the low piglet/sow plasma ratios at mid-lactation to weaning indicate that the piglets were most strongly exposed to DON in early life, despite the high M/P ratios and efficient secretion of DON in milk throughout the entire lactation.
Amin Sayyari; Silvio Uhlig; Christiane Kruse Fæste; Tore Framstad; Tore Sivertsen. Transfer of Deoxynivalenol (DON) through Placenta, Colostrum and Milk from Sows to Their Offspring during Late Gestation and Lactation. Toxins 2018, 10, 517 .
AMA StyleAmin Sayyari, Silvio Uhlig, Christiane Kruse Fæste, Tore Framstad, Tore Sivertsen. Transfer of Deoxynivalenol (DON) through Placenta, Colostrum and Milk from Sows to Their Offspring during Late Gestation and Lactation. Toxins. 2018; 10 (12):517.
Chicago/Turabian StyleAmin Sayyari; Silvio Uhlig; Christiane Kruse Fæste; Tore Framstad; Tore Sivertsen. 2018. "Transfer of Deoxynivalenol (DON) through Placenta, Colostrum and Milk from Sows to Their Offspring during Late Gestation and Lactation." Toxins 10, no. 12: 517.
The skin mucus of fish is in permanent contact with the aquatic environment. Data from the analysis of the chemical composition of skin mucus could potentially be used for monitoring the health status of the fish. Knowledge about mucus composition or change in composition over time could also contribute to understanding the aetiology of certain diseases. The objective of the present study was the development of a workflow for non-invasive sampling of skin mucus from farmed salmon (Salmo salar) for the targeted and untargeted detection of small metabolites. Skin mucus was either scraped off, wiped off using medical wipes, or the mucus’ water phase was absorbed using the same type of medical wipes that was used for the wiping method. Following a simple filtration step, the obtained mucus samples were subjected to hydrophilic interaction chromatography coupled to high-resolution mass spectrometry. Post-acquisition processing included the targeted analysis of 86 small metabolites, of which up to 60 were detected in absorbed mucus. Untargeted analysis of the mucus samples from equally treated salmon revealed that the total variation of the metabolome was lowest in absorbed mucus and highest in the scraped mucus. Thus, future studies including small-molecule metabolomics of skin mucus in fish would benefit from a sampling regime employing absorption of the water phase in order to minimize the bias related to the sampling step. Furthermore, the absorption method is also a less invasive approach allowing for repetitive sampling within short time intervals.
Lada Ivanova; Haitham Tartor; Søren Grove; Anja B. Kristoffersen; Silvio Uhlig. Workflow for the Targeted and Untargeted Detection of Small Metabolites in Fish Skin Mucus. Fishes 2018, 3, 21 .
AMA StyleLada Ivanova, Haitham Tartor, Søren Grove, Anja B. Kristoffersen, Silvio Uhlig. Workflow for the Targeted and Untargeted Detection of Small Metabolites in Fish Skin Mucus. Fishes. 2018; 3 (2):21.
Chicago/Turabian StyleLada Ivanova; Haitham Tartor; Søren Grove; Anja B. Kristoffersen; Silvio Uhlig. 2018. "Workflow for the Targeted and Untargeted Detection of Small Metabolites in Fish Skin Mucus." Fishes 3, no. 2: 21.
Deoxynivalenol (DON) is one of the most prevalent Fusarium mycotoxins in grain and can cause economic losses in pig farming due to reduced feed consumption and lower weight gains. Biodetoxification of mycotoxins using bacterial strains has been a focus of research for many years. However, only a few in vivo studies have been conducted on the effectiveness of microbial detoxification of fusariotoxins. This study was therefore aimed at investigating the effect of a feed additive containing the bacterial strain Coriobacteriaceum DSM 11798 (the active ingredient in Biomin® BBSH 797) on growth performance and blood parameters, as well as uptake and metabolism of DON, in growing pigs. Forty-eight crossbred (Landrace-Yorkshire/Duroc-Duroc) weaning pigs were fed with pelleted feed made from naturally contaminated oats, with DON at four concentration levels: (1) control diet (DON < 0.2 mg kg−1), (2) low-contaminated diet (DON = 0.92 mg kg−1), (3) medium-contaminated diet (DON = 2.2 mg kg−1) and (4) high-contaminated diet (DON = 5.0 mg kg−1) and equivalent diets containing DSM 11798 as feed additive. During the first 7 days of exposure, pigs in the highest-dose group showed a 20–28% reduction in feed intake and a 24–34% reduction in weight gain compared with pigs in the control and low-dose groups. These differences were levelled out by study completion. Towards the end of the experiment, dose-dependent reductions in serum albumin, globulin and total serum protein were noted in the groups fed with DON-contaminated feed compared with the controls. The addition of DSM 11798 had no effect on the DON-related clinical effects or on the plasma concentrations of DON. The ineffectiveness of the feed additive in the present study could be a consequence of its use in pelleted feed, which might have hindered its rapid release, accessibility or detoxification efficiency in the pig’s gastrointestinal tract.
Amin Sayyari; Christiane Kruse Fæste; Ulrik Hansen; Silvio Uhlig; Tore Framstad; Dian Schatzmayr; Tore Sivertsen. Effects and biotransformation of the mycotoxin deoxynivalenol in growing pigs fed with naturally contaminated pelleted grains with and without the addition of Coriobacteriaceum DSM 11798. Food Additives & Contaminants: Part A 2018, 35, 1394 -1409.
AMA StyleAmin Sayyari, Christiane Kruse Fæste, Ulrik Hansen, Silvio Uhlig, Tore Framstad, Dian Schatzmayr, Tore Sivertsen. Effects and biotransformation of the mycotoxin deoxynivalenol in growing pigs fed with naturally contaminated pelleted grains with and without the addition of Coriobacteriaceum DSM 11798. Food Additives & Contaminants: Part A. 2018; 35 (7):1394-1409.
Chicago/Turabian StyleAmin Sayyari; Christiane Kruse Fæste; Ulrik Hansen; Silvio Uhlig; Tore Framstad; Dian Schatzmayr; Tore Sivertsen. 2018. "Effects and biotransformation of the mycotoxin deoxynivalenol in growing pigs fed with naturally contaminated pelleted grains with and without the addition of Coriobacteriaceum DSM 11798." Food Additives & Contaminants: Part A 35, no. 7: 1394-1409.
Deoxynivalenol (DON) is the most prevalent mycotoxin in cereals worldwide. It can cause adverse health effects in humans and animals, and maximum levels in food and feed have been implemented by food authorities based on risk assessments derived from estimated intake levels. The lack of human toxicokinetic data such as absorption, distribution, and elimination characteristics hinders the direct calculation of DON plasma levels and exposure. In the present study, we have, therefore, used in vitro-to-in vivo extrapolation of depletion constants in hepatic microsomes from different species and allometric scaling of reported in vivo animal parameters to predict the plasma clearance [0.24 L/(h × kg)] and volume of distribution (1.24 L/kg) for DON in humans. In addition, we have performed a toxicokinetic study with oral and intravenous administration of DON in pigs to establish benchmark parameters for the in vitro extrapolation approach. The determined human toxicokinetic parameters were then used to calculate the bioavailability (50–90%), maximum concentration, and total exposure in plasma, and urinary concentrations under consideration of typical DON levels in grain-based food products. The results were compared to data from biomonitoring studies in human populations.
Christiane Kruse Fæste; Lada Ivanova; Amin Sayyari; Ulrik Hansen; Tore Sivertsen; Silvio Uhlig. Prediction of deoxynivalenol toxicokinetics in humans by in vitro-to-in vivo extrapolation and allometric scaling of in vivo animal data. Archives of Toxicology 2018, 92, 2195 -2216.
AMA StyleChristiane Kruse Fæste, Lada Ivanova, Amin Sayyari, Ulrik Hansen, Tore Sivertsen, Silvio Uhlig. Prediction of deoxynivalenol toxicokinetics in humans by in vitro-to-in vivo extrapolation and allometric scaling of in vivo animal data. Archives of Toxicology. 2018; 92 (7):2195-2216.
Chicago/Turabian StyleChristiane Kruse Fæste; Lada Ivanova; Amin Sayyari; Ulrik Hansen; Tore Sivertsen; Silvio Uhlig. 2018. "Prediction of deoxynivalenol toxicokinetics in humans by in vitro-to-in vivo extrapolation and allometric scaling of in vivo animal data." Archives of Toxicology 92, no. 7: 2195-2216.
Commercial immunoaffinity columns (IACs) are today available for all major mycotoxins. However, manufacturers give usually no or very limited information on the epitope, i.e. the specific part of the toxin molecule that binds to the antibody. 4-Deoxynivalenol (DON) is a trichothecene mycotoxin that is produced by plant pathogenic field fungi and is regulated in many countries worldwide. DON was shown to be biotransformed via different metabolic pathways, and thus many different biotransformation products may be found in different products or organisms. In addition, several structurally similar mycotoxins may co-occur with DON. We compared five commercial IACs for their retention of a range of DON derivatives modified in the C-3, C-8, C-10, C-13 or C-15 positions, as well as nivalenol (NIV) and T-2 tetraol. The DON-derivatives were deepoxy-DON, DON 3-, 8- and 15-O-β-d-glucuronides, 3- and 15-O-acetyl-DON, DON-3-O-β-d-glucoside, 10- and 13-cysteinyl-adducts of DON, and the 13-mercaptoethanol and 10,13-dimercaptoethanol adducts of DON. The C-3 derivatives and deepoxy-DON were retained by most of the columns. Only one of the five IACs retained C-15 and C-8 derivatives, but it did not retain C-3 derivatives or deepoxy-DON. The antibodies in two of the IACs bound C-10 conjugates, but C-13 derivatives were not retained by any of the columns. This study shows that all of the antibodies in commercial IACs bind a range of DON derivatives, especially those that are modified at C-3. NIV was retained by three of the columns, and T-2 tetraol was partially retained by one IAC.
Silvio Uhlig; Ana Stanic; Fozia Hussain; Christopher O. Miles. Selectivity of commercial immunoaffinity columns for modified forms of the mycotoxin 4-deoxynivalenol (DON). Journal of Chromatography B 2017, 1061-1062, 322 -326.
AMA StyleSilvio Uhlig, Ana Stanic, Fozia Hussain, Christopher O. Miles. Selectivity of commercial immunoaffinity columns for modified forms of the mycotoxin 4-deoxynivalenol (DON). Journal of Chromatography B. 2017; 1061-1062 ():322-326.
Chicago/Turabian StyleSilvio Uhlig; Ana Stanic; Fozia Hussain; Christopher O. Miles. 2017. "Selectivity of commercial immunoaffinity columns for modified forms of the mycotoxin 4-deoxynivalenol (DON)." Journal of Chromatography B 1061-1062, no. : 322-326.
Enniatins (ENNs) are hexadepsipeptidic mycotoxins produced by Fusarium species. They occur in mg/kg levels in grain from Northern climate areas. Major ENNs such as ENN B and B1 have shown considerable cytotoxicity in different in vitro test systems. To adequately assess exposure and in vivo toxicity the toxicokinetic properties need to be investigated. The present study describes the metabolism of ENN B1 both in vitro and in vivo in pigs, comparing metabolites found in vitro in experiments with liver microsomes from different pig strains to those found in the plasma of pigs after single oral or intravenous application of ENN B1. Metabolites of hepatic biotransformation were tentatively identified and characterised by high performance liquid chromatography coupled to ion trap and high-resolution mass spectrometry, as well as chemical derivatisations. Kinetic parameters of metabolite formation and elimination were determined. Metabolite formation was higher when ENN B1 was absorbed from the gut compared to intravenous administration indicating pre-systemic metabolism of ENN B1 after oral uptake. The in vitro approach resulted in the detection of ten ENN B1 metabolites, while six were detected in in vivo samples. The putative ENN B1 metabolites were products of hydroxylation, carbonylation, carboxylation and oxidative demethylation reactions.
Lada Ivanova; Silvio Uhlig; Mathias Devreese; Siska Croubels; Christiane Kruse Fæste. Biotransformation of the mycotoxin enniatin B1 in pigs: A comparative in vitro and in vivo approach. Food and Chemical Toxicology 2017, 105, 506 -517.
AMA StyleLada Ivanova, Silvio Uhlig, Mathias Devreese, Siska Croubels, Christiane Kruse Fæste. Biotransformation of the mycotoxin enniatin B1 in pigs: A comparative in vitro and in vivo approach. Food and Chemical Toxicology. 2017; 105 ():506-517.
Chicago/Turabian StyleLada Ivanova; Silvio Uhlig; Mathias Devreese; Siska Croubels; Christiane Kruse Fæste. 2017. "Biotransformation of the mycotoxin enniatin B1 in pigs: A comparative in vitro and in vivo approach." Food and Chemical Toxicology 105, no. : 506-517.
The peroxisome proliferator-activated receptors (PPARs) function as ligand-activated transcription factors that convert signals in the form of lipids to physiological responses through the activation of metabolic target genes. Due to their key roles in lipid and carbohydrate metabolism, the PPARs are important drug targets. However, for several of the PPAR drugs currently in use, adverse side effects have been reported. In an effort to identify compounds from marine organisms that may serve as molecular scaffolds for the development of novel and safer PPAR-targeting drugs, we performed a bioassay-guided screening of organic extracts made from organisms supplied by the Norwegian Biobank of Arctic Marine Organisms (Marbank). Among several interesting hits, we identified two poorly described isomeric oxo-fatty acids from the microalgae Chaetoceros karianus for which we provide the first evidence that they might display dual specificity towards human PPARα and PPARγ. Principal component analysis showed that C. karianus stood out from other Chaetoceros species, both with respect to the metabolic profile and the PPAR activity. The isolation of these compounds holds the potential of uncovering a PPAR pharmacophore with tunable activity and specificity.
Angel Moldes-Anaya; Thomas Sæther; Silvio Uhlig; Hilde I. Nebb; Terje Larsen; Hans C. Eilertsen; Steinar M. Paulsen. Two Isomeric C16 Oxo-Fatty Acids from the Diatom Chaetoceros karianus Show Dual Agonist Activity towards Human Peroxisome Proliferator-Activated Receptors (PPARs) α/γ. Marine Drugs 2017, 15, 148 .
AMA StyleAngel Moldes-Anaya, Thomas Sæther, Silvio Uhlig, Hilde I. Nebb, Terje Larsen, Hans C. Eilertsen, Steinar M. Paulsen. Two Isomeric C16 Oxo-Fatty Acids from the Diatom Chaetoceros karianus Show Dual Agonist Activity towards Human Peroxisome Proliferator-Activated Receptors (PPARs) α/γ. Marine Drugs. 2017; 15 (6):148.
Chicago/Turabian StyleAngel Moldes-Anaya; Thomas Sæther; Silvio Uhlig; Hilde I. Nebb; Terje Larsen; Hans C. Eilertsen; Steinar M. Paulsen. 2017. "Two Isomeric C16 Oxo-Fatty Acids from the Diatom Chaetoceros karianus Show Dual Agonist Activity towards Human Peroxisome Proliferator-Activated Receptors (PPARs) α/γ." Marine Drugs 15, no. 6: 148.