Monic acid A: a biomarker in clinical intra-nasal mupirocin medication for MRSA decolonisation.

Context: Mupirocin (Bactroban) is widely prescribed for intra-nasal decolonisation of MRSA for in-patients awaiting surgery or self-medicated for out-patients although adherence for the latter is not monitored. Non-adherence is a widespread pharmaceutical problem but could encourage selection of antibiotic resistance. Mupirocin is only a topical antibiotic because it decomposes in stomach acidity to monic acid A, but this has not previously been exploited as a biomarker for clinical intra-nasal medication.

H NMR spectroscopy-based metabolomic assessment of uremic toxicity, with toxicological outcomes, in male rats following an acute, mid-life insult from ochratoxin a.

Overt response to a single 6.25 mg dose of ochratoxin A (OTA) by oral gavage to 15 months male rats was progressive loss of weight during the following four days. Lost weight was restored within one month and animals had a normal life-span without OTA-related terminal disease.

Comments on "Ochratoxin A: In utero Exposure in Mice Induces Adducts in Testicular DNA. Toxins 2010, 2, 1428-1444"-Mis-Citation of Rat Literature to Justify a Hypothetical Role for Ochratoxin A in Testicular Cancer.

A manuscript in the journal recently cited experimental rat data from two manuscripts to support plausibility of a thesis that ochratoxin A might be a cause of human testicular cancer. I believe that there is no experimental evidence that ochratoxin A produces testicular cancer in rats or mice.

HPLC/MS/MS methodology for sensitive quantitation of monic acid A, the metabolic product of the antibiotic mupirocin.

Patients who are treated by self-medication with intranasal mupiricin (Bactroban™) for controlling meticillin-resistant Staphylococcus aureus may, or may not, adhere to their regimen. Herein, we describe a potential methodology for assessing adherence by measuring the gastric degradation product, monic acid A (MA), as a biomarker in urine. MA was isolated (~80% recovery) through a Waters Oasis HLB cartridge and detected (e.

Contrasting nephropathic responses to oral administration of extract of cultured Penicillium polonicum in rat and primate.

Liquid- or solid substrate-cultured Penicillium polonicum administered in feed to rats over several days evokes a histopathological response in kidney involving apoptosis and abnormal mitosis in proximal tubules. The amphoteric toxin is yet only partly characterized, but can be isolated from cultured sporulating biomass in a fraction that is soluble in water and ethanol, and exchangeable on either anion- or cation-exchange resins. After several weeks of treatment renal proximal tubule distortion became striking on account of karyocytomegaly, but even treatment for nearly two years remained asymptomatic.

Pathological outcomes in kidney and brain in male Fischer rats given dietary ochratoxin A, commencing at one year of age.

Malignant renal carcinoma, manifest in morbid ageing rats, is the striking component of an otherwise silent response after about nine months of exposure to ochratoxin A in the first year of life (daily intake ~100-250 µg/kg body weight). Reasons for the long latency are unclear, as is whether there would be a similar carcinogenic response if toxin exposure started at one year of age. Therefore, 24 male Fischer rats were given 100 µg ochratoxin A as a daily dietary contaminant for 35 weeks from age 50 weeks.

Oncological outcomes in rats given nephrocarcinogenic exposure to dietary ochratoxin a, followed by the tumour promoter sodium barbital for life: a pilot study.

The potent experimental renal carcinogenesis of ochratoxin A (OTA) in male rats makes the dietary contaminant a potential factor in human oncology. We explored whether the tumour promoter sodium barbitate could shorten the otherwise long latency between exposure to toxin and tumourigenesis. Young rats, of a hybrid in which mononuclear leukaemia was rare, were given feed contaminated (5 ppm) with OTA for 36 weeks to initiate renal tumourigenesis.

A pilot study of nuclear instability in archived renal and upper urinary tract tumours with putative ochratoxin aetiology.

DNA ploidy measurement has been applied uniquely to wax-embedded tissue of primary renal cell and metastatic tumours of a key experimental researcher on porcine ochratoxicosis, a control, and four transitional cell carcinomas from cases of Balkan endemic nephropathy. Primary renal tumour was diploid, and hyperdiploid metastasis was within the lower ploidy range for typical renal cell carcinoma. Three Balkan primary tumours showed extensive aneuploidy indicating marked nuclear instability, similar to model rat renal carcinoma caused by ochratoxin A.

Structures of covalent adducts between DNA and ochratoxin a: a new factor in debate about genotoxicity and human risk assessment.

The potent renal carcinogenicity of ochratoxin A (OTA) in rats, principally in the male, raises questions about mechanism. Chromatographic evidence of DNA adducts after (32)P-postlabeling analysis contrasts with experimental attempts to demonstrate the absence of OTA in such adducts. Proffered schemes for alternative epigenetic mechanisms in OTA carcinogenicity remain unsatisfying, while structural data substantiating DNA-OTA adducts has also been lacking.

Minimum tolerable exposure period and maximum threshold dietary intake of ochratoxin A for causing renal cancer in male Dark Agouti rats.

In rats fed dietary ochratoxin A (5 ppm for 3, 6 or 9 months) no renal tumours occurred throughout natural life of the group treated for 3 months, during which the ochratoxin dose was 3 times that in the high dose group of the NTP study. Bilateral renal carcinoma occurred in one rat in the 6 month group. Four rats treated for 9 months developed unilateral renal carcinoma.

Binding of ochratoxin A to a urinary globulin: a new concept to account for gender difference in rat nephrocarcinogenic responses.

SDS-gradient mini-gel electrophoresis and immunoblotting of urine of rats given ochratoxin A (OTA), showed OTA binding to an alpha2u-globulin. Perceived potential internalised delivery of OTA to proximal tubule epithelia by the carrier, specific only to adult male rats and augmenting other uptake mechanisms, suggests that some experimental nephrotoxicological data may not be appropriate for human risk assessment. Reexamination of female rat renal tumour histopathology of the NTP high dose OTA study showed all carcinomas were solitary, unilateral, microscopic and clinically insignificant at the 2-year end-stage.

The role of tryptophan as a biosynthetic precursor of indole-diterpenoid fungal metabolites: continuing a debate.

Studies in the 1980s and 1990s on the origin of the indole moiety in fungal indole-diterpenoids using (14)C-labelled tryptophan consistently showed autoradiographic evidence but gave low % incorporation of the probe. Recent studies on a member of the group (nodulisporic acid A), using more specific (13)C methodology, demonstrated a role of the tryptophan biosynthetic pathway but, in failing to show involvement of end-product, concluded that the indole was derived from indole-3-glycerol phosphate and suggested that the previous (14)C data arose via metabolic scrambling of label. In considering the protocol for the (13)C studies, there is concern that the fungal material was starved of an exogenous nitrogen source and thus could have degraded added labelled tryptophan.

Interpretation of the pharmacokinetics of ochratoxin A in blood plasma of rats, during and after acute or chronic ingestion.

Experiments designed to reveal aspects of delivery of circulating ochratoxin A (OTA) to kidneys showed maximum plasma concentration within 3h of acute gavage, but this persisted for 4 days before decline. During long-term daily administration in feed, plasma values stabilised, proportional to dose and, for Fischer males, immediately followed an 8-10 day half-life upon ceasing OTA intake. In mature adult males, plasma OTA accumulated during the month after commencing daily intake of 100 microg.

Biosynthesis of scorpinone, a 2-azaanthraquinone from Amorosia littoralis, a fungus from marine sediment.

The biogenetic origin of the carbon atoms in the 2-azaanthraquinone scorpinone ( 1), produced by the rare fungus Amorosia littoralis isolated from marine sediment, was explored through isotopic enrichment studies utilizing [2- (13)C]-acetate and [1,2- (13)C]-acetate. The labeling results reveal a heptaketide precursor is involved in the biosynthesis of 1, as has been found for the structurally related naphthoquinone dihydrofusarubin. The previously identified naphthoquinone herbarin ( 2) was also isolated and appears to bear the same biogenetic relationship to 1 as the fusarubins do to the fungal 2-azaanthraquinone bostrycoidins.

A radiochemical technique with potential for revealing novel fungal metabolites according to expression of specific biosynthetic activities.

Fungal secondary metabolites are mostly derived from a few key intermediates in primary metabolism, such as acetate and some amino acids. Classical screens for novel fungal compounds of possible industrial interest have used chromatographic displays of extract components, as was the practice for plant natural products, followed by structural determination and pharmacological study. In contrast, modern robotic screens usually focus initially on specific bioassay applied to fermentation products and crude extracts.

An experimental strategy towards optimising directed biosynthesis of communesin analogues by Penicillium marinum in submerged fermentation.

It was previously demonstrated that a fungus producing communesin alkaloids, subsequently identified as Penicillium marinum, could also accept 6-fluoro analogues of tryptophan or tryptamine to form mono-fluoro-communesin analogues in addition to communesins. A strategy to increase the relative yield of analogues by mutation to impair decarboxylation of tryptophan has been studied. Four mutants with much reduced activity of tryptophan decarboxylase, and other phenotypic change, were selected from 1500 colonies from spores that survived a 99% kill treatment with N-methyl N-nitro N-nitrosoguanidine.

DNA ploidy distribution in renal tumours induced in male rats by dietary ochratoxin A.

DNA ploidy distribution, measured in experimental renal tumours that occurred in twelve ageing male Fischer rats derived from carcinogenicity experiments on ochratoxin A (OTA) in response to chronic dietary exposure, was diploid in all renal adenomas and aneuploid in all carcinomas, correlating with their typical organised and disorganised histopathology, respectively. Aneuploidy was also detected in renal tissue in which karyomegaly, induced by OTA, was analogous to that caused by the fungus Penicillium polonicum. Thus, the experimental rat renal carcinoma could arise within an adenoma directly from certain persistent karyomegalic tubular epithelial cells long after their particular genetic damage has been caused during a protracted period of OTA insult.

Amorosia littoralis gen. sp. nov., a new genus and species name for the scorpinone and caffeine-producing hyphomycete from the littoral zone in The Bahamas.

The new generic and species name Amorosia littoralis gen. sp. nov.

Natural and directed biosynthesis of communesin alkaloids.

A role for tryptophan, acetate, mevalonate and methionine in the biosynthesis of communesins A and B, novel structurally-related and biologically-active Penicillium metabolites, has been established by isotopic labelling techniques. The incorporation of (14)C-tryptamine has also been demonstrated. dl-2-(13)C-tryptophan specifically enriched two carbon atoms in the (13)C NMR spectrum, thereby defining the intra-molecular arrangement of the two tryptophan-derived moieties.

Deuterium NMR used to indicate a common mechanism for the biosynthesis of ricinoleic acid by Ricinus communis and Claviceps purpurea.

Previous studies have shown that ricinoleic acid from castor bean oil of Ricinus communis is synthesized by the direct hydroxyl substitution of oleate, while it has been proposed that ricinoleate is formed by hydration of linoleate in the ergot fungus Claviceps purpurea. The mechanism of the enzymes specific to ricinoleate synthesis has not yet been established, but hydroxylation and desaturation of fatty acids in plants apparently involve closely related mechanisms. As mechanistic differences in the enzymes involved in the biosynthesis of natural products can lead to different isotopic distributions in the product, we could expect ricinoleate isolated from castor or ergot oil to show distinct (2)H distribution patterns.

Comparative responses to mode of oral administration and dose of ochratoxin A or nephrotoxic extract of Penicillium polonicum in rats.

Administration of Penicillium polonicum extract to male Sprague-Dawley rats (200 g), either mixed in feed or given daily by gavage, for 5 days, had no clinical effects. However, at necropsy on day 6 marked histopathological changes occurred in renal tubule epithelia, including mitotic figures, karyomegalic nuclei, and frequent apoptosis identified specifically by TUNEL methodology and confocal microscopy. Ochratoxin A given similarly to rats (daily, 1 mg or 0.

Relations Among Sorghum Ergot Isolates from the Americas, Africa, India, and Australia.

Sorghum ergot, initially restricted to Asia and Africa, was recently found in the Americas and Australia. Three species causing the disease have been reported: Claviceps sorghi in India, C. sorghicola in Japan, and C.